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Datta S, Rahman MA, Koka S, Boini KM. Mitigation of nicotine-induced podocyte injury through inhibition of thioredoxin interacting protein. Biomed Pharmacother 2025; 187:118110. [PMID: 40311224 DOI: 10.1016/j.biopha.2025.118110] [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: 01/20/2025] [Revised: 03/20/2025] [Accepted: 04/24/2025] [Indexed: 05/03/2025] Open
Abstract
Nicotine has been reported to initiate NLRP3 inflammasome formation and activation in different pathological conditions. The current study assessed whether thioredoxin-interacting protein (TXNIP) mediates nicotine-induced NLRP3 inflammasome activation and consequent podocyte injury. Co-immunoprecipitation analysis demonstrated that nicotine-induced TXNIP/NLRP3 interaction in podocytes relative to control groups. However, pre-treatment with TXNIP inhibitors, verapamil (Vera) or SRI-37330 (SRI) attenuates nicotine-induced TXNIP/NLRP3 interaction. Confocal microscopic analysis showed that nicotine treatment significantly increased the colocalization of Nlrp3 with Asc, Nlrp3 with caspase-1 and Nlrp3 with TXNIP in podocytes compared to control cells. Pretreatment with TXNIP inhibitor Vera or SRI abolished nicotine-induced Nlrp3/Asc, Nlrp3/caspase-1 or Nlrp3/TXNIP colocalization. Correspondingly, nicotine treatment significantly increased the caspase-1 activity and IL-1β production compared to control cells. However, prior treatment with TXNIP inhibiting Vera or SRI significantly attenuated the nicotine-induced caspase-1 activity and IL-1β production. Further immunofluorescence analysis showed that nicotine treatment significantly decreased podocin and nephrin expression compared to control cells. However, pretreatment with TXNIP inhibiting Vera or SRI attenuated the nicotine-induced podocin and nephrin reduction. In addition, confocal, flow cytometry and biochemical analysis showed that nicotine treatment significantly increased desmin expression, apoptosis and cell permeability compared to control cells. However, prior treatment with TXNIP inhibiting Vera or SRI significantly attenuated the nicotine-induced desmin expression, apoptosis and cell permeability. Taken together, our results demonstrate that TXNIP/NLRP3 interaction constitutes a potentially key signalling mechanism driving nicotine-induced NLRP3 inflammasome formation, activation and subsequent podocyte damage.
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Affiliation(s)
- Sayantap Datta
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, United States
| | - Mohammad Atiqur Rahman
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, United States
| | - Saisudha Koka
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX, United States
| | - Krishna M Boini
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, United States.
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Lu T, Shang J, Pu S, Xu Y, Sun X, Gao X. The role of microglia in the development of diabetic retinopathy and its potential clinical application. Hum Cell 2025; 38:101. [PMID: 40392429 DOI: 10.1007/s13577-025-01226-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 04/21/2025] [Indexed: 05/22/2025]
Abstract
Lately, research on the function of microglia in diabetic retinopathy (DR) is becoming increasingly focused. Microglia are immune cells that dwell in the central nervous system and are crucial to the pathophysiology of DR. According to studies, a hyperglycemic environment can activate microglia, bringing them out of a resting state to an active state. This allows them to release a variety of inflammatory factors and chemokines, which can then cause retinal inflammatory reactions. When it comes to angiogenesis in DR, activated microglia release a variety of angiogenic substances, such as vascular endothelial growth factor (VEGF), to create aberrant new blood vessels. Moreover, microglia contribute to the retina's oxidative stress process by generating and releasing reactive oxygen and nitrogen-free radicals, which exacerbates retinal damage. Researchers have proposed a variety of strategies for the activation of microglia and the inflammatory response it triggers. By inhibiting the excessive activation of microglia and reducing the release of inflammatory factors, the inflammatory response and damage to the retina can be alleviated. Drugs that interfere with retinal microglia can also be used to regulate vascular damage and inhibit the formation of new blood vessels. In addition, antioxidants are used to remove reactive oxygen and free radicals, reduce oxidative stress levels, and protect retinal cells. These therapeutic strategies aim to achieve the purpose of treating DR by regulating the function of microglia. Thus, we highlight the possibility that therapy aimed at microglia could offer fresh ideas for treating DR.
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Affiliation(s)
- Tingting Lu
- The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Jiameng Shang
- The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Shengdan Pu
- The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Yuxin Xu
- The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Xiaotong Sun
- The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Xinyuan Gao
- The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.
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Cao P, Yang Y, Zhang N, Wang B, Gong Z. Inflammasomes: novel therapeutic targets for metabolic syndrome? Front Endocrinol (Lausanne) 2025; 16:1569579. [PMID: 40433411 PMCID: PMC12106043 DOI: 10.3389/fendo.2025.1569579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Accepted: 04/18/2025] [Indexed: 05/29/2025] Open
Abstract
Chronic inflammation is a hallmark for Metabolic Syndrome (MetS). It is also one of the most important risk factors for insulin resistance and metabolic disorders. Inflammasomes, which are intracellular multiprotein complexes within the innate immune system, regulate the production and maturation of pro-inflammatory cytokines including interleukin-1β (IL-1β) and IL-18 upon sensing pathogens or danger signals in the cytosol. A growing body of evidence indicates that inflammasomes play a pivotal role in the pathophysiology and progression of metabolic diseases, as deficiency in the key component of inflammasomes protects mice from high fat diet induced obesity and insulin resistance. Thus, in this review, we will summarize the role of inflammasomes in MetS and how to treat MetS by targeting inflammasomes. This may provide novel insights and therapeutic targets for treating metabolic disorders.
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Affiliation(s)
- Pengyu Cao
- The Second People’s Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, China
| | - Yulin Yang
- The Second People’s Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, China
| | - Ningning Zhang
- The Second People’s Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Bojian Wang
- School of Nursing, Jilin University, Changchun, Jilin, China
| | - Zhenwei Gong
- Division of Endocrinology, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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Tu S, Zhang R, Zheng Q, Wang J, Chen Y, Li X, He J, Zhou Z, Lu Q. Effect of Verapamil on Blood Glucose in Type 1 and Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Cardiovasc Drugs Ther 2025:10.1007/s10557-025-07683-4. [PMID: 40111679 DOI: 10.1007/s10557-025-07683-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/04/2025] [Indexed: 03/22/2025]
Abstract
PURPOSE Verapamil, an L-type calcium channel blocker treating hypertension, arrhythmia, and other cardiovascular diseases, has emerged as a potential drug for lowering blood glucose by regulating cellular calcium homeostasis and affecting expression of apoptosis-related proteins in pancreatic β-cells. However, this promising effect must be weighed against potential risks, including cardiovascular adverse effects of this drug. METHODS We conducted a systematic review and meta-analysis and included randomized controlled trials (RCTs) assessing verapamil in individuals with type 1 or type 2 diabetes. The primary outcomes were glycated hemoglobin (HbA1c) and serum glucose concentration. The secondary outcomes were area under the curve (AUC) values for C-peptide level, body weight, changes in HbA1c and blood glucose concentration pre- and post-intervention, and adverse drug reactions. RESULTS A total of eight RCTs involving 1100 patients were included in the analysis. Meta-analysis showed that verapamil effectively lowered blood glucose levels (weighted mean difference [WMD] -6.38, 95% CI -12.52, -0.25 mg/dL, P = 0.04; 6 trials), decreased HbA1c (WMD -0.45, 95% CI -0.66, -0.23%, P < 0.001; 7 trials), and increased C-peptide AUC (WMD 0.27, 95% CI 0.21, 0.32 pmol/mL, P < 0.0001; 2 trials) in patients with both type 1 and type 2 diabetes, without significant trial-related adverse events (OR 1.33, 95% CI 0.85, 2.09, P = 0.21). CONCLUSION The adjunctive use of verapamil to standard hypoglycemic therapy is a safe and effective means of improving glycemic control in diabetic patients. However, the limited scale of RCTs and heterogeneity of basic glucose-lowering regimens across studies might constrain generalizability of these findings. Future high-quality research is warranted to further elucidate the role of verapamil in diabetes management.
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Affiliation(s)
- Shiqi Tu
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, PR China
- Institute of Clinical Pharmacy, Central South University, Changsha, 410011, PR China
| | - Ruiqi Zhang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, PR China
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Qiyue Zheng
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, PR China
- Institute of Clinical Pharmacy, Central South University, Changsha, 410011, PR China
| | - Jiaojiao Wang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, PR China
- Institute of Clinical Pharmacy, Central South University, Changsha, 410011, PR China
| | - Yun Chen
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, PR China
- Institute of Clinical Pharmacy, Central South University, Changsha, 410011, PR China
| | - Xiaosi Li
- Department of Pharmacy, Hospital of Chengdu Office of People'S Government of Tibetan Autonomous Region, Chengdu, 610000, China
| | - Jieyu He
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, 410011, PR China
| | - Zhaokai Zhou
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, PR China.
- Institute of Clinical Pharmacy, Central South University, Changsha, 410011, PR China.
- Department of Urology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, PR China.
| | - Qiong Lu
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, PR China.
- Institute of Clinical Pharmacy, Central South University, Changsha, 410011, PR China.
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Du F, Wang G, Dai Q, Huang J, Li J, Liu C, Du K, Tian H, Deng Q, Xie L, Zhao X, Zhang Q, Yang L, Li Y, Wu Z, Zhang Z. Targeting novel regulated cell death: disulfidptosis in cancer immunotherapy with immune checkpoint inhibitors. Biomark Res 2025; 13:35. [PMID: 40012016 DOI: 10.1186/s40364-025-00748-4] [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: 01/07/2025] [Accepted: 02/11/2025] [Indexed: 02/28/2025] Open
Abstract
The battle against cancer has evolved over centuries, from the early stages of surgical resection to contemporary treatments including chemotherapy, radiation, targeted therapies, and immunotherapies. Despite significant advances in cancer treatment over recent decades, these therapies remain limited by various challenges. Immune checkpoint inhibitors (ICIs), a cornerstone of tumor immunotherapy, have emerged as one of the most promising advancements in cancer treatment. Although ICIs, such as CTLA-4 and PD-1/PD-L1 inhibitors, have demonstrated clinical efficacy, their therapeutic impact remains suboptimal due to patient-specific variability and tumor immune resistance. Cell death is a fundamental process for maintaining tissue homeostasis and function. Recent research highlights that the combination of induced regulatory cell death (RCD) and ICIs can substantially enhance anti-tumor responses across multiple cancer types. In cells exhibiting high levels of recombinant solute carrier family 7 member 11 (SLC7A11) protein, glucose deprivation triggers a programmed cell death (PCD) pathway characterized by disulfide bond formation and REDOX (reduction-oxidation) reactions, termed "disulfidptosis." Studies suggest that disulfidptosis plays a critical role in the therapeutic efficacy of SLC7A11high cancers. Therefore, to investigate the potential synergy between disulfidptosis and ICIs, this study will explore the mechanisms of both processes in tumor progression, with the goal of enhancing the anti-tumor immune response of ICIs by targeting the intracellular disulfidptosis pathway.
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Affiliation(s)
- Fei Du
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China.
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China.
| | - Guojun Wang
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China
| | - Qian Dai
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China
| | - Jiang Huang
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Junxin Li
- Department of pharmacy, Zigong Fourth People's Hospital, Zigong, 643000, China
| | - Congxing Liu
- Department of Pharmacy, Chengfei Hospital, Chengdu, 610000, China
| | - Ke Du
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China
- Department of Pediatrics, Luzhou Maternal and Child Health Hospital, Luzhou Second People's Hospital, Luzhou, 646000, Sichuan, China
| | - Hua Tian
- School of Nursing, Chongqing College of Humanities, Science & Technology, Chongqing, 401520, China
| | - Qiwei Deng
- Heruida Pharmaceutical Co.,ltd, Haikou, Hainan, 570100, China
| | - Longxiang Xie
- The TCM Hospital of Longquanyi District, Chengdu, 610100, Sichuan, China
| | - Xin Zhao
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China
| | - Qimin Zhang
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China
| | - Lan Yang
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China
| | - Yaling Li
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Zhigui Wu
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Zhuo Zhang
- Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University, Meishan, 620000, Sichuan, China.
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China.
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Chen J, Zhong H, Shen B, Yu H, Zhang Y, Han R, Huang P, Huang S, Zhong Y. Thioredoxin-interacting protein (TXNIP) inhibition promotes retinal ganglion cell survival and facilitates M1-like microglial transformation via the PI3K/Akt pathway in glaucoma. Mol Med 2024; 30:283. [PMID: 39736512 DOI: 10.1186/s10020-024-01058-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 12/19/2024] [Indexed: 01/01/2025] Open
Abstract
BACKGROUND Glaucoma is a group of heterogeneous neurodegenerative diseases with abnormal energy metabolism and imbalanced neuroinflammation in the retina. Thioredoxin-interacting protein (TXNIP) is involved in glucose and lipid metabolism, and associated with oxidative stress and inflammation, however, not known whether to be involved in glaucoma neuropathy and its underlying mechanisms. METHODS To establish the chronic ocular hypertension (COH) mice model. Western blot, RT-PCR, immunofluorescence and F-VEP were used to detect neuroinflammation level, glial activation and RGCs survival in retina of wild type, TXNIP knockout and MCC950 treatment COH mice. Microglia high-pressure cultured model was constructed. Western blot, RT-PCR and immunofluorescence were used to investigate the proinflammatory cytokines secretion, glucose uptake and phenotype transformation in wild type, TXNIP knockout and overexpressed microglia combined with IL-17A treatment. Finally, we explored the possible underlying mechanisms using relevant pathway inhibitor interventions. RESULTS In this study, for the first time we reported that TXNIP expression was remarkably increased in experimental glaucomatous retina of chronic ocular hypertension (COH) mice, and it was mainly expressed in the ganglion cells layer (GCL). In addition, we found that ablation of TXNIP promoted retinal ganglion cells (RGCs) survival and alleviated visual function impairment in experimental glaucoma. Then, we explored the spatiotemporal consistency between glial activation and retinal inflammation levels in COH mice respectively with TXNIP-deficiency and under treatment of a thermo-containing protein domain 3 (NLRP3) inhibitor MCC950, and the results indicated that TXNIP probably mediated neuroinflammation in glaucomatous retina by activating microglia. Furthermore, upregulation of TXNIP was found in pressure-stimulated microglia, whereas silencing TXNIP facilitated microglial polarization trending towards M1 type and reduced glucose transporter-1 (Glut-1) expression on microglia under high pressure in vitro. Moreover, IL-17A was found to play a role in acting synergistically with TXNIP upon the regulation of microglia polarity transformation. Finally, knockout of TXNIP was revealed to promote PI3K phosphorylation, whereas inhibition of PI3K by LY294002 effectively suppressed Glut-1 expression, glucose uptake, and M1-like transformation tendency in microglia obtained from TXNIP-deficiency mice under high pressure stimulation. CONCLUSIONS TXNIP is significantly involved in the inflammation-related neuropathy of experimental glaucoma and probably facilitates M1-like microglial transformation via PI3K/Akt pathway.
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Affiliation(s)
- Junjue Chen
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin er Road, Shanghai, 200025, China
| | - Huimin Zhong
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingqiao Shen
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin er Road, Shanghai, 200025, China
| | - Huan Yu
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin er Road, Shanghai, 200025, China
| | - Yang Zhang
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin er Road, Shanghai, 200025, China
| | - Ruiqi Han
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin er Road, Shanghai, 200025, China
| | - Ping Huang
- Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin er Road, Shanghai, 200025, China.
| | - Shouyue Huang
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin er Road, Shanghai, 200025, China.
| | - Yisheng Zhong
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin er Road, Shanghai, 200025, China.
- Department of Ophthalmology, Zhoushan Branch of Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, Zhoushan, China.
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Chen J, Ni Y, Yao W, Ding X. Clinical observations and mechanistic insights of traditional Chinese medicine in the management of diabetic retinopathy. PHARMACEUTICAL BIOLOGY 2024; 62:529-543. [PMID: 38921697 PMCID: PMC11210421 DOI: 10.1080/13880209.2024.2369292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 06/09/2024] [Indexed: 06/27/2024]
Abstract
CONTEXT Diabetic retinopathy (DR) is one of the leading causes of vision impairment and blindness among diabetic patients globally. Despite advancements in conventional treatments, the quest for more holistic approaches and fewer side effects persists. Traditional Chinese medicine (TCM) has been used for centuries in managing various diseases, including diabetes and its complications. OBJECTIVE This review evaluated the efficacy and underlying mechanisms of TCM in the management of DR, providing information on its potential integration with conventional treatment methods. METHODS A comprehensive literature review was conducted using PubMed, Web of Science, and the China National Knowledge Infrastructure (CNKI) with the search terms 'traditional Chinese medicine', 'diabetic retinopathy', 'clinical efficacies' and their combinations. Studies published before 2023 without language restriction were included, focusing on clinical trials and observational studies that assessed the effectiveness of TCM in DR treatment. RESULTS The review synthesized evidence of empirical traditional Chinese formulas, traditional Chinese patent medicines, and isolated phytochemicals on DR treatment. The key mechanisms identified included the reduction of oxidative stress, inflammation, and neovascularization, as well as the improvement in neurovascular functionality and integrity of the retinal blood barrier. CONCLUSIONS TCM shows promising potential to manage DR. More large-scale, randomized controlled trials are recommended to validate these findings and facilitate the integration of TCM into mainstream DR treatment protocols.
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Affiliation(s)
- Jie Chen
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yadong Ni
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wenhui Yao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xuansheng Ding
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Precision Medicine Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
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Wych J, Brunner M, Stenson R, Chmura PJ, Danne T, Mander AP, Mathieu C, Dayan C, Pieber TR. Investigating the effect of verapamil on preservation of beta-cell function in adults with newly diagnosed type 1 diabetes mellitus (Ver-A-T1D): protocol for a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. BMJ Open 2024; 14:e091597. [PMID: 39613428 PMCID: PMC11605811 DOI: 10.1136/bmjopen-2024-091597] [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: 07/24/2024] [Accepted: 10/25/2024] [Indexed: 12/01/2024] Open
Abstract
INTRODUCTION Type 1 diabetes mellitus (T1DM) is a disorder that arises following the selective autoimmune destruction of the insulin-producing beta cells. Beta-cell protective or beta-cell regenerative approaches have gained wider attention, and pharmacological approaches to protect the patient's own insulin-producing beta-cell mass have been proposed. Verapamil is an L-type calcium channel blocker that has been reported to effectively lowers beta-cell thioredoxin-interacting protein expression in rodent beta cells and islets, as well as in human islets, and thus promotes functional beta-cell mass. METHODS AND ANALYSIS The trial is a multicentre, randomised, double-blind, placebo-controlled trial in participants with T1DM, investigating the effect of verapamil on preservation of beta-cell function (Ver-A-T1D). A total of 120 participants will be randomised in a 2:1 ratio between 360 mg verapamil and placebo, administered orally once daily. T1DM patients aged ≥18 and <45 years will be eligible for recruitment within 6 weeks of diagnosis (defined as day of starting insulin therapy). The primary objective will be to determine the changes in stimulated C-peptide response during the first 2 hours of a mixed meal tolerance test at baseline and after 12 months for 360 mg verapamil administered orally once daily versus placebo. Secondary objectives include the effects of 360 mg verapamil on (1) fasting C-peptide, (2) dried blood spot C-peptide, (3) glycated haemoglobin, (4) daily total insulin dose, (5) time in range by intermittent continuous glucose monitoring measures, (6) other biomarkers related to immunological changes and beta-cell death and (6) safety (vital signs, ECG). ETHICS AND DISSEMINATION Ethics approval was sought from the research ethics committee of all participating countries. All participants provided written informed consent before joining the study. Ver-A-T1D received first regulatory and ethical approvals in Austria. The publication policy is set in the innovative approach towards understanding and arresting type 1 diabetes grant agreement (www.innodia.eu). TRIAL REGISTRATION NUMBER EudraCT, 2020-000435-45; ClinicalTrials.gov, NCT04545151. PROTOCOL VERSION Version 8.0 (08 November 2021).
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Affiliation(s)
- Julie Wych
- Centre for Trials Research, Cardiff University, Cardiff, UK
| | - Martina Brunner
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Rachel Stenson
- Diabetes Research Group, Cardiff University, Cardiff, UK
| | - Piotr Jaroslaw Chmura
- Center for Protein Research, Kobenhavns Universitet Sundhedsvidenskabelige Fakultet, Kobenhavn, Denmark
| | - Thomas Danne
- Department of General Pediatrics Endocrinology/Diabetology & Clinical Research, Auf der Bult Children's Hospital, Hannover, Germany
| | | | | | - Colin Dayan
- Cardiff University School of Medicine, Cardiff University, Cardiff, UK
| | - Thomas R Pieber
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
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Yang B, Lin Y, Huang Y, Shen YQ, Chen Q. Thioredoxin (Trx): A redox target and modulator of cellular senescence and aging-related diseases. Redox Biol 2024; 70:103032. [PMID: 38232457 PMCID: PMC10827563 DOI: 10.1016/j.redox.2024.103032] [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: 10/14/2023] [Revised: 12/03/2023] [Accepted: 01/04/2024] [Indexed: 01/19/2024] Open
Abstract
Thioredoxin (Trx) is a compact redox-regulatory protein that modulates cellular redox state by reducing oxidized proteins. Trx exhibits dual functionality as an antioxidant and a cofactor for diverse enzymes and transcription factors, thereby exerting influence over their activity and function. Trx has emerged as a pivotal biomarker for various diseases, particularly those associated with oxidative stress, inflammation, and aging. Recent clinical investigations have underscored the significance of Trx in disease diagnosis, treatment, and mechanistic elucidation. Despite its paramount importance, the intricate interplay between Trx and cellular senescence-a condition characterized by irreversible growth arrest induced by multiple aging stimuli-remains inadequately understood. In this review, our objective is to present a comprehensive and up-to-date overview of the structure and function of Trx, its involvement in redox signaling pathways and cellular senescence, its association with aging and age-related diseases, as well as its potential as a therapeutic target. Our review aims to elucidate the novel and extensive role of Trx in senescence while highlighting its implications for aging and age-related diseases.
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Affiliation(s)
- Bowen Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Yumeng Lin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Yibo Huang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Ying-Qiang Shen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
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10
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Cai L, Xia M, Zhang F. Redox Regulation of Immunometabolism in Microglia Underpinning Diabetic Retinopathy. Antioxidants (Basel) 2024; 13:423. [PMID: 38671871 PMCID: PMC11047590 DOI: 10.3390/antiox13040423] [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: 01/31/2024] [Revised: 03/24/2024] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness among the working-age population. Microglia, resident immune cells in the retina, are recognized as crucial drivers in the DR process. Microglia activation is a tightly regulated immunometabolic process. In the early stages of DR, the M1 phenotype commonly shifts from oxidative phosphorylation to aerobic glycolysis for energy production. Emerging evidence suggests that microglia in DR not only engage specific metabolic pathways but also rearrange their oxidation-reduction (redox) system. This redox adaptation supports metabolic reprogramming and offers potential therapeutic strategies using antioxidants. Here, we provide an overview of recent insights into the involvement of reactive oxygen species and the distinct roles played by key cellular antioxidant pathways, including the NADPH oxidase 2 system, which promotes glycolysis via enhanced glucose transporter 4 translocation to the cell membrane through the AKT/mTOR pathway, as well as the involvement of the thioredoxin and nuclear factor E2-related factor 2 antioxidant systems, which maintain microglia in an anti-inflammatory state. Therefore, we highlight the potential for targeting the modulation of microglial redox metabolism to offer new concepts for DR treatment.
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Affiliation(s)
- Luwei Cai
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; (L.C.); (M.X.)
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai 200080, China
| | - Mengxue Xia
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; (L.C.); (M.X.)
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai 200080, China
| | - Fang Zhang
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; (L.C.); (M.X.)
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai 200080, China
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11
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Nițulescu IM, Ciulei G, Cozma A, Procopciuc LM, Orășan OH. From Innate Immunity to Metabolic Disorder: A Review of the NLRP3 Inflammasome in Diabetes Mellitus. J Clin Med 2023; 12:6022. [PMID: 37762961 PMCID: PMC10531881 DOI: 10.3390/jcm12186022] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 09/14/2023] [Accepted: 09/16/2023] [Indexed: 09/29/2023] Open
Abstract
The role of the NLRP3 inflammasome is pivotal in the pathophysiology and progression of diabetes mellitus (DM), encompassing both type 1 (T1D), or type 2 (T2D). As part of the innate immune system, NLRP3 is also responsible for the chronic inflammation triggered by hyperglycemia. In both conditions, NLRP3 facilitates the release of interleukin-1β and interleukin-18. For T1D, NLRP3 perpetuates the autoimmune cascade, leading to the destruction of pancreatic islet cells. In T2D, its activation is associated with the presence of insulin resistance. NLRP3 activation is also instrumental for the presence of numerous complications associated with DM, microvascular and macrovascular. A considerable number of anti-diabetic drugs have demonstrated the ability to inhibit the NLRP3 inflammasome.
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Affiliation(s)
- Iris Maria Nițulescu
- Department 4 of Internal Medicine, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (I.M.N.); (A.C.); (O.H.O.)
| | - George Ciulei
- Department 4 of Internal Medicine, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (I.M.N.); (A.C.); (O.H.O.)
| | - Angela Cozma
- Department 4 of Internal Medicine, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (I.M.N.); (A.C.); (O.H.O.)
| | - Lucia Maria Procopciuc
- Department 2 of Molecular Sciences, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Olga Hilda Orășan
- Department 4 of Internal Medicine, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (I.M.N.); (A.C.); (O.H.O.)
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12
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Yang Y, Jiang G, Huang R, Liu Y, Chang X, Fu S. Targeting the NLRP3 inflammasome in diabetic retinopathy: From Pathogenesis to Therapeutic Strategies. Biochem Pharmacol 2023; 212:115569. [PMID: 37100255 DOI: 10.1016/j.bcp.2023.115569] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/16/2023] [Accepted: 04/18/2023] [Indexed: 04/28/2023]
Abstract
Diabetic retinopathy (DR) is a common diabetic microvascular complication and the main cause of vision loss in working-aged people. The NLRP3 inflammasome is a cytosolic multimeric complex that plays a significant role in innate immunity. After sensing injury, the NLRP3 inflammasome induces inflammatory mediator secretion and triggers a form of inflammatory cell death known as pyroptosis. Studies over the past five years have shown increased expression of NLRP3 and related inflammatory mediators in vitreous samples from DR patients at different clinical stages. Many NLRP3-targeted inhibitors have shown great antiangiogenic and anti-inflammatory effects in diabetes mellitus models, suggesting that the NLRP3 inflammasome is involved in the progression of DR. This review covers the molecular mechanisms of NLRP3 inflammasome activation. Furthermore, we discuss the implications of the NLRP3 inflammasome in DR, including the induction of pyroptosis and inflammation and the promotion of microangiopathy and retinal neurodegeneration. We also summarize the research progress on targeting the NLRP3 inflammasome in DR therapeutics with the expectation of providing new insights into DR progression and treatment.
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Affiliation(s)
- Yuxuan Yang
- The First Clinical Medical College, Lanzhou University, Lanzhou, The People's Republic of China, 730000
| | - Gengchen Jiang
- The First Clinical Medical College, Lanzhou University, Lanzhou, The People's Republic of China, 730000
| | - Runchun Huang
- The First Clinical Medical College, Lanzhou University, Lanzhou, The People's Republic of China, 730000
| | - Yi Liu
- The First Clinical Medical College, Lanzhou University, Lanzhou, The People's Republic of China, 730000
| | - Xingyu Chang
- The First Clinical Medical College, Lanzhou University, Lanzhou, The People's Republic of China, 730000
| | - Songbo Fu
- Department of Endocrinology, First Hospital of Lanzhou University, Lanzhou, Gansu, The People's Republic of China, 730000; Gansu Province Clinical Research Center for Endocrine Disease, Gansu, The People's Republic of China, 730000.
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13
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Lu S, Li Y, Qian Z, Zhao T, Feng Z, Weng X, Yu L. Role of the inflammasome in insulin resistance and type 2 diabetes mellitus. Front Immunol 2023; 14:1052756. [PMID: 36993972 PMCID: PMC10040598 DOI: 10.3389/fimmu.2023.1052756] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023] Open
Abstract
The inflammasome is a protein complex composed of a variety of proteins in cells and which participates in the innate immune response of the body. It can be activated by upstream signal regulation and plays an important role in pyroptosis, apoptosis, inflammation, tumor regulation, etc. In recent years, the number of metabolic syndrome patients with insulin resistance (IR) has increased year by year, and the inflammasome is closely related to the occurrence and development of metabolic diseases. The inflammasome can directly or indirectly affect conduction of the insulin signaling pathway, involvement the occurrence of IR and type 2 diabetes mellitus (T2DM). Moreover, various therapeutic agents also work through the inflammasome to treat with diabetes. This review focuses on the role of inflammasome on IR and T2DM, pointing out the association and utility value. Briefly, we have discussed the main inflammasomes, including NLRP1, NLRP3, NLRC4, NLRP6 and AIM2, as well as their structure, activation and regulation in IR were described in detail. Finally, we discussed the current therapeutic options-associated with inflammasome for the treatment of T2DM. Specially, the NLRP3-related therapeutic agents and options are widely developed. In summary, this article reviews the role of and research progress on the inflammasome in IR and T2DM.
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Affiliation(s)
- Shen Lu
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Yanrong Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
| | - Zhaojun Qian
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Tiesuo Zhao
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, Henan, China
| | - Zhiwei Feng
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, Henan, China
| | - Xiaogang Weng
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
- *Correspondence: Lili Yu, ; Xiaogang Weng,
| | - Lili Yu
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, Henan, China
- *Correspondence: Lili Yu, ; Xiaogang Weng,
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14
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Trimethylamine-N-Oxide Promotes High-Glucose-Induced Dysfunction and NLRP3 Inflammasome Activation in Retinal Microvascular Endothelial Cells. J Ophthalmol 2023; 2023:8224752. [PMID: 36895266 PMCID: PMC9991475 DOI: 10.1155/2023/8224752] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 02/09/2023] [Accepted: 02/16/2023] [Indexed: 03/06/2023] Open
Abstract
Introduction Along with blood glucose levels, diabetic retinopathy (DR) development also involves endogenous risk factors, such as trimethylamine-N-oxide (TMAO), a product of intestinal flora metabolic disorder, which exacerbates diabetic microvascular complications. However, the effect of TMAO on retinal cells under high-glucose conditions remains unclear. Therefore, this study examined the effects of TMAO on high-glucose-induced retinal dysfunction in the context of NLRP3 inflammasome activation, which is involved in DR. Materials and Methods TMAO was assessed in the serum and aqueous humor of patients using ELISA. Human retinal microvascular endothelial cells (HRMECs) were treated for 72 h as follows: NG (normal glucose, D-glucose 5.5 mM), NG + TMAO (5 μM), HG (high glucose, D-glucose 30 mM), and HG + TMAO (5 μM). The CCK8 assay was then used to assess cell proliferation; wound healing, cell migration, and tube formation assays were used to verify changes in cell phenotype. ZO-1 expression was determined using immunofluorescence and western blotting. Reactive oxygen species (ROS) formation was assessed using DCFH-DA. NLRP3 inflammasome complex activation was determined using a western blot. Results The serum and aqueous humor from patients with PDR contained higher levels of TMAO compared to patients with nontype 2 diabetes (Control), non-DR (NDR), and non-PDR (NPDR). TMAO showed significant acceleration of high-glucose-induced cell proliferation, wound healing, cell migration, and tube formation. ZO-1 expression decreased remarkably with the combined action of TMAO and a high glucose compared to either treatment alone. TMAO also promoted high-glucose-activated NLRP3 inflammasome complex. Conclusion The combination of TMAO and high-glucose results in increased levels of ROS and NLRP3 inflammasome complex activation in HRMECs, leading to exacerbated retinal dysfunction and barrier failure. Thus, TMAO can accelerate PDR occurrence and development, thus indicating the need for early fundus monitoring in diabetic patients with intestinal flora disorders.
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15
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Ren J, Zhang S, Pan Y, Jin M, Li J, Luo Y, Sun X, Li G. Diabetic retinopathy: Involved cells, biomarkers, and treatments. Front Pharmacol 2022; 13:953691. [PMID: 36016568 PMCID: PMC9396039 DOI: 10.3389/fphar.2022.953691] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic retinopathy (DR), a leading cause of vision loss and blindness worldwide, is caused by retinal neurovascular unit dysfunction, and its cellular pathology involves at least nine kinds of retinal cells, including photoreceptors, horizontal and bipolar cells, amacrine cells, retinal ganglion cells, glial cells (Müller cells, astrocytes, and microglia), endothelial cells, pericytes, and retinal pigment epithelial cells. Its mechanism is complicated and involves loss of cells, inflammatory factor production, neovascularization, and BRB impairment. However, the mechanism has not been completely elucidated. Drug treatment for DR has been gradually advancing recently. Research on potential drug targets relies upon clear information on pathogenesis and effective biomarkers. Therefore, we reviewed the recent literature on the cellular pathology and the diagnostic and prognostic biomarkers of DR in terms of blood, protein, and clinical and preclinical drug therapy (including synthesized molecules and natural molecules). This review may provide a theoretical basis for further DR research.
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Affiliation(s)
- Jiahui Ren
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Jinghong, China
- Yunnan Key Laboratory of Southern Medicine Utilization, Kunming, China
| | - Shuxia Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
| | - Yunfeng Pan
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
| | - Meiqi Jin
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
| | - Jiaxin Li
- Yunnan Key Laboratory of Southern Medicine Utilization, Kunming, China
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yun Luo
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun , ; Guang Li,
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun , ; Guang Li,
| | - Guang Li
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Jinghong, China
- Yunnan Key Laboratory of Southern Medicine Utilization, Kunming, China
- *Correspondence: Yun Luo, ; Xiaobo Sun , ; Guang Li,
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16
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Liu C, Dong W, Lv Z, Kong L, Ren X. Thioredoxin-interacting protein in diabetic retinal neurodegeneration: A novel potential therapeutic target for diabetic retinopathy. Front Neurosci 2022; 16:957667. [PMID: 36017183 PMCID: PMC9396221 DOI: 10.3389/fnins.2022.957667] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic retinopathy (DR) is a common complication of diabetes mellitus and has been considered a microvascular disease for a long time. However, recent evidence suggests that diabetic retinal neurodegeneration (DRN), which manifests as neuronal apoptosis, a decrease in optic nerve axons, and reactive gliosis, occurs prior to retinal microvascular alterations. Thioredoxin-interacting protein (TXNIP) is an endogenous inhibitor of thioredoxin (Trx), and it acts by inhibiting its reducing capacity, thereby promoting cellular oxidative stress. In addition, it participates in regulating multiple signaling pathways as a member of the α-arrestin family of proteins. Accumulating evidence suggests that TXNIP is upregulated in diabetes and plays a pivotal role in the pathophysiological process of DR. In this review, we summarized the role of TXNIP in DRN, aiming to provide evidence for DR treatment in the future.
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Affiliation(s)
- Chengzhi Liu
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Department of Histology and Embryology, College of Basic Medicine, Dalian Medical University, Dalian, China
| | - Wenkang Dong
- Department of Histology and Embryology, College of Basic Medicine, Dalian Medical University, Dalian, China
| | - Zhengshuai Lv
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
- *Correspondence: Zhengshuai Lv,
| | - Li Kong
- Department of Histology and Embryology, College of Basic Medicine, Dalian Medical University, Dalian, China
- Li Kong,
| | - Xiang Ren
- Department of Histology and Embryology, College of Basic Medicine, Dalian Medical University, Dalian, China
- Xiang Ren,
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17
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Chen M, Rong R, Xia X. Spotlight on pyroptosis: role in pathogenesis and therapeutic potential of ocular diseases. J Neuroinflammation 2022; 19:183. [PMID: 35836195 PMCID: PMC9281180 DOI: 10.1186/s12974-022-02547-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 07/05/2022] [Indexed: 11/10/2022] Open
Abstract
Pyroptosis is a programmed cell death characterized by swift plasma membrane disruption and subsequent release of cellular contents and pro-inflammatory mediators (cytokines), including IL‐1β and IL‐18. It differs from other types of programmed cell death such as apoptosis, autophagy, necroptosis, ferroptosis, and NETosis in terms of its morphology and mechanism. As a recently discovered form of cell death, pyroptosis has been demonstrated to be involved in the progression of multiple diseases. Recent studies have also suggested that pyroptosis is linked to various ocular diseases. In this review, we systematically summarized and discussed recent scientific discoveries of the involvement of pyroptosis in common ocular diseases, including diabetic retinopathy, age-related macular degeneration, AIDS-related human cytomegalovirus retinitis, glaucoma, dry eye disease, keratitis, uveitis, and cataract. We also organized new and emerging evidence suggesting that pyroptosis signaling pathways may be potential therapeutic targets in ocular diseases, hoping to provide a summary of overall intervention strategies and relevant multi-dimensional evaluations for various ocular diseases, as well as offer valuable ideas for further research and development from the perspective of pyroptosis.
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Affiliation(s)
- Meini Chen
- Eye Center of Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.,Hunan Key Laboratory of Ophthalmology, Changsha, 410008, Hunan, People's Republic of China.,National Clinical Research Center for Geriatric Diseases (Xiangya Hospital), Changsha, 410008, Hunan, People's Republic of China
| | - Rong Rong
- Eye Center of Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.,Hunan Key Laboratory of Ophthalmology, Changsha, 410008, Hunan, People's Republic of China.,National Clinical Research Center for Geriatric Diseases (Xiangya Hospital), Changsha, 410008, Hunan, People's Republic of China
| | - Xiaobo Xia
- Eye Center of Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China. .,Hunan Key Laboratory of Ophthalmology, Changsha, 410008, Hunan, People's Republic of China. .,National Clinical Research Center for Geriatric Diseases (Xiangya Hospital), Changsha, 410008, Hunan, People's Republic of China.
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18
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El-Azab MF, Wakiel AE, Nafea YK, Youssef ME. Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy. World J Diabetes 2022; 13:387-407. [PMID: 35664549 PMCID: PMC9134026 DOI: 10.4239/wjd.v13.i5.387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/18/2021] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic complications, chiefly seen in long-term situations, are persistently deleterious to a large extent, requiring multi-factorial risk reduction strategies beyond glycemic control. Diabetic cardiomyopathy is one of the most common deleterious diabetic complications, being the leading cause of mortality among diabetic patients. The mechanisms of diabetic cardiomyopathy are multi-factorial, involving increased oxidative stress, accumulation of advanced glycation end products (AGEs), activation of various pro-inflammatory and cell death signaling pathways, and changes in the composition of extracellular matrix with enhanced cardiac fibrosis. The novel lipid signaling system, the endocannabinoid system, has been implicated in the pathogenesis of diabetes and its complications through its two main receptors: Cannabinoid receptor type 1 and cannabinoid receptor type 2, alongside other components. However, the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated. This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy. These mechanisms include oxidative/ nitrative stress, inflammation, accumulation of AGEs, cardiac remodeling, and autophagy. A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.
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Affiliation(s)
- Mona F El-Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed E Wakiel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Yossef K Nafea
- Program of Biochemistry, McMaster University, Hamilton L8S 4L8, Ontario, Canada
| | - Mahmoud E Youssef
- Department of Pharmacology and Biochemistry, Delta University for Science and Technology, Mansoura 35511, New Cairo, Egypt
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19
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Liu L, Jiang Y, Steinle JJ. TNFAIP3 may be key to TLR4-activation of the inflammasome in the retinal vasculature. Exp Eye Res 2022; 220:109108. [PMID: 35568203 DOI: 10.1016/j.exer.2022.109108] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/08/2022] [Accepted: 05/06/2022] [Indexed: 11/04/2022]
Abstract
The goal of these studies were to determine whether tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) regulated toll-like receptor 4 (TLR4) actions on the NOD-like receptor protein 3 (NLRP3) inflammasome. Western blotting was done on retinal lysates from TLR4 floxed and endothelial cell specific TLR4 knockout mice for TNFAIP3, TLR4, and NLRP3 pathway proteins. Retinal endothelial cells (REC) were grown in normal (5mM) and high glucose (25mM) and treated with TNFAIP3 siRNA, followed by Western blotting for TLR4 and NLRP3 pathway proteins. Loss of TLR4 in endothelial cells increased TNFAIP3 levels, while decreasing NLRP3 pathway proteins. High glucose culturing conditions increased TLR4 and NLRP3 proteins, which were also increased by TNFAIP3 siRNA. Data demonstrate that TLR4 regulates NLRP3 pathway proteins. TNFAIP3 can regulate TLR4 and the NLRP3 pathway. TNFAIP3 may offer a new target for therapeutic development against retinal inflammation.
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Affiliation(s)
- Li Liu
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Youde Jiang
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Jena J Steinle
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
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20
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Zhang Y, Jiao Y, Li X, Gao S, Zhou N, Duan J, Zhang M. Pyroptosis: A New Insight Into Eye Disease Therapy. Front Pharmacol 2021; 12:797110. [PMID: 34925047 PMCID: PMC8678479 DOI: 10.3389/fphar.2021.797110] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 11/15/2021] [Indexed: 02/05/2023] Open
Abstract
Pyroptosis is a lytic form of programmed cell death mediated by gasdermins (GSDMs) with pore-forming activity in response to certain exogenous and endogenous stimuli. The inflammasomes are intracellular multiprotein complexes consisting of pattern recognition receptors, an adaptor protein ASC (apoptosis speck-like protein), and caspase-1 and cause autocatalytic activation of caspase-1, which cleaves gasdermin D (GSDMD), inducing pyroptosis accompanied by cytokine release. In recent years, the pathogenic roles of inflammasomes and pyroptosis in multiple eye diseases, including keratitis, dry eyes, cataracts, glaucoma, uveitis, age-related macular degeneration, and diabetic retinopathy, have been continuously confirmed. Inhibiting inflammasome activation and abnormal pyroptosis in eyes generally attenuates inflammation and benefits prognosis. Therefore, insight into the pathogenesis underlying pyroptosis and inflammasome development in various types of eye diseases may provide new therapeutic strategies for ocular disorders. Inhibitors of pyroptosis, such as NLRP3, caspase-1, and GSDMD inhibitors, have been proven to be effective in many eye diseases. The purpose of this article is to illuminate the mechanism underlying inflammasome activation and pyroptosis and emphasize its crucial role in various ocular disorders. In addition, we review the application of pyroptosis modulators in eye diseases.
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Affiliation(s)
- Yun Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Jiao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xun Li
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Sheng Gao
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Nenghua Zhou
- Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Jianan Duan
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Meixia Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
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21
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Song Y, Guo F, Zhao Y, Zhao L, Fan X, Zhang Y, Liu Y, Qin G. Verapamil ameliorates proximal tubular epithelial cells apoptosis and fibrosis in diabetic kidney. Eur J Pharmacol 2021; 911:174552. [PMID: 34627808 DOI: 10.1016/j.ejphar.2021.174552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 11/22/2022]
Abstract
Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus for which there is still no effective treatment. We previously showed that upregulation of thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of thioredoxin (TRX), accelerates the progression of DKD. In this study, we hypothesized whether verapamil, a calcium channel blocker and an established TXNIP inhibitor, might exert a renal-protective effect on DKD by regulating TXNIP expression. Herein, a systemic pharmacological network study was performed and multiple molecules and pathways targeted by verapamil on DKD were characterized. Furthermore, diabetic mice were induced by streptozotocin (STZ), and verapamil (100 mg/kg/day) or saline was intraperitoneally injected into the mice. After 16 weeks, mice were analyzed for blood glucose, blood pressure, and functional parameters followed by sacrifice and evaluation of renal tubular injury, alterations in TXNIP, apoptosis and fibrosis markers. Additionally, the effects of treatment with verapamil (50 μM, 100 μM, 150 μM) under high glucose conditions on the expression of TXNIP and signaling pathway components in proximal tubular epithelial cells (PTEC, HK-2 cells) were explored. According to these findings, we conclude that verapamil might serve as a potential agent for the prevention and treatment of DKD.
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Affiliation(s)
- Yi Song
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Academy of Medical Sciences of Zhengzhou University, Zhengzhou, 450052, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Feng Guo
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Academy of Medical Sciences of Zhengzhou University, Zhengzhou, 450052, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yanyan Zhao
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Lin Zhao
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xunjie Fan
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Academy of Medical Sciences of Zhengzhou University, Zhengzhou, 450052, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yuanyuan Zhang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yanling Liu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Guijun Qin
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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22
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Zhang Y, Yang W, Li W, Zhao Y. NLRP3 Inflammasome: Checkpoint Connecting Innate and Adaptive Immunity in Autoimmune Diseases. Front Immunol 2021; 12:732933. [PMID: 34707607 PMCID: PMC8542789 DOI: 10.3389/fimmu.2021.732933] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Autoimmune diseases are a broad spectrum of human diseases that are characterized by the breakdown of immune tolerance and the production of autoantibodies. Recently, dysfunction of innate and adaptive immunity is considered to be a key step in the initiation and maintenance of autoimmune diseases. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex, which can detect exogenous pathogen irritants and endogenous danger signals. The main function of NLRP3 inflammasome is to promote secretion of interleukin (IL)-1β and IL-18, and pyroptosis mediated by caspase-1. Served as a checkpoint in innate and adaptive immunity, aberrant activation and regulation of NLRP3 inflammasome plays an important role in the pathogenesis of autoimmune diseases. This paper reviewed the roles of NLRP3 inflammasome in autoimmune diseases, which shows NLRP3 inflammasome may be a potential target for autoimmune diseases deserved further study.
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Affiliation(s)
- Yiwen Zhang
- Department of Dermatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenlin Yang
- Department of Dermatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wangen Li
- Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yunjuan Zhao
- Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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