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Jonsson A, Korsgren O, Hedin A. Transcriptomic characterization of human pancreatic CD206- and CD206 + macrophages. Sci Rep 2025; 15:12037. [PMID: 40199933 PMCID: PMC11978877 DOI: 10.1038/s41598-025-96313-y] [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: 11/26/2024] [Accepted: 03/27/2025] [Indexed: 04/10/2025] Open
Abstract
Macrophages reside in all organs and participate in homeostatic- and immune regulative processes. Little is known about pancreatic macrophage gene expression. In the present study, global gene expression was characterized in human pancreatic macrophage subpopulations. CD206- and CD206 + macrophages were sorted separately from pancreatic islets and exocrine tissue to high purity using flow cytometry, followed by RNA-seq analysis. Comparing CD206- with CD206 + macrophages, CD206- showed enrichment in histones, proliferation and cell cycle regulation, glycolysis and SPP1-associated immunosuppressive polarization while CD206 + showed enrichment in complement and coagulation-, IL-10 and IL-2RA immune regulation, as well as scavenging-related gene sets. Comparing islet CD206- with exocrine CD206-, enrichments in islet samples included two sets involved in immune regulation, while enrichments in exocrine samples included sets related to extracellular matrix and immune activation. Fewer differences were found between CD206 + macrophages, with enrichments in islet samples including two IL2-RA related gene sets, while enrichments in exocrine samples included sets related to extracellular matrix and immune activation. Comparing macrophages between individuals with normoglycemia, elevated HbA1c or type 2 diabetes, only a few diverse differentially expressed genes were identified. This work characterizes global gene expression and identifies differences between CD206- and CD206 + macrophage populations within the human pancreas.
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Affiliation(s)
- Alexander Jonsson
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Anders Hedin
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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2
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Ahmed I, Chakraborty R, Faizy AF, Moin S. Exploring the key role of DNA methylation as an epigenetic modulator in oxidative stress related islet cell injury in patients with type 2 diabetes mellitus: a review. J Diabetes Metab Disord 2024; 23:1699-1718. [PMID: 39610516 PMCID: PMC11599646 DOI: 10.1007/s40200-024-01496-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 08/21/2024] [Indexed: 11/30/2024]
Abstract
Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterised by impaired insulin secretion and action, often exacerbated by oxidative stress. Recent research has highlighted the intricate involvement of epigenetic mechanisms, particularly DNA methylation, in the pathogenesis of T2DM. This review aims to elucidate the role of DNA methylation as an epigenetic modifier in oxidative stress-mediated beta cell dysfunction, a key component of T2DM pathophysiology. Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defence mechanisms, is a hallmark feature of T2DM. Beta cells, responsible for insulin secretion, are particularly vulnerable to oxidative damage due to their low antioxidant capacity. Emerging evidence suggests that oxidative stress can induce aberrant DNA methylation patterns in beta cells, leading to altered gene expression profiles associated with insulin secretion and cell survival. Furthermore, studies have identified specific genes involved in beta cell function and survival that undergo DNA methylation changes in response to oxidative stress in T2DM. These epigenetic modifications can perpetuate beta cell dysfunction by dysregulating key pathways essential for insulin secretion, such as the insulin signalling cascade and mitochondrial function. Understanding the interplay between DNA methylation, oxidative stress, and beta cell dysfunction holds promise for developing novel therapeutic strategies for T2DM. Targeting aberrant DNA methylation patterns may offer new avenues for restoring beta cell function and improving glycemic control in patients with T2DM. However, further research is needed to elucidate the complex mechanisms underlying epigenetic regulation in T2DM and to translate these findings into clinical interventions.
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Affiliation(s)
- Istiaque Ahmed
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Ritoja Chakraborty
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Abul Faiz Faizy
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Shagufta Moin
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
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Simha N A, Patil SM, M K J, N C, Wong LS, Kijsomporn J, Raj R, Ramu R. From sugar binders to diabetes fighters: the lectin saga of antihyperglycemic activity through systematic review and meta-analysis. Front Pharmacol 2024; 15:1382876. [PMID: 39323638 PMCID: PMC11422237 DOI: 10.3389/fphar.2024.1382876] [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: 02/06/2024] [Accepted: 08/13/2024] [Indexed: 09/27/2024] Open
Abstract
Introduction Lectins are carbohydrate-binding proteins that are extremely selective for sugar groups in the other molecules. As a result, they perform a variety of roles in biological processes involving cell, carbohydrate, and protein recognition at the cellular and molecular levels. Because lectins can bind to carbohydrates, they may play a role in determining the rate of carbohydrate digestion. They also bind to some proteins involved in diabetes mellitus (DM) pathophysiology. The present review aims to summarize the efficiency of lectins from different sources as potential antihyperglycemic agents. Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were employed for the drafting. In this regard, published scientific articles on the effects of different lectins on blood glucose (BG), glucose tolerance, hormonal effects, carbohydrate-digesting enzymes, oxidative stress, and insulin production process were collected from reputed journals using electronic databases. Furthermore, the toxicity effects of lectins from different sources were collected. A specific keyword search was completed to collect numerous articles with unique experimental designs and significant results. This was followed by the selection of the requisite articles based on the criteria designed by the authors. Data extraction was based on the common research elements included in the articles. Results and Discussion Of 13 identified studies, 11 studies were considered after double screening based on the inclusion criteria. All 11 pharmacological investigations were considered for review. Subsequent studies reflected on the pharmacological properties of lectins on the levels of BG, oxidative stress, β-cell proliferation, insulin resistance, inhibition of carbohydrate digesting enzymes, body weight, food and water intake, lipid profile, and other parameters. This review highlights lectins as potential anti-diabetic agents. Conclusion However, due to limited research, systematic evaluation is recommended for their development and promotion as effective potential antihyperglycemic agents. The clinical efficacy and safety of lectins against diabetes mellitus must also be evaluated.
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Affiliation(s)
- Akshaya Simha N
- Department of Biotechnology and Bioinformatics, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
| | - Shashank M Patil
- Department of Biotechnology and Bioinformatics, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
| | - Jayanthi M K
- Department of Pharmacology, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
| | - Chaitra N
- Division of Medical Statistics, School of Life Sciences, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
| | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai, Malaysia
| | | | - Ranjith Raj
- Department of Pharmacology, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
| | - Ramith Ramu
- Department of Biotechnology and Bioinformatics, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
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Sionov RV, Ahdut-HaCohen R. A Supportive Role of Mesenchymal Stem Cells on Insulin-Producing Langerhans Islets with a Specific Emphasis on The Secretome. Biomedicines 2023; 11:2558. [PMID: 37761001 PMCID: PMC10527322 DOI: 10.3390/biomedicines11092558] [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: 08/15/2023] [Revised: 09/06/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by a gradual destruction of insulin-producing β-cells in the endocrine pancreas due to innate and specific immune responses, leading to impaired glucose homeostasis. T1D patients usually require regular insulin injections after meals to maintain normal serum glucose levels. In severe cases, pancreas or Langerhans islet transplantation can assist in reaching a sufficient β-mass to normalize glucose homeostasis. The latter procedure is limited because of low donor availability, high islet loss, and immune rejection. There is still a need to develop new technologies to improve islet survival and implantation and to keep the islets functional. Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic progenitor cells with high plasticity that can support human pancreatic islet function both in vitro and in vivo and islet co-transplantation with MSCs is more effective than islet transplantation alone in attenuating diabetes progression. The beneficial effect of MSCs on islet function is due to a combined effect on angiogenesis, suppression of immune responses, and secretion of growth factors essential for islet survival and function. In this review, various aspects of MSCs related to islet function and diabetes are described.
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Affiliation(s)
- Ronit Vogt Sionov
- The Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ronit Ahdut-HaCohen
- Department of Medical Neurobiology, Institute of Medical Research, Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel;
- Department of Science, The David Yellin Academic College of Education, Jerusalem 9103501, Israel
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Yudaeva AD, Stafeev IS, Michurina SS, Menshikov MY, Shestakova MV, Parfyonova YV. The interactions between inflammation and insulin resistance: molecular mechanisms in insulin-producing and insulin-dependent tissues. DIABETES MELLITUS 2023. [DOI: 10.14341/dm12981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
In the modern world the prevalence of obesity and type 2 diabetes mellitus (T2DM) significantly increases. In this light the risks of obesity-associated complications also grow up. The crucial linkage between obesity and its metabolic and cardiovascular complications is inflammatory process. The mechanism of this linkage is similar in pancreas and insulin-dependent tissues both on cells, cell-to-cell communication and signaling pathway levels: the catalysts are different lipids (cholesterol, free fatty acids, triglycerides), which are able to activate Toll-like receptors of innate immunity and inflammation. Nextly, IKK- and JNK-dependent cascades activate the secretion of inflammatory cytokines TNFa, IL-1b, IL-6 and others, which act by paracrine and autocrine manner and support inflammation both in local and systemic levels. Thus, insulin-producing and insulin-dependent tissues, which are involved in T2DM pathogenesis, through the inflammatory process integrate in pathogenic and self-maintaining cycle, which leads to the suppression of insulin secretion, pancreatic β-cell failure and the development of insulin-dependent tissues insulin resistance.
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Affiliation(s)
- A. D. Yudaeva
- National Medical Research Centre of Cardiology named after academician E.I.Chazov; Pirogov Russian National Research Medical University
| | - I. S. Stafeev
- National Medical Research Centre of Cardiology named after academician E.I.Chazov; Pirogov Russian National Research Medical University
| | - S. S. Michurina
- National Medical Research Centre of Cardiology named after academician E.I.Chazov; Lomonosov Moscow State University
| | - M. Yu. Menshikov
- National Medical Research Centre of Cardiology named after academician E.I.Chazov
| | | | - Y. V. Parfyonova
- National Medical Research Centre of Cardiology named after academician E.I.Chazov; Lomonosov Moscow State University
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Dinić S, Arambašić Jovanović J, Uskoković A, Mihailović M, Grdović N, Tolić A, Rajić J, Đorđević M, Vidaković M. Oxidative stress-mediated beta cell death and dysfunction as a target for diabetes management. Front Endocrinol (Lausanne) 2022; 13:1006376. [PMID: 36246880 PMCID: PMC9554708 DOI: 10.3389/fendo.2022.1006376] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/05/2022] [Indexed: 11/14/2022] Open
Abstract
The biggest drawback of a current diabetes therapy is the treatment of the consequences not the cause of the disease. Regardless of the diabetes type, preservation and recovery of functional pancreatic beta cells stands as the biggest challenge in the treatment of diabetes. Free radicals and oxidative stress are among the major mediators of autoimmune destruction of beta cells in type 1 diabetes (T1D) or beta cell malfunction and death provoked by glucotoxicity and insulin resistance in type 2 diabetes (T2D). Additionally, oxidative stress reduces functionality of beta cells in T2D by stimulating their de-/trans-differentiation through the loss of transcription factors critical for beta cell development, maturity and regeneration. This review summarizes up to date clarified redox-related mechanisms involved in regulating beta cell identity and death, underlining similarities and differences between T1D and T2D. The protective effects of natural antioxidants on the oxidative stress-induced beta cell failure were also discussed. Considering that oxidative stress affects epigenetic regulatory mechanisms involved in the regulation of pancreatic beta cell survival and insulin secretion, this review highlighted huge potential of epigenetic therapy. Special attention was paid on application of the state-of-the-art CRISPR/Cas9 technology, based on targeted epigenome editing with the purpose of changing the differentiation state of different cell types, making them insulin-producing with ability to attenuate diabetes. Clarification of the above-mentioned mechanisms could provide better insight into diabetes etiology and pathogenesis, which would allow development of novel, potentially more efficient therapeutic strategies for the prevention or reversion of beta cell loss.
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7
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Endocrine role of bone in the regulation of energy metabolism. Bone Res 2021; 9:25. [PMID: 34016950 PMCID: PMC8137703 DOI: 10.1038/s41413-021-00142-4] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 12/20/2020] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
Bone mainly functions as a supportive framework for the whole body and is the major regulator of calcium homeostasis and hematopoietic function. Recently, an increasing number of studies have characterized the significance of bone as an endocrine organ, suggesting that bone-derived factors regulate local bone metabolism and metabolic functions. In addition, these factors can regulate global energy homeostasis by altering insulin sensitivity, feeding behavior, and adipocyte commitment. These findings may provide a new pathological mechanism for related metabolic diseases or be used in the diagnosis, treatment, and prevention of metabolic diseases such as osteoporosis, obesity, and diabetes mellitus. In this review, we summarize the regulatory effect of bone and bone-derived factors on energy metabolism and discuss directions for future research.
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Nano E, Petropavlovskaia M, Rosenberg L. Islet neogenesis associated protein (INGAP) protects pancreatic β cells from IL-1β and IFNγ-induced apoptosis. Cell Death Discov 2021; 7:56. [PMID: 33731692 PMCID: PMC7969959 DOI: 10.1038/s41420-021-00441-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/06/2021] [Accepted: 02/14/2021] [Indexed: 11/11/2022] Open
Abstract
The goal of this study was to determine whether recombinant Islet NeoGenesis Associated Protein (rINGAP) and its active core, a pentadecapeptide INGAP104-118 (Ingap-p), protect β cells against cytokine-induced death. INGAP has been shown to induce islet neogenesis in diabetic animals, to stimulate β-cell proliferation and differentiation, and to improve islet survival and function. Importantly, Ingap-p has shown promising results in clinical trials for diabetes (phase I/II). However, the full potential of INGAP and its mechanisms of action remain poorly understood. Using rat insulinoma cells RINm5F and INS-1 treated with interleukin-1β (IL-1β) and interferon-gamma (IFN-γ), we demonstrate here that both rINGAP and Ingap-p inhibit apoptosis, Caspase-3 activation, inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, and explore the related signaling pathways. As expected, IL-1β induced nuclear factor kappa B (NF-κB), p38, and JNK signaling, whereas interferon-gamma (IFN-γ) activated the JAK2/STAT1 pathway and potentiated the IL-1β effects. Both rINGAP and Ingap-p decreased phosphorylation of IKKα/β, IkBα, and p65, although p65 nuclear translocation was not inhibited. rINGAP, used for further analysis, also inhibited STAT3, p38, and JNK activation. Interestingly, all inhibitory effects of rINGAP were observed for the cytokine cocktail, not IL-1β alone, and were roughly equal to reversing the potentiating effects of INFγ. Furthermore, rINGAP had no effect on IL-1β/NF-κB-induced gene expression (e.g., Ccl2, Sod2) but downregulated several IFNγ-stimulated (Irf1, Socs1, Socs3) or IFNγ-potentiated (Nos2) genes. This, however, was observed again only for the cytokine cocktail, not IFNγ alone, and rINGAP did not inhibit the IFNγ-induced JAK2/STAT1 activation. Together, these intriguing results suggest that INGAP does not target either IL-1β or IFNγ individually but rather inhibits the signaling crosstalk between the two, the exact mechanism of which remains to be investigated. In summary, our study characterizes the anti-inflammatory effects of INGAP, both protein and peptide, and suggests a new therapeutic utility for INGAP in the treatment of diabetes.
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Affiliation(s)
- Eni Nano
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Department of Surgery, Faculty of Medicine, McGill University, 3755, Cote Ste-Catherine Rd, Montreal, QC, H3T 1E2, Canada
| | - Maria Petropavlovskaia
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Department of Surgery, Faculty of Medicine, McGill University, 3755, Cote Ste-Catherine Rd, Montreal, QC, H3T 1E2, Canada.
| | - Lawrence Rosenberg
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Department of Surgery, Faculty of Medicine, McGill University, 3755, Cote Ste-Catherine Rd, Montreal, QC, H3T 1E2, Canada
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9
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Seiron P, Stenwall A, Hedin A, Granlund L, Esguerra JLS, Volkov P, Renström E, Korsgren O, Lundberg M, Skog O. Transcriptional analysis of islets of Langerhans from organ donors of different ages. PLoS One 2021; 16:e0247888. [PMID: 33711030 PMCID: PMC7954335 DOI: 10.1371/journal.pone.0247888] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 02/15/2021] [Indexed: 12/13/2022] Open
Abstract
Insulin secretion is impaired with increasing age. In this study, we aimed to determine whether aging induces specific transcriptional changes in human islets. Laser capture microdissection was used to extract pancreatic islet tissue from 37 deceased organ donors aged 1-81 years. The transcriptomes of the extracted islets were analysed using Ion AmpliSeq sequencing. 346 genes that co-vary significantly with age were found. There was an increased transcription of genes linked to senescence, and several aspects of the cell cycle machinery were downregulated with increasing age. We detected numerous genes not linked to aging in previous studies likely because earlier studies analysed islet cells isolated by enzymatic digestion which might affect the islet transcriptome. Among the novel genes demonstrated to correlate with age, we found an upregulation of SPP1 encoding osteopontin. In beta cells, osteopontin has been seen to be protective against both cytotoxicity and hyperglycaemia. In summary, we present a transcriptional profile of aging in human islets and identify genes that could affect disease course in diabetes.
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Affiliation(s)
- Peter Seiron
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Anton Stenwall
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Anders Hedin
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Louise Granlund
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | | | - Petr Volkov
- Department of Clinical Sciences-Malmö, Lund University Diabetes Centre, Malmö, Sweden
| | - Erik Renström
- Department of Clinical Sciences-Malmö, Lund University Diabetes Centre, Malmö, Sweden
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Marcus Lundberg
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Oskar Skog
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells. Nat Commun 2020; 11:5982. [PMID: 33239617 PMCID: PMC7689468 DOI: 10.1038/s41467-020-19657-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 10/16/2020] [Indexed: 12/12/2022] Open
Abstract
Expanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes. Pancreatic beta cells exhibit an age-dependent decrease in their proliferative activity, partly related to changes in the systemic environment. Here we report the identification of CCN4/Wisp1 as a circulating factor more abundant in pre-weaning than in adult mice. We show that Wisp1 promotes endogenous and transplanted adult beta cell proliferation in vivo. We validate these findings using isolated mouse and human islets and find that the beta cell trophic effect of Wisp1 is dependent on Akt signaling. In summary, our study reveals the role of Wisp1 as an inducer of beta cell replication, supporting the idea that the use of young blood factors may be a useful strategy to expand adult beta cell mass. The proliferation of pancreatic beta cells decreases with age, partly due to systemic changes. Here the authors identify Wisp1 as a circulating factor enriched in young serum that induces adult beta cell proliferation, supporting the idea that young blood factors may be useful to expand beta cell mass.
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Bal T, Inceoglu Y, Karaoz E, Kizilel S. Sensitivity Study for the Key Parameters in Heterospheroid Preparation with Insulin-Secreting β-Cells and Mesenchymal Stem Cells. ACS Biomater Sci Eng 2019; 5:5229-5239. [DOI: 10.1021/acsbiomaterials.9b00570] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Tuğba Bal
- Chemical and Biological Engineering, Koc University, 34450 Sariyer, Istanbul, Turkey
| | - Yasemin Inceoglu
- Chemical and Biological Engineering, Koc University, 34450 Sariyer, Istanbul, Turkey
| | - Erdal Karaoz
- Center for Regenerative Medicine and Stem Cell Research, Liv Hospital, 34340 Besiktas, Istanbul, Turkey
- School of Medicine, Istinye University, 34010 Zeytinburnu, Istanbul, Turkey
| | - Seda Kizilel
- Chemical and Biological Engineering, Koc University, 34450 Sariyer, Istanbul, Turkey
- Biomedical Science and Engineering, Koc University, 34450 Sariyer, Istanbul, Turkey
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12
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Tsalamandris S, Antonopoulos AS, Oikonomou E, Papamikroulis GA, Vogiatzi G, Papaioannou S, Deftereos S, Tousoulis D. The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives. Eur Cardiol 2019; 14:50-59. [PMID: 31131037 PMCID: PMC6523054 DOI: 10.15420/ecr.2018.33.1] [Citation(s) in RCA: 810] [Impact Index Per Article: 135.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 02/18/2019] [Indexed: 02/06/2023] Open
Abstract
Diabetes is a complex metabolic disorder affecting the glucose status of the human body. Chronic hyperglycaemia related to diabetes is associated with end organ failure. The clinical relationship between diabetes and atherosclerotic cardiovascular disease is well established. This makes therapeutic approaches that simultaneously target diabetes and atherosclerotic disease an attractive area for research. The majority of people with diabetes fall into two broad pathogenetic categories, type 1 or type 2 diabetes. The role of obesity, adipose tissue, gut microbiota and pancreatic beta cell function in diabetes are under intensive scrutiny with several clinical trials to have been completed while more are in development. The emerging role of inflammation in both type 1 and type 2 diabetes (T1D and T1D) pathophysiology and associated metabolic disorders, has generated increasing interest in targeting inflammation to improve prevention and control of the disease. After an extensive review of the possible mechanisms that drive the metabolic pattern in T1D and T2D and the inflammatory pathways that are involved, it becomes ever clearer that future research should focus on a model of combined suppression for various inflammatory response pathways.
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Affiliation(s)
- Sotirios Tsalamandris
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Alexios S Antonopoulos
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Evangelos Oikonomou
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - George-Aggelos Papamikroulis
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Georgia Vogiatzi
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Spyridon Papaioannou
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Spyros Deftereos
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Dimitris Tousoulis
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
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Molecular Connection Between Diabetes and Dementia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1128:103-131. [DOI: 10.1007/978-981-13-3540-2_6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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14
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Icer MA, Gezmen-Karadag M. The multiple functions and mechanisms of osteopontin. Clin Biochem 2018; 59:17-24. [PMID: 30003880 DOI: 10.1016/j.clinbiochem.2018.07.003] [Citation(s) in RCA: 392] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 07/03/2018] [Accepted: 07/08/2018] [Indexed: 12/12/2022]
Abstract
Osteopontin (OPN) is a highly phosphorylated glycophosphoprotein having acidic characteristics and rich in aspartic acid. OPN, a multifunctional protein, has important functions on cardiovascular diseases, cancer, diabetes and kidney stone diseases and in the process of inflammation, biomineralization, cell viability and wound healing. Osteopontin acts on organisms by playing a key role in secretion levels of interleukin-10 (IL-10), interleukin-12 (IL-12), interleukin-3 (IL-3), interferon-γ (IFN-γ), integrin αvB3, nuclear factor kappa B (NF-kB), macrophage and T cells, regulating the osteoclast function and affecting CD44 receptors. The aim of the present review is to address majority of different functions of OPN protein which are known, suspected or suggested through the data obtained about this protein yet.
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Affiliation(s)
- Mehmet Arif Icer
- Gazi University, Faculty of Health Sciences, Nutrition and Dietetics Department, 06500 Beşevler, Ankara, Turkey.
| | - Makbule Gezmen-Karadag
- Gazi University, Faculty of Health Sciences, Nutrition and Dietetics Department, 06500 Beşevler, Ankara, Turkey.
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Rojas J, Bermudez V, Palmar J, Martínez MS, Olivar LC, Nava M, Tomey D, Rojas M, Salazar J, Garicano C, Velasco M. Pancreatic Beta Cell Death: Novel Potential Mechanisms in Diabetes Therapy. J Diabetes Res 2018; 2018:9601801. [PMID: 29670917 PMCID: PMC5836465 DOI: 10.1155/2018/9601801] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 11/15/2017] [Accepted: 12/06/2017] [Indexed: 02/07/2023] Open
Abstract
PURPOSE OF REVIEW Describing the diverse molecular mechanisms (particularly immunological) involved in the death of the pancreatic beta cell in type 1 and type 2 diabetes mellitus. RECENT FINDINGS Beta cell death is the final event in a series of mechanisms that, up to date, have not been entirely clarified; it represents the pathophysiological mechanism in the natural history of diabetes mellitus. These mechanisms are not limited to an apoptotic process only, which is characteristic of the immune-mediated insulitis in type 1 diabetes mellitus. They also include the action of proinflammatory cytokines, the production of reactive oxygen species, DNA fragmentation (typical of necroptosis in type 1 diabetic patients), excessive production of islet amyloid polypeptide with the consequent endoplasmic reticulum stress, disruption in autophagy mechanisms, and protein complex formation, such as the inflammasome, capable of increasing oxidative stress produced by mitochondrial damage. SUMMARY Necroptosis, autophagy, and pyroptosis are molecular mechanisms that modulate the survival of the pancreatic beta cell, demonstrating the importance of the immune system in glucolipotoxicity processes and the potential role for immunometabolism as another component of what once known as the "ominous octet."
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Affiliation(s)
- Joselyn Rojas
- Pulmonary and Critical Care Medicine Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Endocrine and Metabolic Research Center, University of Zulia, Maracaibo, Venezuela
| | - Valmore Bermudez
- Endocrine and Metabolic Research Center, University of Zulia, Maracaibo, Venezuela
- Grupo de Investigación Altos Estudios de Frontera (ALEF), Universidad Simón Bolívar, Cúcuta, Colombia
| | - Jim Palmar
- Endocrine and Metabolic Research Center, University of Zulia, Maracaibo, Venezuela
| | - María Sofía Martínez
- Endocrine and Metabolic Research Center, University of Zulia, Maracaibo, Venezuela
| | - Luis Carlos Olivar
- Endocrine and Metabolic Research Center, University of Zulia, Maracaibo, Venezuela
| | - Manuel Nava
- Endocrine and Metabolic Research Center, University of Zulia, Maracaibo, Venezuela
| | - Daniel Tomey
- Endocrine and Metabolic Research Center, University of Zulia, Maracaibo, Venezuela
| | - Milagros Rojas
- Endocrine and Metabolic Research Center, University of Zulia, Maracaibo, Venezuela
| | - Juan Salazar
- Endocrine and Metabolic Research Center, University of Zulia, Maracaibo, Venezuela
| | - Carlos Garicano
- Grupo de Investigación Altos Estudios de Frontera (ALEF), Universidad Simón Bolívar, Cúcuta, Colombia
| | - Manuel Velasco
- Clinical Pharmacology Unit. School of Medicine José María Vargas, Central University of Venezuela, Caracas, Venezuela
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Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases? Int J Mol Sci 2017; 19:ijms19010007. [PMID: 29267211 PMCID: PMC5795959 DOI: 10.3390/ijms19010007] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 12/11/2017] [Accepted: 12/19/2017] [Indexed: 12/15/2022] Open
Abstract
Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed.
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Role of osteopontin and its regulation in pancreatic islet. Biochem Biophys Res Commun 2017; 495:1426-1431. [PMID: 29180017 DOI: 10.1016/j.bbrc.2017.11.147] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 11/22/2017] [Indexed: 12/20/2022]
Abstract
Osteopontin (OPN) is involved in various physiological processes and also implicated in multiple pathological states. It has been suggested that OPN may have a role in type 2 diabetes (T2D) by protecting pancreatic islets and interaction with incretins. However, the regulation and function of OPN in islets, especially in humans, remains largely unexplored. In this study, we performed our investigations on both diabetic mouse model SUR1-E1506K+/+ and islets from human donors. We demonstrated that OPN protein, secretion and gene expression was elevated in the diabetic SUR1-E1506K+/+ islets. We also showed that high glucose and incretins simultaneously stimulated islet OPN secretion. In islets from human cadaver donors, OPN gene expression was elevated in diabetic islets, and externally added OPN significantly increased glucose-stimulated insulin secretion (GSIS) from diabetic but not normal glycemic donors. The increase in GSIS by OPN in diabetic human islets was Ca2+ dependent, which was abolished by Ca2+-channel inhibitor isradipine. Furthermore, we also confirmed that OPN promoted cell metabolic activity when challenged by high glucose. These observations provided evidence on the protective role of OPN in pancreatic islets under diabetic condition, and may point to novel therapeutic targets for islet protection in T2D.
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Roberts DD, Kaur S, Isenberg JS. Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer. Antioxid Redox Signal 2017; 27:874-911. [PMID: 28712304 PMCID: PMC5653149 DOI: 10.1089/ars.2017.7140] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 07/11/2017] [Accepted: 07/13/2017] [Indexed: 12/15/2022]
Abstract
SIGNIFICANCE In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H2S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H2S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. CRITICAL ISSUES Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. FUTURE DIRECTIONS Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.
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Affiliation(s)
- David D. Roberts
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sukhbir Kaur
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Jeffrey S. Isenberg
- Division of Pulmonary, Allergy and Critical Care, Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Fang C, Huang Y, Pei Y, Zhang HH, Chen X, Guo H, Li S, Ji X, Hu J. Genome-wide gene expression profiling reveals that CD274 is up-regulated new-onset type 1 diabetes mellitus. Acta Diabetol 2017; 54:757-767. [PMID: 28577136 DOI: 10.1007/s00592-017-1005-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 05/19/2017] [Indexed: 11/25/2022]
Abstract
AIMS Early studies have identified type 1 diabetes mellitus (T1DM) as a disease that is caused by the autoimmune destruction of the insulin-producing pancreatic β-cells. Genetics, environment and the immune pathogenesis of T1DM are three major pillars of T1DM research. We try to understand the changes in the gene expression profile during the pathogenesis of T1DM. METHODS We performed a systematic search in the Gene Expression Omnibus (GEO) database for microarray studies of T1DM with samples taken at or before the T1DM onset. RESULTS The results of an integrated analysis of different GEO datasets and a comparison of the gene expression level in T1DM samples taken at the time of appearance of the islet autoantibodies, 1 year before T1DM onset, and at the time of T1DM onset showed that CD274, which encodes PD-L1, was up-regulated in the newly onset T1DM samples. CD274 had a stable expression level in the control samples but showed a gradual up-regulation from the appearance of autoantibodies to the onset of T1DM. CONCLUSIONS These results indicate that CD274 up-regulation in T1DM is correlated with disease pathogenesis. PD-L1 might play a protective role in preventing the pancreatic islets from autoimmune destruction, which may help researchers find strategies for preventing the destruction process of pancreas β-cells in T1DM.
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Affiliation(s)
- Chen Fang
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China
| | - Yun Huang
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China
| | - Yufang Pei
- Department of Epidemiology and Health Statistics, School of Public Health, Medical College, Soochow University, Suzhou, 215003, Jiangsu, China
| | - Hong-Hong Zhang
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China
| | - Xiaohong Chen
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China
| | - Heming Guo
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China
| | - Sicheng Li
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China
| | - Xiaoyan Ji
- Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, Suzhou, 215000, Jiangsu, China.
- Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215123, Jiangsu, China.
| | - Ji Hu
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China.
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215123, Jiangsu, China.
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Dickerson MT, Vierra NC, Milian SC, Dadi PK, Jacobson DA. Osteopontin activates the diabetes-associated potassium channel TALK-1 in pancreatic β-cells. PLoS One 2017; 12:e0175069. [PMID: 28403169 PMCID: PMC5389796 DOI: 10.1371/journal.pone.0175069] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 03/20/2017] [Indexed: 12/17/2022] Open
Abstract
Glucose-stimulated insulin secretion (GSIS) relies on β-cell Ca2+ influx, which is modulated by the two-pore-domain K+ (K2P) channel, TALK-1. A gain-of-function polymorphism in KCNK16, the gene encoding TALK-1, increases risk for developing type-2 diabetes. While TALK-1 serves an important role in modulating GSIS, the regulatory mechanism(s) that control β-cell TALK-1 channels are unknown. Therefore, we employed a membrane-specific yeast two-hybrid (MYTH) assay to identify TALK-1-interacting proteins in human islets, which will assist in determining signaling modalities that modulate TALK-1 function. Twenty-one proteins from a human islet cDNA library interacted with TALK-1. Some of these interactions increased TALK-1 activity, including intracellular osteopontin (iOPN). Intracellular OPN is highly expressed in β-cells and is upregulated under pre-diabetic conditions to help maintain normal β-cell function; however, the functional role of iOPN in β-cells is poorly understood. We found that iOPN colocalized with TALK-1 in pancreatic sections and coimmunoprecipitated with human islet TALK-1 channels. As human β-cells express two K+ channel-forming variants of TALK-1, regulation of these TALK-1 variants by iOPN was assessed. At physiological voltages iOPN activated TALK-1 transcript variant 3 channels but not TALK-1 transcript variant 2 channels. Activation of TALK-1 channels by iOPN also hyperpolarized resting membrane potential (Vm) in HEK293 cells and in primary mouse β-cells. Intracellular OPN was also knocked down in β-cells to test its effect on β-cell TALK-1 channel activity. Reducing β-cell iOPN significantly decreased TALK-1 K+ currents and increased glucose-stimulated Ca2+ influx. Importantly, iOPN did not affect the function of other K2P channels or alter Ca2+ influx into TALK-1 deficient β-cells. These results reveal the first protein interactions with the TALK-1 channel and found that an interaction with iOPN increased β-cell TALK-1 K+ currents. The TALK-1/iOPN complex caused Vm hyperpolarization and reduced β-cell glucose-stimulated Ca2+ influx, which is predicted to inhibit GSIS.
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Affiliation(s)
- Matthew T. Dickerson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Nicholas C. Vierra
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Sarah C. Milian
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Prasanna K. Dadi
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - David A. Jacobson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
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Osteopontin Affects Insulin Vesicle Localization and Ca2+ Homeostasis in Pancreatic Beta Cells from Female Mice. PLoS One 2017; 12:e0170498. [PMID: 28107503 PMCID: PMC5249066 DOI: 10.1371/journal.pone.0170498] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 12/15/2016] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetic patients suffer from insulin resistance and reduced insulin secretion. Osteopontin (OPN), a versatile protein expressed in several tissues throughout the body including the islets of Langerhans, has previously been implicated in the development of insulin resistance. Here we have investigated the role of OPN in insulin secretion using an OPN knock out mouse model (OPN-/-). Ultra-structural analyzes of islets from OPN-/- and WT mice indicated weaker cell-cell connections between the islet cells in the OPN-/- mouse compared to WT. Analysis of the insulin granule distribution in the beta cells showed that although OPN-/- and WT beta cells have the same number of insulin granules OPN-/- beta cells have significantly fewer docked granules. Both OPN-/- and WT islets displayed synchronized Ca2+ oscillations indicative of an intact beta cell communication. OPN-/- islets displayed higher intracellular Ca2+ concentrations when stimulated with 16.7 mM glucose than WT islets and the initial dip upon elevated glucose concentrations (which is associated with Ca2+ uptake into ER) was significantly lower in these islets. Glucose-induced insulin secretion was similar in OPN-/- and WT islets. Likewise, non-fasted blood glucose levels were the same in both groups. In summary, deletion of OPN results in several minor beta-cell defects that can be compensated for in a healthy system.
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22
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Broom L, Jenner P, Rose S. Increased neurotrophic factor levels in ventral mesencephalic cultures do not explain the protective effect of osteopontin and the synthetic 15-mer RGD domain against MPP+ toxicity. Exp Neurol 2014; 263:1-7. [PMID: 25218309 DOI: 10.1016/j.expneurol.2014.09.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Revised: 09/02/2014] [Accepted: 09/05/2014] [Indexed: 01/13/2023]
Abstract
The synthetic 15-mer arginine-glycine-aspartic acid (RGD) domain of osteopontin (OPN) is protective in vitro and in vivo against dopaminergic cell death and this protective effect may be mediated through interaction with integrin receptors to regulate neurotrophic factor levels. We now examine this concept in rat primary ventral mesencephalic (VM) cultures. 1-Methyl-4-phenylpyridinium (MPP+) exposure reduced tyrosine hydroxylase (TH)-positive cell number and activated glial cells as shown by increased glial fibrillary acidic protein (GFAP), oxycocin-42 (OX-42) and ectodermal dysplasia 1 (ED-1) immunoreactivity. Both OPN and the RGD domain of OPN were equally protective against MPP+ toxicity in VM cultures and both increased glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) levels. The effects of OPN and the RGD domain were accompanied by a decrease in numbers of activated microglia but with no change in astrocyte number. However, full-length OPN and the RGD domain of OPN remained protective against MPP+ toxicity in the presence of a GDNF neutralising antibody. This suggests that increased GDNF levels do not underlie the protective effect observed with OPN. Rather, OPN's protective effect may be mediated through decreased glial cell activation.
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Affiliation(s)
- Lauren Broom
- Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King's College London, London, SE1 1UL, UK.
| | - Peter Jenner
- Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King's College London, London, SE1 1UL, UK
| | - Sarah Rose
- Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King's College London, London, SE1 1UL, UK
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Akash MSH, Rehman K, Chen S. Role of inflammatory mechanisms in pathogenesis of type 2 diabetes mellitus. J Cell Biochem 2013; 114:525-31. [PMID: 22991242 DOI: 10.1002/jcb.24402] [Citation(s) in RCA: 258] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 09/11/2012] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by progressive β-cell dysfunctioning and insulin resistance. This article reviews recent literature with special focus on inflammatory mechanisms that provoke the pathogenesis of T2DM. We have focused on the recent advances in progression of T2DM including various inflammatory mechanisms that might induce inflammation, insulin resistance, decrease insulin secretion from pancreatic islets and dysfunctioning of β-cells. Here we have also summarized the role of various pro-inflammatory mediators involved in inflammatory mechanisms, which may further alter the normal structure of β-cells by inducing pancreatic islet's apoptosis. In conclusion, it is suggested that the role of inflammation in pathogenesis of T2DM is crucial and cannot be neglected. Moreover, the insight of inflammatory responses in T2DM may provide a new gateway for the better treatment of diabetes mellitus.
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Affiliation(s)
- Muhammad Sajid Hamid Akash
- Institute of Pharmacology, Toxicology, and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
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Hasegawa K, Wakino S, Kimoto M, Minakuchi H, Fujimura K, Hosoya K, Komatsu M, Kaneko Y, Kanda T, Tokuyama H, Hayashi K, Itoh H. The hydrolase DDAH2 enhances pancreatic insulin secretion by transcriptional regulation of secretagogin through a Sirt1-dependent mechanism in mice. FASEB J 2013; 27:2301-15. [PMID: 23430976 DOI: 10.1096/fj.12-226092] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The role of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in glucose metabolism is unknown. Here, we generated DDAH2 transgenic (Tg) mice. These mice had lower plasma glucose levels (60 min: 298±32 vs. 418±35 mg/dl; 120 min: 205±15 vs. 284±20 mg/dl) and higher insulin levels (15 min: 2.1±0.2 vs. 1.5±0.1 ng/ml; 30 min: 1.8±0.1 vs. 1.5±0.1 ng/ml) during intraperitoneal glucose tolerance tests when fed a high-fat diet (HFD) compared with HFD-fed wild-type (WT) mice. Glucose-stimulated insulin secretion (GSIS) was increased in Tg islets by 33%. Pancreatic asymmetrical dimethylarginine, nitric oxide, and oxidative stress levels were not correlated with improvements in insulin secretion in Tg mice. Secretagogin, an insulin vesicle docking protein, was up-regulated by 2.7-fold in Tg mice and in pancreatic MIN-6 cells overexpressing DDAH2. GSIS in MIN-6 cells was dependent on DDAH2-induced secretagogin expression. Pancreatic Sirt1, DDAH2, and secretagogin were down-regulated in HFD-fed WT mice by 70, 75, and 85%, respectively. Overexpression of Sirt1 overexpression by 3.9-fold increased DDAH2 and secretagogin expression in MIN-6 cells by 3.2- and 2.5-fold, respectively. DDAH2 overexpression improved GSIS in pancreas-specific Sirt1-deficient mice. In summary, the Sirt1/DDAH2/secretagogin pathway is a novel regulator of GSIS.
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Affiliation(s)
- Kazuhiro Hasegawa
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
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Cho JM, Chang SY, Kim DB, Needs PW, Jo YH, Kim MJ. Effects of physiological quercetin metabolites on interleukin-1β-induced inducible NOS expression. J Nutr Biochem 2012; 23:1394-402. [DOI: 10.1016/j.jnutbio.2011.08.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Revised: 08/17/2011] [Accepted: 08/30/2011] [Indexed: 11/26/2022]
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Lyssenko V, Eliasson L, Kotova O, Pilgaard K, Wierup N, Salehi A, Wendt A, Jonsson A, De Marinis YZ, Berglund LM, Taneera J, Balhuizen A, Hansson O, Osmark P, Dunér P, Brøns C, Stancáková A, Kuusisto J, Bugliani M, Saxena R, Ahlqvist E, Kieffer TJ, Tuomi T, Isomaa B, Melander O, Sonestedt E, Orho-Melander M, Nilsson P, Bonetti S, Bonadonna R, Miccoli R, Delprato S, Marchetti P, Madsbad S, Poulsen P, Vaag A, Laakso M, Gomez MF, Groop L. Pleiotropic effects of GIP on islet function involve osteopontin. Diabetes 2011; 60:2424-33. [PMID: 21810601 PMCID: PMC3161325 DOI: 10.2337/db10-1532] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies. Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of β-cell viability and proliferation. RESULTS The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. CONCLUSIONS These findings support β-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional β-cell mass in humans.
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Affiliation(s)
- Valeriya Lyssenko
- Diabetes and Endocrinology, Department of Clinical Sciences, University Hospital Malmö, Lund University, Malmö, Sweden.
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Recombinant osteopontin attenuates brain injury after intracerebral hemorrhage in mice. Neurocrit Care 2011; 14:109-17. [PMID: 20440599 DOI: 10.1007/s12028-010-9372-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Osteopontin (OPN), an extracellular matrix glycoprotein, has been reported to inhibit inducible nitric oxide synthase (iNOS). We examined if recombinant OPN (r-OPN) inhibits iNOS and prevents brain injury in a mouse collagenase-induced intracerebral hemorrhage (ICH) model. METHODS One hundred one mice were randomly assigned to five groups: sham, ICH + vehicle, ICH + r-OPN (10, 50, or 100 ng per mouse) groups. Vehicle or r-OPN was administered via an intracerebroventricular infusion 20 min pre-ICH. Neurological scores and brain water content were evaluated at 24 and 72 h, and hemoglobin assay, Nissl staining and Western blot for iNOS, Stat1, matrix metalloproteinase (MMP)-9 and zonula occludens (ZO)-1 were performed at 24 h post-ICH. RESULTS r-OPN did not affect hematoma formation. Middle (50 ng)- and high (100 ng)-dose, but not low (10 ng)-dose of r-OPN treatment significantly improved neurological scores and brain water content compared with the vehicle group. The protective effect of r-OPN was associated with significantly rescued neuronal cells in the peri-hematoma region as well as a decrease in the Stat1 phosphorylation, iNOS induction, MMP-9 activation, and ZO-1 degradation. CONCLUSIONS This study suggests that r-OPN may down-regulate iNOS expression by the inhibition of Stat1 phosphorylation, and therefore suppressing the MMP-9 activation, preventing ICH-induced brain injury in mice.
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Xiong X, Wang X, Li B, Chowdhury S, Lu Y, Srikant CB, Ning G, Liu JL. Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus. Am J Physiol Endocrinol Metab 2011; 300:E669-80. [PMID: 21245462 DOI: 10.1152/ajpendo.00600.2010] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Reg family proteins have been implicated in islet β-cell proliferation, survival, and regeneration. The expression of Reg3β (pancreatitis-associated protein) is highly induced in experimental diabetes and acute pancreatitis, but its precise role has not been established. Through knockout studies, this protein was shown to be mitogenic, antiapoptotic, and anti-inflammatory in the liver and pancreatic acinars. To test whether it can promote islet cell growth or survival against experimental damage, we developed β-cell-specific overexpression using rat insulin I promoter, evaluated the changes in normal islet function, gene expression profile, and the response to streptozotocin-induced diabetes. Significant and specific overexpression of Reg3β was achieved in the pancreatic islets of RIP-I/Reg3β mice, which exhibited normal islet histology, β-cell mass, and in vivo and in vitro insulin secretion in response to high glucose yet were slightly hyperglycemic and low in islet GLUT2 level. Upon streptozotocin treatment, in contrast to wild-type littermates that became hyperglycemic in 3 days and lost 15% of their weight, RIP-I/Reg3β mice were significantly protected from hyperglycemia and weight loss. To identify specific targets affected by Reg3β overexpression, a whole genome DNA microarray on islet RNA isolated from the transgenic mice revealed more than 45 genes significantly either up- or downregulated. Among them, islet-protective osteopontin/SPP1 and acute responsive nuclear protein p8/NUPR1 were significantly induced, a result further confirmed by real-time PCR, Western blots, and immunohistochemistry. Our results suggest that Reg3β is unlikely an islet growth factor but a putative protector that prevents streptozotocin-induced damage by inducing the expression of specific genes.
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Affiliation(s)
- Xiaoquan Xiong
- Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
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Effect of recombinant osteopontin on cerebral vasospasm after subarachnoid hemorrhage in rats. ACTA NEUROCHIRURGICA. SUPPLEMENT 2011; 110:29-32. [PMID: 21125441 DOI: 10.1007/978-3-7091-0356-2_6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/28/2023]
Abstract
BACKGROUND osteopontin (OPN), a pleiotropic extracellular matrix glycoprotein, has been reported to have neuroprotective effects against early brain injury after subarachnoid hemorrhage (SAH). The aim of this study is to examine if osteopontin prevents cerebral vasospasm after SAH in rats. METHOD the endovascular perforation model of SAH was produced, and 62 rats were randomly assigned to sham + vehicle, SAH + vehicle, and SAH+ r-OPN (0.1 microg) groups. Cerebral vasospasm was evaluated by India ink angiography at 24 and 72 h after SAH, as well as neurobehavioral tests. FINDINGS significant vasospasm and neurological impairments occurred over the observed period after SAH. r-OPN significantly prevented vasospasm in the left middle cerebral artery at 24 h and improved neurological impairments at 48 h after SAH. In other time points studied, r-OPN had a tendency toward improving both vasospasm and neurological scores, but the difference was not significant. CONCLUSIONS this study shows that r-OPN has anti-vasospastic effects against cerebral vasospasm after SAH.
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Suzuki H, Ayer R, Sugawara T, Chen W, Sozen T, Hasegawa Y, Kanamaru K, Zhang JH. Role of osteopontin in early brain injury after subarachnoid hemorrhage in rats. ACTA NEUROCHIRURGICA. SUPPLEMENT 2011; 110:75-79. [PMID: 21116919 DOI: 10.1007/978-3-7091-0353-1_14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
BACKGROUND Subarachnoid hemorrhage (SAH)-induced early brain injury (EBI) contributes to delayed ischemic neurological deficits, one of whose key pathologic manifestation is the blood-brain barrier (BBB) disruption. Although post-SAH BBB breakdown is a self-repairable phenomenon, the molecular pathways are unknown. We determined the role of osteopontin (OPN), a pleiotropic extracellular matrix glycoprotein, in the post-SAH BBB disruption in rats. METHOD First, we produced the endovascular perforation model of SAH and studied if OPN is induced in the brain after SAH. Secondly, we examined the effects of blockage of endogenous OPN induction on neurological impairments and BBB disruption. Thirdly, we evaluated the effects of exogenous OPN on neurological impairments, brain edema and BBB disruption, and the related protein expression levels. FINDINGS OPN was significantly induced and peaked at 72 h after SAH, in the recovery phase of EBI. OPN small interfering RNA significantly aggravated neurological impairment and BBB disruption 72 h after SAH. Exogenous OPN significantly prevented neurological impairment, brain edema and BBB disruption associated with the deactivation of nuclear factor-κB activity, the inhibition of matrix metalloproteinase (MMP)-9 induction and tissue inhibitor of MMP-1 reduction, and the consequent preservation of cerebral microvessel basal lamina protein laminin and tight junction protein zona occludens-1. CONCLUSIONS These findings suggest the protective effects of OPN against BBB disruption after SAH, a finding which should provide a novel therapeutic approach for post-SAH EBI.
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Affiliation(s)
- Hidenori Suzuki
- Department of Physiology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA
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Suzuki H, Hasegawa Y, Chen W, Kanamaru K, Zhang JH. Recombinant osteopontin in cerebral vasospasm after subarachnoid hemorrhage. Ann Neurol 2010; 68:650-60. [PMID: 21031580 DOI: 10.1002/ana.22102] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
OBJECTIVE Osteopontin (OPN), a pleiotropic extracellular matrix glycoprotein, has been reported to be protective against ischemic lesions, but effects of OPN on vascular functions have not been investigated. The aim of this study was to assess whether recombinant OPN (r-OPN) could prevent cerebral vasospasm after subarachnoid hemorrhage (SAH) in rats. METHODS r-OPN was administered intraventricularly to rats undergoing SAH by endovascular perforation, and its protective effects were evaluated by measuring the diameter of cerebral arteries and neurobehavioral testing. Western blotting and immunofluorescence were performed to explore the underlying mechanisms. An integrin receptor antagonist GRGDSP or mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 small interfering RNA (siRNA) was also administered to r-OPN-treated SAH rats, and those effects were evaluated. RESULTS Pre-SAH administration of r-OPN prevented vasospasm and neurological impairments at 24-72 hours post-SAH. r-OPN enhanced an endogenous MAPK inhibitor, MKP-1, and suppressed the phosphorylation of MAPKs, caldesmon, and heat shock protein 27 in the spastic cerebral arteries at 24 hours post-SAH. Immunofluorescence revealed that MKP-1 was induced in the arterial smooth muscle layer. GRGDSP prevented r-OPN-induced MKP-1 upregulation, and MKP-1 siRNA abolished both MAPK inactivation and anti-vasospastic effects by r-OPN. Post-SAH r-OPN treatment also prevented vasospasm. INTERPRETATION r-OPN induced MKP-1 in the spastic cerebral arteries via binding to L-arginyl-glycyl-L-aspartate-dependent integrin receptors and prevented vasospasm after SAH. Therapeutic induction of MKP-1 may be a novel approach for the prevention and treatment of cerebral vasospasm.
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Affiliation(s)
- Hidenori Suzuki
- Department of Physiology, Loma Linda University of Medicine, Loma Linda, CA 92354, USA
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Bai-Feng L, Yong-Feng L, Ying C. Silencing inducible nitric oxide synthase protects rat pancreatic islet. Diabetes Res Clin Pract 2010; 89:268-75. [PMID: 20541824 DOI: 10.1016/j.diabres.2010.05.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2010] [Revised: 05/13/2010] [Accepted: 05/17/2010] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To investigate the effect of inducible nitric oxide synthase (iNOS) RNA interference on cytokine-induced injury of pancreatic islet in rats. MATERIALS AND METHODS Islets from Wistar rats were cultured in vitro and then randomly divided into five groups: group A, islets were cultured exclusively; group B, islets were transfected with negative control siRNA; group C, islets were transfected with iNOS siRNA; group D, islets were transfected with iNOS siRNA and then treated with TNF-alpha+IL-1beta; group E, islets were treated with TNF-alpha+IL-1beta. The expression of iNOS, Bax and Fas was determined by RT-PCR and Western blot. The viability of islet was examined by AO/EB staining and function was examined by glucose-stimulated insulin secretion (GSIS) assay. RESULTS The expression of iNOS and the promoting apoptosis gene Bax and Fas were significantly up-regulated by the induction of IL-1beta and TNF-alpha. Thus they led to apoptosis increase and the insulin secretion index decrease (1.87+/-0.31 vs 3.83+/-1.40, P<0.01). Silencing iNOS by RNAi prevented the up-regulation of Bax and Fas induced by cytokine, thus reduced apoptosis of islets and recovered the insulin secretion index (3.43+/-0.24 vs 1.87+/-0.31, P<0.01). CONCLUSION The apoptosis from cytokines to islets mediated by iNOS could be suppressed by RNA interference, which favors the survival and function of islets.
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Affiliation(s)
- Li Bai-Feng
- Department of General Surgery, The First Hospital of China Medical University, North Nanjing Street No 155, Shenyang 110001, Liaoning Province, China.
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Karaoz E, Genç ZS, Demircan PÇ, Aksoy A, Duruksu G. Protection of rat pancreatic islet function and viability by coculture with rat bone marrow-derived mesenchymal stem cells. Cell Death Dis 2010; 1:e36. [PMID: 21364643 PMCID: PMC3032304 DOI: 10.1038/cddis.2010.14] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Revised: 03/10/2010] [Accepted: 03/18/2010] [Indexed: 02/06/2023]
Abstract
The maintenance of viable and functional islets is critical in successful pancreatic islet transplantation from cadaveric sources. During the isolation procedure, islets are exposed to a number of insults including ischemia, oxidative stress and cytokine injury that cause a reduction in the recovered viable islet mass. A novel approach was designed in which streptozotocin (STZ)-damaged rat pancreatic islets (rPIs) were indirectly cocultured with rat bone marrow-derived mesenchymal stem cells (rBM-MSCs) to maintain survival of the cultured rPIs. The results indicated that islets cocultured with rBM-MSCs secreted an increased level of insulin after 14 days, whereas non-cocultured islets gradually deteriorated and cell death occurred. The cocultivation of rBM-MSCs with islets and STZ-damaged islets showed the expression of IL6 and transforming growth factor-β1 in the culture medium, besides the expression of the antiapoptotic genes (Mapkapk2, Tnip1 and Bcl3), implying the cytoprotective, anti-inflammatory and antiapoptotic effects of rBM-SCs through paracrine actions.
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Affiliation(s)
- E Karaoz
- Stem Cell and Gene Therapy Research and Application Center, Kocaeli University, Kocaeli, Turkey.
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Protective effects of recombinant osteopontin on early brain injury after subarachnoid hemorrhage in rats. Crit Care Med 2010; 38:612-8. [PMID: 19851092 DOI: 10.1097/ccm.0b013e3181c027ae] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Accumulated evidence suggests that the primary cause of poor outcome after subarachnoid hemorrhage is not only cerebral arterial narrowing but also early brain injury. Our objective was to determine the effect of recombinant osteopontin, a pleiotropic extracellular matrix glycoprotein, on early brain injury after subarachnoid hemorrhage in rats. DESIGN Controlled in vivo laboratory study. SETTING Animal research laboratory. SUBJECTS One hundred seventy-seven male adult Sprague-Dawley rats weighing 300 to 370 g. INTERVENTIONS The endovascular perforation model of subarachnoid hemorrhage was produced. Subarachnoid hemorrhage or sham-operated rats were treated with an equal volume (1 microL) of pre-subarachnoid hemorrhage intracerebroventricular administration of two dosages (0.02 and 0.1 microg) of recombinant osteopontin, albumin, or vehicle. Body weight, neurologic scores, brain edema, and blood-brain barrier disruption were evaluated, and Western blot analyses were performed to determine the effect of recombinant osteopontin on matrix metalloproteinase-9, substrates of matrix metalloproteinase-9 (zona occludens-1, laminin), tissue inhibitor of matrix metalloproteinase-1, inflammation (interleukin-1beta), and nuclear factor-kappaB signaling pathways. MEASUREMENTS AND MAIN RESULTS Treatment with recombinant osteopontin prevented a significant loss in body weight, neurologic impairment, brain edema, and blood-brain barrier disruption after subarachnoid hemorrhage. These effects were associated with the deactivation of nuclear factor-kappaB activity, inhibition of matrix metalloproteinase-9 induction, the maintenance of tissue inhibitor of matrix metalloproteinase-1, the consequent preservation of the cerebral microvessel basal lamina protein laminin, and the tight junction protein zona occludens-1. CONCLUSIONS These results demonstrate that recombinant osteopontin treatment is effective for early brain injury after subarachnoid hemorrhage.
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Wang C, Guan Y, Yang J. Cytokines in the Progression of Pancreatic β-Cell Dysfunction. Int J Endocrinol 2010; 2010:515136. [PMID: 21113299 PMCID: PMC2989452 DOI: 10.1155/2010/515136] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2010] [Revised: 08/05/2010] [Accepted: 10/07/2010] [Indexed: 12/29/2022] Open
Abstract
The dysfunction of pancreatic β-cell and the reduction in β-cell mass are the decisive events in the progression of type 2 diabetes. There is increasing evidence that cytokines play important roles in the procedure of β-cell failure. Cytokines, such as IL-1β, IFN-γ, TNF-α, leptin, resistin, adiponectin, and visfatin, have been shown to diversely regulate pancreatic β-cell function. Recently, islet-derived cytokine PANcreatic DERived factor (PANDER or FAM3B) has also been demonstrated to be a regulator of islet β-cell function. The change in cytokine profile in islet and plasma is associated with pancreatic β-cell dysfunction and apoptosis. In this paper, we summarize and discuss the recent studies on the effects of certain important cytokines on pancreatic β-cell function. The imbalance in deleterious and protective cytokines plays pivotal roles in the development and progression of pancreatic β-cell dysfunction under insulin-resistant conditions.
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Affiliation(s)
- Chunjiong Wang
- Department of Physiology and Pathophysiology, Peking University Diabetes Center, Peking University Health Science Center, Beijing 100191, China
| | - Youfei Guan
- Department of Physiology and Pathophysiology, Peking University Diabetes Center, Peking University Health Science Center, Beijing 100191, China
| | - Jichun Yang
- Department of Physiology and Pathophysiology, Peking University Diabetes Center, Peking University Health Science Center, Beijing 100191, China
- *Jichun Yang:
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Interleukin-1 receptor antagonist enhances islet engraftment without impacting serum levels of nitrite or osteopontin. Transplant Proc 2009; 41:1781-5. [PMID: 19545727 DOI: 10.1016/j.transproceed.2008.10.099] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2008] [Accepted: 10/06/2008] [Indexed: 01/12/2023]
Abstract
Interleukin-1beta (IL-1beta)-mediated early islet graft dysfunction and loss of islet mass can occur in different phylogenic types of islet transplantation. Large quantities of interleukin-1 receptor antagonist (IL-1RA) have been demonstrated to impede IL-1beta-mediated adverse effects on islet grafts in allo- and xenotransplantation. To clarify the influence of IL-1RA on early function and mass change, as well as long-term hypoglycemic effects of islet isografts, we studied streptozotocin-induced diabetic C57BL/6 mice infected with replication-defective adenovirus carrying the mouse IL-1RA cDNA gene. This vector increased the mean serum level of IL-1RA to 8 ng/mL, approximately three times greater than for mice receiving adenovirus carrying the beta-galactosidase (beta-Gal) gene. The blood glucose levels declined faster and the insulin content of the graft was significantly higher on day 10 following transplantation among mice receiving mIL-1RA gene than the controls. Nevertheless, the insulin content of the pancreatic remnant did not differ among mice in the IL-1RA, beta-Gal, and vehicle control groups. Serum levels of nitrite and osteopontin before and 3 days after islet transplantation did not differ considerably among the IL-1RA, beta-Gal, and vehicle groups. Compared with the beta-Gal group, temporary posttransplantation hyperglycemia was significantly shortened in the IL-1RA group mice. Removal of graft-bearing kidneys at 13 weeks following transplantation caused recurrence of hyperglycemia in all treated diabetic mice. The insulin content of pancreatic remnants removed at 15 weeks following transplantation was similar in the IL-1RA and beta-Gal groups. In conclusion, a mildly elevated serum concentration of IL-1RA protected and enhanced engraftment of islet isografts immediately after transplantation.
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Anderson AA, Helmering J, Juan T, Li CM, McCormick J, Graham M, Baker DM, Damore MA, Véniant MM, Lloyd DJ. Pancreatic islet expression profiling in diabetes-prone C57BLKS/J mice reveals transcriptional differences contributed by DBA loci, including Plagl1 and Nnt. PATHOGENETICS 2009; 2:1. [PMID: 19161594 PMCID: PMC2642818 DOI: 10.1186/1755-8417-2-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2008] [Accepted: 01/22/2009] [Indexed: 01/21/2023]
Abstract
Background C57BLKS/J (BLKS) mice are susceptible to islet exhaustion in insulin-resistant states as compared with C57BL6/J (B6) mice, as observed by the presence of the leptin receptor (Lepr) allele, Leprdb/db. Furthermore, DBA2/J (DBA) mice are also susceptible to β-cell failure and share 25% of their genome with BLKS; thus the DBA genome may contribute to β-cell dysfunction in BLKS mice. Results Here we show that BLKS mice exhibit elevated insulin secretion, as evidenced by improved glucose tolerance and increased islet insulin secretion compared with B6 mice, and describe interstrain transcriptional differences in glucose response. Transcriptional differences between BLKS and B6 mice were identified by expression profiling of isolated islets from both strains. Genomic mapping of gene expression differences demonstrated a significant association of expression differences with DBA loci in BLKS mice (P = 4×10-27). Conclusion Two genes, Nicotinamide nucleotide transhydrogenase (Nnt) and Pleiomorphic adenoma gene like 1 (Plagl1), were 4 and 7.2-fold higher respectively in BLKS islets, and may be major contributors to increased insulin secretion by BLKS islets. Contrary to reports for B6 mice, BLKS mice do not harbor a mutant Nnt gene. We detected 16 synonymous polymorphisms and a two-amino acid deletion in the Plagl1 gene in BLKS mice. Several inflammatory glucose-responsive genes are expressed at a higher level in BLKS, suggesting an inflammatory component to BLKS islet dysfunction. This study describes physiological differences between BLKS and B6 mice, and provides evidence for a causative role of the DBA genome in β-cell dysfunction in BLKS mice.
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Affiliation(s)
- Abraham A Anderson
- Department of Computational Biology, Amgen Inc,, One Amgen Center Dr, Thousand Oaks, CA 91320, USA.
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Li BF, Liu YF, Cheng Y, Zhang KZ, Li TM, Zhao N. Protective effect of inducible nitric oxide synthase inhibitor on pancreas transplantation in rats. World J Gastroenterol 2008; 13:6066-71. [PMID: 18023101 PMCID: PMC4250892 DOI: 10.3748/wjg.v13.45.6066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of inducible nitric oxide synthase inhibitor, aminoguanidine, on pancreas transplantation in rats. METHODS A model of pancreas transplantation was established in rats. Streptozotocin-induced diabetic male Wistar rats were randomly assigned to sham-operation control group (n = 6), transplant control group (n = 6), and aminoguanidine (AG) treatment group (n = 18). In the AG group, aminoguanidine was added to intravascular infusion as the onset of reperfusion at the dose of 60 mg/kg, 80 mg/kg, 100 mg/kg body weight, respectively. Serum nitric oxide (NO) level, blood sugar and amylase activity were detected. Nitric oxide synthase (NOS) test kit was used to detect the pancreas cNOS and inducible NOS (iNOS) activity. Pancreas sections stained with HE and immunohistochemistry were evaluated under a light microscope. RESULTS As compared with the transplant control group, the serum NO level and amylase activity decreased obviously and the evidence for pancreas injury was much less in the AG group. The AG (80 mg/kg body weight) group showed the most significant difference in NO and amylase (NO: 66.0 +/- 16.6 vs 192.3 +/- 60.0, P < 0.01 and amylase: 1426 +/- 177 vs 4477 +/- 630, P < 0.01). The expression and activity of tissue iNOS, and blood sugar in the AG (80 mg/kg body weight) group were much lower than those in the transplant control group (iNOS: 2.01 +/- 0.23 vs 26.59 +/- 5.78, P < 0.01 and blood sugar: 14.2 +/- 0.9 vs 16.8 +/- 1.1, P < 0.01). CONCLUSION Selective iNOS inhibitor, aminoguanidine as a free radical, has a protective effect on pancreas transplantation in rats by inhibiting NO and reducing its toxicity.
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Affiliation(s)
- Bai-Feng Li
- Department of Surgery and Organ Transplant Unit, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
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Wang KX, Shi Y, Denhardt DT. Osteopontin regulates hindlimb-unloading-induced lymphoid organ atrophy and weight loss by modulating corticosteroid production. Proc Natl Acad Sci U S A 2007; 104:14777-82. [PMID: 17785423 PMCID: PMC1976226 DOI: 10.1073/pnas.0703236104] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Osteopontin (OPN), a multifunctional secreted phosphoglycoprotein, plays diverse roles in bone biology, immune regulation, cell survival, inflammation, and cancer metastasis. Here we show its role in determining lymphocyte homeostasis and body mass in response to hindlimb unloading (HU), a model for evaluating effects of weightlessness on the musculoskeletal and other physiological systems. Using this stress model, we compared OPN(-/-) mice with OPN(+/+) mice subjected to HU for 3 days. Whereas OPN(+/+) mice suffered a marked reduction of body weight and significant spleen and thymus atrophy, OPN(-/-) mice exhibited minor weight loss and much less spleen and thymus atrophy. The HU-induced lymphoid organ atrophy was the result of dramatically diminished numbers, respectively, of T and B cells in the spleen and CD4(+)CD8(+) double-positive cells in the thymus of OPN(+/+) mice. Increased levels of corticosterone, which modulates lymphocyte activation responses and apoptosis during stress, were found only in OPN(+/+) mice. Apoptotic cell death was evident in the spleen and thymus of OPN(+/+) mice subjected to HU but not in OPN(-/-)mice. Importantly, lymphocytes from both OPN(+/+) and OPN(-/-) mice were equally sensitive to corticosteroid-induced apoptosis. These results reveal that OPN is required for enhanced corticosterone production, immune organ atrophy, and weight loss in mice subjected to HU.
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Affiliation(s)
| | - Yufang Shi
- Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854
| | - David T. Denhardt
- *Graduate Program in Cell and Developmental Biology
- Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey, Nelson Biological Laboratories, 604 Allison Road, Piscataway, NJ 08854; and
- To whom correspondence should be addressed at:
Nelson Laboratories, 604 Allison Road, Piscataway, NJ 08854. E-mail:
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