International Journal of Molecular Sciences

15 pages, 6435 KiB

Open AccessReview

Glyoxalase Goes Green: The Expanding Roles of Glyoxalase in Plants

by Subramanian Sankaranarayanan^1,2, Muhammad Jamshed¹, Abhinandan Kumar¹

, Logan Skori¹, Sabine Scandola¹, Tina Wang³, David Spiegel³ and Marcus A. Samuel^1,*

¹ Department of Biological Sciences, University of Calgary, Calgary AB T2N 1N4, Canada

² Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan

³ Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06511, USA

Int. J. Mol. Sci. 2017, 18(4), 898; https://doi.org/10.3390/ijms18040898 - 24 Apr 2017

Cited by 71 | Viewed by 8566

Abstract

The ubiquitous glyoxalase enzymatic pathway is involved in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis. The glyoxalase system has been more extensively studied in animals versus plants. Plant glyoxalases have been primarily associated with stress responses and their overexpression is [...] Read more.

The ubiquitous glyoxalase enzymatic pathway is involved in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis. The glyoxalase system has been more extensively studied in animals versus plants. Plant glyoxalases have been primarily associated with stress responses and their overexpression is known to impart tolerance to various abiotic stresses. In plants, glyoxalases exist as multigene families, and new roles for glyoxalases in various developmental and signaling pathways have started to emerge. Glyoxalase-based MG detoxification has now been shown to be important for pollination responses. During self-incompatibility response in Brassicaceae, MG is required to target compatibility factors for proteasomal degradation, while accumulation of glyoxalase leads to MG detoxification and efficient pollination. In this review, we discuss the importance of glyoxalase systems and their emerging biological roles in plants. Full article

(This article belongs to the Special Issue Glyoxalase System)

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31 pages, 824 KiB

Open AccessReview

Health Effects of Psidium guajava L. Leaves: An Overview of the Last Decade

by Elixabet Díaz-de-Cerio^1,2, Vito Verardo³

, Ana María Gómez-Caravaca^1,*, Alberto Fernández-Gutiérrez^1,2 and Antonio Segura-Carretero^1,2

¹ Department of Analytical Chemistry, Faculty of Sciences, University of Granada, Avd. Fuentenueva s/n, 18071 Granada, Spain

² Functional Food Research and Development Center, Health Science Technological Park, Avd. Del Conocimiento, Bioregion Building, 18100 Granada, Spain

³ Department of Nutrition and Food Science, University of Granada, Campus of Cartuja, 18071 Granada, Spain

Int. J. Mol. Sci. 2017, 18(4), 897; https://doi.org/10.3390/ijms18040897 - 24 Apr 2017

Cited by 127 | Viewed by 34688

Abstract

Today, there is increasing interest in discovering new bioactive compounds derived from ethnomedicine. Preparations of guava (Psidium guajava L.) leaves have traditionally been used to manage several diseases. The pharmacological research in vitro as well as in vivo has been widely used [...] Read more.

Today, there is increasing interest in discovering new bioactive compounds derived from ethnomedicine. Preparations of guava (Psidium guajava L.) leaves have traditionally been used to manage several diseases. The pharmacological research in vitro as well as in vivo has been widely used to demonstrate the potential of the extracts from the leaves for the co-treatment of different ailments with high prevalence worldwide, upholding the traditional medicine in cases such as diabetes mellitus, cardiovascular diseases, cancer, and parasitic infections. Moreover, the biological activity has been attributed to the bioactive composition of the leaves, to some specific phytochemical subclasses, or even to individual compounds. Phenolic compounds in guava leaves have been credited with regulating blood-glucose levels. Thus, the aim of the present review was to compile results from in vitro and in vivo studies carried out with guava leaves over the last decade, relating the effects to their clinical applications in order to focus further research for finding individual bioactive compounds. Some food applications (guava tea and supplementary feed for aquaculture) and some clinical, in vitro, and in vivo outcomes are also included. Full article

(This article belongs to the Special Issue Advances in Molecular Research of Functional and Nutraceutical Food 2017)

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13 pages, 6072 KiB

Open AccessReview

Synaptic Homeostasis and Its Immunological Disturbance in Neuromuscular Junction Disorders

by Masaharu Takamori

Neurological Center, Kanazawa-Nishi Hospital, Kanazawa, Ishikawa 920-0025, Japan

Int. J. Mol. Sci. 2017, 18(4), 896; https://doi.org/10.3390/ijms18040896 - 24 Apr 2017

Cited by 14 | Viewed by 8863

Abstract

In the neuromuscular junction, postsynaptic nicotinic acetylcholine receptor (nAChR) clustering, trans-synaptic communication and synaptic stabilization are modulated by the molecular mechanisms underlying synaptic plasticity. The synaptic functions are based presynaptically on the active zone architecture, synaptic vesicle proteins, Ca²⁺ channels and synaptic [...] Read more.

In the neuromuscular junction, postsynaptic nicotinic acetylcholine receptor (nAChR) clustering, trans-synaptic communication and synaptic stabilization are modulated by the molecular mechanisms underlying synaptic plasticity. The synaptic functions are based presynaptically on the active zone architecture, synaptic vesicle proteins, Ca²⁺ channels and synaptic vesicle recycling. Postsynaptically, they are based on rapsyn-anchored nAChR clusters, localized sensitivity to ACh, and synaptic stabilization via linkage to the extracellular matrix so as to be precisely opposed to the nerve terminal. Focusing on neural agrin, Wnts, muscle-specific tyrosine kinase (a mediator of agrin and Wnts signalings and regulator of trans-synaptic communication), low-density lipoprotein receptor-related protein 4 (the receptor of agrin and Wnts and participant in retrograde signaling), laminin-network (including muscle-derived agrin), extracellular matrix proteins (participating in the synaptic stabilization) and presynaptic receptors (including muscarinic and adenosine receptors), we review the functional structures of the synapse by making reference to immunological pathogenecities in postsynaptic disease, myasthenia gravis. The synapse-related proteins including cortactin, coronin-6, caveolin-3, doublecortin, R-spondin 2, amyloid precursor family proteins, glia cell-derived neurotrophic factor and neurexins are also discussed in terms of their possible contribution to efficient synaptic transmission at the neuromuscular junction. Full article

(This article belongs to the Special Issue The Neuromuscular Synapse in Health and Disease)

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16 pages, 5961 KiB

Open AccessArticle

Acteoside and Isoacteoside Protect Amyloid β Peptide Induced Cytotoxicity, Cognitive Deficit and Neurochemical Disturbances In Vitro and In Vivo

by Young-Ji Shiao¹

, Muh-Hwan Su^2,3, Hang-Ching Lin^2,3 and Chi-Rei Wu^4,*

¹ National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11490, Taiwan

² School of Pharmacy, National Defense Medical Center, Taipei 11490, Taiwan

³ Sinphar Pharmaceutical Co., Ltd., Sinphar Group (Taiwan), Research & Development Center, I-Lan 26944, Taiwan

⁴ Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Pharmacy, China Medical University, Taichung 40402, Taiwan

Int. J. Mol. Sci. 2017, 18(4), 895; https://doi.org/10.3390/ijms18040895 - 24 Apr 2017

Cited by 53 | Viewed by 6735

Abstract

Acteoside and isoacteoside, two phenylethanoid glycosides, coexist in some plants. This study investigates the memory-improving and cytoprotective effects of acteoside and isoacteoside in amyloid β peptide 1-42 (Aβ 1-42)-infused rats and Aβ 1-42-treated SH-SY5Y cells. It further elucidates the role of amyloid cascade [...] Read more.

Acteoside and isoacteoside, two phenylethanoid glycosides, coexist in some plants. This study investigates the memory-improving and cytoprotective effects of acteoside and isoacteoside in amyloid β peptide 1-42 (Aβ 1-42)-infused rats and Aβ 1-42-treated SH-SY5Y cells. It further elucidates the role of amyloid cascade and central neuronal function in these effects. Acteoside and isoacteoside ameliorated cognitive deficits, decreased amyloid deposition, and reversed central cholinergic dysfunction that were caused by Aβ 1-42 in rats. Acteoside and isoacteoside further decreased extracellular Aβ 1-40 production and restored the cell viability that was decreased by Aβ 1-42 in SH-SY5Y cells. Acteoside and isoacteoside also promoted Aβ 1-40 degradation and inhibited Aβ 1-42 oligomerization in vitro. However, the memory-improving and cytoprotective effects of isoacteoside exceeded those of acteoside. Isoacteoside promoted exploratory behavior and restored cortical and hippocampal dopamine levels, but acteoside did not. We suggest that acteoside and isoacteoside ameliorated the cognitive dysfunction that was caused by Aβ 1-42 by blocking amyloid deposition via preventing amyloid oligomerization, and reversing central neuronal function via counteracting amyloid cytotoxicity. Full article

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

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21 pages, 4958 KiB

Open AccessArticle

Altered Adipogenesis in Zebrafish Larvae Following High Fat Diet and Chemical Exposure Is Visualised by Stimulated Raman Scattering Microscopy

by Marjo J. Den Broeder^1,2,†

, Miriam J. B. Moester^3,†, Jorke H. Kamstra⁴

, Peter H. Cenijn², Valentina Davidoiu^3,5, Leonie M. Kamminga^6,7

, Freek Ariese³, Johannes F. De Boer³ and Juliette Legler^1,2,*

¹ Institute of Environmental, Health and Societies, Brunel University, UB8 3PH London, UK

² Institute for Environmental Studies, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands

³ Institute for Lasers, Life and Biophotonics, Department of Physics and Astronomy, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands

⁴ Department of Basic Sciences and Aquatic Medicine, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, P.O. BOX 8146, Dep 0033 Oslo, Norway

⁵ Rotterdam Ophthalmic Institute, Rotterdam Eye Hospital, 3011 BH Rotterdam, The Netherlands

⁶ Radboud University Nijmegen, Faculty of Science, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, 6525 GA Nijmegen, The Netherlands

⁷ Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6525 GA Nijmegen, The Netherlands

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(4), 894; https://doi.org/10.3390/ijms18040894 - 24 Apr 2017

Cited by 56 | Viewed by 9981

Abstract

Early life stage exposure to environmental chemicals may play a role in obesity by altering adipogenesis; however, robust in vivo methods to quantify these effects are lacking. The goal of this study was to analyze the effects of developmental exposure to chemicals on [...] Read more.

Early life stage exposure to environmental chemicals may play a role in obesity by altering adipogenesis; however, robust in vivo methods to quantify these effects are lacking. The goal of this study was to analyze the effects of developmental exposure to chemicals on adipogenesis in the zebrafish (Danio rerio). We used label-free Stimulated Raman Scattering (SRS) microscopy for the first time to image zebrafish adipogenesis at 15 days post fertilization (dpf) and compared standard feed conditions (StF) to a high fat diet (HFD) or high glucose diet (HGD). We also exposed zebrafish embryos to a non-toxic concentration of tributyltin (TBT, 1 nM) or Tris(1,3-dichloroisopropyl)phosphate (TDCiPP, 0.5 µM) from 0–6 dpf and reared larvae to 15 dpf under StF. Potential molecular mechanisms of altered adipogenesis were examined by qPCR. Diet-dependent modulation of adipogenesis was observed, with HFD resulting in a threefold increase in larvae with adipocytes, compared to StF and HGD. Developmental exposure to TBT but not TDCiPP significantly increased adipocyte differentiation. The expression of adipogenic genes such as pparda, lxr and lepa was altered in response to HFD or chemicals. This study shows that SRS microscopy can be successfully applied to zebrafish to visualize and quantify adipogenesis, and is a powerful approach for identifying obesogenic chemicals in vivo. Full article

(This article belongs to the Special Issue Zebrafish: A Model for Toxicological Research)

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13 pages, 4103 KiB

Open AccessArticle

Brain-Derived Neurotrophic Factor Mediated Perfluorooctane Sulfonate Induced-Neurotoxicity via Epigenetics Regulation in SK-N-SH Cells

by Xin-Xin Guo^1,†, Qing-Zhi He^2,3,†, Wu Li¹, Ding-Xin Long¹, Xiao-Yuan Pan¹, Cong Chen¹ and Huai-Cai Zeng^1,3,*

¹ Department of Preventive Medicine, School of Public Health, University of South China, Hengyang 421001, China

² School of Pharmacy and Biology, University of South China, Hengyang 421001, China

³ Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang 421001, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(4), 893; https://doi.org/10.3390/ijms18040893 - 24 Apr 2017

Cited by 26 | Viewed by 5762

Abstract

Perfluorooctane sulfonate (PFOS), a new kind of persistent organic pollutant, is widely distributed in the environment and exists in various organisms, where it is also a neurotoxic compound. However, the potential mechanism of its neurotoxicity is still unclear. To examine the role of [...] Read more.

Perfluorooctane sulfonate (PFOS), a new kind of persistent organic pollutant, is widely distributed in the environment and exists in various organisms, where it is also a neurotoxic compound. However, the potential mechanism of its neurotoxicity is still unclear. To examine the role of epigenetics in the neurotoxicity induced by PFOS, SK-N-SH cells were treated with different concentrations of PFOS or control medium (0.1% DMSO) for 48 h. The mRNA levels of DNA methyltransferases (DNMTs) and Brain-derived neurotrophic factor (BDNF), microRNA-16, microRNA-22, and microRNA-30a-5p were detected by Quantitative PCR (QPCR). Enzyme Linked Immunosorbent Assay (ELISA) was used to measure the protein levels of BDNF, and a western blot was applied to analyze the protein levels of DNMTs. Bisulfite sequencing PCR (BSP) was used to detect the methylation status of the BDNF promoter I and IV. Results of MTT assays indicated that treatment with PFOS could lead to a significant decrease of cell viability, and the treated cells became shrunk. In addition, PFOS exposure decreased the expression of BDNF at mRNA and protein levels, increased the expression of microRNA-16, microRNA-22, microRNA-30a-5p, and decreased the expression of DNMT1 at mRNA and protein levels, but increased the expression of DNMT3b at mRNA and protein levels. Our results also demonstrate that PFOS exposure changes the methylation status of BDNF promoter I and IV. The findings of the present study suggest that methylation regulation of BDNF gene promoter and increases of BDNF-related-microRNA might underlie the mechanisms of PFOS-induced neurotoxicity. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology)

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14 pages, 2394 KiB

Open AccessArticle

E2/ER β Enhances Calcineurin Protein Degradation and PI3K/Akt/MDM2 Signal Transduction to Inhibit ISO-Induced Myocardial Cell Apoptosis

by Kuan-Ho Lin^1,2,†, Wei-Wen Kuo^3,†, Marthandam Asokan Shibu⁴, Cecilia-Hsuan Day⁵, You-Liang Hsieh⁶, Li-Chin Chung⁷, Ray-Jade Chen⁸, Su-Ying Wen⁹, Vijaya Padma Viswanadha¹⁰ and Chih-Yang Huang^4,6,11,*

¹ College of Medicine, China Medical University, Taichung 40402, Taiwan

² Department of Emergency Medicine, China Medical University Hospital, Taichung 40402, Taiwan

³ Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan

⁴ Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan

⁵ Department of Nursing, Meiho University, Pingtung 900, Taiwan

⁶ Department of Health and Nutrition Biotechnology, Asia University, Taichung 40402, Taiwan

⁷ Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy & Science, Tainan County 700, Taiwan

⁸ Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 220, Taiwan

⁹ Department of Dermatology, Taipei City Hospital, Renai Branch, Taipei 220, Taiwan

¹⁰ Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India

¹¹ Graduate Institute of Chinese Medical Science, China Medical University, Taichung 40402, Taiwan

^† These authors contributed equally to this work.

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Int. J. Mol. Sci. 2017, 18(4), 892; https://doi.org/10.3390/ijms18040892 - 24 Apr 2017

Cited by 18 | Viewed by 7319

Abstract

Secretion of multifunctional estrogen and its receptor has been widely considered as the reason for markedly higher frequency of heart disease in men than in women. 17β-Estradiol (E2), for instance, has been reported to prevent development of cardiac apoptosis via activation of estrogen [...] Read more.

Secretion of multifunctional estrogen and its receptor has been widely considered as the reason for markedly higher frequency of heart disease in men than in women. 17β-Estradiol (E2), for instance, has been reported to prevent development of cardiac apoptosis via activation of estrogen receptors (ERs). In addition, protein phosphatase such as protein phosphatase 1 (PP1) and calcineurin (PP2B) are also involved in cardiac hypertrophy and cell apoptosis signaling. However, the mechanism by which E2/ERβ suppresses apoptosis is not fully understood, and the role of protein phosphatase in E2/ERβ action also needs further investigation. In this study, we observed that E2/ERβ inhibited isoproterenol (ISO)-induced myocardial cell apoptosis, cytochrome c release and downstream apoptotic markers. Moreover, we found that E2/ERβ blocks ISO-induced apoptosis in H9c2 cells through the enhancement of calcineurin protein degradation through PI3K/Akt/MDM2 signaling pathway. Our results suggest that supplementation with estrogen and/or overexpression of estrogen receptor β gene may prove to be effective means to treat stress-induced myocardial damage. Full article

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

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13 pages, 3573 KiB

Open AccessArticle

Role of RHEB in Regulating Differentiation Fate of Mesenchymal Stem Cells for Cartilage and Bone Regeneration

by Sajjad Ashraf^1,2, In-Bo Han³

, Hansoo Park^2,* and Soo-Hong Lee^1,*

¹ Department of Biomedical Science, CHA University, Seongnam-si 463-400, Korea

² School of Integrative Engineering, Chung-Ang University, Seoul 156-863, Korea

³ Department of Neurosurgery, Bundang Medical Center, CHA University, Seongnam-si 463-400, Korea

Int. J. Mol. Sci. 2017, 18(4), 880; https://doi.org/10.3390/ijms18040880 - 24 Apr 2017

Cited by 13 | Viewed by 5835

Abstract

Advances in mesenchymal stem cells (MSCs) and cell replacement therapies are promising approaches to treat cartilage and bone defects since substantial differentiation capacities of MSCs match the demands of tissue regeneration. Our understanding of the dynamic process requiring indispensable differentiation of MSCs remains [...] Read more.

Advances in mesenchymal stem cells (MSCs) and cell replacement therapies are promising approaches to treat cartilage and bone defects since substantial differentiation capacities of MSCs match the demands of tissue regeneration. Our understanding of the dynamic process requiring indispensable differentiation of MSCs remains limited. Herein, we describe the role of RHEB (Ras homolog enriched in brain) regulating gene signature for differentiation of human adipose derived mesenchymal stem cells (ASCs) into chondrogenic, osteogenic, and adipogenic lineages. RHEB-overexpression increases the proliferation of the ASCs. RHEB enhances the chondrogenic differentiation of ASCs in 3D culture via upregulation of SOX9 with concomitant increase in glycosaminoglycans (GAGs), and type II collagen (COL2). RHEB increases the osteogenesis via upregulation of runt related transcription factor 2 (RUNX2) with an increase in the calcium and phosphate contents. RHEB also increases the expression of osteogenic markers, osteonectin and osteopontin. RHEB knockdown ASCs were incapable of expressing sufficient SRY (Sex determining region Y)-box 9 (SOX9) and RUNX2, and therefore had decreased chondrogenic and osteogenic differentiation. RHEB-overexpression impaired ASCs differentiation into adipogenic lineage, through downregulation of CCAAT/enhancer binding protein beta (C/EBPβ). Conversely, RHEB knockdown abolished the negative regulation of adipogenesis. We demonstrate that RHEB is a novel regulator, with a critical role in ASCs lineage determination, and RHEB-modulated ASCs may be useful as a cell therapy for cartilage and bone defect treatments. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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20 pages, 2427 KiB

Open AccessArticle

CoQ10 Deficiency May Indicate Mitochondrial Dysfunction in Cr(VI) Toxicity

by Xiali Zhong^1,2, Xing Yi¹, Rita De Cássia Da Silveira e Sá³, Yujing Zhang¹, Kaihua Liu¹, Fang Xiao¹ and Caigao Zhong^1,*

¹ Department of Health Toxicology, School of Public Health, Central South University, Changsha 410008, China

² Department of Environmental Health Science, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA

³ Department of Physiology and Pathology, Health Sciences Center, Federal University of Paraíba, 58059-900 João Pessoa, Brazil

Int. J. Mol. Sci. 2017, 18(4), 816; https://doi.org/10.3390/ijms18040816 - 24 Apr 2017

Cited by 28 | Viewed by 7187

Abstract

To investigate the toxic mechanism of hexavalent chromium Cr(VI) and search for an antidote for Cr(VI)-induced cytotoxicity, a study of mitochondrial dysfunction induced by Cr(VI) and cell survival by recovering mitochondrial function was performed. In the present study, we found that the gene [...] Read more.

To investigate the toxic mechanism of hexavalent chromium Cr(VI) and search for an antidote for Cr(VI)-induced cytotoxicity, a study of mitochondrial dysfunction induced by Cr(VI) and cell survival by recovering mitochondrial function was performed. In the present study, we found that the gene expression of electron transfer flavoprotein dehydrogenase (ETFDH) was strongly downregulated by Cr(VI) exposure. The levels of coenzyme 10 (CoQ10) and mitochondrial biogenesis presented by mitochondrial mass and mitochondrial DNA copy number were also significantly reduced after Cr(VI) exposure. The subsequent, Cr(VI)-induced mitochondrial damage and apoptosis were characterized by reactive oxygen species (ROS) accumulation, caspase-3 and caspase-9 activation, decreased superoxide dismutase (SOD) and ATP production, increased methane dicarboxylic aldehyde (MDA) content, mitochondrial membrane depolarization and mitochondrial permeability transition pore (MPTP) opening, increased Ca²⁺ levels, Cyt c release, decreased Bcl-2 expression, and significantly elevated Bax expression. The Cr(VI)-induced deleterious changes were attenuated by pretreatment with CoQ10 in L-02 hepatocytes. These data suggest that Cr(VI) induces CoQ10 deficiency in L-02 hepatocytes, indicating that this deficiency may be a biomarker of mitochondrial dysfunction in Cr(VI) poisoning and that exogenous administration of CoQ10 may restore mitochondrial function and protect the liver from Cr(VI) exposure. Full article

(This article belongs to the Special Issue Chemically-Induced DNA Damage, Mutagenesis, and Cancer)

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20 pages, 2467 KiB

Open AccessArticle

Commitment of Scaffold Proteins in the Onco-Biology of Human Colorectal Cancer and Liver Metastases after Oxaliplatin-Based Chemotherapy

by Deborah Rotoli^1,2

, Manuel Morales^3,4, Julio Ávila¹

, María Del Carmen Maeso⁵, María Del Pino García⁶, Ali Mobasheri^7,8

and Pablo Martín-Vasallo^1,*

¹ Laboratorio de Biología del Desarrollo, UD de Bioquímica y Biología Molecular and Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, Av. Astrofísico Sánchez s/n., 38206 La Laguna, Spain

² CNR—National Research Council, Institute of Endocrinology and Experimental Oncology (IEOS), Via Sergio Pansini 5, 80131 Naples, Italy

³ Service of Medical Oncology, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain

⁴ Service of Medical Oncology, Hospiten® Hospitals, 38001 Santa Cruz de Tenerife, Spain

⁵ Service of Pathology, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain

⁶ Department of Pathology, Hospiten® Hospitals, 38001 Santa Cruz de Tenerife, Spain

⁷ School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH Guildford, UK

⁸ Center of Excellence in Genomic Medicine Research (CEGMR), King Fahd Medical Research Center (KFMRC), Faculty of Applied Medical Sciences, King AbdulAziz University, 21589 Jeddah, Saudi Arabia

Int. J. Mol. Sci. 2017, 18(4), 891; https://doi.org/10.3390/ijms18040891 - 22 Apr 2017

Cited by 16 | Viewed by 7275

Abstract

Scaffold proteins play pivotal roles in the regulation of signaling pathways, integrating external and internal stimuli to various cellular outputs. We report the pattern of cellular and subcellular expression of scaffoldins angiomotin-like 2 (AmotL2), FK506 binding protein 5 (FKBP51) and IQ motif containing [...] Read more.

Scaffold proteins play pivotal roles in the regulation of signaling pathways, integrating external and internal stimuli to various cellular outputs. We report the pattern of cellular and subcellular expression of scaffoldins angiomotin-like 2 (AmotL2), FK506 binding protein 5 (FKBP51) and IQ motif containing GTPase-activating protein 1 (IQGAP1) in colorectal cancer (CRC) and metastases in liver resected after oxaliplatin-based chemotherapy (CT). Positive immunostaining for the three scaffoldins was found in most cells in healthy colon, tumor, healthy liver and metastasized liver. The patterns of expression of AmotL2, FKBP51 and IQGAP1 show the greatest variability in immune system cells and neurons and glia cells and the least in blood vessel cells. The simultaneous subcellular localization in tumor cells and other cell types within the tumor suggest an involvement of these three scaffoldins in cancer biology, including a role in Epithelial Mesenchymal Transition. The display in differential localization and quantitative expression of AmotL2, FKBP51, and IQGAP1 could be used as biomarkers for more accurate tumor staging and as potential targets for anti-cancer therapeutics by blocking or slowing down their interconnecting functions. Tough further research needs to be done in order to improve these assessments. Full article

(This article belongs to the Special Issue Latest Advances in Colorectal Cancer Research: Molecular Mechanisms and Therapies)

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14 pages, 520 KiB

Open AccessReview

Regulatory miRNAs in Colorectal Carcinogenesis and Metastasis

by Yongchen Guo¹, Yonghua Bao¹ and Wancai Yang^1,2,*

¹ Department of Pathology and Institute of Precision Medicine, Jining Medical University, 16 Hehua Road, Jining 272067, China

² Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA

Int. J. Mol. Sci. 2017, 18(4), 890; https://doi.org/10.3390/ijms18040890 - 22 Apr 2017

Cited by 32 | Viewed by 7263

Abstract

Colorectal cancer is one of the most common malignancies and is the second-leading cause of cancer-related death world-wide, which is linked to genetic mutations, epigenetic alterations, and oncogenic signaling activation. MicroRNAs, one of the categories of epigenetics, have been demonstrated significant roles in [...] Read more.

Colorectal cancer is one of the most common malignancies and is the second-leading cause of cancer-related death world-wide, which is linked to genetic mutations, epigenetic alterations, and oncogenic signaling activation. MicroRNAs, one of the categories of epigenetics, have been demonstrated significant roles in carcinogenesis and progression through regulating of oncogenic signaling pathways, stem cells, epithelial-mesenchymal transition, and metastasis. This review summarizes the roles of microRNAs in the regulating of Wnt, Ras, TGF-β, and inflammatory signaling pathways, stemness, and epithelial-mesenchymal transition, for carcinogenesis and metastasis in colorectal cancer. Improving our understanding of the mechanisms of regulatory interactions of microRNAs with signaling pathways in colorectal cancer formation and progression will aid in determining the genes responsible for colorectal cancer initiation, progression, metastasis, and recurrence and, finally, in developing personalized approaches for cancer prevention and therapy. Full article

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

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15 pages, 248 KiB

Open AccessReview

Pathogenic or Therapeutic Extracellular Vesicles in Rheumatic Diseases: Role of Mesenchymal Stem Cell-Derived Vesicles

by Stella Cosenza¹, Maxime Ruiz¹, Marie Maumus¹, Christian Jorgensen^1,2 and Danièle Noël^1,2,*

¹ Institute of Regenerative Medicine and Biotherapies, INSERM, University of Montpellier, 34090 Montpellier, France

² Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Hôpital Lapeyronie, 34090 Montpellier, France

Int. J. Mol. Sci. 2017, 18(4), 889; https://doi.org/10.3390/ijms18040889 - 22 Apr 2017

Cited by 79 | Viewed by 8701

Abstract

Extracellular vesicles (EVs) are important mediators of cell-to-cell communication pathways via the transport of proteins, mRNA, miRNA and lipids. There are three main types of EVs, exosomes, microparticles and apoptotic bodies, which are classified according to their size and biogenesis. EVs are secreted [...] Read more.

Extracellular vesicles (EVs) are important mediators of cell-to-cell communication pathways via the transport of proteins, mRNA, miRNA and lipids. There are three main types of EVs, exosomes, microparticles and apoptotic bodies, which are classified according to their size and biogenesis. EVs are secreted by all cell types and their function reproduces that of the parental cell. They are involved in many biological processes that regulate tissue homeostasis and physiopathology of diseases. In rheumatic diseases, namely osteoarthritis (OA) and rheumatoid arthritis (RA), EVs have been isolated from synovial fluid and shown to play pathogenic roles contributing to progression of both diseases. By contrast, EVs may have therapeutic effect via the delivery of molecules that may stop disease evolution. In particular, EVs derived from mesenchymal stem cells (MSCs) reproduce the main functions of the parental cells and therefore represent the ideal type of EVs for modulating the course of either disease. The aim of this review is to discuss the role of EVs in OA and RA focusing on their potential pathogenic effect and possible therapeutic options. Special attention is given to MSCs and MSC-derived EVs for modulating OA and RA progression with the perspective of developing innovative therapeutic strategies. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)

18 pages, 252 KiB

Open AccessReview

Induced Pluripotent Stem Cell Modeling of Gaucher’s Disease: What Have We Learned?

by Dino Matias Santos^1,2 and Gustavo Tiscornia^1,2,3,*

¹ Department of Biomedical Sciences and Medicine, University of Algarve, Faro 8005-139, Portugal

² Center for Biomedical Research, University of Algarve, Faro 8005-139, Portugal

³ Clínica EUGIN, Barcelona 08028, Spain

Int. J. Mol. Sci. 2017, 18(4), 888; https://doi.org/10.3390/ijms18040888 - 21 Apr 2017

Cited by 11 | Viewed by 6965

Abstract

Gaucher’s disease (GD) is the most frequently inherited lysosomal storage disease, presenting both visceral and neurologic symptoms. Mutations in acid β-glucocerebrosidase disrupt the sphingolipid catabolic pathway promoting glucosylceramide (GlcCer) accumulation in lysosomes. Current treatment options are enzyme replacement therapy (ERT) and substrate reduction [...] Read more.

Gaucher’s disease (GD) is the most frequently inherited lysosomal storage disease, presenting both visceral and neurologic symptoms. Mutations in acid β-glucocerebrosidase disrupt the sphingolipid catabolic pathway promoting glucosylceramide (GlcCer) accumulation in lysosomes. Current treatment options are enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). However, neither of these approaches is effective in treating the neurological aspect of the disease. The use of small pharmacological compounds that act as molecular chaperones is a promising approach that is still experimental. In recent years, an association between GD and Parkinson like synucleinopathies has been discovered. Since 1992, a number of mouse models of GD have been the developed and partially reproduce phenotype of the disease. More recently, the discovery of direct reprograming has allowed the derivation of induced pluripotent stem cells (iPSc) from fibroblasts obtained from GD patients. iPSc can be expanded indefinitely in vitro and differentiated to macrophages and neurons, the main relevant cell types involved in GD. In this work, we review iPSc models of GD and summarize what we have learned from this system. Full article

(This article belongs to the Special Issue Stem Cell Research)

15 pages, 945 KiB

Open AccessReview

Circadian Rhythm Neuropeptides in Drosophila: Signals for Normal Circadian Function and Circadian Neurodegenerative Disease

by Qiankun He^1,†, Binbin Wu^1,†, Jeffrey L. Price^2,* and Zhangwu Zhao^1,*

¹ Department of Entomology, China Agricultural University, 2# Yuanmingyuan West Road, Beijing 100193, China

² Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri–Kansas City, 5100 Rockhill Rd., Kansas City, MO 64110, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(4), 886; https://doi.org/10.3390/ijms18040886 - 21 Apr 2017

Cited by 20 | Viewed by 8349

Abstract

Circadian rhythm is a ubiquitous phenomenon in many organisms ranging from prokaryotes to eukaryotes. During more than four decades, the intrinsic and exogenous regulations of circadian rhythm have been studied. This review summarizes the core endogenous oscillation in Drosophila and then focuses on [...] Read more.

Circadian rhythm is a ubiquitous phenomenon in many organisms ranging from prokaryotes to eukaryotes. During more than four decades, the intrinsic and exogenous regulations of circadian rhythm have been studied. This review summarizes the core endogenous oscillation in Drosophila and then focuses on the neuropeptides, neurotransmitters and hormones that mediate its outputs and integration in Drosophila and the links between several of these (pigment dispersing factor (PDF) and insulin-like peptides) and neurodegenerative disease. These signaling molecules convey important network connectivity and signaling information for normal circadian function, but PDF and insulin-like peptides can also convey signals that lead to apoptosis, enhanced neurodegeneration and cognitive decline in flies carrying circadian mutations or in a senescent state. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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20 pages, 2478 KiB

Open AccessArticle

A Systems Biology Approach Using Transcriptomic Data Reveals Genes and Pathways in Porcine Skeletal Muscle Affected by Dietary Lysine

by Taiji Wang, Jean M. Feugang, Mark A. Crenshaw, Naresh Regmi, John R. Blanton, Jr. and Shengfa F. Liao^*

Department of Animal and Dairy Sciences, Mississippi State University, Starkville, MS 39762, USA

Int. J. Mol. Sci. 2017, 18(4), 885; https://doi.org/10.3390/ijms18040885 - 21 Apr 2017

Cited by 21 | Viewed by 7220

Abstract

Nine crossbred finishing barrows (body weight 94.4 ± 6.7 kg) randomly assigned to three dietary treatments were used to investigate the effects of dietary lysine on muscle growth related metabolic and signaling pathways. Muscle samples were collected from the longissimus dorsi of individual [...] Read more.

Nine crossbred finishing barrows (body weight 94.4 ± 6.7 kg) randomly assigned to three dietary treatments were used to investigate the effects of dietary lysine on muscle growth related metabolic and signaling pathways. Muscle samples were collected from the longissimus dorsi of individual pigs after feeding the lysine-deficient (4.30 g/kg), lysine-adequate (7.10 g/kg), or lysine-excess (9.80 g/kg) diet for five weeks, and the total RNA was extracted afterwards. Affymetrix Porcine Gene 1.0 ST Array was used to quantify the expression levels of 19,211 genes. Statistical ANOVA analysis of the microarray data showed that 674 transcripts were differentially expressed (at p ≤ 0.05 level); 60 out of 131 transcripts (at p ≤ 0.01 level) were annotated in the NetAffx database. Ingenuity pathway analysis showed that dietary lysine deficiency may lead to: (1) increased muscle protein degradation via the ubiquitination pathway as indicated by the up-regulated DNAJA1, HSP90AB1 and UBE2B mRNA; (2) reduced muscle protein synthesis via the up-regulated RND3 and ZIC1 mRNA; (3) increased serine and glycine synthesis via the up-regulated PHGDH and PSPH mRNA; and (4) increased lipid accumulation via the up-regulated ME1, SCD, and CIDEC mRNA. Dietary lysine excess may lead to: (1) decreased muscle protein degradation via the down-regulated DNAJA1, HSP90AA1, HSPH1, and UBE2D3 mRNA; and (2) reduced lipid biosynthesis via the down-regulated CFD and ME1 mRNA. Collectively, dietary lysine may function as a signaling molecule to regulate protein turnover and lipid metabolism in the skeletal muscle of finishing pigs. Full article

(This article belongs to the Special Issue Nutrigenomics of Risk Factors for Disease)

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12 pages, 2216 KiB

Open AccessArticle

The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice

by Lakshini Herat¹, Caroline Rudnicka², Yasunori Okada³, Satsuki Mochizuki⁴, Markus Schlaich^1,5 and Vance Matthews^1,*

¹ Dobney Hypertension Centre, School of Medicine and Pharmacology, University of Western Australia, Crawley WA 6009, Australia

² Research Centre, Royal Perth Hospital, Perth WA 6000, Australia

³ Department of Pathophysiology for Locomotive and Neoplastic Diseases, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan

⁴ Department of Surgery, National Defense Medical College, Saitama 359-8513, Japan

⁵ Department of Cardiology and Department of Nephrology, Royal Perth Hospital, Perth WA 6000, Australia

Int. J. Mol. Sci. 2017, 18(4), 884; https://doi.org/10.3390/ijms18040884 - 21 Apr 2017

Cited by 10 | Viewed by 5129

Abstract

Obesity and diabetes are major causes of morbidity and mortality globally. The current study builds upon our previous association studies highlighting that A Disintegrin And Metalloproteinase 28 (ADAM28) appears to be implicated in the pathogenesis of obesity and type 2 diabetes in humans. [...] Read more.

Obesity and diabetes are major causes of morbidity and mortality globally. The current study builds upon our previous association studies highlighting that A Disintegrin And Metalloproteinase 28 (ADAM28) appears to be implicated in the pathogenesis of obesity and type 2 diabetes in humans. Our novel study characterised the expression of ADAM28 in mice with the metabolic syndrome and used molecular inhibition approaches to investigate the functional role of ADAM28 in the pathogenesis of high fat diet-induced obesity. We identified that ADAM28 mRNA and protein expression was markedly increased in the livers of mice with the metabolic syndrome. In addition, noradrenaline, the major neurotransmitter of the sympathetic nervous system, results in elevated Adam28 mRNA expression in human monocytes. Downregulation of ADAM28 with siRNA technology resulted in a lack of weight gain, promotion of insulin sensitivity/glucose tolerance and decreased liver tumour necrosis factor-α (TNF-α) levels in our diet-induced obesity mouse model as well as reduced blood urea nitrogen, alkaline phosphatase and aspartate aminotransferase. In addition, we show that ADAM28 knock-out mice also displayed reduced body weight, elevated high density lipoprotein cholesterol levels, and reductions in blood urea nitrogen, alkaline phosphatase, and aspartate aminotransferase. The results of this study provide important insights into the pathogenic role of the metalloproteinase ADAM28 in the metabolic syndrome and suggests that downregulation of ADAM28 may be a potential therapeutic strategy in the metabolic syndrome. Full article

(This article belongs to the Special Issue Metalloproteins 2017)

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19 pages, 2940 KiB

Open AccessArticle

Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats

by Zygmunt Warzecha¹

, Paweł Sendur², Piotr Ceranowicz^1,*

, Jakub Cieszkowski¹, Marcin Dembiński³, Ryszard Sendur¹, Joanna Bonior⁴

, Jolanta Jaworek⁴, Tadeusz Ambroży⁵

, Rafał Olszanecki⁶, Beata Kuśnierz-Cabala⁷, Kaczmarzyk Tomasz⁸, Romana Tomaszewska⁹ and Artur Dembiński¹

¹ Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegórzecka St., 31-531 Cracow, Poland

² The University Hospital in Cracow, 31-531 Cracow, Poland

³ Second Department of General Surgery, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland

⁴ Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-531 Cracow, Poland

⁵ Department of Theory of Sport and Kinesiology, Faculty of Physical Education and Sport, University of Physical Education, 31-571 Cracow, Poland

⁶ Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland

⁷ Department of Clinical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland

⁸ Department of Oral Surgery, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland

⁹ Department of Pathology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland

Int. J. Mol. Sci. 2017, 18(4), 882; https://doi.org/10.3390/ijms18040882 - 21 Apr 2017

Cited by 25 | Viewed by 5762 | Correction

Abstract

Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic [...] Read more.

Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic ischemia followed by reperfusion. Acenocoumarol at a dose of 50, 100, or 150 µg/kg/dose was administered intragastrically once a day, starting the first dose 24 h after the initiation of pancreatic reperfusion. Results: Histological examination showed that treatment with acenocoumarol reduces pancreatic edema, necrosis, and hemorrhages in rats with pancreatitis. Moreover, the administration of acenocoumarol decreased pancreatic inflammatory infiltration and vacuolization of pancreatic acinar cells. These findings were accompanied with a reduction in the serum activity of lipase and amylase, concentration of interleukin-1β, and plasma d-Dimer concentration. Moreover, the administration of acenocoumarol improved pancreatic blood flow and pancreatic DNA synthesis. Acenocoumarol given at a dose of 150 µg/kg/dose was the most effective in the treatment of early phase acute pancreatitis. However later, acenocoumarol given at the highest dose failed to exhibit any therapeutic effect; whereas lower doses of acenocoumarol were still effective in the treatment of acute pancreatitis. Conclusion: Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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1 pages, 147 KiB

Open AccessErratum

Erratum: Tingting Lian, et al. Identification of Site-Specific Stroke Biomarker Candidates by Laser Capture Microdissection and Labeled Reference Peptide. Int. J. Mol. Sci. 2015, 16, 13427–13441

by Tingting Lian^†, Daixin Qu^†, Xu Zhao, Lixia Yu and Bing Gao^*

¹ School of Bioscience and Bioengineering, South China University of Technology, Higher Education Mega Center, Guangzhou 510006, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2017, 18(4), 881; https://doi.org/10.3390/ijms18040881 - 21 Apr 2017

Viewed by 3545

Abstract

The authors wish to make a change to their published paper [1]. Since 2013, the authors have performed multiple experiments in many animals, including mice and rats, at both the Sun Yat-Sen University (Guangzhou, China) and China Medical University (Shenyang, China) [...] Full article

11 pages, 2093 KiB

Open AccessArticle

ρ⁰ Cells Feature De-Ubiquitination of SLC Transporters and Increased Levels and Fluxes of Amino Acids

by André Bordinassi Medina¹, Marcin Banaszczak^1,2, Yang Ni¹, Ina Aretz¹ and David Meierhofer^1,*

¹ Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany

² Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24, 71-460 Szczecin, Poland

Int. J. Mol. Sci. 2017, 18(4), 879; https://doi.org/10.3390/ijms18040879 - 20 Apr 2017

Cited by 4 | Viewed by 5939

Abstract

Solute carrier (SLC) transporters are a diverse group of membrane transporter proteins that regulate the cellular flux and distribution of endogenous and xenobiotic compounds. Post-translational modifications (PTMs), such as ubiquitination, have recently emerged as one of the major regulatory mechanisms in protein function [...] Read more.

Solute carrier (SLC) transporters are a diverse group of membrane transporter proteins that regulate the cellular flux and distribution of endogenous and xenobiotic compounds. Post-translational modifications (PTMs), such as ubiquitination, have recently emerged as one of the major regulatory mechanisms in protein function and localization. Previously, we showed that SLC amino acid transporters were on average 6-fold de-ubiquitinated and increased amino acid levels were detected in ρ⁰ cells (lacking mitochondrial DNA, mtDNA) compared to parental cells. Here, we elucidated the altered functionality of SLC transporters and their dynamic ubiquitination status by measuring the uptake of several isotopically labeled amino acids in both human osteosarcoma 143B.TK- and ρ⁰ cells. Our pulse chase analysis indicated that de-ubiquitinated amino acid transporters in ρ⁰ cells were accompanied by an increased transport rate, which leads to higher levels of amino acids in the cell. Finding SLC transport enhancers is an aim of the pharmaceutical industry in order to compensate for loss of function mutations in these genes. Thus, the ubiquitination status of SLC transporters could be an indicator for their functionality, but evidence for a direct connection between de-ubiquitination and transporter activity has to be further elucidated. Full article

(This article belongs to the Special Issue Ubiquitin System)

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18 pages, 1386 KiB

Open AccessReview

EDIM-TKTL1/Apo10 Blood Test: An Innate Immune System Based Liquid Biopsy for the Early Detection, Characterization and Targeted Treatment of Cancer

by Johannes F. Coy

Zyagnum AG, Lyoner Straße 20, D-60528 Frankfurt am Main, Germany

Int. J. Mol. Sci. 2017, 18(4), 878; https://doi.org/10.3390/ijms18040878 - 20 Apr 2017

Cited by 16 | Viewed by 10027

Abstract

Epitope detection in monocytes (EDIM) represents a liquid biopsy exploiting the innate immune system. Activated monocytes (macrophages) phagocytose unwanted cells/cell fragments from the whole body including solid tissues. As they return to the blood, macrophages can be used for a non-invasive detection of [...] Read more.

Epitope detection in monocytes (EDIM) represents a liquid biopsy exploiting the innate immune system. Activated monocytes (macrophages) phagocytose unwanted cells/cell fragments from the whole body including solid tissues. As they return to the blood, macrophages can be used for a non-invasive detection of biomarkers, thereby providing high sensitivity and specificity, because the intracellular presence of biomarkers is due to an innate immune response. Flow cytometry analysis of blood enables the detection of macrophages and phagocytosed intracellular biomarkers. In order to establish a pan-cancer test, biomarkers for two fundamental biophysical mechanisms have been exploited. The DNaseX/Apo10 protein epitope is a characteristic of tumor cells with abnormal apoptosis and proliferation. Transketolase-like 1 (TKTL1) is a marker for an anaerobic glucose metabolism (Warburg effect), which is concomitant with invasive growth/metastasis and resistant to radical and apoptosis inducing therapies. The detection of Apo10 and TKTL1 in blood macrophages allowed a sensitive (95.8%) and specific (97.3%) detection of prostate, breast and oral squamous cell carcinomas. Since TKTL1 represents a drugable target, the EDIM based detection of TKTL1 enables a targeted cancer therapy using the vitamin derivatives oxythiamine or benfo-oxythiamine. Full article

(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)

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9 pages, 873 KiB

Open AccessReview

Regulation of Ubiquitin Enzymes in the TGF-β Pathway

by Prasanna Vasudevan Iyengar

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore

Int. J. Mol. Sci. 2017, 18(4), 877; https://doi.org/10.3390/ijms18040877 - 20 Apr 2017

Cited by 40 | Viewed by 7394

Abstract

The transforming growth factor-β (TGF-β) pathway has a tumor suppressor role in normal and premalignant cells but promotes oncogenesis in advanced cancer cells. Components of the pathway are tightly controlled by ubiquitin modifying enzymes and aberrations in these enzymes are frequently observed to [...] Read more.

The transforming growth factor-β (TGF-β) pathway has a tumor suppressor role in normal and premalignant cells but promotes oncogenesis in advanced cancer cells. Components of the pathway are tightly controlled by ubiquitin modifying enzymes and aberrations in these enzymes are frequently observed to dysregulate the pathway causing diseases such as bone disorders, cancer and metastasis. These enzymes and their counterparts are increasingly being tested as druggable targets, and thus a deeper understanding of the enzymes is required. This review summarizes the roles of specific ubiquitin modifying enzymes in the TGF-β pathway and how they are regulated. Full article

(This article belongs to the Special Issue Ubiquitin System)

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18 pages, 951 KiB

Open AccessArticle

The Peculiar Glycolytic Pathway in Hyperthermophylic Archaea: Understanding Its Whims by Experimentation In Silico

by Yanfei Zhang¹, Theresa Kouril^2,3, Jacky L. Snoep^3,4,5, Bettina Siebers², Matteo Barberis¹ and Hans V. Westerhoff^1,4,5,*

¹ Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands

² Molecular Enzyme Technology and Biochemistry (MEB), Biofilm Centre, Centre for Water and Environment Research (CWE), University Duisburg—Essen, Universitätsstr. 5, 45141 Essen, Germany

³ Department of Biochemistry, University of Stellenbosch, Stellenbosch 7602, South Africa

⁴ The Manchester Centre for Integrative Systems Biology, Manchester Institute for Biotechnology, School for Chemical Engineering and Analytical Science, University of Manchester, Manchester M1 7DN, UK

⁵ Department of Molecular Cell Physiology, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands

Int. J. Mol. Sci. 2017, 18(4), 876; https://doi.org/10.3390/ijms18040876 - 20 Apr 2017

Cited by 9 | Viewed by 5458

Abstract

Mathematical models are key to systems biology where they typically describe the topology and dynamics of biological networks, listing biochemical entities and their relationships with one another. Some (hyper)thermophilic Archaea contain an enzyme, called non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase (GAPN), which catalyzes the direct oxidation [...] Read more.

Mathematical models are key to systems biology where they typically describe the topology and dynamics of biological networks, listing biochemical entities and their relationships with one another. Some (hyper)thermophilic Archaea contain an enzyme, called non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase (GAPN), which catalyzes the direct oxidation of glyceraldehyde-3-phosphate to 3-phosphoglycerate omitting adenosine 5′-triphosphate (ATP) formation by substrate-level-phosphorylation via phosphoglycerate kinase. In this study we formulate three hypotheses that could explain functionally why GAPN exists in these Archaea, and then construct and use mathematical models to test these three hypotheses. We used kinetic parameters of enzymes of Sulfolobus solfataricus (S. solfataricus) which is a thermo-acidophilic archaeon that grows optimally between 60 and 90 °C and between pH 2 and 4. For comparison, we used a model of Saccharomyces cerevisiae (S. cerevisiae), an organism that can live at moderate temperatures. We find that both the first hypothesis, i.e., that the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plus phosphoglycerate kinase (PGK) route (the alternative to GAPN) is thermodynamically too much uphill and the third hypothesis, i.e., that GAPDH plus PGK are required to carry the flux in the gluconeogenic direction, are correct. The second hypothesis, i.e., that the GAPDH plus PGK route delivers less than the 1 ATP per pyruvate that is delivered by the GAPN route, is only correct when GAPDH reaction has a high rate and 1,3-bis-phosphoglycerate (BPG) spontaneously degrades to 3PG at a high rate. Full article

(This article belongs to the Special Issue Computational Modelling of Enzymatic Reaction Mechanisms)

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14 pages, 2570 KiB

Open AccessArticle

Aneurysm-Specific miR-221 and miR-146a Participates in Human Thoracic and Abdominal Aortic Aneurysms

by Premakumari Venkatesh¹

, Julie Phillippi², Sasanka Chukkapalli¹, Mercedes Rivera-Kweh¹, Irina Velsko¹, Thomas Gleason², Paul VanRyzin², Seyed Hossein Aalaei-Andabili³, Ravi Kiran Ghanta⁴, Thomas Beaver³, Edward Kar Leung Chan⁵ and Lakshmyya Kesavalu^1,5,*

¹ Department of Periodontology, University of Florida, Gainesville, FL 32610, USA

² Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA

³ Departments of Surgery, University of Florida, Gainesville, FL 32610, USA

⁴ Michael E. Debakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA

⁵ Department of Oral Biology, University of Florida, Gainesville, FL 32610, USA

Int. J. Mol. Sci. 2017, 18(4), 875; https://doi.org/10.3390/ijms18040875 - 20 Apr 2017

Cited by 28 | Viewed by 6722

Abstract

Altered microRNA expression is implicated in cardiovascular diseases. Our objective was to determine microRNA signatures in thoracic aortic aneurysms (TAAs) and abdominal aortic aneurysms (AAAs) compared with control non-aneurysmal aortic specimens. We evaluated the expression of fifteen selected microRNA in human TAA and [...] Read more.

Altered microRNA expression is implicated in cardiovascular diseases. Our objective was to determine microRNA signatures in thoracic aortic aneurysms (TAAs) and abdominal aortic aneurysms (AAAs) compared with control non-aneurysmal aortic specimens. We evaluated the expression of fifteen selected microRNA in human TAA and AAA operative specimens compared to controls. We observed significant upregulation of miR-221 and downregulation of miR-1 and -133 in TAA specimens. In contrast, upregulation of miR-146a and downregulation of miR-145 and -331-3p were found only for AAA specimens. Upregulation of miR-126 and -486-5p and downregulation of miR-30c-2*, -155, and -204 were observed in specimens of TAAs and AAAs. The data reveal microRNA expression signatures unique to aneurysm location and common to both thoracic and abdominal pathologies. Thus, changes in miR-1, -29a, -133a, and -221 are involved in TAAs and miR-145, -146, and -331-3p impact AAAs. This work validates prior studies on microRNA expression in aneurysmal diseases. Full article

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

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32 pages, 3732 KiB

Open AccessReview

On the Edge of Research and Technological Application: A Critical Review of Electromethanogenesis

by Ramiro Blasco-Gómez¹

, Pau Batlle-Vilanova^1,2, Marianna Villano³

, Maria Dolors Balaguer¹

, Jesús Colprim¹

and Sebastià Puig^1,*

¹ Laboratory of Chemical and Environmental Engineering (LEQUIA), Institute of the Environment, University of Girona, Campus Montilivi, Carrer Maria Aurèlia Capmany, 69, E-17003 Girona, Spain

² Department of Innovation and Technology, FCC Aqualia, Balmes Street, 36, 6th Floor, 08007 Barcelona, Spain

³ Department of Chemistry, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy

Int. J. Mol. Sci. 2017, 18(4), 874; https://doi.org/10.3390/ijms18040874 - 20 Apr 2017

Cited by 168 | Viewed by 11880

Abstract

The conversion of electrical current into methane (electromethanogenesis) by microbes represents one of the most promising applications of bioelectrochemical systems (BES). Electromethanogenesis provides a novel approach to waste treatment, carbon dioxide fixation and renewable energy storage into a chemically stable compound, such as [...] Read more.

The conversion of electrical current into methane (electromethanogenesis) by microbes represents one of the most promising applications of bioelectrochemical systems (BES). Electromethanogenesis provides a novel approach to waste treatment, carbon dioxide fixation and renewable energy storage into a chemically stable compound, such as methane. This has become an important area of research since it was first described, attracting different research groups worldwide. Basics of the process such as microorganisms involved and main reactions are now much better understood, and recent advances in BES configuration and electrode materials in lab-scale enhance the interest in this technology. However, there are still some gaps that need to be filled to move towards its application. Side reactions or scaling-up issues are clearly among the main challenges that need to be overcome to its further development. This review summarizes the recent advances made in the field of electromethanogenesis to address the main future challenges and opportunities of this novel process. In addition, the present fundamental knowledge is critically reviewed and some insights are provided to identify potential niche applications and help researchers to overcome current technological boundaries. Full article

(This article belongs to the Special Issue Bioelectrochemical Systems)

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15 pages, 854 KiB

Open AccessReview

Circadian Clock, Cell Division, and Cancer: From Molecules to Organism

by Anton Shostak

Circadian Rhythms and Molecular Clocks Group, Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany

Int. J. Mol. Sci. 2017, 18(4), 873; https://doi.org/10.3390/ijms18040873 - 20 Apr 2017

Cited by 133 | Viewed by 17387

Abstract

As a response to environmental changes driven by the Earth’s axial rotation, most organisms evolved an internal biological timer—the so called circadian clock—which regulates physiology and behavior in a rhythmic fashion. Emerging evidence suggests an intimate interplay between the circadian clock and another [...] Read more.

As a response to environmental changes driven by the Earth’s axial rotation, most organisms evolved an internal biological timer—the so called circadian clock—which regulates physiology and behavior in a rhythmic fashion. Emerging evidence suggests an intimate interplay between the circadian clock and another fundamental rhythmic process, the cell cycle. However, the precise mechanisms of this connection are not fully understood. Disruption of circadian rhythms has a profound impact on cell division and cancer development and, vice versa, malignant transformation causes disturbances of the circadian clock. Conventional knowledge attributes tumor suppressor properties to the circadian clock. However, this implication might be context-dependent, since, under certain conditions, the clock can also promote tumorigenesis. Therefore, a better understanding of the molecular links regulating the physiological balance between the two cycles will have potential significance for the treatment of cancer and associated disorders. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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19 pages, 3439 KiB

Open AccessArticle

Antioxidant and Anti-Senescence Effect of Metformin on Mouse Olfactory Ensheathing Cells (mOECs) May Be Associated with Increased Brain-Derived Neurotrophic Factor Levels—An Ex Vivo Study

by Agnieszka Śmieszek^1,*, Zuzanna Stręk¹, Katarzyna Kornicka¹, Jakub Grzesiak²

, Christine Weiss³ and Krzysztof Marycz²

¹ Department of Experimental Biology and Electron Microscope Facility, The Faculty of Biology and Animal Science, Wroclaw University of Environmental and Life Sciences, Norwida 25, 50-375 Wroclaw, Poland

² Wroclaw Research Centre EIT+, Stablowicka 147, 54-066 Wroclaw, Poland

³ PferdePraxis Dr. Med. Vet. Daniel Weiss, Postmatte 14, CH-8807 Freienbach, Switzerland

Int. J. Mol. Sci. 2017, 18(4), 872; https://doi.org/10.3390/ijms18040872 - 20 Apr 2017

Cited by 60 | Viewed by 7302

Abstract

Metformin, the popular anti-diabetic drug was shown to exert multiple biological effects. The most recent metformin gained attention as an agent that mobilizes endogenous progenitor cells and enhances regenerative potential of organisms, for example by promoting neurogenesis. In the present study, we examined [...] Read more.

Metformin, the popular anti-diabetic drug was shown to exert multiple biological effects. The most recent metformin gained attention as an agent that mobilizes endogenous progenitor cells and enhances regenerative potential of organisms, for example by promoting neurogenesis. In the present study, we examined the role of metformin on mouse olfactory ensheathing cells (mOECs) derived from animals receiving metformin for eight weeks at a concentration equal to 2.8 mg/day. The mOECs expanded ex vivo were characterized in terms of their cellular phenotype, morphology, proliferative activity, viability and accumulation of oxidative stress factors. Moreover, we determined the mRNA and protein levels of brain-derived neurotrophic factor (BDNF), distinguishing the secretion of BDNF by mOECs in cultures and circulating serum levels of BDNF. The mOECs used in the experiment were glial fibrillary acidic protein (GFAP) and p75 neurotrophin receptor (p75^NTR) positive and exhibited both astrocyte-like and non-myelin Schwann cell-like morphologies. Our results revealed that the proliferation of OECs derived from mice treated with metformin was lowered, when compared to control group. Simultaneously, we noted increased cell viability, reduced expression of markers associated with cellular senescence and a decreased amount of reactive oxygen species. We observed increased mRNA expression of BDNF and its down-stream genes. Obtained results indicate that metformin may exert antioxidant, anti-apoptotic and senolytic action on OECs expanded ex vivo. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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10 pages, 549 KiB

Open AccessReview

Roles of Copper-Binding Proteins in Breast Cancer

by Stéphanie Blockhuys and Pernilla Wittung-Stafshede^*

Department Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden

Int. J. Mol. Sci. 2017, 18(4), 871; https://doi.org/10.3390/ijms18040871 - 20 Apr 2017

Cited by 82 | Viewed by 8278

Abstract

Copper ions are needed in several steps of cancer progression. However, the underlying mechanisms, and involved copper-binding proteins, are mainly elusive. Since most copper ions in the body (in and outside cells) are protein-bound, it is important to investigate what copper-binding proteins participate [...] Read more.

Copper ions are needed in several steps of cancer progression. However, the underlying mechanisms, and involved copper-binding proteins, are mainly elusive. Since most copper ions in the body (in and outside cells) are protein-bound, it is important to investigate what copper-binding proteins participate and, for these, how they are loaded with copper by copper transport proteins. Mechanistic information for how some copper-binding proteins, such as extracellular lysyl oxidase (LOX), play roles in cancer have been elucidated but there is still much to learn from a biophysical molecular viewpoint. Here we provide a summary of copper-binding proteins and discuss ones reported to have roles in cancer. We specifically focus on how copper-binding proteins such as mediator of cell motility 1 (MEMO1), LOX, LOX-like proteins, and secreted protein acidic and rich in cysteine (SPARC) modulate breast cancer from molecular and clinical aspects. Because of the importance of copper for invasion/migration processes, which are key components of cancer metastasis, further insights into the actions of copper-binding proteins may provide new targets to combat cancer. Full article

(This article belongs to the Special Issue Metal Metabolism in Animals II)

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14 pages, 2521 KiB

Open AccessReview

Studying Lactoferrin N-Glycosylation

by Sercan Karav¹, J. Bruce German^2,3,*, Camille Rouquié², Annabelle Le Parc^2,† and Daniela Barile^2,3

¹ Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, 17100 Canakkale, Turkey

² Department of Food Science and Technology, University of California, One Shields Avenue, Davis, CA 95616, USA

³ Foods for Health Institute, University of California, One Shields Avenue, Davis, CA 95616, USA

^† Current address: Prolacta Bioscience^®, 757 Baldwin Park Blvd, City of Industry, CA 91746, USA.

Int. J. Mol. Sci. 2017, 18(4), 870; https://doi.org/10.3390/ijms18040870 - 20 Apr 2017

Cited by 135 | Viewed by 14969

Abstract

Lactoferrin is a multifunctional glycoprotein found in the milk of most mammals. In addition to its well-known role of binding iron, lactoferrin carries many important biological functions, including the promotion of cell proliferation and differentiation, and as an anti-bacterial, anti-viral, and anti-parasitic protein. [...] Read more.

Lactoferrin is a multifunctional glycoprotein found in the milk of most mammals. In addition to its well-known role of binding iron, lactoferrin carries many important biological functions, including the promotion of cell proliferation and differentiation, and as an anti-bacterial, anti-viral, and anti-parasitic protein. These functions differ among lactoferrin homologs in mammals. Although considerable attention has been given to the many functions of lactoferrin, its primary nutritional contribution is presumed to be related to its iron-binding characteristics, whereas the role of glycosylation has been neglected. Given the critical role of glycan binding in many biological processes, the glycan moieties in lactoferrin are likely to contribute significantly to the biological roles of lactoferrin. Despite the high amino acid sequence homology in different lactoferrins (up to 99%), each exhibits a unique glycosylation pattern that may be responsible for heterogeneity of the biological properties of lactoferrins. An important task for the production of biotherapeutics and medical foods containing bioactive glycoproteins is the assessment of the contributions of individual glycans to the observed bioactivities. This review examines how the study of lactoferrin glycosylation patterns can increase our understanding of lactoferrin functionality. Full article

(This article belongs to the Special Issue Lipidomics and Glycomics: New Advances in Food Science and Nutrition)

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19 pages, 1456 KiB

Open AccessReview

Hepatitis E Virus Genotypes and Evolution: Emergence of Camel Hepatitis E Variants

by Siddharth Sridhar¹, Jade L. L. Teng^1,2,3,4, Tsz-Ho Chiu¹

, Susanna K. P. Lau^1,2,3,4

and Patrick C. Y. Woo^1,2,3,4,*

¹ Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

² State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, University Pathology Building, Queen Mary Hospital, Hong Kong, China

³ Research Centre of Infection and Immunology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

⁴ Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Int. J. Mol. Sci. 2017, 18(4), 869; https://doi.org/10.3390/ijms18040869 - 20 Apr 2017

Cited by 180 | Viewed by 10862

Abstract

Hepatitis E virus (HEV) is a major cause of viral hepatitis globally. Zoonotic HEV is an important cause of chronic hepatitis in immunocompromised patients. The rapid identification of novel HEV variants and accumulating sequence information has prompted significant changes in taxonomy of the [...] Read more.

Hepatitis E virus (HEV) is a major cause of viral hepatitis globally. Zoonotic HEV is an important cause of chronic hepatitis in immunocompromised patients. The rapid identification of novel HEV variants and accumulating sequence information has prompted significant changes in taxonomy of the family Hepeviridae. This family includes two genera: Orthohepevirus, which infects terrestrial vertebrates, and Piscihepevirus, which infects fish. Within Orthohepevirus, there are four species, A–D, with widely differing host range. Orthohepevirus A contains the HEV variants infecting humans and its significance continues to expand with new clinical information. We now recognize eight genotypes within Orthohepevirus A: HEV1 and HEV2, restricted to humans; HEV3, which circulates among humans, swine, rabbits, deer and mongooses; HEV4, which circulates between humans and swine; HEV5 and HEV6, which are found in wild boars; and HEV7 and HEV8, which were recently identified in dromedary and Bactrian camels, respectively. HEV7 is an example of a novel genotype that was found to have significance to human health shortly after discovery. In this review, we summarize recent developments in HEV molecular taxonomy, epidemiology and evolution and describe the discovery of novel camel HEV genotypes as an illustrative example of the changes in this field. Full article

(This article belongs to the Special Issue Molecular Research of Emerging Viruses: Viral Evolution, Diagnostics and Pathogenesis and Therapeutics)

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18 pages, 9402 KiB

Open AccessArticle

One Year Follow-Up Risk Assessment in SKH-1 Mice and Wounds Treated with an Argon Plasma Jet

by Anke Schmidt^1,*

, Thomas Von Woedtke^1,2

, Jan Stenzel³, Tobias Lindner³

, Stefan Polei³, Brigitte Vollmar⁴ and Sander Bekeschus¹

¹ Leibniz-Institute for Plasma Science and Technology (INP Greifswald), Departments of Plasma Life Science and ZIK Plasmatis, Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany

² Department of Hygiene and Environmental Medicine, University Medicine Greifswald, 17475 Greifswald, Germany

³ Core Facility Multimodal Small Animal Imaging, 18057 Rostock, Germany

⁴ Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany

Int. J. Mol. Sci. 2017, 18(4), 868; https://doi.org/10.3390/ijms18040868 - 19 Apr 2017

Cited by 92 | Viewed by 6876

Abstract

Multiple evidence in animal models and in humans suggest a beneficial role of cold physical plasma in wound treatment. Yet, risk assessment studies are important to further foster therapeutic advancement and acceptance of cold plasma in clinics. Accordingly, we investigated the longterm side [...] Read more.

Multiple evidence in animal models and in humans suggest a beneficial role of cold physical plasma in wound treatment. Yet, risk assessment studies are important to further foster therapeutic advancement and acceptance of cold plasma in clinics. Accordingly, we investigated the longterm side effects of repetitive plasma treatment over 14 consecutive days in a rodent full-thickness ear wound model. Subsequently, animals were housed for 350 days and sacrificed thereafter. In blood, systemic changes of the proinflammatory cytokines interleukin 1β and tumor necrosis factor α were absent. Similarly, tumor marker levels of α-fetoprotein and calcitonin remained unchanged. Using quantitative PCR, the expression levels of several cytokines and tumor markers in liver, lung, and skin were found to be similar in the control and treatment group as well. Likewise, histological and immunohistochemical analysis failed to detect abnormal morphological changes and the presence of tumor markers such as carcinoembryonic antigen, α-fetoprotein, or the neighbor of Punc 11. Absence of neoplastic lesions was confirmed by non-invasive imaging methods such as anatomical magnetic resonance imaging and positron emission tomography-computed tomography. Our results suggest that the beneficial effects of cold plasma in wound healing come without apparent side effects including tumor formation or chronic inflammation. Full article

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

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Int. J. Mol. Sci., Volume 18, Issue 4 (April 2017) – 217 articles

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