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Wu Y, Wang H, Xu H. Autophagy-lysosome pathway in insulin & glucagon homeostasis. Front Endocrinol (Lausanne) 2025; 16:1541794. [PMID: 39996055 PMCID: PMC11847700 DOI: 10.3389/fendo.2025.1541794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 01/22/2025] [Indexed: 02/26/2025] Open
Abstract
Lysosome, a highly dynamic organelle, is an important nutrient sensing center. They utilize different ion channels and transporters to complete the mission in degradation, trafficking, nutrient sensing and integration of various metabolic pathways to maintain cellular homeostasis. Glucose homeostasis relies on tightly regulated insulin secretion by pancreatic β cells, and their dysfunction is a hallmark of type 2 diabetes. Glucagon also plays an important role in hyperglycemia in diabetic patients. Currently, lysosome has been recognized as a nutrient hub to regulate the homeostasis of insulin and other hormones. In this review, we will discuss recent advances in understanding lysosome-mediated autophagy and lysosomal proteins involved in maintaining insulin and glucagon homeostasis, as well as their contributions to the etiology of diabetes.
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Affiliation(s)
- Yi Wu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
- Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
- Shanghai Key Laboratory of Molecular Imaging, School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Hui Wang
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Huoyan Xu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
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Ou Y, Zhao YL, Su H. Pancreatic β-Cells, Diabetes and Autophagy. Endocr Res 2025; 50:12-27. [PMID: 39429147 DOI: 10.1080/07435800.2024.2413064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 07/23/2024] [Accepted: 08/18/2024] [Indexed: 10/22/2024]
Abstract
PURPOSE Pancreatic β-cells play a critical role in regulating plasma insulin levels and glucose metabolism balance, with their dysfunction being a key factor in the progression of diabetes. This review aims to explore the role of autophagy, a vital cellular self-maintenance process, in preserving pancreatic β-cell functionality and its implications in diabetes pathogenesis. METHODS We examine the current literature on the role of autophagy in β-cells, highlighting its function in maintaining cell structure, quantity, and function. The review also discusses the effects of both excessive and insufficient autophagy on β-cell dysfunction and glucose metabolism imbalance. Furthermore, we discuss potential therapeutic agents that modulate the autophagy pathway to influence β-cell function, providing insights into therapeutic strategies for diabetes management. RESULTS Autophagy acts as a self-protective mechanism within pancreatic β-cells, clearing damaged organelles and proteins to maintain cellular stability. Abnormal autophagy activity, either overactive or deficient, can disrupt β-cell function and glucose regulation, contributing to diabetes progression. CONCLUSION Autophagy plays a pivotal role in maintaining pancreatic β-cell function, and its dysregulation is implicated in the development of diabetes. Targeting the autophagy pathway offers potential therapeutic strategies for diabetes management, with agents that modulate autophagy showing promise in preserving β-cell function.
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Affiliation(s)
- Yang Ou
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, P.R. China
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, P.R. China
| | - Yan-Li Zhao
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan Province, China
| | - Heng Su
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, P.R. China
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3
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Jiang L, Song X, Yan L, Liu Y, Qiao X, Zhang W. Molecular insights into the interplay between type 2 diabetes mellitus and osteoporosis: implications for endocrine health. Front Endocrinol (Lausanne) 2025; 15:1483512. [PMID: 39897963 PMCID: PMC11782046 DOI: 10.3389/fendo.2024.1483512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 12/05/2024] [Indexed: 02/04/2025] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) and osteoporosis are prevalent, interconnected chronic diseases that significantly impact global health. Understanding their complex biological relationship is crucial for improving patient outcomes and treatment strategies. Method This review examines recent research on the mechanisms linking T2DM with osteoporosis. It focuses on how abnormalities in bone metabolism, autophagy, ferroptosis, and vitamin D receptor (VDR) gene polymorphisms contribute to osteoporosis in T2DM patients. Results Our analysis indicates that T2DM is associated with reduced bone formation and increased bone resorption, which are influenced by hormonal changes, inflammation, and disrupted cellular signaling pathways. Additionally, increased perirenal fat thickness worsens osteoporosis through local inflammation and altered adipokine levels. VDR gene polymorphisms provide new molecular insights into this connection. Conclusion Addressing the identified mechanisms with targeted management strategies may improve bone health in individuals with T2DM. Future research should explore these associations in greater detail to develop more effective prevention and treatment strategies.
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Affiliation(s)
- Liyun Jiang
- Medical Laboratory Center, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xia Song
- Medical Laboratory Center, The First Hospital of Lanzhou University, Lanzhou, China
| | - Li Yan
- Medical Laboratory Center, Gansu Provincial People’s Hospital, Lanzhou, China
| | - Yali Liu
- Medical Laboratory Center, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiumei Qiao
- Medical Laboratory Center, The First Hospital of Lanzhou University, Lanzhou, China
| | - Wen Zhang
- Medical Laboratory Center, The First Hospital of Lanzhou University, Lanzhou, China
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El-Akabawy G, Eid N. Enhancing metformin efficacy with cholecalciferol and taurine in diabetes therapy: Potential and limitations. World J Diabetes 2025; 16:100066. [PMID: 39817227 PMCID: PMC11718465 DOI: 10.4239/wjd.v16.i1.100066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/04/2024] [Accepted: 11/15/2024] [Indexed: 11/29/2024] Open
Abstract
Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), poses a significant global health challenge. Traditional management strategies primarily focus on glycemic control; however, there is a growing need for comprehensive approaches addressing the complex pathophysiology of diabetes complications. The recent study by Attia et al explores the potential of a novel therapy combining metformin with cholecalciferol (vitamin D3) and taurine to mitigate T2DM-related complications in a rat model. The findings indicate that this treatment combination improves glycemic control and reduces oxidative stress, inflammation, and lipid abnormalities. However, the study is limited by a lack of safety profile data and in-depth molecular mechanism insights. This editorial critically highlights the study's strengths and weaknesses, compares it against other combination therapy research in T2DM, and underscores the need to explore further the mechanisms underpinning the observed therapeutic effects and investigate the safety profile of this novel approach.
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Affiliation(s)
- Gehan El-Akabawy
- Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman 346, United Arab Emirates
| | - Nabil Eid
- Department of Anatomy, Division of Human Biology, School of Medicine, IMU University, Kuala Lumpur 57000, Malaysia
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Zhu B, Sun L, Tong J, Ding Y, Shan Y, He M, Tian X, Mei W, Zhao L, Wang Y. Neuregulin 4 attenuates pancreatic β-cell apoptosis induced by lipotoxicity via activating mTOR-mediated autophagy. Islets 2024; 16:2429854. [PMID: 39541216 PMCID: PMC11572226 DOI: 10.1080/19382014.2024.2429854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 10/19/2024] [Accepted: 11/11/2024] [Indexed: 11/16/2024] Open
Abstract
Neuregulin 4 (Nrg4) is a brown fat-enriched endocrine factor that ameliorates lipid metabolism disorders. Autophagy is critical for pancreatic β-cell to counteract lipotoxicity-induced apoptosis. This study aimed at exploring whether Nrg4 attenuates lipotoxicity-induced β-cell apoptosis by regulating autophagy. The mouse pancreatic β-cell line MIN6 was cultured in palmitic acid (PA) with or without Nrg4 administration. Apoptosis rate, together with anti-apoptotic and pro-apoptotic protein levels, was investigated. Autophagic flux and autophagy-related protein levels along with related signaling pathways that regulate autophagy were also evaluated. Results showed that Nrg4 decreased PA-induced MIN6 apoptosis, enhanced anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) expression and reduced pro-apoptotic proteins Bcl-2-associated X protein (Bax) and cleaved-caspase 3 expressions. Autophagy levels in MIN6 also decreased with PA treatment and Nrg4 administration reactivated autophagy. Further, Nrg4 administration activated autophagy via the mammalian target of rapamycin (mTOR) signaling pathway. In addition, when the mTOR pathway was stimulated or autophagy was suppressed, the beneficial effects of Nrg4 administration on MIN6 apoptosis were diminished. These results imply that Nrg4 administration attenuates MIN6 apoptosis by promoting mTOR-dependent autophagy and thus may lead to a new therapeutic method for type 2 diabetes mellitus (T2DM).
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Affiliation(s)
- Biao Zhu
- Department of Stomatology, Fuxing Hospital, Capital Medical University, Beijing, China
| | - Lei Sun
- Department of Stomatology, The Ninth Medical Center,Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Junyao Tong
- Department of Stomatology, The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Yan Ding
- Department of Endocrinology, General Hospital of Central Theater Command, Southern Medical University, Wuhan, Hubei Province, China
| | - Yanbo Shan
- Department of Stomatology, The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Mingjuan He
- Department of Endocrinology, General Hospital of Central Theater Command, Southern Medical University, Wuhan, Hubei Province, China
| | - Xiaoyu Tian
- Department of Stomatology, The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Wen Mei
- Department of Endocrinology, General Hospital of Central Theater Command, Southern Medical University, Wuhan, Hubei Province, China
| | - Lisheng Zhao
- Department of Stomatology, The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Ying Wang
- Department of Stomatology, The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
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Long L, Huang Q, Song T, Dai Z. Myo-inositol rescued insulin resistance and dyslipidemia in db/db mice. J Appl Biomed 2024; 22:74-80. [PMID: 38912862 DOI: 10.32725/jab.2024.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 06/12/2024] [Indexed: 06/25/2024] Open
Abstract
Myo-inositol (MI), present in a variety of foods, is essential in several important processes of cell physiology. In this study, we explored the protective effects of MI against hyperglycemia and dyslipidemia in db/db mice, a typical animal model of type 2 diabetes mellitus (T2DM). MI supplement effectively suppressed the high plasma glucose and insulin levels and markedly relieved the insulin resistance (IR) in the db/db mice, comparable to metformin's effects. In MIN6 pancreatic β cells, MI also restrained the upsurge of insulin secretion stimulated by high-concentration glucose but had no impact on the promoted cell proliferation. Moreover, MI abated the enhanced plasma triglyceride and total cholesterol levels in the db/db mice. Notably, the lipid droplet formation of mesenchymal stem cells (MSCs) from db/db mice was significantly diminished after the treatment of MI, indicating that MI could effectively inhibit the differentiation of db/db mouse MSCs into adipocytes. However, MI regretfully failed to control obesity in db/db mice. This work proved that MI significantly helped db/db mice's metabolic disorders, indicating that MI has potential as an effective adjunctive treatment for hyperglycemia and dyslipidemia in T2DM patients.
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Affiliation(s)
- Lingzhi Long
- Hunan Provincial People's Hospital (The First-affiliated Hospital of Hunan Normal University), Department of Pharmacy, Changsha, China
| | - Qi Huang
- Hunan Provincial People's Hospital (The First-affiliated Hospital of Hunan Normal University), Department of Pharmacy, Changsha, China
| | - Tao Song
- Central South University, Xiangya Hospital, Department of Neurosurgery, Changsha, China
| | - Zhijie Dai
- The Second Xiangya Hospital of Central South University, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Changsha, China
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Zamanian MY, Golmohammadi M, Yumashev A, Hjazi A, Toama MA, AbdRabou MA, Gehlot A, Alwaily ER, Shirsalimi N, Yadav PK, Moriasi G. Effects of metformin on cancers in experimental and clinical studies: Focusing on autophagy and AMPK/mTOR signaling pathways. Cell Biochem Funct 2024; 42:e4071. [PMID: 38863255 DOI: 10.1002/cbf.4071] [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: 03/23/2024] [Revised: 05/25/2024] [Accepted: 06/02/2024] [Indexed: 06/13/2024]
Abstract
Metformin (MET) is a preferred drug for the treatment of type 2 diabetes mellitus. Recent studies show that apart from its blood glucose-lowering effects, it also inhibits the development of various tumours, by inducing autophagy. Various studies have confirmed the inhibitory effects of MET on cancer cell lines' propagation, migration, and invasion. The objective of the study was to comprehensively review the potential of MET as an anticancer agent, particularly focusing on its ability to induce autophagy and inhibit the development and progression of various tumors. The study aimed to explore the inhibitory effects of MET on cancer cell proliferation, migration, and invasion, and its impact on key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and PI3K. This review noted that MET exerts its anticancer effects by regulating key signalling pathways such as phosphoinositide 3-kinase (PI3K), LC3-I and LC3-II, Beclin-1, p53, and the autophagy-related gene (ATG), inhibiting the mTOR protein, downregulating the expression of p62/SQSTM1, and blockage of the cell cycle at the G0/G1. Moreover, MET can stimulate autophagy through pathways associated with the 5' AMPK, thereby inhibiting he development and progression of various human cancers, including hepatocellular carcinoma, prostate cancer, pancreatic cancer, osteosarcoma, myeloma, and non-small cell lung cancer. In summary, this detailed review provides a framework for further investigations that may appraise the autophagy-induced anticancer potential of MET and its repurposing for cancer treatment.
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Affiliation(s)
- Mohammad Yasin Zamanian
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Maryam Golmohammadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alexey Yumashev
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Mariam Alaa Toama
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | | | - Anita Gehlot
- Department of Electronics & Communication Engineering, Uttaranchal Institute of Technology, Uttaranchal University, Dehradun, India
| | - Enas R Alwaily
- Microbiology Research Group, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Niyousha Shirsalimi
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Pankaj Kumar Yadav
- Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, India
| | - Gervason Moriasi
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Mount Kenya University, Thika, Kenya
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8
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Theron IJ, Mason S, van Reenen M, Stander Z, Kleynhans L, Ronacher K, Loots DT. Characterizing poorly controlled type 2 diabetes using 1H-NMR metabolomics. Metabolomics 2024; 20:54. [PMID: 38734832 PMCID: PMC11088559 DOI: 10.1007/s11306-024-02127-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 05/02/2024] [Indexed: 05/13/2024]
Abstract
INTRODUCTION The prevalence of type 2 diabetes has surged to epidemic proportions and despite treatment administration/adherence, some individuals experience poorly controlled diabetes. While existing literature explores metabolic changes in type 2 diabetes, understanding metabolic derangement in poorly controlled cases remains limited. OBJECTIVE This investigation aimed to characterize the urine metabolome of poorly controlled type 2 diabetes in a South African cohort. METHOD Using an untargeted proton nuclear magnetic resonance metabolomics approach, urine samples from 15 poorly controlled type 2 diabetes patients and 25 healthy controls were analyzed and statistically compared to identify differentiating metabolites. RESULTS The poorly controlled type 2 diabetes patients were characterized by elevated concentrations of various metabolites associated with changes to the macro-fuel pathways (including carbohydrate metabolism, ketogenesis, proteolysis, and the tricarboxylic acid cycle), autophagy and/or apoptosis, an uncontrolled diet, and kidney and liver damage. CONCLUSION These results indicate that inhibited cellular glucose uptake in poorly controlled type 2 diabetes significantly affects energy-producing pathways, leading to apoptosis and/or autophagy, ultimately contributing to kidney and mild liver damage. The study also suggests poor dietary compliance as a cause of the patient's uncontrolled glycemic state. Collectively these findings offer a first-time comprehensive overview of urine metabolic changes in poorly controlled type 2 diabetes and its association with secondary diseases, offering potential insights for more targeted treatment strategies to prevent disease progression, treatment efficacy, and diet/treatment compliance.
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Affiliation(s)
- Isabella J Theron
- Human Metabolomics, Department of Biochemistry, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
| | - Shayne Mason
- Human Metabolomics, Department of Biochemistry, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
| | - Mari van Reenen
- Human Metabolomics, Department of Biochemistry, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
| | - Zinandré Stander
- Human Metabolomics, Department of Biochemistry, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
| | - Léanie Kleynhans
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa
- Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Katharina Ronacher
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa
- Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia
| | - Du Toit Loots
- Human Metabolomics, Department of Biochemistry, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa.
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Nguyen HT, Wiederkehr A, Wollheim CB, Park KS. Regulation of autophagy by perilysosomal calcium: a new player in β-cell lipotoxicity. Exp Mol Med 2024; 56:273-288. [PMID: 38297165 PMCID: PMC10907728 DOI: 10.1038/s12276-024-01161-x] [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: 05/03/2023] [Revised: 10/16/2023] [Accepted: 11/09/2023] [Indexed: 02/02/2024] Open
Abstract
Autophagy is an essential quality control mechanism for maintaining organellar functions in eukaryotic cells. Defective autophagy in pancreatic beta cells has been shown to be involved in the progression of diabetes through impaired insulin secretion under glucolipotoxic stress. The underlying mechanism reveals the pathologic role of the hyperactivation of mechanistic target of rapamycin (mTOR), which inhibits lysosomal biogenesis and autophagic processes. Moreover, accumulating evidence suggests that oxidative stress induces Ca2+ depletion in the endoplasmic reticulum (ER) and cytosolic Ca2+ overload, which may contribute to mTOR activation in perilysosomal microdomains, leading to autophagic defects and β-cell failure due to lipotoxicity. This review delineates the antagonistic regulation of autophagic flux by mTOR and AMP-dependent protein kinase (AMPK) at the lysosomal membrane, and both of these molecules could be activated by perilysosomal calcium signaling. However, aberrant and persistent Ca2+ elevation upon lipotoxic stress increases mTOR activity and suppresses autophagy. Therefore, normalization of autophagy is an attractive therapeutic strategy for patients with β-cell failure and diabetes.
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Affiliation(s)
- Ha Thu Nguyen
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea
- Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | | | - Claes B Wollheim
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
- Department of Clinical Sciences, Lund University, Malmö, Sweden.
| | - Kyu-Sang Park
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.
- Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.
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Aziel Alvarado-Ojeda Z, Zamilpa A, Costet-Mejia A, Méndez-Martínez M, Trejo-Moreno C, Jiménez-Ferrer JE, Salazar-Martínez AM, Cruz-Muñoz ME, Fragoso G, Rosas-Salgado G. Hydroalcoholic extract from Sechium edule (Jacq.) S.w. root reverses oleic acid-induced steatosis and insulin resistance in vitro. Heliyon 2024; 10:e24567. [PMID: 38312619 PMCID: PMC10835324 DOI: 10.1016/j.heliyon.2024.e24567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 12/17/2023] [Accepted: 01/10/2024] [Indexed: 02/06/2024] Open
Abstract
Steatosis is characterized by fat accumulation and insulin resistance (IR) in hepatocytes, which triggers a pro-oxidant, pro-inflammatory environment that may eventually lead to cirrhosis or liver carcinoma. This work was aimed to assess the effect of Sechium edule root hydroalcoholic extract (rSe-HA) (rich in cinnamic and coumaric acid, among other phenolic compounds) on triglyceride esterification, lipid degradation, AMPK expression, and the phosphorylation of insulin receptor in a Ser312 residue, as well as on the redox status, malondialdehyde (MDA) production, and the production of proinflammatory cytokines in an in vitro model of steatosis induced by oleic acid, to help develop a phytomedicine that could reverse this pathology. rSe-HA reduced triglyceride levels in hepatocyte lysates, increased lipolysis by activating AMPK at Thr172, and improved the redox status, as evidenced by the concentration of glycerol and formazan, respectively. It also prevented insulin resistance (IR), as measured by glucose consumption and the phosphorylation of the insulin receptor at Ser312. It also prevented TNFα and IL6 production and decreased the levels of MDA and nitric oxide (ON). Our results indicate that rSe-HA reversed steatosis and controlled the proinflammatory and prooxidant environment in oleic acid-induced dysfunctional HepG2 hepatocytes, supporting its potential use to control this disorder.
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Affiliation(s)
- Zimri Aziel Alvarado-Ojeda
- Facultad de Medicina, Universidad Autónoma Del Estado de Morelos, Leñeros S/N, Cuernavaca, Morelos, 62350, Mexico
| | - Alejandro Zamilpa
- Laboratorio de Farmacología, Centro de Investigaciones Biomédicas Del Sur, Instituto Mexicano Del Seguro Social, Xochitepec, Morelos, 62790, Mexico
| | - Alejandro Costet-Mejia
- Laboratorio de Farmacología, Centro de Investigaciones Biomédicas Del Sur, Instituto Mexicano Del Seguro Social, Xochitepec, Morelos, 62790, Mexico
| | - Marisol Méndez-Martínez
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana-Xochimilco, 04960, Mexico City, Mexico
| | - Celeste Trejo-Moreno
- Facultad de Medicina, Universidad Autónoma Del Estado de Morelos, Leñeros S/N, Cuernavaca, Morelos, 62350, Mexico
| | - Jesús Enrique Jiménez-Ferrer
- Laboratorio de Farmacología, Centro de Investigaciones Biomédicas Del Sur, Instituto Mexicano Del Seguro Social, Xochitepec, Morelos, 62790, Mexico
| | - Ana Maria Salazar-Martínez
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Coyoacán, 04510, Mexico City, Mexico
| | - Mario Ernesto Cruz-Muñoz
- Facultad de Medicina, Universidad Autónoma Del Estado de Morelos, Leñeros S/N, Cuernavaca, Morelos, 62350, Mexico
| | - Gladis Fragoso
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Coyoacán, 04510, Mexico City, Mexico
| | - Gabriela Rosas-Salgado
- Facultad de Medicina, Universidad Autónoma Del Estado de Morelos, Leñeros S/N, Cuernavaca, Morelos, 62350, Mexico
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Sadeghi A, Niknam M, Momeni-Moghaddam MA, Shabani M, Aria H, Bastin A, Teimouri M, Meshkani R, Akbari H. Crosstalk between autophagy and insulin resistance: evidence from different tissues. Eur J Med Res 2023; 28:456. [PMID: 37876013 PMCID: PMC10599071 DOI: 10.1186/s40001-023-01424-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 10/03/2023] [Indexed: 10/26/2023] Open
Abstract
Insulin is a critical hormone that promotes energy storage in various tissues, as well as anabolic functions. Insulin resistance significantly reduces these responses, resulting in pathological conditions, such as obesity and type 2 diabetes mellitus (T2DM). The management of insulin resistance requires better knowledge of its pathophysiological mechanisms to prevent secondary complications, such as cardiovascular diseases (CVDs). Recent evidence regarding the etiological mechanisms behind insulin resistance emphasizes the role of energy imbalance and neurohormonal dysregulation, both of which are closely regulated by autophagy. Autophagy is a conserved process that maintains homeostasis in cells. Accordingly, autophagy abnormalities have been linked to a variety of metabolic disorders, including insulin resistance, T2DM, obesity, and CVDs. Thus, there may be a link between autophagy and insulin resistance. Therefore, the interaction between autophagy and insulin function will be examined in this review, particularly in insulin-responsive tissues, such as adipose tissue, liver, and skeletal muscle.
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Affiliation(s)
- Asie Sadeghi
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Niknam
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Maryam Shabani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Aria
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Bastin
- Clinical Research Development Center "The Persian Gulf Martyrs" Hospital, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Maryam Teimouri
- Department of Biochemistry, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Reza Meshkani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Akbari
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran.
- Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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Zhao X, Bie LY, Pang DR, Li X, Yang LF, Chen DD, Wang YR, Gao Y. The role of autophagy in the treatment of type II diabetes and its complications: a review. Front Endocrinol (Lausanne) 2023; 14:1228045. [PMID: 37810881 PMCID: PMC10551182 DOI: 10.3389/fendo.2023.1228045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 08/24/2023] [Indexed: 10/10/2023] Open
Abstract
Type II diabetes mellitus (T2DM) is a chronic metabolic disease characterized by prolonged hyperglycemia and insulin resistance (IR). Its incidence is increasing annually, posing a significant threat to human life and health. Consequently, there is an urgent requirement to discover effective drugs and investigate the pathogenesis of T2DM. Autophagy plays a crucial role in maintaining normal islet structure. However, in a state of high glucose, autophagy is inhibited, resulting in impaired islet function, insulin resistance, and complications. Studies have shown that modulating autophagy through activation or inhibition can have a positive impact on the treatment of T2DM and its complications. However, it is important to note that the specific regulatory mechanisms vary depending on the target organ. This review explores the role of autophagy in the pathogenesis of T2DM, taking into account both genetic and external factors. It also provides a summary of reported chemical drugs and traditional Chinese medicine that target the autophagic pathway for the treatment of T2DM and its complications.
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Affiliation(s)
- Xuan Zhao
- Institute of Pharmaceutical Research, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lu-Yao Bie
- Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Dao-Ran Pang
- Institute of Pharmaceutical Research, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiao Li
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Long-Fei Yang
- Institute of Pharmaceutical Research, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Dan-Dan Chen
- Institute of Pharmaceutical Research, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yue-Rui Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yan Gao
- Institute of Pharmaceutical Research, Shandong University of Traditional Chinese Medicine, Jinan, China
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13
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Hela F, Aguayo-Mazzucato C. Interaction between Autophagy and Senescence in Pancreatic Beta Cells. BIOLOGY 2023; 12:1205. [PMID: 37759604 PMCID: PMC10525299 DOI: 10.3390/biology12091205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/01/2023] [Accepted: 09/02/2023] [Indexed: 09/29/2023]
Abstract
Aging leads to an increase in cellular stress due to the fragility of the organism and the inability to cope with it. In this setting, there is a higher chance of developing different cardiometabolic diseases like diabetes. Cellular senescence and autophagy, both hallmarks of aging and stress-coping mechanisms, have gained increased attention for their role in the pathophysiology of diabetes. Studies show that impairing senescence dampens and even prevents diabetes while the role of autophagy is more contradictory, implying a context- and disease-stage-dependent effect. Reports show conflicting data about the effect of autophagy on senescence while the knowledge about this interaction in beta cells remains scarce. Elucidating this interaction between autophagy and senescence in pancreatic beta cells will lead to an identification of their respective roles and the extent of the effect each mechanism has on beta cells and open new horizons for developing novel therapeutic agents. To help illuminate this relationship we will review the latest findings of cellular senescence and autophagy with a special emphasis on pancreatic beta cells and diabetes.
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Affiliation(s)
| | - Cristina Aguayo-Mazzucato
- Section on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
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14
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Kaewin S, Poolsri W, Korkut GG, Patrakka J, Aiebchun T, Rungrotmongkol T, Sungkaworn T, Sukanadi IB, Chavasiri W, Muanprasat C. A sulfonamide chalcone AMPK activator ameliorates hyperglycemia and diabetic nephropathy in db/db mice. Biomed Pharmacother 2023; 165:115158. [PMID: 37473685 DOI: 10.1016/j.biopha.2023.115158] [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: 02/21/2023] [Revised: 07/09/2023] [Accepted: 07/11/2023] [Indexed: 07/22/2023] Open
Abstract
Diabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which currently lacks effective treatments. AMP-activated protein kinase (AMPK) stimulation by chalcones, a class of polyphenols abundantly found in plants, is proposed as a promising therapeutic approach for DM. This study aimed to identify novel chalcone derivatives with improved AMPK-stimulating activity in human podocytes and evaluate their mechanisms of action as well as in vivo efficacy in a mouse model of DN. Among 133 chalcone derivatives tested, the sulfonamide chalcone derivative IP-004 was identified as the most potent AMPK activator in human podocytes. Western blot analyses, intracellular calcium measurements and molecular docking simulation indicated that IP-004 activated AMPK by mechanisms involving direct binding at allosteric site of calcium-dependent protein kinase kinase β (CaMKKβ) without affecting intracellular calcium levels. Interestingly, eight weeks of intraperitoneal administration of IP-004 (20 mg/kg/day) significantly decreased fasting blood glucose level, activated AMPK in the livers, muscles and glomeruli, and ameliorated albuminuria in db/db type II diabetic mice. Collectively, this study identifies a novel chalcone derivative capable of activating AMPK in vitro and in vivo and exhibiting efficacy against hyperglycemia and DN in mice. Further development of AMPK activators based on chalcone derivatives may provide an effective treatment of DN.
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Affiliation(s)
- Suchada Kaewin
- Department of Physiology, Faculty of Science, Mahidol University, Rama VI Road, Ratchathewi, Bangkok 10400, Thailand; Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakarn 10540, Thailand
| | - Wanangkan Poolsri
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakarn 10540, Thailand
| | - Gül Gizem Korkut
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Jaakko Patrakka
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Thitinan Aiebchun
- Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
| | - Thanyada Rungrotmongkol
- Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
| | - Titiwat Sungkaworn
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakarn 10540, Thailand
| | - I Butu Sukanadi
- Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
| | - Warinthorn Chavasiri
- Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
| | - Chatchai Muanprasat
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakarn 10540, Thailand.
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15
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Obradovic M, Zafirovic S, Gluvic Z, Radovanovic J, Isenovic ER. Autophagy and diabetes. EXPLORATION OF MEDICINE 2023:576-588. [DOI: 10.37349/emed.2023.00162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 05/29/2023] [Indexed: 10/13/2023] Open
Abstract
The current literature findings on autophagy’s beneficial and detrimental roles in diabetes mellitus (DM) and diabetes-related comorbidities were reviewed. The effects of oral hypoglycaemic medicines and autophagy in DM. Autophagy plays an important function in cellular homeostasis by promoting cell survival or initiating cell death in physiological settings was also assessed. Although autophagy protects insulin-target tissues, organelle failure caused by autophagy malfunction influences DM and other metabolic diseases. Endoplasmic reticulum and oxidative stress enhance autophagy levels, making it easier to regulate stress-induced intracellular changes. Evidence suggests that autophagy-caused cell death can occur when autophagy is overstimulated and constitutively activated, which might prevent or develop DM. Even though the precise role of autophagy in DM complications is uncertain, deregulation of the autophagic machinery is strongly linked to beta cell destruction and the aetiology of DM. Thus, improving autophagy dysfunction is a possible therapeutic objective in treating DM and other metabolic disorders.
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Affiliation(s)
- Milan Obradovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Sonja Zafirovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Zoran Gluvic
- Department of Endocrinology and Diabetes, Zemun Clinical Hospital, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Jelena Radovanovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Esma R. Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
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16
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Wei P, Wang M, Lin M, Wang Z. Tripterine Serves a Dual Role in Palmitate-Induced Pancreatic Beta-Cell Lipotoxicity. DOKL BIOCHEM BIOPHYS 2023; 511:156-161. [PMID: 37833599 DOI: 10.1134/s1607672923600057] [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] [Indexed: 10/15/2023]
Abstract
Tripterine (TP, also called celastrol), a pentacyclic triterpene extracted from Tripterygium wilfordii, has beneficial effects on multiple diseases, including obesity and diabetes. However, the effects of TP on β‑cell lipotoxicity have not been fully explored. Here, we found that TP modulated β-cell lipotoxicity in a concentration-dependent and bidirectional manner. At low concentrations, TP potentially protected MIN6 β-cells from palmitate (PA)-induced lipotoxicity. At high concentrations, TP significantly promoted β-cell lipotoxicity, further reinforcing PA-induced cell apoptosis. Furthermore, low-concentration TP inhibited the PA-induced increase in reactive oxygen species (ROS) levels, and its protective effects were abolished by the ROS inducer tert-butyl hydroperoxide. Conversely, high-concentration TP significantly exacerbated the PA-triggered ROS generation, and its enhanced cytotoxicity was partially reversed by the ROS inhibitor N-acetyl-L-cysteine. Thus, TP plays a dual role in β-cell lipotoxicity, suggesting that care should be taken when it is used for obesity and diabetes treatment.
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Affiliation(s)
- Pei Wei
- Department of Immunology, Zhuhai Campus of Zunyi Medical University, Zhuhai, China
| | - Min Wang
- Department of Pharmacy, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Mao Lin
- Department of Physiology, Zhuhai Campus of Zunyi Medical University, Zhuhai, China
| | - Zhiyong Wang
- Department of Immunology, Zhuhai Campus of Zunyi Medical University, Zhuhai, China.
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17
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Dong Y, Qi Y, Jiang H, Mi T, Zhang Y, Peng C, Li W, Zhang Y, Zhou Y, Zang Y, Li J. The development and benefits of metformin in various diseases. Front Med 2023; 17:388-431. [PMID: 37402952 DOI: 10.1007/s11684-023-0998-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/01/2023] [Indexed: 07/06/2023]
Abstract
Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.
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Affiliation(s)
- Ying Dong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yingbei Qi
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Haowen Jiang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Tian Mi
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yunkai Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chang Peng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Wanchen Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yongmei Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Yubo Zhou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
| | - Yi Zang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- Lingang Laboratory, Shanghai, 201203, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
| | - Jia Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, 266237, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China.
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18
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Mohammadi-Motlagh HR, Sadeghalvad M, Yavari N, Primavera R, Soltani S, Chetty S, Ganguly A, Regmi S, Fløyel T, Kaur S, Mirza AH, Thakor AS, Pociot F, Yarani R. β Cell and Autophagy: What Do We Know? Biomolecules 2023; 13:biom13040649. [PMID: 37189396 DOI: 10.3390/biom13040649] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 03/27/2023] [Accepted: 03/30/2023] [Indexed: 05/17/2023] Open
Abstract
Pancreatic β cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in β cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in β cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects β cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect β cells' fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to β cell failure.
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Affiliation(s)
- Hamid-Reza Mohammadi-Motlagh
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 67155-1616, Iran
| | - Mona Sadeghalvad
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1416634793, Iran
| | - Niloofar Yavari
- Department of Cellular and Molecular Medicine, The Panum Institute, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Rosita Primavera
- Interventional Regenerative Innovation at Stanford (IRIS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Setareh Soltani
- Clinical Research Development Center, Taleghani and Imam Ali Hospital, Kermanshah University of Medical Sciences, Kermanshah 67145-1673, Iran
| | - Shashank Chetty
- Interventional Regenerative Innovation at Stanford (IRIS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Abantika Ganguly
- Interventional Regenerative Innovation at Stanford (IRIS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Shobha Regmi
- Interventional Regenerative Innovation at Stanford (IRIS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Tina Fløyel
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
| | - Simranjeet Kaur
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
| | - Aashiq H Mirza
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Avnesh S Thakor
- Interventional Regenerative Innovation at Stanford (IRIS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Flemming Pociot
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
- Institute for Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Reza Yarani
- Interventional Regenerative Innovation at Stanford (IRIS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
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19
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Du Y, Zhu YJ, Zhou YX, Ding J, Liu JY. Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study. MOLECULAR BIOMEDICINE 2022; 3:41. [PMID: 36484892 PMCID: PMC9733765 DOI: 10.1186/s43556-022-00108-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/18/2022] [Indexed: 12/13/2022] Open
Abstract
Metformin, a biguanide drug, is the most commonly used first-line medication for type 2 diabetes mellites due to its outstanding glucose-lowering ability. After oral administration of 1 g, metformin peaked plasma concentration of approximately 20-30 μM in 3 h, and then it mainly accumulated in the gastrointestinal tract, liver and kidney. Substantial studies have indicated that metformin exerts its beneficial or deleterious effect by multiple mechanisms, apart from AMPK-dependent mechanism, also including several AMPK-independent mechanisms, such as restoring of redox balance, affecting mitochondrial function, modulating gut microbiome and regulating several other signals, such as FBP1, PP2A, FGF21, SIRT1 and mTOR. On the basis of these multiple mechanisms, researchers tried to repurpose this old drug and further explored the possible indications and adverse effects of metformin. Through investigating with clinical studies, researchers concluded that in addition to decreasing cardiovascular events and anti-obesity, metformin is also beneficial for neurodegenerative disease, polycystic ovary syndrome, aging, cancer and COVID-19, however, it also induces some adverse effects, such as gastrointestinal complaints, lactic acidosis, vitamin B12 deficiency, neurodegenerative disease and offspring impairment. Of note, the dose of metformin used in most studies is much higher than its clinically relevant dose, which may cast doubt on the actual effects of metformin on these disease in the clinic. This review summarizes these research developments on the mechanism of action and clinical evidence of metformin and discusses its therapeutic potential and clinical safety.
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Affiliation(s)
- Yang Du
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Ya-Juan Zhu
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yi-Xin Zhou
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Jing Ding
- grid.54549.390000 0004 0369 4060Department of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan China
| | - Ji-Yan Liu
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
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20
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Çakır Gündoğdu A, Take Kaplanoğlu G, Ören S, Baykal B, Korkmaz C, Gümüşlü S, Karabacak RO. Impact of 5'-AMP-activated protein kinase (AMPK) on Epithelial Sodium Channels (ENaCs) in human sperm. Tissue Cell 2022; 78:101896. [DOI: 10.1016/j.tice.2022.101896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/27/2022] [Accepted: 08/08/2022] [Indexed: 10/15/2022]
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21
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Lu G, Wang Y, Shi Y, Zhang Z, Huang C, He W, Wang C, Shen H. Autophagy in health and disease: From molecular mechanisms to therapeutic target. MedComm (Beijing) 2022; 3:e150. [PMID: 35845350 PMCID: PMC9271889 DOI: 10.1002/mco2.150] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 02/05/2023] Open
Abstract
Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy-related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome-lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington's disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS-Cov-2 and COVID-19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.
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Affiliation(s)
- Guang Lu
- Department of Physiology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Yu Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Yin Shi
- Department of BiochemistryZhejiang University School of MedicineHangzhouChina
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Weifeng He
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn ResearchSouthwest HospitalArmy Medical UniversityChongqingChina
| | - Chuang Wang
- Department of Pharmacology, Provincial Key Laboratory of PathophysiologyNingbo University School of MedicineNingboZhejiangChina
| | - Han‐Ming Shen
- Department of Biomedical Sciences, Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision OncologyUniversity of MacauMacauChina
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22
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Jiang T, Zhao D, Zheng Z, Li Z. Sigma-1 Receptor Alleviates Airway Inflammation and Airway Remodeling Through AMPK/CXCR4 Signal Pathway. Inflammation 2022; 45:1298-1312. [PMID: 35029796 DOI: 10.1007/s10753-022-01621-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 12/27/2021] [Accepted: 01/02/2022] [Indexed: 12/23/2022]
Abstract
Sigma non-opioid intracellular receptor 1 (Sigma-1R) has been proven to play a major role in inflammation and structural remodeling. However, its role in airway inflammation and airway remodeling remains unclear. The purpose of this study aimed to explore the role and mechanism of Sigma-1R in airway remodeling and epithelial-mesenchymal transition (EMT) process in vivo and in vitro. We observed the decrease of Sigma-1R in lung tissue of asthma model. In the mouse model of allergic airway inflammation (AAI), Sigma-1R agonist RPE-084 significantly relieved airway inflammation and airway remodeling, while Sigma-1R antagonist BD1047 (B8562) had opposite effects. Further research showed that RPE-084 treatment increased the expression of pAMPK and inhibited the expression of CXCR4. Furthermore, RPE-084 treatment suppressed the levels of IL-4, IL-5, and IL-13 in BALF. We found that RPE-084 or Sigma-1R overexpression vector treatment regulated cell cycle and inhibited cell proliferation, migration, and EMT process in TGF-β1-induced 16HBE cells. Finally, we confirmed that AMP-activated protein kinase (AMPK) inhibitor compound C or CXCR4 agonist ATI-2341 both reversed the effects of Sigma-1R on TGF-β1-induced 16 HBE cells. In a word, our research shows that Sigma-1R is helpful to improve airway remodeling of asthma, and emphasizes a new candidate molecular for asthma treatment.
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Affiliation(s)
- Te Jiang
- Department of Pediatrics, Qujiang New District, Northwest Women's and Children's Hospital, No. 1616, Yanxiang Road, Xi'anShaanxi Province, 710061, China
| | - Di Zhao
- Department of Pediatrics, Qujiang New District, Northwest Women's and Children's Hospital, No. 1616, Yanxiang Road, Xi'anShaanxi Province, 710061, China
| | - Zhiyuan Zheng
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University and Shanghai Institute of Medical Imaging, Shanghai, 200032, China
| | - Zhankui Li
- Department of Pediatrics, Qujiang New District, Northwest Women's and Children's Hospital, No. 1616, Yanxiang Road, Xi'anShaanxi Province, 710061, China.
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23
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Valle MMR, Vilas-Boas EA, Lucena CF, Teixeira SA, Muscara MN, Carpinelli AR. Metformin disrupts insulin secretion, causes proapoptotic and oxidative effects in rat pancreatic beta-cells in vitro. J Biochem Mol Toxicol 2022; 36:e23007. [PMID: 35199402 DOI: 10.1002/jbt.23007] [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: 01/06/2021] [Revised: 11/28/2021] [Accepted: 01/04/2022] [Indexed: 11/07/2022]
Abstract
Metformin is the first-line drug to treat type 2 diabetes mellitus. Its mechanism of action is still debatable, and recent studies report that metformin attenuates oxidative stress. This study evaluated the in vitro antioxidant effects of a broad range of metformin concentrations on insulin-producing cells. The cell cycle, metabolism, glucose-stimulated insulin secretion, and cell death were evaluated to determine the biguanide effects on beta-cell function and survival. Antioxidant potential was based on reactive oxygen species (ROS), reduced glutathione (GSH), oxidative stress biomarker levels, and antioxidant enzyme and transcriptional factor Nrf2 activities. The results demonstrate that metformin disrupted GSIS in a concentration-dependent manner, lowered insulin content, and attenuated beta-cell metabolism. At high concentrations, metformin induced cell death and cell cycle arrest as well as increased ROS generation, consequently reducing GSH content. Although carbonylated protein content was elevated, indicating oxidative stress, the antioxidant enzyme and Nrf2 activities were not altered. In conclusion, our results show that metformin disrupts pancreatic beta-cell functionality but does not exert a putative antioxidant effect. It is important to note that the drug could potentially affect beta-cells, especially at high circulating levels.
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Affiliation(s)
- Maíra M R Valle
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.,Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil
| | - Eloisa Aparecida Vilas-Boas
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.,Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil
| | - Camila F Lucena
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.,Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil
| | - Simone A Teixeira
- Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil.,Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Marcelo N Muscara
- Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil.,Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Angelo R Carpinelli
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.,Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil
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24
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Marzoog BA, Vlasova TI. Beta-cell autophagy under the scope of hypoglycemic drugs; possible mechanism as a novel therapeutic target. OBESITY AND METABOLISM 2022. [DOI: 10.14341/omet12778] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Physiologically, autophagy is a major protective mechanism of β-cells from apoptosis, through can reserve normal β- cell mass and inhibit the progression of β-cells destruction. Beta-cell mass can be affected by differentiation from progenitors and de-differentiation as well as self-renewal and apoptosis. Shred evidence indicated that hypoglycemic drugs can induce β-cell proliferation capacity and neogenesis via autophagy stimulation. However, prolonged use of selective hypoglycemic drugs has induced pancreatitis besides several other factors that contribute to β-cell destruction and apoptosis initiation. Interestingly, some nonhypoglycemic medications possess the same effects on β-cells but depending on the combination of these drugs and the duration of exposure to β-cells. The paper comprehensively illustrates the role of the hypoglycemic drugs on the insulin-producing cells and the pathogeneses of β-cell destruction in type 2 diabetes mellitus, in addition to the regulation mechanisms of β-cells division in norm and pathology. The grasping of the hypoglycemic drug’s role in beta-cell is clinically crucial to evaluate novel therapeutic targets such as new signaling pathways. The present paper addresses a new strategy for diabetes mellitus management via targeting specific autophagy inducer factors (transcription factors, genes, lipid molecules, etc.).
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25
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Park K, Lee MS. Current Status of Autophagy Enhancers in Metabolic Disorders and Other Diseases. Front Cell Dev Biol 2022; 10:811701. [PMID: 35237600 PMCID: PMC8882819 DOI: 10.3389/fcell.2022.811701] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/13/2022] [Indexed: 12/21/2022] Open
Abstract
Autophagy is pivotal in the maintenance of organelle function and intracellular nutrient balance. Besides the role of autophagy in the homeostasis and physiology of the individual tissues and whole organism in vivo, dysregulated autophagy has been incriminated in the pathogenesis of a variety of diseases including metabolic diseases, neurodegenerative diseases, cardiovascular diseases, inflammatory or immunological disorders, cancer and aging. Search for autophagy modulators has been widely conducted to amend dysregulation of autophagy or pharmacologically modulate autophagy in those diseases. Current data support the view that autophagy modulation could be a new modality for treatment of metabolic syndrome associated with lipid overload, human-type diabetes characterized by deposition of islet amyloid or other diseases including neurodegenerative diseases, infection and cardiovascular diseases. While clinically available bona fide autophagy modulators have not been developed yet, it is expected that on-going investigation will lead to the development of authentic autophagy modulators that can be safely administered to patients in the near future and will open a new horizon for treatment of incurable or difficult diseases.
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26
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Newsholme P, Rowlands J, Rose’Meyer R, Cruzat V. Metabolic Adaptions/Reprogramming in Islet Beta-Cells in Response to Physiological Stimulators—What Are the Consequences. Antioxidants (Basel) 2022; 11:antiox11010108. [PMID: 35052612 PMCID: PMC8773416 DOI: 10.3390/antiox11010108] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 12/25/2022] Open
Abstract
Irreversible pancreatic β-cell damage may be a result of chronic exposure to supraphysiological glucose or lipid concentrations or chronic exposure to therapeutic anti-diabetic drugs. The β-cells are able to respond to blood glucose in a narrow concentration range and release insulin in response, following activation of metabolic pathways such as glycolysis and the TCA cycle. The β-cell cannot protect itself from glucose toxicity by blocking glucose uptake, but indeed relies on alternative metabolic protection mechanisms to avoid dysfunction and death. Alteration of normal metabolic pathway function occurs as a counter regulatory response to high nutrient, inflammatory factor, hormone or therapeutic drug concentrations. Metabolic reprogramming is a term widely used to describe a change in regulation of various metabolic enzymes and transporters, usually associated with cell growth and proliferation and may involve reshaping epigenetic responses, in particular the acetylation and methylation of histone proteins and DNA. Other metabolic modifications such as Malonylation, Succinylation, Hydroxybutyrylation, ADP-ribosylation, and Lactylation, may impact regulatory processes, many of which need to be investigated in detail to contribute to current advances in metabolism. By describing multiple mechanisms of metabolic adaption that are available to the β-cell across its lifespan, we hope to identify sites for metabolic reprogramming mechanisms, most of which are incompletely described or understood. Many of these mechanisms are related to prominent antioxidant responses. Here, we have attempted to describe the key β-cell metabolic adaptions and changes which are required for survival and function in various physiological, pathological and pharmacological conditions.
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Affiliation(s)
- Philip Newsholme
- Curtin Medical School and CHIRI, Curtin University, Perth, WA 6845, Australia
- Correspondence: (P.N.); (J.R.)
| | - Jordan Rowlands
- Curtin Medical School and CHIRI, Curtin University, Perth, WA 6845, Australia
- Correspondence: (P.N.); (J.R.)
| | - Roselyn Rose’Meyer
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, QLD 4222, Australia;
| | - Vinicius Cruzat
- Faculty of Health, Torrens University Australia, Brisbane, QLD 4006, Australia;
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27
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Metformin promotes autophagy activity and constrains HSV-1 replication in neuroblastoma cells. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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28
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Kim M, Jang J. Construction of 3D hierarchical tissue platforms for modeling diabetes. APL Bioeng 2021; 5:041506. [PMID: 34703970 PMCID: PMC8530538 DOI: 10.1063/5.0055128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 09/27/2021] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) is one of the most serious systemic diseases worldwide, and the majority of DM patients face severe complications. However, many of underlying disease mechanisms related to these complications are difficult to understand with the use of currently available animal models. With the urgent need to fundamentally understand DM pathology, a variety of 3D biomimetic platforms have been generated by the convergence of biofabrication and tissue engineering strategies for the potent drug screening platform of pre-clinical research. Here, we suggest key requirements for the fabrication of physiomimetic tissue models in terms of recapitulating the cellular organization, creating native 3D microenvironmental niches for targeted tissue using biomaterials, and applying biofabrication technologies to implement tissue-specific geometries. We also provide an overview of various in vitro DM models, from a cellular level to complex living systems, which have been developed using various bioengineering approaches. Moreover, we aim to discuss the roadblocks facing in vitro tissue models and end with an outlook for future DM research.
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Affiliation(s)
- Myungji Kim
- School of Interdisciplinary Bioscience and Bioengineering, POSTECH, 77 Cheongam-ro, Namgu, Pohang, Kyungbuk, 37673, Republic of Korea
| | - Jinah Jang
- Author to whom correspondence should be addressed:
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29
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Abstract
Autophagy is an evolutionarily conserved, lysosome-dependent catabolic process whereby cytoplasmic components, including damaged organelles, protein aggregates and lipid droplets, are degraded and their components recycled. Autophagy has an essential role in maintaining cellular homeostasis in response to intracellular stress; however, the efficiency of autophagy declines with age and overnutrition can interfere with the autophagic process. Therefore, conditions such as sarcopenic obesity, insulin resistance and type 2 diabetes mellitus (T2DM) that are characterized by metabolic derangement and intracellular stresses (including oxidative stress, inflammation and endoplasmic reticulum stress) also involve the accumulation of damaged cellular components. These conditions are prevalent in ageing populations. For example, sarcopenia is an age-related loss of skeletal muscle mass and strength that is involved in the pathogenesis of both insulin resistance and T2DM, particularly in elderly people. Impairment of autophagy results in further aggravation of diabetes-related metabolic derangements in insulin target tissues, including the liver, skeletal muscle and adipose tissue, as well as in pancreatic β-cells. This Review summarizes the role of autophagy in the pathogenesis of metabolic diseases associated with or occurring in the context of ageing, including insulin resistance, T2DM and sarcopenic obesity, and describes its potential as a therapeutic target.
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Affiliation(s)
- Munehiro Kitada
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan
- Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Daisuke Koya
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
- Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
- Department of General Internal Medicine, Kusatsu General Hospital, Kusatsu, Shiga, Japan.
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30
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Bharath LP, Rockhold JD, Conway R. Selective Autophagy in Hyperglycemia-Induced Microvascular and Macrovascular Diseases. Cells 2021; 10:cells10082114. [PMID: 34440882 PMCID: PMC8392047 DOI: 10.3390/cells10082114] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/07/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Dysregulation of autophagy is an important underlying cause in the onset and progression of many metabolic diseases, including diabetes. Studies in animal models and humans show that impairment in the removal and the recycling of organelles, in particular, contributes to cellular damage, functional failure, and the onset of metabolic diseases. Interestingly, in certain contexts, inhibition of autophagy can be protective. While the inability to upregulate autophagy can play a critical role in the development of diseases, excessive autophagy can also be detrimental, making autophagy an intricately regulated process, the altering of which can adversely affect organismal health. Autophagy is indispensable for maintaining normal cardiac and vascular structure and function. Patients with diabetes are at a higher risk of developing and dying from vascular complications. Autophagy dysregulation is associated with the development of heart failure, many forms of cardiomyopathy, atherosclerosis, myocardial infarction, and microvascular complications in diabetic patients. Here, we review the recent findings on selective autophagy in hyperglycemia and diabetes-associated microvascular and macrovascular complications.
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31
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Nguyen L, Lim LY, Ding SSL, Amirruddin NS, Hoon S, Chan SY, Teo AKK. Metformin Perturbs Pancreatic Differentiation From Human Embryonic Stem Cells. Diabetes 2021; 70:1689-1702. [PMID: 33958328 DOI: 10.2337/db20-0722] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 05/04/2021] [Indexed: 11/13/2022]
Abstract
Metformin is becoming a popular treatment before and during pregnancy, but current literature on in utero exposure to metformin lacks long-term clinical trials and mechanistic studies. Current literature on the effects of metformin on mature pancreatic β-cells highlights its dual, opposing, protective, or inhibitory effects, depending on metabolic environment. However, the impact of metformin on developing human pancreatic β-cells remains unknown. In this study, we investigated the potential effects of metformin exposure on human pancreatic β-cell development and function in vitro. In the absence of metabolic challenges such as high levels of glucose and fatty acids, metformin exposure impaired the development and function of pancreatic β-cells, with downregulation of pancreatic genes and dysfunctional mitochondrial respiration. It also affected the insulin secretion function of pancreatic β-cells. These findings call for further in-depth evaluation of the exposure of human embryonic and fetal tissue during pregnancy to metformin and its implications for long-term offspring health.
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Affiliation(s)
- Linh Nguyen
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Lillian Yuxian Lim
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
| | - Shirley Suet Lee Ding
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
| | - Nur Shabrina Amirruddin
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Shawn Hoon
- Molecular Engineering Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
| | - Shiao-Yng Chan
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Adrian Kee Keong Teo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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32
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Bekhite M, González-Delgado A, Hübner S, Haxhikadrija P, Kretzschmar T, Müller T, Wu JMF, Bekfani T, Franz M, Wartenberg M, Gräler M, Greber B, Schulze PC. The role of ceramide accumulation in human induced pluripotent stem cell-derived cardiomyocytes on mitochondrial oxidative stress and mitophagy. Free Radic Biol Med 2021; 167:66-80. [PMID: 33705961 DOI: 10.1016/j.freeradbiomed.2021.02.016] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 01/19/2021] [Accepted: 02/09/2021] [Indexed: 11/23/2022]
Abstract
Oversupply of fatty acids (FAs) to cardiomyocytes (CMs) is associated with increased ceramide content and elevated the risk of lipotoxic cardiomyopathy. Here we investigate the role of ceramide accumulation on mitochondrial function and mitophagy in cardiac lipotoxicity using CMs derived from human induced pluripotent stem cell (hiPSC). Mature CMs derived from hiPSC exposed to the diabetic-like environment or transfected with plasmids overexpressing serine-palmitoyltransferase long chain base subunit 1 (SPTLC1), a subunit of the serine-palmitoyltransferase (SPT) complex, resulted in increased intracellular ceramide levels. Accumulation of ceramides impaired insulin-dependent phosphorylation of Akt through activating protein phosphatase 2A (PP2A) and disturbed gene and protein levels of key metabolic enzymes including GLUT4, AMPK, PGC-1α, PPARα, CD36, PDK4, and PPARγ compared to controls. Analysis of CMs oxidative metabolism using a Seahorse analyzer showed a significant reduction in ATP synthesis-related O2 consumption, mitochondrial β-oxidation and respiratory capacity, indicating an impaired mitochondrial function under diabetic-like conditions or SPTLC1-overexpression. Further, ceramide accumulation increased mitochondrial fission regulators such as dynamin-related protein 1 (DRP1) and mitochondrial fission factor (MFF) as well as auto/mitophagic proteins LC3B and PINK-1 compared to control. Incubation of CMs with the specific SPT inhibitor (myriocin) showed a significant increase in mitochondrial fusion regulators the mitofusin 2 (MFN2) and optic atrophy 1 (OPA1) as well as p-Akt, PGC-1 α, GLUT-4, and ATP production. In addition, a significant decrease in auto/mitophagy and apoptosis was found in CMs treated with myriocin. Our results suggest that ceramide accumulation has important implications in driving insulin resistance, oxidative stress, increased auto/mitophagy, and mitochondrial dysfunction in the setting of lipotoxic cardiomyopathy. Therefore, modulation of the de novo ceramide synthesis pathway may serve as a novel therapeutic target to treat metabolic cardiomyopathy.
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Affiliation(s)
- Mohamed Bekhite
- Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, Jena, Germany.
| | - Andres González-Delgado
- Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, Jena, Germany
| | - Sascha Hübner
- Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, Jena, Germany
| | - Pëllumb Haxhikadrija
- Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, Jena, Germany
| | - Tom Kretzschmar
- Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, Jena, Germany
| | - Tina Müller
- Clinic for Anesthesiology and Intensive Care Medicine, University Hospital Jena, FSU, Jena, Germany
| | - Jasmine M F Wu
- Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, Jena, Germany
| | - Tarek Bekfani
- Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, Jena, Germany
| | - Marcus Franz
- Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, Jena, Germany
| | - Maria Wartenberg
- Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, Jena, Germany
| | - Markus Gräler
- Clinic for Anesthesiology and Intensive Care Medicine, University Hospital Jena, FSU, Jena, Germany
| | - Boris Greber
- Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - P Christian Schulze
- Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, Jena, Germany
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33
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García-Viñuales S, Sciacca MFM, Lanza V, Santoro AM, Grasso G, Tundo GR, Sbardella D, Coletta M, Grasso G, La Rosa C, Milardi D. The interplay between lipid and Aβ amyloid homeostasis in Alzheimer's Disease: risk factors and therapeutic opportunities. Chem Phys Lipids 2021; 236:105072. [PMID: 33675779 DOI: 10.1016/j.chemphyslip.2021.105072] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 02/15/2021] [Accepted: 03/01/2021] [Indexed: 12/19/2022]
Abstract
Alzheimer's Diseases (AD) is characterized by the accumulation of amyloid deposits of Aβ peptide in the brain. Besides genetic background, the presence of other diseases and an unhealthy lifestyle are known risk factors for AD development. Albeit accumulating clinical evidence suggests that an impaired lipid metabolism is related to Aβ deposition, mechanistic insights on the link between amyloid fibril formation/clearance and aberrant lipid interactions are still unavailable. Recently, many studies have described the key role played by membrane bound Aβ assemblies in neurotoxicity. Moreover, it has been suggested that a derangement of the ubiquitin proteasome pathway and autophagy is significantly correlated with toxic Aβ aggregation and dysregulation of lipid levels. Thus, studies focusing on the role played by lipids in Aβ aggregation and proteostasis could represent a promising area of investigation for the design of valuable treatments. In this review we examine current knowledge concerning the effects of lipids in Aβ aggregation and degradation processes, focusing on the therapeutic opportunities that a comprehensive understanding of all biophysical, biochemical, and biological processes involved may disclose.
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Affiliation(s)
| | - Michele F M Sciacca
- Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Catania, Italy
| | - Valeria Lanza
- Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Catania, Italy
| | - Anna Maria Santoro
- Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Catania, Italy
| | - Giulia Grasso
- Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Catania, Italy
| | - Grazia R Tundo
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | | | - Massimiliano Coletta
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Giuseppe Grasso
- Department of Chemistry, University of Catania, Catania, Italy
| | - Carmelo La Rosa
- Department of Chemistry, University of Catania, Catania, Italy
| | - Danilo Milardi
- Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Catania, Italy.
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34
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Milardi D, Gazit E, Radford SE, Xu Y, Gallardo RU, Caflisch A, Westermark GT, Westermark P, Rosa CL, Ramamoorthy A. Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes. Chem Rev 2021; 121:1845-1893. [PMID: 33427465 PMCID: PMC10317076 DOI: 10.1021/acs.chemrev.0c00981] [Citation(s) in RCA: 117] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures and aggregation pathways of this hormone. Recent studies have reported on the importance of early oligomeric intermediates, the many roles of their interactions with lipid membrane, pH, insulin, and zinc on the mechanism of aggregation of hIAPP. The challenges posed by the transient nature of amyloid oligomers, their structural heterogeneity, and the complex nature of their interaction with lipid membranes have resulted in the development of a wide range of biophysical and chemical approaches to characterize the aggregation process. While the cellular processes and factors activating hIAPP-mediated cytotoxicity are still not clear, it has recently been suggested that its impaired turnover and cellular processing by proteasome and autophagy may contribute significantly toward toxic hIAPP accumulation and, eventually, β-cell death. Therefore, studies focusing on the restoration of hIAPP proteostasis may represent a promising arena for the design of effective therapies. In this review we discuss the current knowledge of the structures and pathology associated with hIAPP self-assembly and point out the opportunities for therapy that a detailed biochemical, biophysical, and cellular understanding of its aggregation may unveil.
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Affiliation(s)
- Danilo Milardi
- Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via P. Gaifami 18, 95126 Catania, Italy
| | - Ehud Gazit
- Department of Molecular Microbiology and Biotechnology, The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Sheena E Radford
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Yong Xu
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Rodrigo U Gallardo
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Amedeo Caflisch
- Department of Biochemistry, University of Zürich, Zürich CH-8057, Switzerland
| | - Gunilla T Westermark
- Department of Medical Cell Biology, Uppsala University, SE-751 23 Uppsala, Sweden
| | - Per Westermark
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden
| | - Carmelo La Rosa
- Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy
| | - Ayyalusamy Ramamoorthy
- Biophysics, Department of Chemistry, Biomedical Engineering, Macromolecular Science and Engineering, University of Michigan, Ann Arbor, Michigan 41809-1055, United States
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35
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Lu G, Wu Z, Shang J, Xie Z, Chen C, Zhang C. The effects of metformin on autophagy. Biomed Pharmacother 2021; 137:111286. [PMID: 33524789 DOI: 10.1016/j.biopha.2021.111286] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 01/11/2021] [Accepted: 01/13/2021] [Indexed: 12/11/2022] Open
Abstract
Metformin is the first-line option for treating newly diagnosed diabetic patients and also involved in other pharmacological actions, including antitumor effect, anti-aging effect, polycystic ovarian syndrome prevention, cardiovascular action, and neuroprotective effect, etc. However, the mechanisms of metformin actions were not fully illuminated. Recently, increasing researches showed that autophagy is a vital medium of metformin playing pharmacological actions. Nevertheless, results on the effects of metformin on autophagy were inconsistent. Apart from few clinical evidences, more data focused on kinds of no-clinical models. First, many studies showed that metformin could induce autophagy via a number of signaling pathways, including AMPK-related signaling pathways (e.g. AMPK/mTOR, AMPK/CEBPD, MiTF/TFE, AMPK/ULK1, and AMPK/miR-221), Redd1/mTOR, STAT, SIRT, Na+/H+ exchangers, MAPK/ERK, PK2/PKR/AKT/ GSK3β, and TRIB3. Secondly, some signaling pathways were involved in the process of metformin inhibiting autophagy, such as AMPK-related signaling pathways (AMPK/NF-κB and other undetermined AMPK-related signaling pathways), Hedgehog, miR-570-3p, miR-142-3p, and MiR-3127-5p. Thirdly, two types of signaling pathways including PI3K/AKT/mTOR and endoplasmic reticulum (ER) stress could bidirectionally impact the effectiveness of metformin on autophagy. Finally, multiple signal pathways were reviewed collectively in terms of affecting the effectiveness of metformin on autophagy. The pharmacological effects of metformin combining its actions on autophagy were also discussed. It would help better apply metformin to treat diseases in term of mediating autophagy.
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Affiliation(s)
- Guangli Lu
- School of Business, Henan University, Henan, Kaifeng, China
| | - Zhen Wu
- Institute of Nursing and Health, College of Nursing and Health, Henan University, Henan, Kaifeng, China
| | - Jia Shang
- School of Kaifeng Culture and Tourism, Henan, Kaifeng, China
| | - Zhenxing Xie
- School of Basic Medicine, Henan University, Henan, Kaifeng, Jinming Avenue, 475004, China.
| | - Chaoran Chen
- Institute of Nursing and Health, College of Nursing and Health, Henan University, Henan, Kaifeng, China.
| | - Chuning Zhang
- Institute of Nursing and Health, College of Nursing and Health, Henan University, Henan, Kaifeng, China
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Lin CJ, Tsao YN, Shu CW. Autophagy modulation as a potential targeted cancer therapy: From drug repurposing to new drug development. Kaohsiung J Med Sci 2021; 37:166-171. [PMID: 33496377 DOI: 10.1002/kjm2.12361] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 12/30/2020] [Accepted: 01/03/2021] [Indexed: 01/04/2023] Open
Abstract
Autophagy is an evolutionarily conserved signaling pathway to deliver dysfunctional proteins or organelles into lysosomes for degradation and recycling, which is an important pathway for normal homeostasis. Autophagy dysfunction can lead to various diseases, particularly cancer. Autophagy not only plays a role in tumor suppression, but it also serves as a tumor promoter in cancer malignancy. In this review, we summarize the involvement of autophagy-related (ATG) proteins in autophagy signaling and the role of autophagy in cancer progression. The effectiveness of US Food and Drug Administration-approved drugs in regulating autophagic flux and suppressing cancer cells is also discussed. Moreover, since clinically available drugs do not specifically target ATG proteins, there is little doubt that their cancer suppression function is autophagy dependent. Therefore, this review also discusses several inhibitors against ATG proteins, such as ULK1/2, ATG4, and VPS34 to suppress cancer cells. Autophagy modulators can be either used alone or combined with chemotherapy or radiation therapy to enhance the efficacy of current treatments for certain types of cancer. This review summarizes current autophagy modulation used as a potential strategy for targeted cancer therapy.
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Affiliation(s)
- Chia-Jung Lin
- Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Yuan-Ni Tsao
- Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Chih-Wen Shu
- Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.,Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.,Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
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Yunvjian-Medicated Serum Protects INS-1 Cells against Glucolipotoxicity-Induced Apoptosis through Autophagic Flux Modulation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2020:8878259. [PMID: 33414841 PMCID: PMC7752277 DOI: 10.1155/2020/8878259] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 11/21/2020] [Accepted: 11/29/2020] [Indexed: 11/17/2022]
Abstract
Yunvjian (YNJ) is a traditional Chinese medicine formula adopted to prevent and treat diabetes. Our previous results from animal experiments showed that YNJ decreased blood glucose. This study aimed to examine the effect of high glucose and high lipid (HG/HL) conditions on the proliferation and apoptosis of INS-1 cells and the possible protective mechanism of YNJ-medicated serum on INS-1 cells exposed to HG/HL conditions. INS-1 cells were cultured in RPMI 1640 medium after being passaged. Then, INS-1 cells in the logarithmic growth phase were collected and divided into five groups: control, HG/HL, HG/HL+5% YNJ-medicated serum, HG/HL+10% YNJ-medicated serum, and HG/HL+20% YNJ-medicated serum. MTT assay and flow cytometry were used to detect proliferation and apoptosis of INS-1 cells, respectively. Protein profiles of INS-1 cells were analyzed using a tandem mass tag (TMT) label-based quantitative proteomic approach. Western blotting was performed to verify the proteomic results. YNJ-medicated serum significantly promoted INS-1 cell proliferation and inhibited apoptosis. Proteomic results from the INS-1 cells in the control, HG/HL, and HG/HL+10% YNJ-medicated serum groups showed that 7,468 proteins were identified, of which 6,423 proteins were quantified. Compared with the HG/HL group,430 differential proteins were upregulated, and 671 were downregulated in the HG/HL+10% YNJ-medicated serum group. Compared with the control group, 711 differential proteins were upregulated and 455 were downregulated in the HG/HL group, whereas 10 differential proteins were upregulated and 9 were downregulated in the HG/HL+10% YNJ-medicated serum group. Furthermore, several proteins related to autophagy, including ATG3, ATG2B, GABARAP, WIPI2, and p62/SQSTM1, were verified by western blotting, and these results were consistent with the results obtained from the proteomics analysis. These results confirmed that the autophagy pathway is critical to glucolipotoxicity in INS-1 cells. YNJ-medicated serum exhibited a protective effect on INS-1 cells cultured under HG/HL conditions by regulating autophagy genes' expression and restoring the autophagic flux.
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Metformin Preserves β-Cell Compensation in Insulin Secretion and Mass Expansion in Prediabetic Nile Rats. Int J Mol Sci 2021; 22:ijms22010421. [PMID: 33401592 PMCID: PMC7794750 DOI: 10.3390/ijms22010421] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 12/24/2020] [Accepted: 12/29/2020] [Indexed: 12/13/2022] Open
Abstract
Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic β-cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and β-cell mass expansion. In people with prediabetes, metformin has been shown to prevent prediabetes conversion to diabetes. However, emerging evidence indicates that metformin has negative effects on β-cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characteristics of human β-cell compensation in function and mass expansion. In this study, we investigated the action of metformin on β-cells in vivo and in vitro. A 7-week metformin treatment improved glucose tolerance by reducing hepatic glucose output and enhancing insulin secretion. Although high-dose metformin inhibited β-cell glucose-stimulated insulin secretion in vitro, stimulation of β-cell insulin secretion was preserved in metformin-treated NRs via an indirect mechanism. Moreover, β-cells in NRs receiving metformin exhibited increased endoplasmic reticulum (ER) chaperones and alleviated apoptotic unfold protein response (UPR) without changes in the expression of cell identity genes. Additionally, metformin did not suppress β-cell mass compensation or proliferation. Taken together, despite the conflicting role indicated by in vitro studies, administration of metformin does not exert a negative effect on β-cell function or cell mass and, instead, early metformin treatment may help protect β-cells from exhaustion and decompensation.
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Sarmah DT, Bairagi N, Chatterjee S. Tracing the footsteps of autophagy in computational biology. Brief Bioinform 2020; 22:5985288. [PMID: 33201177 PMCID: PMC8293817 DOI: 10.1093/bib/bbaa286] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 09/29/2020] [Accepted: 09/30/2020] [Indexed: 12/11/2022] Open
Abstract
Autophagy plays a crucial role in maintaining cellular homeostasis through the degradation of unwanted materials like damaged mitochondria and misfolded proteins. However, the contribution of autophagy toward a healthy cell environment is not only limited to the cleaning process. It also assists in protein synthesis when the system lacks the amino acids’ inflow from the extracellular environment due to diet consumptions. Reduction in the autophagy process is associated with diseases like cancer, diabetes, non-alcoholic steatohepatitis, etc., while uncontrolled autophagy may facilitate cell death. We need a better understanding of the autophagy processes and their regulatory mechanisms at various levels (molecules, cells, tissues). This demands a thorough understanding of the system with the help of mathematical and computational tools. The present review illuminates how systems biology approaches are being used for the study of the autophagy process. A comprehensive insight is provided on the application of computational methods involving mathematical modeling and network analysis in the autophagy process. Various mathematical models based on the system of differential equations for studying autophagy are covered here. We have also highlighted the significance of network analysis and machine learning in capturing the core regulatory machinery governing the autophagy process. We explored the available autophagic databases and related resources along with their attributes that are useful in investigating autophagy through computational methods. We conclude the article addressing the potential future perspective in this area, which might provide a more in-depth insight into the dynamics of autophagy.
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Affiliation(s)
| | - Nandadulal Bairagi
- Centre for Mathematical Biology and Ecology, Department of Mathematics, Jadavpur University, Kolkata, India
| | - Samrat Chatterjee
- Translational Health Science and Technology Institute, Faridabad, India
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40
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Wang XY, Zhu BR, Jia Q, Li YM, Wang T, Wang HY. Cinnamtannin D1 Protects Pancreatic β-Cells from Glucolipotoxicity-Induced Apoptosis by Enhancement of Autophagy In Vitro and In Vivo. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:12617-12630. [PMID: 33125846 DOI: 10.1021/acs.jafc.0c04898] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
In our previous study, cinnamtannin D1 (CD-1), one of the A-type procyanidin oligomers isolated from Cinnamomum tamala, was reported to have the activity of antiapoptosis in palmitic acid-treated pancreatic β cells via alleviating oxidative stress in vitro. In this study, the aim was to further disclose its protective effect and underlying mechanisms against glucolipotoxicity-induced β-cells apoptosis in vitro and in vivo. We found that CD-1 was able to dose-dependently and time-dependently activate autophagy in INS-1 pancreatic β-cells. High glucose and palmitic acid (HG/PA)-induced apoptosis and autophagy impairment could be attenuated by CD-1 in INS-1 cells as well as primary cultured murine islets. We also demonstrated that CD-1-induced autophagy was through AMPK/mTOR/ULK1 pathway. Moreover, it was shown that the effects of CD-1 on activation of Keap1/Nrf2 antioxidant signaling pathway and the amelioration of inflammation, endoplasmic reticulum stress, and apoptosis were through autophagy induction in HG/PA-treated INS-1 cells. These protective effects in vivo and hypoglycemic activity of CD-1 were also observed in diabetic db/db mice. These findings have great significance in revealing the antidiabetic mechanisms of procyanidin oligomers and paving the way for their application in the treatment of diabetes.
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Affiliation(s)
- Xin-Yi Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Bo-Rong Zhu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qi Jia
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yi-Ming Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ting Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - He-Yao Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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Kowluru A. Roles of GTP and Rho GTPases in pancreatic islet beta cell function and dysfunction. Small GTPases 2020; 12:323-335. [PMID: 32867592 DOI: 10.1080/21541248.2020.1815508] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
A growing body of evidence implicates requisite roles for GTP and its binding proteins (Rho GTPases) in the cascade of events leading to physiological insulin secretion from the islet beta cell. Interestingly, chronic exposure of these cells to hyperglycaemic conditions appears to result in sustained activation of specific Rho GTPases (e.g. Rac1) leading to significant alterations in cellular functions including defects in mitochondrial function and nuclear collapse culminating in beta cell demise. One of the objectives of this review is to highlight our current understanding of the regulatory roles of GTP and Rho GTPases in normal islet function (e.g. proliferation and insulin secretion) as well potential defects in these signalling molecules and metabolic pathways that could contribute islet beta cell dysfunction and loss of functional beta cell mass leading to the onset of diabetes. Potential knowledge gaps in this field and possible avenues for future research are also highlighted. ABBREVIATIONS ARNO: ADP-ribosylation factor nucleotide binding site opener; CML: carboxyl methylation; Epac: exchange protein directly activated by cAMP; ER stress: endoplasmic reticulum stress; FTase: farnesyltransferase; GAP: GTPase activating protein; GDI: GDP dissociation inhibitor; GEF: guanine nucleotide exchange factor; GGTase: geranylgeranyltransferase; GGpp: geranylgeranylpyrophosphate; GGPPS: geranylgeranyl pyrophosphate synthase; GSIS: glucose-stimulated insulin secretion; HGPRTase: hypoxanthine-guanine phosphoribosyltransferase; IMPDH: inosine monophosphate dehydrogenase; α-KIC: α-ketoisocaproic acid; MPA: mycophenolic acid; MVA: mevalonic acid; NDPK: nucleoside diphosphate kinase; NMPK: nucleoside monophosphate kinase; Nox2: phagocyte-like NADPH oxidase; PAK-I: p21-activated kinase-I; β-PIX: β-Pak-interacting exchange factor; PRMT: protein arginine methyltransferase; Rac1: ras-related C3 botulinum toxin substrate 1; Tiam1: T-cell lymphoma invasion and metastasis-inducing protein 1; Trx-1: thioredoxin-1; Vav2: vav guanine nucleotide exchange factor 2.
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Affiliation(s)
- Anjaneyulu Kowluru
- Biomedical Research Service, John D. Dingell VA Medical Center and Department of Pharmaceutical Sciences and Medicine, Wayne State University, Detroit, MI, USA
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King BC, Kulak K, Colineau L, Blom AM. Outside in: Roles of complement in autophagy. Br J Pharmacol 2020; 178:2786-2801. [PMID: 32621514 DOI: 10.1111/bph.15192] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/17/2020] [Accepted: 06/24/2020] [Indexed: 12/12/2022] Open
Abstract
The complement system is a well-characterized cascade of extracellular serum proteins that is activated by pathogens and unwanted waste material. Products of activated complement signal to the host cells via cell surface receptors, eliciting responses such as removal of the stimulus by phagocytosis. The complement system therefore functions as a warning system, resulting in removal of unwanted material. This review describes how extracellular activation of the complement system can also trigger autophagic responses within cells, up-regulating protective homeostatic autophagy in response to perceived stress, but also initiating targeted anti-microbial autophagy in order to kill intracellular cytoinvasive pathogens. In particular, we will focus on recent discoveries that indicate that complement may also have roles in detection and autophagy-mediated disposal of unwanted materials within the intracellular environment. We therefore summarize the current evidence for complement involvement in autophagy, both by transducing signals across the cell membrane, as well as roles within the cellular environment. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.
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Affiliation(s)
- Ben C King
- Section of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Klaudia Kulak
- Section of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Lucie Colineau
- Section of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Anna M Blom
- Section of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden
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Gao C, Fang L, Zhang H, Zhang WS, Li XO, Du SY. Metformin Induces Autophagy via the AMPK-mTOR Signaling Pathway in Human Hepatocellular Carcinoma Cells. Cancer Manag Res 2020; 12:5803-5811. [PMID: 32765083 PMCID: PMC7371564 DOI: 10.2147/cmar.s257966] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 07/03/2020] [Indexed: 12/11/2022] Open
Abstract
Background Metformin may exert the anticancer effect on multiple types of cancers and some potential mechanisms have been suggested. Our study was designed to determine the effect of metformin on the cell autophagy and autophagic flux via the AMPK-mTOR signaling pathway in human hepatocellular carcinoma (HCC) cells. Methods MHCC97H and HepG2 cell lines were cultured and treated without and with metformin at various concentrations (2, 5, 10 and 20 mM) for 48 h. Then, 10 mM was determined as the optimal concentration and the HCC cells were treated with metformin for 12, 24, 48, and 72 h. MTT assay was used to assess the cell viability and Western blotting was used to determine the expression of proteins (LC3-II, p62, phospho-AMPKα, phospho-mTOR, mTOR, phospho-p70 S6 Kinase, p70 S6 Kinase, PARP1, Caspase-9 and Caspase-3). Autophagy inhibitor 3-methyladenine, EGFP-LC3 and mCherry-GFP-LC3B plasmid transfection were used for further study. Results Metformin inhibited significantly the viability of MHCC97H and HepG2 cells in a dose- and time-dependent manner. For the apoptotic properties, activation of Caspase-9 and Caspase-3 and PARP cleavage were not observed after treatment with metformin. MHCC97H cells were transfected with a EGFP-LC3 plasmid and treatment with metformin could lead to the increased level of LC3-II and decreased level of p62. In metformin-induced autophagy, AMPK expression was activated, and the phosphorylation levels of mTOR and p70 S6 Kinase were inhibited. Metformin treatment and mCherry-GFP-LC3B plasmid transfection showed that metformin could induce the autophagic flux. 3-Methyladenine (3-MA) partly abolished this effect. Conclusion Metformin could induce the autophagy, autophagic flux, and activate the AMPK-mTOR signaling pathway in human HCC cells.
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Affiliation(s)
- Chun Gao
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, People's Republic of China
| | - Long Fang
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, People's Republic of China
| | - Hui Zhang
- Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, People's Republic of China
| | - Wei-Shuo Zhang
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, People's Republic of China
| | - Xiao-Ou Li
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, People's Republic of China
| | - Shi-Yu Du
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, People's Republic of China
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Yao D, GangYi Y, QiNan W. Autophagic dysfunction of β cell dysfunction in type 2 diabetes, a double-edged sword. Genes Dis 2020; 8:438-447. [PMID: 34179308 PMCID: PMC8209341 DOI: 10.1016/j.gendis.2020.03.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 03/07/2020] [Accepted: 03/12/2020] [Indexed: 12/19/2022] Open
Abstract
Diabetes is an age-related disease, most of which is type 2 diabetes, and islet β cell dysfunction and insulin resistance are the main mechanisms of type 2 diabetes. Recent studies have revealed that autophagy plays an important role in maintaining the structure and function of islet beta cells and inhibiting insulin resistance and apoptosis induced by oxidative stress. In this review, we discussed the positive and negative effects of autophagy and its dysfunction on type 2 diabetes mellitus, which is the so-called double-edged sword, analysed its possible mechanism, and identified possible research hot spots.
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Affiliation(s)
- Ding Yao
- Endocrinology and Nephrology Department, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, 400030, PR China
| | - Yang GangYi
- Endocrinology Department, The Second Affiliated Hospital of the Chongqing Medical University, Chongqing, 400010, PR China
| | - Wu QiNan
- Endocrinology and Nephrology Department, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, 400030, PR China
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45
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Esch N, Jo S, Moore M, Alejandro EU. Nutrient Sensor mTOR and OGT: Orchestrators of Organelle Homeostasis in Pancreatic β-Cells. J Diabetes Res 2020; 2020:8872639. [PMID: 33457426 PMCID: PMC7787834 DOI: 10.1155/2020/8872639] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/06/2020] [Accepted: 11/24/2020] [Indexed: 02/08/2023] Open
Abstract
The purpose of this review is to integrate the role of nutrient-sensing pathways into β-cell organelle dysfunction prompted by nutrient excess during type 2 diabetes (T2D). T2D encompasses chronic hyperglycemia, hyperlipidemia, and inflammation, which each contribute to β-cell failure. These factors can disrupt the function of critical β-cell organelles, namely, the ER, mitochondria, lysosomes, and autophagosomes. Dysfunctional organelles cause defects in insulin synthesis and secretion and activate apoptotic pathways if homeostasis is not restored. In this review, we will focus on mTORC1 and OGT, two major anabolic nutrient sensors with important roles in β-cell physiology. Though acute stimulation of these sensors frequently improves β-cell function and promotes adaptation to cell stress, chronic and sustained activity disturbs organelle homeostasis. mTORC1 and OGT regulate organelle function by influencing the expression and activities of key proteins, enzymes, and transcription factors, as well as by modulating autophagy to influence clearance of defective organelles. In addition, mTORC1 and OGT activity influence islet inflammation during T2D, which can further disrupt organelle and β-cell function. Therapies for T2D that fine-tune the activity of these nutrient sensors have yet to be developed, but the important role of mTORC1 and OGT in organelle homeostasis makes them promising targets to improve β-cell function and survival.
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Affiliation(s)
- Nicholas Esch
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Seokwon Jo
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Mackenzie Moore
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Surgery, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Emilyn U. Alejandro
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
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Lai D, Huang M, Zhao L, Tian Y, Li Y, Liu D, Wu Y, Deng F. Delphinidin-induced autophagy protects pancreatic β cells against apoptosis resulting from high-glucose stress via AMPK signaling pathway. Acta Biochim Biophys Sin (Shanghai) 2019; 51:1242-1249. [PMID: 31781740 DOI: 10.1093/abbs/gmz126] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 09/30/2019] [Accepted: 07/26/2019] [Indexed: 01/11/2023] Open
Abstract
Hyperglycemia, a diagnostic characteristic of diabetes mellitus, is detrimental to pancreatic β cells. Delphinidin, a member of the anthocyanin family, inhibits glucose absorption, increases glucagon-like peptide-1 (GLP-1) secretion, and improves insulin secretion in diabetes. However, whether delphinidin plays a protective role in pancreatic β-cell mass and function is not clear. In this study, delphinidin was found to decrease the high-glucose-induced apoptosis of RIN-m5F pancreatic β cells. In addition, delphinidin induced autophagy in RIN-m5F cells under the normal and high-glucose conditions, while 3-methyladenine (3-MA) inhibition of autophagy significantly diminished the protective role of delphinidin against high-glucose-induced apoptosis of pancreatic β cells. Delphinidin also decreased the level of cleaved caspase 3 and increased the phosphorylation level of AMP-activated protein kinase α (AMPKα) Thr172. Compound C, an AMPK inhibitor, was found to decrease the ratio of LC3-II/LC3-I, and the apoptotic rate of high-glucose-injured cells was increased after treatment with delphinidin, indicating that delphinidin attenuated the negative effects of high-glucose stress to cells. In conclusion, our data demonstrate that delphinidin protects pancreatic β cells against high-glucose-induced injury by autophagy regulation via the AMPK signaling pathway. These findings might shed light on the underlying mechanisms of diabetes and help improve the prevention and therapy of this common disease.
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Affiliation(s)
- Dengni Lai
- Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Mingyong Huang
- Tianxiang Biotechnology Co., Ltd of Hunan, Shaoyang 422000, China
| | - Lingyan Zhao
- Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Yan Tian
- Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Yong Li
- Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Dongpo Liu
- State Key Laboratory of Subhealth Intervention Technology, Changsha 410128, China
| | - Yanyang Wu
- Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Fangming Deng
- Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China
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Kim HI, Lee JS, Kwak BK, Hwang WM, Kim MJ, Kim YB, Chung SS, Park KS. Metformin Ameliorates Lipotoxic β-Cell Dysfunction through a Concentration-Dependent Dual Mechanism of Action. Diabetes Metab J 2019; 43:854-866. [PMID: 31339010 PMCID: PMC6943256 DOI: 10.4093/dmj.2018.0179] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 01/15/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Chronic exposure to elevated levels of free fatty acids contributes to pancreatic β-cell dysfunction. Although it is well known that metformin induces cellular energy depletion and a concomitant activation of AMP-activated protein kinase (AMPK) through inhibition of the respiratory chain, previous studies have shown inconsistent results with regard to the action of metformin on pancreatic β-cells. We therefore examined the effects of metformin on pancreatic β-cells under lipotoxic stress. METHODS NIT-1 cells and mouse islets were exposed to palmitate and treated with 0.05 and 0.5 mM metformin. Cell viability, glucose-stimulated insulin secretion, cellular adenosine triphosphate, reactive oxygen species (ROS) levels and Rho kinase (ROCK) activities were measured. The phosphorylation of AMPK was evaluated by Western blot analysis and mRNA levels of endoplasmic reticulum (ER) stress markers and NADPH oxidase (NOX) were measured by real-time quantitative polymerase chain reaction analysis. RESULTS We found that metformin has protective effects on palmitate-induced β-cell dysfunction. Metformin at a concentration of 0.05 mM inhibits NOX and suppresses the palmitate-induced elevation of ER stress markers and ROS levels in a AMPK-independent manner, whereas 0.5 mM metformin inhibits ROCK activity and activates AMPK. CONCLUSION This study suggests that the action of metformin on β-cell lipotoxicity was implemented by different molecular pathways depending on its concentration. Metformin at a usual therapeutic dose is supposed to alleviate lipotoxic β-cell dysfunction through inhibition of oxidative stress and ER stress.
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Affiliation(s)
- Hong Il Kim
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Korea
- Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Seoul, Korea
| | - Ji Seon Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Byung Kook Kwak
- Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, Seoul, Korea
| | - Won Min Hwang
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Division of Nephrology, Department of Internal Medicine, Konyang University College of Medicine, Seoul, Korea
| | - Min Joo Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Young Bum Kim
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Korea
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Sung Soo Chung
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kyong Soo Park
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
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Lawal SK, Adeniji AA, Sulaiman SO, Akajewole MM, Buhari MO, Osinubi AA. Comparative effects of glibenclamide, metformin and insulin on fetal pancreatic histology and maternal blood glucose in pregnant streptozotocin-induced diabetic rats. Afr Health Sci 2019; 19:2491-2504. [PMID: 32127822 PMCID: PMC7040257 DOI: 10.4314/ahs.v19i3.25] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Oral hypoglycemic agents use during pregnancy was assumed to cause fetal macrosomia and skeletal deformities, and maternal complications due to significant transfer across placenta or ineffective control of blood glucose. OBJECTIVE This study investigated effects of insulin, metformin and glibenclamide on maternal blood glucose; and fetal crown-rump length, gross malformation and pancreatic histology in pregnant streptozotocin-induced diabetic rats. METHODS Twenty-five pregnant rats of groups 1 to 5 as normal and diabetic controls; and diabetic treated with insulin, metformin and glibenclamide were used. Experimental GDM was induced using 45 and 35mg/Kgbw of intraperitoneal streptozotocin. RESULTS Metformin, Insulin and Glibenclamide significantly reduced maternal glucose by 140.6mg/dL, 103.2mg/dL and 98.54mg/dl; respectively and showed islets with regular interlobular ducts, islets with some irregular interlobular ducts, and islets with many irregular interlobular ducts in histological fetal pancreatic photomicrographs respectively. This depicts metformin having highest ameliorative effect. There were no significant differences in maternal and fetal body weights, maternal blood glucose between diabetic groups, and fetal gross examination. CONCLUSION At the doses used in this research, metformin and glibenclamide showed no adverse effects on maternal and fetal features in the treatment of GDM. Thus, they can be used as safe and inexpensive alternatives to insulin.
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Affiliation(s)
- Sodiq Kolawole Lawal
- Department of Anatomy, St. Francis University College of Health Sciences and Allied Sciences, Ifakara, Tanzania
- Discipline of Clinical Anatomy, Nelson Mandela School of Medicine, University of KwaZulu-Natal, 4001, Durban, South Africa
| | - Adeoluwa Akeem Adeniji
- Department of Anatomy, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria
| | - Sheu Oluwadare Sulaiman
- Department of Physiology, Kampala International University Western campus, Ishaka-Bushenyi, Uganda
| | - Mustapha Mas'ud Akajewole
- Department of Human Anatomy, School of Health and Medical Sciences, State University of Zanzibar, Zanzibar, Tanzania
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Wang L, Quan N, Sun W, Chen X, Cates C, Rousselle T, Zhou X, Zhao X, Li J. Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury. Cardiovasc Res 2019; 114:805-821. [PMID: 29409011 DOI: 10.1093/cvr/cvy033] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 02/01/2018] [Indexed: 12/12/2022] Open
Abstract
Aims A longevity gene, Sirtuin 1 (SIRT1) and energy sensor AMP-activated protein kinase (AMPK) have common activators such as caloric restriction, oxidative stress, and exercise. The objective of this study is to characterize the role of cardiomyocyte SIRT1 in age-related impaired ischemic AMPK activation and increased susceptibility to ischemic insults. Methods and results Mice were subjected to ligation of left anterior descending coronary artery for in vivo ischemic models. The glucose and fatty acid oxidation were measured in a working heart perfusion system. The cardiac functions by echocardiography show no difference in young wild-type C57BL/6 J (WT, 4-6 months), aged WT C57BL/6 J (24-26 months), and young inducible cardiomyocyte-specific SIRT1 knockout (icSIRT1 KO) (4-6 months) mice under physiological conditions. However, after 45 mins ischaemia and 24-h reperfusion, the ejection fraction of aged WT and icSIRT1 KO mice was impaired. The aged WT and icSIRT1 KO hearts vs. young WT hearts also show an impaired post-ischemic contractile function in a Langendorff perfusion system. The infarct size of aged WT and icSIRT1 KO hearts was larger than that of young WT hearts. The immunoblotting data demonstrated that aged WT and icSIRT1 KO hearts vs. young WT hearts had impaired phosphorylation of AMPK and downstream acetyl-CoA carboxylase during ischaemia. Intriguingly, AMPK upstream LKB1 is hyper-acetylated in both aged WT and icSIRT1 KO hearts; this could blunt activation of LKB1, leading to an impaired AMPK activation. The working heart perfusion results demonstrated that SIRT1 deficiency significantly impaired substrate metabolism in the hearts; fatty acid oxidation is augmented and glucose oxidation is blunted during ischaemia and reperfusion. Adeno-associated virus (AAV9)-Sirt1 was delivered into the aged hearts via a coronary delivery approach, which significantly rescued the protein level of SIRT1 and the ischemic tolerance of aged hearts. Furthermore, AMPK agonist can rescue the tolerance of aged heart and icSIRT1 KO heart to ischemic insults. Conclusions Cardiac SIRT1 mediates AMPK activation via LKB1 deacetylation, and AMPK modulates SIRT1 activity via regulation of NAD+ level during ischaemia. SIRT1 and AMPK agonists have therapeutic potential for treatment of aging-related ischemic heart disease.
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Affiliation(s)
- Lin Wang
- Department of Cardiovascular Center, The First Hospital of Jilin University, Xinmin Street, Changchun 130021, China.,Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
| | - Nanhu Quan
- Department of Cardiovascular Center, The First Hospital of Jilin University, Xinmin Street, Changchun 130021, China.,Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
| | - Wanqing Sun
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
| | - Xu Chen
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
| | - Courtney Cates
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
| | - Thomas Rousselle
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
| | - Xinchun Zhou
- Department of Pathology, Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Xuezhong Zhao
- Department of Cardiovascular Center, The First Hospital of Jilin University, Xinmin Street, Changchun 130021, China
| | - Ji Li
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, USA
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Breaking Bad and Breaking Good: β-Cell Autophagy Pathways in Diabetes. J Mol Biol 2019; 432:1494-1513. [PMID: 31381897 DOI: 10.1016/j.jmb.2019.07.030] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 07/19/2019] [Accepted: 07/19/2019] [Indexed: 01/01/2023]
Abstract
For many decades the lysosome has been recognized as the terminal center of cellular waste disposal. Products of lysosomal degradation are either recycled in biosynthetic pathways or are further metabolized to produce energy. As such the lysosome was attributed a rather passive role in cellular metabolism merely transforming bulk material into small metabolites. More recently, however, the emerging evidence has brought the lysosome to the center of nutrient sensing as the organelle that harbors a complex signaling machinery which dynamically and actively regulates cell metabolism. The pancreatic β cell is unique in as much as nutrient sensing is directly coupled to insulin secretion. Importantly, defects in insulin secretion constitute a hallmark in the progression of patients from a state of impaired glucose tolerance to full blown type 2 diabetes (T2D). However, mechanisms linking nutrient-dependent lysosomal function to insulin secretion and more generally to β cell health have evolved only very recently. This review discusses emerging concepts in macroautophagy and macroautophagy-independent processes of cargo delivery to lysosomes as well as nutrient-dependent lysosomal signaling specifically in the context of β cell function in health and disease. Such mechanisms may provide a novel source of therapeutic targets to be exploited in the context of β cell failure in diabetes in the near future.
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