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1
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Chong ZZ, Souayah N. Neuroinflammation in diabetic peripheral neuropathy and therapeutic implications. Rev Neurosci 2025:revneuro-2025-0031. [PMID: 40228523 DOI: 10.1515/revneuro-2025-0031] [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: 02/25/2025] [Accepted: 03/28/2025] [Indexed: 04/16/2025]
Abstract
Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes mellitus, which is a common cause of disability in individuals with diabetes mellitus. Multiple mechanisms may be involved in the development of DPN. Neuroinflammation is a critical factor contributing to nerve damage during diabetes. Inflammation can induce the development of diabetes mellitus, and long-term hyperglycemia also causes increased oxidative stress and promotes the release of inflammatory cytokines. After reading through the literature, the association of inflammation with the induction of diabetes and DPN was discussed in the review. Inflammation induces nerve damage and nerve conduction impairment. The neuropathic pain in diabetes-induced DPN is also closely associated with the inflammatory response. Given the important roles of inflammation in diabetes-induced DPN, explicit elucidation of neuroinflammation during diabetes mellitus and DPN should hold the potential for developing novel therapeutic strategies for DPN. Experimental studies and limited clinical trials support the value of anti-inflammatory reagents in treating DPN, and the positive outcomes of these investigations warrant further clinical trials.
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Affiliation(s)
- Zhao Zhong Chong
- Department of Neurology, New Jersey Medical School, Rutgers University, 185 S Orange, Newark, NJ 07103, USA
| | - Nizar Souayah
- Department of Neurology, New Jersey Medical School, Rutgers University, 90 Bergen Street DOC 8100, Newark, NJ 07101, USA
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2
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Moya-Gudiño V, Altamirano-Bustamante NF, Revilla-Monsalve C, Altamirano-Bustamante MM. Decoding the Contribution of IAPP Amyloid Aggregation to Beta Cell Dysfunction: A Systematic Review and Epistemic Meta-Analysis of Type 1 Diabetes. Int J Mol Sci 2025; 26:767. [PMID: 39859479 PMCID: PMC11766435 DOI: 10.3390/ijms26020767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/30/2024] [Accepted: 12/31/2024] [Indexed: 01/27/2025] Open
Abstract
Diabetes Mellitus Type 1 (DM1) is an autoimmune disease characterized by the destruction of beta cells in the pancreas. Although amyloid formation has been well-studied in Diabetes Mellitus Type 2 (DM2), its role in DM1 remains unclear. Understanding how islet amyloid polypeptide (IAPP) contributes to beta cell dysfunction and death in DM1 could provide critical insights into disease mechanisms and pave the way for novel diagnostic and therapeutic strategies. A systematic review and epistemic meta-analysis was conducted using a modified PICO framework, focusing on studies related to DM1 and the IAPP aggregation process. Searches in PubMed, BIREME, and Web of Science yielded 37 relevant articles, which were analyzed and individually evaluated based on specific quality criteria. Studies that experimentally identified the formation of IAPP oligomers in DM1 were selected, along with relevant review articles. Experimental studies from human and animal models detected the presence of IAPP oligomers in DM1 patients, as well as in nonobese diabetic (NOD) and homozygous mice. Techniques like Western Blot (WB), Transmission Electron Microscopy (TEM) and Congo red staining detected various oligomers sizes, with smaller ones showing higher cytotoxicity. IAPP oligomers have been detected in the pancreatic islets of DM1 patients, contributing to beta cell damage and disease progression.
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Affiliation(s)
- Valeria Moya-Gudiño
- Unidad de Investigación en Enfermedades Metabólicas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (V.M.-G.); (C.R.-M.)
| | | | - Cristina Revilla-Monsalve
- Unidad de Investigación en Enfermedades Metabólicas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (V.M.-G.); (C.R.-M.)
| | - Myriam M. Altamirano-Bustamante
- Unidad de Investigación en Enfermedades Metabólicas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (V.M.-G.); (C.R.-M.)
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3
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Menefee K, Larios K, Rinauro DJ, Tun A, Jauregui B, Contreras JI, Nogaj LA, Moffet DA. Identifying the Role of Individual Seal IAPP Amino Acids in Inhibiting the Aggregation of Human IAPP. Protein Pept Lett 2025; 32:44-53. [PMID: 39660516 DOI: 10.2174/0109298665340227241115110404] [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: 08/18/2024] [Revised: 10/11/2024] [Accepted: 10/16/2024] [Indexed: 12/12/2024]
Abstract
INTRODUCTION The progression of type 2 diabetes in humans appears to be linked to the loss of insulin-producing β-cells. One of the major contributors to β-cell loss is the formation of toxic human IAPP amyloid (hIAPP, Islet Amyloid Polypeptide, amylin) in the pancreas. Inhibiting the formation of toxic hIAPP amyloid could slow, if not prevent altogether, the progression of type 2 diabetes. Many non-human organisms also express amyloidogenic IAPP variants known to kill pancreatic cells and give rise to diabetes-like symptoms. Surprisingly, some of these non-human IAPP variants function as inhibitors of hIAPP aggregation, raising the possibility of developing non-human IAPP peptides into anti-diabetic therapeutic peptides. One such inhibitory IAPP variant is seal IAPP, which has been shown to inhibit hIAPP aggregation. Seal IAPP only differs from hIAPP by three amino acids. In this study, each of the six seal/human IAPP permutations was analyzed to identify the role of each of the three amino acid positions in inhibiting hIAPP aggregation. AIMS This study aimed to identify the minimal amino acid substitutions to yield a peptide inhibitor of human IAPP aggregation. OBJECTIVE The goal of the study was to determine the minimal amino acid substitutions necessary to convert human IAPP into an amyloid-inhibiting peptide. METHODS The formation of toxic hIAPP amyloid was monitored using Thioflavin T binding assays, atomic force microscopy, and MTT cell rescue studies. RESULTS One seal IAPP variant retained amyloid-inhibition activity, and two variants appeared to be more amyloidogenic and toxic than wild-type human IAPP. CONCLUSION These results suggest that inhibition of hIAPP requires both the H18R and F23L substitutions of hIAPP.
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Affiliation(s)
- Kate Menefee
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA90045, USA
| | - Kelsy Larios
- Department of Biology, Mount Saint Mary's University, 12001 Chalon Drive, Los Angeles, CA90049, USA
| | - Dillon J Rinauro
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA90045, USA
| | - Angela Tun
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA90045, USA
| | - Betssy Jauregui
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA90045, USA
| | - Jessica I Contreras
- Department of Biology, Mount Saint Mary's University, 12001 Chalon Drive, Los Angeles, CA90049, USA
| | - Luiza A Nogaj
- Department of Biology, Mount Saint Mary's University, 12001 Chalon Drive, Los Angeles, CA90049, USA
| | - David A Moffet
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA90045, USA
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Lu X, Xie Q, Pan X, Zhang R, Zhang X, Peng G, Zhang Y, Shen S, Tong N. Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy. Signal Transduct Target Ther 2024; 9:262. [PMID: 39353925 PMCID: PMC11445387 DOI: 10.1038/s41392-024-01951-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/21/2024] [Accepted: 08/06/2024] [Indexed: 10/03/2024] Open
Abstract
Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet β cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and β cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet β cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. There is currently no cure for T2D, but it can be prevented or in remission by lifestyle intervention and/or some medication. If prevention fails, holistic and personalized management should be taken as soon as possible through timely detection and diagnosis, considering target organ protection, comorbidities, treatment goals, and other factors in reality. T2D is often accompanied by other components of MDS, such as preobesity/obesity, metabolic dysfunction associated steatotic liver disease, dyslipidemia, which usually occurs before it, and they are considered as the upstream diseases of T2D. It is more appropriate to call "diabetic complications" as "MDS-related target organ damage (TOD)", since their development involves not only hyperglycemia but also other metabolic disorders of MDS, promoting an up-to-date management philosophy. In this review, we aim to summarize the underlying mechanism, screening, diagnosis, prevention, and treatment of T2D, especially regarding the personalized selection of hypoglycemic agents and holistic management based on the concept of "MDS-related TOD".
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Affiliation(s)
- Xi Lu
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Qingxing Xie
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaohui Pan
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Ruining Zhang
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyi Zhang
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Ge Peng
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Yuwei Zhang
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Sumin Shen
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Nanwei Tong
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China.
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Chong ZZ, Menkes DL, Souayah N. Targeting neuroinflammation in distal symmetrical polyneuropathy in diabetes. Drug Discov Today 2024; 29:104087. [PMID: 38969091 DOI: 10.1016/j.drudis.2024.104087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 06/24/2024] [Accepted: 07/01/2024] [Indexed: 07/07/2024]
Abstract
Diabetic distal symmetric polyneuropathy is the most common type of peripheral neuropathy complication of diabetes mellitus. Neuroinflammation is emerging as an important contributor to diabetes-induced neuropathy. Long-term hyperglycemia results in increased production of advanced glycation end products (AGEs). AGEs interact with their receptors to activate intracellular signaling, leading to the release of various inflammatory cytokines. Increased release of inflammatory cytokines is associated with diabetes, diabetic neuropathy, and neuropathic pain. Thus, anti-inflammatory intervention is a potential therapy for diabetic distal symmetric polyneuropathy. Further characterization of inflammatory mechanisms might identify novel therapeutic targets to mitigate diabetic neuropathy.
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Affiliation(s)
- Zhao Zhong Chong
- Department of Neurology, Rutgers University, New Jersey Medical School, Newark, NJ 07103, USA.
| | - Daniel L Menkes
- Department of Neurology, Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA
| | - Nizar Souayah
- Department of Neurology, Rutgers University, New Jersey Medical School, Newark, NJ 07103, USA.
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Bi J, Zhou W, Tang Z. Pathogenesis of diabetic complications: Exploring hypoxic niche formation and HIF-1α activation. Biomed Pharmacother 2024; 172:116202. [PMID: 38330707 DOI: 10.1016/j.biopha.2024.116202] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 01/11/2024] [Accepted: 01/22/2024] [Indexed: 02/10/2024] Open
Abstract
Hypoxia is a common feature of diabetic tissues, which highly correlates to the progression of diabetes. The formation of hypoxic context is induced by disrupted oxygen homeostasis that is predominantly driven by vascular remodeling in diabetes. While different types of vascular impairments have been reported, the specific features and underlying mechanisms are yet to be fully understood. Under hypoxic condition, cells upregulate hypoxia-inducible factor-1α (HIF-1α), an oxygen sensor that coordinates oxygen concentration and cell metabolism under hypoxic conditions. However, diabetic context exploits this machinery for pathogenic functions. Although HIF-1α protects cells from diabetic insult in multiple tissues, it also jeopardizes cell function in the retina. To gain a deeper understanding of hypoxia in diabetic complications, we focus on the formation of tissue hypoxia and the outcomes of HIF-1α dysregulation under diabetic context. Hopefully, this review can provide a better understanding on hypoxia biology in diabetes.
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Affiliation(s)
- Jingjing Bi
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education,Southwest Medical University, Ministry of Education, Southwest Medical University, Luzhou, China
| | - Wenhao Zhou
- Yucebio Technology Co., Ltd., Shenzhen, China
| | - Zonghao Tang
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education,Southwest Medical University, Ministry of Education, Southwest Medical University, Luzhou, China; Baylor College of Medicine, Department of Molecular and Cellular Biology, Houston, TX, USA.
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Tang J, Chen X, Shi H, Zhang M, Zhou Z, Zhang C, Ke T, Kong D, Li C. Prebiotic inulin nanocoating for pancreatic islet surface engineering. Biomater Sci 2023; 11:1470-1485. [PMID: 36602201 DOI: 10.1039/d2bm01009g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Pancreatic islet surface engineering has been proposed as an "easy-to-adopt" approach to enhance post-transplantation islet engraftment for treatment against diabetes. Inulin is an FDA-approved dietary prebiotic with reported anti-diabetic, anti-inflammatory, anti-hypoxic and pro-angiogenic properties. We therefore assessed whether inulin would be a viable option for islet surface engineering. Inulin was oxidized to generate inulin-CHO, which would bind to the cell membrane via covalent bond formation between -CHO and -NH2 across the islet cell membrane. In vitro assessments demonstrated enhanced islet viability and better glucose-induced insulin secretion from inulin-coated (5 mg mL-1) islets, which was accompanied by enhanced revascularization, shown as significantly enhanced tube formation and branching of islet endothelial MS1 cells following co-culture with inulin-coated islets. Reduction of cytokine-induced cell death was also observed from inulin-coated islets following exposure to pro-inflammatory cytokine LPS. LPS-induced ROS production was significantly dampened by 44% in inulin-coated islets when compared to controls. RNA-seq analysis of inulin-coated and control islets identified expression alterations of genes involved in islet function, vascular formation and immune regulation, supporting the positive impact of inulin on islet preservation. In vivo examination using streptozotocin (STZ)-induced hyperglycemic mice further showed moderately better maintained plasma glucose levels in mice received transplantation of inulin-coated islets, attributable to ameliorated CD45+ immune cell infiltration and improved in vivo graft vascularization. We therefore propose islet surface engineering with inulin as safe and beneficial, and further assessment is required to verify its applicability in clinical islet transplantation.
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Affiliation(s)
- Jianghai Tang
- Tianjin Key Laboratory of Biomedical Materials, Biomedical Barriers Research Center, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
| | - Xuanjin Chen
- Tianjin Key Laboratory of Biomedical Materials, Biomedical Barriers Research Center, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
| | - Hang Shi
- Tianjin Key Laboratory of Biomedical Materials, Biomedical Barriers Research Center, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
| | - Mingming Zhang
- Tianjin Key Laboratory of Biomedical Materials, Biomedical Barriers Research Center, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
| | - Zhimin Zhou
- Tianjin Key Laboratory of Biomedical Materials, Biomedical Barriers Research Center, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
| | - Chuangnian Zhang
- Tianjin Key Laboratory of Biomedical Materials, Biomedical Barriers Research Center, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
| | - Tingyu Ke
- Department of Endocrinology, The Second Affiliated Hospital of Kunming Medical University, Yunnan 650101, China
| | - Deling Kong
- Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Centre of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
| | - Chen Li
- Tianjin Key Laboratory of Biomedical Materials, Biomedical Barriers Research Center, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
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8
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A new polymorphism of human amylin fibrils with similar protofilaments and a conserved core. iScience 2022; 25:105705. [PMID: 36567711 PMCID: PMC9772857 DOI: 10.1016/j.isci.2022.105705] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/07/2022] [Accepted: 11/29/2022] [Indexed: 12/04/2022] Open
Abstract
Pancreatic amyloid deposits composed of a fibrillar form of the human islet amyloid polypeptide (hIAPP) are the pathological hallmark of type 2 diabetes (T2D). Although various cryo-EM structures of polymorphic hIAPP fibrils were reported, the underlying polymorphic mechanism of hIAPP remains elusive. Meanwhile, the structure of hIAPP fibrils with all residues visible in the fibril core is not available. Here, we report the full-length structures of two different polymorphs of hIAPP fibrils, namely slim form (SF, dimer) and thick form (TF, tetramer), formed in a salt-free environment, which share a similar ζ-shaped protofilament but differ in inter-protofilament interfaces. In the absence of salt, electrostatic interactions were found to play a dominant role in stabilizing the fibril structure, suggesting an antagonistic effect between electrostatic and hydrophobic interactions in different salt concentrations environments. Our results shed light on understanding the mechanism of amyloid fibril polymorphism.
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Miller ME, Li MH, Baghai A, Peetz VH, Zhyvoloup A, Raleigh DP. Analysis of Sheep and Goat IAPP Provides Insight into IAPP Amyloidogenicity and Cytotoxicity. Biochemistry 2022; 61:2531-2545. [PMID: 36286531 PMCID: PMC11132794 DOI: 10.1021/acs.biochem.2c00470] [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] [Indexed: 11/29/2022]
Abstract
Human islet amyloid polypeptide (hIAPP) plays a role in glucose regulation but forms pancreatic amyloid deposits in type 2 diabetes, and that process contributes to β-cell dysfunction. Not all species develop diabetes, and not all secrete an IAPP that is amyloidogenic in vitro under normal conditions, a perfect correlation currently exists between both. Studies of IAPPs from such organisms can provide clues about the high amyloidogenicity of hIAPP and can inform the design of soluble analogues of hIAPP. Sheep and goat IAPP are among the most divergent from hIAPP, with 13 and 11 substitutions, respectively, including an unusual Tyr to His substitution at the C-terminus. The properties of sheep and goat IAPP were examined in solution and in the presence of anionic vesicles, resulting in no observed amyloid formation, even at increased concentrations. Furthermore, both peptides are considerably less toxic to cultured β-cells than hIAPP. The effect of the Y37H replacements was studied in the context of hIAPP, as was a Y37R substitution. Buffer- and salt-dependent effects were observed. There was little impact on the time to form amyloid in phosphate-buffered saline; however, a significant deceleration was observed in Tris buffer, and amyloid formation was slower in the absence of added salt. The Y37H substitution had little impact on toxicity, while the Y37R replacement led to a 30% decrease in toxicity compared with that of hIAPP. The implications for the amyloidogenicity of hIAPP and the design of soluble analogues of the human peptide are discussed.
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Affiliation(s)
- Matthew E.T. Miller
- Department of Chemistry, Stony Brook University, Nicolls Road, Stony Brook, New York 11790, United States
| | - Ming-Hao Li
- Graduate Program in Biochemistry and Structural Biology, Stony Brook University, Stony Brook, New York 11790, United States
| | - Aria Baghai
- Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom
| | - Vincent H. Peetz
- Department of Chemistry, Stony Brook University, Nicolls Road, Stony Brook, New York 11790, United States
| | - Alexander Zhyvoloup
- Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom
| | - Daniel P. Raleigh
- Department of Chemistry, Stony Brook University, Nicolls Road, Stony Brook, New York 11790, United States
- Graduate Program in Biochemistry and Structural Biology, Stony Brook University, Stony Brook, New York 11790, United States
- Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom
- Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York 11794, United States
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10
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Manathunga L, Zhyvoloup A, Baghai A, Raleigh DP. Differential Effects of Aromatic Residues on Amyloid Formation and Cytotoxicity of Human IAPP. Biochemistry 2022; 61:2334-2343. [PMID: 36215164 PMCID: PMC11132793 DOI: 10.1021/acs.biochem.2c00267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Islet amyloid polypeptide (IAPP) is a 37-residue polypeptide hormone secreted by the pancreatic β-cells. IAPP plays a role in glycemic regulation, but in the pre-type-2 diabetic state, it aggregates to form an islet amyloid. The process of islet amyloid formation contributes to β-cell dysfunction and disease progression. The features of the IAPP sequence that modulate amyloid formation are still not understood. Human IAPP contains three aromatic residues, F15, F23, and Y37. F15 and Y37 are highly conserved, while F23 is more commonly a Leu or Ile in other species. The role of the aromatic residues in modulating the time course of amyloid formation and the cytotoxicity was examined using aromatic to Leu mutations. All three single and double mutants and the triple mutant were studied. F23 plays a dominant role in both amyloid formation and toxicity. An F15L mutant accelerated amyloid formation, a Y37L mutant had little effect, while an F23L replacement slowed amyloid formation by a factor of 2.6. Double mutants, which contained an F23L replacement, had a larger effect than those that did not, and there are non-additive effects between pairs of aromatic residues. F23 also plays a key role in toxicity. Single or multiple mutants that contain the F23L replacement were noticeably less toxic than the wild-type or mutants which did not include the F23L substitution. In contrast, the F15L mutant was more toxic than the wild-type one. The implications for IAPP amyloid formation and for the design of non-aggregating analogues of IAPP are discussed.
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Affiliation(s)
- Lakshan Manathunga
- Deartment of Chemistry, Stony Brook University, Nicolls Road, Stony Brook, New York 11790, United States
- Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York 11794, United States
| | - Alexander Zhyvoloup
- Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom
| | - Aria Baghai
- Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom
| | - Daniel P. Raleigh
- Deartment of Chemistry, Stony Brook University, Nicolls Road, Stony Brook, New York 11790, United States
- Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom
- Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York 11794, United States
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11
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Yang H, Li J, Li X, Ma L, Hou M, Zhou H, Zhou R. Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies. Front Mol Neurosci 2022; 15:927530. [PMID: 36117918 PMCID: PMC9470852 DOI: 10.3389/fnmol.2022.927530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Amyloid-β (Aβ) has long been considered as one of the most important pathogenic factors in Alzheimer’s disease (AD), but the specific pathogenic mechanism of Aβ is still not completely understood. In recent years, the development of structural biology technology has led to new understandings about Aβ molecular structures, Aβ generation and clearance from the brain and peripheral tissues, and its pathological toxicity. The purpose of the review is to discuss Aβ metabolism and toxicity, and the therapeutic strategy of AD based on the latest progress in molecular structures of Aβ. The Aβ structure at the atomic level has been analyzed, which provides a new and refined perspective to comprehend the role of Aβ in AD and to formulate therapeutic strategies of AD.
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Affiliation(s)
- Hai Yang
- Department of Neurology, Army Medical Center of PLA, Chongqing, China
| | - Jinping Li
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xiaoxiong Li
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Linqiu Ma
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Mingliang Hou
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Huadong Zhou
- Department of Neurology, Army Medical Center of PLA, Chongqing, China
| | - Rui Zhou
- Southwest Hospital, Army Medical University, Chongqing, China
- *Correspondence: Rui Zhou,
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Abstract
This review focuses on the human pancreatic islet-including its structure, cell composition, development, function, and dysfunction. After providing a historical timeline of key discoveries about human islets over the past century, we describe new research approaches and technologies that are being used to study human islets and how these are providing insight into human islet physiology and pathophysiology. We also describe changes or adaptations in human islets in response to physiologic challenges such as pregnancy, aging, and insulin resistance and discuss islet changes in human diabetes of many forms. We outline current and future interventions being developed to protect, restore, or replace human islets. The review also highlights unresolved questions about human islets and proposes areas where additional research on human islets is needed.
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Affiliation(s)
- John T Walker
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Diane C Saunders
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Marcela Brissova
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Alvin C Powers
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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13
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Babych M, Nguyen PT, Côté-Cyr M, Kihal N, Quittot N, Golizeh M, Sleno L, Bourgault S. Site-Specific Alkylation of the Islet Amyloid Polypeptide Accelerates Self-Assembly and Potentiates Perturbation of Lipid Membranes. Biochemistry 2021; 60:2285-2299. [PMID: 34264642 DOI: 10.1021/acs.biochem.1c00308] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The accumulation of insoluble amyloids in the pancreatic islets is a pathological hallmark of type II diabetes and correlates closely with the loss of β-cell mass. The predominant component of these amyloid deposits is the islet amyloid polypeptide (IAPP). The factors contributing to the conversion of IAPP from a monomeric bioactive peptide hormone into insoluble amyloid fibrils remain partially elusive. In this study, we investigated the effect of the oxidative non-enzymatic post-translational modification induced by the reactive metabolite 4-hydroxynonenal (HNE) on IAPP aggregation and cytotoxicity. Incubation of IAPP with exogenous HNE accelerated its self-assembly into β-sheet fibrils and led to the formation of a Michael adduct on the His-18 side chain. To model this covalent modification, the imidazole N(π) position of histidine was alkylated using a close analogue of HNE, the octyl chain. IAPP lipidated at His-18 showed a hastened random coil-to-β-sheet conformational conversion into fibrillar assemblies with a distinct morphology, a low level of binding to thioflavin T, and a high surface hydrophobicity. Introducing an octyl chain on His-18 enhanced the ability of the peptide to perturb synthetic lipid vesicles, to permeabilize the plasma membrane, and to induce the death of pancreatic β-cells. Alkylated IAPP triggered the self-assembly of unmodified IAPP by prompting primary nucleation and increased its capacity to perturb the plasma membrane, indicating that only a small proportion of the modified peptide is necessary to shift the balance toward the formation of proteotoxic species. This study underlines the importance of studying IAPP post-translational modifications induced by oxidative metabolites in the context of pancreatic amyloids.
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Affiliation(s)
- Margaryta Babych
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Phuong Trang Nguyen
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Mélanie Côté-Cyr
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Nadjib Kihal
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Noé Quittot
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Makan Golizeh
- Department of Mathematical and Physical Sciences, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada
| | - Lekha Sleno
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada
| | - Steve Bourgault
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
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14
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Li MH, Manathunga L, London E, Raleigh DP. The Fluorescent Dye 1,6-Diphenyl-1,3,5-hexatriene Binds to Amyloid Fibrils Formed by Human Amylin and Provides a New Probe of Amylin Amyloid Kinetics. Biochemistry 2021; 60:1964-1970. [PMID: 34128641 DOI: 10.1021/acs.biochem.1c00328] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The fluorescent dye 1,6-diphenyl-1,3,5-hexatriene (DPH) is widely used as a probe of membrane order. We show that DPH also interacts with amyloid fibrils formed by human amylin (h-amylin, also known as islet amyloid polypeptide) in solution, and this results in a 100-fold increase in DPH fluorescence for a sample of 20 μM h-amylin and 0.25 μM DPH. No increase in DPH fluorescence is observed with the non-amyloidogenic rat amylin or with freshly dissolved, nonfibrillar h-amylin. The time course of amyloid formation by amylin was followed by monitoring the fluorescence of added DPH as a function of time and was similar to that monitored by the standard fluorescent probe thioflavin-T. The inclusion of DPH in the buffer did not perturb the time course of amyloid formation under the conditions examined, and the time course was independent of the range of DPH concentrations tested (0.25-5 μM). The maximum final fluorescence intensity is observed at substoichiometric ratios of DPH to amylin. No significant increase in fluorescence was observed during the lag phase of amyloid formation, and the implications for the structure of amylin prefibril oligomers are discussed. h-Amylin contains three aromatic residues. A triple aromatic to leucine mutant forms amyloid, and DPH binds to the resulting fibrils, indicating that interactions with aromatic side chains are not required for DPH-amylin amyloid interactions. DPH may be especially useful for studies of mutant amylins and other polypeptides in which changes in charged residues might complicate interpretation of thioflavin-T fluorescence.
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Affiliation(s)
- Ming-Hao Li
- Graduate Program in Biochemistry and Structural Biology, Stony Brook University, Stony Brook, New York 11794, United States
| | - Lakshan Manathunga
- Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United States.,Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York 11794, United States
| | - Erwin London
- Graduate Program in Biochemistry and Structural Biology, Stony Brook University, Stony Brook, New York 11794, United States.,Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United States.,Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794, United States
| | - Daniel P Raleigh
- Graduate Program in Biochemistry and Structural Biology, Stony Brook University, Stony Brook, New York 11794, United States.,Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United States.,Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York 11794, United States
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15
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Van Hulle F, De Groot K, Stangé G, Suenens K, De Mesmaeker I, De Paep DL, Ling Z, Hilbrands R, Gillard P, Keymeulen B, Kroon E, Westermark GT, Jacobs-Tulleneers-Thevissen D, Pipeleers D. Formation of amyloid in encapsulated human pancreatic and human stem cell-generated beta cell implants. Am J Transplant 2021; 21:2090-2099. [PMID: 33206461 DOI: 10.1111/ajt.16398] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 10/16/2020] [Accepted: 11/02/2020] [Indexed: 01/25/2023]
Abstract
Detection of amyloid in intraportal islet implants of type 1 diabetes patients has been proposed as cause in their functional decline. The present study uses cultured adult human islets devoid of amyloid to examine conditions of its formation. After intraportal injection in patients, amyloid deposits <15 µm diameter were identified in 5%-12% of beta cell containing aggregates, 3-76 months posttransplant. Such deposits also formed in glucose-controlling islet implants in the kidney of diabetic mice but not in failing implants. Alginate-encapsulated islets formed amyloid during culture when functional, and in all intraperitoneal implants that corrected diabetes in mice, exhibiting larger sizes than in functioning nonencapsulated implants. After intraperitoneal injection in a patient, retrieved single capsules presented amyloid near living beta cells, whereas no amyloid occurred in clustered capsules with dead cells. Amyloid was also demonstrated in functional human stem cell-generated beta cell implants in subcutaneous devices of mice. Deposits up to 35 µm diameter were localized in beta cell-enriched regions and related to an elevated IAPP over insulin ratio in the newly generated beta cells. Amyloid in device-encapsulated human stem cell-generated beta cell implants marks the formation of a functional beta cell mass but also an imbalance between its activated state and its microenvironment.
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Affiliation(s)
- Freya Van Hulle
- Diabetes Research Center, Free University Brussels - VUB, Brussels, Belgium.,Internal Medicine, University Hospital Brussels - UZB, Brussels, Belgium
| | - Kaat De Groot
- Diabetes Research Center, Free University Brussels - VUB, Brussels, Belgium.,Internal Medicine, University Hospital Brussels - UZB, Brussels, Belgium
| | - Geert Stangé
- Diabetes Research Center, Free University Brussels - VUB, Brussels, Belgium
| | - Krista Suenens
- Diabetes Research Center, Free University Brussels - VUB, Brussels, Belgium
| | - Ines De Mesmaeker
- Diabetes Research Center, Free University Brussels - VUB, Brussels, Belgium
| | - Diedert L De Paep
- Diabetes Research Center, Free University Brussels - VUB, Brussels, Belgium.,Department Surgery, University Hospital Brussels - UZB, Brussels, Belgium.,Beta Cell Bank, University Hospital Brussels - UZB, Brussels, Belgium
| | - Zhidong Ling
- Diabetes Research Center, Free University Brussels - VUB, Brussels, Belgium.,Beta Cell Bank, University Hospital Brussels - UZB, Brussels, Belgium.,Consortium, Center for Beta Cell Therapy in Diabetes, Brussels, Belgium
| | - Robert Hilbrands
- Diabetes Research Center, Free University Brussels - VUB, Brussels, Belgium.,Diabetes Clinic, University Hospital Brussels - UZB, Brussels, Belgium
| | - Pieter Gillard
- Department Endocrinology, University Hospital Leuven - KUL, Leuven, Belgium
| | - Bart Keymeulen
- Diabetes Research Center, Free University Brussels - VUB, Brussels, Belgium.,Consortium, Center for Beta Cell Therapy in Diabetes, Brussels, Belgium.,Diabetes Clinic, University Hospital Brussels - UZB, Brussels, Belgium
| | - Evert Kroon
- Consortium, Center for Beta Cell Therapy in Diabetes, Brussels, Belgium.,ViaCyte, Inc, San Diego, California, USA
| | | | - Daniel Jacobs-Tulleneers-Thevissen
- Diabetes Research Center, Free University Brussels - VUB, Brussels, Belgium.,Department Surgery, University Hospital Brussels - UZB, Brussels, Belgium.,Consortium, Center for Beta Cell Therapy in Diabetes, Brussels, Belgium
| | - Daniel Pipeleers
- Diabetes Research Center, Free University Brussels - VUB, Brussels, Belgium.,Consortium, Center for Beta Cell Therapy in Diabetes, Brussels, Belgium
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16
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Garnett S, de Bruyns A, Provencher-Tom V, Dutchak K, Shu R, Dankort D. Metabolic Regulator IAPP (Amylin) Is Required for BRAF and RAS Oncogene-Induced Senescence. Mol Cancer Res 2021; 19:874-885. [PMID: 33500359 DOI: 10.1158/1541-7786.mcr-20-0879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/17/2020] [Accepted: 01/21/2021] [Indexed: 11/16/2022]
Abstract
Cellular senescence is characterized by a prolonged and predominantly irreversible cell-cycle arrest state, which is linked to loss of tissue function and aging in mammals. Moreover, in response to aberrant oncogenic signals such as those from oncogenic RAS or BRAF, senescence functions as an intrinsic tumor suppressor mechanism restraining tumor progression. In addition to this durable proliferative block, senescent cells adopt altered morphologies, transcriptional profiles, and metabolism, while often possessing unusual heterochromatin formation termed senescence-associated heterochromatic foci. To uncover genes that are required to permit proliferation in the face of sustained oncogene signaling, we conducted an shRNA-based genetic screen in primary cells expressing inducible BRAF. Here we show that depletion of a known glycolysis regulator, islet amylin polypeptide (IAPP also known as amylin), prevents RAS and BRAF oncogene-induced senescence (OIS) in human cells. Importantly, depletion of IAPP resulted in changes of the cells' metabolome and this metabolic reprogramming was associated with widespread alterations in chromatin modifications compared with senescent cells. Conversely, exogenous treatment of IAPP-depleted cells with amylin restored OIS. Together, our results demonstrate that the metabolic regulator IAPP is important regulator of OIS. Moreover, they suggest that IAPP analog treatment or activation of IAPP signaling in RAS/BRAF mutant tumors may have therapeutic potential through senescence induction. IMPLICATIONS: These findings demonstrate that IAPP is a novel metabolic regulator of oncogene-induced senescence and use of IAPP analogs may be therapeutically effective to restore growth arrest to BRAF and/or RAS mutant cancers.
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Affiliation(s)
- Sam Garnett
- Department of Biology, McGill University, Montréal QC, Canada
| | | | | | - Kendall Dutchak
- Department of Biology, McGill University, Montréal QC, Canada
| | - Ran Shu
- Department of Biology, McGill University, Montréal QC, Canada
| | - David Dankort
- Department of Biology, McGill University, Montréal QC, Canada. .,Goodman Cancer Research Centre, Montréal QC, Canada
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17
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Oakes A, Menefee K, Lamba A, Palato LM, Rinauro DJ, Tun A, Jauregui B, Chang K, Nogaj LA, Moffet DA. Nonhuman IAPP Variants Inhibit Human IAPP Aggregation. Protein Pept Lett 2021; 28:963-971. [PMID: 34365921 PMCID: PMC10712300 DOI: 10.2174/0929866528666210806152706] [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: 02/28/2021] [Revised: 04/13/2021] [Accepted: 05/05/2021] [Indexed: 11/22/2022]
Abstract
AIM To identify naturally occurring variants of IAPP capable of inhibiting the aggregation of human IAPP and protecting living cells from the toxic effects of human IAPP. BACKGROUND The loss of insulin-producing β-cells and the overall progression of type 2 diabetes appears to be linked to the formation of toxic human IAPP (hIAPP, Islet Amyloid Polypeptide, amylin) amyloid in the pancreas. Inhibiting the initial aggregation of hIAPP has the potential to slow, if not stop entirely, the loss of β-cells and halt the progression of the disease. OBJECTIVE To identify and characterize naturally occurring variants of IAPP capable of inhibiting human IAPP aggregation. METHODS Synthetic human IAPP was incubated with synthetic IAPP variants identified from natural sources under conditions known to promote amyloid-based aggregation. To identify IAPP variants capable of inhibiting human IAPP aggregation, Thioflavin T-binding fluorescence, atomic force microscopy, and cell-rescue assays were performed. RESULTS While most IAPP variants showed little to no ability to inhibit human IAPP aggregation, several variants showed some ability to inhibit aggregation, with two variants showing substantial inhibitory potential. CONCLUSION Several naturally occurring IAPP variants capable of inhibiting human IAPP aggregation were identified and characterized.
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Affiliation(s)
- Alissa Oakes
- Department of Biology, Mount Saint Mary’s University, Los Angeles, CA 90049, USA
| | - Kate Menefee
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA 90045, USA
| | - Arleen Lamba
- Department of Biology, Mount Saint Mary’s University, Los Angeles, CA 90049, USA
| | - Larry M. Palato
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA 90045, USA
| | - Dillon J. Rinauro
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA 90045, USA
| | - Angela Tun
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA 90045, USA
| | - Betssy Jauregui
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA 90045, USA
| | - Kevin Chang
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA 90045, USA
| | - Luiza A. Nogaj
- Department of Biology, Mount Saint Mary’s University, Los Angeles, CA 90049, USA
| | - David A. Moffet
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA 90045, USA
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18
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Alkahtane AA, Alghamdi HA, Almutairi B, Khan MM, Hasnain MS, Abdel-Daim MM, Alghamdi WM, Alkahtani S. Inhibition of human amylin aggregation by Flavonoid Chrysin: An in-silico and in-vitro approach. Int J Med Sci 2021; 18:199-206. [PMID: 33390788 PMCID: PMC7738956 DOI: 10.7150/ijms.51382] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 10/16/2020] [Indexed: 12/11/2022] Open
Abstract
Islet amyloid polypeptide (amylin), consecrated by the pancreatic β-cells with insulin, has a significant role to play in maintaining homeostasis of islet cell hormones. Alzheimer's disease is the predominant source of dementia. However, its etiology remains uncertain; it appears that type 2 diabetes mellitus and other prediabetic states of insulin resistance contribute to the intermittent Alzheimer's disease presence. Amylin is abnormally elevated in Type II diabetes patients, accumulated into amylin aggregates, and ultimately causes apoptosis of the β-cells, and till date, its mechanism remains unclear. Several flavonoids have inhibitory effects on amylin amyloidosis, but its inhibition mechanisms are unknown. Screening a collection of traditional compounds revealed the flavone Chrysin, a potential lead compound. Chrysin inhibits amyloid aggregate formation according to Thioflavin T binding, turbidimetry assay. We report results of molecular interaction analysis of Chrysin with amylin which shows potent binding affinity against amylin. Pharmacokinetics and Drug likeness studies of Chrysin also suggest that it is a potential lead compound. Therefore, Chrysin prevented amylin aggregation.
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Affiliation(s)
- Abdullah A Alkahtane
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Hamzah A Alghamdi
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Bader Almutairi
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Mohd Muazzam Khan
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
| | - Md Saquib Hasnain
- Department of Pharmacy, Shri Venkateshwara University, NH-24, Rajabpur, Gajraula, Amroha - 244236, U.P., India
| | - Mohamed M Abdel-Daim
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia.,Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Wadha M Alghamdi
- Medical Services at the Ministry of Interior, Riyadh, Saudi Arabia
| | - Saad Alkahtani
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
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19
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Mitochondrial Dysfunction in Intervertebral Disc Degeneration: From Pathogenesis to Therapeutic Target. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020. [DOI: 10.1155/2020/8880320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Mitochondria are cytosolic organelles essential for cellular function and survival. The function of mitochondria is maintained by mitochondrial quality control systems including mitochondrial fission and fusion to adapt the altered environment and mitophagy for removal of damaged mitochondria. Mitochondrial dysfunction is closely involved in aging-related diseases. Intervertebral disc (IVD) degeneration, an aging-associated process, is the major contributor to low back pain. Growing evidence has suggested that the mitochondrial function in IVD cells is severely compromised during the degenerative process of IVD, and dysfunctional mitochondria along with impaired mitochondrial dynamics and mitophagy cause a series of cascade reactions that have been implicated in increased oxidative stress, senescence, matrix catabolism, and apoptosis of IVD cells, thereby contributing to the degeneration of IVD. Accordingly, therapies that target mitochondrial dysfunction and related mechanisms, such as ROS generation, mitophagy, and specific molecules and signaling, hold great promise. The present review summarizes the current state of the role of mitochondrial dysfunction in the pathophysiology of IVD degeneration and potential therapeutic strategies that could be developed.
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20
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Söderbom G, Zeng BY. The NLRP3 inflammasome as a bridge between neuro-inflammation in metabolic and neurodegenerative diseases. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 154:345-391. [PMID: 32739011 DOI: 10.1016/bs.irn.2020.03.023] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Evidence increasingly suggests that type 2 diabetes mellitus (T2DM) is a risk factor for neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD). These diseases share many pathological processes, including oxidative stress, local inflammation/neuroinflammation and chronic, low-grade (systemic) inflammation, which are exacerbated by aging, a common risk factor for T2DM and NDDs. Here, we focus on the link between chronic inflammation driven by peripheral metabolic disease and how this may impact neurodegeneration in AD and PD. We review the relationship between these common pathological processes in AD and PD from the perspective of the "pro-inflammatory" signaling of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat- (LRR)-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complex. Since the need for effective disease-modifying therapies in T2DM, AD and PD is significant, the relationship between these diseases is important as a positive clinical impact on one may benefit the others. We briefly consider how novel strategies may target neuro-inflammation and provide potential therapies for AD and PD.
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Affiliation(s)
| | - Bai-Yun Zeng
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
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21
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Injury factors alter miRNAs profiles of exosomes derived from islets and circulation. Aging (Albany NY) 2019; 10:3986-3999. [PMID: 30552311 PMCID: PMC6326691 DOI: 10.18632/aging.101689] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 11/26/2018] [Indexed: 12/31/2022]
Abstract
Islets damage is a major abnormality underling diabetes. Recent studies suggested the value of exosomes in diagnosis. This study aimed to investigate the impact of injury factors on the miRNA profiles of islet exosomes and determine whether circulating exosomal miRNAs is suitable as biomarkers of islets damage. Islets were isolated from ICR mice and induced injury in vitro by mixed cytokines (Tumor Necrosis Factor-α, Interleukin -1β and Interferon-γ) or streptozotocin (STZ), and exosomes were derived from the cultural supernatant. Using miRNA microarray analysis, we found 22 and 11 differentially expressed miRNAs in islet exosomes of STZ and cytokines treatment, respectively, including 6 miRNAs as the intersection of two injured conditions. Thereinto, mmu-miR-375-3p and mmu-miR-129-5p could be validated by qRT-PCR. Then, Serum exosomes were isolated from STZ injected mice and subjects with various glucose metabolism states and diabetic duration. qRT-PCR demonstrated exosomal mmu-miR-375-3p dramatically increased in serum of STZ treated mouse prior to the disturbance of blood glucose and insulin. In human serum exosomes, hsa-miR-375-3p was elevated in new-onset diabetes patients. Overall, our results suggest that injury factors changed miRNA profiles of exosomes derived from islets and exosomal miR-375-3p showed promising potential as a biomarker of islets damage.
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22
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Ježek P, Jabůrek M, Plecitá-Hlavatá L. Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes. Antioxid Redox Signal 2019; 31:722-751. [PMID: 30450940 PMCID: PMC6708273 DOI: 10.1089/ars.2018.7656] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 11/05/2018] [Indexed: 12/14/2022]
Abstract
Significance: Type 2 diabetes development involves multiple changes in β-cells, related to the oxidative stress and impaired redox signaling, beginning frequently by sustained overfeeding due to the resulting lipotoxicity and glucotoxicity. Uncovering relationships among the dysregulated metabolism, impaired β-cell "well-being," biogenesis, or cross talk with peripheral insulin resistance is required for elucidation of type 2 diabetes etiology. Recent Advances: It has been recognized that the oxidative stress, lipotoxicity, and glucotoxicity cannot be separated from numerous other cell pathology events, such as the attempted compensation of β-cell for the increased insulin demand and dynamics of β-cell biogenesis and its "reversal" at dedifferentiation, that is, from the concomitantly decreasing islet β-cell mass (also due to transdifferentiation) and low-grade islet or systemic inflammation. Critical Issues: At prediabetes, the compensation responses of β-cells, attempting to delay the pathology progression-when exaggerated-set a new state, in which a self-checking redox signaling related to the expression of Ins gene expression is impaired. The resulting altered redox signaling, diminished insulin secretion responses to various secretagogues including glucose, may lead to excretion of cytokines or chemokines by β-cells or excretion of endosomes. They could substantiate putative stress signals to the periphery. Subsequent changes and lasting glucolipotoxicity promote islet inflammatory responses and further pathology spiral. Future Directions: Should bring an understanding of the β-cell self-checking and related redox signaling, including the putative stress signal to periphery. Strategies to cure or prevent type 2 diabetes could be based on the substitution of the "wrong" signal by the "correct" self-checking signal.
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Affiliation(s)
- Petr Ježek
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Martin Jabůrek
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Lydie Plecitá-Hlavatá
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
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23
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Akter R, Zhyvoloup A, Zheng B, Bhatia SR, Raleigh DP. The triphenylmethane dye brilliant blue G is only moderately effective at inhibiting amyloid formation by human amylin or at disaggregating amylin amyloid fibrils, but interferes with amyloid assays; Implications for inhibitor design. PLoS One 2019; 14:e0219130. [PMID: 31404073 PMCID: PMC6690547 DOI: 10.1371/journal.pone.0219130] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 06/17/2019] [Indexed: 12/21/2022] Open
Abstract
The development of inhibitors of islet amyloid formation is important as pancreatic amyloid deposition contributes to type-2 diabetes and islet transplant failure. The Alzheimer's Aβ peptide and human amylin (h-amylin), the polypeptide responsible for amyloid formation in type-2 diabetes, share common physio-chemical features and some inhibitors of Aβ also inhibit amyloid formation by h-amylin and vice versa. Thus, a popular and potentially useful strategy to find lead compounds for anti-amylin amyloid agents is to examine compounds that have effects on Aβ amyloid formation. The triphenylmethane dye, brilliant blue G (BBG, Sodium;3-[[4-[(E)-[4-(4-ethoxyanilino)phenyl]-[4-[ethyl-[(3-sulfonatophenyl)methyl]azaniumylidene]-2-methylcyclohexa-2,5-dien-1-ylidene]methyl]-N-ethyl-3-methylanilino]methyl]benzenesulfonate) has been shown to modulate Aβ amyloid formation and inhibit Aβ induced toxicity. However, the effects of BBG on h-amylin have not been examined, although other triphenylmethane derivatives inhibit h-amylin amyloid formation. The compound has only a modest impact on h-amylin amyloid formation unless it is added in significant excess. BBG also remodels preformed h-amylin amyloid fibrils if added in excess, however BBG has no significant effect on h-amylin induced toxicity towards cultured β-cells or cultured CHO-T cells except at high concentrations. BBG is shown to interfere with standard thioflavin-T assays of h-amylin amyloid formation and disaggregation, highlighting the difficulty of interpreting such experiments in the absence of other measurements. BBG also interferes with ANS based assays of h-amylin amyloid formation. The work highlights the differences between inhibition of Aβ and h-amylin amyloid formation, illustrates the limitation of using Aβ inhibitors as leads for h-amylin amyloid inhibitors, and reinforces the difficulties in interpreting dye binding assays of amyloid formation.
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Affiliation(s)
- Rehana Akter
- Department of Chemistry, Stony Brook University, Stony Brook, NY, United States of America
| | - Alexander Zhyvoloup
- Institute of Structural and Molecular Biology, University College London, Gower Street, London, United Kingdom
| | - Bingqian Zheng
- Department of Chemistry, Stony Brook University, Stony Brook, NY, United States of America
| | - Surita R Bhatia
- Department of Chemistry, Stony Brook University, Stony Brook, NY, United States of America
| | - Daniel P Raleigh
- Department of Chemistry, Stony Brook University, Stony Brook, NY, United States of America
- Institute of Structural and Molecular Biology, University College London, Gower Street, London, United Kingdom
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24
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Palato LM, Pilcher S, Oakes A, Lamba A, Torres J, Ledesma Monjaraz LI, Munoz C, Njoo E, Rinauro DJ, Menefee KA, Tun A, Jauregui BL, Shapiro S, Nossiff OH, Olivares E, Chang K, Nguyen V, Nogaj LA, Moffet DA. Amyloidogenicity of naturally occurring full-length animal IAPP variants. J Pept Sci 2019; 25:e3199. [PMID: 31231935 DOI: 10.1002/psc.3199] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 05/28/2019] [Accepted: 05/29/2019] [Indexed: 12/15/2022]
Abstract
The aggregation of the 37-amino acid polypeptide human islet amyloid polypeptide (hIAPP), as either insoluble amyloid or as small oligomers, appears to play a direct role in the death of human pancreatic β-islet cells in type 2 diabetes. hIAPP is considered to be one of the most amyloidogenic proteins known. The quick aggregation of hIAPP leads to the formation of toxic species, such as oligomers and fibers, that damage mammalian cells (both human and rat pancreatic cells). Whether this toxicity is necessary for the progression of type 2 diabetes or merely a side effect of the disease remains unclear. If hIAPP aggregation into toxic amyloid is on-path for developing type 2 diabetes in humans, islet amyloid polypeptide (IAPP) aggregation would likely need to play a similar role within other organisms known to develop the disease. In this work, we compared the aggregation potential and cellular toxicity of full-length IAPP from several diabetic and nondiabetic organisms whose aggregation propensities had not yet been determined for full-length IAPP.
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Affiliation(s)
- Larry M Palato
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA
| | - Shannon Pilcher
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA
| | - Alissa Oakes
- Department of Biology, Mount Saint Mary's University, Los Angeles, CA
| | - Arleen Lamba
- Department of Biology, Mount Saint Mary's University, Los Angeles, CA
| | - Jaris Torres
- Department of Biology, Mount Saint Mary's University, Los Angeles, CA
| | | | - Crystabel Munoz
- Department of Biology, Mount Saint Mary's University, Los Angeles, CA
| | - Edward Njoo
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA
| | - Dillon J Rinauro
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA
| | | | - Angela Tun
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA
| | - Betssy L Jauregui
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA
| | - Sarah Shapiro
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA
| | - Olivia H Nossiff
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA
| | - Eileen Olivares
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA
| | - Kevin Chang
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA
| | - Viviane Nguyen
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA
| | - Luiza A Nogaj
- Department of Biology, Mount Saint Mary's University, Los Angeles, CA
| | - David A Moffet
- Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA
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Synthesis and identification of novel pyridazinylpyrazolone based diazo compounds as inhibitors of human islet amyloid polypeptide aggregation. Bioorg Chem 2019; 84:339-346. [DOI: 10.1016/j.bioorg.2018.11.039] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 11/17/2018] [Accepted: 11/24/2018] [Indexed: 02/06/2023]
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26
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Rider SM, Mizuno S, Kang JD. Molecular Mechanisms of Intervertebral Disc Degeneration. Spine Surg Relat Res 2019; 3:1-11. [PMID: 31435545 PMCID: PMC6690117 DOI: 10.22603/ssrr.2017-0095] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 01/24/2018] [Indexed: 12/25/2022] Open
Abstract
Intervertebral disc degeneration is a well-known cause of disability, the result of which includes neck and back pain with associated mobility limitations. The purpose of this article is to provide an overview of the known molecular mechanisms through which intervertebral disc degeneration occurs as a result of complex interactions of exogenous and endogenous stressors. This review will focus on some of the identified molecular changes leading to the deterioration of the extracellular matrix of both the annulus fibrosus and nucleus pulposus. In addition, we will provide a summation of our current knowledge supporting the role of associated DNA and intracellular damage, cellular senescence's catabolic effects, oxidative stress, and the cell's inappropriate response to damage in contributing to intervertebral disc degeneration. Our current understanding of the molecular mechanisms through which intervertebral disc degeneration occurs provides us with abundant insight into how physical and chemical changes exacerbate the degenerative process of the entire spine. Furthermore, we will describe some of the related molecular targets and therapies that may contribute to intervertebral repair and regeneration.
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Affiliation(s)
- Sean M Rider
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Shuichi Mizuno
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - James D Kang
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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IAPP in type II diabetes: Basic research on structure, molecular interactions, and disease mechanisms suggests potential intervention strategies. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2018. [DOI: 10.1016/j.bbamem.2018.02.020] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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28
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Hong SW, Lee J, Cho JH, Kwon H, Park SE, Rhee EJ, Park CY, Oh KW, Park SW, Lee WY. Pioglitazone Attenuates Palmitate-Induced Inflammation and Endoplasmic Reticulum Stress in Pancreatic β-Cells. Endocrinol Metab (Seoul) 2018; 33:105-113. [PMID: 29589392 PMCID: PMC5874186 DOI: 10.3803/enm.2018.33.1.105] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 01/08/2018] [Accepted: 01/09/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The nuclear receptor peroxisome proliferator-activator gamma (PPARγ) is a useful therapeutic target for obesity and diabetes, but its role in protecting β-cell function and viability is unclear. METHODS To identify the potential functions of PPARγ in β-cells, we treated mouse insulinoma 6 (MIN6) cells with the PPARγ agonist pioglitazone in conditions of lipotoxicity, endoplasmic reticulum (ER) stress, and inflammation. RESULTS Palmitate-treated cells incubated with pioglitazone exhibited significant improvements in glucose-stimulated insulin secretion and the repression of apoptosis, as shown by decreased caspase-3 cleavage and poly (adenosine diphosphate [ADP]-ribose) polymerase activity. Pioglitazone also reversed the palmitate-induced expression of inflammatory cytokines (tumor necrosis factor α, interleukin 6 [IL-6], and IL-1β) and ER stress markers (phosphor-eukaryotic translation initiation factor 2α, glucose-regulated protein 78 [GRP78], cleaved-activating transcription factor 6 [ATF6], and C/EBP homologous protein [CHOP]), and pioglitazone significantly attenuated inflammation and ER stress in lipopolysaccharide- or tunicamycin-treated MIN6 cells. The protective effect of pioglitazone was also tested in pancreatic islets from high-fat-fed KK-Ay mice administered 0.02% (wt/wt) pioglitazone or vehicle for 6 weeks. Pioglitazone remarkably reduced the expression of ATF6α, GRP78, and monocyte chemoattractant protein-1, prevented α-cell infiltration into the pancreatic islets, and upregulated glucose transporter 2 (Glut2) expression in β-cells. Moreover, the preservation of β-cells by pioglitazone was accompanied by a significant reduction of blood glucose levels. CONCLUSION Altogether, these results support the proposal that PPARγ agonists not only suppress insulin resistance, but also prevent β-cell impairment via protection against ER stress and inflammation. The activation of PPARγ might be a new therapeutic approach for improving β-cell survival and insulin secretion in patients with diabetes mellitus.
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Affiliation(s)
- Seok Woo Hong
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jinmi Lee
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jung Hwan Cho
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyemi Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se Eun Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun Jung Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Cheol Young Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ki Won Oh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Woo Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Young Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
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29
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Al Mutairi N, Alrqobah D, Haji Hussain N. Prevalence of metabolic syndrome in children with moderate to severe psoriasis treated with TNF inhibitors in comparison to conventional agents. Dermatol Ther 2018; 31. [DOI: 10.1111/dth.12566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 10/02/2017] [Indexed: 12/16/2022]
Affiliation(s)
- Nawaf Al Mutairi
- Department of Medicine, Faculty of Medicine; Kuwait University, Jabriya, Kuwait
| | - Dhuha Alrqobah
- Department of Dermatology; Farwaniya Hospital, Ardiya, Kuwait
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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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31
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Wijesekara N, Gonçalves RA, De Felice FG, Fraser PE. Impaired peripheral glucose homeostasis and Alzheimer's disease. Neuropharmacology 2017; 136:172-181. [PMID: 29169962 DOI: 10.1016/j.neuropharm.2017.11.027] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 11/12/2017] [Accepted: 11/16/2017] [Indexed: 12/19/2022]
Abstract
Alzheimer's disease (AD) is the most common type of dementia. Recent studies suggest that metabolic disturbances, particularly type 2 diabetes (T2D) increase the risk of cognitive decline and AD. AD is also a risk factor for T2D, and a growing body of evidence indicates that these diseases are connected both at clinical and molecular levels. In T2D, peripheral insulin resistance, hyperglycemia and eventually insulin deficiency develops, leading to an overall decline in tissue health. More recently, brain insulin resistance has been shown to be a key feature of AD that is linked to neuronal dysfunction and cognitive impairment. Furthermore, both AD and T2D are amyloidogenic diseases, with abnormal aggregation of amyloid-β peptide (Aβ) and islet amyloid polypeptide (IAPP) respectively contributing to cellular death and disease pathogenesis. Emerging data suggests that Aβ may have peripheral effects including its co-deposition in the pancreas. In this review, we discuss how peripheral effects of Aβ and metabolic disturbances may impact AD pathogenesis. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'
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Affiliation(s)
- Nadeeja Wijesekara
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, M5T 2S8, Canada.
| | - Rafaella Araujo Gonçalves
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, M5T 2S8, Canada; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Fernanda G De Felice
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Paul E Fraser
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, M5T 2S8, Canada; Department of Medical Biophysics, University of Toronto, Canada.
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Yu Q, Canales A, Glover MS, Das R, Shi X, Liu Y, Keller MP, Attie AD, Li L. Targeted Mass Spectrometry Approach Enabled Discovery of O-Glycosylated Insulin and Related Signaling Peptides in Mouse and Human Pancreatic Islets. Anal Chem 2017; 89:9184-9191. [PMID: 28726377 PMCID: PMC6314835 DOI: 10.1021/acs.analchem.7b01926] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
O-Linked glycosylation often involves the covalent attachment of sugar moieties to the hydroxyl group of serine or threonine on proteins/peptides. Despite growing interest in glycoproteins, little attention has been directed to glycosylated signaling peptides, largely due to lack of enabling analytical tools. Here we explore the occurrence of naturally O-linked glycosylation on the signaling peptides extracted from mouse and human pancreatic islets using mass spectrometry (MS). A novel targeted MS-based method is developed to increase the likelihood of capturing these modified signaling peptides and to provide improved sequence coverage and accurate glycosite localization, enabling the first large-scale discovery of O-glycosylation on signaling peptides. Several glycosylated signaling peptides with multiple glycoforms are identified, including the first report of glycosylated insulin-B chain and insulin-C peptide and BigLEN. This discovery may reveal potential novel functions as glycosylation could influence their conformation and biostability. Given the importance of insulin and its related peptide hormones and previous studies of glycosylated insulin analogues, this natural glycosylation may provide important insights into diabetes research and therapeutic treatments.
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Affiliation(s)
- Qing Yu
- School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, United States
| | - Alejandra Canales
- Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
| | - Matthew S. Glover
- School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, United States
| | - Rahul Das
- Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
| | - Xudong Shi
- Department of Surgery, Wisconsin Institute for Medical Research, Madison, Wisconsin 53705, United States
| | - Yang Liu
- Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
| | - Mark P. Keller
- Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
| | - Alan D. Attie
- Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
| | - Lingjun Li
- School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, United States
- Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
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van Raalte DH, Verchere CB. Improving glycaemic control in type 2 diabetes: Stimulate insulin secretion or provide beta-cell rest? Diabetes Obes Metab 2017; 19:1205-1213. [PMID: 28295962 DOI: 10.1111/dom.12935] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 03/06/2017] [Accepted: 03/08/2017] [Indexed: 12/25/2022]
Abstract
Type 2 diabetes (T2D) is characterized by a gradual decline in pancreatic beta cell function that determines the progressive course of the disease. While beta-cell failure is an important contributor to hyperglycaemia, chronic hyperglycaemia itself is also detrimental for beta-cell function, probably by inducing prolonged secretory stress on the beta cell as well as through direct glucotoxic mechanisms that have not been fully defined. For years, research has been carried out in search of therapies targeting hyperglycaemia that preserve long-term beta-cell function in T2D, a quest that is still ongoing. Current strategies aim to improve glycaemic control, either by promoting endogenous insulin secretion, such as sulfonylureas, or by mechanisms that may impact the beta cell indirectly, for example, providing beta-cell rest through insulin treatment. Although overall long-term success is limited with currently available interventions, in this review we argue that strategies that induce beta-cell rest have considerable potential to preserve long-term beta-cell function. This is based on laboratory-based studies involving human islets as well as clinical studies employing intensive insulin therapy, thiazolidinediones, bariatric surgery, short-acting glucagon-like peptide (GLP)-1 receptor agonists and a promising new class of diabetes drugs, sodium-glucose-linked transporter (SGLT)-2 inhibitors. Nevertheless, a lack of long-term clinical studies that focus on beta-cell function for the newer glucose-lowering agents, as well as commonly used combination therapies, preclude a straightforward conclusion; this gap in our knowledge should be a focus of future studies.
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Affiliation(s)
- Daniël H van Raalte
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
- Department of Surgery, The University of British Columbia and Research Institute, BC Children's Hospital, Vancouver, Canada
| | - C Bruce Verchere
- Department of Surgery, The University of British Columbia and Research Institute, BC Children's Hospital, Vancouver, Canada
- Department of Pathology and Laboratory Medicine, The University of British Columbia and Research Institute, BC Children's Hospital, Vancouver, Canada
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Montane J, de Pablo S, Castaño C, Rodríguez-Comas J, Cadavez L, Obach M, Visa M, Alcarraz-Vizán G, Sanchez-Martinez M, Nonell-Canals A, Parrizas M, Servitja JM, Novials A. Amyloid-induced β-cell dysfunction and islet inflammation are ameliorated by 4-phenylbutyrate (PBA) treatment. FASEB J 2017; 31:5296-5306. [PMID: 28821639 DOI: 10.1096/fj.201700236r] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 07/25/2017] [Indexed: 12/28/2022]
Abstract
Human islet amyloid polypeptide (hIAPP) aggregation is associated with β-cell dysfunction and death in type 2 diabetes (T2D). we aimed to determine whether in vivo treatment with chemical chaperone 4-phenylbutyrate (PBA) ameliorates hIAPP-induced β-cell dysfunction and islet amyloid formation. Oral administration of PBA in hIAPP transgenic (hIAPP Tg) mice expressing hIAPP in pancreatic β cells counteracted impaired glucose homeostasis and restored glucose-stimulated insulin secretion. Moreover, PBA treatment almost completely prevented the transcriptomic alterations observed in hIAPP Tg islets, including the induction of genes related to inflammation. PBA also increased β-cell viability and improved insulin secretion in hIAPP Tg islets cultured under glucolipotoxic conditions. Strikingly, PBA not only prevented but even reversed islet amyloid deposition, pointing to a direct effect of PBA on hIAPP. This was supported by in silico calculations uncovering potential binding sites of PBA to monomeric, dimeric, and pentameric fibrillar structures, and by in vitro assays showing inhibition of hIAPP fibril formation by PBA. Collectively, these results uncover a novel beneficial effect of PBA on glucose homeostasis by restoring β-cell function and preventing amyloid formation in mice expressing hIAPP in β cells, highlighting the therapeutic potential of PBA for the treatment of T2D.-Montane, J., de Pablo, S., Castaño, C., Rodríguez-Comas, J., Cadavez, L., Obach, M., Visa, M., Alcarraz-Vizán, G., Sanchez-Martinez, M., Nonell-Canals, A., Parrizas, M., Servitja, J.-M., Novials, A. Amyloid-induced β-cell dysfunction and islet inflammation are ameliorated by 4-phenylbutyrate (PBA) treatment.
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Affiliation(s)
- Joel Montane
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain; .,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Sara de Pablo
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Carlos Castaño
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Júlia Rodríguez-Comas
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Lisa Cadavez
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Mercè Obach
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Montse Visa
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Gema Alcarraz-Vizán
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | | | | | - Marcelina Parrizas
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Joan-Marc Servitja
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Anna Novials
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain; .,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
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Akter R, Abedini A, Ridgway Z, Zhang X, Kleinberg J, Schmidt AM, Raleigh DP. Evolutionary Adaptation and Amyloid Formation: Does the Reduced Amyloidogenicity and Cytotoxicity of Ursine Amylin Contribute to the Metabolic Adaption of Bears and Polar Bears? Isr J Chem 2017; 57:750-761. [PMID: 29955200 PMCID: PMC6018008 DOI: 10.1002/ijch.201600081] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Much of our knowledge of diabetes is derived from studies of rodent models. An alternative approach explores evolutionary solutions to physiological stress by studying organisms that face challenging metabolic environments. Polar bears eat an enormously lipid-rich diet without deleterious metabolic consequences. In contrast, transgenic rodents expressing the human neuropancreatic polypeptide hormone amylin develop hyperglycemia and extensive pancreatic islet amyloid when fed a high fat diet. The process of islet amyloid formation by human amylin contributes to β-cell dysfunction and loss of β-cell mass in type-2 diabetes. We show that ursine amylin is considerably less amyloidogenic and less toxic to β-cells than human amylin, consistent with the hypothesis that part of the adaptation of bears to metabolic challenges might include protection from islet amyloidosis-induced β-cell toxicity. Ursine and human amylin differ at four locations: H18R, S20G, F23L, and S29P. These are interesting from a biophysical perspective since the S20G mutation accelerates amyloid formation but the H18R slows it. An H18RS20G double mutant of human amylin behaves similarly to the H18R mutant, indicating that the substitution at position 18 dominates the S20G replacement. These data suggest one possible mechanism underpinning the protection of bears against metabolic challenges and provide insight into the design of soluble analogs of human amylin.
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Affiliation(s)
- Rehana Akter
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400
| | - Andisheh Abedini
- Diabetes Research Program, NYU School of Medicine, 522 First Avenue, New York, NY 10016
| | - Zachary Ridgway
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400
| | - Xiaoxue Zhang
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400
| | - Joel Kleinberg
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400
| | - Ann Marie Schmidt
- Diabetes Research Program, NYU School of Medicine, 522 First Avenue, New York, NY 10016
| | - Daniel P. Raleigh
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400
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Wu X, Wang K, Hua W, Li S, Liu X, Liu W, Song Y, Zhang Y, Shao Z, Yang C. Down-regulation of islet amyloid polypeptide expression induces death of human annulus fibrosus cells via mitochondrial and death receptor pathways. Biochim Biophys Acta Mol Basis Dis 2017; 1863:1479-1491. [PMID: 28433710 DOI: 10.1016/j.bbadis.2017.04.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 04/10/2017] [Accepted: 04/17/2017] [Indexed: 01/07/2023]
Abstract
Islet amyloid polypeptide (IAPP) exerts its biological effects by participating in the regulation of glucose metabolism and cell apoptosis. The main goal of the present study was to investigate the expression of IAPP in degenerated intervertebral disc tissue and IAPP's modulation of extracellular matrix (ECM) catabolic and anabolic genes in human AF cells. We found that the expression of IAPP, the calcitonin receptor, and receptor activity modifying protein decreased considerably in AF cells during the progression of intervertebral disc degeneration (IDD). Meanwhile, transfection with pLV-siIAPP decreased the expression of IAPP and its receptors and reduced glucose uptake and the expression of aggrecan, Col2A1, and BG. Down-regulation of IAPP also induced a significant increase in reactive oxygen species generation in AF cells, along with a decrease in matrix metalloproteinases and an increase in the concentration of cellular Ca2+, ultimately leading to death. Further analysis revealed that siIAPP intervention promoted the release of cytochrome c from mitochondria, resulting in the activation of Caspase-3 and Caspase-9. In contrast, significantly decreased expression of Caspase-3 and Caspase-9 was observed in AF cells transfected with pLV-IAPP. The concentrations of Fas and FasL proteins were significantly decreased in AF cells transfected with PLV-IAPP, while activation of the Fas/FasL system and cell death were induced by siIAPP intervention. Mechanistically, AMPK/Akt-mTOR signaling pathways were involved. In conclusion, down-regulation of IAPP expression induces the death of human AF cells via mitochondrial and death receptor pathways, potentially offering a novel therapeutic target for the treatment of IDD.
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Affiliation(s)
- Xinghuo Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kun Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wenbin Hua
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shuai Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xianzhe Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wei Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yu Song
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yukun Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Cao Yang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Zhang Y, Song W. Islet amyloid polypeptide: Another key molecule in Alzheimer's pathogenesis? Prog Neurobiol 2017; 153:100-120. [PMID: 28274676 DOI: 10.1016/j.pneurobio.2017.03.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 02/17/2017] [Accepted: 03/02/2017] [Indexed: 12/14/2022]
Abstract
Recent epidemiological evidence reveals that patients suffering from type 2 diabetes mellitus (T2DM) often experience a significant decline in cognitive function, and approximately 70% of those cases eventually develop Alzheimer's disease (AD). Although several pathological processes are shared by AD and T2DM, the exact molecular mechanisms connecting these two diseases are poorly understood. Aggregation of human islet amyloid polypeptide (hIAPP), the pathological hallmark of T2DM, has also been detected in brain tissue and is associated with cognitive decline and AD development. In addition, hIAPP and amyloid β protein (Aβ) share many biophysical and physiological properties as well as exert similar cytotoxic mechanisms. Therefore, it is important to examine the possible role of hIAPP in the pathogenesis of AD. In this article, we introduce the basics on this amyloidogenic protein. More importantly, we discuss the potential mechanisms of hIAPP-induced AD development, which will be beneficial for proposing novel and feasible strategies to optimize AD prevention and/or treatment in diabetics.
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Affiliation(s)
- Yun Zhang
- Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
| | - Weihong Song
- Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
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38
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Martinez-Sanchez A, Rutter GA, Latreille M. MiRNAs in β-Cell Development, Identity, and Disease. Front Genet 2017; 7:226. [PMID: 28123396 PMCID: PMC5225124 DOI: 10.3389/fgene.2016.00226] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 12/21/2016] [Indexed: 12/22/2022] Open
Abstract
Pancreatic β-cells regulate glucose metabolism by secreting insulin, which in turn stimulates the utilization or storage of the sugar by peripheral tissues. Insulin insufficiency and a prolonged period of insulin resistance are usually the core components of type 2 diabetes (T2D). Although, decreased insulin levels in T2D have long been attributed to a decrease in β-cell function and/or mass, this model has recently been refined with the recognition that a loss of β-cell “identity” and dedifferentiation also contribute to the decline in insulin production. MicroRNAs (miRNAs) are key regulatory molecules that display tissue-specific expression patterns and maintain the differentiated state of somatic cells. During the past few years, great strides have been made in understanding how miRNA circuits impact β-cell identity. Here, we review current knowledge on the role of miRNAs in regulating the acquisition of the β-cell fate during development and in maintaining mature β-cell identity and function during stress situations such as obesity, pregnancy, aging, or diabetes. We also discuss how miRNA function could be harnessed to improve our ability to generate β-cells for replacement therapy for T2D.
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Affiliation(s)
- Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London London, UK
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London London, UK
| | - Mathieu Latreille
- Cellular Identity and Metabolism Group, MRC London Institute of Medical SciencesLondon, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College LondonLondon, UK
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Zhang X, St Clair JR, London E, Raleigh DP. Islet Amyloid Polypeptide Membrane Interactions: Effects of Membrane Composition. Biochemistry 2017; 56:376-390. [PMID: 28054763 DOI: 10.1021/acs.biochem.6b01016] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Amyloid formation by islet amyloid polypeptide (IAPP) contributes to β-cell dysfunction in type 2 diabetes. Perturbation of the β-cell membrane may contribute to IAPP-induced toxicity. We examine the effects of lipid composition, salt, and buffer on IAPP amyloid formation and on the ability of IAPP to induce leakage of model membranes. Even low levels of anionic lipids promote amyloid formation and membrane permeabilization. Increasing the percentage of the anionic lipids, 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS) or 1,2-dioleoyl-sn-glycero-3-phospho(1'-rac-glycerol), enhances the rate of amyloid formation and increases the level of membrane permeabilization. The choice of zwitterionic lipid has no noticeable effect on membrane-catalyzed amyloid formation but in most cases affects leakage, which tends to decrease in the following order: 1,2-dioleoyl-sn-glycero-3-phosphocholine > 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine > sphingomyelin. Uncharged lipids that increase the level of membrane order weaken the ability of IAPP to induce leakage. Leakage is due predominately to pore formation rather than complete disruption of the vesicles under the conditions used in these studies. Cholesterol at or below physiological levels significantly reduces the rate of vesicle-catalyzed IAPP amyloid formation and decreases the susceptibility to IAPP-induced leakage. The effects of cholesterol on amyloid formation are masked by 25 mol % POPS. Overall, there is a strong inverse correlation between the time to form amyloid and the extent of vesicle leakage. NaCl reduces the rate of membrane-catalyzed amyloid formation by anionic vesicles, but accelerates amyloid formation in solution. The implications for IAPP membrane interactions are discussed, as is the possibility that the loss of phosphatidylserine asymmetry enhances IAPP amyloid formation and membrane damage in vivo via a positive feedback loop.
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Affiliation(s)
- Xiaoxue Zhang
- Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States
| | - Johnna R St Clair
- Department of Biochemistry and Cell Biology, Stony Brook University , Stony Brook, New York 11794-5215, United States
| | - Erwin London
- Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States.,Department of Biochemistry and Cell Biology, Stony Brook University , Stony Brook, New York 11794-5215, United States
| | - Daniel P Raleigh
- Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States.,Graduate Program in Biochemistry and Structural Biology, Stony Brook University , Stony Brook, New York 11794-5215, United States
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Yu XL, Li YN, Zhang H, Su YJ, Zhou WW, Zhang ZP, Wang SW, Xu PX, Wang YJ, Liu RT. Rutin inhibits amylin-induced neurocytotoxicity and oxidative stress. Food Funct 2016; 6:3296-306. [PMID: 26242245 DOI: 10.1039/c5fo00500k] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Recent evidence showed that amylin deposition is not only found in the pancreas in type 2 diabetes mellitus (T2DM) patients, but also in other peripheral organs, such as kidneys, heart and brain. Circulating amylin oligomers that cross the blood-brain barrier and accumulate in the brain may be an important contributor to diabetic cerebral injury and neurodegeneration. Moreover, increasing epidemiological studies indicate that there is a significant association between T2DM and Alzheimer's disease (AD). Amylin and β-amyloid (Aβ) may share common pathophysiology and show strikingly similar neurotoxicity profiles in the brain. To explore the potential effects of rutin on AD, we here investigated the effect of rutin on amylin aggregation by thioflavin T dyeing, evaluated the effect of rutin on amylin-induced neurocytotoxicity by the MTT assay, and assessed oxidative stress, as well as the generation of nitric oxide (NO) and pro-inflammatory cytokines in neuronal cells. Our results showed that the flavonoid antioxidant rutin inhibited amylin-induced neurocytotoxicity, decreased the production of reactive oxygen species (ROS), NO, glutathione disulfide (GSSG), malondialdehyde (MDA) and pro-inflammatory cytokines TNF-α and IL-1β, attenuated mitochondrial damage and increased the GSH/GSSG ratio. These protective effects of rutin may have resulted from its ability to inhibit amylin aggregation, enhance the antioxidant enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and reduce inducible nitric oxide synthase (iNOS) activity. These in vitro results indicate that rutin is a promising natural product for protecting neuronal cells from amylin-induced neurotoxicity and oxidative stress, and rutin administration could be a feasible therapeutic strategy for preventing AD development and protecting the aging brain or slowing neurodegenerative processes.
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Affiliation(s)
- Xiao-Lin Yu
- National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
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Abstract
The incidence of type 1 diabetes has risen considerably in the past 30 years due to changes in the environment that have been only partially identified. In this Series paper, we critically discuss candidate triggers of islet autoimmunity and factors thought to promote progression from autoimmunity to overt type 1 diabetes. We revisit previously proposed hypotheses to explain the growth in the incidence of type 1 diabetes in light of current data. Finally, we suggest a unified model in which immune tolerance to β cells can be broken by several environmental exposures that induce generation of hybrid peptides acting as neoautoantigens.
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Affiliation(s)
- Marian Rewers
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Johnny Ludvigsson
- Division of Pediatrics, Department of Clinical and Experimental Medicine, Medical Faculty, Linköping University and Linköping University Hospital, Linköping, Sweden.
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42
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Wijesekara N, Kaur A, Westwell-Roper C, Nackiewicz D, Soukhatcheva G, Hayden MR, Verchere CB. ABCA1 deficiency and cellular cholesterol accumulation increases islet amyloidogenesis in mice. Diabetologia 2016; 59:1242-6. [PMID: 26970755 DOI: 10.1007/s00125-016-3907-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Accepted: 01/19/2016] [Indexed: 12/01/2022]
Abstract
AIMS/HYPOTHESIS Islet amyloid, a pathological feature of type 2 diabetes, forms from the aggregation of islet amyloid polypeptide (IAPP), a beta cell peptide that is produced and co-secreted with insulin. Cholesterol regulates amyloid-β processing, deposition and clearance, promoting amyloidogenesis in the brain. ATP-binding cassette transporter 1 (ABCA1) is a cholesterol efflux transporter that when absent increases and when overexpressed reduces brain amyloid-β deposition in mouse models of Alzheimer's disease. We examined whether alterations in ABCA1 expression and islet cholesterol content could also modulate islet amyloidogenesis. METHODS Thioflavin S staining for amyloid was performed in islets isolated from mice with beta cell expression of human IAPP (hIAPP (Tg/o)) and cultured for 8 days following cholesterol loading, microRNA-33 overexpression (to reduce ABCA1 expression) or palmitate treatment in the presence or absence of ABCA1 overexpression or mevastatin treatment (to reduce cholesterol synthesis). hIAPP (Tg/o) mice were crossed with beta cell-specific Abca1-knockout mice (hIAPP (Tg/o) Abca1 (βKO)) and glucose tolerance and amyloid formation were assessed. RESULTS Cholesterol loading and microRNA-33-induced reduction in islet ABCA1 expression increased Thioflavin S-positive amyloid in hIAPP (Tg/o) islets. Palmitate treatment also increased amyloid formation and this was reduced by both ABCA1 overexpression and mevastatin treatment. hIAPP (Tg/o) Abca1 (βKO) mice had increased islet cholesterol, accompanied by fasting hyperglycaemia, glucose intolerance, impaired in vivo insulin secretion and an increased islet proinsulin:insulin ratio. Amyloid area was increased in cultured hIAPP (Tg/o) Abca1 (βKO) islets compared with hIAPP (Tg/o) controls. CONCLUSIONS/INTERPRETATION These data suggest that elevations in islet cholesterol may lead to increases in IAPP aggregation and islet amyloid formation, further worsening beta cell function and glucose homeostasis.
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Affiliation(s)
- Nadeeja Wijesekara
- Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Achint Kaur
- Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Clara Westwell-Roper
- Department of Pathology & Laboratory Medicine, Child & Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada
| | - Dominika Nackiewicz
- Department of Surgery, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Galina Soukhatcheva
- Department of Pathology & Laboratory Medicine, Child & Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada
| | - Michael R Hayden
- Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - C Bruce Verchere
- Department of Pathology & Laboratory Medicine, Child & Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
- Department of Surgery, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
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Fuentes AL, Hennessy K, Pascual J, Pepe N, Wang I, Santiago A, Chaggan C, Martinez J, Rivera E, Cota P, Cunha C, Nogaj LA, Moffet DA. Identification of Plant Extracts that Inhibit the Formation of Diabetes-Linked IAPP Amyloid. J Herb Med 2016; 6:37-41. [PMID: 27042401 DOI: 10.1016/j.hermed.2015.11.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The extracts of 27 vegetables, spices and herbs were screened for their functional ability to inhibit the aggregation of islet amyloid polypeptide (IAPP, amylin) into toxic amyloid aggregates. The aggregation of IAPP has been directly linked to the death of pancreatic β-islet cells in type 2 diabetes. Inhibiting the aggregation of IAPP is believed to have the potential to slow, if not prevent entirely, the progression of this disease. As vegetables, spices and herbs are known to possess many different positive health effects, the extracts of 27 plants (abundant within the United States and spanning several plant families) were screened for their ability to inhibit the formation of toxic IAPP aggregates. Their anti-amyloid activities were assessed through (1) thioflavin T binding assays, (2) visualization of amyloid fibers using atomic force microscopy and (3) cell rescue studies. From this research, mint, peppermint, red bell pepper and thyme emerged as possessing the greatest anti-amyloid activity.
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Affiliation(s)
- Ana Lucia Fuentes
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA 90045
| | - Kathleen Hennessy
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA 90045
| | - Jacob Pascual
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA 90045
| | - Nicole Pepe
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA 90045
| | - In Wang
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA 90045
| | - Alexander Santiago
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA 90045
| | - Cynthia Chaggan
- Department of Biology, Mount Saint Mary's College, 12001 Chalon Drive, Los Angeles, CA 90049
| | - Jessica Martinez
- Department of Biology, Mount Saint Mary's College, 12001 Chalon Drive, Los Angeles, CA 90049
| | - Evelyn Rivera
- Department of Biology, Mount Saint Mary's College, 12001 Chalon Drive, Los Angeles, CA 90049
| | - Paola Cota
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA 90045
| | - Christina Cunha
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA 90045
| | - Luiza A Nogaj
- Department of Biology, Mount Saint Mary's College, 12001 Chalon Drive, Los Angeles, CA 90049
| | - David A Moffet
- Department of Chemistry and Biochemistry, Loyola Marymount University, 1 LMU Drive, Los Angeles, CA 90045
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Wong AG, Wu C, Hannaberry E, Watson MD, Shea JE, Raleigh DP. Analysis of the Amyloidogenic Potential of Pufferfish (Takifugu rubripes) Islet Amyloid Polypeptide Highlights the Limitations of Thioflavin-T Assays and the Difficulties in Defining Amyloidogenicity. Biochemistry 2016; 55:510-8. [PMID: 26694855 PMCID: PMC5502355 DOI: 10.1021/acs.biochem.5b01107] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Islet amyloid polypeptide (IAPP, amylin) forms pancreatic amyloid in type-2 diabetes, a process that contributes to the loss of β-cell mass in the disease. IAPP has been found in all higher organisms examined, but not all species form amyloid and the ability to do so correlates with the primary sequence. The amyloidogenic potential of fish IAPPs has not been examined, although fish have been proposed as a source for xenobiotic transplantation. The sequence of pufferfish IAPP (Takifugu rubripes) is known and is the most divergent from human IAPP of any reported IAPP sequence, differing at 11 positions including seven located within residues 20-29, a segment of the molecule that is important for controlling amyloidogenicity. Several of the substitutions found in pufferfish IAPP are nonconservative including Ser to Pro, Asn to Thr, Ala to Tyr, and Leu to Tyr replacements, and several of these have not been reported in mammalian IAPP sequences. Amyloid prediction programs give conflicting results for pufferfish IAPP. CD spectroscopy, FTIR, and transmission electron microscopy reveal that pufferfish IAPP forms amyloid and does so more rapidly than human IAPP in tris buffer at pH 7.4, but does so more slowly in phosphate buffered saline (PBS) at pH 7.4. Molecular dynamics simulations indicate that the pufferfish sequence is compatible with models of IAPP amyloid. The fish polypeptide does not significantly bind to thioflavin-T in tris and does so only weakly in PBS. The results highlight difficulties with thioflavin-T assays and the ambiguity in defining amyloidogenicity.
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Affiliation(s)
- Amy G. Wong
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400
| | - Chun Wu
- Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, CA 93106-9510
| | - Eleni Hannaberry
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400
| | - Matthew D. Watson
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400
| | - Joan-Emma Shea
- Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, CA 93106-9510
| | - Daniel P. Raleigh
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400
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Montane J, de Pablo S, Obach M, Cadavez L, Castaño C, Alcarraz-Vizán G, Visa M, Rodríguez-Comas J, Parrizas M, Servitja JM, Novials A. Protein disulfide isomerase ameliorates β-cell dysfunction in pancreatic islets overexpressing human islet amyloid polypeptide. Mol Cell Endocrinol 2016; 420:57-65. [PMID: 26607804 DOI: 10.1016/j.mce.2015.11.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 11/13/2015] [Accepted: 11/13/2015] [Indexed: 01/09/2023]
Abstract
Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits in islets of type 2 diabetic patients. hIAPP misfolding and aggregation is one of the factors that may lead to β-cell dysfunction and death. Endogenous chaperones are described to be important for the folding and functioning of proteins. Here, we examine the effect of the endoplasmic reticulum chaperone protein disulfide isomerase (PDI) on β-cell dysfunction. Among other chaperones, PDI was found to interact with hIAPP in human islet lysates. Furthermore, intrinsically recovered PDI levels were able to restore the effect of high glucose- and palmitate-induced β-cell dysfunction by increasing 3.9-fold the glucose-stimulated insulin secretion levels and restoring insulin content up to basal control values. Additionally, PDI transduction decreased induced apoptosis by glucolipotoxic conditions. This approach could reveal a new therapeutic target and aid in the development of strategies to improve β-cell dysfunction in type 2 diabetic patients.
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Affiliation(s)
- Joel Montane
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Sara de Pablo
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Mercè Obach
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Lisa Cadavez
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Carlos Castaño
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Gema Alcarraz-Vizán
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Montserrat Visa
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Júlia Rodríguez-Comas
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Marcelina Parrizas
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Joan Marc Servitja
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Anna Novials
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
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Khodabandehloo H, Gorgani-Firuzjaee S, Panahi G, Meshkani R. Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction. Transl Res 2016; 167:228-56. [PMID: 26408801 DOI: 10.1016/j.trsl.2015.08.011] [Citation(s) in RCA: 206] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 08/29/2015] [Accepted: 08/31/2015] [Indexed: 12/13/2022]
Abstract
Obesity is a major public health problem worldwide, and it is associated with an increased risk of developing type 2 diabetes. It is now commonly accepted that chronic inflammation associated with obesity induces insulin resistance and β-cell dysfunction in diabetic patients. Obesity-associated inflammation is characterized by increased abundance of macrophages and enhanced production of inflammatory cytokines in adipose tissue. Adipose tissue macrophages are suggested to be the major source of local and systemic inflammatory mediators such as tumor necrosis factor α, interleukin (IL)-1β, and IL-6. These cytokines induce insulin resistance in insulin target tissues by activating the suppressors of cytokine signaling proteins, several kinases such as c-Jun N-terminal kinase, IκB kinase β, and protein kinase C, inducible nitric oxide synthase, extracellular signal-regulated kinase, and protein tyrosine phosphatases such as protein tyrosine phosphatase 1B. These activated factors impair the insulin signaling at the insulin receptor and the insulin receptor substrates levels. The same process most likely occurs in the pancreas as it contains a pool of tissue-resident macrophages. High concentrations of glucose or palmitate via the chemokine production promote further immune cell migration and infiltration into the islets. These events ultimately induce inflammatory responses leading to the apoptosis of the pancreatic β cells. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation are discussed, with particular attention being placed on the roles of the molecular players linking inflammation to insulin resistance and β-cell dysfunction.
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Affiliation(s)
- Hadi Khodabandehloo
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Sattar Gorgani-Firuzjaee
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Ghodratollah Panahi
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Reza Meshkani
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.
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Zerze GH, Mittal J. Effect of O-Linked Glycosylation on the Equilibrium Structural Ensemble of Intrinsically Disordered Polypeptides. J Phys Chem B 2015; 119:15583-92. [PMID: 26618856 DOI: 10.1021/acs.jpcb.5b10022] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Glycosylation is one of the most common post-translational modifications (PTMs), which provides a large proteome diversity. Previous work on glycosylation of globular proteins has revealed remarkable effects of glycosylation on protein function, altering the folding stability and structure and/or altering the protein surface which affects their binding characteristics. Intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs) of large proteins are also frequently glycosylated, yet how glycosylation affects their function remains to be elucidated. An important open question is, does glycosylation affect IDP structure or binding characteristics or both? In this work, we particularly address the structural effects of O-linked glycosylation by investigating glycosylated and unglycosylated forms of two different IDPs, tau174-183 and human islet amyloid polypeptide (hIAPP), by all-atom explicit solvent simulations. We simulate these IDPs in aqueous solution for O-linked glycosylated and unglycosylated forms by employing two modern all-atom force fields for which glycan parameters are also available. We find that O-linked glycosylation only has a modest effect on equilibrium structural ensembles of IDPs, for the cases studied here, which suggests that the functional role of glycosylation may be primarily exerted by modulation of the protein binding characteristics rather than structure.
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Affiliation(s)
- Gül H Zerze
- Department of Chemical and Biomolecular Engineering, Lehigh University , Bethlehem, Pennsylvania 18015, United States
| | - Jeetain Mittal
- Department of Chemical and Biomolecular Engineering, Lehigh University , Bethlehem, Pennsylvania 18015, United States
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Inflammasome, mTORC1 activation, and metabolic derangement contribute to the susceptibility of diabetics to infections. Med Hypotheses 2015; 85:997-1001. [DOI: 10.1016/j.mehy.2015.08.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 08/30/2015] [Indexed: 12/12/2022]
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Akter R, Cao P, Noor H, Ridgway Z, Tu LH, Wang H, Wong AG, Zhang X, Abedini A, Schmidt AM, Raleigh DP. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology. J Diabetes Res 2015; 2016:2798269. [PMID: 26649319 PMCID: PMC4662979 DOI: 10.1155/2016/2798269] [Citation(s) in RCA: 173] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 04/24/2015] [Indexed: 01/29/2023] Open
Abstract
The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy.
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Affiliation(s)
- Rehana Akter
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA
| | - Ping Cao
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA
| | - Harris Noor
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA
| | - Zachary Ridgway
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA
| | - Ling-Hsien Tu
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA
| | - Hui Wang
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA
| | - Amy G. Wong
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA
| | - Xiaoxue Zhang
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA
| | - Andisheh Abedini
- Diabetes Research Program, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Ann Marie Schmidt
- Diabetes Research Program, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Daniel P. Raleigh
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA
- Research Department of Structural and Molecule Biology, University College London, Gower Street, London WC1E 6BT, UK
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Wijesekara N, Ahrens R, Wu L, Ha K, Liu Y, Wheeler MB, Fraser PE. Islet amyloid inhibitors improve glucose homeostasis in a transgenic mouse model of type 2 diabetes. Diabetes Obes Metab 2015; 17:1003-6. [PMID: 26095311 DOI: 10.1111/dom.12529] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Revised: 06/03/2015] [Accepted: 06/14/2015] [Indexed: 11/29/2022]
Abstract
Increasing evidence points to the cytotoxicity of islet amyloid polypeptide (IAPP) aggregates as a major contributor to the loss of β-cell mass in type 2 diabetes. Prevention of IAPP formation represents a potential treatment to increase β-cell survival and function. The IAPP inhibitory peptide, D-ANFLVH, has been previously shown to prevent islet amyloid accumulation in cultured human islets. To assess its activity in vivo, D-ANFLVH was administered by intraperitoneal injection into a human IAPP transgenic mouse model, which replicates type 2 diabetes islet amyloid pathology. The peptide was a potent inhibitor of islet amyloid deposition, resulting in reduced islet cell apoptosis and preservation of β-cell area leading to improved glucose tolerance. These findings provide support for a key role of islet amyloid in β-cell survival and validate the application of anti-amyloid compounds as therapeutic strategies to maintain normal insulin secretion in patients with type 2 diabetes.
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Affiliation(s)
- N Wijesekara
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
| | - R Ahrens
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
| | - L Wu
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
| | - K Ha
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
| | - Y Liu
- Department of Physiology, University of Toronto, Toronto, Canada
| | - M B Wheeler
- Department of Physiology, University of Toronto, Toronto, Canada
| | - P E Fraser
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
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