International Journal of Molecular Sciences

13 pages, 1825 KiB

Open AccessArticle

Vitamin B₁₂ Deficiency Induces Imbalance in Melanocytes Homeostasis—A Cellular Basis of Hypocobalaminemia Pigmentary Manifestations

by Zuzanna Rzepka, Michalina Respondek, Jakub Rok, Artur Beberok, Keith Ó Proinsias, Dorota Gryko and Dorota Wrześniok

Int. J. Mol. Sci. 2018, 19(9), 2845; https://doi.org/10.3390/ijms19092845 - 19 Sep 2018

Cited by 22 | Viewed by 8201

Abstract

Vitamin B₁₂ deficiency causes significant changes in cellular metabolism leading to various clinical symptoms, such as hematological, psychiatric, and neurological disorders. We hypothesize that skin pigmentation disorders may be a diagnostically important manifestation of vitamin B₁₂ deficiency, however the cellular and [...] Read more.

Vitamin B₁₂ deficiency causes significant changes in cellular metabolism leading to various clinical symptoms, such as hematological, psychiatric, and neurological disorders. We hypothesize that skin pigmentation disorders may be a diagnostically important manifestation of vitamin B₁₂ deficiency, however the cellular and molecular mechanisms underlying these effects remain unknown. The aim of this study was to examine the effect of vitamin B₁₂ deficiency on melanocytes homeostasis. Hypocobalaminemia in vitro model was developed by treating epidermal melanocytes with synthesized vitamin B₁₂ antagonist—hydroxycobalamin(c-lactam). The cells were examined using immunoenzymatic, spectrophotometric, and fluorimetric assays as well as image cytometry. Significant melanogenesis stimulation—the increase of relative melanin content and tyrosinase activity up to 131% and 135%, respectively—has been indicated. Cobalamin-deficient cells displayed the elevation (by 120%) in reactive oxygen species level. Moreover, the redox status imbalance was stated. The study provided a scientific evidence for melanocytes homeostasis disturbance under hypocobalaminemia, thus indicating a significant element of the hyperpigmentation mechanism due to vitamin B₁₂ deficiency. Furthermore, the implication between pigmentary and hematological and/or neuropsychiatric symptoms in cobalamin-deficient patients may be an important issue. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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15 pages, 4397 KiB

Open AccessArticle

Andrographolide Protects PC12 Cells Against β-Amyloid-Induced Autophagy-Associated Cell Death Through Activation of the Nrf2-Mediated p62 Signaling Pathway

by Lili Gu, Qingqing Yu, Qin Li, Lingxi Zhang, Hong Lu and Xinyue Zhang

Int. J. Mol. Sci. 2018, 19(9), 2844; https://doi.org/10.3390/ijms19092844 - 19 Sep 2018

Cited by 41 | Viewed by 6091

Abstract

Recent studies mentioned that Andrographolide (Andro), the main bioactive component of traditional Chinese medicine Andrographis paniculata, may be a potential natural product for treating Alzheimer's disease, but the underlining mechanism remains to be discovered. In this study, we investigated whether Andro regulates [...] Read more.

Recent studies mentioned that Andrographolide (Andro), the main bioactive component of traditional Chinese medicine Andrographis paniculata, may be a potential natural product for treating Alzheimer's disease, but the underlining mechanism remains to be discovered. In this study, we investigated whether Andro regulates the nuclear factor E2-related factor 2 (Nrf2)/Sequestosome 1 (p62) signaling pathway and activates autophagy to protect neuronal PC12 cells from the toxicity of the β-amyloid (Aβ) peptide. Our results revealed that Andro protected and rescued PC12 cells from Aβ_1–42-induced cell death and restored abnormal changes in nuclear morphology, lactate dehydrogenase, malondialdehyde, intracellular reactive oxygen species, and mitochondrial membrane potential. RT-PCR and Western blotting analysis demonstrated that Andro activated autophagy-related genes and proteins (Beclin-1 and LC3); meanwhile, it also augmented the Nrf2 and p62 expression in mRNA and protein levels, and reduced p-tau and p21 protein expression in Aβ_1–42-stimulated cells. Then, further study showed that the pre-transfection of cells with Nrf2 small interfering RNA (siRNA) resulted in the downregulation of p62, Beclin-1, and LC3 proteins expression, as well as the upregulation of p21. Furthermore, the pre-transfection of cells with p62 siRNA didn’t block the Nrf2 protein expression, accompanying with an elevated p21. Taken together, these results showed that Andro significantly ameliorated cell death due to Aβ_1–42 insult through the activation of autophagy and the Nrf2-mediated p62 signaling pathway. Full article

(This article belongs to the Section Biochemistry)

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49 pages, 627 KiB

Open AccessReview

Aloe Genus Plants: From Farm to Food Applications and Phytopharmacotherapy

by Bahare Salehi, Sevil Albayrak, Hubert Antolak, Dorota Kręgiel, Ewelina Pawlikowska, Mehdi Sharifi-Rad, Yadav Uprety, Patrick Valere Tsouh Fokou, Zubaida Yousef, Zainul Amiruddin Zakaria, Elena Maria Varoni, Farukh Sharopov, Natália Martins, Marcello Iriti and Javad Sharifi-Rad

Int. J. Mol. Sci. 2018, 19(9), 2843; https://doi.org/10.3390/ijms19092843 - 19 Sep 2018

Cited by 128 | Viewed by 19180

Abstract

Aloe genus plants, distributed in Old World, are widely known and have been used for centuries as topical and oral therapeutic agents due to their health, beauty, medicinal, and skin care properties. Among the well-investigated Aloe species are A. arborescens, A. barbadensis [...] Read more.

Aloe genus plants, distributed in Old World, are widely known and have been used for centuries as topical and oral therapeutic agents due to their health, beauty, medicinal, and skin care properties. Among the well-investigated Aloe species are A. arborescens, A. barbadensis, A. ferox, and A. vera. Today, they account among the most economically important medicinal plants and are commonly used in primary health treatment, where they play a pivotal role in the treatment of various types of diseases via the modulation of biochemical and molecular pathways, besides being a rich source of valuable phytochemicals. In the present review, we summarized the recent advances in botany, phytochemical composition, ethnobotanical uses, food preservation, and the preclinical and clinical efficacy of Aloe plants. These data will be helpful to provide future directions for the industrial and medicinal use of Aloe plants. Full article

(This article belongs to the Special Issue Feature Annual Reviews in Molecular Sciences 2019)

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14 pages, 2564 KiB

Open AccessArticle

Beeswax by-Products Efficiently Counteract the Oxidative Damage Induced by an Oxidant Agent in Human Dermal Fibroblasts

by Francesca Giampieri, Massimiliano Gasparrini, Tamara Y. Forbes-Hernández, Piera Pia Manna, Jiaojiao Zhang, Patricia Reboredo-Rodríguez, Danila Cianciosi, Jose L. Quiles, Cristina Torres Fernández-Piñar, Francisco Josè Orantes-Bermejo, Stefano Bompadre, Sadia Afrin and Maurizio Battino

Int. J. Mol. Sci. 2018, 19(9), 2842; https://doi.org/10.3390/ijms19092842 - 19 Sep 2018

Cited by 9 | Viewed by 5639

Abstract

The antioxidant capacity and the phytochemical composition of two by-products from beeswax recycling processes were recently investigated. The aim of the present work was to evaluate the efficacy of one of these by-products, MUD1, against the oxidative stress induced by 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH) [...] Read more.

The antioxidant capacity and the phytochemical composition of two by-products from beeswax recycling processes were recently investigated. The aim of the present work was to evaluate the efficacy of one of these by-products, MUD1, against the oxidative stress induced by 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH) in human dermal fibroblast (HDF) cells. After a preliminary viability assay, the protective effect of MUD1 was investigated through the measurement of apoptosis level, the reactive oxygen species (ROS) and nitrite (NO₂⁻) production, the level of protein and lipid biomarkers (carbonyl groups, total glutathione and thiobarbituric acid-reactive substance) of oxidative damage, and the measurement of antioxidant enzymes activities (glutatione peroxidase, glutathione reductase, glutathione transferase, superoxide dismutase and catalase). The obtained results showed that MUD1 exerted protective effects on HDF, increasing cell viability and counteracted the oxidative stress promoted by AAPH-treatment, and improved mitochondria functionality and wound healing capacities. This work shows the antioxidant effects exerted by beeswax by-products, demonstrating for the first time their potential against oxidative stress in human dermal fibroblast cells; however, further research will be necessary to evaluate their potentiality for human health by more deeply in vitro and in vivo studies. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 2059 KiB

Open AccessArticle

Increased Expression of Maturation Promoting Factor Components Speeds Up Meiosis in Oocytes from Aged Females

by Marketa Koncicka, Anna Tetkova, Denisa Jansova, Edgar Del Llano, Lenka Gahurova, Jana Kracmarova, Sarka Prokesova, Tomas Masek, Martin Pospisek, Alexander W. Bruce, Michal Kubelka and Andrej Susor

Int. J. Mol. Sci. 2018, 19(9), 2841; https://doi.org/10.3390/ijms19092841 - 19 Sep 2018

Cited by 15 | Viewed by 5517

Abstract

The rate of chromosome segregation errors that emerge during meiosis I in the mammalian female germ line are known to increase with maternal age; however, little is known about the underlying molecular mechanism. The objective of this study was to analyze meiotic progression [...] Read more.

The rate of chromosome segregation errors that emerge during meiosis I in the mammalian female germ line are known to increase with maternal age; however, little is known about the underlying molecular mechanism. The objective of this study was to analyze meiotic progression of mouse oocytes in relation to maternal age. Using the mouse as a model system, we analyzed the timing of nuclear envelope breakdown and the morphology of the nuclear lamina of oocytes obtained from young (2 months old) and aged females (12 months old). Oocytes obtained from older females display a significantly faster progression through meiosis I compared to the ones obtained from younger females. Furthermore, in oocytes from aged females, lamin A/C structures exhibit rapid phosphorylation and dissociation. Additionally, we also found an increased abundance of MPF components and increased translation of factors controlling translational activity in the oocytes of aged females. In conclusion, the elevated MPF activity observed in aged female oocytes affects precocious meiotic processes that can multifactorially contribute to chromosomal errors in meiosis I. Full article

(This article belongs to the Special Issue Translational Control)

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16 pages, 2877 KiB

Open AccessArticle

Deep Brain Stimulation Modified Autism-Like Deficits via the Serotonin System in a Valproic Acid-Induced Rat Model

by Han-Fang Wu, Yi-Ju Chen, Ming-Chia Chu, Ya-Ting Hsu, Ting-Yi Lu, I-Tuan Chen, Po See Chen and Hui-Ching Lin

Int. J. Mol. Sci. 2018, 19(9), 2840; https://doi.org/10.3390/ijms19092840 - 19 Sep 2018

Cited by 22 | Viewed by 6812

Abstract

Deep brain stimulation (DBS) is known to be a promising treatment for resistant depression, which acts via the serotonin (5-hydroxytryptamine, 5-HT) system in the infralimbic prefrontal cortex (ILPFC). Previous study revealed that dysfunction of brain 5-HT homeostasis is related to a valproate (VPA)-induced [...] Read more.

Deep brain stimulation (DBS) is known to be a promising treatment for resistant depression, which acts via the serotonin (5-hydroxytryptamine, 5-HT) system in the infralimbic prefrontal cortex (ILPFC). Previous study revealed that dysfunction of brain 5-HT homeostasis is related to a valproate (VPA)-induced rat autism spectrum disorder (ASD) model. Whether ILPFC DBS rescues deficits in VPA-induced offspring through the 5-HT system is not known. Using VPA-induced offspring, we therefore explored the effect of DBS in autistic phenotypes and further investigated the underlying mechanism. Using combined behavioral and molecular approaches, we observed that applying DBS and 5-HT_1A receptor agonist treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reversed sociability deficits, anxiety and hyperactivity in the VPA-exposed offspring. We then administered the selective 5-HT_1A receptor antagonist N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY 100635), following which the effect of DBS in terms of improving autistic behaviors was blocked in the VPA-exposed offspring. Furthermore, we found that both 8-OH-DPAT and DBS treatment rescued autistic behaviors by decreasing the expressions of NR2B subunit of N-methyl-D-aspartate receptors (NMDARs) and the β₃ subunit of γ-aminobutyric acid type A receptors (GABA_AR) in the PFC region. These results provided the first evidence of characteristic behavioral changes in VPA-induced offspring caused by DBS via the 5-HT system in the ILPFC. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2018)

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16 pages, 1330 KiB

Open AccessArticle

The Effect of Pectinase-Assisted Extraction on the Physicochemical and Biological Properties of Polysaccharides from Aster scaber

by Young-Ran Song, Su-Kyung Sung, Eun-Ju Shin, Chang-Won Cho, Chun-Ji Han and Hee-Do Hong

Int. J. Mol. Sci. 2018, 19(9), 2839; https://doi.org/10.3390/ijms19092839 - 19 Sep 2018

Cited by 9 | Viewed by 4522

Abstract

The edible and medicinal perennial herb Aster scaber is known to have anticancer, antioxidant, and immunomodulatory properties. However, the biological effects of its polysaccharides are not well understood. Here, we aimed to extract novel polysaccharides with enhanced biological properties from Aster scaber using [...] Read more.

The edible and medicinal perennial herb Aster scaber is known to have anticancer, antioxidant, and immunomodulatory properties. However, the biological effects of its polysaccharides are not well understood. Here, we aimed to extract novel polysaccharides with enhanced biological properties from Aster scaber using enzyme-assisted methods. Amylase, cellulase, and pectinase were used to extract enzyme-assisted polysaccharide (ASEP)-A, ASEP-C, and ASEP-P, respectively. The yields, physicochemical properties, and immunostimulatory activities of the polysaccharides were investigated and compared with those of hot water extracted polysaccharide (ASWP). The highest yield (3.8%) was achieved for ASEP-P extracted using pectinase digestion. Fourier-transform infrared spectroscopy (FT-IR) and chemical composition analysis revealed that ASWP and three ASEPs were typical acidic heteropolysaccharides, mainly comprising rhamnose, arabinose, galactose, glucose, and galacturonic acid. Immunostimulatory activity assays on RAW264.7 macrophages showed ASEP-P to have the greatest immunostimulatory potential in terms of nitric oxide (NO) and cytokine productions and phagocytic activity. ASEP-P administration improved immune-enhancing effects in normal mice by improving the spleen index and splenic lymphocyte proliferation, and in immunosuppressed mice by modulating lymphocyte proliferation, natural killer (NK) cell activity, and leukocyte counts. The ASEP-P derived from pectinase hydrolysate of Aster scaber demonstrated efficacious immunostimulatory properties and has potential applications as an immune stimulator. Full article

(This article belongs to the Special Issue Bioactive Nutrients, Immunity and Inflammation)

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13 pages, 7183 KiB

Open AccessArticle

Chalcone Derivatives 4′-Amino-1-Naphthyl-Chalcone (D14) and 4′-Amino-4-Methyl-1-Naphthyl-Chalcone (D15) Suppress Migration and Invasion of Osteosarcoma Cells Mediated by p53 Regulating EMT-Related Genes

by Viviane Seba, Gabriel Silva, Mariana Bastos dos Santos, Seung Joon Baek, Suzelei De Castro França, Ana Lúcia Fachin, Luis Octavio Regasini and Mozart Marins

Int. J. Mol. Sci. 2018, 19(9), 2838; https://doi.org/10.3390/ijms19092838 - 19 Sep 2018

Cited by 31 | Viewed by 5522

Abstract

Osteosarcoma (OS) is a primary malignant bone tumor that mainly affects children, adolescents, and young adults. The inhibition of metastasis is a main strategy of OS therapy since the development of metastatic disease due to drug resistance remains the most important cause of [...] Read more.

Osteosarcoma (OS) is a primary malignant bone tumor that mainly affects children, adolescents, and young adults. The inhibition of metastasis is a main strategy of OS therapy since the development of metastatic disease due to drug resistance remains the most important cause of death from this cancer. Considering the severe side effects of current OS chemotherapy, the identification of anti-metastatic drugs with reduced toxicity is of great interest. Chalcones are polyphenols with a basic structure consisting of an α-, β-unsaturated carbonyl system linking two aryl rings. These compounds exhibit anticancer activity against a variety of tumor cell lines through multiple mechanisms, including the regulation of the tumor-suppressor protein p53 and its target genes. An important process regulated by p53 is epithelial-mesenchymal transition (EMT), which facilitates tumor metastasis by conferring migratory and invasive properties to cancer cells. The activation of p53 can revert EMT and reduce migration and invasion. This study aimed to examine the inhibitory effects of two 4′-aminochalcones on the migration/invasion of the U2OS (p53+/+) and SAOS-2 (p53−/−) OS cell lines as well as the underlying molecular mechanisms. Cell viability was examined by MTT assay. Transwell assays were used to evaluate the migratory and invasive ability of the cells. The two 4′-aminochalcones showed low capacity to inhibit the viability of OS cells independent of p53 status, but preferentially suppressed the migration of U2OS cells and of a SAOS-2 cell line expressing p53. Invasion was strongly inhibited by both chalcones independent of p53 status. RT-PCR, zymography, and Western blot were used to study the expression of matrix metalloproteinases and EMT markers after treatment with the chalcones. The results indicated that the 4′-aminochalcone-induced antimigratory and anti-invasive effects are potentially associated with the inhibition of extracellular matrix (ECM) enzymatic degradation in OS cells and with the modulation of EMT genes. These effects probably result from the induced increase of p53 protein expression by the two chalcones. In conclusion, chalcones D14 and D15 have potential anti-metastatic activity mediated by p53 that can be exploited for OS treatment. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT))

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19 pages, 4561 KiB

Open AccessArticle

Guanidinoacetic Acid Regulates Myogenic Differentiation and Muscle Growth Through miR-133a-3p and miR-1a-3p Co-mediated Akt/mTOR/S6K Signaling Pathway

by Yujie Wang, Jideng Ma, Wanling Qiu, Jinwei Zhang, Siyuan Feng, Xiankun Zhou, Xun Wang, Long Jin, Keren Long, Lingyan Liu, Weihang Xiao, Qianzi Tang, Li Zhu, Yanzhi Jiang, Xuewei Li and Mingzhou Li

Int. J. Mol. Sci. 2018, 19(9), 2837; https://doi.org/10.3390/ijms19092837 - 19 Sep 2018

Cited by 41 | Viewed by 6593

Abstract

Guanidinoacetic acid (GAA), an amino acid derivative that is endogenous to animal tissues including muscle and nerve, has been reported to enhance muscular performance. MicroRNA (miRNA) is a post-transcriptional regulator that plays a key role in nutrient-mediated myogenesis. However, the effects of GAA [...] Read more.

Guanidinoacetic acid (GAA), an amino acid derivative that is endogenous to animal tissues including muscle and nerve, has been reported to enhance muscular performance. MicroRNA (miRNA) is a post-transcriptional regulator that plays a key role in nutrient-mediated myogenesis. However, the effects of GAA on myogenic differentiation and skeletal muscle growth, and the potential regulatory mechanisms of miRNA in these processes have not been elucidated. In this study, we investigated the effects of GAA on proliferation, differentiation, and growth in C2C12 cells and mice. The results showed that GAA markedly inhibited the proliferation of myoblasts, along with the down-regulation of cyclin D1 (CCND1) and cyclin dependent kinase 4 (CDK4) mRNA expression, and the upregulation of cyclin dependent kinase inhibitor 1A (P21) mRNA expression. We also demonstrated that GAA treatment stimulated myogenic differentiation 1 (MyoD) and myogenin (MyoG) mRNA expression, resulting in an increase in the myotube fusion rate. Meanwhile, GAA supplementation promoted myotube growth through increase in total myosin heavy chain (MyHC) protein level, myotubes thickness and gastrocnemius muscle cross-sectional area. Furthermore, small RNA sequencing revealed that a total of eight miRNAs, including miR-133a-3p and miR-1a-3p cluster, showed differential expression after GAA supplementation. To further study the function of miR-133a-3p and miR-1a-3p in GAA-induced skeletal muscle growth, we transfected miR-133a-3p and miR-1a-3p mimics into myotube, which also induced muscle growth. Through bioinformatics and a dual-luciferase reporter system, the target genes of miR-133a-3p and miR-1a-3p were determined. These two miRNAs were shown to modulate the Akt/mTOR/S6K signaling pathway by restraining target gene expression. Taken together, these findings suggest that GAA supplementation can promote myoblast differentiation and skeletal muscle growth through miR-133a-3p- and miR-1a-3p-induced activation of the AKT/mTOR/S6K signaling pathway. Full article

(This article belongs to the Special Issue Signaling: From Past to Future)

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11 pages, 2868 KiB

Open AccessArticle

Circulating Serum miRNA-205 as a Diagnostic Biomarker for Ototoxicity in Mice Treated with Aminoglycoside Antibiotics

by Sun Hee Lee, Hyun Mi Ju, Jin Sil Choi, Yeji Ahn, Suhun Lee and Young Joon Seo

Int. J. Mol. Sci. 2018, 19(9), 2836; https://doi.org/10.3390/ijms19092836 - 19 Sep 2018

Cited by 15 | Viewed by 4310

Abstract

Background: To confirm levels and detection timing of circulating microRNAs (miRNAs) in the serum of a mouse model for diagnosis of ototoxicity, circulating miR-205 in the serum was evaluated to reflect damages in the cochlear microstructure and compared to a kidney injury model. [...] Read more.

Background: To confirm levels and detection timing of circulating microRNAs (miRNAs) in the serum of a mouse model for diagnosis of ototoxicity, circulating miR-205 in the serum was evaluated to reflect damages in the cochlear microstructure and compared to a kidney injury model. Method: A microarray for miRNAs in the serum was performed to assess the ototoxic effects of kanamycin-furosemide. Changes in the levels for the selected miRNAs (miR-205, miR-183, and miR-103) were compared in the serum and microstructures of the cochlea (stria vascularis, organ of Corti, and modiolus) between the ototoxicity and normal mouse groups. An acute kidney injury (AKI) mouse model was used to assess changes in miR-205 levels in the kidney by ototoxic drugs. Results: In the mouse model for ototoxicity, the serum levels of circulating miR-205 peaked on day 3 and were sustained from days 7–14. Furthermore, miR-205 expression was highly expressed in the organ of Corti at day 5, continued to be expressed in the modiolus at high levels until day 14, and was finally also in the stria vascularis. The serum miR-205 in the AKI mice did not change significantly compared to the normal group. Conclusions Circulating miR-205 from the cochlea, after ototoxic damage, migrates through the blood vessels to organs, which is then finally found in blood. In conditions of hearing impairment with ototoxic medications, detection of circulating miR-205 in the blood can be used to determine the extent of hearing loss. In the future, inner ear damage can be identified by simply performing a blood test before the hearing impairment due to ototoxic drugs. Full article

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

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17 pages, 841 KiB

Open AccessReview

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

by Etienne Giroux-Leprieur, Adrien Costantini, Vivianne W. Ding and Biao He

Int. J. Mol. Sci. 2018, 19(9), 2835; https://doi.org/10.3390/ijms19092835 - 19 Sep 2018

Cited by 78 | Viewed by 7369

Abstract

Hedgehog signaling pathway is physiologically activated during embryogenesis, especially in lung development. It is also reactivated in many solid tumors. In lung cancer, Hedgehog pathway is closely associated with cancer stem cells (CSCs). Recent works have shown that CSCs produced a full-length Sonic [...] Read more.

Hedgehog signaling pathway is physiologically activated during embryogenesis, especially in lung development. It is also reactivated in many solid tumors. In lung cancer, Hedgehog pathway is closely associated with cancer stem cells (CSCs). Recent works have shown that CSCs produced a full-length Sonic Hedgehog (Shh) protein, with paracrine activity and induction of tumor development. Hedgehog pathway is also involved in tumor drug resistance in lung cancer, as cytotoxic chemotherapy, radiotherapy, and targeted therapies. This review proposes to describe the activation mechanisms of Hedgehog pathway in lung cancer, the clinical implications for overcoming drug resistance, and the perspectives for further research. Full article

(This article belongs to the Special Issue Hedgehog Signaling)

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17 pages, 1087 KiB

Open AccessReview

Molecular Communication of a Dying Neuron in Stroke

by Berta Puig, Santra Brenna and Tim Magnus

Int. J. Mol. Sci. 2018, 19(9), 2834; https://doi.org/10.3390/ijms19092834 - 19 Sep 2018

Cited by 102 | Viewed by 9958

Abstract

When a main artery of the brain occludes, a cellular response involving multiple cell types follows. Cells directly affected by the lack of glucose and oxygen in the neuronal core die by necrosis. In the periphery surrounding the ischemic core (the so-called penumbra) [...] Read more.

When a main artery of the brain occludes, a cellular response involving multiple cell types follows. Cells directly affected by the lack of glucose and oxygen in the neuronal core die by necrosis. In the periphery surrounding the ischemic core (the so-called penumbra) neurons, astrocytes, microglia, oligodendrocytes, pericytes, and endothelial cells react to detrimental factors such as excitotoxicity, oxidative stress, and inflammation in different ways. The fate of the neurons in this area is multifactorial, and communication between all the players is important for survival. This review focuses on the latest research relating to synaptic loss and the release of apoptotic bodies and other extracellular vesicles for cellular communication in stroke. We also point out possible treatment options related to increasing neuronal survival and regeneration in the penumbra. Full article

(This article belongs to the Special Issue Neuron Cell Death)

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19 pages, 2884 KiB

Open AccessArticle

Altered Glucosinolate Profiles and Expression of Glucosinolate Biosynthesis Genes in Ringspot-Resistant and Susceptible Cabbage Lines

by Md. Abuyusuf, Arif Hasan Khan Robin, Hoy-Taek Kim, Md. Rafiqul Islam, Jong-In Park and Ill-Sup Nou

Int. J. Mol. Sci. 2018, 19(9), 2833; https://doi.org/10.3390/ijms19092833 - 19 Sep 2018

Cited by 14 | Viewed by 4483

Abstract

Ringspot, caused by the fungus Mycosphaerella brassicicola, is a serious disease of Brassica crops worldwide. Despite noteworthy progress to reveal the role of glucosinolates in pathogen defense, the host–pathogen interaction between cabbage (Brassica oleracea) and M. brassicicola has not been [...] Read more.

Ringspot, caused by the fungus Mycosphaerella brassicicola, is a serious disease of Brassica crops worldwide. Despite noteworthy progress to reveal the role of glucosinolates in pathogen defense, the host–pathogen interaction between cabbage (Brassica oleracea) and M. brassicicola has not been fully explored. Here, we investigated the glucosinolate profiles and expression of glucosinolate biosynthesis genes in the ringspot-resistant (R) and susceptible (S) lines of cabbage after infection with M. brassicicola. The concomitant rise of aliphatic glucoiberverin (GIV) and indolic glucobrassicin (GBS) and methoxyglucobrassicin (MGBS) was linked with ringspot resistance in cabbage. Pearson’s correlation and principle component analysis showed a significant positive association between GIV contents and the expression of the glucosinolate biosynthesis gene ST5b-Bol026202 and between GBS contents and the expression of the glucosinolate biosynthesis gene MYB34-Bol017062. Our results confirmed that M. brassicicola infection induces the expression of glucosinolate biosynthesis genes in cabbage, which alters the content of individual glucosinolates. This link between the expression of glucosinolate biosynthesis genes and the accumulation of their respective glucosinolates with the resistance to ringspot extends our molecular sense of glucosinolate-negotiated defense against M. brassicicola in cabbage. Full article

(This article belongs to the Section Molecular Plant Sciences)

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15 pages, 2740 KiB

Open AccessArticle

Zingerone Suppresses Tumor Development through Decreasing Cyclin D1 Expression and Inducing Mitotic Arrest

by Jae-Sun Choi, Jaewook Ryu, Woom-Yee Bae, Aron Park, Seungyoon Nam, Ja-Eun Kim and Joo-Won Jeong

Int. J. Mol. Sci. 2018, 19(9), 2832; https://doi.org/10.3390/ijms19092832 - 19 Sep 2018

Cited by 33 | Viewed by 5307

Abstract

Cancer cells undergo uncontrolled proliferation resulting from aberrant activity of various cell-cycle proteins. Therefore, despite recent advances in intensive chemotherapy, it is difficult to cure cancer completely. Recently, cell-cycle regulators became attractive targets in cancer therapy. Zingerone, a phenolic compound isolated from ginger, [...] Read more.

Cancer cells undergo uncontrolled proliferation resulting from aberrant activity of various cell-cycle proteins. Therefore, despite recent advances in intensive chemotherapy, it is difficult to cure cancer completely. Recently, cell-cycle regulators became attractive targets in cancer therapy. Zingerone, a phenolic compound isolated from ginger, is a nontoxic and inexpensive compound with varied pharmacological activities. In this study, the therapeutic effect of zingerone as an anti-mitotic agent in human neuroblastoma cells was investigated. Following treatment of BE(2)-M17 cells with zingerone, we performed a 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and colony-formation assay to evaluate cellular proliferation, in addition to immunofluorescence cytochemistry and flow cytometry to examine the mitotic cells. The association of gene expression with tumor stage and survival was analyzed. Furthermore, to examine the anti-cancer effect of zingerone, we applied a BALB/c mouse-tumor model using a BALB/c-derived adenocarcinoma cell line. In human neuroblastoma cells, zingerone inhibited cellular viability and survival. Moreover, the number of mitotic cells, particularly those in prometaphase, increased in zingerone-treated neuroblastoma cells. Regarding specific molecular mechanisms, zingerone decreased cyclin D1 expression and induced the cleavage of caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1). The decrease in cyclin D1 and increase in histone H3 phosphorylated (p)-Ser10 were confirmed by immunohistochemistry in tumor tissues administered with zingerone. These results suggest that zingerone induces mitotic arrest followed by inhibition of growth of neuroblastoma cells. Collectively, zingerone may be a potential therapeutic drug for human cancers, including neuroblastoma. Full article

(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)

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11 pages, 1857 KiB

Open AccessArticle

MePHD1 as a PHD-Finger Protein Negatively Regulates ADP-Glucose Pyrophosphorylase Small Subunit1a Gene in Cassava

by Ping’an Ma, Xin Chen, Chen Liu, Zhiqiang Xia, Yu Song, Changying Zeng, Youzhi Li and Wenquan Wang

Int. J. Mol. Sci. 2018, 19(9), 2831; https://doi.org/10.3390/ijms19092831 - 19 Sep 2018

Cited by 6 | Viewed by 3931

Abstract

ADP-glucose pyrophosphorylase (AGPase) is an important enzyme in the starch synthesis pathway. Its enzyme activity can determine the efficiency of starch biosynthesis. Cassava (Manihot esculenta Crantz) is the main staple crop worldwide and has a high starch content in its storage root. [...] Read more.

ADP-glucose pyrophosphorylase (AGPase) is an important enzyme in the starch synthesis pathway. Its enzyme activity can determine the efficiency of starch biosynthesis. Cassava (Manihot esculenta Crantz) is the main staple crop worldwide and has a high starch content in its storage root. However, the inner regulatory mechanism of AGPase gene family is unclear. MePHD1; a plant homeodomain transcription factor; was isolated through a yeast one-hybrid screening using the promoter of ADP-glucose pyrophosphorylase small subunit1a (MeAGPS1a) as bait, and cassava storage root cDNA library as prey. This factor could bind to the MeAGPS1a promoter in vitro and in vivo, and its predicted binding region ranged from −400 bp to −201 bp, at the translation initiation site. The transcript level of MePHD1 could be induced by five plant hormones, and a temperature of 42 °C. This was down-regulated during the maturation process of the storage root. MePHD1 protein could repress the promoter activity of MeAGPS1a gene by a dual-luciferase assay; which indicated that MePHD1 is a negative regulator for the transcript level of MeAGPS1a gene. Full article

(This article belongs to the Section Molecular Plant Sciences)

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20 pages, 2531 KiB

Open AccessReview

Ocular Drug Delivery: Role of Degradable Polymeric Nanocarriers for Ophthalmic Application

by Cheng-Han Tsai, Peng-Yuan Wang, I-Chan Lin, Hu Huang, Guei-Sheung Liu and Ching-Li Tseng

Int. J. Mol. Sci. 2018, 19(9), 2830; https://doi.org/10.3390/ijms19092830 - 19 Sep 2018

Cited by 178 | Viewed by 18672

Abstract

Ocular drug delivery has been a major challenge for clinical pharmacologists and biomaterial scientists due to intricate and unique anatomical and physiological barriers in the eye. The critical requirement varies from anterior and posterior ocular segments from a drug delivery perspective. Recently, many [...] Read more.

Ocular drug delivery has been a major challenge for clinical pharmacologists and biomaterial scientists due to intricate and unique anatomical and physiological barriers in the eye. The critical requirement varies from anterior and posterior ocular segments from a drug delivery perspective. Recently, many new drugs with special formulations have been introduced for targeted delivery with modified methods and routes of drug administration to improve drug delivery efficacy. Current developments in nanoformulations of drug carrier systems have become a promising attribute to enhance drug retention/permeation and prolong drug release in ocular tissue. Biodegradable polymers have been explored as the base polymers to prepare nanocarriers for encasing existing drugs to enhance the therapeutic effect with better tissue adherence, prolonged drug action, improved bioavailability, decreased toxicity, and targeted delivery in eye. In this review, we summarized recent studies on sustained ocular drug/gene delivery and emphasized on the nanocarriers made by biodegradable polymers such as liposome, poly lactic-co-glycolic acid (PLGA), chitosan, and gelatin. Moreover, we discussed the bio-distribution of these nanocarriers in the ocular tissue and their therapeutic applications in various ocular diseases. Full article

(This article belongs to the Special Issue Nanomedicine/Molecular Medicine)

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13 pages, 6437 KiB

Open AccessArticle

Ca²⁺ Signaling and IL-8 Secretion in Human Testicular Peritubular Cells Involve the Cation Channel TRPV2

by Katja Eubler, Carola Herrmann, Astrid Tiefenbacher, Frank-Michael Köhn, J. Ullrich Schwarzer, Lars Kunz and Artur Mayerhofer

Int. J. Mol. Sci. 2018, 19(9), 2829; https://doi.org/10.3390/ijms19092829 - 19 Sep 2018

Cited by 16 | Viewed by 4334

Abstract

Peritubular cells are part of the wall of seminiferous tubules in the human testis and their contractile abilities are important for sperm transport. In addition, they have immunological roles. A proteomic analysis of isolated human testicular peritubular cells (HTPCs) revealed expression of the [...] Read more.

Peritubular cells are part of the wall of seminiferous tubules in the human testis and their contractile abilities are important for sperm transport. In addition, they have immunological roles. A proteomic analysis of isolated human testicular peritubular cells (HTPCs) revealed expression of the transient receptor potential channel subfamily V member 2 (TRPV2). This cation channel is linked to mechano-sensation and to immunological processes and inflammation in other organs. We verified expression of TRPV2 in peritubular cells in human sections by immunohistochemistry. It was also found in other testicular cells, including Sertoli cells and interstitial cells. In cultured HTPCs, application of cannabidiol (CBD), a known TRPV2 agonist, acutely induced a transient increase in intracellular Ca²⁺ levels. These Ca²⁺ transients could be blocked both by ruthenium red, an unspecific Ca²⁺ channel blocker, and tranilast (TRA), an antagonist of TRPV2, and were also abolished when extracellular Ca²⁺ was removed. Taken together this indicates functional TRPV2 channels in peritubular cells. When applied for 24 to 48 h, CBD induced expression of proinflammatory factors. In particular, mRNA and secreted protein levels of the proinflammatory chemokine interleukin-8 (IL-8/CXCL8) were elevated. Via its known roles as a major mediator of the inflammatory response and as an angiogenic factor, this chemokine may play a role in testicular physiology and pathology. Full article

(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)

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14 pages, 3288 KiB

Open AccessArticle

MT-Feeding-Induced Impermanent Sex Reversal in the Orange-Spotted Grouper during Sex Differentiation

by Qing Wang, Minwei Huang, Cheng Peng, Xiang Wang, Ling Xiao, Dengdong Wang, Jiaxing Chen, Huihong Zhao, Haifa Zhang, Shuisheng Li, Huirong Yang, Yun Liu, Haoran Lin and Yong Zhang

Int. J. Mol. Sci. 2018, 19(9), 2828; https://doi.org/10.3390/ijms19092828 - 19 Sep 2018

Cited by 25 | Viewed by 4562

Abstract

In this study, we systematically investigated the process of sex reversal induced by 17-methyltestosterone (MT) feeding and MT-feeding withdrawal at the ovary differentiation stage in orange-spotted groupers, Epinephelus coioides. Gonadal histology showed that MT feeding induced a precocious sex reversal from immature [...] Read more.

In this study, we systematically investigated the process of sex reversal induced by 17-methyltestosterone (MT) feeding and MT-feeding withdrawal at the ovary differentiation stage in orange-spotted groupers, Epinephelus coioides. Gonadal histology showed that MT feeding induced a precocious sex reversal from immature ovaries to testes, bypassing the formation of an ovarian cavity, and MT-feeding withdrawal led to an ovarian fate. In both the MT feeding and MT-feeding withdrawal phases, cytochrome P450 family 11 subfamily B (cyp11b) gene expression and serum 11-KT levels were not significantly changed, suggesting that the MT-treated fish did not generate endogenous steroids, even though active spermatogenesis occurred. Finally, by tracing doublesex-expressing and Mab-3-related transcription factor 1 (dmrt1)-expressing cells and TUNEL (terminal deoxynucleotidyl transferase 2-deoxyuridine, 5-triphosphate nick end labeling) assays, we found that the efferent duct formed first, and then, the germ cells and somatic cells of the testicular tissue were generated around the efferent duct during MT-feeding-induced precocious sex reversal. Collectively, our findings provide insights into the molecular and cellular mechanisms underlying sex reversal induced by exogenous hormones during sex differentiation in the protogynous orange-spotted grouper. Full article

(This article belongs to the Section Biochemistry)

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24 pages, 3681 KiB

Open AccessArticle

Protein Phosphatase (PP2C9) Induces Protein Expression Differentially to Mediate Nitrogen Utilization Efficiency in Rice under Nitrogen-Deficient Condition

by Muhammad Waqas, Shizhong Feng, Hira Amjad, Puleng Letuma, Wenshan Zhan, Zhong Li, Changxun Fang, Yasir Arafat, Muhammad Umar Khan, Muhammad Tayyab and Wenxiong Lin

Int. J. Mol. Sci. 2018, 19(9), 2827; https://doi.org/10.3390/ijms19092827 - 19 Sep 2018

Cited by 21 | Viewed by 5775

Abstract

Nitrogen (N) is an essential element usually limiting in plant growth and a basic factor for increasing the input cost in agriculture. To ensure the food security and environmental sustainability it is urgently required to manage the N fertilizer. The identification or development [...] Read more.

Nitrogen (N) is an essential element usually limiting in plant growth and a basic factor for increasing the input cost in agriculture. To ensure the food security and environmental sustainability it is urgently required to manage the N fertilizer. The identification or development of genotypes with high nitrogen utilization efficiency (NUE) which can grow efficiently and sustain yield in low N conditions is a possible solution. In this study, two isogenic rice genotypes i.e., wild-type rice kitaake and its transgenic line PP2C9TL overexpressed protein phosphatase gene (PP2C9) were used for comparative proteomics analysis at control and low level of N to identify specific proteins and encoding genes related to high NUE. 2D gel electrophoresis was used to perform the differential proteome analysis. In the leaf proteome, 30 protein spots were differentially expressed between the two isogenic lines under low N level which were involved in the process of energy, photosynthesis, N metabolism, signaling, and defense mechanisms. In addition, we have found that protein phosphatase enhances nitrate reductase activation by downregulation of SnRK1 and 14-3-3 proteins. Furthermore, we showed that PP2C9TL exhibits higher NUE than WT due to higher activity of nitrate reductase. This study provides new insights on the rice proteome which would be useful in the development of new strategies to increase NUE in cereal crops. Full article

(This article belongs to the Special Issue Plant Proteomic Research 2.0)

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14 pages, 2453 KiB

Open AccessArticle

AMPK Activation Reduces Hepatic Lipid Content by Increasing Fat Oxidation In Vivo

by Marc Foretz, Patrick C. Even and Benoit Viollet

Int. J. Mol. Sci. 2018, 19(9), 2826; https://doi.org/10.3390/ijms19092826 - 19 Sep 2018

Cited by 102 | Viewed by 8340

Abstract

The energy sensor AMP-activated protein kinase (AMPK) is a key player in the control of energy metabolism. AMPK regulates hepatic lipid metabolism through the phosphorylation of its well-recognized downstream target acetyl CoA carboxylase (ACC). Although AMPK activation is proposed to lower hepatic triglyceride [...] Read more.

The energy sensor AMP-activated protein kinase (AMPK) is a key player in the control of energy metabolism. AMPK regulates hepatic lipid metabolism through the phosphorylation of its well-recognized downstream target acetyl CoA carboxylase (ACC). Although AMPK activation is proposed to lower hepatic triglyceride (TG) content via the inhibition of ACC to cause inhibition of de novo lipogenesis and stimulation of fatty acid oxidation (FAO), its contribution to the inhibition of FAO in vivo has been recently questioned. We generated a mouse model of AMPK activation specifically in the liver, achieved by expression of a constitutively active AMPK using adenoviral delivery. Indirect calorimetry studies revealed that liver-specific AMPK activation is sufficient to induce a reduction in the respiratory exchange ratio and an increase in FAO rates in vivo. This led to a more rapid metabolic switch from carbohydrate to lipid oxidation during the transition from fed to fasting. Finally, mice with chronic AMPK activation in the liver display high fat oxidation capacity evidenced by increased [C¹⁴]-palmitate oxidation and ketone body production leading to reduced hepatic TG content and body adiposity. Our findings suggest a role for hepatic AMPK in the remodeling of lipid metabolism between the liver and adipose tissue. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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15 pages, 5152 KiB

Open AccessArticle

Oxidative Stress-Protective and Anti-Melanogenic Effects of Loliolide and Ethanol Extract from Fresh Water Green Algae, Prasiola japonica

by Sang Hee Park, Eunju Choi, Sunggyu Kim, Dong Sam Kim, Ji Hyeon Kim, SeokGu Chang, Jae Seok Choi, Kyung Ja Park, Kyung-Baeg Roh, Jongsung Lee, Byong Chul Yoo and Jae Youl Cho

Int. J. Mol. Sci. 2018, 19(9), 2825; https://doi.org/10.3390/ijms19092825 - 18 Sep 2018

Cited by 33 | Viewed by 5100

Abstract

Loliolide is a monoterpenoid hydroxylactone found in many algae, including fresh water green algae, Prasiola japonica. To date, loliolide and compounds in P. japonica have not been studied systematically with respect to skin pharmacology. In this study, we investigated oxidative stress-protective and [...] Read more.

Loliolide is a monoterpenoid hydroxylactone found in many algae, including fresh water green algae, Prasiola japonica. To date, loliolide and compounds in P. japonica have not been studied systematically with respect to skin pharmacology. In this study, we investigated oxidative stress-protective and anti-melanogenic effects of loliolide and P. japonica ethanol extract (Pj-EE), known to contain loliolide, in human keratinocyte (HaCaT) cells and mouse melanoma (B16F10) cells. Loliolide suppressed the transcription of genes encoding matrix metalloproteinases (MMPS), which were induced in HaCaT cells by hydrogen peroxide (H₂O₂) treatment. Loliolide and Pj-EE not only reduced the melanin secretion and content in B16F10 cells but also increased the expression of the antioxidant proteins nuclear factor (erythroid-derived 2)-like 2 (NRF2) and heme oxygenase-1 (HO-1) in HaCaT cells subjected to H₂O₂ treatment. Furthermore, loliolide and Pj-EE decreased expression of the anti-melanogenic protein microphthalmia-associated transcription factor (MITF) and tyrosinase in B16F10 cells subjected to α-melanocyte-stimulating hormone (α-MSH) treatment. Our findings demonstrate that loliolide and Pj-EE have antioxidant and anti-melanogenic effects on skin. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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17 pages, 2919 KiB

Open AccessArticle

Zinc Supplementation Stimulates Red Blood Cell Formation in Rats

by Yen-Hua Chen, Hui-Lin Feng and Sen-Shyong Jeng

Int. J. Mol. Sci. 2018, 19(9), 2824; https://doi.org/10.3390/ijms19092824 - 18 Sep 2018

Cited by 32 | Viewed by 8489

Abstract

In rats, mice, and humans, it is known that zinc deficiency may be related to anemia, and zinc supplementation influences hemoglobin production. Our previous studies indicate that in fish, zinc supplementation stimulates red blood cell (RBC) formation (erythropoiesis). However, it is not clear [...] Read more.

In rats, mice, and humans, it is known that zinc deficiency may be related to anemia, and zinc supplementation influences hemoglobin production. Our previous studies indicate that in fish, zinc supplementation stimulates red blood cell (RBC) formation (erythropoiesis). However, it is not clear whether the mechanism of zinc-induced erythropoiesis stimulation in fish also occurs in rats. We induced anemia in rats using phenylhydrazine (PHZ) and injected either saline or ZnSO₄ solution. We found that an appropriate amount of zinc stimulated erythropoiesis in the PHZ-induced anemic rats. The effects of ZnSO₄ injection were dose-dependent. When the concentration of ZnSO₄ was higher than 2.8 mg zinc/kg body weight, the RBC level of the anemic rats increased from 60 ± 7% to 88 ± 10% that of the normal rats in two days. Rat bone marrow cells with or without ZnCl₂ supplementation were cultured in suspension in vitro. In the cell culture when the zinc concentration was at 0.3 mM, a 1.6-fold proliferation of nascent immature reticulocytes (new RBCs) was observed after one day. In the rat blood, zinc was combined with serum transferrin to induce erythropoiesis. The stimulation of RBC formation by zinc appears to be common among different animals. Full article

(This article belongs to the Special Issue Zinc Biology 2019)

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5 pages, 206 KiB

Open AccessEditorial

An Overview of the Focus of the International Gap Junction Conference 2017 and Future Perspectives

by Patricia E. Martin and Brenda R. Kwak

Int. J. Mol. Sci. 2018, 19(9), 2823; https://doi.org/10.3390/ijms19092823 - 18 Sep 2018

Cited by 2 | Viewed by 2787

Abstract

n/a Full article

(This article belongs to the Special Issue Interplay of Connexins and Pannexins in Tissue Function and Disease)

18 pages, 1490 KiB

Open AccessReview

Extracellular Vesicles in Bladder Cancer: Biomarkers and Beyond

by Yu-Ru Liu, Carlos J. Ortiz-Bonilla and Yi-Fen Lee

Int. J. Mol. Sci. 2018, 19(9), 2822; https://doi.org/10.3390/ijms19092822 - 18 Sep 2018

Cited by 34 | Viewed by 7252

Abstract

Tumor-derived extracellular vesicles (TEVs) are membrane-bound, nanosized vesicles released by cancer cells and taken up by cells in the tumor microenvironment to modulate the molecular makeup and behavior of recipient cells. In this report, we summarize the pivotal roles of TEVs involved in [...] Read more.

Tumor-derived extracellular vesicles (TEVs) are membrane-bound, nanosized vesicles released by cancer cells and taken up by cells in the tumor microenvironment to modulate the molecular makeup and behavior of recipient cells. In this report, we summarize the pivotal roles of TEVs involved in bladder cancer (BC) development, progression and treatment resistance through transferring their bioactive cargos, including proteins and nucleic acids. We also report on the molecular profiling of TEV cargos derived from urine and blood of BC patients as non-invasive disease biomarkers. The current hurdles in EV research and plausible solutions are discussed. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biological Markers in Bladder Cancer – Illumination of a Vision)

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25 pages, 851 KiB

Open AccessReview

Monocytes and Macrophages as Viral Targets and Reservoirs

by Ekaterina Nikitina, Irina Larionova, Evgeniy Choinzonov and Julia Kzhyshkowska

Int. J. Mol. Sci. 2018, 19(9), 2821; https://doi.org/10.3390/ijms19092821 - 18 Sep 2018

Cited by 162 | Viewed by 15694

Abstract

Viruses manipulate cell biology to utilize monocytes/macrophages as vessels for dissemination, long-term persistence within tissues and virus replication. Viruses enter cells through endocytosis, phagocytosis, macropinocytosis or membrane fusion. These processes play important roles in the mechanisms contributing to the pathogenesis of these agents [...] Read more.

Viruses manipulate cell biology to utilize monocytes/macrophages as vessels for dissemination, long-term persistence within tissues and virus replication. Viruses enter cells through endocytosis, phagocytosis, macropinocytosis or membrane fusion. These processes play important roles in the mechanisms contributing to the pathogenesis of these agents and in establishing viral genome persistence and latency. Upon viral infection, monocytes respond with an elevated expression of proinflammatory signalling molecules and antiviral responses, as is shown in the case of the influenza, Chikungunya, human herpes and Zika viruses. Human immunodeficiency virus initiates acute inflammation on site during the early stages of infection but there is a shift of M1 to M2 at the later stages of infection. Cytomegalovirus creates a balance between pro- and anti-inflammatory processes by inducing a specific phenotype within the M1/M2 continuum. Despite facilitating inflammation, infected macrophages generally display abolished apoptosis and restricted cytopathic effect, which sustains the virus production. The majority of viruses discussed in this review employ monocytes/macrophages as a repository but certain viruses use these cells for productive replication. This review focuses on viral adaptations to enter monocytes/macrophages, immune escape, reprogramming of infected cells and the response of the host cells. Full article

(This article belongs to the Special Issue Macrophages in Inflammation)

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16 pages, 2456 KiB

Open AccessReview

Nucleus, Mitochondrion, or Reticulum? STAT3 à La Carte

by Lidia Avalle and Valeria Poli

Int. J. Mol. Sci. 2018, 19(9), 2820; https://doi.org/10.3390/ijms19092820 - 18 Sep 2018

Cited by 59 | Viewed by 7249

Abstract

The transcription factor signal transducer and activator of transcription (STAT)3 mediates the functions of cytokines, growth factors, and oncogenes under both physiological and pathological conditions. Uncontrolled/constitutive STAT3 activity is often detected in tumors of different types, where its role is mostly that of [...] Read more.

The transcription factor signal transducer and activator of transcription (STAT)3 mediates the functions of cytokines, growth factors, and oncogenes under both physiological and pathological conditions. Uncontrolled/constitutive STAT3 activity is often detected in tumors of different types, where its role is mostly that of an oncogene, contributing in multiple ways to tumor transformation, growth, and progression. For this reason, many laboratories and pharmaceutical companies are making efforts to develop specific inhibitors. However, STAT3 has also been shown to act as a tumor suppressor in a number of cases, suggesting that its activity is strongly context-specific. Here, we discuss the bases that can explain the multiple roles of this factor in both physiological and pathological contexts. In particular, we focus on the following four features: (i) the distinct properties of the STAT3α and β isoforms; (ii) the multiple post-translational modifications (phosphorylation on tyrosine or serine, acetylation and methylation on different residues, and oxidation and glutathionylation) that can affect its activities downstream of multiple different signals; (iii) the non-canonical functions in the mitochondria, contributing to the maintenance of energy homeostasis under stress conditions; and (iv) the recently discovered functions in the endoplasmic reticulum, where STAT3 contributes to the regulation of calcium homeostasis, energy production, and apoptosis. Full article

(This article belongs to the Special Issue Advances in Biological Functions of STAT3)

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16 pages, 2173 KiB

Open AccessArticle

Nitric Oxide Enhancing Resistance to PEG-Induced Water Deficiency is Associated with the Primary Photosynthesis Reaction in Triticum aestivum L.

by Ruixin Shao, Huifang Zheng, Shuangjie Jia, Yanping Jiang, Qinghua Yang and Guozhang Kang

Int. J. Mol. Sci. 2018, 19(9), 2819; https://doi.org/10.3390/ijms19092819 - 18 Sep 2018

Cited by 13 | Viewed by 4528

Abstract

Photosynthesis is affected by water-deficiency (WD) stress, and nitric oxide (NO) is a free radical that participates in the photosynthesis process. Previous studies have suggested that NO regulates excitation-energy distribution of photosynthesis under WD stress. Here, quantitative phosphoproteomic profiling was conducted using iTRAQ. [...] Read more.

Photosynthesis is affected by water-deficiency (WD) stress, and nitric oxide (NO) is a free radical that participates in the photosynthesis process. Previous studies have suggested that NO regulates excitation-energy distribution of photosynthesis under WD stress. Here, quantitative phosphoproteomic profiling was conducted using iTRAQ. Differentially phosphorylated protein species (DEPs) were identified in leaves of NO- or polyethylene glycol (PEG)-treated wheat seedlings (D), and in control seedlings. From 1396 unique phosphoproteins, 2257 unique phosphorylated peptides and 2416 phosphorylation sites were identified. Of these, 96 DEPs displayed significant changes (≥1.50-fold, p < 0.01). These DEPs are involved in photosynthesis, signal transduction, etc. Furthermore, phosphorylation of several DEPs was upregulated by both D and NO treatments, but downregulated only in NO treatment. These differences affected the chlorophyll A–B binding protein, chloroplast post-illumination chlorophyll-fluorescence-increase protein, and SNT7, implying that NO indirectly regulated the absorption and transport of light energy in photosynthesis in response to WD stress. The significant difference of chlorophyll (Chl) content, Chl a fluorescence-transient, photosynthesis index, and trapping and transport of light energy further indicated that exogenous NO under D stress enhanced the primary photosynthesis reaction compared to D treatment. A putative pathway is proposed to elucidate NO regulation of the primary reaction of photosynthesis under WD. Full article

(This article belongs to the Special Issue Chloroplast)

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9 pages, 479 KiB

Open AccessCommentary

STAT3 in Breast Cancer Onset and Progression: A Matter of Time and Context

by Ilenia Segatto, Gustavo Baldassarre and Barbara Belletti

Int. J. Mol. Sci. 2018, 19(9), 2818; https://doi.org/10.3390/ijms19092818 - 18 Sep 2018

Cited by 29 | Viewed by 4271

Abstract

Signal transducer and activator of transcription 3 (STAT3) is responsible for mediating the transcriptional programs downstream of several cytokine, growth factor, and oncogenic stimuli. Its expression and activity are consistently linked to cellular transformation, as well as tumor initiation and progression. Due to [...] Read more.

Signal transducer and activator of transcription 3 (STAT3) is responsible for mediating the transcriptional programs downstream of several cytokine, growth factor, and oncogenic stimuli. Its expression and activity are consistently linked to cellular transformation, as well as tumor initiation and progression. Due to this central role, STAT3 is widely considered a good target for anti-cancer therapy; however, the success of these approaches has been, so far, very limited. Notably, on one side, STAT3 is aberrantly active in many breast cancers, on the other, at the physiological level, it is the main mediator of epithelial cell death during post-lactation mammary-gland involution, thus strongly suggesting that its biological functions are highly context-specific. One of the most peculiar features of STAT3 is that it can act both in cell-autonomous and non-cell-autonomous manners, simultaneously modulating the phenotypes of the tumor cells and their microenvironment. Here, we focus on the role of STAT3 in breast cancer progression, discussing the potential contrasting roles of STAT3 activation in the establishment of locally recurrent and distant metastatic disease. Based on the most recent literature, depending on the tumor cell type, the local microenvironment status, and the stage of the disease, either STAT3 activation or inactivation can support disease progression. Accordingly, cancer cells dynamically exploit STAT3 activity to carry out transcriptional programs somehow contrasting and complementary, such as supporting survival and growth, dormancy and awakening, stem cell-like features, and inflammation, immune response, and immune evasion. As a consequence, to achieve clinical efficacy, the conception and testing of anti-STAT3 targeted therapies will need a very careful evaluation of these opposing roles and of the most appropriate tumor context, disease stage and patient population to treat. Full article

(This article belongs to the Special Issue Advances in Biological Functions of STAT3)

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11 pages, 2364 KiB

Open AccessArticle

A Hybrid Deep Learning Model for Predicting Protein Hydroxylation Sites

by Haixia Long, Bo Liao, Xingyu Xu and Jialiang Yang

Int. J. Mol. Sci. 2018, 19(9), 2817; https://doi.org/10.3390/ijms19092817 - 18 Sep 2018

Cited by 30 | Viewed by 5691

Abstract

Protein hydroxylation is one type of post-translational modifications (PTMs) playing critical roles in human diseases. It is known that protein sequence contains many uncharacterized residues of proline and lysine. The question that needs to be answered is: which residue can be hydroxylated, and [...] Read more.

Protein hydroxylation is one type of post-translational modifications (PTMs) playing critical roles in human diseases. It is known that protein sequence contains many uncharacterized residues of proline and lysine. The question that needs to be answered is: which residue can be hydroxylated, and which one cannot. The answer will not only help understand the mechanism of hydroxylation but can also benefit the development of new drugs. In this paper, we proposed a novel approach for predicting hydroxylation using a hybrid deep learning model integrating the convolutional neural network (CNN) and long short-term memory network (LSTM). We employed a pseudo amino acid composition (PseAAC) method to construct valid benchmark datasets based on a sliding window strategy and used the position-specific scoring matrix (PSSM) to represent samples as inputs to the deep learning model. In addition, we compared our method with popular predictors including CNN, iHyd-PseAAC, and iHyd-PseCp. The results for 5-fold cross-validations all demonstrated that our method significantly outperforms the other methods in prediction accuracy. Full article

(This article belongs to the Special Issue Special Protein or RNA Molecules Computational Identification 2018)

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17 pages, 5095 KiB

Open AccessArticle

Increased Oral Bioavailability of Resveratrol by Its Encapsulation in Casein Nanoparticles

by Rebeca Peñalva, Jorge Morales, Carlos J. González-Navarro, Eneko Larrañeta, Gemma Quincoces, Ivan Peñuelas and Juan M. Irache

Int. J. Mol. Sci. 2018, 19(9), 2816; https://doi.org/10.3390/ijms19092816 - 18 Sep 2018

Cited by 127 | Viewed by 7900

Abstract

Resveratrol is a naturally occurring polyphenol that provides several health benefits including cardioprotection and cancer prevention. However, its biological activity is limited by a poor bioavailability when taken orally. The aim of this work was to evaluate the capability of casein nanoparticles as [...] Read more.

Resveratrol is a naturally occurring polyphenol that provides several health benefits including cardioprotection and cancer prevention. However, its biological activity is limited by a poor bioavailability when taken orally. The aim of this work was to evaluate the capability of casein nanoparticles as oral carriers for resveratrol. Nanoparticles were prepared by a coacervation process, purified and dried by spray-drying. The mean size of nanoparticles was around 200 nm with a resveratrol payload close to 30 μg/mg nanoparticle. In vitro studies demonstrated that the resveratrol release from casein nanoparticles was not affected by the pH conditions and followed a zero-order kinetic. When nanoparticles were administered orally to rats, they remained within the gut, displaying an important capability to reach the intestinal epithelium. No evidence of nanoparticle “translocation” were observed. The resveratrol plasma levels were high and sustained for at least 8 h with a similar profile to that observed for the presence of the major metabolite in plasma. The oral bioavailability of resveratrol when loaded in casein nanoparticles was calculated to be 26.5%, 10 times higher than when the polyphenol was administered as oral solution. Finally, a good correlation between in vitro and in vivo data was observed. Full article

(This article belongs to the Special Issue Nanomedicine/Molecular Medicine)

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