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Andersen PAK, Reeh RH, Sanders I, Overlund EB, Katsioudi G, Jiménez-Sánchez C, Skovhøj EZ, Lubberding AF, Dibner C, Mandrup-Poulsen T. Circadian synchronization differentially modifies cytokine-mediated transcriptomic remodeling and cell death in INS-1 cells and mouse islets. iScience 2025; 28:112431. [PMID: 40352732 PMCID: PMC12063125 DOI: 10.1016/j.isci.2025.112431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 01/30/2025] [Accepted: 04/10/2025] [Indexed: 05/14/2025] Open
Abstract
Perturbation of the β-cell circadian clock causes oxidative stress and secretory failure, and proinflammatory cytokines disrupt the β-cell core clock. We hypothesized that cytokine-mediated clock perturbation in β-cells depends on circadian synchronization status. Cytokine-mediated core clock mRNA expression in non-synchronized insulin-producing INS-1 cells were potentiated upon synchronization, which were differentially translated into alterations in protein levels. Synchronization sensitized INS-1 cells to cytokine-mediated cytotoxicity, associated with potentiation of NF-κB activity. Inhibition of NF-κB abrogated cytokine-mediated clock gene-expression independent of synchronization status and reversed cytokine-mediated period lengthening. In contrast, in murine islets, cytokines generally reduced core clock mRNA expression independently of synchronization status or NF-κB activity. Synchronization prevented cytokine-mediated cytotoxicity, but not NF-κB activity to a degree comparable to that of KINK-1, while alterations in islet rhythmicity were unaffected by NF-κB inhibition. In conclusion, circadian synchronization differentially modifies cytokine-mediated transcriptomic remodeling and cell death in INS-1 cells and murine islets, depending on NF-κB involvement.
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Affiliation(s)
| | - Rasmus H. Reeh
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Isabel Sanders
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Emilie Bender Overlund
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Georgia Katsioudi
- Department of Surgery, Division of Thoracic and Endocrine Surgery, University Hospitals of Geneva, 1211 Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Institute of Genetics and Genomics of Geneva (iGE3), 1211 Geneva, Switzerland
| | - Cecilia Jiménez-Sánchez
- Department of Surgery, Division of Thoracic and Endocrine Surgery, University Hospitals of Geneva, 1211 Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Institute of Genetics and Genomics of Geneva (iGE3), 1211 Geneva, Switzerland
| | - Emil Zeng Skovhøj
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Anniek Frederike Lubberding
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Charna Dibner
- Department of Surgery, Division of Thoracic and Endocrine Surgery, University Hospitals of Geneva, 1211 Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Institute of Genetics and Genomics of Geneva (iGE3), 1211 Geneva, Switzerland
| | - Thomas Mandrup-Poulsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
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Hansen MS, Pokharel P, Piganelli J, Sussel L. The Chicken or the Egg Dilemma: Understanding the Interplay between the Immune System and the β Cell in Type 1 Diabetes. Cold Spring Harb Perspect Med 2025; 15:a041591. [PMID: 38951031 PMCID: PMC11960692 DOI: 10.1101/cshperspect.a041591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
In this review, we explore the complex interplay between the immune system and pancreatic β cells in the context of type 1 diabetes (T1D). While T1D is predominantly considered a T-cell-mediated autoimmune disease, the inability of human leukocyte antigen (HLA)-risk alleles alone to explain disease development suggests a role for β cells in initiating and/or propagating disease. This review delves into the vulnerability of β cells, emphasizing their susceptibility to endoplasmic reticulum (ER) stress and protein modifications, which may give rise to neoantigens. Additionally, we discuss the role of viral infections as contributors to T1D onset, and of genetic factors with dual impacts on the immune system and β cells. A greater understanding of the interplay between environmental triggers, autoimmunity, and the β cell will not only lead to insight as to why the islet β cells are specifically targeted by the immune system in T1D but may also reveal potential novel therapeutic interventions.
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Affiliation(s)
- Maria Skjøtt Hansen
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
| | - Pravil Pokharel
- Division of Endocrinology Diabetes and Metabolism, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | - Jon Piganelli
- Division of Endocrinology Diabetes and Metabolism, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | - Lori Sussel
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
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Gao Z, Hu H, Huang Y, Yu F, Lou B. Mesencephalic astrocyte-derived neurotrophic factor upregulates CHOP and ATF6 in the rat retina with retinitis pigmentosa. Ophthalmic Genet 2025:1-9. [PMID: 40113270 DOI: 10.1080/13816810.2025.2482610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 02/27/2025] [Accepted: 03/17/2025] [Indexed: 03/22/2025]
Abstract
PURPOSE In the current work, we investigated the potential protective function of MANF against the degeneration of RP in S334ter-3 rats and the mechanism underlying these effects. METHODS The left eye of rat was injected with MANF, and the right eye injected PBS as a control. The levels of those ER stress associated proteins were determined by western blot analysis. RESULTS First, those ER stress associated proteins were detected in S334ter-3 rats. Among these proteins, a decrease in the expression of PERK was only showed from PD 6 to PD 12. Surprisingly, a dramatic increase of ATF6 was induced by injection MANF. Then, the expression of ATF6 protein declined rapidly to the control eye. Furthermore, a remarkable increase in the expression of CHOP was examined at 6 h, which peaked at 12 h and maintained the level until 48 h. At the same time, CHOP was detected in Müller cells but not in photoreceptor; nevertheless, photoreceptor survival clearly improved. The increasing expressions of CHOP and ATF6 in SD rats were similar to the changes in S33ter-3 rats after injection MANF. CONCLUSIONS These results indicate that MANF may play an important role in protecting photoreceptor degeneration in RP.
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Affiliation(s)
- Zhenya Gao
- School of Medicine, Xuchang University, Xuchang, China
- Ophthalmology, Xuchang Central Hospital, Xuchang, China
- Ophthalmology, Xuchang Aier Eye Hospital, Xuchang, China
| | - Hongge Hu
- Ophthalmology, Xuchang Central Hospital, Xuchang, China
| | | | - Fang Yu
- School of Medicine, Xuchang University, Xuchang, China
| | - Bin Lou
- Ophthalmology, Xuchang Central Hospital, Xuchang, China
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Jørgensen KS, Pedersen SS, Hjorth SA, Billestrup N, Prause M. Protection of beta cells against cytokine-induced apoptosis by the gut microbial metabolite butyrate. FEBS J 2024. [PMID: 39569473 DOI: 10.1111/febs.17334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/28/2024] [Accepted: 11/12/2024] [Indexed: 11/22/2024]
Abstract
Type 1 diabetes (T1D) is characterized by immune cell infiltration in the islets of Langerhans, leading to the destruction of insulin-producing beta cells. This destruction is driven by secreted cytokines and cytotoxic T cells inducing apoptosis in beta cells. Butyrate, a metabolite produced by the gut microbiota, has been shown to have various health benefits, including anti-inflammatory and anti-diabetic effects. In this study, we investigated the potential protective effects of butyrate on cytokine-induced apoptosis in beta cells and explored the underlying mechanisms. Insulin-secreting INS-1E cells and isolated mouse islets were treated with interleukin-1beta (IL-1β) or a combination of IL-1β and interferon-gamma (IFN-γ) in the presence or absence of butyrate. We analyzed apoptosis, nitric oxide (NO) levels, expression of stress-related genes, and immune cell migration. Our results demonstrated that butyrate significantly attenuated cytokine-induced apoptosis in both INS-1E cells and mouse islets, accompanied by a reduction in NO levels. Butyrate also decreased the expression of endoplasmic reticulum (ER) stress markers such as Chop, phosphorylated eIF2α and Atf4, as well as some pro-apoptotic genes including Dp5 and Puma. Butyrate reduced the cytokine-induced expression of the chemokine genes Cxcl1 and Cxcl10 in mouse islets, as well as the chemotactic activity of THP-1 monocytes toward conditioned media from IL-1β-exposed islets. In conclusion, these findings indicate that butyrate protects beta cells from cytokine-induced apoptosis and ER stress, suggesting its potential as a therapeutic agent to prevent beta cell destruction in T1D.
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Affiliation(s)
- Kasper Suhr Jørgensen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Signe Schultz Pedersen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Siv Annegrethe Hjorth
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Nils Billestrup
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Michala Prause
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
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Veli Ö, Kaya Ö, Varanda AB, Hildebrandt X, Xiao P, Estornes Y, Poggenberg M, Wang Y, Pasparakis M, Bertrand MJM, Walczak H, Annibaldi A, Cardozo AK, Peltzer N. RIPK1 is dispensable for cell death regulation in β-cells during hyperglycemia. Mol Metab 2024; 87:101988. [PMID: 39004142 PMCID: PMC11295703 DOI: 10.1016/j.molmet.2024.101988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 07/05/2024] [Accepted: 07/06/2024] [Indexed: 07/16/2024] Open
Abstract
OBJECTIVE Receptor-interacting protein kinase 1 (RIPK1) orchestrates the decision between cell survival and cell death in response to tumor necrosis factor (TNF) and other cytokines. Whereas the scaffolding function of RIPK1 is crucial to prevent TNF-induced apoptosis and necroptosis, its kinase activity is required for necroptosis and partially for apoptosis. Although TNF is a proinflammatory cytokine associated with β-cell loss in diabetes, the mechanism by which TNF induces β-cell demise remains unclear. METHODS Here, we dissected the contribution of RIPK1 scaffold versus kinase functions to β-cell death regulation using mice lacking RIPK1 specifically in β-cells (Ripk1β-KO mice) or expressing a kinase-dead version of RIPK1 (Ripk1D138N mice), respectively. These mice were challenged with streptozotocin, a model of autoimmune diabetes. Moreover, Ripk1β-KO mice were further challenged with a high-fat diet to induce hyperglycemia. For mechanistic studies, pancreatic islets were subjected to various killing and sensitising agents. RESULTS Inhibition of RIPK1 kinase activity (Ripk1D138N mice) did not affect the onset and progression of hyperglycemia in a type 1 diabetes model. Moreover, the absence of RIPK1 expression in β-cells did not affect normoglycemia under basal conditions or hyperglycemia under diabetic challenges. Ex vivo, primary pancreatic islets are not sensitised to TNF-induced apoptosis and necroptosis in the absence of RIPK1. Intriguingly, we found that pancreatic islets display high levels of the antiapoptotic cellular FLICE-inhibitory protein (cFLIP) and low levels of apoptosis (Caspase-8) and necroptosis (RIPK3) components. Cycloheximide treatment, which led to a reduction in cFLIP levels, rendered primary islets sensitive to TNF-induced cell death which was fully blocked by caspase inhibition. CONCLUSIONS Unlike in many other cell types (e.g., epithelial, and immune), RIPK1 is not required for cell death regulation in β-cells under physiological conditions or diabetic challenges. Moreover, in vivo and in vitro evidence suggest that pancreatic β-cells do not undergo necroptosis but mainly caspase-dependent death in response to TNF. Last, our results show that β-cells have a distinct mode of regulation of TNF-cytotoxicity that is independent of RIPK1 and that may be highly dependent on cFLIP.
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Affiliation(s)
- Önay Veli
- Department of Translational Genomics, Faculty of Medicine, University of Cologne, Cologne, Germany; Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
| | - Öykü Kaya
- Department of Translational Genomics, Faculty of Medicine, University of Cologne, Cologne, Germany; Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
| | - Ana Beatriz Varanda
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany; Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Ximena Hildebrandt
- Department of Translational Genomics, Faculty of Medicine, University of Cologne, Cologne, Germany; Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
| | - Peng Xiao
- Inflammation and Cell Death Signalling group, Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, Brussels, Belgium
| | - Yann Estornes
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Matea Poggenberg
- Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Yuan Wang
- Department of Translational Genomics, Faculty of Medicine, University of Cologne, Cologne, Germany; Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
| | - Manolis Pasparakis
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany; Institute for Genetics, University of Cologne, Cologne, Germany
| | - Mathieu J M Bertrand
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Henning Walczak
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany; Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Alessandro Annibaldi
- Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Alessandra K Cardozo
- Inflammation and Cell Death Signalling group, Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, Brussels, Belgium
| | - Nieves Peltzer
- Department of Translational Genomics, Faculty of Medicine, University of Cologne, Cologne, Germany; Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.
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Wreven E, Ruiz de Adana MS, Hardivillé S, Gmyr V, Kerr-Conte J, Chetboun M, Pasquetti G, Delalleau N, Thévenet J, Coddeville A, Vallejo Herrera MJ, Hinden L, Benavides Espínola IC, Gómez Duro M, Sanchez Salido L, Linares F, Bermúdez-Silva FJ, Tam J, Bonner C, Egan JM, Olveira G, Colomo N, Pattou F, González-Mariscal I. Pharmaceutical targeting of the cannabinoid type 1 receptor impacts the crosstalk between immune cells and islets to reduce insulitis in humans. Diabetologia 2024; 67:1877-1896. [PMID: 38864887 PMCID: PMC11410908 DOI: 10.1007/s00125-024-06193-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 04/22/2024] [Indexed: 06/13/2024]
Abstract
AIMS/HYPOTHESIS Insulitis, a hallmark of inflammation preceding autoimmune type 1 diabetes, leads to the eventual loss of functional beta cells. However, functional beta cells can persist even in the face of continuous insulitis. Despite advances in immunosuppressive treatments, maintaining functional beta cells to prevent insulitis progression and hyperglycaemia remains a challenge. The cannabinoid type 1 receptor (CB1R), present in immune cells and beta cells, regulates inflammation and beta cell function. Here, we pioneer an ex vivo model mirroring human insulitis to investigate the role of CB1R in this process. METHODS CD4+ T lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) from male and female individuals at the onset of type 1 diabetes and from non-diabetic individuals, RNA was extracted and mRNA expression was analysed by real-time PCR. Single beta cell expression from donors with type 1 diabetes was obtained from data mining. Patient-derived human islets from male and female cadaveric donors were 3D-cultured in solubilised extracellular matrix gel in co-culture with the same donor PBMCs, and incubated with cytokines (IL-1β, TNF-α, IFN-γ) for 24-48 h in the presence of vehicle or increasing concentrations of the CB1R blocker JD-5037. Expression of CNR1 (encoding for CB1R) was ablated using CRISPR/Cas9 technology. Viability, intracellular stress and signalling were assayed by live-cell probing and real-time PCR. The islet function measured as glucose-stimulated insulin secretion was determined in a perifusion system. Infiltration of immune cells into the islets was monitored by microscopy. Non-obese diabetic mice aged 7 weeks were treated for 1 week with JD-5037, then euthanised. Profiling of immune cells infiltrated in the islets was performed by flow cytometry. RESULTS CNR1 expression was upregulated in circulating CD4+ T cells from individuals at type 1 diabetes onset (6.9-fold higher vs healthy individuals) and in sorted islet beta cells from donors with type 1 diabetes (3.6-fold higher vs healthy counterparts). The peripherally restricted CB1R inverse agonist JD-5037 arrested the initiation of insulitis in humans and mice. Mechanistically, CB1R blockade prevented islet NO production and ameliorated the ATF6 arm of the unfolded protein response. Consequently, cyto/chemokine expression decreased in human islets, leading to sustained islet cell viability and function. CONCLUSIONS/INTERPRETATION These results suggest that CB1R could be an interesting target for type 1 diabetes while highlighting the regulatory mechanisms of insulitis. Moreover, these findings may apply to type 2 diabetes where islet inflammation is also a pathophysiological factor. DATA AVAILABILITY Transcriptomic analysis of sorted human beta cells are from Gene Expression Omnibus database, accession no. GSE121863, available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM3448161 .
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Affiliation(s)
- Elise Wreven
- Inserm UMR1190 - Translational Research for Diabetes, Université de Lille, CHU Lille, Institut Pasteur de Lille, Inserm, European Genomic Institute for Diabetes, Lille, France
| | - María Soledad Ruiz de Adana
- Servicio de Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA-Plataforma BIONAND, Málaga, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Málaga, Spain
| | - Stéphan Hardivillé
- CNRS UMR8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille, France
| | - Valery Gmyr
- Inserm UMR1190 - Translational Research for Diabetes, Université de Lille, CHU Lille, Institut Pasteur de Lille, Inserm, European Genomic Institute for Diabetes, Lille, France
| | - Julie Kerr-Conte
- Inserm UMR1190 - Translational Research for Diabetes, Université de Lille, CHU Lille, Institut Pasteur de Lille, Inserm, European Genomic Institute for Diabetes, Lille, France
| | - Mikael Chetboun
- Inserm UMR1190 - Translational Research for Diabetes, Université de Lille, CHU Lille, Institut Pasteur de Lille, Inserm, European Genomic Institute for Diabetes, Lille, France
| | - Gianni Pasquetti
- Inserm UMR1190 - Translational Research for Diabetes, Université de Lille, CHU Lille, Institut Pasteur de Lille, Inserm, European Genomic Institute for Diabetes, Lille, France
| | - Nathalie Delalleau
- Inserm UMR1190 - Translational Research for Diabetes, Université de Lille, CHU Lille, Institut Pasteur de Lille, Inserm, European Genomic Institute for Diabetes, Lille, France
| | - Julien Thévenet
- Inserm UMR1190 - Translational Research for Diabetes, Université de Lille, CHU Lille, Institut Pasteur de Lille, Inserm, European Genomic Institute for Diabetes, Lille, France
| | - Anaïs Coddeville
- Inserm UMR1190 - Translational Research for Diabetes, Université de Lille, CHU Lille, Institut Pasteur de Lille, Inserm, European Genomic Institute for Diabetes, Lille, France
| | - María José Vallejo Herrera
- Servicio de Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA-Plataforma BIONAND, Málaga, Spain
| | - Liad Hinden
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Inmaculada Concepción Benavides Espínola
- Servicio de Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA-Plataforma BIONAND, Málaga, Spain
| | - Mireia Gómez Duro
- Inserm UMR1190 - Translational Research for Diabetes, Université de Lille, CHU Lille, Institut Pasteur de Lille, Inserm, European Genomic Institute for Diabetes, Lille, France
| | - Lourdes Sanchez Salido
- Servicio de Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA-Plataforma BIONAND, Málaga, Spain
| | - Francisca Linares
- Servicio de Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA-Plataforma BIONAND, Málaga, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Málaga, Spain
| | - Francisco-Javier Bermúdez-Silva
- Servicio de Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA-Plataforma BIONAND, Málaga, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Málaga, Spain
| | - Joseph Tam
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Caroline Bonner
- Inserm UMR1190 - Translational Research for Diabetes, Université de Lille, CHU Lille, Institut Pasteur de Lille, Inserm, European Genomic Institute for Diabetes, Lille, France
| | - Josephine M Egan
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Gabriel Olveira
- Servicio de Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA-Plataforma BIONAND, Málaga, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Málaga, Spain
- Departamento de Medicina y Cirugía, Facultad de Medicina, Universidad de Málaga, Málaga, Spain
| | - Natalia Colomo
- Servicio de Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA-Plataforma BIONAND, Málaga, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Málaga, Spain
| | - François Pattou
- Inserm UMR1190 - Translational Research for Diabetes, Université de Lille, CHU Lille, Institut Pasteur de Lille, Inserm, European Genomic Institute for Diabetes, Lille, France
| | - Isabel González-Mariscal
- Inserm UMR1190 - Translational Research for Diabetes, Université de Lille, CHU Lille, Institut Pasteur de Lille, Inserm, European Genomic Institute for Diabetes, Lille, France.
- Servicio de Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA-Plataforma BIONAND, Málaga, Spain.
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Málaga, Spain.
- Grupo de Trabajo de Investigación Básica en Diabetes, Sociedad Española de Diabetes, Madrid, Spain.
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Naatz A, Yeo CT, Hogg N, Corbett JA. β-Cell-selective regulation of gene expression by nitric oxide. Am J Physiol Regul Integr Comp Physiol 2024; 326:R552-R566. [PMID: 38586887 PMCID: PMC11381020 DOI: 10.1152/ajpregu.00240.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 04/09/2024]
Abstract
Nitric oxide is produced at low micromolar levels following the induction of inducible nitric oxide synthase (iNOS) and is responsible for mediating the inhibitory actions of cytokines on glucose-stimulated insulin secretion by islets of Langerhans. It is through the inhibition of mitochondrial oxidative metabolism, specifically aconitase and complex 4 of the electron transport chain, that nitric oxide inhibits insulin secretion. Nitric oxide also attenuates protein synthesis, induces DNA damage, activates DNA repair pathways, and stimulates stress responses (unfolded protein and heat shock) in β-cells. In this report, the time- and concentration-dependent effects of nitric oxide on the expression of six genes known to participate in the response of β-cells to this free radical were examined. The genes included Gadd45α (DNA repair), Puma (apoptosis), Hmox1 (antioxidant defense), Hsp70 (heat shock), Chop (UPR), and Ppargc1α (mitochondrial biogenesis). We show that nitric oxide stimulates β-cell gene expression in a narrow concentration range of ∼0.5-1 µM or levels corresponding to iNOS-derived nitric oxide. At concentrations greater than 1 µM, nitric oxide fails to stimulate gene expression in β-cells, and this is associated with the inhibition of mitochondrial oxidative metabolism. This narrow concentration range of responses is β-cell selective, as the actions of nitric oxide in non-β-cells (α-cells, mouse embryonic fibroblasts, and macrophages) are concentration dependent. Our findings suggest that β-cells respond to a narrow concentration range of nitric oxide that is consistent with the levels produced following iNOS induction, and that these concentration-dependent actions are selective for insulin-containing cells.
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Affiliation(s)
- Aaron Naatz
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Chay Teng Yeo
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Neil Hogg
- Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
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8
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Dobson JR, Jacobson DA. Disrupted Endoplasmic Reticulum Ca 2+ Handling: A Harβinger of β-Cell Failure. BIOLOGY 2024; 13:379. [PMID: 38927260 PMCID: PMC11200644 DOI: 10.3390/biology13060379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/17/2024] [Accepted: 05/17/2024] [Indexed: 06/28/2024]
Abstract
The β-cell workload increases in the setting of insulin resistance and reduced β-cell mass, which occurs in type 2 and type 1 diabetes, respectively. The prolonged elevation of insulin production and secretion during the pathogenesis of diabetes results in β-cell ER stress. The depletion of β-cell Ca2+ER during ER stress activates the unfolded protein response, leading to β-cell dysfunction. Ca2+ER is involved in many pathways that are critical to β-cell function, such as protein processing, tuning organelle and cytosolic Ca2+ handling, and modulating lipid homeostasis. Mutations that promote β-cell ER stress and deplete Ca2+ER stores are associated with or cause diabetes (e.g., mutations in ryanodine receptors and insulin). Thus, improving β-cell Ca2+ER handling and reducing ER stress under diabetogenic conditions could preserve β-cell function and delay or prevent the onset of diabetes. This review focuses on how mechanisms that control β-cell Ca2+ER are perturbed during the pathogenesis of diabetes and contribute to β-cell failure.
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Affiliation(s)
| | - David A. Jacobson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA;
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9
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Peng J, Lu C, Luo Y, Su X, Li S, Ho CT. Hypoglycemic effects and associated mechanisms of resveratrol and related stilbenes in diet. Food Funct 2024; 15:2381-2405. [PMID: 38376230 DOI: 10.1039/d3fo04761j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2024]
Abstract
Hyperglycemia has become a global health problem due to changes in diet and lifestyle. Most importantly, persistent hyperglycemia can eventually develop into type II diabetes. While the usage of current drugs is limited by their side effects, stilbenes derived from fruits and herbal/dietary plants are considered as important phytochemicals with potential hypoglycemic properties. Herein, the most common stilbenoids in consumed foods, i.e. resveratrol, pterostilbene, piceatannol, oxyresveratrol, and 2,3,5,4'-tetrahydroxystilbene-2-O-β-glucopyranoside (THSG), are reviewed in this paper. These stilbenes are found to regulate glucose homeostasis via (a) modulation of feeding behaviour and nutrition absorption; (b) restoration of insulin signalling by enhancing insulin production/insulin sensitivity; (c) improvement of gut permeability, gut microbial profile and resulting metabolomes; and (d) amelioration of circadian rhythm disruption. In this review, we have summarized the underlying mechanisms for the hypoglycemic effects of the five most common dietary stilbenoids listed above, providing a comprehensive framework for future study and applications.
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Affiliation(s)
- Jie Peng
- Department of Food Science, Rutgers University, New Brunswick 08901, USA
| | - Chenyang Lu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products and School of Marine Science, Ningbo University, Ningbo 315211, China.
| | - Yue Luo
- Department of Food Science, Rutgers University, New Brunswick 08901, USA
| | - Xiurong Su
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products and School of Marine Science, Ningbo University, Ningbo 315211, China.
| | - Shiming Li
- Department of Food Science, Rutgers University, New Brunswick 08901, USA
- College of Life Sciences, Huanggang Normal University, Hubei 438000, China
| | - Chi-Tang Ho
- Department of Food Science, Rutgers University, New Brunswick 08901, USA
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10
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Peng M, Zhao S, Hu Y, Zhang L, Zhou T, Wu M, Xu M, Jiang K, Huang Y, Li D, Lun ZR, Wu Z, Shen J. Nitric oxide-induced endoplasmic reticulum stress of Schistosoma japonicum inhibits the worm development in rats. Free Radic Biol Med 2024; 212:295-308. [PMID: 38141890 DOI: 10.1016/j.freeradbiomed.2023.12.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 12/12/2023] [Accepted: 12/20/2023] [Indexed: 12/25/2023]
Abstract
Schistosomiasis, caused by Schistosoma spp., is a zoonotic parasitic disease affecting human health. Rattus norvegicus (rats) are a non-permissive host of Schistosoma, in which the worms cannot mature and cause typical egg granuloma. We previously demonstrated that inherent high levels of nitric oxide (NO), produced by inducible NO synthase (iNOS), is a key molecule in blocking the development of S. japonicum in rats. To further explore the mechanism of NO inhibiting S. japonicum development in rats, we performed S-nitrosocysteine proteomics of S. japonicum collected from infected rats and mice. The results suggested that S. japonicum in rats may have undergone endoplasmic reticulum (ER) stress. Interestingly, we found that the ER of S. japonicum in rats showed marked damage, while the ER of the worm in iNOS-/- rats and mice were relatively normal. Moreover, the expression of ER stress markers in S. japonicum from WT rats was significantly increased, compared with S. japonicum from iNOS-/- rats and mice. Using the NO donor sodium nitroprusside in vitro, we demonstrated that NO could induce ER stress in S. japonicum in a dose-dependent manner, and the NO-induced ER stress in S. japonicum could be inhibited by ER stress inhibitor 4-Phenyl butyric acid. We further verified that inhibiting ER stress of S. japonicum in rats promoted parasite development and survival. Furthermore, we demonstrated that NO-induced ER stress of S. japonicum was related to the efflux of Ca2+ from ER and the impairment of mitochondrial function. Collectively, these findings show that high levels of NO in rats could induce ER stress in S. japonicum by promoting the efflux of Ca2+ from ER and damaging the mitochondrial function, which block the worm development. Thus, this study further clarifies the mechanism of anti-schistosome in rats and provides potential strategies for drug development against schistosomiasis and other parasitosis.
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Affiliation(s)
- Mei Peng
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China; Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China; Department of Laboratory Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China
| | - Siyu Zhao
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China; Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China
| | - Yunyi Hu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China; Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China
| | - Lichao Zhang
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China; Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China
| | - Tao Zhou
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China; Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China
| | - Mingrou Wu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China; Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China
| | - Meiyining Xu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China; Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China
| | - Kefeng Jiang
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China; Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China
| | - Yun Huang
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China; Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China
| | - Dinghao Li
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China; Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China
| | - Zhao-Rong Lun
- Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Zhongdao Wu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China; Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China
| | - Jia Shen
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China; Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China.
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11
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Kwon J, Aoki Y, Takahashi H, Nakata R, Kawarasaki S, Ni Z, Yu R, Inoue H, Inoue K, Kawada T, Goto T. Inflammation-induced nitric oxide suppresses PPARα expression and function via downregulation of Sp1 transcriptional activity in adipocytes. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194987. [PMID: 37739218 DOI: 10.1016/j.bbagrm.2023.194987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/05/2023] [Accepted: 09/15/2023] [Indexed: 09/24/2023]
Abstract
The activation of peroxisome proliferator-activated receptor alpha (PPARα), a ligand-dependent transcription factor that regulates lipid oxidation-related genes, has been employed to treat hyperlipidemia. Emerging evidence indicates that Ppara gene expression decreases in adipose tissue under obese conditions; however, the underlying molecular mechanisms remain elusive. Here, we demonstrate that nitric oxide (NO) suppresses Ppara expression by regulating its promoter activity via suppression of specificity protein 1 (Sp1) transcriptional activity in adipocytes. NO derived from lipopolysaccharide (LPS) -activated macrophages or a NO donor (NOR5) treatment, suppressed Ppara mRNA expression in 10T1/2 adipocytes. In addition, Ppara transcript levels were reduced in the white adipose tissue (WAT) in both acute and chronic inflammation mouse models; however, such suppressive effects were attenuated via a nitric oxide synthase 2 (NOS2) inhibitor. Endoplasmic reticulum (ER) stress inhibitors attenuated the NO-induced repressive effects on Ppara gene expression in 10T1/2 adipocytes. Promoter mutagenesis and chromatin immunoprecipitation assays revealed that NO decreased the Sp1 occupancy in the proximal promoter regions of the Ppara gene, which might partially result from the reduced Sp1 expression levels by NO. This study delineated the molecular mechanism that modulates Ppara gene transcription upon NO stimulation in white adipocytes, suggesting a possible mechanism for the transcriptional downregulation of Ppara in WAT under obese conditions.
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Affiliation(s)
- Jungin Kwon
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan
| | - Yumeko Aoki
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan
| | - Haruya Takahashi
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan
| | - Rieko Nakata
- Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Satoko Kawarasaki
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan
| | - Zheng Ni
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan
| | - Rina Yu
- Department of Food Science and Nutrition, University of Ulsan, Ulsan 44610, Republic of Korea
| | - Hiroyasu Inoue
- Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Kazuo Inoue
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan; Research Unit for Physiological Chemistry, The Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan
| | - Teruo Kawada
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan; Research Unit for Physiological Chemistry, The Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan
| | - Tsuyoshi Goto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan; Research Unit for Physiological Chemistry, The Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan.
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12
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Kobiita A, Silva PN, Schmid MW, Stoffel M. FoxM1 coordinates cell division, protein synthesis, and mitochondrial activity in a subset of β cells during acute metabolic stress. Cell Rep 2023; 42:112986. [PMID: 37590136 DOI: 10.1016/j.celrep.2023.112986] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 06/06/2023] [Accepted: 07/31/2023] [Indexed: 08/19/2023] Open
Abstract
Pancreatic β cells display functional and transcriptional heterogeneity in health and disease. The sequence of events leading to β cell heterogeneity during metabolic stress is poorly understood. Here, we characterize β cell responses to early metabolic stress in vivo by employing RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), single-cell RNA-seq (scRNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and real-time imaging to decipher temporal events of chromatin remodeling and gene expression regulating the unfolded protein response (UPR), protein synthesis, mitochondrial function, and cell-cycle progression. We demonstrate that a subpopulation of β cells with active UPR, decreased protein synthesis, and insulin secretary capacities is more susceptible to proliferation after insulin depletion. Alleviation of endoplasmic reticulum (ER) stress precedes the progression of the cell cycle and mitosis and ensures appropriate insulin synthesis. Furthermore, metabolic stress rapidly activates key transcription factors including FoxM1, which impacts on proliferative and quiescent β cells by regulating protein synthesis, ER stress, and mitochondrial activity via direct repression of mitochondrial-encoded genes.
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Affiliation(s)
- Ahmad Kobiita
- Institute of Molecular Health Sciences, ETH Zürich, Otto-Stern-Weg 7, 8093 Zürich, Switzerland
| | - Pamuditha N Silva
- Institute of Molecular Health Sciences, ETH Zürich, Otto-Stern-Weg 7, 8093 Zürich, Switzerland
| | - Marc W Schmid
- MWSchmid GmbH, Hauptstrasse 34, 8750 Glarus, Switzerland
| | - Markus Stoffel
- Institute of Molecular Health Sciences, ETH Zürich, Otto-Stern-Weg 7, 8093 Zürich, Switzerland; Medical Faculty, Universitäts-Spital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland.
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13
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Zhang Y, Han S, Liu C, Zheng Y, Li H, Gao F, Bian Y, Liu X, Liu H, Hu S, Li Y, Chen ZJ, Zhao S, Zhao H. THADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic β-cell function and preserving β-cell mass. Nat Commun 2023; 14:1020. [PMID: 36823211 PMCID: PMC9950491 DOI: 10.1038/s41467-023-36680-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
Impaired insulin secretion is a hallmark in type 2 diabetes mellitus (T2DM). THADA has been identified as a candidate gene for T2DM, but its role in glucose homeostasis remains elusive. Here we report that THADA is strongly activated in human and mouse islets of T2DM. Both global and β-cell-specific Thada-knockout mice exhibit improved glycemic control owing to enhanced β-cell function and decreased β-cell apoptosis. THADA reduces endoplasmic reticulum (ER) Ca2+ stores in β-cells by inhibiting Ca2+ re-uptake via SERCA2 and inducing Ca2+ leakage through RyR2. Upon persistent ER stress, THADA interacts with and activates the pro-apoptotic complex comprising DR5, FADD and caspase-8, thus aggravating ER stress-induced apoptosis. Importantly, THADA deficiency protects mice from high-fat high-sucrose diet- and streptozotocin-induced hyperglycemia by restoring insulin secretion and preserving β-cell mass. Moreover, treatment with alnustone inhibits THADA's function, resulting in ameliorated hyperglycemia in obese mice. Collectively, our results support pursuit of THADA as a potential target for developing T2DM therapies.
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Affiliation(s)
- Yuqing Zhang
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Shan Han
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Congcong Liu
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Yuanwen Zheng
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong, China
| | - Hao Li
- Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, Shandong, China
| | - Fei Gao
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, 100101, Beijing, China
| | - Yuehong Bian
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Xin Liu
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Hongbin Liu
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Shourui Hu
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Yuxuan Li
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Zi-Jiang Chen
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China. .,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China. .,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China. .,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, 200135, Shanghai, China. .,Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Shandong, 250012, Jinan, China.
| | - Shigang Zhao
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China. .,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China. .,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China.
| | - Han Zhao
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China. .,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China. .,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China.
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14
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Enhanced IRE1α Phosphorylation/Oligomerization-Triggered XBP1 Splicing Contributes to Parkin-Mediated Prevention of SH-SY5Y Cell Death under Nitrosative Stress. Int J Mol Sci 2023; 24:ijms24032017. [PMID: 36768338 PMCID: PMC9917145 DOI: 10.3390/ijms24032017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/10/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
Mutations in parkin, a neuroprotective protein, are the predominant cause of autosomal recessive juvenile Parkinson's disease. Neuroinflammation-derived nitrosative stress has been implicated in the etiology of the chronic neurodegeneration. However, the interactions between genetic predisposition and nitrosative stress contributing to the degeneration of dopaminergic (DA) neurons remain incompletely understood. Here, we used the SH-SY5Y neuroblastoma cells to investigate the function of parkin and its pathogenic mutants in relation to cell survival under nitric oxide (NO) exposure. The results showed that overexpression of wild-type parkin protected SH-SY5Y cells from NO-induced apoptosis in a reactive oxygen species-dependent manner. Under nitrosative stress conditions, parkin selectively upregulated the inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) signaling axis, an unfolded protein response signal through the sensor IRE1α, which controls the splicing of XBP1 mRNA. Inhibition of XBP1 mRNA splicing either by pharmacologically inhibiting IRE1α endoribonuclease activity or by genetically knocking down XBP1 interfered with the protective activity of parkin. Furthermore, pathogenic parkin mutants with a defective protective capacity showed a lower ability to activate the IRE1α/XBP1 signaling. Finally, we demonstrated that IRE1α activity augmented by parkin was possibly mediated through interacting with IRE1α to regulate its phosphorylation/oligomerization processes, whereas mutant parkin diminished its binding to and activation of IRE1α. Thus, these results support a direct link between the protective activity of parkin and the IRE1α/XBP1 pathway in response to nitrosative stress, and mutant parkin disrupts this function.
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15
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Li W, Qiao J, Lin K, Sun P, Wang Y, Peng Q, Ye X, Liu W, Sun B. Ethyl-acetate fraction from a cinnamon-cortex extract protects pancreatic β-cells from oxidative stress damage. Front Pharmacol 2023; 14:1111860. [PMID: 36950010 PMCID: PMC10025376 DOI: 10.3389/fphar.2023.1111860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Background: The pathogenesis of diabetes mellitus is mediated mainly by oxidative stress produced by damaged pancreatic β-cells. We identified that an ethyl-acetate fraction (EA) from a cinnamon-cortex extract (CCE) is rich in flavonoid, and showed no toxicity to β cells. Objective: In this study, we evaluated the pharmacologic activities of EA on pancreatic β cells using a model of oxidative stress induced by H2O2 or alloxan. Results: The results showed that EA could significantly reduce reactive oxygen (ROS) accumulation to improve the survival of cells. Western blot showed that EA treatment upregulated expression of nuclear factor erythroid 2 related factor 2, heme oxygenase-1, and gamma glutamylcysteine synthetase. The same model study found that EA also can protect β cells against the apoptosis induced by oxidative stress. Furthermore, EA can enhance insulin secretion in rat and mouse β cell lines treated or not with alloxan or H2O2. The expression of the insulin transcription factor PDX-1 increased in an EA concentration-dependent manner. At last, the major functional compounds of EA analysis showed that three compounds, cinnamyl alcohol, coumarin, and cinnamic acid, had similar effects as EA. Conclusions: In sum, our data suggested that EA fraction from CCE can protect β cells from oxidative stress, and increase insulin secretion to improve the function of β cells. This function might be due to these three compounds found in EA. Our findings provide a theoretical basis and functional molecules for the use of CCE against diabetes mellitus.
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Affiliation(s)
| | | | | | | | | | | | | | - Wei Liu
- *Correspondence: Binlian Sun, ; Wei Liu,
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16
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Simpson DS, Pang J, Weir A, Kong IY, Fritsch M, Rashidi M, Cooney JP, Davidson KC, Speir M, Djajawi TM, Hughes S, Mackiewicz L, Dayton M, Anderton H, Doerflinger M, Deng Y, Huang AS, Conos SA, Tye H, Chow SH, Rahman A, Norton RS, Naderer T, Nicholson SE, Burgio G, Man SM, Groom JR, Herold MJ, Hawkins ED, Lawlor KE, Strasser A, Silke J, Pellegrini M, Kashkar H, Feltham R, Vince JE. Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway. Immunity 2022; 55:423-441.e9. [PMID: 35139355 PMCID: PMC8822620 DOI: 10.1016/j.immuni.2022.01.003] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 11/19/2021] [Accepted: 01/05/2022] [Indexed: 12/12/2022]
Abstract
Cell death plays an important role during pathogen infections. Here, we report that interferon-γ (IFNγ) sensitizes macrophages to Toll-like receptor (TLR)-induced death that requires macrophage-intrinsic death ligands and caspase-8 enzymatic activity, which trigger the mitochondrial apoptotic effectors, BAX and BAK. The pro-apoptotic caspase-8 substrate BID was dispensable for BAX and BAK activation. Instead, caspase-8 reduced pro-survival BCL-2 transcription and increased inducible nitric oxide synthase (iNOS), thus facilitating BAX and BAK signaling. IFNγ-primed, TLR-induced macrophage killing required iNOS, which licensed apoptotic caspase-8 activity and reduced the BAX and BAK inhibitors, A1 and MCL-1. The deletion of iNOS or caspase-8 limited SARS-CoV-2-induced disease in mice, while caspase-8 caused lethality independent of iNOS in a model of hemophagocytic lymphohistiocytosis. These findings reveal that iNOS selectively licenses programmed cell death, which may explain how nitric oxide impacts disease severity in SARS-CoV-2 infection and other iNOS-associated inflammatory conditions.
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Affiliation(s)
- Daniel S. Simpson
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Jiyi Pang
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia,College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Ashley Weir
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Isabella Y. Kong
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Melanie Fritsch
- Institute for Molecular Immunology, Centre for Molecular Medicine Cologne and Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, Cologne, 50931, Germany
| | - Maryam Rashidi
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - James P. Cooney
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Kathryn C. Davidson
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Mary Speir
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia
| | - Tirta M. Djajawi
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia
| | - Sebastian Hughes
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Liana Mackiewicz
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia
| | - Merle Dayton
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia
| | - Holly Anderton
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Marcel Doerflinger
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Yexuan Deng
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Allan Shuai Huang
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Stephanie A. Conos
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia
| | - Hazel Tye
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia
| | - Seong H. Chow
- The Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
| | - Arfatur Rahman
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia
| | - Raymond S. Norton
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia,ARC Centre for Fragment-Based Design, Monash University, Parkville, VIC, 3052, Australia
| | - Thomas Naderer
- The Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
| | - Sandra E. Nicholson
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Gaetan Burgio
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia
| | - Si Ming Man
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia
| | - Joanna R. Groom
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Marco J. Herold
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Edwin D. Hawkins
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Kate E. Lawlor
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia
| | - Andreas Strasser
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - John Silke
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Marc Pellegrini
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Hamid Kashkar
- Institute for Molecular Immunology, Centre for Molecular Medicine Cologne and Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, Cologne, 50931, Germany
| | - Rebecca Feltham
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
| | - James E. Vince
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia,The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia,Corresponding author
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17
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Li J, Inoue R, Togashi Y, Okuyama T, Satoh A, Kyohara M, Nishiyama K, Tsuno T, Miyashita D, Kin T, Shapiro AMJ, Chew RSE, Teo AKK, Oyadomari S, Terauchi Y, Shirakawa J. Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway. Diabetes 2022; 71:424-439. [PMID: 34588186 DOI: 10.2337/db21-0123] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 09/20/2021] [Indexed: 02/05/2023]
Abstract
The effects of imeglimin, a novel antidiabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules, including Chop (Ddit3), Gadd34 (Ppp1r15a), Atf3, and Sdf2l1, and decreased eIF2α phosphorylation after treatment with thapsigargin and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect against ER stress-induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell-derived β-like cells. Taken together, imeglimin modulates the ER homeostasis pathway, which results in the prevention of β-cell apoptosis both in vitro and in vivo.
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Affiliation(s)
- Jinghe Li
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Ryota Inoue
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Aoi Satoh
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Kuniyuki Nishiyama
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Takahiro Tsuno
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Daisuke Miyashita
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Tatsuya Kin
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada
| | - A M James Shapiro
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada
| | - Resilind Su Ern Chew
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore
| | - Adrian Kee Keong Teo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore
- Departments of Biochemistry and Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Seiichi Oyadomari
- Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, Kuramoto, Tokushima, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Jun Shirakawa
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
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18
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Sahebnasagh A, Saghafi F, Negintaji S, Hu T, Shabani-Borujeni M, Safdari M, Ghaleno HR, Miao L, Qi Y, Wang M, Liao P, Sureda A, Simal-Gándara J, Nabavi SM, Xiao J. Nitric Oxide and Immune Responses in Cancer: Searching for New Therapeutic Strategies. Curr Med Chem 2022; 29:1561-1595. [PMID: 34238142 DOI: 10.2174/0929867328666210707194543] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 05/05/2021] [Accepted: 05/15/2021] [Indexed: 02/08/2023]
Abstract
In recent years, there has been an increasing interest in understanding the mysterious functions of nitric oxide (NO) and how this pleiotropic signaling molecule contributes to tumorigenesis. This review attempts to expose and discuss the information available on the immunomodulatory role of NO in cancer and recent approaches to the role of NO donors in the area of immunotherapy. To address the goal, the following databases were searched to identify relevant literature concerning empirical evidence: The Cochrane Library, Pubmed, Medline, and EMBASE from 1980 through March 2020. Valuable attempts have been made to develop distinctive NO-based cancer therapy. Although the data do not allow generalization, the evidence seems to indicate that low/moderate levels may favor tumorigenesis, while higher levels would exert antitumor effects. In this sense, the use of NO donors could have an important therapeutic potential within immunotherapy, although there are still no clinical trials. The emerging understanding of NO-regulated immune responses in cancer may help unravel the recent features of this "doubleedged sword" in cancer physiological and pathologic processes and its potential use as a therapeutic agent for cancer treatment. In short, in this review, we discuss the complex cellular mechanism in which NO, as a pleiotropic signaling molecule, participates in cancer pathophysiology. We also debate the dual role of NO in cancer and tumor progression and clinical approaches for inducible nitric oxide synthase (iNOS) based therapy against cancer.
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Affiliation(s)
- Adeleh Sahebnasagh
- Clinical Research Center, Department of Internal Medicine, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Fatemeh Saghafi
- Department of Clinical Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Sina Negintaji
- Student Research Committee, School of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Tingyan Hu
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Mojtaba Shabani-Borujeni
- Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammadreza Safdari
- Department of Orthopedic Surgery, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Hassan Rezai Ghaleno
- Department of Surgery, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Lingchao Miao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao
| | - Yaping Qi
- Purdue Quantum Science and Engineering Institute, Purdue University, West Lafayette, IN 47907, USA
| | - Mingfu Wang
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Pan Liao
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Antoni Sureda
- Research Group on Community Nutrition and Oxidative Stress, and Balearic Islands Health Research Institute (IdISBa), University of the Balearic Islands, Palma de Mallorca, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Instituto de Salud Carlos III, Madrid, Spain
| | - Jesus Simal-Gándara
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E-32004 Ourense, Spain
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Jianbo Xiao
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E-32004 Ourense, Spain
- International Research Centre for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
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19
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Yang Y, Chen Z, Zhao X, Xie H, Du L, Gao H, Xie C. Mechanisms of Kaempferol in the treatment of diabetes: A comprehensive and latest review. Front Endocrinol (Lausanne) 2022; 13:990299. [PMID: 36157449 PMCID: PMC9490412 DOI: 10.3389/fendo.2022.990299] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 08/17/2022] [Indexed: 01/07/2023] Open
Abstract
Obesity-insulin resistance-β-cells apoptosis" is an important trilogy of the pathogenesis of type 2 diabetes. With the global pandemic of obesity and diabetes, continuous research and development of new drugs focuses on the prevention of the pathological progress of these diseases. According to a recent study, the natural product kaempferol has excellent antidiabetic effects. Therefore, this review comprehensively summarized the frontier studies and pharmacological mechanisms of kaempferol in the treatment of diabetes. The successful research and development of kaempferol may yield a significant leap in the treatment of diabetes and its complications.
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Affiliation(s)
- Yan Yang
- Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Zhengtao Chen
- Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoyan Zhao
- Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Hongyan Xie
- Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Lian Du
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hong Gao
- Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Hong Gao, ; Chunguang Xie,
| | - Chunguang Xie
- Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Hong Gao, ; Chunguang Xie,
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20
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He E, Ma Y, Kong L, Huang Y, Huang C, Yang W, Yi J, Zhu L. Suppression of endoplasmic reticulum stress-associated pathways and hepatocyte apoptosis participates in the attenuation of betulinic acid on alcohol-provoked liver injury in mice. Food Funct 2022; 13:11489-11502. [DOI: 10.1039/d2fo01042a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
BA protects against alcohol-induced liver damage through the alleviation of oxidative stress and suppression of ERS-induced apoptosis.
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Affiliation(s)
- Enqi He
- Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China
- College of Food Science and Technology, Hunan Agricultural University, Changsha, 410128, China
| | - Yurong Ma
- Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China
- Changsha University of Science & Technology, Changsha 410114, China
| | - Li Kong
- Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China
| | - You Huang
- Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China
| | - Chunlin Huang
- Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China
| | - Wenjiang Yang
- Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China
| | - Jine Yi
- Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China
| | - Lijuan Zhu
- Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China
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21
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Miyake M, Zhang J, Yasue A, Hisanaga S, Tsugawa K, Sakaue H, Oyadomari M, Kiyonari H, Oyadomari S. Integrated stress response regulates GDF15 secretion from adipocytes, preferentially suppresses appetite for a high-fat diet and improves obesity. iScience 2021; 24:103448. [PMID: 34877504 PMCID: PMC8633987 DOI: 10.1016/j.isci.2021.103448] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/28/2021] [Accepted: 11/11/2021] [Indexed: 01/03/2023] Open
Abstract
The eIF2α phosphorylation-dependent integrated stress response (ISR) is a signaling pathway that maintains homeostasis in mammalian cells exposed to various stresses. Here, ISR activation in adipocytes improves obesity and diabetes by regulating appetite in a non-cell-autonomous manner. Adipocyte-specific ISR activation using transgenic mice decreases body weight and improves glucose tolerance and obesity induced by a high-fat diet (HFD) via preferential inhibition of HFD intake. The transcriptome analysis of ISR-activated adipose tissue reveals that growth differentiation factor 15 (GDF15) expression is induced by the ISR through the direct regulation of the transcription factors ATF4 and DDIT3. Deficiency in the GDF15 receptor GFRAL abolishes the adipocyte ISR-dependent preferential inhibition of HFD intake and the anti-obesity effects. Pharmacologically, 10(E), 12(Z)-octadecadienoic acid induces ISR-dependent GDF15 expression in adipocytes and decreases the intake of the HFD. Based on our findings the specific activation of the ISR in adipocytes controls the non-cell-autonomous regulation of appetite.
Activation of ISR in adipocytes suppresses intake of high-fat diet and prevents obesity ATF4 and DDIT3 induced by ISR directly regulate GDF15 expression GDF15-GFRAL axis mediates the control of appetite for high-fat diet by ISR activation One of conjugated linoleic acids induces ISR and GDF15 expression in adipocytes
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Affiliation(s)
- Masato Miyake
- Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.,Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.,Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan
| | - Jun Zhang
- Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.,Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.,ER Stress Research Institute Inc., Tokushima 770-8503, Japan
| | - Akihiro Yasue
- Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, 770-8504, Japan
| | - Satoshi Hisanaga
- Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.,Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Kazue Tsugawa
- Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan
| | - Hiroshi Sakaue
- Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.,Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Miho Oyadomari
- Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan
| | - Hiroshi Kiyonari
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
| | - Seiichi Oyadomari
- Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.,Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.,Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.,ER Stress Research Institute Inc., Tokushima 770-8503, Japan
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22
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Sahin GS, Lee H, Engin F. An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis. Mol Metab 2021; 54:101365. [PMID: 34728341 PMCID: PMC8606542 DOI: 10.1016/j.molmet.2021.101365] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/23/2021] [Accepted: 10/26/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Pancreatic β-cells are the insulin factory of an organism with a mission to regulate glucose homeostasis in the body. Due to their high secretory activity, β-cells rely on a functional and intact endoplasmic reticulum (ER). Perturbations to ER homeostasis and unmitigated stress lead to β-cell dysfunction and death. Type 1 diabetes (T1D) is a chronic inflammatory disease caused by the autoimmune-mediated destruction of β-cells. Although autoimmunity is an essential component of T1D pathogenesis, accumulating evidence suggests an important role of β-cell ER stress and aberrant unfolded protein response (UPR) in disease initiation and progression. SCOPE OF REVIEW In this article, we introduce ER stress and the UPR, review β-cell ER stress in various mouse models, evaluate its involvement in inflammation, and discuss the effects of ER stress on β-cell plasticity and demise, and islet autoimmunity in T1D. We also highlight the relationship of ER stress with other stress response pathways and provide insight into ongoing clinical studies targeting ER stress and the UPR for the prevention or treatment of T1D. MAJOR CONCLUSIONS Evidence from ex vivo studies, in vivo mouse models, and tissue samples from patients suggest that β-cell ER stress and a defective UPR contribute to T1D pathogenesis. Thus, restoration of β-cell ER homeostasis at various stages of disease presents a plausible therapeutic strategy for T1D. Identifying the specific functions and regulation of each UPR sensor in β-cells and uncovering the crosstalk between stressed β-cells and immune cells during T1D progression would provide a better understanding of the molecular mechanisms of disease process, and may reveal novel targets for development of effective therapies for T1D.
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Affiliation(s)
- Gulcan Semra Sahin
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, 53706, USA
| | - Hugo Lee
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, 53706, USA
| | - Feyza Engin
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, 53706, USA; Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, 53705, USA; Department of Cell & Regenerative Biology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, 53705, USA.
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Sato K, Sato T, Ohno-Oishi M, Ozawa M, Maekawa S, Shiga Y, Yabana T, Yasuda M, Himori N, Omodaka K, Fujita K, Nishiguchi KM, Ge S, Nakazawa T. CHOP deletion and anti-neuroinflammation treatment with hesperidin synergistically attenuate NMDA retinal injury in mice. Exp Eye Res 2021; 213:108826. [PMID: 34752818 DOI: 10.1016/j.exer.2021.108826] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 08/26/2021] [Accepted: 11/01/2021] [Indexed: 11/17/2022]
Abstract
Glaucoma is a leading cause of blindness worldwide and is characterized by degeneration associated with the death of retinal ganglion cells (RGCs). It is believed that glaucoma is a group of heterogeneous diseases with multifactorial pathomechanisms. Here, we investigate whether anti-inflammation treatment with an ER stress blockade can selectively promote neuroprotection against NMDA injury in the RGCs. Retinal excitotoxicity was induced with an intravitreal NMDA injection. Microglial activation and neuroinflammation were evaluated with Iba1 immunostaining and cytokine gene expression. A stable HT22 cell line transfected with an NF-kB reporter was used to assess NF-kB activity after hesperidin treatment. CHOP-deficient mice were used as a model of ER stress blockade. Retinal cell death was evaluated with a TUNEL assay. As results, in the NMDA injury group, Iba1-positive microglia increased 6 h after NMDA injection. Also at 6 h, pro-inflammatory cytokines and chemokine increased, including TNFα, IL-1b, IL-6 and MCP-1. In addition, the MCP-1 promoter-driven EGFP signal, which we previously identified as a stress signal in injured RGCs, also increased; hesperidin treatment suppressed this inflammatory response and reduced stressed RGCs. In CHOP-deficient mice that received an NMDA injection, the gene expression of pro-inflammatory cytokines, chemokines, markers of active microglia, and inflammatory regulators was greater than in WT mice. In WT mice, hesperidin treatment partially prevented retinal cell death after NMDA injury; this neuroprotective effect was enhanced in CHOP-deficient mice. These findings demonstrate that ER stress blockade is not enough by itself to prevent RGC loss due to neuroinflammation in the retina, but it has a synergistic neuroprotective effect after NMDA injury when combined with an anti-inflammatory treatment based on hesperidin.
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Affiliation(s)
- Kota Sato
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan; Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Taimu Sato
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Michiko Ohno-Oishi
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Mikako Ozawa
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Shigeto Maekawa
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Yukihiro Shiga
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Takeshi Yabana
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Masayuki Yasuda
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Noriko Himori
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Kazuko Omodaka
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Kosuke Fujita
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Koji M Nishiguchi
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shi Ge
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Toru Nakazawa
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan; Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Miyagi, Japan; Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Miyagi, Japan; Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan; Department of Collaborative Program for Ophthalmic Drug Discovery, Tohoku University Graduate School of Medicine, Miyagi, Japan.
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Human Islet Amyloid Polypeptide Overexpression in INS-1E Cells Influences Amylin Oligomerization under ER Stress and Oxidative Stress. Int J Mol Sci 2021; 22:ijms222111341. [PMID: 34768769 PMCID: PMC8583535 DOI: 10.3390/ijms222111341] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/12/2021] [Accepted: 10/19/2021] [Indexed: 02/07/2023] Open
Abstract
Human amylin or islet amyloid polypeptide (hIAPP) is synthesized in the pancreatic β-cells and has been shown to contribute to the pathogenesis of type 2 diabetes (T2D) in vitro and in vivo. This study compared amylin oligomerization/expression and signal transduction under endoplasmic reticulum (ER) stress and oxidative stress. pCMV-hIAPP-overexpressing INS-1E cells presented different patterns of amylin oligomerization/expression under ER stress and oxidative stress. Amylin oligomerization/expression under ER stress showed three amylin oligomers of less than 15 kDa size in pCMV-hIAPP-overexpressing cells, while one band was detected under oxidative stress. Under ER stress conditions, HIF1α, p-ERK, CHOP, Cu/Zn-SOD, and Bax were significantly increased in pCMV-hIAPP-overexpressing cells compared to the pCMV-Entry-expressing cells (control), whereas p-Akt, p-mTOR, Mn-SOD, catalase, and Bcl-2 were significantly decreased. Under oxidative stress conditions, HIF1α, p-ERK, CHOP, Mn-SOD, catalase, and Bcl-2 were significantly reduced in pCMV-hIAPP-overexpressing cells compared to the control, whereas p-mTOR, Cu/Zn-SOD, and Bax were significantly increased. In mitochondrial oxidative phosphorylation (OXPHOS), the mitochondrial complex I and complex IV were significantly decreased under ER stress conditions and significantly increased under oxidative stress conditions in pCMV-hIAPP-overexpressing cells compared to the control. The present study results demonstrate that amylin undergoes oligomerization under ER stress in pCMV-hIAPP-overexpressing cells. In addition, human amylin overexpression under ER stress in the pancreatic β cells may enhance amylin protein aggregation, resulting in β-cell dysfunction.
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ATF4-mediated transcriptional regulation protects against β-cell loss during endoplasmic reticulum stress in a mouse model. Mol Metab 2021; 54:101338. [PMID: 34547510 PMCID: PMC8487982 DOI: 10.1016/j.molmet.2021.101338] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/02/2021] [Accepted: 09/02/2021] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE Activating transcription factor 4 (ATF4) is a transcriptional regulator of the unfolded protein response and integrated stress response (ISR) that promote the restoration of normal endoplasmic reticulum (ER) function. Previous reports demonstrated that dysregulation of the ISR led to development of severe diabetes. However, the contribution of ATF4 to pancreatic β-cells remains poorly understood. In this study, we aimed to analyze the effect of ISR enhancer Sephin1 and ATF4-deficient β-cells to clarify the role of ATF4 in β-cells under ER stress conditions. METHODS To examine the role of ATF4 in vivo, ISR enhancer Sephin1 (5 mg/kg body weight, p.o.) was administered daily for 21 days to Akita mice. We also established β-cell-specific Atf4 knockout (βAtf4-KO) mice that were further crossed with Akita mice. These mice were analyzed for characteristics of diabetes, β-cell function, and morphology of the islets. To identify the downstream factors of ATF4 in β-cells, the islets of βAtf4-KO mice were subjected to cDNA microarray analyses. To examine the transcriptional regulation by ATF4, we also performed in situ PCR analysis of pancreatic sections from mice and ChIP-qPCR analysis of CT215 β-cells. RESULTS Administration of the ISR enhancer Sephin1 improved glucose metabolism in Akita mice. Sephin1 also increased the insulin-immunopositive area and ATF4 expression in the pancreatic islets. Akita/βAtf4-KO mice exhibited dramatically exacerbated diabetes, shown by hyperglycemia at an early age, as well as a remarkably short lifespan owing to diabetic ketoacidosis. Moreover, the islets of Akita/βAtf4-KO mice presented increased numbers of cells stained for glucagon, somatostatin, and pancreatic polypeptide and increased expression of aldehyde dehydrogenase 1 family member 3, a marker of dedifferentiation. Using microarray analysis, we identified atonal BHLH transcription factor 8 (ATOH8) as a downstream factor of ATF4. Deletion of ATF4 in β-cells showed reduced Atoh8 expression and increased expression of undifferentiated markers, Nanog and Pou5f1. Atoh8 expression was also abolished in the islets of Akita/βAtf4-KO mice. CONCLUSIONS We conclude that transcriptional regulation by ATF4 maintains β-cell identity via ISR modulation. This mechanism provides a promising target for the treatment of diabetes.
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Sims SG, Cisney RN, Lipscomb MM, Meares GP. The role of endoplasmic reticulum stress in astrocytes. Glia 2021; 70:5-19. [PMID: 34462963 PMCID: PMC9292588 DOI: 10.1002/glia.24082] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/18/2021] [Accepted: 08/21/2021] [Indexed: 12/12/2022]
Abstract
Astrocytes are glial cells that support neurological function in the central nervous system (CNS), in part, by providing structural support for neuronal synapses and blood vessels, participating in electrical and chemical transmission, and providing trophic support via soluble factors. Dysregulation of astrocyte function contributes to neurological decline in CNS diseases. Neurological diseases are highly heterogeneous but share common features of cellular stress including the accumulation of misfolded proteins. Endoplasmic reticulum (ER) stress has been reported in nearly all neurological and neurodegenerative diseases. ER stress occurs when there is an accumulation of misfolded proteins in the ER lumen and the protein folding demand of the ER is overwhelmed. ER stress initiates the unfolded protein response (UPR) to restore homeostasis by abating protein translation and, if the cell is irreparably damaged, initiating apoptosis. Although protein aggregation and misfolding in neurological disease has been well described, cell-specific contributions of ER stress and the UPR in physiological and disease states are poorly understood. Recent work has revealed a role for active UPR signaling that may drive astrocytes toward a maladaptive phenotype in various model systems. In response to ER stress, astrocytes produce inflammatory mediators, have reduced trophic support, and can transmit ER stress to other cells. This review will discuss the current known contributions and consequences of activated UPR signaling in astrocytes.
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Affiliation(s)
- Savannah G Sims
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia, USA
| | - Rylee N Cisney
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia, USA
| | - Marissa M Lipscomb
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia, USA
| | - Gordon P Meares
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia, USA.,Department of Neuroscience, West Virginia University, Morgantown, West Virginia, USA.,Rockefeller Neuroscience Institute, Morgantown, West Virginia, USA
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Nakamura T, Oh CK, Zhang X, Lipton SA. Protein S-nitrosylation and oxidation contribute to protein misfolding in neurodegeneration. Free Radic Biol Med 2021; 172:562-577. [PMID: 34224817 PMCID: PMC8579830 DOI: 10.1016/j.freeradbiomed.2021.07.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 12/19/2022]
Abstract
Neurodegenerative disorders like Alzheimer's disease and Parkinson's disease are characterized by progressive degeneration of synapses and neurons. Accumulation of misfolded/aggregated proteins represents a pathological hallmark of most neurodegenerative diseases, potentially contributing to synapse loss and neuronal damage. Emerging evidence suggests that misfolded proteins accumulate in the diseased brain at least in part as a consequence of excessively generated reactive oxygen species (ROS) and reactive nitrogen species (RNS). Mechanistically, not only disease-linked genetic mutations but also known risk factors for neurodegenerative diseases, such as aging and exposure to environmental toxins, can accelerate production of ROS/RNS, which contribute to protein misfolding - in many cases mimicking the effect of rare genetic mutations known to be linked to the disease. This review will focus on the role of RNS-dependent post-translational modifications, such as S-nitrosylation and tyrosine nitration, in protein misfolding and aggregation. Specifically, we will discuss molecular mechanisms whereby RNS disrupt the activity of the cellular protein quality control machinery, including molecular chaperones, autophagy/lysosomal pathways, and the ubiquitin-proteasome system (UPS). Because chronic accumulation of misfolded proteins can trigger mitochondrial dysfunction, synaptic damage, and neuronal demise, further characterization of RNS-mediated protein misfolding may establish these molecular events as therapeutic targets for intervention in neurodegenerative diseases.
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Affiliation(s)
- Tomohiro Nakamura
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA.
| | - Chang-Ki Oh
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Xu Zhang
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Stuart A Lipton
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA; Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA.
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Borg DJ, Faridi P, Giam KL, Reeves P, Fotheringham AK, McCarthy DA, Leung S, Ward MS, Harcourt BE, Ayala R, Scheijen JL, Briskey D, Dudek NL, Schalkwijk CG, Steptoe R, Purcell AW, Forbes JM. Short Duration Alagebrium Chloride Therapy Prediabetes Does Not Inhibit Progression to Autoimmune Diabetes in an Experimental Model. Metabolites 2021; 11:426. [PMID: 34203471 PMCID: PMC8305727 DOI: 10.3390/metabo11070426] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 12/17/2022] Open
Abstract
Mechanisms by which advanced glycation end products (AGEs) contribute to type 1 diabetes (T1D) pathogenesis are poorly understood. Since life-long pharmacotherapy with alagebrium chloride (ALT) slows progression to experimental T1D, we hypothesized that acute ALT therapy delivered prediabetes, may be effective. However, in female, non-obese diabetic (NODShiLt) mice, ALT administered prediabetes (day 50-100) did not protect against experimental T1D. ALT did not decrease circulating AGEs or their precursors. Despite this, pancreatic β-cell function was improved, and insulitis and pancreatic CD45.1+ cell infiltration was reduced. Lymphoid tissues were unaffected. ALT pre-treatment, prior to transfer of primed GC98 CD8+ T cell receptor transgenic T cells, reduced blood glucose concentrations and delayed diabetes, suggesting islet effects rather than immune modulation by ALT. Indeed, ALT did not reduce interferon-γ production by leukocytes from ovalbumin-pre-immunised NODShiLt mice and NODscid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate β-cell effects, NOD-derived MIN6N8 β-cell major histocompatibility complex (MHC) Class Ia surface antigens were examined using immunopeptidomics. Overall, no major changes in the immunopeptidome were observed during the various treatments with all peptides exhibiting allele specific consensus binding motifs. As expected, longer MHC Class Ia peptides were captured bound to H-2Db than H-2Kb under all conditions. Moreover, more 10-12 mer peptides were isolated from H-2Db after AGE modified bovine serum albumin (AGE-BSA) treatment, compared with bovine serum albumin (BSA) or AGE-BSA+ALT treatment. Proteomics of MIN6N8 cells showed enrichment of processes associated with catabolism, the immune system, cell cycling and presynaptic endocytosis with AGE-BSA compared with BSA treatments. These data show that short-term ALT intervention, given prediabetes, does not arrest experimental T1D but transiently impacts β-cell function.
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Affiliation(s)
- Danielle J. Borg
- Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (D.J.B.); (A.K.F.); (D.A.M.); (S.L.); (M.S.W.); (B.E.H.)
- Pregnancy and Development, Mater Research Institute, The University of Queensland, South Brisbane, QLD 4101, Australia
| | - Pouya Faridi
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; (P.F.); (K.L.G.); (R.A.); (N.L.D.); (A.W.P.)
| | - Kai Lin Giam
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; (P.F.); (K.L.G.); (R.A.); (N.L.D.); (A.W.P.)
| | - Peta Reeves
- Tolerance and Autoimmunity Group, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4102, Australia; (P.R.); (R.S.)
| | - Amelia K. Fotheringham
- Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (D.J.B.); (A.K.F.); (D.A.M.); (S.L.); (M.S.W.); (B.E.H.)
| | - Domenica A. McCarthy
- Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (D.J.B.); (A.K.F.); (D.A.M.); (S.L.); (M.S.W.); (B.E.H.)
| | - Sherman Leung
- Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (D.J.B.); (A.K.F.); (D.A.M.); (S.L.); (M.S.W.); (B.E.H.)
| | - Micheal S. Ward
- Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (D.J.B.); (A.K.F.); (D.A.M.); (S.L.); (M.S.W.); (B.E.H.)
| | - Brooke E. Harcourt
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia
| | - Rochelle Ayala
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; (P.F.); (K.L.G.); (R.A.); (N.L.D.); (A.W.P.)
| | - Jean L. Scheijen
- Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, 6211 Maastricht, The Netherlands; (J.L.S.); (C.G.S.)
- Cardiovascular Research Institute Maastricht, 6211 Maastricht, The Netherlands
| | - David Briskey
- School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane, QLD 4067, Australia;
| | - Nadine L. Dudek
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; (P.F.); (K.L.G.); (R.A.); (N.L.D.); (A.W.P.)
| | - Casper G. Schalkwijk
- Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, 6211 Maastricht, The Netherlands; (J.L.S.); (C.G.S.)
- Cardiovascular Research Institute Maastricht, 6211 Maastricht, The Netherlands
| | - Raymond Steptoe
- Tolerance and Autoimmunity Group, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4102, Australia; (P.R.); (R.S.)
| | - Anthony W. Purcell
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; (P.F.); (K.L.G.); (R.A.); (N.L.D.); (A.W.P.)
| | - Josephine M. Forbes
- Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (D.J.B.); (A.K.F.); (D.A.M.); (S.L.); (M.S.W.); (B.E.H.)
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia
- Mater Clinical School, The University of Queensland, Brisbane, QLD 4101, Australia
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Dhounchak S, Popp SK, Brown DJ, Laybutt DR, Biden TJ, Bornstein SR, Parish CR, Simeonovic CJ. Heparan sulfate proteoglycans in beta cells provide a critical link between endoplasmic reticulum stress, oxidative stress and type 2 diabetes. PLoS One 2021; 16:e0252607. [PMID: 34086738 PMCID: PMC8177513 DOI: 10.1371/journal.pone.0252607] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 05/19/2021] [Indexed: 12/24/2022] Open
Abstract
Heparan sulfate proteoglycans (HSPGs) consist of a core protein with side chains of the glycosaminoglycan heparan sulfate (HS). We have previously identified (i) the HSPGs syndecan-1 (SDC1), and collagen type XVIII (COL18) inside mouse and human islet beta cells, and (ii) a critical role for HS in beta cell survival and protection from reactive oxygen species (ROS). The objective of this study was to investigate whether endoplasmic reticulum (ER) stress contributes to oxidative stress and type 2 diabetes (T2D) by depleting beta cell HSPGs/HS. A rapid loss of intra-islet/beta cell HSPGs, HS and heparanase (HPSE, an HS-degrading enzyme) accompanied upregulation of islet ER stress gene expression in both young T2D-prone db/db and Akita Ins2WT/C96Y mice. In MIN6 beta cells, HSPGs, HS and HPSE were reduced following treatment with pharmacological inducers of ER stress (thapsigargin or tunicamycin). Treatment of young db/db mice with Tauroursodeoxycholic acid (TUDCA), a chemical protein folding chaperone that relieves ER stress, improved glycemic control and increased intra-islet HSPG/HS. In vitro, HS replacement with heparin (a highly sulfated HS analogue) significantly increased the survival of wild-type and db/db beta cells and restored their resistance to hydrogen peroxide-induced death. We conclude that ER stress inhibits the synthesis/maturation of HSPG core proteins which are essential for HS assembly, thereby exacerbating oxidative stress and promoting beta cell failure. Diminished intracellular HSPGs/HS represent a previously unrecognized critical link bridging ER stress, oxidative stress and beta cell failure in T2D.
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Affiliation(s)
- Sarita Dhounchak
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Sarah K. Popp
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Debra J. Brown
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - D. Ross Laybutt
- Garvan Institute of Medical Research, St Vincent’s Clinical School, The University of NSW (UNSW), Sydney, New South Wales, Australia
| | - Trevor J. Biden
- Garvan Institute of Medical Research, St Vincent’s Clinical School, The University of NSW (UNSW), Sydney, New South Wales, Australia
| | - Stefan R. Bornstein
- Department of Internal Medicine III, Carl Gustav Carus Medical School, Technical University of Dresden, Dresden, Germany
| | - Christopher R. Parish
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Charmaine J. Simeonovic
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
- * E-mail:
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Intermedin 1-53 attenuates atherosclerotic plaque vulnerability by inhibiting CHOP-mediated apoptosis and inflammasome in macrophages. Cell Death Dis 2021; 12:436. [PMID: 33934111 PMCID: PMC8088440 DOI: 10.1038/s41419-021-03712-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 12/19/2022]
Abstract
Atherosclerotic plaque vulnerability and rupture increase the risk of acute coronary syndromes. Advanced lesion macrophage apoptosis plays important role in the rupture of atherosclerotic plaque, and endoplasmic reticulum stress (ERS) has been proved to be a key mechanism of macrophage apoptosis. Intermedin (IMD) is a regulator of ERS. Here, we investigated whether IMD enhances atherosclerotic plaque stability by inhibiting ERS-CHOP-mediated apoptosis and subsequent inflammasome in macrophages. We studied the effects of IMD on features of plaque vulnerability in hyperlipemia apolipoprotein E-deficient (ApoE−/−) mice. Six-week IMD1-53 infusion significantly reduced atherosclerotic lesion size. Of note, IMD1-53 lowered lesion macrophage content and necrotic core size and increased fibrous cap thickness and vascular smooth muscle cells (VSMCs) content thus reducing overall plaque vulnerability. Immunohistochemical analysis indicated that IMD1-53 administration prevented ERS activation in aortic lesions of ApoE−/− mice, which was further confirmed in oxidized low-density lipoproteins (ox-LDL) induced macrophages. Similar to IMD, taurine (Tau), a non-selective ERS inhibitor significantly reduced atherosclerotic lesion size and plaque vulnerability. Moreover, C/EBP-homologous protein (CHOP), a pro-apoptosis transcription factor involved in ERS, was significantly increased in advanced lesion macrophages, and deficiency of CHOP stabilized atherosclerotic plaques in AopE−/− mice. IMD1-53 decreased CHOP level and apoptosis in vivo and in macrophages treated with ox-LDL. In addition, IMD1-53 infusion ameliorated NLRP3 inflammasome and subsequent proinflammatory cytokines in vivo and in vitro. IMD may attenuate the progression of atherosclerotic lesions and plaque vulnerability by inhibiting ERS-CHOP-mediated macrophage apoptosis, and subsequent NLRP3 triggered inflammation. The inhibitory effect of IMD on ERS-induced macrophages apoptosis was probably mediated by blocking CHOP activation.
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Cyathus striatus Extract Induces Apoptosis in Human Pancreatic Cancer Cells and Inhibits Xenograft Tumor Growth In Vivo. Cancers (Basel) 2021; 13:cancers13092017. [PMID: 33922003 PMCID: PMC8122434 DOI: 10.3390/cancers13092017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 12/31/2022] Open
Abstract
Simple Summary The main aim of the present study is to test the effect of Cyathus striatus extract on the cell growth of human pancreatic cancer cells in vitro and in vivo. In addition, the effect of the extract on the gene expression was detected. The results indicated that Cyathus striatus extract significantly inhibited the cell viability and induced apoptosis. The treatment of xenograft mice harboring human pancreatic cancer cells significantly inhibited tumor growth through the induction of apoptosis. RNAseq experiments revealed the involvement of the MAPK and P53 signaling pathways and pointed toward endoplasmic reticulum stress induced apoptosis. These results may suggest that Cyathus striatus extract may contain pro-apoptotic factors that can be identified and used for the treatment of human cancer. Abstract Pancreatic cancer is a highly lethal disease with limited options for effective therapy and the lowest survival rate of all cancer forms. Therefore, a new, effective strategy for cancer treatment is in need. Previously, we found that a culture liquid extract of Cyathus striatus (CS) has a potent antitumor activity. In the present study, we aimed to investigate the effects of Cyathus striatus extract (CSE) on the growth of pancreatic cancer cells, both in vitro and in vivo. The proliferation assay (XTT), cell cycle analysis, Annexin/PI staining and TUNEL assay confirmed the inhibition of cell growth and induction of apoptosis by CSE. A Western blot analysis demonstrated the involvement of both the extrinsic and intrinsic apoptosis pathways. In addition, a RNAseq analysis revealed the involvement of the MAPK and P53 signaling pathways and pointed toward endoplasmic reticulum stress induced apoptosis. The anticancer activity of the CSE was also demonstrated in mice harboring pancreatic cancer cell line-derived tumor xenografts when CSE was given for 5 weeks by weekly IV injections. Our findings suggest that CSE could potentially be useful as a new strategy for treating pancreatic cancer.
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Benito-Vicente A, Jebari-Benslaiman S, Galicia-Garcia U, Larrea-Sebal A, Uribe KB, Martin C. Molecular mechanisms of lipotoxicity-induced pancreatic β-cell dysfunction. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 359:357-402. [PMID: 33832653 DOI: 10.1016/bs.ircmb.2021.02.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes (T2D), a heterogeneous disorder derived from metabolic dysfunctions, leads to a glucose overflow in the circulation due to both defective insulin secretion and peripheral insulin resistance. One of the critical risk factor for T2D is obesity, which represents a global epidemic that has nearly tripled since 1975. Obesity is characterized by chronically elevated free fatty acid (FFA) levels, which cause deleterious effects on glucose homeostasis referred to as lipotoxicity. Here, we review the physiological FFA roles onto glucose-stimulated insulin secretion (GSIS) and the pathological ones affecting many steps of the mechanisms and modulation of GSIS. We also describe in vitro and in vivo experimental evidences addressing lipotoxicity in β-cells and the role of saturation and chain length of FFA on the potency of GSIS stimulation. The molecular mechanisms underpinning lipotoxic-β-cell dysfunction are also reviewed. Among them, endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, inflammation, impaired autophagy and β-cell dedifferentiation. Finally therapeutic strategies for the β-cells dysfunctions such as the use of metformin, glucagon-like peptide 1, thiazolidinediones, anti-inflammatory drugs, chemical chaperones and weight are discussed.
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Affiliation(s)
- Asier Benito-Vicente
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Shifa Jebari-Benslaiman
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Unai Galicia-Garcia
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Molecular Biophysics, Fundación Biofísica Bizkaia, Leioa, Spain
| | - Asier Larrea-Sebal
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Molecular Biophysics, Fundación Biofísica Bizkaia, Leioa, Spain
| | - Kepa B Uribe
- Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Donostia San Sebastián, Spain
| | - Cesar Martin
- Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain.
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Eguchi N, Vaziri ND, Dafoe DC, Ichii H. The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes. Int J Mol Sci 2021; 22:ijms22041509. [PMID: 33546200 PMCID: PMC7913369 DOI: 10.3390/ijms22041509] [Citation(s) in RCA: 158] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/29/2021] [Accepted: 01/30/2021] [Indexed: 02/07/2023] Open
Abstract
Diabetes is a chronic metabolic disorder characterized by inappropriately elevated glucose levels as a result of impaired pancreatic β cell function and insulin resistance. Extensive studies have been conducted to elucidate the mechanism involved in the development of β cell failure and death under diabetic conditions such as hyperglycemia, hyperlipidemia, and inflammation. Of the plethora of proposed mechanisms, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and oxidative stress have been shown to play a central role in promoting β cell dysfunction. It has become more evident in recent years that these 3 factors are closely interrelated and importantly aggravate each other. Oxidative stress in particular is of great interest to β cell health and survival as it has been shown that β cells exhibit lower antioxidative capacity. Therefore, this review will focus on discussing factors that contribute to the development of oxidative stress in pancreatic β cells and explore the downstream effects of oxidative stress on β cell function and health. Furthermore, antioxidative capacity of β cells to counteract these effects will be discussed along with new approaches focused on preserving β cells under oxidative conditions.
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Affiliation(s)
- Natsuki Eguchi
- Department of Surgery, University of California, Irvine, CA 92697, USA; (N.E.); (D.C.D.)
| | | | - Donald C. Dafoe
- Department of Surgery, University of California, Irvine, CA 92697, USA; (N.E.); (D.C.D.)
| | - Hirohito Ichii
- Department of Surgery, University of California, Irvine, CA 92697, USA; (N.E.); (D.C.D.)
- Correspondence: ; Tel.: +1-714-456-8590
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Fløyel T, Meyerovich K, Prause MC, Kaur S, Frørup C, Mortensen HB, Nielsen LB, Pociot F, Cardozo AK, Størling J. SKAP2, a Candidate Gene for Type 1 Diabetes, Regulates β-Cell Apoptosis and Glycemic Control in Newly Diagnosed Patients. Diabetes 2021; 70:464-476. [PMID: 33203694 PMCID: PMC7881866 DOI: 10.2337/db20-0092] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 11/10/2020] [Indexed: 01/27/2023]
Abstract
The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2 (SKAP2) gene is associated with type 1 diabetes (T1D), suggesting SKAP2 as a causal candidate gene. The objective of the study was to investigate if SKAP2 has a functional role in the β-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycemic control and residual β-cell function during the 1st year after diagnosis. In INS-1E cells and rat and human islets, proinflammatory cytokines reduced the content of SKAP2. Functional studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat β-cells, suggesting an antiapoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced apoptosis, which correlated with reduced nuclear content of S536-phosphorylated nuclear factor-κB (NF-κB) subunit p65, lower nitric oxide production, and diminished CHOP expression indicative of decreased endoplasmic reticulum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls β-cell sensitivity to cytokines possibly by affecting the NF-κB-inducible nitric oxide synthase-endoplasmic reticulum stress pathway.
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Affiliation(s)
- Tina Fløyel
- Translational Type 1 Diabetes Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Kira Meyerovich
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Michala C Prause
- Translational Type 1 Diabetes Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Simranjeet Kaur
- Translational Type 1 Diabetes Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Caroline Frørup
- Translational Type 1 Diabetes Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Henrik B Mortensen
- Department of Pediatrics E, Herlev and Gentofte Hospital, Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Lotte B Nielsen
- Department of Pediatrics E, Herlev and Gentofte Hospital, Herlev, Denmark
| | - Flemming Pociot
- Translational Type 1 Diabetes Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Alessandra K Cardozo
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Joachim Størling
- Translational Type 1 Diabetes Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Stafford JD, Yeo CT, Corbett JA. Inhibition of oxidative metabolism by nitric oxide restricts EMCV replication selectively in pancreatic beta-cells. J Biol Chem 2020; 295:18189-18198. [PMID: 33100269 PMCID: PMC7939444 DOI: 10.1074/jbc.ra120.015893] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/08/2020] [Indexed: 01/27/2023] Open
Abstract
Environmental factors, such as viral infection, are proposed to play a role in the initiation of autoimmune diabetes. In response to encephalomyocarditis virus (EMCV) infection, resident islet macrophages release the pro-inflammatory cytokine IL-1β, to levels that are sufficient to stimulate inducible nitric oxide synthase (iNOS) expression and production of micromolar levels of the free radical nitric oxide in neighboring β-cells. We have recently shown that nitric oxide inhibits EMCV replication and EMCV-mediated β-cell lysis and that this protection is associated with an inhibition of mitochondrial oxidative metabolism. Here we show that the protective actions of nitric oxide against EMCV infection are selective for β-cells and associated with the metabolic coupling of glycolysis and mitochondrial oxidation that is necessary for insulin secretion. Inhibitors of mitochondrial respiration attenuate EMCV replication in β-cells, and this inhibition is associated with a decrease in ATP levels. In mouse embryonic fibroblasts (MEFs), inhibition of mitochondrial metabolism does not modify EMCV replication or decrease ATP levels. Like most cell types, MEFs have the capacity to uncouple the glycolytic utilization of glucose from mitochondrial respiration, allowing for the maintenance of ATP levels under conditions of impaired mitochondrial respiration. It is only when MEFs are forced to use mitochondrial oxidative metabolism for ATP generation that mitochondrial inhibitors attenuate viral replication. In a β-cell selective manner, these findings indicate that nitric oxide targets the same metabolic pathways necessary for glucose stimulated insulin secretion for protection from viral lysis.
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Affiliation(s)
- Joshua D Stafford
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Chay Teng Yeo
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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Stafford JD, Shaheen ZR, Yeo CT, Corbett JA. Inhibition of mitochondrial oxidative metabolism attenuates EMCV replication and protects β-cells from virally mediated lysis. J Biol Chem 2020; 295:16655-16664. [PMID: 32972972 PMCID: PMC7864063 DOI: 10.1074/jbc.ra120.014851] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/06/2020] [Indexed: 12/15/2022] Open
Abstract
Viral infection is one environmental factor that may contribute to the initiation of pancreatic β-cell destruction during the development of autoimmune diabetes. Picornaviruses, such as encephalomyocarditis virus (EMCV), induce a pro-inflammatory response in islets leading to local production of cytokines, such as IL-1, by resident islet leukocytes. Furthermore, IL-1 is known to stimulate β-cell expression of iNOS and production of the free radical nitric oxide. The purpose of this study was to determine whether nitric oxide contributes to the β-cell response to viral infection. We show that nitric oxide protects β-cells against virally mediated lysis by limiting EMCV replication. This protection requires low micromolar, or iNOS-derived, levels of nitric oxide. At these concentrations nitric oxide inhibits the Krebs enzyme aconitase and complex IV of the electron transport chain. Like nitric oxide, pharmacological inhibition of mitochondrial oxidative metabolism attenuates EMCV-mediated β-cell lysis by inhibiting viral replication. These findings provide novel evidence that cytokine signaling in β-cells functions to limit viral replication and subsequent β-cell lysis by attenuating mitochondrial oxidative metabolism in a nitric oxide-dependent manner.
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Affiliation(s)
- Joshua D Stafford
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Zachary R Shaheen
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Chay Teng Yeo
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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Developmental Programming and Glucolipotoxicity: Insights on Beta Cell Inflammation and Diabetes. Metabolites 2020; 10:metabo10110444. [PMID: 33158303 PMCID: PMC7694373 DOI: 10.3390/metabo10110444] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/23/2020] [Accepted: 10/09/2020] [Indexed: 12/12/2022] Open
Abstract
Stimuli or insults during critical developmental transitions induce alterations in progeny anatomy, physiology, and metabolism that may be transient, sometimes reversible, but often durable, which defines programming. Glucolipotoxicity is the combined, synergistic, deleterious effect of simultaneously elevated glucose (chronic hyperglycemia) and saturated fatty acids (derived from high-fat diet overconsumption and subsequent metabolism) that are harmful to organs, micro-organs, and cells. Glucolipotoxicity induces beta cell death, dysfunction, and failure through endoplasmic reticulum and oxidative stress and inflammation. In beta cells, the misfolding of pro/insulin proteins beyond the cellular threshold triggers the unfolded protein response and endoplasmic reticulum stress. Consequentially there is incomplete and inadequate pro/insulin biosynthesis and impaired insulin secretion. Cellular stress triggers cellular inflammation, where immune cells migrate to, infiltrate, and amplify in beta cells, leading to beta cell inflammation. Endoplasmic reticulum stress reciprocally induces beta cell inflammation, whereas beta cell inflammation can self-activate and further exacerbate its inflammation. These metabolic sequelae reflect the vicious cycle of beta cell stress and inflammation in the pathophysiology of diabetes.
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Xiao X, Erukainure OL, Beseni B, Koorbanally NA, Islam MS. Sequential extracts of red honeybush (Cyclopia genistoides) tea: Chemical characterization, antioxidant potentials, and anti-hyperglycemic activities. J Food Biochem 2020; 44:e13478. [PMID: 32984977 DOI: 10.1111/jfbc.13478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 08/24/2020] [Accepted: 08/30/2020] [Indexed: 11/29/2022]
Abstract
The antioxidant, antidiabetic, and anti-obesogenic potentials of different extracts (dichloromethane, ethyl acetate, ethanol, and aqueous) of the red honeybush (Cyclopia genistoides) tea were investigated in vitro and ex vivo. All extracts exhibited significant scavenging and reducing power activities, with the aqueous and ethyl acetate extracts being the most potent. In vitro antidiabetic analysis revealed the extracts to be potent inhibitors of α-glucosidase and lipase activities. All extracts increased catalase and SOD activities, and glutathione level in oxidative pancreatic injury. GC-MS analysis revealed the presence of fatty acids, fatty acid ester, phytols, sterols, saccharide, ketones, and triterpenes. These results imply that the sequential extracts of honeybush tea (particularly the aqueous and ethyl acetate extracts) may not only exhibit antioxidant potentials but also mediate anti-hyperglycemia activities by inhibiting lipid and carbohydrate digestion. PRACTICAL APPLICATIONS: Red honeybush tea is enjoyed widely in South Africa and around the world due to its no caffeine and very low tannin content, as well as many healthcare attributes. There are however no scientific reports for its sequential extraction of different solvents on antidiabetic effects. The different extracts of honeybush tea (particularly the aqueous and ethyl acetate extracts) inhibited lipid and carbohydrate digestive enzymes linked to type 2 diabetes (T2D), as well as modulate oxidative pancreatic injury. These findings will promote its utilization as a potential nutraceutical in the management of diabetes and its complications.
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Affiliation(s)
- Xin Xiao
- Department of Biochemistry, University of KwaZulu-Natal, Durban, South Africa
| | - Ochuko L Erukainure
- Department of Biochemistry, University of KwaZulu-Natal, Durban, South Africa.,Department of Pharmacology, University of the Free State, Bloemfontein, South Africa
| | - Brian Beseni
- Department of Biochemistry, University of KwaZulu-Natal, Durban, South Africa
| | - Neil A Koorbanally
- School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa
| | - Md Shahidul Islam
- Department of Biochemistry, University of KwaZulu-Natal, Durban, South Africa
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Deng B, Feng J, Wang L, Chen X. Silencing of CRT relieves Ang II-Induced injury of HUVECs with insulin resistance. J Recept Signal Transduct Res 2020; 41:321-330. [PMID: 32873146 DOI: 10.1080/10799893.2020.1808677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
In this study, we investigated the effects of Angiotensin II (Ang II) on insulin-resistant endothelial cells. High glucose and insulin at series of concentrations were used to induce IR in Human Umbilical Vein Endothelial Cells (HUVECs). Successful IR induction was confirmed according to glucose consumption and glycogen content levels. Cell morphology was observed under a microscope. Expression levels of Ang II and Calreticulin (CRT) were measured by ELISA, qRT-PCR and Western blot as appropriate. Cell viability and apoptosis were measured by CCK-8 assay and flow cytometry, respectively. HUVECs with IR were exposed to Ang II at series of concentrations, and then the cell viability, apoptosis and CRT were detected. Rescue assays were performed by transfection of siCRT or overexpression of CRT with or without Ang II stimulation into the HUVECs with IR. Expressions of cell apoptosis-related proteins Bcl-2 and Bax were measured by qRT-PCR and Western blot. Glucose (33.3 mmol/L) and insulin (4 µmol/L) induced significantly strong IR to the HUVECs, with a pathological appearance. Levels of Agn II and CRT were both up-regulated by IR. Cell viability of HUVECs was slightly reduced after IR induction for 2 h, and cell apoptosis rate was increased. In addition, Ang II (10-7 mol/l) suppressed cell viability and glucose uptake, promoted cell apoptosis and increased CRT, and these effects could be weakened by silencing CRT. Thus, we preliminarily proved that Ang II up-regulates CRT, and CRT knockdown can relieve Ang II-induced injury of HUVECs with IR.
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Affiliation(s)
- Biyong Deng
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jing Feng
- Department of Cardiology, Jing'an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Lei Wang
- Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai, Jiaotong University School of Medicine, Shanghai, China
| | - Xin Chen
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Damame HH, Rooge SB, Patil RS, Arvindekar AU. In vitro model using cytokine cocktail to evaluate apoptosis in Min6 pancreatic beta cells. J Pharmacol Toxicol Methods 2020; 106:106914. [PMID: 32828949 DOI: 10.1016/j.vascn.2020.106914] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 08/08/2020] [Accepted: 08/13/2020] [Indexed: 01/23/2023]
Abstract
INTRODUCTION Development of therapy options for treatment of type 1 diabetes mellitus is hampered by non-availability of appropriate experimental models that can exactly mimic the in vivo situation. Apoptosis of beta cells by T cells and cytokine action leads to loss of beta cells. We propose a simple and elegant model using cytokine cocktail of TNF-α, IFN-γ and IL-1β, the major cytokines responsible for apoptosis in Min6 beta cell line. METHODS A cocktail of TNF-α, IFN-γ and IL-1β was used to induce apoptosis in Min6 beta cell line. Apoptosis was assessed by flow cytometry using CytoFLEX (Beckman Coulter). The destruction of beta cells is through production of nitric oxide (NO), oxidative stress and change in mitochondrial membrane permeability. NO was measured using Griess reagent. Oxidative stress was assessed using 2',7'-dichlorofluorescein diacetate, a cell-permeable fluorogenic dye and mitochondrial membrane potential was determined on the basis of retention of rhodamine 123 using flow cytometer. RESULTS AND DISCUSSION Very low concentration of the cocktail viz. TNF-α 25 ng/ml, IFN-γ 25 ng/ml and IL-1β 50 ng/ml has demonstrated effective early and late apoptosis in as short a time period as 6 h. The experimental model used demonstrated 1.5 fold higher production of NO, 1.2 fold increased oxidative stress and lower mitochondrial membrane potential as compared to the positive control used. Hence the above model can be easily used for assessment and screening of drugs that can prevent apoptosis of beta cells and stop progression of type 1 diabetes.
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Affiliation(s)
- Hemangee H Damame
- Department of Biochemistry, Shivaji University, Kolhapur 416 004, Maharashtra, India
| | - Sheetalnath B Rooge
- Department of Biochemistry, Shivaji University, Kolhapur 416 004, Maharashtra, India
| | - Rahul S Patil
- Department of Biochemistry, Shivaji University, Kolhapur 416 004, Maharashtra, India
| | - Akalpita U Arvindekar
- Department of Biochemistry, Shivaji University, Kolhapur 416 004, Maharashtra, India.
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Singh S. Updates on Versatile Role of Putative Gasotransmitter Nitric Oxide: Culprit in Neurodegenerative Disease Pathology. ACS Chem Neurosci 2020; 11:2407-2415. [PMID: 32564594 DOI: 10.1021/acschemneuro.0c00230] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Nitric oxide (NO) is a versatile gasotransmitter that contributes in a range of physiological and pathological mechanims depending on its cellular levels. An appropriate concentration of NO is essentially required for cellular physiology; however, its increased level triggers pathological mechanisms like altered cellular redox regulation, functional impairment of mitochondrion, and modifications in cellular proteins and DNA. Its increased levels also exhibit post-translational modifications in protein through S-nitrosylation of their thiol amino acids, which critically affect the cellular physiology. Along with such modifications, NO could also nitrosylate the endoplasmic reticulum (ER)-membrane located sensors of ER stress, which subsequently affect the cellular protein degradation capacity and lead to aggregation of misfolded/unfolded proteins. Since protein aggregation is one of the pathological hallmarks of neurodegenerative disease, NO should be taken into account during development of disease therapies. In this Review, we shed light on the diverse role of NO in both cellular physiology and pathology and discussed its involvement in various pathological events in the context of neurodegenerative diseases.
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Affiliation(s)
- Sarika Singh
- Department of Neurosciences and Ageing Biology and Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India
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Sharmin MM, Mizusawa M, Hayashi S, Arai W, Sakata S, Yonekura S. Effects of fatty acids on inducing endoplasmic reticulum stress in bovine mammary epithelial cells. J Dairy Sci 2020; 103:8643-8654. [PMID: 32622599 DOI: 10.3168/jds.2019-18080] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/20/2020] [Indexed: 12/23/2022]
Abstract
Fatty acids play important roles in the regulation of endoplasmic reticulum (ER) stress-induced apoptosis in different cells. Currently, the effects of fatty acids on bovine mammary epithelial cells (MEC) remain unknown. Our study examined bovine MEC viability and measured unfolded protein response (UPR)-related gene and protein expressions following fatty acid treatments. To evaluate the role of fatty acids, we treated MAC-T cells (a line of MEC) with 100 to 400 μM of saturated (palmitic and stearic acid) and unsaturated (palmitoleic, oleic, linoleic, and linolenic acid) fatty acids and 1 to 5 mM of short- and medium-chain fatty acids (acetic, propionic, butyric, and octanoic acid). Thereafter, we determined UPR-related gene expression using quantitative real-time PCR. Palmitic acid stimulated expression of XBP1s, ATF4, ATF6A, and C/EBP homologous protein (CHOP). Stearic acid increased expression of XBP1s and CHOP and decreased expression of ATF4 and ATF6A. Results of Western blot analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that palmitic and stearic acid reduced MAC-T cell viability and induced extreme ER stress by increasing the protein expression of ER stress markers, such as phospho-PKR-like endoplasmic reticulum kinase, phospho-eIF2α, cleaved CASP-3, and CHOP. Among unsaturated long-chain fatty acids, palmitoleic acid increased expression of ATF4 and ATF6A. Oleic acid increased expression of XBP1s, ATF4, and ATF6A. Linoleic and linolenic acids increased expression of XBP1s, ATF4, and ATF6A but decreased expression of XBP1s and ATF6A at the highest dose. Although palmitoleic, oleic, and linoleic acid decreased CHOP expression, only palmitoleic acid increased MAC-T cell viability. Therefore, unsaturated long-chain fatty acids did not induce severe ER stress. Acetic, propionic, and butyric acids decreased expression of ATF4, ATF6A, and CHOP and increased XBP1s expression. Although only octanoic acid increased ATF4 and ATF6A expressions, it lowered expression of XBP1s and CHOP. Although fatty acid treatment did not increase the levels of ER stress proteins, butyric and octanoic acids reduced cell viability, possibly because of early differentiation. These results suggest that saturated fatty acids play important roles in MEC viability by inducing severe ER stress compared with unsaturated fatty acids. In addition, acetic and propionic acids (short- and medium-chain fatty acids) reduced ER stress. Therefore, the present study reflects the new insight that serum fatty acid concentration plays an important role in maintaining the lactation physiology of dairy cows.
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Affiliation(s)
- Mst Mamuna Sharmin
- Graduate School of Medicine, Science and Technology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano 399-4598, Japan
| | - Moeko Mizusawa
- Graduate School of Science and Technology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano 399-4598, Japan
| | - Satoko Hayashi
- Graduate School of Medicine, Science and Technology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano 399-4598, Japan
| | - Wataru Arai
- Graduate School of Science and Technology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano 399-4598, Japan
| | - Shotaro Sakata
- Graduate School of Science and Technology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano 399-4598, Japan
| | - Shinichi Yonekura
- Graduate School of Medicine, Science and Technology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano 399-4598, Japan; Graduate School of Science and Technology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano 399-4598, Japan; Department of Biomolecular Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano 399-4598, Japan.
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Choi YK, Kang JI, Han S, Kim YR, Jo J, Kang YW, Choo DR, Hyun JW, Koh YS, Yoo ES, Kang HK. L-Ascorbic Acid Inhibits Breast Cancer Growth by Inducing IRE/JNK/CHOP-Related Endoplasmic Reticulum Stress-Mediated p62/SQSTM1 Accumulation in the Nucleus. Nutrients 2020; 12:nu12051351. [PMID: 32397306 PMCID: PMC7284633 DOI: 10.3390/nu12051351] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 04/24/2020] [Accepted: 05/02/2020] [Indexed: 12/11/2022] Open
Abstract
Anticancer effects of L-ascorbic acid (Vitamin C, L-AA) have been reported in various types of cancers. L-AA intake reduces breast cancer recurrence and mortality; however, the role of L-AA in the treatment of breast cancer remains poorly understood. In this study, we investigated the effect and mechanism action of L-AA on breast cancer growth. L-AA inhibited the growth of breast cancer cells by inducing apoptotic cell death at the evaluated treatment concentrations without affecting normal cells. Moreover, L-AA induces autophagosome formation via regulation of mammalian target of rapamycin (mTOR), Beclin1, and autophagy-related genes (ATGs) and increased autophagic flux. Notably, we observed that L-AA increased p62/SQSTM1 (sequestosome 1) protein levels. Accumulation of p62 protein in cancer cells in response to stress has been reported, but its role in cancer regulation remains controversial. Here, we demonstrated that L-AA-induced p62 accumulation is related to L-AA-induced breast cancer growth inhibition. Furthermore, L-AA induced endoplasmic reticulum (ER) stress via the IRE–JNK–CHOP (inositol-requiring endonuclease–c-Jun N-terminal kinase–C/EBP homologous protein) signaling pathways, which increased the nuclear levels of p62/SQSTM1. These findings provide evidence that L-AA-induced ER stress could be crucial for p62 accumulation-dependent cell death, and L-AA can be useful in breast cancer treatment.
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Affiliation(s)
- Youn Kyung Choi
- Department of Medicine, School of Medicine, Jeju National University 102 Jejudaehakno, Jeju 63243, Korea; (Y.K.C.); (J.-I.K.); (S.H.); (Y.R.K.); (J.J.); (Y.W.K.); (D.R.C.); (J.W.H.); (Y.S.K.); (E.-S.Y.)
| | - Jung-Il Kang
- Department of Medicine, School of Medicine, Jeju National University 102 Jejudaehakno, Jeju 63243, Korea; (Y.K.C.); (J.-I.K.); (S.H.); (Y.R.K.); (J.J.); (Y.W.K.); (D.R.C.); (J.W.H.); (Y.S.K.); (E.-S.Y.)
| | - Sanghoon Han
- Department of Medicine, School of Medicine, Jeju National University 102 Jejudaehakno, Jeju 63243, Korea; (Y.K.C.); (J.-I.K.); (S.H.); (Y.R.K.); (J.J.); (Y.W.K.); (D.R.C.); (J.W.H.); (Y.S.K.); (E.-S.Y.)
| | - Young Ree Kim
- Department of Medicine, School of Medicine, Jeju National University 102 Jejudaehakno, Jeju 63243, Korea; (Y.K.C.); (J.-I.K.); (S.H.); (Y.R.K.); (J.J.); (Y.W.K.); (D.R.C.); (J.W.H.); (Y.S.K.); (E.-S.Y.)
| | - Jaemin Jo
- Department of Medicine, School of Medicine, Jeju National University 102 Jejudaehakno, Jeju 63243, Korea; (Y.K.C.); (J.-I.K.); (S.H.); (Y.R.K.); (J.J.); (Y.W.K.); (D.R.C.); (J.W.H.); (Y.S.K.); (E.-S.Y.)
| | - Yong Woo Kang
- Department of Medicine, School of Medicine, Jeju National University 102 Jejudaehakno, Jeju 63243, Korea; (Y.K.C.); (J.-I.K.); (S.H.); (Y.R.K.); (J.J.); (Y.W.K.); (D.R.C.); (J.W.H.); (Y.S.K.); (E.-S.Y.)
| | - Do Ryeon Choo
- Department of Medicine, School of Medicine, Jeju National University 102 Jejudaehakno, Jeju 63243, Korea; (Y.K.C.); (J.-I.K.); (S.H.); (Y.R.K.); (J.J.); (Y.W.K.); (D.R.C.); (J.W.H.); (Y.S.K.); (E.-S.Y.)
| | - Jin Won Hyun
- Department of Medicine, School of Medicine, Jeju National University 102 Jejudaehakno, Jeju 63243, Korea; (Y.K.C.); (J.-I.K.); (S.H.); (Y.R.K.); (J.J.); (Y.W.K.); (D.R.C.); (J.W.H.); (Y.S.K.); (E.-S.Y.)
- Jeju Research Center for Natural Medicine, Jeju National University; 102 Jejudaehakno, Jeju 63243, Korea
| | - Young Sang Koh
- Department of Medicine, School of Medicine, Jeju National University 102 Jejudaehakno, Jeju 63243, Korea; (Y.K.C.); (J.-I.K.); (S.H.); (Y.R.K.); (J.J.); (Y.W.K.); (D.R.C.); (J.W.H.); (Y.S.K.); (E.-S.Y.)
- Jeju Research Center for Natural Medicine, Jeju National University; 102 Jejudaehakno, Jeju 63243, Korea
| | - Eun-Sook Yoo
- Department of Medicine, School of Medicine, Jeju National University 102 Jejudaehakno, Jeju 63243, Korea; (Y.K.C.); (J.-I.K.); (S.H.); (Y.R.K.); (J.J.); (Y.W.K.); (D.R.C.); (J.W.H.); (Y.S.K.); (E.-S.Y.)
- Jeju Research Center for Natural Medicine, Jeju National University; 102 Jejudaehakno, Jeju 63243, Korea
| | - Hee-Kyoung Kang
- Department of Medicine, School of Medicine, Jeju National University 102 Jejudaehakno, Jeju 63243, Korea; (Y.K.C.); (J.-I.K.); (S.H.); (Y.R.K.); (J.J.); (Y.W.K.); (D.R.C.); (J.W.H.); (Y.S.K.); (E.-S.Y.)
- Jeju Research Center for Natural Medicine, Jeju National University; 102 Jejudaehakno, Jeju 63243, Korea
- Correspondence: ; Tel.:+82-10-6214-5464
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Oleson BJ, Corbett JA. Can insulin secreting pancreatic β-cells provide novel insights into the metabolic regulation of the DNA damage response? Biochem Pharmacol 2020; 176:113907. [PMID: 32171728 DOI: 10.1016/j.bcp.2020.113907] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 03/06/2020] [Indexed: 12/18/2022]
Abstract
Insulin, produced by pancreatic β-cells, is responsible for the control of whole-body glucose metabolism. Insulin is secreted by pancreatic β-cells in a tightly regulated process that is controlled by the serum level of glucose, glucose sensing and glucose oxidative metabolism. The regulation of intermediary metabolism in β-cells is unique as these cells oxidize glucose to CO2 on substrate supply while mitochondrial oxidative metabolism occurs on demand, for the production of intermediates or energy production, in most cell types. This review discusses recent findings that the regulation of intermediary metabolism by nitric oxide attenuates the DNA damage response (DDR) and DNA damage-dependent apoptosis in a β-cell selective manner. Specific focus is placed on the mechanisms by which iNOS derived nitric oxide (low micromolar levels) regulates DDR activation via the inhibition of intermediary metabolism. The physiological significance of the association of metabolism, nitric oxide and DDR signaling for cancer biology and diabetes is discussed.
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Affiliation(s)
- Bryndon J Oleson
- From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - John A Corbett
- From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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Johar D, Ahmed SM, El Hayek S, Al-Dewik N, Bahbah EI, Omar NH, Mustafa M, Salman DO, Fahmey A, Mottawea M, Azouz RAM, Bernstein L. Diabetes-induced Proteome Changes Throughout Development. Endocr Metab Immune Disord Drug Targets 2020; 19:732-743. [PMID: 31038056 DOI: 10.2174/1871530319666190305153810] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 10/31/2018] [Accepted: 11/25/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND Diabetes Mellitus (DM) is a multisystemic disease involving the homeostasis of insulin secretion by the pancreatic islet beta cells (β-cells). It is associated with hypertension, renal disease, and arterial and arteriolar vascular diseases. DISCUSSION The classification of diabetes is identified as type 1 (gene linked β-cell destruction in childhood) and type 2 (late onset associated with β-cell overload and insulin resistance in peripheral tissues. Type 1 diabetes is characterized by insulin deficiency, type 2 diabetes by both insulin deficiency and insulin resistance. The former is a genetically programmed loss of insulin secretion whereas the latter constitutes a disruption of the homeostatic relationship between the opposing activity of β- cell insulin and alpha cell (α-cell) glucagon of the Islets of Langerhans. The condition could also occur in pregnancy, as a prenatal occurring event, possibly triggered by the hormonal changes of pregnancy combined with β-cell overload. This review discusses the molecular basis of the biomolecular changes that occur with respect to glucose homeostasis and related diseases in DM. The underlying link between pancreatic, renal, and microvascular diseases in DM is based on oxidative stress and the Unfolded Protein Response (UPR). CONCLUSION Studying proteome changes in diabetes can deepen our understanding of the biomolecular basis of disease and help us acquire more efficient therapies.
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Affiliation(s)
- Dina Johar
- Biomedical Science Program, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt and Biochemistry and Nutrition Department, Ain Shams University Faculty of Women for Arts, Sciences and Education, Heliopolis, Cairo, Egypt
| | - Sara M Ahmed
- Clinical Pathology Department, Faculty of Medicine (Girls), Al-Azhar University, Nasr City, Cairo, Egypt
| | - Samer El Hayek
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Nader Al-Dewik
- Qatar Medical Genetic Center, Pediatrics Department, Hamad General Hospital (HGH), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Eshak I Bahbah
- Faculty of Medicine, Al-Azhar University, Damietta, P.C. 34511, Egypt
| | - Nabil H Omar
- Pharmacy Department, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | | | - Doaa O Salman
- Genetics Unit, Histology and Cell biology department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Asmaa Fahmey
- Faculty of Pharmacy, Al-Mansoura University, Al-Mansoura, Egypt
| | - Mohamed Mottawea
- Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Rasha A M Azouz
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, Dokki, 12622 Giza, Egypt
| | - Larry Bernstein
- Triplex Consulting, 54 Firethorn Lane, Northampton, MA 01060, United States
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Liu J, Huang Y, Cai F, Dang Y, Liu C, Wang J. MicroRNA-181a regulates endoplasmic reticulum stress in offspring of mice following prenatal microcystin-LR exposure. CHEMOSPHERE 2020; 240:124905. [PMID: 31563103 DOI: 10.1016/j.chemosphere.2019.124905] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 09/17/2019] [Accepted: 09/17/2019] [Indexed: 06/10/2023]
Abstract
Microcystin-LR (MCLR) was commonly regarded as a potent hepatotoxin and has been reported to cause neurotoxicity. This study was aimed to investigate how maternal MCLR exposure during pregnancy alters behavioral responses in offspring mice and the possible molecular mechanism involved in this procedure. Three doses of MCLR solutions (0, 3 or 15 μg/kg body weight) were administered subcutaneously to pregnant C57bl/6 from gestation day (GD) 6-19. Our results showed that MCLR prenatal exposure led to the impairment of learning and memory function in offspring on postnatal days (PND) 35, accompanied by endoplasmic reticulum (ER) stress and neuronal apoptosis in hippocampal CA1 regions of mice. Sixteen miRNAs in hippocampus of pups on PND 35 were significantly affected by MCLR exposure with the markedly decreased transcription of miR-181a-5p. We then found that miR-181a-5p was down-regulated, accompanied by activation of ER stress after prenatal exposure to MCLR using qPCR analysis. Furthermore, glucose-regulated protein, 78kDa/binding immunoglobulin protein (Grp78/BIP), a major ER chaperone and signaling regulator, was identified as a target of miR-181a-5p. Our study showed that miR-181a could lead to a decrease in the mRNA expression and protein levels of Grp78 by directly binding to its 3'-untranslated region (3'-UTR) in primary hippocampal neurons. Our findings indicate that the up-regulation of Grp78 mediated by inhibition of miR-181a-5p is a possible mechanism resulting in ER stress and cognitive impairment in pups following prenatal MCLR exposure.
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Affiliation(s)
- Jue Liu
- Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China
| | - Yangyang Huang
- Fisheries College, Huazhong Agricultural University, Wuhan, 430070, China
| | - Fei Cai
- Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, 437100, Hubei, China; Department of Pharmacology, Hubei University of Science and Technology, Xianning, 437100, China
| | - Yao Dang
- Fisheries College, Huazhong Agricultural University, Wuhan, 430070, China
| | - Chunsheng Liu
- Fisheries College, Huazhong Agricultural University, Wuhan, 430070, China
| | - Jianghua Wang
- Fisheries College, Huazhong Agricultural University, Wuhan, 430070, China.
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Calcium Signaling in ß-cell Physiology and Pathology: A Revisit. Int J Mol Sci 2019; 20:ijms20246110. [PMID: 31817135 PMCID: PMC6940736 DOI: 10.3390/ijms20246110] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 11/28/2019] [Accepted: 12/02/2019] [Indexed: 12/12/2022] Open
Abstract
Pancreatic beta (β) cell dysfunction results in compromised insulin release and, thus, failed regulation of blood glucose levels. This forms the backbone of the development of diabetes mellitus (DM), a disease that affects a significant portion of the global adult population. Physiological calcium (Ca2+) signaling has been found to be vital for the proper insulin-releasing function of β-cells. Calcium dysregulation events can have a dramatic effect on the proper functioning of the pancreatic β-cells. The current review discusses the role of calcium signaling in health and disease in pancreatic β-cells and provides an in-depth look into the potential role of alterations in β-cell Ca2+ homeostasis and signaling in the development of diabetes and highlights recent work that introduced the current theories on the connection between calcium and the onset of diabetes.
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Minogue PJ, Beyer EC, Berthoud VM. CHOP is dispensable for lens transparency in wild-type and connexin50 mutant mice. Mol Vis 2019; 25:535-545. [PMID: 31908399 PMCID: PMC6925666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 07/03/2019] [Indexed: 11/29/2022] Open
Abstract
PURPOSE CCAAT/enhancer-binding homologous protein (CHOP), a transcription factor that has been implicated in differentiation, apoptosis, and autophagy, is greatly elevated in lenses with cataracts due to mutations of several different lens proteins. To test the possible role of CHOP in the cataractous lens, we studied the effect of knocking out Chop in mice that were homozygous for the Cx50D47A mutation of the lens fiber gap junction protein connexin50 (Cx50). METHODS Mouse lenses were examined by dark-field microscopy. Lens equatorial diameters and intensities of the opacities were quantified using ImageJ. Transcript levels were assessed by real-time quantitative PCR. Protein levels were determined by immunoblotting. RESULTS Homozygous Chop knockout lenses were transparent. Deletion of Chop in Cx50D47A mice did not improve lens transparency and had no effect on lens size. In Chop null-Cx50D47A lenses, the protein kinase R-like endoplasmic reticulum kinase (PERK)-dependent pathway was activated similarly to Cx50D47A lenses. In Cx50D47A mice, Chop deletion did not improve connexin levels or lens fiber cell differentiation, and it did not decrease the levels of Trib3 or Irs2 transcripts to wild-type values. However, homozygous Chop knockout significantly diminished the increased levels of Cebpb transcripts of Cx50D47A lenses. CONCLUSIONS The results show that CHOP is not required for lens transparency. They also suggest that CHOP is not the critical etiological factor for the cataracts observed in homozygous Cx50D47A lenses, further supporting a major role for connexins in the disease.
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Oleson BJ, Broniowska KA, Yeo CT, Flancher M, Naatz A, Hogg N, Tarakanova VL, Corbett JA. The Role of Metabolic Flexibility in the Regulation of the DNA Damage Response by Nitric Oxide. Mol Cell Biol 2019; 39:e00153-19. [PMID: 31235477 PMCID: PMC6712938 DOI: 10.1128/mcb.00153-19] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 05/07/2019] [Accepted: 06/18/2019] [Indexed: 12/24/2022] Open
Abstract
In this report, we show that nitric oxide suppresses DNA damage response (DDR) signaling in the pancreatic β-cell line INS 832/13 and rat islets by inhibiting intermediary metabolism. Nitric oxide is known to inhibit complex IV of the electron transport chain and aconitase of the Krebs cycle. Non-β cells compensate by increasing glycolytic metabolism to maintain ATP levels; however, β cells lack this metabolic flexibility, resulting in a nitric oxide-dependent decrease in ATP and NAD+ Like nitric oxide, mitochondrial toxins inhibit DDR signaling in β cells by a mechanism that is associated with a decrease in ATP. Non-β cells compensate for the effects of mitochondrial toxins with an adaptive shift to glycolytic ATP generation that allows for DDR signaling. Forcing non-β cells to derive ATP via mitochondrial respiration (replacing glucose with galactose in the medium) and glucose deprivation sensitizes these cells to nitric oxide-mediated inhibition of DDR signaling. These findings indicate that metabolic flexibility is necessary to maintain DDR signaling under conditions in which mitochondrial oxidative metabolism is inhibited and support the inhibition of oxidative metabolism (decreased ATP) as one protective mechanism by which nitric oxide attenuates DDR-dependent β-cell apoptosis.
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Affiliation(s)
- Bryndon J Oleson
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | | | - Chay Teng Yeo
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Michael Flancher
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Aaron Naatz
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Neil Hogg
- Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Vera L Tarakanova
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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Abstract
The loss of functional beta cell mass characterises all forms of diabetes. Beta cells are highly susceptible to stress, including cytokine, endoplasmic reticulum (ER) and oxidative stress. This study examined the role of pleckstrin homology-like, domain family A, member 3 (Phlda3) in beta cell survival under stress conditions and the regulatory basis. We found that the mRNA levels of Phlda3 were markedly upregulated in vivo in the islets of diabetic humans and mice. In vitro, exposure of MIN6 cells or islets to cytokines, palmitate, thapsigargin or ribose upregulated Phlda3 mRNA and protein levels, concurrent with the induction of ER stress (Ddit3 and Trb3) and antioxidant (Hmox1) genes. Furthermore, H2O2 treatment markedly increased PHLDA3 immunostaining in human islets. Phlda3 expression was differentially regulated by adaptive (Xbp1) and apoptotic (Ddit3) unfolded protein response (UPR) mediators. siRNA-mediated knockdown of Xbp1 inhibited the induction of Phlda3 by cytokines and palmitate, whereas knockdown of Ddit3 upregulated Phlda3. Moreover, knockdown of Phlda3 potentiated cytokine-induced apoptosis in association with upregulation of inflammatory genes (iNos, IL1β and IκBα) and NFκB phosphorylation and downregulation of antioxidant (Gpx1 and Srxn1) and adaptive UPR (Xbp1, Hspa5 and Fkbp11) genes. Knockdown of Phlda3 also potentiated apoptosis under oxidative stress conditions induced by ribose treatment. These findings suggest that Phlda3 is crucial for beta cell survival under stress conditions. Phlda3 regulates the cytokine, oxidative and ER stress responses in beta cells via the repression of inflammatory gene expression and the maintenance of antioxidant and adaptive UPR gene expression. Phlda3 may promote beta cell survival in diabetes.
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