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Li R, Yan X, Zhao Y, Liu H, Wang J, Yuan Y, Li Q, Su J. Oxidative Stress Induced by Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) Dysfunction Aggravates Chronic Inflammation Through the NAD +/SIRT3 Axis and Promotes Renal Injury in Diabetes. Antioxidants (Basel) 2025; 14:267. [PMID: 40227196 PMCID: PMC11939224 DOI: 10.3390/antiox14030267] [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: 01/29/2025] [Revised: 02/18/2025] [Accepted: 02/24/2025] [Indexed: 04/15/2025] Open
Abstract
Diabetic nephropathy (DN), one of the most common and severe microvascular complications of diabetes, significantly increases the risk of renal failure and cardiovascular events. A high-glucose environment can lead to mitochondrial dysfunction in macrophages, which, through remodeling of energy metabolism, mediates the polarization of a pro-inflammatory phenotype and contributes to the formation of a chronic inflammatory microenvironment. Recent studies have found that high-glucose stimulation induces dysregulation of the nuclear factor erythroid 2-related factor 2 (NRF2) redox pathway in macrophages, leading to the generation of oxidative stress (OS) that further drives chronic inflammation. Therefore, it is crucial to fully understand how OS affects macrophage phenotypes and functions following NRF2 inhibition. This review analyzes the role of OS induced by NRF2 dysfunction in the chronic inflammation of DN and explores the relationship between OS and macrophage mitochondrial energy metabolism through the NAD⁺/NADH-SIRT3 axis, providing new therapeutic targets for targeting OS to improve the inflammatory microenvironment and vascular damage in DN.
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Affiliation(s)
| | | | | | | | | | | | | | - Jing Su
- Key Laboratory of Pathobiology, Department of Pathophysiology, Ministry of Education, College of Basical Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130012, China
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Hsu SY, Huang YP, Hsia TC, Chen JC, Peng SF, Hsieh WT, Chueh FS, Kuo CL. PEITC Induces DNA Damage and Inhibits DNA Repair-Associated Proteins in Human Retinoblastoma Cells In Vitro. ENVIRONMENTAL TOXICOLOGY 2024; 39:5274-5283. [PMID: 39177411 DOI: 10.1002/tox.24393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 06/25/2024] [Accepted: 07/23/2024] [Indexed: 08/24/2024]
Abstract
Phenethyl isothiocyanate (PEITC), a natural product, exists in biological activities, including anticancer activity in many human cancer cells. No information shows that PEITC affects DNA damage in human retinoblastoma (RB) cells in vitro. In this study, the aim of experiments was to determine whether PEITC decreased total viable cell number or not by inducing protein expressions involved in DNA damage and repair in Y79 RB cells in vitro. Total cell viability was measured by PI exclusion assay, and PEITC reduced the total Y79 viable cell numbers in a dose-dependent manner. DNA condensation and DNA impairment were conducted by DAPI staining and comet assays, respectively, in Y79 cells. The findings show that PEITC induced DNA condensation dose-dependently based on the brighter fluorescence of cell nuclei stained by DAPI staining. PEITC-induced DNA damage showed a more extended DNA migration smears than that of the control, which was performed by a comet assay. Western blotting was performed to measure the protein expressions involved in DNA damage and repair, which showed that PEITC at 2.5-10 μM increased NRF2, HO-1, SOD (Mn), and catalase; however, it decreased SOD (Cu/Zn) except 10 μM PEITC treatment, and decreased glutathione, which were associated with oxidative stress. Furthermore, PEITC increased DNA-PK, MDC1, H2A.XpSer139, ATMpSer1981, p53, p53pSer15, PARP, HSP70, and HSP90, but decreased TOPIIα, TOPIIβ, and MDM2pSer166 that were associated with DNA damage and repair mechanism in Y79 cells. The examination from confocal laser microscopy shows that PEITC increased H2A.XpSer139 and p53pSer15, and decreased glutathione and TOPIIα in Y79 cells. In conclusion, the cytotoxic effects of PEITC on reducing the number of viable cells may be due to the induction of DNA damage and the alteration of DNA repair proteins in Y79 cells in vitro.
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Affiliation(s)
- Sheng-Yao Hsu
- Department of Ophthalmology, An Nan Hospital, China Medical University, Tainan, Taiwan
- Department of Optometry, Chung Hwa University of Medical Technology, Tainan, Taiwan
- Department of Medicine, School of Medicine, China Medical University, Taichung, Taiwan
| | - Yi-Ping Huang
- Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Te-Chun Hsia
- Department of Respiratory Therapy, China Medical University, Taichung, Taiwan
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jaw-Chyun Chen
- Department of Medicinal Botanicals and Foods on Health Applications, Da-Yeh University, Changhua, Taiwan
| | - Shu-Fen Peng
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Wen-Tsong Hsieh
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
- Department of Pharmacology, China Medical University, Taichung, Taiwan
| | - Fu-Shin Chueh
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
| | - Chao-Lin Kuo
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan
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3
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Wang C, Zhao X, Wang K, Liang H, Chen S, Liu Y, Yao H, Jiang J. Prospective Application of Mesenchymal Stem Cell-Derived Exosomes in the Treatment of Disseminated Intravascular Coagulation. Int J Nanomedicine 2024; 19:11957-11971. [PMID: 39569063 PMCID: PMC11577934 DOI: 10.2147/ijn.s467158] [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: 08/19/2024] [Accepted: 11/05/2024] [Indexed: 11/22/2024] Open
Abstract
Disseminated intravascular coagulation (DIC) is an acquired disorder characterized by systemic activation of blood coagulation, which can arise from various causes. Owing to its abrupt onset, rapid progression, and high mortality rate, DIC presents a major clinical challenge. Anticoagulant drugs, such as heparin or low-molecular-weight heparin, are the current gold standard of treatment; however, these interventions pose considerable bleeding risks. Thus, safer and more effective therapeutic strategies are urgently required. Owing to their strong anti-inflammatory and tissue repair capabilities, mesenchymal stem cell-derived exosomes (MSC-Exos) have gained considerable attention as novel therapeutic options for numerous disorders, including DIC. Their stability in diverse pathological states highlights their potential as promising candidates for DIC therapy. This review presents the latest insights on the pathogenesis of DIC and anti-inflammatory and anticoagulant properties of MSC-Exos. We aimed to elucidate the potential mechanisms by which MSC-Exos influence DIC pathogenesis. We speculate that MSC-Exos offer a multifaceted approach to DIC treatment by attenuating neutrophil extracellular trap formation, modulating M1/M2 macrophage polarization, altering Nrf2/NF-κB signalling pathway to downregulate pro-inflammatory factors, and correcting imbalances in the coagulation-fibrinolysis system through anticoagulant routes. This suggests that MSC-Exos are a potential paradigm in DIC therapy, offering novel targets and treatment modalities for DIC management.
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Affiliation(s)
- Chengran Wang
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China
| | - Xiaoqing Zhao
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China
| | - Keyan Wang
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China
| | - Huixin Liang
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China
| | - Shuhan Chen
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China
| | - Yajie Liu
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China
| | - Hua Yao
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China
| | - Jinlan Jiang
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China
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Xiao W, Lee LY, Loscalzo J. Metabolic Responses to Redox Stress in Vascular Cells. Antioxid Redox Signal 2024; 41:793-817. [PMID: 38985660 PMCID: PMC11876825 DOI: 10.1089/ars.2023.0476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 11/11/2023] [Indexed: 07/12/2024]
Abstract
Significance: Redox stress underlies numerous vascular disease mechanisms. Metabolic adaptability is essential for vascular cells to preserve energy and redox homeostasis. Recent Advances: Single-cell technologies and multiomic studies demonstrate significant metabolic heterogeneity among vascular cells in health and disease. Increasing evidence shows that reductive or oxidative stress can induce metabolic reprogramming of vascular cells. A recent example is intracellular L-2-hydroxyglutarate accumulation in response to hypoxic reductive stress, which attenuates the glucose flux through glycolysis and mitochondrial respiration in pulmonary vascular cells and provides protection against further reductive stress. Critical Issues: Regulation of cellular redox homeostasis is highly compartmentalized and complex. Vascular cells rely on multiple metabolic pathways, but the precise connectivity among these pathways and their regulatory mechanisms is only partially defined. There is also a critical need to understand better the cross-regulatory mechanisms between the redox system and metabolic pathways as perturbations in either systems or their cross talk can be detrimental. Future Directions: Future studies are needed to define further how multiple metabolic pathways are wired in vascular cells individually and as a network of closely intertwined processes given that a perturbation in one metabolic compartment often affects others. There also needs to be a comprehensive understanding of how different types of redox perturbations are sensed by and regulate different cellular metabolic pathways with specific attention to subcellular compartmentalization. Lastly, integration of dynamic changes occurring in multiple metabolic pathways and their cross talk with the redox system is an important goal in this multiomics era. Antioxid. Redox Signal. 41,793-817.
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Affiliation(s)
- Wusheng Xiao
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Toxicology, School of Public Health, Peking University, Beijing, China
| | - Laurel Y. Lee
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Joseph Loscalzo
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Laorodphun P, Chaisen S, Amattat S, Maphet P, Printrakul N, Pandith H, Panya A, Kongmali B, Swe MT, Arjinajarn P. Sphagnum cuspidatulum extract prevents acute kidney injury induced by high-fat diet and streptozotocin via alleviation of oxidative stress and apoptosis in pre-diabetic rats. Front Pharmacol 2024; 15:1464463. [PMID: 39502526 PMCID: PMC11534586 DOI: 10.3389/fphar.2024.1464463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 10/10/2024] [Indexed: 11/08/2024] Open
Abstract
Context Obesity and pre-diabetes are associated with renal dysfunction via elevated oxidative stress. Peat moss, or Sphagnum cuspidatulum Müll. Hal., Sphagnaceae (SC), are rich in phenolic compounds that enhance antioxidant activity. Objective SC might show beneficial effects in pre-diabetes-associated renal dysfunction. Materials and methods Male Wistar rats, after 4 weeks on a high-fat diet, received low-dose streptozotocin to induce pre-diabetes. Then, the pre-diabetic rats were randomly divided into 4 groups: untreated pre-diabetic rats (P-DM), pre-diabetic rats treated with SC 50 or 100 mg/kg/day (P-DM50 or P-DM100), and pre-diabetic rats treated with metformin 100 mg/kg/day (MET). The drugs were fed by gavage for 4 weeks. Results Treatment with SC100 dramatically lowered serum creatinine (S.Cr.), blood urea nitrogen (BUN), and augmented creatinine clearance in pre-diabetic rats. Additionally, SC100 significantly decreased the malondialdehyde level. Furthermore, pre-diabetic rats treated with SC100 significantly upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream mediators, with downregulated apoptotic markers. Discussion and conclusion Our findings provide a scientific basis for the clinical application of SC and a new strategy for the prevention of nephrotoxicity and other kidney disease in the future.
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Affiliation(s)
- Pongrapee Laorodphun
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
| | - Sutheera Chaisen
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
| | - Sarocha Amattat
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
| | - Pornchita Maphet
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
| | - Narin Printrakul
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
| | - Hataichanok Pandith
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
| | - Aussara Panya
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
| | - Burit Kongmali
- Interdisciplinary Program in Biotechnology, Faculty of Graduate School, Chiang Mai University, Chiang Mai, Thailand
| | - Myat Theingi Swe
- Department of Physiology, University of Medicine 2, Yangon, Myanmar
| | - Phatchawan Arjinajarn
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
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Luo Y, Li C. Advances in Research Related to MicroRNA for Diabetic Retinopathy. J Diabetes Res 2024; 2024:8520489. [PMID: 38375094 PMCID: PMC10876316 DOI: 10.1155/2024/8520489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 08/21/2023] [Accepted: 01/27/2024] [Indexed: 02/21/2024] Open
Abstract
Diabetic retinopathy (DR) is a severe microvascular complication of diabetes and is one of the primary causes of blindness in the working-age population in Europe and the United States. At present, no cure is available for DR, but early detection and timely intervention can prevent the rapid progression of the disease. Several treatments for DR are known, primarily ophthalmic treatment based on glycemia, blood pressure, and lipid control, which includes laser photocoagulation, glucocorticoids, vitrectomy, and antivascular endothelial growth factor (anti-VEGF) medications. Despite the clinical efficacy of the aforementioned therapies, none of them can entirely shorten the clinical course of DR or reverse retinopathy. MicroRNAs (miRNAs) are vital regulators of gene expression and participate in cell growth, differentiation, development, and apoptosis. MicroRNAs have been shown to play a significant role in DR, particularly in the molecular mechanisms of inflammation, oxidative stress, and neurodegeneration. The aim of this review is to systematically summarize the signaling pathways and molecular mechanisms of miRNAs involved in the occurrence and development of DR, mainly from the pathogenesis of oxidative stress, inflammation, and neovascularization. Meanwhile, this article also discusses the research progress and application of miRNA-specific therapies for DR.
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Affiliation(s)
- Yahan Luo
- Shanghai TCM-Integrated Hospital, Shanghai University of TCM, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chunxia Li
- Shanghai TCM-Integrated Hospital, Shanghai University of TCM, Shanghai, China
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Rodriguez-Mateos A, Le Sayec M, Cheok A. Dietary (poly)phenols and cardiometabolic health: from antioxidants to modulators of the gut microbiota. Proc Nutr Soc 2024:1-11. [PMID: 38316606 DOI: 10.1017/s0029665124000156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
(Poly)phenols are plant secondary metabolites widely abundant in plant foods and beverages comprising a very large number of compounds with diverse structure and biological activities. Accumulating evidence indicates that these compounds exert beneficial effects against cardiometabolic diseases, and this review will provide a summary of current knowledge in this area. Epidemiological and clinical data collectively suggest that intake of flavonoids reduces the risk of cardiovascular disease (CVD), with the evidence being particularly strong for the flavan-3-ol subclass. However, to provide adequate dietary recommendations, a better understanding of their estimated content in foods and intake among the general public is needed. Regarding mechanisms of action, we now know that it is unlikely that (poly)phenols act as direct antioxidants in vivo, as it was hypothesised for decades with the popularity of in vitro antioxidant capacity assays. One of the reasons is that upon ingestion, (poly)phenols are extensively metabolised into a wide array of circulating metabolites with different bioactivities than their precursors. Well-conducted in vitro and in vivo studies and human nutrigenomic analysis have revealed new molecular targets that may be underlying the health benefits of (poly)phenols, such as the nitric oxide pathway. Recently, a bi-directional relationship was established between (poly)phenols and the gut microbiota, suggesting that individual gut microbial metabolising capacity may be a key factor explaining the variability in the cardiometabolic response to (poly)phenols. Future research is needed to elucidate which are the key factors affecting such capacity, and whether it can be modulated, along with the mechanisms of action.
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Affiliation(s)
- Ana Rodriguez-Mateos
- Department of Nutritional Sciences, School of Life Course and Population Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Melanie Le Sayec
- Department of Nutritional Sciences, School of Life Course and Population Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Alex Cheok
- Department of Nutritional Sciences, School of Life Course and Population Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
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Min SH, Kang GM, Park JW, Kim MS. Beneficial Effects of Low-Grade Mitochondrial Stress on Metabolic Diseases and Aging. Yonsei Med J 2024; 65:55-69. [PMID: 38288646 PMCID: PMC10827639 DOI: 10.3349/ymj.2023.0131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 11/07/2023] [Accepted: 12/04/2023] [Indexed: 02/01/2024] Open
Abstract
Mitochondria function as platforms for bioenergetics, nutrient metabolism, intracellular signaling, innate immunity regulators, and modulators of stem cell activity. Thus, the decline in mitochondrial functions causes or correlates with diabetes mellitus and many aging-related diseases. Upon stress or damage, the mitochondria elicit a series of adaptive responses to overcome stress and restore their structural integrity and functional homeostasis. These adaptive responses to low-level or transient mitochondrial stress promote health and resilience to upcoming stress. Beneficial effects of low-grade mitochondrial stress, termed mitohormesis, have been observed in various organisms, including mammals. Accumulated evidence indicates that treatments boosting mitohormesis have therapeutic potential in various human diseases accompanied by mitochondrial stress. Here, we review multiple cellular signaling pathways and interorgan communication mechanisms through which mitochondrial stress leads to advantageous outcomes. We also discuss the relevance of mitohormesis in obesity, diabetes, metabolic liver disease, aging, and exercise.
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Affiliation(s)
- Se Hee Min
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Diabetes Center, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea
- Appetite Regulation Laboratory, Asan Institute for Life Science, Seoul, Korea
| | - Gil Myoung Kang
- Appetite Regulation Laboratory, Asan Institute for Life Science, Seoul, Korea
| | - Jae Woo Park
- Appetite Regulation Laboratory, Asan Institute for Life Science, Seoul, Korea
| | - Min-Seon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Diabetes Center, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea
- Appetite Regulation Laboratory, Asan Institute for Life Science, Seoul, Korea.
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Shen H, Lei Y, Xie W, Ma T, Bao L, Gao Q, Chen B, Dai B, Qin D. Bioactive peptides PDBSN improve mitochondrial function and suppression the oxidative stress in human adiposity cells. Adipocyte 2023:2278213. [PMID: 37942520 DOI: 10.1080/21623945.2023.2278213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 10/27/2023] [Indexed: 11/10/2023] Open
Abstract
Introduction: Mitochondria are essential for generating cellular energy and are significant in the pathogenesis of obesity. Peptide PDBSN has been demonstrated to inhibit the adipogenic differentiation of adipocytes in vitro and improves metabolic homoeostasis in vivo. Therefore, in this study, we further investigated the effects of PDBSN on the morphology, synthesis, and function of adipocyte mitochondria. Methods: Human visceral and subcutaneous primary preadipocytes (HPA-v and HPA-s) were cultured into mature adipocytes. Intracellular triglyceride content was assessed using oil-red O staining and tissue triglyceride determination. Gene and protein levels associated with mitochondrial synthesis were detected using real-time quantitative polymerase chain reaction and western blotting. Mitochondrial membrane potentials and ROS were detected using fluorescent indicators. Morphological changes were observed by electron microscopy. Results: PDBSN significantly increased mitochondrial membrane potential (MMP), while decreasing intracellular triglyceride (TG) and intracellular reactive oxygen species (ROS) levels. On the other hand, the transcription and protein levels of genetic marker genes PGC1-α and MTFA were significantly up-regulated after PDBSN administration. Further studies showed that transcriptional and protein levels of mitochondrial fusion and fission genetic markers MFN1, MFN2, NRF1, and DRP1 increased. Conclusion: PDBSN significantly reduces intracellular TG and ROS levels and increases MMP. The maximum respiratory capacity in adults significantly increases after PDBSN administration, and ROS levels are significantly reduced. This suggests that PDBSN improves mitochondrial function to some extent, which not only provides an essential basis for the pathophysiology of obesity but also provides insights for the development of new drugs to treat obesity and metabolic diseases.
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Affiliation(s)
- Huiping Shen
- Department of Pediatrics, Yixing People's Hospital, China
| | - Yong Lei
- Department of Pediatrics, Yixing People's Hospital, China
| | - Wen Xie
- Department of Pediatrics, Yixing People's Hospital, China
| | - Tieliang Ma
- Department of Pediatrics, Yixing People's Hospital, China
| | - Li Bao
- Department of Pediatrics, Yixing People's Hospital, China
| | - Qin Gao
- Department of Pediatrics, Yixing People's Hospital, China
| | - Bingyu Chen
- Department of Pediatrics, Yixing People's Hospital, China
| | - Biao Dai
- Department of Pediatrics, Yixing People's Hospital, China
| | - Dani Qin
- Department of Pediatrics, Yixing People's Hospital, China
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Amin KN, Rajaguru P, Suzuki T, Sarkar K, Ganesan K, Ramkumar KM. Quantitative proteomic analyses uncover regulatory roles of Nrf2 in human endothelial cells. Cell Stress Chaperones 2023; 28:731-747. [PMID: 37488350 PMCID: PMC10746666 DOI: 10.1007/s12192-023-01366-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/13/2023] [Accepted: 07/10/2023] [Indexed: 07/26/2023] Open
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional regulator, is the predominant factor in modulating oxidative stress and other cellular signaling responses. Studies from our lab and others highlighted that activation of the Nrf2 pathway by small molecules improves endothelial function by suppressing oxidative and endoplasmic reticulum (ER) stress. However, the exact mechanisms by which Nrf2 elicits these effects are unknown. In the present study, we developed CRISPR/Cas9-mediated Nrf2 knocked-out human endothelial cells, and proteomic signature was studied using LC-MS/MS. We identified 723 unique proteins, of which 361 proteins were found to be differentially regulated and further screened in the Nrf2ome online database, where we identified a highly interconnected signaling network in which 70 proteins directly interact with Nrf2. These proteins were found to regulate some key cellular and metabolic processes in the regulation actin cytoskeleton, ER stress, angiogenesis, inflammation, Hippo signaling pathway, and epidermal growth factor/fibroblast growth factor (EGF/FGF) signaling pathway. Our findings suggest the role of Nrf2 in maintaining endothelium integrity and its relationship with the crucial cellular processes which help develop novel therapeutics against endothelial dysfunction and its associated complications.
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Affiliation(s)
- Karan Naresh Amin
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - Palanichamy Rajaguru
- Department of Biotechnology, Central University of Tamil Nadu, Tiruvarur, 610005, India
| | - Takayoshi Suzuki
- Division Cellular and Gene Therapy Products, National Institute of Health Sciences, Setagaya-Ku, Tokyo, 158-8501, Japan
| | - Koustav Sarkar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - Kumar Ganesan
- School of Chinese Medicine, LKS Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Hong Kong, 999077, China
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India.
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Wang Q, Li H, Lu H, Wang S, Li Y, Zhang Z, Han J, Yang Z, Yang Y, Hong Y. SAA1 exacerbates pancreatic β-cell dysfunction through activation of NF-κB signaling in high-fat diet-induced type 2 diabetes mice. Mol Cell Endocrinol 2023; 576:112043. [PMID: 37574124 DOI: 10.1016/j.mce.2023.112043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 08/08/2023] [Accepted: 08/10/2023] [Indexed: 08/15/2023]
Abstract
Insufficient decompensated insulin secretion and insulin resistance caused by pancreatic β-cell dysfunction are the pathological bases of type 2 diabetes mellitus (T2DM). Glucolipotoxicity in pancreatic β-cells is an important factor leading to their dysfunction, closely related to inflammatory signals, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress (ERs). However, there may be other unproven regulatory mechanisms that govern pancreatic β-cell dysfunction. Therefore, further elucidation of the underlying mechanisms that lead to pancreatic β-cells dysfunction will provide a sufficient theoretical basis for the more effective prevention and treatment of T2DM. As a stress protein with pro-inflammatory properties, Serum Amyloid 1 (SAA1) promotes the progression of metabolic syndrome-related diseases by activating immune cells and damaging endothelial cells. In the development of T2DM, the activation of nuclear factor-kappa B (NF-κB) signaling aggravates pancreatic β-cells dysfunction under the stimulation of free fatty acids (FFAs), inflammatory factors, and chemokines. Moreover, the facilitating effect of SAA1 on the activation of the NF-κB signaling pathway has been demonstrated in other studies. In the present study, we demonstrated that SAA1 inhibits insulin secretion and promotes apoptotic molecular expression in pancreatic cells and islets and that NF-κB signaling inhibitors could reduce this effect of SAA1. SAA1 deficiency improved high-fat diet (HFD)-induced pancreatic β-cell dysfunction and decreased expression of NF-κB signaling molecules. Our findings suggested that HFD-induced SAA1 might exacerbate T2DM by enhancing pancreatic β-cell dysfunction; such a function of SAA1 might depend on NF-κB signaling activation.
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Affiliation(s)
- Qi Wang
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Hong Li
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Henghao Lu
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Shumin Wang
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Yuxiu Li
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Zhenfen Zhang
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Jing Han
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Zhe Yang
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Yanping Yang
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Yan Hong
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China.
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12
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Guo T, Pan Y, Yang L, Chen G, Deng J, Zhu L. Flavonoid compound from Agrimonia pilosa Ledeb improves adipose insulin resistance by alleviating oxidative stress and inflammation. BMC Complement Med Ther 2023; 23:322. [PMID: 37710214 PMCID: PMC10503054 DOI: 10.1186/s12906-023-04114-5] [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: 09/25/2022] [Accepted: 08/02/2023] [Indexed: 09/16/2023] Open
Abstract
BACKGROUND Researches and practice of traditional Chinese medicine indicated that Agrimonia pilosa Ledeb could improve insulin resistance (IR) and treat type 2 diabetes (T2DM). To reveal its underling mechanisms, we isolated Flavonoid component (FC) from Agrimonia pilosa Ledeb and elucidated its effects on glucose metabolism to improve IR by suppressing oxidative stress and inflammation. METHODS Adipocytes or mice IR model was established with overdosed glucose and insulin or high-fat diet. The uptake of 2-NBDG and glucose consumption were measured to verify insulin sensitivity in vitro and vivo. Reactive oxidative species (ROS) were detected by flow cytometry, and superoxide dismutase (SOD) activity as well as the malondialdehyde (MDA) content were also measured. Meanwhile, factors associated with insulin signal pathway including PPARγ, insulin receptor substrate-1 (IRS-1), GLUT4, and oxidative stress including NF-E2-related factor 2 (Nrf2), as well as the related inflammatory cytokines such as NF-κB, IL-1β, IL-6 and TNF-α were tested. Furthermore, the JNK/PI3K/Akt signal pathway was also explored. RESULTS FC extracted from Agrimonia pilosa Ledeb ameliorated the impaired glucose metabolism significantly. Further study indicated that FC could regulate the insulin signal pathway to improve insulin resistance. Moreover, it could upregulate PPARγ with the similar efficacy as pioglitazone (Piog) straightway. FC also decreased the endogenous ROS and MDA content, increased SOD activity and Nrf2 expression to facilitate oxidative homeostasis. It attenuated expression and secretion of inflammatory cytokines obviously. At last, our results indicated JNK/PI3K/Akt pathway was regulated by FC in adipocytes and adipose tissue. CONCLUSION FC could ameliorate glucose metabolism and improve IR. It exerted these effects by suppressing oxidative stress and inflammation. FC from Agrimonia pilosa Ledeb has a good prospect to be drugs or functional foods for IR and T2DM.
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Affiliation(s)
- Tingwang Guo
- Department of Gastroenterology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
- College of Environment and Resources, Chongqing Technology and Business University, Chongqing, China
| | - Yun Pan
- Department of Gastroenterology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China.
| | - Lin Yang
- College of Environment and Resources, Chongqing Technology and Business University, Chongqing, China
| | - Gang Chen
- College of Environment and Resources, Chongqing Technology and Business University, Chongqing, China
| | - Jia Deng
- College of Environment and Resources, Chongqing Technology and Business University, Chongqing, China
| | - Liancai Zhu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
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13
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Alsharairi NA. Exploring the Diet-Gut Microbiota-Epigenetics Crosstalk Relevant to Neonatal Diabetes. Genes (Basel) 2023; 14:genes14051017. [PMID: 37239377 DOI: 10.3390/genes14051017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/24/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Neonatal diabetes (NDM) is a rare monogenic disorder that presents as hyperglycemia during the first six months of life. The link between early-life gut microbiota dysbiosis and susceptibility to NDM remains uncertain. Experimental studies have demonstrated that gestational diabetes mellitus (GDM) could develop into meconium/gut microbiota dysbiosis in newborns, and thus, it is thought to be a mediator in the pathogenesis of NDM. Epigenetic modifications have been considered as potential mechanisms by which the gut microbiota and susceptibility genes interact with the neonatal immune system. Several epigenome-wide association studies have revealed that GDM is associated with neonatal cord blood and/or placental DNA methylation alterations. However, the mechanisms linking diet in GDM with gut microbiota alterations, which may in turn induce the expression of genes linked to NDM, are yet to be unraveled. Therefore, the focus of this review is to highlight the impacts of diet, gut microbiota, and epigenetic crosstalk on altered gene expression in NDM.
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Affiliation(s)
- Naser A Alsharairi
- Heart, Mind & Body Research Group, Griffith University, Gold Coast, QLD P.O. Box 4222, Australia
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14
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Chen L, Li H, Ru Y, Song Y, Shen Y, Zhao L, Huang G, Chen Y, Qi Z, Li R, Dong C, Fang J, Lam TKY, Yang Z, Cai Z. Xanthine-derived reactive oxygen species exacerbates adipose tissue disorders in male db/db mice induced by real-ambient PM2.5 exposure. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 882:163592. [PMID: 37087002 DOI: 10.1016/j.scitotenv.2023.163592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 04/11/2023] [Accepted: 04/15/2023] [Indexed: 05/03/2023]
Abstract
Epidemiological and experimental data have associated exposure to fine particulate matter (PM2.5) with various metabolic dysfunctions and diseases, including overweight and type 2 diabetes. Adipose tissue is an energy pool for storing lipids, a necessary regulator of glucose homeostasis, and an active endocrine organ, playing an essential role in developing various related diseases such as diabetes and obesity. However, the molecular mechanisms underlying PM2.5-impaired functions in adipose tissue have rarely been explored. In this work, metabolomics based on liquid chromatography-mass spectrometry was performed to study the adverse impacts of PM2.5 exposure on brown adipose tissue (BAT) and white adipose tissue (WAT) in the diabetic mouse model. We found the effects of PM2.5 exposure by comparing the different metabolites in both adipose tissues of male db/db mice using real-ambient PM2.5 exposure. The results showed that PM2.5 exposure changed the purine metabolism in mice, especially the dramatic increase of xanthine content in both WAT and BAT. These changes led to significant oxidative stress. Then the results from real-time quantitative polymerase chain reaction showed that PM2.5 exposure could cause the production of inflammatory factors in both adipose tissues. Moreover, the increased reactive oxygen species (ROS) promoted triglyceride accumulation in WAT and inhibited its decomposition, causing increased WAT content in db/db mice. In addition, PM2.5 exposure significantly suppressed thermogenesis and affected energy metabolism in the BAT of male db/db mice, which may deteriorate insulin sensitivity and blood glucose regulation. This research demonstrated the impact of PM2.5 on the adipose tissue of male db/db mice, which may be necessary for public health.
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Affiliation(s)
- Leijian Chen
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong
| | - Huankai Li
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong
| | - Yi Ru
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong
| | - Yuanyuan Song
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong
| | - Yuting Shen
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong
| | - Lifang Zhao
- Institute of Environmental Science, Shanxi University, Taiyuan 030006, China
| | - Gefei Huang
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong
| | - Yi Chen
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong
| | - Zenghua Qi
- School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Ruijin Li
- Institute of Environmental Science, Shanxi University, Taiyuan 030006, China
| | - Chuan Dong
- Institute of Environmental Science, Shanxi University, Taiyuan 030006, China
| | - Jiacheng Fang
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong
| | - Thomas Ka-Yam Lam
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong
| | - Zhu Yang
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong.
| | - Zongwei Cai
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong
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15
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Chen L, Chen S, Yang XF, Min JW. Antioxidants attenuate mitochondrial oxidative damage through the Nrf2 pathway: A promising therapeutic strategy for stroke. J Neurosci Res 2023. [PMID: 36977650 DOI: 10.1002/jnr.25194] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 02/05/2023] [Accepted: 03/10/2023] [Indexed: 03/30/2023]
Abstract
Stroke represents one of the leading causes of disability and death worldwide. Reactive oxygen species overproduction-induced oxidative stress in mitochondria results in mitochondrial DNA damage, mitochondrial autophagy (mitophagy), inflammation, and apoptosis during the pathologic progression of stroke. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator that induces the transcription of a wide range of antioxidant genes to attenuate mitochondrial oxidative stress. Different antioxidative compounds, including polyphenols, mitochondrial antioxidants, triterpenoids, and others, have been shown to be able to activate Nrf2 and, thus, exert neuroprotective effects on stroke by ameliorating mitochondrial oxidative damage. In this review, we briefly discussed the role of mitochondrial oxidative stress in the pathophysiology of stroke and focused on the protective effects of antioxidative compounds through attenuating mitochondrial oxidative damage by activating Nrf2 in stroke. In conclusion, these antioxidants may represent novel therapeutic strategies against stroke.
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Affiliation(s)
- Ling Chen
- Key Laboratory of Cognitive Science, Laboratory of Membrane Ion Channels and Medicine, Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, College of Biomedical Engineering, South-Central Minzu University, Wuhan, China
| | - Su Chen
- Key Laboratory of Cognitive Science, Laboratory of Membrane Ion Channels and Medicine, Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, College of Biomedical Engineering, South-Central Minzu University, Wuhan, China
| | - Xiao-Fei Yang
- Key Laboratory of Cognitive Science, Laboratory of Membrane Ion Channels and Medicine, Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, College of Biomedical Engineering, South-Central Minzu University, Wuhan, China
| | - Jia-Wei Min
- Key Laboratory of Cognitive Science, Laboratory of Membrane Ion Channels and Medicine, Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, College of Biomedical Engineering, South-Central Minzu University, Wuhan, China
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16
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Gao J, Ma C, Xia D, Chen N, Zhang J, Xu F, Li F, He Y, Gong Q. Icariside II preconditioning evokes robust neuroprotection against ischaemic stroke, by targeting Nrf2 and the OXPHOS/NF-κB/ferroptosis pathway. Br J Pharmacol 2023; 180:308-329. [PMID: 36166825 DOI: 10.1111/bph.15961] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 08/28/2022] [Accepted: 08/30/2022] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND AND PURPOSE Astrocytic nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a potential therapeutic target of ischaemic preconditioning (IPC). Icariside II (ICS II) is a naturally occurring flavonoid derived from Herba Epimedii with Nrf2 induction potency. This study was designed to clarify if exposure to ICS II mimicks IPC neuroprotection and if Nrf2 from astrocytes contributes to ICS II preconditioning against ischaemic stroke. EXPERIMENTAL APPROACH Mice with transient middle cerebral artery occlusion (MCAO)-induced focal cerebral ischaemia and primary astrocytes challenged with oxygen-glucose deprivation (OGD) were used to explore the neuroprotective effect of ICS II preconditioning. Additionally, Nrf2-deficient mice were pretreated with ICS II to determine whether ICS II exerts its neuroprotection by activating Nrf2. KEY RESULTS ICS II pretreatment mitigated cerebral injury in the mouse model of ischaemic stroke along with improving long-term recovery. Furthermore, proteomics screening identified Nrf2 as a crucial gene evoked by ICS II treatment and required for the anti-oxidative effect and anti-inflammatory effect of ICS II. Also, ICS II directly bound to Nrf2 and reinforced the transcriptional activity of Nrf2 after MCAO. Moreover, ICS II pretreatment exerted cytoprotective effects on astrocyte cultures following lethal OGD exposure, by promoting Nrf2 nuclear translocation and activating the OXPHOS/NF-κB/ferroptosis axis, while neuroprotection was decreased in Nrf2-deficient mice and Nrf2 siRNA blocked effects of ICS II. CONCLUSION AND IMPLICATIONS ICS II preconditioning provides robust neuroprotection against ischaemic stroke via the astrocytic Nrf2-mediated OXPHOS/NF-κB/ferroptosis axis. Thus, ICS II could be a promising Nrf2 activator to treat ischaemic stroke.
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Affiliation(s)
- Jianmei Gao
- School of Pharmacy, Zunyi Medical University, Zunyi, China.,Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.,Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Congjian Ma
- School of Pharmacy, Zunyi Medical University, Zunyi, China.,Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.,Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Dianya Xia
- School of Pharmacy, Zunyi Medical University, Zunyi, China.,Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.,Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Nana Chen
- School of Pharmacy, Zunyi Medical University, Zunyi, China.,Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.,Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Jianyong Zhang
- School of Pharmacy, Zunyi Medical University, Zunyi, China.,Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.,Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Fan Xu
- Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
| | - Fei Li
- School of Pharmacy, Zunyi Medical University, Zunyi, China.,Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.,Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Yuqi He
- School of Pharmacy, Zunyi Medical University, Zunyi, China.,Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.,Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Qihai Gong
- School of Pharmacy, Zunyi Medical University, Zunyi, China.,Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.,Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi, China
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17
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Mitochondrial Dysfunction: The Hidden Player in the Pathogenesis of Atherosclerosis? Int J Mol Sci 2023; 24:ijms24021086. [PMID: 36674602 PMCID: PMC9861427 DOI: 10.3390/ijms24021086] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/29/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023] Open
Abstract
Atherosclerosis is a multifactorial inflammatory pathology that involves metabolic processes. Improvements in therapy have drastically reduced the prognosis of cardiovascular disease. Nevertheless, a significant residual risk is still relevant, and is related to unmet therapeutic targets. Endothelial dysfunction and lipid infiltration are the primary causes of atherosclerotic plaque progression. In this contest, mitochondrial dysfunction can affect arterial wall cells, in particular macrophages, smooth muscle cells, lymphocytes, and endothelial cells, causing an increase in reactive oxygen species (ROS), leading to oxidative stress, chronic inflammation, and intracellular lipid deposition. The detection and characterization of mitochondrial DNA (mtDNA) is crucial for assessing mitochondrial defects and should be considered the goal for new future therapeutic interventions. In this review, we will focus on a new idea, based on the analysis of data from many research groups, namely the link between mitochondrial impairment and endothelial dysfunction and, in particular, its effect on atherosclerosis and aging. Therefore, we discuss known and novel mitochondria-targeting therapies in the contest of atherosclerosis.
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18
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Kuppuswami J, Senthilkumar GP. Nutri-stress, mitochondrial dysfunction, and insulin resistance-role of heat shock proteins. Cell Stress Chaperones 2023; 28:35-48. [PMID: 36441381 PMCID: PMC9877269 DOI: 10.1007/s12192-022-01314-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 10/05/2022] [Accepted: 11/17/2022] [Indexed: 11/29/2022] Open
Abstract
Excess nutrient flux into the cellular energy system results in a scenario of cellular metabolic stress in diseases involving insulin resistance, such as type 2 diabetes, referred to as nutri-stress and results in cellular bioenergetic imbalance, which leads to insulin resistance and disease. Under nutri-stress, the heat shock response system is compromised due to metabolic abnormalities that disturb energy homeostasis. Heat shock proteins (HSPs) are the chief protectors of intracellular homeostasis during stress. Heat shock response (HSR) impairment contributes to several metabolic pathways that aggravate chronic hyperglycaemia and insulin resistance, highlighting a central role in disease pathogenesis. This article discusses the role of nutri-stress-related molecular events in causing insulin resistance and the nature of the roles played by heat shock proteins in some of the crucial checkpoints of the molecular networks involved in insulin resistance. Ample evidence suggests that the heat shock machinery regulates critical pathways in mitochondrial function and energy metabolism and that cellular energy status highly influences it. Weakening of HSPs, therefore, leads to loss of their vital cytoprotective functions, propagating nutri-stress in the system. Further research into the mechanistic roles of HSPs in metabolic homeostasis will help widen our understanding of lifestyle diseases, their onset, and complications. These inducible proteins may be crucial to attenuating lifestyle risk factors and disease management.
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Affiliation(s)
- Jayashree Kuppuswami
- Department of Biochemistry, Jawaharlal Institute of Post-Graduate Medical Education and Research (JIPMER), Puducherry, 605006 India
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19
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Thengchaisri N, Kuo L, Hein TW. H 2O 2 Mediates VEGF- and Flow-Induced Dilations of Coronary Arterioles in Early Type 1 Diabetes: Role of Vascular Arginase and PI3K-Linked eNOS Uncoupling. Int J Mol Sci 2022; 24:ijms24010489. [PMID: 36613929 PMCID: PMC9820654 DOI: 10.3390/ijms24010489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/17/2022] [Accepted: 12/24/2022] [Indexed: 12/29/2022] Open
Abstract
In diabetes, the enzyme arginase is upregulated, which may compete with endothelial nitric oxide (NO) synthase (eNOS) for their common substrate L-arginine and compromise NO-mediated vasodilation. However, this eNOS uncoupling can lead to superoxide production and possibly vasodilator hydrogen peroxide (H2O2) formation to compensate for NO deficiency. This hypothesis was tested in coronary arterioles isolated from pigs with 2-week diabetes after streptozocin injection. The NO-mediated vasodilation induced by flow and VEGF was abolished by NOS inhibitor L-NAME and phosphoinositide 3-kinase (PI3K) inhibitor wortmannin but was not affected by arginase inhibitor Nω-hydroxy-nor-L-arginine (nor-NOHA) or H2O2 scavenger catalase in control pigs. With diabetes, this vasodilation was partially blunted, and the remaining vasodilation was abolished by catalase and wortmannin. Administration of L-arginine or nor-NOHA restored flow-induced vasodilation in an L-NAME sensitive manner. Diabetes did not alter vascular superoxide dismutase 1, catalase, and glutathione peroxidase mRNA levels. This study demonstrates that endothelium-dependent NO-mediated coronary arteriolar dilation is partially compromised in early type 1 diabetes by reducing eNOS substrate L-arginine via arginase activation. It appears that upregulated arginase contributes to endothelial NO deficiency in early diabetes, but production of H2O2 during PI3K-linked eNOS uncoupling likely compensates for and masks this disturbance.
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Affiliation(s)
- Naris Thengchaisri
- Department of Medical Physiology, Cardiovascular Research Institute, School of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA
- Department of Companion Animal Clinical Sciences, Faculty of Veterinary Medicine, Kasetsart University, Bangkok 10900, Thailand
| | - Lih Kuo
- Department of Medical Physiology, Cardiovascular Research Institute, School of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA
- Correspondence: (L.K.); (T.W.H.)
| | - Travis W. Hein
- Department of Medical Physiology, Cardiovascular Research Institute, School of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA
- Correspondence: (L.K.); (T.W.H.)
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20
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Wu W, Hendrix A, Nair S, Cui T. Nrf2-Mediated Dichotomy in the Vascular System: Mechanistic and Therapeutic Perspective. Cells 2022; 11:cells11193042. [PMID: 36231004 PMCID: PMC9563590 DOI: 10.3390/cells11193042] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/25/2022] [Accepted: 09/27/2022] [Indexed: 12/14/2022] Open
Abstract
Nuclear factor-erythroid 2-related factor 2 (Nrf2), a transcription factor, controls the expression of more than 1000 genes that can be clustered into different categories with distinct functions ranging from redox balance and metabolism to protein quality control in the cell. The biological consequence of Nrf2 activation can be either protective or detrimental in a context-dependent manner. In the cardiovascular system, most studies have focused on the protective properties of Nrf2, mainly as a key transcription factor of antioxidant defense. However, emerging evidence revealed an unexpected role of Nrf2 in mediating cardiovascular maladaptive remodeling and dysfunction in certain disease settings. Herein we review the role of Nrf2 in cardiovascular diseases with a focus on vascular disease. We discuss the negative effect of Nrf2 on the vasculature as well as the potential underlying mechanisms. We also discuss the clinical relevance of targeting Nrf2 pathways for the treatment of cardiovascular and other diseases.
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Affiliation(s)
- Weiwei Wu
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao 266071, China
| | - Andrew Hendrix
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA
| | - Sharad Nair
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA
- Columbia VA Health System, Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC 29209, USA
| | - Taixing Cui
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA
- Columbia VA Health System, Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC 29209, USA
- Correspondence: ; Tel.: +1-803-216-3804
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21
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Wang M, Pang Y, Guo Y, Tian L, Liu Y, Shen C, Liu M, Meng Y, Cai Z, Wang Y, Zhao W. Metabolic reprogramming: A novel therapeutic target in diabetic kidney disease. Front Pharmacol 2022; 13:970601. [PMID: 36120335 PMCID: PMC9479190 DOI: 10.3389/fphar.2022.970601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes mellitus. However, the pathological mechanisms contributing to DKD are multifactorial and poorly understood. Diabetes is characterized by metabolic disorders that can bring about a series of changes in energy metabolism. As the most energy-consuming organs secondary only to the heart, the kidneys must maintain energy homeostasis. Aberrations in energy metabolism can lead to cellular dysfunction or even death. Metabolic reprogramming, a shift from mitochondrial oxidative phosphorylation to glycolysis and its side branches, is thought to play a critical role in the development and progression of DKD. This review focuses on the current knowledge about metabolic reprogramming and the role it plays in DKD development. The underlying etiologies, pathological damages in the involved cells, and potential molecular regulators of metabolic alterations are also discussed. Understanding the role of metabolic reprogramming in DKD may provide novel therapeutic approaches to delay its progression to end-stage renal disease.
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22
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The Beneficial Role of Nrf2 in the Endothelial Dysfunction of Atherosclerosis. Cardiol Res Pract 2022; 2022:4287711. [PMID: 35600333 PMCID: PMC9119788 DOI: 10.1155/2022/4287711] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 04/21/2022] [Indexed: 11/18/2022] Open
Abstract
Cardiovascular disease (CVD) is a serious public health issue in China, accounting for more than 40% of all mortality, and it is the leading cause of death worldwide. Atherosclerosis is the pathological basis for much CVD, including coronary heart disease, acute myocardial infarction, and stroke. Endothelial dysfunction is an initiating and exacerbating factor in atherosclerosis. Recent research has linked oxidative stress and mitochondrial damage to endothelial dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor with antioxidant effects that is strongly connected to several CVDs. However, the mechanism by which Nrf2 reduces CVD is unknown. Research indicates that Nrf2 improves endothelial function by resisting oxidative stress and mitochondrial damage, thereby delaying atherosclerosis. This article examines the mechanisms and potential targets of Nrf2 affecting endothelial cell function to improve atherosclerosis and to provide ideas for the development of new CVD treatments.
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23
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Cardiac NF-κB Acetylation Increases While Nrf2-Related Gene Expression and Mitochondrial Activity Are Impaired during the Progression of Diabetes in UCD-T2DM Rats. Antioxidants (Basel) 2022; 11:antiox11050927. [PMID: 35624791 PMCID: PMC9137621 DOI: 10.3390/antiox11050927] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 05/03/2022] [Indexed: 02/04/2023] Open
Abstract
The onset of type II diabetes increases the heart’s susceptibility to oxidative damage because of the associated inflammation and diminished antioxidant response. Transcription factor NF-κB initiates inflammation while Nrf2 controls antioxidant defense. Current evidence suggests crosstalk between these transcription factors that may become dysregulated during type II diabetes mellitus (T2DM) manifestation. The objective of this study was to examine the dynamic changes that occur in both transcription factors and target genes during the progression of T2DM in the heart. Novel UC Davis T2DM (UCD-T2DM) rats at the following states were utilized: (1) lean, control Sprague-Dawley (SD; n = 7), (2) insulin-resistant pre-diabetic UCD-T2DM (Pre; n = 9), (3) 2-week recently diabetic UCD-T2DM (2Wk; n = 9), (4) 3-month diabetic UCD-T2DM (3Mo; n = 14), and (5) 6-month diabetic UCD-T2DM (6Mo; n = 9). NF-κB acetylation increased 2-fold in 3Mo and 6Mo diabetic animals compared to SD and Pre animals. Nox4 protein increased 4-fold by 6Mo compared to SD. Nrf2 translocation increased 82% in Pre compared to SD but fell 47% in 6Mo animals. GCLM protein fell 35% in 6Mo animals compared to Pre. Hmox1 mRNA decreased 45% in 6Mo animals compared to SD. These data suggest that during the progression of T2DM, NF-κB related genes increase while Nrf2 genes are suppressed or unchanged, perpetuating inflammation and a lesser ability to handle an oxidant burden altering the heart’s redox state. Collectively, these changes likely contribute to the diabetes-associated cardiovascular complications.
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Araújo MC, Soczek SHS, Pontes JP, Marques LAC, Santos GS, Simão G, Bueno LR, Maria-Ferreira D, Muscará MN, Fernandes ES. An Overview of the TRP-Oxidative Stress Axis in Metabolic Syndrome: Insights for Novel Therapeutic Approaches. Cells 2022; 11:cells11081292. [PMID: 35455971 PMCID: PMC9030853 DOI: 10.3390/cells11081292] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/19/2022] [Accepted: 04/05/2022] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome (MS) is a complex pathology characterized by visceral adiposity, insulin resistance, arterial hypertension, and dyslipidaemia. It has become a global epidemic associated with increased consumption of high-calorie, low-fibre food and sedentary habits. Some of its underlying mechanisms have been identified, with hypoadiponectinemia, inflammation and oxidative stress as important factors for MS establishment and progression. Alterations in adipokine levels may favour glucotoxicity and lipotoxicity which, in turn, contribute to inflammation and cellular stress responses within the adipose, pancreatic and liver tissues, in addition to hepatic steatosis. The multiple mechanisms of MS make its clinical management difficult, involving both non-pharmacological and pharmacological interventions. Transient receptor potential (TRP) channels are non-selective calcium channels involved in a plethora of physiological events, including energy balance, inflammation and oxidative stress. Evidence from animal models of disease has contributed to identify their specific contributions to MS and may help to tailor clinical trials for the disease. In this context, the oxidative stress sensors TRPV1, TRPA1 and TRPC5, play major roles in regulating inflammatory responses, thermogenesis and energy expenditure. Here, the interplay between these TRP channels and oxidative stress in MS is discussed in the light of novel therapies to treat this syndrome.
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Affiliation(s)
- Mizael C. Araújo
- Programa de Pós-Graduação, Universidade CEUMA, São Luís 65075-120, MA, Brazil; (M.C.A.); (G.S.S.)
| | - Suzany H. S. Soczek
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80250-060, PR, Brazil; (S.H.S.S.); (G.S.); (L.R.B.); (D.M.-F.)
- Programa de Pós-Graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba 80230-020, PR, Brazil
| | - Jaqueline P. Pontes
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís 565085-080, MA, Brazil;
| | - Leonardo A. C. Marques
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil; (L.A.C.M.); (M.N.M.)
| | - Gabriela S. Santos
- Programa de Pós-Graduação, Universidade CEUMA, São Luís 65075-120, MA, Brazil; (M.C.A.); (G.S.S.)
| | - Gisele Simão
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80250-060, PR, Brazil; (S.H.S.S.); (G.S.); (L.R.B.); (D.M.-F.)
- Programa de Pós-Graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba 80230-020, PR, Brazil
| | - Laryssa R. Bueno
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80250-060, PR, Brazil; (S.H.S.S.); (G.S.); (L.R.B.); (D.M.-F.)
- Programa de Pós-Graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba 80230-020, PR, Brazil
| | - Daniele Maria-Ferreira
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80250-060, PR, Brazil; (S.H.S.S.); (G.S.); (L.R.B.); (D.M.-F.)
- Programa de Pós-Graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba 80230-020, PR, Brazil
| | - Marcelo N. Muscará
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil; (L.A.C.M.); (M.N.M.)
| | - Elizabeth S. Fernandes
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80250-060, PR, Brazil; (S.H.S.S.); (G.S.); (L.R.B.); (D.M.-F.)
- Programa de Pós-Graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba 80230-020, PR, Brazil
- Correspondence:
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Yi X, Zhu QX, Wu XL, Tan TT, Jiang XJ. Histone Methylation and Oxidative Stress in Cardiovascular Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6023710. [PMID: 35340204 PMCID: PMC8942669 DOI: 10.1155/2022/6023710] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/17/2022] [Accepted: 03/05/2022] [Indexed: 11/18/2022]
Abstract
Oxidative stress occurs when ROS overproduction overwhelms the elimination ability of antioxidants. Accumulated studies have found that oxidative stress is regulated by histone methylation and plays a critical role in the development and progression of cardiovascular diseases. Targeting the underlying molecular mechanism to alter the interplay of oxidative stress and histone methylation may enable creative and effective therapeutic strategies to be developed against a variety of cardiovascular disorders. Recently, some drugs targeting epigenetic modifiers have been used to treat specific types of cancers. However, the comprehensive signaling pathways bridging oxidative stress and histone methylation need to be deeply explored in the contexts of cardiovascular physiology and pathology before clinical therapies be developed. In the present review, we summarize and update information on the interplay between histone methylation and oxidative stress during the development of cardiovascular diseases such as atherosclerosis, coronary artery disease, pulmonary hypertension, and diabetic macro- and microvascular pathologies.
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Affiliation(s)
- Xin Yi
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Qiu-Xia Zhu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Xing-Liang Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Tuan-Tuan Tan
- Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Xue-Jun Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
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Bioactive Compounds in Oxidative Stress-Mediated Diseases: Targeting the NRF2/ARE Signaling Pathway and Epigenetic Regulation. Antioxidants (Basel) 2021; 10:antiox10121859. [PMID: 34942962 PMCID: PMC8698417 DOI: 10.3390/antiox10121859] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/18/2021] [Accepted: 11/20/2021] [Indexed: 12/14/2022] Open
Abstract
Oxidative stress is a pathological condition occurring due to an imbalance between the oxidants and antioxidant defense systems in the body. Nuclear factor E2-related factor 2 (NRF2), encoded by the gene NFE2L2, is the master regulator of phase II antioxidant enzymes that protect against oxidative stress and inflammation. NRF2/ARE signaling has been considered as a promising target against oxidative stress-mediated diseases like diabetes, fibrosis, neurotoxicity, and cancer. The consumption of dietary phytochemicals acts as an effective modulator of NRF2/ARE in various acute and chronic diseases. In the present review, we discussed the role of NRF2 in diabetes, Alzheimer's disease (AD), Parkinson's disease (PD), cancer, and atherosclerosis. Additionally, we discussed the phytochemicals like curcumin, quercetin, resveratrol, epigallocatechin gallate, apigenin, sulforaphane, and ursolic acid that have effectively modified NRF2 signaling and prevented various diseases in both in vitro and in vivo models. Based on the literature, it is clear that dietary phytochemicals can prevent diseases by (1) blocking oxidative stress-inhibiting inflammatory mediators through inhibiting Keap1 or activating Nrf2 expression and its downstream targets in the nucleus, including HO-1, SOD, and CAT; (2) regulating NRF2 signaling by various kinases like GSK3beta, PI3/AKT, and MAPK; and (3) modifying epigenetic modulation, such as methylation, at the NRF2 promoter region; however, further investigation into other upstream signaling molecules like NRF2 and the effect of phytochemicals on them still need to be investigated in the near future.
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Wächter K, Navarrete Santos A, Großkopf A, Baldensperger T, Glomb MA, Szabó G, Simm A. AGE-Rich Bread Crust Extract Boosts Oxidative Stress Interception via Stimulation of the NRF2 Pathway. Nutrients 2021; 13:nu13113874. [PMID: 34836129 PMCID: PMC8622267 DOI: 10.3390/nu13113874] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 10/26/2021] [Accepted: 10/28/2021] [Indexed: 12/30/2022] Open
Abstract
Advanced glycation end products (AGEs) result from a non-enzymatic reaction of proteins with reactive carbohydrates. Heat-processed food, such as bread, contains high amounts of AGEs. The activation of the NF-κB signaling pathway by bread crust extract (BCE) is well understood. However, it is largely unknown whether NRF2, the master regulator of oxidative stress resistance in mammalian cells, is affected by BCE. We have investigated the molecular mechanisms by which BCE induces antioxidant gene expression in cellular models. Our data showed that soluble extracts from bread crust are capable of stimulating the NRF2 signaling pathway. Furthermore, NRF2 pathway activation was confirmed by microarray and reporter-cell analyses. QRT-PCR measurements and Western blot analyses indicated an induction of antioxidative genes such as HMOX1, GCLM and NQO1 upon BCE treatment. Moreover, BCE pretreated cells had a survival advantage compared to control cells when exposed to oxidative stress. BCE induces phosphorylation of AKT and ERK kinase in EA.hy926 cells. By mass spectrometry, several new, potentially active modifications in BCE were identified. Our findings indicate that BCE activates NRF2-dependent antioxidant gene expression, thus provoking a protection mechanism against oxidative stress-mediated tissue injury. Hence, BCE can be considered as functional food with antioxidative and cardioprotective potential.
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Affiliation(s)
- Kristin Wächter
- Department for Cardiac Surgery, University Hospital Halle (Saale), Martin-Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; (A.G.); (G.S.); (A.S.)
- Correspondence: ; Tel.: +49-345-557-7068
| | - Alexander Navarrete Santos
- Center for Medical Basic Research, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany;
| | - Anne Großkopf
- Department for Cardiac Surgery, University Hospital Halle (Saale), Martin-Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; (A.G.); (G.S.); (A.S.)
| | - Tim Baldensperger
- German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany;
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany;
| | - Marcus A. Glomb
- Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany;
| | - Gábor Szabó
- Department for Cardiac Surgery, University Hospital Halle (Saale), Martin-Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; (A.G.); (G.S.); (A.S.)
| | - Andreas Simm
- Department for Cardiac Surgery, University Hospital Halle (Saale), Martin-Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; (A.G.); (G.S.); (A.S.)
- Center for Medical Basic Research, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany;
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Jin M, Wang Y, An X, Kang H, Wang Y, Wang G, Gao Y, Wu S, Reinach PS, Liu Z, Xue Y, Li C. Phenotypic and transcriptomic changes in the corneal epithelium following exposure to cigarette smoke. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 287:117540. [PMID: 34147784 DOI: 10.1016/j.envpol.2021.117540] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 06/01/2021] [Accepted: 06/02/2021] [Indexed: 06/12/2023]
Abstract
Cigarette smoke extract (CSE), a complex mixture of compounds, contributes to a range of eye diseases; however, the underlying pathophysiological responses to tobacco smoke remain ambiguous. The purpose of the present study was to evaluate the cigarette smoke-induced phenotypic and transcriptomic changes in the corneal epithelium with a view to elucidating the likely underlying mechanism. Accordingly, for the first time, we characterized the genome-wide effects of CSE on the corneal epithelium. The ocular surface of the mice in the experimental groups was exposed to CSE for 1 h per day for a period of one week, while mice in the control group were exposed to preservative-free artificial tears. Corneal fluorescein staining, in vivo confocal microscopy and scanning electron microscopy were performed to examine the corneal ultrastructure. Transcriptome sequencing and bioinformatics analysis were performed followed by RT-qPCR to validate gene expression changes. The results indicate that CSE exposure disrupted the structural integrity of the superficial epithelium, decreased the density of microvilli, and compromised the corneal epithelial barrier intactness. RNA-seq revealed 667 differentially expressed genes, and functional analysis highlighted the enhancement of several biological processes such as antioxidant activity and the response to oxidative stress. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that glutathione metabolism and drug metabolism cytochrome P450 were the most relevant pathways contributing to the effects of CSE on the corneal epithelium. Protein-protein interaction (PPI) network analysis illustrated that GCLC, NQO1, and HMOX1 were the most relevant nodes. In conclusion, the present study indicates that CSE exposure induces changes in the phenotype and genotype of the corneal epithelium. The antioxidant response element is essential for counteracting the effects of cigarette smoke on this tissue layer. These results shed novel insights into how cigarette smoke damages this ocular surface.
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Affiliation(s)
- Mengyi Jin
- Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Yanzi Wang
- Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Xiaoya An
- Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, 361102, China; School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Honghua Kang
- Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Yixin Wang
- Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, 361102, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Guoliang Wang
- Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, 361102, China; School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Yang Gao
- College of Environment and Ecology, Xiamen University, Xiamen, 361102, China
| | - Shuiping Wu
- College of Environment and Ecology, Xiamen University, Xiamen, 361102, China
| | - Peter S Reinach
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Zuguo Liu
- Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, 361102, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Yuhua Xue
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Cheng Li
- Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, 361102, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China.
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Ye Z, Li X, Zheng D, Pei S, Cheng P, Zhang L, Zhu L. Intravitreally Injected Methylene Blue Protects Retina against Acute Ocular Hypertension in Rats. Curr Eye Res 2021; 47:91-101. [PMID: 34165383 DOI: 10.1080/02713683.2021.1948062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Purpose: To assess the neuroprotective effects of methylene blue (MB) in a rat model of acute ocular hypertension (AOH) and explore its possible mechanisms.Methods: Our AOH rat model was obtained with anterior chamber perfusion for 60 min. After that, 100 μM MB was injected into the vitreous cavity immediately after injury. Electroretinogram, fundus photography, optical coherence tomography (OCT) and retina morphology examination were utilized to quantify retinal damage before surgery, as well as 7, 14 and 28 days after. The average number of surviving retinal ganglion cells (RGCs) was counted after fluorescent retrograde labelling with 4% DiI. And TUNEL assay was used to investigate retinal cell apoptosis at 24 hours after AOH. Nrf2 and BACE1 in the retina were determined by RT-qPCR analysis.Results: AOH did produce a severe degeneration effect on the whole retinal layer. Intravitreally injected MB maintained certain retinal thickness after AOH, reduced the destruction of electroretinograms, and enhanced RGCs survival. The average number of TUNEL-labelled cells statistically reduced in the MB-treated retina tissue compared with retina treated with normal saline. The relative mRNA level of Nrf2 was also much higher in the MB-treated retinas after AOH, and the expression of BACE1 had a decline in the AOH + MB group.Conclusions: MB can protect the retina from AOH injury and the possible mechanism might involve the inhibition of BACE1 expression and the activation of Nrf2 antioxidant pathway.
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Affiliation(s)
- Zhiqiang Ye
- Institute of Advanced Materials for Nano-Bio Applications, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaoli Li
- Institute of Advanced Materials for Nano-Bio Applications, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Henan Eye Institute, Henan Eye Hospital, Zhengzhou, Henan, China
| | - Dongliang Zheng
- Institute of Advanced Materials for Nano-Bio Applications, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shuaili Pei
- Institute of Advanced Materials for Nano-Bio Applications, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Pei Cheng
- Institute of Advanced Materials for Nano-Bio Applications, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lishu Zhang
- Institute of Advanced Materials for Nano-Bio Applications, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lin Zhu
- Institute of Advanced Materials for Nano-Bio Applications, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
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Liu R, Yan X. Oxidative stress in corneal stromal cells contributes to the development of keratoconus in a rabbit model. Eur J Ophthalmol 2021; 31:3518-3524. [PMID: 34213382 DOI: 10.1177/11206721211028745] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
PURPOSE To investigate the role of oxidative stress in keratocytes in the pathogenesis of keratoconus (KC) using the rabbit cornea as a model. METHODS Immerse the rabbit cornea in collagenase type II solution at room temperature for 30 min in the KC group. The central cornea thickness (CCT), and mean keratometry (Km) were examined before and after the procedure. Reactive oxygen species (ROS), the nuclear translocation of nuclear factor E2-related factor 2 (NRF-2), the expression of heme oxygenase-1 (HO-1) protein, and nicotinamide adenine dinucleotide phosphate (NADPH) Oxidase (NOX) family members NOX-2 and NOX-4 protein levels were examined by immunohistochemistry analysis and Western Blot. The expression levels of HO-1, NOX-2, NOX-4, and NRF-2 mRNA were quantitatively detected by Real-time PCR. RESULTS A significant increase in Km and a significant decrease in CCT were observed in the KC group compared with the control group after the surgery (both p < 0.001). Immunofluorescence staining showed the rabbit KC model induced a significant increase in ROS production (p < 0.001). The expression of HO-1, NOX-2, NOX-4, and NRF-2 proteins in the KC group were significantly higher than those in the control group (all p < 0.001). RT-PCR results showed the levels of HO-1, NOX-2, NOX-4, and NRF-2 mRNA in KC groups were all significantly increased compared with control groups (all p < 0.05). CONCLUSIONS Oxidative stress and compensatory activation of antioxidant proteins suggest oxidative stress injury in corneal stromal cells plays an important role in the development of KC in a rabbit model.
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Affiliation(s)
- Ruixing Liu
- Henan Provincial People's Hospital, Henan Eye Hospital, Henan Eye Institute, People's Hospital of Zhengzhou University, Henan University People's Hospital, Zhengzhou, Henan, China.,Department of Ophthalmology, The First Hospital of Peking University, Beijing, China
| | - Xiaoming Yan
- Department of Ophthalmology, The First Hospital of Peking University, Beijing, China
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Protective Effects of Almond Oil on Streptozotocin-Induced Diabetic Rats via Regulating Nrf2/HO-1 Pathway and Gut Microbiota. J FOOD QUALITY 2021. [DOI: 10.1155/2021/5599219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Almond oil has been used as a medicine substitution for its numerous health benefits. This study aimed to evaluate the effect of almond oil on streptozotocin- (STZ-) induced diabetic rats for 4 weeks. The results showed that the administration of almond oil could significantly increase body weight, attenuate abnormally elevated blood glucose, promote insulin secretion, and improve glucose tolerance. Almond oil treatment also suppressed oxidative stress, reduced inflammation reaction, improved liver and kidney function, upregulated the expressions of Nrf2, HO-1, and NQO1, while downregulating the expression of Keap1. Furthermore, almond oil reversed the gut microbiota change by STZ and regulated the gut microbiota associated with glucose metabolism. At the phylum level, the relative abundance of Firmicutes was decreased, while Bacteroidetes was increased by almond oil treatment. More importantly, the ratio of Firmicutes/Bacteroidetes was significantly increased. At the genus level, administration of almond oil increased the abundances of Lactobacillus, Bacteroides, and Lachnospiraceae_NK4A136_group, while decreased the abundances of Ruminococcaceae_UCG-014, Clostridium_sensu_stricto_1, and Fusicatenibacter. These results provided evidence for the regulating effect of almond oil on diabetic rats via the Nrf2/HO-1 pathway and gut microbiota.
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Pleiotropic and Potentially Beneficial Effects of Reactive Oxygen Species on the Intracellular Signaling Pathways in Endothelial Cells. Antioxidants (Basel) 2021; 10:antiox10060904. [PMID: 34205032 PMCID: PMC8229098 DOI: 10.3390/antiox10060904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/28/2021] [Accepted: 05/31/2021] [Indexed: 02/06/2023] Open
Abstract
Endothelial cells (ECs) are exposed to molecular dioxygen and its derivative reactive oxygen species (ROS). ROS are now well established as important signaling messengers. Excessive production of ROS, however, results in oxidative stress, a significant contributor to the development of numerous diseases. Here, we analyze the experimental data and theoretical concepts concerning positive pro-survival effects of ROS on signaling pathways in endothelial cells (ECs). Our analysis of the available experimental data suggests possible positive roles of ROS in induction of pro-survival pathways, downstream of the Gi-protein-coupled receptors, which mimics insulin signaling and prevention or improvement of the endothelial dysfunction. It is, however, doubtful, whether ROS can contribute to the stabilization of the endothelial barrier.
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Wang J, Dai L, Yue X, Shen C, Li T, Long L, Zhi Y, Wang Y, Shen G, Shi C, Liu Y, Fang Q, Li W. IR-61 Improves Voiding Function via Mitochondrial Protection in Diabetic Rats. Front Pharmacol 2021; 12:608637. [PMID: 33935703 PMCID: PMC8080033 DOI: 10.3389/fphar.2021.608637] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 02/26/2021] [Indexed: 12/26/2022] Open
Abstract
Diabetic bladder dysfunction (DBD) afflicts nearly half of diabetic patients, but effective treatment is lacking. In this study, IR-61, a novel heptamethine cyanine dye with potential antioxidant effects, was investigated to determine whether it can alleviate DBD. Rats were intraperitoneally injected with IR-61 or vehicle after diabetes was induced with streptozotocin. Before evaluating the effects of IR-61 in improving DBD by filling cystometry, we detected its distribution in tissues and subcellular organelles by confocal fluorescence imaging. Near infrared (NIR) imaging showed that IR-61 could accumulate at high levels in the bladders of diabetic rats, and confocal images demonstrated that it was mainly taken up by bladder smooth muscle cells (BSMCs) and localized in mitochondria. Then, filling cystometry illustrated that IR-61 significantly improved the bladder function of diabetic rats. The histomorphometry results showed that IR-61 effectively mitigated the pathological changes in bladder smooth muscle (BSM) in diabetic rats. Furthermore, IR-61 remarkably reduced the number of apoptotic BSMCs and the unfavorable expression of proteins related to the mitochondrial apoptotic pathway (Bcl-2, BAX, Cytochrome C, and cleaved Caspase-9) in diabetic rats. Moreover, the frozen section staining and transmission electron microscopy results proved that IR-61 significantly reduced the reactive oxygen species (ROS) levels and prevented the mitochondrial mass and morphology damage in the BSM of diabetic rats. In addition, IR-61 upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its associated antioxidant proteins in the BSM of diabetic rats. Together, these results indicate that IR-61 can improve the voiding function of rats with DBD by protecting the mitochondria of BSMCs from oxidative stress, which is possibly mediated through the activation of the Nrf2 pathway.
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Affiliation(s)
- Jianwu Wang
- Department of Urology, The Third Affiliated Hospital (Gener Hospital) of Chongqing Medical University, Chongqing, China
| | - Linyong Dai
- Department of Urology, The Third Affiliated Hospital (Gener Hospital) of Chongqing Medical University, Chongqing, China
| | - Xiaofeng Yue
- Department of Urology, The Third Affiliated Hospital (Gener Hospital) of Chongqing Medical University, Chongqing, China
| | - Chongxing Shen
- Department of Urology, The Third Affiliated Hospital (Gener Hospital) of Chongqing Medical University, Chongqing, China
| | - Tong Li
- Department of Urology, The Third Affiliated Hospital (Gener Hospital) of Chongqing Medical University, Chongqing, China
| | - Lei Long
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Rocket Force Medicine, Third Military Medical University, Chongqing, China
| | - Yi Zhi
- Department of Urology, The Third Affiliated Hospital (Gener Hospital) of Chongqing Medical University, Chongqing, China
| | - Yawei Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Rocket Force Medicine, Third Military Medical University, Chongqing, China
| | - Gufang Shen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Rocket Force Medicine, Third Military Medical University, Chongqing, China
| | - Chunmeng Shi
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Rocket Force Medicine, Third Military Medical University, Chongqing, China
| | - Yunsheng Liu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Rocket Force Medicine, Third Military Medical University, Chongqing, China
| | - Qiang Fang
- Department of Urology, The Third Affiliated Hospital (Gener Hospital) of Chongqing Medical University, Chongqing, China
| | - Weibing Li
- Department of Urology, The Third Affiliated Hospital (Gener Hospital) of Chongqing Medical University, Chongqing, China
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Redox regulation of the insulin signalling pathway. Redox Biol 2021; 42:101964. [PMID: 33893069 PMCID: PMC8113030 DOI: 10.1016/j.redox.2021.101964] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 03/19/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022] Open
Abstract
The peptide hormone insulin is a key regulator of energy metabolism, proliferation and survival. Binding of insulin to its receptor activates the PI3K/AKT signalling pathway, which mediates fundamental cellular responses. Oxidants, in particular H2O2, have been recognised as insulin-mimetics. Treatment of cells with insulin leads to increased intracellular H2O2 levels affecting the activity of downstream signalling components, thereby amplifying insulin-mediated signal transduction. Specific molecular targets of insulin-stimulated H2O2 include phosphatases and kinases, whose activity can be altered via redox modifications of critical cysteine residues. Over the past decades, several of these redox-sensitive cysteines have been identified and their impact on insulin signalling evaluated. The aim of this review is to summarise the current knowledge on the redox regulation of the insulin signalling pathway.
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Huang S, Chen G, Sun J, Chen Y, Wang N, Dong Y, Shen E, Hu Z, Gong W, Jin L, Cong W. Histone deacetylase 3 inhibition alleviates type 2 diabetes mellitus-induced endothelial dysfunction via Nrf2. Cell Commun Signal 2021; 19:35. [PMID: 33736642 PMCID: PMC7977318 DOI: 10.1186/s12964-020-00681-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 11/02/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The mechanism underlying endothelial dysfunction leading to cardiovascular disease in type 2 diabetes mellitus (T2DM) remains unclear. Here, we show that inhibition of histone deacetylase 3 (HDAC3) reduced inflammation and oxidative stress by regulating nuclear factor-E2-related factor 2 (Nrf2), which mediates the expression of anti-inflammatory- and pro-survival-related genes in the vascular endothelium, thereby improving endothelial function. METHODS Nrf2 knockout (Nrf2 KO) C57BL/6 background mice, diabetic db/db mice, and control db/m mice were used to investigate the relationship between HDAC3 and Nrf2 in the endothelium in vivo. Human umbilical vein endothelial cells (HUVECs) cultured under high glucose-palmitic acid (HG-PA) conditions were used to explore the role of Kelch-like ECH-associated protein 1 (Keap1) -Nrf2-NAPDH oxidase 4 (Nox4) redox signaling in the vascular endothelium in vitro. Activity assays, immunofluorescence, western blotting, qRT-PCR, and immunoprecipitation assays were used to examine the effect of HDAC3 inhibition on inflammation, reactive oxygen species (ROS) production, and endothelial impairment, as well as the activity of Nrf2-related molecules. RESULTS HDAC3 activity, but not its expression, was increased in db/db mice. This resulted in de-endothelialization and increased oxidative stress and pro-inflammatory marker expression in cells treated with the HDAC3 inhibitor RGFP966, which activated Nrf2 signaling. HDAC3 silencing decreased ROS production, inflammation, and damage-associated tube formation in HG-PA-treated HUVECs. The underlying mechanism involved the Keap1-Nrf2-Nox4 signaling pathway. CONCLUSION The results of this study suggest the potential of HDAC3 as a therapeutic target for the treatment of endothelial dysfunction in T2DM. Video Abstract.
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Affiliation(s)
- Shuai Huang
- Zhejiang Provincial Key Laboratory of Interventional Pulmonology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Gen Chen
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Jia Sun
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Yunjie Chen
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Nan Wang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Yetong Dong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Enzhao Shen
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Zhicheng Hu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Wenjie Gong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Litai Jin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
| | - Weitao Cong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000 People’s Republic of China
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Wang X, Bai J, Wang W, Zhang G, Yin S, Wang D. A comparative metabolomics analysis of the halophyte Suaeda salsa and Salicornia europaea. ENVIRONMENTAL GEOCHEMISTRY AND HEALTH 2021; 43:1109-1122. [PMID: 32323170 DOI: 10.1007/s10653-020-00569-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 04/10/2020] [Indexed: 05/09/2023]
Abstract
Suaeda salsa and Salicornia europaea are both annual herbaceous species belonging to the Chenopodiaceae family, and often grow together through our observations in the Yellow River Delta Nature Reserve, and could be used as raw material to produce food and beverages in food industry due to its high nutritional value. In this study, we adopted widely targeted metabolomics to identify 822 and 694 metabolites in the leaves of S. salsa and S. europaea, respectively, to provide a basic data for the future development and utilization of these two species. We found that these two plants were rich in metabolic components with high medical value, such as flavonoids, alkaloids and coumarins. The high contents of branched chain amino acid in these two species may be an important factor for their adaptation to saline-alkali environments. In addition, the contents of glucosamine (FC = 7.70), maltose (FC = 9.34) and D-(+)-sucrose (FC = 7.19) increased significantly, and the contents of D-(+)-glucose, 2-propenyl (sinigrin) and fructose 1-phosphate were significantly increased in the leaves of S. salsa compared to S. europaea, indicating that some certain compounds in different plants have different sensitivity to salt stress. Our work provides new perspectives about important second metabolism pathways in salt tolerance between these two plants, which could be helpful for studying the tolerance mechanisms of wetland plants.
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Affiliation(s)
- Xin Wang
- State Key Laboratory of Water Environment Simulation, School of Environment, Beijing Normal University, Beijing, 100875, China
| | - Junhong Bai
- State Key Laboratory of Water Environment Simulation, School of Environment, Beijing Normal University, Beijing, 100875, China.
| | - Wei Wang
- State Key Laboratory of Water Environment Simulation, School of Environment, Beijing Normal University, Beijing, 100875, China
| | - Guangliang Zhang
- State Key Laboratory of Water Environment Simulation, School of Environment, Beijing Normal University, Beijing, 100875, China
| | - Shuo Yin
- State Key Laboratory of Water Environment Simulation, School of Environment, Beijing Normal University, Beijing, 100875, China
| | - Dawei Wang
- State Key Laboratory of Water Environment Simulation, School of Environment, Beijing Normal University, Beijing, 100875, China
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Xu J, Fu C, Li T, Xia X, Zhang H, Wang X, Zhao Y. Protective effect of acorn (Quercus liaotungensis Koidz) on streptozotocin-damaged MIN6 cells and type 2 diabetic rats via p38 MAPK/Nrf2/HO-1 pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 266:113444. [PMID: 33027641 DOI: 10.1016/j.jep.2020.113444] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 09/18/2020] [Accepted: 09/29/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Acorn obtained from the Quercus liaotungensis Koidz tree is consumed as a Chinese folk medicine for the treatment of diarrhea, abdominal pain, and inflammation, also having strong antioxidant activity and have been utilized for the treatment of diabetes in China. However, its mechanism of action on complications of diabetes and oxidative stress is unclear. AIM OF THE STUDY The purpose of this research was to assess the effects of acorn (Quercus liaotungensis Koidz) ethanol extract (AE) on pancreatic β-cell dysfunction through a streptozotocin (STZ)-damaged mouse normal pancreatic β-cell (MIN6 cell) model in vitro, and by using a high-fat and high-sugar diet with STZ-induced diabetic rat model in vivo to explore the possible mechanism of action against diabetes. MATERIALS AND METHODS MIN6 cells were pretreated with AE (20, 40, 80 μM) for 2 h and then treated with 3 mM STZ for 24 h. Cell viability was measured by MTT assay. The amount of intracellular reactive oxygen species was measured by 2,7-dichlorodi-hydrofluorescein diacetate. The activities of insulin secretion, superoxide dismutase, catalase and glutathione were determined by kits. Sprague Dawley rats were either given normal feed or a high sugar and fat diet for four weeks, followed STZ (25 mg/kg, via i. p.) was given. Rats with fasting blood glucose ≥11.1 mmol/l after one week were deemed to be diabetic. Animals were divided into 5 groups, which received saline (10 mL/kg), metformin (200 mg/kg), or AE at doses of 200 and 400 mg/kg during 4 weeks by oral gavage. Blood samples were used to evaluate hematological and biochemical indicators, and pancreas was removed for post-analysis. Body weight and fasting blood glucose were recorded weekly. The expression levels of Bax, Bcl-2, p38, p-p38, Nrf2 and HO-1 were determined by Western blot. RESULTS Data showed that AE inhibited apoptosis and increased antioxidant level in STZ-induced MIN6 cells. In addition, the AE-administered group lowered blood glucose, increased insulin secretion, and alleviated weight loss in the diabetic rats. Histopathologically, the AE-administered group reduced pancreatic injury by significantly restoring the insulin content in β-islets. It was observed that the anti-diabetic effects of AE were associated with the suppressed the p38 MAPK pathway and actived the Nrf2 pathway. CONCLUSIONS The ameliorative impact of AE on diabetes may be attributed to protection of the function of pancreatic β islets and by improving serum insulin levels, hence reducing the blood glucose, which involved in the p38 MAPK and Nrf2 pathways.
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Affiliation(s)
- Jing Xu
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Chaofan Fu
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Tao Li
- College of Life Sciences and Biological Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Xiaoyan Xia
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Huixing Zhang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Xude Wang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Yuqing Zhao
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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Onyango IG, Bennett JP, Stokin GB. Regulation of neuronal bioenergetics as a therapeutic strategy in neurodegenerative diseases. Neural Regen Res 2021; 16:1467-1482. [PMID: 33433460 PMCID: PMC8323696 DOI: 10.4103/1673-5374.303007] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases.
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Affiliation(s)
- Isaac G Onyango
- Center for Translational Medicine, International Clinical Research Centre (ICRC), St. Anne's University Hospital, Brno, Czech Republic
| | - James P Bennett
- Neurodegeneration Therapeutics, 3050A Berkmar Drive, Charlottesville, VA, USA
| | - Gorazd B Stokin
- Center for Translational Medicine, International Clinical Research Centre (ICRC), St. Anne's University Hospital, Brno, Czech Republic
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Sun J, Huang X, Niu C, Wang X, Li W, Liu M, Wang Y, Huang S, Chen X, Li X, Wang Y, Jin L, Xiao J, Cong W. aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2. Redox Biol 2020; 39:101811. [PMID: 33360774 PMCID: PMC7772795 DOI: 10.1016/j.redox.2020.101811] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/16/2020] [Accepted: 11/20/2020] [Indexed: 12/13/2022] Open
Abstract
Vascular complications of diabetes are a serious challenge in clinical practice, and effective treatments are an unmet clinical need. Acidic fibroblast growth factor (aFGF) has potent anti-oxidative properties and therefore has become a research focus for the treatment of diabetic vascular complications. However, the specific mechanisms by which aFGF regulates these processes remain unclear. The purpose of this study was to investigate whether aFGF alleviates diabetic endothelial dysfunction by suppressing mitochondrial oxidative stress. We found that aFGF markedly decreased mitochondrial superoxide generation in both db/db mice and endothelial cells incubated with high glucose (30 mM) plus palmitic acid (PA, 0.1 mM), and restored diabetes-impaired Wnt/β-catenin signaling. Pretreatment with the Wnt/β-catenin signaling inhibitors IWR-1-endo (IWR) and ICG-001 abolished aFGF-mediated attenuation of mitochondrial superoxide generation and endothelial protection. Furthermore, the effects of aFGF on endothelial protection under diabetic conditions were suppressed by c-Myc knockdown. Mechanistically, c-Myc knockdown triggered mitochondrial superoxide generation, which was related to decreased expression and subsequent impaired mitochondrial localization of hexokinase 2 (HXK2). The role of HXK2 in aFGF-mediated attenuation of mitochondrial superoxide levels and EC protection was further confirmed by si-Hxk2 and a cell-permeable form of hexokinase II VDAC binding domain (HXK2VBD) peptide, which inhibits mitochondrial localization of HXK2. Taken together, these findings suggest that the endothelial protective effect of aFGF under diabetic conditions could be partly attributed to its role in suppressing mitochondrial superoxide generation via HXK2, which is mediated by the Wnt/β-catenin/c-Myc axis.
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Affiliation(s)
- Jia Sun
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Xiaozhong Huang
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, PR China
| | - Chao Niu
- Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, PR China
| | - Xuejiao Wang
- Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, 325000, China
| | - Wanqian Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Mengxue Liu
- Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, 325000, China
| | - Ying Wang
- Department of Pharmacy, Jinhua Women & Children Health Hospital, Jinhua, PR China
| | - Shuai Huang
- Zhejiang Provincial Key Laboratory of Interventional Pulmonology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, PR China
| | - Xixi Chen
- Department of Pharmacy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, PR China
| | - Xiaokun Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Yang Wang
- Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, 325000, China.
| | - Litai Jin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China.
| | - Jian Xiao
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China.
| | - Weitao Cong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China.
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Venditti A, Bianco A. Sulfur-containing Secondary Metabolites as Neuroprotective Agents. Curr Med Chem 2020; 27:4421-4436. [PMID: 30207214 DOI: 10.2174/0929867325666180912105036] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 08/03/2018] [Accepted: 08/03/2018] [Indexed: 12/15/2022]
Abstract
Sulfur-containing secondary metabolites are a relatively small group of substances of plant origin. The present review is focused on their neuroprotective properties. The results obtained in a series of in vitro and in vivo studies are reported. Among glucosinolates, the wide class of compounds in the sulfur-containing metabolites, glucoraphanin, sulforaphane and isothiocyanates proved to be the more studied in this context and showed interesting properties as modulators of several systems involved in the pathogenesis of neurologic diseases such as oxidative stress, inflammation and apoptosis. Allium sativum L. (garlic) is widely known for its sulfur-containing components endowed with health-promoting activities and its medicinal properties are known from ancient times. In recent studies, garlic components proved active in neuroprotection due to the direct and indirect antioxidant properties, modulation of apoptosis mediators and inhibiting the formation of amyloid protein. Dihydroasparagusic acid, the first dimercaptanic compound isolated from a natural source, effectively inhibited inflammatory and oxidative processes that are important factors for the etiopathogenesis of neurodegenerative diseases, not only for its antioxidant and radical scavenging properties but also because it may down-regulate the expression of several microglial-derived inflammatory mediators. Serofendic acid represents a rare case of sulfur-containing animal-derived secondary metabolite isolated from fetal calf serum extract. It proved effective in the suppression of ROS generation and in the expression of several inflammatory and apoptosis mediators and showed a cytotrophic property in astrocytes, promoting the stellation process. Lastly, the properties of hydrogen sulfide were also reported since in recent times it has been recognized as a signaling molecule and as a mediator in regulating neuron death or survival. It may be produced endogenously from cysteine but may also be released by sulfur-containing secondary metabolites, mainly from those present in garlic.
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Affiliation(s)
- Alessandro Venditti
- Dipartimento di Chimica, Universita di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Armandodoriano Bianco
- Dipartimento di Chimica, Universita di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185, Rome, Italy
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Shetty T, Sishtla K, Park B, Repass MJ, Corson TW. Heme Synthesis Inhibition Blocks Angiogenesis via Mitochondrial Dysfunction. iScience 2020; 23:101391. [PMID: 32755804 PMCID: PMC7399258 DOI: 10.1016/j.isci.2020.101391] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 04/10/2020] [Accepted: 07/17/2020] [Indexed: 01/01/2023] Open
Abstract
The relationship between heme metabolism and angiogenesis is poorly understood. The final synthesis of heme occurs in mitochondria, where ferrochelatase (FECH) inserts Fe2+ into protoporphyrin IX to produce proto-heme IX. We previously showed that FECH inhibition is antiangiogenic in human retinal microvascular endothelial cells (HRECs) and in animal models of ocular neovascularization. In the present study, we sought to understand the mechanism of how FECH and thus heme is involved in endothelial cell function. Mitochondria in endothelial cells had several defects in function after heme inhibition. FECH loss changed the shape and mass of mitochondria and led to significant oxidative stress. Oxidative phosphorylation and mitochondrial Complex IV were decreased in HRECs and in murine retina ex vivo after heme depletion. Supplementation with heme partially rescued phenotypes of FECH blockade. These findings provide an unexpected link between mitochondrial heme metabolism and angiogenesis.
Heme synthesis inhibition changes mitochondrial morphology in endothelial cells Loss of heme causes buildup of mitochondrial ROS and depolarized membrane potential Endothelial cells have damaged oxidative phosphorylation and glycolysis on heme loss Damage is due to loss of heme-containing Complex IV, restored by exogenous heme
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Affiliation(s)
- Trupti Shetty
- Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Kamakshi Sishtla
- Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Bomina Park
- Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Matthew J Repass
- Angio BioCore, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Timothy W Corson
- Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Guo Z, Mo Z. Keap1‐Nrf2 signaling pathway in angiogenesis and vascular diseases. J Tissue Eng Regen Med 2020; 14:869-883. [PMID: 32336035 DOI: 10.1002/term.3053] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 04/14/2020] [Accepted: 04/22/2020] [Indexed: 02/06/2023]
Affiliation(s)
- Zi Guo
- Department of EndocrinologyThe Third Xiangya Hospital, Central South University Changsha China
| | - Zhaohui Mo
- Department of EndocrinologyThe Third Xiangya Hospital, Central South University Changsha China
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Kasai S, Shimizu S, Tatara Y, Mimura J, Itoh K. Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology. Biomolecules 2020; 10:biom10020320. [PMID: 32079324 PMCID: PMC7072240 DOI: 10.3390/biom10020320] [Citation(s) in RCA: 343] [Impact Index Per Article: 68.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/13/2020] [Accepted: 02/13/2020] [Indexed: 02/06/2023] Open
Abstract
Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence has shown that mitochondrial ROS (mtROS) activate Nrf2, often mediated by certain protein kinases, and induce the expression of antioxidant genes and genes involved in mitochondrial quality/quantity control. Mild physiological stress, such as caloric restriction and exercise, elicits beneficial effects through a process known as “mitohormesis”. Exercise induces NOX4 expression in the heart, which activates Nrf2 and increases endurance capacity. Mice transiently depleted of SOD2 or overexpressing skeletal muscle-specific UCP1 exhibit Nrf2-mediated antioxidant gene expression and PGC1α-mediated mitochondrial biogenesis. ATF4 activation may induce a transcriptional program that enhances NADPH synthesis in the mitochondria and might cooperate with the Nrf2 antioxidant system. In response to severe oxidative stress, Nrf2 induces Klf9 expression, which represses mtROS-eliminating enzymes to enhance cell death. Nrf2 is inactivated in certain pathological conditions, such as diabetes, but Keap1 down-regulation or mtROS elimination rescues Nrf2 expression and improves the pathology. These reports aid us in understanding the roles of Nrf2 in pathophysiological alterations involving mtROS.
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Affiliation(s)
- Shuya Kasai
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; (S.K.); (S.S.); (J.M.)
| | - Sunao Shimizu
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; (S.K.); (S.S.); (J.M.)
- Department of Nature & Wellness Research, Innovation Division, Kagome Co., Ltd. Nasushiobara, Tochigi 329-2762, Japan
| | - Yota Tatara
- Department of Glycotechnology, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan;
| | - Junsei Mimura
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; (S.K.); (S.S.); (J.M.)
| | - Ken Itoh
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; (S.K.); (S.S.); (J.M.)
- Correspondence: ; Tel.: +81-172-39-5158
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Gong DJ, Wang L, Yang YY, Zhang JJ, Liu XH. Diabetes aggravates renal ischemia and reperfusion injury in rats by exacerbating oxidative stress, inflammation, and apoptosis. Ren Fail 2020; 41:750-761. [PMID: 31441362 PMCID: PMC6720228 DOI: 10.1080/0886022x.2019.1643737] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Diabetic patients are more susceptible to renal ischemia/reperfusion (I/R) injury (RI/RI) and have a poor prognosis, but the underlying mechanism remains unclear. The present study aimed to examine whether diabetes could worsen acute kidney injury induced by I/R in rats and clarify its mechanism. Control and streptozotocin-induced diabetic rats were subjected to 45 min renal pedicle occlusion followed by 24 h reperfusion. Tert-butylhydroquinone (TBHQ, 16.7 mg/kg) was administrated intraperitoneally 3 times at intervals of 8 h before ischemia. Serum and kidneys were harvested after reperfusion to evaluate renal function and histological injury. Enzyme-linked immunosorbent assays were used to test pro-inflammatory cytokines. Terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling assays were used to detect apoptotic cells, and western blotting was performed to determine the expression of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved caspase-3, as well as oxidative stress and inflammation-related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB). Compared with control animals, diabetic rats undergoing I/R exhibited more severe tubular damage and renal dysfunction. Diabetes exacerbated oxidative stress, the inflammatory response, and apoptosis after renal I/R by enhancing TLR4/NF-κB signaling and blocking the Nrf2/HO-1 pathway. RI/RI in diabetic rats was attenuated by pretreatment with TBHQ (a Nrf2 agonist), which exerted anti-inflammatory and anti-apoptotic properties by inhibiting NF-κB signaling. These findings indicate that hyperglycemia exacerbates RI/RI by intensifying oxidative stress, inflammation, and apoptosis. Antioxidant pretreatment may alleviate RI/RI in diabetic patients.
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Affiliation(s)
- Dao-Jing Gong
- Department of Urology, Renmin Hospital of Wuhan University , Wuhan , Hubei , P.R. China
| | - Lei Wang
- Department of Urology, Renmin Hospital of Wuhan University , Wuhan , Hubei , P.R. China
| | - Yuan-Yuan Yang
- Department of Urology, Renmin Hospital of Wuhan University , Wuhan , Hubei , P.R. China
| | - Jian-Jian Zhang
- Department of Urology, Renmin Hospital of Wuhan University , Wuhan , Hubei , P.R. China
| | - Xiu-Heng Liu
- Department of Urology, Renmin Hospital of Wuhan University , Wuhan , Hubei , P.R. China
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Hui Q, Karlstetter M, Xu Z, Yang J, Zhou L, Eilken HM, Terjung C, Cho H, Gong J, Lai MJ, Nassar K, Duh EJ. Inhibition of the Keap1-Nrf2 protein-protein interaction protects retinal cells and ameliorates retinal ischemia-reperfusion injury. Free Radic Biol Med 2020; 146:181-188. [PMID: 31669760 PMCID: PMC6942228 DOI: 10.1016/j.freeradbiomed.2019.10.414] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 10/23/2019] [Indexed: 12/26/2022]
Abstract
The Nrf2-Keap1 pathway regulates transcription of a wide array of antioxidant and cytoprotective genes and offers critical protection against oxidative stress. This pathway has demonstrated benefit for a variety of retinal conditions. Retinal ischemia plays a pivotal role in many vision threatening diseases. Retinal vascular endothelial cells are an important participant in ischemic injury. In this setting, Nrf2 provides a protective pathway via amelioration of oxidative stress and inflammation. In this study, we investigated a potent small molecule inhibitor of the Nrf2-Keap1 protein-protein interaction (PPI), CPUY192018, for its therapeutic potential in retinal cells and retinal ischemia-reperfusion injury. In human retinal endothelial cells (HREC), treatment with CPUY192018 increased Nrf2 protein levels and nuclear translocation, stimulated Nrf2-ARE-induced transcriptional capacity, and induced Nrf2 target gene expression. Furthermore, CPUY192018 protected HREC against oxidative stress and inflammatory activation. CPUY192018 also activated Nrf2 and suppressed inflammatory response in macrophages. In the retinal ischemia-reperfusion (I/R) model, administration of CPUY192018 induced Nrf2 target gene activation in the retina. Both systemic and topical treatment with CPUY192018 rescued visual function after ischemia-reperfusion injury. Taken together, these findings indicate that small molecule Keap1-Nrf2 PPI inhibitors can activate the Nrf2 pathway in the retina and provide protection against retinal ischemic and inflammatory injury, suggesting Keap1-Nrf2 PPI inhibition in the treatment of retinal conditions.
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Affiliation(s)
- Qiaoyan Hui
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | | | - Zhenhua Xu
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jing Yang
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Lingli Zhou
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | | | - Hongkwan Cho
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Junsong Gong
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael J Lai
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Elia J Duh
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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46
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Wu B, Yue H, Zhou GH, Zhu YY, Wu TH, Wen JF, Cho KW, Jin SN. Protective effects of oxymatrine on homocysteine-induced endothelial injury: Involvement of mitochondria-dependent apoptosis and Akt-eNOS-NO signaling pathways. Eur J Pharmacol 2019; 864:172717. [DOI: 10.1016/j.ejphar.2019.172717] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 09/26/2019] [Accepted: 10/02/2019] [Indexed: 12/19/2022]
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Oxidative Stress and Microvascular Alterations in Diabetic Retinopathy: Future Therapies. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:4940825. [PMID: 31814880 PMCID: PMC6878793 DOI: 10.1155/2019/4940825] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 09/06/2019] [Accepted: 09/14/2019] [Indexed: 02/07/2023]
Abstract
Diabetes is a disease that can be treated with oral antidiabetic agents and/or insulin. However, patients' metabolic control is inadequate in a high percentage of them and a major cause of chronic diseases like diabetic retinopathy. Approximately 15% of patients have some degree of diabetic retinopathy when diabetes is first diagnosed, and most will have developed this microvascular complication after 20 years. Early diagnosis of the disease is the best tool to prevent or delay vision loss and reduce the involved costs. However, diabetic retinopathy is an asymptomatic disease and its development to advanced stages reduces the effectiveness of treatments. Today, the recommended treatment for severe nonproliferative and proliferative diabetic retinopathy is photocoagulation with an argon laser and intravitreal injections of anti-VEGF associated with, or not, focal laser for diabetic macular oedema. The use of these therapeutic approaches is severely limited, such as uncomfortable administration for patients, long-term side effects, the costs they incur, and the therapeutic effectiveness of the employed management protocols. Hence, diabetic retinopathy is the widespread diabetic eye disease and a leading cause of blindness in adults in developed countries. The growing interest in using polyphenols, e.g., resveratrol, in treatments related to oxidative stress diseases has spread to diabetic retinopathy. This review focuses on analysing the sources and effects of oxidative stress and inflammation on vascular alterations and diabetic retinopathy development. Furthermore, current and antioxidant therapies, together with new molecular targets, are postulated for diabetic retinopathy treatment.
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48
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Houghton CA. Sulforaphane: Its "Coming of Age" as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:2716870. [PMID: 31737167 PMCID: PMC6815645 DOI: 10.1155/2019/2716870] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 06/24/2019] [Accepted: 09/06/2019] [Indexed: 12/17/2022]
Abstract
A growing awareness of the mechanisms by which phytochemicals can influence upstream endogenous cellular defence processes has led to intensified research into their potential relevance in the prevention and treatment of disease. Pharmaceutical medicine has historically looked to plants as sources of the starting materials for drug development; however, the focus of nutraceutical medicine is to retain the plant bioactive in as close to its native state as possible. As a consequence, the potency of a nutraceutical concentrate or an extract may be lower than required for significant gene expression. The molecular structure of bioactive phytochemicals to a large extent determines the molecule's bioavailability. Polyphenols are abundant in dietary phytochemicals, and extensive in vitro research has established many of the signalling mechanisms involved in favourably modulating human biochemical pathways. Such pathways are associated with core processes such as redox modulation and immune modulation for infection control and for downregulating the synthesis of inflammatory cytokines. Although the relationship between oxidative stress and chronic disease continues to be affirmed, direct-acting antioxidants such as vitamins A, C, and E, beta-carotene, and others have not yielded the expected preventive or therapeutic responses, even though several large meta-analyses have sought to evaluate the potential benefit of such supplements. Because polyphenols exhibit poor bioavailability, few of their impressive in vitro findings have been replicated in vivo. SFN, an aliphatic isothiocyanate, emerges as a phytochemical with comparatively high bioavailability. A number of clinical trials have demonstrated its ability to produce favourable outcomes in conditions for which there are few satisfactory pharmaceutical solutions, foreshadowing the potential for SFN as a clinically relevant nutraceutical. Although myrosinase-inert broccoli sprout extracts are widely available, there now exist myrosinase-active broccoli sprout supplements that yield sufficient SFN to match the doses used in clinical trials.
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49
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Santos JLD, Araújo SSD, Silva AMDOE, Lima CA, Vieira Souza LM, Costa RA, Aidar Martins FJ, Voltarelli FA, Estevam CDS, Marçal AC. Ethanolic extract and ethyl acetate fraction of Coutoubea spicata attenuate hyperglycemia, oxidative stress, and muscle damage in alloxan-induced diabetic rats subjected to resistance exercise training program. Appl Physiol Nutr Metab 2019; 45:401-410. [PMID: 31539486 DOI: 10.1139/apnm-2019-0331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Gentianaceae family (such as Coutoubea spicata) contains iridoids and flavonoids with antidiabetic properties. However, there is no information available about the antidiabetic effects of C. spicata when combined with resistance exercise training (RET). This study evaluated the effects of the ethanolic extract (EE) and ethyl acetate fraction (EAF) of C. spicata on biochemical markers, muscle damage, and oxidative stress in diabetic rats submitted to RET. Alloxan-induced diabetic rats were distributed into 4 groups (each group, n = 8) treated with distilled water (TD), EE, EAF, or metformin and submitted to RET. Two groups without the disease (each group, n = 8) (sedentary control and trained control), as well as a sedentary diabetic group (n = 8) were included. Body weight and glycemia were evaluated weekly. After 30 days, lipid/lipoprotein profile, aspartate aminotransferase, alanine aminotransferase, muscle damage ((creatine kinase (CK) and lactate dehydrogenase (LDH)), and oxidative stress (malondialdehyde (MDA), sulfhydryl groups (SH), and ferric reducing antioxidant power) were evaluated. MDA and SH for pancreas, liver, heart, and muscle were evaluated. C. spicata extract and fraction combined with RET recovered body weight and reduced glycemia, muscle damage (CK: 36.83% and 21.45%; LDH: 49.83% and 68.55%), and low-density lipoprotein cholesterol (70.63%; 59.18%) and improved redox status (MDA: 50.33%, 39.74%; and SH: 53.97%; 76.41%), respectively, when compared with the TD group. C. spicata plus RET promoted anti-hyperglycemic, lipid-reducing, and antioxidant effects in diabetic rats. Novelty C. spicata presents anti-hyperglycemic and lipid-lowering effects potentiated by RET. C. spicata reduces muscle injury and increases antioxidant defense.
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Affiliation(s)
- Jymmys Lopes Dos Santos
- Laboratory of Natural Product Chemistry and Biochemistry, Department of Physiology, Federal University of Sergipe, São Cristóvão, SE 49100-000, Brazil
| | - Silvan Silva de Araújo
- Laboratory of Natural Product Chemistry and Biochemistry, Department of Physiology, Federal University of Sergipe, São Cristóvão, SE 49100-000, Brazil
| | | | - Clésio Andrade Lima
- Laboratory of Natural Product Chemistry and Biochemistry, Department of Physiology, Federal University of Sergipe, São Cristóvão, SE 49100-000, Brazil
| | - Lúcio Marques Vieira Souza
- Laboratory of Natural Product Chemistry and Biochemistry, Department of Physiology, Federal University of Sergipe, São Cristóvão, SE 49100-000, Brazil
| | - Rôas Araújo Costa
- Laboratory of Natural Product Chemistry and Biochemistry, Department of Physiology, Federal University of Sergipe, São Cristóvão, SE 49100-000, Brazil
| | | | - Fabrício Azevedo Voltarelli
- Graduate Program of Health Sciences, Faculty of Medicine, Federal University of Mato Grosso, Cuiabá, MT 78060-900, Brazil
| | - Charles Dos Santos Estevam
- Laboratory of Natural Product Chemistry and Biochemistry, Department of Physiology, Federal University of Sergipe, São Cristóvão, SE 49100-000, Brazil
| | - Anderson Carlos Marçal
- Department of Morphology, Federal University of Sergipe, São Cristóvão, SE 49100-000, Brazil
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Jha JC, Dai A, Holterman CE, Cooper ME, Touyz RM, Kennedy CR, Jandeleit-Dahm KAM. Endothelial or vascular smooth muscle cell-specific expression of human NOX5 exacerbates renal inflammation, fibrosis and albuminuria in the Akita mouse. Diabetologia 2019; 62:1712-1726. [PMID: 31222503 DOI: 10.1007/s00125-019-4924-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 05/10/2019] [Indexed: 02/07/2023]
Abstract
AIMS/HYPOTHESIS Excessive production of reactive oxygen species (ROS) plays a detrimental role in the progression of diabetic kidney disease (DKD). Renal oxidative stress activates proinflammatory cytokines, chemokines and profibrotic factors in DKD. Increased expression of the prooxidant enzyme NADPH oxidase (NOX) 5 in kidneys of diabetic individuals has been hypothesised to correlate with renal injury and progression of DKD. Since the gene encoding NOX5 is not expressed in the mouse genome, we examined the effect of inducible human NOX5 expression in renal cells, selectively in either endothelial cells or vascular smooth muscle cells (VSMCs)/mesangial cells in a model of insulin-deficient diabetes, the Akita mouse. METHODS Renal structural injury, including glomerulosclerosis, mesangial expansion and extracellular matrix protein accumulation, as well as renal inflammation, ROS formation and albuminuria, were examined in the NOX5 transgenic Akita mouse model of DKD. RESULTS Expression of NOX5 in either endothelial cells or VSMCs/mesangial cells in diabetic Akita mice was associated with increased renal inflammation (monocyte chemoattractant protein-1, NF-κB and toll-like receptor-4) and glomerulosclerosis, as well as upregulation of protein kinase C-α and increased expression of extracellular matrix genes (encoding collagen III, fibronectin and α-smooth muscle actin) and proteins (collagen IV), most likely mediated via enhanced renal ROS production. The effect of VSMC/mesangial cell-specific NOX5 expression resulted in more pronounced renal fibrosis in comparison with endothelial cell-specific NOX5 expression in diabetic mice. In addition, albuminuria was significantly increased in diabetic VEcad+NOX5+ mice (1192 ± 194 μg/24 h) when compared with diabetic VEcad+NOX5- mice (770 ± 98 μg/24 h). Furthermore, the regulatory components of NOX5 activation, including heat shock protein 90 and transient receptor potential cation channel subfamily C member 6, were upregulated only in the presence of both NOX5 and diabetes. CONCLUSIONS/INTERPRETATION The findings from this study highlight the importance of NOX5 in promoting diabetes-related renal injury and provide the rationale for the development of a selective NOX5 inhibitor for the prevention and/or treatment of DKD.
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Affiliation(s)
- Jay C Jha
- Department of Diabetes, Central Clinical School, Monash University, 99 Commercial Road, Level 5, Melbourne, VIC, 3004, Australia
| | - Aozhi Dai
- Department of Diabetes, Central Clinical School, Monash University, 99 Commercial Road, Level 5, Melbourne, VIC, 3004, Australia
| | - Chet E Holterman
- Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Mark E Cooper
- Department of Diabetes, Central Clinical School, Monash University, 99 Commercial Road, Level 5, Melbourne, VIC, 3004, Australia
| | - Rhian M Touyz
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Chris R Kennedy
- Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Karin A M Jandeleit-Dahm
- Department of Diabetes, Central Clinical School, Monash University, 99 Commercial Road, Level 5, Melbourne, VIC, 3004, Australia.
- German Diabetes Centre, Institute for Clinical Diabetology, Leibniz Centre for Diabetes Research, Heinrich-Heine University, Duesseldorf, Germany.
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