1
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Zhao C, Zhang Y, Qian L, Guo Q, Zhu N. Causal association between endocrine diseases and lymphoid malignancies explored through two-sample Mendelian randomization analysis. Sci Rep 2025; 15:14231. [PMID: 40275078 PMCID: PMC12022301 DOI: 10.1038/s41598-025-99010-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 04/16/2025] [Indexed: 04/26/2025] Open
Abstract
Endocrine diseases are suspected contributors to lymphoid malignancies, but their precise association is unclear. This study aimed to investigate the causal relationship between various endocrine diseases-specifically type 2 diabetes, obesity, diabetic hypoglycemia, hyperlipidemia, and hyperthyroidism-and lymphoid malignancies, including lymphocytic leukemia and non-Hodgkin's lymphoma with subtypes like diffuse large B-cell lymphoma and follicular lymphoma. Utilizing data from genome-wide association studies, a two-sample Mendelian randomization analysis was performed. The primary approach involved the inverse-variance weighted method, supplemented by other robust techniques such as the weighted median and MR-Egger regression to ensure reliability. The analysis indicated a significant causal connection between genetically predicted diabetic hypoglycemia and lymphocytic leukemia (Odds ratio = 1.0004, 95% Confidence interval = 1-1.0007, P = 0.03). Conversely, no associations were found for the other endocrine diseases with lymphoid malignancies (P > 0.05 for all). The findings suggest that while diabetic hypoglycemia may influence lymphocytic leukemia risk, further research is necessary to clarify the roles of other endocrine diseases in lymphoid malignancies, including cross-population validations and biological investigations.
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Affiliation(s)
- Chenze Zhao
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China
| | - Yu Zhang
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, 310006, China
| | - Lili Qian
- Department of Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, 310006, China
| | - Qing Guo
- International Mongolia Hospital of Inner Mongolia, Hohhot, 010065, China
| | - Ni Zhu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, 310006, China.
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2
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Guo S, Zhang Y, Lian J, Su C, Wang H. The role of hydrogen sulfide in the regulation of necroptosis across various pathological processes. Mol Cell Biochem 2025; 480:1999-2013. [PMID: 39138751 DOI: 10.1007/s11010-024-05090-1] [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: 05/06/2024] [Accepted: 08/05/2024] [Indexed: 08/15/2024]
Abstract
Necroptosis is a programmed cell death form executed by receptor-interacting protein kinase (RIPK) 1, RIPK3 and mixed lineage kinase domain-like protein (MLKL), which assemble into an oligomer called necrosome. Accumulating evidence reveals that necroptosis participates in many types of pathological processes. Hence, clarifying the mechanism of necroptosis in pathological processes is particularly important for the prevention and treatment of various diseases. For over 300 years, hydrogen sulfide (H2S) has been widely known in the scientific community as a toxic and foul-smelling gas. However, after discovering the important physiological and pathological functions of H2S, human understanding of this small molecule changed, believing that H2S is the third gas signaling molecule after carbon monoxide (CO) and nitric oxide (NO). H2S plays an important role in various diseases, but the related mechanisms are not yet fully understood. In recent years, more and more studies have shown that H2S regulation of necroptosis is involved in various pathological processes. Herein, we focus on the recent progress on the role of H2S regulation of necroptosis in different pathological processes and profoundly analyze the related mechanisms.
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Affiliation(s)
- Shiyun Guo
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Yanting Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Jingwen Lian
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Chunqi Su
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Honggang Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China.
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3
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Guo B, Gu J, Zhuang T, Zhang J, Fan C, Li Y, Zhao M, Chen R, Wang R, Kong Y, Xu S, Gao W, Liang L, Yu H, Han T. MicroRNA-126: From biology to therapeutics. Biomed Pharmacother 2025; 185:117953. [PMID: 40036996 DOI: 10.1016/j.biopha.2025.117953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/22/2025] [Accepted: 02/27/2025] [Indexed: 03/06/2025] Open
Abstract
MicroRNA-126 (miR-126) has emerged as one of the most extensively studied microRNAs in the context of human diseases, particularly in vascular disorders and cancer. Its high degree of conservation across vertebrates underscores its evolutionary significance and essential functional roles. Extensive research has been devoted to elucidating the molecular mechanisms through which miR-126 modulates key physiological and pathological processes, including angiogenesis, immune response, inflammation, tumor growth, and metastasis. Furthermore, miR-126 plays a causal role in the pathogenesis of various diseases, serving as potential biomarkers for disease prediction, diagnosis, prognosis and drug response, as well as a promising therapeutic target. In this review, we synthesize findings from 283 articles, focusing on the roles of miR-126 in critical biological processes such as cell development, survival, cycle regulation, proliferation, migration, invasion, communication, and metabolism. Additionally, miR-126 represents a promising candidate for miRNA-based therapeutic strategies. A comprehensive understanding and evaluation of miR-126 are crucial for advancing its clinical applications and therapeutic potential.
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Affiliation(s)
- Bei Guo
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Jia Gu
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Tongtian Zhuang
- Department of Dermatology, Air Force Hospital of Northern Theater Command, Shenyang, China
| | - Jingbin Zhang
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Chunyang Fan
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Yiyao Li
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Mengdi Zhao
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Ruoran Chen
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Rui Wang
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Yuan Kong
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Shuang Xu
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Wei Gao
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Linlang Liang
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Hao Yu
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China.
| | - Tao Han
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
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4
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Li X, Guan R, Zhang S. Factors Contributing to the High Malignancy Level of Cholangiocarcinoma and Its Epidemiology: Literature Review and Data. BIOLOGY 2025; 14:351. [PMID: 40282217 PMCID: PMC12025278 DOI: 10.3390/biology14040351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 03/18/2025] [Accepted: 03/25/2025] [Indexed: 04/29/2025]
Abstract
CCA is a highly desmoplastic malignant cancer and is the second most common primary liver malignancy after hepatocellular carcinoma (HCC), accounting for approximately 15% of all primary liver tumors. CCA has a poor prognosis, with an average five-year survival rate of 9%, which is lower than that of pancreatic cancer. Although considerable efforts have been invested into the genomics, epigenetics, and risk factors, very little is known about what might have been the key causes for the high malignancy level of CCA. In this review, we analyze the incidence and mortality of CCA in different regions based on data from 1994 to 2022 obtained from the International Agency for Research on Cancer (IARC), discuss the current status of treatment of the disease, and focus on what might be the main factors contributing to the high malignancy level of CCA: alkalosis caused by the Fenton reaction, hypoxia, and the TIME. The review includes studies published from 1979 to 2024, aiming to provide an updated synthesis of basic early classical theoretical knowledge and current knowledge about CCA. By revealing the epidemiological characteristics of CCA, the potential mechanisms of high malignancy, and the current challenges of treatment, this review aims to provide new directions for future cancer research, promote the development of personalized treatment strategies, and facilitate a deeper understanding and the more effective management of CCA worldwide.
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Affiliation(s)
- Xuan Li
- Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun 130012, China;
| | - Renchu Guan
- Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun 130012, China;
| | - Shuangquan Zhang
- School of Cyber Science and Engineering, Nanjing University of Science and Technology, Nanjing 210094, China
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5
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Sun W, Wang Y, Liu Z, Wu Q, Guo X, Li Z, Li X, Shi C, Gao R, Bai L, Wang J, Zhang Y, Li L, Ren G. Synergistic effect of canine FGF-21 combined with insulin in the treatment of canine diabetes. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03803-x. [PMID: 39836254 DOI: 10.1007/s00210-025-03803-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 01/08/2025] [Indexed: 01/22/2025]
Abstract
Previous studies have shown that FGF-21 can ameliorate hyperglycemia and improve the level of oxidative stress in vivo in diabetic mice. The hypoglycemic effect is safe and lasting, but it takes a longer time to exert its effect. Insulin treatment of canine diabetes takes effect quickly; however, its action time is short, and it is prone to cause hypoglycemia. In the present study, we investigated the synergistic effect of cFGF-21 combined with insulin in the treatment of canine diabetes. In the short and long-term treatment of diabetic dogs, cFGF-21 combined with insulin showed an obvious synergistic effect, and its hypoglycemic effect was significantly better than that of cFGF-21 or insulin injection alone. The combination, exhibited the advantage of the fast onset of insulin and the long-term hypoglycemic effect of cFGF-21. Additionally, cFGF-21 combined with insulin effectively relieved the oxidative stress in diabetic dogs. Studies of the synergistic mechanism showed that cFGF-21 combined with insulin could effectively inhibit liver gluconeogenesis and the synthesis of long-chain fatty acids and promote the phosphorylation of the common factor AKT in the pathway to better regulate hyperglycemia in diabetic dogs. In conclusion, cFGF-21 combined with insulin is a promising candidate for canine diabetes therapeutics.
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Affiliation(s)
- Wenying Sun
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Yaoqun Wang
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Ziran Liu
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Qing Wu
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Xiaochen Guo
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Zhitong Li
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Xinyu Li
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Chunxu Shi
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Rui Gao
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Lin Bai
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Jingming Wang
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Yuhan Zhang
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Lu Li
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China.
- Biopharmaceutical Teaching and Research Section, College of Life Science, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China.
| | - Guiping Ren
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin, 150030, China.
- Research Center of Genetic Engineering of Pharmaceuticals of Heilongjiang Province, Northeast Agricultural University, Harbin, 150030, China.
- Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin, 150030, China.
- Biopharmaceutical Teaching and Research Section, College of Life Science, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China.
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6
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Aydin S, Tekinalp SG, Tuzcu B, Cam F, Sevik MO, Tatar E, Kalaskar D, Cam ME. The role of AMP-activated protein kinase activators on energy balance and cellular metabolism in type 2 diabetes mellitus. OBESITY MEDICINE 2025; 53:100577. [DOI: 10.1016/j.obmed.2024.100577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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7
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Hannouneh ZA, Cervantes CE, Hanouneh M, Atta MG. Sodium-Glucose Cotransporter 2 Inhibitors in Diabetic Kidney Disease and beyond. GLOMERULAR DISEASES 2025; 5:119-132. [PMID: 40084183 PMCID: PMC11906174 DOI: 10.1159/000543685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/14/2025] [Indexed: 03/16/2025]
Abstract
Background Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have significantly impacted the management of diabetic kidney disease (DKD) and heart failure (HF), providing benefits beyond glycemic control. This review examines the mechanisms through which SGLT2is provide renal and cardiovascular protection and assesses their clinical efficacy. Summary By inducing glucosuria and natriuresis, SGLT2is alleviate multiple complications induced by chronic hyperglycemia. Moreover, SGLT2is reduce albuminuria, improve tubular function, and modulate erythropoiesis. Additionally, they mitigate inflammation and fibrosis by decreasing oxidative stress and downregulating proinflammatory pathways. Clinical trials have demonstrated significant reductions in renal and cardiovascular events among patients with type 2 diabetes mellitus. A comprehensive review of the literature was conducted through PubMed, highlighting the effects of SGLT2is and the results of major clinical trials involving SGLT2is. Key Messages SGLT2is play a crucial role in the management of DKD and HF by addressing multiple pathogenic pathways. Currently, SGLT2is are included in clinical guidelines for DKD and HF management, and their benefits extend to nondiabetic populations. Further research is needed to explore SGLT2is' multifaceted mechanisms and potential applications across diverse patient populations and different disease etiologies.
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Affiliation(s)
| | - C. Elena Cervantes
- Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Mohamad Hanouneh
- Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
- Nephrology Center of Maryland, Baltimore, MD, USA
| | - Mohamed G. Atta
- Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
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8
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Packer M, Ferreira JP, Butler J, Filippatos G, Januzzi JL, González Maldonado S, Panova-Noeva M, Pocock SJ, Prochaska JH, Saadati M, Sattar N, Sumin M, Anker SD, Zannad F. Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure: A Validation Cohort of the EMPEROR Program. J Am Coll Cardiol 2024; 84:1979-1994. [PMID: 39217550 DOI: 10.1016/j.jacc.2024.07.013] [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: 06/10/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined. OBJECTIVES We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure. METHODS In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously. RESULTS In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, ≥15% between-group difference and false discovery rate <1% at 12 weeks with known effects on the heart or kidney): 1) 13 proteins promote autophagy and other cellular quality-control functions (IGFBP1, OTUB1, DNAJB1, DNAJC9, RBP2, IST1, HSPA8, H-FABP, FABP6, ATPIFI, TfR1, EPO, IGBP1); 2) 12 proteins enhance mitochondrial health and ATP production (UMtCK, TBCA, L-FABP, H-FABP, FABP5, FABP6, RBP2, IST1, HSPA8, ATPIFI, TfR1, EPO); 3) 7 proteins augment cellular iron mobilization or erythropoiesis (TfR1, EPO, IGBP1, ERMAP, UROD, ATPIF1, SNCA); 4) 3 proteins influence renal tubular sodium handling; and 5) 9 proteins have restorative effects in the heart or kidneys, with many proteins exerting effects in >1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to ≥10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same. CONCLUSIONS The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors-to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function-are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977).
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, USA; Imperial College London, London, United Kingdom.
| | - João Pedro Ferreira
- UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal; Baylor Scott and White Research Institute, Dallas, Texas, USA
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, Texas, USA; University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Gerasimos Filippatos
- National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece
| | - James L Januzzi
- National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece; Massachusetts General Hospital and Baim Institute for Clinical Research, Boston, Massachusetts, USA
| | | | - Marina Panova-Noeva
- Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; Center for Thrombosis and Haemostasis, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Stuart J Pocock
- London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Jürgen H Prochaska
- Boehringer Ingelheim International GmbH, Ingelheim, Germany; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Maral Saadati
- Elderbrook Solutions GmbH, on behalf of Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany
| | - Naveed Sattar
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Mikhail Sumin
- Boehringer Ingelheim International GmbH, Ingelheim, Germany
| | - Stefan D Anker
- Department of Cardiology (CVK) of German Heart Center Charité, Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin, Berlin, Germany
| | - Faiez Zannad
- Centre d'Investigations Cliniques Plurithématique 1433, INSERM, Université de Lorraine, Nancy, France; F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), INSERM U1116, Centre Hospitalier Régional Universitaire de Nancy, Nancy, France
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9
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Gong S, Sui Y, Xiao M, Fu D, Xiong Z, Zhang L, Tian Q, Fu Y, Xiong W. Canagliflozin Mediates Mitophagy Through the AMPK/PINK1/Parkin Pathway to Alleviate ISO-induced Cardiac Remodeling. J Cardiovasc Pharmacol 2024; 84:496-505. [PMID: 39150485 DOI: 10.1097/fjc.0000000000001625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 07/26/2024] [Indexed: 08/17/2024]
Abstract
ABSTRACT Heart failure has always been a prevalent, disabling, and potentially life-threatening disease. For the treatment of heart failure, controlling cardiac remodeling is very important. In recent years, clinical trials have shown that sodium-glucose cotransporter-2 (SGLT-2) inhibitors not only excel in lowering glucose levels but also demonstrate favorable cardiovascular protective effects. However, the precise mechanisms behind the cardiovascular benefits of SGLT-2 inhibitors remain elusive. In this research, we assessed the impact of canagliflozin (CANA, an SGLT-2 inhibitor) on cardiac remodeling progression in mice and preliminarily elucidated the possible mechanism of action of the SGLT-2 inhibitor. Our results indicate that the administration of canagliflozin significantly attenuates myocardial hypertrophy and fibrosis and enhances cardiac ejection function in mice with isoprenaline (ISO)-induced cardiac remodeling. Notably, excessive mitophagy, along with mitochondrial structural abnormalities observed in ISO-induced cardiac remodeling, was mitigated by canagliflozin treatment, thereby attenuating cardiac remodeling progression. Furthermore, the differential expression of AMPK/PINK1/Parkin pathway-related proteins in ISO-induced cardiac remodeling was effectively reversed by canagliflozin, suggesting the therapeutic potential of targeting this pathway with the drug. Thus, our study indicates that canagliflozin holds promise in mitigating cardiac injury, enhancing cardiac function, and potentially exerting cardioprotective effects by modulating mitochondrial function and mitophagy through the AMPK/PINK1/Parkin pathway.
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MESH Headings
- Animals
- Male
- Mice
- AMP-Activated Protein Kinases/metabolism
- Canagliflozin/pharmacology
- Disease Models, Animal
- Fibrosis
- Isoproterenol
- Mice, Inbred C57BL
- Mitochondria, Heart/drug effects
- Mitochondria, Heart/enzymology
- Mitochondria, Heart/pathology
- Mitochondria, Heart/metabolism
- Mitophagy/drug effects
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/pathology
- Myocytes, Cardiac/enzymology
- Myocytes, Cardiac/metabolism
- Protein Kinases/metabolism
- Signal Transduction/drug effects
- Sodium-Glucose Transporter 2 Inhibitors/pharmacology
- Stroke Volume/drug effects
- Ubiquitin-Protein Ligases/metabolism
- Ventricular Function, Left/drug effects
- Ventricular Remodeling/drug effects
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Affiliation(s)
- Shaolin Gong
- Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China ; and
| | - Yuan Sui
- Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China ; and
| | - Mengxuan Xiao
- Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China ; and
| | - Daoyao Fu
- Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China ; and
| | - Zhiping Xiong
- Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China ; and
| | - Liuping Zhang
- Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China ; and
| | - Qingshan Tian
- Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China ; and
| | - Yongnan Fu
- Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China ; and
| | - Wenjun Xiong
- Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China ; and
- Center of Reproduction, Development and Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
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10
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Jang S, Yoo C, Kim HS, Kim J, Lee DY. Oxygenating respiratoid biosystem for therapeutic cell transplantation. Nat Commun 2024; 15:9151. [PMID: 39443443 PMCID: PMC11500001 DOI: 10.1038/s41467-024-53246-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] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 10/07/2024] [Indexed: 10/25/2024] Open
Abstract
In this study, we address the persistent challenge of providing adequate oxygen to transplanted cells by introducing a respiratoid biosystem. Central to our strategy is the chloroplast-transit-peptide (CTP), crucial for optimal oxygenation. Through conjugation of CTP with alginate, we achieve stabilization of chloroplast structure. Strategically anchored to the outer chloroplast membrane, CTP not only ensures structural integrity but also upregulates key photosynthesis-associated genes. This biosystem demonstrates exceptional efficacy in spontaneously generating oxygen, particularly under hypoxic conditions (~1% pO2). In an application, pancreatic islets encapsulated within the respiratoid biosystem and intraperitoneally implanted in diabetic mice maintain normal glucose levels effectively. Insulin secretion persists for 100 days post-xenotransplantation without the need for immunosuppressant administration, highlighting the reliance on the respiratoid biosystem's oxygen supply and structural stability. Our study demonstrates the respiratoid biosystem as a platform in tissue engineering, offering a nature-inspired solution to the critical challenge of spontaneous oxygen supply.
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Affiliation(s)
- Seonmi Jang
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul, Republic of Korea
| | - Chaerim Yoo
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul, Republic of Korea
| | - Hyung Shik Kim
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul, Republic of Korea
- Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA, USA
| | - Jiyun Kim
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul, Republic of Korea
| | - Dong Yun Lee
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul, Republic of Korea.
- Institute of Nano Science and Technology (INST), Hanyang University, Seoul, Republic of Korea.
- Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Republic of Korea.
- Elixir Pharmatech Inc, Seoul, Republic of Korea.
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11
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Lou Y, Luan YT, Rong WQ, Gai Y. Corilagin alleviates podocyte injury in diabetic nephropathy by regulating autophagy via the SIRT1-AMPK pathway. World J Diabetes 2024; 15:1916-1931. [PMID: 39280180 PMCID: PMC11372637 DOI: 10.4239/wjd.v15.i9.1916] [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: 03/06/2024] [Revised: 06/04/2024] [Accepted: 07/02/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is the most frequent chronic microvascular consequence of diabetes, and podocyte injury and malfunction are closely related to the development of DN. Studies have shown that corilagin (Cor) has hepatoprotective, anti-inflammatory, antibacterial, antioxidant, anti-hypertensive, anti-diabetic, and anti-tumor activities. AIM To explore the protective effect of Cor against podocyte injury in DN mice and the underlying mechanisms. METHODS Streptozotocin and a high-fat diet were combined to generate DN mice models, which were then divided into either a Cor group or a DN group (n = 8 in each group). Mice in the Cor group were intraperitoneally injected with Cor (30 mg/kg/d) for 12 wk, and mice in the DN group were treated with saline. Biochemical analysis was used to measure the blood lipid profiles. Hematoxylin and eosin staining was used to detect pathological changes in kidney tissue. Immunohistochemistry and Western blotting were used to assess the protein expression of nephrin and podocin. Mouse podocyte cells (MPC5) were cultured and treated with glucose (5 mmol/L), Cor (50 μM), high glucose (HG) (30 mmol/L), and HG (30 mmol/L) plus Cor (50 μM). Real-time quantitative PCR and Western blotting were performed to examine the effects of Cor on podocyte autophagy. RESULTS Compared with the control group, the DN mice models had increased fasting blood glucose, glycosylated hemoglobin, triglycerides, and total cholesterol, decreased nephrin and podocin expression, increased apoptosis rate, elevated inflammatory cytokines, and enhanced oxidative stress. All of the conditions mentioned above were alleviated after intervention with Cor. In addition, Cor therapy improved SIRT1 and AMPK expression (P < 0.001), inhibited reactive oxygen species and oxidative stress, and elevated autophagy in HG-induced podocytes (P < 0.01). CONCLUSION Cor alleviates podocyte injury by regulating autophagy via the SIRT1-AMPK pathway, thereby exerting its protective impact on renal function in DN mice.
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Affiliation(s)
- Yu Lou
- Department of Preventive Treatment of Disease, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China
| | - Yu-Ting Luan
- Department of Infectious Diseases, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China
| | - Wen-Qing Rong
- Department of General Practice (Including Medical Oncology), Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China
| | - Yun Gai
- Department of General Practice (Including Medical Oncology), Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China
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12
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Huang XD, Jiang DS, Feng X, Fang ZM. The benefits of oral glucose-lowering agents: GLP-1 receptor agonists, DPP-4 and SGLT-2 inhibitors on myocardial ischaemia/reperfusion injury. Eur J Pharmacol 2024; 976:176698. [PMID: 38821168 DOI: 10.1016/j.ejphar.2024.176698] [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: 03/09/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 06/02/2024]
Abstract
Myocardial infarction (MI) is a life-threatening cardiovascular disease that, on average, results in 8.5 million deaths worldwide each year. Timely revascularization of occluded vessels is a critical method of myocardial salvage. However, reperfusion paradoxically leads to the worsening of myocardial damage known as myocardial ischaemia/reperfusion injury (MI/RI). Therefore, reducing the size of myocardial infarction after reperfusion is critical and remains an important therapeutic goal. The susceptibility of the myocardium to MI/RI may be increased by diabetes. Currently, some traditional antidiabetic agents such as metformin reduce MI/RI by decreasing inflammation, inhibiting oxidative stress, and improving vascular endothelial function. This appears to be a new direction for the treatment of MI/RI. Recent cardiovascular outcome trials have shown that several oral antidiabetic agents, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4is), and sodium-glucose-linked transporter-2 inhibitors (SGLT-2is), not only have good antidiabetic effects but also have a protective effect on myocardial protection. This article aims to discuss the mechanisms and effects of oral antidiabetic agents, including GLP-1RAs, DPP-4is, and SGLT-2is, on MI/RI to facilitate their clinical application.
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Affiliation(s)
- Xu-Dong Huang
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Cardiothoracic Surgery, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Ding-Sheng Jiang
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China
| | - Xin Feng
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Ze-Min Fang
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Cardiothoracic Surgery, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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13
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Wu Y, Zou Y, Song C, Cao K, Cai K, Chen S, Zhang Z, Geng D, Zhang N, Feng H, Tang M, Li Z, Sun G, Zhang Y, Sun Y, Zhang Y. The role of serine/threonine protein kinases in cardiovascular disease and potential therapeutic methods. Biomed Pharmacother 2024; 177:117093. [PMID: 38971012 DOI: 10.1016/j.biopha.2024.117093] [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: 04/17/2024] [Revised: 07/02/2024] [Accepted: 07/02/2024] [Indexed: 07/08/2024] Open
Abstract
Protein phosphorylation is an important link in a variety of signaling pathways, and most of the important life processes in cells involve protein phosphorylation. Based on the amino acid residues of phosphorylated proteins, protein kinases can be categorized into the following families: serine/threonine protein kinases, tyrosine-specific protein kinases, histidine-specific protein kinases, tryptophan kinases, and aspartate/glutamyl protein kinases. Of all the protein kinases, most are serine/threonine kinases, where serine/threonine protein kinases are protein kinases that catalyze the phosphorylation of serine or threonine residues on target proteins using ATP as a phosphate donor. The current socially accepted classification of serine/threonine kinases is to divide them into seven major groups: protein kinase A, G, C (AGC), CMGC, Calmodulin-dependent protein kinase (CAMK), Casein kinase (CK1), STE, Tyrosine kinase (TKL) and others. After decades of research, a preliminary understanding of the specific classification and respective functions of serine/threonine kinases has entered a new period of exploration. In this paper, we review the literature of the previous years and introduce the specific signaling pathways and related therapeutic modalities played by each of the small protein kinases in the serine/threonine protein kinase family, respectively, in some common cardiovascular system diseases such as heart failure, myocardial infarction, ischemia-reperfusion injury, and diabetic cardiomyopathy. To a certain extent, the current research results, including molecular mechanisms and therapeutic methods, are fully summarized and a systematic report is made for the prevention and treatment of cardiovascular diseases in the future.
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Affiliation(s)
- Yanjiao Wu
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Yuanming Zou
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Chunyu Song
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Kexin Cao
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Kexin Cai
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Shuxian Chen
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Zhaobo Zhang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Danxi Geng
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China
| | - Naijin Zhang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China; Institute of health sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning Province 110001, People's Republic of China; Key Laboratory of Reproductive and Genetic Medicine (China Medical University), National Health Commission, Shenyang 110004, China.
| | - Hao Feng
- Department of Ophthalmology, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China.
| | - Man Tang
- Department of clinical pharmacology, College of Pharmacy, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning Province 110001, People's Republic of China.
| | - Zhao Li
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China.
| | - Guozhe Sun
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China.
| | - Yixiao Zhang
- Department of Urology Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, Liaoning Province 110004, People's Republic of China.
| | - Yingxian Sun
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China; Institute of health sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning Province 110001, People's Republic of China; Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning Province 110001, People's Republic of China.
| | - Ying Zhang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province 110001, People's Republic of China; Institute of health sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning Province 110001, People's Republic of China.
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14
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Pan X, Hao E, Zhang F, Wei W, Du Z, Yan G, Wang X, Deng J, Hou X. Diabetes cardiomyopathy: targeted regulation of mitochondrial dysfunction and therapeutic potential of plant secondary metabolites. Front Pharmacol 2024; 15:1401961. [PMID: 39045049 PMCID: PMC11263127 DOI: 10.3389/fphar.2024.1401961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 06/11/2024] [Indexed: 07/25/2024] Open
Abstract
Diabetic cardiomyopathy (DCM) is a specific heart condition in diabetic patients, which is a major cause of heart failure and significantly affects quality of life. DCM is manifested as abnormal cardiac structure and function in the absence of ischaemic or hypertensive heart disease in individuals with diabetes. Although the development of DCM involves multiple pathological mechanisms, mitochondrial dysfunction is considered to play a crucial role. The regulatory mechanisms of mitochondrial dysfunction mainly include mitochondrial dynamics, oxidative stress, calcium handling, uncoupling, biogenesis, mitophagy, and insulin signaling. Targeting mitochondrial function in the treatment of DCM has attracted increasing attention. Studies have shown that plant secondary metabolites contribute to improving mitochondrial function and alleviating the development of DCM. This review outlines the role of mitochondrial dysfunction in the pathogenesis of DCM and discusses the regulatory mechanism for mitochondrial dysfunction. In addition, it also summarizes treatment strategies based on plant secondary metabolites. These strategies targeting the treatment of mitochondrial dysfunction may help prevent and treat DCM.
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Affiliation(s)
- Xianglong Pan
- Department of Pharmaceutical, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Erwei Hao
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Fan Zhang
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Wei Wei
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Zhengcai Du
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Guangli Yan
- Department of Pharmaceutical, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Xijun Wang
- Department of Pharmaceutical, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Jiagang Deng
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xiaotao Hou
- Department of Pharmaceutical, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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15
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Mao TH, Huang HQ, Zhang CH. Clinical characteristics and treatment compounds of obesity-related kidney injury. World J Diabetes 2024; 15:1091-1110. [PMID: 38983811 PMCID: PMC11229974 DOI: 10.4239/wjd.v15.i6.1091] [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: 12/06/2023] [Revised: 12/22/2023] [Accepted: 04/08/2024] [Indexed: 06/11/2024] Open
Abstract
Disorders in energy homeostasis can lead to various metabolic diseases, particularly obesity. The obesity epidemic has led to an increased incidence of obesity-related nephropathy (ORN), a distinct entity characterized by proteinuria, glomerulomegaly, progressive glomerulosclerosis, and renal function decline. Obesity and its associated renal damage are common in clinical practice, and their incidence is increasing and attracting great attention. There is a great need to identify safe and effective therapeutic modalities, and therapeutics using chemical compounds and natural products are receiving increasing attention. However, the summary is lacking about the specific effects and mechanisms of action of compounds in the treatment of ORN. In this review, we summarize the important clinical features and compound treatment strategies for obesity and obesity-induced kidney injury. We also summarize the pathologic and clinical features of ORN as well as its pathogenesis and potential therapeutics targeting renal inflammation, oxidative stress, insulin resistance, fibrosis, kidney lipid accumulation, and dysregulated autophagy. In addition, detailed information on natural and synthetic compounds used for the treatment of obesity-related kidney disease is summarized. The synthesis of detailed information aims to contribute to a deeper understanding of the clinical treatment modalities for obesity-related kidney diseases, fostering the anticipation of novel insights in this domain.
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Affiliation(s)
- Tuo-Hua Mao
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Han-Qi Huang
- Department of Endocrinology, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan 430033, Hubei Province, China
| | - Chuan-Hai Zhang
- Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, United States
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16
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Madonna R, Biondi F, Alberti M, Ghelardoni S, Mattii L, D'Alleva A. Cardiovascular outcomes and molecular targets for the cardiac effects of Sodium-Glucose Cotransporter 2 Inhibitors: A systematic review. Biomed Pharmacother 2024; 175:116650. [PMID: 38678962 DOI: 10.1016/j.biopha.2024.116650] [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: 02/19/2024] [Revised: 04/21/2024] [Accepted: 04/24/2024] [Indexed: 05/01/2024] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new class of glucose-lowering drugs traditionally used to control blood glucose levels in patients with type 2 diabetes mellitus, have been proven to reduce major adverse cardiovascular events, including cardiovascular death, in patients with heart failure irrespective of ejection fraction and independently of the hypoglycemic effect. Because of their favorable effects on the kidney and cardiovascular outcomes, their use has been expanded in all patients with any combination of diabetes mellitus type 2, chronic kidney disease and heart failure. Although mechanisms explaining the effects of these drugs on the cardiovascular system are not well understood, their effectiveness in all these conditions suggests that they act at the intersection of the metabolic, renal and cardiac axes, thus disrupting maladaptive vicious cycles while contrasting direct organ damage. In this systematic review we provide a state of the art of the randomized controlled trials investigating the effect of SGLT2i on cardiovascular outcomes in patients with chronic kidney disease and/or heart failure irrespective of ejection fraction and diabetes. We also discuss the molecular targets and signaling pathways potentially explaining the cardiac effects of these pharmacological agents, from a clinical and experimental perspective.
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Affiliation(s)
- Rosalinda Madonna
- Department of Pathology, Cardiology Division, University of Pisa, Via Paradisa, Pisa 56124, Italy.
| | - Filippo Biondi
- Department of Pathology, Cardiology Division, University of Pisa, Via Paradisa, Pisa 56124, Italy
| | - Mattia Alberti
- Department of Pathology, Cardiology Division, University of Pisa, Via Paradisa, Pisa 56124, Italy
| | - Sandra Ghelardoni
- Department of Pathology, Laboratory of Biochemistry, University of Pisa, Italy
| | - Letizia Mattii
- Department of Clinical and Experimental Medicine, Histology Division, University of Pisa, Pisa, Italy
| | - Alberto D'Alleva
- Cardiac Intensive Care and Interventional Cardiology Unit, Santo Spirito Hospital, Pescara, Italy
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17
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Yasasilka XR, Lee M. Role of β-cell autophagy in β-cell physiology and the development of diabetes. J Diabetes Investig 2024; 15:656-668. [PMID: 38470018 PMCID: PMC11143416 DOI: 10.1111/jdi.14184] [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: 12/15/2023] [Revised: 02/14/2024] [Accepted: 02/28/2024] [Indexed: 03/13/2024] Open
Abstract
Elucidating the molecular mechanism of autophagy was a landmark in understanding not only the physiology of cells and tissues, but also the pathogenesis of diverse diseases, including diabetes and metabolic disorders. Autophagy of pancreatic β-cells plays a pivotal role in the maintenance of the mass, structure and function of β-cells, whose dysregulation can lead to abnormal metabolic profiles or diabetes. Modulators of autophagy are being developed to improve metabolic profile and β-cell function through the removal of harmful materials and rejuvenation of organelles, such as mitochondria and endoplasmic reticulum. Among the known antidiabetic drugs, glucagon-like peptide-1 receptor agonists enhance the autophagic activity of β-cells, which might contribute to the profound effects of glucagon-like peptide-1 receptor agonists on systemic metabolism. In this review, the results from studies on the role of autophagy in β-cells and their implication in the development of diabetes are discussed. In addition to non-selective (macro)autophagy, the role and mechanisms of selective autophagy and other minor forms of autophagy that might occur in β-cells are discussed. As β-cell failure is the ultimate cause of diabetes and unresponsiveness to conventional therapy, modulation of β-cell autophagy might represent a future antidiabetic treatment approach, particularly in patients who are not well managed with current antidiabetic therapy.
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Affiliation(s)
- Xaviera Riani Yasasilka
- Soonchunhyang Institute of Medi‐bio Science and Division of Endocrinology, Department of Internal MedicineSoonchunhyang University College of MedicineCheonanKorea
| | - Myung‐Shik Lee
- Soonchunhyang Institute of Medi‐bio Science and Division of Endocrinology, Department of Internal MedicineSoonchunhyang University College of MedicineCheonanKorea
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18
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Li M, Liu L, Zhang C, Deng L, Zhong Y, Liao B, Li X, Wan Y, Feng J. The latest emerging drugs for the treatment of diabetic cardiomyopathy. Expert Opin Pharmacother 2024; 25:641-654. [PMID: 38660817 DOI: 10.1080/14656566.2024.2347468] [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: 02/05/2024] [Accepted: 04/22/2024] [Indexed: 04/26/2024]
Abstract
INTRODUCTION Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus involving multiple pathophysiologic mechanisms. In addition to hypoglycemic agents commonly used in diabetes, metabolism-related drugs, natural plant extracts, melatonin, exosomes, and rennin-angiotensin-aldosterone system are cardioprotective in DCM. However, there is a lack of systematic summarization of drugs for DCM. AREAS COVERED In this review, the authors systematically summarize the most recent drugs used for the treatment of DCM and discusses them from the perspective of DCM pathophysiological mechanisms. EXPERT OPINION We discuss DCM drugs from the perspective of the pathophysiological mechanisms of DCM, mainly including inflammation and metabolism. As a disease with multiple pathophysiological mechanisms, the combination of drugs may be more advantageous, and we have discussed some of the current studies on the combination of drugs.
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Affiliation(s)
- Minghao Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Lin Liu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Chunyu Zhang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Li Deng
- Department of Rheumatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yi Zhong
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Bin Liao
- Department of Cardiovascular Surgery, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiuying Li
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University; Department of Pathophysiology, School of Basic Medical Science, Southwest Medical University, Luzhou, China
| | - Ying Wan
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University; Department of Pathophysiology, School of Basic Medical Science, Southwest Medical University, Luzhou, China
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
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19
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Hewedy WA, Abdulmalek SA, Ghareeb DA, Habiba ES. AMPK-mediated autophagy is involved in the protective effect of canagliflozin in the vitamin D3 plus nicotine calcification model in rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:873-888. [PMID: 37522915 PMCID: PMC10791829 DOI: 10.1007/s00210-023-02627-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 07/12/2023] [Indexed: 08/01/2023]
Abstract
Vascular calcification (VC) is a major risk factor for cardiovascular events. A mutual interplay between inflammation, oxidative stress, apoptosis, and autophagy is implicated in its development. Herein, we aimed to evaluate the potential protective effects of canagliflozin in a vitamin D3 plus nicotine (VDN) model of VC, and to explore potential mechanisms. VC was induced by VDN in adult male Wistar rats on day one. Then, rats were randomly assigned into three groups to receive canagliflozin (10 mg or 20 mg/kg/day) or its vehicle for 4 weeks. Age-matched normal rats served as a control group. After euthanization, aorta and kidneys were harvested for biochemical and histopathological evaluation of calcification. Aortic markers of oxidative stress, alkaline phosphatase (ALP) activity, runt-related transcription factor (Runx2) and bone morphogenic protein-2 (BMP-2) levels were determined. Additionally, the protein expression of autophagic markers, LC3 and p62, and adenosine monophosphate activated protein kinase (AMPK) were also assessed in aortic homogenates. Canagliflozin dose-dependently improved renal function, enhanced the antioxidant capacity of aortic tissues and reduced calcium deposition in rat aortas and kidneys. Both doses of canagliflozin attenuated ALP and osteogenic markers while augmented the expression of autophagic markers and AMPK. Histopathological examination of aortas and kidneys by H&E and Von Kossa stain further support the beneficial effect of canagliflozin. Canagliflozin could alleviate VDN-induced vascular calcification, in a dose dependent manner, via its antioxidant effect and modulation of autophagy. Further studies are needed to verify whether this effect is a member or a class effect.
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Affiliation(s)
- Wafaa A Hewedy
- Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
- Al-Moassat Medical Campus, Elhadara, Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, 21561, Alexandria, Egypt.
| | - Shaymaa A Abdulmalek
- Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Doaa A Ghareeb
- Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Esraa S Habiba
- Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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Connelly KA, Wu E, Visram A, Friedberg MK, Batchu SN, Yerra VG, Thai K, Nghiem L, Zhang Y, Kabir G, Desjardins JF, Advani A, Gilbert RE. The SGLT2i Dapagliflozin Reduces RV Mass Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding. Cardiovasc Drugs Ther 2024; 38:57-68. [PMID: 36173474 DOI: 10.1007/s10557-022-07377-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/18/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class is efficacious in the treatment and prevention of right heart failure has not been explored. HYPOTHESIS We hypothesized that SGLT2 inhibition would reduce the structural, functional, and molecular responses to pressure overload of the right ventricle. METHODS Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5 mg/kg/day) or vehicle by oral gavage. After 6 weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses. RESULTS PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content, and alteration in calcium handling protein expression (all p < 0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, phospho-AMPK and LC3I/II ratio expression (all p < 0.05). SIGNIFICANCE Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.
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Affiliation(s)
- Kim A Connelly
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada.
| | - Ellen Wu
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada
| | - Aylin Visram
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada
| | - Mark K Friedberg
- Division of Cardiology, Labatt Family Heart Center Toronto, Toronto, ON, Canada
- Physiology and Experimental Medicine, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada
| | - Sri Nagarjun Batchu
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada
| | - Veera Ganesh Yerra
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada
| | - Kerri Thai
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada
| | - Linda Nghiem
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada
| | - Yanling Zhang
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada
| | - Golam Kabir
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada
| | - J F Desjardins
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada
| | - Andrew Advani
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada
| | - Richard E Gilbert
- Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada.
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Packer M. Mechanisms of enhanced renal and hepatic erythropoietin synthesis by sodium-glucose cotransporter 2 inhibitors. Eur Heart J 2023; 44:5027-5035. [PMID: 37086098 PMCID: PMC10733737 DOI: 10.1093/eurheartj/ehad235] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 03/06/2023] [Accepted: 04/03/2023] [Indexed: 04/23/2023] Open
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major heart failure events, an action that is statistically linked to enhanced erythropoiesis, suggesting that stimulation of erythropoietin and cardioprotection are related to a shared mechanism. Four hypotheses have been proposed to explain how these drugs increase erythropoietin production: (i) renal cortical reoxygenation with rejuvenation of erythropoietin-producing cells; (ii) counterregulatory distal sodium reabsorption leading to increased tubular workload and oxygen consumption, and thus, to localized hypoxia; (iii) increased iron mobilization as a stimulus of hypoxia-inducible factor-2α (HIF-2α)-mediated erythropoietin synthesis; and (iv) direct HIF-2α activation and enhanced erythropoietin gene transcription due to increased sirtuin-1 (SIRT1) signaling. The first two hypotheses assume that the source of increased erythropoietin is the interstitial fibroblast-like cells in the deep renal cortex. However, SGLT2 inhibitors do not alter regional tissue oxygen tension in the non-diabetic kidney, and renal erythropoietin synthesis is markedly impaired in patients with anemia due to chronic kidney disease, and yet, SGLT2 inhibitors produce an unattenuated erythrocytic response in these patients. This observation raises the possibility that the liver contributes to the production of erythropoietin during SGLT2 inhibition. Hypoxia-inducible factor-2α and erythropoietin are coexpressed not only in the kidney but also in hepatocytes; the liver is a major site of production when erythropoietin stimulation is maintained for prolonged periods. The ability of SGLT2 inhibitors to improve iron mobilization by derepressing hepcidin and ferritin would be expected to increase cytosolic ferrous iron, which might stimulate HIF-2α expression in both the kidney and liver through the action of iron regulatory protein 1. Alternatively, the established ability of SGLT2 inhibitors to enhance SIRT1 might be the mechanism of enhanced erythropoietin production with these drugs. In hepatic cell lines, SIRT1 can directly activate HIF-2α by deacetylation, and additionally, through an effect of SIRT in the liver, peroxisome proliferator-activated receptor-γ coactivator-1α binds to hepatic nuclear factor 4 to promote transcription of the erythropoietin gene and synthesis of erythropoietin. Since SIRT1 up-regulation exerts direct cytoprotective effects on the heart and stimulates erythropoietin, it is well-positioned to represent the shared mechanism that links erythropoiesis to cardioprotection during SGLT2 inhibition.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, 621 North Hall Street, Dallas, TX 75226, USA
- Imperial College, London, UK
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22
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Speedtsberg ES, Tepel M. Narrative review investigating the nephroprotective mechanisms of sodium glucose cotransporter type 2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease. Front Endocrinol (Lausanne) 2023; 14:1281107. [PMID: 38174341 PMCID: PMC10761498 DOI: 10.3389/fendo.2023.1281107] [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: 08/21/2023] [Accepted: 11/16/2023] [Indexed: 01/05/2024] Open
Abstract
Background and aims Outcome trials using sodium glucose cotransporter type 2 inhibitors have consistently shown their potential to preserve kidney function in diabetic and nondiabetic patients. Several mechanisms have been introduced which may explain the nephroprotective effect of sodium glucose cotransporter type 2 inhibitors beyond lowering blood glucose. This current narrative review has the objective to describe main underlying mechanisms causing a nephroprotective effect and to show similarities as well as differences between proposed mechanisms which can be observed in patients with diabetic and nondiabetic chronic kidney disease. Methods We performed a narrative review of the literature on Pubmed and Embase. The research string comprised various combinations of items including "chronic kidney disease", "sodium glucose cotransporter 2 inhibitor" and "mechanisms". We searched for original research and review articles published until march, 2022. The databases were searched independently and the agreements by two authors were jointly obtained. Results Sodium glucose cotransporter type 2 inhibitors show systemic, hemodynamic, and metabolic effects. Systemic effects include reduction of blood pressure without compensatory activation of the sympathetic nervous system. Hemodynamic effects include restoration of tubuloglomerular feedback which may improve pathologic hyperfiltration observed in most cases with chronic kidney disease. Current literature indicates that SGLT2i may not improve cortical oxygenation and may reduce medullar oxygenation. Conclusion Sodium glucose cotransporter type 2 inhibitors cause nephroprotective effects by several mechanisms. However, several mediators which are involved in the underlying pathophysiology may be different between diabetic and nondiabetic patients.
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Affiliation(s)
- Emma S Speedtsberg
- Institute of Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
- Institute of Clinical Medicine, University of Southern Denmark, Odense, Denmark
- Department of Nephrology, Odense University Hospital, Odense, Denmark
| | - Martin Tepel
- Institute of Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
- Institute of Clinical Medicine, University of Southern Denmark, Odense, Denmark
- Department of Nephrology, Odense University Hospital, Odense, Denmark
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Song XM, Zhao MN, Li GZ, Li N, Wang T, Zhou H. Atorvastatin ameliorated myocardial fibrosis in db/db mice by inhibiting oxidative stress and modulating macrophage polarization. World J Diabetes 2023; 14:1849-1861. [PMID: 38222782 PMCID: PMC10784803 DOI: 10.4239/wjd.v14.i12.1849] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 09/29/2023] [Accepted: 10/23/2023] [Indexed: 12/14/2023] Open
Abstract
BACKGROUND People with diabetes mellitus (DM) suffer from multiple chronic complications due to sustained hyperglycemia, especially diabetic cardiomyopathy (DCM). Oxidative stress and inflammatory cells play crucial roles in the occurrence and progression of myocardial remodeling. Macrophages polarize to two distinct phenotypes: M1 and M2, and such plasticity in phenotypes provide macrophages various biological functions. AIM To investigate the effect of atorvastatin on cardiac function of DCM in db/db mice and its underlying mechanisms. METHODS DCM mouse models were established and randomly divided into DM, atorvastatin, and metformin groups. C57BL/6 mice were used as the control. Cardiac function was evaluated by echocardiography. Hematoxylin and eosin and Masson staining was used to examine the morphology and collagen fibers in myocardial tissues. The expression of transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β),M1 macrophages (iNOS+), and M2 macrophages (CD206+) were demonstrated by immunohistochemistry and immunofluorescence staining. The levels of TGF-β1, IL-1β, and TNF-α were detected by ELISA and real-time quantitative polymerase chain reaction. Malondialdehyde (MDA) concentrations and superoxide dismutase (SOD) ac-tivities were also measured. RESULTS Treatment with atorvastatin alleviated cardiac dysfunction and decreased db/db mice. The broken myocardial fibers and deposition of collagen in the myocardial interstitium were relieved especially by atorvastatin treatment. Atorvastatin also reduced the levels of serum lactate dehydrogenase, creatine kinase isoenzyme, and troponin; lowered the levels of TGF-β1, TNF-α and IL-1β in serum and myocardium; decreased the concentration of MDA and increased SOD activity in myocardium of db/db mice; inhibited M1 macrophages; and promoted M2 macrophages. CONCLUSION Administration of atorvastatin attenuates myocardial fibrosis in db/db mice, which may be associated with the antioxidative stress and anti-inflammatory effects of atorvastatin on diabetic myocardium through modulating macrophage polarization.
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Affiliation(s)
- Xian-Min Song
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
- Department of Geriatrics, Handan Central Hospital, Handan 056001, Hebei Province, China
| | - Meng-Nan Zhao
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Gui-Zhi Li
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Na Li
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Ting Wang
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Hong Zhou
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
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Cho M, Woo YR, Cho SH, Lee JD, Kim HS. Metformin: A Potential Treatment for Acne, Hidradenitis Suppurativa and Rosacea. Acta Derm Venereol 2023; 103:adv18392. [PMID: 38078688 PMCID: PMC10726377 DOI: 10.2340/actadv.v103.18392] [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: 08/10/2023] [Accepted: 11/08/2023] [Indexed: 12/18/2023] Open
Abstract
Metformin is a widely used drug for treatment of diabetes mellitus, due to its safety and efficacy. In addition to its role as an antidiabetic drug, numerous beneficial effects of metformin have enabled its use in various diseases. Considering the anti-androgenic, anti-angiogenic, anti-fibrotic and antioxidant properties of metformin, it may have the potential to improve chronic inflammatory skin diseases. However, further evidence is needed to confirm the efficacy of metformin in dermatological conditions, This review focuses on exploring the therapeutic targets of metformin in acne vulgaris, hidradenitis suppurativa and rosacea, by studying their pathogeneses.
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Affiliation(s)
- Minah Cho
- Department of Dermatology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yu Ri Woo
- Department of Dermatology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sang Hyun Cho
- Department of Dermatology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong Deuk Lee
- Department of Dermatology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hei Sung Kim
- Department of Dermatology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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25
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Liu C, Guo X, Zhou Y, Wang H. AMPK Signalling Pathway: A Potential Strategy for the Treatment of Heart Failure with Chinese Medicine. J Inflamm Res 2023; 16:5451-5464. [PMID: 38026240 PMCID: PMC10676094 DOI: 10.2147/jir.s441597] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 11/10/2023] [Indexed: 12/01/2023] Open
Abstract
Heart failure (HF) is a complex clinical syndrome that represents the advanced stage of cardiovascular disease, characterized by systolic and diastolic dysfunction of the heart. Despite continuous updates in HF treatment drugs, the morbidity and mortality rates remain high, necessitating ongoing exploration for new therapeutic targets. Adenosine monophosphate-activated protein kinase (AMPK) is the serine/threonine protein kinase which responds to adenosine monophosphate (AMP) levels.Activation of AMPK shifts cellular metabolic patterns from synthesis to catabolism, enhancing energy metabolism in pathological conditions such as inflammation, ischemia, obesity, and aging. Numerous studies have identified AMPK as a vital target for HF treatment, with herbal monomers/extracts and compounds affecting key signaling factors including rapamycin targeting protein (mTOR), silencing regulator protein 1 (SIRT1), nuclear transcription factor E2-related factor 2 (Nrf2), and nuclear transcription factor-κB (NF-κB) through regulation of the AMPK signaling pathway.This modulation can achieve the effects of improving metabolism, autophagy, reducing oxidative stress and inflammatory response in the treatment of heart failure, with the advantages of multi-targeting, comprehensive action and low toxicity.The modulation of the AMPK pathway by Traditional Chinese Medicine (TCM) has emerged as a crucial research direction for the prevention and treatment of HF, but a systematic summary and generalization in this field is lacking. This article provides an overview of the composition, regulation, and mechanism of the AMPK signaling pathway's influence on HF, as well as a summary of current research on the regulation of the AMPK pathway by TCM for HF prevention and treatment. The aim is to serve as a reference for the diagnosis and treatment of HF using TCM and the development of new drugs.
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Affiliation(s)
- Changxing Liu
- First Clinical Medical School, Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China
| | - Xinyi Guo
- Clinical Medical School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, People’s Republic of China
| | - Yabin Zhou
- Department of Cardiology, The First Hospital of Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China
| | - He Wang
- Department of Cardiology, The First Hospital of Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China
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26
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Kim YJ, Jin J, Kim DH, Kim D, Lee YM, Byun JK, Choi YK, Park KG. SGLT2 inhibitors prevent LPS-induced M1 macrophage polarization and alleviate inflammatory bowel disease by downregulating NHE1 expression. Inflamm Res 2023; 72:1981-1997. [PMID: 37770568 DOI: 10.1007/s00011-023-01796-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/01/2023] [Accepted: 09/09/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND Classically activated M1 macrophages, characterized by aberrant glycolysis and secretion of inflammatory cytokines, play pivotal roles in inflammatory diseases, including inflammatory bowel disease (IBD). Recently, sodium-glucose co-transporter 2 (SGLT2) inhibitors were shown to suppress Na+/H+ exchanger 1 (NHE1) and Na+/Ca2+ exchanger 1 (NCX1) activity, regulating downstream intracellular Ca2+ concentrations in cardiomyocytes. However, whether SGLT2 inhibitors regulate M1 macrophage polarization by downregulating NHE1 and NCX1 remains unknown. METHODS We analyzed cellular responses to SGLT2 inhibitors using mouse bone marrow-derived macrophages and peritoneal macrophages treated with lipopolysaccharide (LPS). To induce IBD, we used a dextran sulfate sodium salt-induced colitis mouse model. RESULTS We observed that NHE1 and NCX1 were overexpressed in LPS-treated macrophages, leading to M1 macrophage polarization. Mechanistically, NHE1 and NCX1-mediated Ca2+ accumulation in the macrophage resulted in enhanced glycolysis by promoting PI3K/AKT/mTORC1 signaling. SGLT2 inhibitors suppressed both the expression levels and activities of NHE1 and NCX1, and consequently downregulated PI3K/AKT/mTORC1 signaling and glycolysis in LPS-treated macrophages. We observed inhibition of LPS-stimulated M1 polarization and cytokine production by SGLT2 inhibitors in vitro, ex vivo, and in an IBD mouse model. CONCLUSIONS NHE1 promotes M1 macrophage polarization and SGLT2 inhibitors are a novel strategy to treat M1 macrophage-mediated inflammatory diseases, including IBD.
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Affiliation(s)
- Ye Jin Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 130 Dongdeok-Ro, Jung-Gu, Daegu, 41944, Republic of Korea
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Jonghwa Jin
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 130 Dongdeok-Ro, Jung-Gu, Daegu, 41944, Republic of Korea
| | - Dong-Ho Kim
- Department of Biomedical Science, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Daehoon Kim
- Department of Biomedical Science, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - You Mie Lee
- College of Pharmacy, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, Daegu, 41566, Republic of Korea
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Jun-Kyu Byun
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Yeon-Kyung Choi
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, 41566, Republic of Korea.
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, 807 Hoguk-Ro, Buk-Gu, Daegu, 41404, Republic of Korea.
| | - Keun-Gyu Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 130 Dongdeok-Ro, Jung-Gu, Daegu, 41944, Republic of Korea.
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, 41566, Republic of Korea.
- Department of Biomedical Science, Kyungpook National University, Daegu, 41566, Republic of Korea.
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Jarosz-Popek J, Eyileten C, Gager GM, Nowak A, Szwed P, Wicik Z, Palatini J, von Lewinski D, Sourij H, Siller-Matula JM, Postula M. The interaction between non-coding RNAs and SGLT2: A review. Int J Cardiol 2023; 398:131419. [PMID: 39492411 DOI: 10.1016/j.ijcard.2023.131419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 09/19/2023] [Accepted: 10/03/2023] [Indexed: 11/05/2024]
Abstract
Sodium-glucose cotransporter 2 (SGLT2, SLC5A2) is a promising target for a new class of drug primarily established as kidney-targeting as well as emerging class of glucose-lowering drugs in diabetes. Studies showed that SGLT2 inhibitors also have a systemic impact via indirectly targeting the heart and kidneys which exerts broad cardio- and nephroprotective effects. Additionally, as cancer cells tightly require glucose supply, studies also questioned how SGLT2 inhibitors impact molecular pathology and cellular metabolism in cancer hallmarks. However, the exact molecular mechanisms responsible for those benefits have not been fully discovered. MicroRNAs (miRNA) and circularRNAs (circRNAs) are endogenous, single-stranded, non-coding RNAs (ncRNAs) that can control protein-coding genes, affecting significant molecular and cellular processes regulating homeostasis. CircRNAs particularly regulate gene expression at the transcriptional and post-transcriptional level by sponging to miRNAs and by altering interactions between proteins.
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Affiliation(s)
- Joanna Jarosz-Popek
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Gloria M Gager
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna 1090, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna 1090, Austria
| | - Anna Nowak
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Szwed
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
| | - Zofia Wicik
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego 9 Street, Warsaw 02-957, Poland
| | - Jeff Palatini
- Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Dirk von Lewinski
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Harald Sourij
- Division of Endocrinology and Diabetology, Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria
| | - Jolanta M Siller-Matula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna 1090, Austria
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland.
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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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Li Y, Liu X, Wan L, Han B, Ma S, Pan H, Wei J, Cui X. Metformin suppresses cardiac fibroblast proliferation under high-glucose conditions via regulating the mitochondrial complex I protein Grim-19 involved in the Sirt1/Stat3 signaling pathway. Free Radic Biol Med 2023; 206:1-12. [PMID: 37353174 DOI: 10.1016/j.freeradbiomed.2023.06.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/23/2023] [Accepted: 06/14/2023] [Indexed: 06/25/2023]
Abstract
Hyperglycemia associated with myocardial oxidative stress and fibrosis is the main cause of diabetic cardiomyopathy. Currently, no approved drug is available for preventing or treating diabetes-induced cardiac fibrosis. Metformin has been reported to improve glycemic control and ameliorate diabetic cardiomyopathy. This study aimed to investigate the effects and mechanism of metformin on diabetes-induced cardiac fibrosis and high glucose-induced proliferation of cardiac fibroblasts (CFs). In this study, db/db mice were treated with metformin [250 mg/kg⋅d, gavage]. CFs were cultured in high-glucose medium to mimic an in vitro diabetes model and then subjected to treatment with or without metformin. Cardiac fibrosis was analyzed using immunohistochemistry, Masson's trichrome staining, and Western blot analysis. Cell Counting Kit-8 (CCK-8) assays and cell colony formation assays were used to examine cell proliferation capacity. Transwell and scratch-wound assays were used to detect the migration ability of CFs. Retinoid-interferon-induced mortality-19 (Grim-19), sirtuin1 (Sirt1), and signal transducer and activator of transcription 3 (Stat3) were detected using Western blot analysis. The genes downstream of the Stat3 pathway were detected using quantitative reverse transcription PCR (qRT‒PCR). Metformin treatment markedly attenuated cardiac fibrosis in db/db mice and the proliferation and migration of CFs under high-glucose conditions. Mechanistically, we found an intersection between metformin and Grim-19 using bioinformatics. Metformin was found to suppress the expression of p-Stat3 and elevate the expression of mitochondrial complex I protein Grim-19 and Sirt1, thus inhibiting the proliferation and migration of CFs under high-glucose conditions. Our data suggested that metformin inhibited the proliferation and migration of CFs by regulating the expression of mitochondrial complex I Grim-19 protein involved in the Sirt1/Stat3 signaling pathway under high-glucose conditions, thus providing new ideas for treating diabetes-induced cardiac fibrosis.
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Affiliation(s)
- Yongguang Li
- Department of Cardiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 600 Yishan Road, Shanghai, 200233, People's Republic of China
| | - Xiangdong Liu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200000, People's Republic of China
| | - Lili Wan
- Division of Pharmacy, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 600 Yishan Road, Shanghai, 200233, People's Republic of China
| | - Beibei Han
- Department of Cardiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 600 Yishan Road, Shanghai, 200233, People's Republic of China
| | - Shixin Ma
- Department of Cardiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 600 Yishan Road, Shanghai, 200233, People's Republic of China
| | - Hongyuan Pan
- Saint Paul's School, 325 Pleasant Street, Concord, NH, 03301, USA
| | - Junbo Wei
- Department of Cardiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 600 Yishan Road, Shanghai, 200233, People's Republic of China; Department of Cardiology, Renhe Hospital, 1999 Changjiang West Road, Shanghai, 200431, People's Republic of China.
| | - Xiaofang Cui
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China.
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30
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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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31
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Bielawska M, Warszyńska M, Stefańska M, Błyszczuk P. Autophagy in Heart Failure: Insights into Mechanisms and Therapeutic Implications. J Cardiovasc Dev Dis 2023; 10:352. [PMID: 37623365 PMCID: PMC10456056 DOI: 10.3390/jcdd10080352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/15/2023] [Accepted: 08/16/2023] [Indexed: 08/26/2023] Open
Abstract
Autophagy, a dynamic and complex process responsible for the clearance of damaged cellular components, plays a crucial role in maintaining myocardial homeostasis. In the context of heart failure, autophagy has been recognized as a response mechanism aimed at counteracting pathogenic processes and promoting cellular health. Its relevance has been underscored not only in various animal models, but also in the human heart. Extensive research efforts have been dedicated to understanding the significance of autophagy and unravelling its complex molecular mechanisms. This review aims to consolidate the current knowledge of the involvement of autophagy during the progression of heart failure. Specifically, we provide a comprehensive overview of published data on the impact of autophagy deregulation achieved by genetic modifications or by pharmacological interventions in ischemic and non-ischemic models of heart failure. Furthermore, we delve into the intricate molecular mechanisms through which autophagy regulates crucial cellular processes within the three predominant cell populations of the heart: cardiomyocytes, cardiac fibroblasts, and endothelial cells. Finally, we emphasize the need for future research to unravel the therapeutic potential associated with targeting autophagy in the management of heart failure.
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Affiliation(s)
- Magdalena Bielawska
- Department of Clinical Immunology, Jagiellonian University Medical College, University Children’s Hospital, Wielicka 265, 30-663 Cracow, Poland; (M.B.)
| | - Marta Warszyńska
- Department of Clinical Immunology, Jagiellonian University Medical College, University Children’s Hospital, Wielicka 265, 30-663 Cracow, Poland; (M.B.)
| | - Monika Stefańska
- Department of Clinical Immunology, Jagiellonian University Medical College, University Children’s Hospital, Wielicka 265, 30-663 Cracow, Poland; (M.B.)
| | - Przemysław Błyszczuk
- Department of Clinical Immunology, Jagiellonian University Medical College, University Children’s Hospital, Wielicka 265, 30-663 Cracow, Poland; (M.B.)
- Department of Rheumatology, University Hospital Zurich, University of Zurich, 8952 Schlieren, Switzerland
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Liang Q, Guo R, Tsao JR, He Y, Wang C, Jiang J, Zhang D, Chen T, Yue T, Hu K. Salidroside alleviates oxidative stress in dry eye disease by activating autophagy through AMPK-Sirt1 pathway. Int Immunopharmacol 2023; 121:110397. [PMID: 37302369 DOI: 10.1016/j.intimp.2023.110397] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 05/14/2023] [Accepted: 05/24/2023] [Indexed: 06/13/2023]
Abstract
Dry eye disease (DED) is a multifactorial disease, and oxidative stress plays a crucial role in its pathogenesis. Recently, multiple studies have shown that upregulation of autophagy can protect the cornea from oxidative stress damage. The present study investigated the therapeutic effects of salidroside, the main component of Rhodiola crenulata, in both in vivo and in vitro dry eye models. The results showed that topical eye drop treatment with salidroside restored corneal epithelium damage, increased tear secretion, and reduced cornea inflammation in the DED mice. Salidroside activated autophagy through AMP-activated protein kinase (AMPK)-sirtuin-1 (Sirt1) signaling pathway, which promoted the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) and increased the expression of downstream antioxidant factors heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). This process restored antioxidant enzyme activity, reduced reactive oxygen species (ROS) accumulation, and alleviated oxidative stress. The application of autophagy inhibitor chloroquine and AMPK inhibitor Compound C reversed the therapeutic efficacy of salidroside, validating the above findings. In conclusion, our data suggest that salidroside is a promising candidate for DED treatment.
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Affiliation(s)
- Qi Liang
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Rongjie Guo
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Jia-Ruei Tsao
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Yun He
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Chenchen Wang
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, 618 Fengqi East Rd, Hangzhou, Zhejiang, China
| | - Jiaxuan Jiang
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Di Zhang
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Taige Chen
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China; Department of Rheumatology and Immunology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Tingting Yue
- Department of Neurosurgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China.
| | - Kai Hu
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China.
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Sanz RL, Inserra F, García Menéndez S, Mazzei L, Ferder L, Manucha W. Metabolic Syndrome and Cardiac Remodeling Due to Mitochondrial Oxidative Stress Involving Gliflozins and Sirtuins. Curr Hypertens Rep 2023; 25:91-106. [PMID: 37052810 DOI: 10.1007/s11906-023-01240-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2023] [Indexed: 04/14/2023]
Abstract
PURPOSE OF REVIEW To address the mechanistic pathways focusing on mitochondria dysfunction, oxidative stress, sirtuins imbalance, and other contributors in patient with metabolic syndrome and cardiovascular disease. Sodium glucose co-transporter type 2 (SGLT-2) inhibitors deeply influence these mechanisms. Recent randomized clinical trials have shown impressive results in improving cardiac function and reducing cardiovascular and renal events. These unexpected results generate the need to deepen our understanding of the molecular mechanisms able to generate these effects to help explain such significant clinical outcomes. RECENT FINDINGS Cardiovascular disease is highly prevalent among individuals with metabolic syndrome and diabetes. Furthermore, mitochondrial dysfunction is a principal player in its development and persistence, including the consequent cardiac remodeling and events. Another central protagonist is the renin-angiotensin system; the high angiotensin II (Ang II) activity fuel oxidative stress and local inflammatory responses. Additionally, sirtuins decline plays a pivotal role in the process; they enhance oxidative stress by regulating adaptive responses to the cellular environment and interacting with Ang II in many circumstances, including cardiac and vascular remodeling, inflammation, and fibrosis. Fasting and lower mitochondrial energy generation are conditions that substantially reduce most of the mentioned cardiometabolic syndrome disarrangements. In addition, it increases sirtuins levels, and adenosine monophosphate-activated protein kinase (AMPK) signaling stimulates hypoxia-inducible factor-1β (HIF-1 beta) and favors ketosis. All these effects favor autophagy and mitophagy, clean the cardiac cells with damaged organelles, and reduce oxidative stress and inflammatory response, giving cardiac tissue protection. In this sense, SGLT-2 inhibitors enhance the level of at least four sirtuins, some located in the mitochondria. Moreover, late evidence shows that SLGT-2 inhibitors mimic this protective process, improving mitochondria function, oxidative stress, and inflammation. Considering the previously described protection at the cardiovascular level is necessary to go deeper in the knowledge of the effects of SGLT-2 inhibitors on the mitochondria function. Various of the protective effects these drugs clearly had shown in the trials, and we briefly describe it could depend on sirtuins enhance activity, oxidative stress reduction, inflammatory process attenuation, less interstitial fibrosis, and a consequent better cardiac function. This information could encourage investigating new therapeutic strategies for metabolic syndrome, diabetes, heart and renal failure, and other diseases.
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Affiliation(s)
- Raúl Lelio Sanz
- Laboratorio de Farmacología Experimental Básica y Traslacional, Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Felipe Inserra
- Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina
| | - Sebastián García Menéndez
- Laboratorio de Farmacología Experimental Básica y Traslacional, Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
- Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigación Científica y Tecnológica (IMBECU-CONICET), Mendoza, Argentina
| | - Luciana Mazzei
- Laboratorio de Farmacología Experimental Básica y Traslacional, Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
- Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigación Científica y Tecnológica (IMBECU-CONICET), Mendoza, Argentina
| | - León Ferder
- Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina
| | - Walter Manucha
- Laboratorio de Farmacología Experimental Básica y Traslacional, Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
- Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina.
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34
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Jhuo SJ, Lin YH, Liu IH, Lin TH, Wu BN, Lee KT, Lai WT. Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor Ameliorate Metabolic Disorder and Obesity Induced Cardiomyocyte Injury and Mitochondrial Remodeling. Int J Mol Sci 2023; 24:ijms24076842. [PMID: 37047815 PMCID: PMC10095421 DOI: 10.3390/ijms24076842] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/31/2023] [Accepted: 04/02/2023] [Indexed: 04/09/2023] Open
Abstract
Sodium-glucose transporter 2 inhibitors (SGLT2is) exert significant cardiovascular and heart failure benefits in type 2 diabetes mellitus (DM) patients and can help reduce cardiac arrhythmia incidence in clinical practice. However, its effect on regulating cardiomyocyte mitochondria remain unclear. To evaluate its effect on myocardial mitochondria, C57BL/6J mice were divided into four groups, including: (1) control, (2) high fat diet (HFD)-induced metabolic disorder and obesity (MDO), (3) MDO with empagliflozin (EMPA) treatment, and (4) MDO with glibenclamide (GLI) treatment. All mice were sacrificed after 16 weeks of feeding and the epicardial fat secretome was collected. H9c2 cells were treated with the different secretomes for 18 h. ROS production, Ca2+ distribution, and associated proteins expression in mitochondria were investigated to reveal the underlying mechanisms of SGLT2is on cardiomyocytes. We found that lipotoxicity, mitochondrial ROS production, mitochondrial Ca2+ overload, and the levels of the associated protein, SOD1, were significantly lower in the EMPA group than in the MDO group, accompanied with increased ATP production in the EMPA-treated group. The expression of mfn2, SIRT1, and SERCA were also found to be lower after EMPA-secretome treatment. EMPA-induced epicardial fat secretome in mice preserved a better cardiomyocyte mitochondrial biogenesis function than the MDO group. In addition to reducing ROS production in mitochondria, it also ameliorated mitochondrial Ca2+ overload caused by MDO-secretome. These findings provide evidence and potential mechanisms for the benefit of SGLT2i in heart failure and arrhythmias.
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Affiliation(s)
- Shih-Jie Jhuo
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yi-Hsiung Lin
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - I-Hsin Liu
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Tsung-Hsien Lin
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Bin-Nan Wu
- Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Kun-Tai Lee
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Wen-Ter Lai
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
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Kobayashi S, Hahn Y, Silverstein B, Singh M, Fleitz A, Van J, Chen H, Liang Q. Lysosomal dysfunction in diabetic cardiomyopathy. FRONTIERS IN AGING 2023; 4:1113200. [PMID: 36742461 PMCID: PMC9894896 DOI: 10.3389/fragi.2023.1113200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/10/2023] [Indexed: 01/21/2023]
Abstract
Diabetes is a major risk factor for a variety of cardiovascular complications, while diabetic cardiomyopathy, a disease specific to the myocardium independent of vascular lesions, is an important causative factor for increased risk of heart failure and mortality in diabetic populations. Lysosomes have long been recognized as intracellular trash bags and recycling facilities. However, recent studies have revealed that lysosomes are sophisticated signaling hubs that play remarkably diverse roles in adapting cell metabolism to an ever-changing environment. Despite advances in our understanding of the physiological roles of lysosomes, the events leading to lysosomal dysfunction and how they relate to the overall pathophysiology of the diabetic heart remain unclear and are under intense investigation. In this review, we summarize recent advances regarding lysosomal injury and its roles in diabetic cardiomyopathy.
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36
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Yang J, Ni Z, Pi H, Bohnert A, Deng Z. Editorial: Autophagy in diseases-From basic to clinic. Front Physiol 2023; 13:1115511. [PMID: 36685179 PMCID: PMC9856833 DOI: 10.3389/fphys.2022.1115511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 12/14/2022] [Indexed: 01/05/2023] Open
Affiliation(s)
- Jie Yang
- Institute of Cardiovascular Diseases of PLA, The Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, China,Department of Cardiology, The Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, China,*Correspondence: Jie Yang,
| | - Zhenhong Ni
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Rehabilitation Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Huifeng Pi
- Institute of Military Preventive Medicine, Army Medical Univeristy, Chongqing, China
| | - Adam Bohnert
- Louisiana State University, Baton Rouge, LA, United States
| | - Zhiqiang Deng
- School of Chinese Medicine, Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
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37
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Gao Z, Bao J, Hu Y, Tu J, Ye L, Wang L. Sodium-glucose Cotransporter 2 Inhibitors and Pathological Myocardial Hypertrophy. Curr Drug Targets 2023; 24:1009-1022. [PMID: 37691190 PMCID: PMC10879742 DOI: 10.2174/1389450124666230907115831] [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: 05/02/2023] [Revised: 08/18/2023] [Accepted: 08/23/2023] [Indexed: 09/12/2023]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new type of oral hypoglycemic drugs that exert a hypoglycemic effect by blocking the reabsorption of glucose in the proximal renal tubules, thus promoting the excretion of glucose from urine. Their hypoglycemic effect is not dependent on insulin. Increasing data shows that SGLT2 inhibitors improve cardiovascular outcomes in patients with type 2 diabetes. Previous studies have demonstrated that SGLT2 inhibitors can reduce pathological myocardial hypertrophy with or without diabetes, but the exact mechanism remains to be elucidated. To clarify the relationship between SGLT2 inhibitors and pathological myocardial hypertrophy, with a view to providing a reference for the future treatment thereof, this study reviewed the possible mechanisms of SGLT2 inhibitors in attenuating pathological myocardial hypertrophy. We focused specifically on the mechanisms in terms of inflammation, oxidative stress, myocardial fibrosis, mitochondrial function, epicardial lipids, endothelial function, insulin resistance, cardiac hydrogen and sodium exchange, and autophagy.
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Affiliation(s)
- Zhicheng Gao
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jiaqi Bao
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yilan Hu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Junjie Tu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Lifang Ye
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lihong Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
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38
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Ma Y, Liu H, Wang Y, Xuan J, Gao X, Ding H, Ma C, Chen Y, Yang Y. Roles of physical exercise-induced MiR-126 in cardiovascular health of type 2 diabetes. Diabetol Metab Syndr 2022; 14:169. [PMID: 36376958 PMCID: PMC9661802 DOI: 10.1186/s13098-022-00942-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 11/04/2022] [Indexed: 11/16/2022] Open
Abstract
Although physical activity is widely recommended for preventing and treating cardiovascular complications of type 2 diabetes mellitus (T2DM), the underlying mechanisms remain unknown. MicroRNA-126 (miR-126) is an angiogenetic regulator abundant in endothelial cells (ECs) and endothelial progenitor cells (EPCs). It is primarily involved in angiogenesis, inflammation and apoptosis for cardiovascular protection. According to recent studies, the levels of miR-126 in the myocardium and circulation are affected by exercise protocol. High-intensity interval training (HIIT) or moderate-and high-intensity aerobic exercise, whether acute or chronic, can increase circulating miR-126 in healthy adults. Chronic aerobic exercise can effectively rescue the reduction of myocardial and circulating miR-126 and vascular endothelial growth factor (VEGF) in diabetic mice against diabetic vascular injury. Resistance exercise can raise circulating VEGF levels, but it may have a little influence on circulating miR-126. The Several targets of miR-126 have been suggested for cardiovascular fitness, such as sprouty-related EVH1 domain-containing protein 1 (SPRED1), phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2), vascular cell adhesion molecule 1 (VCAM1), high-mobility group box 1 (HMGB1), and tumor necrosis factor receptor-associated factor 7 (TRAF7). Here, we present a comprehensive review of the roles of miR-126 and its downstream proteins as exercise mechanisms, and propose that miR-126 can be applied as an exercise indicator for cardiovascular prescriptions and as a preventive or therapeutic target for cardiovascular complications in T2DM.
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Affiliation(s)
- Yixiao Ma
- Graduate School, Wuhan Sports University, Wuhan, 430079, China
| | - Hua Liu
- Laboratory of Physical Fitness Monitoring & Chronic Disease Intervention, Wuhan Sports University, Wuhan, 430079, China
| | - Yong Wang
- Laboratory of Physical Fitness Monitoring & Chronic Disease Intervention, Wuhan Sports University, Wuhan, 430079, China
| | - Junjie Xuan
- Graduate School, Wuhan Sports University, Wuhan, 430079, China
| | - Xing Gao
- Graduate School, Wuhan Sports University, Wuhan, 430079, China
| | - Huixian Ding
- Graduate School, Wuhan Sports University, Wuhan, 430079, China
| | - Chunlian Ma
- Laboratory of Physical Fitness Monitoring & Chronic Disease Intervention, Wuhan Sports University, Wuhan, 430079, China
| | - Yanfang Chen
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH, 45435, USA
| | - Yi Yang
- Hubei Key Laboratory of Exercise Training and Monitoring, Wuhan Sports University, Wuhan, 430079, China.
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Zhang Y, Zhou XA, Liu C, Shen Q, Wu Y. Vitamin B6 Inhibits High Glucose-Induced Islet β Cell Apoptosis by Upregulating Autophagy. Metabolites 2022; 12:1048. [PMID: 36355132 PMCID: PMC9695582 DOI: 10.3390/metabo12111048] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 07/27/2023] Open
Abstract
Vitamin B6 may alleviate diabetes by regulating insulin secretion and increasing insulin sensitivity, but its mechanism remains to be explored. In this study, vitamin B6-mediated autophagy and high glucose-induced apoptosis were tested to investigate the mechanism by which vitamin B6 regulates insulin release. The results showed that 20 mM glucose increased the apoptosis rate from 10.39% to 22.44%. Vitamin B6 reduced the apoptosis rate of RIN-m5F cells from 22.44% to 11.31%. Our data also showed that the vitamin B6 content in processed eggs was decreased and that the hydrothermal process did not affect the bioactivity of vitamin B6. Vitamin B6 increased the number of autophagosomes and the ratio of autophagosome marker protein microtubule associated protein 1 light chain 3 beta to microtubule associated protein 1 light chain 3 alpha (LC3-II/LC3-I). It also decreased the amount of sequetosome 1 (SQSTM1/p62) and inhibited the phosphorylation of p70 ribosomal protein S6 kinase (p70S6K) under normal and high glucose stress. Another study showed that vitamin B6 inhibited the apoptosis rate, whereas the autophagy inhibitor 3-methyladenine (3-MA) blocked the protective effect of vitamin B6 against apoptosis induced by high glucose. The hydrothermal process decreased the vitamin B6 content in eggs but had no effect on the cytoprotective function of vitamin B6 in RIN-m5f cells. In conclusion, we demonstrated that vitamin B6-mediated autophagy protected RIN-m5f cells from high glucose-induced apoptosis might via the mTOR-dependent pathway. Our data also suggest that low temperatures and short-term hydrothermal processes are beneficial for dietary eggs.
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Affiliation(s)
- Yu Zhang
- Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China
- Horticulture and Landscape College, Hunan Agricultural University, Changsha 410128, China
| | - Xi-an Zhou
- Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China
- Horticulture and Landscape College, Hunan Agricultural University, Changsha 410128, China
| | - Chuxin Liu
- Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China
- Horticulture and Landscape College, Hunan Agricultural University, Changsha 410128, China
| | - Qingwu Shen
- Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China
- Horticulture and Landscape College, Hunan Agricultural University, 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
- Horticulture and Landscape College, Hunan Agricultural University, Changsha 410128, China
- Hunan Co-Innovation Center for Utilization of Botanical Functional Ingredients, Changsha 410128, China
- State Key Laboratory of Subhealth Intervention Technology, Changsha 410128, China
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Wang H, Wang L, Hu F, Wang P, Xie Y, Li F, Guo B. Neuregulin-4 attenuates diabetic cardiomyopathy by regulating autophagy via the AMPK/mTOR signalling pathway. Cardiovasc Diabetol 2022; 21:205. [PMID: 36221104 PMCID: PMC9554973 DOI: 10.1186/s12933-022-01643-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 09/26/2022] [Indexed: 11/17/2022] Open
Abstract
Background Diabetic cardiomyopathy is characterized by left ventricle dysfunction, cardiomyocyte apoptosis, and interstitial fibrosis and is a serious complication of diabetes mellitus (DM). Autophagy is a mechanism that is essential for maintaining normal heart morphology and function, and its dysregulation can produce pathological effects on diabetic hearts. Neuregulin-4 (Nrg4) is an adipokine that exerts protective effects against metabolic disorders and insulin resistance. The aim of this study was to explore whether Nrg4 could ameliorate DM-induced myocardial injury by regulating autophagy. Methods Four weeks after the establishment of a model of type 1 diabetes in mice, the mice received Nrg4 treatment (with or without an autophagy inhibitor) for another 4 weeks. The cardiac functions, histological structures and cardiomyocyte apoptosis were investigated. Autophagy-related protein levels along with related signalling pathways that regulate autophagy were evaluated. In addition, the effects of Nrg4 on autophagy were also determined in cultured primary cardiomyocytes. Results Nrg4 alleviated myocardial injury both in vivo and in vitro. The autophagy level was decreased in type 1 diabetic mice, and Nrg4 intervention reactivated autophagy. Furthermore, Nrg4 intervention was found to activate autophagy via the AMPK/mTOR signalling pathway. Moreover, when autophagy was suppressed or the AMPK/mTOR pathway was inhibited, the beneficial effects of Nrg4 were diminished. Conclusion Nrg4 intervention attenuated diabetic cardiomyopathy by promoting autophagy in type 1 diabetic mice. Additionally, Nrg4 induced autophagy via the AMPK/mTOR signalling pathway. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-022-01643-0.
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Affiliation(s)
- Hongchao Wang
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Heping West Road No. 215, Shijiazhuang, 050000, China
| | - Lijie Wang
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Heping West Road No. 215, Shijiazhuang, 050000, China
| | - Fuli Hu
- Department of Cardiology, Shijiazhuang Great Wall Hospital of Integrated Traditional Chinese and Western Medicine, Shijiazhuang, 050000, China
| | - Pengfei Wang
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Heping West Road No. 215, Shijiazhuang, 050000, China
| | - Yanan Xie
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Heping West Road No. 215, Shijiazhuang, 050000, China
| | - Fang Li
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Heping West Road No. 215, Shijiazhuang, 050000, China
| | - Bingyan Guo
- Department of Cardiovascular Medicine, The Second Hospital of Hebei Medical University, Heping West Road No. 215, Shijiazhuang, 050000, China. .,Hebei Key Laboratory of Laboratory Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
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Sweed E, Sweed D, Galal N, Abd-Elhafiz HI. Dapagliflozin Protection against Myocardial Ischemia by Modulating Sodium-glucose Transporter 2 Inhibitor, Silent Information Regulator 1, and Fatty Acid Synthase Expressions. Open Access Maced J Med Sci 2022; 10:1544-1554. [DOI: 10.3889/oamjms.2022.10861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND: The emerging role of sodium-glucose transporter 2 (SGLT2) inhibitors drugs as potential therapeutic agents in myocardial ischemic (MI) injury treatment has raised the concern for possible mechanisms of action.
AIM: The current experimental study aimed to investigate the possible protective effects of dapagliflozin (DAPA) a SGLT2i, on isoproterenol (ISO)-induced MI in rats.
MATERIALS AND METHODS: Thirty Wistar rats were divided randomly and equally into three groups. Group 1 (control group): Received 1.0 mL of normal saline through an orogastric tube for 14 days. Group 2 (ISO group): Received 1.0 mL of normal saline orally through an orogastric tube for 14 days. In the last 2 days (days 13 and 14), ISO (100 mg/kg) was freshly dissolved in normal saline and injected subcutaneously once daily. Group 3 (ISO + DAPA-treated group): Received DAPA 1.0 mg/kg/day orally for 14 days. In the last 2 days (days 13 and 14), ISO (100 mg/kg) was introduced like that described in Group 2.
RESULTS: DAPA protects MI development by reversal of blood pressure changes, electrocardiographic alterations, stabilization of cardiac enzymes, inflammation restoration, oxidative stress, and lipid profile. SGLT2 was overexpressed in the ISO-induced MI, which declined in the ISO + DAPA group. Moreover, DAPA induced silent information regulator 1 (SIRT1)/fatty acid synthase (FASN) overexpression in ISO-induced MI. DAPA could have a potential protective role against acute MI.
CONCLUSION: DAPA protects against acute MI by modulating SIRT1 and FASN expression in cardiac muscles, suppressing oxidative stress, and downregulating inflammatory mediators.
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Sun W, Xing Y, Kong D, Zhang Z, Ma H, Yang L. Meta-analysis of the effect of sodium-dependent glucose transporter 2 inhibitors on C-reactive protein in type 2 diabetes. Medicine (Baltimore) 2022; 101:e30553. [PMID: 36197267 PMCID: PMC9509164 DOI: 10.1097/md.0000000000030553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/10/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND As novel hypoglycemic drugs, the effects of sodium-dependent glucose transporter 2 inhibitors (SGLT-2I) on inflammatory factors such as C-reactive protein (CRP) remain unclear. METHODS We conducted a meta-analysis of studies on SGLT-2I in the treatment of type 2 diabetes (T2DM) to observe the changes of CRP in patients with T2DM. We searched 4 electronic databases (CNKI, PubMed, EMBASE, and Cochrane Library) for articles published up to December 31, 2021. Studies were analyzed using a random-effects model to obtain standard deviation mean differences (SMDs) and 95% confidence intervals (CIs). Sensitivity and subgroup analyses were performed. Publication bias was evaluated using funnel plots and Egger test. RESULTS We included data from 927 patients in 13 confirmatory trials that showed a significant decrease in CRP among patients with T2DM treated with SGLT-2I. The decrease was more significant with than without SGLT-2I. In subgroup analysis according to nationality, medication, and comorbidities, CRP reduction was associated with nationality, SGLT-2I type, and the presence of comorbidities. Sensitivity analysis showed that our results were reliable and found no evidence of substantial publication bias. CONCLUSIONS SGLT-2I could reduce CRP levels in patients with T2DM. REGISTRATION International Prospective Register for Systematic Reviews (PROSPERO) number CRD42021268079.
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Affiliation(s)
- Wenwen Sun
- North China University of Science and Technology, 21 Bohai Dadao, Caofeidian District, Tangshan, Hebei 063210, China
- Endocrinology Department, Hebei General Hospital, 348 Heping West Road, Xinhua District, Shijiazhuang, Hebei 050051, China
| | - Yuling Xing
- Endocrinology Department, Hebei General Hospital, 348 Heping West Road, Xinhua District, Shijiazhuang, Hebei 050051, China
| | - Dexian Kong
- Endocrinology Department, Hebei General Hospital, 348 Heping West Road, Xinhua District, Shijiazhuang, Hebei 050051, China
- Hebei North University, 11 Diamond South Road, High-tech Zone, Zhangjiakou, Hebei 075000, China
| | - Zhimin Zhang
- Endocrinology Department, Hebei General Hospital, 348 Heping West Road, Xinhua District, Shijiazhuang, Hebei 050051, China
- Hebei Medical University, 361 East Zhongshan Road, Chang ‘an District, Shijiazhuang, Hebei 050017
| | - Huijuan Ma
- Endocrinology Department, Hebei General Hospital, 348 Heping West Road, Xinhua District, Shijiazhuang, Hebei 050051, China
- Hebei Medical University, 361 East Zhongshan Road, Chang ‘an District, Shijiazhuang, Hebei 050017
- Hebei Key Laboratory of Metabolic Diseases, 348 Heping West Road, Xinhua District, Shijiazhuang, Hebei 050051, China
| | - Linlin Yang
- Hebei Key Laboratory of Metabolic Diseases, 348 Heping West Road, Xinhua District, Shijiazhuang, Hebei 050051, China
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Tao LC, Wang TT, Zheng L, Hua F, Li JJ. The Role of Mitochondrial Biogenesis Dysfunction in Diabetic Cardiomyopathy. Biomol Ther (Seoul) 2022; 30:399-408. [PMID: 35410981 PMCID: PMC9424338 DOI: 10.4062/biomolther.2021.192] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 01/28/2022] [Accepted: 02/22/2022] [Indexed: 11/26/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is described as abnormalities of myocardial structure and function in diabetic patients without other well-established cardiovascular factors. Although multiple pathological mechanisms involving in this unique myocardial disorder, mitochondrial dysfunction may play an important role in its development of DCM. Recently, considerable progresses have suggested that mitochondrial biogenesis is a tightly controlled process initiating mitochondrial generation and maintaining mitochondrial function, appears to be associated with DCM. Nonetheless, an outlook on the mechanisms and clinical relevance of dysfunction in mitochondrial biogenesis among patients with DCM is not completely understood. In this review, hence, we will summarize the role of mitochondrial biogenesis dysfunction in the development of DCM, especially the molecular underlying mechanism concerning the signaling pathways beyond the stimulation and inhibition of mitochondrial biogenesis. Additionally, the evaluations and potential therapeutic strategies regarding mitochondrial biogenesis dysfunction in DCM is also presented.
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Affiliation(s)
- Li-Chan Tao
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou 213000, China
| | - Ting-ting Wang
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou 213000, China
| | - Lu Zheng
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou 213000, China
| | - Fei Hua
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou 213000, China
| | - Jian-Jun Li
- State Key Laboratory of Cardiovascular Diseases, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
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Penugurti V, Mishra YG, Manavathi B. AMPK: An odyssey of a metabolic regulator, a tumor suppressor, and now a contextual oncogene. Biochim Biophys Acta Rev Cancer 2022; 1877:188785. [PMID: 36031088 DOI: 10.1016/j.bbcan.2022.188785] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 08/21/2022] [Accepted: 08/22/2022] [Indexed: 11/29/2022]
Abstract
Metabolic reprogramming is a unique but complex biochemical adaptation that allows solid tumors to tolerate various stresses that challenge cancer cells for survival. Under conditions of metabolic stress, mammalian cells employ adenosine monophosphate (AMP)-activated protein kinase (AMPK) to regulate energy homeostasis by controlling cellular metabolism. AMPK has been described as a cellular energy sensor that communicates with various metabolic pathways and networks to maintain energy balance. Earlier studies characterized AMPK as a tumor suppressor in the context of cancer. Later, a paradigm shift occurred in support of the oncogenic nature of AMPK, considering it a contextual oncogene. In support of this, various cellular and mouse models of tumorigenesis and clinicopathological studies demonstrated increased AMPK activity in various cancers. This review will describe AMPK's pro-tumorigenic activity in various malignancies and explain the rationale and context for using AMPK inhibitors in combination with anti-metabolite drugs to treat AMPK-driven cancers.
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Affiliation(s)
- Vasudevarao Penugurti
- Molecular and Cellular Oncology Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad 500046, Telangana, India
| | - Yasaswi Gayatri Mishra
- Molecular and Cellular Oncology Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad 500046, Telangana, India
| | - Bramanandam Manavathi
- Molecular and Cellular Oncology Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad 500046, Telangana, India.
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Parmar UM, Jalgaonkar MP, Kulkarni YA, Oza MJ. Autophagy-nutrient sensing pathways in diabetic complications. Pharmacol Res 2022; 184:106408. [PMID: 35988870 DOI: 10.1016/j.phrs.2022.106408] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 08/05/2022] [Accepted: 08/16/2022] [Indexed: 11/24/2022]
Abstract
The incidence of diabetes has been increasing in recent decades which is affecting the population of both, developed and developing countries. Diabetes is associated with micro and macrovascular complications which predominantly result from hyperglycemia and disrupted metabolic pathways. Persistent hyperglycemia leads to increased reactive oxygen species (ROS) generation, formation of misfolded and abnormal proteins, and disruption of normal cellular functioning. The inability to maintain metabolic homeostasis under excessive energy and nutrient input, which induces insulin resistance, is a crucial feature during the transition from obesity to diabetes. According to various study reports, redox alterations, intracellular stress and chronic inflammation responses have all been linked to dysregulated energy metabolism and insulin resistance. Autophagy has been considered a cleansing mechanism to prevent these anomalies and restore cellular homeostasis. However, disrupted autophagy has been linked to the pathogenesis of metabolic disorders such as obesity and diabetes. Recent studies have reported that the regulation of autophagy has a beneficial role against these conditions. When there is plenty of food, nutrient-sensing pathways activate anabolism and storage, but the shortage of food activates homeostatic mechanisms like autophagy, which mobilises internal stockpiles. These nutrient-sensing pathways are well conserved in eukaryotes and are involved in the regulation of autophagy which includes SIRT1, mTOR and AMPK. The current review focuses on the role of SIRT1, mTOR and AMPK in regulating autophagy and suggests autophagy along with these nutrient-sensing pathways as potential therapeutic targets in reducing the progression of various diabetic complications.
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Affiliation(s)
- Urvi M Parmar
- SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai 400056, India
| | - Manjiri P Jalgaonkar
- SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai 400056, India
| | - Yogesh A Kulkarni
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, Mumbai 400056, India
| | - Manisha J Oza
- SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai 400056, India.
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Wicik Z, Nowak A, Jarosz-Popek J, Wolska M, Eyileten C, Siller-Matula JM, von Lewinski D, Sourij H, Filipiak KJ, Postuła M. Characterization of the SGLT2 Interaction Network and Its Regulation by SGLT2 Inhibitors: A Bioinformatic Analysis. Front Pharmacol 2022; 13:901340. [PMID: 36046822 PMCID: PMC9421436 DOI: 10.3389/fphar.2022.901340] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/22/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Sodium–glucose cotransporter 2 (SGLT2), also known as solute carrier family 5 member 2 (SLC5A2), is a promising target for a new class of drugs primarily established as kidney-targeting, effective glucose-lowering agents used in diabetes mellitus (DM) patients. Increasing evidence indicates that besides renal effects, SGLT2 inhibitors (SGLT2i) have also a systemic impact via indirectly targeting the heart and other tissues. Our hypothesis states that the pleiotropic effects of SGLT2i are associated with their binding force, location of targets in the SGLT2 networks, targets involvement in signaling pathways, and their tissue-specific expression. Methods: Thus, to investigate differences in SGLT2i impact on human organisms, we re-created the SGLT2 interaction network incorporating its inhibitors and metformin and analyzed its tissue-specific expression using publicly available datasets. We analyzed it in the context of the so-called key terms ( autophagy, oxidative stress, aging, senescence, inflammation, AMPK pathways, and mTOR pathways) which seem to be crucial to elucidating the SGLT2 role in a variety of clinical manifestations. Results: Analysis of SGLT2 and its network components’ expression confidence identified selected organs in the following order: kidney, liver, adipose tissue, blood, heart, muscle, intestine, brain, and artery according to the TISSUES database. Drug repurposing analysis of known SGLT2i pointed out the influence of SGLT1 regulators on the heart and intestine tissue. Additionally, dapagliflozin seems to also have a stronger impact on brain tissue through the regulation of SGLT3 and SLC5A11. The shortest path analysis identified interaction SIRT1-SGLT2 among the top five interactions across six from seven analyzed networks associated with the key terms. Other top first-level SGLT2 interactors associated with key terms were not only ADIPOQ, INS, GLUT4, ACE, and GLUT1 but also less recognized ILK and ADCY7. Among other interactors which appeared in multiple shortest-path analyses were GPT, COG2, and MGAM. Enrichment analysis of SGLT2 network components showed the highest overrepresentation of hypertensive disease, DM-related diseases for both levels of SGLT2 interactors. Additionally, for the extended SGLT2 network, we observed enrichment in obesity (including SGLT1), cancer-related terms, neuroactive ligand–receptor interaction, and neutrophil-mediated immunity. Conclusion: This study provides comprehensive and ranked information about the SGLT2 interaction network in the context of tissue expression and can help to predict the clinical effects of the SGLT2i.
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Affiliation(s)
- Zofia Wicik
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
| | - Anna Nowak
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
- Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Joanna Jarosz-Popek
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
- Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Marta Wolska
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
- Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Ceren Eyileten
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
- Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Jolanta M. Siller-Matula
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
- Department of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Dirk von Lewinski
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Harald Sourij
- Division of Endocrinology and Diabetology, Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria
| | | | - Marek Postuła
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
- *Correspondence: Marek Postuła,
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Koniari I, Velissaris D, Kounis NG, Koufou E, Artopoulou E, de Gregorio C, Mplani V, Paraskevas T, Tsigkas G, Hung MY, Plotas P, Lambadiari V, Ikonomidis I. Anti-Diabetic Therapy, Heart Failure and Oxidative Stress: An Update. J Clin Med 2022; 11:4660. [PMID: 36012897 PMCID: PMC9409680 DOI: 10.3390/jcm11164660] [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: 06/23/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 11/17/2022] Open
Abstract
Diabetes mellitus (DM) and heart failure (HF) are two chronic disorders that affect millions worldwide. Hyperglycemia can induce excessive generation of highly reactive free radicals that promote oxidative stress and further exacerbate diabetes progression and its complications. Vascular dysfunction and damage to cellular proteins, membrane lipids and nucleic acids can stem from overproduction and/or insufficient removal of free radicals. The aim of this article is to review the literature regarding the use of antidiabetic drugs and their role in glycemic control in patients with heart failure and oxidative stress. Metformin exerts a minor benefit to these patients. Thiazolidinediones are not recommended in diabetic patients, as they increase the risk of HF. There is a lack of robust evidence on the use of meglinitides and acarbose. Insulin and dipeptidyl peptidase-4 (DPP-4) inhibitors may have a neutral cardiovascular effect on diabetic patients. The majority of current research focuses on sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. SGLT2 inhibitors induce positive cardiovascular effects in diabetic patients, leading to a reduction in cardiovascular mortality and HF hospitalization. GLP-1 receptor agonists may also be used in HF patients, but in the case of chronic kidney disease, SLGT2 inhibitors should be preferred.
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Affiliation(s)
- Ioanna Koniari
- Department of Cardiology, University Hospital of South Manchester NHS Foundation Trust, Manchester M23 9LT, UK
| | - Dimitrios Velissaris
- Department of Internal Medicine, University Hospital of Patras, 26500 Patras, Greece
| | - Nicholas G. Kounis
- Department of Cardiology, University Hospital of Patras, 26500 Patras, Greece
| | - Eleni Koufou
- Department of Cardiology, University Hospital of Patras, 26500 Patras, Greece
| | - Eleni Artopoulou
- Department of Internal Medicine, University Hospital of Patras, 26500 Patras, Greece
| | - Cesare de Gregorio
- Department of Clinical and Experimental Medicine, University of Messina Medical School, 98122 Messina, Italy
| | - Virginia Mplani
- Intensive Care Unit, Patras University Hospital, 26500 Patras, Greece
| | | | - Grigorios Tsigkas
- Department of Cardiology, University Hospital of Patras, 26500 Patras, Greece
| | - Ming-Yow Hung
- Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
| | - Panagiotis Plotas
- Laboratory Primary Health Care, School of Health Rehabilitation Sciences, University of Patras, 26504 Patras, Greece
| | - Vaia Lambadiari
- Second Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Ignatios Ikonomidis
- Second Cardiology Department, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
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Ge X, Wang L, Fei A, Ye S, Zhang Q. Research progress on the relationship between autophagy and chronic complications of diabetes. Front Physiol 2022; 13:956344. [PMID: 36003645 PMCID: PMC9393249 DOI: 10.3389/fphys.2022.956344] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/11/2022] [Indexed: 12/01/2022] Open
Abstract
Diabetes is a common metabolic disease whose hyperglycemic state can induce diverse complications and even threaten human health and life security. Currently, the treatment of diabetes is restricted to drugs that regulate blood glucose and have certain accompanying side effects. Autophagy, a research hotspot, has been proven to be involved in the occurrence and progression of the chronic complications of diabetes. Autophagy, as an essential organismal defense mechanism, refers to the wrapping of cytoplasmic proteins, broken organelles or pathogens by vesicles, which are then degraded by lysosomes to maintain the stability of the intracellular environment. Here, we review the relevant aspects of autophagy and the molecular mechanisms of autophagy in diabetic chronic complications, and further analyze the impact of improving autophagy on diabetic chronic complications, which will contribute to a new direction for further prevention and treatment of diabetic chronic complications.
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Affiliation(s)
- Xia Ge
- Department of Endocrinology, The Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Ling Wang
- Graduate School of Anhui University of Chinese Medicine, Hefei, China
| | - Aihua Fei
- Department of Endocrinology, The Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Shandong Ye
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- *Correspondence: Shandong Ye, ; Qingping Zhang,
| | - Qingping Zhang
- College of Acupuncture-Moxibustion and Tuina, Anhui University of Chinese Medicine, Hefei, China
- *Correspondence: Shandong Ye, ; Qingping Zhang,
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Stamerra CA, Di Giosia P, Giorgini P, Ferri C, Sukhorukov VN, Sahebkar A. Mitochondrial Dysfunction and Cardiovascular Disease: Pathophysiology and Emerging Therapies. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9530007. [PMID: 35958017 PMCID: PMC9363184 DOI: 10.1155/2022/9530007] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/15/2022] [Indexed: 11/24/2022]
Abstract
Mitochondria ensure the supply of cellular energy through the production of ATP via oxidative phosphorylation. The alteration of this process, called mitochondrial dysfunction, leads to a reduction in ATP and an increase in the production of reactive oxygen species (ROS). Mitochondrial dysfunction can be caused by mitochondrial/nuclear DNA mutations, or it can be secondary to pathological conditions such as cardiovascular disease, aging, and environmental stress. The use of therapies aimed at the prevention/correction of mitochondrial dysfunction, in the context of the specific treatment of cardiovascular diseases, is a topic of growing interest. In this context, the data are conflicting since preclinical studies are numerous, but there are no large randomized studies.
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Affiliation(s)
- Cosimo Andrea Stamerra
- University of L'Aquila, Department of Life, Health and Environmental Sciences, Building Delta 6, San Salvatore Hospital, Via Vetoio, Coppito 67100 L'Aquila, Italy
- Department of Internal Medicine, Mazzoni Hospital, Ascoli Piceno, Italy
| | - Paolo Di Giosia
- University of L'Aquila, Department of Life, Health and Environmental Sciences, Building Delta 6, San Salvatore Hospital, Via Vetoio, Coppito 67100 L'Aquila, Italy
- Department of Internal Medicine, Mazzoni Hospital, Ascoli Piceno, Italy
| | - Paolo Giorgini
- University of L'Aquila, Department of Life, Health and Environmental Sciences, Building Delta 6, San Salvatore Hospital, Via Vetoio, Coppito 67100 L'Aquila, Italy
| | - Claudio Ferri
- University of L'Aquila, Department of Life, Health and Environmental Sciences, Building Delta 6, San Salvatore Hospital, Via Vetoio, Coppito 67100 L'Aquila, Italy
| | - Vasily N. Sukhorukov
- Institute for Atherosclerosis Research, Osennyaya Street 4-1-207, Moscow 121609, Russia
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Mei Y, Hu H, Deng L, Sun X, Tan W. Therapeutic effects of isosteviol sodium on non-alcoholic fatty liver disease by regulating autophagy via Sirt1/AMPK pathway. Sci Rep 2022; 12:12857. [PMID: 35896572 PMCID: PMC9329321 DOI: 10.1038/s41598-022-16119-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 07/05/2022] [Indexed: 12/17/2022] Open
Abstract
Isosteviol sodium (STVNa) is a beyerane diterpene synthesized via acid hydrolysis of stevioside, which can improve glucose and lipid metabolism in animals with diabetes. However, it remains unknown whether STVNa can exhibit a therapeutic effect on nonalcoholic fatty liver disease (NAFLD) and its underlying mechanism. We hypothesize that autophagic initiation may play a key role in mediating the development of NAFLD. Herein, we assessed the effects of STVNa on NAFLD and its underlying mechanisms. The results demonstrated that STVNa treatment effectively ameliorated NAFLD in rats fed high-fat diet (HFD). Moreover, STVNa decreased the expression of inflammation-related genes and maintained a balance of pro-inflammatory cytokines in NAFLD rats. STVNa also reduced lipid accumulation in free fatty acid (FFA)-exposed LO2 cells. In addition, STVNa attenuated hepatic oxidative stress and fibrosis in NAFLD rats. Furthermore, STVNa enhanced autophagy and activated Sirtuin 1/adenosine monophosphate-activated protein kinase (Sirt1/AMPK) pathway both in vivo and in vitro, thus attenuating intracellular lipid accumulation. In summary, STVNa could improve lipid metabolism in NAFLD by initiating autophagy via Sirt1/AMPK pathway. Therefore, STVNa may be an alternative therapeutic agent for treatment of NAFLD.
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Affiliation(s)
- Ying Mei
- School of Pharmacy, Jinan University, Guangzhou, 510632, China
- YZ Health-Tech Inc., Hengqin District, Zhuhai, 519000, China
| | - Hui Hu
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China
| | - Liangjun Deng
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China
| | - Xiaoou Sun
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China
| | - Wen Tan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500, Bandar Sunway, Malaysia.
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