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Zhong X, Wei Q, Tiwari A, Wang Q, Tan Y, Chen R, Yan Y, Cox NJ, Li B. A Genetics-guided Integrative Framework for Drug Repurposing: Identifying Anti-hypertensive Drug Telmisartan for Type 2 Diabetes. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.03.22.25324223. [PMID: 40166562 PMCID: PMC11957187 DOI: 10.1101/2025.03.22.25324223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Drug development is a long and costly process, and repurposing existing drugs for use toward a different disease or condition may serve as a cost-effective alternative. As drug targets with genetic support have a doubled success rate, genetics-informed drug repurposing holds promise in translating genetic findings into therapeutics. In this study, we developed a Genetics Informed Network-based Drug Repurposing via in silico Perturbation (GIN-DRIP) framework and applied the framework to repurpose drugs for type-2 diabetes (T2D). In GIN-DRIP for T2D, it integrates multi-level omics data to translate T2D GWAS signals into a genetics-informed network that simultaneously encodes gene importance scores and a directional effect (up/down) of risk genes for T2D; it then bases on the GIN to perform signature matching with drug perturbation experiments to identify drugs that can counteract the effect of T2D risk alleles. With this approach, we identified 3 high-confidence FDA-approved candidate drugs for T2D, and validated telmisartan, an anti-hypertensive drug, in our EHR data with over 3 million patients. We found that telmisartan users were associated with a reduced incidence of T2D compared to users of other anti-hypertensive drugs and non-users, supporting the therapeutic potential of telmisartan for T2D. Our framework can be applied to other diseases for translating GWAS findings to aid drug repurposing for complex diseases.
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Affiliation(s)
- Xue Zhong
- Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN
| | - Qiang Wei
- Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN
| | - Anshul Tiwari
- Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN
| | - Quan Wang
- Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN
| | - Yuting Tan
- Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN
| | - Rui Chen
- Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN
| | - Yan Yan
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Nancy J Cox
- Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN
| | - Bingshan Li
- Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN
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Wang XR, Wu Z, He TT, Chen XH, Jin XF, Zuo CY, Yang SZ, Gao Y, Zhou XH, Gao WJ. Global research hotspots and trends in oxidative stress-related diabetic nephropathy: a bibliometric study. Front Endocrinol (Lausanne) 2025; 15:1451954. [PMID: 39866738 PMCID: PMC11757133 DOI: 10.3389/fendo.2024.1451954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 12/19/2024] [Indexed: 01/28/2025] Open
Abstract
Background Oxidative stress is widely acknowledged as a key pathogenic mechanism in diabetic nephropathy (DN). In recent years, the role of oxidative stress in DN has garnered increasing attention. However, no bibliometric analysis has yet been conducted on the relationship between oxidative stress and DN. This study aims to systematically analyze the relevant literature, identify trends in research, assess current hotspots, and predict future directions. Methods We retrieved literature related to oxidative stress and DN from the Web of Science Core Collection database. We analyzed data on publication volume, countries/regions, institutions, journals, keywords, and other relevant metrics using VOSviewer, the Bibliometrix R package, and CiteSpace. Results From 2014 to 2024, a total of 4076 publications related to oxidative stress and DN were published across 755 journals, showing a consistent upward trend each year. China and the United States are the leading contributors in this field and demonstrate close collaborative efforts. The top contributors by country, institution, journal, and author include: China (1919 publications), Jilin University and Central South University (69 publications each), BIOMEDICINE & PHARMACOTHERAPY (117 publications), and Prof. Sun Lin (33 publications). The most frequent keyword is "oxidative stress" (3683 occurrences). In the co-citation analysis, Alicic RZ's 2017 study was the most cited (144 citations). These findings highlight the critical importance of investigating the pathogenesis of DN from the oxidative stress perspective. Conclusion This study demonstrates a steady increase in research on oxidative stress in DN since 2014, highlighting its central role in the pathogenesis of DN. Future research should focus on the molecular mechanisms of oxidative stress in DN and explore its therapeutic potential, to provide new strategies for the prevention and treatment of DN.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Xiao-hong Zhou
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Wei-juan Gao
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, China
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Hashmat A, Ya J, Kadir R, Alwjwaj M, Bayraktutan U. Hyperglycaemia perturbs blood-brain barrier integrity through its effects on endothelial cell characteristics and function. Tissue Barriers 2025; 13:2350821. [PMID: 38712515 PMCID: PMC11970753 DOI: 10.1080/21688370.2024.2350821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/24/2024] [Accepted: 04/29/2024] [Indexed: 05/08/2024] Open
Abstract
Breakdown of blood-brain barrier (BBB) represents a key pathology in hyperglycemia-mediated cerebrovascular damage after an ischemic stroke. As changes in the level and nature of vasoactive agents released by endothelial cells (ECs) may contribute to BBB dysfunction, this study first explored the specific impact of hyperglycemia on EC characteristics and secretome. It then assessed whether secretome obtained from ECs subjected to normoglycaemia or hyperglycemia might regulate pericytic cytokine profile differently. Using a triple cell culture model of human BBB, composed of brain microvascular EC (BMEC), astrocytes and pericytes, this study showed that exposure to hyperglycemia (25 mM D-glucose) for 72 h impaired the BBB integrity and function as evidenced by decreases in transendothelial electrical resistance and increases in paracellular flux of sodium fluorescein. Dissolution of zonula occludens-1, a tight junction protein, and appearance of stress fibers appeared to play a key role in this pathology. Despite elevations in angiogenin, endothelin-1, interleukin-8 and basic fibroblast growth factor levels and a decrease in placental growth factor levels in BMEC subjected to hyperglycemia vs normoglycaemia (5.5 mM D-glucose), tubulogenic capacity of BMECs remained similar in both settings. Similarly, pericytes subjected to secretome obtained from hyperglycemic BMEC released higher quantities of macrophage migration inhibitory factor and serpin and lower quantities of monocyte chemoattractant protein-1, intercellular adhesion molecule, interleukin-6 and interleukin-8. Taken together these findings indicate the complexity of the mechanisms leading to BBB disruption in hyperglycemic settings and emphasize the importance of endothelial cell-pericyte axis in the development of novel therapeutic strategies.
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Affiliation(s)
- Arshad Hashmat
- Academic Unit of Mental Health and Clinical Neurosciences, School of Medicine, The University of Nottingham, Nottingham, UK
| | - Jingyuan Ya
- Academic Unit of Mental Health and Clinical Neurosciences, School of Medicine, The University of Nottingham, Nottingham, UK
| | - Rais Kadir
- Academic Unit of Mental Health and Clinical Neurosciences, School of Medicine, The University of Nottingham, Nottingham, UK
| | - Mansour Alwjwaj
- Academic Unit of Mental Health and Clinical Neurosciences, School of Medicine, The University of Nottingham, Nottingham, UK
| | - Ulvi Bayraktutan
- Academic Unit of Mental Health and Clinical Neurosciences, School of Medicine, The University of Nottingham, Nottingham, UK
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Ruscitti P, Currado D, Rivellese F, Vomero M, Navarini L, Cipriani P, Pitzalis C, Giacomelli R. Diminished expression of the ubiquitin-proteasome system in early treatment-naïve patients with rheumatoid arthritis and concomitant type 2 diabetes may be linked to IL-1 pathway hyper-activity; results from PEAC cohort. Arthritis Res Ther 2024; 26:171. [PMID: 39342401 PMCID: PMC11437779 DOI: 10.1186/s13075-024-03392-9] [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: 01/06/2024] [Accepted: 09/03/2024] [Indexed: 10/01/2024] Open
Abstract
OBJECTIVE Based on the recent evidence of IL-1 inhibition in patients with rheumatoid arthritis (RA) and concomitant type 2 diabetes (T2D), we evaluated the synovial tissue expression of IL-1 related genes in relationship to the ubiquitin-proteasome system and the effects of insulin on ubiquitinated proteins in fibroblast-like synoviocytes (FLSs). METHODS The synovial expression of IL-1 pathway genes was compared in early (< 1 year) treatment-naïve RA patients with T2D (RA/T2D n = 16) and age- and sex-matched RA patients without T2D (n = 16), enrolled in the Pathobiology of Early Arthritis Cohort (PEAC). The synovial expression of ubiquitin in macrophages and synovial lining fibroblasts was also assessed by Immunohistochemistry/immunofluorescence and correlated with synovial pathotypes. Finally, FLSs from RA patients (n = 5) were isolated and treated with human insulin (200 and 500 nM) and ubiquitinated proteins were assessed by western blot. RESULTS Synovial tissues of RA/T2D patients were characterised by a consistent reduced expression of ubiquitin-proteasome genes. More specifically, ubiquitin genes (UBB, UBC, and UBA52) and genes codifying proteasome subunits (PSMA2, PSMA6, PSMA7, PSMB1, PSMB3, PSMB4, PSMB6, PSMB8, PSMB9, PSMB10, PSMC1, PSMD9, PSME1, and PSME2) were significantly lower in RA/T2D patients. On the contrary, genes regulating fibroblast functions (FGF7, FGF10, FRS2, FGFR3, and SOS1), and genes linked to IL-1 pathway hyper-activity (APP, IRAK2, and OSMR) were upregulated in RA/T2D. Immunohistochemistry showed a significant reduction of the percentage of ubiquitin-positive cells in synovial tissues of RA/T2D patients. Ubiquitin-positive cells were also increased in patients with a lympho-myeloid pathotype compared to diffuse myeloid or pauci-immune-fibroid. Finally, in vitro experiments showed a reduction of ubiquitinated proteins in RA-FLSs treated with a high concentration of insulin (500 nM). CONCLUSIONS A different IL-1 pathway gene expression was observed in the synovial tissues of early treatment-naïve RA/T2D patients, linked to decreased expression of the ubiquitin-proteasome system. These findings may provide a mechanistic explanation of the observed clinical benefits of IL-1 inhibition in patients with RA and concomitant T2D.
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Affiliation(s)
- Piero Ruscitti
- Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Delta 6 Building, PO box 67100, L'Aquila, Italy.
| | - Damiano Currado
- Clinical and Research Section of Rheumatology and Clinical Immunology, Fondazione Policlinico Campus Bio-Medico, Via Álvaro del Portillo 200, 00128, Rome, Italy
- Rheumatology and Clinical Immunology, Department of Medicine, University of Rome "Campus Biomedico", School of Medicine, Rome, Italy
| | - Felice Rivellese
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK
- Barts Health NHS Trust & Barts Biomedical Research Centre (BRC) National Institute for Health and Care Research (NIHR), London, UK
| | - Marta Vomero
- Clinical and Research Section of Rheumatology and Clinical Immunology, Fondazione Policlinico Campus Bio-Medico, Via Álvaro del Portillo 200, 00128, Rome, Italy
- Rheumatology and Clinical Immunology, Department of Medicine, University of Rome "Campus Biomedico", School of Medicine, Rome, Italy
| | - Luca Navarini
- Clinical and Research Section of Rheumatology and Clinical Immunology, Fondazione Policlinico Campus Bio-Medico, Via Álvaro del Portillo 200, 00128, Rome, Italy
- Rheumatology and Clinical Immunology, Department of Medicine, University of Rome "Campus Biomedico", School of Medicine, Rome, Italy
| | - Paola Cipriani
- Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Delta 6 Building, PO box 67100, L'Aquila, Italy
| | - Costantino Pitzalis
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK
- Barts Health NHS Trust & Barts Biomedical Research Centre (BRC) National Institute for Health and Care Research (NIHR), London, UK
- IRCCS Humanitas Research Hospital, Milan, Italy
| | - Roberto Giacomelli
- Clinical and Research Section of Rheumatology and Clinical Immunology, Fondazione Policlinico Campus Bio-Medico, Via Álvaro del Portillo 200, 00128, Rome, Italy
- Rheumatology and Clinical Immunology, Department of Medicine, University of Rome "Campus Biomedico", School of Medicine, Rome, Italy
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Gong W, Sun P, Li X, Wang X, Zhang X, Cui H, Yang J. Investigating the Molecular Mechanisms of Resveratrol in Treating Cardiometabolic Multimorbidity: A Network Pharmacology and Bioinformatics Approach with Molecular Docking Validation. Nutrients 2024; 16:2488. [PMID: 39125368 PMCID: PMC11314475 DOI: 10.3390/nu16152488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/14/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND Resveratrol is a potent phytochemical known for its potential in treating cardiometabolic multimorbidity. However, its underlying mechanisms remain unclear. Our study systematically investigates the effects of resveratrol on cardiometabolic multimorbidity and elucidates its mechanisms using network pharmacology and molecular docking techniques. METHODS We screened cardiometabolic multimorbidity-related targets using the OMIM, GeneCards, and DisGeNET databases, and utilized the DSigDB drug characterization database to predict resveratrol's effects on cardiometabolic multimorbidity. Target identification for resveratrol was conducted using the TCMSP, SymMap, DrugBank, Swiss Target Prediction, CTD, and UniProt databases. SwissADME and ADMETlab 2.0 simulations were used to predict drug similarity and toxicity profiles of resveratrol. Protein-protein interaction (PPI) networks were constructed using Cytoscape 3.9.1 software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed via the DAVID online platform, and target-pathway networks were established. Molecular docking validated interactions between core targets and resveratrol, followed by molecular dynamics simulations on the optimal core proteins identified through docking. Differential analysis using the GEO dataset validated resveratrol as a core target in cardiometabolic multimorbidity. RESULTS A total of 585 cardiometabolic multimorbidity target genes were identified, and the predicted results indicated that the phytochemical resveratrol could be a major therapeutic agent for cardiometabolic multimorbidity. SwissADME simulations showed that resveratrol has potential drug-like activity with minimal toxicity. Additionally, 6703 targets of resveratrol were screened. GO and KEGG analyses revealed that the main biological processes involved included positive regulation of cell proliferation, positive regulation of gene expression, and response to estradiol. Significant pathways related to MAPK and PI3K-Akt signaling pathways were also identified. Molecular docking and molecular dynamics simulations demonstrated strong interactions between resveratrol and core targets such as MAPK and EGFR. CONCLUSIONS This study predicts potential targets and pathways of resveratrol in treating cardiometabolic multimorbidity, offering a new research direction for understanding its molecular mechanisms. Additionally, it establishes a theoretical foundation for the clinical application of resveratrol.
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Affiliation(s)
- Wei Gong
- Public Health School, Ningxia Medical University, Yinchuan 750004, China; (W.G.)
- Key Laboratory of Environmental Factors and Chronic Disease Control, Yinchuan 750004, China
- School of Medical Information and Engineering, Ningxia Medical University, Yinchuan 750004, China
| | - Peng Sun
- Public Health School, Ningxia Medical University, Yinchuan 750004, China; (W.G.)
- Science and Technology Center, Ningxia Medical University, Yinchuan 750001, China
- Ningxia Hui Autonomous Region Institute of Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Xiujing Li
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
| | - Xi Wang
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
| | - Xinyu Zhang
- School of Medical Information and Engineering, Ningxia Medical University, Yinchuan 750004, China
| | - Huimin Cui
- Public Health School, Ningxia Medical University, Yinchuan 750004, China; (W.G.)
- Key Laboratory of Environmental Factors and Chronic Disease Control, Yinchuan 750004, China
| | - Jianjun Yang
- Public Health School, Ningxia Medical University, Yinchuan 750004, China; (W.G.)
- Key Laboratory of Environmental Factors and Chronic Disease Control, Yinchuan 750004, China
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Ullah S, Burki S, Munir AB, Yousaf G, Shafique M. Nanocarrier-based localized and effective treatment of renal disorders: currently employed targeting strategies. Nanomedicine (Lond) 2024; 19:345-361. [PMID: 38293889 DOI: 10.2217/nnm-2023-0251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2024] Open
Abstract
Renal disorders pose a global health threat, with targeted drug-delivery systems emerging as a promising strategy to enhance therapy safety and efficacy. Recent efforts have harnessed targeted nanomaterials for kidney disease treatment. While some systems remain in the early stages, they show immense potential in delivering cargo to specific sites. Through animal model experimentations, it has been demonstrated to reduce systemic side effects and enhance treatment effectiveness. This review presents current strategies for kidney disorder treatment, emphasizing site-specific targeting critical to renal disease pathophysiology. Recent advancements in nano-drug delivery systems for kidney targeting are explored. Finally, toxicological aspects and prospects of the most promising kidney-targeting delivery systems are discussed in this review article.
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Affiliation(s)
- Shafi Ullah
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Superior University, Lahore, Punjab, 54000, Pakistan
| | - Samiullah Burki
- Department of Pharmacology, Jinnah Sindh Medical University, Karachi, 75510, Pakistan
| | - Abu Bakar Munir
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Superior University, Lahore, Punjab, 54000, Pakistan
| | - Ghulam Yousaf
- PAF Ruth Pfau Medical College and Hospital Faisal Base Karachi, Karachi, 75350, Pakistan
| | - Muhammad Shafique
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, 11961, Saudi Arabia
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Xourafa G, Korbmacher M, Roden M. Inter-organ crosstalk during development and progression of type 2 diabetes mellitus. Nat Rev Endocrinol 2024; 20:27-49. [PMID: 37845351 DOI: 10.1038/s41574-023-00898-1] [Citation(s) in RCA: 74] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/29/2023] [Indexed: 10/18/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by tissue-specific insulin resistance and pancreatic β-cell dysfunction, which result from the interplay of local abnormalities within different tissues and systemic dysregulation of tissue crosstalk. The main local mechanisms comprise metabolic (lipid) signalling, altered mitochondrial metabolism with oxidative stress, endoplasmic reticulum stress and local inflammation. While the role of endocrine dysregulation in T2DM pathogenesis is well established, other forms of inter-organ crosstalk deserve closer investigation to better understand the multifactorial transition from normoglycaemia to hyperglycaemia. This narrative Review addresses the impact of certain tissue-specific messenger systems, such as metabolites, peptides and proteins and microRNAs, their secretion patterns and possible alternative transport mechanisms, such as extracellular vesicles (exosomes). The focus is on the effects of these messengers on distant organs during the development of T2DM and progression to its complications. Starting from the adipose tissue as a major organ relevant to T2DM pathophysiology, the discussion is expanded to other key tissues, such as skeletal muscle, liver, the endocrine pancreas and the intestine. Subsequently, this Review also sheds light on the potential of multimarker panels derived from these biomarkers and related multi-omics for the prediction of risk and progression of T2DM, novel diabetes mellitus subtypes and/or endotypes and T2DM-related complications.
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Affiliation(s)
- Georgia Xourafa
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Düsseldorf, Germany
| | - Melis Korbmacher
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Düsseldorf, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Düsseldorf, Germany.
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
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Lv C, Cheng T, Zhang B, Sun K, Lu K. Triptolide protects against podocyte injury in diabetic nephropathy by activating the Nrf2/HO-1 pathway and inhibiting the NLRP3 inflammasome pathway. Ren Fail 2023; 45:2165103. [PMID: 36938748 PMCID: PMC10035962 DOI: 10.1080/0886022x.2023.2165103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2023] Open
Abstract
Objectives: Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus. This study investigated the mechanism of triptolide (TP) in podocyte injury in DN.Methods: DN mouse models were established by feeding with a high-fat diet and injecting with streptozocin and MPC5 podocyte injury models were induced by high-glucose (HG), followed by TP treatment. Fasting blood glucose and renal function indicators, such as 24 h urine albumin (UAlb), serum creatinine (SCr), blood urea nitrogen (BUN), and kidney/body weight ratio of mice were examined. H&E and TUNEL staining were performed for evaluating pathological changes and apoptosis in renal tissue. The podocyte markers, reactive oxygen species (ROS), oxidative stress (OS), serum inflammatory cytokines, nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway-related proteins, and pyroptosis were detected by Western blotting and corresponding kits. MPC5 cell viability and pyroptosis were evaluated by MTT and Hoechst 33342/PI double-fluorescence staining. Nrf2 inhibitor ML385 was used to verify the regulation of TP on Nrf2.Results: TP improved renal function and histopathological injury of DN mice, alleviated podocytes injury, reduced OS and ROS by activating the Nrf2/heme oxygenase-1 (HO-1) pathway, and weakened pyroptosis by inhibiting the nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome pathway. In vitro experiments further verified the inhibition of TP on OS and pyroptosis by mediating the Nrf2/HO-1 and NLRP3 inflammasome pathways. Inhibition of Nrf2 reversed the protective effect of TP on MPC5 cells.Conclusions: Overall, TP alleviated podocyte injury in DN by inhibiting OS and pyroptosis via Nrf2/ROS/NLRP3 axis.
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Affiliation(s)
- Chenlei Lv
- Department of Nephrology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Tianyang Cheng
- Department of Nephrology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Bingbing Zhang
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Ke Sun
- Department of Nephrology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Keda Lu
- Department of Nephrology, The Third Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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Tseng CH, Shah KM, Chiu IJ, Hsiao LL. The Role of Autophagy in Type 2 Diabetic Kidney Disease Management. Cells 2023; 12:2691. [PMID: 38067119 PMCID: PMC10705810 DOI: 10.3390/cells12232691] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/17/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023] Open
Abstract
Diabetic kidney disease (DKD), or diabetic nephropathy (DN), is one of the most prevalent complications of type 2 diabetes mellitus (T2DM) and causes severe burden on the general welfare of T2DM patients around the world. While several new agents have shown promise in treating this condition and potentially halting the progression of the disease, more work is needed to understand the complex regulatory network involved in the disorder. Recent studies have provided new insights into the connection between autophagy, a physiological metabolic process known to maintain cellular homeostasis, and the pathophysiological pathways of DKD. Typically, autophagic activity plays a role in DKD progression mainly by promoting an inflammatory response to tissue damage, while both overactivated and downregulated autophagy worsen disease outcomes in different stages of DKD. This correlation demonstrates the potential of autophagy as a novel therapeutic target for the disease, and also highlights new possibilities for utilizing already available DN-related medications. In this review, we summarize findings on the relationship between autophagy and DKD, and the impact of these results on clinical management strategies.
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Affiliation(s)
- Che-Hao Tseng
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (C.-H.T.); (K.M.S.)
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Kavya M. Shah
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (C.-H.T.); (K.M.S.)
| | - I-Jen Chiu
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (C.-H.T.); (K.M.S.)
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- TMU-Research Center of Urology and Kidney (TMU-RCUK), Taipei Medical University, Taipei 11031, Taiwan
| | - Li-Li Hsiao
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (C.-H.T.); (K.M.S.)
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Huang C, Ding L, Ji J, Qiao Y, Xia Z, Shi H, Zhang S, Gan W, Zhang A. Expression profiles and potential roles of serum tRNA‑derived fragments in diabetic nephropathy. Exp Ther Med 2023; 26:311. [PMID: 37273759 PMCID: PMC10236146 DOI: 10.3892/etm.2023.12010] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 03/29/2023] [Indexed: 06/06/2023] Open
Abstract
Diabetic nephropathy (DN) is one of the most important causes of end-stage renal disease and current treatments are ineffective in preventing its progression. Transfer RNA (tRNA)-derived fragments (tRFs), which are small non-coding fragments derived from tRNA precursors or mature tRNAs, have a critical role in various human diseases. The present study aimed to investigate the expression profile and potential functions of tRFs in DN. High-throughput sequencing technology was employed to detect the differential serum levels of tRFs between DN and diabetes mellitus and to validate the reliability of the sequencing results using reverse transcription-quantitative PCR. Ultimately, six differentially expressed (DE) tRFs were identified (P<0.05; |log2fold change| ≥1), including three upregulated (tRF5-GluCTC, tRF5-AlaCGC and tRF5-ValCAC) and three downregulated tRFs (tRF5-GlyCCC, tRF3-GlyGCC and tRF3-IleAAT). Potential functions and regulatory mechanisms of these DE tRFs were further evaluated using an applied bioinformatics-based analysis. Gene ontology analysis revealed that the DE tRFs are mainly enriched in biological processes, including axon guidance, Rad51 paralog (Rad51)B-Rad51C-Rad51D-X-Ray repair cross-complementing 2 complex, nuclear factor of activated T-cells protein binding and fibroblast growth factor-activated receptor activity. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that they are associated with axon guidance, neurotrophin signaling, mTOR signaling, AMPK signaling and epidermal growth factor receptor family signaling pathways. In conclusion, the present findings indicated that tRFs were DE in DN and may be involved in the regulation of DN pathology through multiple pathways, thereby providing a new perspective for the study of DN therapeutic targets.
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Affiliation(s)
- Chan Huang
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, P.R. China
| | - Ling Ding
- Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210031, P.R. China
| | - Jialing Ji
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, P.R. China
| | - Yunyang Qiao
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, P.R. China
| | - Zihuan Xia
- School of Pediatrics, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Huimin Shi
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, P.R. China
| | - Shiting Zhang
- Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210031, P.R. China
| | - Weihua Gan
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, P.R. China
| | - Aiqing Zhang
- Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210031, P.R. China
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Ornitz DM, Itoh N. New developments in the biology of fibroblast growth factors. WIREs Mech Dis 2022; 14:e1549. [PMID: 35142107 PMCID: PMC10115509 DOI: 10.1002/wsbm.1549] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 01/28/2023]
Abstract
The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltage-gated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases. This article is categorized under: Cardiovascular Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology Congenital Diseases > Stem Cells and Development Cancer > Stem Cells and Development.
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Affiliation(s)
- David M Ornitz
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Nobuyuki Itoh
- Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo, Kyoto, Japan
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Ma Y, Wang Q, Chen Y, Su J, Gao Q, Fan Y, Feng J, Liu M, He Q. Correlation of DHEA with diabetic nephropathy and its clinical value in early detection. J Diabetes Investig 2022; 13:1695-1702. [PMID: 35726691 PMCID: PMC9533038 DOI: 10.1111/jdi.13862] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/08/2022] [Accepted: 05/30/2022] [Indexed: 11/30/2022] Open
Abstract
Aims/Introduction This study was carried out to assess the association of dehydroepiandrosterone (DHEA) with diabetic nephropathy (DN) in patients with type 2 diabetes mellitus to better predict the progression of diabetic nephropathy. Materials and Methods A total of 1,082 patients with type 2 diabetes mellitus in the Department of Endocrinology and Metabolism of Tianjin Medical University General Hospital were enrolled in this study, and grouped for comparison. The effect of serum DHEA on DN was evaluated by multivariate logistic regression analysis, and receiver operating characteristic curves were established to explore the optimal concentration of DHEA in patients with DN and non‐DN. Results DHEA was significantly decreased in patients with DN (P < 0.001). The prevalence of DN was significantly higher in the low DHEA quartile than in the other quartiles (P < 0.001). Spearman‐related analysis showed that DHEA levels were negatively correlated with patient age, course of diabetes, systolic blood pressure, blood creatinine, uric acid, urine albumin‐to‐creatinine ratio, 24‐h urine microalbumin, 24‐h urine protein quantification and glomerular filtration rate, and positively correlated with body mass index, total cholesterol and low density lipoprotein. Logistic regression analysis showed that the effect of DHEA on DN was statistically significant (P < 0.001). The receiver operating characteristic curve showed that the sensitivity was 81.4%, the specificity was 70% and the area under the curve was 0.812 when the optimal cut‐off value was 1,640 (pg/mL). Conclusion DHEA is significantly associated with DN and might be a protective factor for DN, and is important for the prediction of DN.
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Affiliation(s)
- Ying Ma
- Tianjin Medical University;No.22, Meteorological Observatory Road, Heping District, Tianjin, Tianjin, China, 300070
| | - Qian Wang
- Tianjin Medical University General Hospital, Department of Clinical Laboratory, 154 Anshan Road Heping District Tianjin, Tianjin, China, 300052
| | - Yunxia Chen
- Cangzhou People's Hospital,Department of Endocrinology and Metabolis, No.7 Qingchi Road, Cangzhou, Hebei Province, China, 061000
| | - Junping Su
- Cangzhou People's Hospital,Department of Endocrinology and Metabolis, No.7 Qingchi Road, Cangzhou, Hebei Province, China, 061000
| | - Qian Gao
- Cangzhou People's Hospital,Department of Endocrinology and Metabolis, No.7 Qingchi Road, Cangzhou, Hebei Province, China, 061000
| | - Yuxin Fan
- Tianjin Medical University General Hospital, Department of Endocrinology and Metabolis, 54 Anshan Road Heping District Tianjin, Tianjin, China, 300052
| | - Jing Feng
- Tianjin Medical University General Hospital, Department of Respiratory and Critical Care Medicine, 154 Anshan Road, Heping District, Tianjin, China
| | - Ming Liu
- Tianjin Medical University General Hospital, Department of Endocrinology and Metabolis, 54 Anshan Road Heping District Tianjin, Tianjin, China, 300052
| | - Qing He
- Tianjin Medical University General Hospital, Department of Endocrinology and Metabolis, 54 Anshan Road Heping District Tianjin, Tianjin, China, 300052
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Bibliometric Study of Trends in the Diabetic Nephropathy Research Space from 2016 to 2020. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8050137. [PMID: 35450407 PMCID: PMC9018194 DOI: 10.1155/2022/8050137] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 03/02/2022] [Accepted: 03/17/2022] [Indexed: 12/15/2022]
Abstract
Background Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes mellitus (DM), but no bibliometric studies pertaining to DN have been published within the last 5 years. Objectives Most prior studies have focused on specific problems in the DN field. This study attempts to sort out and visualize the knowledge framework in this research space from a holistic and highly generalized perspective. Readers can quickly understand and master the knowledge regarding DN research conducted from 2016 to 2020, in addition to predicting future research hotspots and possible directions for development in this field in a comprehensive and scientifically valid manner. Methods Literature information, discourse matrices, and co-occurrence matrices were generated using BICOMB. gCLUTO was used for biclustering analyses and visualization. Strategic diagrams were generated using GraphPad Prism 5. The social network analysis (SNA) was analyzed and plotted using Ucinet 6.0 and Netdraw. Results In total, 55 high-frequency MeSH terms/MeSH subheadings were selected and grouped into 5 clusters in a biclustering analysis. These analyses revealed that extensive studies of the etiology, diagnosis, and treatment of DN have been conducted over the last 5 years, while further research regarding DN-related single nucleotide polymorphisms, miRNAs, and signal transduction are warranted as these research areas remain relatively immature. Conclusion Together, these results outline a robust knowledge structure pertaining to the field of DN-related research over the last 5 years, providing a valuable resource for readers by enabling the easy comprehension of relevant information. In addition, this analysis highlights predicted DN-related research directions and hotspots.
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