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Shah W, Gong Y, Qiao X, Lu Y, Ding Y, Zhang Z, Gao Y. Exploring Endothelial Cell Dysfunction's Impact on the Brain-Retina Microenvironment Connection: Molecular Mechanisms and Implications. Mol Neurobiol 2025; 62:7484-7505. [PMID: 39904964 DOI: 10.1007/s12035-025-04714-x] [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: 06/24/2024] [Accepted: 01/19/2025] [Indexed: 02/06/2025]
Abstract
The intricate linking between the health of blood vessels and the functioning of neurons has attracted growing attention in the context of disorders that affect the neurological environment. Endothelial cells, forming the blood-brain barrier and blood-retinal barrier, play a fundamental role in maintaining the integrity of the brain-retina microenvironment connection. This review explores the molecular foundations of endothelial cell dysfunction and its implications for the brain-retina interaction. A comprehensive analysis of the complex factors contributing to endothelial dysfunction is presented, including oxidative stress, inflammation, reduced nitric oxide signaling, and disrupted vascular autoregulation. The significance of endothelial dysfunction extends to neurovascular coupling, synaptic plasticity, and trophic support. To our knowledge, there is currently no existing literature review addressing endothelial microvascular dysfunction and its interplay with the brain-retina microenvironment. The review also explains bidirectional communication between the brain and retina, highlighting how compromised endothelial function can disrupt this vital crosstalk and inhibit normal physiological processes. As neurodegenerative diseases frequently exhibit vascular involvement, a deeper comprehension of the interaction between endothelial cells and neural tissue holds promise for innovative therapeutic strategies. By targeting endothelial dysfunction, we may enhance our ability to preserve the intricate dynamics of the brain-retina microenvironment connection and ameliorate the progression of neurological disorders.
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Affiliation(s)
- Wahid Shah
- Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, 030001, China
- Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, 030002, China
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, 030001, China
| | - Yuxing Gong
- Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, 030001, China
| | - Xin Qiao
- Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, 030002, China
| | - Yaling Lu
- Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, 030002, China
| | - Yufei Ding
- Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, 030002, China
| | - Ziting Zhang
- Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, 030002, China
| | - Yuan Gao
- Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, 030002, China.
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, 030001, China.
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J C, Me C, Mt C. Renoprotective mechanisms of glucagon-like peptide-1 receptor agonists. DIABETES & METABOLISM 2025; 51:101641. [PMID: 40127835 DOI: 10.1016/j.diabet.2025.101641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 03/26/2025]
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin hormone, secreted from gut endocrine cells, which acts to potentiate nutrient-induced insulin secretion. Activation of its receptor, GLP-1R, decreases glucagon secretion and gastric emptying, thereby decreasing blood glucose and body weight. It is largely through these mechanisms that Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the treatment of type 2 diabetes. More recently, preclinical and clinical studies have reported that these agents have potent extra-pancreatic effects, exhibiting cardioprotective and renoprotective actions. The recent FLOW trial was the first multicentre clinical trial investigating the effect of GLP-1RAs on a primary renal outcome and reported robust evidence that GLP-1RAs are renoprotective. Studies in rodent models of renal injury have shown that gain and loss of GLP-1R signalling improves or deteriorates kidney function. However, the precise mechanisms responsible for renal benefits of GLP-1RAs are not yet fully understood. While prolonged activation of GLP-1 receptors (GLP-1R) has been shown to reverse diabetes-related disruptions in gene expression across various renal cell populations, GLP-1R expression in both rodent and human kidneys is thought to be primarily confined to certain vascular smooth muscle cells. This review discusses recent advances in our understanding of the effects of GLP-1 medicines on the kidney with a focus on indirect and direct mechanisms of action.
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Affiliation(s)
- Chen J
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia
| | - Cooper Me
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia
| | - Coughlan Mt
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia; Baker Heart and Diabetes Institute, Melbourne, 3004, Victoria, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University Parkville Campus, 381 Royal Parade, Parkville, 3052, Victoria, Australia.
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Trambas IA, Bowen L, Thallas-Bonke V, Snelson M, Sourris KC, Laskowski A, Tauc M, Rubera I, Zheng G, Harris DCH, Kantharidis P, Shimizu T, Cooper ME, Tan SM, Coughlan MT. Proximal tubular deletion of superoxide dismutase-2 reveals disparate effects on kidney function in diabetes. Redox Biol 2025; 82:103601. [PMID: 40127616 PMCID: PMC11979990 DOI: 10.1016/j.redox.2025.103601] [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: 12/18/2024] [Revised: 03/09/2025] [Accepted: 03/17/2025] [Indexed: 03/26/2025] Open
Abstract
There is a large body of evidence implicating mitochondrial reactive oxygen species (ROS) overproduction and oxidative stress in the development of diabetic kidney disease and the deficiency of mitochondrial antioxidant systems in the kidney, such as manganese superoxide dismutase (MnSOD/SOD2) have been identified. The proximal tubules of the kidney are densely packed with mitochondria thereby providing energy via oxidative phosphorylation in order to drive active transport for proximal tubular reabsorption of solutes from the glomerular filtrate. We hypothesized that maintenance of MnSOD function in the proximal tubules would be critical to maintain kidney health in diabetes. Here, we induced targeted deletion of SOD2 in the proximal tubules of the kidney in Ins2Akita diabetic mice (SODptKO mice) and show that 20 weeks of SOD2 deletion leads to no major impairment of kidney function and structure, despite these mice displaying enhanced albuminuria and kidney lipid peroxidation (8-isoprostanes). Plasma cystatin C, which is a surrogate marker of glomerular filtration was not altered in SODptKO diabetic mice and histological assessment of the kidney cortex revealed no change in kidney fibrosis. Thus, our findings suggest that deletion of SOD2 in the proximal tubular compartment of the kidney induces a more subtle phenotype than expected, shedding light on the involvement of SOD2 and the proximal tubular compartment in the pathogenesis of diabetic kidney disease.
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Affiliation(s)
- Inez A Trambas
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, 3004, Victoria, Australia
| | - Lilliana Bowen
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, 3004, Victoria, Australia
| | - Vicki Thallas-Bonke
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, 3004, Victoria, Australia
| | - Matthew Snelson
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, 3004, Victoria, Australia
| | - Karly C Sourris
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, 3004, Victoria, Australia
| | - Adrienne Laskowski
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, 3004, Victoria, Australia
| | - Michel Tauc
- Laboratoire de Physiomédecine Moléculaire, Université Côte D'Azur, CNRS, LP2M, 7370, Nice Cedex 2, France
| | - Isabelle Rubera
- Laboratoire de Physiomédecine Moléculaire, Université Côte D'Azur, CNRS, LP2M, 7370, Nice Cedex 2, France
| | - Guoping Zheng
- Centre for Transplantation and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, 2145, Australia
| | - David C H Harris
- Centre for Transplantation and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, 2145, Australia
| | - Phillip Kantharidis
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, 3004, Victoria, Australia
| | - Takahiko Shimizu
- Department of Food and Reproductive Function Advanced Research, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Mark E Cooper
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, 3004, Victoria, Australia
| | - Sih Min Tan
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, 3004, Victoria, Australia
| | - Melinda T Coughlan
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, 3004, Victoria, Australia; Baker Heart and Diabetes Institute, Melbourne, 3004, Victoria, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University Parkville Campus, 381 Royal Parade, Parkville, 3052, Victoria, Australia.
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Li Q, Shang J, Inagi R. Control of Mitochondrial Quality: A Promising Target for Diabetic Kidney Disease Treatment. Kidney Int Rep 2025; 10:994-1010. [PMID: 40303215 PMCID: PMC12034889 DOI: 10.1016/j.ekir.2024.12.029] [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: 07/29/2024] [Revised: 12/05/2024] [Accepted: 12/23/2024] [Indexed: 05/02/2025] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), affecting over 40% of patients with diabetes. DKD progression involves fibrosis and damage to glomerular and tubulointerstitial regions, with mitochondrial dysfunction playing a critical role. Impaired mitochondria lead to reduced adenosine triphosphate (ATP) production, damaged mitochondria accumulation, and increased reactive oxygen species (ROS), contributing to renal deterioration. Maintaining mitochondrial quality control (MQC) is essential for preventing cell death, tissue injury, and kidney failure. Recent clinical trials show that enhancing MQC can alleviate DKD. However, current treatments cannot halt kidney function decline, underscoring the need for new therapeutic strategies. Mitochondrial-targeted drugs show potential; however, challenges remain because of adverse effects and unclear mechanisms. Future research should aim to comprehensively explore therapeutic potential of MQC in DKD. This review highlights the significance of MQC in DKD treatment, emphasizing the need to maintain mitochondrial quality for developing new therapies.
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Affiliation(s)
- Qi Li
- Division of Chronic Kidney Disease Pathophysiology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Jin Shang
- Division of Chronic Kidney Disease Pathophysiology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Reiko Inagi
- Division of Chronic Kidney Disease Pathophysiology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
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Zhang Q, Xiao S, Zou F, Jiao X, Shen Y. Continuous glucose monitoring‑derived time in range and CV are associated with elevated risk of adverse kidney outcomes for patients with type 2 diabetes. DIABETES & METABOLISM 2025; 51:101616. [PMID: 39933649 DOI: 10.1016/j.diabet.2025.101616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 11/30/2024] [Accepted: 01/14/2025] [Indexed: 02/13/2025]
Abstract
Current guidelines recommend assessing glycemic control using continuous glucose monitoring (CGM), which provides a comprehensive glycemic profile to supplement HbA1c measurement. However, the association between CGM-derived metrics and risk of adverse kidney outcomes is not entirely clear. This retrospective cohort study included 1274 patients with type 2 diabetes hospitalized from July 2020 to December 2022, with a median follow-up time of 923 days. Monitor using CGM at baseline and evaluate renal function indicators of participants at baseline and end of follow-up. Multiple CGM-derived metrics, particularly time in range (TIR) and glucose coefficient of variation (CV), were calculated from 3-day glucose profiles obtained from CGM. Relevant clinical data was collected from clinical records and/or patient interviews. The primary outcome was chronic-kidney-disease (CKD) progression. Secondary outcomes included worsening of albuminuria and, all-cause mortality and major-adverse-cardiac-events(MACE). Multivariate regression models were employed to analyze the association between CGM-derived indices, particularly TIR and CV, and the risk of adverse kidney outcomes. We demonstrated that the lower TIR categories had a remarkably increased risk of CKD progression, with a HR per 10 % increment of 0.90 (95 %CI:0.83-0.91). Conversely, higher CV was positively related to the subsequent risk of CKD progression, with an HR per 10 % increment of 1.30 (95 %CI:1.07-1.59). These results were consistent across various subgroups and sensitivity analyses. This study found that TIR and CV are significantly associated with CKD progression, proteinuria deterioration, all-cause mortality, and the risk of MACE. These findings have elasticity in adjusting for multiple covariates and have been confirmed in different subgroups and sensitivity analyses.
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Affiliation(s)
- Qin Zhang
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi 330006, Nanchang, China
| | - Shucai Xiao
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi 330006, Nanchang, China
| | - Fang Zou
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi 330006, Nanchang, China
| | - Xiaojuan Jiao
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi 330006, Nanchang, China
| | - Yunfeng Shen
- Department of Metabolism and Endocrinology, The Eighth Affiliated Hospital, Sun Yat-sen University, Guangdong 518000, Shenzhen, China.
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Ma Y, Wang X, Lin S, King L, Liu L. The Potential Role of Advanced Glycation End Products in the Development of Kidney Disease. Nutrients 2025; 17:758. [PMID: 40077627 PMCID: PMC11902189 DOI: 10.3390/nu17050758] [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] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/10/2025] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
Advanced glycation end products (AGEs) represent a class of toxic and irreversible compounds formed through non-enzymatic reactions between proteins or lipids and carbonyl compounds. AGEs can arise endogenously under normal metabolic conditions and in pathological states such as diabetes, kidney disease, and inflammatory disorders. Additionally, they can be obtained exogenously through dietary intake, particularly from foods high in fat or sugar, as well as grilled and processed items. AGEs accumulate in various organs and have been increasingly recognized as significant contributors to the progression of numerous diseases, particularly kidney disease. As the kidney plays a crucial role in AGE metabolism and excretion, it is highly susceptible to AGE-induced damage. In this review, we provide a comprehensive discussion on the role of AGEs in the onset and progression of various kidney diseases, including diabetic nephropathy, chronic kidney disease, and acute kidney injury. We explore the potential biological mechanisms involved, such as AGE accumulation, the AGEs-RAGE axis, oxidative stress, inflammation, gut microbiota dysbiosis, and AGE-induced DNA damage. Furthermore, we discuss recent findings on the metabolic characteristics of AGEs in vivo and their pathogenic impact on renal function. Additionally, we examine the clinical significance of AGEs in the early diagnosis, treatment, and prognosis of kidney diseases, highlighting their potential as biomarkers and therapeutic targets. By integrating recent advancements in AGE research, this review aims to provide new insights and strategies for mitigating AGE-related renal damage and improving kidney disease management.
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Affiliation(s)
- Yibin Ma
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.M.); (X.W.); (S.L.); (L.K.)
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xinyu Wang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.M.); (X.W.); (S.L.); (L.K.)
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shan Lin
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.M.); (X.W.); (S.L.); (L.K.)
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lei King
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.M.); (X.W.); (S.L.); (L.K.)
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Liegang Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.M.); (X.W.); (S.L.); (L.K.)
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Empitu MA, Rinastiti P, Kadariswantiningsih IN. Targeting endothelin signaling in podocyte injury and diabetic nephropathy-diabetic kidney disease. J Nephrol 2025; 38:49-60. [PMID: 39302622 DOI: 10.1007/s40620-024-02072-w] [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: 05/25/2024] [Accepted: 08/08/2024] [Indexed: 09/22/2024]
Abstract
Despite advances in diabetes management, there is an urgent need for novel therapeutic strategies since the current treatments remain insufficient in halting the progression of diabetic nephropathy-diabetic kidney disease (DN-DKD). This review is mainly addressed on the pivotal role of endothelin-1 in the pathophysiology of DN, with a specific focus on its effects on podocytes and the glomerular filtration barrier. Endothelin-1 promotes mesangial cell proliferation, sclerosis, and direct podocyte injury via the activation of endothelin type A and B receptors, that drive the progression of glomerulosclerosis in DN-DKD. Endothelin receptor antagonists, including drugs like atrasentan and sparsentan, have demonstrated nephroprotective effects in experimental models by reducing proteinuria and podocyte injury. The therapeutic potential to slow the progression of DN to end-stage kidney disease (ESKD) of these endothelin receptor antagonists in clinical practice is currently under evaluation. However, fluid retention and increased risk of heart failure associated with endothelin receptor antagonists need careful consideration. This review aims to provide an in-depth analysis of the pathophysiological role of endothelin and the emerging therapeutic implications of targeting this pathway in DN-DKD and discusses efficacy, safety, and the possibility of combining the new generation of endothelin receptor antagonists with the standard treatment of CKD and DN-DKD.
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Affiliation(s)
- Maulana Antiyan Empitu
- Faculty of Medicine, Airlangga University, Surabaya, Indonesia
- Faculty of Health, Medicine and Natural Sciences (FIKKIA), Airlangga University, Banyuwangi, Indonesia
| | - Pranindya Rinastiti
- Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, Kobe, Japan
- Department of Clinical Pathology, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University, Yogyakarta, Indonesia
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Yu S, Lu X, Li C, Han Z, Li Y, Zhang X, Guo D. TFAM and Mitochondrial Protection in Diabetic Kidney Disease. Diabetes Metab Syndr Obes 2024; 17:4355-4365. [PMID: 39588133 PMCID: PMC11586499 DOI: 10.2147/dmso.s487815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 11/12/2024] [Indexed: 11/27/2024] Open
Abstract
Diabetic kidney disease (DKD) is a significant complication of diabetes and a major cause of end-stage renal disease. Affecting around 40% of diabetic patients, DKD poses substantial economic burdens due to its prevalence worldwide. The primary clinical features of DKD include the leakage of proteins into the urine, altered glomerular filtration, and an increased risk of cardiovascular diseases. Current treatments focus on managing hypertension and hyperglycemia to slow the progression of DKD. These include the use of SGLT2 inhibitors to control blood sugar and ACE inhibitors to reduce blood pressure. Despite these measures, current treatments do not cure DKD and fail to address its underlying causes. Emerging research highlights mitochondrial dysfunction as a pivotal factor in DKD progression. The kidneys' high energy requirements make them particularly susceptible to disturbances in mitochondrial function. In DKD, mitochondrial damage leads to reduced energy production and increased oxidative stress, exacerbating tissue damage. Mitochondrial DNA (mtDNA) damage is a key aspect of this dysfunction, with studies suggesting that changes in mtDNA copy number can serve as biomarkers for the progression of the disease. Efforts to target mitochondrial dysfunction are gaining traction as a potential therapeutic strategy. This includes promoting mitochondrial health through pharmacological and lifestyle interventions aimed at enhancing mitochondrial function and reducing oxidative stress. Such approaches could lead to more effective treatments that directly address the DKD.
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Affiliation(s)
- Siming Yu
- The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, People’s Republic of China
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Xinxin Lu
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Chunsheng Li
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Zehui Han
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Yue Li
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Xianlong Zhang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
| | - Dandan Guo
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
- The Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, People’s Republic of China
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Zhao L, Zhang X, He L, Li Y, Yu Y, Lu Q, Liu R. Diet with high content of advanced glycation end products induces oxidative stress damage and systemic inflammation in experimental mice: protective effect of peanut skin procyanidins. FOOD SCIENCE AND HUMAN WELLNESS 2024; 13:3570-3581. [DOI: 10.26599/fshw.2023.9250039] [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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Banerjee A, Singh P, Sheikh PA, Kumar A, Koul V, Bhattacharyya J. Simultaneous regulation of AGE/RAGE signaling and MMP-9 expression by an immunomodulating hydrogel accelerates healing in diabetic wounds. BIOMATERIALS ADVANCES 2024; 163:213937. [PMID: 38968788 DOI: 10.1016/j.bioadv.2024.213937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/10/2024] [Accepted: 06/27/2024] [Indexed: 07/07/2024]
Abstract
PURPOSE In chronic hyperglycemia, the advanced glycation end product (AGE) interacts with its receptor (RAGE) and contributes to impaired wound healing by inducing oxidative stress, generating dysfunctional macrophages, and prolonging the inflammatory response. Additionally, uncontrolled levels of proteases, including metallomatrix protease-9 (MMP-9), in the diabetic wound bed degrade the extracellular matrix (ECM) and biological cues that augment healing. A multifunctional antimicrobial hydrogel (Immuno-gel) containing RAGE and MMP-9 inhibitors can regulate the wound microenvironment and promote scar-free healing. RESULTS Immuno-gel was characterized and the wound healing efficacy was determined in vitro cell culture and in vivo diabetic Wistar rat wound model using ELISA, Western blot, and Immunofluorescence staining. The Immuno-gel exhibited a highly porous morphology with excellent in vitro cytocompatibility. AGE-stimulated macrophages treated with the Immuno-gel released higher levels of pro-healing cytokines in vitro. In the hydrogel-wound interface of diabetic Wistar rats, Immuno-gel treatment significantly reduced MMP-9 and NF-κB expression and enhanced pro-healing (M2) macrophage population and pro-healing cytokines. CONCLUSION Altogether, this study suggests that Immuno-gel simultaneously attenuates macrophage dysfunction through the inhibition of AGE/RAGE signaling and reduces MMP-9 overexpression, both of which favor scar-free healing. The combinatorial treatment with RAGE and MMP-9 inhibitors via Immuno-gel simultaneously modulates the diabetic wound microenvironment, making it a promising novel treatment to accelerate diabetic wound healing.
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Affiliation(s)
- Ahana Banerjee
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India; Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, New Delhi 110029, India
| | - Prerna Singh
- Department of Biological sciences and Bioengineering, Indian Institute of Technology Kanpur, Kalyanpur, Kanpur, Uttar Pradesh 208016, India; Centre for Environmental Science and Engineering, Indian Institute of Technology Kanpur, Kalyanpur, Kanpur, Uttar Pradesh 208016, India
| | - Parvaiz A Sheikh
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India
| | - Ashok Kumar
- Department of Biological sciences and Bioengineering, Indian Institute of Technology Kanpur, Kalyanpur, Kanpur, Uttar Pradesh 208016, India; Centre for Environmental Science and Engineering, Indian Institute of Technology Kanpur, Kalyanpur, Kanpur, Uttar Pradesh 208016, India; The Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur, Kalyanpur, Kanpur, Uttar Pradesh 208016, India; Centre of Excellence for Orthopedics and Prosthetics, Indian Institute of Technology Kanpur, Kalyanpur, Kanpur, Uttar Pradesh 208016, India; Gangwal School of Medical Sciences and Technology, Indian Institute of Technology Kanpur, Kalyanpur, Kanpur, Uttar Pradesh 208016, India
| | - Veena Koul
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India; Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, New Delhi 110029, India
| | - Jayanta Bhattacharyya
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India; Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, New Delhi 110029, India.
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Fewkes JJ, Dordevic AL, Murray M, Williamson G, Kellow NJ. Association between endothelial function and skin advanced glycation end-products (AGEs) accumulation in a sample of predominantly young and healthy adults. Cardiovasc Diabetol 2024; 23:332. [PMID: 39251982 PMCID: PMC11386354 DOI: 10.1186/s12933-024-02428-3] [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: 07/21/2024] [Accepted: 08/31/2024] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND In populations with chronic disease, skin autofluorescence (SAF), a measure of long-term fluorescent advanced glycation end-products (AGEs) accumulation in body tissues, has been associated with vascular endothelial function, measured using flow-mediated dilation (FMD). The primary aim of this study was to quantify the relationship between endothelial function and tissue accumulation of AGEs in adults from the general population to determine whether SAF could be used as a marker to predict early impairment of the endothelium. METHODS A cross-sectional study was conducted with 125 participants (median age: 28.5 y, IQR: 24.4-36.0; 54% women). Endothelial function was measured by fasting FMD. Skin AGEs were measured as SAF using an AGE Reader. Participant anthropometry, blood pressure, and blood biomarkers were also measured. Associations were evaluated using multivariable regression analysis and were adjusted for significant covariates. RESULTS FMD was inversely correlated with SAF (ρ = -0.50, P < 0.001) and chronological age (ρ = -0.51, P < 0.001). In the multivariable analysis, SAF, chronological age, and male sex were independently associated with reduced FMD (B [95% CI]; -2.60 [-4.40, -0.80]; -0.10 [-0.16, -0.03]; 1.40 [0.14, 2.67], respectively), with the multivariable model adjusted R2 = 0.31, P < 0.001. CONCLUSIONS Higher skin AGE levels, as measured by SAF, were associated with lower FMD values, in a predominantly young, healthy population. Additionally, older age and male participants exhibited significantly lower FMD values, corresponding with compromised endothelial function. These results suggest that SAF, a simple and inexpensive marker, could be used to predict endothelial impairment before the emergence of any structural artery pathophysiology or classic cardiovascular disease risk markers. TRIAL REGISTRATION The study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000821897) and concurrently entered into the WHO International Clinical Trials Registry Platform under the same ID number.
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Affiliation(s)
- Juanita J Fewkes
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia
- Victorian Heart Institute, Victoria Heart Hospital, 631 Blackburn Road, Clayton, VIC, 3168, Australia
| | - Aimee L Dordevic
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia
- Victorian Heart Institute, Victoria Heart Hospital, 631 Blackburn Road, Clayton, VIC, 3168, Australia
| | - Margaret Murray
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia
- School of Chemistry, Faculty of Science, Monash University, Clayton, VIC, 3800, Australia
| | - Gary Williamson
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia
- Victorian Heart Institute, Victoria Heart Hospital, 631 Blackburn Road, Clayton, VIC, 3168, Australia
| | - Nicole J Kellow
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia.
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
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12
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Shafaati T, Gopal K. Forkhead box O1 transcription factor; a therapeutic target for diabetic cardiomyopathy. JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES : A PUBLICATION OF THE CANADIAN SOCIETY FOR PHARMACEUTICAL SCIENCES, SOCIETE CANADIENNE DES SCIENCES PHARMACEUTIQUES 2024; 27:13193. [PMID: 39206323 PMCID: PMC11349536 DOI: 10.3389/jpps.2024.13193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024]
Abstract
Cardiovascular disease including diabetic cardiomyopathy (DbCM) represents the leading cause of death in people with diabetes. DbCM is defined as ventricular dysfunction in the absence of underlying vascular diseases and/or hypertension. The known molecular mediators of DbCM are multifactorial, including but not limited to insulin resistance, altered energy metabolism, lipotoxicity, endothelial dysfunction, oxidative stress, apoptosis, and autophagy. FoxO1, a prominent member of forkhead box O transcription factors, is involved in regulating various cellular processes in different tissues. Altered FoxO1 expression and activity have been associated with cardiovascular diseases in diabetic subjects. Herein we provide an overview of the role of FoxO1 in various molecular mediators related to DbCM, such as altered energy metabolism, lipotoxicity, oxidative stress, and cell death. Furthermore, we provide valuable insights into its therapeutic potential by targeting these perturbations to alleviate cardiomyopathy in settings of type 1 and type 2 diabetes.
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Affiliation(s)
- Tanin Shafaati
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Cardiovascular Research Institute, University of Alberta, Edmonton, AB, Canada
| | - Keshav Gopal
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Cardiovascular Research Institute, University of Alberta, Edmonton, AB, Canada
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13
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Ahmad MM, Hassan HA, Saadawy SF, Ahmad EA, Elsawy NAM, Morsy MM. Antox targeting AGE/RAGE cascades to restore submandibular gland viability in rat model of type 1 diabetes. Sci Rep 2024; 14:18160. [PMID: 39103403 PMCID: PMC11300852 DOI: 10.1038/s41598-024-68268-z] [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: 10/08/2023] [Accepted: 07/22/2024] [Indexed: 08/07/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic disorder of glucose metabolism that threatens several organs, including the submandibular (SMG) salivary glands. Antox (ANX) is a strong multivitamin with significant antioxidant benefits. The goal of this study was to demonstrate the beneficial roles of ANX supplementation in combination with insulin in alleviating diabetic SMG changes. For four weeks, 30 rats were divided into equal five groups (n = 6): (1) control group; (2) diabetic group (DM), with DM induced by streptozotocin (STZ) injection (50 mg/kg i.p.); (3) DM + ANX group: ANX was administrated (10 mg/kg/day/once daily/orally); (4) DM + insulin group: insulin was administrated 1U once/day/s.c.; and (5) DM + insulin + ANX group: co-administrated insulin. The addition of ANX to insulin in diabetic rats alleviated hyposalivation and histopathological alterations associated with diabetic rats. Remarkably, combined ANX and insulin exerted significant antioxidant effects, suppressing inflammatory and apoptotic pathways associated with increased salivary advanced glycation end-product (AGE) production and receptor for advanced glycation end-product expression (RAGE) activation in diabetic SMG tissues. Combined ANX and insulin administration in diabetic rats was more effective in alleviating SMG changes (functions and structures) than administration of insulin alone, exerting suppressive effects on AGE production and frustrating RAGE downstream pathways.
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Affiliation(s)
- Marwa M Ahmad
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
| | - Heba A Hassan
- Clinical Pharmacology Department, Faculty of Medicine, Zagazig University, Zagazig, 45519, Egypt
- Department of Pharmacology, Faculty of Medicine, Mutah University, Al-Karak, 61710, Jordan
| | - Sara F Saadawy
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Enssaf Ahmad Ahmad
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | | | - Manal Mohammad Morsy
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Wilson-Verdugo M, Bustos-García B, Adame-Guerrero O, Hersch-González J, Cano-Domínguez N, Soto-Nava M, Acosta CA, Tusie-Luna T, Avila-Rios S, Noriega LG, Valdes VJ. Reversal of high-glucose-induced transcriptional and epigenetic memories through NRF2 pathway activation. Life Sci Alliance 2024; 7:e202302382. [PMID: 38755006 PMCID: PMC11099870 DOI: 10.26508/lsa.202302382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 04/29/2024] [Accepted: 04/30/2024] [Indexed: 05/18/2024] Open
Abstract
Diabetes complications such as nephropathy, retinopathy, or cardiovascular disease arise from vascular dysfunction. In this context, it has been observed that past hyperglycemic events can induce long-lasting alterations, a phenomenon termed "metabolic memory." In this study, we evaluated the genome-wide gene expression and chromatin accessibility alterations caused by transient high-glucose exposure in human endothelial cells (ECs) in vitro. We found that cells exposed to high glucose exhibited substantial gene expression changes in pathways known to be impaired in diabetes, many of which persist after glucose normalization. Chromatin accessibility analysis also revealed that transient hyperglycemia induces persistent alterations, mainly in non-promoter regions identified as enhancers with neighboring genes showing lasting alterations. Notably, activation of the NRF2 pathway through NRF2 overexpression or supplementation with the plant-derived compound sulforaphane, effectively reverses the glucose-induced transcriptional and chromatin accessibility memories in ECs. These findings underscore the enduring impact of transient hyperglycemia on ECs' transcriptomic and chromatin accessibility profiles, emphasizing the potential utility of pharmacological NRF2 pathway activation in mitigating and reversing the high-glucose-induced transcriptional and epigenetic alterations.
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Affiliation(s)
- Martí Wilson-Verdugo
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
| | - Brandon Bustos-García
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
| | - Olga Adame-Guerrero
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
| | - Jaqueline Hersch-González
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
| | - Nallely Cano-Domínguez
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
| | - Maribel Soto-Nava
- Centre for Research in Infectious Diseases of the National Institute of Respiratory Diseases (CIENI/INER), Mexico City, Mexico
| | | | - Teresa Tusie-Luna
- Unidad de Biología Molecular y Medicina Genómica Instituto de Investigaciones Biomédicas UNAM/Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, Ciudad de México, Mexico
| | - Santiago Avila-Rios
- Centre for Research in Infectious Diseases of the National Institute of Respiratory Diseases (CIENI/INER), Mexico City, Mexico
| | - Lilia G Noriega
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Victor J Valdes
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
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15
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Gasparotto J, Somensi N, Girardi CS, Bittencourt RR, de Oliveira LM, Hoefel LP, Scheibel IM, Peixoto DO, Moreira JCF, Outeiro TF, Gelain DP. Is it all the RAGE? Defining the role of the receptor for advanced glycation end products in Parkinson's disease. J Neurochem 2024; 168:1608-1624. [PMID: 37381043 DOI: 10.1111/jnc.15890] [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: 03/27/2023] [Revised: 05/09/2023] [Accepted: 06/08/2023] [Indexed: 06/30/2023]
Abstract
The receptor for advanced glycation end products (RAGE) is a transmembrane receptor that belongs to the immunoglobulin superfamily and is extensively associated with chronic inflammation in non-transmissible diseases. As chronic inflammation is consistently present in neurodegenerative diseases, it was largely assumed that RAGE could act as a critical modulator of neuroinflammation in Parkinson's disease (PD), similar to what was reported for Alzheimer's disease (AD), where RAGE is postulated to mediate pro-inflammatory signaling in microglia by binding to amyloid-β peptide. However, accumulating evidence from studies of RAGE in PD models suggests a less obvious scenario. Here, we review physiological aspects of RAGE and address the current questions about the potential involvement of this receptor in the cellular events that may be critical for the development and progression of PD, exploring possible mechanisms beyond the classical view of the microglial activation/neuroinflammation/neurodegeneration axis that is widely assumed to be the general mechanism of RAGE action in the adult brain.
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Affiliation(s)
- Juciano Gasparotto
- Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, MG, Brazil
| | - Nauana Somensi
- Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Carolina Saibro Girardi
- Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Reykla Ramon Bittencourt
- Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Laura Martinewski de Oliveira
- Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Laura Piloneto Hoefel
- Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Ingrid Matsubara Scheibel
- Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Daniel Oppermann Peixoto
- Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - José Claudio Fonseca Moreira
- Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Tiago Fleming Outeiro
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany
- Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
- Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle, UK
- Scientific employee with an honorary contract at Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany
| | - Daniel Pens Gelain
- Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
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Xiao L, Ye G. RUNX3 alleviates mitochondrial dysfunction and tubular damage by inhibiting TLR4/NF-κB signalling pathway in diabetic kidney disease. Nephrology (Carlton) 2024; 29:470-481. [PMID: 38735649 DOI: 10.1111/nep.14307] [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: 11/28/2023] [Revised: 01/16/2024] [Accepted: 04/05/2024] [Indexed: 05/14/2024]
Abstract
AIM The impaired function of tubular mitochondria is critical in diabetic kidney disease (DKD) progression. RUNX3 is down-regulated in DKD models. We intend to explore the effects of RUNX3 on mitochondrial dysfunction and renal tubule injury in DKD and related mechanisms. METHODS The development of diabetes models involved injecting mice with streptozotocin while treating HK-2 cells with high glucose (HG). By using immunohistochemical techniques, the renal localizations of RUNX3 were identified. Levels of adenosine triphosphate (ATP), mitochondrial membrane potential, and biochemical index were detected by appropriate kits. Reactive oxygen species (ROS) generation was assessed with dihydroethidium and MitoSOX Red staining. Apoptosis was assessed by flow cytometry and TUNEL. RUNX3 ubiquitination was measured. RESULTS RUNX3 was mainly present in renal tubules. Overexpressing RUNX3 increased Mfn2, Mfn1, ATP levels, and mitochondrial membrane potential, reduced Drp1 and ROS levels and cell apoptosis, as well as Cyt-C release into the cytoplasm. RUNX3 overexpression displayed a reduction in urinary albumin to creatinine ratio, Hemoglobin A1c, serum creatinine, and blood urea nitrogen. Overexpressing TLR4 attenuated the inhibitory effect of RUNX3 overexpression on mitochondrial dysfunction and cell apoptosis. HG promoted RUNX3 ubiquitination and SMURF2 expression. RUNX3 knockdown cancelled the inhibitory effect of SMURF2 on mitochondrial dysfunction and cell apoptosis. CONCLUSION SMURF2 interference inhibits RUNX3 ubiquitination and TLR4/NF-κB signalling pathway, thereby alleviating renal tubule injury.
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Affiliation(s)
- Ling Xiao
- Department of Nephrology, Wuhan Third Hospital, Wuhan, China
| | - Gang Ye
- Department of Nephrology, Wuhan Third Hospital, Wuhan, China
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17
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Qiyan Zheng, Zhang X, Guo J, Wang Y, Jiang Y, Li S, Liu YN, Liu WJ. JinChan YiShen TongLuo Formula ameliorate mitochondrial dysfunction and apoptosis in diabetic nephropathy through the HIF-1α-PINK1-Parkin pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 328:117863. [PMID: 38325670 DOI: 10.1016/j.jep.2024.117863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/19/2024] [Accepted: 02/03/2024] [Indexed: 02/09/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The JinChan YiShen TongLuo (JCYSTL) formula, a traditional Chinese medicine (TCM), has been used clinically for decades to treat diabetic nephropathy (DN). TCM believes that the core pathogenesis of DN is "kidney deficiency and collateral obstruction," and JCYSTL has the effect of "tonifying kidney and clearing collateral," thus alleviating the damage to kidney structure and function caused by diabetes. From the perspective of modern medicine, mitochondrial damage is an important factor in DN pathogenesis. Our study suggests that the regulation of mitophagy and mitochondrial function by JCYSTL may be one of the internal mechanisms underlying its good clinical efficacy. AIM OF THE STUDY This study aimed to investigate the mechanisms underlying the renoprotective effects of JCYSTL. MATERIALS AND METHODS Unilateral nephrectomy combined with low-dose streptozotocin intraperitoneally injected in a DN rat model and high glucose (HG) plus hypoxia-induced HK-2 cells were used to explore the effects of JCYSTL on the HIF-1α/mitophagy pathway, mitochondrial function and apoptosis. RESULTS JCYSTL treatment significantly decreased albuminuria, serum creatinine, blood urea nitrogen, and uric acid levels and increased creatinine clearance levels in DN rats. In vitro, medicated serum containing JCYSTL formula increased mitochondrial membrane potential (MMP); improved activities of mitochondrial respiratory chain complexes I, III, and IV; decreased the apoptotic cell percentage and apoptotic protein Bax expression; and increased anti-apoptotic protein Bcl-2 expression in HG/hypoxia-induced HK-2 cells. The treatment group exhibited increased accumulation of PINK1, Parkin, and LC3-II and reduced P62 levels in HG/hypoxia-induced HK-2 cells, whereas in PINK1 knockdown HK-2 cells, JCYSTL did not improve the HG/hypoxia-induced changes in Parkin, LC3-II, and P62. When mitophagy was impaired by PINK1 knockdown, the inhibitory effect of JCYSTL on Bax and its promoting effect on MMP and Bcl-2 disappeared. The JCYSTL-treated group displayed significantly higher HIF-1α expression than the model group in vivo, which was comparable to the effects of FG-4592 in DN rats. PINK1 knockdown did not affect HIF-1α accumulation in JCYSTL-treated HK-2 cells exposed to HG/hypoxia. Both JCYSTL and FG-4592 ameliorated mitochondrial morphological abnormalities and reduced the mitochondrial respiratory chain complex activity in the renal tubules of DN rats. Mitochondrial apoptosis signals in DN rats, such as increased Bax and Caspase-3 expression and apoptosis ratio, were weakened by JCYSTL or FG-4592 administration. CONCLUSION This study demonstrates that the JCYSTL formula activates PINK1/Parkin-mediated mitophagy by stabilizing HIF-1α to protect renal tubules from mitochondrial dysfunction and apoptosis in diabetic conditions, presenting a promising therapy for the treatment of DN.
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Affiliation(s)
- Qiyan Zheng
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518000, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China; Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Xueqin Zhang
- Hebei University of Chinese Medicine, Hebei, 050020, China
| | - Jing Guo
- China Academy of Chinese Medicine Science, Beijing, 100700, China
| | - Yahui Wang
- Fangshan Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 102400, China
| | - Yuhua Jiang
- China Academy of Chinese Medicine Science, Beijing, 100700, China
| | - Shunmin Li
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518000, China.
| | - Yu Ning Liu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China; Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Wei Jing Liu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China; Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China.
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18
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Juin SK, Pushpakumar S, Sen U. Nimbidiol protects from renal injury by alleviating redox imbalance in diabetic mice. Front Pharmacol 2024; 15:1369408. [PMID: 38835661 PMCID: PMC11148448 DOI: 10.3389/fphar.2024.1369408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 04/17/2024] [Indexed: 06/06/2024] Open
Abstract
Introduction Chronic hyperglycemia-induced oxidative stress plays a crucial role in the development of diabetic nephropathy (DN). Moreover, adverse extracellular matrix (ECM) accumulation elevates renal resistive index leading to progressive worsening of the pathology in DN. Nimbidiol is an alpha-glucosidase inhibitor, isolated from the medicinal plant, 'neem' (Azadirachta indica) and reported as a promising anti-diabetic compound. Previously, a myriad of studies demonstrated an anti-oxidative property of a broad-spectrum neem-extracts in various diseases including diabetes. Our recent study has shown that Nimbidiol protects diabetic mice from fibrotic renal dysfunction in part by mitigating adverse ECM accumulation. However, the precise mechanism remains poorly understood. Methods The present study aimed to investigate whether Nimbidiol ameliorates renal injury by reducing oxidative stress in type-1 diabetes. To test the hypothesis, wild-type (C57BL/6J) and diabetic Akita (C57BL/6-Ins2Akita/J) mice aged 10-14 weeks were used to treat with saline or Nimbidiol (400 μg kg-1 day-1) for 8 weeks. Results Diabetic mice showed elevated blood pressure, increased renal resistive index, and decreased renal vasculature compared to wild-type control. In diabetic kidney, reactive oxygen species and the expression levels of 4HNE, p22phox, Nox4, and ROMO1 were increased while GSH: GSSG, and the expression levels of SOD-1, SOD-2, and catalase were decreased. Further, eNOS, ACE2, Sirt1 and IL-10 were found to be downregulated while iNOS and IL-17 were upregulated in diabetic kidney. The changes were accompanied by elevated expression of the renal injury markers viz., lipocalin-2 and KIM-1 in diabetic kidney. Moreover, an upregulation of p-NF-κB and a downregulation of IkBα were observed in diabetic kidney compared to the control. Nimbidiol ameliorated these pathological changes in diabetic mice. Conclusion Altogether, the data of our study suggest that oxidative stress largely contributes to the diabetic renal injury, and Nimbidiol mitigates redox imbalance and thereby protects kidney in part by inhibiting NF-κB signaling pathway in type-1 diabetes.
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Affiliation(s)
- Subir Kumar Juin
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY, United States
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, United States
| | - Sathnur Pushpakumar
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY, United States
| | - Utpal Sen
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY, United States
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Wang N, Zhang C. Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression. Int J Mol Sci 2024; 25:3086. [PMID: 38542060 PMCID: PMC10970506 DOI: 10.3390/ijms25063086] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 01/03/2025] Open
Abstract
Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD), and it heightens the risk of cardiovascular incidents. The pathogenesis of DKD is thought to involve hemodynamic, inflammatory, and metabolic factors that converge on the fibrotic pathway. Genetic predisposition and unhealthy lifestyle practices both play a significant role in the development and progression of DKD. In spite of the recent emergence of angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptors antagonists (NS-MRAs), current therapies still fail to effectively arrest the progression of DKD. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), a promising class of agents, possess the potential to act as renal protectors, effectively slowing the progression of DKD. Other agents, including pentoxifylline (PTF), selonsertib, and baricitinib hold great promise as potential therapies for DKD due to their anti-inflammatory and antifibrotic properties. Multidisciplinary treatment, encompassing lifestyle modifications and drug therapy, can effectively decelerate the progression of DKD. Based on the treatment of heart failure, it is recommended to use multiple drugs in combination rather than a single-use drug for the treatment of DKD. Unearthing the mechanisms underlying DKD is urgent to optimize the management of DKD. Inflammatory and fibrotic factors (including IL-1, MCP-1, MMP-9, CTGF, TNF-a and TGF-β1), along with lncRNAs, not only serve as diagnostic biomarkers, but also hold promise as therapeutic targets. In this review, we delve into the potential mechanisms and the current therapies of DKD. We also explore the additional value of combing these therapies to develop novel treatment strategies. Drawing from the current understanding of DKD pathogenesis, we propose HIF inhibitors, AGE inhibitors, and epigenetic modifications as promising therapeutic targets for the future.
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Affiliation(s)
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
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Gallo G, Rubattu S, Volpe M. Mitochondrial Dysfunction in Heart Failure: From Pathophysiological Mechanisms to Therapeutic Opportunities. Int J Mol Sci 2024; 25:2667. [PMID: 38473911 DOI: 10.3390/ijms25052667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 02/17/2024] [Accepted: 02/24/2024] [Indexed: 03/14/2024] Open
Abstract
Mitochondrial dysfunction, a feature of heart failure, leads to a progressive decline in bioenergetic reserve capacity, consisting in a shift of energy production from mitochondrial fatty acid oxidation to glycolytic pathways. This adaptive process of cardiomyocytes does not represent an effective strategy to increase the energy supply and to restore the energy homeostasis in heart failure, thus contributing to a vicious circle and to disease progression. The increased oxidative stress causes cardiomyocyte apoptosis, dysregulation of calcium homeostasis, damage of proteins and lipids, leakage of mitochondrial DNA, and inflammatory responses, finally stimulating different signaling pathways which lead to cardiac remodeling and failure. Furthermore, the parallel neurohormonal dysregulation with angiotensin II, endothelin-1, and sympatho-adrenergic overactivation, which occurs in heart failure, stimulates ventricular cardiomyocyte hypertrophy and aggravates the cellular damage. In this review, we will discuss the pathophysiological mechanisms related to mitochondrial dysfunction, which are mainly dependent on increased oxidative stress and perturbation of the dynamics of membrane potential and are associated with heart failure development and progression. We will also provide an overview of the potential implication of mitochondria as an attractive therapeutic target in the management and recovery process in heart failure.
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Affiliation(s)
- Giovanna Gallo
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Via di Grottarossa 1035-1039, 00189 Rome, RM, Italy
| | - Speranza Rubattu
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Via di Grottarossa 1035-1039, 00189 Rome, RM, Italy
- IRCCS Neuromed, 86077 Pozzilli, IS, Italy
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21
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Pasupulati AK, Nagati V, Paturi ASV, Reddy GB. Non-enzymatic glycation and diabetic kidney disease. VITAMINS AND HORMONES 2024; 125:251-285. [PMID: 38997166 DOI: 10.1016/bs.vh.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/14/2024]
Abstract
Chronic diabetes leads to various complications including diabetic kidney disease (DKD). DKD is a major microvascular complication and the leading cause of morbidity and mortality in diabetic patients. Varying degrees of proteinuria and reduced glomerular filtration rate are the cardinal clinical manifestations of DKD that eventually progress into end-stage renal disease. Histopathologically, DKD is characterized by renal hypertrophy, mesangial expansion, podocyte injury, glomerulosclerosis, and tubulointerstitial fibrosis, ultimately leading to renal replacement therapy. Amongst the many mechanisms, hyperglycemia contributes to the pathogenesis of DKD via a mechanism known as non-enzymatic glycation (NEG). NEG is the irreversible conjugation of reducing sugars onto a free amino group of proteins by a series of events, resulting in the formation of initial Schiff's base and an Amadori product and to a variety of advanced glycation end products (AGEs). AGEs interact with cognate receptors and evoke aberrant signaling cascades that execute adverse events such as oxidative stress, inflammation, phenotypic switch, complement activation, and cell death in different kidney cells. Elevated levels of AGEs and their receptors were associated with clinical and morphological manifestations of DKD. In this chapter, we discussed the mechanism of AGEs accumulation, AGEs-induced cellular and molecular events in the kidney and their impact on the pathogenesis of DKD. We have also reflected upon the possible options to curtail the AGEs accumulation and approaches to prevent AGEs mediated adverse renal outcomes.
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Affiliation(s)
- Anil K Pasupulati
- Department of Biochemistry, University of Hyderabad, Hyderabad, India.
| | - Veerababu Nagati
- Department of Biochemistry, University of Hyderabad, Hyderabad, India
| | - Atreya S V Paturi
- Department of Biochemistry, University of Hyderabad, Hyderabad, India
| | - G Bhanuprakash Reddy
- Department of Biochemistry, ICMR-National Institute of Nutrition, Hyderabad, India.
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22
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Veluthakal R, Esparza D, Hoolachan JM, Balakrishnan R, Ahn M, Oh E, Jayasena CS, Thurmond DC. Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression. Int J Mol Sci 2024; 25:1504. [PMID: 38338783 PMCID: PMC10855860 DOI: 10.3390/ijms25031504] [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: 12/22/2023] [Revised: 01/15/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Type 2 diabetes (T2D) is a heterogenous disease, and conventionally, peripheral insulin resistance (IR) was thought to precede islet β-cell dysfunction, promoting progression from prediabetes to T2D. New evidence suggests that T2D-lean individuals experience early β-cell dysfunction without significant IR. Regardless of the primary event (i.e., IR vs. β-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may be a driver of T2D onset and progression. Oxidative stress, defined as the generation of reactive oxygen species (ROS), is mediated by hyperglycemia alone or in combination with lipids. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress promotes inter-tissue mis-communication, and new evidence suggests that this is mediated via extracellular vesicles (EVs), including mitochondria containing EVs. Under metabolic-related stress conditions, EV-mediated cross-talk between β-cells and skeletal muscle likely trigger mitochondrial anomalies leading to prediabetes and T2D. This article reviews the underlying molecular mechanisms in ROS-related pathogenesis of prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress. Further, this review will describe the potential of various therapeutic avenues for attenuating oxidative damage, reversing prediabetes and preventing progression to T2D.
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Affiliation(s)
- Rajakrishnan Veluthakal
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Beckman Research Institute, 1500 E. Duarte Rd, Duarte, CA 91010, USA; (D.E.); (J.M.H.); (R.B.); (M.A.); (E.O.); (C.S.J.)
| | | | | | | | | | | | | | - Debbie C. Thurmond
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Beckman Research Institute, 1500 E. Duarte Rd, Duarte, CA 91010, USA; (D.E.); (J.M.H.); (R.B.); (M.A.); (E.O.); (C.S.J.)
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23
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Sourris KC, Ding Y, Maxwell SS, Al-Sharea A, Kantharidis P, Mohan M, Rosado CJ, Penfold SA, Haase C, Xu Y, Forbes JM, Crawford S, Ramm G, Harcourt BE, Jandeleit-Dahm K, Advani A, Murphy AJ, Timmermann DB, Karihaloo A, Knudsen LB, El-Osta A, Drucker DJ, Cooper ME, Coughlan MT. Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products-induced inflammation. Kidney Int 2024; 105:132-149. [PMID: 38069998 DOI: 10.1016/j.kint.2023.09.029] [Citation(s) in RCA: 41] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 09/16/2023] [Accepted: 09/25/2023] [Indexed: 01/07/2024]
Abstract
Glucagon like peptide-1 (GLP-1) is a hormone produced and released by cells of the gastrointestinal tract following meal ingestion. GLP-1 receptor agonists (GLP-1RA) exhibit kidney-protective actions through poorly understood mechanisms. Here we interrogated whether the receptor for advanced glycation end products (RAGE) plays a role in mediating the actions of GLP-1 on inflammation and diabetic kidney disease. Mice with deletion of the GLP-1 receptor displayed an abnormal kidney phenotype that was accelerated by diabetes and improved with co-deletion of RAGE in vivo. Activation of the GLP-1 receptor pathway with liraglutide, an anti-diabetic treatment, downregulated kidney RAGE, reduced the expansion of bone marrow myeloid progenitors, promoted M2-like macrophage polarization and lessened markers of kidney damage in diabetic mice. Single cell transcriptomics revealed that liraglutide induced distinct transcriptional changes in kidney endothelial, proximal tubular, podocyte and macrophage cells, which were dominated by pathways involved in nutrient transport and utilization, redox sensing and the resolution of inflammation. The kidney-protective action of liraglutide was corroborated in a non-diabetic model of chronic kidney disease, the subtotal nephrectomised rat. Thus, our findings identify a novel glucose-independent kidney-protective action of GLP-1-based therapies in diabetic kidney disease and provide a valuable resource for exploring the cell-specific kidney transcriptional response ensuing from pharmacological GLP-1R agonism.
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Affiliation(s)
- Karly C Sourris
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia; Diabetes Complications Division, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
| | - Yi Ding
- Diabetes Complications Division, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia; Diabetes Complications Research, Novo Nordisk, Måløv, Denmark
| | - Scott S Maxwell
- Epigenetics in Human Health and Disease Program, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Annas Al-Sharea
- Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Phillip Kantharidis
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia
| | - Muthukumar Mohan
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia
| | - Carlos J Rosado
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia
| | - Sally A Penfold
- Diabetes Complications Division, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Claus Haase
- Diabetes Complications Research, Novo Nordisk, Måløv, Denmark
| | - Yangsong Xu
- Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Josephine M Forbes
- Mater Research Institute, the University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Simon Crawford
- Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Clayton, Victoria, Australia
| | - Georg Ramm
- Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Clayton, Victoria, Australia
| | - Brooke E Harcourt
- Murdoch Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia
| | - Karin Jandeleit-Dahm
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia
| | - Andrew Advani
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michaels Hospital, Toronto, Ontario, Canada
| | - Andrew J Murphy
- Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | | | - Anil Karihaloo
- Novo Nordisk Research Center Seattle, Inc., Seattle, Washington, USA
| | | | - Assam El-Osta
- Epigenetics in Human Health and Disease Program, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Daniel J Drucker
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Mark E Cooper
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia
| | - Melinda T Coughlan
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia; Diabetes Complications Division, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University Parkville Campus, Parkville, Victoria, Australia.
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24
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Agarwal S, Saha S, Ghosh R, Sarmadhikari D, Asthana S, Maiti TK, Khadgawat R, Guchhait P. Elevated glycosylation of CD36 in platelets is a risk factor for oxLDL-mediated platelet activation in type 2 diabetes. FEBS J 2024; 291:376-391. [PMID: 37845743 DOI: 10.1111/febs.16976] [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: 06/27/2023] [Revised: 08/19/2023] [Accepted: 10/12/2023] [Indexed: 10/18/2023]
Abstract
Platelet activation and related cardiovascular complications are the hallmarks of type 2 diabetes (T2D). We investigated the mechanism of platelet activation in T2D using MS-based identification of differentially expressed platelet proteins with a focus on glycosylated forms. Glycosylation is considered one of the common post-translational modifications in T2D, and N/O-linked glycosylation of glycoproteins (GPs)/integrins is known to play crucial roles in platelet activation. Our platelet proteome data revealed elevated levels of GPs GPIbα, GPIIbIIIa, GPIV (CD36), GPV and integrins in T2D patients. T2D platelets had elevated N-linked glycosylation of CD36 at asparagine (Asn)408,417 . Enrichment analysis revealed a close association of glycosylated CD36 with thrombospondin-1, fibrinogen and SERPINA1 in T2D platelets. The glycosylation of CD36 has previously been reported to increase cellular uptake of long-chain fatty acids. Our in silico molecular docking data also showed a favorable binding of cholesterol with glycosylated Asn417 CD36 compared to the non-glycosylated form. We further investigated the CD36:LDL cholesterol axis in T2D. Elevated levels of oxidized-low density lipoprotein (oxLDL) were found to cause significant platelet activation via CD36-mediated stimulation of Lyn-JNK signaling. Sulfo-N-succinimidyl oleate, an inhibitor of CD36, effectively inhibited oxLDL-mediated platelet activation and adhesion in vitro. Our study suggests increased glycosylation of CD36 in T2D platelets as a potential route for oxLDL-mediated platelet activation. The oxLDL:CD36 axis may thus be exploited as a prospective target to develop therapeutics against thrombosis in T2D.
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Affiliation(s)
- Sakshi Agarwal
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Sandhini Saha
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Riya Ghosh
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Debapriyo Sarmadhikari
- Translational Health Science Technology Institute, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Shailendra Asthana
- Translational Health Science Technology Institute, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Tushar K Maiti
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | | | - Prasenjit Guchhait
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
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25
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Stadler K, Ilatovskaya DV. Renal Epithelial Mitochondria: Implications for Hypertensive Kidney Disease. Compr Physiol 2023; 14:5225-5242. [PMID: 38158371 PMCID: PMC11194858 DOI: 10.1002/cphy.c220033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
According to the Centers for Disease Control and Prevention, 1 in 2 U.S. adults have hypertension, and more than 1 in 7 chronic kidney disease. In fact, hypertension is the second leading cause of kidney failure in the United States; it is a complex disease characterized by, leading to, and caused by renal dysfunction. It is well-established that hypertensive renal damage is accompanied by mitochondrial damage and oxidative stress, which are differentially regulated and manifested along the nephron due to the diverse structure and functions of renal cells. This article provides a summary of the relevant knowledge of mitochondrial bioenergetics and metabolism, focuses on renal mitochondrial function, and discusses the evidence that has been accumulated regarding the role of epithelial mitochondrial bioenergetics in the development of renal tissue dysfunction in hypertension. © 2024 American Physiological Society. Compr Physiol 14:5225-5242, 2024.
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Affiliation(s)
- Krisztian Stadler
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Daria V. Ilatovskaya
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
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26
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Kato T, Shinohara I, Mifune Y, Inui A, Nishimoto H, Yoshikawa T, Furukawa T, Tanaka S, Kusunose M, Hoshino Y, Matsushita T, Kuroda R. Intra-articular site-specific distribution of advanced glycation end products in the shoulder of patients with diabetes mellitus having rotator cuff tears. Mol Biol Rep 2023; 50:10339-10349. [PMID: 37982930 DOI: 10.1007/s11033-023-08861-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 09/27/2023] [Indexed: 11/21/2023]
Abstract
BACKGROUND Advanced glycation end products (AGEs) are compounds formed due to aging and diabetes mellitus (DM). They activate NADPH oxidase (NOX) by binding to their receptors, thereby increasing the production of reactive oxygen species (ROS), which cause oxidative stress. In this study, we investigated the effects of AGEs on the tissues of the shoulder joint (such as rotator cuff synovium, and capsule) in patients with DM having rotator cuff tears. METHODS This study included eight patients with DM who underwent surgical treatment for rotator cuff tears with contracture. The rotator cuff, synovium, and joint capsule were harvested at the time of surgery and evaluated by hematoxylin-eosin staining. Furthermore, immunostaining was used for evaluating AGEs and receptor for AGEs (RAGE), cell activity, ROS, and apoptosis. Quantitative real-time polymerase chain reaction (qPCR) was employed for the cellular evaluation of NOX, interleukins, RAGE, and collagen. RESULTS The AGEs and RAGE staining as well as the ratio of ROS and apoptosis were in the following order: rotator cuff > joint capsule > synovium. In contrast, the cellular activity was significantly higher in the synovium than in the other regions. The type I collagen expression (as shown by qPCR) as well as the RAGE and NOX expressions were as follows: rotator cuff > joint capsule > synovium. Conversely, the expression of inflammatory cytokines (i.e., IL-6 and IL-1β) was higher in the synovium than in the other regions. CONCLUSIONS Our study is among the first to evaluate the effects of AGEs on each tissue of the shoulder joint in patients with DM having rotator cuff tears and contractures. The accumulation of AGEs in each tissue of the shoulder joint could reveal the locations affected by DM, which can lead to a better understanding of the pathophysiology of DM-related shoulder diseases.
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Affiliation(s)
- Tatsuo Kato
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 5-2, Kusunoki-cho7, Chuo-ku, Kobe-shi, 650-0017, Hyogo, Japan
| | - Issei Shinohara
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 5-2, Kusunoki-cho7, Chuo-ku, Kobe-shi, 650-0017, Hyogo, Japan
| | - Yutaka Mifune
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 5-2, Kusunoki-cho7, Chuo-ku, Kobe-shi, 650-0017, Hyogo, Japan.
| | - Atsuyuki Inui
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 5-2, Kusunoki-cho7, Chuo-ku, Kobe-shi, 650-0017, Hyogo, Japan
| | - Hanako Nishimoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 5-2, Kusunoki-cho7, Chuo-ku, Kobe-shi, 650-0017, Hyogo, Japan
| | - Tomoya Yoshikawa
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 5-2, Kusunoki-cho7, Chuo-ku, Kobe-shi, 650-0017, Hyogo, Japan
| | - Takahiro Furukawa
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 5-2, Kusunoki-cho7, Chuo-ku, Kobe-shi, 650-0017, Hyogo, Japan
| | - Shuya Tanaka
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 5-2, Kusunoki-cho7, Chuo-ku, Kobe-shi, 650-0017, Hyogo, Japan
| | - Masaya Kusunose
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 5-2, Kusunoki-cho7, Chuo-ku, Kobe-shi, 650-0017, Hyogo, Japan
| | - Yuichi Hoshino
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 5-2, Kusunoki-cho7, Chuo-ku, Kobe-shi, 650-0017, Hyogo, Japan
| | - Takehiko Matsushita
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 5-2, Kusunoki-cho7, Chuo-ku, Kobe-shi, 650-0017, Hyogo, Japan
| | - Ryosuke Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 5-2, Kusunoki-cho7, Chuo-ku, Kobe-shi, 650-0017, Hyogo, Japan
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Chen M, Chen Y, Zhu W, Yan X, Xiao J, Zhang P, Liu P, Li P. Advances in the pharmacological study of Chinese herbal medicine to alleviate diabetic nephropathy by improving mitochondrial oxidative stress. Biomed Pharmacother 2023; 165:115088. [PMID: 37413900 DOI: 10.1016/j.biopha.2023.115088] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/25/2023] [Accepted: 06/26/2023] [Indexed: 07/08/2023] Open
Abstract
Diabetic nephropathy (DN) is one of the serious complications of diabetes mellitus, primarily arising from type 2 diabetes (T2DM), and can progress to chronic kidney disease (CKD) and end stage renal disease (ESRD). The pathogenesis of DN involves various factors such as hemodynamic changes, oxidative stress, inflammatory response, and lipid metabolism disorders. Increasing attention is being given to DN caused by oxidative stress in the mitochondrial pathway, prompting researchers to explore drugs that can regulate these target pathways. Chinese herbal medicine, known for its accessibility, rich historical usage, and remarkable efficacy, has shown promise in ameliorating renal injury caused by DN by modulating oxidative stress in the mitochondrial pathway. This review aims to provide a reference for the prevention and treatment of DN. Firstly, we outline the mechanisms by which mitochondrial dysfunction impairs DN, focusing on outlining the damage to mitochondria by oxidative stress. Subsequently, we describe the process by which formulas, herbs and monomeric compounds protect the kidney by ameliorating oxidative stress in the mitochondrial pathway. Finally, the rich variety of Chinese herbal medicine, combined with modern extraction techniques, has great potential, and as we gradually understand the pathogenesis of DN and research techniques are constantly updated, there will be more and more promising therapeutic targets and herbal drug candidates. This paper aims to provide a reference for the prevention and treatment of DN.
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Affiliation(s)
- Ming Chen
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Yao Chen
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Wenhui Zhu
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Xiaoming Yan
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Jing Xiao
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Peiqing Zhang
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China.
| | - Peng Liu
- Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, China.
| | - Ping Li
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, China-Japan Friendship Hospital, Beijing, China.
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Kuntic M, Kuntic I, Hahad O, Lelieveld J, Münzel T, Daiber A. Impact of air pollution on cardiovascular aging. Mech Ageing Dev 2023; 214:111857. [PMID: 37611809 DOI: 10.1016/j.mad.2023.111857] [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: 07/06/2023] [Accepted: 08/19/2023] [Indexed: 08/25/2023]
Abstract
The world population is aging rapidly, and by some estimates, the number of people older than 60 will double in the next 30 years. With the increase in life expectancy, adverse effects of environmental exposures start playing a more prominent role in human health. Air pollution is now widely considered the most detrimental of all environmental risk factors, with some studies estimating that almost 20% of all deaths globally could be attributed to poor air quality. Cardiovascular diseases are the leading cause of death worldwide and will continue to account for the most significant percentage of non-communicable disease burden. Cardiovascular aging with defined pathomechanisms is a major trigger of cardiovascular disease in old age. Effects of environmental risk factors on cardiovascular aging should be considered in order to increase the health span and reduce the burden of cardiovascular disease in older populations. In this review, we explore the effects of air pollution on cardiovascular aging, from the molecular mechanisms to cardiovascular manifestations of aging and, finally, the age-related cardiovascular outcomes. We also explore the distinction between the effects of air pollution on healthy aging and disease progression. Future efforts should focus on extending the health span rather than the lifespan.
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Affiliation(s)
- Marin Kuntic
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany
| | - Ivana Kuntic
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany
| | - Omar Hahad
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany
| | - Jos Lelieveld
- Max Planck Institute for Chemistry, Atmospheric Chemistry, Mainz, Germany
| | - Thomas Münzel
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany.
| | - Andreas Daiber
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany.
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29
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Coppola S, Paparo L, Trinchese G, Rivieri AM, Masino A, De Giovanni Di Santa Severina AF, Cerulo M, Escolino M, Turco A, Esposito C, Mollica MP, Berni Canani R. Increased dietary intake of ultraprocessed foods and mitochondrial metabolism alterations in pediatric obesity. Sci Rep 2023; 13:12609. [PMID: 37537205 PMCID: PMC10400566 DOI: 10.1038/s41598-023-39566-9] [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: 02/06/2023] [Accepted: 07/26/2023] [Indexed: 08/05/2023] Open
Abstract
The increased intake of ultraprocessed foods (UPFs) in the pediatric age paralleled with the risen prevalence of childhood obesity. The Ultraprocessed Foods in Obesity (UFO) Project aimed at investigating the potential mechanisms for the effects of UPFs in facilitating pediatric obesity, focusing on the direct role of advanced glycation end-products (AGEs) on mitochondrial function, the key regulator of obesity pathophysiology. We comparatively investigated the daily dietary intake of UPFs, energy, nutrients, dietary AGEs [Nε -(carboxymethyl)lysine (CML), Nε -(1-carboxyethyl)lysine (CEL), and Nδ -(5-hydro-5- methyl-4-imidazolon-2-yl)-ornithine (MG-H1)] in 53 obese patients and in 100 healthy controls visiting the Tertiary Center for Pediatric Nutrition of the Department of Translational Medical Science at the University of Naples "Federico II". AGEs skin accumulation and mitochondrial function in peripheral blood mononuclear cells (PBMCs) were also assessed. A higher intake of UPFs and AGEs, energy, protein, fat, and saturated fatty acids was observed in obese patients. Obese children presented significantly higher skin AGEs accumulation and alterations in mitochondrial metabolism. PBMCs from healthy controls exposed to AGEs showed the same mitochondrial alterations observed in patients. These findings support the UPFs role in pediatric obesity, and the need for dietary strategies limiting UPFs exposure for obesity prevention and treatment.
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Affiliation(s)
- Serena Coppola
- Department of Translational Medical Science, University Federico II, Naples, Italy
- ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | - Lorella Paparo
- Department of Translational Medical Science, University Federico II, Naples, Italy
- ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | | | | | - Antonio Masino
- Department of Translational Medical Science, University Federico II, Naples, Italy
- ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | - Anna Fiorenza De Giovanni Di Santa Severina
- Department of Translational Medical Science, University Federico II, Naples, Italy
- ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | - Mariapina Cerulo
- Department of Translational Medical Science, University Federico II, Naples, Italy
| | - Maria Escolino
- Department of Translational Medical Science, University Federico II, Naples, Italy
| | - Assunta Turco
- Department of Translational Medical Science, University Federico II, Naples, Italy
| | - Ciro Esposito
- Department of Translational Medical Science, University Federico II, Naples, Italy
| | | | - Roberto Berni Canani
- Department of Translational Medical Science, University Federico II, Naples, Italy.
- ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy.
- European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy.
- Task Force for Microbiome Studies, University Federico II, Naples, Italy.
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30
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Daehn IS, Ekperikpe US, Stadler K. Redox regulation in diabetic kidney disease. Am J Physiol Renal Physiol 2023; 325:F135-F149. [PMID: 37262088 PMCID: PMC10393330 DOI: 10.1152/ajprenal.00047.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/08/2023] [Accepted: 05/20/2023] [Indexed: 06/03/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the most devastating complications of diabetes mellitus, where currently there is no cure available. Several important mechanisms contribute to the pathogenesis of this complication, with oxidative stress being one of the key factors. The past decades have seen a large number of publications with various aspects of this topic; however, the specific details of redox regulation in DKD are still unclear. This is partly because redox biology is very complex, coupled with a complex and heterogeneous organ with numerous cell types. Furthermore, often times terms such as "oxidative stress" or reactive oxygen species are used as a general term to cover a wide and rich variety of reactive species and their differing reactions. However, no reactive species are the same, and not all of them are capable of biologically relevant reactions or "redox signaling." The goal of this review is to provide a biochemical background for an array of specific reactive oxygen species types with varying reactivity and specificity in the kidney as well as highlight some of the advances in redox biology that are paving the way to a better understanding of DKD development and risk.
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Affiliation(s)
- Ilse S Daehn
- Division of Nephrology, Department of Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States
| | - Ubong S Ekperikpe
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Krisztian Stadler
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States
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31
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Yubero-Serrano EM, Gutiérrez-Mariscal FM, Gómez-Luna P, Alcalá-Diaz JF, Pérez-Martinez P, López-Miranda J. Dietary modulation of advanced glycation end products metabolism on carotid intima-media thickness in type 2 diabetes patients: From the CORDIOPREV study. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ARTERIOSCLEROSIS 2023; 35:105-114. [PMID: 36184301 DOI: 10.1016/j.arteri.2022.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Advanced glycation end products (AGEs) are pro-oxidant and cytotoxic compounds involved in the progression of chronic diseases as cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). The total body burden of AGEs also depend of those consume through the diet. Our aim was to analyze whether the reduction of AGE levels, after the consumption of two-healthy diets were associated with a greater decrease of intima-media thickness of both common carotid arteries (IMT-CC) in patients with T2DM and coronary heart disease (CHD). METHODS 540 CHD patients with T2DM, at baseline, from the CORDIOPREV study, were divided into two groups: (1) Responders, patients whose IMT-CC was reduced or not changed after dietary intervention and (2) Non-responders, patients whose IMT-CC was increased after dietary intervention. A total of 423 completed baseline and the 5-year follow-up carotid ultrasounds were analyzed in this study. RESULTS Our data showed that Responders, despite had a higher baseline IMT-CC and serum methylglyoxal (MG) levels than Non-responders, showed a reduction of serum levels of this glycotoxin after dietary intervention. Conversely, in patients whose IMT-CC was increased after dietary intervention (Non-responders), serum MG levels were increased. Moreover, an increase of circulating level of AGEs (and in particular, MG), after dietary intervention, could be considered a risk factor for the progression of atherosclerosis in patients with T2DM and CHD. CONCLUSION These results support the importance of identifying underlying mechanisms in the context of secondary prevention of CVD that would provide therapeutic targets to reduce the high risk of cardiovascular events of these patients. CLINICAL TRIAL REGISTRATION-URL https://clinicaltrials.gov/ct2/show/NCT00924937. Unique Identifier: NCT00924937.
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Affiliation(s)
- Elena M Yubero-Serrano
- Unidad de Gestión Clinica Medicina Interna, Lipids and Atherosclerosis Unit, Maimonides Institute for Biomedical Research in Córdoba, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain.
| | - Francisco M Gutiérrez-Mariscal
- Unidad de Gestión Clinica Medicina Interna, Lipids and Atherosclerosis Unit, Maimonides Institute for Biomedical Research in Córdoba, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain
| | - Purificación Gómez-Luna
- Unidad de Gestión Clinica Medicina Interna, Lipids and Atherosclerosis Unit, Maimonides Institute for Biomedical Research in Córdoba, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain
| | - Juan F Alcalá-Diaz
- Unidad de Gestión Clinica Medicina Interna, Lipids and Atherosclerosis Unit, Maimonides Institute for Biomedical Research in Córdoba, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain
| | - Pablo Pérez-Martinez
- Unidad de Gestión Clinica Medicina Interna, Lipids and Atherosclerosis Unit, Maimonides Institute for Biomedical Research in Córdoba, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain
| | - José López-Miranda
- Unidad de Gestión Clinica Medicina Interna, Lipids and Atherosclerosis Unit, Maimonides Institute for Biomedical Research in Córdoba, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain.
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32
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Li Y, Liu Y, Liu S, Gao M, Wang W, Chen K, Huang L, Liu Y. Diabetic vascular diseases: molecular mechanisms and therapeutic strategies. Signal Transduct Target Ther 2023; 8:152. [PMID: 37037849 PMCID: PMC10086073 DOI: 10.1038/s41392-023-01400-z] [Citation(s) in RCA: 207] [Impact Index Per Article: 103.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 02/19/2023] [Accepted: 02/28/2023] [Indexed: 04/12/2023] Open
Abstract
Vascular complications of diabetes pose a severe threat to human health. Prevention and treatment protocols based on a single vascular complication are no longer suitable for the long-term management of patients with diabetes. Diabetic panvascular disease (DPD) is a clinical syndrome in which vessels of various sizes, including macrovessels and microvessels in the cardiac, cerebral, renal, ophthalmic, and peripheral systems of patients with diabetes, develop atherosclerosis as a common pathology. Pathological manifestations of DPDs usually manifest macrovascular atherosclerosis, as well as microvascular endothelial function impairment, basement membrane thickening, and microthrombosis. Cardiac, cerebral, and peripheral microangiopathy coexist with microangiopathy, while renal and retinal are predominantly microangiopathic. The following associations exist between DPDs: numerous similar molecular mechanisms, and risk-predictive relationships between diseases. Aggressive glycemic control combined with early comprehensive vascular intervention is the key to prevention and treatment. In addition to the widely recommended metformin, glucagon-like peptide-1 agonist, and sodium-glucose cotransporter-2 inhibitors, for the latest molecular mechanisms, aldose reductase inhibitors, peroxisome proliferator-activated receptor-γ agonizts, glucokinases agonizts, mitochondrial energy modulators, etc. are under active development. DPDs are proposed for patients to obtain more systematic clinical care requires a comprehensive diabetes care center focusing on panvascular diseases. This would leverage the advantages of a cross-disciplinary approach to achieve better integration of the pathogenesis and therapeutic evidence. Such a strategy would confer more clinical benefits to patients and promote the comprehensive development of DPD as a discipline.
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Affiliation(s)
- Yiwen Li
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Yanfei Liu
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100091, China
- The Second Department of Gerontology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Shiwei Liu
- Department of Nephrology and Endocrinology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Mengqi Gao
- Department of Nephrology and Endocrinology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Wenting Wang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Keji Chen
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100091, China.
| | - Luqi Huang
- China Center for Evidence-based Medicine of TCM, China Academy of Chinese Medical Sciences, Beijing, 100010, China.
| | - Yue Liu
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100091, China.
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Chadwick W, Maudsley S, Hull W, Havolli E, Boshoff E, Hill MDW, Goetghebeur PJD, Harrison DC, Nizami S, Bedford DC, Coope G, Real K, Thiemermann C, Maycox P, Carlton M, Cole SL. The oDGal Mouse: A Novel, Physiologically Relevant Rodent Model of Sporadic Alzheimer's Disease. Int J Mol Sci 2023; 24:ijms24086953. [PMID: 37108119 PMCID: PMC10138655 DOI: 10.3390/ijms24086953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/17/2023] [Accepted: 03/30/2023] [Indexed: 04/29/2023] Open
Abstract
Sporadic Alzheimer's disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase.
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Affiliation(s)
- Wayne Chadwick
- Takeda Cambridge, 418 Cambridge Science Park, Cambridge CB4 0PZ, UK
| | - Stuart Maudsley
- Receptor Biology Lab, University of Antwerp, 2000 Antwerp, Belgium
| | - William Hull
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Centre for Translational Medicine and Therapeutics, Queen Mary University of London, London E1 4NS, UK
| | - Enes Havolli
- Takeda Cambridge, 418 Cambridge Science Park, Cambridge CB4 0PZ, UK
| | - Eugene Boshoff
- Takeda Cambridge, 418 Cambridge Science Park, Cambridge CB4 0PZ, UK
| | - Mark D W Hill
- Takeda Cambridge, 418 Cambridge Science Park, Cambridge CB4 0PZ, UK
| | | | - David C Harrison
- Takeda Cambridge, 418 Cambridge Science Park, Cambridge CB4 0PZ, UK
| | - Sohaib Nizami
- Takeda Cambridge, 418 Cambridge Science Park, Cambridge CB4 0PZ, UK
| | - David C Bedford
- Takeda Cambridge, 418 Cambridge Science Park, Cambridge CB4 0PZ, UK
| | - Gareth Coope
- Takeda Cambridge, 418 Cambridge Science Park, Cambridge CB4 0PZ, UK
| | - Katia Real
- Takeda Cambridge, 418 Cambridge Science Park, Cambridge CB4 0PZ, UK
| | - Christoph Thiemermann
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Centre for Translational Medicine and Therapeutics, Queen Mary University of London, London E1 4NS, UK
| | - Peter Maycox
- Takeda Cambridge, 418 Cambridge Science Park, Cambridge CB4 0PZ, UK
| | - Mark Carlton
- Takeda Cambridge, 418 Cambridge Science Park, Cambridge CB4 0PZ, UK
| | - Sarah L Cole
- Takeda Cambridge, 418 Cambridge Science Park, Cambridge CB4 0PZ, UK
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Shen Q, Fang J, Guo H, Su X, Zhu B, Yao X, Wang Y, Cao A, Wang H, Wang L. Astragaloside IV attenuates podocyte apoptosis through ameliorating mitochondrial dysfunction by up-regulated Nrf2-ARE/TFAM signaling in diabetic kidney disease. Free Radic Biol Med 2023; 203:45-57. [PMID: 37030337 DOI: 10.1016/j.freeradbiomed.2023.03.022] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 03/01/2023] [Accepted: 03/23/2023] [Indexed: 04/10/2023]
Abstract
Defective antioxidant system as well as mitochondrial dysfunction contributes to the pathogenesis and progression of diabetic kidney disease (DKD). Nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling is the central defensive mechanism against oxidative stress and therefore pharmacological activation of Nrf2 is a promising therapeutic strategy. In this study, using molecular docking we found that Astragaloside IV (AS-IV), an active ingredient from traditional formula of Huangqi decoction (HQD), exerted a higher potential to promote Nrf2 escape from Keap1-Nrf2 interaction via competitively bind to amino acid sites in Keap1. When podocyte exposed to high glucose (HG) stimulation, mitochondrial morphological alterations and podocyte apoptosis were presented and accompanied by Nrf2 and mitochondrial transcription factor A (TFAM) downregulation. Mechanistically, HG promoted a decrease in mitochondria-specific electron transport chain (ETC) complexes, ATP synthesis and mtDNA content as well as increased ROS production. Conversely, all these mitochondrial defects were dramatically alleviated by AS-IV, but suppression of Nrf2 with inhibitor or siRNA and TFAM siRNA simultaneously alleviated the AS-IV efficacy. Moreover, experimental diabetic mice exhibited significant renal injury as well as mitochondrial disorder, corresponding with the decreased expression of Nrf2 and TFAM. On the contrary, AS-IV reversed the abnormality and the Nrf2 and TFAM expression were also restored. Taken together, the present findings demonstrate the improvement of AS-IV on mitochondrial function, thereby resistance to oxidative stress-induced diabetic kidney injury and podocyte apoptosis, and the process is closely associated with activation of Nrf2-ARE/TFAM signaling.
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Affiliation(s)
- Qian Shen
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ji Fang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hengjiang Guo
- Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Anesthesiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China; Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Hefei, 230032, China
| | - Xue Su
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bingbing Zhu
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xingmei Yao
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yunman Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Aili Cao
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hao Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Li Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Hefei, 230032, China.
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35
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Lu HC, Lin T, Ng MY, Hsieh CW, Liao YW, Chen CC, Yu CC, Chen CJ. Anti-inflammaging effects of vitamin D in human gingival fibroblasts with advanced glycation end product stimulation. J Dent Sci 2023; 18:666-673. [PMID: 37021258 PMCID: PMC10068372 DOI: 10.1016/j.jds.2022.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/03/2022] [Indexed: 04/05/2023] Open
Abstract
Background/purpose :Both periodontal disease and diabetes mellitus (DM) are long-term inflammatory disorders that are highly prevalent and have a significant health impact. Inflammaging, a state of pre-aging and hyperinflammatory state has been acknowledged for its role in DM patients to have heightened risk of periodontitis. Numerous evidences revealed that inflammaging contributed by cell senescence, acceleration of inflammation and oxidative stress participates in the destruction of periodontium in DM. Abilities of vitamin D in suppressing inflammation and oxidative stress have been revealed in a range of tissues, however in DM’s gingival cells, the effect remain undefined. Materials and methods : Under the stimulation of advanced glycation end-products (AGEs), we assessed the cell proliferation in human gingival fibroblast (HGF), IL-6 and IL-8 secretions, cellular senescence expression and generation of reactive oxygen species (ROS) with or without vitamin D intervention. Following that, we examined the expression of Nrf2 and HO-1 to see if vitamin D was able to modulate the anti-oxidant signaling. A knockdown experiment was then conducted to proof the participation of Nrf2 on the secretion of pro-inflammatory IL-6 and IL-8. Results : Following the treatment of vitamin D, AGEs-elicited IL-6 and IL-8 production and cell senescence were dose-dependently repressed. Moreover, vitamin D attenuated AGEs-induced ROS in a dose-dependent pattern. Results from qRT-PCR demonstrated vitamin D reversed the suppression of Nrf2 and HO-1 induced by AGEs. Our findings revealed that the anti-inflammatory and anti-oxidant effect in vitamin D was mediated via the upregulation of Nrf2 expression. Conclusion : These data showed that high levels of AGEs in the gingiva lead to inflammaging reflected by increased pro-inflammatory cytokines, cell senescence expression and oxidative stress. Vitamin D supplementation can reduce oxidative stress and inflammation via the upregulation of Nrf2 signaling and hence, may be a potential approach for treatment of diabetes-associated periodontitis.
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Affiliation(s)
- Hung-Chieh Lu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
| | - Taichen Lin
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Min Yee Ng
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
| | - Chang-Wei Hsieh
- Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan
| | - Yi-Wen Liao
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Chun-Cheng Chen
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Cheng-Chia Yu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- Corresponding author. Institute of Oral Sciences, Chung Shan Medical University, No.110, Sec.1, Jianguo N. Rd., Taichung 40201, Taiwan.
| | - Chun-Jung Chen
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
- Division of Periodontics, Department of Dentistry, Chi Mei Medical Center, Tainan, Taiwan
- Corresponding author. Division of Periodontics, Department of Dentistry, Chi Mei Medical Center, No. 901, Zhonghua Rd. Yongkang Dist., Tainan 71004, Taiwan.
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Kamimura N, Wolf AM, Yokota T, Nito C, Takahashi H, Ohta S. Transgenic type2 diabetes mouse models for in vivo redox measurement of hepatic mitochondrial oxidative stress. Biochim Biophys Acta Gen Subj 2023; 1867:130302. [PMID: 36577487 DOI: 10.1016/j.bbagen.2022.130302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/02/2022] [Accepted: 12/21/2022] [Indexed: 12/26/2022]
Abstract
BACKGROUND Oxidative stress is involved in the progression of diabetes and its associated complications. However, it is unclear whether increased oxidative stress plays a primary role in the onset of diabetes or is a secondary indicator caused by tissue damage. Previous methods of analyzing oxidative stress have involved measuring the changes in oxidative stress biomarkers. Our aim is to identify a novel approach to clarify whether oxidative stress plays a primary role in the onset of diabetes. METHODS We constructed transgenic type 2 diabetes mouse models expressing redox-sensitive green fluorescent proteins (roGFPs) that distinguished between mitochondria and whole cells. Pancreas, liver, skeletal muscle, and kidney redox states were measured in vivo. RESULTS Hepatic mitochondrial oxidation increased when the mice were 4 weeks old and continued to increase in an age-dependent manner. The increase in hepatic mitochondrial oxidation occurred simultaneously with weight gain and increased blood insulin levels before the blood glucose levels increased. Administering the oxidative stress inducer acetaminophen increased the vulnerability of the liver mitochondria to oxidative stress. CONCLUSIONS This study demonstrates that oxidative stress in liver mitochondria in mice begins at the onset of diabetes rather than after the disease has progressed. GENERAL SIGNIFICANCE RoGFP-expressing transgenic type 2 diabetes mouse models are effective and convenient tools for measuring hepatic mitochondrial redox statuses in vivo. These models may be used to assess mitochondria-targeting antioxidants and establish the role of oxidative stress in type 2 diabetes.
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Affiliation(s)
- Naomi Kamimura
- Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; Laboratory for Clinical Research, Collaborative Research Center, Nippon Medical School, Tokyo, Japan.
| | - Alexander M Wolf
- Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Takashi Yokota
- Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Chikako Nito
- Laboratory for Clinical Research, Collaborative Research Center, Nippon Medical School, Tokyo, Japan
| | - Hiroshi Takahashi
- Laboratory for Clinical Research, Collaborative Research Center, Nippon Medical School, Tokyo, Japan; Department of Ophthalmology, Nippon Medical School, Tokyo, Japan
| | - Shigeo Ohta
- Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; Department of Neurology Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Rajlic S, Treede H, Münzel T, Daiber A, Duerr GD. Early Detection Is the Best Prevention-Characterization of Oxidative Stress in Diabetes Mellitus and Its Consequences on the Cardiovascular System. Cells 2023; 12:583. [PMID: 36831253 PMCID: PMC9954643 DOI: 10.3390/cells12040583] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/05/2023] [Accepted: 02/08/2023] [Indexed: 02/16/2023] Open
Abstract
Previous studies demonstrated an important role of oxidative stress in the pathogenesis of cardiovascular disease (CVD) in diabetic patients due to hyperglycemia. CVD remains the leading cause of premature death in the western world. Therefore, diabetes mellitus-associated oxidative stress and subsequent inflammation should be recognized at the earliest possible stage to start with the appropriate treatment before the onset of the cardiovascular sequelae such as arterial hypertension or coronary artery disease (CAD). The pathophysiology comprises increased reactive oxygen and nitrogen species (RONS) production by enzymatic and non-enzymatic sources, e.g., mitochondria, an uncoupled nitric oxide synthase, xanthine oxidase, and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Considering that RONS originate from different cellular mechanisms in separate cellular compartments, adequate, sensitive, and compartment-specific methods for their quantification are crucial for early detection. In this review, we provide an overview of these methods with important information for early, appropriate, and effective treatment of these patients and their cardiovascular sequelae.
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Affiliation(s)
- Sanela Rajlic
- Department of Cardiothoracic and Vascular Surgery, University of Medicine Mainz, 55131 Mainz, Germany
| | - Hendrik Treede
- Department of Cardiothoracic and Vascular Surgery, University of Medicine Mainz, 55131 Mainz, Germany
| | - Thomas Münzel
- Center for Cardiology, Department of Cardiology, Molecular Cardiology, University Medical Center, 55131 Mainz, Germany
| | - Andreas Daiber
- Center for Cardiology, Department of Cardiology, Molecular Cardiology, University Medical Center, 55131 Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany
| | - Georg Daniel Duerr
- Department of Cardiothoracic and Vascular Surgery, University of Medicine Mainz, 55131 Mainz, Germany
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38
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The Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Empagliflozin Reverses Hyperglycemia-Induced Monocyte and Endothelial Dysfunction Primarily through Glucose Transport-Independent but Redox-Dependent Mechanisms. J Clin Med 2023; 12:jcm12041356. [PMID: 36835891 PMCID: PMC9962711 DOI: 10.3390/jcm12041356] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 02/02/2023] [Indexed: 02/10/2023] Open
Abstract
PURPOSE Hyperglycaemia-induced oxidative stress and inflammation contribute to vascular cell dysfunction and subsequent cardiovascular events in T2DM. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin significantly improves cardiovascular mortality in T2DM patients (EMPA-REG trial). Since SGLT-2 is known to be expressed on cells other than the kidney cells, we investigated the potential ability of empagliflozin to regulate glucose transport and alleviate hyperglycaemia-induced dysfunction of these cells. METHODS Primary human monocytes were isolated from the peripheral blood of T2DM patients and healthy individuals. Primary human umbilical vein endothelial cells (HUVECs) and primary human coronary artery endothelial cells (HCAECs), and fetoplacental endothelial cells (HPECs) were used as the EC model cells. Cells were exposed to hyperglycaemic conditions in vitro in 40 ng/mL or 100 ng/mL empagliflozin. The expression levels of the relevant molecules were analysed by RT-qPCR and confirmed by FACS. Glucose uptake assays were carried out with a fluorescent derivative of glucose, 2-NBDG. Reactive oxygen species (ROS) accumulation was measured using the H2DFFDA method. Monocyte and endothelial cell chemotaxis were measured using modified Boyden chamber assays. RESULTS Both primary human monocytes and endothelial cells express SGLT-2. Hyperglycaemic conditions did not significantly alter the SGLT-2 levels in monocytes and ECs in vitro or in T2DM conditions. Glucose uptake assays carried out in the presence of GLUT inhibitors revealed that SGLT-2 inhibition very mildly, but not significantly, suppressed glucose uptake by monocytes and endothelial cells. However, we detected the significant suppression of hyperglycaemia-induced ROS accumulation in monocytes and ECs when empagliflozin was used to inhibit SGLT-2 function. Hyperglycaemic monocytes and endothelial cells readily exhibited impaired chemotaxis behaviour. The co-treatment with empagliflozin reversed the PlGF-1 resistance phenotype of hyperglycaemic monocytes. Similarly, the blunted VEGF-A responses of hyperglycaemic ECs were also restored by empagliflozin, which could be attributed to the restoration of the VEGFR-2 receptor levels on the EC surface. The induction of oxidative stress completely recapitulated most of the aberrant phenotypes exhibited by hyperglycaemic monocytes and endothelial cells, and a general antioxidant N-acetyl-L-cysteine (NAC) was able to mimic the effects of empagliflozin. CONCLUSIONS This study provides data indicating the beneficial role of empagliflozin in reversing hyperglycaemia-induced vascular cell dysfunction. Even though both monocytes and endothelial cells express functional SGLT-2, SGLT-2 is not the primary glucose transporter in these cells. Therefore, it seems likely that empagliflozin does not directly prevent hyperglycaemia-mediated enhanced glucotoxicity in these cells by inhibiting glucose uptake. We identified the reduction of oxidative stress by empagliflozin as a primary reason for the improved function of monocytes and endothelial cells in hyperglycaemic conditions. In conclusion, empagliflozin reverses vascular cell dysfunction independent of glucose transport but could partially contribute to its beneficial cardiovascular effects.
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Mason SA, Parker L, van der Pligt P, Wadley GD. Vitamin C supplementation for diabetes management: A comprehensive narrative review. Free Radic Biol Med 2023; 194:255-283. [PMID: 36526243 DOI: 10.1016/j.freeradbiomed.2022.12.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022]
Abstract
Growing evidence suggests that vitamin C supplementation may be an effective adjunct therapy in the management of people with diabetes. This paper critically reviews the current evidence on effects of vitamin C supplementation and its potential mechanisms in diabetes management. Evidence from meta-analyses of randomized controlled trials (RCTs) show favourable effects of vitamin C on glycaemic control and blood pressure that may be clinically meaningful, and mixed effects on blood lipids and endothelial function. However, evidence is mostly of low evidence certainty. Emerging evidence is promising for effects of vitamin C supplementation on some diabetes complications, particularly diabetic foot ulcers. However, there is a notable lack of robust and well-designed studies exploring effects of vitamin C as a single compound supplement on diabetes prevention and patient-important outcomes (i.e. prevention and amelioration of diabetes complications). RCTs are also required to investigate potential preventative or ameliorative effects of vitamin C on gestational diabetes outcomes. Oral vitamin C doses of 500-1000 mg per day are potentially effective, safe, and affordable for many individuals with diabetes. However, personalisation of supplementation regimens that consider factors such as vitamin C status, disease status, current glycaemic control, vitamin C intake, redox status, and genotype is important to optimize vitamin C's therapeutic effects safely. Finally, given a high prevalence of vitamin C deficiency in patients with complications, it is recommended that plasma vitamin C concentration be measured and monitored in the clinic setting.
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Affiliation(s)
- Shaun A Mason
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia.
| | - Lewan Parker
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
| | - Paige van der Pligt
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia; Department of Nutrition and Dietetics, Western Health, Footscray, Australia
| | - Glenn D Wadley
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
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40
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Sun J, Guan X, Niu C, Chen P, Li Y, Wang X, Luo L, Liu M, Shou Y, Huang X, Cai Y, Zhu J, Fan J, Li X, Jin L, Cong W. FGF13-Sensitive Alteration of Parkin Safeguards Mitochondrial Homeostasis in Endothelium of Diabetic Nephropathy. Diabetes 2023; 72:97-111. [PMID: 36256844 DOI: 10.2337/db22-0231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 10/06/2022] [Indexed: 11/13/2022]
Abstract
Studies of diabetic glomerular injury have raised the possibility of developing useful early biomarkers and therapeutic approaches for the treatment of type 2 diabetic nephropathy (T2DN). In this study, we found that FGF13 expression is induced in glomerular endothelial cells (GECs) during T2DN progression. Endothelial-specific deletion of Fgf13 potentially alleviates T2DN damage, while Fgf13 overexpression has the opposite effect. Mechanistically, Fgf13 deficiency results in improved mitochondrial homeostasis and endothelial barrier integrity in T2DN. Moreover, FGF13-sensitive alteration of Parkin safeguards mitochondrial homeostasis in endothelium of T2DN through promotion of mitophagy and inhibition of apoptosis. Additionally, it is confirmed that the beneficial effects of Fgf13 deficiency on T2DN are abolished by endothelial-specific double deletion of Fgf13 and Prkn. The effects of Fgf13 deficiency on mitophagy and apoptosis through Parkin-dependent regulation may be distinct and separable events under diabetic conditions. These data show that the bifunctional role of Fgf13 deficiency in promoting mitophagy and inhibiting apoptosis through Parkin can shape mitochondrial homeostasis regulation in GECs and T2DN progression. As a potential therapeutic target for prevention and control of T2DN, a mechanistic understanding of the biofunction of FGF13 may also be relevant to the pathogenesis of other FGF13- and Parkin-associated diseases.
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Affiliation(s)
- Jia Sun
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
- Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, People's Republic of China
- Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Xueqiang Guan
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Chao Niu
- Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, People's Republic of China
- Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Peng Chen
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yuankuan Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju, Korea
| | - Xuejiao Wang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Lan Luo
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Mengxue Liu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yanni Shou
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Xiaozhong Huang
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yan Cai
- Ningbo Ninth Hospital, Ningbo, People's Republic of China
| | - Junjie Zhu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Junfu Fan
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Xiaokun Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Litai Jin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Weitao Cong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
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McCrimmon A, Corbin S, Shrestha B, Roman G, Dhungana S, Stadler K. Redox phospholipidomics analysis reveals specific oxidized phospholipids and regions in the diabetic mouse kidney. Redox Biol 2022; 58:102520. [PMID: 36334379 PMCID: PMC9640328 DOI: 10.1016/j.redox.2022.102520] [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: 09/16/2022] [Revised: 10/18/2022] [Accepted: 10/22/2022] [Indexed: 11/08/2022] Open
Abstract
While it is generally accepted that oxidative stress impacts the diabetic kidney and contributes to pathogenesis, there is a substantial lack of knowledge about the molecular entity and anatomic location of a variety of reactive species. Here we provide a novel "oxidative stress map" of the diabetic kidney - the first of its kind, and identify specific, oxidized and other reactive lipids and their location. We used the db/db mouse model and Desorption Electrospray Ionization (DESI) mass spectrometry combined with heatmap image analysis. We analyzed a comprehensive array of phospholipid peroxide species in normal (db/m) and diabetic (db/db) kidneys using DESI imaging. Oxilipidomics heatmaps of the kidneys were generated focusing on phospholipids and their potential peroxidized products. We identified those lipids that undergo peroxidation in diabetic nephropathy. Several phospholipid peroxides and their spatial distribution were identified that were specific to the diabetic kidney, with significant enrichment in oxygenated phosphatidylethanolamines (PE) and lysophosphatidylethanolamine. Beyond qualitative and semi-quantitative information about the targets, the approach also reveals the anatomic location and the extent of lipid peroxide signal propagation across the kidney. Our approach provides novel, in-depth information of the location and molecular entity of reactive lipids in an organ with a very heterogeneous landscape. Many of these reactive lipids have been previously linked to programmed cell death mechanisms. Thus, the findings may be relevant to understand what impact phospholipid peroxidation has on cell and mitochondria membrane integrity and redox lipid signaling in diabetic nephropathy.
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Affiliation(s)
- Allison McCrimmon
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, 70808, LA, USA
| | - Sydney Corbin
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, 70808, LA, USA
| | | | | | | | - Krisztian Stadler
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, 70808, LA, USA.
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Drake AM, Coughlan MT, Christophersen CT, Snelson M. Resistant Starch as a Dietary Intervention to Limit the Progression of Diabetic Kidney Disease. Nutrients 2022; 14:4547. [PMID: 36364808 PMCID: PMC9656781 DOI: 10.3390/nu14214547] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/24/2022] [Accepted: 10/27/2022] [Indexed: 08/15/2023] Open
Abstract
Diabetes is the leading cause of kidney disease, and as the number of individuals with diabetes increases there is a concomitant increase in the prevalence of diabetic kidney disease (DKD). Diabetes contributes to the development of DKD through a number of pathways, including inflammation, oxidative stress, and the gut-kidney axis, which may be amenable to dietary therapy. Resistant starch (RS) is a dietary fibre that alters the gut microbial consortium, leading to an increase in the microbial production of short chain fatty acids. Evidence from animal and human studies indicate that short chain fatty acids are able to attenuate inflammatory and oxidative stress pathways, which may mitigate the progression of DKD. In this review, we evaluate and summarise the evidence from both preclinical models of DKD and clinical trials that have utilised RS as a dietary therapy to limit the progression of DKD.
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Affiliation(s)
- Anna M. Drake
- Glycation, Nutrition and Metabolism Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne 3004, Australia
| | - Melinda T. Coughlan
- Glycation, Nutrition and Metabolism Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne 3004, Australia
- Baker Heart & Diabetes Institute, Melbourne 3004, Australia
| | - Claus T. Christophersen
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
- WA Human Microbiome Collaboration Centre, School of Molecular Life Sciences, Curtin University, Bentley 6102, Australia
| | - Matthew Snelson
- Glycation, Nutrition and Metabolism Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne 3004, Australia
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Qrareya AN, Wise NS, Hodges ER, Mahdi F, Stewart JA, Paris JJ. HIV-1 Tat Upregulates the Receptor for Advanced Glycation End Products and Superoxide Dismutase-2 in the Heart of Transgenic Mice. Viruses 2022; 14:v14102191. [PMID: 36298745 PMCID: PMC9607872 DOI: 10.3390/v14102191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/23/2022] [Accepted: 09/27/2022] [Indexed: 11/29/2022] Open
Abstract
Cardiovascular disorder (CVD) is a common comorbidity in people living with HIV (PLWH). Although the underlying mechanisms are unknown, virotoxic HIV proteins, such as the trans-activator of transcription (Tat), likely contribute to CVD pathogenesis. Tat expression in mouse myocardium has been found to induce cardiac dysfunction and increase markers of endothelial toxicity. However, the role that Tat may play in the development of CVD pathogenesis is unclear. The capacity for Tat to impact cardiac function was assessed using AC16 human cardiomyocyte cells and adult male and female transgenic mice that conditionally expressed Tat [Tat(+)], or did not [Tat(-)]. In AC16 cardiomyocytes, Tat increased intracellular calcium. In Tat(+) mice, Tat expression was detected in both atrial and ventricular heart tissue. Tat(+) mice demonstrated an increased expression of the receptor for advanced glycation end products and superoxide dismutase-2 (SOD-2) in ventricular tissues compared to Tat(-) controls. No changes in SOD-1 or α-smooth muscle actin were observed. Despite Tat-mediated changes at the cellular level, no changes in echocardiographic measures were detected. Tat(+) mice had a greater proportion of ventricular mast cells and collagen; however, doxycycline exposure offset the latter effect. These data suggest that Tat exposure promotes cellular changes that can precede progression to CVD.
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Affiliation(s)
- Alaa N. Qrareya
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA
| | - Nason S. Wise
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA
| | - Emmanuel R. Hodges
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA
| | - Fakhri Mahdi
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA
| | - James A. Stewart
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA
- Research Institute of Pharmaceutical Sciences, University of Mississippi, Oxford, MS 38677, USA
- Correspondence: (J.A.S.J.); (J.J.P.); Tel.: +1-662-915-2309 (J.A.S.J.); +1-662-915-3096 (J.J.P.)
| | - Jason J. Paris
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA
- Research Institute of Pharmaceutical Sciences, University of Mississippi, Oxford, MS 38677, USA
- Correspondence: (J.A.S.J.); (J.J.P.); Tel.: +1-662-915-2309 (J.A.S.J.); +1-662-915-3096 (J.J.P.)
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Patel S, Khan H, Majumdar A. Crosstalk between Sirtuins and Nrf2: SIRT1 activators as emerging treatment for diabetic neuropathy. Metab Brain Dis 2022; 37:2181-2195. [PMID: 35616799 DOI: 10.1007/s11011-022-00956-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 03/09/2022] [Indexed: 10/18/2022]
Abstract
About 50% of the diabetic patients worldwide suffer from Diabetic peripheral neuropathy (DPN) which is characterized by chronic pain and loss of sensation, frequent foot ulcerations, and risk for amputation. Numerous factors like hyperglycemia, oxidative stress (OS), impaired glucose signaling, inflammatory responses, neuronal cell death are known to be the various mechanisms underlying DACD and DPN. Development of tolerance, insufficient and inadequate relief and potential toxicity of classical antinociceptives still remains a challenge in the clinical setting. Therefore, there is an emerging need for novel treatments which are both without any potential side effects as well as which focus more on the pathophysiological mechanisms underlying the disease. Also, sirtuins are known to deacetylate Nrf2 and contribute to its action of reducing ROS by generation of anti-oxidant enzymes. Therefore, targeting sirtuins could be a favourable therapeutic strategy to treat diabetic neuropathy by reducing ROS and thereby alleviating OS in DPN. In the present review, we outline the potential use of SIRT1 activators as therapeutic alternatives in treating DPN. We have tried to highlight how sirtuins are interlinked with Nrf2 and NF-κB and put forth how SIRT activators could serve as potential therapy for DPN.
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Affiliation(s)
- Shivangi Patel
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, 400098, India
| | - Hasnat Khan
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, 400098, India
| | - Anuradha Majumdar
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, 400098, India.
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Li X, Wu J, Xu F, Chu C, Li X, Shi X, Zheng W, Wang Z, Jia Y, Xiao W. Use of Ferulic Acid in the Management of Diabetes Mellitus and Its Complications. Molecules 2022; 27:molecules27186010. [PMID: 36144745 PMCID: PMC9503003 DOI: 10.3390/molecules27186010] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/05/2022] [Accepted: 09/13/2022] [Indexed: 12/06/2022] Open
Abstract
Diabetes mellitus, a metabolic disease mainly characterized by hyperglycemia, is becoming a serious social health problem worldwide with growing prevalence. Many natural compounds have been found to be effective in the prevention and treatment of diabetes, with negligible toxic effects. Ferulic acid (FA), a phenolic compound commonly found in medicinal herbs and the daily diet, was proved to have several pharmacological effects such as antihyperglycemic, antihyperlipidemic and antioxidant actions, which are beneficial to the management of diabetes and its complications. Data from PubMed, EM-BASE, Web of Science and CNKI were searched with the keywords ferulic acid and diabetes mellitus. Finally, 28 articles were identified after literature screening, and the research progress of FA for the management of DM and its complications was summarized in the review, in order to provide references for further research and medical applications of FA.
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Affiliation(s)
- Xu Li
- Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China
| | - Jingxian Wu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Fanxing Xu
- Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Chun Chu
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xiang Li
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xinyi Shi
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Wen Zheng
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Zhenzhong Wang
- Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China
| | - Ying Jia
- Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, China
- Correspondence: (Y.J.); (W.X.)
| | - Wei Xiao
- Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China
- Correspondence: (Y.J.); (W.X.)
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Li J, Zhou L, Gong H. New insights and advances of sodium-glucose cotransporter 2 inhibitors in heart failure. Front Cardiovasc Med 2022; 9:903902. [PMID: 36186974 PMCID: PMC9520058 DOI: 10.3389/fcvm.2022.903902] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are newly emerging insulin-independent anti-hyperglycemic agents that work independently of β-cells. Quite a few large-scale clinical trials have proven the cardiovascular protective function of SGLT2is in both diabetic and non-diabetic patients. By searching all relevant terms related to our topics over the previous 3 years, including all the names of agents and their brands in PubMed, here we review the mechanisms underlying the improvement of heart failure. We also discuss the interaction of various mechanisms proposed by diverse works of literature, including corresponding and opposing viewpoints to support each subtopic. The regulation of diuresis, sodium excretion, weight loss, better blood pressure control, stimulation of hematocrit and erythropoietin, metabolism remodeling, protection from structural dysregulation, and other potential mechanisms of SGLT2i contributing to heart failure improvement have all been discussed in this manuscript. Although some remain debatable or even contradictory, those newly emerging agents hold great promise for the future in cardiology-related therapies, and more research needs to be conducted to confirm their functionality, particularly in metabolism, Na+-H+ exchange protein, and myeloid angiogenic cells.
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Affiliation(s)
- Juexing Li
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
- Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lei Zhou
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
- Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hui Gong
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
- Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
- *Correspondence: Hui Gong
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Chen X, Shi C, Wang Y, Yu H, Zhang Y, Zhang J, Li P, Gao J. The mechanisms of glycolipid metabolism disorder on vascular injury in type 2 diabetes. Front Physiol 2022; 13:952445. [PMID: 36117707 PMCID: PMC9473659 DOI: 10.3389/fphys.2022.952445] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/12/2022] [Indexed: 11/13/2022] Open
Abstract
Patients with diabetes have severe vascular complications, such as diabetic nephropathy, diabetic retinopathy, cardiovascular disease, and neuropathy. Devastating vascular complications lead to increased mortality, blindness, kidney failure, and decreased overall quality of life in people with type 2 diabetes (T2D). Glycolipid metabolism disorder plays a vital role in the vascular complications of T2D. However, the specific mechanism of action remains to be elucidated. In T2D patients, vascular damage begins to develop before insulin resistance and clinical diagnosis. Endothelial dysregulation is a significant cause of vascular complications and the early event of vascular injury. Hyperglycemia and hyperlipidemia can trigger inflammation and oxidative stress, which impair endothelial function. Furthermore, during the pathogenesis of T2D, epigenetic modifications are aberrant and activate various biological processes, resulting in endothelial dysregulation. In the present review, we provide an overview and discussion of the roles of hyperglycemia- and hyperlipidemia-induced endothelial dysfunction, inflammatory response, oxidative stress, and epigenetic modification in the pathogenesis of T2D. Understanding the connections of glucotoxicity and lipotoxicity with vascular injury may reveal a novel potential therapeutic target for diabetic vascular complications.
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Affiliation(s)
- Xiatian Chen
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- School of Basic Medicine, Qingdao University, Qingdao, China
| | | | - Yin Wang
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Hua Yu
- The Affiliated Cardiovascular Hospital of Qingdao University, Qingdao, China
| | - Yu Zhang
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Jiaxuan Zhang
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Peifeng Li
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Jinning Gao
- Center for Molecular Genetics, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
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Großkopf A, Saemann L, Szabó G, Simm A. [Biological mechanisms of aging in the cardiovascular system]. Z Gerontol Geriatr 2022; 55:455-460. [PMID: 36018385 DOI: 10.1007/s00391-022-02094-8] [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] [Accepted: 07/15/2022] [Indexed: 11/25/2022]
Abstract
Cardiovascular diseases, which are at the end of a spectrum of degenerative processes, are one of the leading causes of death worldwide. A causal contribution to these and many other diseases is made by key biological aging mechanisms that have been summarized as the hallmarks of aging. These include accumulation of macromolecular damage, epigenetic changes, impaired proteostasis, telomere shortening, mitochondrial dysfunction, cellular senescence, inflammatory reactions, altered metabolism, impaired cellular communication and changes in the stem cell niche. In the cardiovascular system, oxidative and glycative stress are particularly important as sources of macromolecular damage. These induced insidious changes reduce the resilience and resistance of the heart and vessels to stress, ultimately leading to functional impairments and diseases. A possible novel approach, which does not aim at an intervention against the classical cardiovascular diseases but against the hallmarks of aging, and is termed geroscience, provides valuable concepts but still has to prove itself in the future.
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Affiliation(s)
- Anne Großkopf
- Universitätsklinik und Poliklinik für Herzchirurgie, Universitätsklinikum der Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube Str. 40, 06120, Halle (Saale), Deutschland
| | - Lars Saemann
- Universitätsklinik und Poliklinik für Herzchirurgie, Universitätsklinikum der Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube Str. 40, 06120, Halle (Saale), Deutschland
| | - Gábor Szabó
- Universitätsklinik und Poliklinik für Herzchirurgie, Universitätsklinikum der Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube Str. 40, 06120, Halle (Saale), Deutschland
| | - Andreas Simm
- Universitätsklinik und Poliklinik für Herzchirurgie, Universitätsklinikum der Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube Str. 40, 06120, Halle (Saale), Deutschland.
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Melia F, Udomjarumanee P, Zinovkin D, Arghiani N, Pranjol MZI. Pro-tumorigenic role of type 2 diabetes-induced cellular senescence in colorectal cancer. Front Oncol 2022; 12:975644. [PMID: 36059680 PMCID: PMC9434004 DOI: 10.3389/fonc.2022.975644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 08/01/2022] [Indexed: 12/04/2022] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. The disease still remains incurable and highly lethal in the advanced stage, representing a global health concern. Therefore, it is essential to understand the causes and risk factors leading to its development. Because age-related cellular senescence and type 2 diabetes (T2D) have been recognised as risk factors for CRC development, the recent finding that type 2 diabetic patients present an elevated circulating volume of senescent cells raises the question whether type 2 diabetes facilitates the process of CRC tumorigenesis by inducing premature cell senescence. In this review, we will discuss the mechanisms according to which T2D induces cellular senescence and the role of type 2 diabetes-induced cellular senescence in the pathogenesis and progression of colorectal cancer. Lastly, we will explore the current therapeutic approaches and challenges in targeting senescence.
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Affiliation(s)
- Francesco Melia
- Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, United Kingdom
| | - Palita Udomjarumanee
- Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Dmitry Zinovkin
- Department of Pathology, Gomel State Medical University, Gomel, Belarus
| | - Nahid Arghiani
- Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, United Kingdom
- Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
- *Correspondence: Nahid Arghiani, ; Md Zahidul Islam Pranjol,
| | - Md Zahidul Islam Pranjol
- Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, United Kingdom
- *Correspondence: Nahid Arghiani, ; Md Zahidul Islam Pranjol,
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Cruz N, Flores M, Urquiaga I, Ávila F. Modulation of 1,2-Dicarbonyl Compounds in Postprandial Responses Mediated by Food Bioactive Components and Mediterranean Diet. Antioxidants (Basel) 2022; 11:1513. [PMID: 36009232 PMCID: PMC9405221 DOI: 10.3390/antiox11081513] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/16/2022] [Accepted: 07/26/2022] [Indexed: 01/17/2023] Open
Abstract
Glycoxidative stress with the consequent generation of advanced glycation end products has been implied in the etiology of numerous non-communicable chronic diseases. During the postprandial state, the levels of 1,2-dicarbonyl compounds can increase, depending on numerous factors, including characteristics of the subjects mainly related to glucose metabolism disorders and nutritional status, as well as properties related to the chemical composition of meals, including macronutrient composition and the presence of dietary bioactive molecules and macromolecules. In this review, we examine the chemical, biochemical, and physiological pathways that contribute to postprandial generation of 1,2-dicarbonyl compounds. The modulation of postprandial 1,2-dicarbonyl compounds is discussed in terms of biochemical pathways regulating the levels of these compounds, as well as the effect of phenolic compounds, dietary fiber, and dietary patterns, such as Mediterranean and Western diets.
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Affiliation(s)
- Nadia Cruz
- Escuela de Nutrición y Dietética, Facultad de Ciencias de la Salud, Universidad de Talca, Campus Lircay, Talca 3460000, Chile;
| | - Marcos Flores
- Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomás, Talca 3460000, Chile;
| | - Inés Urquiaga
- Center for Molecular Nutrition and Chronic Diseases, Pontificia Universidad Católica de Chile, Casilla 114-D, Santiago 8331150, Chile;
| | - Felipe Ávila
- Escuela de Nutrición y Dietética, Facultad de Ciencias de la Salud, Universidad de Talca, Campus Lircay, Talca 3460000, Chile;
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