International Journal of Molecular Sciences

13 pages, 5449 KiB

Open AccessArticle

Transcriptional Response of Silkworm (Bombyx mori) Eggs to O₂ or HCl Treatment

by Jing Gong, Sha Tian, Xia Zhou, Huan Yang, Yong Zhu^* and Yong Hou^*

State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing 400715, China

Int. J. Mol. Sci. 2016, 17(12), 1838; https://doi.org/10.3390/ijms17121838 - 7 Dec 2016

Cited by 11 | Viewed by 6280

Abstract

Diapause is a common biological phenomenon that occurs in many organisms, including fish, insects, and nematodes. In the silkworm (Bombyx mori), diapause generally occurs in the egg stage. Treatment with O₂, HCl, or other compounds can prevent egg diapause. [...] Read more.

Diapause is a common biological phenomenon that occurs in many organisms, including fish, insects, and nematodes. In the silkworm (Bombyx mori), diapause generally occurs in the egg stage. Treatment with O₂, HCl, or other compounds can prevent egg diapause. Here, we characterized the transcriptomic responses of newly laid eggs treated with O₂ or HCl. Digital gene expression analysis showed that 610 genes in O₂-treated eggs and 656 in HCl-treated eggs were differentially expressed. Of these, 343 genes were differentially expressed in both treatments. In addition to trehalases, sorbic acid dehydrogenases, and some enzymes involved in the carbohydrate metabolism, we also identified heat shock proteins, cytochrome P450, and GADD45, which are related to stress tolerance. Gene ontology enrichment analysis showed differentially expressed genes in O₂-treated eggs were involved in oxidoreductase activity as well as in binding, catalytic, and metabolic processes. The Kyoto Encyclopedia of Genes and Genomes analysis showed that the pathways for ribosome biogenesis, spliceosome, and circadian rhythm were significantly enriched in HCl-treated eggs. The reliability of the data was confirmed by qRT-PCR analysis. Our results improved the understanding of the mechanism of diapause blocking in silkworm eggs treated with O₂ or HCl and identified novel molecular targets for future studies. Full article

(This article belongs to the Section Biochemistry)

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10 pages, 2558 KiB

Open AccessArticle

by Yuan-Ping Lu¹, Ren-Liang Chen¹, Ying Long¹, Xiao Li¹, Yu-Ji Jiang^2,* and Bao-Gui Xie^1,*

¹ Mycological Research Center, College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China

² College of Food Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China

Int. J. Mol. Sci. 2016, 17(12), 1884; https://doi.org/10.3390/ijms17121884 - 28 Nov 2016

Cited by 23 | Viewed by 6629

Abstract

Flammulina velutipes, one of the most popular mushroom species in the world, has been recognized as a useful model system to study the biochemical and physiological aspects of the formation and elongation of fruit body. However, few reports have been published on [...] Read more.

Flammulina velutipes, one of the most popular mushroom species in the world, has been recognized as a useful model system to study the biochemical and physiological aspects of the formation and elongation of fruit body. However, few reports have been published on the regulation of fruiting body formation in F. velutipes at the molecular level. In this study, a jacalin-related lectin gene from F. velutipes was characterized. The phylogenetic tree revealed that Fv-JRL1 clustered with other basidiomycete jacalin-like lectins. Moreover, the transcriptional pattern of the Fv-JRL1 gene in different developmental stages of F. velutipes implied that Fv-JRL1 could be important for formation of fruit body. Additionally, RNA interference (RNAi) and overexpression analyses provided powerful evidence that the lectin gene Fv-JRL1 from F. velutipes plays important roles in fruiting body formation. Full article

(This article belongs to the Section Biochemistry)

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11 pages, 7469 KiB

Open AccessArticle

Rapid, Sensitive Detection of Bartonella quintana by Loop-Mediated Isothermal Amplification of the groEL Gene

by Shoukui Hu^1,2,†, Lina Niu^3,4,†, Lijuan Luo^1,†, Xiuping Song^2,†, Jimin Sun^2,5 and Qiyong Liu^2,*

¹ Clinical Laboratory of Peking University Shougang Hospital, Beijing100144, China

² State Key Laboratory of Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Changping, Beijing 102206, China

³ School of Tropical and Laboratory Medicine, Hainan Medical University, Haikou 571199, China

⁴ School of Life Science, Shanxi University, Taiyuan 030006, China

⁵ Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 1902; https://doi.org/10.3390/ijms17121902 - 1 Dec 2016

Cited by 3 | Viewed by 4951

Abstract

Trench fever, caused by Bartonella quintana, is recognized as a re-emerging and neglected disease. Rapid and sensitive detection approaches are urgently required to monitor and help control B. quintana infections. Here, loop-mediated isothermal amplification (LAMP), which amplifies target DNA at a fixed [...] Read more.

Trench fever, caused by Bartonella quintana, is recognized as a re-emerging and neglected disease. Rapid and sensitive detection approaches are urgently required to monitor and help control B. quintana infections. Here, loop-mediated isothermal amplification (LAMP), which amplifies target DNA at a fixed temperature with high sensitivity, specificity and rapidity, was employed to detect B. quintana. Thirty-six strains, including 10 B. quintana, 13 other Bartonella spp., and 13 other common pathogens, were applied to verify and evaluate the LAMP assay. The specificity of the LAMP assay was 100%, and the limit of detection was 125 fg/reaction. The LAMP assay was compared with qPCR in the examination of 100 rhesus and 20 rhesus-feeder blood samples; the diagnostic accuracy was found to be 100% when LAMP was compared to qPCR, but the LAMP assay was significantly more sensitive (p < 0.05). Thus, LAMP methodology is a useful for diagnosis of trench fever in humans and primates, especially in low-resource settings, because of its rapid, sensitive detection that does not require sophisticated equipment. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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16 pages, 4302 KiB

Open AccessArticle

Histone H3 Methyltransferase Suv39h1 Prevents Myogenic Terminal Differentiation by Repressing MEF2 Activity in Muscle Cells

by Wei Jin¹, Yangyang Shang¹, Jian Peng^2,† and Siwen Jiang^1,3,*,†

¹ Key Laboratory of Pig Genetics and Breeding of Ministry of Agriculture & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China

² Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China

³ Key Projects in the Cooperative Innovation Center for Sustainable Pig Production of Wuhan, Wuhan 430070, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 1908; https://doi.org/10.3390/ijms17121908 - 28 Nov 2016

Cited by 7 | Viewed by 6901

Abstract

The myogenic regulatory factors (MRFs) and myocyte enhancer factor 2 (MEF2) transcription factors have been extensively studied as key transcription factors that regulate myogenic gene expression. However, few reports on the molecular mechanism that modulates chromatin remodeling during skeletal muscle differentiation are available. [...] Read more.

The myogenic regulatory factors (MRFs) and myocyte enhancer factor 2 (MEF2) transcription factors have been extensively studied as key transcription factors that regulate myogenic gene expression. However, few reports on the molecular mechanism that modulates chromatin remodeling during skeletal muscle differentiation are available. We reported here that the expression of the H3-K9 methyltransferase Suv39h1 was decreased during myoblast differentiation. Ectopic expression of Suv39h1 could inhibit myoblast differentiation, increasing H3-K9 methylation levels, whereas knockdown of Suv39h1 stimulated myoblast differentiation. Furthermore, Suv39h1 interacted with MEF2C directly and inhibited MEF2 transcription activity in a dose-dependent manner. Together, our studies revealed a molecular mechanism wherein Suv39h1 modulated myogenic gene expression and activation during skeletal muscle differentiation. Full article

(This article belongs to the Special Issue Advances in Proteomic Research)

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11 pages, 1455 KiB

Open AccessArticle

Aspirin down Regulates Hepcidin by Inhibiting NF-κB and IL6/JAK2/STAT3 Pathways in BV-2 Microglial Cells Treated with Lipopolysaccharide

by Wan-Ying Li^1,2,†, Fei-Mi Li^1,†, Yu-Fu Zhou¹, Zhong-Min Wen^2,*, Juan Ma^1,3, Ke Ya^3,* and Zhong-Ming Qian^1,*

¹ Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Shanghai 201203, China

² Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China

³ School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 1921; https://doi.org/10.3390/ijms17121921 - 16 Dec 2016

Cited by 29 | Viewed by 6781

Abstract

Aspirin down regulates transferrin receptor 1 (TfR1) and up regulates ferroportin 1 (Fpn1) and ferritin expression in BV-2 microglial cells treated without lipopolysaccharides (LPS), as well as down regulates hepcidin and interleukin 6 (IL-6) in cells treated with LPS. However, the relevant mechanisms [...] Read more.

Aspirin down regulates transferrin receptor 1 (TfR1) and up regulates ferroportin 1 (Fpn1) and ferritin expression in BV-2 microglial cells treated without lipopolysaccharides (LPS), as well as down regulates hepcidin and interleukin 6 (IL-6) in cells treated with LPS. However, the relevant mechanisms are unknown. Here, we investigate the effects of aspirin on expression of hepcidin and iron regulatory protein 1 (IRP1), phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) and P65 (nuclear factor-κB), and the production of nitric oxide (NO) in BV-2 microglial cells treated with and without LPS. We demonstrated that aspirin inhibited hepcidin mRNA as well as NO production in cells treated with LPS, but not in cells without LPS, suppresses IL-6, JAK2, STAT3, and P65 (nuclear factor-κB) phosphorylation and has no effect on IRP1 in cells treated with or without LPS. These findings provide evidence that aspirin down regulates hepcidin by inhibiting IL6/JAK2/STAT3 and P65 (nuclear factor-κB) pathways in the cells under inflammatory conditions, and imply that an aspirin-induced reduction in TfR1 and an increase in ferritin are not associated with IRP1 and NO. Full article

(This article belongs to the Special Issue Lipopolysaccharides (LPSs))

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16 pages, 2994 KiB

Open AccessArticle

Evidence of Bioactive Compounds from Vernonia polyanthes Leaves with Topical Anti-Inflammatory Potential

by Kamilla C. M. Rodrigues¹, Lucas A. Chibli¹, Bruna C. S. Santos¹, Vanessa S. Temponi¹, Nícolas C. C. Pinto²

, Elita Scio², Glauciemar Del-Vechio-Vieira¹, Maria S. Alves¹ and Orlando V. Sousa^1,*

¹ Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, s/n, Campus Universitário, Juiz de Fora, Minas Gerais 36036-900, Brazil

² Department of Biochemistry, Institute of Biological Sciences, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, s/n, Campus Universitário, Juiz de Fora, Minas Gerais 36036-900, Brazil

Int. J. Mol. Sci. 2016, 17(12), 1929; https://doi.org/10.3390/ijms17121929 - 1 Dec 2016

Cited by 23 | Viewed by 5339

Abstract

Vernonia polyanthes Less. (Asteraceae), popularly known as “assa-peixe”, is a plant species used in Brazilian traditional medicine for the treatment of cutaneous damage, cicatrization, inflammation, and rheumatism. Based on these ethnopharmacological findings, the current study evaluated the topical anti-inflammatory effects of the hexane [...] Read more.

Vernonia polyanthes Less. (Asteraceae), popularly known as “assa-peixe”, is a plant species used in Brazilian traditional medicine for the treatment of cutaneous damage, cicatrization, inflammation, and rheumatism. Based on these ethnopharmacological findings, the current study evaluated the topical anti-inflammatory effects of the hexane (HEVP) and ethyl acetate (EAEVP) extracts from V. polyanthes leaves in experimental models of skin inflammation. Chemical characterization was carried out by HPLC–UV/DAD analysis. Anti-inflammatory activity was evaluated using Croton oil-, arachidonic acid (AA)-, phenol-, ethyl phenylpropiolate (EPP)-, and capsaicin-induced ear edema models in mice. Histopathological evaluation and measurements of myeloperoxidase (MPO) and N-acetyl-β-d-glucosaminidase (NAG) enzymes were also performed. Rutin, luteolin, and apigenin were identified in EAEVP. Topically applied HEVP and EAEVP significantly (p < 0.05, p < 0.01 or p < 0.001) reduced edema induced by five different irritants at the doses tested (0.1, 0.5 and 1.0 mg/ear). Histopathological analysis revealed a reduction of edema, inflammatory cell infiltration, and vasodilation. In addition, the enzymes activity (MPO and NAG) in the ear tissues was reduced by the topical treatment of HEVP and EAEVP (p < 0.05, p < 0.01 or p < 0.001). The results suggest that V. polyanthes leaves are effective against cutaneous damage, which support its traditional use and open up new possibilities for the treatment of skin disorders. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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13 pages, 2946 KiB

Open AccessArticle

Comprehensive Transcriptome Analysis Provides Evidence of Local Thermal Adaptation in Three Loaches (Genus: Misgurnus)

by Shaokui Yi^1,2, Sai Wang^1,2, Jia Zhong^1,2 and Weimin Wang^1,2,*

¹ Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China

² Key Lab of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China

Int. J. Mol. Sci. 2016, 17(12), 1943; https://doi.org/10.3390/ijms17121943 - 24 Nov 2016

Cited by 13 | Viewed by 4522

Abstract

The geographic distribution of three Misgurnus species, M. anguillicaudatus, M. bipartitus, and M. mohoity, displays a specific pattern in China, coincident with temperature zones. In this study, we sequenced the transcriptomes of these three species and used the sequences to [...] Read more.

The geographic distribution of three Misgurnus species, M. anguillicaudatus, M. bipartitus, and M. mohoity, displays a specific pattern in China, coincident with temperature zones. In this study, we sequenced the transcriptomes of these three species and used the sequences to investigate the lineage-specific adaptations within the genus Misgurnus. In total, 51 orphan genes (19 in M. anguillicaudatus, 18 in M. bipartitus, and 14 in M. mohoity) that may contribute to the species-specific adaptations were identified. An analysis of 1392 one-to-one orthologous genes revealed significantly higher ratios of nonsynonymous-to-synonymous substitutions in the M. mohoity lineage than in M. anguillicaudatus. The genes displaying signatures of positive selection and rapid evolution in Misgurnus were involved in four function categories, (1) energy metabolism; (2) signal transduction; (3) membrane; and (4) cell proliferation or apoptosis, implying that these candidate genes play critical roles in the thermal adaptation of the fish to their living environments. We also detected more than five positively selected sites in cldn15lb and isca1, which function as important factors in paracellular Na⁺ transport and Fe/S cluster assembly, respectively. Overall, our study provides valuable insights into the adaptive evolution of loaches from different temperature zones in China and is a foundation for future studies to clarify the genetic basis of temperature adaptation in fishes. Full article

(This article belongs to the Section Biochemistry)

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18 pages, 8148 KiB

Open AccessArticle

Elevated O₃ and TYLCV Infection Reduce the Suitability of Tomato as a Host for the Whitefly Bemisia tabaci

by Hongying Cui^1,2, Yucheng Sun², Fajun Chen³, Youjun Zhang^1,* and Feng Ge^2,*

¹ Department of Plant Protection, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing 100081, China

² State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

³ Department of Entomology, College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China

Int. J. Mol. Sci. 2016, 17(12), 1964; https://doi.org/10.3390/ijms17121964 - 28 Nov 2016

Cited by 13 | Viewed by 5639

Abstract

The effects of elevated atmospheric ozone (O₃) levels on herbivorous insects have been well studied, but little is known about the combined effects of elevated O₃ and virus infection on herbivorous insect performance. Using open-top chambers in the field, we [...] Read more.

The effects of elevated atmospheric ozone (O₃) levels on herbivorous insects have been well studied, but little is known about the combined effects of elevated O₃ and virus infection on herbivorous insect performance. Using open-top chambers in the field, we determined the effects of elevated O₃ and Tomato yellow leaf curl virus (TYLCV) infection on wild-type (Wt) tomato and 35S tomato (jasmonic acid (JA) defense-enhanced genotype) in association with whitefly, Bemisia tabaci Gennadius biotype B. Elevated O₃ and TYLCV infection, alone and in combination, significantly reduced the contents of soluble sugars and free amino acids, increased the contents of total phenolics and condensed tannins, and increased salicylic acid (SA) content and the expression of SA-related genes in leaves. The JA signaling pathway was upregulated by elevated O₃, but downregulated by TYLCV infection and O₃ + TYLCV infection. Regardless of plant genotype, elevated O₃, TYLCV infection, or O₃ + TYLCV infection significantly decreased B. tabaci fecundity and abundance. These results suggest that elevated O₃ and TYLCV infection, alone and in combination, reduce the nutrients available for B. tabaci, increase SA content and SA-related gene expression, and increase secondary metabolites, resulting in decreases in fecundity and abundance of B. tabaci in both tomato genotypes. Full article

(This article belongs to the Special Issue Plant-Insect Interactions)

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11 pages, 1518 KiB

Open AccessArticle

Gender Differences in the Application of Spanish Criteria for Initiation of Enzyme Replacement Therapy for Fabry Disease in the Fabry Outcome Survey

by Miguel-Ángel Barba-Romero^1,* and Guillem Pintos-Morell²

¹ Department of Internal Medicine, Albacete University Hospital, Castilla-La Mancha University, 37 Hermanos Falcó St., 02006 Albacete, Spain

² Department of Pediatrics, Germans Trias i Pujol University Hospital and Research Institute (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain

Int. J. Mol. Sci. 2016, 17(12), 1965; https://doi.org/10.3390/ijms17121965 - 24 Nov 2016

Cited by 10 | Viewed by 5344

Abstract

Both male/female patients with Fabry disease (FD) may receive enzyme replacement therapy (ERT). Previously published analyses of the Fabry Outcome Survey (FOS; Shire-sponsored) database suggested gender differences in timing of ERT initiation. We assessed alignment of criteria for ERT initiation in the Spanish [...] Read more.

Both male/female patients with Fabry disease (FD) may receive enzyme replacement therapy (ERT). Previously published analyses of the Fabry Outcome Survey (FOS; Shire-sponsored) database suggested gender differences in timing of ERT initiation. We assessed alignment of criteria for ERT initiation in the Spanish adult population included in FOS with recommendations of a Spanish national consensus. This retrospective analysis examined baseline clinical data of 88 adults (49 females) enrolled in the FOS database up to August 2014. Thirty-five (39.8%) patients were not receiving ERT: five (12.8%) males and 30 (61.2%) females. Baseline disease severity on the FOS-derived Mainz Severity Score Index was lower in untreated males (median (interquartile range), 0.0 (0.0–1.0)) than treated males (TM; 15.0 (7.5–26.5)), and was similar in untreated and treated females. The percentage of untreated females with at least one criterion for treatment initiation was 76.7% versus 100.0% of treated females (p = 0.0340) and 97.1% (p = 0.0210) of TM. In discordance with Spanish consensus recommendations, a substantial number of females with evidence of FD who might benefit from ERT have not yet initiated treatment. These results suggest unequal gender perceptions with respect to ERT initiation in Spain. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Novel Concepts, Therapeutic Aspects and Beyond)

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19 pages, 7410 KiB

Open AccessReview

Cuticular Lipids as a Cross-Talk among Ants, Plants and Butterflies

by Francesca Barbero

Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Turin, Italy

Int. J. Mol. Sci. 2016, 17(12), 1966; https://doi.org/10.3390/ijms17121966 - 24 Nov 2016

Cited by 36 | Viewed by 13487

Abstract

Even though insects and plants are distantly related organisms, they developed an integument which is functionally and structurally similar. Besides functioning as a physical barrier to cope with abiotic and biotic stress, this interface, called cuticle, is also a source of chemical signaling. [...] Read more.

Even though insects and plants are distantly related organisms, they developed an integument which is functionally and structurally similar. Besides functioning as a physical barrier to cope with abiotic and biotic stress, this interface, called cuticle, is also a source of chemical signaling. Crucial compounds with this respect are surface lipids and especially cuticular hydrocarbons (CHCs). This review is focused on the role of CHCs in fostering multilevel relationships among ants, plants and Lepidoptera (primarily butterflies). Indeed, particular traits of ants as eusocial organisms allowed the evolution and the maintenance of a variety of associations with both plants and animals. Basic concepts of myrmecophilous interactions and chemical deception strategies together with chemical composition, biosynthetic pathways and functions of CHCs as molecular cues of multitrophic systems are provided. Finally, the need to adopt a multidisciplinary and comprehensive approach in the survey of complex models is discussed. Full article

(This article belongs to the Special Issue Plant-Insect Interactions)

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53 pages, 3459 KiB

Open AccessReview

Update on Inflammatory Biomarkers and Treatments in Ischemic Stroke

by Aldo Bonaventura¹

, Luca Liberale¹, Alessandra Vecchié¹, Matteo Casula¹, Federico Carbone¹

, Franco Dallegri^1,2 and Fabrizio Montecucco^1,2,3,*

¹ First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy

² IRCCS Azienda Ospedaliera Universitaria San Martino—IST Istituto Nazionale per la Ricerca sul Cancro, Genova, 10 Largo Benzi, 16132 Genoa, Italy

³ Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 9 viale Benedetto XV, 16132 Genoa, Italy

Int. J. Mol. Sci. 2016, 17(12), 1967; https://doi.org/10.3390/ijms17121967 - 25 Nov 2016

Cited by 135 | Viewed by 16801

Abstract

After an acute ischemic stroke (AIS), inflammatory processes are able to concomitantly induce both beneficial and detrimental effects. In this narrative review, we updated evidence on the inflammatory pathways and mediators that are investigated as promising therapeutic targets. We searched for papers on [...] Read more.

After an acute ischemic stroke (AIS), inflammatory processes are able to concomitantly induce both beneficial and detrimental effects. In this narrative review, we updated evidence on the inflammatory pathways and mediators that are investigated as promising therapeutic targets. We searched for papers on PubMed and MEDLINE up to August 2016. The terms searched alone or in combination were: ischemic stroke, inflammation, oxidative stress, ischemia reperfusion, innate immunity, adaptive immunity, autoimmunity. Inflammation in AIS is characterized by a storm of cytokines, chemokines, and Damage-Associated Molecular Patterns (DAMPs) released by several cells contributing to exacerbate the tissue injury both in the acute and reparative phases. Interestingly, many biomarkers have been studied, but none of these reflected the complexity of systemic immune response. Reperfusion therapies showed a good efficacy in the recovery after an AIS. New therapies appear promising both in pre-clinical and clinical studies, but still need more detailed studies to be translated in the ordinary clinical practice. In spite of clinical progresses, no beneficial long-term interventions targeting inflammation are currently available. Our knowledge about cells, biomarkers, and inflammatory markers is growing and is hoped to better evaluate the impact of new treatments, such as monoclonal antibodies and cell-based therapies. Full article

(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment 2016)

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15 pages, 754 KiB

Open AccessReview

Role of Endogenous and Exogenous Tocopherols in the Lipid Stability of Marine Oil Systems: A Review

by Guadalupe Miroslava Suárez-Jiménez^1,2, Carmen María López-Saiz³, Hugo Enrique Ramírez-Guerra⁴, Josafat Marina Ezquerra-Brauer⁴, Saul Ruiz-Cruz¹

and Wilfrido Torres-Arreola^4,*

¹ Departamento de Biotecnología y Ciencias Alimentarias, Instituto Tecnológico de Sonora, 85000 Ciudad Obregón, Sonora, México

² Departamento de Ciencias Químico Biológicas, Universidad de Sonora, Blvd. Luis Encinas y Rosales s/n, 83000 Hermosillo, Sonora, México

³ Ingeniería Ambiental, Universidad Estatal de Sonora, Unidad Académica Hermosillo, Ley Federal del Trabajo s/n, 83100 Hermosillo, Sonora, México

⁴ Departamento de Investigación y Posgrado en Alimentos, Universidad de Sonora, Blvd. Luis Encinas y Rosales s/n, 83000 Hermosillo, Sonora, México

Int. J. Mol. Sci. 2016, 17(12), 1968; https://doi.org/10.3390/ijms17121968 - 24 Nov 2016

Cited by 25 | Viewed by 7111

Abstract

In marine organisms primarily intended for human consumption, the quality of the muscle and the extracted oils may be affected by lipid oxidation during storage, even at low temperatures. This has led to a search for alternatives to maintain quality. In this sense, [...] Read more.

In marine organisms primarily intended for human consumption, the quality of the muscle and the extracted oils may be affected by lipid oxidation during storage, even at low temperatures. This has led to a search for alternatives to maintain quality. In this sense, antioxidant compounds have been used to prevent such lipid deterioration. Among the most used compounds are tocopherols, which, due to their natural origin, have become an excellent alternative to prevent or retard lipid oxidation and maintain the quality of marine products. Tocopherols as antioxidants have been studied both exogenously and endogenously. Exogenous tocopherols are often used by incorporating them into plastic packaging films or adding them directly to fish oil. It has been observed that exogenous tocopherols incorporated in low concentrations maintain the quality of both muscle and the extracted oils during food storage. However, it has been reported that tocopherols applied at higher concentrations act as a prooxidant molecule, probably because their reactions with singlet oxygen may generate free radicals and cause the oxidation of polyunsaturated fatty acids in fish oils. However, when tocopherols are included in a fish diet (endogenous tocopherols), the antioxidant effect on the muscle lipids is more effective due to their incorporation into the membrane lipids, which can help extend the shelf life of seafood by reducing the lipid deterioration that occurs due to antioxidant synergy with other phenolic compounds used supplements in fish muscle. This review focuses on the most important studies in this field and highlights the potential of using tocopherols as antioxidants in marine oils. Full article

(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)

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24 pages, 6791 KiB

Open AccessReview

Effects of Glycosylation on the Enzymatic Activity and Mechanisms of Proteases

by Peter Goettig

Structural Biology Group, Faculty of Molecular Biology, University of Salzburg, Billrothstrasse 11, 5020 Salzburg, Austria

Int. J. Mol. Sci. 2016, 17(12), 1969; https://doi.org/10.3390/ijms17121969 - 25 Nov 2016

Cited by 97 | Viewed by 13621

Abstract

Posttranslational modifications are an important feature of most proteases in higher organisms, such as the conversion of inactive zymogens into active proteases. To date, little information is available on the role of glycosylation and functional implications for secreted proteases. Besides a stabilizing effect [...] Read more.

Posttranslational modifications are an important feature of most proteases in higher organisms, such as the conversion of inactive zymogens into active proteases. To date, little information is available on the role of glycosylation and functional implications for secreted proteases. Besides a stabilizing effect and protection against proteolysis, several proteases show a significant influence of glycosylation on the catalytic activity. Glycans can alter the substrate recognition, the specificity and binding affinity, as well as the turnover rates. However, there is currently no known general pattern, since glycosylation can have both stimulating and inhibiting effects on activity. Thus, a comparative analysis of individual cases with sufficient enzyme kinetic and structural data is a first approach to describe mechanistic principles that govern the effects of glycosylation on the function of proteases. The understanding of glycan functions becomes highly significant in proteomic and glycomic studies, which demonstrated that cancer-associated proteases, such as kallikrein-related peptidase 3, exhibit strongly altered glycosylation patterns in pathological cases. Such findings can contribute to a variety of future biomedical applications. Full article

(This article belongs to the Special Issue Glycan–Receptor Interaction)

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10 pages, 1285 KiB

Open AccessArticle

Inherited Variants in Wnt Pathway Genes Influence Outcomes of Prostate Cancer Patients Receiving Androgen Deprivation Therapy

by Jiun-Hung Geng^1,2, Victor C. Lin^3,4, Chia-Cheng Yu^5,6,7, Chao-Yuan Huang^8,9, Hsin-Ling Yin^10,11, Ta-Yuan Chang¹², Te-Ling Lu¹³

, Shu-Pin Huang^1,14,15,* and Bo-Ying Bao^13,16,17,*

¹ Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

² Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan

³ Department of Urology, E-Da Hospital, Kaohsiung 824, Taiwan

⁴ School of Medicine for International Students, I-Shou University, Kaohsiung 840, Taiwan

⁵ Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan

⁶ Department of Urology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan

⁷ Department of Pharmacy, Tajen University, Pingtung 907, Taiwan

⁸ Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan

⁹ Department of Urology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu 300, Taiwan

¹⁰ Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

¹¹ Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

¹² Department of Occupational Safety and Health, China Medical University, Taichung 404, Taiwan

¹³ Department of Pharmacy, China Medical University, Taichung 404, Taiwan

¹⁴ Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

¹⁵ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

¹⁶ Sex Hormone Research Center, China Medical University Hospital, Taichung 404, Taiwan

¹⁷ Department of Nursing, Asia University, Taichung 413, Taiwan

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Int. J. Mol. Sci. 2016, 17(12), 1970; https://doi.org/10.3390/ijms17121970 - 26 Nov 2016

Cited by 16 | Viewed by 4788

Abstract

Aberrant Wnt signaling has been associated with many types of cancer. However, the association of inherited Wnt pathway variants with clinical outcomes in prostate cancer patients receiving androgen deprivation therapy (ADT) has not been determined. Here, we comprehensively studied the contribution of common [...] Read more.

Aberrant Wnt signaling has been associated with many types of cancer. However, the association of inherited Wnt pathway variants with clinical outcomes in prostate cancer patients receiving androgen deprivation therapy (ADT) has not been determined. Here, we comprehensively studied the contribution of common single nucleotide polymorphisms (SNPs) in Wnt pathway genes to the clinical outcomes of 465 advanced prostate cancer patients treated with ADT. Two SNPs, adenomatous polyposis coli (APC) rs2707765 and rs497844, were significantly (p ≤ 0.009 and q ≤ 0.043) associated with both prostate cancer progression and all-cause mortality, even after multivariate analyses and multiple testing correction. Patients with a greater number of favorable alleles had a longer time to disease progression and better overall survival during ADT (p for trend ≤ 0.003). Additional, cDNA array and in silico analyses of prostate cancer tissue suggested that rs2707765 affects APC expression, which in turn is correlated with tumor aggressiveness and patient prognosis. This study identifies the influence of inherited variants in the Wnt pathway on the efficacy of ADT and highlights a preclinical rationale for using APC as a prognostic marker in advanced prostate cancer. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer)

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13 pages, 5300 KiB

Open AccessArticle

Limb Remote Ischemic Postconditioning Reduces Ischemia-Reperfusion Injury by Inhibiting NADPH Oxidase Activation and MyD88-TRAF6-P38MAP-Kinase Pathway of Neutrophils

by Gangling Chen^1,2, Xinyi Ye², Jiangwei Zhang², Tingli Tang¹, Lin Li¹, Peirong Lu¹, Qi Wu³, Boyang Yu^2,*

and Junping Kou^2,*

¹ Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China

² Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China

³ State Key Laboratory of Natural Medicines, Research Department of Pharmacognosy, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China

Int. J. Mol. Sci. 2016, 17(12), 1971; https://doi.org/10.3390/ijms17121971 - 25 Nov 2016

Cited by 50 | Viewed by 6391

Abstract

Limb remote ischemic postconditioning (LRIP) has been confirmed to reduce the ischemia-reperfusion injury but its mechanisms are still not clear. This study clarified the mechanism of LRIP based on the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and Myeloid differentiation factor 88 (MyD88)-Tumor necrosis factor [...] Read more.

Limb remote ischemic postconditioning (LRIP) has been confirmed to reduce the ischemia-reperfusion injury but its mechanisms are still not clear. This study clarified the mechanism of LRIP based on the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and Myeloid differentiation factor 88 (MyD88)-Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6)-P38 pathway of neutrophils. Rat middle cerebral artery occlusion (MCAO) model was used in this study. Ischemia-reperfusion injury was carried out by MCAO 1.5 h followed by 24 h reperfusion. LRIP operation was performed to the left femoral artery at 0, 1 or 3 h after reperfusion. Behavioral testing, including postural reflex test, vibrissae-elicited forelimb placing test and tail hang test, showed that LRIP operated at 0 h of reperfusion could significantly ameliorate these behavioral scores. Pathological examinations, infarct size, Myeloperoxidase (MPO) activity showed that LRIP operated at 0 h of reperfusion could significantly ameliorate the pathological scores, reduce the infarct size and MPO activity in the brain and increase the MPO activity in the left leg. By using Neutrophil counting, immunofluorescence and real-time PCR techniques, we found that LRIP operated at 0 h of reperfusion could reduce neutrophil counts in the peripheral blood and downregulate the activation of neutrophil in the peripheral blood and rat brain. Western blots revealed that MyD88, TRAF6, p38 mitogen-activated protein kinase (p38-MAPK) in neutrophils and the phosphorylation of p47phox (Ser 304 and Ser 345) in neutrophil could be downregulated by LRIP. Our study suggests that LRIP inhibits the number and activation of neutrophils in the rat brain and peripheral blood linked to down-regulating the activation of NADPH oxidase in neutrophils by MyD88/TRAF6/p38-MAPK pathway. Full article

(This article belongs to the Section Biochemistry)

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18 pages, 3077 KiB

Open AccessArticle

Identification and Characterization of MicroRNAs in the Liver of Blunt Snout Bream (Megalobrama amblycephala) Infected by Aeromonas hydrophila

by Lei Cui¹, Hongtao Hu², Wei Wei^1,3, Weimin Wang¹ and Hong Liu^1,3,*

¹ College of Fisheries, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture, Huazhong Agricultural University, Wuhan 430070, China

² Center for Bio-Pesticide Research, Hubei Academy of Agricultural Sciences, Wuhan 430064, China

³ Freshwater Aquaculture Collaborative Innovation Center of Hubei Province, Wuhan 430070, China

Int. J. Mol. Sci. 2016, 17(12), 1972; https://doi.org/10.3390/ijms17121972 - 25 Nov 2016

Cited by 21 | Viewed by 5047

Abstract

MicroRNAs (miRNAs) are small RNA molecules that play key roles in regulation of various biological processes. In order to better understand the biological significance of miRNAs in the context of Aeromonas hydrophila infection in Megalobrama amblycephala, small RNA libraries obtained from fish [...] Read more.

MicroRNAs (miRNAs) are small RNA molecules that play key roles in regulation of various biological processes. In order to better understand the biological significance of miRNAs in the context of Aeromonas hydrophila infection in Megalobrama amblycephala, small RNA libraries obtained from fish liver at 0 (non-infection), 4, and 24 h post infection (poi) were sequenced using Illumina deep sequencing technology. A total of 11,244,207, 9,212,958, and 7,939,157 clean reads were obtained from these three RNA libraries, respectively. Bioinformatics analysis identified 171 conserved miRNAs and 62 putative novel miRNAs. The existence of ten randomly selected novel miRNAs was validated by RT-PCR. Pairwise comparison suggested that 61 and 44 miRNAs were differentially expressed at 4 and 24 h poi, respectively. Furthermore, the expression profiles of nine randomly selected miRNAs were validated by qRT-PCR. MicroRNA target prediction, gene ontology (GO) annotation, and Kyoto Encylopedia of Genes and Genomes (KEGG) analysis indicated that a variety of biological pathways could be affected by A. hydrophila infection. Additionally, transferrin (TF) and transferrin receptor (TFR) genes were confirmed to be direct targets of miR-375. These results will expand our knowledge of the role of miRNAs in the immune response of M. amblycephala to A. hydrophila infection, and facilitate the development of effective strategies against A. hydrophila infection in M. amblycephala. Full article

(This article belongs to the Section Biochemistry)

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25 pages, 1775 KiB

Open AccessArticle

Protective Effects of α-Tocopherol, γ-Tocopherol and Oleic Acid, Three Compounds of Olive Oils, and No Effect of Trolox, on 7-Ketocholesterol-Induced Mitochondrial and Peroxisomal Dysfunction in Microglial BV-2 Cells

by Meryam Debbabi^1,2, Thomas Nury¹, Amira Zarrouk^1,2,3, Nadia Mekahli¹, Maryem Bezine^1,4, Randa Sghaier^1,3, Stéphane Grégoire⁵, Lucy Martine⁵, Philippe Durand⁶, Emmanuelle Camus⁶

, Anne Vejux¹, Aymen Jabrane⁷, Lionel Bretillon⁵, Michel Prost⁶, Thibault Moreau⁸, Sofien Ben Ammou⁹, Mohamed Hammami² and Gérard Lizard^1,*

¹ Team ‘Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism’ EA 7270/INSERM, University Bourgogne Franche-Comté, 21000 Dijon, France

² Lab-NAFS ‘Nutrition—Functional Food & Vascular Health’, University Monastir, LR12ES05, 5000 Monastir, Tunisia

³ Faculty of Medicine, University Sousse, 4000 Sousse, Tunisia

⁴ Laboratory ‘Venoms & Therapeutic Biomolecules’, Pasteur Institute, University Tunis El Manar, 1000 Tunis, Tunisia

⁵ Eye & Nutrition Research Group, CSGA, UMR 1324 INRA, 6265 CNRS, University Bourgogne Franche-Comté, 21000 Dijon, France

⁶ Kirial International/Laboratoires Spiral, 21560 Couternon, France

⁷ Société Nopal Nutra, 21000 Dijon, France

⁸ Department of Neurology, University Hospital of Dijon, 21000 Dijon, France

⁹ Department of Neurology, University Hospital Sahloul, 4000 Sousse, Tunisia

Int. J. Mol. Sci. 2016, 17(12), 1973; https://doi.org/10.3390/ijms17121973 - 25 Nov 2016

Cited by 69 | Viewed by 9052

Abstract

Lipid peroxidation products, such as 7-ketocholesterol (7KC), may be increased in the body fluids and tissues of patients with neurodegenerative diseases and trigger microglial dysfunction involved in neurodegeneration. It is therefore important to identify synthetic and natural molecules able to impair the toxic [...] Read more.

Lipid peroxidation products, such as 7-ketocholesterol (7KC), may be increased in the body fluids and tissues of patients with neurodegenerative diseases and trigger microglial dysfunction involved in neurodegeneration. It is therefore important to identify synthetic and natural molecules able to impair the toxic effects of 7KC. We determined the impact of 7KC on murine microglial BV-2 cells, especially its ability to trigger mitochondrial and peroxisomal dysfunction, and evaluated the protective effects of α- and γ-tocopherol, Trolox, and oleic acid (OA). Multiple complementary chemical assays, flow cytometric and biochemical methods were used to evaluate the antioxidant and cytoprotective properties of these molecules. According to various complementary assays to estimate antioxidant activity, only α-, and γ-tocopherol, and Trolox had antioxidant properties. However, only α-tocopherol, γ-tocopherol and OA were able to impair 7KC-induced loss of mitochondrial transmembrane potential, which is associated with increased permeability to propidium iodide, an indicator of cell death. In addition, α-and γ-tocopherol, and OA were able to prevent the decrease in Abcd3 protein levels, which allows the measurement of peroxisomal mass, and in mRNA levels of Abcd1 and Abcd2, which encode for two transporters involved in peroxisomal β-oxidation. Thus, 7KC-induced side effects are associated with mitochondrial and peroxisomal dysfunction which can be inversed by natural compounds, thus supporting the hypothesis that the composition of the diet can act on the function of organelles involved in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)

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31 pages, 2605 KiB

Open AccessReview

Future Prospects for Scaffolding Methods and Biomaterials in Skin Tissue Engineering: A Review

by Atul A. Chaudhari, Komal Vig, Dieudonné Radé Baganizi, Rajnish Sahu, Saurabh Dixit, Vida Dennis, Shree Ram Singh

and Shreekumar R. Pillai^*

Center for Nanobiotechnology Research, Alabama State University, Montgomery, AL 36104, USA

Int. J. Mol. Sci. 2016, 17(12), 1974; https://doi.org/10.3390/ijms17121974 - 25 Nov 2016

Cited by 461 | Viewed by 28066

Abstract

Over centuries, the field of regenerative skin tissue engineering has had several advancements to facilitate faster wound healing and thereby restoration of skin. Skin tissue regeneration is mainly based on the use of suitable scaffold matrices. There are several scaffold types, such as [...] Read more.

Over centuries, the field of regenerative skin tissue engineering has had several advancements to facilitate faster wound healing and thereby restoration of skin. Skin tissue regeneration is mainly based on the use of suitable scaffold matrices. There are several scaffold types, such as porous, fibrous, microsphere, hydrogel, composite and acellular, etc., with discrete advantages and disadvantages. These scaffolds are either made up of highly biocompatible natural biomaterials, such as collagen, chitosan, etc., or synthetic materials, such as polycaprolactone (PCL), and poly-ethylene-glycol (PEG), etc. Composite scaffolds, which are a combination of natural or synthetic biomaterials, are highly biocompatible with improved tensile strength for effective skin tissue regeneration. Appropriate knowledge of the properties, advantages and disadvantages of various biomaterials and scaffolds will accelerate the production of suitable scaffolds for skin tissue regeneration applications. At the same time, emphasis on some of the leading challenges in the field of skin tissue engineering, such as cell interaction with scaffolds, faster cellular proliferation/differentiation, and vascularization of engineered tissues, is inevitable. In this review, we discuss various types of scaffolding approaches and biomaterials used in the field of skin tissue engineering and more importantly their future prospects in skin tissue regeneration efforts. Full article

(This article belongs to the Section Materials Science)

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13 pages, 1010 KiB

Open AccessReview

The Double Role of p53 in Cancer and Autoimmunity and Its Potential as Therapeutic Target

by Alessandra Fierabracci^*

and Marsha Pellegrino

Infectivology and Clinical Trials Area, Children’s Hospital Bambino Gesù, 00146 Rome, Italy

Int. J. Mol. Sci. 2016, 17(12), 1975; https://doi.org/10.3390/ijms17121975 - 25 Nov 2016

Cited by 23 | Viewed by 8066

Abstract

p53 is a sequence-specific short-lived transcription factor expressed at low concentrations in various tissues while it is upregulated in damaged, tumoral or inflamed tissue. In normally proliferating cells, p53 protein levels and function are tightly controlled by main regulators, i.e., MDM2 (mouse double [...] Read more.

p53 is a sequence-specific short-lived transcription factor expressed at low concentrations in various tissues while it is upregulated in damaged, tumoral or inflamed tissue. In normally proliferating cells, p53 protein levels and function are tightly controlled by main regulators, i.e., MDM2 (mouse double minute 2) and MDM4 proteins. p53 plays an important role due to its ability to mediate tumor suppression. In addition to its importance as a tumor suppressor, p53 coordinates diverse cellular responses to stress and damage and plays an emerging role in various physiological processes, including fertility, cell metabolism, mitochondrial respiration, autophagy, cell adhesion, stem cell maintenance and development. Interestingly, it has been recently implicated in the suppression of autoimmune and inflammatory diseases in both mice and humans. In this review based on current knowledge on the functional properties of p53 and its regulatory pathways, we discuss the potential utility of p53 reactivation from a therapeutic perspective in oncology and chronic inflammatory disorders leading to autoimmunity. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

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11 pages, 978 KiB

Open AccessReview

Applications of Alginate-Based Bioinks in 3D Bioprinting

by Eneko Axpe^* and Michelle L. Oyen

Nanoscience Centre, Department of Engineering, Cambridge University, Cambridge CB3 0FF, UK

Int. J. Mol. Sci. 2016, 17(12), 1976; https://doi.org/10.3390/ijms17121976 - 25 Nov 2016

Cited by 542 | Viewed by 27280

Abstract

Three-dimensional (3D) bioprinting is on the cusp of permitting the direct fabrication of artificial living tissue. Multicellular building blocks (bioinks) are dispensed layer by layer and scaled for the target construct. However, only a few materials are able to fulfill the considerable requirements [...] Read more.

Three-dimensional (3D) bioprinting is on the cusp of permitting the direct fabrication of artificial living tissue. Multicellular building blocks (bioinks) are dispensed layer by layer and scaled for the target construct. However, only a few materials are able to fulfill the considerable requirements for suitable bioink formulation, a critical component of efficient 3D bioprinting. Alginate, a naturally occurring polysaccharide, is clearly the most commonly employed material in current bioinks. Here, we discuss the benefits and disadvantages of the use of alginate in 3D bioprinting by summarizing the most recent studies that used alginate for printing vascular tissue, bone and cartilage. In addition, other breakthroughs in the use of alginate in bioprinting are discussed, including strategies to improve its structural and degradation characteristics. In this review, we organize the available literature in order to inspire and accelerate novel alginate-based bioink formulations with enhanced properties for future applications in basic research, drug screening and regenerative medicine. Full article

(This article belongs to the Special Issue Frontiers of Marine Biomaterials)

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13 pages, 2284 KiB

Open AccessArticle

Enhanced and Extended Anti-Hypertensive Effect of VP5 Nanoparticles

by Ting Yu^1,2,3,†, Shengnan Zhao^2,3,†, Ziqiang Li^3,†, Yi Wang⁴, Bei Xu³, Dailong Fang³, Fazhan Wang³, Zhi Zhang³, Lili He², Xiangrong Song^3,* and Jian Yang^1,*

¹ School of Applied Chemistry and Biological Technology, Shenzhen Polytechnic, Shenzhen 518055, China

² College of Pharmacy, Southwest University for Nationalities, Chengdu 610041, China

³ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu 610041, China

⁴ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 1977; https://doi.org/10.3390/ijms17121977 - 25 Nov 2016

Cited by 23 | Viewed by 4959

Abstract

Hypertension has become a significant global public health concern and is also one of the most common risk factors of cardiovascular disease. Recent studies have shown the promising result of peptides inhibiting angiotensin converting enzyme (ACE) in lowering the blood pressure in both [...] Read more.

Hypertension has become a significant global public health concern and is also one of the most common risk factors of cardiovascular disease. Recent studies have shown the promising result of peptides inhibiting angiotensin converting enzyme (ACE) in lowering the blood pressure in both animal models and humans. However, the oral bioavailability and continuous antihypertensive effectiveness require further optimization. Novel nanoparticle-based drug delivery systems are helpful to overcome these barriers. Therefore, a poly-(lactic-co-glycolic) acid nanoparticle (PLGANPs) oral delivery system, of the antihypertensive small peptides Val-Leu-Pro-Val-Pro (VLPVP, VP5) model, was developed in this study and its antihypertensive effect was investigated in spontaneously hypertensive rats (SHRs) for the first time. The obtained VP5 nanoparticles (VP5-NPs) showed a small particle size of 223.7 ± 2.3 nm and high entrapment efficiency (EE%) of 87.37% ± 0.92%. Transmission electronic microscopy (TEM) analysis showed that the nanoparticles were spherical and homogeneous. The optimal preparation of VP5-NPs exhibited sustained release of VP5 in vitro and a 96 h long-term antihypertensive effect with enhanced efficacy in vivo. This study illustrated that PLGANPs might be an optimal formulation for oral delivery of antihypertensive small peptides and VP5-NPs might be worthy of further development and use as a potential therapeutic strategy for hypertension in the future. Full article

(This article belongs to the Section Materials Science)

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13 pages, 4959 KiB

Open AccessArticle

Salivary Microbiome Diversity in Caries-Free and Caries-Affected Children

by Shan Jiang, Xiaoli Gao^*, Lijian Jin and Edward C. M. Lo

Faculty of Dentistry, The University of Hong Kong, Prince Philip Dental Hospital, 34 Hospital Road, Sai Ying Pun, Hong Kong, China

Int. J. Mol. Sci. 2016, 17(12), 1978; https://doi.org/10.3390/ijms17121978 - 25 Nov 2016

Cited by 122 | Viewed by 10912

Abstract

Dental caries (tooth decay) is an infectious disease. Its etiology is not fully understood from the microbiological perspective. This study characterizes the diversity of microbial flora in the saliva of children with and without dental caries. Children (3–4 years old) with caries ( [...] Read more.

Dental caries (tooth decay) is an infectious disease. Its etiology is not fully understood from the microbiological perspective. This study characterizes the diversity of microbial flora in the saliva of children with and without dental caries. Children (3–4 years old) with caries (n = 20) and without caries (n = 20) were recruited. Unstimulated saliva (2 mL) was collected from each child and the total microbial genomic DNA was extracted. DNA amplicons of the V3-V4 hypervariable region of the bacterial 16S rRNA gene were generated and subjected to Illumina Miseq sequencing. A total of 17 phyla, 26 classes, 40 orders, 80 families, 151 genera, and 310 bacterial species were represented in the saliva samples. There was no significant difference in the microbiome diversity between caries-affected and caries-free children (p > 0.05). The relative abundance of several species (Rothia dentocariosa, Actinomyces graevenitzii, Veillonella sp. oral taxon 780, Prevotella salivae, and Streptococcus mutans) was higher in the caries-affected group than in the caries-free group (p < 0.05). Fusobacterium periodonticum and Leptotrichia sp. oral clone FP036 were more abundant in caries-free children than in caries-affected children (p < 0.05). The salivary microbiome profiles of caries-free and caries-affected children were similar. Salivary counts of certain bacteria such as R. dentocariosa and F. periodonticum may be useful for screening/assessing children’s risk of developing caries. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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16 pages, 5673 KiB

Open AccessArticle

The Antiproliferative Effect of Chakasaponins I and II, Floratheasaponin A, and Epigallocatechin 3-O-Gallate Isolated from Camellia sinensis on Human Digestive Tract Carcinoma Cell Lines

by Niichiro Kitagawa^1,2,†, Toshio Morikawa^1,3,*,†

, Chiaki Motai^1,2, Kiyofumi Ninomiya^1,3, Shuhei Okugawa^1,2, Ayaka Nishida¹, Masayuki Yoshikawa¹ and Osamu Muraoka^1,3,*

¹ Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan

² Koshiro Company Ltd., 2-5-8 Doshomachi, Chuo-ku, Osaka 541-0045, Japan

³ Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 1979; https://doi.org/10.3390/ijms17121979 - 26 Nov 2016

Cited by 17 | Viewed by 5774

Abstract

Acylated oleanane-type triterpene saponins, namely chakasaponins I (1) and II (2), floratheasaponin A (3), and their analogs, together with catechins—including (–)-epigallocatechin 3-O-gallate (4), flavonoids, and caffeine—have been isolated as characteristic functional constituents from [...] Read more.

Acylated oleanane-type triterpene saponins, namely chakasaponins I (1) and II (2), floratheasaponin A (3), and their analogs, together with catechins—including (–)-epigallocatechin 3-O-gallate (4), flavonoids, and caffeine—have been isolated as characteristic functional constituents from the extracts of “tea flower”, the flower buds of Camellia sinensis (Theaceae), which have common components with that of the leaf part. These isolates exhibited antiproliferative activities against human digestive tract carcinoma HSC-2, HSC-4, MKN-45, and Caco-2 cells. The antiproliferative activities of the saponins (1–3, IC₅₀ = 4.4–14.1, 6.2–18.2, 4.5–17.3, and 19.3–40.6 µM, respectively) were more potent than those of catechins, flavonoids, and caffeine. To characterize the mechanisms of action of principal saponin constituents 1–3, a flow cytometric analysis using annexin-V/7-aminoactinomycin D (7-AAD) double staining in HSC-2 cells was performed. The percentage of apoptotic cells increased in a concentration-dependent manner. DNA fragmentation and caspase-3/7 activation were also detected after 48 h. These results suggested that antiproliferative activities of 1–3 induce apoptotic cell death via activation of caspase-3/7. Full article

(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)

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17 pages, 5423 KiB

Open AccessArticle

Perinatal Arterial Ischemic Stroke Is Associated to Materno-Fetal Immune Activation and Intracranial Arteritis

by Clémence Guiraut¹, Nicole Cauchon², Martin Lepage² and Guillaume Sébire^1,3,*

¹ Département de Pédiatrie, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada

² Département de Médecine Nucléaire et Radiobiologie, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada

³ Child Neurology Division, Department of Pediatrics, McGill University, Montréal, QC H4A 3J1, Canada

Int. J. Mol. Sci. 2016, 17(12), 1980; https://doi.org/10.3390/ijms17121980 - 25 Nov 2016

Cited by 18 | Viewed by 7580

Abstract

The medium-size intra-cranial arteries arising from the carotid bifurcation are prone to perinatal arterial ischemic strokes (PAIS). PAIS’ physiopathology needs to be better understood to develop preventive and therapeutic interventions that are currently missing. We hypothesized that materno-fetal inflammation leads to a vasculitis [...] Read more.

The medium-size intra-cranial arteries arising from the carotid bifurcation are prone to perinatal arterial ischemic strokes (PAIS). PAIS’ physiopathology needs to be better understood to develop preventive and therapeutic interventions that are currently missing. We hypothesized that materno-fetal inflammation leads to a vasculitis affecting selectively the carotidian tree and promoting a focal thrombosis and subsequent stroke. Dams were injected with saline or lipopolysaccharide (LPS) from Escherichia coli. A prothrombotic stress was applied on LPS-exposed vs. saline (S)-exposed middle cerebral arteries (MCA). Immunolabeling detected the inflammatory markers of interest. In S-exposed newborn pups, a constitutive higher density of macrophages combined to higher expressions of tumor necrosis factor-α (TNF-α), and interleukin 1β (IL-1β) was observed within the wall of intra- vs. extra-cranial cervicocephalic arteries. LPS-induced maternal and placental inflammatory responses mediated by IL-1β, TNF-α and monocyte chemotactic protein 1 (MCP-1) were associated with: (i) increased density of pro-inflammatory macrophages (M1 phenotype); and (ii) pro-inflammatory orientation of the IL-1 system (IL-1β/IL-1 receptor antagonist (IL-1Ra) ratio) within the wall of LPS-, vs. S-exposed, intra-cranial arteries susceptible to PAIS. LPS plus photothrombosis, but not sole photothrombosis, triggered ischemic strokes and subsequent motor impairments. Based on these preclinical results, the combination of pro-thrombotic stress and selective intra-cranial arteritis arising from end gestational maternal immune activation seem to play a role in the pathophysiology of human PAIS. Full article

(This article belongs to the Special Issue Vascular Biology and Therapeutics)

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16 pages, 450 KiB

Open AccessReview

Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans

by Aren Bezdjian, Véronique J. C. Kraaijenga

, Dyan Ramekers, Huib Versnel^*, Hans G. X. M. Thomeer, Sjaak F. L. Klis and Wilko Grolman

Department of Otorhinolaryngology and Head & Neck Surgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands

Int. J. Mol. Sci. 2016, 17(12), 1981; https://doi.org/10.3390/ijms17121981 - 26 Nov 2016

Cited by 11 | Viewed by 5564

Abstract

Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our [...] Read more.

Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our literature search included disorder, neurotrophic factor, administration route, therapeutic outcome, and adverse event. From 2103 articles retrieved, 20 randomized controlled trials including 3974 patients were selected. Amyotrophic lateral sclerosis (53%) was the most frequently reported indication for neurotrophic therapy followed by diabetic polyneuropathy (28%). Ciliary neurotrophic factor (50%), nerve growth factor (24%) and insulin-like growth factor (21%) were most often used. Injection site reaction was a frequently occurring adverse event (61%) followed by asthenia (24%) and gastrointestinal disturbances (20%). Eighteen out of 20 trials deemed neurotrophic therapy to be safe, and six out of 17 studies concluded the neurotrophic therapy to be effective. Positive outcomes were generally small or contradicted by other studies. Most non-neurodegenerative diseases treated by targeted deliveries of neurotrophic factors were considered safe and effective. Hence, since local delivery to the cochlea is feasible, translation from animal studies to human trials in treating auditory nerve degeneration seems promising. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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30 pages, 3822 KiB

Open AccessReview

Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness

by David J. Olivos^1,2 and Lindsey D. Mayo^2,3,*

¹ Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

² Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA

³ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

Int. J. Mol. Sci. 2016, 17(12), 1982; https://doi.org/10.3390/ijms17121982 - 26 Nov 2016

Cited by 46 | Viewed by 9649

Abstract

Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution [...] Read more.

Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution of p53 detailing the significant discoveries of each decade since its first report in 1979. In this review, we will highlight the emerging non-canonical functions and regulation of p53 in stem cells. We will focus on general themes shared among p53’s functions in non-malignant stem cells and cancer stem-like cells (CSCs) and the influence of p53 on the microenvironment and CSC niche. We will also examine p53 gain of function (GOF) roles in stemness. Mutant p53 (mutp53) GOFs that lead to survival, drug resistance and colonization are reviewed in the context of the acquisition of advantageous transformation processes, such as differentiation and dedifferentiation, epithelial-to-mesenchymal transition (EMT) and stem cell senescence and quiescence. Finally, we will conclude with therapeutic strategies that restore wild-type p53 (wtp53) function in cancer and CSCs, including RING finger E3 ligases and CSC maintenance. The mechanisms by which wtp53 and mutp53 influence stemness in non-malignant stem cells and CSCs or tumor-initiating cells (TICs) are poorly understood thus far. Further elucidation of p53’s effects on stemness could lead to novel therapeutic strategies in cancer research. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

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15 pages, 1047 KiB

Open AccessReview

Biological Activities of Extracts from Loquat (Eriobotrya japonica Lindl.): A Review

by Yilong Liu^1,†, Wenna Zhang^1,2,†, Changjie Xu^1,3 and Xian Li^1,3,*

¹ Zhejiang Provincial Key Laboratory of Horticultural Plant Integrative Biology, Zhejiang University, Zijingang Campus, Hangzhou 310058, China

² Catch Bio-Science & Technology Co., Ltd., 5F of Building G, No. 1 North Guotai Road, Zhangjiagang 215600, China

³ The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Zijingang Campus, Hangzhou 310058, China

^† These authors contributed equally to this study.

Int. J. Mol. Sci. 2016, 17(12), 1983; https://doi.org/10.3390/ijms17121983 - 6 Dec 2016

Cited by 135 | Viewed by 16176

Abstract

Loquat (Eriobotrya japonica Lindl.) is a subtropical fruit tree with high medicinal value native to China. Different organs of loquat have been used historically as folk medicines and this has been recorded in Chinese history for thousands of years. Research shows that [...] Read more.

Loquat (Eriobotrya japonica Lindl.) is a subtropical fruit tree with high medicinal value native to China. Different organs of loquat have been used historically as folk medicines and this has been recorded in Chinese history for thousands of years. Research shows that loquat extracts contain many antioxidants, and different extracts exhibit bioactivity capable of counteracting inflammation, diabetes, cancer, bacterial infection, aging, pain, allergy and other health issues. Bioactive compounds such as phenolics and terpenoids have been isolated and characterized to provide a better understanding of the chemical mechanisms underlying the biological activities of loquat extracts. As the identification of compounds progresses, studies investigating the in vivo metabolism, bioavailability, and structure–activity relationships, as well as potential toxicity of loquat extracts in animal or cell models are receiving more attention. In addition, genetic studies and breeding of loquat germplasms for high contents of health-benefiting compounds may provide new insight for the loquat industry and research. This review is focused on the main medicinal properties reported and the possible pharmaceutically active compounds identified in different loquat extracts. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables 2016)

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20 pages, 6076 KiB

Open AccessArticle

DNA Damage-Inducible Transcript 4 Is an Innate Surveillant of Hair Follicular Stress in Vitamin D Receptor Knockout Mice and a Regulator of Wound Re-Epithelialization

by Hengguang Zhao^1,*

, Sandra Rieger², Koichiro Abe³, Martin Hewison⁴ and Thomas S. Lisse^2,5,*

¹ Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

² Kathryn W. Davis Center for Regenerative Biology and Medicine, Mount Desert Island Biological Laboratory, 159 Old Bar Harbor Road, Salisbury Cove, ME 04672, USA

³ Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan

⁴ Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, The University of Birmingham, Birmingham B15 2TH, UK

⁵ The Jackson Laboratory, Bar Harbor, ME 04609, USA

Int. J. Mol. Sci. 2016, 17(12), 1984; https://doi.org/10.3390/ijms17121984 - 26 Nov 2016

Cited by 17 | Viewed by 7889

Abstract

Mice and human patients with impaired vitamin D receptor (VDR) signaling have normal developmental hair growth but display aberrant post-morphogenic hair cycle progression associated with alopecia. In addition, VDR^–/– mice exhibit impaired cutaneous wound healing. We undertook experiments to determine whether the [...] Read more.

Mice and human patients with impaired vitamin D receptor (VDR) signaling have normal developmental hair growth but display aberrant post-morphogenic hair cycle progression associated with alopecia. In addition, VDR^–/– mice exhibit impaired cutaneous wound healing. We undertook experiments to determine whether the stress-inducible regulator of energy homeostasis, DNA damage-inducible transcript 4 (Ddit4), is involved in these processes. By analyzing hair cycle activation in vivo, we show that VDR^−/− mice at day 14 exhibit increased Ddit4 expression within follicular stress compartments. At day 29, degenerating VDR^−/− follicular keratinocytes, but not bulge stem cells, continue to exhibit an increase in Ddit4 expression. At day 47, when normal follicles and epidermis are quiescent and enriched for Ddit4, VDR^−/− skin lacks Ddit4 expression. In a skin wound healing assay, the re-epithelialized epidermis in wildtype (WT) but not VDR^−/− animals harbor a population of Ddit4- and Krt10-positive cells. Our study suggests that VDR regulates Ddit4 expression during epidermal homeostasis and the wound healing process, while elevated Ddit4 represents an early growth-arresting stress response within VDR^−/− follicles. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration)

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15 pages, 1056 KiB

Open AccessReview

Dendritic Cell-Based Immunotherapies to Fight HIV: How Far from a Success Story? A Systematic Review and Meta-Analysis

by Antonio Victor Campos Coelho¹

, Ronald Rodrigues De Moura¹, Anselmo Jiro Kamada¹, Ronaldo Celerino Da Silva², Rafael Lima Guimarães^1,2

, Lucas André Cavalcanti Brandão^2,3, Luiz Cláudio Arraes De Alencar^4,5 and Sergio Crovella^6,*

¹ Department of Genetics, Federal University of Pernambuco, Avenida da Engenharia, Cidade Universitária, Recife 50740-600, Brazil

² Laboratory of Immunopathology Keizo Asami (LIKA), Federal University of Pernambuco, Avenida da Engenharia, Cidade Universitária, Recife 50740-600, Brazil

³ Department of Pathology, Federal University of Pernambuco, Avenida Prof. Moraes Rego, 1235, Cidade Universitária, Recife 50670-901, Brazil

⁴ Department of Tropical Medicine, Federal University of Pernambuco. Avenida Prof. Moraes Rego, 1235, Cidade Universitária, Recife 50670-901, Brazil

⁵ Instituto de Medicina Integral Professor Fernando Figueira (IMIP), Boa Vista, Recife 50070-550, Brazil

⁶ IRCCS Burlo Garofolo and University of Trieste, Via dell’ Istria 65/1, Trieste 34137, Italy

Int. J. Mol. Sci. 2016, 17(12), 1985; https://doi.org/10.3390/ijms17121985 - 26 Nov 2016

Cited by 32 | Viewed by 7296

Abstract

The scientific community still faces the challenge of developing strategies to cure HIV-1. One of these pursued strategies is the development of immunotherapeutic vaccines based on dendritic cells (DCs), pulsed with the virus, that aim to boost HIV-1 specific immune response. We aimed [...] Read more.

The scientific community still faces the challenge of developing strategies to cure HIV-1. One of these pursued strategies is the development of immunotherapeutic vaccines based on dendritic cells (DCs), pulsed with the virus, that aim to boost HIV-1 specific immune response. We aimed to review DCs-based therapeutic vaccines reports and critically assess evidence to gain insights for the improvement of these strategies. We performed a systematic review, followed by meta-analysis and meta-regression, of clinical trial reports. Twelve studies were selected for meta-analysis. The experimental vaccines had low efficiency, with an overall success rate around 38% (95% confidence interval = 26.7%–51.3%). Protocols differed according to antigen choice, DC culture method, and doses, although multivariate analysis did not show an influence of any of them on overall success rate. The DC-based vaccines elicited at least some immunogenicity, that was sometimes associated with plasmatic viral load transient control. The protocols included both naïve and antiretroviral therapy (ART)-experienced individuals, and used different criteria for assessing vaccine efficacy. Although the vaccines did not work as expected, they are proof of concept that immune responses can be boosted against HIV-1. Protocol standardization and use of auxiliary approaches, such as latent HIV-1 reservoir activation and patient genomics are paramount for fine-tuning future HIV-1 cure strategies. Full article

(This article belongs to the Special Issue Immuno- and Neuropathogenesis of HIV Disease: Mechanisms, Prevention, Treatment, and Cure)

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9 pages, 976 KiB

Open AccessArticle

Pro- and Antioxidant Activity of Three Selected Flavan Type Flavonoids: Catechin, Eriodictyol and Taxifolin

by Vladimir Chobot^1,*

, Franz Hadacek²

, Gert Bachmann¹

, Wolfram Weckwerth¹ and Lenka Kubicova¹

¹ Division of Molecular Systems Biology, Department of Ecogenomics and Systems Biology, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria

² Department of Plant Biochemistry, Albrecht-von-Haller Institut, Georg-August-Universität Göttingen, Justus-von-Liebig-Weg 11, D-37077 Göttingen, Germany

Int. J. Mol. Sci. 2016, 17(12), 1986; https://doi.org/10.3390/ijms17121986 - 26 Nov 2016

Cited by 46 | Viewed by 6991

Abstract

The flavanol (±)-catechin shows an OH group but no 4-keto group on ring C (C3), and no conjugation between ring A and B. The related flavanone (+)-eriodictyol has a keto group on C4 but no 3-OH group on ring C. (+)-Taxifolin, another flavanone, [...] Read more.

The flavanol (±)-catechin shows an OH group but no 4-keto group on ring C (C3), and no conjugation between ring A and B. The related flavanone (+)-eriodictyol has a keto group on C4 but no 3-OH group on ring C. (+)-Taxifolin, another flavanone, has an OH on C3 and a keto group on C4 of the C ring. Deoxyribose degradation assay systems, with hydrogen peroxide and ascorbic acid either added or omitted, were performed in variants in which Fe(III) was added in a complex with ethylenediaminetetraacetic acid (EDTA). In combination with differential pulse voltammetry (DVP), the specific redox-chemical contributions of the ring A m-dihydroxyl groups could be explored more specifically in addition to those of the traditionally investigated o-dihydroxyl groups of ring B. Full article

(This article belongs to the Special Issue Nutraceuticals in Human Health and Disease)

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18 pages, 1038 KiB

Open AccessReview

Tools for Sequence-Based miRNA Target Prediction: What to Choose?

by Ángela L. Riffo-Campos^1,2, Ismael Riquelme^1,2 and Priscilla Brebi-Mieville^1,2,*

¹ Molecular Pathology Laboratory, Department of Pathology, Faculty of Medicine, Universidad de La Frontera, Avenida Alemania 0458, 3rd Floor, Temuco 4810296, Chile

² Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Avenida Francisco Salazar 01145, Casilla 54-D, Temuco 4811230, Chile

Int. J. Mol. Sci. 2016, 17(12), 1987; https://doi.org/10.3390/ijms17121987 - 9 Dec 2016

Cited by 331 | Viewed by 20015

Abstract

MicroRNAs (miRNAs) are defined as small non-coding RNAs ~22 nt in length. They regulate gene expression at a post-transcriptional level through complementary base pairing with the target mRNA, leading to mRNA degradation and therefore blocking translation. In the last decade, the dysfunction of [...] Read more.

MicroRNAs (miRNAs) are defined as small non-coding RNAs ~22 nt in length. They regulate gene expression at a post-transcriptional level through complementary base pairing with the target mRNA, leading to mRNA degradation and therefore blocking translation. In the last decade, the dysfunction of miRNAs has been related to the development and progression of many diseases. Currently, researchers need a method to identify precisely the miRNA targets, prior to applying experimental approaches that allow a better functional characterization of miRNAs in biological processes and can thus predict their effects. Computational prediction tools provide a rapid method to identify putative miRNA targets. However, since a large number of tools for the prediction of miRNA:mRNA interactions have been developed, all with different algorithms, the biological researcher sometimes does not know which is the best choice for his study and many times does not understand the bioinformatic basis of these tools. This review describes the biological fundamentals of these prediction tools, characterizes the main sequence-based algorithms, and offers some insights into their uses by biologists. Full article

(This article belongs to the Special Issue microRNA Regulation 2017)

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17 pages, 2769 KiB

Open AccessArticle

Extraction, Structural Characterization, and Potential Antioxidant Activity of the Polysaccharides from Four Seaweeds

by Jinzhe He¹, Yaoyang Xu¹, Hongbo Chen² and Peilong Sun^1,*

¹ Department of Food Science and Engineering, Zhejiang University of Technology, Hangzhou 310014, Zhejiang, China

² Zhejing Fangyan Test Group Co., Ltd., Hangzhou 310018, Zhejiang, China

Int. J. Mol. Sci. 2016, 17(12), 1988; https://doi.org/10.3390/ijms17121988 - 28 Nov 2016

Cited by 121 | Viewed by 9489

Abstract

Four seaweed polysaccharides were extracted from Sarcodia ceylonensis, Ulva lactuca L., Gracilaria lemaneiformis, and Durvillaea antarctica, respectively, by microwave-assisted extraction. The effect of three significant variables (extraction time, extraction temperature, and the ratio of water to raw material) on the [...] Read more.

Four seaweed polysaccharides were extracted from Sarcodia ceylonensis, Ulva lactuca L., Gracilaria lemaneiformis, and Durvillaea antarctica, respectively, by microwave-assisted extraction. The effect of three significant variables (extraction time, extraction temperature, and the ratio of water to raw material) on the process for extracting polysaccharides was investigated, along with the optimization of the extraction using the response surface method (RSM) with a Box–Behnken design. The polysaccharide structure, monosaccharide composition, degree of sulfation, and molecular weight (M_W) distribution were analyzed by infrared (IR) spectrometry, gas chromatography (GC), and high-performance gel permeation chromatography (HPGPC). IR spectrometry showed that Sarcodia ceylonensis polysaccharide (SCP), Ulva lactuca L. polysaccharide (ULLP), and Durvillaea antarctica polysaccharide (DAP) were all sulfated polysaccharides and, except Gracilaria lemaneiformis polysaccharide (GLP), all belong to β-pyranosidic polysaccharides. The average molecular weight (M_W) of SCP, ULLP, GLP, and DAP was 466, 404, 591, and 482 kDa, respectively. The quantitative and comparative results with external standards indicated that the main monosaccharide in SCP and ULLP was mannose; and GLP and DAP were mainly composed of galactose and glucose, respectively. Then the in vitro antioxidant activity of all of the polysaccharides was evaluated using different assays—2,2–azino –bis (3-ethylbenzthiazoline-6- sulfonate) (ABTS), hydroxyl radical, nitrite scavenging capacity, and reducing power—and the relationship between their antioxidant activity and chemical characteristics were also examined. ULLP presented the highest ABTS radical scavenging activity; ULLP, SCP and DAP also showed a strong effect on the ABTS radical scavenging activity. SCP and ULLP exhibited excellent hydroxyl radical scavenging activities, about 83.33% ± 2.31% and 80.07% ± 2.17%, respectively, at 4 mg/mL. The reducing power of DAP was relatively more pronounced than that of the three other polysaccharides. However, the nitrite scavenging activities of the four seaweed polysaccharides were weaker than other antioxidant activity (ABTS), hydroxyl radical scavenging capacity, and reducing power. In addition, GLP exhibited lower activities than the other three samples in all of the tests for the antioxidant activity. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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14 pages, 5228 KiB

Open AccessArticle

Macromolecular Interactions Control Structural and Thermal Properties of Regenerated Tri-Component Blended Films

by Ashley Lewis¹, Joshua C. Waters¹, John Stanton², Joseph Hess² and David Salas-de la Cruz^2,3,*

¹ Department of Biology, Rutgers University-Camden, 315 Penn Street, Camden, NJ 08102, USA

² Department of Chemistry, Rutgers University-Camden, 315 Penn Street, Camden, NJ 08102, USA

³ Center for Computational and Integrative Biology, Rutgers University-Camden, 315 Penn Street, Camden, NJ 08102, USA

Int. J. Mol. Sci. 2016, 17(12), 1989; https://doi.org/10.3390/ijms17121989 - 28 Nov 2016

Cited by 11 | Viewed by 5771

Abstract

With a growing need for sustainable resources research has become highly interested in investigating the structure and physical properties of biomaterials composed of natural macromolecules. In this study, we assessed the structural, morphological, and thermal properties of blended, regenerated films comprised of cellulose, [...] Read more.

With a growing need for sustainable resources research has become highly interested in investigating the structure and physical properties of biomaterials composed of natural macromolecules. In this study, we assessed the structural, morphological, and thermal properties of blended, regenerated films comprised of cellulose, lignin, and hemicellulose (xylan) using the ionic liquid 1-allyl-3-methylimidazolium chloride (AMIMCl). Attenuated total reflectance Fourier transform infrared (ATR-FTIR) analysis, scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray scattering, and thermogravimetric analysis (TGA) were used to qualitatively and quantitatively measure bonding interactions, morphology, and thermal stability of the regenerated films. The results demonstrated that the regenerated films’ structural, morphological, and thermal character changed as a function of lignin-xylan concentration. The decomposition temperature rose according to an increase in lignin content and the surface topography of the regenerated films changed from fibrous to spherical patterns. This suggests that lignin-xylan concentration alters the self-assembly of lignin and the cellulose microfibril development. X-ray scattering confirms the extent of the morphological and molecular changes. Our data reveals that the inter- and intra-molecular interactions with the cellulose crystalline domains, along with the amount of disorder in the system, control the microfibril dimensional characteristics, lignin self-assembly, and possibly the overall material′s structural and thermal properties. Full article

(This article belongs to the Special Issue Ionic Liquids 2016 and Selected Papers from ILMAT III)

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17 pages, 5682 KiB

Open AccessArticle

Immune-Related Gene Expression Patterns in GPV- or H9N2-Infected Goose Spleens

by Shun Chen^1,2,3,*,†, Anqi Wang^1,†, Lipei Sun^1,†, Fei Liu^3,†, Mingshu Wang^1,2,3, Renyong Jia^1,2,3, Dekang Zhu^2,3, Mafeng Liu^1,2,3, Qiao Yang^1,2,3, Ying Wu^1,2,3, Kunfeng Sun^1,2,3, Xiaoyue Chen^2,3 and Anchun Cheng^1,2,3,*

¹ Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China

² Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu 611130, China

³ Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 1990; https://doi.org/10.3390/ijms17121990 - 1 Dec 2016

Cited by 13 | Viewed by 5561

Abstract

Goose parvovirus (GPV) and avian influenza virus subtype H9N2 are single-stranded DNA (ssDNA) and single-stranded RNA (ssRNA) viruses, respectively, both of which can spread in goslings and cause a significant economic loss. To explore the comprehensive transcriptome of GPV- or H9N2-infected goose spleens [...] Read more.

Goose parvovirus (GPV) and avian influenza virus subtype H9N2 are single-stranded DNA (ssDNA) and single-stranded RNA (ssRNA) viruses, respectively, both of which can spread in goslings and cause a significant economic loss. To explore the comprehensive transcriptome of GPV- or H9N2-infected goose spleens and to understand the immune responses induced by a DNA virus (GPV) or a RNA virus (H9N2), RNA-seq was performed on the spleens of goslings at the fifth day post infection. In the present study, 2604 and 2409 differentially expressed unigenes were identified in the GPV- and H9N2-infected groups, respectively. Through KEGG pathway enrichment analyses, the up-regulated transcripts in the two virus-infected groups were mainly involved in immune-related pathways. In addition, the two virus-infected groups displayed similar expression patterns in the immune response pathways, including pattern-recognition receptor signaling pathways, the antigen processing and presentation pathway, the NF-κB signaling pathway and the JAK-STAT signaling pathway, as well as cytokines. Furthermore, most of the immune-related genes, particularly TLR7, TRAF3, Mx, TRIM25, CD4, and CD8α, increased in response to GPV and H9N2 infection. However, the depression of NF-κB signaling may be a mechanism by which the viruses evade the host immune system or a strategy to achieve immune homeostasis. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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15 pages, 2205 KiB

Open AccessReview

Pseudogenes and Their Genome-Wide Prediction in Plants

by Jin Xiao^1,2, Manoj Kumar Sekhwal^1,3, Pingchuan Li¹, Raja Ragupathy⁴, Sylvie Cloutier⁵, Xiue Wang² and Frank M. You^1,*

¹ Morden Research and Development Centre, Agriculture and Agri-Food Canada, Morden, MB R6M 1Y5, Canada

² Department of Agronomy, Nanjing Agricultural University, Nanjing 210095, China

³ Department of Soil Science, University of Saskatchewan, Saskatoon, SK S7N 5A8, Canada

⁴ Department of Plant Science, University of Saskatchewan, Saskatoon, SK S7N 5A2, Canada

⁵ Ottawa Research and Development Centre, Agriculture and Agri-Food Canada, Ottawa, ON K1A 0C6, Canada

Int. J. Mol. Sci. 2016, 17(12), 1991; https://doi.org/10.3390/ijms17121991 - 28 Nov 2016

Cited by 33 | Viewed by 10167

Abstract

Pseudogenes are paralogs generated from ancestral functional genes (parents) during genome evolution, which contain critical defects in their sequences, such as lacking a promoter, having a premature stop codon or frameshift mutations. Generally, pseudogenes are functionless, but recent evidence demonstrates that some of [...] Read more.

Pseudogenes are paralogs generated from ancestral functional genes (parents) during genome evolution, which contain critical defects in their sequences, such as lacking a promoter, having a premature stop codon or frameshift mutations. Generally, pseudogenes are functionless, but recent evidence demonstrates that some of them have potential roles in regulation. The majority of pseudogenes are generated from functional progenitor genes either by gene duplication (duplicated pseudogenes) or retro-transposition (processed pseudogenes). Pseudogenes are primarily identified by comparison to their parent genes. Bioinformatics tools for pseudogene prediction have been developed, among which PseudoPipe, PSF and Shiu’s pipeline are publicly available. We compared these three tools using the well-annotated Arabidopsis thaliana genome and its known 924 pseudogenes as a test data set. PseudoPipe and Shiu’s pipeline identified ~80% of A. thaliana pseudogenes, of which 94% were shared, while PSF failed to generate adequate results. A need for improvement of the bioinformatics tools for pseudogene prediction accuracy in plant genomes was thus identified, with the ultimate goal of improving the quality of genome annotation in plants. Full article

(This article belongs to the Section Molecular Plant Sciences)

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26 pages, 2034 KiB

Open AccessReview

Advances in Lipidomics for Cancer Biomarkers Discovery

by Francesca Perrotti^1,2

, Consuelo Rosa^1,2

, Ilaria Cicalini^3,4,5

, Paolo Sacchetta^4,5

, Piero Del Boccio^3,4,5

, Domenico Genovesi^1,2

and Damiana Pieragostino^4,5,*

¹ Department of Neurosciences and Imaging, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy

² Radiation Oncology Unit, SS Annunziata Hospital, 66100 Chieti, Italy

³ Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy

⁴ Department of Medical Oral and Biotechnological Sciences, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy

⁵ Analitical Biochemistry and Proteomics Unit, Research Centre on Aging (Ce.S.I), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy

Int. J. Mol. Sci. 2016, 17(12), 1992; https://doi.org/10.3390/ijms17121992 - 28 Nov 2016

Cited by 154 | Viewed by 10982

Abstract

Lipids play critical functions in cellular survival, proliferation, interaction and death, since they are involved in chemical-energy storage, cellular signaling, cell membranes, and cell–cell interactions. These cellular processes are strongly related to carcinogenesis pathways, particularly to transformation, progression, and metastasis, suggesting the bioactive [...] Read more.

Lipids play critical functions in cellular survival, proliferation, interaction and death, since they are involved in chemical-energy storage, cellular signaling, cell membranes, and cell–cell interactions. These cellular processes are strongly related to carcinogenesis pathways, particularly to transformation, progression, and metastasis, suggesting the bioactive lipids are mediators of a number of oncogenic processes. The current review gives a synopsis of a lipidomic approach in tumor characterization; we provide an overview on potential lipid biomarkers in the oncology field and on the principal lipidomic methodologies applied. The novel lipidomic biomarkers are reviewed in an effort to underline their role in diagnosis, in prognostic characterization and in prediction of therapeutic outcomes. A lipidomic investigation through mass spectrometry highlights new insights on molecular mechanisms underlying cancer disease. This new understanding will promote clinical applications in drug discovery and personalized therapy. Full article

(This article belongs to the Special Issue Metabolomic Technologies in Medicine)

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11 pages, 7306 KiB

Open AccessArticle

Enhanced Autophagy in Polycystic Kidneys of AQP11 Null Mice

by Yasuko Tanaka^1,*, Mayumi Watari¹, Tatsuya Saito¹, Yoshiyuki Morishita² and Kenichi Ishibashi¹

¹ Department of Pathophysiology, Faculty of Pharmacy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

² Department of Nephrology, Saitama Medical Center, Jichi Medical University, 1-847 Ohmiya, Saitama-City, Saitama 330-8503, Japan

Int. J. Mol. Sci. 2016, 17(12), 1993; https://doi.org/10.3390/ijms17121993 - 30 Nov 2016

Cited by 28 | Viewed by 6087

Abstract

Aquaporin-11 (AQP11) is an intracellular water channel expressed at the endoplasmic reticulum (ER) of the proximal tubule. Its gene disruption in mice leads to intracellular vacuole formation at one week and the subsequent development of polycystic kidneys by three weeks. As the damaged [...] Read more.

Aquaporin-11 (AQP11) is an intracellular water channel expressed at the endoplasmic reticulum (ER) of the proximal tubule. Its gene disruption in mice leads to intracellular vacuole formation at one week and the subsequent development of polycystic kidneys by three weeks. As the damaged proximal tubular cells with intracellular vacuoles form cysts later, we postulated that autophagy may play a role in the cyst formation and examined autophagy activity before and after cyst development in AQP11(−/−) kidneys. PCR analysis showed the increased expression of the transcript encoding LC3 (Map1lc3b) as well as other autophagy-related genes in AQP11(−/−) mice. Using green fluorescent protein (GFP)-LC3 transgenic mice and AQP11(−/−) mice, we found that the number of GFP-LC3–positive puncta was increased in the proximal tubule of AQP11(−/−) mice before the cyst formation. Interestingly, they were also observed in the cyst-lining epithelial cell. Further PCR analyses revealed the enhanced expression of apoptosis-related and ER stress–related caspase genes before and after the cyst formation, which may cause the enhanced autophagy. These results suggest the involvement of autophagy in the development and maintenance of kidney cysts in AQP11(−/−) mice. Full article

(This article belongs to the Special Issue Aquaporin)

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12 pages, 824 KiB

Open AccessReview

Roles of MicroRNA across Prenatal and Postnatal Periods

by Ilaria Floris^†,‡, Jamie D. Kraft^† and Illimar Altosaar^*

¹ Biochemistry, Microbiology & Immunology Department, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H8M5, Canada

^† These authors contributed equally to this work.

^‡ Current address: Labo’Life France, Pescalis, Les Magnys, 79320 Moutiers-sous-Chantemerle, France.

Int. J. Mol. Sci. 2016, 17(12), 1994; https://doi.org/10.3390/ijms17121994 - 28 Nov 2016

Cited by 39 | Viewed by 7746

Abstract

Communication between mother and offspring in mammals starts at implantation via the maternal–placental–fetal axis, and continues postpartum via milk targeted to the intestinal mucosa. MicroRNAs (miRNAs), short, noncoding single-stranded RNAs, of about 22 nucleotides in length, are actively involved in many developmental and [...] Read more.

Communication between mother and offspring in mammals starts at implantation via the maternal–placental–fetal axis, and continues postpartum via milk targeted to the intestinal mucosa. MicroRNAs (miRNAs), short, noncoding single-stranded RNAs, of about 22 nucleotides in length, are actively involved in many developmental and physiological processes. Here we highlight the role of miRNA in the dynamic signaling that guides infant development, starting from implantation of conceptus and persisting through the prenatal and postnatal periods. miRNAs in body fluids, particularly in amniotic fluid, umbilical cord blood, and breast milk may offer new opportunities to investigate physiological and/or pathological molecular mechanisms that portend to open novel research avenues for the identification of noninvasive biomarkers. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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15 pages, 5471 KiB

Open AccessArticle

Graphene Oxide Nanoribbons Induce Autophagic Vacuoles in Neuroblastoma Cell Lines

by Emanuela Mari^1,*, Stefania Mardente^1,*, Emanuela Morgante¹, Marco Tafani^1,3, Emanuela Lococo¹, Flavia Fico¹, Federica Valentini² and Alessandra Zicari¹

¹ Department of Experimental Medicine, University of Rome Sapienza, 00161 Roma, Italy

² Department of Chemistry, University of Rome Tor Vergata, 00173 Roma, Italy

³ Laboratory of Molecular and Cellular Pathology, IRCCS San Raffaele Pisana, 00163 Rome, Italy

Int. J. Mol. Sci. 2016, 17(12), 1995; https://doi.org/10.3390/ijms17121995 - 29 Nov 2016

Cited by 41 | Viewed by 6656

Abstract

Since graphene nanoparticles are attracting increasing interest in relation to medical applications, it is important to understand their potential effects on humans. In the present study, we prepared graphene oxide (GO) nanoribbons by oxidative unzipping of single-wall carbon nanotubes (SWCNTs) and analyzed their [...] Read more.

Since graphene nanoparticles are attracting increasing interest in relation to medical applications, it is important to understand their potential effects on humans. In the present study, we prepared graphene oxide (GO) nanoribbons by oxidative unzipping of single-wall carbon nanotubes (SWCNTs) and analyzed their toxicity in two human neuroblastoma cell lines. Neuroblastoma is the most common solid neoplasia in children. The hallmark of these tumors is the high number of different clinical variables, ranging from highly metastatic, rapid progression and resistance to therapy to spontaneous regression or change into benign ganglioneuromas. Patients with neuroblastoma are grouped into different risk groups that are characterized by different prognosis and different clinical behavior. Relapse and mortality in high risk patients is very high in spite of new advances in chemotherapy. Cell lines, obtained from neuroblastomas have different genotypic and phenotypic features. The cell lines SK-N-BE(2) and SH-SY5Y have different genetic mutations and tumorigenicity. Cells were exposed to low doses of GO for different times in order to investigate whether GO was a good vehicle for biological molecules delivering individualized therapy. Cytotoxicity in both cell lines was studied by measuring cellular oxidative stress (ROS), mitochondria membrane potential, expression of lysosomial proteins and cell growth. GO uptake and cytoplasmic distribution of particles were studied by Transmission Electron Microscopy (TEM) for up to 72 h. The results show that GO at low concentrations increased ROS production and induced autophagy in both neuroblastoma cell lines within a few hours of exposure, events that, however, are not followed by growth arrest or death. For this reason, we suggest that the GO nanoparticle can be used for therapeutic delivery to the brain tissue with minimal effects on healthy cells. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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8 pages, 1172 KiB

Open AccessArticle

Prognostic Relevance of Methylenetetrahydrofolate Reductase Polymorphisms for Prostate Cancer

by Victor C. Lin^1,2,†, Te-Ling Lu^3,†

, Hsin-Ling Yin^4,5, Sheau-Fang Yang^4,5, Yung-Chin Lee^6,7, Chia-Chu Liu^6,7, Chao-Yuan Huang^8,9, Chia-Cheng Yu^10,11,12, Ta-Yuan Chang¹³, Shu-Pin Huang^6,7,14,* and Bo-Ying Bao^3,15,16,*

¹ Department of Urology, E-Da Hospital, Kaohsiung 824, Taiwan

² School of Medicine for International Students, I-Shou University, Kaohsiung 840, Taiwan

³ Department of Pharmacy, China Medical University, Taichung 404, Taiwan

⁴ Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

⁵ Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

⁶ Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

⁷ Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

⁸ Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan

⁹ Department of Urology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu 300, Taiwan

¹⁰ Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan

¹¹ Department of Urology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan

¹² Department of Pharmacy, Tajen University, Pingtung 907, Taiwan

¹³ Department of Occupational Safety and Health, China Medical University, Taichung 404, Taiwan

¹⁴ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

¹⁵ Sex Hormone Research Center, China Medical University Hospital, Taichung 404, Taiwan

¹⁶ Department of Nursing, Asia University, Taichung 413, Taiwan

^† These authors contributed equally to this work.

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Int. J. Mol. Sci. 2016, 17(12), 1996; https://doi.org/10.3390/ijms17121996 - 29 Nov 2016

Cited by 7 | Viewed by 4794

Abstract

Folate metabolism has been associated with cancers via alterations in nucleotide synthesis, DNA methylation, and DNA repair. We hypothesized that genetic variants in methylenetetrahydrofolate reductase (MTHFR), a key enzyme of folate metabolism, would affect the prognosis of prostate cancer. Three haplotype-tagging [...] Read more.

Folate metabolism has been associated with cancers via alterations in nucleotide synthesis, DNA methylation, and DNA repair. We hypothesized that genetic variants in methylenetetrahydrofolate reductase (MTHFR), a key enzyme of folate metabolism, would affect the prognosis of prostate cancer. Three haplotype-tagging single-nucleotide polymorphisms (SNPs) across the MTHFR gene region were genotyped in a cohort of 458 patients with clinically localized prostate cancer treated with radical prostatectomy. One SNP, rs9651118, was associated with disease recurrence, and the association persisted after multivariate analyses adjusting for known risk factors. Public dataset analyses suggested that rs9651118 affects MTHFR expression. Quantitative real-time polymerase chain reaction analysis revealed that MTHFR expression is significantly upregulated in prostate tumor tissues when compared with adjacent normal tissues. Furthermore, overexpression of MTHFR correlates with cancer recurrence and death in two independent publicly available prostate cancer datasets. In conclusion, our data provide rationale to further validate the clinical utility of MTHFR rs9651118 as a biomarker for prognosis in prostate cancer. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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10 pages, 801 KiB

Open AccessCommunication

Mechanisms of p53 Functional De-Regulation: Role of the IκB-α/p53 Complex

by Giovanna Carrà¹, Sabrina Crivellaro¹, Riccardo Taulli², Angelo Guerrasio¹, Giuseppe Saglio¹ and Alessandro Morotti^1,*

¹ Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043 Turin, Italy

² Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Turin, Italy

Int. J. Mol. Sci. 2016, 17(12), 1997; https://doi.org/10.3390/ijms17121997 - 29 Nov 2016

Cited by 14 | Viewed by 5178

Abstract

TP53 is one of the most frequently-mutated and deleted tumor suppressors in cancer, with a dramatic correlation with dismal prognoses. In addition to genetic inactivation, the p53 protein can be functionally inactivated in cancer, through post-transductional modifications, changes in cellular compartmentalization, and interactions [...] Read more.

TP53 is one of the most frequently-mutated and deleted tumor suppressors in cancer, with a dramatic correlation with dismal prognoses. In addition to genetic inactivation, the p53 protein can be functionally inactivated in cancer, through post-transductional modifications, changes in cellular compartmentalization, and interactions with other proteins. Here, we review the mechanisms of p53 functional inactivation, with a particular emphasis on the interaction between p53 and IκB-α, the NFKBIA gene product. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

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17 pages, 6303 KiB

Open AccessArticle

Enhancing Anticancer Effect of Gefitinib across the Blood–Brain Barrier Model Using Liposomes Modified with One α-Helical Cell-Penetrating Peptide or Glutathione and Tween 80

by Kuan-Hung Lin¹, Shu-Ting Hong¹, Hsiang-Tsui Wang¹, Yu-Li Lo^1,2,*, Anya Maan-Yuh Lin^1,2,3,* and James Chih-Hsin Yang⁴

¹ Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan

² Faculty of Pharmacy, National Yang-Ming University, Taipei 112, Taiwan

³ Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan

⁴ Institute of Oncology, National Taiwan University, Taipei 106, Taiwan

Int. J. Mol. Sci. 2016, 17(12), 1998; https://doi.org/10.3390/ijms17121998 - 29 Nov 2016

Cited by 36 | Viewed by 8578

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been demonstrated to effectively treat the patients of extracranial non-small cell lung cancer (NSCLC). However, these patients often develop brain metastasis (BM) during their disease course. The major obstacle to [...] Read more.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been demonstrated to effectively treat the patients of extracranial non-small cell lung cancer (NSCLC). However, these patients often develop brain metastasis (BM) during their disease course. The major obstacle to treat BM is the limited penetration of anticancer drugs across the blood–brain barrier (BBB). In the present study, we utilized gefitinib-loaded liposomes with different modifications to improve gefitinib delivery across the in vitro BBB model of bEnd.3 cells. Gefitinib was encapsulated in small unilamellar liposomes modified with glutathione (GSH) and Tween 80 (SUV-G+T; one ligand plus one surfactant) or RF (SUV-RF; one α-helical cell-penetrating peptide). GSH, Tween 80, and RF were tested by the sulforhodamine B (SRB) assay to find their non-cytotoxic concentrations on bEnd.3 cells. The enhancement on gefitinib across the BBB was evaluated by cytotoxicity assay on human lung adenocarcinoma PC9 cells under the bEnd.3 cells grown on the transwell inserts. Our findings showed that gefitinib incorporated in SUV-G+T or SUV-RF across the bEnd.3 cells significantly reduced the viability of PC9 cells more than that of free gefitinib. Furthermore, SUV-RF showed no cytotoxicity on bEnd.3 cells and did not affect the transendothelial electrical resistance (TEER) and transendothelial permeability of sodium fluorescein across the BBB model. Moreover, flow cytometry and confocal laser scanning microscopy were employed to evaluate the endocytosis pathways of SUV-RF. The results indicated that the uptake into bEnd.3 cells was mainly through adsorptive-mediated mechanism via electrostatic interaction and partially through clathrin-mediated endocytosis. In conclusion, cell penetrating peptide-conjugated SUV-RF shed light on improving drug transport across the BBB via modulating the transcytosis pathway(s). Full article

(This article belongs to the Section Materials Science)

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12 pages, 2013 KiB

Open AccessArticle

Coriandrum sativum and Lavandula angustifolia Essential Oils: Chemical Composition and Activity on Central Nervous System

by Lucia Caputo¹

, Lucéia Fátima Souza^1,2, Susanna Alloisio³, Laura Cornara⁴ and Vincenzo De Feo^1,*

¹ Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano (Salerno), Italy

² Department of Agronomy, University of Rio Grande do Sul (UFRGS), 91501-970 Porto Alegre, Brazil

³ ETT Spa, via Sestri 37, 16154 Genova, Italy

⁴ Dipartimento di Scienze della Terra, dell’Ambiente e della Vita, University of Genoa, Corso Europa 26, 16132 Genoa, Italy

Int. J. Mol. Sci. 2016, 17(12), 1999; https://doi.org/10.3390/ijms17121999 - 30 Nov 2016

Cited by 53 | Viewed by 8882

Abstract

The aims of this study are to determine the chemical composition of Lavandula angustifolia Mill. and Coriandrum sativum L. essential oils, to evaluate their cytotoxic effects in SH-SY5Y human neuroblastoma cells, to investigate whether an alteration of adenylate cyclase 1 (ADCY1) and of [...] Read more.

The aims of this study are to determine the chemical composition of Lavandula angustifolia Mill. and Coriandrum sativum L. essential oils, to evaluate their cytotoxic effects in SH-SY5Y human neuroblastoma cells, to investigate whether an alteration of adenylate cyclase 1 (ADCY1) and of extracellular signal-regulated kinase (ERK) expression can take part in the molecular mechanisms of the essential oils, and to study their possible neuronal electrophysiological effects. The essential oils were obtained by hydrodistillation, and studied by GC and GC-MS. In the oils from L. angustifolia and C. sativum, linalool was the main component (33.1% and 67.8%, respectively). SH-SY5Y cells were incubated with different concentrations of essential oils and of linalool. Cell viability and effects on ADCY1 and ERK expression were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MTT and Western blotting, respectively. Variation in cellular electrophysiology was studied in primary cultures of rat cortical neurons with a multi-electrode array (MEA)-based approach. The essential oils and linalool revealed different cytotoxic activities. Linalool inhibited ADCY1 and ERK expression. Neuronal networks subjected to L. angustifolia and C. sativum essential oils showed a concentration-dependent inhibition of spontaneous electrical activity. Full article

(This article belongs to the Special Issue Effective Mechanisms of Plant Bioactive Essential Fats and Oils)

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14 pages, 11366 KiB

Open AccessArticle

Metformin Inhibits TGF-β1-Induced Epithelial-to-Mesenchymal Transition via PKM2 Relative-mTOR/p70s6k Signaling Pathway in Cervical Carcinoma Cells

by Keyan Cheng and Min Hao^*

Department of Obstetrics and Gynecology, The Second Hospital of Shanxi Medical University, Taiyuan 030000, China

Int. J. Mol. Sci. 2016, 17(12), 2000; https://doi.org/10.3390/ijms17122000 - 30 Nov 2016

Cited by 61 | Viewed by 9524

Abstract

Background: Epithelial-to-mesenchymal transition (EMT) plays a prominent role in tumorigenesis. Metformin exerts antitumorigenic effects in various cancers. This study investigated the mechanisms of metformin in TGF-β1-induced Epithelial-to-mesenchymal transition (EMT) in cervical carcinoma cells. Methods: cells were cultured with 10 ng/mL TGF-β1 to induce [...] Read more.

Background: Epithelial-to-mesenchymal transition (EMT) plays a prominent role in tumorigenesis. Metformin exerts antitumorigenic effects in various cancers. This study investigated the mechanisms of metformin in TGF-β1-induced Epithelial-to-mesenchymal transition (EMT) in cervical carcinoma cells. Methods: cells were cultured with 10 ng/mL TGF-β1 to induce EMT and treated with or without metformin. Cell viability was evaluated by CCK-8 (Cell Counting Kit 8, CCK-8) assay; apoptosis were analyzed by flow cytometry; cell migration was evaluated by wound-healing assay. Western blotting was performed to detect E-cadherin, vimentin, signal transducer and activator of transcription 3 (STAT3), snail family transcriptional repressor 2 (SNAIL2), phosphorylation of p70s6k (p-p70s6k) and -Pyruvate kinase M2 (PKM2) Results: TGF-β1 promoted proliferation and migration, and it attenuated apoptosis compared with cells treated with metformin with or without TGF-β1 in cervical carcinoma cells. Moreover, metformin partially abolished TGF-β1-induced EMT cell proliferation and reversed TGF-β1-induced EMT. In addition, the anti-EMT effects of metformin could be partially in accord with rapamycin, a specific mTOR inhibitor. Metformin decreased the p-p70s6k expression and the blockade of mTOR/p70s6k signaling decreased PKM2 expression. Conclusion: Metformin abolishes TGF-β1-induced EMT in cervical carcinoma cells by inhibiting mTOR/p70s6k signaling to down-regulate PKM2 expression. Our study provides a novel mechanistic insight into the anti-tumor effects of metformin. Full article

(This article belongs to the Special Issue Chemical and Molecular Approach to Tumor Metastases)

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17 pages, 497 KiB

Open AccessReview

The Role of ERK1/2 in the Development of Diabetic Cardiomyopathy

by Zheng Xu^1,2, Jian Sun¹, Qian Tong¹, Qian Lin³, Lingbo Qian^2,4, Yongsoo Park^2,5,* and Yang Zheng^1,*

¹ Cardiovascular Center, The First Hospital of Jilin University, Changchun 130021, China

² Department of Pediatrics, Kosair Children’s Hospital Research Institute, University of Louisville, Louisville, KY 40202, USA

³ Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA

⁴ Department of Basic Medical Sciences, Hangzhou Medical College, Hangzhou 310053, China

⁵ College of Medicine & Engineering, Hanyang University, Seoul 04963, Korea

Int. J. Mol. Sci. 2016, 17(12), 2001; https://doi.org/10.3390/ijms17122001 - 8 Dec 2016

Cited by 105 | Viewed by 11761

Abstract

Diabetes mellitus is a chronic metabolic condition that affects carbohydrate, lipid and protein metabolism and may impair numerous organs and functions of the organism. Cardiac dysfunction afflicts many patients who experience the oxidative stress of the heart. Diabetic cardiomyopathy (DCM) is one of [...] Read more.

Diabetes mellitus is a chronic metabolic condition that affects carbohydrate, lipid and protein metabolism and may impair numerous organs and functions of the organism. Cardiac dysfunction afflicts many patients who experience the oxidative stress of the heart. Diabetic cardiomyopathy (DCM) is one of the major complications that accounts for more than half of diabetes-related morbidity and mortality cases. Chronic hyperglycemia and hyperlipidemia from diabetes mellitus cause cardiac oxidative stress, endothelial dysfunction, impaired cellular calcium handling, mitochondrial dysfunction, metabolic disturbances, and remodeling of the extracellular matrix, which ultimately lead to DCM. Although many studies have explored the mechanisms leading to DCM, the pathophysiology of DCM has not yet been fully clarified. In fact, as a potential mechanism, the associations between DCM development and mitogen-activated protein kinase (MAPK) activation have been the subjects of tremendous interest. Nonetheless, much remains to be investigated, such as tissue- and cell-specific processes of selection of MAPK activation between pro-apoptotic vs. pro-survival fate, as well as their relation with the pathogenesis of diabetes and associated complications. In general, it turns out that MAPK signaling pathways, such as extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase, are demonstrated to be actively involved in myocardial dysfunction, hypertrophy, fibrosis and heart failure. As one of MAPK family members, the activation of ERK1/2 has also been known to be involved in cardiac hypertrophy and dysfunction. However, many recent studies have demonstrated that ERK1/2 signaling activation also plays a crucial role in FGF21 signaling and exerts a protective environment of glucose and lipid metabolism, therefore preventing abnormal healing and cardiac dysfunction. The duration, extent, and subcellular compartment of ERK1/2 activation are vital to differential biological effects of ERK1/2. Moreover, many intracellular events, including mitochondrial signaling and protein kinases, manipulate signaling upstream and downstream of MAPK, to influence myocardial survival or death. In this review, we will summarize the roles of ERK1/2 pathways in DCM development by the evidence from current studies and will present novel opinions on “differential influence of ERK1/2 action in cardiac dysfunction, and protection against myocardial ischemia-reperfusion injury”. Full article

(This article belongs to the Special Issue Diabetic Complications: Pathophysiology, Mechanisms, and Therapies)

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11 pages, 1951 KiB

Open AccessArticle

Autoimmune Regulator Expression in DC2.4 Cells Regulates the NF-κB Signaling and Cytokine Expression of the Toll-Like Receptor 3 Pathway

by Jitong Sun^†, Kunwei Niu^†, Haiying Fu, Haijun Li, Yi Li^* and Wei Yang^*

¹ Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2002; https://doi.org/10.3390/ijms17122002 - 1 Dec 2016

Cited by 3 | Viewed by 7248

Abstract

Autoimmune regulator (Aire) mutations result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), which manifests as multi-organ autoimmunity and chronic mucocutaneous candidiasis (CMC). Indendritic cells (DCs), pattern recognition receptors (PRR), such as Toll-like receptors (TLRs), are closely involved in the recognition of various pathogens, [...] Read more.

Autoimmune regulator (Aire) mutations result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), which manifests as multi-organ autoimmunity and chronic mucocutaneous candidiasis (CMC). Indendritic cells (DCs), pattern recognition receptors (PRR), such as Toll-like receptors (TLRs), are closely involved in the recognition of various pathogens, activating the intercellular signaling pathway, followed by the activation of transcription factors and the expression of downstream genes, which take part in mediating the immune response and maintaining immune tolerance. In this study, we found that Aire up-regulated TLR3 expression and modulated the downstream cytokine expression and nuclear factor-κB (NF-κB) of the TLR3 signaling pathway. Full article

(This article belongs to the Section Biochemistry)

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18 pages, 714 KiB

Open AccessReview

Molecular Mechanisms of p53 Deregulation in Cancer: An Overview in Multiple Myeloma

by Ana B. Herrero^1,2,†, Elizabeta A. Rojas^1,2,†, Irena Misiewicz-Krzeminska^1,2,3

, Patryk Krzeminski^1,2 and Norma C. Gutiérrez^1,2,4,*

¹ Cancer Research Center-IBMCC (USAL-CSIC), 37007 Salamanca, Spain

² Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain

³ National Medicines Institute, 00725 Warsaw, Poland

⁴ Hematology Department, University Hospital of Salamanca, 37007 Salamanca, Spain

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2003; https://doi.org/10.3390/ijms17122003 - 30 Nov 2016

Cited by 74 | Viewed by 12946

Abstract

The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 [...] Read more.

The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 negative regulators, such as murine double minute 2 (MDM2) or murine double minute 4 (MDM4), epigenetic deregulation, or even alterations in TP53 mRNA splicing. In this work, we will review the different mechanisms of p53 pathway inhibition in cancer with special focus on multiple myeloma (MM), the second most common hematological malignancy, with low incidence of p53 mutations/deletions but growing evidence of indirect p53 pathway deregulation. Translational implications for MM and cancer prognosis and treatment are also reviewed. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

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7 pages, 732 KiB

Open AccessArticle

Aortic Root Dilatation in Mucopolysaccharidosis I–VII

by Meena Bolourchi^1,2, Pierangelo Renella^1,2,3 and Raymond Y. Wang^2,4,*

¹ Department of Pediatrics, Children’s Hospital of Orange County, Orange, CA 92868, USA

² Department of Pediatrics, University of California-Irvine School of Medicine, Orange, CA 92868, USA

³ Pediatric Heart Institute, Children’s Hospital of Orange County, Orange, CA 92868, USA

⁴ Division of Metabolic Disorders, Children’s Hospital of Orange County, Orange, CA 92868, USA

Int. J. Mol. Sci. 2016, 17(12), 2004; https://doi.org/10.3390/ijms17122004 - 29 Nov 2016

Cited by 24 | Viewed by 8985

Abstract

The prevalence of aortic root dilatation (ARD) in mucopolysaccharidosis (MPS) is not well documented. We investigated aortic root measurements in 34 MPS patients at the Children’s Hospital of Orange County (CHOC). The diagnosis, treatment status, age, gender, height, weight and aortic root parameters [...] Read more.

The prevalence of aortic root dilatation (ARD) in mucopolysaccharidosis (MPS) is not well documented. We investigated aortic root measurements in 34 MPS patients at the Children’s Hospital of Orange County (CHOC). The diagnosis, treatment status, age, gender, height, weight and aortic root parameters (aortic valve annulus (AVA), sinuses of Valsalva (SoV), and sinotubular junction (STJ)) were extracted by retrospective chart review and echocardiographic measurements. Descriptive statistics, ANOVA, and paired post-hoc t-tests were used to summarize the aortic dimensions. Exact binomial 95% confidence intervals (CIs) were constructed for ARD, defined as a z-score greater than 2 at the SoV. The patient age ranged from 3.4–25.9 years (mean 13.3 ± 6.1), the height from 0.87–1.62 meters (mean 1.24 ± 0.21), and the weight from 14.1–84.5 kg (mean 34.4 ± 18.0). The prevalence of dilation at the AVA was 41% (14/34; 95% CI: 25%–59%); at the SoV was 35% (12/34; 95% CI: 20%–54%); and at the STJ was 30% (9/30; 95% CI: 15%–49%). The highest prevalence of ARD was in MPS IVa (87.5%). There was no significant difference between mean z-scores of MPS patients who received treatment with hematopoietic stem cell transplantation (HSCT) or enzyme replacement therapy (ERT) vs. untreated MPS patients at the AVA (z = 1.9 ± 2.5 vs. z = 1.5 ± 2.4; p = 0.62), SoV (z = 1.2 ± 1.6 vs. z = 1.3 ± 2.2; p = 0.79), or STJ (z = 1.0 ± 1.8 vs. z = 1.2 ± 1.6; p = 0.83). The prevalence of ARD was 35% in our cohort of MPS I–VII patients. Thus, we recommend screening for ARD on a routine basis in this patient population. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Novel Concepts, Therapeutic Aspects and Beyond)

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12 pages, 1673 KiB

Open AccessArticle

The Impact of CXCR4 Blockade on the Survival of Rat Brain Cortical Neurons

by José Joaquín Merino^1,2,*, Alba Garcimartín³, María Elvira López-Oliva⁴

, Juana Benedí³ and María Pilar González¹

¹ Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid (U.C.M.), Ciudad Universitaria, 28040 Madrid, Spain

² Instituto de Investigación Neuroquímica (I.U.I.N.), Universidad Complutense de Madrid (U.C.M.), Ciudad Universitaria, 28040 Madrid, Spain

³ Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid (U.C.M.), Ciudad Universitaria, 28040 Madrid, Spain

⁴ Sección Departamental de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid (U.C.M.), Ciudad Universitaria, 28040 Madrid, Spain

Int. J. Mol. Sci. 2016, 17(12), 2005; https://doi.org/10.3390/ijms17122005 - 30 Nov 2016

Cited by 4 | Viewed by 5406

Abstract

Background: Chemokine receptor type 4 (CXCR4) plays a role in neuronal survival/cell repair and also contributes to the progression of cancer and neurodegenerative diseases. Chemokine ligand 12 (CXCL12) binds to CXCR4. In this study, we have investigated whether CXCR4 blockade by AMD3100 (a [...] Read more.

Background: Chemokine receptor type 4 (CXCR4) plays a role in neuronal survival/cell repair and also contributes to the progression of cancer and neurodegenerative diseases. Chemokine ligand 12 (CXCL12) binds to CXCR4. In this study, we have investigated whether CXCR4 blockade by AMD3100 (a CXCR4 antagonist, member of bicyclam family) may affect neuronal survival in the absence of insult. Thus, we have measured the mitochondrial membrane potential (MMP), Bax and Bcl-2 protein translocation, and cytochrome c release in AMD3100-treated brain cortical neurons at 7 DIV (days in vitro). Methods: For this aim, AMD3100 (200 nM) was added to cortical neurons for 24 h, and several biomarkers like cell viability, reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) release, caspase-3/9 activity, proteins Bax and Bcl-2 translocation, and cytochrome c release were analyzed by immunoblot. Results: CXCR4 blockade by AMD3100 (200 nM, 24 h) induces mitochondrial hyperpolarization and increases caspase-3/9 hyperpolarization without affecting LDH release as compared to untreated controls. AMD3100 also increases cytochrome c release and promotes Bax translocation to the mitochondria, whereas it raises cytosolic Bcl-2 levels in brain cortical neurons. Conclusion: CXCR4 blockade induces cellular death via intrinsic apoptosis in rat brain cortical neurons in absence of insult. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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10 pages, 3343 KiB

Open AccessArticle

Green Synthesis of Silver Nanoparticles Stabilized with Mussel-Inspired Protein and Colorimetric Sensing of Lead(II) and Copper(II) Ions

by Ja Young Cheon and Won Ho Park^*

Department of Advanced Organic Materials and Textile System Engneering, Chungnam National University, Daejeon 34134, Korea

Int. J. Mol. Sci. 2016, 17(12), 2006; https://doi.org/10.3390/ijms17122006 - 30 Nov 2016

Cited by 70 | Viewed by 10320

Abstract

This articles reports a simple and green method for preparing uniform silver nanoparticles (AgNPs), for which self-polymerized 3,4-dihydroxy-l-phenylalanine (polyDOPA) is used as the reducing and stabilizing agent in aqueous media. The AgNPs functionalized by polyDOPA were analyzed by UV–Vis spectroscopy, high-resolution [...] Read more.

This articles reports a simple and green method for preparing uniform silver nanoparticles (AgNPs), for which self-polymerized 3,4-dihydroxy-l-phenylalanine (polyDOPA) is used as the reducing and stabilizing agent in aqueous media. The AgNPs functionalized by polyDOPA were analyzed by UV–Vis spectroscopy, high-resolution transmission electron microscopy (HR-TEM), Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), Raman spectrophotometry, and X-ray diffraction (XRD) techniques. The results revealed that the polyDOPA-AgNPs with diameters of 25 nm were well dispersed due to the polyDOPA. It was noted that the polyDOPA-AgNPs showed selectivity for Pb²⁺ and Cu²⁺ detection with the detection limits for the two ions as low as 9.4 × 10⁻⁵ and 8.1 × 10⁻⁵ μM, respectively. Therefore, the polyDOPA-AgNPs can be applied to both Pb²⁺ and Cu²⁺ detection in real water samples. The proposed method will be useful for colorimetric detection of heavy metal ions in aqueous media. Full article

(This article belongs to the Special Issue Melanin Based Functional Materials)

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19 pages, 505 KiB

Open AccessReview

Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models?

by Urs Christen^*

and Edith Hintermann

Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany

Int. J. Mol. Sci. 2016, 17(12), 2007; https://doi.org/10.3390/ijms17122007 - 1 Dec 2016

Cited by 33 | Viewed by 8373

Abstract

Autoimmune hepatitis (AIH) is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. The current treatment of autoimmune hepatitis is still largely dependent on the administration of corticosteroids and cytostatic drugs. For a long time the development of novel [...] Read more.

Autoimmune hepatitis (AIH) is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. The current treatment of autoimmune hepatitis is still largely dependent on the administration of corticosteroids and cytostatic drugs. For a long time the development of novel therapeutic strategies has been hampered by a lack of understanding the basic immunopathogenic mechanisms of AIH and the absence of valid animal models. However, in the past decade, knowledge from clinical observations in AIH patients and the development of innovative animal models have led to a situation where critical factors driving the disease have been identified and alternative treatments are being evaluated. Here we will review the insight on the immunopathogenesis of AIH as gained from clinical observation and from animal models. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)

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9 pages, 880 KiB

Open AccessArticle

Epidermal Growth Factor Receptor Status in Circulating Tumor Cells as a Predictive Biomarker of Sensitivity in Castration-Resistant Prostate Cancer Patients Treated with Docetaxel Chemotherapy

by Takatsugu Okegawa^*, Naoshi Itaya, Hidehiko Hara, Mitsuhiro Tambo and Kikuo Nutahara

Department of Urology, The University of Kyorin, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan

Int. J. Mol. Sci. 2016, 17(12), 2008; https://doi.org/10.3390/ijms17122008 - 30 Nov 2016

Cited by 20 | Viewed by 4741

Abstract

Objective: We examined whether epidermal growth factor receptor (EGFR) expression in circulating tumor cells (CTCs) can be used to predict survival in a population of bone-metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel chemotherapy. Methods: All patients with mCRPC who had experienced [...] Read more.

Objective: We examined whether epidermal growth factor receptor (EGFR) expression in circulating tumor cells (CTCs) can be used to predict survival in a population of bone-metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel chemotherapy. Methods: All patients with mCRPC who had experienced treatment failure with androgen-deprivation therapy and had received docetaxel chemotherapy were eligible. CTCs and EGFR expression in CTCs were enumerated with the CellSearch System in whole blood. This system is a semi-automated system that detects and enriches epithelial cells from whole blood using an EpCAM antibody-based immunomagnetic capture. In addition, the EGFR-positive CTCs were assessed using CellSearch^® Tumor Phenotyping Reagent EGFR. Results: The median CTC count at baseline before starting trial treatment was eight CTCs per 7.5 mL of blood (range 0–184). There were 37 patients (61.7%) who had ≥5 CTCs, with median overall survival of 11.5 months compared with 20.0 months for 23 patients (38.3%) with <5 CTCs (p < 0.001). A total of 15 patients (40.5%, 15/37) with five or more CTCs were subjected to automated immunofluorescence staining and cell sorting for EGFR protein. Patients with EGFR-positive CTCs had a shorter overall survival (OS) (5.5 months) than patients with EGFR-negative CTCs (20.0 months). CTCs, EGFR-positive CTCs, and alkaline phosphatase (ALP) were independent predictors of overall survival time (p = 0.002, p < 0.001, and p = 0.017, respectively). Conclusion: CTCs may be an independent predictor of OS in CRPC treated with docetaxel chemotherapy. The EGFR expression detected in CTCs was important for assessing the response to chemotherapy and predicting disease outcome. Full article

(This article belongs to the Special Issue Circulating Tumor Cells)

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12 pages, 1349 KiB

Open AccessArticle

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients

by Maria Di Bari^1,†, Marcella Reale^2,†

, Marta Di Nicola², Viviana Orlando¹, Sabrina Galizia¹, Italo Porfilio³, Erica Costantini²

, Chiara D’Angelo²

, Serena Ruggieri^4,5, Stefano Biagioni¹

, Claudio Gasperini⁵ and Ada Maria Tata^1,*

¹ Department of Biology and Biotechnologies Charles Darwin, Research, Center of Neurobiology Daniel Bovet, Sapienza University of Rome, 00185 Rome, Italy

² Department of Medical, Oral and Biotechnological Science, University “G. d’Annunzio” Chieti-Pescara, 66100 Chieti, Italy

³ School of Hygiene and Preventive Medicine, University “G. d’Annunzio” Chieti-Pescara, 66100 Chieti, Italy

⁴ Department of Neurology and Psichiatry, Sapienza University of Rome, 00185 Rome, Italy

⁵ Department of Neurosciences, San Camillo Forlanini Hospital, 00185 Rome, Italy

^† These authors equally contributed to this work.

Int. J. Mol. Sci. 2016, 17(12), 2009; https://doi.org/10.3390/ijms17122009 - 30 Nov 2016

Cited by 28 | Viewed by 5839

Abstract

Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. [...] Read more.

Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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16 pages, 933 KiB

Open AccessArticle

The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations

by Valentina Citro¹, Marco Cammisa², Ludovica Liguori³

, Chiara Cimmaruta^1,3, Jan Lukas^4,*, Maria Vittoria Cubellis^1,*

and Giuseppina Andreotti³

¹ Dipartimento di Biologia, Università Federico II, 80126 Napoli, Italy

² Istituto di Genetica e Biofisica ‘A. Buzzati-Traverso’, CNR, 80131 Napoli, Italy

³ Istituto di Chimica Biomolecolare, CNR, 80078 Pozzuoli, Italy

⁴ Albrecht-Kossel-Institute for Neuroregeneration, University Rostock Medical Center, 18147 Rostock, Germany

Int. J. Mol. Sci. 2016, 17(12), 2010; https://doi.org/10.3390/ijms17122010 - 1 Dec 2016

Cited by 28 | Viewed by 7585

Abstract

Fabry disease is caused by mutations in the GLA gene and is characterized by a large genotypic and phenotypic spectrum. Missense mutations pose a special problem for graduating diagnosis and choosing a cost-effective therapy. Some mutants retain enzymatic activity, but are less stable [...] Read more.

Fabry disease is caused by mutations in the GLA gene and is characterized by a large genotypic and phenotypic spectrum. Missense mutations pose a special problem for graduating diagnosis and choosing a cost-effective therapy. Some mutants retain enzymatic activity, but are less stable than the wild type protein. These mutants can be stabilized by small molecules which are defined as pharmacological chaperones. The first chaperone to reach clinical trial is 1-deoxygalactonojirimycin, but others have been tested in vitro. Residual activity of GLA mutants has been measured in the presence or absence of pharmacological chaperones by several authors. Data obtained from transfected cells correlate with those obtained in cells derived from patients, regardless of whether 1-deoxygalactonojirimycin was present or not. The extent to which missense mutations respond to 1-deoxygalactonojirimycin is variable and a reference table of the results obtained by independent groups that is provided with this paper can facilitate the choice of eligible patients. A review of other pharmacological chaperones is provided as well. Frequent mutations can have residual activity as low as one-fourth of normal enzyme in vitro. The reference table with residual activity of the mutants facilitates the identification of non-pathological variants. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Novel Concepts, Therapeutic Aspects and Beyond)

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12 pages, 4359 KiB

Open AccessArticle

Comprehensive Analysis of miRNome Alterations in Response to Sorafenib Treatment in Colorectal Cancer Cells

by Anna-Maria Pehserl^1,2, Anna Lena Ress^1,2, Stefanie Stanzer¹, Margit Resel^1,2, Michael Karbiener³, Elke Stadelmeyer⁴, Verena Stiegelbauer^1,2, Armin Gerger¹, Christian Mayr^5,6, Marcel Scheideler^7,8,9,10

, Georg C. Hutterer¹¹, Thomas Bauernhofer¹, Tobias Kiesslich^5,6 and Martin Pichler^1,2,12,*

¹ Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria

² Research Unit of Non-Coding RNA and Genome Editing in Cancer, Medical University of Graz, 8010 Graz, Austria

³ Department of Phoniatrics, ENT University Hospital, Medical University, 8010 Graz, Austria

⁴ Institute of Pathology, Medical University of Graz, 8010 Graz, Austria

⁵ Laboratory for Tumour Biology and Experimental Therapies (TREAT), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria

⁶ Department of Internal Medicine I, Salzburger Landeskliniken, Paracelsus Medical University, 5020 Salzburg, Austria

⁷ Institute for Diabetes and Cancer (IDC), Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany

⁸ Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, 69120 Heidelberg, Germany

⁹ Molecular Metabolic Control, Medical Faculty, Technical University Munich, 85764 Munich, Germany

¹⁰ German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany

¹¹ Department of Urology, Medical University of Graz, 8010 Graz, Austria

¹² Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA

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Int. J. Mol. Sci. 2016, 17(12), 2011; https://doi.org/10.3390/ijms17122011 - 1 Dec 2016

Cited by 31 | Viewed by 6243

Abstract

MicroRNAs (miRNAs) are master regulators of drug resistance and have been previously proposed as potential biomarkers for the prediction of therapeutic response in colorectal cancer (CRC). Sorafenib, a multi-kinase inhibitor which has been approved for the treatment of liver, renal and thyroid cancer, [...] Read more.

MicroRNAs (miRNAs) are master regulators of drug resistance and have been previously proposed as potential biomarkers for the prediction of therapeutic response in colorectal cancer (CRC). Sorafenib, a multi-kinase inhibitor which has been approved for the treatment of liver, renal and thyroid cancer, is currently being studied as a monotherapy in selected molecular subtypes or in combination with other drugs in metastatic CRC. In this study, we explored sorafenib-induced cellular effects in Kirsten rat sarcoma viral oncogene homolog olog (KRAS) wild-type and KRAS-mutated CRC cell lines (Caco-2 and HRT-18), and finally profiled expression changes of specific miRNAs within the miRNome (>1000 human miRNAs) after exposure to sorafenib. Overall, sorafenib induced a time- and dose-dependent growth-inhibitory effect through S-phase cell cycle arrest in KRAS wild-type and KRAS-mutated CRC cells. In HRT-18 cells, two human miRNAs (hsa-miR-597 and hsa-miR-720) and two small RNAs (SNORD 13 and hsa-miR-3182) were identified as specifically sorafenib-induced. In Caco-2 cells, nine human miRNAs (hsa-miR-3142, hsa-miR-20a, hsa-miR-4301, hsa-miR-1290, hsa-miR-4286, hsa-miR-3182, hsa-miR-3142, hsa-miR-1246 and hsa-miR-720) were identified to be differentially regulated post sorafenib treatment. In conclusion, we confirmed sorafenib as a potential anti-neoplastic treatment strategy for CRC cells by demonstrating a growth-inhibitory and cell cycle–arresting effect of this drug. Changes in the miRNome indicate that some specific miRNAs might be relevant as indicators for sorafenib response, drug resistance and potential targets for combinatorial miRNA-based drug strategies. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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15 pages, 3415 KiB

Open AccessArticle

Natural Non-Mulberry Silk Nanoparticles for Potential-Controlled Drug Release

by Juan Wang^1,2

, Zhuping Yin¹, Xiang Xue¹, Subhas C. Kundu³

, Xiumei Mo²

and Shenzhou Lu^1,*

¹ National Engineering Laboratory for Modern Silk, College of Textile and Clothing Engineering, Soochow University, Suzhou 215123, China

² College of Chemistry and Chemical Engineering and Biological Engineering, Donghua University, Shanghai 201620, China

³ Department of Biotechnology, Indian Institute of Technology Kharagpur, West Bengal 721302, India

Int. J. Mol. Sci. 2016, 17(12), 2012; https://doi.org/10.3390/ijms17122012 - 1 Dec 2016

Cited by 20 | Viewed by 7869

Abstract

Natural silk protein nanoparticles are a promising biomaterial for drug delivery due to their pleiotropic properties, including biocompatibility, high bioavailability, and biodegradability. Chinese oak tasar Antheraea pernyi silk fibroin (ApF) nanoparticles are easily obtained using cations as reagents under mild conditions. [...] Read more.

Natural silk protein nanoparticles are a promising biomaterial for drug delivery due to their pleiotropic properties, including biocompatibility, high bioavailability, and biodegradability. Chinese oak tasar Antheraea pernyi silk fibroin (ApF) nanoparticles are easily obtained using cations as reagents under mild conditions. The mild conditions are potentially advantageous for the encapsulation of sensitive drugs and therapeutic molecules. In the present study, silk fibroin protein nanoparticles are loaded with differently-charged small-molecule drugs, such as doxorubicin hydrochloride, ibuprofen, and ibuprofen-Na, by simple absorption based on electrostatic interactions. The structure, morphology and biocompatibility of the silk nanoparticles in vitro are investigated. In vitro release of the drugs from the nanoparticles depends on charge-charge interactions between the drugs and the nanoparticles. The release behavior of the compounds from the nanoparticles demonstrates that positively-charged molecules are released in a more prolonged or sustained manner. Cell viability studies with L929 demonstrated that the ApF nanoparticles significantly promoted cell growth. The results suggest that Chinese oak tasar Antheraea pernyi silk fibroin nanoparticles can be used as an alternative matrix for drug carrying and controlled release in diverse biomedical applications. Full article

(This article belongs to the Special Issue Silk-Based Materials: From Production to Characterization)

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13 pages, 749 KiB

Open AccessArticle

Cytokinins and Expression of SWEET, SUT, CWINV and AAP Genes Increase as Pea Seeds Germinate

by Paula E. Jameson^1,*

, Pragatheswari Dhandapani¹

, Ondrej Novak²

and Jiancheng Song^1,3

¹ School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand

² Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Institute of Experimental Botany CAS & Faculty of Science of Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic

³ School of Life Sciences, Yantai University, Yantai 264005, China

Int. J. Mol. Sci. 2016, 17(12), 2013; https://doi.org/10.3390/ijms17122013 - 1 Dec 2016

Cited by 29 | Viewed by 5768

Abstract

Transporter genes and cytokinins are key targets for crop improvement. These genes are active during the development of the seed and its establishment as a strong sink. However, during germination, the seed transitions to being a source for the developing root and shoot. [...] Read more.

Transporter genes and cytokinins are key targets for crop improvement. These genes are active during the development of the seed and its establishment as a strong sink. However, during germination, the seed transitions to being a source for the developing root and shoot. To determine if the sucrose transporter (SUT), amino acid permease (AAP), Sugar Will Eventually be Exported Transporter (SWEET), cell wall invertase (CWINV), cytokinin biosynthesis (IPT), activation (LOG) and degradation (CKX) gene family members are involved in both the sink and source activities of seeds, we used RT-qPCR to determine the expression of multiple gene family members, and LC-MS/MS to ascertain endogenous cytokinin levels in germinating Pisum sativum L. We show that genes that are actively expressed when the seed is a strong sink during its development, are also expressed when the seed is in the reverse role of being an active source during germination and early seedling growth. Cytokinins were detected in the imbibing seeds and were actively biosynthesised during germination. We conclude that, when the above gene family members are targeted for seed yield improvement, a downstream effect on subsequent seed germination or seedling vigour must be taken into consideration. Full article

(This article belongs to the Special Issue Pulses)

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11 pages, 2564 KiB

Open AccessArticle

Preparation of a Bis-GMA-Free Dental Resin System with Synthesized Fluorinated Dimethacrylate Monomers

by Shuzhen Luo, Wenbin Zhu, Fang Liu and Jingwei He^*

College of Materials Science and Engineering, South China University of Technology, Guangzhou 510641, China

Int. J. Mol. Sci. 2016, 17(12), 2014; https://doi.org/10.3390/ijms17122014 - 1 Dec 2016

Cited by 43 | Viewed by 8160

Abstract

With the aim of reducing human exposure to Bisphenol A (BPA) derivatives in dentistry, a fluorinated dimethacrylate monomer was synthesized to replace 2,2-bis[4-(2-hydroxy-3-methacryloy-loxypropyl)-phenyl]propane (Bis-GMA) as the base monomer of dental resin. After mixing with reactive diluent triethyleneglycol dimethacrylate (TEGDMA), fluorinated dimethacrylate (FDMA)/TEGDMA was [...] Read more.

With the aim of reducing human exposure to Bisphenol A (BPA) derivatives in dentistry, a fluorinated dimethacrylate monomer was synthesized to replace 2,2-bis[4-(2-hydroxy-3-methacryloy-loxypropyl)-phenyl]propane (Bis-GMA) as the base monomer of dental resin. After mixing with reactive diluent triethyleneglycol dimethacrylate (TEGDMA), fluorinated dimethacrylate (FDMA)/TEGDMA was prepared and compared with Bis-GMA/TEGDMA in physicochemical properties, such as double bond conversion (DC), volumetric shrinkage (VS), water sorption (WS) and solubility (WSL), flexural strength (FS) and modulus (FM). The results showed that, when compared with Bis-GMA based resin, FDMA-based resin had several advantages, such as higher DC, lower VS, lower WS, and higher FS after water immersion. All of these revealed that FDMA had potential to be used as a substitute for Bis-GMA. Of course, many more studies, such as biocompatibility testing, should be undertaken to prove whether FDMA could be applied in clinic. Full article

(This article belongs to the Section Materials Science)

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12 pages, 1669 KiB

Open AccessArticle

High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer

by Marion Jeantet^1,2,3, David Tougeron^1,4,5

, Gaelle Tachon^1,2, Ulrich Cortes^1,2, Céline Archambaut^1,2, Gaelle Fromont³ and Lucie Karayan-Tapon^1,2,6,*

¹ Faculté de Médecine Pharmacie, Université de Poitiers, 86021 Poitiers, France

² Département de Cancérologie Biologique, Centre Hospitalo-Universitaire de Poitiers, 86021 Poitiers, France

³ Département d’anatomopathologie, Centre Hospitalo-Universitaire de Poitiers, 86021 Poitiers, France

⁴ Département de Gastroentérologie, Centre Hospitalo-Universitaire de Poitiers, 86021 Poitiers, France

⁵ Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, EA 4331, Université de Poitiers, 86021 Poitiers, France

⁶ INSERM1084, Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, 86021 Poitiers, France

Int. J. Mol. Sci. 2016, 17(12), 2015; https://doi.org/10.3390/ijms17122015 - 1 Dec 2016

Cited by 34 | Viewed by 6087

Abstract

Approximately 30% of patients with wild type RAS metastatic colorectal cancer are non-responders to anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), possibly due to undetected tumoral subclones harboring RAS mutations. The aim of this study was to analyze the distribution of RAS [...] Read more.

Approximately 30% of patients with wild type RAS metastatic colorectal cancer are non-responders to anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), possibly due to undetected tumoral subclones harboring RAS mutations. The aim of this study was to analyze the distribution of RAS mutations in different areas of the primary tumor, metastatic lymph nodes and distant metastasis. A retrospective cohort of 18 patients with a colorectal cancer (CRC) was included in the study. Multiregion analysis was performed in 60 spatially separated tumor areas according to the pathological tumor node metastasis (pTNM) staging and KRAS, NRAS and BRAF mutations were tested using pyrosequencing. In primary tumors, intra-tumoral heterogeneity for RAS mutation was found in 33% of cases. Inter-tumoral heterogeneity for RAS mutation between primary tumors and metastatic lymph nodes or distant metastasis was found in 36% of cases. Moreover, 28% of tumors had multiple RAS mutated subclones in the same tumor. A high proportion of CRCs presented intra- and/or inter-tumoral heterogeneity, which has relevant clinical implications for anti-EGFR mAbs prescription. These results suggest the need for multiple RAS testing in different parts of the same tumor and/or more sensitive techniques. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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29 pages, 2879 KiB

Open AccessReview

Functional Diversity of Neurotrophin Actions on the Oculomotor System

by Beatriz Benítez-Temiño^†, María A. Davis-López de Carrizosa^†

, Sara Morcuende

, Esperanza R. Matarredona, Rosa R. De la Cruz

and Angel M. Pastor^*

¹ Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, 41012 Sevilla, Spain

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2016; https://doi.org/10.3390/ijms17122016 - 1 Dec 2016

Cited by 20 | Viewed by 6836

Abstract

Neurotrophins play a principal role in neuronal survival and differentiation during development, but also in the maintenance of appropriate adult neuronal circuits and phenotypes. In the oculomotor system, we have demonstrated that neurotrophins are key regulators of developing and adult neuronal properties, but [...] Read more.

Neurotrophins play a principal role in neuronal survival and differentiation during development, but also in the maintenance of appropriate adult neuronal circuits and phenotypes. In the oculomotor system, we have demonstrated that neurotrophins are key regulators of developing and adult neuronal properties, but with peculiarities depending on each neurotrophin. For instance, the administration of NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor) or NT-3 (neurotrophin-3) protects neonatal extraocular motoneurons from cell death after axotomy, but only NGF and BDNF prevent the downregulation in ChAT (choline acetyltransferase). In the adult, in vivo recordings of axotomized extraocular motoneurons have demonstrated that the delivery of NGF, BDNF or NT-3 recovers different components of the firing discharge activity of these cells, with some particularities in the case of NGF. All neurotrophins have also synaptotrophic activity, although to different degrees. Accordingly, neurotrophins can restore the axotomy-induced alterations acting selectively on different properties of the motoneuron. In this review, we summarize these evidences and discuss them in the context of other motor systems. Full article

(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)

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10 pages, 1474 KiB

Open AccessCommunication

Light/Dark Shifting Promotes Alcohol-Induced Colon Carcinogenesis: Possible Role of Intestinal Inflammatory Milieu and Microbiota

by Faraz Bishehsari^1,*, Abdulrahman Saadalla², Khashayarsha Khazaie², Phillip A. Engen¹

, Robin M. Voigt¹, Brandon B. Shetuni³, Christopher Forsyth¹, Maliha Shaikh¹, Martha Hotz Vitaterna⁴, Fred Turek⁴ and Ali Keshavarzian¹

¹ Department of Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA

² Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA

³ Northwestern Medicine, Central DuPage Hospital, Winfield, IL 60190, USA

⁴ Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL 60208, USA

Int. J. Mol. Sci. 2016, 17(12), 2017; https://doi.org/10.3390/ijms17122017 - 2 Dec 2016

Cited by 36 | Viewed by 6671

Abstract

Background: Colorectal cancer (CRC) is associated with the modern lifestyle. Chronic alcohol consumption—a frequent habit of majority of modern societies—increases the risk of CRC. Our group showed that chronic alcohol consumption increases polyposis in a mouse mode of CRC. Here we assess the [...] Read more.

Background: Colorectal cancer (CRC) is associated with the modern lifestyle. Chronic alcohol consumption—a frequent habit of majority of modern societies—increases the risk of CRC. Our group showed that chronic alcohol consumption increases polyposis in a mouse mode of CRC. Here we assess the effect of circadian disruption—another modern life style habit—in promoting alcohol-associated CRC. Method: TS4Cre × adenomatous polyposis coli (APC)^lox468 mice underwent (a) an alcohol-containing diet while maintained on a normal 12 h light:12 h dark cycle; or (b) an alcohol-containing diet in conjunction with circadian disruption by once-weekly 12 h phase reversals of the light:dark (LD) cycle. Mice were sacrificed after eight weeks of full alcohol and/or LD shift to collect intestine samples. Tumor number, size, and histologic grades were compared between animal groups. Mast cell protease 2 (MCP2) and 6 (MCP6) histology score were analyzed and compared. Stool collected at baseline and after four weeks of experimental manipulations was used for microbiota analysis. Results: The combination of alcohol and LD shifting accelerated intestinal polyposis, with a significant increase in polyp size, and caused advanced neoplasia. Consistent with a pathogenic role of stromal tryptase-positive mast cells in colon carcinogenesis, the ratio of mMCP6 (stromal)/mMCP2 (intraepithelial) mast cells increased upon LD shifting. Baseline microbiota was similar between groups, and experimental manipulations resulted in a significant difference in the microbiota composition between groups. Conclusions: Circadian disruption by Light:dark shifting exacerbates alcohol-induced polyposis and CRC. Effect of circadian disruption could, at least partly, be mediated by promoting a pro-tumorigenic inflammatory milieu via changes in microbiota. Full article

(This article belongs to the Special Issue Inflammation and Cancer)

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22 pages, 268 KiB

Open AccessReview

Metabolomics and Its Application in the Development of Discovering Biomarkers for Osteoporosis Research

by Huanhuan Lv^1,2, Feng Jiang^1,2, Daogang Guan¹, Cheng Lu^1,3, Baosheng Guo¹, Chileung Chan¹, Songlin Peng⁴, Baoqin Liu⁵, Wenwei Guo⁵, Hailong Zhu¹, Xuegong Xu^5,*, Aiping Lu^1,6,* and Ge Zhang^1,*

¹ Institute for Advancing Translational Medicine in Bone & Joint Disease, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, China

² Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology, Haimen 226133, China

³ Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China

⁴ Department of Spine Surgery, Shenzheng People’s Hospital, Shenzheng 518020, China

⁵ Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou 450007, China

⁶ Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Guanghua Integrative Medicine Hospital/Shanghai University of Traditional Chinese Medicine, Shanghai 200052, China

Int. J. Mol. Sci. 2016, 17(12), 2018; https://doi.org/10.3390/ijms17122018 - 2 Dec 2016

Cited by 59 | Viewed by 8844

Abstract

Osteoporosis is a progressive skeletal disorder characterized by low bone mass and increased risk of fracture in later life. The incidence and costs associated with treating osteoporosis cause heavy socio-economic burden. Currently, the diagnosis of osteoporosis mainly depends on bone mineral density and [...] Read more.

Osteoporosis is a progressive skeletal disorder characterized by low bone mass and increased risk of fracture in later life. The incidence and costs associated with treating osteoporosis cause heavy socio-economic burden. Currently, the diagnosis of osteoporosis mainly depends on bone mineral density and bone turnover markers. However, these indexes are not sensitive and accurate enough to reflect the osteoporosis progression. Metabolomics offers the potential for a holistic approach for clinical diagnoses and treatment, as well as understanding of the pathological mechanism of osteoporosis. In this review, we firstly describe the study subjects of osteoporosis and bio-sample preparation procedures for different analytic purposes, followed by illustrating the biomarkers with potentially predictive, diagnosis and pharmaceutical values when applied in osteoporosis research. Then, we summarize the published metabolic pathways related to osteoporosis. Furthermore, we discuss the importance of chronological data and combination of multi-omics in fully understanding osteoporosis. The application of metabolomics in osteoporosis could provide researchers the opportunity to gain new insight into the metabolic profiling and pathophysiological mechanisms. However, there is still much to be done to validate the potential biomarkers responsible for the progression of osteoporosis and there are still many details needed to be further elucidated. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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21 pages, 2424 KiB

Open AccessArticle

Human Intervention Study to Assess the Effects of Supplementation with Olive Leaf Extract on Peripheral Blood Mononuclear Cell Gene Expression

by Anna Boss¹, Chi Hsiu-Juei Kao^1,2, Pamela M. Murray², Gareth Marlow³, Matthew P. G. Barnett⁴ and Lynnette R. Ferguson^1,2,*

¹ Discipline of Nutrition and Dietetics, The University of Auckland, Auckland 1142, New Zealand

² Auckland Cancer Research Society, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand

³ Institute of Medical Genetics, UHW Main Building, Cardiff University, Cardiff CF10 3XQ, UK

⁴ Food Nutrition & Health Team, Food & Bio-Based Products Group, AgResearch Limited, Palmerston North 4442, New Zealand

Int. J. Mol. Sci. 2016, 17(12), 2019; https://doi.org/10.3390/ijms17122019 - 2 Dec 2016

Cited by 24 | Viewed by 9486

Abstract

Olive leaf extract (OLE) has been used for many years for its putative health benefits, but, to date, scientific evidence for the basis of these effects has been weak. Although recent literature has described a link between ailments such as cardiovascular disease, diabetes [...] Read more.

Olive leaf extract (OLE) has been used for many years for its putative health benefits, but, to date, scientific evidence for the basis of these effects has been weak. Although recent literature has described a link between ailments such as cardiovascular disease, diabetes and cancer and a protective effect of polyphenols in the OLE, the mode of action is still unclear. Here, we describe a double-blinded placebo (PBO)-controlled trial, in which gene expression profiles of peripheral blood mononuclear cells from healthy male volunteers (n = 29) were analysed to identify genes that responded to OLE, following an eight-week intervention with 20 mL daily consumption of either OLE or PBO. Differences between groups were determined using an adjusted linear model. Subsequent analyses indicated downregulation of genes important in inflammatory pathways, lipid metabolism and cancer as a result of OLE consumption. Gene expression was verified by real-time PCR for three genes (EGR1, COX-2 and ID3). The results presented here suggest that OLE consumption may result in health benefits through influencing the expression of genes in inflammatory and metabolic pathways. Future studies with a larger study group, including male and female participants, looking into direct effects of OLE on lipid metabolism and inflammation are warranted. Full article

(This article belongs to the Special Issue The Mechanism of Action of Food Components in Disease Prevention)

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10 pages, 455 KiB

Open AccessReview

Targeting on Asymmetric Dimethylarginine-Related Nitric Oxide-Reactive Oxygen Species Imbalance to Reprogram the Development of Hypertension

by You-Lin Tain^1,2

and Chien-Ning Hsu^3,4,*

¹ Departments of Pediatrics, College of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, Kaohsiung 833, Taiwan

² Institute for Translational Research in Biomedicine, College of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, Kaohsiung 833, Taiwan

³ Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan

⁴ School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan

Int. J. Mol. Sci. 2016, 17(12), 2020; https://doi.org/10.3390/ijms17122020 - 2 Dec 2016

Cited by 57 | Viewed by 4914

Abstract

Adult-onset diseases, including hypertension, can originate from early life, known as the developmental origins of health and disease (DOHaD). Because the developing kidney is vulnerable to early-life insults, renal programming is considered key in the developmental programming of hypertension. Asymmetric dimethylarginine (ADMA), an [...] Read more.

Adult-onset diseases, including hypertension, can originate from early life, known as the developmental origins of health and disease (DOHaD). Because the developing kidney is vulnerable to early-life insults, renal programming is considered key in the developmental programming of hypertension. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide (NO) synthase inhibitor, can regulate the NO–reactive oxygen species (ROS) balance, and is involved in the development of hypertension. Reprogramming interventions aimed at NO-ROS balance can be protective in both genetic and developmentally programmed hypertension. Here we review several emergent themes of the DOHaD approach regarding the impact of ADMA-related NO-ROS imbalance on programmed hypertension. We focus on the kidney in the following areas: mechanistic insights to interpret programmed hypertension; the impact of ADMA-related NO-ROS imbalance in both genetic and acquired animal models of hypertension; alterations of the renal transcriptome in response to ADMA in the developing kidney; and reprogramming strategies targeting ADMA-related NO-ROS balance to prevent programmed hypertension. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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1 pages, 151 KiB

Open AccessAddendum

Addendum: Bedoya-Pérez, L.P. et al. Role of UPR Pathway in Defense Response of Aedes aegypti against Cry11Aa Toxin from Bacillus thuringiensis. Int. J. Mol. Sci. 2013, 14, 8467–8478

by Leidy P. Bedoya-Pérez, Angeles Cancino-Rodezno, Biviana Flores-Escobar, Mario Soberón and Alejandra Bravo^*

Instituto de Biotecnología, Universidad Nacional Autónoma de México. AP 510-3, Cuernavaca 62250, Morelos, Mexico

Int. J. Mol. Sci. 2016, 17(12), 2021; https://doi.org/10.3390/ijms17122021 - 2 Dec 2016

Viewed by 2841

Abstract

The authors would like to indicate that Dr. Angeles Cancino-Rodezno and Leidy P. Bedoya-Pérez participated equally in their paper published in the International Journal of Molecular Sciences [1].[...] Full article

13 pages, 815 KiB

Open AccessReview

Peripheral Inflammatory Parameters in Late-Life Depression: A Systematic Review

by Mónica Martínez-Cengotitabengoa^1,2,*, Lucía Carrascón^1,3, John T. O’Brien⁴, María-José Díaz-Gutiérrez⁵, Cristina Bermúdez-Ampudia¹, Kenji Sanada^1,6, Marta Arrasate^7,8 and Ana González-Pinto^1,8

¹ Biomedical Research Centre in Mental Health Network (CIBERSAM), BioAraba, Health Research Institute, Araba University Hospital, 01004 Vitoria, Spain

² Psychobiology Department, National Distance Education University (UNED), 01008 Vitoria, Spain

³ Gregorio Marañón University General Hospital, 28007 Madrid, Spain

⁴ Department of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, UK

⁵ Community Pharmacist, Getxo, 48992 Vizcaya, Spain

⁶ Department of Psychiatry, Showa University School of Medicine, Tokyo 157-8577, Japan

⁷ RSMB-CSM Uribe, 48990 Algorta-Getxo, Spain

⁸ Neurosciences Department, University of the Basque Country, 48940 Vizcaya, Spain

Int. J. Mol. Sci. 2016, 17(12), 2022; https://doi.org/10.3390/ijms17122022 - 2 Dec 2016

Cited by 67 | Viewed by 8558

Abstract

Depressive disorders appear relatively frequently in older patients, and therefore represent an important disease burden worldwide. Given the high levels of inflammatory parameters found in depressed elderly patients, the “inflammaging” hypothesis is gaining strength. In this systematic review, we summarize current evidence regarding [...] Read more.

Depressive disorders appear relatively frequently in older patients, and therefore represent an important disease burden worldwide. Given the high levels of inflammatory parameters found in depressed elderly patients, the “inflammaging” hypothesis is gaining strength. In this systematic review, we summarize current evidence regarding the relationship between inflammatory parameters and late-life depression, with a unique focus on longitudinal studies to guarantee temporality. According to the data summarized in this review, the levels of some proinflammatory parameters—especially interleukin (IL)-8, IL-6, and tumor necrosis factor (TNF)-α—could serve as biomarkers for the future development of depressive symptoms in elderly patients. Proinflammatory cytokines seem to be associated with the future development of clinically significant depression, irrespective of baseline scores, thus indicating that inflammation temporally precedes and increases depression risk. As insufficient research has been conducted in this field, further prospective studies are clearly warranted. Full article

(This article belongs to the Collection Feature Annual Reviews in Molecular Sciences)

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13 pages, 2649 KiB

Open AccessArticle

Secondary Structure Adopted by the Gly-Gly-X Repetitive Regions of Dragline Spider Silk

by Geoffrey M. Gray¹, Arjan Van der Vaart¹, Chengchen Guo²

, Justin Jones³, David Onofrei⁴, Brian R. Cherry², Randolph V. Lewis³, Jeffery L. Yarger²

and Gregory P. Holland^4,*

¹ Department of Chemistry, University of South Florida, 4202 East Fowler Avenue CHE 205, Tampa, FL 33620-9998, USA

² School of Molecular Sciences and the Magnetic Resonance Research Center, Arizona State University, Tempe, AZ 85287-1604, USA

³ Department of Biology and Synthetic Biomanufacturing Center, Utah State University, 650 East 1600 North, North Logan, UT 84341, USA

⁴ Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182-1030, USA

Int. J. Mol. Sci. 2016, 17(12), 2023; https://doi.org/10.3390/ijms17122023 - 2 Dec 2016

Cited by 33 | Viewed by 7611

Abstract

Solid-state NMR and molecular dynamics (MD) simulations are presented to help elucidate the molecular secondary structure of poly(Gly-Gly-X), which is one of the most common structural repetitive motifs found in orb-weaving dragline spider silk proteins. The combination of NMR and computational experiments provides [...] Read more.

Solid-state NMR and molecular dynamics (MD) simulations are presented to help elucidate the molecular secondary structure of poly(Gly-Gly-X), which is one of the most common structural repetitive motifs found in orb-weaving dragline spider silk proteins. The combination of NMR and computational experiments provides insight into the molecular secondary structure of poly(Gly-Gly-X) segments and provides further support that these regions are disordered and primarily non-β-sheet. Furthermore, the combination of NMR and MD simulations illustrate the possibility for several secondary structural elements in the poly(Gly-Gly-X) regions of dragline silks, including β-turns, 3₁₀-helicies, and coil structures with a negligible population of α-helix observed. Full article

(This article belongs to the Special Issue Silk-Based Materials: From Production to Characterization)

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17 pages, 2970 KiB

Open AccessArticle

Screening the Expression Changes in MicroRNAs and Their Target Genes in Mature Cementoblasts Stimulated with Cyclic Tensile Stress

by Liao Wang¹, Haikun Hu², Ye Cheng¹, Jianwei Chen¹, Chongyun Bao¹, Shujuan Zou^1,* and Gang Wu^3,*

¹ State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section, South Renmin Road, Chengdu 610041, China

² China Dental Implantology Center, West China Dental Implantology Hospital, Sichuan University, No. 75 Xiaotianzhu Street, Chengdu 610041, China

³ Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), VU University Amsterdam and University of Amsterdam, MOVE Research Institute, Gustav Mahlerlaan 3004, 1081LA Amsterdam, The Netherlands

Int. J. Mol. Sci. 2016, 17(12), 2024; https://doi.org/10.3390/ijms17122024 - 7 Dec 2016

Cited by 11 | Viewed by 5540

Abstract

Cementum is a thin layer of cementoblast-produced mineralized tissue covering the root surfaces of teeth. Mechanical forces, which are produced during masticatory activity, play a paramount role in stimulating cementoblastogenesis, which thereby facilitates the maintenance, remodeling and integrity of cementum. However, hitherto, the [...] Read more.

Cementum is a thin layer of cementoblast-produced mineralized tissue covering the root surfaces of teeth. Mechanical forces, which are produced during masticatory activity, play a paramount role in stimulating cementoblastogenesis, which thereby facilitates the maintenance, remodeling and integrity of cementum. However, hitherto, the extent to which a post-transcriptional modulation mechanism is involved in this process has rarely been reported. In this study, a mature murine cementoblast cell line OCCM-30 cells (immortalized osteocalcin positive cementoblasts) was cultured and subjected to cyclic tensile stress (0.5 Hz, 2000 µstrain). We showed that the cyclic tensile stress could not only rearrange the cell alignment, but also influence the proliferation in an S-shaped manner. Furthermore, cyclic tensile stress could significantly promote cementoblastogenesis-related genes, proteins and mineralized nodules. From the miRNA array analyses, we found that 60 and 103 miRNAs were significantly altered 6 and 18 h after the stimulation using cyclic tensile stress, respectively. Based on a literature review and bioinformatics analyses, we found that miR-146b-5p and its target gene Smad4 play an important role in this procedure. The upregulation of miR-146b-5p and downregulation of Smad4 induced by the tensile stress were further confirmed by qRT-PCR. The direct binding of miR-146b-5p to the three prime untranslated region (3′ UTR) of Smad4 was established using a dual-luciferase reporter assay. Taken together, these results suggest an important involvement of miR-146b-5p and its target gene Smad4 in the cementoblastogenesis of mature cementoblasts. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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11 pages, 1748 KiB

Open AccessArticle

Comparative Evaluation of TRAIL, FGF-2 and VEGF-A-Induced Angiogenesis In Vitro and In Vivo

by Siân P. Cartland^1,2

, Scott W. Genner¹, Amna Zahoor¹ and Mary M. Kavurma^1,2,*

¹ Heart Research Institute, Sydney 2042, Australia

² Sydney Medical School, University of Sydney, Sydney 2006, Australia

Int. J. Mol. Sci. 2016, 17(12), 2025; https://doi.org/10.3390/ijms17122025 - 2 Dec 2016

Cited by 48 | Viewed by 7363

Abstract

Tumor necrosis-factor-related apoptosis-inducing ligand (TRAIL) has been implicated in angiogenesis; the growth of new blood vessels from an existing vessel bed. Our aim was to compare pro-angiogenic responses of TRAIL, vascular endothelial growth-factor-A (VEGF-A) and fibroblast growth-factor-2 (FGF-2) either separately (10 ng/mL) or [...] Read more.

Tumor necrosis-factor-related apoptosis-inducing ligand (TRAIL) has been implicated in angiogenesis; the growth of new blood vessels from an existing vessel bed. Our aim was to compare pro-angiogenic responses of TRAIL, vascular endothelial growth-factor-A (VEGF-A) and fibroblast growth-factor-2 (FGF-2) either separately (10 ng/mL) or in combination, followed by the assessment of proliferation, migration and tubule formation using human microvascular endothelial-1 (HMEC-1) cells in vitro. Angiogenesis was also measured in vivo using the Matrigel plug assay. TRAIL and FGF-2 significantly augmented HMEC-1 cell proliferation and migration, with combination treatment having an enhanced effect on cell migration only. In contrast, VEGF-A did not stimulate HMEC-1 migration at 10 ng/mL. Tubule formation was induced by all three factors, with TRAIL more effective compared to VEGF-A, but not FGF-2. TRAIL at 400 ng/mL, but not VEGF-A, promoted CD31-positive staining into the Matrigel plug. However, FGF-2 was superior, stimulating cell infiltration and angiogenesis better than TRAIL and VEGF-A in vivo. These findings demonstrate that each growth factor is more effective at different processes of angiogenesis in vitro and in vivo. Understanding how these molecules stimulate different processes relating to angiogenesis may help identify new strategies and treatments aimed at inhibiting or promoting dysregulated angiogenesis in people. Full article

(This article belongs to the Special Issue Vascular Biology and Therapeutics)

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9 pages, 405 KiB

Open AccessReview

Prolactin: Friend or Foe in Central Nervous System Autoimmune Inflammation?

by Massimo Costanza^* and Rosetta Pedotti^*

Department of Clinical Neuroscience, Neurological Institute Foundation IRCCS Carlo Besta, 20133 Milan, Italy

Int. J. Mol. Sci. 2016, 17(12), 2026; https://doi.org/10.3390/ijms17122026 - 2 Dec 2016

Cited by 29 | Viewed by 9517

Abstract

The higher prevalence of multiple sclerosis (MS) in females, along with the modulation of disease activity observed during pregnancy and the post-partum period, has suggested a hormonal influence in MS. Even if prolactin (PRL) does not belong to the sex hormones family, its [...] Read more.

The higher prevalence of multiple sclerosis (MS) in females, along with the modulation of disease activity observed during pregnancy and the post-partum period, has suggested a hormonal influence in MS. Even if prolactin (PRL) does not belong to the sex hormones family, its crucial role in female reproduction and lactation has prompted great efforts to understand if PRL could represent a gender factor in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), the animal model for this disease. Extensive literature has documented a remarkable immune-stimulating potential for this hormone, indicating PRL as a disease-promoting factor in MS and EAE. However, recent work has pointed out that PRL is endowed with important neuroprotective and remyelinating properties and has encouraged a reinterpretation of the involvement of this hormone in MS. In this review we summarize both the protective functions that PRL exerts in central nervous system tissue as well as the inflammatory activity of this hormone in the context of autoimmune responses against myelin. Last, we draw future lines of research that might help to better clarify the impact of PRL on MS pathology. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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16 pages, 2066 KiB

Open AccessArticle

New Electrochemically-Modified Carbon Paste Inclusion β-Cyclodextrin and Carbon Nanotubes Sensors for Quantification of Dorzolamide Hydrochloride

by Nawal Ahmad Alarfaj¹ and Maha Farouk El-Tohamy^1,2,*

¹ Department of Chemistry, College of Science, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia

² General Administration and Medical Affairs, Zagazig University, Zagazig 44519, Egypt

Int. J. Mol. Sci. 2016, 17(12), 2027; https://doi.org/10.3390/ijms17122027 - 2 Dec 2016

Cited by 5 | Viewed by 5645

Abstract

The present article introduces a new approach to fabricate carbon paste sensors, including carbon paste, modified carbon paste inclusion β-cyclodextrin, and carbon nanotubes for the quantification of dorzolamide hydrochloride (DRZ). This study is mainly based on the construction of three different carbon paste [...] Read more.

The present article introduces a new approach to fabricate carbon paste sensors, including carbon paste, modified carbon paste inclusion β-cyclodextrin, and carbon nanotubes for the quantification of dorzolamide hydrochloride (DRZ). This study is mainly based on the construction of three different carbon paste sensors by the incorporation of DRZ with phosphotungstic acid (PTA) to form dorzolamide-phosphotungstate (DRZ-PT) as an electroactive material in the presence of the solvent mediator ortho-nitrophenyloctyl ether (o-NPOE). The fabricated conventional carbon paste sensor (sensor I), as well as the other modified carbon paste sensors using β-cyclodextrin (sensor II) and carbon nanotubes (sensor III), have been investigated. The sensors displayed Nernstian responses of 55.4 ± 0.6, 56.4 ± 0.4 and 58.1 ± 0.2 mV·decade⁻¹ over concentration ranges of 1.0 × 10⁻⁵–1.0 × 10⁻², 1.0 × 10⁻⁶–1.0 × 10⁻², and 5.0 × 10⁻⁸–1.0 × 10⁻² mol·L⁻¹ with lower detection limits of 5.0 × 10⁻⁶, 5.0 × 10⁻⁷, and 2.5 × 10⁻⁹ mol·L⁻¹ for sensors I, II, and III, respectively. The critical performance of the developed sensors was checked with respect to the effect of various parameters, including pH, selectivity, response time, linear concentration relationship, lifespan, etc. Method validation was applied according to the international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use ICH guidelines. The developed sensors were employed for the determination of DRZ in its bulk and dosage forms, as well as bio-samples. The observed data were statistically analyzed and compared with those obtained from other published methods. Full article

(This article belongs to the Special Issue Bioelectrochemical Systems)

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12 pages, 725 KiB

Open AccessReview

Exosomes as miRNA Carriers: Formation–Function–Future

by Xiaojie Yu^1,2, Margarete Odenthal^1,2,* and Jochen W. U. Fries¹

¹ Institute for Pathology, University Hospital of Cologne, 50924 Cologne, Germany

² Center for Molecular Medicine Cologne, University of Cologne, 50924 Cologne, Germany

Int. J. Mol. Sci. 2016, 17(12), 2028; https://doi.org/10.3390/ijms17122028 - 2 Dec 2016

Cited by 315 | Viewed by 21103

Abstract

Exosomes, which are one of the smallest extracellular vesicles released from cells, have been shown to carry different nucleic acids, including microRNAs (miRNAs). miRNAs significantly regulate cell growth and metabolism by posttranscriptional inhibition of gene expression. The rapidly changing understanding of exosomes’ formation [...] Read more.

Exosomes, which are one of the smallest extracellular vesicles released from cells, have been shown to carry different nucleic acids, including microRNAs (miRNAs). miRNAs significantly regulate cell growth and metabolism by posttranscriptional inhibition of gene expression. The rapidly changing understanding of exosomes’ formation and function in delivering miRNAs from cell to cell has prompted us to review current knowledge in exosomal miRNA secretion mechanisms as well as possible therapeutic applications for personalized medicine. Full article

(This article belongs to the Special Issue Focus on Extracellular Vesicles)

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20 pages, 1359 KiB

Open AccessReview

TP53/MicroRNA Interplay in Hepatocellular Carcinoma

by Daniela Pollutri¹, Laura Gramantieri^1,*, Luigi Bolondi^1,2 and Francesca Fornari^1,2,*

¹ Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy

² Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy

Int. J. Mol. Sci. 2016, 17(12), 2029; https://doi.org/10.3390/ijms17122029 - 2 Dec 2016

Cited by 29 | Viewed by 7645

Abstract

The role of microRNAs as oncogenes and tumor suppressor genes has emerged in several cancers, including hepatocellular carcinoma (HCC). The pivotal tumor suppressive role of p53-axis is indicated by the presence of inactivating mutations in TP53 gene in nearly all cancers. A close [...] Read more.

The role of microRNAs as oncogenes and tumor suppressor genes has emerged in several cancers, including hepatocellular carcinoma (HCC). The pivotal tumor suppressive role of p53-axis is indicated by the presence of inactivating mutations in TP53 gene in nearly all cancers. A close interaction between these two players, as well as the establishment of complex p53/miRNAs loops demonstrated the strong contribution of p53-effector miRNAs in enhancing the p53-mediated tumor suppression program. On the other hand, the direct and indirect targeting of p53, as well as the regulation of its stability and activity by specific microRNAs, underlie the importance of the fine-tuning of p53 pathway, affecting the cell fate of damaged/transformed cells. The promising results of miRNAs-based therapeutic approaches in preclinical studies and their entrance in clinical trials demonstrate the feasibility of this strategy in several diseases, including cancer. Molecularly targeted drugs approved so far for HCC treatment show intrinsic or acquired resistances with disease progression in many cases, therefore the identification of effective and non-toxic agents for the treatment of HCC is actually an unmet clinical need. The knowledge of p53/miRNA inter-relations in HCC may provide useful elements for the identification of novel combined approaches in the context of the “personalized-medicine” era. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

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27 pages, 1590 KiB

Open AccessReview

Checkpoints to the Brain: Directing Myeloid Cell Migration to the Central Nervous System

by Meredith Harrison-Brown^1,2,*, Guo-Jun Liu^1,2

and Richard Banati^1,2,3

¹ Discipline of Medical Imaging & Radiation Sciences, Faculty of Health Sciences, The University of Sydney, Sydney, NSW 2141, Australia

² Australian Nuclear Science and Technology Organisation, Sydney, NSW 2234, Australia

³ Brain and Mind Centre, The University of Sydney, Sydney, NSW 2006, Australia

Int. J. Mol. Sci. 2016, 17(12), 2030; https://doi.org/10.3390/ijms17122030 - 2 Dec 2016

Cited by 11 | Viewed by 8326

Abstract

Myeloid cells are a unique subset of leukocytes with a diverse array of functions within the central nervous system during health and disease. Advances in understanding of the unique properties of these cells have inspired interest in their use as delivery vehicles for [...] Read more.

Myeloid cells are a unique subset of leukocytes with a diverse array of functions within the central nervous system during health and disease. Advances in understanding of the unique properties of these cells have inspired interest in their use as delivery vehicles for therapeutic genes, proteins, and drugs, or as “assistants” in the clean-up of aggregated proteins and other molecules when existing drainage systems are no longer adequate. The trafficking of myeloid cells from the periphery to the central nervous system is subject to complex cellular and molecular controls with several ‘checkpoints’ from the blood to their destination in the brain parenchyma. As important components of the neurovascular unit, the functional state changes associated with lineage heterogeneity of myeloid cells are increasingly recognized as important for disease progression. In this review, we discuss some of the cellular elements associated with formation and function of the neurovascular unit, and present an update on the impact of myeloid cells on central nervous system (CNS) diseases in the laboratory and the clinic. We then discuss emerging strategies for harnessing the potential of site-directed myeloid cell homing to the CNS, and identify promising avenues for future research, with particular emphasis on the importance of untangling the functional heterogeneity within existing myeloid subsets. Full article

(This article belongs to the Special Issue Advances in Cell Transplantation)

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8 pages, 841 KiB

Open AccessCommunication

Somatic Cell Nuclear Transfer Followed by CRIPSR/Cas9 Microinjection Results in Highly Efficient Genome Editing in Cloned Pigs

by Timothy P. Sheets^1,2,†, Chi-Hun Park^1,2,†, Ki-Eun Park^1,2,3,†, Anne Powell², David M. Donovan² and Bhanu P. Telugu^1,2,3,*

¹ Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA

² Animal Bioscience and Biotechnology Laboratory, USDA-ARS, Beltsville, MD 20705, USA

³ Renovate Biosciences Inc., Reisterstown, MD 21136, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2031; https://doi.org/10.3390/ijms17122031 - 3 Dec 2016

Cited by 32 | Viewed by 12189

Abstract

The domestic pig is an ideal “dual purpose” animal model for agricultural and biomedical research. With the availability of genome editing tools such as clustered regularly interspaced short palindromic repeat (CRISPR) and associated nuclease Cas9 (CRISPR/Cas9), it is now possible to perform site-specific [...] Read more.

The domestic pig is an ideal “dual purpose” animal model for agricultural and biomedical research. With the availability of genome editing tools such as clustered regularly interspaced short palindromic repeat (CRISPR) and associated nuclease Cas9 (CRISPR/Cas9), it is now possible to perform site-specific alterations with relative ease, and will likely help realize the potential of this valuable model. In this article, we investigated for the first time a combination of somatic cell nuclear transfer (SCNT) and direct injection of CRISPR/Cas ribonucleoprotein complex targeting GRB10 into the reconstituted oocytes to generate GRB10 ablated Ossabaw fetuses. This strategy resulted in highly efficient (100%) generation of biallelic modifications in cloned fetuses. By combining SCNT with CRISPR/Cas9 microinjection, genome edited animals can now be produced without the need to manage a founder herd, while simultaneously eliminating the need for laborious in vitro culture and screening. Our approach utilizes standard cloning techniques while simultaneously performing genome editing in the cloned zygotes of a large animal model for agriculture and biomedical applications. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 5609 KiB

Open AccessArticle

Ghrelin Attenuates Intestinal Barrier Dysfunction Following Intracerebral Hemorrhage in Mice

by Yijun Cheng^1,†, Yongxu Wei^1,†, Wenlei Yang¹, Yu Cai¹, Bin Chen¹, Guoyuan Yang^2,3, Hanbing Shang¹ and Weiguo Zhao^1,*

¹ Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

² Department of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

³ Neuroscience and Neuroengineering Research Center, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2032; https://doi.org/10.3390/ijms17122032 - 6 Dec 2016

Cited by 23 | Viewed by 5893

Abstract

Intestinal barrier dysfunction remains a critical problem in patients with intracerebral hemorrhage (ICH) and is associated with poor prognosis. Ghrelin, a brain-gut peptide, has been shown to exert protection in animal models of gastrointestinal injury. However, the effect of ghrelin on intestinal barrier [...] Read more.

Intestinal barrier dysfunction remains a critical problem in patients with intracerebral hemorrhage (ICH) and is associated with poor prognosis. Ghrelin, a brain-gut peptide, has been shown to exert protection in animal models of gastrointestinal injury. However, the effect of ghrelin on intestinal barrier dysfunction post-ICH and its possible underlying mechanisms are still unknown. This study was designed to investigate whether ghrelin administration attenuates intestinal barrier dysfunction in experimental ICH using an intrastriatal autologous blood infusion mouse model. Our data showed that treatment with ghrelin markedly attenuated intestinal mucosal injury at both histomorphometric and ultrastructural levels post-ICH. Ghrelin reduced ICH-induced intestinal permeability according to fluorescein isothiocyanate conjugated-dextran (FITC-D) and Evans blue extravasation assays. Concomitantly, the intestinal tight junction-related protein markers, Zonula occludens-1 (ZO-1) and claudin-5 were upregulated by ghrelin post-ICH. Additionally, ghrelin reduced intestinal intercellular adhesion molecule-1 (ICAM-1) expression at the mRNA and protein levels following ICH. Furthermore, ghrelin suppressed the translocation of intestinal endotoxin post-ICH. These changes were accompanied by improved survival rates and an attenuation of body weight loss post-ICH. In conclusion, our results suggest that ghrelin reduced intestinal barrier dysfunction, thereby reducing mortality and weight loss, indicating that ghrelin is a potential therapeutic agent in ICH-induced intestinal barrier dysfunction therapy. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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14 pages, 1404 KiB

Open AccessArticle

Transcriptome Profiling Analysis of Wolf Spider Pardosa pseudoannulata (Araneae: Lycosidae) after Cadmium Exposure

by Chang-Chun Li^1,2, Yong Wang², Guo-Yuan Li², Yue-Li Yun¹, Yu-Jun Dai², Jian Chen¹ and Yu Peng^1,*

¹ Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, College of Life Sciences, Hubei University, Wuhan 430062, China

² Hubei Key Laboratory of Quality Control of Characteristic Fruits and Vegetables, Hubei Engineering University, Xiaogan 432000, China

Int. J. Mol. Sci. 2016, 17(12), 2033; https://doi.org/10.3390/ijms17122033 - 3 Dec 2016

Cited by 33 | Viewed by 5932

Abstract

Pardosa pseudoannulata is one of the most common wandering spiders in agricultural fields and a potentially good bioindicator for heavy metal contamination. However, little is known about the mechanisms by which spiders respond to heavy metals at the molecular level. In the present [...] Read more.

Pardosa pseudoannulata is one of the most common wandering spiders in agricultural fields and a potentially good bioindicator for heavy metal contamination. However, little is known about the mechanisms by which spiders respond to heavy metals at the molecular level. In the present study, high-throughput transcriptome sequencing was employed to characterize the de novo transcriptome of the spiders and to identify differentially expressed genes (DEGs) after cadmium exposure. We obtained 60,489 assembled unigenes, 18,773 of which were annotated in the public databases. A total of 2939 and 2491 DEGs were detected between the libraries of two Cd-treated groups and the control. Functional enrichment analysis revealed that metabolism processes and digestive system function were predominately enriched in response to Cd stress. At the cellular and molecular levels, significantly enriched pathways in lysosomes and phagosomes as well as replication, recombination and repair demonstrated that oxidative damage resulted from Cd exposure. Based on the selected DEGs, certain critical genes involved in defence and detoxification were analysed. These results may elucidate the molecular mechanisms underlying spiders’ responses to heavy metal stress. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 954 KiB

Open AccessReview

The Emergence of the Dose–Response Concept in Biology and Medicine

by Edward J. Calabrese

School of Public Health & Health Sciences, Environmental Health Sciences, Morrill I-N344, University of Massachusetts, Amherst, MA 01003, USA

Int. J. Mol. Sci. 2016, 17(12), 2034; https://doi.org/10.3390/ijms17122034 - 5 Dec 2016

Cited by 67 | Viewed by 8038

Abstract

A historical assessment of the origin of the dose–response in modern toxicology and its integration as a central concept in biology and medicine is presented. This article provides an overview of how the threshold, linear and biphasic (i.e., hormetic) dose–response models emerged in [...] Read more.

A historical assessment of the origin of the dose–response in modern toxicology and its integration as a central concept in biology and medicine is presented. This article provides an overview of how the threshold, linear and biphasic (i.e., hormetic) dose–response models emerged in the late 19th and early 20th centuries and competed for acceptance and dominance. Particular attention is directed to the hormetic model for which a general description and evaluation is provided, including its historical basis, and how it was marginalized by the medical and pharmacology communities in the early decades of the 20th century. Full article

(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)

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12 pages, 935 KiB

Open AccessArticle

A Systematic Evaluation of Blood Serum and Plasma Pre-Analytics for Metabolomics Cohort Studies

by Elodie Jobard^1,2, Olivier Trédan³, Déborah Postoly⁴, Fabrice André⁵, Anne-Laure Martin⁶, Bénédicte Elena-Herrmann^1,*

and Sandrine Boyault⁴

¹ Univ Lyon, CNRS, Université Claude Bernard Lyon 1, ENS de Lyon, Institut des Sciences Analytiques UMR 5280, 5 rue de la Doua, F-69100 Villeurbanne, France

² Centre Léon Bérard, Département de Recherche Translationnelle et de l’Innovation, 28 rue Laënnec, 69373 Lyon, CEDEX 08, France

³ Centre Léon Bérard, Département d’oncologie Médicale, 28 rue Laënnec, 69373 Lyon, CEDEX 08, France

⁴ Centre Léon Bérard, Département de Recherche Translationnelle et de l’Innovation, Génomique des Cancers, 28 rue Laënnec, 69373 Lyon, CEDEX 08, France

⁵ Department of Medical Oncology, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France

⁶ R&D UNICANCER, 101 rue de Tolbiac, 75654 Paris, CEDEX 13, France

Int. J. Mol. Sci. 2016, 17(12), 2035; https://doi.org/10.3390/ijms17122035 - 5 Dec 2016

Cited by 62 | Viewed by 8516

Abstract

The recent thriving development of biobanks and associated high-throughput phenotyping studies requires the elaboration of large-scale approaches for monitoring biological sample quality and compliance with standard protocols. We present a metabolomic investigation of human blood samples that delineates pitfalls and guidelines for the [...] Read more.

The recent thriving development of biobanks and associated high-throughput phenotyping studies requires the elaboration of large-scale approaches for monitoring biological sample quality and compliance with standard protocols. We present a metabolomic investigation of human blood samples that delineates pitfalls and guidelines for the collection, storage and handling procedures for serum and plasma. A series of eight pre-processing technical parameters is systematically investigated along variable ranges commonly encountered across clinical studies. While metabolic fingerprints, as assessed by nuclear magnetic resonance, are not significantly affected by altered centrifugation parameters or delays between sample pre-processing (blood centrifugation) and storage, our metabolomic investigation highlights that both the delay and storage temperature between blood draw and centrifugation are the primary parameters impacting serum and plasma metabolic profiles. Storing the blood drawn at 4 °C is shown to be a reliable routine to confine variability associated with idle time prior to sample pre-processing. Based on their fine sensitivity to pre-analytical parameters and protocol variations, metabolic fingerprints could be exploited as valuable ways to determine compliance with standard procedures and quality assessment of blood samples within large multi-omic clinical and translational cohort studies. Full article

(This article belongs to the Special Issue Metabolomic Technologies in Medicine)

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16 pages, 5667 KiB

Open AccessArticle

The Coexistence of Hypertension and Ovariectomy Additively Increases Cardiac Apoptosis

by Yi-Yuan Lin¹

, Yu-Jung Cheng², Jun Hu³, Li-Xi Chu³, Woei-Cherng Shyu^4,5,6, Chung-Lan Kao^7,8, Tzer-Bin Lin^9,10,11, Chia-Hua Kuo^2,12, Ai-Lun Yang^12,† and Shin-Da Lee^{1,2,3,11,13,*,†}

¹ Graduate Institute of Clinical Medical Science, China Medical University, Taichung 40402, Taiwan

² Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, Taichung 40402, Taiwan

³ School of Rehabilitation Science, Shanghai University of TCM, Shanghai 201203, China

⁴ Translational Medicine Research Center, China Medical University Hospital, Taichung 40402, Taiwan

⁵ Graduate Institute of Immunology, China Medical University, Taichung 40402, Taiwan

⁶ Center for Neuropsychiatry, Department of Neurology, China Medical University Hospital, Taichung 40402, Taiwan

⁷ Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei 11217, Taiwan

⁸ Department of Physical Medicine and Rehabilitation, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan

⁹ Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan

¹⁰ Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung 40402, Taiwan

¹¹ Department of Biotechnology, Asia University, Taichung 41354, Taiwan

¹² Department of Sports Sciences, University of Taipei, Taipei 11153, Taiwan

¹³ Department of Occupational Therapy, Asia University, Taichung 41354, Taiwan

^† These authors contributed equally to this work.

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Int. J. Mol. Sci. 2016, 17(12), 2036; https://doi.org/10.3390/ijms17122036 - 6 Dec 2016

Cited by 18 | Viewed by 5997

Abstract

To investigate whether the coexistence of hypertension and ovariectomy will increase cardiac Fas receptor and mitochondrial-dependent apoptotic pathways, histopathological analysis, the TUNEL assay and Western blotting were performed on the excised hearts from three groups of female spontaneously hypertensive rats (SHR), which were [...] Read more.

To investigate whether the coexistence of hypertension and ovariectomy will increase cardiac Fas receptor and mitochondrial-dependent apoptotic pathways, histopathological analysis, the TUNEL assay and Western blotting were performed on the excised hearts from three groups of female spontaneously hypertensive rats (SHR), which were divided into a sham-operated group (SHR-Sham), bilaterally ovariectomized group (SHR-OVX) and normotensive Wistar Kyoto rats (WKY). Compared with the WKY group, the SHR-Sham group exhibited decreased protein levels of ERα, ERβ, p-Akt/Akt, Bcl-2, Bcl-xL and p-Bad and decreased further in the SHR-OVX group, as well as protein levels of t-Bid, Bak, Bad, Bax, cytochrome c, activated caspase-9 and activated caspase-3 (mitochondria-dependent apoptosis) increased in the SHR-Sham group and increased further in the SHR-OVX group. Compared with the WKY group, protein levels of Fas ligand, TNF-α, Fas death receptors, TNFR1, FADD and activated caspase-8 (Fas receptor-dependent apoptosis) increased in the SHR-Sham group, but did not increase in the SHR-OVX group, except Fas ligand and TNF-α. The coexistence of hypertension and ovariectomy attenuated the estrogen receptor survival pathway and appeared to additively increase the cardiac mitochondria-dependent, but not the Fas receptor-dependent apoptosis pathway, which might provide one possible mechanism for the development of cardiac abnormalities in hypertensive postmenopausal women. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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27 pages, 2027 KiB

Open AccessReview

Integrins in the Spotlight of Cancer

by Daniela Bianconi, Matthias Unseld and Gerald W. Prager^*

Department of Internal Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, A-1090 Vienna, Austria

Int. J. Mol. Sci. 2016, 17(12), 2037; https://doi.org/10.3390/ijms17122037 - 6 Dec 2016

Cited by 123 | Viewed by 10578

Abstract

Integrins are heterodimeric cell surface receptors that bind to different extracellular ligands depending on their composition and regulate all processes which enable multicellular life. In cancer, integrins trigger and play key roles in all the features that were once described as the Hallmarks [...] Read more.

Integrins are heterodimeric cell surface receptors that bind to different extracellular ligands depending on their composition and regulate all processes which enable multicellular life. In cancer, integrins trigger and play key roles in all the features that were once described as the Hallmarks of Cancer. In this review, we will discuss the contribution of integrins to these hallmarks, including uncontrolled and limitless proliferation, invasion of tumor cells, promotion of tumor angiogenesis and evasion of apoptosis and resistance to growth suppressors, by highlighting the latest findings. Further on, given the paramount role of integrins in cancer, we will present novel strategies for integrin inhibition that are starting to emerge, promising a hopeful future regarding cancer treatment. Full article

(This article belongs to the Special Issue Integrins in Cancer)

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15 pages, 1149 KiB

Open AccessArticle

Serum Soluble Fms-Like Tyrosine Kinase 1 (sFlt-1) Predicts the Severity of Acute Pancreatitis

by Paulina Dumnicka¹, Mateusz Sporek^2,3, Małgorzata Mazur-Laskowska⁴, Piotr Ceranowicz^5,*

, Marek Kuźniewski⁶, Ryszard Drożdż¹, Tadeusz Ambroży⁷

, Rafał Olszanecki⁸ and Beata Kuśnierz-Cabala⁹

¹ Department of Medical Diagnostics, Jagiellonian University Medical College, 30-688 Kraków, Poland

² Surgery Department, The District Hospital, 34-200 Sucha Beskidzka, Poland

³ Department of Anatomy, Jagiellonian University Medical College, 31-034 Kraków, Poland

⁴ Department of Diagnostics, University Hospital, 31-501 Kraków, Poland

⁵ Department of Physiology, Jagiellonian University Medical College, 31-531 Kraków, Poland

⁶ Chair and Department of Nephrology, Jagiellonian University Medical College, 31-501 Kraków, Poland

⁷ Department of Theory of Sport and Kinesiology, Faculty of Physical Education and Sport, University of Physical Education, 31-571 Kraków, Poland

⁸ Department of Pharmacology, Jagiellonian University Medical College, 31-531 Kraków, Poland

⁹ Department of Diagnostics, Chair of Clinical Biochemistry, Jagiellonian University Medical College, 31-501 Kraków, Poland

Int. J. Mol. Sci. 2016, 17(12), 2038; https://doi.org/10.3390/ijms17122038 - 6 Dec 2016

Cited by 26 | Viewed by 5472

Abstract

Organ failure is the most important determinant of the severity of acute pancreatitis (AP). Soluble fms-like tyrosine kinase 1 (sFlt-1) is positively associated with organ failure in sepsis. Our aim was to evaluate the diagnostic utility of automated sFlt-1 measurements for early prediction [...] Read more.

Organ failure is the most important determinant of the severity of acute pancreatitis (AP). Soluble fms-like tyrosine kinase 1 (sFlt-1) is positively associated with organ failure in sepsis. Our aim was to evaluate the diagnostic utility of automated sFlt-1 measurements for early prediction of AP severity. Adult patients (66) with AP were recruited, including 46 with mild (MAP), 15 with moderately-severe (MSAP) and 5 with severe AP (SAP). Serum and urine samples were collected twice. Serum sFlt-1 was measured with automated electrochemiluminescence immunoassay. Serum concentrations of sFlt-1 were significantly higher in patients with MSAP and SAP as compared to MAP. SAP patients had the highest concentrations. At 24 and 48 h, sFlt-1 positively correlated with inflammatory markers (leukocyte count, C-reactive protein), kidney function (creatinine, urea, cystatin C, serum and urine neutrophil gelatinase-associated lipocalin, urine albumin/creatinine ratio), D-dimer and angiopoietin-2. sFlt-1 positively correlated with the bedside index of severity in AP (BISAP) score and the duration of hospital stay. Serum sFlt-1 above 139 pg/mL predicted more severe AP (MSAP + SAP). In the early phase of AP, sFlt-1 is positively associated with the severity of AP and predicts organ failure, in particular kidney failure. Serum sFlt-1 may be a practical way to improve early assessment of AP severity. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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24 pages, 2143 KiB

Open AccessReview

Internet Databases of the Properties, Enzymatic Reactions, and Metabolism of Small Molecules—Search Options and Applications in Food Science

by Piotr Minkiewicz^*

, Małgorzata Darewicz

, Anna Iwaniak, Justyna Bucholska, Piotr Starowicz and Emilia Czyrko^†

¹ Department of Food Biochemistry, University of Warmia and Mazury in Olsztyn, Plac Cieszyński 1, 10-726 Olsztyn-Kortowo, Poland

^† Current address: Faculty of Physical Education, Jędrzej Śniadecki Academy of Physical Education and Sport, ul. Kazimierza Górskiego 1, 80-336 Gdańsk, Poland.

Int. J. Mol. Sci. 2016, 17(12), 2039; https://doi.org/10.3390/ijms17122039 - 6 Dec 2016

Cited by 21 | Viewed by 7579

Abstract

Internet databases of small molecules, their enzymatic reactions, and metabolism have emerged as useful tools in food science. Database searching is also introduced as part of chemistry or enzymology courses for food technology students. Such resources support the search for information about single [...] Read more.

Internet databases of small molecules, their enzymatic reactions, and metabolism have emerged as useful tools in food science. Database searching is also introduced as part of chemistry or enzymology courses for food technology students. Such resources support the search for information about single compounds and facilitate the introduction of secondary analyses of large datasets. Information can be retrieved from databases by searching for the compound name or structure, annotating with the help of chemical codes or drawn using molecule editing software. Data mining options may be enhanced by navigating through a network of links and cross-links between databases. Exemplary databases reviewed in this article belong to two classes: tools concerning small molecules (including general and specialized databases annotating food components) and tools annotating enzymes and metabolism. Some problems associated with database application are also discussed. Data summarized in computer databases may be used for calculation of daily intake of bioactive compounds, prediction of metabolism of food components, and their biological activity as well as for prediction of interactions between food component and drugs. Full article

(This article belongs to the Special Issue New Foodomics Approaches in Food Science)

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9 pages, 7177 KiB

Open AccessArticle

HER2 Analysis in Sporadic Thyroid Cancer of Follicular Cell Origin

by Rosaria M. Ruggeri^1,*, Alfredo Campennì², Giuseppe Giuffrè³, Luca Giovanella⁴, Massimiliano Siracusa², Angela Simone³, Giovanni Branca³, Rosa Scarfì³, Francesco Trimarchi¹, Antonio Ieni³

and Giovanni Tuccari³

¹ Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Messina, AOU Policlinico G. Martino, 98125 Messina, Italy

² Department of Biomedical Sciences and Morphological and Functional Images, Unit of Nuclear Medicine, University of Messina, AOU Policlinico G. Martino, 98125 Messina, Italy

³ Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, Unit of Pathological Anatomy, University of Messina, AOU Policlinico G. Martino, 98125 Messina, Italy

⁴ Department of Nuclear Medicine, Thyroid and PET/CT Center, Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland

Int. J. Mol. Sci. 2016, 17(12), 2040; https://doi.org/10.3390/ijms17122040 - 6 Dec 2016

Cited by 17 | Viewed by 5121

Abstract

The Epidermal Growth Factor Receoptor (EGFR) family member human epidermal growth factor receptor 2 (HER2) is overexpressed in many human epithelial malignancies, representing a molecular target for specific anti-neoplastic drugs. Few data are available on HER2 status in differentiated thyroid cancer (DTC). The [...] Read more.

The Epidermal Growth Factor Receoptor (EGFR) family member human epidermal growth factor receptor 2 (HER2) is overexpressed in many human epithelial malignancies, representing a molecular target for specific anti-neoplastic drugs. Few data are available on HER2 status in differentiated thyroid cancer (DTC). The present study was aimed to investigate HER2 status in sporadic cancers of follicular cell origin to better clarify the role of this receptor in the stratification of thyroid cancer. By immunohistochemistry and fluorescence in-situ hybridization, HER2 expression was investigated in formalin-fixed paraffin-embedded surgical specimens from 90 DTC patients, 45 follicular (FTC) and 45 papillary (PTC) histotypes. No HER2 immunostaining was recorded in background thyroid tissue. By contrast, overall HER2 overexpression was found in 20/45 (44%) FTC and 8/45 (18%) PTC, with a significant difference between the two histotypes (p = 0.046). Five of the six patients who developed metastatic disease during a median nine-year follow-up had a HER2-positive tumor. Therefore, we suggest that HER2 expression may represent an additional aid to identify a subset of patients who are characterized by a worse prognosis and are potentially eligible for targeted therapy. Full article

(This article belongs to the Special Issue Current Knowledge in Thyroid Cancer—From Bench to Bedside)

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11 pages, 1043 KiB

Open AccessReview

The Regulation of Tumor Suppressor p63 by the Ubiquitin-Proteasome System

by Stephen R. Armstrong¹, Hong Wu¹, Benfan Wang¹, Yasser Abuetabh¹, Consolato Sergi² and Roger P. Leng^1,*

¹ 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada

² Department of Laboratory Medicine and Pathology (5B4. 09), University of Alberta, Edmonton, AB T6G 2B7, Canada

Int. J. Mol. Sci. 2016, 17(12), 2041; https://doi.org/10.3390/ijms17122041 - 6 Dec 2016

Cited by 36 | Viewed by 7678

Abstract

The protein p63 has been identified as a homolog of the tumor suppressor protein p53 and is capable of inducing apoptosis, cell cycle arrest, or senescence. p63 has at least six isoforms, which can be divided into two major groups: the TAp63 variants [...] Read more.

The protein p63 has been identified as a homolog of the tumor suppressor protein p53 and is capable of inducing apoptosis, cell cycle arrest, or senescence. p63 has at least six isoforms, which can be divided into two major groups: the TAp63 variants that contain the N-terminal transactivation domain and the ΔNp63 variants that lack the N-terminal transactivation domain. The TAp63 variants are generally considered to be tumor suppressors involved in activating apoptosis and suppressing metastasis. ΔNp63 variants cannot induce apoptosis but can act as dominant negative inhibitors to block the function of TAp53, TAp73, and TAp63. p63 is rarely mutated in human tumors and is predominately regulated at the post-translational level by phosphorylation and ubiquitination. This review focuses primarily on regulation of p63 by the ubiquitin E-3 ligase family of enzymes via ubiquitination and proteasome-mediated degradation, and introduces a new key regulator of the p63 protein. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

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14 pages, 517 KiB

Open AccessReview

Nutraceutical Supplements in the Management and Prevention of Osteoarthritis

by Paola Castrogiovanni¹

, Francesca Maria Trovato²

, Carla Loreto¹

, Houda Nsir³, Marta Anna Szychlinska¹

and Giuseppe Musumeci^1,*

¹ Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, 95100 Catania, Italy

² Department of Clinical and Experimental Medicine, University of Catania, 95100 Catania, Italy

³ Department of Molecular and Cellular Biology and Plant Physiology, Centre of Biotechnology of Borj Cedreya, University of Carthage, Carthage 2050, Tunisia

Int. J. Mol. Sci. 2016, 17(12), 2042; https://doi.org/10.3390/ijms17122042 - 6 Dec 2016

Cited by 82 | Viewed by 15509

Abstract

Nutraceuticals are dietary compounds which have a role in the balance of anabolic and catabolic signals in joints. Their regulatory function on homeostasis of cartilage metabolism nutraceuticals is increasingly considered for the management and, above all, the prevention of osteoarthritis (OA). OA is [...] Read more.

Nutraceuticals are dietary compounds which have a role in the balance of anabolic and catabolic signals in joints. Their regulatory function on homeostasis of cartilage metabolism nutraceuticals is increasingly considered for the management and, above all, the prevention of osteoarthritis (OA). OA is a degenerative disease characterized by cartilage and synovium inflammation that can cause joint stiffness, swelling, pain, and loss of mobility. It is a multifactorial disease and, due to the great percentage of people suffering from it and the general increase in life expectancy, OA is considered as one of the most significant causes of disability in the world. OA impairs the structural integrity of articular cartilage that greatly depends on a balance between the anabolic and catabolic processes which occur in chondrocytes and synovial fluid of the joints, therefore the integration with nutraceutical compounds in diet increases the treatment options for patients with established OA beyond traditional rehabilitation, medications, and surgical strategies. In our review, with respect to the current literature, we highlight some of many existing nutraceutical compounds that could be used as integrators in a daily diet thanks to their easy availability, such as in olive oil, fish oil, and botanical extracts used as non-pharmacologic treatment. Full article

(This article belongs to the Collection Feature Annual Reviews in Molecular Sciences)

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20 pages, 2049 KiB

Open AccessArticle

Comparison of Small RNA Profiles of Glycine max and Glycine soja at Early Developmental Stages

by Yuzhe Sun^1,†, Zeta Mui^2,3,†, Xuan Liu^4,†, Aldrin Kay-Yuen Yim^2,3, Hao Qin², Fuk-Ling Wong^2,3, Ting-Fung Chan^2,3

, Siu-Ming Yiu⁴, Hon-Ming Lam^2,3,*

and Boon Leong Lim^1,3,*

¹ School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China

² School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China

³ Center for Soybean Research of the Partner State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, Hong Kong, China

⁴ Department of Computer Science, The University of Hong Kong, Pokfulam, Hong Kong, China

^† The authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2043; https://doi.org/10.3390/ijms17122043 - 6 Dec 2016

Cited by 8 | Viewed by 6456

Abstract

Small RNAs, including microRNAs (miRNAs) and phased small interfering RNAs (phasiRNAs; from PHAS loci), play key roles in plant development. Cultivated soybean, Glycine max, contributes a great deal to food production, but, compared to its wild kin, Glycine soja, it may [...] Read more.

Small RNAs, including microRNAs (miRNAs) and phased small interfering RNAs (phasiRNAs; from PHAS loci), play key roles in plant development. Cultivated soybean, Glycine max, contributes a great deal to food production, but, compared to its wild kin, Glycine soja, it may lose some genetic information during domestication. In this work, we analyzed the sRNA profiles of different tissues in both cultivated (C08) and wild soybeans (W05) at three stages of development. A total of 443 known miRNAs and 15 novel miRNAs showed varying abundances between different samples, but the miRNA profiles were generally similar in both accessions. Based on a sliding window analysis workflow that we developed, 50 PHAS loci generating 55 21-nucleotide phasiRNAs were identified in C08, and 46 phasiRNAs from 41 PHAS loci were identified in W05. In germinated seedlings, phasiRNAs were more abundant in C08 than in W05. Disease resistant TIR-NB-LRR genes constitute a very large family of PHAS loci. PhasiRNAs were also generated from several loci that encode for NAC transcription factors, Dicer-like 2 (DCL2), Pentatricopeptide Repeat (PPR), and Auxin Signaling F-box 3 (AFB3) proteins. To investigate the possible involvement of miRNAs in initiating the PHAS-phasiRNA pathway, miRNA target predictions were performed and 17 C08 miRNAs and 15 W05 miRNAs were predicted to trigger phasiRNAs biogenesis. In summary, we provide a comprehensive description of the sRNA profiles of wild versus cultivated soybeans, and discuss the possible roles of sRNAs during soybean germination. Full article

(This article belongs to the Special Issue Pulses)

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12 pages, 851 KiB

Open AccessReview

Aortic Stiffness as a Surrogate Endpoint to Micro- and Macrovascular Complications in Patients with Type 2 Diabetes

by Claudia R. L. Cardoso and Gil F. Salles^*

Department of Internal Medicine, School of Medicine and University Hospital Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rua Rodolpho Rocco 255, Cidade Universitária, Rio de Janeiro-RJ 21941-901, Brazil

Int. J. Mol. Sci. 2016, 17(12), 2044; https://doi.org/10.3390/ijms17122044 - 6 Dec 2016

Cited by 37 | Viewed by 6638

Abstract

Increased aortic stiffness has been recognized as a predictor of adverse cardiovascular outcomes in some clinical conditions, such as in patients with arterial hypertension and end-stage renal disease, in population-based samples and, more recently, in type 2 diabetic patients. Patients with type 2 [...] Read more.

Increased aortic stiffness has been recognized as a predictor of adverse cardiovascular outcomes in some clinical conditions, such as in patients with arterial hypertension and end-stage renal disease, in population-based samples and, more recently, in type 2 diabetic patients. Patients with type 2 diabetes have higher aortic stiffness than non-diabetic individuals, and increased aortic stiffness has been correlated to the presence of micro- and macrovascular chronic diabetic complications. We aimed to review the current knowledge on the relationships between aortic stiffness and diabetic complications, their possible underlying physiopathological mechanisms, and their potential applications to clinical type 2 diabetes management. Full article

(This article belongs to the Special Issue Diabetic Complications: Pathophysiology, Mechanisms, and Therapies)

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17 pages, 2721 KiB

Open AccessReview

Cell Death in Chondrocytes, Osteoblasts, and Osteocytes

by Toshihisa Komori

Department of Cell Biology, Unit of Basic Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan

Int. J. Mol. Sci. 2016, 17(12), 2045; https://doi.org/10.3390/ijms17122045 - 6 Dec 2016

Cited by 136 | Viewed by 14568

Abstract

Cell death in skeletal component cells, including chondrocytes, osteoblasts, and osteocytes, plays roles in skeletal development, maintenance, and repair as well as in the pathogenesis of osteoarthritis and osteoporosis. Chondrocyte proliferation, differentiation, and apoptosis are important steps for endochondral ossification. Although the inactivation [...] Read more.

Cell death in skeletal component cells, including chondrocytes, osteoblasts, and osteocytes, plays roles in skeletal development, maintenance, and repair as well as in the pathogenesis of osteoarthritis and osteoporosis. Chondrocyte proliferation, differentiation, and apoptosis are important steps for endochondral ossification. Although the inactivation of P53 and RB is involved in the pathogenesis of osteosarcomas, the deletion of p53 and inactivation of Rb are insufficient to enhance chondrocyte proliferation, indicating the presence of multiple inhibitory mechanisms against sarcomagenesis in chondrocytes. The inflammatory processes induced by mechanical injury and chondrocyte death through the release of danger-associated molecular patterns (DAMPs) are involved in the pathogenesis of posttraumatic osteoarthritis. The overexpression of BCLXL increases bone volume with a normal structure and maintains bone during aging by inhibiting osteoblast apoptosis. p53 inhibits osteoblast proliferation and enhances osteoblast apoptosis, thereby reducing bone formation, but also exerts positive effects on osteoblast differentiation through the Akt–FoxOs pathway. Apoptotic osteocytes release ATP, which induces the receptor activator of nuclear factor κ-B ligand (Rankl) expression and osteoclastogenesis, from pannexin 1 channels. Osteocyte death ultimately results in necrosis; DAMPs are released to the bone surface and promote the production of proinflammatory cytokines, which induce Rankl expression, and osteoclastogenesis is further enhanced. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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18 pages, 979 KiB

Open AccessArticle

Comparative Study of Green Sub- and Supercritical Processes to Obtain Carnosic Acid and Carnosol-Enriched Rosemary Extracts with in Vitro Anti-Proliferative Activity on Colon Cancer Cells

by Andrea Del Pilar Sánchez-Camargo, Virginia García-Cañas, Miguel Herrero, Alejandro Cifuentes

and Elena Ibáñez^*

Laboratory of Foodomics, Institute of Food Science Research, Instituto de Investigación en Ciencias de la Alimentación, Consejo Superior de Investigaciones Científicas, Nicolas Cabrera 9, 28049 Madrid, Spain

Int. J. Mol. Sci. 2016, 17(12), 2046; https://doi.org/10.3390/ijms17122046 - 7 Dec 2016

Cited by 37 | Viewed by 8068

Abstract

In the present work, four green processes have been compared to evaluate their potential to obtain rosemary extracts with in vitro anti-proliferative activity against two colon cancer cell lines (HT-29 and HCT116). The processes, carried out under optimal conditions, were: (1) pressurized liquid [...] Read more.

In the present work, four green processes have been compared to evaluate their potential to obtain rosemary extracts with in vitro anti-proliferative activity against two colon cancer cell lines (HT-29 and HCT116). The processes, carried out under optimal conditions, were: (1) pressurized liquid extraction (PLE, using an hydroalcoholic mixture as solvent) at lab-scale; (2) Single-step supercritical fluid extraction (SFE) at pilot scale; (3) Intensified two-step sequential SFE at pilot scale; (4) Integrated PLE plus supercritical antisolvent fractionation (SAF) at pilot scale. Although higher extraction yields were achieved by using PLE (38.46% dry weight), this extract provided the lowest anti-proliferative activity with no observed cytotoxic effects at the assayed concentrations. On the other hand, extracts obtained using the PLE + SAF process provided the most active rosemary extracts against both colon cancer cell lines, with LC₅₀ ranging from 11.2 to 12.4 µg/mL and from 21.8 to 31.9 µg/mL for HCT116 and HT-29, respectively. In general, active rosemary extracts were characterized by containing carnosic acid (CA) and carnosol (CS) at concentrations above 263.7 and 33.9 mg/g extract, respectively. Some distinct compounds have been identified in the SAF extracts (rosmaridiphenol and safficinolide), suggesting their possible role as additional contributors to the observed strong anti-proliferative activity of CA and CS in SAF extracts. Full article

(This article belongs to the Special Issue New Foodomics Approaches in Food Science)

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16 pages, 12301 KiB

Open AccessArticle

miR-429 Inhibits Differentiation and Promotes Proliferation in Porcine Preadipocytes

by Ying Peng¹, Fen-Fen Chen^1,2, Jing Ge¹, Jia-Yu Zhu¹, Xin-E Shi¹, Xiao Li¹

, Tai-Yong Yu¹, Gui-Yan Chu¹ and Gong-She Yang^1,*

¹ Laboratory of Animal Fat Deposition & Muscle Development, College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China

² School of Life Sciences, Southwest Forestry University, Kunming 650224, China

Int. J. Mol. Sci. 2016, 17(12), 2047; https://doi.org/10.3390/ijms17122047 - 7 Dec 2016

Cited by 46 | Viewed by 5753

Abstract

MicroRNAs (miRNAs) are crucial regulatory molecules for adipogenesis. They contribute to the controlling of proliferation and differentiation of preadipocytes. Previous studies revealed an important role of miR-429 in cell invasion, migration, and apoptosis. Our previous work has shown that the expression of miR-429 [...] Read more.

MicroRNAs (miRNAs) are crucial regulatory molecules for adipogenesis. They contribute to the controlling of proliferation and differentiation of preadipocytes. Previous studies revealed an important role of miR-429 in cell invasion, migration, and apoptosis. Our previous work has shown that the expression of miR-429 in subcutaneous fat can be observed in newly born (3-day-old) Rongchang piglets rather than their adult counterparts (180-day-old). This expression pattern suggests that miR-429 might be functionally related to postnatal adipogenesis. However, we currently lack a mechanistic understanding of miR-429 within the context of preadipocyte differentiation. In this study, we investigated the function of miR-429 in porcine subcutaneous and intramuscular preadipocyte proliferation and differentiation. In our porcine preadipocyte differentiation model, miR-429 expression decreased remarkably upon adipogenic induction. Overexpression of miR-429 notably down-regulated the expression of adipogenic marker genes: PPARγ, aP2, FAS and impaired the triglyceride accumulation, while the expression of lipolytic gene ATGL was not affected. In addition, we observed that miR-429 significantly promoted the proliferation of porcine preadipocytes. We also found that miR-429 could directly bind to the 3′-UTRs of KLF9 and p27, which have been well documented to promote preadipocyte differentiation and repress cell cycle progression. Taken together, our data support a novel role of miR-429 in regulating porcine preadipocyte differentiation and proliferation, and KLF9 and p27 are potent targets of miR-429 during these processes. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 8449 KiB

Open AccessArticle

Cellular Localization and Regulation of Expression of the PLET1 Gene in Porcine Placenta

by Liu Teng, Linjun Hong, Ruize Liu, Ran Chen, Xinyun Li and Mei Yu^*

Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education and the Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430070, Hubei, China

Int. J. Mol. Sci. 2016, 17(12), 2048; https://doi.org/10.3390/ijms17122048 - 7 Dec 2016

Cited by 10 | Viewed by 5894

Abstract

The placenta expressed transcript 1 (PLET1) gene, which is expressed in placentas of pigs and mice, has been found to have a potential role in trophoblast cell fate decision in mice. Results of this study showed that the porcine PLET1 mRNA [...] Read more.

The placenta expressed transcript 1 (PLET1) gene, which is expressed in placentas of pigs and mice, has been found to have a potential role in trophoblast cell fate decision in mice. Results of this study showed that the porcine PLET1 mRNA and protein were expressed exclusively in trophoblast cells on Days 15, 26, 50, and 95 of gestation (gestation length in the pig is 114 days), indicating that the PLET1 could be a useful marker for porcine trophoblast cells. Additionally, PLET1 protein was found to be redistributed from cytoplasm to the apical side of trophoblast cells as gestation progresses, which suggests a role of PLET1 in the establishment of a stable trophoblast and endometrial epithelial layers. In addition, two transcripts that differ in the 3′ UTR length but encode identical protein were identified to be generated by the alternative cleavage and polyadenylation (APA), and the expression of PLET1-L transcript was significantly upregulated in porcine placentas as gestation progresses. Furthermore, we demonstrated the interaction between the miR-365-3p and PLET1 gene using luciferase assay system. Our findings imply an important role of PLET1 in the placental development in pigs. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 1147 KiB

Open AccessArticle

Mutations in the Mitochondrial ND1 Gene Are Associated with Postoperative Prognosis of Localized Renal Cell Carcinoma

by Hakushi Kim^1,*, Tomoyoshi Komiyama², Chie Inomoto³, Hiroshi Kamiguchi⁴, Hiroshi Kajiwara³, Hiroyuki Kobayashi², Naoya Nakamura³ and Toshiro Terachi¹

¹ Department of Urology, Tokai University School of Medicine, Kanagawa, Isehara 259-1193, Japan

² Department of Clinical Pharmacology, Tokai University School of Medicine, Kanagawa, Isehara 259-1193, Japan

³ Department of Pathology, Tokai University School of Medicine, Kanagawa, Isehara 259-1193, Japan

⁴ Support Center for Medical Research and Education, Tokai University, Kanagawa, Isehara 259-1193, Japan

Int. J. Mol. Sci. 2016, 17(12), 2049; https://doi.org/10.3390/ijms17122049 - 7 Dec 2016

Cited by 26 | Viewed by 4666

Abstract

We analyzed mutations in the mitochondrial ND1 gene to determine their association with clinicopathological parameters and postoperative recurrence of renal cell carcinoma (RCC) in Japanese patients. Among 62 RCC cases for which tumor pathology was confirmed by histopathology, ND1 sequencing revealed the presence [...] Read more.

We analyzed mutations in the mitochondrial ND1 gene to determine their association with clinicopathological parameters and postoperative recurrence of renal cell carcinoma (RCC) in Japanese patients. Among 62 RCC cases for which tumor pathology was confirmed by histopathology, ND1 sequencing revealed the presence of 30 mutation sites in 19 cases. Most mutations were heteroplasmic, with 16 of 19 cases harboring one or more heteroplasmic sites. Additionally, 12 sites had amino acid mutations, which were frequent in 10 of the cases. The 5-year recurrence-free survival (RFS) rate was significantly worse in patients with tumors >40 mm in diameter (p = 0.0091), pathological T (pT) stage ≥3 (p = 0.0122), Fuhrman nuclear atypia grade ≥III (p = 0.0070), and ND1 mutations (p = 0.0006). Multivariate analysis using these factors revealed that mutations in ND1 were significantly associated with the 5-year RFS rate (p = 0.0044). These results suggest a strong correlation between the presence of ND1 mutations in cancer tissue and postoperative recurrence of localized RCC in Japanese patients. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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18 pages, 13335 KiB

Open AccessReview

Aquaporins in the Spinal Cord

by Michal K. Oklinski¹, Mariusz T. Skowronski²

, Agnieszka Skowronska³, Michael Rützler¹, Kirsten Nørgaard¹, John D. Nieland¹, Tae-Hwan Kwon^4,* and Søren Nielsen^1,*

¹ Department of Health Science and Technology, Aalborg University, 9220 Aalborg, Denmark

² Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, 10-752 Olsztyn, Poland

³ Department of Human Physiology, University of Warmia and Mazury in Olsztyn, 10-752 Olsztyn, Poland

⁴ Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Taegu 41944, Korea

Int. J. Mol. Sci. 2016, 17(12), 2050; https://doi.org/10.3390/ijms17122050 - 7 Dec 2016

Cited by 41 | Viewed by 8460

Abstract

Aquaporins (AQPs) are water channel proteins robustly expressed in the central nervous system (CNS). A number of previous studies described the cellular expression sites and investigated their major roles and function in the brain and spinal cord. Among thirteen different mammalian AQPs, AQP1 [...] Read more.

Aquaporins (AQPs) are water channel proteins robustly expressed in the central nervous system (CNS). A number of previous studies described the cellular expression sites and investigated their major roles and function in the brain and spinal cord. Among thirteen different mammalian AQPs, AQP1 and AQP4 have been mainly studied in the CNS and evidence has been presented that they play important roles in the pathogenesis of CNS injury, edema and multiple diseases such as multiple sclerosis, neuromyelitis optica spectrum disorders, amyotrophic lateral sclerosis, glioblastoma multiforme, Alzheimer’s disease and Parkinson’s disease. The objective of this review is to highlight the current knowledge about AQPs in the spinal cord and their proposed roles in pathophysiology and pathogenesis related to spinal cord lesions and injury. Full article

(This article belongs to the Special Issue Aquaporin)

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13 pages, 1684 KiB

Open AccessArticle

Low Concentration of Exogenous Carbon Monoxide Modulates Radiation-Induced Bystander Effect in Mammalian Cell Cluster Model

by Wenqing Wu^1,†, Lili Nie^1,†, K. N. Yu^1,2, Lijun Wu^1,3, Peizhong Kong¹, Lingzhi Bao¹, Guodong Chen¹, Haoran Yang¹ and Wei Han^1,4,*

¹ Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China

² Department of Physics and Materials Science, City University of Hong Kong, TatChee Avenue, Kowloon Tong, Hong Kong, China

³ Institute of Technical Biology & Agricultural Engineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China

⁴ Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Suzhou 215000, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2051; https://doi.org/10.3390/ijms17122051 - 8 Dec 2016

Cited by 4 | Viewed by 6769

Abstract

During radiotherapy procedures, radiation-induced bystander effect (RIBE) can potentially lead to genetic hazards to normal tissues surrounding the targeted regions. Previous studies showed that RIBE intensities in cell cluster models were much higher than those in monolayer cultured cell models. On the other [...] Read more.

During radiotherapy procedures, radiation-induced bystander effect (RIBE) can potentially lead to genetic hazards to normal tissues surrounding the targeted regions. Previous studies showed that RIBE intensities in cell cluster models were much higher than those in monolayer cultured cell models. On the other hand, low-concentration carbon monoxide (CO) was previously shown to exert biological functions via binding to the heme domain of proteins and then modulating various signaling pathways. In relation, our previous studies showed that exogenous CO generated by the CO releasing molecule, tricarbonyldichlororuthenium (CORM-2), at a relatively low concentration (20 µM), effectively attenuated the formation of RIBE-induced DNA double-strand breaks (DSB) and micronucleus (MN). In the present work, we further investigated the capability of a low concentration of exogenous CO (CORM-2) of attenuating or inhibiting RIBE in a mixed-cell cluster model. Our results showed that CO (CORM-2) with a low concentration of 30 µM could effectively suppress RIBE-induced DSB (p53 binding protein 1, p53BP1), MN formation and cell proliferation in bystander cells but not irradiated cells via modulating the inducible nitric oxide synthase (iNOS) andcyclooxygenase-2 (COX-2). The results can help mitigate RIBE-induced hazards during radiotherapy procedures. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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17 pages, 4429 KiB

Open AccessArticle

Identification of Potential Biomarkers for Rhegmatogenous Retinal Detachment Associated with Choroidal Detachment by Vitreous iTRAQ-Based Proteomic Profiling

by Zhifeng Wu^1,2,†, Nannan Ding^2,†

, Mengxi Yu², Ke Wang³, Shasha Luo², Wenjun Zou², Ying Zhou², Biao Yan⁴ and Qin Jiang^1,4,*

¹ Eye Hospital, Nanjing Medical University, Nanjing 210000, China

² Department of Ophthalmology, Wuxi No. 2 People’s Hospital, Nanjing Medical University, Wuxi 214002, China

³ Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China

⁴ The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210000, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2052; https://doi.org/10.3390/ijms17122052 - 7 Dec 2016

Cited by 18 | Viewed by 6969

Abstract

Rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD) is a complicated and serious type of rhegmatogenous retinal detachment (RRD). In this study, we identified differentially expressed proteins in the vitreous humors of RRDCD and RRD using isobaric tags for relative and absolute quantitation [...] Read more.

Rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD) is a complicated and serious type of rhegmatogenous retinal detachment (RRD). In this study, we identified differentially expressed proteins in the vitreous humors of RRDCD and RRD using isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano-liquid chromatography-electrospray ion trap-mass spectrometry-mass spectrometry (nano-LC-ESI-MS/MS) and bioinformatic analysis. Our result shows that 103 differentially expressed proteins, including 54 up-regulated and 49 down-regulated proteins were identified in RRDCD. Gene ontology (GO) analysis suggested that most of the differentially expressed proteins were extracellular．The Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis suggested that proteins related to complement and coagulation cascades were significantly enriched. iTRAQ-based proteomic profiling reveals that complement and coagulation cascades and inflammation may play important roles in the pathogenesis of RRDCD. This study may provide novel insights into the pathogenesis of RRDCD and offer potential opportunities for the diagnosis and treatment of RRDCD. Full article

(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)

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15 pages, 7866 KiB

Open AccessArticle

Relevance of MicroRNA200 Family and MicroRNA205 for Epithelial to Mesenchymal Transition and Clinical Outcome in Biliary Tract Cancer Patients

by Romana Urbas^1,†, Christian Mayr^2,3,†, Eckhard Klieser¹, Julia Fuereder³, Doris Bach³, Stefan Stättner⁴, Florian Primavesi⁴, Tarkan Jaeger⁵

, Stefanie Stanzer⁶, Anna Lena Ress⁶, Magdalena Löffelberger², Andrej Wagner³, Frieder Berr^2,3, Markus Ritter^2,7, Martin Pichler⁶

, Daniel Neureiter^1,*,† and Tobias Kiesslich^2,3,†

¹ Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg 5020, Austria

² Laboratory for Tumour Biology and Experimental Therapies (TREAT), Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg 5020, Austria

³ Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg 5020, Austria

⁴ Department of Visceral-, Transplant- and Thoracic Surgery, Medical University of Innsbruck, Innsbruck 6020, Austria

⁵ Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg 5020, Austria

⁶ Research Unit for Non-Coding RNA and Genome Editing in Cancer, Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz 8036, Austria

⁷ Department for Radon Therapy Research, Ludwig Boltzmann Cluster for Arthritis and Rehabilitation, Salzburg 5020, Austria

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2053; https://doi.org/10.3390/ijms17122053 - 7 Dec 2016

Cited by 17 | Viewed by 6231

Abstract

Extensive stromal interaction is one reason for the dismal outcome of biliary tract cancer (BTC) patients. Epithelial to mesenchymal transition (EMT) is involved in tumor invasion and metastasis and is partly regulated by microRNAs (miRs). This study explores the expression of anti-EMT miR200 [...] Read more.

Extensive stromal interaction is one reason for the dismal outcome of biliary tract cancer (BTC) patients. Epithelial to mesenchymal transition (EMT) is involved in tumor invasion and metastasis and is partly regulated by microRNAs (miRs). This study explores the expression of anti-EMT miR200 family (miR141, −200a/b/c, −429) and miR205 as well as the EMT-related proteins E-cadherin and vimentin in a panel of BTC cell lines and clinical specimens by quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry, respectively. MicroRNA expression was correlated to (i) the expression patterns of E-cadherin and vimentin; (ii) clinicopathological characteristics; and (iii) survival data. MicroRNA-200 family and miR205 were expressed in all BTC cells and clinical specimens. E-cadherin and vimentin showed a mutually exclusive expression pattern in both, in vitro and in vivo. Expression of miR200 family members positively correlated with E-cadherin and negatively with vimentin expression in BTC cells and specimens. High expression of miR200 family members (but not miR205) and E-cadherin was associated with longer survival, while low miR200 family and high vimentin expression was a predictor of unfavorable survival. Overall, the current study demonstrates the relevance of the miR200 family in EMT of BTC tumors and suggests these miRs as predictors for positive outcome. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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8 pages, 430 KiB

Open AccessReview

The Telomerase-Derived Anticancer Peptide Vaccine GV1001 as an Extracellular Heat Shock Protein-Mediated Cell-Penetrating Peptide

by Hong Kim^1,†, Eun-Hye Seo^2,†

, Seung-Hyun Lee²

and Bum-Joon Kim^1,*

¹ Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea

² Department of Microbiology, Konkuk University School of Medicine, Seoul 05030, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2054; https://doi.org/10.3390/ijms17122054 - 7 Dec 2016

Cited by 42 | Viewed by 6746

Abstract

Cell-penetrating peptides (CPPs), which can facilitate the transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular delivery of macromolecules. GV1001, a peptide derived from a reverse-transcriptase subunit of telomerase (hTERT) and developed as a vaccine against [...] Read more.

Cell-penetrating peptides (CPPs), which can facilitate the transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular delivery of macromolecules. GV1001, a peptide derived from a reverse-transcriptase subunit of telomerase (hTERT) and developed as a vaccine against various cancers, reportedly has unexpected CPP properties. Unlike typical CPPs, such as the HIV-1 TAT peptide, GV1001 enabled the cytosolic delivery of macromolecules such as proteins, DNA and siRNA via extracellular heat shock protein 90 (eHSP90) and 70 (eHSP70) complexes. The eHSP-GV1001 interaction may have biological effects in addition to its cytosolic delivery function. GV1001 was originally designed as a major histocompatibility complex (MHC) class II-binding cancer epitope, but its CPP properties may contribute to its strong anti-cancer immune response relative to other telomerase peptide-based vaccines. Cell signaling via eHSP-GV1001 binding may lead to unexpected biological effects, such as direct anticancer or antiviral effects. In this review, we focus on the CPP effects of GV1001 bound to eHSP90 and eHSP70. Full article

(This article belongs to the Special Issue Cell-Penetrating Peptides 2016)

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22 pages, 1161 KiB

Open AccessReview

Pathophysiological Significance of Store-Operated Calcium Entry in Megakaryocyte Function: Opening New Paths for Understanding the Role of Calcium in Thrombopoiesis

by Christian A. Di Buduo^1,2, Alessandra Balduini^1,2,3,* and Francesco Moccia^4,*

¹ Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy

² Laboratory of Biotechnology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Matteo Foundation, 27100 Pavia, Italy

³ Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA

⁴ Laboratory of General Physiology, Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy

Int. J. Mol. Sci. 2016, 17(12), 2055; https://doi.org/10.3390/ijms17122055 - 8 Dec 2016

Cited by 11 | Viewed by 8596

Abstract

Store-Operated Calcium Entry (SOCE) is a universal calcium (Ca²⁺) influx mechanism expressed by several different cell types. It is now known that Stromal Interaction Molecule (STIM), the Ca²⁺ sensor of the intracellular compartments, together with Orai and Transient Receptor Potential [...] Read more.

Store-Operated Calcium Entry (SOCE) is a universal calcium (Ca²⁺) influx mechanism expressed by several different cell types. It is now known that Stromal Interaction Molecule (STIM), the Ca²⁺ sensor of the intracellular compartments, together with Orai and Transient Receptor Potential Canonical (TRPC), the subunits of Ca²⁺ permeable channels on the plasma membrane, cooperate in regulating multiple cellular functions as diverse as proliferation, differentiation, migration, gene expression, and many others, depending on the cell type. In particular, a growing body of evidences suggests that a tight control of SOCE expression and function is achieved by megakaryocytes along their route from hematopoietic stem cells to platelet production. This review attempts to provide an overview about the SOCE dynamics in megakaryocyte development, with a focus on most recent findings related to its involvement in physiological and pathological thrombopoiesis. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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11 pages, 3791 KiB

Open AccessArticle

Hepatoprotective Effect of Cuscuta campestris Yunck. Whole Plant on Carbon Tetrachloride Induced Chronic Liver Injury in Mice

by Wen-Huang Peng^1,†, Yi-Wen Chen^1,†, Meng-Shiou Lee¹, Wen-Te Chang¹, Jen-Chieh Tsai², Ying-Chih Lin³ and Ming-Kuem Lin^1,4,*

¹ Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Biopharmaceutical and Food Sciences, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan

² Department of Health and Nutrition Biotechnology, College of Health Science, Asia University, 500 Liufeng Rd., Wufeng, Taichung 41354, Taiwan

³ Department of Optometry, Jen-Teh Junior College of Medicine, Nursing and Management, 79-9 Sha-Luen Hu Xi-Zhou Li Hou-Loung Town, Miaoli 356, Taiwan

⁴ Graduate Institute of Biotechnology, National Chung Hsing University, 145 Xingda Rd., South Dist., Taichung 402, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2056; https://doi.org/10.3390/ijms17122056 - 7 Dec 2016

Cited by 16 | Viewed by 5920

Abstract

Cuscuta seeds and whole plant have been used to nourish the liver and kidney. This study was aimed to investigate the hepatoprotective activity of the ethanol extract of Cuscuta campestris Yunck. whole plant (CC_EtOH). The hepatoprotective effect of CC_EtOH (20, [...] Read more.

Cuscuta seeds and whole plant have been used to nourish the liver and kidney. This study was aimed to investigate the hepatoprotective activity of the ethanol extract of Cuscuta campestris Yunck. whole plant (CC_EtOH). The hepatoprotective effect of CC_EtOH (20, 100 and 500 mg/kg) was evaluated on carbon tetrachloride (CCl₄)-induced chronic liver injury. Serum alanine aminotransferase, aspartate aminotransferase, triglyceride and cholesterol were measured and the fibrosis was histologically examined. CC_EtOH exhibited a significant inhibition of the increase of serum alanine aminotransferase, aspartate aminotransferase, triglyceride and cholesterol. Histological analyses showed that fibrosis of liver induced by CCl₄ were significantly reduced by CC_EtOH. In addition, 20, 100 and 500 mg/kg of the extract decreased the level of malondialdehyde (MDA) and enhanced the activities of anti-oxidative enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRd) in the liver. We demonstrate that the hepatoprotective mechanisms of CC_EtOH were likely to be associated to the decrease in MDA level by increasing the activities of antioxidant enzymes such as SOD, GPx and GRd. In addition, our findings provide evidence that C. campestris Yunck. whole plant possesses a hepatoprotective activity to ameliorate chronic liver injury. Full article

(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)

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12 pages, 1027 KiB

Open AccessArticle

The Relationship between Serum Bilirubin and Elevated Fibrotic Indices among HBV Carriers: A Cross-Sectional Study of a Chinese Population

by Min Du¹, Shanshan Zhang¹, Lin Xiao¹, Yanyan Xu¹, Peiyi Liu¹, Yuhan Tang¹, Sheng Wei², Mingyou Xing³, Xiaoping Miao^2,*,† and Ping Yao^1,*,†

¹ Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety and the Ministry of Education (MOE) Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan 430030, China

² Department of Epidemiology and Biostatistics and the Ministry of Education (MOE) Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan 430030, China

³ Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan 430030, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2057; https://doi.org/10.3390/ijms17122057 - 9 Dec 2016

Cited by 15 | Viewed by 10239

Abstract

The study probed the association between bilirubin and hepatitis B virus (HBV) infection and progression. A cross-sectional analysis of 28,500 middle aged and elderly Chinese participants was performed to analyze the differences of bilirubin in terms of hepatitis B surface antigen (HBsAg) positive [...] Read more.

The study probed the association between bilirubin and hepatitis B virus (HBV) infection and progression. A cross-sectional analysis of 28,500 middle aged and elderly Chinese participants was performed to analyze the differences of bilirubin in terms of hepatitis B surface antigen (HBsAg) positive or negative and the correlation between bilirubin and severity of hepatic fibrosis estimated by non-invasive indices. Bilirubin was significantly higher in the HBsAg (+) group than the HBsAg (−) group. Higher bilirubin levels were consistently associated with elevated liver fibrosis indices among HBsAg carriers. Compared with quartile 1 of total bilirubin (TBil), the multivariable-adjusted ORs (95% CIs) for elevated fibrosis indices of quartile 4 were 2.24 (95% CIs, 1.57–3.21) estimated by fibrosis 4 score (FIB-4) and 2.22 (95% CIs, 1.60–3.08) estimated by aspartate transaminase to platelet ratio index (APRI). In addition, direct bilirubin (DBil) had a stronger association with elevated liver fibrosis indices than did indirect bilirubin (IBil). Furthermore, the relationship between DBil and elevated fibrosis indices was more robust among participants who were female, overweight or had central fat distribution. These findings suggested that bilirubin levels, especially DBil, were independently associated with an increased risk of increased fibrosis indices. Full article

(This article belongs to the Special Issue Hepatitis Virus Infection and Research)

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13 pages, 1858 KiB

Open AccessArticle

Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic Neural Progenitor Cells

by Xinjin Wang, Mengling Yan, Lina Zhao, Qing Wu, Chunhua Wu, Xiuli Chang^* and Zhijun Zhou

School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China

Int. J. Mol. Sci. 2016, 17(12), 2058; https://doi.org/10.3390/ijms17122058 - 9 Dec 2016

Cited by 22 | Viewed by 4425

Abstract

Mitochondria are essential organelles and important targets for environmental pollutants. The detection of mitochondrial biogenesis and generation of reactive oxygen species (ROS) and p53 levels following low-dose methylmercury (MeHg) exposure could expand our understanding of underlying mechanisms. Here, the sensitivity of immortalized human [...] Read more.

Mitochondria are essential organelles and important targets for environmental pollutants. The detection of mitochondrial biogenesis and generation of reactive oxygen species (ROS) and p53 levels following low-dose methylmercury (MeHg) exposure could expand our understanding of underlying mechanisms. Here, the sensitivity of immortalized human neural progenitor cells (ihNPCs) upon exposure to MeHg was investigated. We found that MeHg altered cell viability and the number of 5-ethynyl-2′-deoxyuridine (EdU)-positive cells. We also observed that low-dose MeHg exposure increased the mRNA expression of cell cycle regulators. We observed that MeHg induced ROS production in a dose-dependent manner. In addition, mRNA levels of peroxisome-proliferator-activated receptor gammacoactivator-1α (PGC-1α), mitochondrial transcription factor A (TFAM) and p53-controlled ribonucleotide reductase (p53R2) were significantly elevated, which were correlated with the increase of mitochondrial DNA (mtDNA) copy number at a concentration as low as 10 nM. Moreover, we examined the expression of microRNAs (miRNAs) known as regulatory miRNAs of p53 (i.e., miR-30d, miR-1285, miR-25). We found that the expression of these miRNAs was significantly downregulated upon MeHg treatment. Furthermore, the overexpression of miR-25 resulted in significantly reducted p53 protein levels and decreased mRNA expression of genes involved in mitochondrial biogenesis regulation. Taken together, these results demonstrated that MeHg could induce developmental neurotoxicity in ihNPCs through altering mitochondrial functions and the expression of miRNA. Full article

(This article belongs to the Section Molecular Toxicology)

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10 pages, 977 KiB

Open AccessReview

Roles of Erythroid Differentiation Regulator 1 (Erdr1) on Inflammatory Skin Diseases

by Youn Kyung Houh^1,†, Kyung Eun Kim^2,†

, Hyun Jeong Park^3,*,† and Daeho Cho^1,2,*,†

¹ Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea

² Department of Cosmetic Sciences, Sookmyung Women’s University, Seoul 04310, Korea

³ Department of Dermatology, Yeouido St. Mary’s Hospital, The Catholic University of Korea, Seoul 07345, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2059; https://doi.org/10.3390/ijms17122059 - 8 Dec 2016

Cited by 13 | Viewed by 7414

Abstract

Erythroid Differentiation Regulator 1 (Erdr1) is known as a hemoglobin synthesis factor which also regulates cell survival under conditions of stress. In addition, previous studies have revealed the effects of Erdr1 on cancer progression and its negative correlation with interleukin (IL)-18, a pro-inflammatory [...] Read more.

Erythroid Differentiation Regulator 1 (Erdr1) is known as a hemoglobin synthesis factor which also regulates cell survival under conditions of stress. In addition, previous studies have revealed the effects of Erdr1 on cancer progression and its negative correlation with interleukin (IL)-18, a pro-inflammatory cytokine. Based on this evidence, the therapeutic effects of Erdr1 have been demonstrated in several inflammatory skin diseases such as malignant skin cancer, psoriasis, and rosacea. This article reviews the roles of Erdr1 in skin inflammation, suggesting that Erdr1 is a potential therapeutic molecule on inflammatory disorders. Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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19 pages, 4384 KiB

Open AccessArticle

Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer

by Tanja Grimmig¹, Romana Moench¹, Jennifer Kreckel¹, Stephanie Haack¹, Felix Rueckert², Roberta Rehder³, Sudipta Tripathi⁴, Carmen Ribas³, Anil Chandraker⁴, Christoph T. Germer⁵, Martin Gasser^5,† and Ana Maria Waaga-Gasser^1,4,*,†

¹ Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany

² Surgical Clinic Mannheim, University of Heidelberg, 68167 Mannheim, Germany

³ Medical School, Evangelic Faculty of Paraná, 80730-000 Curitiba, Brazil

⁴ Brigham and Women’s Hospital, Transplant Research Center, Harvard Medical School, Boston, MA 02115, USA

⁵ Department of Surgery I, University of Wuerzburg, 97080 Wuerzburg, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2060; https://doi.org/10.3390/ijms17122060 - 8 Dec 2016

Cited by 55 | Viewed by 7184

Abstract

Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of [...] Read more.

Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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18 pages, 3481 KiB

Open AccessArticle

Functional Divergence of Poplar Histidine-Aspartate Kinase HK1 Paralogs in Response to Osmotic Stress

by François Héricourt¹, Françoise Chefdor¹, Inès Djeghdir¹, Mélanie Larcher¹, Florent Lafontaine², Vincent Courdavault²

, Daniel Auguin¹, Franck Coste³, Christiane Depierreux¹, Mirai Tanigawa⁴, Tatsuya Maeda⁴, Gaëlle Glévarec² and Sabine Carpin^1,*

¹ Laboratoire de Biologie des Ligneux et des Grandes Cultures (LBLGC), Université d’Orléans, INRA, USC1328, 45067 Orléans, France

² Biomolécules et Biotechnologies Végétales (BBV), EA 2106, Université François Rabelais de Tours, 31 avenue Monge, 37200 Tours, France

³ Centre de Biophysique Moléculaire (CBM), CNRS, 45071 Orléans, France

⁴ Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

Int. J. Mol. Sci. 2016, 17(12), 2061; https://doi.org/10.3390/ijms17122061 - 8 Dec 2016

Cited by 21 | Viewed by 6051

Abstract

Previous works have shown the existence of protein partnerships belonging to a MultiStep Phosphorelay (MSP) in Populus putatively involved in osmosensing. This study is focused on the identification of a histidine-aspartate kinase, HK1b, paralog of HK1a. The characterization of HK1b showed its ability [...] Read more.

Previous works have shown the existence of protein partnerships belonging to a MultiStep Phosphorelay (MSP) in Populus putatively involved in osmosensing. This study is focused on the identification of a histidine-aspartate kinase, HK1b, paralog of HK1a. The characterization of HK1b showed its ability to homo- and hetero-dimerize and to interact with a few Histidine-containing Phosphotransfer (HPt) proteins, suggesting a preferential partnership in poplar MSP linked to drought perception. Furthermore, determinants for interaction specificity between HK1a/1b and HPts were studied by mutagenesis analysis, identifying amino acids involved in this specificity. The HK1b expression analysis in different poplar organs revealed its co-expression with three HPts, reinforcing the hypothesis of partnership participation in the MSP in planta. Moreover, HK1b was shown to act as an osmosensor with kinase activity in a functional complementation assay of an osmosensor deficient yeast strain. These results revealed that HK1b showed a different behaviour for canonical phosphorylation of histidine and aspartate residues. These phosphorylation modularities of canonical amino acids could explain the improved osmosensor performances observed in yeast. As conserved duplicates reflect the selective pressures imposed by the environmental requirements on the species, our results emphasize the importance of HK1 gene duplication in poplar adaptation to drought stress. Full article

(This article belongs to the Section Molecular Plant Sciences)

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12 pages, 454 KiB

Open AccessArticle

Association of Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms with Osteoporotic Vertebral Compression Fractures (OVCFs) in Postmenopausal Women

by Jung Oh Kim^1,†, Soo Hong Han^2,†, Yeon Ho Lee², Tae Keun Ahn², Jae Joon Lim³, Young Sun Chung⁴, Dong Eun Shin², Woo Sik Lee⁵, In Bo Han^3,*

and Nam Keun Kim^1,*

¹ Department of Biomedical Science, College of Life Science, CHA University, Seongnam 13488, Korea

² Department of Orthopedics, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea

³ Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea

⁴ Department of Neurosurgery, Konkuk University Chungju Hospital, Chungju 27376, Korea

⁵ Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul 06135, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2062; https://doi.org/10.3390/ijms17122062 - 9 Dec 2016

Cited by 10 | Viewed by 4260

Abstract

Osteoporosis and osteoporotic fractures are strongly associated with mortality and morbidity, both in developing and developed countries. Menopause accelerates bone loss due to estrogen deficiency and age-related linear bone loss. We investigated plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms in postmenopausal women [...] Read more.

Osteoporosis and osteoporotic fractures are strongly associated with mortality and morbidity, both in developing and developed countries. Menopause accelerates bone loss due to estrogen deficiency and age-related linear bone loss. We investigated plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms in postmenopausal women with osteoporotic vertebral compression fractures (OVCFs). In this case-control study, 355 postmenopausal women were genotyped for the presence of PAI-1 gene polymorphisms −844A > G, −675 4G > 5G, 43G > A, 9785A > G, and 11053T > G. Genetic polymorphisms of PAI-1 were analyzed by the polymerization chain reaction restriction fragment length polymorphism assay, and their association with disease status and folate and homocysteine levels was determined in 158 OVCF patients and 197 control subjects. The PAI-1 −675 5G5G (adjusted odds ratio (AOR), 3.302; p = 0.017) and 43GA + AA (AOR, 2.087; p = 0.042) genotype frequencies showed significant association with the increased prevalence of OVCFs in postmenopausal women. In addition, we performed gene–environment interaction studies and demonstrated an association between PAI-1 gene polymorphisms and OVCF prevalence. Our novel finding is the identification of several PAI-1 genetic variants that increase susceptibility to OVCF. Our findings suggest that polymorphisms in PAI-1 may contribute to OVCF, and that they can be developed as biomarkers for evaluating OVCF risk. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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16 pages, 820 KiB

Open AccessReview

The Roles of Autophagy and the Inflammasome during Environmental Stress-Triggered Skin Inflammation

by Rong-Jane Chen^1,†

, Yu-Hsuan Lee^1,†, Ya-Ling Yeh¹, Ying-Jan Wang^1,2,3,4,* and Bour-Jr Wang^1,5,6,*

¹ Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan

² Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan

³ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan

⁴ Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei 110, Taiwan

⁵ Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan 70428, Taiwan

⁶ Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2063; https://doi.org/10.3390/ijms17122063 - 9 Dec 2016

Cited by 47 | Viewed by 9164

Abstract

Inflammatory skin diseases are the most common problem in dermatology. The induction of skin inflammation by environmental stressors such as ultraviolet radiation (UVR), hexavalent chromium (Cr(VI)) and TiO₂/ZnO/Ag nanoparticles (NPs) has been demonstrated previously. Recent studies have indicated that the inflammasome [...] Read more.

Inflammatory skin diseases are the most common problem in dermatology. The induction of skin inflammation by environmental stressors such as ultraviolet radiation (UVR), hexavalent chromium (Cr(VI)) and TiO₂/ZnO/Ag nanoparticles (NPs) has been demonstrated previously. Recent studies have indicated that the inflammasome is often wrongly activated by these environmental irritants, thus inducing massive inflammation and resulting in the development of inflammatory diseases. The regulation of the inflammasome with respect to skin inflammation is complex and is still not completely understood. Autophagy, an intracellular degradation system that is associated with the maintenance of cellular homeostasis, plays a key role in inflammasome inactivation. As a housekeeping pathway, cells utilize autophagy to maintain the homeostasis of the organ structure and function when exposed to environmental stressors. However, only a few studies have examined the effect of autophagy and/or the inflammasome on skin pathogenesis. Here we review recent findings regarding the involvement of autophagy and inflammasome activation during skin inflammation. We posit that autophagy induction is a novel mechanism inter-modulating environmental stressor-induced skin inflammation. We also attempt to highlight the role of the inflammasome and the possible underlying mechanisms and pathways reflecting the pathogenesis of skin inflammation induced by UVR, Cr(VI) and TiO₂/ZnO/Ag NPs. A more profound understanding about the crosstalk between autophagy and the inflammasome will contribute to the development of prevention and intervention strategies against human skin disease. Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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18 pages, 2131 KiB

Open AccessArticle

PEDF Inhibits the Activation of NLRP3 Inflammasome in Hypoxia Cardiomyocytes through PEDF Receptor/Phospholipase A2

by Zhongxin Zhou^1,†, Zhu Wang^1,†, Qiuhua Guan^2,†, Fan Qiu¹, Yufeng Li¹, Zhiwei Liu³, Hao Zhang¹, Hongyan Dong^3,* and Zhongming Zhang^1,*

¹ Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou 221006, China

² Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou 221004, China

³ Research Facility Center for Morphology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2064; https://doi.org/10.3390/ijms17122064 - 12 Dec 2016

Cited by 42 | Viewed by 8019

Abstract

The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome has been linked to sterile inflammation, which is involved in ischemic injury in myocardial cells. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein with many biological activities, such as anti-inflammatory, antioxidant and anti-angiogenic [...] Read more.

The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome has been linked to sterile inflammation, which is involved in ischemic injury in myocardial cells. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein with many biological activities, such as anti-inflammatory, antioxidant and anti-angiogenic properties. However, it is not known whether and how PEDF acts to regulate the activation of the NLRP3 inflammasome in cardiomyocytes. In the present study, we used the neonatal cardiomyocytes models of ischemia-like conditions to evaluate the mitochondrial fission and the activation of the NLRP3 inflammasome. We also determined the mechanism by which PEDF inhibits hypoxia-induced activation of the NLRP3 inflammasome. We found that PEDF decreased the activation of the NLRP3 inflammasome in neonatal cardiomyocytes through pigment epithelial-derived factor receptor/calcium-independent phospholipase A2 (PEDFR/iPLA2). Meanwhile, PEDF reduced Drp1-induced mitochondrial fission and mitochondrial fission-induced mitochondrial DNA (mtDNA), as well as mitochondrial reactive oxygen species (mtROS) release into cytosol through PEDFR/iPLA2. We also found that PEDF inhibited mitochondrial fission-induced NLRP3 inflammasome activation. Furthermore, previous research has found that endogenous cytosolic mtDNA and mtROS can serve as activators of NLRP3 inflammasome activity. Therefore, we hypothesized that PEDF can protect against hypoxia-induced activation of the NLRP3 inflammasome by inhibiting mitochondrial fission though PEDFR/iPLA2. Full article

(This article belongs to the Section Biochemistry)

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18 pages, 3459 KiB

Open AccessArticle

Procyanidins Mitigate Osteoarthritis Pathogenesis by, at Least in Part, Suppressing Vascular Endothelial Growth Factor Signaling

by Angela Wang^1,2, Daniel J. Leong^1,2, Zhiyong He^1,2, Lin Xu^1,2, Lidi Liu^1,2, Sun Jin Kim¹, David M. Hirsh¹, John A. Hardin¹, Neil J. Cobelli¹ and Hui B. Sun^1,2,*

¹ Departments of Orthopedic Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA

² Departments of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA

Int. J. Mol. Sci. 2016, 17(12), 2065; https://doi.org/10.3390/ijms17122065 - 9 Dec 2016

Cited by 15 | Viewed by 7207

Abstract

Procyanidins are a family of plant metabolites that have been suggested to mitigate osteoarthritis pathogenesis in mice. However, the underlying mechanism is largely unknown. This study aimed to determine whether procyanidins mitigate traumatic injury-induced osteoarthritis (OA) disease progression, and whether procyanidins exert a [...] Read more.

Procyanidins are a family of plant metabolites that have been suggested to mitigate osteoarthritis pathogenesis in mice. However, the underlying mechanism is largely unknown. This study aimed to determine whether procyanidins mitigate traumatic injury-induced osteoarthritis (OA) disease progression, and whether procyanidins exert a chondroprotective effect by, at least in part, suppressing vascular endothelial growth factor signaling. Procyanidins (extracts from pine bark), orally administered to mice subjected to surgery for destabilization of the medial meniscus, significantly slowed OA disease progression. Real-time polymerase chain reaction revealed that procyanidin treatment reduced expression of vascular endothelial growth factor and effectors in OA pathogenesis that are regulated by vascular endothelial growth factor. Procyanidin-suppressed vascular endothelial growth factor expression was correlated with reduced phosphorylation of vascular endothelial growth factor receptor 2 in human OA primary chondrocytes. Moreover, components of procyanidins, procyanidin B2 and procyanidin B3 exerted effects similar to those of total procyanidins in mitigating the OA-related gene expression profile in the primary culture of human OA chondrocytes in the presence of vascular endothelial growth factor. Together, these findings suggest procyanidins mitigate OA pathogenesis, which is mediated, at least in part, by suppressing vascular endothelial growth factor signaling. Full article

(This article belongs to the Special Issue The Mechanism of Action of Food Components in Disease Prevention)

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17 pages, 4932 KiB

Open AccessArticle

Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich’s Ataxia Transgenic Mice

by Lucía Calatrava-Ferreras^1,†, Rafael Gonzalo-Gobernado^1,†

, Diana Reimers¹, Antonio S. Herranz¹, María J. Casarejos¹, Adriano Jiménez-Escrig², Javier Regadera³, Juan Velasco-Martín³, Manuela Vallejo-Muñoz¹, Juan José Díaz-Gil^1,‡ and Eulalia Bazán^1,*

¹ Service of Neurobiology, Ramón y Cajal Institute for Health Research (IRYCIS), 28034 Madrid, Spain

² Service of Neurology, Ramón y Cajal Hospital, 28034 Madrid, Spain

³ Departamento de Anatomía, Histología y Neurociencia Facultad de Medicina Universidad Autónoma de Madrid, 28400 Madrid, Spain

^† These authors contributed equally to this work.

^‡ Deceased on 4 November 2016.

Int. J. Mol. Sci. 2016, 17(12), 2066; https://doi.org/10.3390/ijms17122066 - 9 Dec 2016

Cited by 6 | Viewed by 6543

Abstract

Friedreich’s ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that [...] Read more.

Friedreich’s ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that includes neurological and non-neurological damage. Recent studies have proven the effectiveness of neurotrophic factors in a number of neurodegenerative diseases. Therefore, we intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 μg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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12 pages, 3417 KiB

Open AccessArticle

Crystal Structure of a Putative Cytochrome P450 Alkane Hydroxylase (CYP153D17) from Sphingomonas sp. PAMC 26605 and Its Conformational Substrate Binding

by Chang Woo Lee^1,2,†, Sang-Cheol Yu^3,†, Joo-Ho Lee^3,†, Sun-Ha Park¹, Hyun Park^1,2, Tae-Jin Oh^3,* and Jun Hyuck Lee^1,2,*

¹ Unit of Polar Genomics, Korea Polar Research Institute, Incheon 406-840, Korea

² Department of Polar Sciences, University of Science and Technology, Incheon 406-840, Korea

³ Department of BT-Convergent Pharmaceutical Engineering, Sunmoon University, Asansi 336-708, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2067; https://doi.org/10.3390/ijms17122067 - 9 Dec 2016

Cited by 8 | Viewed by 5273

Abstract

Enzymatic alkane hydroxylation reactions are useful for producing pharmaceutical and agricultural chemical intermediates from hydrocarbons. Several cytochrome P450 enzymes catalyze the regio- and stereo-specific hydroxylation of alkanes. We evaluated the substrate binding of a putative CYP alkane hydroxylase (CYP153D17) from the bacterium Sphingomonas [...] Read more.

Enzymatic alkane hydroxylation reactions are useful for producing pharmaceutical and agricultural chemical intermediates from hydrocarbons. Several cytochrome P450 enzymes catalyze the regio- and stereo-specific hydroxylation of alkanes. We evaluated the substrate binding of a putative CYP alkane hydroxylase (CYP153D17) from the bacterium Sphingomonas sp. PAMC 26605. Substrate affinities to C10–C12 n-alkanes and C10–C14 fatty acids with K_d values varied from 0.42 to 0.59 μM. A longer alkane (C12) bound more strongly than a shorter alkane (C10), while shorter fatty acids (C10, capric acid; C12, lauric acid) bound more strongly than a longer fatty acid (C14, myristic acid). These data displayed a broad substrate specificity of CYP153D17, hence it was named as a putative CYP alkane hydroxylase. Moreover, the crystal structure of CYP153D17 was determined at 3.1 Å resolution. This is the first study to provide structural information for the CYP153D family. Structural analysis showed that a co-purified alkane-like compound bound near the active-site heme group. The alkane-like substrate is in the hydrophobic pocket containing Thr74, Met90, Ala175, Ile240, Leu241, Val244, Leu292, Met295, and Phe393. Comparison with other CYP structures suggested that conformational changes in the β1–β2, α3–α4, and α6–α7 connecting loop are important for incorporating the long hydrophobic alkane-like substrate. These results improve the understanding of the catalytic mechanism of CYP153D17 and provide valuable information for future protein engineering studies. Full article

(This article belongs to the Section Biochemistry)

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19 pages, 3201 KiB

Open AccessReview

Non-Canonical Cell Death Induced by p53

by Atul Ranjan and Tomoo Iwakuma^*

Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA

Int. J. Mol. Sci. 2016, 17(12), 2068; https://doi.org/10.3390/ijms17122068 - 9 Dec 2016

Cited by 108 | Viewed by 17054

Abstract

Programmed cell death is a vital biological process for multicellular organisms to maintain cellular homeostasis, which is regulated in a complex manner. Over the past several years, apart from apoptosis, which is the principal mechanism of caspase-dependent cell death, research on non-apoptotic forms [...] Read more.

Programmed cell death is a vital biological process for multicellular organisms to maintain cellular homeostasis, which is regulated in a complex manner. Over the past several years, apart from apoptosis, which is the principal mechanism of caspase-dependent cell death, research on non-apoptotic forms of programmed cell death has gained momentum. p53 is a well characterized tumor suppressor that controls cell proliferation and apoptosis and has also been linked to non-apoptotic, non-canonical cell death mechanisms. p53 impacts these non-canonical forms of cell death through transcriptional regulation of its downstream targets, as well as direct interactions with key players involved in these mechanisms, in a cell type- or tissue context-dependent manner. In this review article, we summarize and discuss the involvement of p53 in several non-canonical modes of cell death, including caspase-independent apoptosis (CIA), ferroptosis, necroptosis, autophagic cell death, mitotic catastrophe, paraptosis, and pyroptosis, as well as its role in efferocytosis which is the process of clearing dead or dying cells. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

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15 pages, 5238 KiB

Open AccessReview

Glucose-6-Phosphate Dehydrogenase: Update and Analysis of New Mutations around the World

by Saúl Gómez-Manzo^1,*

, Jaime Marcial-Quino^2,*, America Vanoye-Carlo³, Hugo Serrano-Posada⁴

, Daniel Ortega-Cuellar⁵

, Abigail González-Valdez⁶, Rosa Angélica Castillo-Rodríguez²

, Beatriz Hernández-Ochoa⁷

, Edgar Sierra-Palacios⁸, Eduardo Rodríguez-Bustamante⁹ and Roberto Arreguin-Espinosa⁹

¹ Laboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Secretaría de Salud 04530, Mexico

² Consejo Nacional de Ciencia y Tecnología (CONACYT), Instituto Nacional de Pediatría, Secretaría de Salud 04530, Mexico

³ Laboratorio de Neurociencias, Instituto Nacional de Pediatría, Secretaría de Salud 04530, Mexico

⁴ Consejo Nacional de Ciencia y Tecnología (CONACYT), Laboratorio de Bioingeniería, Universidad de Colima, Colima 28400, Mexico

⁵ Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, Secretaría de Salud 04530, Mexico

⁶ Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico

⁷ Laboratorio de Inmunoquímica, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico

⁸ Colegio de Ciencias y Humanidades, Plantel Casa Libertad, Universidad Autónoma de la Ciudad de México, Mexico City 09620, Mexico

⁹ Departamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Mexico City 04510, Mexico

Int. J. Mol. Sci. 2016, 17(12), 2069; https://doi.org/10.3390/ijms17122069 - 9 Dec 2016

Cited by 166 | Viewed by 26177

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) is a key regulatory enzyme in the pentose phosphate pathway which produces nicotinamide adenine dinucleotide phosphate (NADPH) to maintain an adequate reducing environment in the cells and is especially important in red blood cells (RBC). Given its central role in [...] Read more.

Glucose-6-phosphate dehydrogenase (G6PD) is a key regulatory enzyme in the pentose phosphate pathway which produces nicotinamide adenine dinucleotide phosphate (NADPH) to maintain an adequate reducing environment in the cells and is especially important in red blood cells (RBC). Given its central role in the regulation of redox state, it is understandable that mutations in the gene encoding G6PD can cause deficiency of the protein activity leading to clinical manifestations such as neonatal jaundice and acute hemolytic anemia. Recently, an extensive review has been published about variants in the g6pd gene; recognizing 186 mutations. In this work, we review the state of the art in G6PD deficiency, describing 217 mutations in the g6pd gene; we also compile information about 31 new mutations, 16 that were not recognized and 15 more that have recently been reported. In order to get a better picture of the effects of new described mutations in g6pd gene, we locate the point mutations in the solved three-dimensional structure of the human G6PD protein. We found that class I mutations have the most deleterious effects on the structure and stability of the protein. Full article

(This article belongs to the Collection Computational, Structural and Spectroscopic Studies of Enzyme Mechanisms, Inhibition and Dynamics)

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14 pages, 1373 KiB

Open AccessArticle

Chromosomal Microarray Analysis of Consecutive Individuals with Autism Spectrum Disorders Using an Ultra-High Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

by Karen S. Ho^1,2,*

, E. Robert Wassman¹, Adrianne L. Baxter¹, Charles H. Hensel¹, Megan M. Martin¹, Aparna Prasad¹, Hope Twede¹, Rena J. Vanzo¹

and Merlin G. Butler³

¹ Lineagen, Inc., Salt Lake City, UT 84109, USA

² Department of Pediatrics, University of Utah, Salt Lake City, UT 84132, USA

³ Departments of Psychiatry, Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, UT 66160, USA

Int. J. Mol. Sci. 2016, 17(12), 2070; https://doi.org/10.3390/ijms17122070 - 9 Dec 2016

Cited by 61 | Viewed by 10575

Abstract

Copy number variants (CNVs) detected by chromosomal microarray analysis (CMA) significantly contribute to understanding the etiology of autism spectrum disorder (ASD) and other related conditions. In recognition of the value of CMA testing and its impact on medical management, CMA is in medical [...] Read more.

Copy number variants (CNVs) detected by chromosomal microarray analysis (CMA) significantly contribute to understanding the etiology of autism spectrum disorder (ASD) and other related conditions. In recognition of the value of CMA testing and its impact on medical management, CMA is in medical guidelines as a first-tier test in the evaluation of children with these disorders. As CMA becomes adopted into routine care for these patients, it becomes increasingly important to report these clinical findings. This study summarizes the results of over 4 years of CMA testing by a CLIA-certified clinical testing laboratory. Using a 2.8 million probe microarray optimized for the detection of CNVs associated with neurodevelopmental disorders, we report an overall CNV detection rate of 28.1% in 10,351 consecutive patients, which rises to nearly 33% in cases without ASD, with only developmental delay/intellectual disability (DD/ID) and/or multiple congenital anomalies (MCA). The overall detection rate for individuals with ASD is also significant at 24.4%. The detection rate and pathogenic yield of CMA vary significantly with the indications for testing, age, and gender, as well as the specialty of the ordering doctor. We note discrete differences in the most common recurrent CNVs found in individuals with or without a diagnosis of ASD. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders 2017)

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11 pages, 4351 KiB

Open AccessArticle

Pioglitazone, a Peroxisome Proliferator-Activated Receptor γ Agonist, Suppresses Rat Prostate Carcinogenesis

by Shugo Suzuki^1,2,*, Yukiko Mori¹, Aya Nagano¹, Aya Naiki-Ito¹

, Hiroyuki Kato¹, Yuko Nagayasu¹, Mizuho Kobayashi¹, Toshiya Kuno¹ and Satoru Takahashi¹

¹ Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan

² Pathology Division, Nagoya City East Medical Center, Nagoya 464-8547, Japan

Int. J. Mol. Sci. 2016, 17(12), 2071; https://doi.org/10.3390/ijms17122071 - 10 Dec 2016

Cited by 25 | Viewed by 4773

Abstract

Pioglitazone (PGZ), a peroxisome proliferator-activated receptor γ agonist, which is known as a type 2 diabetes drug, inhibits cell proliferation in various cancer cell lines, including prostate carcinomas. This study focused on the effect of PGZ on prostate carcinogenesis using a transgenic rat [...] Read more.

Pioglitazone (PGZ), a peroxisome proliferator-activated receptor γ agonist, which is known as a type 2 diabetes drug, inhibits cell proliferation in various cancer cell lines, including prostate carcinomas. This study focused on the effect of PGZ on prostate carcinogenesis using a transgenic rat for an adenocarcinoma of prostate (TRAP) model. Adenocarcinoma lesions as a percentage of overall lesions in the ventral prostate were significantly reduced by PGZ treatment in a dose-dependent manner. The number of adenocarcinomas per given area in the ventral prostate was also significantly reduced by PGZ treatment. The Ki67 labeling index in the ventral prostate was also significantly reduced by PGZ. Decreased cyclin D1 expression in addition to the inactivation of both p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)κB were detected in PGZ-treated TRAP rat groups. In LNCaP, a human androgen-dependent prostate cancer cell line, PGZ also inhibited cyclin D1 expression and the activation of both p38 MAPK and NFκB. The suppression of cultured cell growth was mainly regulated by the NFκB pathway as detected using specific inhibitors in both LNCaP and PC3, a human androgen-independent prostate cancer cell line. These data suggest that PGZ possesses a chemopreventive potential for prostate cancer. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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16 pages, 232 KiB

Open AccessReview

Nutrimetabolomics: An Update on Analytical Approaches to Investigate the Role of Plant-Based Foods and Their Bioactive Compounds in Non-Communicable Chronic Diseases

by Oscar Daniel Rangel-Huerta¹

and Angel Gil^1,2,*

¹ Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology “José Mataix”, Center for Biomedical Research, University of Granada, 18100 Granada, Spain

² Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Ciberobn, 28029 Madrid, Spain

Int. J. Mol. Sci. 2016, 17(12), 2072; https://doi.org/10.3390/ijms17122072 - 9 Dec 2016

Cited by 32 | Viewed by 6496

Abstract

Metabolomics is the study of low-weight molecules present in biological samples such as biofluids, tissue/cellular extracts, and culture media. Metabolomics research is increasing, and at the moment, it has several applications in the food science and nutrition fields. In the present review, we [...] Read more.

Metabolomics is the study of low-weight molecules present in biological samples such as biofluids, tissue/cellular extracts, and culture media. Metabolomics research is increasing, and at the moment, it has several applications in the food science and nutrition fields. In the present review, we provide an update about the most frequently used methodologies and metabolomic platforms in these areas. Also, we discuss different metabolomic strategies regarding the discovery of new bioactive compounds (BACs) in plant-based foods. Furthermore, we review the existing literature related to the use of metabolomics to investigate the potential protective role of BACs in the prevention and treatment of non-communicable chronic diseases, namely cardiovascular disease, diabetes, and cancer. Full article

(This article belongs to the Special Issue Lipidomics and Glycomics: New Advances in Food Science and Nutrition)

16 pages, 548 KiB

Open AccessReview

Influence of Tyrosine Kinase Inhibitors on Hypertension and Nephrotoxicity in Metastatic Renal Cell Cancer Patients

by Aleksandra Semeniuk-Wojtaś, Arkadiusz Lubas^*

, Rafał Stec, Cezary Szczylik and Stanisław Niemczyk

Military Institute of Medicine Szaserów, 128 Street, 04-141 Warsaw, Poland

Int. J. Mol. Sci. 2016, 17(12), 2073; https://doi.org/10.3390/ijms17122073 - 9 Dec 2016

Cited by 39 | Viewed by 7156

Abstract

Renal cell carcinoma (RCC) is one of the most common kidney malignancies. An upgraded comprehension of the molecular biology implicated in the development of cancer has stimulated an increase in research and development of innovative antitumor therapies. The aim of the study was [...] Read more.

Renal cell carcinoma (RCC) is one of the most common kidney malignancies. An upgraded comprehension of the molecular biology implicated in the development of cancer has stimulated an increase in research and development of innovative antitumor therapies. The aim of the study was to analyze the medical literature for hypertension and renal toxicities as the adverse events of the vascular endothelial growth factor (VEGF) signaling pathway inhibitor (anti-VEGF) therapy. Relevant studies were identified in PubMed and ClinicalTrials.gov databases. Eligible studies were phase III and IV prospective clinical trials, meta-analyses and retrospective studies that had described events of hypertension or nephrotoxicity for patients who received anti-VEGF therapy. A total of 48 studies were included in the systematic review. The incidence of any grade hypertension ranged from 17% to 49.6%. Proteinuria and increased creatinine levels were ascertained in 8% to 73% and 5% to 65.6% of patients, respectively. These adverse events are most often mild in severity but may sometimes lead to treatment discontinuation. Nephrotoxicity and hypertension are related to multiple mechanisms; however, one of the main disturbances in those patients is VEGF inhibition. There is a significant risk of developing hypertension and renal dysfunction among patients receiving anti-VEGF treatment; however, there is also some evidence that these side effects may be used as biomarkers of response to antiangiogenic agents. Full article

(This article belongs to the Special Issue Nephrotoxicity)

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11 pages, 937 KiB

Open AccessReview

p53 as a Regulator of Lipid Metabolism in Cancer

by Alejandro Parrales and Tomoo Iwakuma^*

Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA

Int. J. Mol. Sci. 2016, 17(12), 2074; https://doi.org/10.3390/ijms17122074 - 10 Dec 2016

Cited by 81 | Viewed by 11018

Abstract

Enhanced proliferation and survival are common features of cancer cells. Cancer cells are metabolically reprogrammed which aids in their survival in nutrient-poor environments. Indeed, changes in metabolism of glucose and glutamine are essential for tumor progression. Thus, metabolic reprogramming is now well accepted [...] Read more.

Enhanced proliferation and survival are common features of cancer cells. Cancer cells are metabolically reprogrammed which aids in their survival in nutrient-poor environments. Indeed, changes in metabolism of glucose and glutamine are essential for tumor progression. Thus, metabolic reprogramming is now well accepted as a hallmark of cancer. Recent findings suggest that reprogramming of lipid metabolism also occurs in cancer cells, since lipids are used for biosynthesis of membranes, post-translational modifications, second messengers for signal transduction, and as a source of energy during nutrient deprivation. The tumor suppressor p53 is a transcription factor that controls the expression of proteins involved in cell cycle arrest, DNA repair, apoptosis, and senescence. p53 also regulates cellular metabolism, which appears to play a key role in its tumor suppressive activities. In this review article, we summarize non-canonical functions of wild-type and mutant p53 on lipid metabolism and discuss their association with cancer progression. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

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18 pages, 3383 KiB

Open AccessArticle

Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction

by Remi Neviere^1,2,*, Florian Delguste², Arthur Durand^2,3, Jocelyn Inamo⁴, Eric Boulanger² and Sebastien Preau^2,3

¹ Département de Physiologie, Faculté de Médecine, Université Lille, 1 Place de Verdun, F-59000 Lille CEDEX 59045, France

² INSERM LIRIC U995/Team “Glycation: From Inflammation to Aging”, Université Lille, F-59000 Lille, France

³ Pôle Réanimation Médicale, CHU Lille, Bd Pr Leclercq, F-59000 Lille, France

⁴ Département de Cardiologie, CHU Martinique, Faculté de Médecine, Université des Antilles, F-97200 Fort de France, France

Int. J. Mol. Sci. 2016, 17(12), 2075; https://doi.org/10.3390/ijms17122075 - 10 Dec 2016

Cited by 34 | Viewed by 7165

Abstract

Adrenergic receptors couple to Gs-proteins leading to transmembrane adenylyl cyclase activation and cytosolic cyclic adenosine monophosphate (cAMP) production. Cyclic AMP is also produced in the mitochondrial matrix, where it regulates respiration through protein kinase A (PKA)-dependent phosphorylation of respiratory chain complexes. We hypothesized [...] Read more.

Adrenergic receptors couple to Gs-proteins leading to transmembrane adenylyl cyclase activation and cytosolic cyclic adenosine monophosphate (cAMP) production. Cyclic AMP is also produced in the mitochondrial matrix, where it regulates respiration through protein kinase A (PKA)-dependent phosphorylation of respiratory chain complexes. We hypothesized that a blunted mitochondrial cAMP-PKA pathway would participate in sepsis-induced heart dysfunction. Adult male mice were subjected to intra-abdominal sepsis. Mitochondrial respiration of cardiac fibers and myocardial contractile performance were evaluated in response to 8Br-cAMP, PKA inhibition (H89), soluble adenylyl cyclase inhibition (KH7), and phosphodiesterase inhibition (IBMX; BAY60-7550). Adenosine diphosphate (ADP)-stimulated respiratory rates of cardiac fibers were reduced in septic mice. Compared with controls, stimulatory effects of 8Br-cAMP on respiration rates were enhanced in septic fibers, whereas inhibitory effects of H89 were reduced. Ser-58 phosphorylation of cytochrome c oxidase subunit IV-1 was reduced in septic hearts. In vitro, incubation of septic cardiac fibers with BAY60-7550 increased respiratory control ratio and improved cardiac MVO₂ efficiency in isolated septic heart. In vivo, BAY60-7550 pre-treatment of septic mice have limited impact on myocardial function. Mitochondrial cAMP-PKA signaling is impaired in the septic myocardium. PDE2 phosphodiesterase inhibition by BAY60-7550 improves mitochondrial respiration and cardiac MVO₂ efficiency in septic mice. Full article

(This article belongs to the Special Issue Mitochondria Crosstalks with other Organelles in Pathophysiology)

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21 pages, 8994 KiB

Open AccessArticle

Structural Characterization of Oligochitosan Elicitor from Fusarium sambucinum and Its Elicitation of Defensive Responses in Zanthoxylum bungeanum

by Peiqin Li^1,*, Robert J. Linhardt^2,3

and Zhimin Cao¹

¹ Department of Forest Pathology, College of Forestry, Northwest A&F University, Yangling 712100, Shaanxi, China

² Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA

³ Department of Chemistry and Chemical Biology, Chemical and Biological Engineering, and Biology and Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA

Int. J. Mol. Sci. 2016, 17(12), 2076; https://doi.org/10.3390/ijms17122076 - 10 Dec 2016

Cited by 30 | Viewed by 5302

Abstract

Oligosaccharide elicitors from pathogens have been shown to play major roles in host plant defense responses involving plant–pathogen chemoperception and interaction. In the present study, chitosan and oligochitosan were prepared from pathogen Fusarium sambucinum, and their effects on infection of Zanthoxylum bungeanum [...] Read more.

Oligosaccharide elicitors from pathogens have been shown to play major roles in host plant defense responses involving plant–pathogen chemoperception and interaction. In the present study, chitosan and oligochitosan were prepared from pathogen Fusarium sambucinum, and their effects on infection of Zanthoxylum bungeanum stems were investigated. Results showed that oligochitosan inhibited the infection of the pathogen, and that the oligochitosan fraction with a degree of polymerization (DP) between 5 and 6 showed the optimal effect. Oligochitosan DP5 was purified from fraction DP5-6 and was structurally characterized using electrospray ionization mass spectrometry, Fourier transform infrared spectroscopy, and nuclear magnetic resonance spectroscopy. Oligochitosan DP5 showed significant inhibition against the infection of the pathogenic fungi on host plant stems. An investigation of the mechanism underlying this effect showed that oligochitosan DP5 increased the activities of defensive enzymes and accumulation of phenolics in host Z. bungeanum. These results suggest that oligochitosan from pathogenic fungi can mediate the infection of host plants with a pathogen by acting as an elicitor that triggers the defense system of a plant. This information will be valuable for further exploration of the interactions between the pathogen F. sambucinum and host plant Z. bungeanum. Full article

(This article belongs to the Section Molecular Plant Sciences)

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17 pages, 2622 KiB

Open AccessArticle

Differential Cytotoxic Potential of Silver Nanoparticles in Human Ovarian Cancer Cells and Ovarian Cancer Stem Cells

by Yun-Jung Choi¹, Jung-Hyun Park¹, Jae Woong Han¹, Eunsu Kim¹, Oh Jae-Wook¹, Seung Yoon Lee², Jin-Hoi Kim¹

and Sangiliyandi Gurunathan^1,*

¹ Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 143-701, Korea

² Swine Consulting Group, HanByol Farm Tech, Gyeonggi 463-785, Korea

Int. J. Mol. Sci. 2016, 17(12), 2077; https://doi.org/10.3390/ijms17122077 - 12 Dec 2016

Cited by 36 | Viewed by 6448

Abstract

The cancer stem cell (CSC) hypothesis postulates that cancer cells are composed of hierarchically-organized subpopulations of cells with distinct phenotypes and tumorigenic capacities. As a result, CSCs have been suggested as a source of disease recurrence. Recently, silver nanoparticles (AgNPs) have been used [...] Read more.

The cancer stem cell (CSC) hypothesis postulates that cancer cells are composed of hierarchically-organized subpopulations of cells with distinct phenotypes and tumorigenic capacities. As a result, CSCs have been suggested as a source of disease recurrence. Recently, silver nanoparticles (AgNPs) have been used as antimicrobial, disinfectant, and antitumor agents. However, there is no study reporting the effects of AgNPs on ovarian cancer stem cells (OvCSCs). In this study, we investigated the cytotoxic effects of AgNPs and their mechanism of causing cell death in A2780 (human ovarian cancer cells) and OvCSCs derived from A2780. In order to examine these effects, OvCSCs were isolated and characterized using positive CSC markers including aldehyde dehydrogenase (ALDH) and CD133 by fluorescence-activated cell sorting (FACS). The anticancer properties of the AgNPs were evaluated by assessing cell viability, leakage of lactate dehydrogenase (LDH), reactive oxygen species (ROS), and mitochondrial membrane potential (mt-MP). The inhibitory effect of AgNPs on the growth of ovarian cancer cells and OvCSCs was evaluated using a clonogenic assay. Following 1–2 weeks of incubation with the AgNPs, the numbers of A2780 (bulk cells) and ALDH⁺/CD133⁺ colonies were significantly reduced. The expression of apoptotic and anti-apoptotic genes was measured by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Our observations showed that treatment with AgNPs resulted in severe cytotoxicity in both ovarian cancer cells and OvCSCs. In particular, AgNPs showed significant cytotoxic potential in ALDH⁺/CD133⁺ subpopulations of cells compared with other subpopulation of cells and also human ovarian cancer cells (bulk cells). These findings suggest that AgNPs can be utilized in the development of novel nanotherapeutic molecules for the treatment of ovarian cancers by specific targeting of the ALDH⁺/CD133⁺ subpopulation of cells. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles)

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14 pages, 613 KiB

Open AccessReview

Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies

by Mingyi Zhao^1,†, Ping Zhu^2,†, Masayuki Fujino^3,4, Jian Zhuang², Huiming Guo², IdrisAhmed Sheikh¹, Lingling Zhao^1,* and Xiao-Kang Li^1,3,*

¹ Department of Pediatrics, the Third Xiangya Hospital, Central South University, Changsha 410006, China

² Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510100, China

³ National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan

⁴ National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2078; https://doi.org/10.3390/ijms17122078 - 10 Dec 2016

Cited by 172 | Viewed by 11445

Abstract

Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of morbidity and mortality in neonates. Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply [...] Read more.

Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of morbidity and mortality in neonates. Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply and is, thus, extremely sensitive to hypoxia. Strong evidence indicates that oxidative stress plays an important role in pathogenesis and progression. Following hypoxia and ischemia, reactive oxygen species (ROS) production rapidly increases and overwhelms antioxidant defenses. A large excess of ROS will directly modify or degenerate cellular macromolecules, such as membranes, proteins, lipids, and DNA, and lead to a cascading inflammatory response, and protease secretion. These derivatives are involved in a complex interplay of multiple pathways (e.g., inflammation, apoptosis, autophagy, and necrosis) which finally lead to brain injury. In this review, we highlight the molecular mechanism for oxidative stress in HIE, summarize current research on therapeutic strategies utilized in combating oxidative stress, and try to explore novel potential clinical approaches. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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14 pages, 495 KiB

Open AccessReview

Development of Cell-SELEX Technology and Its Application in Cancer Diagnosis and Therapy

by Man Chen^1,2,†, Yuanyuan Yu^1,3,†, Feng Jiang^1,2,4, Junwei Zhou¹, Yongshu Li¹, Chao Liang¹, Lei Dang¹, Aiping Lu^1,2,3,* and Ge Zhang^1,2,3,*

¹ Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China

² Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology, Haimen 226100, China

³ Shenzhen Lab of Comninatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and Continuing Education, Shenzhen 518000, China

⁴ The State Key Laboratory Base of Novel Functional Materials and Preparation Science, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2079; https://doi.org/10.3390/ijms17122079 - 10 Dec 2016

Cited by 95 | Viewed by 11824

Abstract

SELEX (systematic evolution of ligands by exponential enrichment) is a process involving the progressive isolation of high selective ssDNA/RNA from a combinatorial single-stranded oligonucleotide library through repeated rounds of binding, partitioning and amplification. SELEX-derived single-stranded DNA/RNA molecules, called aptamers, are selected against a [...] Read more.

SELEX (systematic evolution of ligands by exponential enrichment) is a process involving the progressive isolation of high selective ssDNA/RNA from a combinatorial single-stranded oligonucleotide library through repeated rounds of binding, partitioning and amplification. SELEX-derived single-stranded DNA/RNA molecules, called aptamers, are selected against a wide range of targets, including purified proteins, live cells, tissues, microorganisms, small molecules and so on. With the development of SELEX technology over the last two decades, various modified SELEX processes have been arisen. A majority of aptamers are selected against purified proteins through traditional SELEX. Unfortunately, more and more evidence showed aptamers selected against purified membrane proteins failed to recognize their targets in live cells. Cell-SELEX could develop aptamers against a particular target cell line to discriminate this cell line from others. Therefore, cell-SELEX has been widely used to select aptamers for the application of both diagnosis and therapy of various diseases, especially for cancer. In this review, the advantages and limitations of cell-SELEX and SELEX against purified protein will be compared. Various modified cell-SELEX techniques will be summarized, and application of cell-SELEX in cancer diagnosis and therapy will be discussed. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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18 pages, 676 KiB

Open AccessReview

Therapeutic Resistance in Acute Myeloid Leukemia: The Role of Non-Coding RNAs

by Armin Zebisch^1,*, Stefan Hatzl¹, Martin Pichler²

, Albert Wölfler¹ and Heinz Sill¹

¹ Division of Hematology, Medical University of Graz, 8036 Graz, Austria

² Division of Oncology, Medical University of Graz, 8036 Graz, Austria

Int. J. Mol. Sci. 2016, 17(12), 2080; https://doi.org/10.3390/ijms17122080 - 10 Dec 2016

Cited by 59 | Viewed by 7759

Abstract

Acute myeloid leukemia (AML) is caused by malignant transformation of hematopoietic stem or progenitor cells and displays the most frequent acute leukemia in adults. Although some patients can be cured with high dose chemotherapy and allogeneic hematopoietic stem cell transplantation, the majority still [...] Read more.

Acute myeloid leukemia (AML) is caused by malignant transformation of hematopoietic stem or progenitor cells and displays the most frequent acute leukemia in adults. Although some patients can be cured with high dose chemotherapy and allogeneic hematopoietic stem cell transplantation, the majority still succumbs to chemoresistant disease. Micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNA fragments and act as key players in the regulation of both physiologic and pathologic gene expression profiles. Aberrant expression of various non-coding RNAs proved to be of seminal importance in the pathogenesis of AML, as well in the development of resistance to chemotherapy. In this review, we discuss the role of miRNAs and lncRNAs with respect to sensitivity and resistance to treatment regimens currently used in AML and provide an outlook on potential therapeutic targets emerging thereof. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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11 pages, 1740 KiB

Open AccessArticle

Antithymocyte Globulin Induces a Tolerogenic Phenotype in Human Dendritic Cells

by Tobias Roider¹, Michael Katzfuß¹, Carina Matos¹, Katrin Singer¹, Kathrin Renner¹, Peter J. Oefner², Katja Dettmer-Wilde², Wolfgang Herr¹, Ernst Holler¹, Marina Kreutz¹ and Katrin Peter^1,*

¹ Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany

² Institute of Functional Genomics, University of Regensburg, Am BioPark 9, 93053 Regensburg, Germany

Int. J. Mol. Sci. 2016, 17(12), 2081; https://doi.org/10.3390/ijms17122081 - 11 Dec 2016

Cited by 14 | Viewed by 5714

Abstract

Antithymocyte globulin (ATG) is used in the prevention of graft-versus-host disease during allogeneic hematopoietic stem cell transplantation. It is generally accepted that ATG mediates its immunosuppressive effect primarily via depletion of T cells. Here, we analyzed the impact of ATG-Fresenius (now Grafalon^® [...] Read more.

Antithymocyte globulin (ATG) is used in the prevention of graft-versus-host disease during allogeneic hematopoietic stem cell transplantation. It is generally accepted that ATG mediates its immunosuppressive effect primarily via depletion of T cells. Here, we analyzed the impact of ATG-Fresenius (now Grafalon^®) on human monocyte-derived dendritic cells (DC). ATG induced a semi-mature phenotype in DC with significantly reduced expression of CD14, increased expression of HLA-DR, and intermediate expression of CD54, CD80, CD83, and CD86. ATG-DC showed an increase in IL-10 secretion but no IL-12 production. In line with this tolerogenic phenotype, ATG caused a significant induction of indoleamine 2,3-dioxygenase expression and a concomitant increase in levels of tryptophan metabolites in the supernatants of DC. Further, ATG-DC did not induce the proliferation of allogeneic T cells in a mixed lymphocyte reaction but actively suppressed the T cell proliferation induced by mature DC. These data suggest that besides its well-known effect on T cells, ATG modulates the phenotype of DC in a tolerogenic way, which might constitute an essential part of its immunosuppressive action in vivo. Full article

(This article belongs to the Special Issue Advances in Cell Transplantation)

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26 pages, 516 KiB

Open AccessReview

Pathophysiology of Non Alcoholic Fatty Liver Disease

by Salvatore Petta¹, Amalia Gastaldelli²

, Eleni Rebelos³, Elisabetta Bugianesi⁴, Piergiorgio Messa⁵

, Luca Miele⁶

, Gianluca Svegliati-Baroni⁷, Luca Valenti⁸

and Ferruccio Bonino^3,9,*

¹ Gastroenterology, Di.Bi.M.I.S Policlinic Paolo Giaccone Hospital, University of Palermo, PC 90127, Palermo, Italy

² Cardiometabolic Risk Unit—Institute of Clinical Physiology, CNR, PC 56124, Pisa, Italy

³ Department of Clinical and Experimental Medicine, University of Pisa, PC 56122, Pisa, Italy

⁴ Gastroenterology and Hepatology, Department of Medical Sciences, Città della, Salute e della Scienza di Torino Hospital, University of Turin, PC 10122, Turin, Italy

⁵ Department of Nephrology, Urology and Renal Transplant—Fondazione IRCCS Ca’, Granda, PC 20122 Milano, Italy

⁶ Institute of Internal Medicine, Gastroenterology and Liver Diseases Unit, Fondazione Policlinico Gemelli, Catholic University of Rome, PC 00168, Rome, Italy

⁷ Department of Gastroenterology 1 and Obesity 2, Polytechnic University of Marche, PC 60121, Ancona, Italy

⁸ Metabolic Liver Diseases—Università degli Studi Milano-Fondazione IRCCS Ca’, Granda via F Sforza 35, PC 20122 Milano, Italy

⁹ Institute for Health, PC 53042, Chianciano Terme, Italy

Int. J. Mol. Sci. 2016, 17(12), 2082; https://doi.org/10.3390/ijms17122082 - 11 Dec 2016

Cited by 136 | Viewed by 27018

Abstract

The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of [...] Read more.

The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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17 pages, 3108 KiB

Open AccessArticle

Down-Regulation of Ca²⁺-Activated K⁺ Channel K_Ca1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists

by Anowara Khatun¹, Mayu Fujimoto¹, Hiroaki Kito¹, Satomi Niwa¹, Takayoshi Suzuki² and Susumu Ohya^1,*

¹ Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan

² Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 403-8334, Japan

Int. J. Mol. Sci. 2016, 17(12), 2083; https://doi.org/10.3390/ijms17122083 - 11 Dec 2016

Cited by 15 | Viewed by 5959

Abstract

Vitamin D (VD) reduces the risk of breast cancer and improves disease prognoses. Potential VD analogs are being developed as therapeutic agents for breast cancer treatments. The large-conductance Ca²⁺-activated K⁺ channel K_Ca1.1 regulates intracellular Ca²⁺ signaling pathways [...] Read more.

Vitamin D (VD) reduces the risk of breast cancer and improves disease prognoses. Potential VD analogs are being developed as therapeutic agents for breast cancer treatments. The large-conductance Ca²⁺-activated K⁺ channel K_Ca1.1 regulates intracellular Ca²⁺ signaling pathways and is associated with high grade tumors and poor prognoses. In the present study, we examined the effects of treatments with VD receptor (VDR) agonists on the expression and activity of K_Ca1.1 in human breast cancer MDA-MB-453 cells using real-time PCR, Western blotting, flow cytometry, and voltage-sensitive dye imaging. Treatments with VDR agonists for 72 h markedly decreased the expression levels of K_Ca1.1 transcripts and proteins in MDA-MB-453 cells, resulting in the significant inhibition of depolarization responses induced by paxilline, a specific K_Ca1.1 blocker. The specific proteasome inhibitor MG132 suppressed VDR agonist-induced decreases in K_Ca1.1 protein expression. These results suggest that K_Ca1.1 is a new downstream target of VDR signaling and the down-regulation of K_Ca1.1 through the transcriptional repression of K_Ca1.1 and enhancement of K_Ca1.1 protein degradation contribute, at least partly, to the antiproliferative effects of VDR agonists in breast cancer cells. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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16 pages, 1494 KiB

Open AccessArticle

In Vitro Antitumor Active Gold(I) Triphenylphosphane Complexes Containing 7-Azaindoles

by Pavel Štarha¹

, Zdeněk Trávníček^1,*

, Bohuslav Drahoš¹ and Zdeněk Dvořák²

¹ Department of Inorganic Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University Olomouc, 17. listopadu 12, 771 46 Olomouc, Czech Republic

² Department of Cell Biology and Genetics, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 783 71 Olomouc, Czech Republic

Int. J. Mol. Sci. 2016, 17(12), 2084; https://doi.org/10.3390/ijms17122084 - 11 Dec 2016

Cited by 11 | Viewed by 4799

Abstract

A series of gold(I) complexes of the general composition [Au(naza)(PPh₃)] (1–8) was prepared and thoroughly characterized (e.g., electrospray ionization (ESI) mass spectrometry and multinuclear nuclear magnetic resonance (NMR) spectroscopy). The N1-deprotonated anions of 7-azaindole [...] Read more.

A series of gold(I) complexes of the general composition [Au(naza)(PPh₃)] (1–8) was prepared and thoroughly characterized (e.g., electrospray ionization (ESI) mass spectrometry and multinuclear nuclear magnetic resonance (NMR) spectroscopy). The N1-deprotonated anions of 7-azaindole or its derivatives (naza) are coordinated to the metal centre through the N1 atom of their pyrrole ring, as proved by a single crystal X-ray analysis of the complexes [Au(3I5Braza)(PPh₃)] (7) and [Au(2Me4Claza)(PPh₃)]·½H₂O (8′). The in vitrocytotoxicity of the complexes 1–8 was studied against both the cisplatin-sensitive and -resistant variants of the A2780 human ovarian carcinoma cell line, as well as against the MRC-5 human normal fibroblast cell line. The complexes 4, 5, and 8, containing deprotonated 3-iodo-7-azaindole, 5-bromo-7-azaindole, and 2-methyl-4-chloro-7-azaindole (2Me4Claza), respectively, showed significantly higher potency (IC₅₀ = 2.8–3.5 µM) than cisplatin (IC₅₀ = 20.3 µM) against the A2780 cells and markedly lower effect towards the MRC-5 non-cancerous cells (IC₅₀ = 26.0–29.2 µM), as compared with the mentioned A2780 cancer cells. The results of the flow cytometric studies of the A2780 cell cycle perturbations revealed a G₂-cell cycle phase arrest of the cells treated by the representative complexes 1 and 5, which is indicative of a different mechanism of action from cisplatin (induced S-cell cycle phase arrest). The stability of the representative complex 8 in the water-containing solution as well as its ability to interact with the reduced glutathione, cysteine and bovine serum albumin was also studied using ¹H and ³¹P-NMR spectroscopy (studied in the 50% DMF-d₇/50% D₂O mixture) and ESI+ mass spectrometry (studied in the 50% DMF/50% H₂O mixture); DMF = dimethylformamide. The obtained results are indicative for the release of the N-donor azaindole-based ligand in the presence of the used biomolecules. Full article

(This article belongs to the Section Bioinorganic Chemistry)

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14 pages, 629 KiB

Open AccessReview

Inflammation in Chronic Wounds

by Ruilong Zhao¹, Helena Liang¹, Elizabeth Clarke², Christopher Jackson¹

and Meilang Xue^1,*

¹ Sutton Arthritis Research Laboratory, Kolling Institute of Medical Research, University of Sydney, NSW 2065, Australia

² Murray Maxwell Biomechanics Laboratory, Kolling Institute of Medical Research, University of Sydney, NSW 2065, Australia

Int. J. Mol. Sci. 2016, 17(12), 2085; https://doi.org/10.3390/ijms17122085 - 11 Dec 2016

Cited by 790 | Viewed by 32730

Abstract

Non-healing chronic wounds present a major biological, psychological, social, and financial burden on both individual patients and the broader health system. Pathologically extensive inflammation plays a major role in the disruption of the normal healing cascade. The causes of chronic wounds (venous, arterial, [...] Read more.

Non-healing chronic wounds present a major biological, psychological, social, and financial burden on both individual patients and the broader health system. Pathologically extensive inflammation plays a major role in the disruption of the normal healing cascade. The causes of chronic wounds (venous, arterial, pressure, and diabetic ulcers) can be examined through a juxtaposition of normal healing and the rogue inflammatory response created by the common components within chronic wounds (ageing, hypoxia, ischaemia-reperfusion injury, and bacterial colonisation). Wound bed care through debridement, dressings, and antibiotics currently form the basic mode of treatment. Despite recent setbacks, pharmaceutical adjuncts form an interesting area of research. Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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62 pages, 7776 KiB

Open AccessReview

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

by Mark Preciados¹, Changwon Yoo² and Deodutta Roy^1,*

¹ Department of Environmental & Occupational Health, Florida International University, Miami, FL 33199, USA

² Department of Biostatistics, Florida International University, Miami, FL 33199, USA

Int. J. Mol. Sci. 2016, 17(12), 2086; https://doi.org/10.3390/ijms17122086 - 13 Dec 2016

Cited by 81 | Viewed by 17110

Abstract

During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are [...] Read more.

During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese. Also we discuss the brain health effects associated from exposure to EEDs including the promotion of neurodegeneration, protection against neurodegeneration, and involvement in various neurological deficits; changes in rearing behavior, locomotion, anxiety, learning difficulties, memory issues, and neuronal abnormalities. The effects of EEDs on the brain are varied during the entire life span and far-reaching with many different mechanisms. To understand endocrine disrupting chemicals mechanisms, we use bioinformatics, molecular, and epidemiologic approaches. Through those approaches, we learn how the effects of EEDs on the brain go beyond known mechanism to disrupt the circulatory and neural estrogen function and estrogen-mediated signaling. Effects on EEDs-modified estrogen and nuclear respiratory factor 1 (NRF1) signaling genes with exposure to natural estrogen, pharmacological estrogen-ethinyl estradiol, PCBs, phthalates, BPA, and metalloestrogens are presented here. Bioinformatics analysis of gene-EEDs interactions and brain disease associations identified hundreds of genes that were altered by exposure to estrogen, phthalate, PCBs, BPA or metalloestrogens. Many genes modified by EEDs are common targets of both 17 β-estradiol (E2) and NRF1. Some of these genes are involved with brain diseases, such as Alzheimer’s Disease (AD), Parkinson’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorder, and Brain Neoplasms. For example, the search of enriched pathways showed that top ten E2 interacting genes in AD—APOE, APP, ATP5A1, CALM1, CASP3, GSK3B, IL1B, MAPT, PSEN2 and TNF—underlie the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD pathway. With AD, the six E2-responsive genes are NRF1 target genes: APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1. These genes are also responsive to the following EEDs: ethinyl estradiol (APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1), BPA (APBB2, EIF2S1, ENO1, MAPT, and PAXIP1), dibutyl phthalate (DPYSL2, EIF2S1, and ENO1), diethylhexyl phthalate (DPYSL2 and MAPT). To validate findings from Comparative Toxicogenomics Database (CTD) curated data, we used Bayesian network (BN) analysis on microarray data of AD patients. We observed that both gender and NRF1 were associated with AD. The female NRF1 gene network is completely different from male human AD patients. AD-associated NRF1 target genes—APLP1, APP, GRIN1, GRIN2B, MAPT, PSEN2, PEN2, and IDE—are also regulated by E2. NRF1 regulates targets genes with diverse functions, including cell growth, apoptosis/autophagy, mitochondrial biogenesis, genomic instability, neurogenesis, neuroplasticity, synaptogenesis, and senescence. By activating or repressing the genes involved in cell proliferation, growth suppression, DNA damage/repair, apoptosis/autophagy, angiogenesis, estrogen signaling, neurogenesis, synaptogenesis, and senescence, and inducing a wide range of DNA damage, genomic instability and DNA methylation and transcriptional repression, NRF1 may act as a major regulator of EEDs-induced brain health deficits. In summary, estrogenic endocrine disrupting chemicals-modified genes in brain health deficits are part of both estrogen and NRF1 signaling pathways. Our findings suggest that in addition to estrogen signaling, EEDs influencing NRF1 regulated communities of genes across genomic and epigenomic multiple networks may contribute in the development of complex chronic human brain health disorders. Full article

(This article belongs to the Special Issue Gene–Environment Interactions)

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14 pages, 1773 KiB

Open AccessReview

MicroRNAs, DNA Damage Response, and Cancer Treatment

by Mingyang He, Weiwei Zhou, Chuang Li and Mingxiong Guo^*

Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China

Int. J. Mol. Sci. 2016, 17(12), 2087; https://doi.org/10.3390/ijms17122087 - 12 Dec 2016

Cited by 49 | Viewed by 7858

Abstract

As a result of various stresses, lesions caused by DNA-damaging agents occur constantly in each cell of the human body. Generally, DNA damage is recognized and repaired by the DNA damage response (DDR) machinery, and the cells survive. When repair fails, the genomic [...] Read more.

As a result of various stresses, lesions caused by DNA-damaging agents occur constantly in each cell of the human body. Generally, DNA damage is recognized and repaired by the DNA damage response (DDR) machinery, and the cells survive. When repair fails, the genomic integrity of the cell is disrupted—a hallmark of cancer. In addition, the DDR plays a dual role in cancer development and therapy. Cancer radiotherapy and chemotherapy are designed to eliminate cancer cells by inducing DNA damage, which in turn can promote tumorigenesis. Over the past two decades, an increasing number of microRNAs (miRNAs), small noncoding RNAs, have been identified as participating in the processes regulating tumorigenesis and responses to cancer treatment with radiation therapy or genotoxic chemotherapies, by modulating the DDR. The purpose of this review is to summarize the recent findings on how miRNAs regulate the DDR and discuss the therapeutic functions of miRNAs in cancer in the context of DDR regulation. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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13 pages, 7256 KiB

Open AccessArticle

Crystallization of Galectin-8 Linker Reveals Intricate Relationship between the N-terminal Tail and the Linker

by Yunlong Si, Yue Wang, Jin Gao, Chenyang Song, Shiqiong Feng, Yifa Zhou, Guihua Tai and Jiyong Su^*

Jilin Province Key Laboratory on Chemistry and Biology of Natural Drugs in Changbai Mountain, School of Life Sciences, Northeast Normal University, Changchun 130024, China

Int. J. Mol. Sci. 2016, 17(12), 2088; https://doi.org/10.3390/ijms17122088 - 12 Dec 2016

Cited by 25 | Viewed by 5357

Abstract

Galectin-8 (Gal-8) plays a significant role in normal immunological function as well as in cancer. This lectin contains two carbohydrate recognition domains (CRD) connected by a peptide linker. The N-terminal CRD determines ligand binding specificity, whereas the linker has been proposed to regulate [...] Read more.

Galectin-8 (Gal-8) plays a significant role in normal immunological function as well as in cancer. This lectin contains two carbohydrate recognition domains (CRD) connected by a peptide linker. The N-terminal CRD determines ligand binding specificity, whereas the linker has been proposed to regulate overall Gal-8 function, including multimerization and biological activity. Here, we crystallized the Gal-8 N-terminal CRD with the peptide linker using a crystallization condition that contains Ni²⁺. The Ni²⁺ ion was found to be complexed between two CRDs via crystal packing contacts. The coordination between Ni²⁺ and Asp25 plays an indirect role in determining the structure of β-strand F0 and in influencing the linker conformation which could not be defined due to its dynamic nature. The linker was also shortened in situ and crystallized under a different condition, leading to a higher resolution structure refined to 1.08 Å. This crystal structure allowed definition of a short portion of the linker interacting with the Gal-8 N-terminal tail via ionic interactions and hydrogen bonds. Observation of two Gal-8 N-terminal CRD structures implies that the N-terminal tail and the linker may influence each other’s conformation. In addition, under specific crystallization conditions, glycerol could replace lactose and was observed at the carbohydrate binding site. However, glycerol did not show inhibition activity in hemagglutination assay. Full article

(This article belongs to the Special Issue Molecular Recognition of Carbohydrates)

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16 pages, 2356 KiB

Open AccessArticle

Using CRISPR/Cas9-Mediated GLA Gene Knockout as an In Vitro Drug Screening Model for Fabry Disease

by Hui-Yung Song^1,†

, Huai-Chih Chiang^2,†, Wei-Lien Tseng², Ping Wu², Chian-Shiu Chien², Hsin-Bang Leu^2,3,4, Yi-Ping Yang², Mong-Lien Wang²

, Yuh-Jyh Jong⁵, Chung-Hsuan Chen⁶, Wen-Chung Yu^3,4,* and Shih-Hwa Chiou^1,2,3,7

¹ Institute of Pharmacology, National Yang-Ming University, Taipei 11221, Taiwan

² Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan

³ School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan

⁴ Division of Cardiology & Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan

⁵ Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

⁶ Genomics Research Center, Academia Sinica, Taipei 11574, Taiwan

⁷ Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2089; https://doi.org/10.3390/ijms17122089 - 13 Dec 2016

Cited by 22 | Viewed by 9868

Abstract

The CRISPR/Cas9 Genome-editing system has revealed promising potential for generating gene mutation, deletion, and correction in human cells. Application of this powerful tool in Fabry disease (FD), however, still needs to be explored. Enzyme replacement therapy (ERT), a regular administration of recombinant human [...] Read more.

The CRISPR/Cas9 Genome-editing system has revealed promising potential for generating gene mutation, deletion, and correction in human cells. Application of this powerful tool in Fabry disease (FD), however, still needs to be explored. Enzyme replacement therapy (ERT), a regular administration of recombinant human α Gal A (rhα-GLA), is a currently available and effective treatment to clear the accumulated Gb3 in FD patients. However, the short half-life of rhα-GLA in human body limits its application. Moreover, lack of an appropriate in vitro disease model restricted the high-throughput screening of drugs for improving ERT efficacy. Therefore, it is worth establishing a large-expanded in vitro FD model for screening potential candidates, which can enhance and prolong ERT potency. Using CRISPR/Cas9-mediated gene knockout of GLA in HEK-293T cells, we generated GLA-null cells to investigate rhα-GLA cellular pharmacokinetics. The half-life of administrated rhα-GLA was around 24 h in GLA-null cells; co-administration of proteasome inhibitor MG132 and rhα-GLA significantly restored the GLA enzyme activity by two-fold compared with rhα-GLA alone. Furthermore, co-treatment of rhα-GLA/MG132 in patient-derived fibroblasts increased Gb3 clearance by 30%, compared with rhα-GLA treatment alone. Collectively, the CRISPR/Cas9-mediated GLA-knockout HEK-293T cells provide an in vitro FD model for evaluating the intracellular pharmacokinetics of the rhα-GLA as well as for screening candidates to prolong rhα-GLA potency. Using this model, we demonstrated that MG132 prolongs rhα-GLA half-life and enhanced Gb3 clearance, shedding light on the direction of enhancing ERT efficacy in FD treatment. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Novel Concepts, Therapeutic Aspects and Beyond)

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19 pages, 2237 KiB

Open AccessArticle

Rat Aquaporin-5 Is pH-Gated Induced by Phosphorylation and Is Implicated in Oxidative Stress

by Claudia Rodrigues^1,2,†

, Andreia Filipa Mósca^1,2,†

, Ana Paula Martins^1,2, Tatiana Nobre^1,2, Catarina Prista³, Fernando Antunes⁴

, Ana Cipak Gasparovic⁵

and Graça Soveral^1,2,*

¹ Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal

² Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal

³ Linking Landscape, Environment, Agriculture and Food, Instituto Superior de Agronomia, Universidade de Lisboa, 1349-017 Lisboa, Portugal

⁴ Centro de Química e Bioquímica e Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal

⁵ Rudjer Boskovic Institute, HR 10000 Zagreb, Croatia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2090; https://doi.org/10.3390/ijms17122090 - 13 Dec 2016

Cited by 62 | Viewed by 6976

Abstract

Aquaporin-5 (AQP5) is a membrane water channel widely distributed in human tissues that was found up-regulated in different tumors and considered implicated in carcinogenesis in different organs and systems. Despite its wide distribution pattern and physiological importance, AQP5 short-term regulation was not reported [...] Read more.

Aquaporin-5 (AQP5) is a membrane water channel widely distributed in human tissues that was found up-regulated in different tumors and considered implicated in carcinogenesis in different organs and systems. Despite its wide distribution pattern and physiological importance, AQP5 short-term regulation was not reported and mechanisms underlying its involvement in cancer are not well defined. In this work, we expressed rat AQP5 in yeast and investigated mechanisms of gating, as well as AQP5’s ability to facilitate H₂O₂ plasma membrane diffusion. We found that AQP5 can be gated by extracellular pH in a phosphorylation-dependent manner, with higher activity at physiological pH 7.4. Moreover, similar to other mammalian AQPs, AQP5 is able to increase extracellular H₂O₂ influx and to affect oxidative cell response with dual effects: whereas in acute oxidative stress conditions AQP5 induces an initial higher sensitivity, in chronic stress AQP5 expressing cells show improved cell survival and resistance. Our findings support the involvement of AQP5 in oxidative stress and suggest AQP5 modulation by phosphorylation as a novel tool for therapeutics. Full article

(This article belongs to the Special Issue Aquaporin)

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11 pages, 791 KiB

Open AccessArticle

Transcriptome of Cultured Lung Fibroblasts in Idiopathic Pulmonary Fibrosis: Meta-Analysis of Publically Available Microarray Datasets Reveals Repression of Inflammation and Immunity Pathways

by Laurent Plantier^1,2,3,*, Hélène Renaud⁴, Renaud Respaud^1,2,5

, Sylvain Marchand-Adam^1,2,3 and Bruno Crestani^4,6,7

¹ Centre d’Étude des Pathologies Respiratoires-CEPR, Institut National de la Santé et de la Recherche Médicale-INSERM, Unité Mixte de Recherche-UMR1100, Labex Mabimprove, 37000 Tours, France

² Université François Rabelais, 37000 Tours, France

³ Centre Hospitalier Régional Universitaire-CHRU de Tours, Hôpital Bretonneau, Service de Pneumologie et Explorations Fonctionnelles Respiratoires, 37000 Tours, France

⁴ Institut National de la Santé et de la Recherche Médicale-INSERM, Unité Mixte de Recherche-UMR1152, Labex Inflamex, 75018 Paris, France

⁵ Centre Hospitalier Régional Universitaire-CHRU de Tours, Hôpital Trousseau, Service de Pharmacie, 37170 Chambray-les-Tours, France

⁶ Université Paris Diderot, PRES Sorbonne Paris Cité, 75018 Paris, France

⁷ AP-HP, Hôpital Bichat, Service de Pneumologie A, DHU FIRE, 75018 Paris, France

Int. J. Mol. Sci. 2016, 17(12), 2091; https://doi.org/10.3390/ijms17122091 - 13 Dec 2016

Cited by 24 | Viewed by 6627

Abstract

Heritable profibrotic differentiation of lung fibroblasts is a key mechanism of idiopathic pulmonary fibrosis (IPF). Its mechanisms are yet to be fully understood. In this study, individual data from four independent microarray studies comparing the transcriptome of fibroblasts cultured in vitro from normal [...] Read more.

Heritable profibrotic differentiation of lung fibroblasts is a key mechanism of idiopathic pulmonary fibrosis (IPF). Its mechanisms are yet to be fully understood. In this study, individual data from four independent microarray studies comparing the transcriptome of fibroblasts cultured in vitro from normal (total n = 20) and IPF (total n = 20) human lung were compiled for meta-analysis following normalization to z-scores. One hundred and thirteen transcripts were upregulated and 115 were downregulated in IPF fibroblasts using the Significance Analysis of Microrrays algorithm with a false discovery rate of 5%. Downregulated genes were highly enriched for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional classes related to inflammation and immunity such as Defense response to virus, Influenza A, tumor necrosis factor (TNF) mediated signaling pathway, interferon-inducible absent in melanoma2 (AIM2) inflammasome as well as Apoptosis. Although upregulated genes were not enriched for any functional class, select factors known to play key roles in lung fibrogenesis were overexpressed in IPF fibroblasts, most notably connective tissue growth factor (CTGF) and serum response factor (SRF), supporting their role as drivers of IPF. The full data table is available as a supplement. Full article

(This article belongs to the Special Issue Transcriptome Profiling in Human Diseases)

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9 pages, 2365 KiB

Open AccessArticle

Zinc Up-Regulates Insulin Secretion from β Cell-Like Cells Derived from Stem Cells from Human Exfoliated Deciduous Tooth (SHED)

by Gyuyoup Kim¹, Ki-Hyuk Shin² and Eung-Kwon Pae^3,*

¹ School of Medicine Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland, Baltimore, MD 21201, USA

² UCLA School of Dentistry, Los Angeles, CA 90095, USA

³ Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Maryland, Baltimore, MD 21201, USA

Int. J. Mol. Sci. 2016, 17(12), 2092; https://doi.org/10.3390/ijms17122092 - 13 Dec 2016

Cited by 12 | Viewed by 6399

Abstract

Stem cells from human exfoliated deciduous tooth (SHED) offer several advantages over other stem cell sources. Using SHED, we examined the roles of zinc and the zinc uptake transporter ZIP8 (Zrt- and irt-like protein 8) while inducing SHED into insulin secreting β cell-like [...] Read more.

Stem cells from human exfoliated deciduous tooth (SHED) offer several advantages over other stem cell sources. Using SHED, we examined the roles of zinc and the zinc uptake transporter ZIP8 (Zrt- and irt-like protein 8) while inducing SHED into insulin secreting β cell-like stem cells (i.e., SHED-β cells). We observed that ZIP8 expression increased as SHED differentiated into SHED-β cells, and that zinc supplementation at day 10 increased the levels of most pancreatic β cell markers—particularly Insulin and glucose transporter 2 (GLUT2). We confirmed that SHED-β cells produce insulin successfully. In addition, we note that zinc supplementation significantly increases insulin secretion with a significant elevation of ZIP8 transporters in SHED-β cells. We conclude that SHED can be converted into insulin-secreting β cell-like cells as zinc concentration in the cytosol is elevated. Insulin production by SHED-β cells can be regulated via modulation of zinc concentration in the media as ZIP8 expression in the SHED-β cells increases. Full article

(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)

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24 pages, 1123 KiB

Open AccessReview

Regulation of Ketone Body Metabolism and the Role of PPARα

by Maja Grabacka^1,*

, Malgorzata Pierzchalska¹, Matthew Dean² and Krzysztof Reiss²

¹ Department of Food Biotechnology, Faculty of Food Technology, University of Agriculture, ul. Balicka 122, 30-149 Kraków, Poland

² Neurological Cancer Research, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA 70112, USA

Int. J. Mol. Sci. 2016, 17(12), 2093; https://doi.org/10.3390/ijms17122093 - 13 Dec 2016

Cited by 246 | Viewed by 37159

Abstract

Ketogenesis and ketolysis are central metabolic processes activated during the response to fasting. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator activated receptor α (PPARα) is one of the key transcription factors taking part in this regulation. PPARα is [...] Read more.

Ketogenesis and ketolysis are central metabolic processes activated during the response to fasting. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator activated receptor α (PPARα) is one of the key transcription factors taking part in this regulation. PPARα is an important element in the metabolic network, where it participates in signaling driven by the main nutrient sensors, such as AMP-activated protein kinase (AMPK), PPARγ coactivator 1α (PGC-1α), and mammalian (mechanistic) target of rapamycin (mTOR) and induces hormonal mediators, such as fibroblast growth factor 21 (FGF21). This work describes the regulation of ketogenesis and ketolysis in normal and malignant cells and briefly summarizes the positive effects of ketone bodies in various neuropathologic conditions. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

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11 pages, 519 KiB

Open AccessReview

Genetic Variations Involved in Vitamin E Status

by Patrick Borel^*,†

and Charles Desmarchelier^†

¹ NORT, Aix-Marseille Université, INRA, INSERM, 13005 Marseille, France

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2094; https://doi.org/10.3390/ijms17122094 - 13 Dec 2016

Cited by 29 | Viewed by 6946

Abstract

Vitamin E (VE) is the generic term for four tocopherols and four tocotrienols that exhibit the biological activity of α-tocopherol. VE status, which is usually estimated by measuring fasting blood VE concentration, is affected by numerous factors, such as dietary VE intake, VE [...] Read more.

Vitamin E (VE) is the generic term for four tocopherols and four tocotrienols that exhibit the biological activity of α-tocopherol. VE status, which is usually estimated by measuring fasting blood VE concentration, is affected by numerous factors, such as dietary VE intake, VE absorption efficiency, and VE catabolism. Several of these factors are in turn modulated by genetic variations in genes encoding proteins involved in these factors. To identify these genetic variations, two strategies have been used: genome-wide association studies and candidate gene association studies. Each of these strategies has its advantages and its drawbacks, nevertheless they have allowed us to identify a list of single nucleotide polymorphisms associated with fasting blood VE concentration and α-tocopherol bioavailability. However, much work remains to be done to identify, and to replicate in different populations, all the single nucleotide polymorphisms involved, to assess the possible involvement of other kind of genetic variations, e.g., copy number variants and epigenetic modifications, in order to establish a reliable list of genetic variations that will allow us to predict the VE status of an individual by knowing their genotype in these genetic variations. Yet, the potential usefulness of this area of research is exciting with regard to personalized nutrition and for future clinical trials dedicated to assessing the biological effects of the various isoforms of VE. Full article

(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)

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21 pages, 3208 KiB

Open AccessReview

Molecular Mechanisms and Translational Therapies for Human Epidermal Receptor 2 Positive Breast Cancer

by Quanxia Lv^1,2,†, Ziyuan Meng^1,2,†, Yuanyuan Yu^1,†, Feng Jiang^1,2,3, Daogang Guan¹

, Chao Liang¹, Junwei Zhou¹, Aiping Lu^1,2,* and Ge Zhang^1,2,*

¹ Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China

² Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology (IST), Haimen 226133, China

³ The State Key Laboratory Base of Novel Functional Materials and Preparation Science, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2095; https://doi.org/10.3390/ijms17122095 - 14 Dec 2016

Cited by 45 | Viewed by 15872

Abstract

Breast cancer is the second leading cause of cancer death among women. Human epidermal receptor 2 (HER2) positive breast cancer (HER2+ BC) is the most aggressive subtype of breast cancer, with poor prognosis and a high rate of recurrence. About one third of [...] Read more.

Breast cancer is the second leading cause of cancer death among women. Human epidermal receptor 2 (HER2) positive breast cancer (HER2+ BC) is the most aggressive subtype of breast cancer, with poor prognosis and a high rate of recurrence. About one third of breast cancer is HER2+ BC with significantly high expression level of HER2 protein compared to other subtypes. Therefore, HER2 is an important biomarker and an ideal target for developing therapeutic strategies for the treatment HER2+ BC. In this review, HER2 structure and physiological and pathological roles in HER2+ BC are discussed. Two diagnostic tests, immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), for evaluating HER2 expression levels are briefly introduced. The current mainstay targeted therapies for HER2+ BC include monoclonal antibodies, small molecule tyrosine kinase inhibitors, antibody–drug conjugates (ADC) and other emerging anti-HER2 agents. In clinical practice, combination therapies are commonly adopted in order to achieve synergistic drug response. This review will help to better understand the molecular mechanism of HER2+ BC and further facilitate the development of more effective therapeutic strategies against HER2+ BC. Full article

(This article belongs to the Special Issue Molecule- and Cell-Targeted Drug Design and Screening and Identification of Natural Product)

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15 pages, 2194 KiB

Open AccessArticle

Effect of the CRAC Peptide, VLNYYVW, on mPTP Opening in Rat Brain and Liver Mitochondria

by Tamara Azarashvili^1,*, Olga Krestinina¹, Yulia Baburina¹, Irina Odinokova¹, Vladimir Akatov¹, Igor Beletsky¹, John Lemasters² and Vassilios Papadopoulos³

¹ Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya Str., Pushchino, Moscow Region 142290, Russia

² Departments of Drug Discovery & Biomedical Sciences and Biochemistry & Molecular Biology, Medical University of South Carolina, DD504 Drug Discovery Bldg., 70 President St., MSC 140, Charleston, SC 29425, USA

³ The Research Institute of the McGill University Health Center, and Departments of Medicine, Biochemistry, Pharmacology and Therapeutics, McGill University, 2155 Guy Street, Montreal, QC H3H 2R9, Canada

Int. J. Mol. Sci. 2016, 17(12), 2096; https://doi.org/10.3390/ijms17122096 - 13 Dec 2016

Cited by 11 | Viewed by 5161

Abstract

The translocator protein (TSPO; 18 kDa) is a high-affinity cholesterol-binding protein located in the outer membrane of mitochondria. A domain in the C-terminus of TSPO was characterized as the cholesterol recognition/interaction amino acid consensus (CRAC). The ability of the CRAC domain to bind [...] Read more.

The translocator protein (TSPO; 18 kDa) is a high-affinity cholesterol-binding protein located in the outer membrane of mitochondria. A domain in the C-terminus of TSPO was characterized as the cholesterol recognition/interaction amino acid consensus (CRAC). The ability of the CRAC domain to bind to cholesterol led us to hypothesize that this peptide may participate in the regulation of mitochondrial membrane permeability. Herein, we report the effect of the synthetic CRAC peptide, VLNYYVW, on mitochondrial permeability transition pore (mPTP) opening. It was found that the CRAC peptide alone prevents the mPTP from opening, as well as the release of apoptotic factors (cytochrome c, AIF, and EndoG) in rat brain mitochondria (RBM). Co-incubation of CRAC, together with the TSPO drug ligand, PK 11195, resulted in the acceleration of mPTP opening and in the increase of apoptotic factor release. VLNYYVW did not induce swelling in rat liver mitochondria (RLM). 3,17,19-androsten-5-triol (19-Atriol; an inhibitor of the cholesterol-binding activity of the CRAC peptide) alone and in combination with the peptide was able to stimulate RLM swelling, which was Ca²⁺- and CsA-sensitive. Additionally, a combination of 19-Atriol with 100 nM PK 11195 or with 100 µM PK 11195 displayed the opposite effect: namely, the addition of 19-Atriol with 100 µM PK 11195 in a suspension of RLM suppressed the Ca²⁺-induced swelling of RLM by 40%, while the presence of 100 nM PK 11195 with 19-Atriol enhanced the swelling of RLM by 60%. Taken together, these data suggest the participation of the TSPO’s CRAC domain in the regulation of permeability transition. Full article

(This article belongs to the Special Issue Translocator Protein (TSPO))

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19 pages, 4578 KiB

Open AccessReview

Differential Impacts of Alternative Splicing Networks on Apoptosis

by Jung-Chun Lin^1,*, Mei-Fen Tsao² and Ying-Ju Lin³

¹ School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan

² Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan

³ School of Chinese Medicine, China Medical University, Taichung 404, Taiwan

Int. J. Mol. Sci. 2016, 17(12), 2097; https://doi.org/10.3390/ijms17122097 - 14 Dec 2016

Cited by 25 | Viewed by 8244

Abstract

Apoptosis functions as a common mechanism to eliminate unnecessary or damaged cells during cell renewal and tissue development in multicellular organisms. More than 200 proteins constitute complex networks involved in apoptotic regulation. Imbalanced expressions of apoptosis-related factors frequently lead to malignant diseases. The [...] Read more.

Apoptosis functions as a common mechanism to eliminate unnecessary or damaged cells during cell renewal and tissue development in multicellular organisms. More than 200 proteins constitute complex networks involved in apoptotic regulation. Imbalanced expressions of apoptosis-related factors frequently lead to malignant diseases. The biological functions of several apoptotic factors are manipulated through alternative splicing mechanisms which expand gene diversity by generating discrete variants from one messenger RNA precursor. It is widely observed that alternatively-spliced variants encoded from apoptosis-related genes exhibit differential effects on apoptotic regulation. Alternative splicing events are meticulously regulated by the interplay between trans-splicing factors and cis-responsive elements surrounding the regulated exons. The major focus of this review is to highlight recent studies that illustrate the influences of alternative splicing networks on apoptotic regulation which participates in diverse cellular processes and diseases. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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14 pages, 2703 KiB

Open AccessArticle

RNA Interference of the Ecdysone Receptor Genes EcR and USP in Grain Aphid (Sitobion avenae F.) Affects Its Survival and Fecundity upon Feeding on Wheat Plants

by Ting Yan^†, Hongmei Chen^†, Yongwei Sun, Xiudao Yu and Lanqin Xia^*

¹ Institute of Crop Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100081, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2098; https://doi.org/10.3390/ijms17122098 - 14 Dec 2016

Cited by 53 | Viewed by 6733

Abstract

RNA interference (RNAi) has been widely used in functional genomics of insects and received intensive attention in the development of RNAi-based plants for insect control. Ecdysone receptor (EcR) and ultraspiracle protein (USP) play important roles in molting, metamorphosis, and reproduction of insects. EcR [...] Read more.

RNA interference (RNAi) has been widely used in functional genomics of insects and received intensive attention in the development of RNAi-based plants for insect control. Ecdysone receptor (EcR) and ultraspiracle protein (USP) play important roles in molting, metamorphosis, and reproduction of insects. EcR and USP orthologs and their function in grain aphid (Sitobion avenae F.) have not been documented yet. Here, RT-PCR, qRT-PCR, dsRNA feeding assay and aphid bioassay were employed to isolate EcR and USP orthologs in grain aphid, investigate their expression patterns, and evaluate the effect of RNAi on aphid survival and fecundity, and its persistence. The results indicated that SaEcR and SaUSP exhibited similar expression profiles at different developmental stages. Oral administration of dsRNAs of SaEcR and dsSaUSP significantly decreased the survival of aphids due to the down-regulation of these two genes, respectively. The silencing effect was persistent and transgenerational, as demonstrated by the reduced survival and fecundity due to knock-down of SaEcR and SaUSP in both the surviving aphids and their offspring, even after switching to aphid-susceptible wheat plants. Taken together, our results demonstrate that SaEcR and SaUSP are essential genes in aphid growth and development, and could be used as RNAi targets for wheat aphid control. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 6149 KiB

Open AccessArticle

Discovery of Anti-Hypertensive Oligopeptides from Adlay Based on In Silico Proteolysis and Virtual Screening

by Liansheng Qiao, Bin Li, Yankun Chen, Lingling Li, Xi Chen, Lingzhi Wang, Fang Lu, Ganggang Luo, Gongyu Li and Yanling Zhang^*

Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, University of Chinese Medicine, Beijing 100102, China

Int. J. Mol. Sci. 2016, 17(12), 2099; https://doi.org/10.3390/ijms17122099 - 14 Dec 2016

Cited by 31 | Viewed by 5722

Abstract

Adlay (Coix larchryma-jobi L.) was the commonly used Traditional Chinese Medicine (TCM) with high content of seed storage protein. The hydrolyzed bioactive oligopeptides of adlay have been proven to be anti-hypertensive effective components. However, the structures and anti-hypertensive mechanism of bioactive oligopeptides [...] Read more.

Adlay (Coix larchryma-jobi L.) was the commonly used Traditional Chinese Medicine (TCM) with high content of seed storage protein. The hydrolyzed bioactive oligopeptides of adlay have been proven to be anti-hypertensive effective components. However, the structures and anti-hypertensive mechanism of bioactive oligopeptides from adlay were not clear. To discover the definite anti-hypertensive oligopeptides from adlay, in silico proteolysis and virtual screening were implemented to obtain potential oligopeptides, which were further identified by biochemistry assay and molecular dynamics simulation. In this paper, ten sequences of adlay prolamins were collected and in silico hydrolyzed to construct the oligopeptide library with 134 oligopeptides. This library was reverse screened by anti-hypertensive pharmacophore database, which was constructed by our research team and contained ten anti-hypertensive targets. Angiotensin-I converting enzyme (ACE) was identified as the main potential target for the anti-hypertensive activity of adlay oligopeptides. Three crystal structures of ACE were utilized for docking studies and 19 oligopeptides were finally identified with potential ACE inhibitory activity. According to mapping features and evaluation indexes of pharmacophore and docking, three oligopeptides were selected for biochemistry assay. An oligopeptide sequence, NPATY (IC₅₀ = 61.88 ± 2.77 µM), was identified as the ACE inhibitor by reverse-phase high performance liquid chromatography (RP-HPLC) assay. Molecular dynamics simulation of NPATY was further utilized to analyze interactive bonds and key residues. ALA354 was identified as a key residue of ACE inhibitors. Hydrophobic effect of VAL518 and electrostatic effects of HIS383, HIS387, HIS513 and Zn²⁺ were also regarded as playing a key role in inhibiting ACE activities. This study provides a research strategy to explore the pharmacological mechanism of Traditional Chinese Medicine (TCM) proteins based on in silico proteolysis and virtual screening, which could be beneficial to reveal the pharmacological action of TCM proteins and provide new lead compounds for peptides-based drug design. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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17 pages, 269 KiB

Open AccessReview

Genetic Marker Discovery in Complex Traits: A Field Example on Fat Content and Composition in Pigs

by Ramona Natacha Pena^1,*

, Roger Ros-Freixedes^1,2

, Marc Tor¹ and Joan Estany¹

¹ Departament de Ciència Animal, Universitat de Lleida—Agrotecnio, 25198 Lleida, Spain

² The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Scotland EH25 9RG, UK

Int. J. Mol. Sci. 2016, 17(12), 2100; https://doi.org/10.3390/ijms17122100 - 14 Dec 2016

Cited by 34 | Viewed by 6207

Abstract

Among the large number of attributes that define pork quality, fat content and composition have attracted the attention of breeders in the recent years due to their interaction with human health and technological and sensorial properties of meat. In livestock species, fat accumulates [...] Read more.

Among the large number of attributes that define pork quality, fat content and composition have attracted the attention of breeders in the recent years due to their interaction with human health and technological and sensorial properties of meat. In livestock species, fat accumulates in different depots following a temporal pattern that is also recognized in humans. Intramuscular fat deposition rate and fatty acid composition change with life. Despite indication that it might be possible to select for intramuscular fat without affecting other fat depots, to date only one depot-specific genetic marker (PCK1 c.2456C>A) has been reported. In contrast, identification of polymorphisms related to fat composition has been more successful. For instance, our group has described a variant in the stearoyl-coA desaturase (SCD) gene that improves the desaturation index of fat without affecting overall fatness or growth. Identification of mutations in candidate genes can be a tedious and costly process. Genome-wide association studies can help in narrowing down the number of candidate genes by highlighting those which contribute most to the genetic variation of the trait. Results from our group and others indicate that fat content and composition are highly polygenic and that very few genes explain more than 5% of the variance of the trait. Moreover, as the complexity of the genome emerges, the role of non-coding genes and regulatory elements cannot be disregarded. Prediction of breeding values from genomic data is discussed in comparison with conventional best linear predictors of breeding values. An example based on real data is given, and the implications in phenotype prediction are discussed in detail. The benefits and limitations of using large SNP sets versus a few very informative markers as predictors of genetic merit of breeding candidates are evaluated using field data as an example. Full article

(This article belongs to the Special Issue Exploring the Genotype–Phenotype Map to Explain Complex Traits)

12 pages, 215 KiB

Open AccessReview

Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer

by Robert Sullivan^†, Travis Dailey^†, Kelsey Duncan^†, Naomi Abel^* and Cesario V. Borlongan^*

¹ Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2101; https://doi.org/10.3390/ijms17122101 - 14 Dec 2016

Cited by 165 | Viewed by 11788

Abstract

Peripheral nerve injury can lead to great morbidity in those afflicted, ranging from sensory loss, motor loss, chronic pain, or a combination of deficits. Over time, research has investigated neuronal molecular mechanisms implicated in nerve damage, classified nerve injury, and developed surgical techniques [...] Read more.

Peripheral nerve injury can lead to great morbidity in those afflicted, ranging from sensory loss, motor loss, chronic pain, or a combination of deficits. Over time, research has investigated neuronal molecular mechanisms implicated in nerve damage, classified nerve injury, and developed surgical techniques for treatment. Despite these advancements, full functional recovery remains less than ideal. In this review, we discuss historical aspects of peripheral nerve injury and introduce nerve transfer as a therapeutic option, as well as an adjunct therapy to transplantation of Schwann cells and their stem cell derivatives for repair of the damaged nerve. This review furthermore, will provide an elaborated discussion on the sources of Schwann cells, including sites to harvest their progenitor and stem cell lines. This reflects the accessibility to an additional, concurrent treatment approach with nerve transfers that, predicated on related research, may increase the efficacy of the current approach. We then discuss the experimental and clinical investigations of both Schwann cells and nerve transfer that are underway. Lastly, we provide the necessary consideration that these two lines of therapeutic approaches should not be exclusive, but conversely, should be pursued as a combined modality given their mutual role in peripheral nerve regeneration. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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16 pages, 8390 KiB

Open AccessArticle

Decrease in Circulating Fatty Acids Is Associated with Islet Dysfunction in Chronically Sleep-Restricted Rats

by Shanshan Zhan, Yangyang Wu, Peng Sun, Haiyan Lin, Yunxia Zhu and Xiao Han^*

Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing 210029, China

Int. J. Mol. Sci. 2016, 17(12), 2102; https://doi.org/10.3390/ijms17122102 - 14 Dec 2016

Cited by 14 | Viewed by 4432

Abstract

Previous studies have shown that sleep restriction-induced environmental stress is associated with abnormal metabolism, but the underlying mechanism is poorly understood. In the current study, we investigated the possible lipid and glucose metabolism patterns in chronically sleep-restricted rat. Without changes in food intake, [...] Read more.

Previous studies have shown that sleep restriction-induced environmental stress is associated with abnormal metabolism, but the underlying mechanism is poorly understood. In the current study, we investigated the possible lipid and glucose metabolism patterns in chronically sleep-restricted rat. Without changes in food intake, body weight was decreased and energy expenditure was increased in sleep-restricted rats. The effects of chronic sleep disturbance on metabolites in serum were examined using ¹H NMR metabolomics and GC-FID/MS analysis. Six metabolites (lipoproteins, triglycerides, isoleucine, valine, choline, and phosphorylcholine) exhibited significant alteration, and all the fatty acid components were decreased, which suggested fatty acid metabolism was impaired after sleep loss. Moreover, increased blood glucose, reduced serum insulin, decreased glucose tolerance, and impaired glucose-stimulated insulin secretion of islets were also observed in sleep-restricted rats. The islet function of insulin secretion could be partially restored by increasing dietary fat to sleep-disturbed rats suggested that a reduction in circulating fatty acids was related to islet dysfunction under sleep deficiency-induced environmental stress. This study provides a new perspective on the relationship between insufficient sleep and lipid/glucose metabolism, which offers insights into the role of stressful challenges in a healthy lifestyle. Full article

(This article belongs to the Section Biochemistry)

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8 pages, 599 KiB

Open AccessArticle

Skin Involvement and Pulmonary Hypertension Are Associated with Vitamin D Insufficiency in Scleroderma

by Marco Atteritano^*

, Domenico Santoro

, Giorgio Corallo, Elisa Visalli, Michele Buemi, Antonino Catalano

, Antonino Lasco, Alessandra Bitto and Francesco Squadrito

Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy

Int. J. Mol. Sci. 2016, 17(12), 2103; https://doi.org/10.3390/ijms17122103 - 14 Dec 2016

Cited by 27 | Viewed by 5420

Abstract

Vitamin D status has been linked to immune system and autoimmune disorders; in fact, low levels of vitamin D are common in many autoimmune disorders. The aims of our study were to assess the prevalence of vitamin D insufficiency and the possible correlation [...] Read more.

Vitamin D status has been linked to immune system and autoimmune disorders; in fact, low levels of vitamin D are common in many autoimmune disorders. The aims of our study were to assess the prevalence of vitamin D insufficiency and the possible correlation with clinical parameters in systemic sclerosis (SSc). We recruited 40 patients (38 female and two male) with scleroderma and 40 healthy controls matched for age and gender. Demographic and clinical parameters were recorded and the 25-hydroxivitamin D3 serum levels were measured. Serum 25-hydroxivitamin D3 levels were significantly lower in patients with systemic sclerosis than in the control group. The prevalence of 25-hydroxivitamin D3 insufficiency was 50% in the patients and 22.5% in the control group. A statistically significant association was observed between the insufficiency of 25-hydroxivitamin D3 and skin involvement (p = 0.02) and echocardiography systolic pulmonary artery pressure >35 mmHg (p = 0.02). Our data show that the systemic sclerosis group has significantly lower serum 25-hydroxivitamin D3 concentrations compared to the control group; skin involvement and pulmonary hypertension are associated with vitamin D3 insufficiency. Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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6 pages, 1502 KiB

Open AccessCommunication

Cre Fused with RVG Peptide Mediates Targeted Genome Editing in Mouse Brain Cells In Vivo

by Zhiyuan Zou^1,2,†, Zhaolin Sun^1,†, Pan Li^1,†, Tao Feng¹ and Sen Wu^1,*

¹ State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China

² College of Life Science, Liaoning University, Shenyang 110036, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2104; https://doi.org/10.3390/ijms17122104 - 14 Dec 2016

Cited by 11 | Viewed by 6120

Abstract

Cell penetrating peptides (CPPs) are short peptides that can pass through cell membranes. CPPs can facilitate the cellular entry of proteins, macromolecules, nanoparticles and drugs. RVG peptide (RVG hereinafter) is a 29-amino-acid CPP derived from a rabies virus glycoprotein that can cross the [...] Read more.

Cell penetrating peptides (CPPs) are short peptides that can pass through cell membranes. CPPs can facilitate the cellular entry of proteins, macromolecules, nanoparticles and drugs. RVG peptide (RVG hereinafter) is a 29-amino-acid CPP derived from a rabies virus glycoprotein that can cross the blood-brain barrier (BBB) and enter brain cells. However, whether RVG can be used for genome editing in the brain has not been reported. In this work, we combined RVG with Cre recombinase for bacterial expression. The purified RVG-Cre protein cut plasmids in vitro and traversed cell membranes in cultured Neuro2a cells. By tail vein-injecting RVG-Cre into Cre reporter mouse lines mTmG and Rosa26^lacZ, we demonstrated that RVG-Cre could target brain cells and achieve targeted somatic genome editing in adult mice. This direct delivery of the gene-editing enzyme protein into mouse brains with RVG is much safer than plasmid- or viral-based methods, holding promise for further applications in the treatment of various brain diseases. Full article

(This article belongs to the Special Issue Cell-Penetrating Peptides 2016)

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6 pages, 172 KiB

Open AccessEditorial

Data Analysis in Chemistry and Bio-Medical Sciences

by Roberto Todeschini¹, Alejandro Pazos²

, Sonia Arrasate³ and Humberto González-Díaz^3,4,*

¹ Milano Chemometrics and QSAR Research Group, Department of Earth and Environmental Sciences, University of Milano-Bicocca, 20126 Milano, Italy

² Research Center on Information and Communication Technologies (CITIC), Institute of Biomedical Research (INIBIC), University of Coruña (UDC), Campus de Elviña s/n, 15071 A Coruña, Spain

³ Department of Organic Chemistry II, University of the Basque Country UPV/EHU, Sarriena w/n, 48940 Leioa, Bizkaia, Spain

⁴ IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Biscay, Spain

Int. J. Mol. Sci. 2016, 17(12), 2105; https://doi.org/10.3390/ijms17122105 - 14 Dec 2016

Cited by 2 | Viewed by 4783

Abstract

There is an increasing necessity for multidisciplinary collaborations in molecular science between experimentalists and theoretical scientists, as well as among theoretical scientists from different fields.[...] Full article

(This article belongs to the Special Issue Big Data Analysis and QSAR/QSPR Research in Chemistry, Bio-Medical, and Network Sciences)

13 pages, 18937 KiB

Open AccessReview

Fingolimod Associated Bilateral Cystoid Macular Edema—Wait and See?

by Refik Pul^1,*,†, Alma Osmanovic^1,†, Holger Schmalstieg², Amelie Pielen³, Kaweh Pars¹, Philipp Schwenkenbecher¹, Kurt Wolfram Sühs¹

, Özlem Yildiz¹, Benedikt Frank⁴, Martin Stangel¹

and Thomas Skripuletz¹

¹ Department of Neurology, Hannover Medical School, 30625 Hannover, Germany

² Private Ophthalmology Office, 30851 Langenhagen, Germany

³ Department of Ophthalmology, Hannover Medical School, 30625 Hannover, Germany

⁴ Department of Neurology, University of Duisburg-Essen, 45147 Essen, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2106; https://doi.org/10.3390/ijms17122106 - 14 Dec 2016

Cited by 10 | Viewed by 6205

Abstract

Fingolimod 0.5-mg once-daily is an approved therapy for patients with relapsing–remitting multiple sclerosis (MS). Several pivotal and real-world studies have demonstrated that fingolimod is associated with the development of macular edema (ME). Herein, we present a case of a diabetic MS patient who [...] Read more.

Fingolimod 0.5-mg once-daily is an approved therapy for patients with relapsing–remitting multiple sclerosis (MS). Several pivotal and real-world studies have demonstrated that fingolimod is associated with the development of macular edema (ME). Herein, we present a case of a diabetic MS patient who developed severe bilateral ME during fingolimod treatment. By means of this case study we provide a detailed review about fingolimod associated macular edema (FAME), its current incidence with or without diabetes mellitus, and previous therapy attempts and outcomes in MS patients. Intravitreal administration of antibodies raised against vascular endothelial growth factor A (VEGF-A) has not yet been used in the management of FAME, however, the excellent therapeutic response in our patient may justify the use of anti-VEGF-A agents in combination with cessation of fingolimod to achieve fast resolution of FAME and to prevent visual deficits, particularly in bilateral FAME. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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32 pages, 1594 KiB

Open AccessReview

α-Tocopherol and Hippocampal Neural Plasticity in Physiological and Pathological Conditions

by Patrizia Ambrogini^1,*, Michele Betti¹, Claudia Galati¹, Michael Di Palma¹, Davide Lattanzi¹, David Savelli¹, Francesco Galli²

, Riccardo Cuppini¹ and Andrea Minelli¹

¹ Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy

² Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy

Int. J. Mol. Sci. 2016, 17(12), 2107; https://doi.org/10.3390/ijms17122107 - 15 Dec 2016

Cited by 31 | Viewed by 7949

Abstract

Neuroplasticity is an “umbrella term” referring to the complex, multifaceted physiological processes that mediate the ongoing structural and functional modifications occurring, at various time- and size-scales, in the ever-changing immature and adult brain, and that represent the basis for fundamental neurocognitive behavioral functions; [...] Read more.

Neuroplasticity is an “umbrella term” referring to the complex, multifaceted physiological processes that mediate the ongoing structural and functional modifications occurring, at various time- and size-scales, in the ever-changing immature and adult brain, and that represent the basis for fundamental neurocognitive behavioral functions; in addition, maladaptive neuroplasticity plays a role in the pathophysiology of neuropsychiatric dysfunctions. Experiential cues and several endogenous and exogenous factors can regulate neuroplasticity; among these, vitamin E, and in particular α-tocopherol (α-T), the isoform with highest bioactivity, exerts potent effects on many plasticity-related events in both the physiological and pathological brain. In this review, the role of vitamin E/α-T in regulating diverse aspects of neuroplasticity is analyzed and discussed, focusing on the hippocampus, a brain structure that remains highly plastic throughout the lifespan and is involved in cognitive functions. Vitamin E-mediated influences on hippocampal synaptic plasticity and related cognitive behavior, on post-natal development and adult hippocampal neurogenesis, as well as on cellular and molecular disruptions in kainate-induced temporal seizures are described. Besides underscoring the relevance of its antioxidant properties, non-antioxidant functions of vitamin E/α-T, mainly involving regulation of cell signaling molecules and their target proteins, have been highlighted to help interpret the possible mechanisms underlying the effects on neuroplasticity. Full article

(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)

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21 pages, 294 KiB

Open AccessReview

Zebrafish as an In Vivo Model to Assess Epigenetic Effects of Ionizing Radiation

by Eva Yi Kong¹, Shuk Han Cheng^2,3,* and Kwan Ngok Yu^1,3,*

¹ Department of Physics and Materials Science, City University of Hong Kong, Hong Kong, China

² Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China

³ State Key Laboratory in Marine Pollution, City University of Hong Kong, Hong Kong, China

Int. J. Mol. Sci. 2016, 17(12), 2108; https://doi.org/10.3390/ijms17122108 - 15 Dec 2016

Cited by 14 | Viewed by 5896

Abstract

Exposure to ionizing radiations (IRs) is ubiquitous in our environment and can be categorized into “targeted” effects and “non-targeted” effects. In addition to inducing deoxyribonucleic acid (DNA) damage, IR exposure leads to epigenetic alterations that do not alter DNA sequence. Using an appropriate [...] Read more.

Exposure to ionizing radiations (IRs) is ubiquitous in our environment and can be categorized into “targeted” effects and “non-targeted” effects. In addition to inducing deoxyribonucleic acid (DNA) damage, IR exposure leads to epigenetic alterations that do not alter DNA sequence. Using an appropriate model to study the biological effects of radiation is crucial to better understand IR responses as well as to develop new strategies to alleviate exposure to IR. Zebrafish, Danio rerio, is a scientific model organism that has yielded scientific advances in several fields and recent studies show the usefulness of this vertebrate model in radiation biology. This review briefly describes both “targeted” and “non-targeted” effects, describes the findings in radiation biology using zebrafish as a model and highlights the potential of zebrafish to assess the epigenetic effects of IR, including DNA methylation, histone modifications and miRNA expression. Other in vivo models are included to compare observations made with zebrafish, or to illustrate the feasibility of in vivo models when the use of zebrafish was unavailable. Finally, tools to study epigenetic modifications in zebrafish, including changes in genome-wide DNA methylation, histone modifications and miRNA expression, are also described in this review. Full article

(This article belongs to the Special Issue Zebrafish: A Model for Toxicological Research)

14 pages, 2891 KiB

Open AccessArticle

Lunasin Attenuates Obesity-Associated Metastasis of 4T1 Breast Cancer Cell through Anti-Inflammatory Property

by Chia-Chien Hsieh^*, Chih-Hsuan Wang and Yu-Shan Huang

Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 10610, Taiwan

Int. J. Mol. Sci. 2016, 17(12), 2109; https://doi.org/10.3390/ijms17122109 - 15 Dec 2016

Cited by 32 | Viewed by 10746

Abstract

Obesity prevalence is increasing worldwide and is accompanied by low-grade inflammation with macrophage infiltration, which is linked with a poorer breast cancer prognosis. Lunasin is a natural seed peptide with chemopreventive properties and multiple bioactivities. This is the first study to explore the [...] Read more.

Obesity prevalence is increasing worldwide and is accompanied by low-grade inflammation with macrophage infiltration, which is linked with a poorer breast cancer prognosis. Lunasin is a natural seed peptide with chemopreventive properties and multiple bioactivities. This is the first study to explore the chemopreventive effects of lunasin in the obesity-related breast cancer condition using 4T1 breast cancer cells, 3T3-L1 adipocytes, and conditioned media. An obesity-related environment, such as leptin-treatment or adipocyte-conditioned medium (Ad-CM), promoted 4T1 cell proliferation and metastasis. Lunasin treatment inhibited metastasis of breast cancer cells, partially through modestly inhibiting production of the angiogenesis-mediator vascular endothelial growth factor (VEGF) and significantly by inhibiting secretion in the Ad-CM condition. Subsequently, two adipocytes inflammation models, 3T3-L1 adipocytes were stimulated by tumor necrosis factor (TNF)-α, and RAW 264.7 cell-conditioned medium (RAW-CM) was used to mimic the obese microenvironment. Lunasin significantly inhibited interleukin (IL)-6 and macrophage chemoattractant protein (MCP)-1 secretion by TNF-α stimulation, and MCP-1 secretion in the RAW-CM model. This study highlights that lunasin suppressed 3T3-L1 adipocyte inflammation and inhibited 4T1 breast cancer cell migration. Interestingly, lunasin exerted more effective anti-metastasis activity in the obesity-related condition models, indicating that it possesses anti-inflammatory properties and blocks adipocyte-cancer cell cross-talk. Full article

(This article belongs to the Special Issue Adipokines)

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12 pages, 7720 KiB

Open AccessArticle

Validating Intravascular Imaging with Serial Optical Coherence Tomography and Confocal Fluorescence Microscopy

by Pier-Luc Tardif^1,2,*, Marie-Jeanne Bertrand^2,3, Maxime Abran^1,2, Alexandre Castonguay¹, Joël Lefebvre¹, Barbara E. Stähli², Nolwenn Merlet², Teodora Mihalache-Avram², Pascale Geoffroy², Mélanie Mecteau², David Busseuil², Feng Ni⁴, Abedelnasser Abulrob⁴, Éric Rhéaume^2,3, Philippe L’Allier^2,3, Jean-Claude Tardif^2,3 and Frédéric Lesage^1,2,*

¹ Département de Génie Électrique et Institut de Génie Biomédical, École Polytechnique de Montréal, Montreal, QC H3T 1J4, Canada

² Montreal Heart Institute, Montreal, QC H1T 1C8, Canada

³ Département de Médecine, Université de Montréal, Montreal, QC H3C 3J7, Canada

⁴ National Research Council Canada (NRCC), Montreal, QC H3A 1A3, Canada

Int. J. Mol. Sci. 2016, 17(12), 2110; https://doi.org/10.3390/ijms17122110 - 15 Dec 2016

Cited by 7 | Viewed by 6494

Abstract

Atherosclerotic cardiovascular diseases are characterized by the formation of a plaque in the arterial wall. Intravascular ultrasound (IVUS) provides high-resolution images allowing delineation of atherosclerotic plaques. When combined with near infrared fluorescence (NIRF), the plaque can also be studied at a molecular level [...] Read more.

Atherosclerotic cardiovascular diseases are characterized by the formation of a plaque in the arterial wall. Intravascular ultrasound (IVUS) provides high-resolution images allowing delineation of atherosclerotic plaques. When combined with near infrared fluorescence (NIRF), the plaque can also be studied at a molecular level with a large variety of biomarkers. In this work, we present a system enabling automated volumetric histology imaging of excised aortas that can spatially correlate results with combined IVUS/NIRF imaging of lipid-rich atheroma in cholesterol-fed rabbits. Pullbacks in the rabbit aortas were performed with a dual modality IVUS/NIRF catheter developed by our group. Ex vivo three-dimensional (3D) histology was performed combining optical coherence tomography (OCT) and confocal fluorescence microscopy, providing high-resolution anatomical and molecular information, respectively, to validate in vivo findings. The microscope was combined with a serial slicer allowing for the imaging of the whole vessel automatically. Colocalization of in vivo and ex vivo results is demonstrated. Slices can then be recovered to be tested in conventional histology. Full article

(This article belongs to the Special Issue Atherosclerosis and Vascular Imaging 2016)

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9 pages, 199 KiB

Open AccessReview

Lung Involvement in Children with Hereditary Autoinflammatory Disorders

by Giusyda Tarantino¹, Susanna Esposito²

, Laura Andreozzi¹, Benedetta Bracci¹, Francesca D’Errico¹ and Donato Rigante^1,*

¹ Institute of Pediatrics, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, 00168 Rome, Italy

² Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy

Int. J. Mol. Sci. 2016, 17(12), 2111; https://doi.org/10.3390/ijms17122111 - 15 Dec 2016

Cited by 24 | Viewed by 5857

Abstract

Short-lived systemic inflammatory reactions arising from disrupted rules in the innate immune system are the operating platforms of hereditary autoinflammatory disorders (HAIDs). Multiple organs may be involved and aseptic inflammation leading to disease-specific phenotypes defines most HAIDs. Lungs are infrequently involved in children [...] Read more.

Short-lived systemic inflammatory reactions arising from disrupted rules in the innate immune system are the operating platforms of hereditary autoinflammatory disorders (HAIDs). Multiple organs may be involved and aseptic inflammation leading to disease-specific phenotypes defines most HAIDs. Lungs are infrequently involved in children with HAIDs: the most common pulmonary manifestation is pleuritis in familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), respectively caused by mutations in the MEFV and TNFRSF1A genes, while interstitial lung disease can be observed in STING-associated vasculopathy with onset in infancy (SAVI), caused by mutations in the TMEM173 gene. The specific pleuropulmonary diseases may range from sub-clinical abnormalities during inflammatory flares of FMF and TRAPS to a severe life-threatening disorder in children with SAVI. Full article

(This article belongs to the Special Issue Pneumonia: Pathogenesis, Diagnostics, Therapeutics, and Prevention)

11 pages, 2226 KiB

Open AccessArticle

Characterization of Starch Degradation Related Genes in Postharvest Kiwifruit

by Xiong Hu^1,2, Sheng Kuang¹, Ai-Di Zhang¹, Wang-Shu Zhang³, Miao-Jin Chen⁴, Xue-Ren Yin^1,2,* and Kun-Song Chen^1,2

¹ Zhejiang Provincial Key Laboratory of Horticultural Plant Integrative Biology, Zhejiang University, Zijingang Campus, Hangzhou 310058, China

² The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Zijingang Campus, Hangzhou 310058, China

³ Ningbo Fullharvest Agriculture Technology Co., Ltd., Ningbo 315202, China

⁴ Fenghua Peach Research Institute, Ningbo 315502, China

Int. J. Mol. Sci. 2016, 17(12), 2112; https://doi.org/10.3390/ijms17122112 - 15 Dec 2016

Cited by 68 | Viewed by 6649

Abstract

Starch is one of the most important storage carbohydrates in plants. Kiwifruit typically accumulate large amounts of starch during development. The fruit retain starch until commercial maturity, and its postharvest degradation is essential for consumer acceptance. The activity of genes related to starch [...] Read more.

Starch is one of the most important storage carbohydrates in plants. Kiwifruit typically accumulate large amounts of starch during development. The fruit retain starch until commercial maturity, and its postharvest degradation is essential for consumer acceptance. The activity of genes related to starch degradation has, however, rarely been investigated. Based on the kiwifruit genome sequence and previously reported starch degradation-related genes, 17 novel genes were isolated and the relationship between their expression and starch degradation was examined using two sets of materials: ethylene-treated (100 µL/L, 20 °C; ETH) vs. control (20 °C; CK) and controlled atmosphere stored (CA, 5% CO₂ + 2% O₂, 0 °C) vs. normal atmosphere in cold storage (NA, 0 °C). Physiological analysis indicated that ETH accelerated starch degradation and increased soluble solids content (SSC) and soluble sugars (glucose, fructose and sucrose), while CA inhibited starch reduction compared with NA. Using these materials, expression patterns of 24 genes that may contribute to starch degradation (seven previously reported and 17 newly isolated) were analyzed. Among the 24 genes, AdAMY1, AdAGL3 and AdBAM3.1/3L/9 were significantly induced by ETH and positively correlated with starch degradation. Furthermore, these five genes were also inhibited by CA, conforming the likely involvement of these genes in starch degradation. Thus, the present study has identified the genes with potential for involvement in starch degradation in postharvest kiwifruit, which will be useful for understanding the regulation of kiwifruit starch content and metabolism. Full article

(This article belongs to the Special Issue Ripening Control and Induction of the Defence and Antioxidant Systems)

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23 pages, 1821 KiB

Open AccessReview

Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment

by Veronica Rojas¹, Kim M. Hirshfield^2,3, Shridar Ganesan^2,3 and Lorna Rodriguez-Rodriguez^3,4,*

¹ Department Obstetrics/Gynecology and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, 125 Paterson Street, New Brunswick, NJ 08901, USA

² Department of Medicine, Division of Medical Oncology, Rutgers Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA

³ Precision Medicine Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA

⁴ Department Obstetrics/Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Rutgers Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA

Int. J. Mol. Sci. 2016, 17(12), 2113; https://doi.org/10.3390/ijms17122113 - 15 Dec 2016

Cited by 179 | Viewed by 33633

Abstract

Epithelial ovarian cancer is a highly heterogeneous disease characterized by multiple histological subtypes. Molecular diversity has been shown to occur within specific histological subtypes of epithelial ovarian cancer, between different tumors of an individual patient, as well as within individual tumors. Recent advances [...] Read more.

Epithelial ovarian cancer is a highly heterogeneous disease characterized by multiple histological subtypes. Molecular diversity has been shown to occur within specific histological subtypes of epithelial ovarian cancer, between different tumors of an individual patient, as well as within individual tumors. Recent advances in the molecular characterization of epithelial ovarian cancer tumors have provided the basis for a simplified classification scheme in which these cancers are classified as either type I or type II tumors, and these two categories have implications regarding disease pathogenesis and prognosis. Molecular analyses, primarily based on next-generation sequencing, otherwise known as high-throughput sequencing, are allowing for further refinement of ovarian cancer classification, facilitating the elucidation of the site(s) of precursor lesions of high-grade serous ovarian cancer, and providing insight into the processes of clonal selection and evolution that may be associated with development of chemoresistance. Potential therapeutic targets have been identified from recent molecular profiling studies of these tumors, and the effectiveness and safety of a number of specific targeted therapies have been evaluated or are currently being studied for the treatment of women with this disease. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies)

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14 pages, 2675 KiB

Open AccessArticle

Systematic Understanding of Mechanisms of a Chinese Herbal Formula in Treatment of Metabolic Syndrome by an Integrated Pharmacology Approach

by Meimei Chen^1,2,*, Fafu Yang^1,*, Xuemei Yang², Xinmei Lai² and Yuxing Gao³

¹ College of Chemistry and Chemical Engineering, Fujian Normal University, Fuzhou 350007, China

² College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China

³ College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China

Int. J. Mol. Sci. 2016, 17(12), 2114; https://doi.org/10.3390/ijms17122114 - 16 Dec 2016

Cited by 18 | Viewed by 5396

Abstract

Metabolic syndrome (MS) is becoming a worldwide health problem. Wendan decoction (WDD)—a famous traditional Chinese medicine formula—has been extensively employed to relieve syndromes related to MS in clinical practice in China. However, its pharmacological mechanisms still remain vague. In this study, a comprehensive [...] Read more.

Metabolic syndrome (MS) is becoming a worldwide health problem. Wendan decoction (WDD)—a famous traditional Chinese medicine formula—has been extensively employed to relieve syndromes related to MS in clinical practice in China. However, its pharmacological mechanisms still remain vague. In this study, a comprehensive approach that integrated chemomics, principal component analysis, molecular docking simulation, and network analysis was established to elucidate the multi-component and multi-target mechanism of action of WDD in treatment of MS. The compounds in WDD were found to possess chemical diversity, complexity and drug-likeness compared to MS drugs. Six nuclear receptors were obtained to have strong binding affinity with 217 compounds of five herbs in WDD. The importance roles of targets and herbs were also identified due to network parameters. Five compounds from Radix Glycyrrhizae Preparata can hit all six targets, which can assist in screening new MS drugs. The pathway network analysis demonstrated that the main pharmacological effects of WDD might lie in maintaining lipid and glucose metabolisms and anticancer activities as well as immunomodulatory and hepatoprotective effects. This study provided a comprehensive system approach for understanding the multi-component, multi-target and multi-pathway mechanisms of WDD during the treatment of MS. Full article

(This article belongs to the Section Biochemistry)

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10 pages, 1549 KiB

Open AccessArticle

Maternal Food Restriction during Pregnancy and Lactation Adversely Affect Hepatic Growth and Lipid Metabolism in Three-Week-Old Rat Offspring

by Sangmi Lee^1,2,†, Young-Ah You^1,†, Eun Jin Kwon¹, Sung-Chul Jung³

, Inho Jo⁴

and Young Ju Kim^1,*

¹ Department of Obstetrics and Gynecology and Ewha Medical Research Institute, Ewha Womans University Medical School, Seoul 07985, Korea

² Department of Molecular Medicine and Ewha Medical Research Institute, Ewha Womans University Medical School, Seoul 07985, Korea

³ Department of Biochemistry, Ewha Womans University Medical School, Seoul 07985, Korea

⁴ Department of Molecular Medicine, Ewha Womans University Medical School, Seoul 07985, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2115; https://doi.org/10.3390/ijms17122115 - 15 Dec 2016

Cited by 20 | Viewed by 4987

Abstract

Maternal malnutrition influences the early development of foetal adaptive changes for survival. We explored the effects of maternal undernutrition during gestation and lactation on hepatic growth and function. Sprague-Dawley rats were fed a normal or a food-restricted (FR) diet during gestation and/or lactation. [...] Read more.

Maternal malnutrition influences the early development of foetal adaptive changes for survival. We explored the effects of maternal undernutrition during gestation and lactation on hepatic growth and function. Sprague-Dawley rats were fed a normal or a food-restricted (FR) diet during gestation and/or lactation. We performed analyses of covariance (adjusting for the liver weight/body weight ratio) to compare hepatic growth and lipid metabolism among the offspring. Maternal FR during gestation triggered the development of wide spaces between hepatic cells and increased the expression of mammalian target of rapamycin (mTOR) in three-week-old male offspring compared with controls (both p < 0.05). Offspring nursed by FR dams exhibited wider spaces between hepatic cells and a lower liver weight/body weight ratio than control offspring, and increased mTOR expression (p < 0.05). Interestingly, the significant decrease in expression of lipogenic-related genes was dependent on carbohydrate-responsive element-binding protein, despite the increased expression of sterol regulatory element-binding protein 1 (SREBP1) (p < 0.05). This study demonstrated increased expression of key metabolic regulators (mTOR and SREBP1), alterations in lipid metabolism, and deficits in hepatic growth in the offspring of FR-treated dams. Full article

(This article belongs to the Section Biochemistry)

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18 pages, 6301 KiB

Open AccessArticle

Discovery of a New Class of Cathepsin K Inhibitors in Rhizoma Drynariae as Potential Candidates for the Treatment of Osteoporosis

by Zuo-Cheng Qiu¹, Xiao-Li Dong^2,3, Yi Dai¹, Gao-Keng Xiao¹, Xin-Luan Wang⁴, Ka-Chun Wong², Man-Sau Wong^2,5,*

and Xin-Sheng Yao^1,*

¹ Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China

² Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China

³ Shenzhen Key Laboratory of Food Biological Safety Control, Shenzhen 518057, China

⁴ Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518000, China

⁵ State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen 518057, China

Int. J. Mol. Sci. 2016, 17(12), 2116; https://doi.org/10.3390/ijms17122116 - 16 Dec 2016

Cited by 23 | Viewed by 6007

Abstract

Rhizoma Drynariae (RD), as one of the most common clinically used folk medicines, has been reported to exert potent anti-osteoporotic activity. The bioactive ingredients and mechanisms that account for its bone protective effects are under active investigation. Here we adopt a novel in [...] Read more.

Rhizoma Drynariae (RD), as one of the most common clinically used folk medicines, has been reported to exert potent anti-osteoporotic activity. The bioactive ingredients and mechanisms that account for its bone protective effects are under active investigation. Here we adopt a novel in silico target fishing method to reveal the target profile of RD. Cathepsin K (Ctsk) is one of the cysteine proteases that is over-expressed in osteoclasts and accounts for the increase in bone resorption in metabolic bone disorders such as postmenopausal osteoporosis. It has been the focus of target based drug discovery in recent years. We have identified two components in RD, Kushennol F and Sophoraflavanone G, that can potentially interact with Ctsk. Biological studies were performed to verify the effects of these compounds on Ctsk and its related bone resorption process, which include the use of in vitro fluorescence-based Ctsk enzyme assay, bone resorption pit formation assay, as well as Receptor Activator of Nuclear factor κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis using murine RAW264.7 cells. Finally, the binding mode and stability of these two compounds that interact with Ctsk were determined by molecular docking and dynamics methods. The results showed that the in silico target fishing method could successfully identify two components from RD that show inhibitory effects on the bone resorption process related to protease Ctsk. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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10 pages, 212 KiB

Open AccessReview

Clinical Application of Targeted Next Generation Sequencing for Colorectal Cancers

by Quitterie Fontanges, Ricardo De Mendonca, Isabelle Salmon, Marie Le Mercier and Nicky D’Haene^*

Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium

Int. J. Mol. Sci. 2016, 17(12), 2117; https://doi.org/10.3390/ijms17122117 - 16 Dec 2016

Cited by 20 | Viewed by 5890

Abstract

Promising targeted therapy and personalized medicine are making molecular profiling of tumours a priority. For colorectal cancer (CRC) patients, international guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-epidermal growth factor receptor agents (anti-EGFR). Daily, new [...] Read more.

Promising targeted therapy and personalized medicine are making molecular profiling of tumours a priority. For colorectal cancer (CRC) patients, international guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-epidermal growth factor receptor agents (anti-EGFR). Daily, new data emerge on the theranostic and prognostic role of molecular biomarkers, which is a strong incentive for a validated, sensitive and broadly available molecular screening test in order to implement and improve multi-modal therapy strategy and clinical trials. Next generation sequencing (NGS) has begun to supplant other technologies for genomic profiling. Targeted NGS is a method that allows parallel sequencing of thousands of short DNA sequences in a single test offering a cost-effective approach for detecting multiple genetic alterations with a minimum amount of DNA. In the present review, we collected data concerning the clinical application of NGS technology in the setting of colorectal cancer. Full article

(This article belongs to the Special Issue Next-Generation Sequencing for Clinical Application)

13 pages, 1223 KiB

Open AccessReview

Recent Progress in Machine Learning-Based Methods for Protein Fold Recognition

by Leyi Wei

and Quan Zou^*

School of Computer Science and Technology, Tianjin University, Tianjin 300354, China

Int. J. Mol. Sci. 2016, 17(12), 2118; https://doi.org/10.3390/ijms17122118 - 16 Dec 2016

Cited by 81 | Viewed by 8655

Abstract

Knowledge on protein folding has a profound impact on understanding the heterogeneity and molecular function of proteins, further facilitating drug design. Predicting the 3D structure (fold) of a protein is a key problem in molecular biology. Determination of the fold of a protein [...] Read more.

Knowledge on protein folding has a profound impact on understanding the heterogeneity and molecular function of proteins, further facilitating drug design. Predicting the 3D structure (fold) of a protein is a key problem in molecular biology. Determination of the fold of a protein mainly relies on molecular experimental methods. With the development of next-generation sequencing techniques, the discovery of new protein sequences has been rapidly increasing. With such a great number of proteins, the use of experimental techniques to determine protein folding is extremely difficult because these techniques are time consuming and expensive. Thus, developing computational prediction methods that can automatically, rapidly, and accurately classify unknown protein sequences into specific fold categories is urgently needed. Computational recognition of protein folds has been a recent research hotspot in bioinformatics and computational biology. Many computational efforts have been made, generating a variety of computational prediction methods. In this review, we conduct a comprehensive survey of recent computational methods, especially machine learning-based methods, for protein fold recognition. This review is anticipated to assist researchers in their pursuit to systematically understand the computational recognition of protein folds. Full article

(This article belongs to the Special Issue Protein Folding)

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14 pages, 5533 KiB

Open AccessArticle

Knockdown of ELMO3 Suppresses Growth, Invasion and Metastasis of Colorectal Cancer

by Hui-Yun Peng^1,†, Qiong-Fang Yu^2,†, Wei Shen³, Cheng-Ming Guo², Zhen Li¹, Xiao-Yan Zhou⁴, Nan-Jin Zhou⁵, Wei-Ping Min¹ and Dian Gao^1,*

¹ Department of Pathogen Biology and Immunology, Medical College of Nanchang University, Nanchang 330006, China

² Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Nanchang University, Nanchang 330006, China

³ Department of Gastrointestinal Surgery, Second Affiliated Hospital of Nanchang University, Nanchang 330006, China

⁴ Department of Pathophysiology, Medical College of Nanchang University, Nanchang 330006, China

⁵ Institute of Molecular Medicine, Jiangxi Academy of Medical Sciences, Nanchang 330006, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2119; https://doi.org/10.3390/ijms17122119 - 16 Dec 2016

Cited by 15 | Viewed by 5830

Abstract

The engulfment and cell motility (ELMOs) family of proteins plays a crucial role in tumor cell migration and invasion. However, the function of ELMO3 is poorly defined. To elucidate its role in the development and progression of colorectal cancer (CRC), we examined the [...] Read more.

The engulfment and cell motility (ELMOs) family of proteins plays a crucial role in tumor cell migration and invasion. However, the function of ELMO3 is poorly defined. To elucidate its role in the development and progression of colorectal cancer (CRC), we examined the expression of ELMO3 in 45 cases of paired CRC tumor tissues and adjacent normal tissues. Furthermore, we assessed the effect of the knockdown of ELMO3 on cell proliferation, cell cycle, migration, invasion and F-actin polymerization in HCT116 cells. The result shows that the expression of ELMO3 in CRC tissues was significantly increased in comparison to the adjacent normal colorectal tissues. Moreover, this overexpression was associated with tumor size (p = 0.007), tumor differentiation (p = 0.001), depth of invasion (p = 0.009), lymph node metastasis (p = 0.003), distant metastasis (p = 0.013) and tumor, node, metastasis (TNM)-based classification (p = 0.000). In in vitro experiments, the silencing of ELMO3 inhibited cell proliferation, invasion, metastasis, and F-actin polymerization, and induced Gap 1 (G1) phase cell cycle arrest. Our study demonstrates that ELMO3 is involved in the processes of growth, invasion and metastasis of CRC, and could be used a potential molecular diagnostic tool or therapy target of CRC. Full article

(This article belongs to the Special Issue Latest Advances in Colorectal Cancer Research: Molecular Mechanisms and Therapies)

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18 pages, 1040 KiB

Open AccessReview

Microbial Etiology of Pneumonia: Epidemiology, Diagnosis and Resistance Patterns

by Catia Cilloniz¹

, Ignacio Martin-Loeches²

, Carolina Garcia-Vidal³, Alicia San Jose¹ and Antoni Torres^1,*

¹ Department of Pneumology, Institut Clinic del Tórax, Hospital Clinic of Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Ciber de Enfermedades Respiratorias (CIBERES), 08036 Barcelona, Spain

² Department of Clinical Medicine, Trinity Centre for Health Sciences, Multidisciplinary Intensive Care Research Organization (MICRO), Welcome Trust-HRB Clinical Research, St James’s Hospital, St James’s University Hospital, Dublin, Ireland

³ Department of Infectious Diseases, Hospital Clinic of Barcelona, 08036 Barcelona, Spain

Int. J. Mol. Sci. 2016, 17(12), 2120; https://doi.org/10.3390/ijms17122120 - 16 Dec 2016

Cited by 177 | Viewed by 37690

Abstract

Globally, pneumonia is a serious public health concern and a major cause of mortality and morbidity. Despite advances in antimicrobial therapies, microbiological diagnostic tests and prevention measures, pneumonia remains the main cause of death from infectious disease in the world. An important reason [...] Read more.

Globally, pneumonia is a serious public health concern and a major cause of mortality and morbidity. Despite advances in antimicrobial therapies, microbiological diagnostic tests and prevention measures, pneumonia remains the main cause of death from infectious disease in the world. An important reason for the increased global mortality is the impact of pneumonia on chronic diseases, along with the increasing age of the population and the virulence factors of the causative microorganism. The increasing number of multidrug-resistant bacteria, difficult-to-treat microorganisms, and the emergence of new pathogens are a major problem for clinicians when deciding antimicrobial therapy. A key factor for managing and effectively guiding appropriate antimicrobial therapy is an understanding of the role of the different causative microorganisms in the etiology of pneumonia, since it has been shown that the adequacy of initial antimicrobial therapy is a key factor for prognosis in pneumonia. Furthermore, broad-spectrum antibiotic therapies are sometimes given until microbiological results are available and de-escalation cannot be performed quickly. This review provides an overview of microbial etiology, resistance patterns, epidemiology and microbial diagnosis of pneumonia. Full article

(This article belongs to the Special Issue Pneumonia: Pathogenesis, Diagnostics, Therapeutics, and Prevention)

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11 pages, 921 KiB

Open AccessCommunication

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

by Angela Lopomo^1,2, Roberta Ricciardi^3,4, Michelangelo Maestri³, Anna De Rosa³, Franca Melfi⁴, Marco Lucchi⁴, Alfredo Mussi⁴, Fabio Coppedè^1,* and Lucia Migliore¹

¹ Department of Translational Research and New Technologies in Medicine and Surgery, Division of Medical Genetics, University of Pisa, Medical School, Via Roma 55, 56126 Pisa, Italy

² Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy

³ Department of Clinical and Experimental Medicine, Neurology Unit, University of Pisa, Medical School, Via Roma 55, 56126 Pisa, Italy

⁴ Division of Thoracic Surgery, Cardiothoracic and Vascular Surgery Department, University of Pisa, Medical School, Via Roma 55, 56126 Pisa, Italy

Int. J. Mol. Sci. 2016, 17(12), 2121; https://doi.org/10.3390/ijms17122121 - 16 Dec 2016

Cited by 18 | Viewed by 5079

Abstract

Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is known, however, concerning epigenetic changes occurring in [...] Read more.

Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is known, however, concerning epigenetic changes occurring in thymomas from MG individuals. To further address this issue, we analyzed DNA methylation levels of genes involved in one-carbon metabolism (MTHFR) and DNA methylation (DNMT1, DNMT3A, and DNMT3B) in blood, tumor tissue, and healthy thymic epithelial cells from MG patients that underwent a surgical resection of a thymic neoplasm. For the analyses we applied the methylation-sensitive high-resolution melting technique. Both MTHFR and DNMT3A promoters showed significantly higher methylation in tumor tissue with respect to blood, and MTHFR also showed significantly higher methylation levels in tumor tissue respect to healthy adjacent thymic epithelial cells. Both DNMT1 and DNMT3B promoter regions were mostly hypomethylated in all the investigated tissues. The present study suggests that MTHFR methylation is increased in thymomas obtained from MG patients; furthermore, some degrees of methylation of the DNMT3A gene were observed in thymic tissue with respect to blood. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)

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28 pages, 1029 KiB

Open AccessReview

Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer’s Disease

by Andrea Kwakowsky^1,*

, Michael R. Milne², Henry J. Waldvogel¹ and Richard L. Faull¹

¹ Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand

² School of Biomedical Sciences, Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane 4072, QLD, Australia

Int. J. Mol. Sci. 2016, 17(12), 2122; https://doi.org/10.3390/ijms17122122 - 17 Dec 2016

Cited by 35 | Viewed by 7887

Abstract

The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological [...] Read more.

The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer’s disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer’s disease. Full article

(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)

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16 pages, 1232 KiB

Open AccessReview

Zebrafish as a Vertebrate Model System to Evaluate Effects of Environmental Toxicants on Cardiac Development and Function

by Swapnalee Sarmah^* and James A. Marrs^*

Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA

Int. J. Mol. Sci. 2016, 17(12), 2123; https://doi.org/10.3390/ijms17122123 - 16 Dec 2016

Cited by 128 | Viewed by 10097

Abstract

Environmental pollution is a serious problem of the modern world that possesses a major threat to public health. Exposure to environmental pollutants during embryonic development is particularly risky. Although many pollutants have been verified as potential toxicants, there are new chemicals in the [...] Read more.

Environmental pollution is a serious problem of the modern world that possesses a major threat to public health. Exposure to environmental pollutants during embryonic development is particularly risky. Although many pollutants have been verified as potential toxicants, there are new chemicals in the environment that need assessment. Heart development is an extremely sensitive process, which can be affected by environmentally toxic molecule exposure during embryonic development. Congenital heart defects are the most common life-threatening global health problems, and the etiology is mostly unknown. The zebrafish has emerged as an invaluable model to examine substance toxicity on vertebrate development, particularly on cardiac development. The zebrafish offers numerous advantages for toxicology research not found in other model systems. Many laboratories have used the zebrafish to study the effects of widespread chemicals in the environment on heart development, including pesticides, nanoparticles, and various organic pollutants. Here, we review the uses of the zebrafish in examining effects of exposure to external molecules during embryonic development in causing cardiac defects, including chemicals ubiquitous in the environment and illicit drugs. Known or potential mechanisms of toxicity and how zebrafish research can be used to provide mechanistic understanding of cardiac defects are discussed. Full article

(This article belongs to the Special Issue Zebrafish: A Model for Toxicological Research)

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21 pages, 1536 KiB

Open AccessReview

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

by Dun-Xian Tan^*, Lucien C. Manchester, Lilan Qin and Russel J. Reiter^*

Department of Cell System and Anatomy, The University of Texas Health Science Center, San Antonio, TX 78229, USA

Int. J. Mol. Sci. 2016, 17(12), 2124; https://doi.org/10.3390/ijms17122124 - 16 Dec 2016

Cited by 320 | Viewed by 15207

Abstract

Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin [...] Read more.

Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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16 pages, 4152 KiB

Open AccessArticle

Testosterone Deficiency Induces Changes of the Transcriptomes of Visceral Adipose Tissue in Miniature Pigs Fed a High-Fat and High-Cholesterol Diet

by Lifan Zhang^1,*, Yueqin Cai², Shengjuan Wei¹, Yun Ling², Liang Zhu², Dongfeng Li¹ and Zhaowei Cai^2,*

¹ College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China

² Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou 310053, China

Int. J. Mol. Sci. 2016, 17(12), 2125; https://doi.org/10.3390/ijms17122125 - 16 Dec 2016

Cited by 5 | Viewed by 6646

Abstract

Testosterone deficiency causes fat deposition, particularly in visceral fat, and its replacement might reverse fat accumulation, however, the underlying mechanisms of such processes under diet-induced adiposity are largely unknown. To gain insights into the genome-wide role of androgen on visceral adipose tissue (VAT), [...] Read more.

Testosterone deficiency causes fat deposition, particularly in visceral fat, and its replacement might reverse fat accumulation, however, the underlying mechanisms of such processes under diet-induced adiposity are largely unknown. To gain insights into the genome-wide role of androgen on visceral adipose tissue (VAT), RNA-Seq was used to investigate testosterone deficiency induced changes of VAT in miniature pigs fed a high-fat and high-cholesterol (HFC) diet among intact male pigs (IM), castrated male pigs (CM), and castrated male pigs with testosterone replacement (CMT) treatments. The results showed that testosterone deficiency significantly increased VAT deposition and serum leptin concentrations. Moreover, a total of 1732 differentially expressed genes (DEGs) were identified between any two groups. Compared with gene expression profiles in IM and CMT pigs, upregulated genes in CM pigs, i.e., LOC100520753 (CD68), LCN2, EMR1, S100A9, NCF1 (p47phox), and LEP, were mainly involved in inflammatory response, oxidation-reduction process, and lipid metabolic process, while downregulated genes in CM pigs, i.e., ABHD5, SPP1, and GAS6, were focused on cell differentiation and cell adhesion. Taken together, our study demonstrates that testosterone deficiency alters the expression of numerous genes involved in key biological processes of VAT accumulation under HFC diet and provides a novel genome-wide view on the role of androgen on VAT deposition under HFC diet, thus improving our understanding of the molecular mechanisms involved in VAT changes induced by testosterone deficiency. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 843 KiB

Open AccessReview

A Possible Role of Intestinal Microbiota in the Pathogenesis of Ankylosing Spondylitis

by Lianjun Yang^1,†, Liping Wang^1,2,†

, Xin Wang³, Cory J. Xian^1,2,*

and Hai Lu^1,*

¹ Academy of Orthopedics of Guangdong Province, Orthopaedic Hospital of Guangdong Province, Department of Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China

² Sansom Institute for Health Research and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide SA5001, Australia

³ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane QLD4059, Australia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2126; https://doi.org/10.3390/ijms17122126 - 17 Dec 2016

Cited by 51 | Viewed by 16699

Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the sacroiliac joints and the spine, for which the pathogenesis is thought to be a result of the combination of host genetic factors and environmental triggers. However, the precise factors that determine one’s [...] Read more.

Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the sacroiliac joints and the spine, for which the pathogenesis is thought to be a result of the combination of host genetic factors and environmental triggers. However, the precise factors that determine one’s susceptibility to AS remain to be unraveled. With 100 trillion bacteria residing in the mammalian gut having established a symbiotic relation with their host influencing many aspects of host metabolism, physiology, and immunity, a growing body of evidence suggests that intestinal microbiota may play an important role in AS. Several mechanisms have been suggested to explain the potential role of the microbiome in the etiology of AS, such as alterations of intestinal permeability, stimulation of immune responses, and molecular mimicry. In this review, the existing evidence for the involvement of the microbiome in AS pathogenesis was discussed and the potential of intestinal microbiome-targeting strategies in the prevention and treatment of AS was evaluated. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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9 pages, 1144 KiB

Open AccessArticle

Characterization of the Microenvironment of Nodular Lymphocyte Predominant Hodgkin Lymphoma

by Ahmad Sattarzadeh^*, Lydia Visser^*, Bea Rutgers^*, Arjan Diepstra^*

and Anke Van den Berg^*

Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands

Int. J. Mol. Sci. 2016, 17(12), 2127; https://doi.org/10.3390/ijms17122127 - 16 Dec 2016

Cited by 24 | Viewed by 5365

Abstract

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is characterized by a low percentage of neoplastic lymphocyte predominant (LP) cells in a background of lymphocytes. The goal of this study is to characterize the microenvironment in NLPHL. Ten NLPHL cases and seven reactive lymph nodes [...] Read more.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is characterized by a low percentage of neoplastic lymphocyte predominant (LP) cells in a background of lymphocytes. The goal of this study is to characterize the microenvironment in NLPHL. Ten NLPHL cases and seven reactive lymph nodes (RLN) were analyzed by flow cytometry for the main immune cells and multiple specific subpopulations. To discriminate between cells in or outside the tumor cell area, we used CD26. We observed significantly lower levels of CD20+ B-cells and CD56+ NK cells and higher levels of CD4+ T-cells in NLPHL in comparison to RLN. In the subpopulations, we observed increased numbers of PD-1+CD4+ T follicular helper cells (TFH), CD69+CD4+ and CD69+CD8+ T-cells and CCR7-CD45RA-CD4+ effector memory T-cells, while FoxP3+CD4+ T regulatory cells (Tregs) and CCR7-CD45RA+ terminally differentiated CD4+ T-cells were decreased in NLPHL compared to RLN. CD69+ cells were increased in the tumor cell area in CD4+ and CD8+ T-cells, while FoxP3+CD25+CD4+ Tregs and CD25+CD8+ T-cells were significantly increased outside the tumor area. Thus, we show a markedly altered microenvironment in NLPHL, with lower numbers of NK cells and Tregs. PD-1+CD4+ and CD69+ T-cells were located inside, and Tregs and CD25+CD8+ cells outside the tumor cell area. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)

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16 pages, 8570 KiB

Open AccessArticle

Metabolomic Approaches to Explore Chemical Diversity of Human Breast-Milk, Formula Milk and Bovine Milk

by Linxi Qian^1,2,†, Aihua Zhao^3,†, Yinan Zhang³, Tianlu Chen³, Steven H. Zeisel⁴, Wei Jia^3,* and Wei Cai^1,2,*

¹ Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai 200092, China

² Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai 200092, China

³ Center for Translational Medicine, Six People’s Hospital, Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China

⁴ Nutrition Research Institute, University of North Carolina, Chapel Hill, Kannapolis, NC 28081, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2128; https://doi.org/10.3390/ijms17122128 - 17 Dec 2016

Cited by 45 | Viewed by 7934

Abstract

Although many studies have been conducted on the components present in human breast milk (HM), research on the differences of chemical metabolites between HM, bovine milk (BM) and formula milk (FM) is limited. This study was to explore the chemical diversity of HM, [...] Read more.

Although many studies have been conducted on the components present in human breast milk (HM), research on the differences of chemical metabolites between HM, bovine milk (BM) and formula milk (FM) is limited. This study was to explore the chemical diversity of HM, BM and FM by metabolomic approaches. GC-TOFMS and UPLC-QTOFMS were applied to investigate the metabolic compositions in 30 HM samples, 20 FM samples and 20 BM samples. Metabolite profiling identified that most of the non-esterified fatty acids, which reflected the hydrolysis of triglycerides, were much more abundant in HM than those in FM and BM, except for palmitic acid and stearic acid. The levels of tricarboxylic acid (TCA) intermediates were much higher in FM and BM than those in HM. Each type of milk also showed its unique composition of free amino acids and free carbohydrates. In conclusion, higher levels of non-esterified saturated fatty acids with aliphatic tails <16 carbons, monounsaturated fatty acids and polyunsaturated fatty acids and lower levels of TCA intermediates are characteristic of HM, as compared with FM and BM. The content of non-esterified fatty acids may reflect the hydrolysis of triglycerides in different milk types. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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12 pages, 2035 KiB

Open AccessArticle

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid

by Hai-Zhi Jiang, Shu-Yu Wang, Xiang Yin, Hong-Quan Jiang, Xu-Dong Wang, Jing Wang, Tian-Hang Wang, Yan Qi, Yue-Qing Yang, Ying Wang, Chun-Ting Zhang and Hong-Lin Feng^*

Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China

Int. J. Mol. Sci. 2016, 17(12), 2129; https://doi.org/10.3390/ijms17122129 - 17 Dec 2016

Cited by 15 | Viewed by 7604

Abstract

Background: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important [...] Read more.

Background: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS. Results: In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice. Conclusion: The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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21 pages, 6077 KiB

Open AccessArticle

Identification of Heat Shock Transcription Factor Genes Involved in Thermotolerance of Octoploid Cultivated Strawberry

by Wan-Yu Liao^1,†, Lee-Fong Lin^2,†, Jing-Lian Jheng³, Chun-Chung Wang^4,5, Jui-Hung Yang⁵ and Ming-Lun Chou^2,*

¹ Institute of Medical Sciences, Tzu-Chi University, Hualien 97004, Taiwan

² Department of Life Sciences, Tzu-Chi University, Hualien 97004, Taiwan

³ Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 97004, Taiwan

⁴ Institute of Molecular Medicine, National Tsing-Hua University, Hsinchu 30013, Taiwan

⁵ Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 30011, Taiwan

^† These authors contributed equally to this study.

Int. J. Mol. Sci. 2016, 17(12), 2130; https://doi.org/10.3390/ijms17122130 - 17 Dec 2016

Cited by 17 | Viewed by 7433

Abstract

Heat shock transcription factors (HSFs) are mainly involved in the activation of genes in response to heat stress as well as other abiotic and biotic stresses. The growth, development, reproduction, and yield of strawberry are strongly limited by extreme temperatures and droughts. In [...] Read more.

Heat shock transcription factors (HSFs) are mainly involved in the activation of genes in response to heat stress as well as other abiotic and biotic stresses. The growth, development, reproduction, and yield of strawberry are strongly limited by extreme temperatures and droughts. In this study, we used Illumina sequencing and obtained transcriptome data set from Fragaria × ananassa Duchessne cv. Toyonoka. Six contigs and three unigenes were confirmed to encode HSF proteins (FaTHSFs). Subsequently, we characterized the biological functions of two particularly selected unigenes, FaTHSFA2a and FaTHSFB1a, which were classified into class A2 and B HSFs, respectively. Expression assays revealed that FaTHSFA2a and FaTHSFB1a expression was induced by heat shock and correlated well with elevated ambient temperatures. Overexpression of FaTHSFA2a and FaTHSFB1a resulted in the activation of their downstream stress-associated genes, and notably enhanced the thermotolerance of transgenic Arabidopsis plants. Besides, both FaTHSFA2a and FaTHSFB1a fusion proteins localized in the nucleus, indicating their similar subcellular distributions as transcription factors. Our yeast one-hybrid assay suggested that FaTHSFA2a has trans-activation activity, whereas FaTHSFB1a expresses trans-repression function. Altogether, our annotated transcriptome sequences provide a beneficial resource for identifying most genes expressed in octoploid strawberry. Furthermore, HSF studies revealed the possible insights into the molecular mechanisms of thermotolerance, thus rendering valuable molecular breeding to improve the tolerance of strawberry in response to high-temperature stress. Full article

(This article belongs to the Section Molecular Plant Sciences)

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10 pages, 751 KiB

Open AccessArticle

Circulating Cell-Free DNA Levels Could Predict Oncological Outcomes of Patients Undergoing Esophagectomy for Esophageal Squamous Cell Carcinoma

by Chih-Cheng Hsieh^1,2,3, Han-Shui Hsu^2,4, Shih-Ching Chang^3,5 and Yann-Jang Chen^1,6,7,*

¹ Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan

² Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 11217, Taiwan

³ Department of Surgery, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan

⁴ Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan

⁵ Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 11217, Taiwan

⁶ Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 11221, Taiwan

⁷ Department of Pediatrics, Renai Branch, Taipei City Hospital, Taipei 10629, Taiwan

Int. J. Mol. Sci. 2016, 17(12), 2131; https://doi.org/10.3390/ijms17122131 - 17 Dec 2016

Cited by 44 | Viewed by 5317

Abstract

Circulating cell-free DNA (cfDNA) is a potential biomarker for cancer progression but its role is unclear in patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. We investigated relationships between plasma cfDNA levels and clinicopathological parameters in ESCC patients. Eighty-one ESCC patients who [...] Read more.

Circulating cell-free DNA (cfDNA) is a potential biomarker for cancer progression but its role is unclear in patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. We investigated relationships between plasma cfDNA levels and clinicopathological parameters in ESCC patients. Eighty-one ESCC patients who received esophagectomy were enrolled. Plasma samples from these patients and 95 normal controls were collected. DNA copy numbers were measured by real-time quantitative PCR. Subjects were divided into two groups by cfDNA level. Clinicopathological data were collected retrospectively and relationships between cfDNA levels and clinical parameters were evaluated. The cfDNA level in normal controls ranged from 0–4157 copies/mL. The cfDNA level of 96.3% ESCC patients was higher than the cutoff value (2447.26 copies/mL) with a specificity of 94.1%. The mean cfDNA concentration was 5918 copies/mL in lower and 53,311 copies/mL in higher cfDNA groups. No correlations were found between clinicopathological factors and cfDNA levels except for lymphovascular invasion. Higher cfDNA levels were associated with tumor relapse (p = 0.018). Five-year disease-free survival (DFS) and overall survival (OS) rates were 34.7% and 33.8%, respectively. Patients with higher cfDNA levels had poorer DFS (p = 0.013). Patients with higher cfDNA levels had poorer OS, but not significantly (p = 0.164). Circulating cfDNA could be a biomarker for tumor relapse of ESCC with high sensitivity and specificity. Higher cfDNA levels were associated with tumor relapse and shorter DFS after esophagectomy in ESCC patients. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment 2016)

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12 pages, 234 KiB

Open AccessArticle

EGFR and KRAS Mutations Predict the Incidence and Outcome of Brain Metastases in Non-Small Cell Lung Cancer

by Pascale Tomasini^1,2,*, Cindy Serdjebi^1,3, Nataliya Khobta¹, Philippe Metellus⁴, L’Houcine Ouafik^2,3, Isabelle Nanni³, Laurent Greillier^1,2, Anderson Loundou⁵, Frederic Fina³, Celine Mascaux^1,2 and Fabrice Barlesi^1,2

¹ Assistance Publique Hôpitaux de Marseille, Multidisciplinary Oncology & Therapeutic Innovations department. Aix Marseille University, Marseille 13015, France

² Inserm U911 CRO2 (Centre de Recherche en Oncologie biologique et Onco-pharmacologie), Aix Marseille University, Marseille 13005, France

³ Assistance Publique Hôpitaux de Marseille, Transfer Oncology Laboratory, Aix Marseille University, Marseille 13015, France

⁴ Department of Neurosurgery, Aix-Marseille University, Marseille 13005, France

⁵ Statistics Department, Aix Marseille University, Marseille 13005, France

Int. J. Mol. Sci. 2016, 17(12), 2132; https://doi.org/10.3390/ijms17122132 - 18 Dec 2016

Cited by 54 | Viewed by 8180

Abstract

Background: Lung cancer is the leading cause of brain metastases (BM). The identification of driver oncogenes and matched targeted therapies has improved outcome in non-small cell lung cancer (NSCLC) patients; however, a better understanding of BM molecular biology is needed to further drive [...] Read more.

Background: Lung cancer is the leading cause of brain metastases (BM). The identification of driver oncogenes and matched targeted therapies has improved outcome in non-small cell lung cancer (NSCLC) patients; however, a better understanding of BM molecular biology is needed to further drive the process in this field. Methods: In this observational study, stage IV NSCLC patients tested for EGFR and KRAS mutations were selected, and BM incidence, recurrence and patients’ outcome were assessed. Results: A total of 144 patients (142 Caucasian and two Asian) were selected, including 11.27% with EGFR-mutant and 33.10% with KRAS-mutant tumors, and 57.04% patients had developed BM. BM incidence was more frequent in patients with EGFR mutation according to multivariate analyses (MVA) (Odds ratio OR = 8.745 [1.743–43.881], p = 0.008). Among patients with treated BM, recurrence after local treatment was less frequent in patients with KRAS mutation (OR = 0.234 [0.078–0.699], p = 0.009). Among patients with untreated BM, overall survival (OS) was shorter for patients with KRAS mutation according to univariate analysis (OR = 7.130 [1.240–41.012], p = 0.028), but not MVA. Conclusions: EGFR and KRAS mutations have a predictive role on BM incidence, recurrence and outcome in Caucasian NSCLC patients. These results may impact the routine management of disease in these patients. Further studies are required to assess the influence of other biomarkers on NSCLC BM. Full article

(This article belongs to the Special Issue Brain Metastasis 2016)

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16 pages, 2256 KiB

Open AccessArticle

Modulation of GLO1 Expression Affects Malignant Properties of Cells

by Antje Hutschenreuther^1,2, Marina Bigl¹, Nasr Y. A. Hemdan¹, Tewodros Debebe^3,4, Frank Gaunitz⁵

and Gerd Birkenmeier^1,*

¹ Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, Leipzig 04103, Germany

² Max Planck Institute of Evolutionary Anthropology, Deutscher Platz 6, Leipzig 04103, Germany

³ Institute of Medical Microbiology, Faculty of Medicine, University of Leipzig, Liebigstrasse 21, Leipzig 04103, Germany

⁴ College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar P.O. Box 79, Ethiopia

⁵ Department of Neurosurgery, University Hospital Leipzig, Liebigstrasse 20, Leipzig 04103, Germany

Int. J. Mol. Sci. 2016, 17(12), 2133; https://doi.org/10.3390/ijms17122133 - 18 Dec 2016

Cited by 27 | Viewed by 5257

Abstract

The energy metabolism of most tumor cells relies on aerobic glycolysis (Warburg effect) characterized by an increased glycolytic flux that is accompanied by the increased formation of the cytotoxic metabolite methylglyoxal (MGO). Consequently, the rate of detoxification of this reactive glycolytic byproduct needs [...] Read more.

The energy metabolism of most tumor cells relies on aerobic glycolysis (Warburg effect) characterized by an increased glycolytic flux that is accompanied by the increased formation of the cytotoxic metabolite methylglyoxal (MGO). Consequently, the rate of detoxification of this reactive glycolytic byproduct needs to be increased in order to prevent deleterious effects to the cells. This is brought about by an increased expression of glyoxalase 1 (GLO1) that is the rate-limiting enzyme of the MGO-detoxifying glyoxalase system. Here, we overexpressed GLO1 in HEK 293 cells and silenced it in MCF-7 cells using shRNA. Tumor-related properties of wild type and transformed cells were compared and key glycolytic enzyme activities assessed. Furthermore, the cells were subjected to hypoxic conditions to analyze the impact on cell proliferation and enzyme activities. Our results demonstrate that knockdown of GLO1 in the cancer cells significantly reduced tumor-associated properties such as migration and proliferation, whereas no functional alterations where found by overexpression of GLO1 in HEK 293 cells. In contrast, hypoxia caused inhibition of cell growth of all cells except of those overexpressing GLO1. Altogether, we conclude that GLO1 on one hand is crucial to maintaining tumor characteristics of malignant cells, and, on the other hand, supports malignant transformation of cells in a hypoxic environment when overexpressed. Full article

(This article belongs to the Special Issue Glyoxalase System)

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16 pages, 570 KiB

Open AccessReview

Recent Methods for Purification and Structure Determination of Oligonucleotides

by Qiulong Zhang^1,3,4,†, Huanhuan Lv^1,3,4,†, Lili Wang^1,3,4, Man Chen^1,3,4, Fangfei Li^1,3,4, Chao Liang^1,3,4, Yuanyuan Yu^1,3,4, Feng Jiang^1,2,3,4,*, Aiping Lu^1,3,4,* and Ge Zhang^1,3,4,*

¹ Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong, China

² The State Key Laboratory Base of Novel Functional Materials and Preparation Science, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China

³ Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology, Haimen 226100, China

⁴ Shenzhen Lab of Combinatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and Continuing Education, Shenzhen 518000, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2134; https://doi.org/10.3390/ijms17122134 - 18 Dec 2016

Cited by 19 | Viewed by 8486

Abstract

Aptamers are single-stranded DNA or RNA oligonucleotides that can interact with target molecules through specific three-dimensional structures. The excellent features, such as high specificity and affinity for target proteins, small size, chemical stability, low immunogenicity, facile chemical synthesis, versatility in structural design and [...] Read more.

Aptamers are single-stranded DNA or RNA oligonucleotides that can interact with target molecules through specific three-dimensional structures. The excellent features, such as high specificity and affinity for target proteins, small size, chemical stability, low immunogenicity, facile chemical synthesis, versatility in structural design and engineering, and accessible for site-specific modifications with functional moieties, make aptamers attractive molecules in the fields of clinical diagnostics and biopharmaceutical therapeutics. However, difficulties in purification and structural identification of aptamers remain a major impediment to their broad clinical application. In this mini-review, we present the recently attractive developments regarding the purification and identification of aptamers. We also discuss the advantages, limitations, and prospects for the major methods applied in purifying and identifying aptamers, which could facilitate the application of aptamers. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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11 pages, 1338 KiB

Open AccessReview

Review of Toxic Epidermal Necrolysis

by Victoria Harris^1,*, Christopher Jackson²

and Alan Cooper³

¹ Sydney Medical School—Northern, University of Sydney, 2065 Sydney, Australia

² Sutton Arthritis Research Laboratory, Kolling Institute, University of Sydney, 2065 Sydney, Australia

³ Dermatology Department, Royal North Shore Hospital, 2065 Sydney, Australia

Int. J. Mol. Sci. 2016, 17(12), 2135; https://doi.org/10.3390/ijms17122135 - 18 Dec 2016

Cited by 46 | Viewed by 23927

Abstract

Toxic epidermal necrolysis (TEN) is a rare but life threatening mucocutaneous reaction to drugs or their metabolites. It is characterised by widespread keratinocyte apoptosis and sloughing of the skin, erosions of the mucous membranes, painful blistering, and severe systemic disturbance. The pathophysiology of [...] Read more.

Toxic epidermal necrolysis (TEN) is a rare but life threatening mucocutaneous reaction to drugs or their metabolites. It is characterised by widespread keratinocyte apoptosis and sloughing of the skin, erosions of the mucous membranes, painful blistering, and severe systemic disturbance. The pathophysiology of TEN is incompletely understood. Historically, it has been regarded as a drug-induced immune reaction initiated by cytotoxic lymphocytes via a human leukocyte antigen (HLA)-restricted pathway. Several mediators have been identified as contributors to the cell death seen in TEN, including; granulysin, soluble Fas ligand, perforin/granzyme, tumour necrosis factor-α (TNF-α), and TNF-related apoptosis-inducing ligand. Currently, granulysin is accepted as the most important mediator of T cell proliferation. There is uncertainty around the accepted management of TEN. The lack of definitive management guidelines for TEN is explained in part by the rarity of the disease and its high mortality rate, which makes it difficult to conduct randomised control trials on emerging therapies. Developments have been made in pharmacogenomics, with numerous HLA alleles identified; however, these have largely been ethnically specific. These associations have translated into screening recommendations for Han Chinese. Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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10 pages, 381 KiB

Open AccessReview

Diabetic Cardiomyopathy: Does the Type of Diabetes Matter?

by Maximilian E. Hölscher, Christoph Bode and Heiko Bugger^*

Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany

Int. J. Mol. Sci. 2016, 17(12), 2136; https://doi.org/10.3390/ijms17122136 - 18 Dec 2016

Cited by 135 | Viewed by 13302

Abstract

In recent years, type 2 diabetes mellitus has evolved as a rapidly increasing epidemic that parallels the increased prevalence of obesity and which markedly increases the risk of cardiovascular disease across the globe. While ischemic heart disease represents the major cause of death [...] Read more.

In recent years, type 2 diabetes mellitus has evolved as a rapidly increasing epidemic that parallels the increased prevalence of obesity and which markedly increases the risk of cardiovascular disease across the globe. While ischemic heart disease represents the major cause of death in diabetic subjects, diabetic cardiomyopathy (DC) summarizes adverse effects of diabetes mellitus on the heart that are independent of coronary artery disease (CAD) and hypertension. DC increases the risk of heart failure (HF) and may lead to both heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). Numerous molecular mechanisms have been proposed to underlie DC that partially overlap with mechanisms believed to contribute to heart failure. Nevertheless, the existence of DC remains a topic of controversy, although the clinical relevance of DC is increasingly recognized by scientists and clinicians. In addition, relatively little attention has been attributed to the fact that both underlying mechanisms and clinical features of DC may be partially distinct in type 1 versus type 2 diabetes. In the following review, we will discuss clinical and preclinical literature on the existence of human DC in the context of the two different types of diabetes mellitus. Full article

(This article belongs to the Special Issue Diabetic Complications: Pathophysiology, Mechanisms, and Therapies)

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17 pages, 4406 KiB

Open AccessArticle

Neurotoxicity of a Biopesticide Analog on Zebrafish Larvae at Nanomolar Concentrations

by Ahmed Nasri^1,2,3,4, Audrey J. Valverde^1,2,3, Daniel B. Roche^5,6

, Catherine Desrumaux^1,2,3, Philippe Clair⁷, Hamouda Beyrem⁶, Laurent Chaloin⁸, Alain Ghysen^1,2,3,* and Véronique Perrier^1,2,3

¹ U1198 MMDN (Molecular Mechanisms of Neurodegenerative Diseases), Inserm (National Institute for Health and Medical Research), 34095 Montpellier, France

² BioCampus, University of Montpellier, 34095 Montpellier, France

³ EPHE (Ecole Pratique des Hautes Etudes), 75007 Paris, France

⁴ Laboratory of Environment Biomonitoring, Faculty of Sciences of Bizerta, University of Carthage, 7021 Zarzouna, Tunisia

⁵ IBC (Computational Biology Institute), CNRS (National Center for Scientific Research), University of Montpellier, 860 rue Saint Priest, 34095 Montpellier, France

⁶ CRBM (Research Center for Cell Biology in Montpellier), UMR 5237, CNRS, 1919 route de Mende, 34293 Montpellier, France

⁷ MGX (Montpellier GenomiX), BioCampus, University of Montpellier, 34095 Montpellier, France

⁸ CPBS (Center for Study of Pathogens and Biotechnologies for Health), FRE 3689, CNRS, University of Montpellier, 1919 route de Mende, 34293 Montpellier, France

Int. J. Mol. Sci. 2016, 17(12), 2137; https://doi.org/10.3390/ijms17122137 - 19 Dec 2016

Cited by 12 | Viewed by 6406

Abstract

Despite the ever-increasing role of pesticides in modern agriculture, their deleterious effects are still underexplored. Here we examine the effect of A6, a pesticide derived from the naturally-occurring α-terthienyl, and structurally related to the endocrine disrupting pesticides anilinopyrimidines, on living zebrafish larvae. We [...] Read more.

Despite the ever-increasing role of pesticides in modern agriculture, their deleterious effects are still underexplored. Here we examine the effect of A6, a pesticide derived from the naturally-occurring α-terthienyl, and structurally related to the endocrine disrupting pesticides anilinopyrimidines, on living zebrafish larvae. We show that both A6 and an anilinopyrimidine, cyprodinyl, decrease larval survival and affect central neurons at micromolar concentrations. Focusing on a superficial and easily observable sensory system, the lateral line system, we found that defects in axonal and sensory cell regeneration can be observed at much lower doses, in the nanomolar range. We also show that A6 accumulates preferentially in lateral line neurons and hair cells. We examined whether A6 affects the expression of putative target genes, and found that genes involved in apoptosis/cell proliferation are down-regulated, as well as genes reflecting estrogen receptor activation, consistent with previous reports that anilinopyrimidines act as endocrine disruptors. On the other hand, canonical targets of endocrine signaling are not affected, suggesting that the neurotoxic effect of A6 may be due to the binding of this compound to a recently identified, neuron-specific estrogen receptor. Full article

(This article belongs to the Special Issue Zebrafish: A Model for Toxicological Research)

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18 pages, 815 KiB

Open AccessReview

Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications

by Brittany R. Silverman and Jiaqi Shi^*

Department of Pathology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA

Int. J. Mol. Sci. 2016, 17(12), 2138; https://doi.org/10.3390/ijms17122138 - 19 Dec 2016

Cited by 26 | Viewed by 8478

Abstract

Pancreatic cancer is one of the most aggressive human cancer types with a five-year survival less than 7%. Emerging evidence revealed that many genetic alterations in pancreatic cancer target epigenetic regulators. Some of these mutations are driver mutations in cancer development. Several most [...] Read more.

Pancreatic cancer is one of the most aggressive human cancer types with a five-year survival less than 7%. Emerging evidence revealed that many genetic alterations in pancreatic cancer target epigenetic regulators. Some of these mutations are driver mutations in cancer development. Several most important mechanisms of epigenetic regulations include DNA methylation, histone modifications (methylation, acetylation, and ubiquitination), chromatin remodeling, and non-coding ribonucleic acids (RNAs). These modifications can alter chromatin structure and promoter accessibility, and thus lead to aberrant gene expression. However, exactly how these alterations affect epigenetic reprogramming in pancreatic cancer cells and in different stages of tumor development is still not clear. This mini-review summarizes the current knowledge of epigenetic alterations in pancreatic cancer development and progression, and discusses the clinical applications of epigenetic regulators as diagnostic biomarkers and therapeutic targets in pancreatic cancer. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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16 pages, 12552 KiB

Open AccessArticle

Triptolide Combined with Radiotherapy for the Treatment of Nasopharyngeal Carcinoma via NF-κB-Related Mechanism

by Weiying Zhang, Min Kang, Tingting Zhang, Bo Li, Xueyin Liao and Rensheng Wang^*

Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, China

Int. J. Mol. Sci. 2016, 17(12), 2139; https://doi.org/10.3390/ijms17122139 - 19 Dec 2016

Cited by 19 | Viewed by 5785

Abstract

Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis because of the lack of an effective treatment. Here we explored the efficiency and the molecular mechanisms of combined treatment with triptolide and ionizing radiation for treating NPC. Human nasopharyngeal carcinoma (CNE) cells were treated [...] Read more.

Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis because of the lack of an effective treatment. Here we explored the efficiency and the molecular mechanisms of combined treatment with triptolide and ionizing radiation for treating NPC. Human nasopharyngeal carcinoma (CNE) cells were treated with triptolide, ionizing radiation, or triptolide plus ionizing radiation in vitro. Tumor potency was examined in an in vivo CNE cell xenograft mouse model, which was treated as above. Our results demonstrated that triptolide caused a significant reduction in cell growth and colony number, and induced a marked apoptosis that was further enhanced with increasing doses of ionizing radiation. Combination treatment synergistically reduced tumor weight and volume without obvious toxicity. Western blot analysis in vitro and in vivo showed that triptolide induced apoptotic protein Bax expression and inhibited phosph-NF-κB p65, Bcl-2 and VEGF proteins without affecting other NF-κB related protein expression. In conclusion, our findings revealed that triptolide plus ionizing radiation had synergistic anti-tumor and anti-angiogenesis effects in NPC via down-regulating NF-κB p65 phosphorylation. The combination therapy may provide novel mechanism insights into inhibit NPC. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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17 pages, 1544 KiB

Open AccessReview

Effect of Lead (Pb) on Inflammatory Processes in the Brain

by Karina Chibowska¹, Irena Baranowska-Bosiacka^1,*

, Anna Falkowska¹, Izabela Gutowska²

, Marta Goschorska¹

and Dariusz Chlubek¹

¹ Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland

² Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24, 71-460 Szczecin, Poland

Int. J. Mol. Sci. 2016, 17(12), 2140; https://doi.org/10.3390/ijms17122140 - 19 Dec 2016

Cited by 122 | Viewed by 9863

Abstract

That the nervous system is the main target of lead (Pb) has long been considered an established fact until recent evidence has linked the Pb effect on the immune system to the toxic effects of Pb on the nervous system. In this paper, [...] Read more.

That the nervous system is the main target of lead (Pb) has long been considered an established fact until recent evidence has linked the Pb effect on the immune system to the toxic effects of Pb on the nervous system. In this paper, we present recent literature reports on the effect of Pb on the inflammatory processes in the brain, particularly the expression of selected cytokines in the brain (interleukin 6, TGF-β1, interleukin 16, interleukin 18, and interleukin 10); expression and activity of enzymes participating in the inflammatory processes, such as cyclooxygenase 2, caspase 1, nitrogen oxide synthase (NOS 2) and proteases (carboxypeptidases, metalloproteinases and chymotrypsin); and the expression of purine receptors P2X4 and P2X7. A significant role in the development of inflammatory processes in the brain is also played by microglia (residual macrophages in the brain and the spinal cord), which act as the first line of defense in the central nervous system, and astrocytes—Whose most important function is to maintain homeostasis for the proper functioning of neurons. In this paper, we also present evidence that exposure to Pb may result in micro and astrogliosis by triggering TLR4-MyD88-NF-κB signaling cascade and the production of pro-inflammatory cytokines. Full article

(This article belongs to the Section Bioinorganic Chemistry)

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14 pages, 416 KiB

Open AccessReview

Moringa oleifera Seeds and Oil: Characteristics and Uses for Human Health

by Alessandro Leone^1,2,*,†

, Alberto Spada^3,†

, Alberto Battezzati^1,2, Alberto Schiraldi², Junior Aristil³ and Simona Bertoli^1,2

¹ International Center for the Assessment of Nutritional Status (ICANS), University of Milan, Via Sandro Botticelli 21, 20133 Milan, Italy

² Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Mangiagalli 25, 20133 Milan, Italy

³ Department of Agricultural and Environmental Sciences-Production, Landscape, Agroenergy (DISAA), University of Milan, Via Celoria 2, 20133 Milan, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2141; https://doi.org/10.3390/ijms17122141 - 20 Dec 2016

Cited by 275 | Viewed by 30264

Abstract

Moringa oleifera seeds are a promising resource for food and non-food applications, due to their content of monounsaturated fatty acids with a high monounsaturated/saturated fatty acids (MUFA/SFA) ratio, sterols and tocopherols, as well as proteins rich in sulfated amino acids. The rapid growth [...] Read more.

Moringa oleifera seeds are a promising resource for food and non-food applications, due to their content of monounsaturated fatty acids with a high monounsaturated/saturated fatty acids (MUFA/SFA) ratio, sterols and tocopherols, as well as proteins rich in sulfated amino acids. The rapid growth of Moringa trees in subtropical and tropical areas, even under conditions of prolonged drought, makes this plant a reliable resource to enhance the nutritional status of local populations and, if rationalized cultivation practices are exploited, their economy, given that a biodiesel fuel could be produced from a source not in competition with human food crops. Despite the relatively diffuse use of Moringa seeds and their oil in traditional medicine, no pharmacological activity study has been conducted on humans. Some encouraging evidence, however, justifies new efforts to obtain clear and definitive information on the benefits to human health arising from seed consumption. A critical review of literature data concerning the composition of Moringa oil has set in motion a plan for future investigations. Such investigations, using the seeds and oil, will focus on cultivation conditions to improve plant production, and will study the health effects on human consumers of Moringa seeds and their oil. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables 2016)

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19 pages, 1180 KiB

Open AccessReview

Tumour Heterogeneity: The Key Advantages of Single-Cell Analysis

by Marta Tellez-Gabriel^1,*

, Benjamin Ory², Francois Lamoureux², Marie-Francoise Heymann^2,3,4 and Dominique Heymann^2,3,4,*

¹ Laboratorio Hematologia Oncologica y de Transplantes, Institut Investigacions Biomèdiques (IBB) Sant Pau, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain

² Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 957, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, Equipe Ligue 2012, Faculty of Medicine, University of Nantes, Nantes 44035, France

³ Department of Oncology and Metabolism, Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK

⁴ European Associated Laboratory, INSERM, Sarcoma Research Unit, Medical School, University of Sheffield, Sheffield S10 2RX, UK

Int. J. Mol. Sci. 2016, 17(12), 2142; https://doi.org/10.3390/ijms17122142 - 20 Dec 2016

Cited by 136 | Viewed by 17102

Abstract

Tumour heterogeneity refers to the fact that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity), and it [...] Read more.

Tumour heterogeneity refers to the fact that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity), and it is caused by genetic and non-genetic factors. The heterogeneity of cancer cells introduces significant challenges in using molecular prognostic markers as well as for classifying patients that might benefit from specific therapies. Thus, research efforts for characterizing heterogeneity would be useful for a better understanding of the causes and progression of disease. It has been suggested that the study of heterogeneity within Circulating Tumour Cells (CTCs) could also reflect the full spectrum of mutations of the disease more accurately than a single biopsy of a primary or metastatic tumour. In previous years, many high throughput methodologies have raised for the study of heterogeneity at different levels (i.e., RNA, DNA, protein and epigenetic events). The aim of the current review is to stress clinical implications of tumour heterogeneity, as well as current available methodologies for their study, paying specific attention to those able to assess heterogeneity at the single cell level. Full article

(This article belongs to the Special Issue Circulating Tumor Cells)

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12 pages, 1589 KiB

Open AccessArticle

Prediction of Hepatocellular Carcinoma Development after Hepatitis C Virus Eradication Using Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein

by Shunsuke Sato¹, Takuya Genda^1,*, Takafumi Ichida², Nozomi Amano¹, Sho Sato¹, Ayato Murata¹, Hironori Tsuzura¹, Yutaka Narita¹, Yoshio Kanemitsu¹, Katsuharu Hirano², Yuji Shimada¹, Katsuyori Iijima¹, Ryo Wada³, Akihito Nagahara¹ and Sumio Watanabe⁴

¹ Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka 410-2295, Japan

² Department of Hepatology, East Shonan General Hospital, Kanagawa 253-0083, Japan

³ Department of Pathology, Juntendo University Shizuoka Hospital, Shizuoka 410-2295, Japan

⁴ Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8431, Japan

Int. J. Mol. Sci. 2016, 17(12), 2143; https://doi.org/10.3390/ijms17122143 - 20 Dec 2016

Cited by 30 | Viewed by 5549

Abstract

We aimed to clarify the association between a novel serum fibrosis marker, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA⁺-M2BP), and hepatocellular carcinoma (HCC) development in 355 patients with chronic hepatitis C who achieved sustained virologic response (SVR) through interferon-based antiviral therapy. Pretreatment [...] Read more.

We aimed to clarify the association between a novel serum fibrosis marker, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA⁺-M2BP), and hepatocellular carcinoma (HCC) development in 355 patients with chronic hepatitis C who achieved sustained virologic response (SVR) through interferon-based antiviral therapy. Pretreatment serum WFA⁺-M2BP levels were quantified and the hazard ratios (HRs) for HCC development were retrospectively analyzed by Cox proportional hazard analysis. During the median follow-up time of 2.9 years, 12 patients developed HCC. Multivariate analysis demonstrated that high serum WFA⁺-M2BP (≥2.80 cut off index (COI), HR = 15.20, p = 0.013) and high fibrosis-4 (FIB-4) index (≥3.7, HR = 5.62, p = 0.034) were independent risk factors for HCC development. The three- and five-year cumulative incidence of HCC in patients with low WFA⁺-M2BP were 0.4% and 0.4%, respectively, whereas those of patients with high WFA⁺-M2BP were 7.7% and 17.6%, respectively (p < 0.001). In addition, combination of serum WFA⁺-M2BP and FIB-4 indices successfully stratified the risk of HCC: the five-year cumulative incidences of HCC were 26.9%, 6.8%, and 0.0% in patients with both, either, and none of these risk factors, respectively (p < 0.001). In conclusion, pretreatment serum WFA⁺-M2BP level is a useful predictor for HCC development after achieving SVR. Full article

(This article belongs to the Special Issue Hepatitis Virus Infection and Research)

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15 pages, 1370 KiB

Open AccessReview

Apoptosis in Cellular Society: Communication between Apoptotic Cells and Their Neighbors

by Yuhei Kawamoto^1,2, Yu-ichiro Nakajima^3,4 and Erina Kuranaga^1,2,3,*

¹ Laboratory for Histogenetic Dynamics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara 630-0192, Japan

² Laboratory for Histogenetic Dynamics, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan

³ Laboratory for Histogenetic Dynamics, Graduate School of Life Sciences, Tohoku University, Sendai 980-8578, Japan

⁴ Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai 980-8578, Japan

Int. J. Mol. Sci. 2016, 17(12), 2144; https://doi.org/10.3390/ijms17122144 - 20 Dec 2016

Cited by 47 | Viewed by 12984

Abstract

Apoptosis is one of the cell-intrinsic suicide programs and is an essential cellular behavior for animal development and homeostasis. Traditionally, apoptosis has been regarded as a cell-autonomous phenomenon. However, recent in vivo genetic studies have revealed that apoptotic cells actively influence the behaviors [...] Read more.

Apoptosis is one of the cell-intrinsic suicide programs and is an essential cellular behavior for animal development and homeostasis. Traditionally, apoptosis has been regarded as a cell-autonomous phenomenon. However, recent in vivo genetic studies have revealed that apoptotic cells actively influence the behaviors of surrounding cells, including engulfment, proliferation, and production of mechanical forces. Such interactions can be bidirectional, and apoptosis is non-autonomously induced in a cellular community. Of note, it is becoming evident that active communication between apoptotic cells and living cells contributes to physiological processes during tissue remodeling, regeneration, and morphogenesis. In this review, we focus on the mutual interactions between apoptotic cells and their neighbors in cellular society and discuss issues relevant to future studies of apoptosis. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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9 pages, 2586 KiB

Open AccessArticle

A Novel Pathogenic BRCA1 Splicing Variant Produces Partial Intron Retention in the Mature Messenger RNA

by Maria Valeria Esposito¹, Marcella Nunziato^1,2, Flavio Starnone¹, Antonella Telese¹, Alessandra Calabrese^1,3, Giuseppe D’Aiuto³, Pietro Pucci¹, Massimiliano D’Aiuto³, Francisco Baralle⁴, Valeria D’Argenio^1,5,*

and Francesco Salvatore^1,5,6,*

¹ CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy

² Department of Movement Sciences and Wellness (DiSMEB), University of Naples Parthenope, via Medina 40, 80133 Naples, Italy

³ Department of Senology, Istituto Nazionale Tumori–IRCCS Fondazione Pascale, via Mariano Semmola, 52, 80131 Naples, Italy

⁴ International Centre for Genetic Engineering and Biotechnology, Science Park, Padriciano 99, 34149 Trieste, Italy

⁵ Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, via Sergio Pansini 5, 80131 Naples, Italy

⁶ IRCCS-Fondazione SDN, via Emanuele Gianturco 113, 80143 Naples, Italy

Int. J. Mol. Sci. 2016, 17(12), 2145; https://doi.org/10.3390/ijms17122145 - 21 Dec 2016

Cited by 12 | Viewed by 6109

Abstract

About 10% of all breast cancers arise from hereditary mutations that increase the risk of breast and ovarian cancers; and about 25% of these are associated with the BRCA1 or BRCA2 genes. The identification of BRCA1/BRCA2 mutations can enable physicians to [...] Read more.

About 10% of all breast cancers arise from hereditary mutations that increase the risk of breast and ovarian cancers; and about 25% of these are associated with the BRCA1 or BRCA2 genes. The identification of BRCA1/BRCA2 mutations can enable physicians to better tailor the clinical management of patients; and to initiate preventive measures in healthy carriers. The pathophysiological significance of newly identified variants poses challenges for genetic counseling. We characterized a new BRCA1 variant discovered in a breast cancer patient during BRCA1/2 screening by next-generation sequencing. Bioinformatic predictions; indicating that the variant is probably pathogenetic; were verified using retro-transcription of the patient’s RNA followed by PCR amplifications performed on the resulting cDNA. The variant causes the loss of a canonic donor splice site at position +2 in BRCA1 intron 21; and consequently the partial retention of 156 bp of intron 21 in the patient’s transcript; which demonstrates that this novel BRCA1 mutation plays a pathogenetic role in breast cancer. These findings enabled us to initiate appropriate counseling and to tailor the clinical management of this family. Lastly; these data reinforce the importance of studying the effects of sequence variants at the RNA level to verify their potential role in disease onset. Full article

(This article belongs to the Special Issue Next-Generation Sequencing for Clinical Application)

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36 pages, 1154 KiB

Open AccessReview

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

by Edith Charlier^*, Biserka Relic, Céline Deroyer, Olivier Malaise

, Sophie Neuville, Julie Collée, Michel G. Malaise and Dominique De Seny

Laboratory of Rheumatology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA) Research, Centre Hospitalier Universitaire (CHU) de Liège, University of Liège, 4000 Liège, Belgium

Int. J. Mol. Sci. 2016, 17(12), 2146; https://doi.org/10.3390/ijms17122146 - 20 Dec 2016

Cited by 271 | Viewed by 15718

Abstract

Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs [...] Read more.

Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Apoptosis, chondroptosis, necrosis, and autophagic cell death are described in this review. The question of cell death causality in OA progression is also addressed, as well as the molecular pathways leading to cell death in response to the following inducers: Fas, Interleukin-1β (IL-1β), Tumor Necrosis factor-α (TNF-α), leptin, nitric oxide (NO) donors, and mechanical stresses. Furthermore, the protective role of autophagy in chondrocytes is highlighted, as well as its decline during OA progression, enhancing chondrocyte cell death; the transition being mainly controlled by HIF-1α/HIF-2α imbalance. Finally, we have considered whether interfering in chondrocyte apoptosis or promoting autophagy could constitute therapeutic strategies to impede OA progression. Full article

(This article belongs to the Special Issue Apoptotic Chondrocytes and Osteoarthritis)

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8 pages, 199 KiB

Open AccessReview

Neuroprotection via Reduction in Stress: Altered Menstrual Patterns as a Marker for Stress and Implications for Long-Term Neurologic Health in Women

by David Prokai and Sarah L. Berga^*

Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA

Int. J. Mol. Sci. 2016, 17(12), 2147; https://doi.org/10.3390/ijms17122147 - 20 Dec 2016

Cited by 22 | Viewed by 6696

Abstract

Individuals under chronic psychological stress can be difficult to identify clinically. There is often no outwardly visible phenotype. Chronic stress of sufficient magnitude not only impacts reproductive function, but also concomitantly elicits a constellation of neuroendocrine changes that may accelerate aging in general [...] Read more.

Individuals under chronic psychological stress can be difficult to identify clinically. There is often no outwardly visible phenotype. Chronic stress of sufficient magnitude not only impacts reproductive function, but also concomitantly elicits a constellation of neuroendocrine changes that may accelerate aging in general and brain aging in particular. Functional hypothalamic amenorrhea, a phenotypically recognizable form of stress, is due to stress-induced suppression of endogenous gonadotropin-releasing hormone secretion. Reversal of functional hypothalamic amenorrhea includes restoration of ovulatory ovarian function and fertility and amelioration of hypercortisolism and hypothyroidism. Taken together, recovery from functional hypothalamic amenorrhea putatively offers neuroprotection and ameliorates stress-induced premature brain aging and possibly syndromic Alzheimer’s disease. Amenorrhea may be viewed as a sentinel indicator of stress. Hypothalamic hypogonadism is less clinically evident in men and the diagnosis is difficult to establish. Whether there are other sex differences in the impact of stress on brain aging remains to be better investigated, but it is likely that both low estradiol from stress-induced anovulation and low testosterone from stress-induced hypogonadism compromise brain health. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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16 pages, 1057 KiB

Open AccessArticle

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

by Andrea Párniczky^1,†, Eszter Hegyi^1,†, Anna Zsófia Tóth¹, Ákos Szücs², Andrea Szentesi^3,4, Áron Vincze⁵, Ferenc Izbéki⁶, Balázs Csaba Németh⁴, Péter Hegyi^3,4 and Miklós Sahin-Tóth^1,*

¹ Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA

² First Department of Surgery, Semmelweis University, 1082 Budapest, Hungary

³ Institute for Translational Medicine, University of Pécs, 7624 Pécs, Hungary

⁴ First Department of Medicine, University of Szeged, 6720 Szeged, Hungary

⁵ First Department of Medicine, University of Pécs, 7624 Pécs, Hungary

⁶ Department of Gastroenterology, St. George Teaching Hospital of County Fejér, 8000 Székesfehérvár, Hungary

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2148; https://doi.org/10.3390/ijms17122148 - 20 Dec 2016

Cited by 14 | Viewed by 6003

Abstract

Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 [...] Read more.

Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 with Gly in exon 7. Since position 241 is polymorphic both in CELA3A (p.G241A) and CELA3B (p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 of CELA3A and CELA3B in a cohort of 225 subjects with chronic pancreatitis (120 alcoholic and 105 non-alcoholic) and 300 controls of Hungarian origin. Allele frequencies were 2.5% for CELA3A p.G241A and 1.5% for CELA3B p.A241G in controls, and no significant difference was observed in patients. Additionally, we identified six synonymous variants, two missense variants, a gene conversion event and ten variants in the flanking intronic regions. Variant c.643-7G>T in CELA3B showed an association with alcoholic chronic pancreatitis with a small protective effect (OR = 0.59, 95% CI = 0.39–0.89, p = 0.01). Functional analysis of missense variants revealed no major defects in secretion or activity. We conclude that variants affecting amino-acid position 241 in CELA3A and CELA3B are not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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13 pages, 1631 KiB

Open AccessArticle

Dermal Delivery of Constructs Encoding Cre Recombinase to Induce Skin Tumors in Pten^LoxP/LoxP;Braf^CA/+ Mice

by Marcel A. Deken¹, Ji-Ying Song², Jules Gadiot¹, Adriaan D. Bins³, Paula Kroon¹, Inge Verbrugge¹ and Christian U. Blank^1,4,*

¹ Department of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

² Department of Experimental Animal Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

³ Division of Medical Oncology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

⁴ Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Int. J. Mol. Sci. 2016, 17(12), 2149; https://doi.org/10.3390/ijms17122149 - 20 Dec 2016

Cited by 2 | Viewed by 7453

Abstract

Current genetically-engineered mouse melanoma models are often based on Tyr::CreER^T2-controlled MAPK pathway activation by the BRAF^V600E mutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness [...] Read more.

Current genetically-engineered mouse melanoma models are often based on Tyr::CreER^T2-controlled MAPK pathway activation by the BRAF^V600E mutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness of the Tyr::CreER^T2 system, hampering long-term experiments. To address this problem, we investigated several approaches to optimally provide local delivery of Cre recombinase, including injection of lentiviral particles, DNA tattoo administration and particle-mediated gene transfer, to induce melanomas in Pten^LoxP/LoxP;Braf^CA/+ mice lacking the Tyr::CreER^T2 allele. We found that dermal delivery of the Cre recombinase gene under the control of a non-specific CAG promoter induced the formation of melanomas, but also keratoacanthoma and squamous cell carcinomas. Delivery of Cre recombinase DNA under the control of melanocyte-specific promoters in Pten^LoxP/LoxP;Braf^CA/+ mice resulted in sole melanoma induction. The growth rate and histological features of the induced tumors were similar to 4-hydroxytamoxifen-induced tumors in Tyr::CreER^T2;Pten^LoxP/LoxP;Braf^CA/+ mice, while the onset of spontaneous tumors was prevented completely. These novel induction methods will allow long-term experiments in mouse models of skin malignancies. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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13 pages, 3296 KiB

Open AccessArticle

Neuropeptide Y1 Receptor Regulates Glucocorticoid-Induced Inhibition of Osteoblast Differentiation in Murine MC3T3-E1 Cells via ERK Signaling

by Wei Yu^†, Chao Zhu^†, Wenning Xu, Leisheng Jiang^* and Shengdan Jiang^*

¹ Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2150; https://doi.org/10.3390/ijms17122150 - 21 Dec 2016

Cited by 18 | Viewed by 6895

Abstract

High dose glucocorticoid (GC) administration impairs the viability and function of osteoblasts, thus causing osteoporosis and osteonecrosis. Neuropeptide Y1 receptor (Y1 receptor) is expressed in bone tissues and cells, and regulates bone remodeling. However, the role of Y1 receptor in glucocorticoid-induced inhibition of [...] Read more.

High dose glucocorticoid (GC) administration impairs the viability and function of osteoblasts, thus causing osteoporosis and osteonecrosis. Neuropeptide Y1 receptor (Y1 receptor) is expressed in bone tissues and cells, and regulates bone remodeling. However, the role of Y1 receptor in glucocorticoid-induced inhibition of osteoblast differentiation remains unknown. In the present study, osteoblastic cell line MC3T3-E1 cultured in osteogenic differentiation medium was treated with or without of 10⁻⁷ M dexamethasone (Dex), Y1 receptor shRNA interference, Y1 receptor agonist [Leu³¹, Pro³⁴]-NPY, and antagonist BIBP3226. Cell proliferation and apoptosis were assessed by cell counting kit-8 (CCK-8) assay and cleaved caspase expression, respectively. Osteoblast differentiation was evaluated by Alizarin Red S staining and osteogenic marker gene expressions. Protein expression was detected by Western blot analysis. Dex upregulated the expression of Y1 receptor in MC3T3-E1 cells associated with reduced osteogenic gene expressions and mineralization. Blockade of Y1 receptor by shRNA transfection and BIBP3226 significantly attenuated the inhibitory effects of Dex on osteoblastic activity. Y1 receptor signaling modulated the activation of extracellular signal-regulated kinases (ERK) as well as the expressions of osteogenic genes. Y1 receptor agonist inhibited ERK phosphorylation and osteoblast differentiation, while Y1 receptor blockade exhibited the opposite effects. Activation of ERK signaling by constitutive active mutant of MEK1 (caMEK) abolished Y1 receptor-mediated Dex inhibition of osteoblast differentiation in MC3T3-E1 cells. Taken together, Y1 receptor regulates Dex-induced inhibition of osteoblast differentiation in murine MC3T3-E1 cells via ERK signaling. This study provides a novel role of Y1 receptor in the process of GC-induced suppression in osteoblast survival and differentiation. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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