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Rani P, Koulmane Laxminarayana SL, Swaminathan SM, Nagaraju SP, Bhojaraja MV, Shetty S, Kanakalakshmi ST. TGF-β: elusive target in diabetic kidney disease. Ren Fail 2025; 47:2483990. [PMID: 40180324 PMCID: PMC11980245 DOI: 10.1080/0886022x.2025.2483990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 02/17/2025] [Accepted: 03/14/2025] [Indexed: 04/05/2025] Open
Abstract
Transforming growth factor-beta (TGF-β), a cytokine with near omnipresence, is an integral part of many vital cellular processes across the human body. The family includes three isoforms: Transforming growth factor-beta 1, 2, and 3. These cytokines play a significant role in the fibrosis cascade. Diabetic kidney disease (DKD), a major complication of diabetes, is increasing in prevalence daily, and the classical diagnosis of diabetes is based on the presence of albuminuria. The occurrence of nonalbuminuric DKD has provided new insight into the pathogenesis of this disease. The emphasis on multifactorial pathways involved in developing DKD has highlighted some markers associated with tissue fibrosis. In diabetic nephropathy, TGF-β is significantly involved in its pathology. Its presence in serum and urine means that it could be a diagnostic tool while its regulation provides potential therapeutic targets. Completely blocking TGF-β signaling could reach untargeted regions and cause unanticipated effects. This paper reviews the basic details of TGF-β as a cytokine, its role in DKD, and updates on research carried out to validate its candidacy.
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Affiliation(s)
- Priya Rani
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | | | - Shilna Muttickal Swaminathan
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Shankar Prasad Nagaraju
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | | | - Sahana Shetty
- Department of Endocrinology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
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Li W, Xu G, Li M. Diabetic kidney disease: m6A modification as a marker of disease progression and subtype classification. Front Med (Lausanne) 2025; 12:1494162. [PMID: 40103797 PMCID: PMC11914134 DOI: 10.3389/fmed.2025.1494162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 02/14/2025] [Indexed: 03/20/2025] Open
Abstract
This paper aims to investigate m6A modification during DKD progression. We evaluated m6A regulators expression in peripheral blood mononuclear cells, whole kidney tissue, glomerular, and tubulointerstitial samples. CIBERSORT and single-sample gene set enrichment analysis analyzed glomerular immune characteristics. Logistic-LASSO regression were used to develop the m6A regulators model that can identify early DKD. Consensus clustering algorithms were used to classify DKD in glomerular samples into m6A modified subtypes based on the expression of m6A regulators. Gene set variation analysis algorithm was used to evaluate the functional pathway enrichment of m6A modified subtypes. Weighted gene co-expression network analysis and protein-protein interaction networks identified m6A modified subtype marker genes. The Nephroseq V5 tool was used to evaluate the correlation between m6A modified subtypes marker genes and renal function. DKD patients' m6A regulators expression differed from the control group in various tissue types. DKD stages have various immune characteristics. The m6A regulators model with YTHDC1, METTL3, and ALKBH5 better identified early DKD. DKD was divided into two subtypes based on the expression of 26 m6A regulators. Subtype 1 was enriched in myogenesis, collagen components, and cytokine receptor interaction, while subtype 2 was enriched in protein secretion, proliferation, apoptosis, and various signaling pathways (e.g., TGFβ signaling pathway, PI3K/AKT/mTOR pathway, and etc.). Finally, AXIN1 and GOLGA4 were identified as possible biomarkers associated with glomerular filtration rate. From the viewpoint of m6A modification, the immune characteristics and molecular mechanisms of DKD at various stages are different, and targeted treatment would improve efficacy.
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Affiliation(s)
- Wenzhe Li
- The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Gaosi Xu
- The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Manna Li
- Department of Nephrology, Second Affiliated Hospital of Nanchang University, Nanchang, China
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3
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Zhang B, Geng H, Zhao K, Omorou M, Liu S, Ye Z, Zhang F, Luan H, Zhang X. FSTL1 aggravates high glucose-induced oxidative stress and transdifferentiation in HK-2 cells. Sci Rep 2025; 15:434. [PMID: 39748077 PMCID: PMC11696259 DOI: 10.1038/s41598-024-84462-5] [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: 07/10/2024] [Accepted: 12/23/2024] [Indexed: 01/04/2025] Open
Abstract
Chronic hyperglycemia, a hallmark of diabetes, can trigger inflammatory responses in the kidney, leading to diabetic nephropathy (DN). Follistatin-like protein 1 (FSTL1) has emerged as a potential therapeutic target in various kidney diseases. This study investigated the effect of high glucose on FSTL1 expression and its role in oxidative stress and cellular transdifferentiation injury in HK-2 human proximal tubule epithelial cells, a model of DN. We investigated FSTL1's level in HK-2 cells exposed to high glucose using Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). FSTL1 was manipulated using recombinant human FSTL1 (rhFSTL1) or lentiviral shFSTL1. We then analyzed proliferation, oxidative stress, transdifferentiation, cell migration, and the nuclear factor kappa-B (NF-κB) signaling pathway potentially involved in FSTL1 effects. Finally, we blocked the NF-κB pathway to see its influence on these cellular processes. High glucose exposure significantly increased FSTL1 in HK-2 cells, with longer/higher glucose further amplifying this effect. Silencing of FSTL1 ameliorates cellular damage by promoting proliferation, enhancing superoxide dismutase (SOD) and glutathione (GSH) activity, and reducing malondialdehyde (MDA) production, inhibiting cell migration. Furthermore, it prevented the harmful conversion of HK-2 cells from epithelial to myofibroblast-like phenotypes, evidenced by decreased fibronectin (FN) and α-smooth muscle actin (α-SMA) and preserved E-cadherin. Notably, silencing FSTL1 also inhibited the NF-κB signaling pathway. Conversely, rhFSTL1 exhibited opposite effects. Importantly, blocking NF-κB reversed the detrimental effects of FSTL1. These findings suggest that FSTL1 contributes to high glucose-induced kidney injury by promoting oxidative stress and cellular transdifferentiation potentially via the NF-κB pathway. Targeting FSTL1 may represent a novel therapeutic strategy for preventing or mitigating DN progression.
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Affiliation(s)
- Baoyuan Zhang
- Department of Histology and Embryology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
| | - Hang Geng
- Medical Imaging Center, First Affiliated Hospital, Jiamusi University, Jiamusi, Heilongjiang, China
| | - Kai Zhao
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
- Department of Physiology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
| | - Moussa Omorou
- Laboratory of Medical Biochemistry, First Affiliated Hospital, University of Lomé, Lomé, Togo
| | - Shuang Liu
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
- Department of Biology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
| | - Zhihui Ye
- Department of Orthodontics, Second Affiliated Hospital, Jiamusi University, Jiamusi, Heilongjiang, China
| | - Fanting Zhang
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
- Department of Physiology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
| | - Haiyan Luan
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China.
- Department of Physiology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China.
| | - Xuesong Zhang
- Medical Imaging Center, First Affiliated Hospital, Jiamusi University, Jiamusi, Heilongjiang, China.
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Das S, Ramanathan G. Assessing the Inhibitory Potential of Pregnenolone Sulfate on Pentraxin 3 in Diabetic Kidney Disease: A Molecular Docking and Simulation Study. J Cell Biochem 2025; 126:e30661. [PMID: 39344977 DOI: 10.1002/jcb.30661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/07/2024] [Accepted: 09/11/2024] [Indexed: 10/01/2024]
Abstract
Diabetic Kidney Disease (DKD), a frequent consequence of diabetes, has substantial implications for both morbidity and mortality rates, prompting the exploration of new metabolic biomarkers due to limitations in current methods like creatinine and albumin measurements. Pentraxin 3 (PTX3) shows promise for assessing renal inflammation in DKD. This study investigates how DKD metabolites could influence PTX3 expression through molecular docking, ADMET profiling, and dynamic simulation. Network and pathway analyses were conducted to explore metabolite interactions with DKD genes and their contributions to DKD pathogenesis. Thirty-three DKD-associated metabolites were screened, using pentoxifylline (PEN) as a reference. The pharmacokinetic properties of these compounds were evaluated through molecular docking and ADMET profiling. Molecular dynamics simulations over 200 ns assessed the stability of PTX3 (apo), the PRE-PTX3 complex, and PEN-PTX3 across multiple parameters. Cytoscape identified 1082 nodes and 1381 edges linking metabolites with DKD genes. KEGG pathway analysis underscored PTX3's role in inflammation. Molecular docking revealed pregnenolone sulfate (PRE) with the highest binding affinity (-6.25 kcal/mol), followed by hydrocortisone (-6.03 kcal/mol) and 2-arachidonoylglycerol (-5.92 kcal/mol), compared to PEN (-5.35 kcal/mol). ADMET profiling selected PRE for dynamic simulation alongside PEN. Analysis of RMSD, RMSF, RG, SASA, H-bond, PCA, FEL, and MM-PBSA indicated stable complex behavior over time. Our findings suggest that increasing PRE levels could be beneficial in managing DKD, potentially through isolating PRE from fungal sources, synthesizing it as dietary supplements, or enhancing endogenous PRE synthesis within the body.
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Affiliation(s)
- Soumik Das
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Gnanasambandan Ramanathan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
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Liu X, Zhai X, Wang X, Zhu X, Wang Z, Jiang Z, Bao H, Chen Z. Nuclear Factor Erythroid 2-Related Factor 2 Activator DDO-1039 Ameliorates Podocyte Injury in Diabetic Kidney Disease via Suppressing Oxidative Stress, Inflammation, and Ferroptosis. Antioxid Redox Signal 2024. [PMID: 39723566 DOI: 10.1089/ars.2024.0653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2024]
Abstract
Aims: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and podocyte injury is one of the major contributors to DKD. As a crucial transcriptional factor that regulates cellular response to oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) is an attractive therapeutic target for DKD. In this study, we evaluated the therapeutic potential of DDO-1039, a novel small-molecule Nrf2 activator developed with protein-protein interaction strategy, on podocyte injury in DKD. Results: DDO-1039 treatment significantly increased Nrf2 protein level and Nrf2 nuclear translocation, thereby upregulating Nrf2 target genes [heme oxygenase 1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase modifier, and tyrosine-protein kinase receptor] both in vitro and in vivo. DDO-1039 attenuated glomerular sclerosis and podocyte injury in the high-fat diet/streptozotocin-induced (HFD/STZ) diabetic mice and db/db diabetic mice. It also significantly improved hyperglycemia in both diabetic mice and mitigated proteinuria in HFD/STZ mice. Meanwhile, DDO-1039 attenuated oxidative stress and inflammation as well as apoptosis in vivo and in podocytes stimulated with palmitic acid and high glucose. Interestingly, we identified podocyte protective factor Tyro3 as a novel Nrf2-regulated gene. In addition, podocyte ferroptosis is reduced via activation of glutathione peroxidase 4 by the novel Nrf2 activator. Innovation and conclusion: DDO-1039 activates the Nrf2-based cytoprotective system to mitigate podocyte injury in the context of diabetes, suggesting the potential of DDO-1039 in the treatment of DKD. Antioxid. Redox Signal. 00, 000-000.
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Affiliation(s)
- Xing Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
- Clinical Research Center, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiuwen Zhai
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Xiaoyu Wang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Xiaodong Zhu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Ziyue Wang
- Nanjing University School of Medicine, Nanjing, China
| | - Zhengyu Jiang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
| | - Hao Bao
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
- Nanjing University School of Medicine, Nanjing, China
| | - ZhaoHong Chen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
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Dimu PS, Icksan AG, Farhat, Jonny, Hernowo BA, Putranto TA. Clinical Trial of Autologous Dendritic Cell Administration Effect on Water Molecule Diffusion and Anti-Inflammatory Biomarkers in Diabetic Kidney Disease. Curr Issues Mol Biol 2024; 46:13767-13779. [PMID: 39727950 PMCID: PMC11727518 DOI: 10.3390/cimb46120822] [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: 10/23/2024] [Revised: 11/21/2024] [Accepted: 11/25/2024] [Indexed: 12/28/2024] Open
Abstract
Diabetic kidney disease (DKD) significantly increases mortality, with patients facing a fourfold risk of death within ten years. Chronic inflammation, marked by transforming growth factor-β (TGF-β) and intracellular adhesion molecule-1 (ICAM-1) activity, contributes to kidney damage and fibrosis. This study investigates the effect of autologous dendritic cells on inflammation and kidney function, focusing on apparent diffusion coefficient (ADC), TGF-β, and ICAM-1 levels. This quasi-experimental clinical trial involved 22 DKD patients at Gatot Soebroto Army Hospital. Patients received autologous dendritic cell injections. Baseline and post-intervention magnetic resonance imaging (MRI) scans measured ADC values, and ICAM-1 and TGF-β levels were analyzed. Post intervention, the median ADC decreased from 1.75 mm2/s to 1.64 mm2/s (p = 0.223). ICAM-1 levels increased significantly in females (p = 0.04) but not in males (p = 0.35). No significant changes were found in TGF-β levels (p = 0.506). ADC changes were statistically insignificant and did not correlate with CKD severity. ICAM-1 increases in females correlated with improved creatinine levels, suggesting kidney function improvement. Autologous dendritic cell therapy revealed potential gender-specific immune responses but showed limited overall biomarker improvements. Further studies are required to validate its therapeutic value.
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Affiliation(s)
- Paulus Stefanus Dimu
- Faculty of Medicine, Dentistry, and Health Science, Universitas Prima Indonesia, Medan 20118, Indonesia; (P.S.D.); (F.); (J.); (B.A.H.); (T.A.P.)
- Department of Radiology, Slamet Riyadi Army Hospital, Surakarta 57148, Indonesia
| | - Aziza Ghanie Icksan
- Faculty of Medicine, Dentistry, and Health Science, Universitas Prima Indonesia, Medan 20118, Indonesia; (P.S.D.); (F.); (J.); (B.A.H.); (T.A.P.)
| | - Farhat
- Faculty of Medicine, Dentistry, and Health Science, Universitas Prima Indonesia, Medan 20118, Indonesia; (P.S.D.); (F.); (J.); (B.A.H.); (T.A.P.)
| | - Jonny
- Faculty of Medicine, Dentistry, and Health Science, Universitas Prima Indonesia, Medan 20118, Indonesia; (P.S.D.); (F.); (J.); (B.A.H.); (T.A.P.)
- Faculty of Medicine, Universitas Pembangunan Nasional “Veteran” Jakarta, Jakarta 12450, Indonesia
- Faculty of Military Medicine, Indonesia Defense University, Bogor 16810, Indonesia
- Nephrology Division, Department of Internal Medicine, Gatot Soebroto Central Army Hospital, Jakarta 10410, Indonesia
| | - Bhimo Aji Hernowo
- Faculty of Medicine, Dentistry, and Health Science, Universitas Prima Indonesia, Medan 20118, Indonesia; (P.S.D.); (F.); (J.); (B.A.H.); (T.A.P.)
- Indonesia Army Cellcure Center, Gatot Soebroto Central Army Hospital, Jakarta 10410, Indonesia
| | - Terawan Agus Putranto
- Faculty of Medicine, Dentistry, and Health Science, Universitas Prima Indonesia, Medan 20118, Indonesia; (P.S.D.); (F.); (J.); (B.A.H.); (T.A.P.)
- Faculty of Medicine, Universitas Pembangunan Nasional “Veteran” Jakarta, Jakarta 12450, Indonesia
- Indonesia Army Cellcure Center, Gatot Soebroto Central Army Hospital, Jakarta 10410, Indonesia
- Department of Radiology, Gatot Soebroto Central Army Hospital, Jakarta 10410, Indonesia
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Zhang X, Fang Y, Weng M, Chen C, Xu Y, Wan J. Systemic immune-inflammation index as an independent risk factor for diabetic nephropathy: a retrospective, single-center study. PeerJ 2024; 12:e18493. [PMID: 39677959 PMCID: PMC11639188 DOI: 10.7717/peerj.18493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/17/2024] [Indexed: 12/17/2024] Open
Abstract
Purpose Systemic immune-inflammation index (SII) was an indicator which could reflect immune response and systemic inflammation. We aim to explore the relationship between SII and diabetic nephropathy (DN). Methods SII was calculated as neutrophil count × platelet count/lymphocyte count. The receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnosis power of SII. Univariate and multivariate logistic analysis were conducted to assess SII as the risk factor for DN. A restricted cubic spline model was carried out to show the nonlinear association between SII and DN. Results Two hundred participants were enrolled, with an average age of 56.6 ± 13.4 years; 54% participants were categorized as DN. Spearman association analysis showed SII was positive associated with increased urinary albumin to creatinine ratio and serum creatinine, while negative associated with eGFR and serum albumin. The ROC curve revealed that the maximum area under the curve (AUC) was 0.761 (95% CI, 0.694-0.828, P < 0.001). After univariate and multivariate logistic analysis, SII (OR=1.004, P = 0.002) and serum creatinine (OR=1.146, P < 0.001) were risk factors for the occurrence of DN, while age (OR=0.920, P = 0.011) and serum albumin (OR=0.708, P < 0.001) were protective factors for the occurrence of DN. The restricted cubic spline model showed that there was a significant nonlinear association between DN incidence and continuous SII value when it exceeded 624*10ˆ 9/L. Conclusion SII is a novel diagnostic biomarker which is independently associated with DN. Further large-scale prospective studies are needed to validate our findings before SII can be considered a reliable diagnostic or prognostic tool for DN.
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Affiliation(s)
- Xiaohong Zhang
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Yuan Fang
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Mengjie Weng
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Caiming Chen
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Yanfang Xu
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Jianxin Wan
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
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Deng J, Wu P. Integrated bioinformatics analysis and in vivo validation of potential immune-related genes linked to diabetic nephropathy. Heliyon 2024; 10:e40151. [PMID: 39583850 PMCID: PMC11582746 DOI: 10.1016/j.heliyon.2024.e40151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 11/04/2024] [Accepted: 11/04/2024] [Indexed: 11/26/2024] Open
Abstract
Background Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus and the main cause of chronic renal failure. This study explored the potential immunomodulation-related genes (IRGs) in DN using bioinformatics. Methods IRGs were identified using GeneCards, and differentially expressed genes were identified using the GSE99339, GSE96804, and GSE30122 datasets. We conducted enrichment analyses using Gene Ontology, gene set enrichment analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes to identify the associated signaling pathways. Prognostic models were constructed using Least Absolute Shrinkage and Selection Operator regression. The predictive power of IRGs was evaluated using receiver operating characteristic (ROC) curves. Furthermore, we utilized ssGSEA to determine the relative abundance of immune cell infiltration. The expression of five significant IRGs was further validated using immunohistochemistry (IHC) in individuals with DN and real-time PCR (RT-PCR) in animal experiments. Results In total, 17 immunomodulation-related differentially expressed genes were identified, which were enriched in immune-associated pathways and inflammation. GSEA unveiled substantial enrichments in metabolic irregularities and the structural composition of the extracellular matrix. ROC analysis results revealed that the diagnostic efficacy of IFNAR2 and CASP3 was comparatively high. Notably, we identified potential IRGs for DN, including CASP3, LGALS9, and SST, using IHC and RT-PCR. Conclusions CASP3, LGALS9, and SST are potential IRGs in patients with DN. Our findings may offer a theoretical basis for developing more focused and innovative immunotherapy approaches for patients with DN.
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Affiliation(s)
- Jinxiu Deng
- Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350005, China
- Department of Nephrology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China
| | - Peiwen Wu
- Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350005, China
- Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350212, China
- Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China
- Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China
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Ao Y, Ye H, Liu X, Li Y, Liu H, Ye S, Hu Y, Zhuang P, Zhang Y, Zheng C, Jiao J. Fish oil supplementation in relation to the risk of chronic kidney disease among patients with diabetes. Diabetes Obes Metab 2024; 26:5283-5292. [PMID: 39192528 DOI: 10.1111/dom.15880] [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: 06/27/2024] [Revised: 07/29/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024]
Abstract
AIM To investigate the association between fish oil supplementation and subsequent risk of chronic kidney disease (CKD) among patients with diabetes, and further evaluate the mediation effect of typical glycolipid and inflammatory biomarkers. METHODS In total, 24 497 patients with diabetes from the UK Biobank were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for CKD risk, and the rate advancement period was calculated to quantify and communicate the impact of fish oil upon that risk. In addition, we also used mediation analysis to assess the mediating role of plasma biomarkers. RESULTS Overall, 7122 patients reported taking fish oil supplements. During a mean of 11.3 years of follow-up, 3533 CKD cases occurred. In the fully adjusted model, fish oil use was inversely associated with the incidence of CKD (HR 0.90; 95% CI: 0.83, 0.97), which was mediated by serum levels of HbA1c (4.7%), C-reactive protein (CRP) (3.4%) and high-density lipoprotein cholesterol (HDL-C) (2.3%). Participants who took fish oil supplements displayed the same risk of CKD events, but that risk was delayed by approximately 2.79 years compared with non-users of fish oil. CONCLUSIONS Our findings advocate the beneficial role of fish oil use in preventing CKD among patients with diabetes, which may be mediated by serum levels of HbA1c, CRP and HDL-C, and support public health policies aiming to promote fish oil supplementation for the prevention of diabetes complications.
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Affiliation(s)
- Yang Ao
- Department of Endocrinology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Nutrition, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Hao Ye
- Department of Endocrinology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Nutrition, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaohui Liu
- Department of Endocrinology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Nutrition, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Yin Li
- Department of Endocrinology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Nutrition, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Haoyin Liu
- Department of Endocrinology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Nutrition, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Shu Ye
- Department of Nutrition, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Yepeng Hu
- Department of Nutrition, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Pan Zhuang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Key Laboratory for Agro-Food Processing, Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China
| | - Chao Zheng
- Department of Endocrinology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jingjing Jiao
- Department of Endocrinology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Nutrition, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
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10
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Sardar A, Abid OUR, Rehman W, Rasheed L, Alanazi MM, Daud S, Rafiq M, Wadood A, Shakeel M. Synthesis and biological evaluation of diclofenac acid derivatives as potential lipoxygenase and α-glucosidase inhibitors. ROYAL SOCIETY OPEN SCIENCE 2024; 11:240543. [PMID: 39569345 PMCID: PMC11576109 DOI: 10.1098/rsos.240543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/25/2024] [Accepted: 09/17/2024] [Indexed: 11/22/2024]
Abstract
Inflammation is a complex physiological response associated with the onset and progression of various disorders, including diabetes. In this study, we synthesized a series of diclofenac acid derivatives and evaluated their potential anti-diabetic and anti-inflammatory activities. The compounds were specifically assessed for their ability to inhibit 15-lipoxygenase (15-LOX) and α-glucosidase enzymes. The structures of synthesized derivatives were confirmed through 1H nuclear magnetic resonance (NMR), 13C-NMR and high-resolution mass spectrometry (electron ionization) analysis. All these synthesized derivatives exhibited varying degrees of inhibitory activity against LOX, when compared with standard drugs, compounds 5a (half-maximal inhibitory concentration (IC50) 14 ± 1 µM), 5b (IC50 61 ± 1 µM) and 7c (IC50 67 ± 1 µM) showed good activity against the LOX enzyme. While the α-glucosidase inhibitory results revealed that most of the compounds exhibited significant activity when compared with the standard drug acarbose (376 ± 1 µM). The most potent compounds as α-glucosidase inhibitors were 7b (3 ± 1 µM), 4b (5 ± 1 µM), 7a (7 ± 1 µM) and 8b (11 ± 1 µM). All these active compounds were found to be least toxic and maintained the mononuclear cells viability at 96-97% compared with that of controls as determined by multi-transaction translator assay. Molecular docking studies further reiterated the significance of these 'lead' compounds with great potential against the target enzymes in the process of drug discovery.
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Affiliation(s)
- Asma Sardar
- Department of Chemistry, Hazara University, Mansehra 21300, Pakistan
| | | | - Wajid Rehman
- Department of Chemistry, Hazara University, Mansehra 21300, Pakistan
| | - Liaqat Rasheed
- Department of Chemistry, Hazara University, Mansehra 21300, Pakistan
| | - Mohammed M Alanazi
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Saima Daud
- Department of Chemistry, Hazara University, Mansehra 21300, Pakistan
| | - Muhammad Rafiq
- South China University of Technology School of Chemistry and Chemical Engineering, Guangzhou, People's Republic of China
| | - Abdul Wadood
- Department of Biochemistry, Abdul Wali Khan University, Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Muhammed Shakeel
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, People's Republic of China
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11
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Ting KH, Yang PJ, Su SC, Tsai PY, Yang SF. Effect of SDF-1 and CXCR4 gene variants on the development of diabetic kidney disease. Int J Med Sci 2024; 21:2851-2861. [PMID: 39512693 PMCID: PMC11539390 DOI: 10.7150/ijms.103186] [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: 09/03/2024] [Accepted: 10/21/2024] [Indexed: 11/15/2024] Open
Abstract
Diabetic kidney disease (DKD) is the gradual loss of renal function occurring in patients with diabetes. Stromal cell-derived factor-1 (SDF-1, encoded by SDF-1 gene) is a chemokine that binds to its receptor, CXCR4, to mediate many aspects of renal biology. To test the potential impact of SDF-1/CXCR4 gene variations on the risk for DKD, single-nucleotide polymorphisms (SNPs) of SDF-1/CXCR4 genes were genotyped in 388 DKD patients and 335 DKD-free diabetic controls. Among 6 SNPs examined, we demonstrated that rs1801157 of SDF-1 gene was associated with an increased risk for DKD (GA vs GG, AOR=2.252, p=0.035; GA+AA vs GG, AOR=2.156, p=0.036). Further stratification revealed that the correlation of rs1801157 with DKD was particularly detected in diabetic patients with early CKD but not in those with severe renal impairment. Instead, another SNP of SDF-1 gene, rs266085, was found in association with the advanced form of DKD (TC vs TT, AOR=2.106, p=0.027; TC+CC vs TT, AOR=2.130, p=0.019), indicating differential impacts of SDF-1 gene polymorphisms on the progressive loss of renal function in diabetic patients. Moreover, preliminary survey of public gene expression datasets showed that rs1801157 and rs266085 modulated SDF-1 expression in many human tissues, and SDF-1/CXCR4 levels were elevated in renal tissues of DKD patients. These data suggest that allele-specific expression of SDF-1 gene may influence DKD progression.
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Affiliation(s)
- Ke-Hsin Ting
- Division of Cardiology, Department of Internal Medicine, Changhua Christian Hospital, Yunlin Branch, Yunlin, Taiwan
- Department of Nursing, Hungkuang University, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Po-Jen Yang
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Family and Community Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shih-Chi Su
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Po-Yu Tsai
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Division of Nephrology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
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12
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Lu X, Xie Q, Pan X, Zhang R, Zhang X, Peng G, Zhang Y, Shen S, Tong N. Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy. Signal Transduct Target Ther 2024; 9:262. [PMID: 39353925 PMCID: PMC11445387 DOI: 10.1038/s41392-024-01951-9] [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: 06/01/2023] [Revised: 07/21/2024] [Accepted: 08/06/2024] [Indexed: 10/03/2024] Open
Abstract
Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet β cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and β cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet β cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. There is currently no cure for T2D, but it can be prevented or in remission by lifestyle intervention and/or some medication. If prevention fails, holistic and personalized management should be taken as soon as possible through timely detection and diagnosis, considering target organ protection, comorbidities, treatment goals, and other factors in reality. T2D is often accompanied by other components of MDS, such as preobesity/obesity, metabolic dysfunction associated steatotic liver disease, dyslipidemia, which usually occurs before it, and they are considered as the upstream diseases of T2D. It is more appropriate to call "diabetic complications" as "MDS-related target organ damage (TOD)", since their development involves not only hyperglycemia but also other metabolic disorders of MDS, promoting an up-to-date management philosophy. In this review, we aim to summarize the underlying mechanism, screening, diagnosis, prevention, and treatment of T2D, especially regarding the personalized selection of hypoglycemic agents and holistic management based on the concept of "MDS-related TOD".
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Affiliation(s)
- Xi Lu
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Qingxing Xie
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaohui Pan
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Ruining Zhang
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyi Zhang
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Ge Peng
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Yuwei Zhang
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Sumin Shen
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Nanwei Tong
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China.
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13
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Machado PAB, Lass A, Pilger BI, Fornazari R, de Moraes TP, Pinho RA. SGLT2 inhibitors and NLRP3 inflammasome: potential target in diabetic kidney disease. J Bras Nefrol 2024; 46:e20230187. [PMID: 39412512 PMCID: PMC11539899 DOI: 10.1590/2175-8239-jbn-2023-0187en] [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: 12/11/2023] [Accepted: 05/28/2024] [Indexed: 11/08/2024] Open
Abstract
Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease (CKD) worldwide. The pathogenesis of DKD is influenced by functional, histopathological, and immune mechanisms, including NLRP3 inflammasome activity and oxidative stress. The sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown metabolic benefits and the ability to slow the progression of DKD in several clinical studies over the years. Recent studies suggest that the antidiabetic activity also extends to inhibition of the inflammatory response, including modulation of the NLRP3 inflammasome, reduction of pro-inflammatory markers and reduction of oxidative stress. Here we review the efficacy of SGLT2i in the treatment of CKD and discuss the role of the inflammatory response in the development of DKD, including its relationship to the NLRP3 inflammasome and oxidative stress.
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Affiliation(s)
- Paulo André Bispo Machado
- Pontifícia Universidade Católica do Paraná, Laboratório de Bioquímica do Exercício em Saúde, Curitiba, PR, Brazil
- Pontificia Universidade Católica do Paraná, Pós-graduação em Ciências da Saúde, Curitiba, PR, Brazil
| | - André Lass
- Pontifícia Universidade Católica do Paraná, Laboratório de Bioquímica do Exercício em Saúde, Curitiba, PR, Brazil
- Pontificia Universidade Católica do Paraná, Pós-graduação em Ciências da Saúde, Curitiba, PR, Brazil
| | - Bruna Isadora Pilger
- Pontifícia Universidade Católica do Paraná, Laboratório de Bioquímica do Exercício em Saúde, Curitiba, PR, Brazil
- Pontificia Universidade Católica do Paraná, Pós-graduação em Ciências da Saúde, Curitiba, PR, Brazil
| | - Raphaella Fornazari
- Pontifícia Universidade Católica do Paraná, Laboratório de Bioquímica do Exercício em Saúde, Curitiba, PR, Brazil
- Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil
| | - Thyago Proença de Moraes
- Pontifícia Universidade Católica do Paraná, Laboratório de Bioquímica do Exercício em Saúde, Curitiba, PR, Brazil
- Pontificia Universidade Católica do Paraná, Pós-graduação em Ciências da Saúde, Curitiba, PR, Brazil
| | - Ricardo Aurino Pinho
- Pontifícia Universidade Católica do Paraná, Laboratório de Bioquímica do Exercício em Saúde, Curitiba, PR, Brazil
- Pontificia Universidade Católica do Paraná, Pós-graduação em Ciências da Saúde, Curitiba, PR, Brazil
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14
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Mohammadi S, Khorasani M. Implications of the cGAS-STING pathway in diabetes: Risk factors and therapeutic strategies. Int J Biol Macromol 2024; 278:134210. [PMID: 39069057 DOI: 10.1016/j.ijbiomac.2024.134210] [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: 05/12/2024] [Revised: 07/20/2024] [Accepted: 07/25/2024] [Indexed: 07/30/2024]
Abstract
Diabetes mellitus is an increasingly prevalent metabolic disorder characterized by chronic hyperglycemia and impaired insulin action. Although the pathogenesis of diabetes is multifactorial, emerging evidence suggests that chronic low-grade inflammation plays a significant role in the development and progression of the disease. The cyclic GMP-AMP synthase (cGAS) and its downstream signaling pathway, the stimulator of interferon genes (STING), have recently gained attention in the field of diabetes research. This article aims to provide an overview of the role of cGAS-STING in diabetes, focusing on its involvement in the regulation of immune responses, inflammation, insulin resistance, and β-cell dysfunction. Understanding the contribution of cGAS-STING signaling in diabetes may lead to the development of targeted therapeutic strategies for this prevalent metabolic disorder. The results section presents key findings from multiple studies on the impact of STING in diabetes. It discusses the influence of STING on inflammation levels within a diabetic environment, its effect on insulin resistance, and its implications for the development and progression of diabetes. The cGAS-STING signaling pathway plays a crucial role in the development and progression of diabetes.
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Affiliation(s)
- Saeed Mohammadi
- Natural and Medical Sciences Research Center, University of Nizwa, 611, Oman
| | - Milad Khorasani
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran; Department of Biochemistry and Nutrition, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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15
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Katar M, Gevrek F. Relation of the intense physical exercise and asprosin concentrations in type 2 diabetic rats. Tissue Cell 2024; 90:102501. [PMID: 39146675 DOI: 10.1016/j.tice.2024.102501] [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: 05/14/2024] [Revised: 06/27/2024] [Accepted: 07/26/2024] [Indexed: 08/17/2024]
Abstract
AIM Asprosin, a protein hormone, is released by unilocular adipocytes in reaction to low blood sugar. We aimed to examine how exercise affects asprosin hormone levels and associated organs, including the liver and pancreas, in diabetes. METHODS Twenty-one male Wistar albino rats were firstly allocated into two main groups: control (n = 7) and diabetes (n = 14). Then, the diabetes group was further separated into two subgroups: sedentary (n = 7) and exercise (n = 7). The exercise group participated in a swimming training regimen (30 min/daily, six weeks). Serum levels of asprosin and various other biochemical parameters were evaluated through commercial ELISA kits. The liver was analyzed histopathologically, and pancreatic islet cells were examined for Cas-3 immune expression. RESULTS Asprosin and total oxidant status decreased significantly in the exercise diabetic subgroup (p < 0.05). Glucose, insulin, creatinine, IL-6, and HomaIR concentrations decreased slightly with exercise (p > 0.05). Liver tissue injury scores and Cas-3 immune expression in pancreas islet cells decreased in exercise diabetic rats. CONCLUSIONS Reducing asprosin may lower glucose, insulin, and HOMA-IR. Physical activity decreases asprosin and total oxidative status, fostering anti-apoptosis and tissue healing in diabetes, potentially enhancing health. Monitoring asprosin levels offers insights into diabetes progression. Our findings imply that asprosin can be a therapeutic target for diabetes.
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Affiliation(s)
- Muzaffer Katar
- Department of Biochemistry, Faculty of Medicine, Tokat Gaziosmanpaşa University, Tokat, Turkiye
| | - Fikret Gevrek
- Department of Histology and Embryology, Faculty of Medicine, Tokat Gaziosmanpaşa University, Tokat, Turkiye.
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16
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Sinha SK, Carpio MB, Nicholas SB. Fiery Connections: Macrophage-Mediated Inflammation, the Journey from Obesity to Type 2 Diabetes Mellitus and Diabetic Kidney Disease. Biomedicines 2024; 12:2209. [PMID: 39457523 PMCID: PMC11503991 DOI: 10.3390/biomedicines12102209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/12/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
The high prevalence of diabetes mellitus (DM) poses a significant public health challenge, with diabetic kidney disease (DKD) as one of its most serious consequences. It has become increasingly clear that type 2 DM (T2D) and the complications of DKD are not purely metabolic disorders. This review outlines emerging evidence related to the step-by-step contribution of macrophages to the development and progression of DKD in individuals who specifically develop T2D as a result of obesity. The macrophage is a prominent inflammatory cell that contributes to obesity, where adipocyte hypertrophy leads to macrophage recruitment and eventually to the expansion of adipose tissue. The recruited macrophages secrete proinflammatory cytokines, which cause systemic inflammation, glucose dysregulation, and insulin sensitivity, ultimately contributing to the development of T2D. Under such pathological changes, the kidney is susceptible to elevated glucose and thereby activates signaling pathways that ultimately drive monocyte recruitment. In particular, the early recruitment of proinflammatory macrophages in the diabetic kidney produces inflammatory cytokines/chemokines that contribute to inflammation and tissue damage associated with DKD pathology. Macrophage activation and recruitment are crucial inciting factors that also persist as DKD progresses. Thus, targeting macrophage activation and function could be a promising therapeutic approach, potentially offering significant benefits for managing DKD at all stages of progression.
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Affiliation(s)
- Satyesh K. Sinha
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
- Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Maria Beatriz Carpio
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
| | - Susanne B. Nicholas
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
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17
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Kallem CJ, Alghwiri AA, Yabes JG, Roumelioti ME, Erickson S, Rollman BL, Weisbord S, Unruh M, Vodovotz Y, Jhamb M, Steel JL. Association of Symptoms and Collaborative Care Intervention with Systemic Inflammation Biomarkers in ESKD. KIDNEY360 2024; 5:1299-1310. [PMID: 39012260 PMCID: PMC11441811 DOI: 10.34067/kid.0000000000000512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 07/10/2024] [Indexed: 07/17/2024]
Abstract
Key Points There were no associations between biomarkers and patient-reported pain, fatigue, and depression in a large ESKD cohort at baseline. Compared with control, the Technology-Assisted stepped Collaborative Care intervention had a short-term impact on reducing inflammatory burden. Treatment modified the association between changes in symptoms and in certain proinflammatory biomarkers (TNF-α and high sensitivity C-reactive protein) over time. Background Patient-reported symptoms are associated with inflammation biomarkers in many chronic diseases. We examined associations of inflammation biomarkers with pain, fatigue, and depression in patients with ESKD and the effects of a Technology-Assisted stepped Collaborative Care (TĀCcare) intervention on these biomarkers. Methods In the TĀCcare multisite randomized control trial, data on patient-reported symptoms were collected at baseline and 3 and 6 months. Anti-inflammatory (IL-1 receptor agonist, IL-10), proinflammatory (TNF-α , high sensitivity C-reactive protein, IL-6), and regulatory (IL-2) biomarkers were assayed. Linear mixed-effects modeling was used to examine within-group and between-group differences after adjusting for age, sex, race, and comorbidities. Results Among the 160 patients (mean age 58±14 years, 55% men, 52% white), there were no significant associations between inflammation biomarkers and pain, fatigue, or depression at baseline. Both intervention and control groups demonstrated reductions in IL-10 and IL-1 receptor agonist over 6 months (β range=−1.22 to −0.40, P range=<0.001–0.02) At 3 months, the treatment group exhibited decreases in TNF-α (β =−0.22, P < 0.001) and IL-2 (β =−0.71, P < 0.001), whereas the control group showed increases in IL-6/IL-10 ratio (β =0.33, P = 0.03). At 6 months, both groups exhibited decreases in IL-2 (β range=−0.66 to −0.57, P < 0.001); the control group showed significant increases in the ratio of IL-6/IL-10 (β =0.75, P < 0.001) and decrease in TNF-α (β =−0.16, P = 0.02). Compared with controls, the treatment group demonstrated significantly decreased IL-2 at 3 months (β =−0.53, P < 0.001). Significant interaction effects of treatment were observed on the association between changes in proinflammatory biomarkers (TNF-α and high sensitivity C-reactive protein) levels and changes in symptom scores from baseline to 6 months. Conclusions The TĀCcare intervention had a short-term impact on reducing inflammatory burden in patients with ESKD. More studies are needed to confirm our findings and to determine whether these biomarkers mediate the link between symptoms and disease progression. Clinical Trial registration number: ClinicalTrials.gov NCT03440853 .
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Affiliation(s)
- Cramer J. Kallem
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Alaa A. Alghwiri
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jonathan G. Yabes
- Division of General Internal Medicine, Department of Medicine and Biostatistics, Center for Research on Heath Care Data Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Maria-Eleni Roumelioti
- Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico
| | - Sarah Erickson
- Department of Psychology, University of New Mexico, Albuquerque, New Mexico
| | - Bruce L. Rollman
- Division of General Internal Medicine, Center for Behavioral Health, Media, and Technology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Steven Weisbord
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Renal Section and Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
| | - Mark Unruh
- Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico
| | - Yoram Vodovotz
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Manisha Jhamb
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jennifer L. Steel
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Psychology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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18
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Yang PJ, Ting KH, Tsai PY, Su SC, Yang SF. Association of long noncoding RNA GAS5 gene polymorphism with progression of diabetic kidney disease. Int J Med Sci 2024; 21:2201-2207. [PMID: 39239549 PMCID: PMC11373544 DOI: 10.7150/ijms.99545] [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: 06/12/2024] [Accepted: 08/04/2024] [Indexed: 09/07/2024] Open
Abstract
Diabetic kidney disease (DKD) is a common microvascular complication of diabetes, whose complex etiology involves a genetic component. Growth arrest-specific 5 (GAS5), a long noncoding RNA (lncRNA) gene, has been recently shown to regulate renal fibrosis. Here, we aimed to explore the potential role of GAS5 gene polymorphisms in the predisposition to DKD. One single-nucleotide (rs55829688) and one insertion/deletion polymorphism (rs145204276) of GAS5 gene were surveyed in 778 DKD cases and 788 DKD-free diabetic controls. We demonstrated that diabetic subjects who are heterozygous at rs55829688 (TC; AOR, 1.737; 95% CI, 1.028-2.937; p=0.039) are more susceptible to advanced DKD but not early-staged DKD, as compared to diabetic subjects who are homozygous for the major allele of rs55829688 (TT). Carriers of at least one minor allele (C) of rs55829688 (TC and CC; AOR, 1.317; 95% CI, 1.023-1.696; p=0.033) more frequently suffer from advanced DKD than do those homozygotes for the major allele (TT). Furthermore, in comparison to those who do not carry the minor allele of rs55829688 (TT), advanced DKD patients possessing at least one minor allele of rs55829688 (TC and CC) exhibited a lower glomerular filtration rate, revealing an impact of rs55829688 on renal co-morbidities of diabetes. In conclusion, our data indicate an association of GAS5 gene polymorphisms with the progression of DKD.
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Affiliation(s)
- Po-Jen Yang
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Family and Community Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Ke-Hsin Ting
- Division of Cardiology, Department of Internal Medicine, Changhua Christian Hospital, Yunlin Branch, Yunlin, Taiwan
- Department of Medicine and Nursing, Hungkuang University, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Po-Yu Tsai
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Division of Nephrology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shih-Chi Su
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
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19
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Zhuang L, Jin G, Wang Q, Ge X, Pei X. Long Non-coding RNA ZFAS1 Regulates Fibrosis and Scortosis in the Cell Model of Diabetic Nephropathy Through miR-525-5p/SGK1 Axis. Appl Biochem Biotechnol 2024; 196:3731-3746. [PMID: 37768477 DOI: 10.1007/s12010-023-04721-5] [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] [Accepted: 09/12/2023] [Indexed: 09/29/2023]
Abstract
Diabetic nephropathy (DN) is a common clinical syndrome in diabetic patients. Functional characterization of non-coding (ncRNAs) involved in the progression of DN can provide insights into the diagnosis and therapeutic management of DN. Human kidney proximal tubular epithelial cells (HK-2) were challenged by high glucose (HG, 50 mM) as a cell model of DN. The expression level of long non-coding RNA (lncRNA) ZFAS1 was quantified by qRT-PCR. The proteins and cytokines related to fibrosis and scortosis in DN (NLRP3, GSDMD-N, IL-1β and Caspase 1, fibronectin, collagen I, collagen III, IL-1β, and IL-18) were examined by western blot or ELISA. RNA precipitation and luciferase reporter activity experiments were conducted to assess the molecular associations. ZFAS1 and SGK1 were highly induced in HK-2 cells challenged with HG, while miR-525-5p downregulated upon HG treatment. ZFAS1 knockdown attenuated HG-induced fibrosis and scortosis in HK-2 cells by reducing the levels of NLRP3, GSDMD-N, Caspase 1, fibronectin, collagen I/III, IL-1β, and IL-18. Mechanically, ZFAS1 knockdown protected HK-2 cells from HG-induced injury by upregulating miR-525-5p and repressing SGK1 expression. Overall, our results suggest that knocking down ZFAS1 may be formulated as a protective strategy in ameliorating DN progression through regulating miR-525-5p/SGK1 pathway. Targeting ZFAS1 could be further explored as a potential approach for the management of DN.
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Affiliation(s)
- Langen Zhuang
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, No. 287, Changhuai Road, Bengbu, 233004, Anhui, China.
| | - Guoxi Jin
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, No. 287, Changhuai Road, Bengbu, 233004, Anhui, China
| | - Qiong Wang
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, No. 287, Changhuai Road, Bengbu, 233004, Anhui, China
| | - Xiaoxu Ge
- Department of Endocrinology Tongren Hospital Affiliated to Jiaotong University, No. 1111, Xianxia Road, Changning District, Shanghai, 200336, China
| | - Xiaoyan Pei
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, No. 287, Changhuai Road, Bengbu, 233004, Anhui, China
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20
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Wang L, Su J, Liu Z, Ding S, Li Y, Hou B, Hu Y, Dong Z, Tang J, Liu H, Liu W. Identification of immune-associated biomarkers of diabetes nephropathy tubulointerstitial injury based on machine learning: a bioinformatics multi-chip integrated analysis. BioData Min 2024; 17:20. [PMID: 38951833 PMCID: PMC11218417 DOI: 10.1186/s13040-024-00369-x] [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: 01/17/2024] [Accepted: 06/10/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is a major microvascular complication of diabetes and has become the leading cause of end-stage renal disease worldwide. A considerable number of DN patients have experienced irreversible end-stage renal disease progression due to the inability to diagnose the disease early. Therefore, reliable biomarkers that are helpful for early diagnosis and treatment are identified. The migration of immune cells to the kidney is considered to be a key step in the progression of DN-related vascular injury. Therefore, finding markers in this process may be more helpful for the early diagnosis and progression prediction of DN. METHODS The gene chip data were retrieved from the GEO database using the search term ' diabetic nephropathy '. The ' limma ' software package was used to identify differentially expressed genes (DEGs) between DN and control samples. Gene set enrichment analysis (GSEA) was performed on genes obtained from the molecular characteristic database (MSigDB. The R package 'WGCNA' was used to identify gene modules associated with tubulointerstitial injury in DN, and it was crossed with immune-related DEGs to identify target genes. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on differentially expressed genes using the 'ClusterProfiler' software package in R. Three methods, least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE) and random forest (RF), were used to select immune-related biomarkers for diagnosis. We retrieved the tubulointerstitial dataset from the Nephroseq database to construct an external validation dataset. Unsupervised clustering analysis of the expression levels of immune-related biomarkers was performed using the 'ConsensusClusterPlus 'R software package. The urine of patients who visited Dongzhimen Hospital of Beijing University of Chinese Medicine from September 2021 to March 2023 was collected, and Elisa was used to detect the mRNA expression level of immune-related biomarkers in urine. Pearson correlation analysis was used to detect the effect of immune-related biomarker expression on renal function in DN patients. RESULTS Four microarray datasets from the GEO database are included in the analysis : GSE30122, GSE47185, GSE99340 and GSE104954. These datasets included 63 DN patients and 55 healthy controls. A total of 9415 genes were detected in the data set. We found 153 differentially expressed immune-related genes, of which 112 genes were up-regulated, 41 genes were down-regulated, and 119 overlapping genes were identified. GO analysis showed that they were involved in various biological processes including leukocyte-mediated immunity. KEGG analysis showed that these target genes were mainly involved in the formation of phagosomes in Staphylococcus aureus infection. Among these 119 overlapping genes, machine learning results identified AGR2, CCR2, CEBPD, CISH, CX3CR1, DEFB1 and FSTL1 as potential tubulointerstitial immune-related biomarkers. External validation suggested that the above markers showed diagnostic efficacy in distinguishing DN patients from healthy controls. Clinical studies have shown that the expression of AGR2, CX3CR1 and FSTL1 in urine samples of DN patients is negatively correlated with GFR, the expression of CX3CR1 and FSTL1 in urine samples of DN is positively correlated with serum creatinine, while the expression of DEFB1 in urine samples of DN is negatively correlated with serum creatinine. In addition, the expression of CX3CR1 in DN urine samples was positively correlated with proteinuria, while the expression of DEFB1 in DN urine samples was negatively correlated with proteinuria. Finally, according to the level of proteinuria, DN patients were divided into nephrotic proteinuria group (n = 24) and subrenal proteinuria group. There were significant differences in urinary AGR2, CCR2 and DEFB1 between the two groups by unpaired t test (P < 0.05). CONCLUSIONS Our study provides new insights into the role of immune-related biomarkers in DN tubulointerstitial injury and provides potential targets for early diagnosis and treatment of DN patients. Seven different genes ( AGR2, CCR2, CEBPD, CISH, CX3CR1, DEFB1, FSTL1 ), as promising sensitive biomarkers, may affect the progression of DN by regulating immune inflammatory response. However, further comprehensive studies are needed to fully understand their exact molecular mechanisms and functional pathways in DN.
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Affiliation(s)
- Lin Wang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Jiaming Su
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Zhongjie Liu
- Beijing University of Chinese Medicine, Beijing, China
| | - Shaowei Ding
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Yaotan Li
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Baoluo Hou
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Yuxin Hu
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Zhaoxi Dong
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Jingyi Tang
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Hongfang Liu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China.
| | - Weijing Liu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China.
- Beijing University of Chinese Medicine, Beijing, China.
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Jia X, Zhu L, Zhu Q, Zhang J. The role of mitochondrial dysfunction in kidney injury and disease. Autoimmun Rev 2024; 23:103576. [PMID: 38909720 DOI: 10.1016/j.autrev.2024.103576] [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: 01/22/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 06/25/2024]
Abstract
Mitochondria are the main sites of aerobic respiration in the cell and mainly provide energy for the organism, and play key roles in adenosine triphosphate (ATP) synthesis, metabolic regulation, and cell differentiation and death. Mitochondrial dysfunction has been identified as a contributing factor to a variety of diseases. The kidney is rich in mitochondria to meet energy needs, and stable mitochondrial structure and function are essential for normal kidney function. Recently, many studies have shown a link between mitochondrial dysfunction and kidney disease, maintaining mitochondrial homeostasis has become an important target for kidney therapy. In this review, we integrate the role of mitochondrial dysfunction in different kidney diseases, and specifically elaborate the mechanism of mitochondrial reactive oxygen species (mtROS), autophagy and ferroptosis involved in the occurrence and development of kidney diseases, providing insights for improved treatment of kidney diseases.
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Affiliation(s)
- Xueqian Jia
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, PR China
| | - Lifu Zhu
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, PR China
| | - Qixing Zhu
- Institute of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China; Key Laboratory of Dermatology, Ministry of Education, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China.
| | - Jiaxiang Zhang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, PR China; Key Laboratory of Dermatology, Ministry of Education, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China; The Center for Scientific Research, Anhui Medical University, Hefei, PR China.
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22
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Gao JL, Shen J, Yang LP, Liu L, Zhao K, Pan XR, Li L, Xu JJ. Neutrophil-to-lymphocyte ratio associated with renal function in type 2 diabetic patients. World J Clin Cases 2024; 12:2308-2315. [PMID: 38765748 PMCID: PMC11099408 DOI: 10.12998/wjcc.v12.i14.2308] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 02/14/2024] [Accepted: 04/02/2024] [Indexed: 04/29/2024] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is a leading risk factor for the development and progression of chronic kidney disease (CKD). However, an accurate and convenient marker for early detection and appropriate management of CKD in individuals with T2DM is limited. Recent studies have demonstrated a strong correlation between the neutrophil-to-lymphocyte ratio (NLR) and CKD. Nonetheless, the predictive value of NLR for renal damage in type 2 diabetic patients remains understudied. AIM To investigate the relationship between NLR and renal function in T2DM patients. METHODS This study included 1040 adults aged 65 or older with T2DM from Shanghai's Community Health Service Center. The total number of neutrophils and lymphocytes was detected, and NLR levels were calculated. CKD was defined as an estimated glomerular filtration rate ≤ 60 mL/min/1.73 m². Participants were divided into four groups based on NLR levels. The clinical data and biochemical characteristics were compared among groups. A multivariate logistic regression model was used to analyze the association between NLR levels and CKD. RESULTS Significant differences were found in terms of sex, serum creatinine, blood urea nitrogen, total cholesterol, and low-density lipoprotein cholesterol among patients with T2DM in different NLR groups (P < 0.0007). T2DM patients in the highest NLR quartile had a higher prevalence of CKD (P for trend = 0.0011). Multivariate logistic regression analysis indicated that a high NLR was an independent risk factor for CKD in T2DM patients even after adjustment for important clinical and pathological parameters (P = 0.0001, odds ratio = 1.41, 95% confidence intervals: 1.18-1.68). CONCLUSION An elevated NLR in patients with T2DM is associated with higher prevalence of CKD, suggesting that it could be a marker for the detection and evaluation of diabetic kidney disease.
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Affiliation(s)
- Jin-Li Gao
- Department of Prevention and Health Care, Community Health Service Center of Miaohang Town, Shanghai 200443, China
| | - Jue Shen
- Department of Prevention and Health Care, Community Health Service Center of Songnan Town, Shanghai 200434, China
| | - Li-Ping Yang
- Department of Prevention and Health Care, Community Health Service Center of Songnan Town, Shanghai 200434, China
| | - Li Liu
- Department of General Practice, Community Health Service Center of Songnan Town, Shanghai 200434, China
| | - Kai Zhao
- Department of General Practice, Community Health Service Center of Songnan Town, Shanghai 200434, China
| | - Xiao-Rong Pan
- Department of General Practice, Community Health Service Center of Songnan Town, Shanghai 200434, China
| | - Lei Li
- Department of Administrative, Community Health Service Center of Songnan Town, Shanghai 200434, China
| | - Ji-Ji Xu
- Department of General Practice, Community Health Service Center of Songnan Town, Shanghai 200434, China
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23
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Vernì F. Vitamin B6 and diabetes and its role in counteracting advanced glycation end products. VITAMINS AND HORMONES 2024; 125:401-438. [PMID: 38997171 DOI: 10.1016/bs.vh.2024.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/14/2024]
Abstract
Naturally occurring forms of vitamin B6 include six interconvertible water-soluble compounds: pyridoxine (PN), pyridoxal (PL), pyridoxamine (PM), and their respective monophosphorylated derivatives (PNP, PLP, and PMP). PLP is the catalytically active form which works as a cofactor in approximately 200 reactions that regulate the metabolism of glucose, lipids, amino acids, DNA, and neurotransmitters. Most of vitamers can counteract the formation of reactive oxygen species and the advanced glycation end-products (AGEs) which are toxic compounds that accumulate in diabetic patients due to prolonged hyperglycemia. Vitamin B6 levels have been inversely associate with diabetes, while vitamin B6 supplementation reduces diabetes onset and its vascular complications. The mechanisms at the basis of the relation between vitamin B6 and diabetes onset are still not completely clarified. In contrast more evidence indicates that vitamin B6 can protect from diabetes complications through its role as scavenger of AGEs. It has been demonstrated that in diabetes AGEs can destroy the functionality of macromolecules such as protein, lipids, and DNA, thus producing tissue damage that result in vascular diseases. AGEs can be in part also responsible for the increased cancer risk associated with diabetes. In this chapter the relationship between vitamin B6, diabetes and AGEs will be discussed by showing the acquired knowledge and questions that are still open.
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Affiliation(s)
- F Vernì
- Department of Biology and Biotechnology "Charles Darwin" Sapienza University of Rome, Rome, Italy.
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24
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Zhou TY, Tian N, Li L, Yu R. Iridoids modulate inflammation in diabetic kidney disease: A review. JOURNAL OF INTEGRATIVE MEDICINE 2024; 22:210-222. [PMID: 38631983 DOI: 10.1016/j.joim.2024.03.010] [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: 05/09/2023] [Accepted: 02/18/2024] [Indexed: 04/18/2024]
Abstract
In recent years, preclinical research on diabetic kidney disease (DKD) has surged to the forefront of scientific and clinical attention. DKD has become a pervasive complication of type 2 diabetes. Given the complexity of its etiology and pathological mechanisms, current interventions, including drugs, dietary modifications, exercise, hypoglycemic treatments and lipid-lowering methods, often fall short in achieving desired therapeutic outcomes. Iridoids, primarily derived from the potent components of traditional herbs, have been the subject of long-standing research. Preclinical data suggest that iridoids possess notable renal protective properties; however, there has been no summary of the research on their efficacy in the management and treatment of DKD. This article consolidates findings from in vivo and in vitro research on iridoids in the context of DKD and highlights their shared anti-inflammatory activities in treating this condition. Additionally, it explores how certain iridoid components modify their chemical structures through the regulation of intestinal flora, potentially bolstering their therapeutic effects. This review provides a focused examination of the mechanisms through which iridoids may prevent or treat DKD, offering valuable insights for future research endeavors. Please cite this article as: Zhou TY, Tian N, Li L, Yu R. Iridoids modulate inflammation in diabetic kidney disease: A review. J Integr Med. 2024; 22(3): 210-222.
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Affiliation(s)
- Tong-Yi Zhou
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Na Tian
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Liu Li
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Rong Yu
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China; Hunan Provincial Key Laboratory of Translational Research in Traditional Chinese Medicine Prescriptions and Zheng, Changsha 410208, Hunan Province, China.
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25
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Yang C, Huang F, Fang H, Zang Y. Jiawei Shengjiangsan's Effect on Renal Injury in Diabetic Nephropathy Mice is Investigated via the PI3K/Akt/NF-κB Signaling Pathway. Diabetes Metab Syndr Obes 2024; 17:1687-1698. [PMID: 38629025 PMCID: PMC11020332 DOI: 10.2147/dmso.s456205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 03/21/2024] [Indexed: 04/19/2024] Open
Abstract
Purpose This study aimed to investigate the intervention mechanism of Jiawei Shengjiangsan (JWSJS) on kidney injury in diabetic nephropathy mice. Methods Thirty 8-week-old db/db mice were randomly divided into five groups: model group, Perindopril group, and JWSJS low-, medium-, and high-dose groups (n=6 per group) based on body weight. Additionally, a blank control group was established consisting of 6 db/m mice aged 8 weeks. The blank and model groups received daily intragastric administration of 7g/kg/d pure water. The remaining groups were assigned to JWSJS low (3.5g/kg/d), medium (7g/kg/d), high (14g/kg/d) dosage groups, and perindopril positive control group (0.48mg/kg/d) for 12 weeks. Post-experiment, serum creatinine (SCr) and blood urea nitrogen (BUN) were analyzed using an automatic biochemical analyzer. Enzyme-linked immunosorbent assay (ELISA) measured 24-hour urinary albumin, neutrophil gelatinase-associated lipocalin (NGAL), TNF-α, IL-1β, VCAM-1, MCP-1, and HbA1c. Western blot assessed the protein expressions of p-PI3K, p-Akt, and p-NF-κB p65, while pathological kidney changes were observed. Results Compared to the blank group, the model group exhibited increased SCr, BUN, 24-hour urinary albumin, serum NGAL, TNF-α, IL-1β, VCAM-1, MCP-1, HbA1c, p-PI3K, and p-Akt, alongside increased p-NF-κB p65 expression, indicating significant kidney pathology. After treatment, the JWSJS group showed decreased SCr, BUN, 24-hour urinary microalbumin, NGAL, HbA1c, TNF-α, IL-1β, VCAM-1, MCP-1 levels, increased p-PI3K and p-Akt expression (P<0.05), and reduced p-NF-κB p65 content (P<0.05). Histopathological analysis revealed that JWSJS ameliorated renal tubular epithelial cell damage, glomerular capillary and basement membrane injuries, and facilitated the repair of damaged podocytes in diabetic nephropathy mice. Conclusion JWSJS demonstrated efficacy in reducing renal inflammation in diabetic nephropathy mice, with its mechanism likely associated with the inhibition of the PI3K/Akt/NF-κB signaling pathway.
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Affiliation(s)
- Chenhua Yang
- General Medicine, Bao’an Authentic TCM Therapy Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Fengling Huang
- College of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, People’s Republic of China
| | - Huiqin Fang
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China
| | - Yunhua Zang
- General Medicine, Bao’an Authentic TCM Therapy Hospital, Shenzhen, Guangdong, People’s Republic of China
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Chen J, Zhang Q, Guo J, Gu D, Liu J, Luo P, Bai Y, Chen J, Zhang X, Nie S, Chen C, Feng Y, Wang J. Single-cell transcriptomics reveals the ameliorative effect of rosmarinic acid on diabetic nephropathy-induced kidney injury by modulating oxidative stress and inflammation. Acta Pharm Sin B 2024; 14:1661-1676. [PMID: 38572101 PMCID: PMC10985035 DOI: 10.1016/j.apsb.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 12/11/2023] [Accepted: 01/04/2024] [Indexed: 04/05/2024] Open
Abstract
Diabetic nephropathy (DN) is a severe complication of diabetes, characterized by changes in kidney structure and function. The natural product rosmarinic acid (RA) has demonstrated therapeutic effects, including anti-inflammation and anti-oxidative-stress, in renal damage or dysfunction. In this study, we characterized the heterogeneity of the cellular response in kidneys to DN-induced injury and RA treatment at single cell levels. Our results demonstrated that RA significantly alleviated renal tubular epithelial injury, particularly in the proximal tubular S1 segment and on glomerular epithelial cells known as podocytes, while attenuating the inflammatory response of macrophages, oxidative stress, and cytotoxicity of natural killer cells. These findings provide a comprehensive understanding of the mechanisms by which RA alleviates kidney damage, oxidative stress, and inflammation, offering valuable guidance for the clinical application of RA in the treatment of DN.
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Affiliation(s)
- Junhui Chen
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
| | - Qian Zhang
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jinan Guo
- Department of Urology, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, China
| | - Di Gu
- Department of Urology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, China
| | - Jing Liu
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
| | - Piao Luo
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yunmeng Bai
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
| | - Jiayun Chen
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xinzhou Zhang
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, China
| | - Sheng Nie
- Department of Nephrology, Nanfang Hospital, the First Affiliated Hospital of Southern Medical University, Guangzhou 510515, China
| | - Chunbo Chen
- Department of Critical Care Medicine, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China
| | - Yulin Feng
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China
| | - Jigang Wang
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen 518020, China
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
- State Key Laboratory for Quality Esurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
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Chen L, Lu S, Wu Z, Zhang E, Cai Q, Zhang X. Innate immunity in diabetic nephropathy: Pathogenic mechanisms and therapeutic targets. MEDCOMM – FUTURE MEDICINE 2024; 3. [DOI: 10.1002/mef2.76] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 02/18/2024] [Indexed: 01/02/2025]
Abstract
AbstractDiabetic nephropathy (DN) represents a prevalent chronic microvascular complication of diabetes mellitus (DM) and is a major cause of end‐stage renal disease. The anfractuous surrounding of DN pathogenesis and the intricate nature of this metabolic disorder often pose challenges in both the diagnosis and treatment of DN compared to other kidney diseases. Hyperglycaemia in DM predispose vulnerable renal cells into microenvironmental disequilibrium and thereby results in innate immunocytes infiltration including neutrophils, macrophages, myeloid‐derived suppressor cells, dendritic cells, and so forth. These immune cells play dual roles in kidney injury and closely correlated with the degree of proteinuria in DN patients. Additionally, innate immune signaling cascades, initiated by altered metabolic and hemodynamic in diabetic context, are crucial in instigating and perpetuating renal inflammation, which detrimentally contribute to DN pathogenesis. As such, anti‐inflammatory therapies, particularly those targeting innate immunity, hold renoprotective promise in DN. In this article, we reviewed the origin and feature of the above four prominent kidney innate immune cells, analyze their pathogenic role in DN, and discuss potential targeted‐therapeutic strategies, aiming to enhance the current understanding of renal innate immunity and hence help to discover promising therapeutic approaches for DN.
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Affiliation(s)
- Le‐Xin Chen
- School of Pharmaceutical Science Guangzhou University of Chinese Medicine Guangzhou PR China
| | - Shu‐Ru Lu
- School of Pharmaceutical Science Guangzhou University of Chinese Medicine Guangzhou PR China
| | - Zhi‐Hao Wu
- School of Pharmaceutical Science Guangzhou University of Chinese Medicine Guangzhou PR China
| | - En‐Xin Zhang
- Shenzhen Bao'an Authentic TCM Therapy Hospital Shenzhen PR China
| | - Qing‐Qun Cai
- The First Affiliated Hospital Guangzhou University of Chinese Medicine Guangzhou PR China
| | - Xiao‐Jun Zhang
- School of Pharmaceutical Science Guangzhou University of Chinese Medicine Guangzhou PR China
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Liu PY, Hong KF, Liu YD, Sun ZY, Zhao TT, Li XL, Lao CC, Tan SF, Zhang HY, Zhao YH, Xie Y, Xu YH. Total flavonoids of Astragalus protects glomerular filtration barrier in diabetic kidney disease. Chin Med 2024; 19:27. [PMID: 38365794 PMCID: PMC10870499 DOI: 10.1186/s13020-024-00903-3] [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: 12/07/2023] [Accepted: 02/06/2024] [Indexed: 02/18/2024] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD) is a prevalent complication of diabetes and the leading cause of end-stage renal disease. Recent evidence suggests that total flavonoids of Astragalus (TFA) has promising effects on diabetes; however, its influence on DKD and the underlying mechanism remains unclear. METHODS In this study, we induced the DKD model using streptozotocin (STZ) in male C57BL/6J mice and utilized glomerular endothelial cell (GEC) lines for in vitro investigations. We constructed a network pharmacology analysis to understand the mechanism of TFA in DKD. The mechanism of TFA action on DKD was investigated through Western blot analysis and multi-immunological methods. RESULTS Our findings revealed that TFA significantly reduced levels of urinary albumin (ALB). Network pharmacology and intracellular pathway experiments indicated the crucial involvement of the PI3K/AKT signaling pathway in mediating these effects. In vitro experiments showed that TFA can preserve the integrity of the glomerular filtration barrier by inhibiting the expression of inflammatory factors TNF-alpha and IL-8, reducing oxidative stress. CONCLUSION Our findings demonstrated that TFA can ameliorates the progression of DKD by ameliorating renal fibrosis and preserving the integrity of the kidney filtration barrier. These results provide pharmacological evidence supporting the use of TFA in the treatment of kidney diseases.
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Affiliation(s)
- Pei-Yu Liu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, People's Republic of China
| | - Kin-Fong Hong
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, People's Republic of China
| | - Ya-Di Liu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, People's Republic of China
| | - Zhong-Yan Sun
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, People's Republic of China
| | - Ting-Ting Zhao
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, People's Republic of China
| | - Xu-Ling Li
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, People's Republic of China
| | - Chi-Chou Lao
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, People's Republic of China
| | - Shu-Feng Tan
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, People's Republic of China
| | - Hai-Ying Zhang
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, People's Republic of China
| | - Yong-Hua Zhao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Ying Xie
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - You-Hua Xu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, People's Republic of China.
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Swaminathan SM, Rao IR, Bhojaraja MV, Attur RP, Nagri SK, Rangaswamy D, Shenoy SV, Nagaraju SP. Role of novel biomarker monocyte chemo-attractant protein-1 in early diagnosis & predicting progression of diabetic kidney disease: A comprehensive review. J Natl Med Assoc 2024; 116:33-44. [PMID: 38195327 DOI: 10.1016/j.jnma.2023.12.001] [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: 06/20/2023] [Revised: 09/11/2023] [Accepted: 12/03/2023] [Indexed: 01/11/2024]
Abstract
Diabetic kidney disease (DKD) is the most devastating complication of diabetes mellitus. Identification of patients at the early stages of progression may reduce the disease burden. The limitation of conventional markers such as serum creatinine and proteinuria intensify the need for novel biomarkers. The traditional paradigm of DKD pathogenesis has expanded to the activation of the immune system and inflammatory pathways. Monocyte chemo-attractant protein-1 (MCP-1) is extensively studied, as a key inflammatory mediator that modulates the development of DKD. Recent evidence supports the diagnostic role of MCP-1 in patients with or without proteinuria in DKD, as well as a significant role in the early prediction and risk stratification of DKD. In this review, we will summarize and update present evidence for MCP-1 for diagnostic ability and predicting the progression of DKD.
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Affiliation(s)
- Shilna Muttickal Swaminathan
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Indu Ramachandra Rao
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Mohan V Bhojaraja
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Ravindra Prabhu Attur
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Shivashankara Kaniyoor Nagri
- Department of Medicine, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Dharshan Rangaswamy
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Srinivas Vinayak Shenoy
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Shankar Prasad Nagaraju
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India.
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Liu W, Zheng S, Du X. Association of Systemic Immune-Inflammation Index and Systemic Inflammation Response Index with Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2024; 17:517-531. [PMID: 38327734 PMCID: PMC10849098 DOI: 10.2147/dmso.s447026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 01/12/2024] [Indexed: 02/09/2024] Open
Abstract
Purpose To evaluate the association of the systemic immune-inflammatory index (SII) and systemic inflammatory response index (SIRI) with the clinical and pathological features and progression of diabetic kidney disease (DKD). Patients and Methods We analyzed 303 patients with type 2 diabetes mellitus (T2DM), classifying them into distinct groups: T2DM, early DKD (EDKD), and clinical DKD (Cli-DKD). Variations in SII and SIRI levels across these groups and their association with renal function were assessed. Logistic regression analysis was used to identify independent risk factors for DKD. Additionally, in 43 patients with biopsy-confirmed DKD, we analyzed the relationship between SII, SIRI, and pathological changes. Kaplan-Meier survival analysis and the Cox proportional hazards model were used to assess the influence of SII and SIRI levels on outcomes in patients with DKD. Results SII and SIRI were significantly higher in the Cli-DKD group than in the T2DM and EDKD groups, and were positively correlated with the urinary albumin-creatinine ratio and negatively correlated with estimated glomerular filtration rate. Notably, SIRI was identified as an independent risk factor for DKD development. Additionally, a lower SII score was associated with a higher cumulative survival rate. Conclusion This study demonstrates an association between SII, SIRI, and renal function in patients with T2DM. A high SIRI was an independent risk factor for DKD, while an elevated SII was associated with an increased risk of kidney disease progression in biopsy-confirmed DKD cases. Our findings underscore the potential implications of utilizing SII and SIRI as cost-effective and readily available inflammatory indicators for monitoring DKD in primary care settings.
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Affiliation(s)
- Wenli Liu
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Shuran Zheng
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Xiaogang Du
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
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Li X, Wang L, Liu M, Zhou H, Xu H. Association between neutrophil-to-lymphocyte ratio and diabetic kidney disease in type 2 diabetes mellitus patients: a cross-sectional study. Front Endocrinol (Lausanne) 2024; 14:1285509. [PMID: 38239986 PMCID: PMC10795842 DOI: 10.3389/fendo.2023.1285509] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 11/30/2023] [Indexed: 01/22/2024] Open
Abstract
Aims This investigation examined the possibility of a relationship between neutrophil-to-lymphocyte ratio (NLR) and diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) patients. Methods Adults with T2DM who were included in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2020 were the subjects of the current cross-sectional investigation. Low estimated glomerular filtration rate (eGFR) (< 60 mL/min/1.73 m2) or albuminuria (urinary albumin-to-creatinine ratio (ACR) ≥ 30 mg/g) in T2DM patients were the diagnostic criteria for DKD. Weighted multivariable logistic regression models and generalized additive models were used to investigate the independent relationships between NLR levels with DKD, albuminuria, and low-eGFR. Additionally, we examined the relationships between DKD, albuminuria, and low-eGFR with other inflammatory markers, such as the aggregate index of systemic inflammation (AISI), systemic immune-inflammation index (SII), system inflammation response index (SIRI), and platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR). Their diagnostic capabilities were evaluated and contrasted using receiver operating characteristic (ROC) curves. Results 44.65% of the 7,153 participants who were recruited for this study were males. DKD, albuminuria, and low-eGFR were prevalent in 31.76%, 23.08%, and 14.55% of cases, respectively. Positive correlations were seen between the NLR with the prevalences of DKD, albuminuria, and low-eGFR. Subgroup analysis and interaction tests revealed that the associations of NLR with DKD, albuminuria, and low-eGFR were not significantly different across populations. In addition, MLR, SII and SIRI showed positive associations with the prevalence of DKD. ROC analysis discovered that when compared to other inflammatory markers (MLR, PLR, SII, SIRI, and AISI), NLR may demonstrate more discriminatory power and accuracy in assessing the risk of DKD, albuminuria, and low-eGFR. Conclusion Compared to other inflammatory markers (MLR, PLR, SII, SIRI, and AISI), NLR may serve as the more effective potential inflammatory marker for identifying the risk of DKD, albuminuria, and low-eGFR in US T2DM patients. T2DM patients with elevated levels of NLR, MLR, SII, and SIRI should be closely monitored for their potential risk to renal function.
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Affiliation(s)
- Xiaowan Li
- Department of Critical Care Medicine, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Lanyu Wang
- Department of Urology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Min Liu
- Department of Critical Care Medicine, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Hongyi Zhou
- Department of Urology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Hongyang Xu
- Department of Critical Care Medicine, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
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Du H, Wang Y, Zhu Y, Li X, Zhu T, Wu Q, Zha F. MiR-29b Alleviates High Glucose-induced Inflammation and Apoptosis in Podocytes by Down-regulating PRKAB2. Endocr Metab Immune Disord Drug Targets 2024; 24:981-990. [PMID: 38204237 PMCID: PMC11275309 DOI: 10.2174/0118715303267375231204103200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 10/16/2023] [Accepted: 10/23/2023] [Indexed: 01/12/2024]
Abstract
BACKGROUND Podocyte injury and inflammatory response are the core contributors to the pathogenesis of diabetic nephropathy. This study aims to identify novel regulatory miRNAs and elucidate their underlying mechanisms, which will help us understand the pathogenesis of diabetic nephropathy more comprehensively. MATERIALS AND METHODS Different glucose concentrations were used to treat podocytes to mimic the pathology of diabetic nephropathy in vitro. Flow cytometry was used to determine cell apoptosis. Inflammatory cytokines released by podocytes were measured by using an enzymelinked immunosorbent assay (ELISA). Western Blot was used to detect the expression of PRKAB2 protein in podocytes. RESULTS Genecard and g: profiler results revealed that miR-29b might be involved in regulating HG-induced cell injury. QRT-PCR indicated that HG-induced downregulation of miR-29b in podocytes. MiR-29b knockdown promoted cell apoptosis and inflammatory response in podocytes. MiR-29b overexpression repressed cell apoptosis and inflammatory response induced by high glucose treatment in podocytes. Luciferase reporter assay and Western Blot showed that miR-29b targeted PRKAB2 to negatively regulate PRKAB2 expression directly. Knockdown of PRKAB2 reversed the increased cell apoptosis and inflammation induced by miR-29b inhibitors. CONCLUSION MiR-29b plays a role in inhibiting inflammation and apoptosis in high glucose (HG) treated podocytes by negatively regulating PRKAB2 expression. This study provides new potential targets and ideas for the treatment of diabetic nephropathy.
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Affiliation(s)
- Hongxiu Du
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai, 201799, China
| | - Yakun Wang
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai, 201799, China
| | - Yingchun Zhu
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai, 201799, China
| | - Xiaoying Li
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai, 201799, China
| | - Tingying Zhu
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai, 201799, China
| | - Qianqian Wu
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai, 201799, China
| | - Fangfang Zha
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai, 201799, China
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万 璐, 钱 宇, 倪 文, 卢 宇, 李 巍, 潘 艳, 陈 卫. [Linagliptin improves diabetic kidney disease in rats by promoting mitochondrial biogenesis through the AMPK/PGC-1 α/TFAM pathway]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2023; 43:2053-2060. [PMID: 38189391 PMCID: PMC10774113 DOI: 10.12122/j.issn.1673-4254.2023.12.09] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Indexed: 01/09/2024]
Abstract
OBJECTIVE To investigate whether linagliptin improves diabetic kidney disease (DKD) by promoting mitochondrial biosynthesis via activating adenosine monophosphate activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1α/mitochondrial transcription factor A (AMPK/PGC-1α/TFAM) pathway. METHODS With 6 male SD rats feeding normal chow as the control group, 16 SD rat models of DKD induced by intraperitoneal injection of 45 mg/kg STZ and high-fat and high-glucose feeding for 4 weeks were randomized into DKD model group and linagliptin treatment group. The rats in the latter two groups were subjected to daily intragastric administration of vehicle or 5 mg/kg linagliptin (dissolved in 5 g/L sodium carboxymethylcellulose, final concentration of 2 mg/mL) for 12 weeks with further high-fat and high-glucose feeding. After the treatments, the rats were sacrificed and blood samples from the abdominal aorta and kidney tissues were collected for testing blood glucose, liver function and lipid metabolism; HE, PAS, Masson, Sirius red staining and electron microscopy were used to observe renal tissue damage. Renal expressions of transforming growth factor β1 (TGF-β1), fibronectin (FN) and collagen I (Col I) were detected by immunohistochemistry, and the changes in membrane potential (ΔψM) and ATP enzyme content were analyzed to assess mitochondrial damage; The expressions of AMPK/PGC-1α/TFAM pathway proteins were detected using Western blotting. RESULTS Compared with DKD model rats, the rats receiving linagliptin treatment showed significantly decreased blood glucose level (P < 0.01) and improved proteinuria (P < 0.05) with obviously alleviated renal ultrastructural damage and fibrosis, increased ATPase content and ΔψM (P < 0.0001), and enhanced renal expressions of P-AMPK/AMPK, PGC-1α and TFAM (P < 0.05). CONCLUSIONS Linagliptin improves proteinuria and renal fibrosis in rat models of DKD possibly by activating the AMPK/PGC-1α/TFAM pathway to promote mitochondrial biosynthesis.
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Affiliation(s)
- 璐 万
- 蚌埠医科大学第一附属医院肾内科，安徽 蚌埠 233000Department of Nephrology, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
| | - 宇池 钱
- 蚌埠医科大学第一附属医院肾内科，安徽 蚌埠 233000Department of Nephrology, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
- 蚌埠医科大学基础医学机能学综合实验室，安徽 蚌埠 233000Functional Science laboratory, School of Basic Medicine, Bengbu Medical University, Bengbu 233000, China
| | - 文静 倪
- 蚌埠医科大学第一附属医院肾内科，安徽 蚌埠 233000Department of Nephrology, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
- 蚌埠医科大学临床检验诊断实验室，安徽 蚌埠 233000Experimental Center of Clinical Laboratory Diagnostics, School of Basic Medicine, Bengbu Medical University, Bengbu 233000, China
| | - 宇欣 卢
- 蚌埠医科大学第一附属医院肾内科，安徽 蚌埠 233000Department of Nephrology, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
| | - 巍 李
- 蚌埠医科大学第一附属医院肾内科，安徽 蚌埠 233000Department of Nephrology, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
| | - 艳 潘
- 蚌埠医科大学第一附属医院肾内科，安徽 蚌埠 233000Department of Nephrology, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
| | - 卫东 陈
- 蚌埠医科大学第一附属医院肾内科，安徽 蚌埠 233000Department of Nephrology, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
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Wang J, Tao Y, Zhao F, Liu T, Shen X, Zhou L. Expression of urinary exosomal miRNA-615-3p and miRNA-3147 in diabetic kidney disease and their association with inflammation and fibrosis. Ren Fail 2023; 45:2121929. [PMID: 36695327 PMCID: PMC9879181 DOI: 10.1080/0886022x.2022.2121929] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD) is one of the most common chronic complications of type 2 diabetes mellitus (T2DM), and it is particularly important to identify a high-quality method for evaluating disease progression. Urinary exosomes contain microRNA that might promise early diagnostic and monitoring markers of DKD. The present study aimed to identify novel exosome-related markers associated with inflammation and fibrosis to assess the progression of DKD. METHOD Exosomes were extracted from the urine of 83 participants to determine the expression levels of miRNA-615-3p and miRNA-3147 in 20 healthy people, 21 patients with T2DM and 42 patients with DKD, as determined by RT-qPCR. The circulating expression level of TGF-β1 was detected by ELISA. Serum Cystatin C was measured by a latex-enhanced immunoturbidimetric method. The correlation analyses were performed for all clinical and laboratory parameters. RESULT The expression level of urinary exosomal miRNA-615-3p in DKD patients was significantly higher than that in the control group and the T2DM group by RT-qPCR. The expression of miRNA-3147 showed an upward trend in the three groups of subjects, but it was not statistically significant. The urinary exosomal miRNA-615-3p was positively correlated with serum Cystatin C, plasma TGF-β1, creatinine, BUN, PCR and 24-h urine protein, and negatively correlated with eGFR and albumin. The diagnostic efficacy of urinary exosomal miRNA-615-3p combined with the ACR was higher than that of ACR alone. CONCLUSIONS Urinary exosomal miRNA-615-3p may be used as a novel biomarker for evaluating the progression of DKD, and may be involved in the process of inflammation and fibrosis in DKD. The combined diagnosis of urinary exosomal miRNA-615-3p and ACR may be used as more stable and sensitive diagnostic criteria for DKD.
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Affiliation(s)
- Jiaxin Wang
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yiying Tao
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fan Zhao
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Tong Liu
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiahong Shen
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ling Zhou
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China,CONTACT Ling Zhou Department of Nephrology, The First Affiliated Hospital of Soochow University, 889 Pinghai Rd, Suzhou, 215000, People’s Republic of China
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Wu C, Zhang R, Wang J, Chen Y, Zhu W, Yi X, Wang Y, Wang L, Liu P, Li P. Dioscorea nipponica Makino: A comprehensive review of its chemical composition and pharmacology on chronic kidney disease. Biomed Pharmacother 2023; 167:115508. [PMID: 37716118 DOI: 10.1016/j.biopha.2023.115508] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/06/2023] [Accepted: 09/12/2023] [Indexed: 09/18/2023] Open
Abstract
Chronic kidney disease (CKD) is a widespread ailment that significantly impacts global health. It is characterized by high prevalence, poor prognosis, and substantial healthcare costs, making it a major public health concern. The current clinical treatments for CKD are not entirely satisfactory, leading to a high demand for alternative therapeutic options. Chinese herbal medicine, with its long history, diverse varieties, and proven efficacy, offers a promising avenue for exploration. One such Chinese herbal medicine, Dioscorea nipponica Makino (DNM), is frequently used to treat kidney diseases. In this review, we have compiled studies examining the mechanisms of action of DNM in the context of CKD, focusing on five primary areas: improvement of oxidative stress, inhibition of renal fibrosis, regulation of metabolism, reduction of inflammatory response, and regulation of autophagy.
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Affiliation(s)
- Chenguang Wu
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Rui Zhang
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Jingjing Wang
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Yao Chen
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Wenhui Zhu
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Xiang Yi
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Yan Wang
- Department of Nephrology, Peking University People's Hospital, Beijing, China
| | - Lifan Wang
- Renal Division, Department of Medicine, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China.
| | - Peng Liu
- Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, China.
| | - Ping Li
- Beijing Key Lab for Immune-Mediated Inflammatory Diseases, China-Japan Friendship Hospital, Beijing, China.
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Sultan S, Alharbi M, Alrayes N, Makki N, Faruqui H, Basuni L, Alhozali A, Abdulnoor R, Borai A, Almalki A, Alzahrani A, Alamoudi R, Almaghrabi M. Association of a single nucleotide polymorphism in SOD2 with susceptibility for the development of diabetic nephropathy in patients with type 2 diabetes: A Saudi population study. Endocrinol Diabetes Metab 2023; 6:e449. [PMID: 37698290 PMCID: PMC10638619 DOI: 10.1002/edm2.449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 09/01/2023] [Accepted: 09/04/2023] [Indexed: 09/13/2023] Open
Abstract
INTRODUCTION One of the complications of diabetes mellitus (DM) is diabetic nephropathy (DN), which plays a significant role in the progression of end-stage renal disease. Oxidative stress is implicated in DN pathogenesis, and genetic variations in antioxidant enzymes such as superoxide dismutase 2 (SOD2) and catalase (CAT) may contribute to the susceptibility. This study aimed to investigate the potential association between single nucleotide polymorphisms (SNPs) in antioxidant enzymes, specifically SOD2 rs4880 and CAT rs769217, and the risk of T2D and susceptibility to DN within the Saudi population. METHODS This case-control study included 150 participants, comprising 50 patients with T2D without DN (group 1), 50 patients with T2D with DN (group 2), and 50 healthy participants (group 3). The samples were genotyped using real-time PCR for SOD2 rs4880 and CAT rs769217 SNPs. Sanger sequencing was used for validation. Statistical analyses were performed to explore associations between these SNPs and T2D with or without DN. RESULTS No significant difference was observed in CAT rs769217 expression between the groups. However, a significant difference was observed in SOD2 rs4880 expression between the healthy controls and patients with T2D with DN (p = .028). Furthermore, SOD2 rs4880 was associated with approximately threefold increased risk of DN in patients with T2D compared to that in healthy participants (odds ratio [OR] = 2.99 [1.31-6.83]). Validation through Sanger sequencing further confirmed these findings. CONCLUSIONS The findings of this study provide evidence that SOD2 rs4880 SNP may contribute to inadequate defence by the antioxidant enzyme, SOD2, against DM-induced oxidative stress and thus cause DN in Saudi patients with T2D. Therefore, SOD2 rs4880 may serve as a predictive marker to prevent the development and progression of DN in patients with T2D.
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Affiliation(s)
- Samar Sultan
- Medical Laboratory Sciences, Faculty of Applied Medical SciencesKing Abdulaziz UniversityJeddahSaudi Arabia
| | - Meshari Alharbi
- Medical Laboratory Sciences, Faculty of Applied Medical SciencesKing Abdulaziz UniversityJeddahSaudi Arabia
- King Abdulaziz Medical CityNational Guard HospitalJeddahSaudi Arabia
| | - Nuha Alrayes
- Medical Laboratory Sciences, Faculty of Applied Medical SciencesKing Abdulaziz UniversityJeddahSaudi Arabia
- Princes Al‐Jawhara center of excellence in research of hereditary disorders, King Abdulaziz UniversityJeddahSaudi Arabia
| | - Nehad Makki
- Department of Medicine, Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia
| | - Hanan Faruqui
- Department of Medicine, Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia
| | - Lama Basuni
- Department of Medicine, Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia
| | - Amani Alhozali
- Department of Medicine, Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia
| | - Reham Abdulnoor
- Department of Medicine, Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia
| | - Anwar Borai
- King Abdullah International Medical Research Center (KAIMRC)King Saud bin Abdulaziz University for Health Sciences (KSAU‐HS), King Abdulaziz Medical City, Ministry of National GuardJeddahSaudi Arabia
| | - Abdullah Almalki
- King saud bin Abdulaziz university for health sciences, king abdulaziz medical cityking Abdullah international research center (KAIMRC)JeddahSaudi Arabia
| | - Abdullah Alzahrani
- King Abdulaziz Medical city, College of MedicineKing Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research centerJeddahSaudi Arabia
| | - Reem Alamoudi
- King Abdulaziz Medical city, College of MedicineKing Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research centerJeddahSaudi Arabia
| | - Mazin Almaghrabi
- King Abdulaziz Medical CityNational Guard HospitalJeddahSaudi Arabia
- Department of Internal Medicine/EndocrinologyKing Abdulaziz Medical CityJeddahSaudi Arabia
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AlTamimi JZ, AlFaris NA, Alshammari GM, Alagal RI, Aljabryn DH, Abdo Yahya M. Protective effect of eriodictyol against hyperglycemia-induced diabetic nephropathy in rats entails antioxidant and anti-inflammatory effects mediated by activating Nrf2. Saudi Pharm J 2023; 31:101817. [PMID: 37915829 PMCID: PMC10616554 DOI: 10.1016/j.jsps.2023.101817] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/02/2023] [Indexed: 11/03/2023] Open
Abstract
The pathogenesis of diabetic nephropathy (DN) involves cellular activation of oxidative stress and inflammation. Eriodictyol is a citrus-derived flavonoid with multiple pharmacological and protective effects in various conditions. The protective role of Eriodictyol against diabetes and diabetic nephropathy is less investigated. The current research aimed to explore the role of eriodictyol in protecting against DN prompted by streptozotocin in male rats and investigate some possible mechanisms of action. Diabetes was brought about in rats by an i.p injection of a lone dose (65 mg/kg). Five groups of rats were included (n = 8 each) as control (non-diabetic), eriodictyol (20 mg/kg, orally), STZ-diabetic, STZ + eriodictyol (20 mg/kg, orally), and STZ + eriodictyol (20 mg/kg, orally) + ML385 (30 µg/kg, i.p.). Kidney histology and the levels of some markers of kidney function, renal oxidative stress, and renal inflammation were analyzed in all groups of rats. Treatment with eriodictyol prevented the damage in the renal glomeruli and tubules and reduced renal immune cell infiltration in STZ-treated animals. It also spiked urinary creatinine excretion and reduced urine volume and urinary levels of albumin, monocyte chemoattractant protein 1 (MCP-1), urinary kidney injury molecule-1 (KIM-1), and nephrin in these diabetic rats. In addition, eriodictyol stimulated the nuclear protein accumulation of Nrf2 and boosted the expression of superoxide dismutase (SOD), glutathione (GSH), heme oxygenase-1 (HO-1), and catalase (CAT) in the diabetic rat kidneys. In concomitance, it reduced the nuclear levels of NF-κB and levels of interleukine-6 (IL-6), malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α) and attenuated the reduction in renal ATP levels and the increase in the mitochondria transition pore opening (mtTPT). However, the administration of eriodictyol did not affect rats' body weights and fasting glucose and insulin levels but significantly reduced serum levels of cholesterol, triglycerides, LDL-c, and oxidized LDL-c (ox-LDL-c). In conclusion, eriodictyol prevents STZ-induced nephropathy by a hypolipidemic effect and concomitant antioxidant and anti-inflammatory effects mediated by activating Nrf2/NF-κB/antioxidant axis.
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Affiliation(s)
- Jozaa Z. AlTamimi
- Department of Physical Sports Sciences, College of Education, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Nora A. AlFaris
- Department of Physical Sports Sciences, College of Education, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Ghedeir M. Alshammari
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, P.O. Box 84428, Riyadh 11451, Saudi Arabia
| | - Reham I. Alagal
- Department of Health Sciences, College of Health and Rehabilitation Sciences, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Dalal H. Aljabryn
- Department of Physical Sports Sciences, College of Education, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Mohammed Abdo Yahya
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, P.O. Box 84428, Riyadh 11451, Saudi Arabia
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Li MY, Duan JQ, Wang XH, Liu M, Yang QY, Li Y, Cheng K, Liu HQ, Wang F. Inulin Inhibits the Inflammatory Response through Modulating Enteric Glial Cell Function in Type 2 Diabetic Mellitus Mice by Reshaping Intestinal Flora. ACS OMEGA 2023; 8:36729-36743. [PMID: 37841129 PMCID: PMC10568710 DOI: 10.1021/acsomega.3c03055] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 09/13/2023] [Indexed: 10/17/2023]
Abstract
Inulin, a commonly used dietary fiber supplement, is capable of modulating the gut microbiome. Chronic inflammation resulting from metabolic abnormalities and gut flora dysfunction plays a significant role in the development of type 2 diabetes mellitus (T2DM). Our research has demonstrated that inulin administration effectively reduced colonic inflammation in T2DM mice by inducing changes in the gut microbiota and increasing the concentration of butyric acid, which in turn modulated the function of enteric glial cells (EGCs). Experiments conducted on T2DM mice revealed that inulin administration led to an increase in the Bacteroidetes/Firmicutes ratio and the concentration of butyric acid in the colon. The anti-inflammatory effects of altered gastrointestinal flora and its metabolites were further confirmed through fecal microbiota transplantation. Butyric acid was found to inhibit the activation of the κB inhibitor kinase β/nuclear factor κB pathway, regulate the expression levels of interleukin-6 and tumor necrosis factor-α, suppress the abnormal activation of EGCs, and prevent the release of inflammatory factors by EGCs. Similar results were observed in vitro experiments with butyric acid. Our findings demonstrate that inulin, by influencing the intestinal flora, modifies the activity of EGCs to effectively reduce colonic inflammation in T2DM mice.
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Affiliation(s)
- Meng-Ying Li
- The
Ministry of Education Key Lab of Hazard Assessment and Control in
Special Operational Environment, The Shaanxi Provincial Key Laboratory
of Environmental Health Hazard Assessment and Protection, The Shaanxi
Provincial Key Laboratory of Free Radical Biology and Medicine, Department
of Health Education and Management, School of Preventive Medicine, Air Force Medical University, West Changle Road No. 169, Xi’an, Shaanxi 710032, China
- Department
of Endocrinology, Xijing Hospital, Air Force
Medical University, West
Changle Road No. 127, Xi’an, Shaanxi 710032, China
| | - Jia-Qi Duan
- The
Ministry of Education Key Lab of Hazard Assessment and Control in
Special Operational Environment, The Shaanxi Provincial Key Laboratory
of Environmental Health Hazard Assessment and Protection, The Shaanxi
Provincial Key Laboratory of Free Radical Biology and Medicine, Department
of Health Education and Management, School of Preventive Medicine, Air Force Medical University, West Changle Road No. 169, Xi’an, Shaanxi 710032, China
| | - Xiao-Hui Wang
- The
Ministry of Education Key Lab of Hazard Assessment and Control in
Special Operational Environment, The Shaanxi Provincial Key Laboratory
of Environmental Health Hazard Assessment and Protection, The Shaanxi
Provincial Key Laboratory of Free Radical Biology and Medicine, Department
of Health Education and Management, School of Preventive Medicine, Air Force Medical University, West Changle Road No. 169, Xi’an, Shaanxi 710032, China
| | - Meng Liu
- School
of Environmental and Municipal Engineering, Xi’an University of Architecture and Technology, Middle of Yanta Road No. 13, Xi’an 710055, China
| | - Qiao-Yi Yang
- The
Ministry of Education Key Lab of Hazard Assessment and Control in
Special Operational Environment, The Shaanxi Provincial Key Laboratory
of Environmental Health Hazard Assessment and Protection, The Shaanxi
Provincial Key Laboratory of Free Radical Biology and Medicine, Department
of Health Education and Management, School of Preventive Medicine, Air Force Medical University, West Changle Road No. 169, Xi’an, Shaanxi 710032, China
| | - Yan Li
- Department
of Anatomy, Histology and Embryology and K. K. Leung Brain Research
Centre, Air Force Medical University, West Changle Road No. 169, Xi’an, Shaanxi 710032, China
| | - Kun Cheng
- Department
of Endocrinology, Xijing Hospital, Air Force
Medical University, West
Changle Road No. 127, Xi’an, Shaanxi 710032, China
| | - Han-Qiang Liu
- The
Ministry of Education Key Lab of Hazard Assessment and Control in
Special Operational Environment, The Shaanxi Provincial Key Laboratory
of Environmental Health Hazard Assessment and Protection, The Shaanxi
Provincial Key Laboratory of Free Radical Biology and Medicine, Department
of Health Education and Management, School of Preventive Medicine, Air Force Medical University, West Changle Road No. 169, Xi’an, Shaanxi 710032, China
| | - Feng Wang
- The
Ministry of Education Key Lab of Hazard Assessment and Control in
Special Operational Environment, The Shaanxi Provincial Key Laboratory
of Environmental Health Hazard Assessment and Protection, The Shaanxi
Provincial Key Laboratory of Free Radical Biology and Medicine, Department
of Health Education and Management, School of Preventive Medicine, Air Force Medical University, West Changle Road No. 169, Xi’an, Shaanxi 710032, China
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Mao X, Xu DQ, Yue SJ, Fu RJ, Zhang S, Tang YP. Potential Medicinal Value of Rhein for Diabetic Kidney Disease. Chin J Integr Med 2023; 29:951-960. [PMID: 36607584 DOI: 10.1007/s11655-022-3591-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2022] [Indexed: 01/07/2023]
Abstract
Diabetic kidney disease (DKD) is the primary cause of mortality among diabetic patients. With the increasing prevalence of diabetes, it has become a major concern around the world. The therapeutic effect of clinical use of drugs is far from expected, and therapy choices to slow the progression of DKD remain restricted. Therefore, research on new drugs and treatments for DKD has been a hot topic in the medical field. It has been found that rhein has the potential to target the pathogenesis of DKD and has a wide range of pharmacological effects on DKD, such as anti-nephritis, decreasing blood glucose, controlling blood lipids and renal protection. In recent years, the medical value of rhein in the treatment of diabetes, DKD and renal disease has gradually attracted worldwide attention, especially its potential in the treatment of DKD. Currently, DKD can only be treated with medications from a single symptom and are accompanied by adverse effects, while rhein improves DKD with a multi-pathway and multi-target approach. Therefore, this paper reviews the therapeutic effects of rhein on DKD, and proposes solutions to the limitations of rhein itself, in order to provide valuable references for the clinical application of rhein in DKD and the development of new drugs.
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Affiliation(s)
- Xi Mao
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xi'an, 712046, China
| | - Ding-Qiao Xu
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xi'an, 712046, China
| | - Shi-Jun Yue
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xi'an, 712046, China
| | - Rui-Jia Fu
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xi'an, 712046, China
| | - Sai Zhang
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xi'an, 712046, China
| | - Yu-Ping Tang
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xi'an, 712046, China.
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Zare S, Hasani M, Estêvão MD, Tahmasebi R, Azadbakht L, Shidfar F, Heshmati J, Ziaei S. Muscle Strength and Biochemical Markers as Predictors of Depression in Hemodialysis Patients: A Cross-Sectional Study. Clin Nutr Res 2023; 12:293-303. [PMID: 37969939 PMCID: PMC10641328 DOI: 10.7762/cnr.2023.12.4.293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/29/2023] [Accepted: 10/06/2023] [Indexed: 11/17/2023] Open
Abstract
Patients with chronic renal failure, many of which treated with hemodialysis, present a high prevalence of impaired muscle strength which suggest that muscle mass parameters may be used as markers for changes in muscle in these patients. Measurement of handgrip strength (HGS) is a common, simple, and quick measure of muscle function an indicator of overall muscle strength which has been associated with physical activity and several anthropometric traits. Intercellular adhesion molecule-1 (ICAM-1) and insulin-like growth factor-1 (IGF-1) are biochemical markers associated with inflammatory processes which are a common consequence of dialysis. Additionally, hemodialysis patients frequently present signs of malnutrition and depression. This cross-sectional study aimed to evaluate if muscle and biochemical markers could be used to predict the risk of depression in hemodialysis patients. Several anthropometric parameters, nutrient intake, depression state and the serum levels of ICAM-1 and IGF-1 were determined and Pearson's correlation coefficient and/or Spearman's correlation coefficient were used to test the correlation between them. Our results do not show a correlation between HGF, IGF-1 and ICAM-1 with the depression status of the patients, but mid-arm muscle circumference (MAMC) was statistically and positively correlated with depression. Additionally, ICAM-1 levels were negatively correlated with HGS, MAMC, and IGF-1. Overall, the results of the present study suggest that HGS may be used as an indicator of cardiovascular diseases and MAMC may be a good predictor of the level of depression in hemodialysis patients, although further studies are required.
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Affiliation(s)
- Soudabeh Zare
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Motahareh Hasani
- Department of Nutritional Sciences, School of Health, Golestan University of Medical Sciences, Gorgan 49341-74515, Iran
| | - M. Dulce Estêvão
- Universidade do Algarve, Escola Superior de Saúde, Campus de Gambelas, Faro 8005-139, Portugal
| | - Rahim Tahmasebi
- Department of Epidemiology & Biostatistics, School of Health, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
| | - Leila Azadbakht
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran 141556117, Iran
| | - Farzad Shidfar
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Javad Heshmati
- ICU Department, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah 6714415333, Iran
| | - Somayeh Ziaei
- ICU Department, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah 6714415333, Iran
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Su X, Guo H, Zhou Y, Cao A, Shen Q, Zhu B, Yao X, Wang Y, Wang H, Wang L. Astragaloside IV attenuates high glucose-induced NF-κB-mediated inflammation through activation of PI3K/AKT-ERK-dependent Nrf2/ARE signaling pathway in glomerular mesangial cells. Phytother Res 2023; 37:4133-4148. [PMID: 37189016 DOI: 10.1002/ptr.7875] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 04/16/2023] [Accepted: 05/07/2023] [Indexed: 05/17/2023]
Abstract
Inflammation is a key contributor to diabetic kidney disease pathogenesis, including reactive oxidation stress (ROS)-mediated nuclear factor-κB (NF-κB) signaling pathway. In this study, we examined the effect of Astragaloside IV (AS-IV) on anti-inflammatory and anti-oxidative properties under high glucose (HG) condition and the potential mechanism in glomerular mesangial cells (GMCs). We showed that AS-IV concentration-dependently reduced GMCs proliferation, restrained ROS release and hydrogen peroxide content, and suppressed pro-inflammatory cytokines as well as pro-fibrotic factors expression, which were associated with the inhibition of NF-κB and nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling activation. Accordingly, both NF-κB overexpression by using RNA plasmid and Nrf2 gene silencing by using RNA interference weakened the ability of AS-IV to ameliorate HG-induced oxidative stress, inflammation, and cell proliferation. Furthermore, phosphatidylinositide 3-kinases (PI3K)/serine/threonine protein kinase (Akt) and extracellular regulated protein kinases (ERK) signaling pathway regulated the process of AS-IV-induced Nrf2 activation and antioxidant capacity, which evidenced by using PI3K inhibitor LY294002 or ERK inhibitor PD98059 that largely abolished the AS-IV efficacy. Taken together, these results indicated that AS-IV protected against HG-induced GMCs damage by inhibiting ROS/NF-kB-induced increases of inflammatory cytokines, fibrosis biomarkers, and cell proliferation via up-regulation of Nrf2-dependent antioxidant enzyme expression, which were mediated by PI3K/Akt and ERK signaling pathway activation.
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Affiliation(s)
- Xue Su
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hengjiang Guo
- Department of Anesthesiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yuying Zhou
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Aili Cao
- Department of Nephrology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Shen
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bingbing Zhu
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xingmei Yao
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yunman Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hao Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Li Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Hefei, China
- Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Gao X, Ren C, Li L, Zhao H, Liu K, Zhuang M, Lv X, Zhi X, Jiang H, Chen Q, Zhao X, Li Y. Pharmacological action of Hedysarum polysaccharides: a review. Front Pharmacol 2023; 14:1119224. [PMID: 37701035 PMCID: PMC10494935 DOI: 10.3389/fphar.2023.1119224] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 04/10/2023] [Indexed: 09/14/2023] Open
Abstract
Hedysarum, a traditional Chinese herbal medicine and food with a long history of clinical application, is used to improve health conditions and treat various diseases. Hedysarum polysaccharides (HPS), flavonoids, saponins, and alkaloids, are the primary components of Hedysarum. HPS is the most important natural active ingredient of Hedysarum, which has many pharmacological effects. Currently, HPS exhibits significant promise in drug development for various ailments such as tumors, diabetes, cardiovascular diseases, Alzheimer's disease, and fibrosis. This review paper discusses the extraction, separation, and content determination techniques of HPS, along with the investigation of its chemical constituents. More importantly, we reviewed the anti-inflammatory pharmacological effects of HPS, such as inhibition of inflammatory factors and NF-κB signaling pathway; antitumor activity through apoptosis induction in tumor cells and blocking tumor cell proliferation and metastasis; antioxidant effects; regulation of various cytokines and immune cells; regulation of blood sugar levels, such as in type I and type II diabetes and in diabetic complications; improvement in symptoms of Alzheimer disease; anti-aging and anti-fibrosis properties; and improvement in cerebral ischemia-reperfusion injury. This review paper establishes the theoretical foundation for future studies on the structure, mechanism, and clinical use of HPS.
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Affiliation(s)
- Xiang Gao
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou, China
- Key Clinical Specialty of the National Health Commission of the People’s Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou, China
- Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, China
| | - Chunzhen Ren
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou, China
- Key Clinical Specialty of the National Health Commission of the People’s Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou, China
| | - Linyu Li
- Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou, China
- Key Clinical Specialty of the National Health Commission of the People’s Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou, China
- First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Huilin Zhao
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou, China
- Key Clinical Specialty of the National Health Commission of the People’s Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou, China
| | - Kai Liu
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou, China
- Key Clinical Specialty of the National Health Commission of the People’s Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou, China
| | - Mengjie Zhuang
- Xinjiang Medical University School of Basic Medicine, Urumqi, China
| | - Xinfang Lv
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou, China
- Key Clinical Specialty of the National Health Commission of the People’s Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou, China
- Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, China
| | - Xiaodong Zhi
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou, China
- Key Clinical Specialty of the National Health Commission of the People’s Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou, China
- Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, China
| | - Hugang Jiang
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou, China
- Key Clinical Specialty of the National Health Commission of the People’s Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou, China
| | - Qilin Chen
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou, China
- Key Clinical Specialty of the National Health Commission of the People’s Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou, China
| | - Xinke Zhao
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou, China
- Key Clinical Specialty of the National Health Commission of the People’s Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou, China
- Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, China
| | - Yingdong Li
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou, China
- Key Clinical Specialty of the National Health Commission of the People’s Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou, China
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Wang J, Ni R, Jiang T, Peng D, Ming Y, Cui H, Liu Y. The applications of functional materials-based nano-formulations in the prevention, diagnosis and treatment of chronic inflammation-related diseases. Front Pharmacol 2023; 14:1222642. [PMID: 37593176 PMCID: PMC10427346 DOI: 10.3389/fphar.2023.1222642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/17/2023] [Indexed: 08/19/2023] Open
Abstract
Chronic inflammation, in general, refers to systemic immune abnormalities most often caused by the environment or lifestyle, which is the basis for various skin diseases, autoimmune diseases, cardiovascular diseases, liver diseases, digestive diseases, cancer, and so on. Therapeutic strategies have focused on immunosuppression and anti-inflammation, but conventional approaches have been poor in enhancing the substantive therapeutic effect of drugs. Nanomaterials continue to attract attention for their high flexibility, durability and simplicity of preparation, as well as high profitability. Nanotechnology is used in various areas of clinical medicine, such as medical diagnosis, monitoring and treatment. However, some related problems cannot be ignored, including various cytotoxic and worsening inflammation caused by the nanomaterials themselves. This paper provides an overview of functional nanomaterial formulations for the prevention, diagnosis and treatment of chronic inflammation-related diseases, with the intention of providing some reference for the enhancement and optimization of existing therapeutic approaches.
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Affiliation(s)
- Jingjing Wang
- Department of pharmacy, Daping Hospital, Army Medical University, Chongqing, China
- Medical Research Institute, Southwest University, Chongqing, China
| | - Rui Ni
- Department of pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Tingting Jiang
- Department of pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Dan Peng
- Department of pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Yue Ming
- Department of pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Hongjuan Cui
- Medical Research Institute, Southwest University, Chongqing, China
| | - Yao Liu
- Department of pharmacy, Daping Hospital, Army Medical University, Chongqing, China
- Medical Research Institute, Southwest University, Chongqing, China
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Fukuda T, Fujii A, Akihisa T, Otsubo N, Murakami M, Yamada T, Maki C. Association between Diabetic Peripheral Neuropathy as Measured Using a Point-of-Care Sural Nerve Conduction Device and Urinary Albumin Excretion in Patients with Type 2 Diabetes. J Clin Med 2023; 12:4089. [PMID: 37373782 DOI: 10.3390/jcm12124089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND It is not well known whether diabetic peripheral neuropathy diagnosed using a non-invasive point-of-care nerve conduction device called DPN-Check® is associated with diabetic nephropathy. Thus, we aimed to evaluate the association of diabetic peripheral neuropathy with urinary albumin excretion in patients with type 2 diabetes using DPN-Check®. METHODS This retrospective observational study included 323 Japanese patients with type 2 diabetes. The urinary albumin-to-creatinine ratio in a spot urine sample was defined as urinary albumin excretion. Multiple linear regression analysis was used to determine the association of DPN-Check®-determined diabetic peripheral neuropathy with urinary albumin excretion. RESULTS Patients with DPN-Check®-determined diabetic peripheral neuropathy had significantly higher urinary albumin excretion than those without, while there was no difference in urinary albumin excretion between patients with and without diabetic peripheral neuropathy determined by simplified diagnostic criteria. In the multivariate model, the DPN-Check® determined that diabetic peripheral neuropathy was significantly associated with urinary albumin excretion even after adjustment for covariates (standardized β, 0.123; p = 0.012). CONCLUSIONS Our study found a significant association between diabetic peripheral neuropathy diagnosed using DPN-Check® and urinary albumin excretion in patients with type 2 diabetes.
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Affiliation(s)
- Tatsuya Fukuda
- Department of Endocrinology and Metabolism, Tokyo Metropolitan Okubo Hospital, Tokyo 160-8488, Japan
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Akiko Fujii
- Department of Endocrinology and Metabolism, Tokyo Metropolitan Okubo Hospital, Tokyo 160-8488, Japan
| | - Taro Akihisa
- Department of Endocrinology and Metabolism, Tokyo Metropolitan Okubo Hospital, Tokyo 160-8488, Japan
| | - Naoya Otsubo
- Department of Endocrinology and Metabolism, Tokyo Metropolitan Okubo Hospital, Tokyo 160-8488, Japan
| | - Masanori Murakami
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Tetsuya Yamada
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Chisato Maki
- Department of Endocrinology and Metabolism, Tokyo Metropolitan Okubo Hospital, Tokyo 160-8488, Japan
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Wei M, Liu X, Tan Z, Tian X, Li M, Wei J. Ferroptosis: a new strategy for Chinese herbal medicine treatment of diabetic nephropathy. Front Endocrinol (Lausanne) 2023; 14:1188003. [PMID: 37361521 PMCID: PMC10289168 DOI: 10.3389/fendo.2023.1188003] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 05/23/2023] [Indexed: 06/28/2023] Open
Abstract
Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. It has become a leading cause of death in patients with diabetes and end-stage renal disease. Ferroptosis is a newly discovered pattern of programmed cell death. Its main manifestation is the excessive accumulation of intracellular iron ion-dependent lipid peroxides. Recent studies have shown that ferroptosis is an important driving factor in the onset and development of DN. Ferroptosis is closely associated with renal intrinsic cell (including renal tubular epithelial cells, podocytes, and mesangial cells) damage in diabetes. Chinese herbal medicine is widely used in the treatment of DN, with a long history and definite curative effect. Accumulating evidence suggests that Chinese herbal medicine can modulate ferroptosis in renal intrinsic cells and show great potential for improving DN. In this review, we outline the key regulators and pathways of ferroptosis in DN and summarize the herbs, mainly monomers and extracts, that target the inhibition of ferroptosis.
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Affiliation(s)
- Maoying Wei
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xingxing Liu
- Department of Emergency, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhijuan Tan
- Department of Traditional Chinese Medicine, The Seventh Hospital of Xingtai, Xingtai, Heibei, China
| | - Xiaochan Tian
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Mingdi Li
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Junping Wei
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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De Leon-Oliva D, Garcia-Montero C, Fraile-Martinez O, Boaru DL, García-Puente L, Rios-Parra A, Garrido-Gil MJ, Casanova-Martín C, García-Honduvilla N, Bujan J, Guijarro LG, Alvarez-Mon M, Ortega MA. AIF1: Function and Connection with Inflammatory Diseases. BIOLOGY 2023; 12:biology12050694. [PMID: 37237507 DOI: 10.3390/biology12050694] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/29/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023]
Abstract
Macrophages are a type of immune cell distributed throughout all tissues of an organism. Allograft inflammatory factor 1 (AIF1) is a calcium-binding protein linked to the activation of macrophages. AIF1 is a key intracellular signaling molecule that participates in phagocytosis, membrane ruffling and F-actin polymerization. Moreover, it has several cell type-specific functions. AIF1 plays important roles in the development of several diseases: kidney disease, rheumatoid arthritis, cancer, cardiovascular diseases, metabolic diseases and neurological disorders, and in transplants. In this review, we present a comprehensive review of the known structure, functions and role of AIF1 in inflammatory diseases.
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Affiliation(s)
- Diego De Leon-Oliva
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Cielo Garcia-Montero
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Diego Liviu Boaru
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Luis García-Puente
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Antonio Rios-Parra
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Cancer Registry and Pathology Department, Principe de Asturias University Hospital, 28806 Alcala de Henares, Spain
| | - Maria J Garrido-Gil
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Carlos Casanova-Martín
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Julia Bujan
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Luis G Guijarro
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Unit of Biochemistry and Molecular Biology, Department of System Biology (CIBEREHD), University of Alcalá, 28801 Alcala de Henares, Spain
| | - Melchor Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Immune System Diseases-Rheumatology, Oncology Service an Internal Medicine (CIBEREHD), University Hospital Príncipe de Asturias, 28806 Alcala de Henares, Spain
| | - Miguel A Ortega
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Cancer Registry and Pathology Department, Principe de Asturias University Hospital, 28806 Alcala de Henares, Spain
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Feng B, Yang F, Liu J, Sun Q, Meng R, Zhu D. Amelioration of diabetic kidney injury with dapagliflozin is associated with suppressing renal HMGB1 expression and restoring autophagy in obese mice. J Diabetes Complications 2023; 37:108409. [PMID: 36731146 DOI: 10.1016/j.jdiacomp.2023.108409] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 01/12/2023] [Accepted: 01/23/2023] [Indexed: 01/29/2023]
Abstract
Diabetic kidney disease (DKD) is a major cause of chronic and end-stage renal disease in diabetic patients. Here, we investigated protective effects and possible mechanisms of dapagliflozin on renal injury in diabetic mice. DKD mice were established by high fat diet (HFD) feeding. Half of DKD mice were randomly assigned to receive dapagliflozin treatment (200 μg/day) for 8 weeks. Renal lipid droplets, fibrosis, oxidative and endoplasmic reticulum stress were evaluated. Glomerular injury was assessed by immunohistochemistry and transmission electron microscopy. Dapagliflozin led to marked inhibition of ROS levels and endoplasmic reticulum stress in diabetic mice. HFD-induced loss of Podocin and Nephrin, and impaired podocytes were also improved with the treatment. Importantly, overexpression of HMGB1 and suppressed autophagy in the kidney were partly reversed by dapagliflozin. Therefore, we speculate that protective effects of dapagliflozin on DKD may be associated with suppression of HMGB1 expression and restoration of autophagy in the kidney.
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Affiliation(s)
- Bin Feng
- Department of Endocrinology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Fan Yang
- Department of Endocrinology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China
| | - Jie Liu
- Department of Endocrinology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China
| | - Qichao Sun
- Department of Endocrinology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China
| | - Ran Meng
- Department of Endocrinology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China.
| | - Dalong Zhu
- Department of Endocrinology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China.
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Ma Y, Deng Y, Li N, Dong A, Li H, Chen S, Zhang S, Zhang M. Network pharmacology analysis combined with experimental validation to explore the therapeutic mechanism of Schisandra Chinensis Mixture on diabetic nephropathy. JOURNAL OF ETHNOPHARMACOLOGY 2023; 302:115768. [PMID: 36280016 DOI: 10.1016/j.jep.2022.115768] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/17/2022] [Accepted: 09/25/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Diabetic nephropathy (DN) is one of the most common and serious microvascular complications of Diabetes mellitus (DM). The inflammatory response plays a critical role in DN. Schisandra Chinensis Mixture (SM) has shown promising clinical efficacy in the treatment of DN while the pharmacological mechanisms are still unclear. AIM OF THE STUDY In this study, a network pharmacology approach and bioinformatic analysis were adopted to predict the pharmacological mechanisms of SM in DN therapy. Based on the predicted results, molecular docking and in vivo experiments were used for verification. MATERIALS AND METHODS In this study, the candidate bioactive ingredients of SM were obtained via Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and supplementing according to the literature. SM putative targets and the verified targets were acquired from TCMSP and SiwssTartgetPrediction Database. DN-related target genes were collected from GeneCards, OMIM, DisGeNET databases, and microarray data analysis. Biological function and pathway analysis were performed to further explore the pharmacological mechanisms of SM in DN therapy. The protein-protein interaction (PPI) network was established to screen the hub gene. The Receiver Operating Characteristic (ROC) analysis and the molecular docking simulations were performed to validate the potential target-drug interactions. The fingerprint spectrum of multi-components of the SM was characterized by UPLC-MS/MS. The signaling pathways associated with inflammation and hub genes were partially validated in SD rats. RESULTS A total of 36 bioactive ingredients were contained, and 666 component-related targets were screened from SM, of which 50 intersected with DN targets and were considered potential therapeutic targets. GO analyses revealed that the 50 intersection targets were mainly enriched in the inflammatory response, positive regulation of angiogenesis, and positive regulation of phosphatidylinositol 3-kinase(PI3K) signaling. KEGG analyses indicated that the PI3K-Akt signaling pathway was considered as the most important pathway for SM antagonism to the occurrence and development of DN, with the highest target count enrichment. PPI network results showed that the top 15 protein targets in degree value, VEGFA, JAK2, CSF1R, NOS3, CCR2, CCR5, TLR7, FYN, BTK, LCK, PLAT, NOS2, TEK, MMP1 and MCL1, were identified as hub genes. The results of ROC analysis showed that VEGFA and NOS3 were valuable in the diagnosis of DN. The molecular docking confirmed that the core bioactive ingredients had well-binding affinity for VEGFA and NOS3. The in vivo experiments confirmed that SM significantly inhibited the over-release of inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor receptor (TNF)-α in DN rats, while regulating the PI3K-AKT and VEGFA-NOS3 signaling pathways. CONCLUSION This study revealed the multi-component, multi-target and multi-pathway characteristics of SM therapeutic DN. SM inhibited the inflammatory response and improved renal pathological damage in DN rats, which was related to the regulation of the PI3K-Akt and VEGFA-NOS3 signaling pathways.
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Affiliation(s)
- Yu Ma
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078, China.
| | - Yuanyuan Deng
- Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Na Li
- Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Ao Dong
- Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Hongdian Li
- Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Shu Chen
- Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Sai Zhang
- Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Mianzhi Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078, China; Tianjin Academy of Traditional Chinese Medicine, Tianjin, 300120, China.
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Screening of Diabetic Nephropathy Progression-Related Genes Based on Weighted Gene Co-expression Network Analysis. Biochem Genet 2023; 61:221-237. [PMID: 35834115 DOI: 10.1007/s10528-022-10250-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 06/20/2022] [Indexed: 01/24/2023]
Abstract
The purpose of this study is to explore the progression-related genes of diabetic nephropathy (DN) through weighted gene co-expression network analysis (WGCNA). The gene expression dataset GSE14202 was downloaded from the GEO database for differential expression analysis. WGCNA v1.69 was used to perform co-expression analysis on differentially expressed genes. 25 modular genes were selected through WGCNA. The motif enrichment analysis was performed on 25 genes, and 34 motifs were obtained, of which 8 transcription factors (TFs) were differentially expressed. GENIE3 was applied to analyze the expression correlation of 8 differentially expressed TFs and 25 genes. Combined with the predicted TF-target gene relationship, 69 interactions between 8 TFs and 18 genes were obtained. The functional enrichment analysis of 18 genes showed that 7 key genes were obviously enriched in adaptive immune response and were clearly up-regulated in advanced DN patients. The expression of C1S, LAIR1, CD84, SIT1, SASH3, and CD180 in glomerular samples from DN patients was significantly up-regulated in compared with normal samples, and the expression of these genes was negatively correlated with GFR. We observed that in the in vitro cell model of DN, the relative expression levels of 5 key genes (except SASH3) were obviously elevated in the high-glucose group. Five key genes were identified to be related to the progression of DN. The findings of this study may provide new ideas and therapeutic targets for exploring the pathogenesis of DN.
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Gliflozins Have an Anti-Inflammatory Effect on Renal Proximal Tubular Epithelial Cells in a Diabetic and Inflammatory Microenvironment In Vitro. Int J Mol Sci 2023; 24:ijms24031811. [PMID: 36768138 PMCID: PMC9916320 DOI: 10.3390/ijms24031811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/04/2023] [Accepted: 01/14/2023] [Indexed: 01/18/2023] Open
Abstract
Inflammation is intimately involved in the pathogenesis of diabetic kidney disease. Inhibition of SGLT-2 by a specific class of drugs, gliflozins, has been shown to reduce inflammation and attenuate the progression of diabetic nephropathy, in addition to its main effect of inhibiting renal glucose reabsorption. We used highly purified human renal proximal tubular epithelial cells (PTCs) as an in vitro model to study the cellular response to a diabetic (high glucose) and inflammatory (cytokines) microenvironment and the effect of gliflozins. In this context, we investigated the influence of SGLT-2 inhibition by empa- and dapagliflozin (500 nM) on the expression of pro-inflammatory factors (IL-1β, IL-6, TNF-α, MCP-1, and ICAM-1). The results clearly indicate an anti-inflammatory effect of both gliflozins. Although induced expression of the four cytokines was only slightly attenuated, there was a clear effect on the expression of the adhesion molecule ICAM-1, a master regulator of cellular responses in inflammation and injury resolution. The induced expression of ICAM-1 mRNA was significantly reduced by approximately 13.5% by empagliflozin and also showed an inhibitory trend with dapagliflozin. However, induced ICAM-1 protein expression was significantly inhibited from 24.71 ± 1.0 ng/mL to 18.81 ± 3.9 (empagliflozin) and 19.62 ± 2.1 ng/mL (dapagliflozin). In conclusion, an additional anti-inflammatory effect of empa- and dapagliflozin in therapeutically observed concentrations was demonstrated in primary human PTCs in vitro.
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