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Zhou J, Yang F, Zhang X, Wang C, Wu Z, Gao J. Jiangniaosuan formula inhibits hyperuricemia-induced apoptosis of renal tubular epithelial cells via ROS/HIF-1α/EZH2 pathway: A network pharmacology analysis and experimental validation. Bioorg Chem 2025; 159:108363. [PMID: 40088688 DOI: 10.1016/j.bioorg.2025.108363] [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: 01/03/2025] [Revised: 02/28/2025] [Accepted: 03/09/2025] [Indexed: 03/17/2025]
Abstract
OBJECTIVE This study aimed to explore the main chemical components of Jiangniaosuan Formula (JNSF), the therapeutic effect of JNSF on hyperuricemia (HUA) mice, and the underlying mechanism by which JNSF inhibits renal tubular epithelial cell apoptosis. METHODS Ultra Performance Liquid Chromatography-Quadrupole-Time of Flight Mass Spectrometry (UPLC-Q-TOF-MS) was used to analyze the chemical composition of JNSF and its serum metabolites. Network pharmacology was performed to predict the potential target genes and pathways. In vitro and in vivo models were established to verify the lower serum uric acid (SUA) and renal protective effects. RESULTS UPLC-Q-TOF-MS identified 61 chemical compounds in JNSF and 56 metabolites in serum after oral administration. Network pharmacology suggested that Hypoxia-Inducible Factor 1-Alpha (HIF-1α), Cysteine-dependent Aspartate-specific Protease-3 (Caspase-3) and B-cell Lymphoma 2 (Bcl-2) might be the therapeutic targets of JNSF for the HUA treatment and JNSF may exert the therapeutic effect on uric acid nephropathy (UAN) through regulating HIF-1α signaling pathway and apoptosis pathway. In vivo experiments showed that JNSF could reduce SUA, protect renal function and tubular function, alleviate renal interstitial edema and fibrosis, reduce the expression of Reactive Oxygen Species (ROS), HIF-1α and Enhancer of Zeste Homolog 2 (EZH2), and inhibit cell apoptosis in HUA mice. In vitro experiments demonstrated that JNSF reversed apoptosis induced by EZH2 overexpression plasmid. Furthermore, we found that UA could promote the binding of HIF-1α to EZH2 protein and its promoter, enhancing EZH2 transcription, suggesting that JNSF could alleviate the progression of HUA-induced kidney injury by inhibiting the activation of ROS/HIF-1α/EZH2 pathway. CONCLUSION JNSF may attenuate HUA-induced renal injury by inhibiting apoptosis through the downregulation of ROS/HIF-1α/EZH2 pathway.
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Affiliation(s)
- Jiabao Zhou
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, China; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, China
| | - Feng Yang
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, China; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, China
| | - Xuming Zhang
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, China; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, China
| | - Chuanxu Wang
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, China; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, China
| | - Zhiyuan Wu
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, China; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, China
| | - Jiandong Gao
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, China; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, China.
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Zhu L, Ding M, Liu L, Yuan P, Shao T, Liu C, Xi C, Han J, Zhou Y, Zhang D, Wang G. Burdock Fructooligosaccharide Protects Against Diabetic Nephropathy in Mice by Regulating Nrf2 Signaling. Pharmacol Res Perspect 2025; 13:e70094. [PMID: 40264355 PMCID: PMC12015130 DOI: 10.1002/prp2.70094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 03/21/2025] [Accepted: 03/29/2025] [Indexed: 04/24/2025] Open
Abstract
Diabetic nephropathy (DN) is a common complication of diabetes mellitus, with oxidative stress playing a critical role in its development. Burdock fructooligosaccharide (BFO), a major compound in Burdock, exhibits antioxidative effects. However, its mechanisms of action and effects on diabetic nephropathy are not clear enough. This study aims to explore the mechanisms of BFO and its impact on streptozotocin-induced diabetic nephropathy in mice. Male C57BL/6J mice were randomly divided into normal control, DN, and BFO groups. Relevant serum biochemical parameters were detected using kits. Renal injury was evaluated through fluorescence microscopy, histopathology, and transmission electron microscopy. Nrf2/HO-1 signaling was analyzed via quantitative real-time PCR, western blotting, and immunohistochemistry. In DN mice, BFO significantly reduced fasting blood glucose, kidney index, urine protein, serum creatinine, blood urea nitrogen, total cholesterol, triglyceride, and low-density lipoprotein cholesterol, while significantly increasing high-density lipoprotein, SOD, and CAT levels. Additionally, BFO protected against streptozotocin-induced renal injury, restored podocyte function, increased both mRNA and protein expression of Nrf2, HO-1, and Bcl-2, and decreased those of Bax. In conclusion, BFO can be used to treat streptozotocin-induced renal injury in mice and is a promising candidate for diabetic nephropathy treatment.
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Affiliation(s)
- Lei Zhu
- School of PharmacyWannan Medical CollegeWuhuChina
- Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re‐evaluation of Active Compounds of Herbal Medicines in Southern AnhuiAnhui Innovative Center for Drug Basic Research of Metabolic DiseasesWuhuChina
| | - Mengru Ding
- School of PharmacyWannan Medical CollegeWuhuChina
- Department of PharmacyFuyang Tumor HospitalFuyangChina
| | - Lina Liu
- Department of Thyroid and Breast SurgeryThe First Affiliated Hospital, Yijishan Hospital of Wannan Medical CollegeWuhuChina
| | - Pingchuan Yuan
- School of PharmacyWannan Medical CollegeWuhuChina
- Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re‐evaluation of Active Compounds of Herbal Medicines in Southern AnhuiAnhui Innovative Center for Drug Basic Research of Metabolic DiseasesWuhuChina
| | - Taili Shao
- School of PharmacyWannan Medical CollegeWuhuChina
- Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re‐evaluation of Active Compounds of Herbal Medicines in Southern AnhuiAnhui Innovative Center for Drug Basic Research of Metabolic DiseasesWuhuChina
| | - Chunyan Liu
- School of PharmacyWannan Medical CollegeWuhuChina
- Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re‐evaluation of Active Compounds of Herbal Medicines in Southern AnhuiAnhui Innovative Center for Drug Basic Research of Metabolic DiseasesWuhuChina
| | - Chuanhu Xi
- School of PharmacyWannan Medical CollegeWuhuChina
| | - Jun Han
- School of PharmacyWannan Medical CollegeWuhuChina
- Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re‐evaluation of Active Compounds of Herbal Medicines in Southern AnhuiAnhui Innovative Center for Drug Basic Research of Metabolic DiseasesWuhuChina
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHMWannan Medical CollegeWuhuChina
| | - Yuyan Zhou
- School of PharmacyWannan Medical CollegeWuhuChina
- Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re‐evaluation of Active Compounds of Herbal Medicines in Southern AnhuiAnhui Innovative Center for Drug Basic Research of Metabolic DiseasesWuhuChina
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHMWannan Medical CollegeWuhuChina
| | - Donglin Zhang
- School of StomatologyWannan Medical CollegeWuhuChina
| | - Guodong Wang
- School of PharmacyWannan Medical CollegeWuhuChina
- Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re‐evaluation of Active Compounds of Herbal Medicines in Southern AnhuiAnhui Innovative Center for Drug Basic Research of Metabolic DiseasesWuhuChina
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Cao Y, Hu L, Chen R, Chen Y, Liu H, Wei J. Unfolded protein response-activated NLRP3 inflammasome contributes to pyroptotic and apoptotic podocyte injury in diabetic kidney disease via the CHOP-TXNIP axis. Cell Signal 2025; 130:111702. [PMID: 40020889 DOI: 10.1016/j.cellsig.2025.111702] [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: 08/17/2024] [Revised: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 03/03/2025]
Abstract
BACKGROUND Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease worldwide. Podocyte injury and death is a key event in DKD progression. Emerging evidence has indicated that crosstalk between unfolded protein response (UPR) and NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an essential role in DKD progression. However, the involvement of these pathways in podocyte injury and death during DKD remains unclear. RESULTS Here, we found that inositol-requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) branches of the UPR, NLRP3 inflammasome, and apoptosis were activated in podocytes under DKD and high glucose (HG) conditions. In vitro, inducing ER stress by thapsigargin, and IRE1 or PERK overexpression upon HG treatment stimulated NLRP3 inflammasome-mediated pyroptosis and apoptosis, whereas inhibiting IRE1 or PERK suppressed them. Importantly, we discovered that the newly identified NLRP3-binding partner, thioredoxin-interacting protein (TXNIP), upon activation by the transcription factor (TF) PERK/CCAAT-enhancer-binding protein homologous protein (CHOP), served as a link between IRE1 or PERK branches with NLRP3 inflammasome-mediated pyroptosis and apoptosis. TXNIP expression was promoted in podocytes from DKD patients and db/db mice, as well as in HG-exposed conditionally immortalized human podocyte (HPC). In HG-exposed HPC, IRE1 or PERK overexpression upregulated TXNIP expression, while IRE1 or PERK inhibition downregulated it. TXNIP or CHOP silencing both inhibited HG-upregulated TXNIP, further blocking NLRP3 inflammasome-mediated pyroptosis and apoptosis. Furthermore, NLRP3 overexpression aggravated HG-induced pyroptosis and apoptosis, whereas additional TXNIP silencing reversed them without affecting IRE1 or PERK branches. CONCLUSION In conclusion, our results suggested that UPR/NLRP3 inflammasome-mediated pyroptosis/apoptosis pathway was involved in diabetic podocyte injury, and that targeting the CHOP-TXNIP axis may serve as a promising therapeutic target for DKD.
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Affiliation(s)
- Yun Cao
- Department of Nephrology, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou, Hainan, China; Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Langtao Hu
- Department of Nephrology, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou, Hainan, China
| | - Ruike Chen
- Department of Nephrology, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou, Hainan, China
| | - Yao Chen
- Department of Nephrology, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou, Hainan, China
| | - Huafeng Liu
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Jiali Wei
- Department of Nephrology, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou, Hainan, China.
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Ali M, Irfan HM, Alamgeer, Ullah A, Abdellattif MH, Elodemi M, Zubair M, Khan A, Al-Harrasi A. Therapeutic role of Crateva religiosa in diabetic nephropathy: Insights into key signaling pathways. PLoS One 2025; 20:e0324028. [PMID: 40435181 PMCID: PMC12118869 DOI: 10.1371/journal.pone.0324028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 04/16/2025] [Indexed: 06/01/2025] Open
Abstract
Crateva religiosa, a plant used in traditional medicine, is valued for its bioactive properties. Traditional approaches are more accepted worldwide as a cost effective alternatives being used in network pharmacology to explore the complex interactions of drug targets among molecular pathways. The study investigated the potential of Crateva religiosa's phytoconstituents using meticulous computational analysis and empirical confirmation. The IMPPAT, GeneCards and DisGeNET data bases were used to obtain the active moieties and disease targets respectively. Crateva phytoconstituent's DN-target network and protein-protein interaction (PPI) network were developed and analyzed using the STRING online platform and Cytoscape software. GO and KEGG analyses were conducted using the g: profiler databases while the process of molecular docking involved the use of MOE software. The screening process identified dillapiole (CR-C1), beta ionone (CR-C2) 10-epi-γ-eudesmol (CR-C3), cis/trans linalool oxide (CR-C4/5) and nerolidol (CR-C6), as potential active phytoconstituents of C. religiosa and AKT1, PPARG, PTGS2, EGFR, ESR1, JAK2, MAPK1, PARP1, GSK3B, and PPARA as matching targets in DN. The enrichment analysis revealed that the common targets were primarily linked to inflammatory response, oxidative stress, immunological modulation, and cell death. The main signal pathways suggested were PI3K-Akt, AGE-RAGE, and IL-17. Moreover, molecular docking analysis determined that the AKT1, PPARG and PTGS2 are the essential targets that had a good affinity for their respective active molecules.
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Affiliation(s)
- Muhammad Ali
- College of Pharmacy, University of Sargodha, Sargodha, Pakistan
| | - Hafiz M. Irfan
- College of Pharmacy, University of Sargodha, Sargodha, Pakistan
| | - Alamgeer
- Punjab University College of Pharmacy, University of the Punjab, Lahore, Pakistan
| | - Aman Ullah
- Department of Pharmacy, Saba Medical Centre, Abu Dhabi, United Arab Emirates
| | - Magda H. Abdellattif
- Chemistry Department, College of Sciences, University College of Taraba, Taif University, Taif, Saudi Arabia
| | - Mahmoud Elodemi
- Department of Pharmacology, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Mohammad Zubair
- Department of Medical Microbiology, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Ajmal Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
- Department of Chemical and Biological Engineering, College of Engineering, Korea University, Seoul, Republic of Korea
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
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Okabe M, Okabayashi Y, Sasaki T, Koike K, Tsuboi N, Matsusaka T, Yokoo T. Podocyte Injury and Long-Term Kidney Prognosis in Patients with Lupus Nephritis. KIDNEY360 2025; 6:606-615. [PMID: 39714942 PMCID: PMC12045515 DOI: 10.34067/kid.0000000688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024]
Abstract
Key Points Podocyte injury, as indicated by early growth response 1 expression, was correlated with the clinical and histopathological activities of lupus nephritis (LN). Podocyte injury was associated with poor long-term kidney prognosis in patients with active LN. To improve the prognosis of patients with LN, treatment strategies on the basis of the degree of podocyte injury may be considered. Background Lupus nephritis (LN) is a major complication of SLE. Like other types of GN, podocyte injury has been observed in patients with LN. However, the association between podocyte injury and kidney prognosis in patients with LN has not been well elucidated. The aim of this study was to explore the association between podocyte injury and clinical and histological status and kidney prognosis in patients with LN. Methods Seventy-five patients histopathologically diagnosed with LN were enrolled in this study. Early growth response 1 (EGR1) expression in podocytes, representing podocyte injury, was detected through immunohistochemistry. The correlation between the proportion of glomeruli with podocytes expressing EGR1 (%EGR1glo) and the clinical and histological features of LN were evaluated. Subsequently, the association between %EGR1glo and kidney prognosis was examined in a group of patients with LN class 3, 4, or 5 who showed ≥0.5 g/g of urinary protein–creatinine ratio and received immunosuppressive therapy. Hazard ratio was calculated using univariate Cox proportional hazards regression. Results %EGR1glo was highest in patients with LN class 4, significantly correlated with the SLE Disease Activity Index score, urinary protein level, and prevalence of glomeruli showing cellular/fibrocellular crescents, endocapillary hypercellularity, and fibrinoid necrosis and inversely correlated with eGFR. Higher %EGR1glo was significantly associated with sustained ≥30% eGFR decline over 10 years in patients with LN class 3, 4, or 5 (n =42; hazard ratio, 1.58 [95% confidence interval, 1.07 to 2.36] per 10% increase in %EGR1glo). There was no significant interaction between patients grouped by kidney function, urinary protein level, presence of cellular/fibrocellular crescents, degree of tubulointerstitial fibrosis, and LN classification. Conclusions Podocyte damage, as indicated by EGR1 expression, was associated with poor long-term kidney prognosis in patients with active LN. Treatment strategies on the basis of the extent of podocyte injury may be necessary.
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Affiliation(s)
- Masahiro Okabe
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Yusuke Okabayashi
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Takaya Sasaki
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Kentaro Koike
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Nobuo Tsuboi
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Taiji Matsusaka
- Department of Basic Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
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Zhang Y, Pan R, Shou Z, Zhao Y. Xanthohumol attenuates TXNIP-mediated renal tubular injury in vitro and in vivo diabetic models. J Nat Med 2025; 79:314-327. [PMID: 39752106 DOI: 10.1007/s11418-024-01863-6] [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: 07/18/2024] [Accepted: 11/13/2024] [Indexed: 01/04/2025]
Abstract
Thioredoxin-interacting protein (TXNIP), as a pivotal protein in the cellular stress response, plays a significant role in the progression of diabetic nephropathy (DN). Consequently, therapeutic strategies aimed at targeting TXNIP may offer novel interventions for patients with DN. Our study is to explore the therapeutic potential of targeting TXNIP in mitigating renal tubular injury induced by hyperglycemia. Cell viability and apoptosis of renal tubular epithelial cells (RTECs) were evaluated using CCK-8, Annexin V/7-AAD, and TUNEL staining after exposure to normal glucose (NG; 5 mM), high glucose (HG; 30 mM), or treatment with TXNIP inhibitors (Xanthohumol, Xan). Furthermore, histochemical staining was utilized to assess the morphological changes in the kidney. Xan was determined to be a potential inhibitor of TXNIP due to its low binding energy value of - 7.433 kcal/mol. Both genetic inhibition of TXNIP using sh-RNA and pharmacological inhibition with Xan were found to reverse HG-induced RTEC apoptosis and inflammatory response. In diabetic mice, administration of Xan resulted in significant improvements in pathological features such as tubular atrophy, tubular injury score, and collagen deposition in the tubulointerstitium. Additionally, treatment with Xan effectively reduced the up-regulation of TXNIP protein expression caused by hyperglycemia. In conclusion, Xan, as a bioactive natural product, has been shown to attenuate hyperglycemia-induced renal tubular injury in both in vitro and in vivo models, potentially through the inhibition of TXNIP expression. Xan has the potential to serve as a therapeutic compound for the treatment of DN.
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Affiliation(s)
- Yan Zhang
- Department of Endocrinology, Cangzhou Central Hospital, No. 16 West Xinhua Road, Cangzhou, 061000, Hebei, China
| | - Runzhou Pan
- Department of Endocrinology, Cangzhou Central Hospital, No. 16 West Xinhua Road, Cangzhou, 061000, Hebei, China
| | - Zhang Shou
- Department of Endocrinology, Cangzhou Central Hospital, No. 16 West Xinhua Road, Cangzhou, 061000, Hebei, China
| | - Yongcai Zhao
- Department of Endocrinology, Cangzhou Central Hospital, No. 16 West Xinhua Road, Cangzhou, 061000, Hebei, China.
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Maimaiti Y, Abulitifu M, Ajimu Z, Su T, Zhang Z, Yu Z, Xu H. FOXO regulation of TXNIP induces ferroptosis in satellite cells by inhibiting glutathione metabolism, promoting Sarcopenia. Cell Mol Life Sci 2025; 82:81. [PMID: 39982519 PMCID: PMC11845654 DOI: 10.1007/s00018-025-05592-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/30/2024] [Accepted: 01/12/2025] [Indexed: 02/22/2025]
Abstract
Aging-related sarcopenia represents a significant health concern due to its impact on the quality of life in the elderly. This study elucidates the molecular mechanisms underlying sarcopenia by employing single-cell sequencing and public transcriptome databases to compare young and aged mouse skeletal muscles. Cellular classification and pseudotime analyses differentiated cell types and their interrelationships, revealing a marked reduction in satellite cell numbers and a consistent upregulation of TXNIP (Thioredoxin interacting protein) across various muscle cell populations in aged mice. Further transcriptomic data integration and batch correction from the GEO (Gene Expression Omnibus) database highlighted key differentially expressed genes. The role of TXNIP and its transcriptional regulation by FOXO1 (Forkhead box O1) was confirmed through in vitro experiments, which demonstrated FOXO1's influence on TXNIP expression and its subsequent suppression of glutathione metabolism, leading to satellite cell ferroptosis. Additionally, in vivo studies showed that overexpression of TXNIP in young mice's muscle tissues significantly reduced muscle mass, suggesting its potential role in the initiation of sarcopenia. Our findings suggest that FOXO1-mediated regulation of TXNIP and the disruption of glutathione metabolism are central to the process of sarcopenia, offering new insights into its pathogenesis.
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Affiliation(s)
- Yasenjiang Maimaiti
- Gerontology Center, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumqi, Xinjiang, China
| | - Mukedasi Abulitifu
- Gerontology Center, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumqi, Xinjiang, China
| | - Zulifeiya Ajimu
- Gerontology Center, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumqi, Xinjiang, China
| | - Ting Su
- Gerontology Center, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumqi, Xinjiang, China
| | - Zhanying Zhang
- Gerontology Center, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumqi, Xinjiang, China
| | - Zhichao Yu
- Gerontology Center, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumqi, Xinjiang, China
| | - Hong Xu
- Gerontology Center, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumqi, Xinjiang, China.
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Kuang Y, Wu Z, Liu Y. Deoxynivalenol induces spleen damage, apoptosis, and inflammation in mice by increasing mitochondrial reactive oxygen species: Protective effects of curcumin. Food Chem Toxicol 2025; 196:115200. [PMID: 39672452 DOI: 10.1016/j.fct.2024.115200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/19/2024] [Accepted: 12/10/2024] [Indexed: 12/15/2024]
Abstract
Deoxynivalenol (DON), a Fusarium mycotoxin, causes spleen apoptosis and inflammation, which damage the organ. Curcumin (Cur) is a member of the ginger family. It has anti-apoptotic and anti-inflammatory effects that maintain the health of the organism's immune system. Here, the protective effects of Cur against DON-induced spleen damage were explored. First, we found DON (2.4 mg/kg body weight) decreased the expression of manganese superoxide dismutase, mitochondrial membrane potential, adenosine triphosphate, and disturbed hematoxylin and eosin staining in mice spleen. The results confirmed that DON causes mitochondrial reactive oxygen species (mtROS) overproduction leading to spleen damage. Second, we found DON decreased the expression of mitochondrial apoptosis-inducing factor (AIF) and B-cell lymphoma-2 (Bcl-2), and increased the expression of nuclear AIF, Bcl2-associated X (Bax), cysteine-aspartate protease-3 (caspase-3), caspase-9. Mitoquinone is a mitochondria-targeted antioxidant that can prevent of mitochondrial oxidative damage. These expression increases were not observed in the mitoquinone-treated group, confirming that mtROS was an upstream regulatory target of apoptosis and inflammation in DON-exposed mice spleens. Finally, we confirmed that Cur (50 or 100 mg/kg body weight) attenuated DON-induced apoptosis and inflammation by inactivating mtROS. Collectively, these results confirm that DON causes spleen damage by increasing mtROS, and the protective effects of curcumin.
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Affiliation(s)
- Yuming Kuang
- Department of Pharmacy, Infectious Disease Hospital of Heilongjiang Province, Harbin, 150500, China
| | - Zuoyao Wu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China; Charoen Pokphand Group, Anhui District, 230000, China
| | - Yuqin Liu
- Department of Pharmacy, Infectious Disease Hospital of Heilongjiang Province, Harbin, 150500, China.
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Yang M, Liu C, Jiang N, Liu Y, Luo S, Li C, Zhao H, Han Y, Li L, Xiao L, Chen W, Sun L. Sesamol Ameliorates Lipid Deposition by Maintaining the Integrity of the Lipid Droplet-Mitochondria Connection in Diabetic Nephropathy. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:2124-2137. [PMID: 39772609 DOI: 10.1021/acs.jafc.4c06122] [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: 01/11/2025]
Abstract
Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and an important cause of end-stage renal disease (ESRD). However, there is still a lack of effective prevention and treatment strategies in clinical practice. As a metabolic disease, DN is accompanied by renal ectopic lipid deposition, and the deposited lipids further aggravate kidney injury. However, the molecular mechanism of renal ectopic lipid deposition is currently unknown. In this study, we observed changes in lipid droplet (LD)-mitochondria connections in the kidney for the first time. Destruction of LD-mitochondria connection was involved in renal lipid deposition in the kidneys of patients and mice with DN or in high-glucose-treated HK-2 cells. Furthermore, sesamol treatment significantly increased the integrity of the LD-mitochondria connection and ameliorated renal lipotoxicity. Finally, we demonstrated that sesamol maintains the integrity of the LD-mitochondria connection by activating the peroxisome proliferator-activated receptor α (PPARα)/perilipin 5 (PLIN5) signaling pathway. Our study is the first to show that the LD-mitochondria connection may be a target for ameliorating lipid deposition in diabetic kidneys.
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Affiliation(s)
- Ming Yang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Middle Road, Changsha 410011, Hunan, China
| | - Chongbin Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Middle Road, Changsha 410011, Hunan, China
| | - Na Jiang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Middle Road, Changsha 410011, Hunan, China
| | - Yan Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Middle Road, Changsha 410011, Hunan, China
| | - Shilu Luo
- Department of Nephrology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Middle Road, Changsha 410011, Hunan, China
| | - Chenrui Li
- Department of Nephrology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Middle Road, Changsha 410011, Hunan, China
| | - Hao Zhao
- Department of Nephrology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Middle Road, Changsha 410011, Hunan, China
| | - Yachun Han
- Department of Nephrology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Middle Road, Changsha 410011, Hunan, China
| | - Li Li
- Department of Nephrology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Middle Road, Changsha 410011, Hunan, China
| | - Li Xiao
- Department of Nephrology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Middle Road, Changsha 410011, Hunan, China
| | - Wei Chen
- Department of Nephrology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Middle Road, Changsha 410011, Hunan, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Middle Road, Changsha 410011, Hunan, China
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Lin ZM, Gao HY, Shi SH, Li YT. Mizagliflozin ameliorates diabetes induced kidney injury by inhibitor inhibit inflammation and oxidative stress. World J Diabetes 2025; 16:92711. [PMID: 39817219 PMCID: PMC11718448 DOI: 10.4239/wjd.v16.i1.92711] [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: 02/05/2024] [Revised: 04/26/2024] [Accepted: 10/08/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Mizagliflozin (MIZ) is a specific inhibitor of sodium-glucose cotransport protein 1 (SGLT1) originally developed as a medication for diabetes. AIM To explore the impact of MIZ on diabetic nephropathy (DN). METHODS Diabetic mice were created using db/db mice. They were administered either a low dose (0.5 mg/kg) or a high dose (1.0 mg/kg) of the SGLT1 inhibitor MIZ via stomach gavage for 8 weeks. Subsequently, mesangial cells (MCs) were isolated and subjected to high glucose conditions in culture to assess the effects of MIZ on DN. RESULTS The results showed that low doses of MIZ significantly reduced albuminuria to a level comparable to that achieved with high doses in db/db mice. High doses of MIZ led to a substantial increase in body weight in mice, along with decreased blood glucose levels and food intake. Moreover, the intervention with high-dose MIZ notably decreased the expression of extracellular matrix genes, such as collagen type 1 alpha 1 mRNA levels. While the expression of SGLT1 increased after exposure to high glucose, it decreased following treatment with MIZ. Furthermore, MIZ intervention was more effective in improving lactate dehydrogenase levels in MCs induced by high glucose compared to canagliflozin. MIZ also significantly elevated levels of antioxidant enzymes superoxide dismutase, catalase, and glutathione, while reducing malondialdehyde levels. CONCLUSION These findings indicate that MIZ can ameliorate DN by inhibiting SGLT1, inflammation, and oxidative stress.
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Affiliation(s)
- Zhi-Min Lin
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Han-Yuan Gao
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Shu-Han Shi
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Yue-Ting Li
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
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11
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Liu Y, Wang Y, Yan P, Cui N, Xu K, Liu D, Tian Y, Cao L. NLRP3 Inflammasome-Mediated Osteoarthritis: The Role of Epigenetics. BIOLOGY 2025; 14:71. [PMID: 39857301 PMCID: PMC11761621 DOI: 10.3390/biology14010071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/11/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025]
Abstract
The prevalence of osteoarthritis (OA) notably surges with age and weight gain. The most common clinical therapeutic drugs are painkillers, yet they cannot impede the deteriorating course of OA. Thus, understanding OA's pathogenesis and devising effective therapies is crucial. It is generally recognized that inflammation, pyroptosis, and OA progression are tightly linked. The activation of NLRP3 inflammasome can lead to the discharge of the pro-inflammatory cytokines Interleukin-1β and IL-18, intensifying subsequent inflammatory reactions and promoting OA development. Conversely, the imbalance caused by deacetylase-regulated NLRP3 inflammasome underlies the chronic mild inflammation related to degenerative diseases. Therefore, this article expounds on the mechanism of OA pathogenesis and the role of histone deacetylases (HDACs) in NLRP3 inflammasome-triggered OA, and illustrates the application of HDAC inhibitors in OA, striving to provide more insights into novel OA treatment approaches.
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Affiliation(s)
- Yuzhou Liu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China; (Y.L.); (Y.W.); (K.X.)
| | - Ying Wang
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China; (Y.L.); (Y.W.); (K.X.)
| | - Ping Yan
- College of Traditional Chinese Medicine, Changchun University of Traditional Chinese Medicine, Changchun 130117, China; (P.Y.); (N.C.)
| | - Ning Cui
- College of Traditional Chinese Medicine, Changchun University of Traditional Chinese Medicine, Changchun 130117, China; (P.Y.); (N.C.)
| | - Kejin Xu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China; (Y.L.); (Y.W.); (K.X.)
| | - Da Liu
- Public Laboratory Centre, Changchun University of Chinese Medicine, Changchun 130117, China;
| | - Yuan Tian
- Clinical School of Medicine, Changchun University of Traditional Chinese Medicine, Changchun 130117, China
| | - Lingling Cao
- Clinical School of Medicine, Changchun University of Traditional Chinese Medicine, Changchun 130117, China
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12
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Centner FS, Brohm K, Mindt S, Jaeger E, Hahn B, Fuderer T, Lindner HA, Schneider-Lindner V, Krebs J, Neumaier M, Thiel M, Schoettler JJ. Evaluation of Hypoxia Markers in Critically Ill Patients Categorized by Their Burden of Organ Dysfunction: A Novel Approach to Detect Pathophysiological and Clinical Relevance in a Secondary Analysis of a Prospective Observational Study. Int J Mol Sci 2025; 26:659. [PMID: 39859374 PMCID: PMC11766418 DOI: 10.3390/ijms26020659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 01/03/2025] [Accepted: 01/12/2025] [Indexed: 01/27/2025] Open
Abstract
In critically ill patients, compromised microcirculation causes tissue hypoxia, organ failure, and death. These pathophysiological processes occur particularly in patients with high illness severity, so reliable hypoxia biomarkers should reflect this in their occurrence. This secondary analysis of a prospective study categorized patients by their burden of organ dysfunction (BOD) using the cohort's median initial sequential organ failure assessment (SOFA) score of 8 as a cutoff. The kinetic parameters of the hypoxia markers lactate and S-adenosylhomocysteine (SAH) were analyzed for correlation with organ dysfunction severity and mortality prediction. In low BOD patients, neither marker correlated with SOFA. In high BOD patients, lactate showed a moderate correlation and SAH showed a strong correlation. Lactate correlated with organ dysfunction in survivors but not in non-survivors, while SAH correlated strongly in non-survivors but not in survivors. In univariate logistic regression, lactate predicted mortality moderately in low BOD (areas under the receiver operating characteristic curves (AUROCs) 0.7-0.8) but poorly in high BOD patients (AUROCs 0.5-0.7). SAH's prediction improved from poor to excellent (AUROCs 0.8-0.9) with higher BOD. Thus, SAH appears superior to lactate in the detection of organ dysfunction severity and mortality prediction in high BOD patients.
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Affiliation(s)
- Franz-Simon Centner
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (F.-S.C.); (J.J.S.)
| | - Kathrin Brohm
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (F.-S.C.); (J.J.S.)
- Merck KGaA (SQ-Animal Affairs), Frankfurterstrasse 250, 64293 Darmstadt, Germany
| | - Sonani Mindt
- Institute for Clinical Chemistry, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
- Institute for Laboratory and Transfusion Medicine, Hospital Passau, Innstrasse 76, 94032 Passau, Germany
| | - Evelyn Jaeger
- Institute for Clinical Chemistry, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
| | - Bianka Hahn
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (F.-S.C.); (J.J.S.)
| | - Tanja Fuderer
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (F.-S.C.); (J.J.S.)
| | - Holger A. Lindner
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (F.-S.C.); (J.J.S.)
| | - Verena Schneider-Lindner
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (F.-S.C.); (J.J.S.)
| | - Joerg Krebs
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (F.-S.C.); (J.J.S.)
| | - Michael Neumaier
- Institute for Clinical Chemistry, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
| | - Manfred Thiel
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (F.-S.C.); (J.J.S.)
| | - Jochen J. Schoettler
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (F.-S.C.); (J.J.S.)
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13
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Zhao K, Zhang Y, Liao Z, Zhang W, Li G, Shi P, Cheng Z, Chen Y, Li S, Wang K, Song Y, Feng X, An R, Yang C. Melatonin mitigates intervertebral disc degeneration by suppressing NLRP3 inflammasome activation via the EGR1/DDX3X pathway. FASEB J 2024; 38:e70143. [PMID: 39708233 DOI: 10.1096/fj.202302453rrr] [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: 11/30/2023] [Revised: 10/02/2024] [Accepted: 10/21/2024] [Indexed: 12/23/2024]
Abstract
Intervertebral disc degeneration (IVDD), is one of the leading causes of low back pain. Inflammation is considered to be the main pathophysiological process of IVDD. The nucleotide-binding domain and leucine-rich pyrin domain containing 3 (NLRP3) inflammasome-mediated inflammatory responses are critically involved in the progression of IVDD. Melatonin is known for its anti-inflammatory and antioxidant effects. However, little is known about the potential effects of melatonin in the pathological process of IVDD. We found that the expression of EGR1, DDX3X, and NLRP3 inflammasome increased and extracellular matrix (ECM) degraded in IVDD. With the application of EGR1 siRNA, the expression of DDX3X and the activation of NLRP3 inflammasome were inhibited in stress-induced NP cells. DDX3X/NLRP3 was regulated on dependence of EGR1. Besides, the utility of melatonin mitigated the EGR1-induced overproduction of DDX3X and activation of NLRP3 inflammasome, thus protecting cells from pyroptosis and ECM degradation. In vivo, in a rat IVDD model, melatonin was found to be able to delay the development of IVDD by imageological and histological evaluation. In conclusion, our study demonstrated that melatonin prevented IVDD progression by regulating EGR1/DDX3X/NLRP3 axis. Our study provides insight into melatonin as a new target for therapeutic approaches for IVDD.
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Affiliation(s)
- Kangcheng Zhao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yukun Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiwei Liao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weifeng Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gaocai Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pengzhi Shi
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhangrong Cheng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhang Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Song
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaobo Feng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ran An
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cao Yang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Wang Y, Wang Q, Wang M, Wang X, Liu Q, Lv S, Nie H, Liu G. Epigallocatechin-3-Gallate Ameliorates Diabetic Kidney Disease by Inhibiting the TXNIP/NLRP3/IL-1β Signaling Pathway. Food Sci Nutr 2024; 12:10800-10815. [PMID: 39723074 PMCID: PMC11666909 DOI: 10.1002/fsn3.4617] [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: 08/17/2024] [Revised: 10/14/2024] [Accepted: 11/06/2024] [Indexed: 12/28/2024] Open
Abstract
Recent research indicates that the activation of the NLRP3 inflammasome is crucial in the development of diabetic kidney disease (DKD). Epigallocatechin-3-gallate (EGCG), the predominant catechin in green tea, has been noted for its anti-inflammatory properties in DKD. However, the specific mechanisms are not yet fully understood. In this study, our objective was to explore the effects of EGCG on podocytes and in diabetic kidney disease (DKD) mice and investigate how EGCG modulates the TXNIP/NLRP3/IL-1β signaling pathway in DKD, both in podocytes and animal models. In vitro, we co-cultured podocytes with EGCG and detected the viability, apoptosis, inflammation and the TXNIP/NLRP3/IL-1β signaling pathway. In vivo, DKD mice were given EGCG via oral gavage, followed by evaluations of renal function, inflammation, and the aforementioned signaling pathway. Our findings revealed that oxidative stress, inflammatory cytokines, and the TXNIP/NLRP3/IL-1β pathway were upregulated in podocytes exposed to high glucose (HG) and in the kidneys of DKD mice. However, EGCG treatment reduced the expression of the NLRP3 inflammasome and its associated proteins, including TXNIP, ASC, caspase-1, and IL-1β, as well as the levels of ROS and inflammatory factors such as TNF-α, IL-6, and IL-18. Furthermore, in vivo, EGCG improved kidney function, reduced albuminuria and body weight, and alleviated renal pathological damage. In summary, our study suggests that EGCG mitigates inflammation in podocytes and DKD through the TXNIP/NLRP3/IL-1β signaling pathway, indicating potential benefits of EGCG or green tea in managing DKD.
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Affiliation(s)
- Yinghui Wang
- Department of Nephrology, Multidisciplinary Innovation Center for NephrologyThe Second Hospital of Shandong UniversityJinanShandongChina
- Nephrology Research Institute of Shandong UniversityJinanShandongChina
| | - Qimeng Wang
- Department of Nephrology, Multidisciplinary Innovation Center for NephrologyThe Second Hospital of Shandong UniversityJinanShandongChina
- Nephrology Research Institute of Shandong UniversityJinanShandongChina
| | - Mingming Wang
- Department of Nephrology, Multidisciplinary Innovation Center for NephrologyThe Second Hospital of Shandong UniversityJinanShandongChina
- Nephrology Research Institute of Shandong UniversityJinanShandongChina
| | - Xueling Wang
- Department of Nephrology, Multidisciplinary Innovation Center for NephrologyThe Second Hospital of Shandong UniversityJinanShandongChina
- Nephrology Research Institute of Shandong UniversityJinanShandongChina
| | - Qingzhen Liu
- Department of Nephrology, Multidisciplinary Innovation Center for NephrologyThe Second Hospital of Shandong UniversityJinanShandongChina
- Nephrology Research Institute of Shandong UniversityJinanShandongChina
| | - Shasha Lv
- Department of Nephrology, Multidisciplinary Innovation Center for NephrologyThe Second Hospital of Shandong UniversityJinanShandongChina
- Nephrology Research Institute of Shandong UniversityJinanShandongChina
| | - Huibin Nie
- Department of Nephrology, Chengdu First People's HospitalIntegrated TCM and Western Medicine Hospital Affiliated to Chengdu University of TCMChengduSichuanChina
| | - Gang Liu
- Department of Nephrology, Multidisciplinary Innovation Center for NephrologyThe Second Hospital of Shandong UniversityJinanShandongChina
- Nephrology Research Institute of Shandong UniversityJinanShandongChina
- Key Laboratory of Reproductive Endocrinology of Ministry of EducationShandong UniversityJinanShandongChina
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15
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Xu J, Zhang J, Liu Q, Wang B. Bone marrow mesenchymal stem cells-derived exosomes promote spinal cord injury repair through the miR-497-5p/TXNIP/NLRP3 axis. J Mol Histol 2024; 56:16. [PMID: 39611985 DOI: 10.1007/s10735-024-10289-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/30/2024] [Indexed: 11/30/2024]
Abstract
Bone marrow mesenchymal stem cells (BMSCs) indicate a repairing prospect to treat spinal cord injury, a major traumatic disease. This study investigated the repair effect of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) on spinal cord injury. BMSCs were collected to extract BMSC-Exos which were identified by different means. The SCI model of rats was established, the motor behavior was scored by BBB field test, and the spinal cord tissues were separated and stained by HE, Nissl, and Tunel, respectively, as well as analyzed to measure inflammatory and oxidative stress responses. PC12 cells were co-cultured with Exos and analyzed by CCK-8 and flow cytometry to measure cell proliferation and apoptosis. BMSC-Exos improved SCI in rats with the recovery of motor function, alleviation of pathological conditions, and reduction of apoptosis, inflammatory responses, and oxidative stress. BMSC-Exos increased miR-497-5p expression, and miR-497-5p overexpression strengthened the protective effect of BMSC-Exos on SCI. miR-497-5p targeted inactivation of TXNIP/NLRP3 pathway. TXNIP saved the repair effect of miR-497-5p-carrying BMSC-Exos on SCI rats. miR-497-5p-carrying BMSC-Exos alleviated apoptosis and induced proliferation of H2O2-treated PC12 cells. BMSC-Exos promote SCI repair via the miR-497-5p/TXNIP/NLRP3 axis, which may be a target for alleviating SCI-associated nerve damage.
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Affiliation(s)
- JiXu Xu
- Department of Rehabilitation Medicine, Wuxi No.8 People's Hospital, Jiangsu Province, Wuxi City, 214000, China
| | - Jun Zhang
- Department of Rehabilitation Medicine, Ezhou Central Hospital, Hubei Province, Ezhou City, 436000, China
| | - QiaoYun Liu
- Department of Rehabilitation Medicine, Nantong Third People's Hospital, Affiliated Nantong Hospital 3 of Nantong UniversityChongchuan DistrictJiangsu Province, No. 60 Qingnian Middle Road, Nantong City, 226000, China
| | - Bin Wang
- Department of Rehabilitation Medicine, Nantong Third People's Hospital, Affiliated Nantong Hospital 3 of Nantong UniversityChongchuan DistrictJiangsu Province, No. 60 Qingnian Middle Road, Nantong City, 226000, China.
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Liu J, Ren J, Zhou L, Tan K, Du D, Xu L, Cao W, Zhang Y. Proteomic and lipidomic analysis of the mechanism underlying astragaloside IV in mitigating ferroptosis through hypoxia-inducible factor 1α/heme oxygenase 1 pathway in renal tubular epithelial cells in diabetic kidney disease. JOURNAL OF ETHNOPHARMACOLOGY 2024; 334:118517. [PMID: 38972525 DOI: 10.1016/j.jep.2024.118517] [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: 04/05/2024] [Revised: 06/19/2024] [Accepted: 07/01/2024] [Indexed: 07/09/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The limitations of modern medicine in mitigating the pathological process of diabetic kidney disease (DKD) necessitate novel, precise, and effective prevention and treatment methods. Huangqi, the root of Astragalus membranaceus Fisch. ex Bunge has been used in traditional Chinese medicine for various kidney ailments. Astragaloside IV (AS-IV), the primary pharmacologically active compound in A. membranaceus, is involved in lipid metabolism regulation; however, its potential in ameliorating renal damage in DKD remains unexplored. AIM OF THE STUDY To elucidate the specific mechanism by which AS-IV moderates DKD progression. MATERIALS AND METHODS A murine model of DKD and high glucose-induced HK-2 cells were treated with AS-IV. Furthermore, multiomics analysis, molecular docking, and molecular dynamics simulations were performed to elucidate the mechanism of action of AS-IV in DKD, which was validated using molecular biological methods. RESULTS AS-IV regulated glucose and lipid metabolism in DKD, thereby mitigating lipid deposition in the kidneys. Proteomic analysis identified 12 proteins associated with lipid metabolism regulated by AS-IV in the DKD renal tissue. Additionally, lipid metabolomic analysis revealed that AS-IV upregulated and downregulated 4 beneficial and 79 harmful lipid metabolites, respectively. Multiomics analysis further indicated a positive correlation between the top-ranked differential protein heme oxygenase (HMOX)1 and the levels of various harmful lipid metabolites and a negative correlation with the levels of beneficial lipid metabolites. Furthermore, enrichment of both ferroptosis and hypoxia-inducible factor (HIF)-1 signaling pathways during the AS-IV treatment of DKD was observed using proteomic analysis. Validation results showed that AS-IV effectively reduced ferroptosis in DKD-affected renal tubular epithelial cells by inhibiting HIF-1α/HMOX1 pathway activity, upregulating glutathione peroxidase-4 and ferritin heavy chain-1 expression, and downregulating acyl-CoA synthetase long-chain family member-4 and transferrin receptor-1 expression. Our findings demonstrate the potential of AS-IV in mitigating DKD pathology by downregulating the HIF-1α/HMOX1 signaling pathway, thereby averting ferroptosis in renal tubular epithelial cells. CONCLUSIONS AS-IV is a promising treatment strategy for DKD via the inhibition of ferroptosis in renal tubular epithelial cells. The findings of this study may help facilitate the development of novel therapeutic strategies.
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Affiliation(s)
- Jun Liu
- Department of Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, No. 1., Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, PR China.
| | - Jing Ren
- College of Traditional Chinese Medicine, Chongqing Medical and Pharmaceutical College, No. 82, University Town Middle Road, Shapingba District, Chongqing, 401331, PR China.
| | - Linlan Zhou
- Department of Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, No. 1., Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, PR China.
| | - Kaiyue Tan
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, 400016, PR China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, PR China.
| | - Donglin Du
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, PR China.
| | - Lei Xu
- Laboratory Animal Center, Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, 400016, PR China.
| | - Wenfu Cao
- Department of Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, No. 1., Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, PR China; College of Traditional Chinese Medicine, Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, 400016, PR China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, PR China.
| | - Yudi Zhang
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, 400016, PR China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, PR China; College of Combination of Chinese and Western Medicine, Chongqing College of Traditional Chinese Medicine, No. 61, Puguobao Road, Bicheng Street, Bishan District, Chongqing, 402760, PR China.
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Xia K, Luo P, Yu J, He S, Dong L, Gao F, Chen X, Ye Y, Gao Y, Ma Y, Yang C, Zhang Y, Yang Q, Han D, Feng X, Wan Z, Cai H, Ke Q, Wang T, Li W, Tu X, Sun X, Deng C, Xiang AP. Single-cell RNA sequencing reveals transcriptomic landscape and potential targets for human testicular ageing. Hum Reprod 2024; 39:2189-2209. [PMID: 39241251 PMCID: PMC11447013 DOI: 10.1093/humrep/deae199] [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: 05/24/2023] [Revised: 07/05/2024] [Indexed: 09/08/2024] Open
Abstract
STUDY QUESTION What is the molecular landscape underlying the functional decline of human testicular ageing? SUMMARY ANSWER The present study provides a comprehensive single-cell transcriptomic atlas of testes from young and old humans and offers insights into the molecular mechanisms and potential targets for human testicular ageing. WHAT IS KNOWN ALREADY Testicular ageing is known to cause male age-related fertility decline and hypogonadism. Dysfunction of testicular cells has been considered as a key factor for testicular ageing. STUDY DESIGN, SIZE, DURATION Human testicular biopsies were collected from three young individuals and three old individuals to perform single-cell RNA sequencing (scRNA-seq). The key results were validated in a larger cohort containing human testicular samples from 10 young donors and 10 old donors. PARTICIPANTS/MATERIALS, SETTING, METHODS scRNA-seq was used to identify gene expression signatures for human testicular cells during ageing. Ageing-associated changes of gene expression in spermatogonial stem cells (SSCs) and Leydig cells (LCs) were analysed by gene set enrichment analysis and validated by immunofluorescent and functional assays. Cell-cell communication analysis was performed using CellChat. MAIN RESULTS AND THE ROLE OF CHANCE The single-cell transcriptomic landscape of testes from young and old men was surveyed, revealing age-related changes in germline and somatic niche cells. In-depth evaluation of the gene expression dynamics in germ cells revealed that the disruption of the base-excision repair pathway is a prominent characteristic of old SSCs, suggesting that defective DNA repair in SSCs may serve as a potential driver for increased de novo germline mutations with age. Further analysis of ageing-associated transcriptional changes demonstrated that stress-related changes and cytokine pathways accumulate in old somatic cells. Age-related impairment of redox homeostasis in old LCs was identified and pharmacological treatment with antioxidants alleviated this cellular dysfunction of LCs and promoted testosterone production. Lastly, our results revealed that decreased pleiotrophin signalling was a contributing factor for impaired spermatogenesis in testicular ageing. LARGE SCALE DATA The scRNA-seq sequencing and processed data reported in this paper were deposited at the Genome Sequence Archive (https://ngdc.cncb.ac.cn/), under the accession number HRA002349. LIMITATIONS, REASONS FOR CAUTION Owing to the difficulty in collecting human testis tissue, the sample size was limited. Further in-depth functional and mechanistic studies are warranted in future. WIDER IMPLICATIONS OF THE FINDINGS These findings provide a comprehensive understanding of the cell type-specific mechanisms underlying human testicular ageing at a single-cell resolution, and suggest potential therapeutic targets that may be leveraged to address age-related male fertility decline and hypogonadism. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Key Research and Development Program of China (2022YFA1104100), the National Natural Science Foundation of China (32130046, 82171564, 82101669, 82371611, 82371609, 82301796), the Natural Science Foundation of Guangdong Province, China (2022A1515010371), the Major Project of Medical Science and Technology Development Research Center of National Health Planning Commission, China (HDSL202001000), the Open Project of NHC Key Laboratory of Male Reproduction and Genetics (KF202001), the Guangdong Province Regional Joint Fund-Youth Fund Project (2021A1515110921, 2022A1515111201), and the China Postdoctoral Science Foundation (2021M703736). The authors declare no conflict of interest.
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Affiliation(s)
- Kai Xia
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Peng Luo
- Reproductive Medicine Centre, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Key Laboratory of Reproductive Medicine, Guangzhou, Guangdong, China
| | - Jiajie Yu
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Siyuan He
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Lin Dong
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Feng Gao
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Reproductive Medicine Centre, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xuren Chen
- Reproductive Medicine Centre, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yunlin Ye
- Department of Urology, Sun Yat-Sen University Cancer Centre, Guangzhou, China
| | - Yong Gao
- Reproductive Medicine Centre, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Key Laboratory of Reproductive Medicine, Guangzhou, Guangdong, China
| | - Yuanchen Ma
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Cuifeng Yang
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yadong Zhang
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qiyun Yang
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Dayu Han
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xin Feng
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zi Wan
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hongcai Cai
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qiong Ke
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
- Guangdong Key Laboratory of Reproductive Medicine, Guangzhou, Guangdong, China
| | - Tao Wang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
- National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Weiqiang Li
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
- Guangdong Key Laboratory of Reproductive Medicine, Guangzhou, Guangdong, China
- National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Xiang'an Tu
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiangzhou Sun
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chunhua Deng
- Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
- National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
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Satheesan A, Kumar J, Leela KV, Murugesan R, Chaithanya V, Angelin M. Review on the role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome pathway in diabetes: mechanistic insights and therapeutic implications. Inflammopharmacology 2024; 32:2753-2779. [PMID: 39160391 DOI: 10.1007/s10787-024-01556-2] [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: 07/04/2024] [Accepted: 08/10/2024] [Indexed: 08/21/2024]
Abstract
This review explores the pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the pathogenesis of diabetes and its complications, highlighting the therapeutic potential of various oral hypoglycemic drugs targeting this pathway. NLRP3 inflammasome activation, triggered by metabolic stressors like hyperglycemia, hyperlipidemia, and free fatty acids (FFAs), leads to the release of pro-inflammatory cytokines interleukin-1β and interleukin-18, driving insulin resistance, pancreatic β-cell dysfunction, and systemic inflammation. These processes contribute to diabetic complications such as nephropathy, neuropathy, retinopathy, and cardiovascular diseases (CVD). Here we discuss the various transcriptional, epigenetic, and gut microbiome mediated regulation of NLRP3 activation in diabetes. Different classes of oral hypoglycemic drugs modulate NLRP3 inflammasome activity through various mechanisms: sulfonylureas inhibit NLRP3 activation and reduce inflammatory cytokine levels; sodium-glucose co-transporter 2 inhibitors (SGLT2i) suppress inflammasome activity by reducing oxidative stress and modulating intracellular signaling pathways; dipeptidyl peptidase-4 inhibitors mitigate inflammasome activation, protecting against renal and vascular complications; glucagon-like peptide-1 receptor agonists attenuate NLRP3 activity, reducing inflammation and improving metabolic outcomes; alpha-glucosidase inhibitors and thiazolidinediones exhibit anti-inflammatory properties by directly inhibiting NLRP3 activation. Agents that specifically target NLRP3 and inhibit their activation have been identified recently such as MCC950, Anakinra, CY-09, and many more. Targeting the NLRP3 inflammasome, thus, presents a promising strategy for managing diabetes and its complications, with oral hypoglycemic drugs offering dual benefits of glycemic control and inflammation reduction. Further research into the specific mechanisms and long-term effects of these drugs on NLRP3 inflammasome activity is warranted.
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Affiliation(s)
- Abhishek Satheesan
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalpattu, Tamil Nadu, 603203, India
| | - Janardanan Kumar
- Department of General Medicine, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalpattu, Tamil Nadu, 603203, India.
| | - Kakithakara Vajravelu Leela
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalpattu, Tamil Nadu, 603203, India
| | - Ria Murugesan
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalpattu, Tamil Nadu, 603203, India
| | - Venkata Chaithanya
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalpattu, Tamil Nadu, 603203, India
| | - Matcha Angelin
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalpattu, Tamil Nadu, 603203, India
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Sun T, Guo Y, Su Y, Shan S, Qian W, Zhang F, Li M, Zhang Z. Molecular mechanisms of diabetic nephropathy: A narrative review. Cell Biol Int 2024; 48:1240-1253. [PMID: 38946126 DOI: 10.1002/cbin.12212] [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: 04/23/2024] [Revised: 06/01/2024] [Accepted: 06/16/2024] [Indexed: 07/02/2024]
Abstract
Diabetic nephropathy (DN) is the predominant secondary nephropathy resulting in global end-stage renal disease. It is attracting significant attention in both domestic and international research due to its widespread occurrence, fast advancement, and limited choices for prevention and treatment. The pathophysiology of this condition is intricate and involves multiple molecular and cellular pathways at various levels. This article provides a concise overview of the molecular processes involved in the development of DN. It discusses various factors, such as signaling pathways, cytokines, inflammatory responses, oxidative stress, cellular damage, autophagy, and epigenetics. The aim is to offer clinicians a valuable reference for DN's diagnosis, treatment, and intervention.
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Affiliation(s)
- Tian Sun
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Yina Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Yanting Su
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Shigang Shan
- School of Public Health and Nursing, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Wenbin Qian
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Feixue Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Mengxi Li
- School of Nuclear Technology and Chemistry & Biology, Hubei University of Science and Technology, Xianning, China
| | - Zhenwang Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
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Zhou W, Zhu C, Zhou F. TXNIP mediated by EZH2 regulated osteogenic differentiation in hBmscs and MC3T3-E1 cells through the modulation of oxidative stress and PI3K/AKT/Nrf2 pathway. Connect Tissue Res 2024; 65:293-303. [PMID: 38884152 DOI: 10.1080/03008207.2024.2358361] [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: 11/30/2023] [Revised: 03/19/2024] [Accepted: 05/17/2024] [Indexed: 06/18/2024]
Abstract
BACKGROUND Previous research has identified a significant role of Thioredoxin-interacting protein (TXNIP) in bone loss. The purpose of this investigation was to assess the role and the underlying molecular mechanisms of TXNIP in the osteogenic differentiation of human bone marrow stromal cells (hBMSCs) and pre-osteoblast MC3T3-E1 cells. METHODS Human bone marrow stem cells (hBMSCs) and MC3T3-E1 cells were used to induce osteogenic differentiation. The expression of genes and proteins was assessed using RT-qPCR and western blot, respectively. ChIP assay was used to validate the interaction between genes. The osteogenic differentiation ability of cells was reflected using ALP staining and detection of ALP activity. The mineralization ability of cells was assessed using ARS staining. DCFCA staining was employed to evaluate the intracellular ROS level. RESULTS Initially, downregulation of TXNIP and upregulation of EZH2 were observed during osteogenesis in hBMSCs and MC3T3-E1 cells. Additionally, it was discovered that EZH2 negatively regulates TXNIP expression in these cells. Furthermore, experiments indicated that the knockdown of TXNIP stimulated the activation of the PI3K/AKT/Nrf2 signaling pathway in hBMSCs and MC3T3- E1 cells, thus inhibiting the production of reactive oxygen species (ROS). Further functional experiments revealed that overexpression of TXNIP inhibited the osteogenic differentiation in hBMSCs and MC3T3-E1 cells by enhancing ROS produc-tion. On the other hand, knockdown of TXNIP promoted the osteogenic differentiation capacity of hBMSCs and MC3T3-E1 cells through the activation of the PI3K/AKT/Nrf2 pathway. CONCLUSION In conclusion, this study demonstrated that TXNIP expression, under the regulation of EZH2, plays a crucial role in the osteogenic differentiation of hBMSCs and MC3T3-E1 cells by regulating ROS production and the PI3K/AKT/Nrf2 pathway.
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Affiliation(s)
- Weibo Zhou
- Department of Orthopedics, Changzhou No. 2 People's Hospital, Changzhou, China
| | - Chunhui Zhu
- Department of Orthopedics, Changzhou No. 2 People's Hospital, Changzhou, China
| | - Fulin Zhou
- Department of Orthopedics, Changzhou No. 2 People's Hospital, Changzhou, China
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Cueto R, Shen W, Liu L, Wang X, Wu S, Mohsin S, Yang L, Khan M, Hu W, Snyder N, Wu Q, Ji Y, Yang XF, Wang H. SAH is a major metabolic sensor mediating worsening metabolic crosstalk in metabolic syndrome. Redox Biol 2024; 73:103139. [PMID: 38696898 PMCID: PMC11070633 DOI: 10.1016/j.redox.2024.103139] [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: 03/19/2024] [Accepted: 03/26/2024] [Indexed: 05/04/2024] Open
Abstract
In this study, we observed worsening metabolic crosstalk in mouse models with concomitant metabolic disorders such as hyperhomocysteinemia (HHcy), hyperlipidemia, and hyperglycemia and in human coronary artery disease by analyzing metabolic profiles. We found that HHcy worsening is most sensitive to other metabolic disorders. To identify metabolic genes and metabolites responsible for the worsening metabolic crosstalk, we examined mRNA levels of 324 metabolic genes in Hcy, glucose-related and lipid metabolic systems. We examined Hcy-metabolites (Hcy, SAH and SAM) by LS-ESI-MS/MS in 6 organs (heart, liver, brain, lung, spleen, and kidney) from C57BL/6J mice. Through linear regression analysis of Hcy-metabolites and metabolic gene mRNA levels, we discovered that SAH-responsive genes were responsible for most metabolic changes and all metabolic crosstalk mediated by Serine, Taurine, and G3P. SAH-responsive genes worsen glucose metabolism and cause upper glycolysis activation and lower glycolysis suppression, indicative of the accumulation of glucose/glycogen and G3P, Serine synthesis inhibition, and ATP depletion. Insufficient Serine due to negative correlation of PHGDH with SAH concentration may inhibit the folate cycle and transsulfurarion pathway and consequential reduced antioxidant power, including glutathione, taurine, NADPH, and NAD+. Additionally, we identified SAH-activated pathological TG loop as the consequence of increased fatty acid (FA) uptake, FA β-oxidation and Ac-CoA production along with lysosomal damage. We concluded that HHcy is most responsive to other metabolic changes in concomitant metabolic disorders and mediates worsening metabolic crosstalk mainly via SAH-responsive genes, that organ-specific Hcy metabolism determines organ-specific worsening metabolic reprogramming, and that SAH, acetyl-CoA, Serine and Taurine are critical metabolites mediating worsening metabolic crosstalk, redox disturbance, hypomethylation and hyperacetylation linking worsening metabolic reprogramming in metabolic syndrome.
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Affiliation(s)
- Ramon Cueto
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Wen Shen
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA; Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, China
| | - Lu Liu
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Xianwei Wang
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Sheng Wu
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Sadia Mohsin
- Cardiovascular Research Center, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Ling Yang
- Medical Genetics & Molecular Biochemistry, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Mohsin Khan
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Wenhui Hu
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Nathaniel Snyder
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Qinghua Wu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, China
| | - Yong Ji
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China
| | - Xiao-Feng Yang
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA; Cardiovascular Research Center, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Hong Wang
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA.
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Schoettler JJ, Brohm K, Mindt S, Jäger E, Hahn B, Fuderer T, Lindner HA, Schneider-Lindner V, Krebs J, Neumaier M, Thiel M, Centner FS. Mortality Prediction by Kinetic Parameters of Lactate and S-Adenosylhomocysteine in a Cohort of Critically Ill Patients. Int J Mol Sci 2024; 25:6391. [PMID: 38928097 PMCID: PMC11204002 DOI: 10.3390/ijms25126391] [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: 04/29/2024] [Revised: 06/01/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Tissue hypoxia is associated with the development of organ dysfunction and death in critically ill patients commonly captured using blood lactate. The kinetic parameters of serial lactate evaluations are superior at predicting mortality compared with single values. S-adenosylhomocysteine (SAH), which is also associated with hypoxia, was recently established as a useful predictor of septic organ dysfunction and death. We evaluated the performance of kinetic SAH parameters for mortality prediction compared with lactate parameters in a cohort of critically ill patients. For lactate and SAH, maxima and means as well as the normalized area scores were calculated for two periods: the first 24 h and the total study period of up to five days following ICU admission. Their performance in predicting in-hospital mortality were compared in 99 patients. All evaluated parameters of lactate and SAH were significantly higher in non-survivors compared with survivors. In univariate analysis, the predictive power for mortality of SAH was higher compared with lactate in all forms of application. Multivariable models containing SAH parameters demonstrated higher predictive values for mortality than models based on lactate parameters. The optimal models for mortality prediction incorporated both lactate and SAH parameters. Compared with lactate, SAH displayed stronger predictive power for mortality in static and dynamic application in critically ill patients.
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Affiliation(s)
- Jochen J. Schoettler
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (J.J.S.); (F.-S.C.)
| | - Kathrin Brohm
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (J.J.S.); (F.-S.C.)
- Merck KGaA (SQ-Animal Affairs), Frankfurterstrasse 250, 64293 Darmstadt, Germany
| | - Sonani Mindt
- Institute for Clinical Chemistry, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
- Institute for Laboratory and Transfusion Medicine, Hospital Passau, Innstrasse 76, 94032 Passau, Germany
| | - Evelyn Jäger
- Institute for Clinical Chemistry, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
| | - Bianka Hahn
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (J.J.S.); (F.-S.C.)
| | - Tanja Fuderer
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (J.J.S.); (F.-S.C.)
| | - Holger A. Lindner
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (J.J.S.); (F.-S.C.)
| | - Verena Schneider-Lindner
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (J.J.S.); (F.-S.C.)
| | - Joerg Krebs
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (J.J.S.); (F.-S.C.)
| | - Michael Neumaier
- Institute for Clinical Chemistry, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
| | - Manfred Thiel
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (J.J.S.); (F.-S.C.)
| | - Franz-Simon Centner
- Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; (J.J.S.); (F.-S.C.)
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Wang J, Gu D, Jin K, Shen H, Qian Y. Egr1 promotes Nlrc4-dependent neuronal pyroptosis through phlda1 in an in-vitro model of intracerebral hemorrhage. Neuroreport 2024; 35:590-600. [PMID: 38652514 DOI: 10.1097/wnr.0000000000002035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2024]
Abstract
Intracerebral hemorrhage (ICH) is a fatal brain injury, but the current treatments for it are inadequate to reduce the severity of secondary brain injury. Our study aims to explore the molecular mechanism of Egr1 and Phlda1 in regulating hemin-induced neuronal pyroptosis, and hope to provide novel therapeutic targets for ICH treatment. Mouse hippocampal neuron cells treated with hemin were used to simulate an in-vitro ICH model. Using qRT-PCR and western blot to evaluate mRNA and protein concentrations. MTT assay was utilized to assess cell viability. LDH levels were determined by lactate Dehydrogenase Activity Assay Kit. IL-1β and IL-18 levels were examined by ELISA. The interaction of Egr1 and Phlda1 promoter was evaluated using chromatin immunoprecipitation and dual-luciferase reporter assays. Egr1 and Phlda1 were both upregulated in HT22 cells following hemin treatment. Hemin treatment caused a significant reduction in HT22 cell viability, an increase in Nlrc4 and HT22 cell pyroptosis, and heightened inflammation. However, knocking down Egr1 neutralized hemin-induced effects on HT22 cells. Egr1 bound to the promoter of Phlda1 and transcriptionally activated Phlda1. Silencing Phlda1 significantly reduced Nlrc4-dependent neuronal pyroptosis. Conversely, overexpressing Phlda1 mitigated the inhibitory effects of Egr1 knockdown on Nlrc4 and neuronal pyroptosis during ICH. Egr1 enhanced neuronal pyroptosis mediated by Nlrc4 under ICH via transcriptionally activating Phlda1.
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Affiliation(s)
- Jian Wang
- Department of Neurosurgery, Taicang Hospital of Traditional Chinese Medicine, Taicang, Jiangsu Province, China
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Zeng JY, Wang Y, Hong FY, Miao M, Jiang YY, Qiao ZX, Wang YT, Bao XR. Tanshinone IIA is superior to paricalcitol in ameliorating tubulointerstitial fibrosis through regulation of VDR/Wnt/β-catenin pathway in rats with diabetic nephropathy. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:3959-3977. [PMID: 37991543 PMCID: PMC11111530 DOI: 10.1007/s00210-023-02853-3] [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: 08/16/2023] [Accepted: 11/11/2023] [Indexed: 11/23/2023]
Abstract
Glomerulosclerosis and tubulointerstitial fibrosis (TIF) are closely involved in the development of diabetic nephropathy (DN). Moreover, the development of TIF is closely related to epithelial-to-mesenchymal transition (EMT). Tanshinone IIA (Tan) has various pharmacological effects, especially the anti-fibrotic effect. And it is mainly used in the clinical treatment of cardiovascular diseases. Currently, the protective effect of Tan on DN and its possible mechanism have not been clearly elucidated. Our previous studies illustrated that Tan could improve the EMT of HK-2 cells induced by high glucose by regulating the vitamin D receptor (VDR)/Wnt/β-catenin pathway. Here, we collected demographic information and laboratory results from the National Health and Nutrition Examination Survey (NHANES) database in order to investigate the relationship between VD and DN. Then, we established a DN model and treated DN rats with Tan and paricalcitol (Par) for 6 weeks. We subsequently compared the changes in general condition, renal function, pathological changes, and TIF-related protein expression levels of control rats, DN rats induced by STZ, DN rats with Tan at 5.4 mg/kg, DN rats with Tan at 10.8 mg/kg, and DN rats with Par at 0.054 µg/kg, to explore the effect and mechanism of Tan and Par on DN rats. The results showed that VD had a protective effect against DN in diabetic patients. And we found that Tan had a protective effect on renal fibrosis in DN rats, which was superior to Par in improving the symptoms of "three more and one less," reducing fasting blood glucose level, improving renal index, BUN/SCr, and UACR, reducing histopathological damage of kidney, and improving the expression of fibrosis-related proteins in kidney tissue by regulating VDR/Wnt/β-catenin pathway. Tan was superior to Par in ameliorating tubulointerstitial fibrosis by regulating VDR/Wnt/β-catenin pathway in rats with diabetic nephropathy.
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Affiliation(s)
- Jing-Yi Zeng
- Department of Nephrology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Nephrology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Yu Wang
- Department of Nephrology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Fu-Yuan Hong
- Department of Nephrology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Miao Miao
- Department of Nephrology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Yu-Ying Jiang
- Department of Nephrology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Zi-Xuan Qiao
- Department of Nephrology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Yun-Tao Wang
- Department of Nephrology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Xiao-Rong Bao
- Department of Nephrology, Jinshan Hospital of Fudan University, Shanghai, China.
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Zhang M, Yang J, Liang G, Yuan H, Wu Y, Li L, Yu T, Zhang Y, Wang J. FOXA1-Driven pathways exacerbate Radiotherapy-Induced kidney injury in colorectal cancer. Int Immunopharmacol 2024; 131:111689. [PMID: 38471364 DOI: 10.1016/j.intimp.2024.111689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 02/07/2024] [Accepted: 02/09/2024] [Indexed: 03/14/2024]
Abstract
OBJECTIVE This study aimed to investigate the role of FOXA1 in acute kidney injury (AKI) induced by radiotherapy in colorectal cancer. Although FOXA1 is known to be aberrantly expressed in malignant tumors, its contribution to AKI remains unclear. This study aimed to explore the involvement of FOXA1 in AKI induced by radiotherapy in colorectal cancer and its influence on the regulation of downstream target genes. METHODS Firstly, a transcriptome analysis was performed on mice to establish a radiation-induced AKI model, and qPCR was used to determine the expression of FOXA1 in renal cell injury models induced by X-ray irradiation. Additionally, FOXA1 was silenced using lentiviral vectors to investigate its effects on the apoptosis of mice with radiation-induced AKI and HK-2 cells. Next, bioinformatics analysis and various experimental validation methods such as ChIP assays, co-immunoprecipitation, and dual-luciferase reporter assays were employed to explore the relationship between FOXA1 and the downstream regulatory factors ITCH promoter and the ubiquitin ligase-degradable TXNIP. Finally, lentiviral overexpression or knockout techniques were used to investigate the impact of the FOXA1/ITCH/TXNIP axis on oxidative stress and the activation of inflammatory body NLRP3. RESULTS This study revealed that FOXA1 was significantly upregulated in the renal tissues of mice with radiation-induced AKI and in the injured HK-2 cells. Furthermore, in vitro cell experiments and animal experiments demonstrated that FOXA1 suppressed the transcription of the E3 ubiquitin ligase ITCH, thereby promoting apoptosis of renal tubular cells and causing renal tissue damage. Further in vivo animal experiments confirmed that TXNIP, a protein degraded by ITCH ubiquitination, could inhibit oxidative stress and the activation of NLRP3 inflammasome in the AKI mouse model. CONCLUSION FOXA1 enhances oxidative stress, cell apoptosis, and NLRP3 inflammasome activation by regulating the ITCH/TXNIP axis, thereby exacerbating radiotherapy-induced AKI.
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Affiliation(s)
- Minhai Zhang
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Jingyuan Yang
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University, Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou 310009, China
| | - Guodong Liang
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Huiqiong Yuan
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Yanni Wu
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Li Li
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Tao Yu
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Yuling Zhang
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, China.
| | - Jingfeng Wang
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, China.
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Jin J, Liu XM, Shao W, Meng XM. Nucleic acid and protein methylation modification in renal diseases. Acta Pharmacol Sin 2024; 45:661-673. [PMID: 38102221 PMCID: PMC10943093 DOI: 10.1038/s41401-023-01203-6] [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: 06/27/2023] [Accepted: 11/18/2023] [Indexed: 12/17/2023]
Abstract
Although great efforts have been made to elucidate the pathological mechanisms of renal diseases and potential prevention and treatment targets that would allow us to retard kidney disease progression, we still lack specific and effective management methods. Epigenetic mechanisms are able to alter gene expression without requiring DNA mutations. Accumulating evidence suggests the critical roles of epigenetic events and processes in a variety of renal diseases, involving functionally relevant alterations in DNA methylation, histone methylation, RNA methylation, and expression of various non-coding RNAs. In this review, we highlight recent advances in the impact of methylation events (especially RNA m6A methylation, DNA methylation, and histone methylation) on renal disease progression, and their impact on treatments of renal diseases. We believe that a better understanding of methylation modification changes in kidneys may contribute to the development of novel strategies for the prevention and management of renal diseases.
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Affiliation(s)
- Juan Jin
- School of Basic Medicine, Anhui Medical University, Hefei, 230032, China
- Research Center for Translational Medicine, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Xue-Mei Liu
- School of Basic Medicine, Anhui Medical University, Hefei, 230032, China
| | - Wei Shao
- School of Basic Medicine, Anhui Medical University, Hefei, 230032, China.
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China.
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27
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Qu C, Tan X, Hu Q, Tang J, Wang Y, He C, He Z, Li B, Fu X, Du Q. A systematic review of astragaloside IV effects on animal models of diabetes mellitus and its complications. Heliyon 2024; 10:e26863. [PMID: 38439832 PMCID: PMC10909731 DOI: 10.1016/j.heliyon.2024.e26863] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 02/17/2024] [Accepted: 02/21/2024] [Indexed: 03/06/2024] Open
Abstract
Context Diabetes mellitus (DM) is one of the fastest-growing diseases worldwide; however, its pathogenesis remains unclear. Complications seriously affect the quality of life of patients in the later stages of diabetes, ultimately leading to suffering. Natural small molecules are an important source of antidiabetic agents. Objective Astragaloside IV (AS-IV) is an active ingredient of Astragalus mongholicus (Fisch.) Bunge. We reviewed the efficacy and mechanism of action of AS-IV in animal and cellular models of diabetes and the mechanism of action of AS-IV on diabetic complications in animal and cellular models. We also summarized the safety of AS-IV and provided ideas and rationales for its future clinical application. Methods Articles on the intervention in DM and its complications using AS-IV, such as those published in SCIENCE, PubMed, Springer, ACS, SCOPUS, and CNKI from the establishment of the database to February 2022, were reviewed. The following points were systematically summarized: dose/concentration, route of administration, potential mechanisms, and efficacy of AS-IV in animal models of DM and its complications. Results AS-IV has shown therapeutic effects in animal models of DM, such as alleviating gestational diabetes, delaying diabetic nephropathy, preventing myocardial cell apoptosis, and inhibiting vascular endothelial dysfunction; however, the potential effects of AS-IV on DM should be investigated. Conclusion AS-IV is a potential drug for the treatment of diabetes and its complications, including diabetic vascular disease, cardiomyopathy, retinopathy, peripheral neuropathy, and nephropathy. In addition, preclinical toxicity studies indicate that it appears to be safe, but the safe human dose limit is yet to be determined, and formal assessments of adverse drug reactions among humans need to be further investigated. However, additional formulations or structural modifications are required to improve the pharmacokinetic parameters and facilitate the clinical use of AS-IV.
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Affiliation(s)
- Caiyan Qu
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
- Nanjiang County Hospital of Chinese Medicine, Bazhong, 635600, China
| | - Xiyue Tan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qichao Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Jiao Tang
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Yangyang Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Caiying He
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - ZiJia He
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Bin Li
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Xiaoxu Fu
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Quanyu Du
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, 610072, China
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Wen T, Xie J, Ma L, Hao Z, Zhang W, Wu T, Li L. Vitamin D Receptor Activation Reduces Hepatic Inflammation via Enhancing Macrophage Autophagy in Cholestatic Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:369-383. [PMID: 38104651 DOI: 10.1016/j.ajpath.2023.11.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/09/2023] [Accepted: 11/28/2023] [Indexed: 12/19/2023]
Abstract
Macrophage autophagy dysfunction aggravates liver injury by activating inflammasomes, which can cleave pro-IL-1β to its active, secreted form. We investigated whether the vitamin D/vitamin D receptor (VDR) axis could up-regulate macrophage autophagy function to inhibit the activation of inflammasome-dependent IL-1β during cholestasis. Paricalcitol (PAL; VDR agonist) was intraperitoneally injected into bile duct-ligated mice for 5 days. Up-regulation of VDR expression by PAL reduced liver injury by reducing the oxidative stress-induced inflammatory reaction in macrophages. Moreover, PAL inhibited inflammasome-dependent IL-1β generation. Mechanistically, the knockdown of VDR increased IL-1β generation, whereas VDR overexpression exerted the opposite effect following tert-butyl hydroperoxide treatment. The inflammasome antagonist glyburide, the caspase-1-specific inhibitor YVAD, and the reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) blocked the increase in Vdr shRNA-induced IL-1β production. Interestingly, up-regulation of VDR also enhanced macrophage autophagy. Autophagy reduction impaired the up-regulation of VDR-inhibited macrophage inflammasome-generated IL-1β, whereas autophagy induction showed a synergistic effect with VDR overexpression through ROS-p38 mitogen-activated protein kinase (MAPK) pathway. This result was confirmed by p38 MAPK inhibitor, MAPK activator, and ROS inhibitor NAC. Collectively, PAL triggered macrophage autophagy by suppressing activation of the ROS-p38 MAPK pathway, which, in turn, suppressed inflammasome-generated cleaved, active forms of IL-1β, eventually leading to reduced inflammation. Thus, triggering the VDR may be a potential target for the anti-inflammatory treatment of cholestatic liver disease.
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Affiliation(s)
- Tianfu Wen
- Department of General Surgery, The Affiliated Wenling First People's Hospital, Taizhou University, Taizhou, China
| | - Jing Xie
- Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, China
| | - Liman Ma
- Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, China
| | - Zhiqing Hao
- Department of Pathophysiology, School of Basic Medicine, Shenyang Medical College, Shenyang, China
| | - Weiwei Zhang
- Department of Pathophysiology, School of Basic Medicine, Shenyang Medical College, Shenyang, China
| | - Tingyao Wu
- Department of Hematology, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Lihua Li
- Department of General Surgery, The Affiliated Wenling First People's Hospital, Taizhou University, Taizhou, China.
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Guo X, Chen K, Ji L, Wang S, Ye X, Xu L, Feng L. Ultrasound-targeted microbubble technology facilitates SAHH gene delivery to treat diabetic cardiomyopathy by activating AMPK pathway. iScience 2024; 27:108852. [PMID: 38303706 PMCID: PMC10831940 DOI: 10.1016/j.isci.2024.108852] [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: 09/12/2023] [Revised: 11/13/2023] [Accepted: 01/04/2024] [Indexed: 02/03/2024] Open
Abstract
Diabetic cardiomyopathy (DCM) is a cardiovascular complication with no known cure. In this study, we evaluated the combination of ultrasound-targeted microbubble destruction (UTMD) and cationic microbubbles (CMBs) for cardiac S-adenosyl homocysteine hydrolase (SAHH) gene transfection as potential DCM therapy. Models of high glucose/fat (HG/HF)-induced H9C2 cells and streptozotocin-induced DCM rats were established. Ultrasound-mediated SAHH delivery using CMBs was a safe and noninvasive approach for spatially localized drug administration both in vitro and in vivo. Notably, SAHH overexpression increased cell viability and antioxidative stress and inhibited apoptosis of HG/HF-induced H9C2 cells. Likewise, UTMD-mediated SAHH delivery attenuated apoptosis, oxidative stress, cardiac fibrosis, and myocardial dysfunction in DCM rats. Activation of the AMPK/FOXO3/SIRT3 signaling pathway may be a key mechanism mediating the role of SAHH in regulating myocardial injury. Thus, UTMD-mediated SAHH transfection may be an important advancement in cardiac gene therapy for restoring ventricular function after DCM.
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Affiliation(s)
- Xiaohui Guo
- Department of Clinical Laboratory, First Affiliated Hospital of Harbin Medical University, Harbin 150081, P.R. China
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin 150086, P.R. China
| | - Kegong Chen
- Department of Thoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, P.R. China
| | - Lin Ji
- Department of Orthopedics, The First Hospital of Harbin, Harbin 150010, P.R. China
| | - Shanjie Wang
- The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin 150086, P.R. China
| | - Xiangmei Ye
- Department of Clinical Laboratory, First Affiliated Hospital of Harbin Medical University, Harbin 150081, P.R. China
| | - Liang Xu
- Department of Cardiology, The Second Hospital of Harbin, Harbin 150056, P.R. China
| | - Leiguang Feng
- Department of Clinical Laboratory, First Affiliated Hospital of Harbin Medical University, Harbin 150081, P.R. China
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Tang S, An X, Sun W, Zhang Y, Yang C, Kang X, Sun Y, Jiang L, Zhao X, Gao Q, Ji H, Lian F. Parallelism and non-parallelism in diabetic nephropathy and diabetic retinopathy. Front Endocrinol (Lausanne) 2024; 15:1336123. [PMID: 38419958 PMCID: PMC10899692 DOI: 10.3389/fendo.2024.1336123] [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: 11/10/2023] [Accepted: 01/23/2024] [Indexed: 03/02/2024] Open
Abstract
Diabetic nephropathy (DN) and diabetic retinopathy (DR), as microvascular complications of diabetes mellitus, are currently the leading causes of end-stage renal disease (ESRD) and blindness, respectively, in the adult working population, and they are major public health problems with social and economic burdens. The parallelism between the two in the process of occurrence and development manifests in the high overlap of disease-causing risk factors and pathogenesis, high rates of comorbidity, mutually predictive effects, and partial concordance in the clinical use of medications. However, since the two organs, the eye and the kidney, have their unique internal environment and physiological processes, each with specific influencing molecules, and the target organs have non-parallelism due to different pathological changes and responses to various influencing factors, this article provides an overview of the parallelism and non-parallelism between DN and DR to further recognize the commonalities and differences between the two diseases and provide references for early diagnosis, clinical guidance on the use of medication, and the development of new drugs.
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Affiliation(s)
- Shanshan Tang
- College of Traditional Chinese Medicine, Changchun University of Traditional Chinese Medicine, Changchun, China
| | - Xuedong An
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenjie Sun
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuehong Zhang
- Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Cunqing Yang
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaomin Kang
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuting Sun
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Linlin Jiang
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Xuefei Zhao
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Qing Gao
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Hangyu Ji
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengmei Lian
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
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Jin J, Shang Y, Zheng S, Dai L, Tang J, Bian X, He Q. Exosomes as nanostructures deliver miR-204 in alleviation of mitochondrial dysfunction in diabetic nephropathy through suppressing methyltransferase-like 7A-mediated CIDEC N6-methyladenosine methylation. Aging (Albany NY) 2024; 16:3302-3331. [PMID: 38334961 PMCID: PMC10929828 DOI: 10.18632/aging.205535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/03/2024] [Indexed: 02/10/2024]
Abstract
OBJECTIVE The exosomal cargo mainly comprises proteins, lipids, and microRNAs (miRNAs). Among these, miRNAs undertake multiple biological effects of exosomes (Exos). Some stem cell-derived exosomal miRNAs have shown the potential to treat diabetic nephropathy (DN). However, there is little research into the therapeutic effects of adipose-derived stem cell (ADSC)-derived exosomal miRNAs on DN. We aimed to explore the potential of miR-204-modified ADSC-derived Exos to mitigate DN. METHODS Exos were extracted and identified from ADSCs. Histopathological injury, oxidative stress (OS), mitochondrial function, cell viability, and apoptosis were assessed to explore the effects of ADSC-derived Exos on DN. For mechanism exploration, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to measure miR-204, methyltransferase (METTL3, METTL14, and METTL7A), and CIDEC. Also, CIDEC m6A methylation and miR-204-METTL7A, and METTL7A-CIDEC interactions were determined. RESULTS Initially, OS-induced mitochondrial dysfunction was observed in DN rats. ADSC-derived Exos inhibited histopathological injury, cell apoptosis, OS, and mitochondrial dysfunction in DN rats. The similar therapeutic effects of ADSC-derived Exos were detected in the in vitro model. Intriguingly, miR-204 was released by ADSC-derived Exos and its upregulation enhanced the anti-DN effects of Exos. Mechanically, miR-204 reduced METTL7A expression to CIDEC m6A methylation, thus suppressing OS and mitochondrial dysfunction. CONCLUSIONS ADSC-derived exosomal miR-204 rescued OS-induced mitochondrial dysfunction by inhibiting METTL7A-mediated CIDEC m6A methylation. This study first revealed the significant role of ADSC-derived exosomal miR-204 in DN, paving the way for the development of novel therapeutic strategies to improve the clinical outcomes of DN patients.
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Affiliation(s)
- Juan Jin
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China
| | - Yiwei Shang
- Clinical School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310004, China
| | - Siqiang Zheng
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China
| | - Limiao Dai
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China
| | - Jiyu Tang
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China
| | - Xueyan Bian
- Department of Nephrology, Ningbo First Hospital, Ningbo, Zhejiang 315010, China
| | - Qiang He
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310000, China
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HUANG H, YANG M, LI T, WANG D, LI Y, TANG X, YUAN L, GU S, XU Y. Neferine inhibits the progression of diabetic nephropathy by modulating the miR-17-5p/nuclear factor E2-related factor 2 axis. J TRADIT CHIN MED 2024; 44:44-53. [PMID: 38213238 PMCID: PMC10774715 DOI: 10.19852/j.cnki.jtcm.20231204.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 03/17/2023] [Indexed: 01/13/2024]
Abstract
OBJECTIVE To investigate the effect of Neferine (Nef) on diabetic nephropathy (DN) and to explore the mechanism of Nef in DN based on miRNA regulation theory. METHODS A DN mouse model was constructed and treated with Nef. Serum creatinine (Crea), blood urea (UREA) and urinary albumin were measured in mice by kits, and renal histopathological changes and fibrosis were observed by hematoxylin-eosin staining and Masson staining. Renal tissue superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) activities were measured by enzyme-linked immunosorbent assay (ELISA). Western blotting was used to detect the expression of nuclear factor E2-related factor 2 (Nrf2)/ heme oxygenase 1 (HO-1) signaling pathway-related proteins in kidney tissues. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-17-5p in kidney tissues. Subsequently, a DN in vitro model was constructed by high glucose culture of human mesangial cells (HMCs), cells were transfected with miR-17-5p mimic and/or treated with Nef, and we used qRT-PCR to detect cellular miR-17 expression, flow cytometry to detect apoptosis, ELISAs to detect cellular SOD, MDA, and GSH-Px activities, Western blots to detect Nrf2/HO-1 signaling pathway-related protein expression, and dual luciferase reporter gene assays to verify the targeting relationship between Nrf2 and miR-17-5p. RESULTS Administration of Nef significantly reduced the levels of blood glucose, Crea, and UREA and the expression of miR-17-5p, improved renal histopathology and fibrosis, significantly reduced MDA levels, elevated SOD and GSH-Px activities, and activated Nrf2 expression in kidney tissues from mice with DN. Nrf2 is a post-transcriptional target of miR-17-5p. In HMCs transfected with miR-17-5p mimics, the mRNA and protein levels of Nrf2 were significantly suppressed. Furthermore, miR-17-5p overexpression and Nef intervention resulted in a significant increase in high glucose-induced apoptosis and MDA levels in HMCs and a significant decrease in the protein expression of HO-1 and Nrf2. CONCLUSION Collectively, these results indicate that Nef has an ameliorative effect on DN, and the mechanism may be through the miR-17-5p/Nrf2 pathway.
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Affiliation(s)
- Hongmei HUANG
- 1 Department of Endocrinology, Chengdu Shuangliu District First People's Hospital (West China Airport of Sichuan University), Chengdu 610200, China
| | - Maojun YANG
- 1 Department of Endocrinology, Chengdu Shuangliu District First People's Hospital (West China Airport of Sichuan University), Chengdu 610200, China
| | - Ting LI
- 1 Department of Endocrinology, Chengdu Shuangliu District First People's Hospital (West China Airport of Sichuan University), Chengdu 610200, China
| | - Dandan WANG
- 1 Department of Endocrinology, Chengdu Shuangliu District First People's Hospital (West China Airport of Sichuan University), Chengdu 610200, China
| | - Ying LI
- 1 Department of Endocrinology, Chengdu Shuangliu District First People's Hospital (West China Airport of Sichuan University), Chengdu 610200, China
| | - Xiaochi TANG
- 1 Department of Endocrinology, Chengdu Shuangliu District First People's Hospital (West China Airport of Sichuan University), Chengdu 610200, China
| | - Lu YUAN
- 1 Department of Endocrinology, Chengdu Shuangliu District First People's Hospital (West China Airport of Sichuan University), Chengdu 610200, China
| | - Shi GU
- 1 Department of Endocrinology, Chengdu Shuangliu District First People's Hospital (West China Airport of Sichuan University), Chengdu 610200, China
| | - Yong XU
- 2 Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
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Qin H, Liu C, Li C, Feng C, Bo Huang. Advances in bi-directional relationships for EZH2 and oxidative stress. Exp Cell Res 2024; 434:113876. [PMID: 38070859 DOI: 10.1016/j.yexcr.2023.113876] [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: 08/07/2023] [Revised: 11/14/2023] [Accepted: 12/03/2023] [Indexed: 12/23/2023]
Abstract
Over the past two decades, polycomb repressive complex 2(PRC2) has emerged as a vital repressive complex in overall cell fate determination. In mammals, enhancer of zeste homolog 2 (EHZ2), which is the core component of PRC2, has also been recognized as an important regulator of inflammatory, redox, tumorigenesis and damage repair signalling networks. To exert these effects, EZH2 must regulate target genes epigenetically or interact directly with other gene expression-regulating factors, such as LncRNAs and microRNAs. Our review provides a comprehensive summary of research advances, discoveries and trends regarding the regulatory mechanisms between EZH2 and reactive oxygen species (ROS). First, we outline novel findings about how EZH2 regulates the generation of ROS at the molecular level. Then, we summarize how oxidative stress controls EHZ2 alteration (upregulation, downregulation, or phosphorylation) via various molecules and signalling pathways. Finally, we address why EZH2 and oxidative stress have an undefined relationship and provide potential future research ideas.
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Affiliation(s)
- Heng Qin
- Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Army Medical University, Chongqing, 400037, PR China.
| | - Chang Liu
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, PR China.
| | - Changqing Li
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, PR China.
| | - Chencheng Feng
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, PR China.
| | - Bo Huang
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, PR China.
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Okabe M, Koike K, Yamamoto I, Tsuboi N, Matsusaka T, Yokoo T. Early growth response 1 as a podocyte injury marker in human glomerular diseases. Clin Kidney J 2024; 17:sfad289. [PMID: 38186896 PMCID: PMC10768762 DOI: 10.1093/ckj/sfad289] [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: 04/22/2023] [Indexed: 01/09/2024] Open
Abstract
Background In human glomerular diseases, visualizing podocyte injury is desirable since podocytes do not regenerate and podocyte injury leads to podocyte loss. Herein, we investigated the utility of immunostaining for early growth response 1 (EGR1), which is expressed in injured podocytes from the early stages of injury in animal experiments, as a podocyte injury marker in human glomerular diseases. Methods This study included 102 patients with biopsy-proven glomerular diseases between 2018 and 2021. The proportion of EGR1 expression in podocytes (%EGR1pod) was analyzed in relation to clinical and histopathological features, including glomerular and urinary podocyte-specific markers. Results %EGR1pod correlated significantly with the urinary protein:creatinine ratio, urinary nephrin and podocin mRNA levels, and glomerular podocin staining (rho = 0.361, 0.514, 0.487 and -0.417, respectively; adjusted P = .002, <.001, <.001 and <.001, respectively). Additionally, %EGR1pod correlated with cellular/fibrocellular crescents (rho = 0.479, adjusted P <.001). %EGR1pod was high in patients with glomerulonephritis, such as immunoglobulin A nephropathy (IgAN), lupus nephritis and antineutrophil cytoplasmic antibody-associated glomerulonephritis, and in those with podocytopathies, such as membranous nephropathy and primary focal segmental glomerulosclerosis, while %EGR1pod was low in patients with minimal change disease. In a subgroup analysis of IgAN, %EGR1pod was higher in Oxford C1 patients than in C0 patients. However, unexpectedly, patients with higher %EGR1pod were more prone to attain proteinuria remission, suggesting that EGR1 in the context of IgAN reflects reversible early injury. Conclusions Our findings indicate that EGR1 is a promising potential marker for identifying active early podocyte injury in human glomerular diseases.
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Affiliation(s)
- Masahiro Okabe
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Kentaro Koike
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Izumi Yamamoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Nobuo Tsuboi
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Taiji Matsusaka
- Departments of Basic Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
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Shankland SJ, Rule AD, Kutz JN, Pippin JW, Wessely O. Podocyte Senescence and Aging. KIDNEY360 2023; 4:1784-1793. [PMID: 37950369 PMCID: PMC10758523 DOI: 10.34067/kid.0000000000000284] [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: 06/07/2023] [Accepted: 10/11/2023] [Indexed: 11/12/2023]
Abstract
As the population in many industrial countries is aging, the risk, incidence, and prevalence of CKD increases. In the kidney, advancing age results in a progressive decrease in nephron number and an increase in glomerulosclerosis. In this review, we focus on the effect of aging on glomerular podocytes, the post-mitotic epithelial cells critical for the normal integrity and function of the glomerular filtration barrier. The podocytes undergo senescence and transition to a senescence-associated secretory phenotype typified by the production and secretion of inflammatory cytokines that can influence neighboring glomerular cells by paracrine signaling. In addition to senescence, the aging podocyte phenotype is characterized by ultrastructural and functional changes; hypertrophy; cellular, oxidative, and endoplasmic reticulum stress; reduced autophagy; and increased expression of aging genes. This results in a reduced podocyte health span and a shortened life span. Importantly, these changes in the pathways/processes characteristic of healthy podocyte aging are also often similar to pathways in the disease-induced injured podocyte. Finally, the better understanding of podocyte aging and senescence opens therapeutic options to slow the rate of podocyte aging and promote kidney health.
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Affiliation(s)
- Stuart J. Shankland
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
| | - Andrew D. Rule
- Division of Nephrology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - J. Nathan Kutz
- Department of Applied Mathematics, University of Washington, Seattle, Washington
| | - Jeffrey W. Pippin
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
| | - Oliver Wessely
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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Li X, Zhang Y, Xing X, Li M, Liu Y, Xu A, Zhang J. Podocyte injury of diabetic nephropathy: Novel mechanism discovery and therapeutic prospects. Biomed Pharmacother 2023; 168:115670. [PMID: 37837883 DOI: 10.1016/j.biopha.2023.115670] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/24/2023] [Accepted: 10/06/2023] [Indexed: 10/16/2023] Open
Abstract
Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, posing significant challenges in terms of early prevention, clinical diagnosis, and treatment. Consequently, it has emerged as a major contributor to end-stage renal disease. The glomerular filtration barrier, composed of podocytes, endothelial cells, and the glomerular basement membrane, plays a vital role in maintaining renal function. Disruptions in podocyte function, including hypertrophy, shedding, reduced density, and apoptosis, can impair the integrity of the glomerular filtration barrier, resulting in elevated proteinuria, abnormal glomerular filtration rate, and increased creatinine levels. Hence, recent research has increasingly focused on the role of podocyte injury in DN, with a growing emphasis on exploring therapeutic interventions targeting podocyte injury. Studies have revealed that factors such as lipotoxicity, hemodynamic abnormalities, oxidative stress, mitochondrial dysfunction, and impaired autophagy can contribute to podocyte injury. This review aims to summarize the underlying mechanisms of podocyte injury in DN and provide an overview of the current research status regarding experimental drugs targeting podocyte injury in DN. The findings presented herein may offer potential therapeutic targets and strategies for the management of DN associated with podocyte injury.
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Affiliation(s)
- Xiandeng Li
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; College of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Ying Zhang
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiaodong Xing
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; College of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Mi Li
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yan Liu
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Ajing Xu
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
| | - Jian Zhang
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
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Qin Y, Wu S, Zhang F, Zhou X, You C, Tan F. N6-methyladenosine methylation regulator RBM15 promotes the progression of diabetic nephropathy by regulating cell proliferation, inflammation, oxidative stress, and pyroptosis through activating the AGE-RAGE pathway. ENVIRONMENTAL TOXICOLOGY 2023; 38:2772-2782. [PMID: 37551785 DOI: 10.1002/tox.23917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/05/2023] [Accepted: 07/21/2023] [Indexed: 08/09/2023]
Abstract
BACKGROUND Diabetic nephropathy (DN) is a major cause of end-stage renal disease throughout the world, and m6A modification plays a critical role in the progression of DN. We aimed to find m6A-related genes and their regulatory mechanisms in DN. METHODS The expression levels of four important m6A-related genes (METTL16, RBM15, IGF2BP1, and ALKBH5) were detected by quantitative real-time PCR (RT-qPCR). RBM15 was chosen and its function was explored. The downstream pathway of RBM15 was screened by transcriptome sequencing. The levels of AGE, inflammation, and oxidative stress were determined with enzyme-linked immunosorbent assay, and the expression of AGE-RAGE pathway-related proteins were detected by Western blot (WB). Cell proliferation was assessed by Cell counting Kit-8 (CCK-8). The levels of pyroptosis-related proteins were evaluated by RT-qPCR or WB. RESULTS METTL16 and RBM15 were up regulated in the mouse model of DN, in which RBM15 was more significant. Silencing RBM15 recovered cell proliferation, reduced the levels of inflammation factors, and inhibited cell pyroptosis in high glucose-induced HK-2 cells. Transcriptome sequencing suggested that the AGE-RAGE pathway might be downstream of RBM15. RBM15 knockdown reduced AGE level and the expression of AGE-RAGE pathway-related proteins. After silencing RBM15, we found that activating the AGE-RAGE pathway inhibited cell proliferation, increased the levels of inflammation factors, promoted oxidative stress, and induced cell pyroptosis in HK-2 cell model of DN. CONCLUSION The m6A-related gene RBM15 inhibited cell proliferation, promoted inflammation, oxidative stress, and cell pyroptosis, thereby facilitating the progression of DN through the activation of the AGE-RAGE pathway.
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Affiliation(s)
- Yongzhang Qin
- Department of Endocrinology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Ganzhou Key Laboratory of Thyroid Cancer, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Institute of Thyroid Diseases, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Suzhen Wu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Fengxia Zhang
- Department of Nephrology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xueyan Zhou
- Department of Endocrinology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Cong You
- Department of Dermatology and Venereology, Candidate Branch of National Clinical Research Centre for Skin and Immune Diseases, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Fei Tan
- Department of Nephrology, Ganzhou People's Hospital, Ganzhou, Jiangxi, China
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Sui J, Dai F, Shi J, Zhou C. Ubiquitin-specific peptidase 25 exacerbated osteoarthritis progression through facilitating TXNIP ubiquitination and NLRP3 inflammasome activation. J Orthop Surg Res 2023; 18:762. [PMID: 37814350 PMCID: PMC10561454 DOI: 10.1186/s13018-023-04083-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 08/06/2023] [Indexed: 10/11/2023] Open
Abstract
Several members of the ubiquitin-specific proteases (USPs) family have been revealed to regulate the progression of osteoarthritis (OA). The current study aimed to investigate the role and the underlying mechanism of USP25 in IL-1β-induced chondrocytes and OA rat model. It was discovered that IL-1β stimulation upregulated USP25, increased ROS level, and suppressed cell viability in rat chondrocytes. Besides, USP25 knockdown alleviated IL-1β-induced injury by decreasing ROS level, attenuating pyroptosis, and downregulating the expression of IL-18, NLRP3, GSDMD-N, active caspase-1, MMP-3, and MMP-13. Furthermore, we discovered that USP25 affected the IL-1β-induced injury in chondrocytes in a ROS-dependent manner. Moreover, USP25 was revealed to interact with TXNIP, and USP25 knockdown increased the ubiquitination of TXNIP. The pro-OA effect of USP25 abundance could be overturned by TXNIP suppression in IL-1β-induced chondrocytes. Finally, in vivo experiment results showed that USP25 inhibition alleviated cartilage destruction in OA rats. In conclusion, we demonstrated that USP25 stimulated the overproduction of ROS to activate the NLRP3 inflammasome via regulating TXNIP, resulting in increased pyroptosis and inflammation in OA.
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Affiliation(s)
- Jie Sui
- Department of Orthopedics, 904 Hospital of PLA Joint Logistic Support Force, 55 Heping North Road, Changzhou, 213003, Jiangsu Province, China
| | - Fei Dai
- Department of Orthopedics, 904 Hospital of PLA Joint Logistic Support Force, 55 Heping North Road, Changzhou, 213003, Jiangsu Province, China
| | - Jiusheng Shi
- Department of Orthopedics, 904 Hospital of PLA Joint Logistic Support Force, 55 Heping North Road, Changzhou, 213003, Jiangsu Province, China.
| | - Changcheng Zhou
- Department of Orthopedics, 904 Hospital of PLA Joint Logistic Support Force, 55 Heping North Road, Changzhou, 213003, Jiangsu Province, China.
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Liu H, Yang X, Liu G. Regulation of cell proliferation and transdifferentiation compensates for ventilator-induced lung injury mediated by NLRP3 inflammasome activation. Immun Inflamm Dis 2023; 11:e1062. [PMID: 37904713 PMCID: PMC10599283 DOI: 10.1002/iid3.1062] [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: 05/31/2023] [Revised: 10/01/2023] [Accepted: 10/11/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND Mechanical ventilation is an important means of respiratory support and treatment for various diseases. However, its use can lead to serious complications, especially ventilator-induced lung injury (VILI). The mechanisms underlying this disease are complex, but activation of inflammatory signalling pathways results in activation of cytokines and inflammatory mediators, which play key roles in VILI. Recent studies have demonstrated that nod-like receptor protein 3 (NLRP3) inflammasome activation mediates VILI and also accompanied by cell proliferation and transdifferentiation to compensate for alveolar membrane damage. Type I alveolar epithelial cells (AECs I), which are involved in the formation of the blood-air barrier, are vulnerable to damage but cannot proliferate by themselves; thus, replacing AECs I relies on type II alveolar epithelial cells (AECs II). OBJECTIVE The review aims to introduce the mechanisms of NLRP3 inflammasome activation and its inhibitors, as well as the mechanisms that regulate cell proliferation and transdifferentiation. METHODS A large number of relevant literature was searched, then the key content was summarized and figures were also made. RESULTS The mechanism of NLRP3 inflammasome activation has been further explored, including but not limited to pathogenic and aseptic inflammatory signals, such as, pathogenic molecular patterns and host-derived danger-associated molecular patterns activate toll-like receptor 4/nuclear factor-kappaB pathway or reactive oxygen species, cyclic stretch, adenosine triphosphate induce K+ efflux through P2X7, Ca2+ inflow, mitochondrial damage, etc, eventually induce NIMA-related kinase 7/NLRP3 binding and NLRP3 inflammasome activation. Not only that, the review also described in detail the inhibitors of NLRP3 inflammasome. And the mechanisms regulating cell proliferation and transdifferentiation are complex and unclear, including the Wnt/β-catenin, Yap/Taz, BMP/Smad and Notch signalling pathways. CONCLUSIONS NLRP3 inflammasome activation mediated VILI, and VILI is alleviated after interfering with its activation, and inflammation and repair exist simultaneously in VILI. Clarifying these mechanisms is expected to provide theoretical guidance for alleviating VILI by inhibiting the inflammatory response and accelerating alveolar epithelial cell regeneration in the early stage.
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Affiliation(s)
- Huan Liu
- Department of AnesthesiologyQilu Hospital of Shandong UniversityJi'nanChina
| | - Xuepeng Yang
- Department of OphtalmologyJinan Second People's HospitalJi'nanChina
| | - Ge Liu
- Department of OphtalmologyQilu Hospital of Shandong UniversityJi'nanChina
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Heng YY, Shang HJ, Zhang XZ, Wei W. Sodium tanshinone IIA sulfonate ameliorates neointima by protecting endothelial progenitor cells in diabetic mice. BMC Cardiovasc Disord 2023; 23:446. [PMID: 37697234 PMCID: PMC10494373 DOI: 10.1186/s12872-023-03485-4] [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: 08/20/2022] [Accepted: 08/31/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND Endothelial progenitor cells (EPCs) transplantation is one of the effective therapies for neointima associated with endothelial injury. Diabetes impairs the function of EPCs and cumbers neointima prevention of EPC transplantation with an ambiguous mechanism. Sodium Tanshinone IIA Sulfonate (STS) is an endothelium-protective drug but whether STS protects EPCs in diabetes is still unknown. METHODS EPCs were treated with High Glucose (HG), STS, and Nucleotide-binding Domain-(NOD) like Receptor 3 (NLRP3), caspase-1, the Receptor of Advanced Glycation End products (AGEs) (RAGE) inhibitors, Thioredoxin-Interacting Protein (TXNIP) siRNA, and EPC proliferation, differentiation functions, and senescence were detected. The treated EPCs were transplanted into db/db mice with the wire-injured Common Carotid Artery (CCA), and the CD31 expression and neointima were detected in the CCA inner wall. RESULTS We found that STS inhibited HG-induced expression of NLRP3, the production of active caspase-1 (p20) and mature IL-1β, the expression of catalase (CAT) cleavage, γ-H2AX, and p21 in EPCs. STS restored the expression of Ki67, CD31 and von Willebrand Factor (vWF) in EPCs; AGEs were found in the HG-treated EPCs supernatant, and RAGE blocking inhibited the expression of TXNIP and the production of p20, which was mimicked by STS. STS recovered the expression of CD31 in the wire-injured CCA inner wall and the prevention of neointima in diabetic mice with EPCs transplantation. CONCLUSION STS inhibits the aggravated neointima hyperplasia by protecting the proliferation and differentiation functions of EPC and inhibiting EPC senescence in diabetic mice. The mechanism is related to the preservation of CAT activity by inhibiting the RAGE-TXNIP-NLRP3 inflammasome pathway.
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Affiliation(s)
- Yan-Yan Heng
- Department of Nephrology, Heping Hospital Affiliated to Changzhi Medical College, No.110, Yanan Road South, Changzhi, Shanxi, China
| | - Hui-Juan Shang
- Department of Foreign Language Teaching, Changzhi Medical College, No.161, Jiefang East Street, Changzhi, Shanxi, China
| | - Xia-Ze Zhang
- The First Clinical Acadamy of Changzhi Medical College, No.161, Jiefang East Street, Changzhi, Shanxi, China
| | - Wei Wei
- Department of Pharmacology, Changzhi Medical College, No.161, Jiefang East Street, Changzhi, 046000, Shanxi, China.
- Department of Phase I Clinical Trial Laboratory, National Institute for Clinical Trials of Drugs, Heping Hospital Affiliated to Changzhi Medical College, No.110, South Yan'an Road, Changzhi, 046000, Shanxi, China.
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Gu X, Zhao L, Ye J, Chen L, Sui C, Li B, Wang X, Zhang J, Du Y. 1,25(OH) 2D 3 ameliorates doxorubicin‑induced cardiomyopathy by inhibiting the NLRP3 inflammasome and oxidative stress. Exp Ther Med 2023; 26:413. [PMID: 37559932 PMCID: PMC10407981 DOI: 10.3892/etm.2023.12112] [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: 12/14/2022] [Accepted: 06/16/2023] [Indexed: 08/11/2023] Open
Abstract
Doxorubicin (DOX), as a chemotherapy agent with marked therapeutic effect, can be used to treat certain types of cancer such as leukemia, lymphoma and breast cancer. However, the toxic effects of DOX on cardiomyocytes limit its clinical application. Oxidative stress has been documented to serve a pivotal role in DOX-induced cardiomyopathy. Previous studies have reported that 1,25(OH)2D3 has antioxidant and anti-inflammatory effects and can inhibit the renin-angiotensin system. However, the effects of 1,25(OH)2D3 on the pathophysiological processes of DOX-induced cardiomyopathy and its mechanisms remain poorly understood. To investigate these potential effects, C57BL/6J mice were used to construct a DOX-induced cardiomyopathy model and treated with 1,25(OH)2D3. At 4 weeks after the first injection of DOX, cardiac function and myocardial injury were evaluated by echocardiograph and ELISA. Masson's trichrome staining and RT-qPCR were used to assess myocardial fibrosis, and immunohistochemistry and western blotting were performed to analyze expression levels of inflammation and oxidative stress, and the NLRP3 inflammasome pathway. ChIP assay was used to assess the effects of 1,25(OH)2D3 on histone modification in the NLRP3 and Nrf2 promoters. The results showed that 1,25(OH)2D3 treatment increased LVEF and LVFS, reduced serum levels of BNP and cTnT, inhibited the collagen deposition and profibrotic molecular expression, and downregulated the levels of inflammatory cytokines in DOX-induced cardiomyopathy. ROS and antioxidant indices were also ameliorated after 1,25(OH)2D3 treatment. In addition, 1,25(OH)2D3 was found to inhibit the NLRP3 inflammasome and KEAP-Nrf2 pathways through regulation of the levels of H3K4me3, H3K27me3 and H2AK119Ub in the NLRP3 and Nrf2 promoters. In conclusion, the present study demonstrated that 1,25(OH)2D3 regulated histone modification in the NLRP3 and Nrf2 promoters, which in turn inhibits the activation of NLRP3 inflammasome and oxidative stress in cardiomyocytes, alleviating DOX-induced cardiomyopathy. Therefore, 1,25(OH)2D3 may be a potential drug candidate for the treatment of DOX-induced cardiomyopathy.
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Affiliation(s)
- Xin Gu
- Department of Cardiology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, P.R. China
| | - Lin Zhao
- Department of Cardiology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, P.R. China
| | - Jiabao Ye
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215008, P.R. China
| | - Lin Chen
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215008, P.R. China
| | - Chenyan Sui
- Department of Neurology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, P.R. China
| | - Baihong Li
- Department of Cardiology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, P.R. China
| | - Xiaoyan Wang
- Department of Cardiology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, P.R. China
| | - Jun Zhang
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215008, P.R. China
| | - Yingqiang Du
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215008, P.R. China
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Ma Z, Chen L, Wang Y, Zhang S, Zheng J, Luo Y, Wang C, Zeng H, Xue L, Tan Z, Wang D. Novel insights of EZH2-mediated epigenetic modifications in degenerative musculoskeletal diseases. Ageing Res Rev 2023; 90:102034. [PMID: 37597667 DOI: 10.1016/j.arr.2023.102034] [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: 12/14/2022] [Revised: 07/06/2023] [Accepted: 08/16/2023] [Indexed: 08/21/2023]
Abstract
Degenerative musculoskeletal diseases (Osteoporosis, Osteoarthritis, Degenerative Spinal Disease and Sarcopenia) are pathological conditions that affect the function and pain of tissues such as bone, cartilage, and muscles, and are closely associated with ageing and long-term degeneration. Enhancer of zeste homolog 2 (EZH2), an important epigenetic regulator, regulates gene expression mainly through the PRC2-dependent trimethylation of histone H3 at lysine 27 (H3K27me3). Increasing evidence suggests that EZH2 is involved in several biological processes closely related to degenerative musculoskeletal diseases, such as osteogenic-adipogenic differentiation of bone marrow mesenchymal stem cells, osteoclast activation, chondrocyte functional status, and satellite cell proliferation and differentiation, mainly through epigenetic regulation (H3K27me3). Therefore, the synthesis and elucidation of the role of EZH2 in degenerative musculoskeletal diseases have attracted increasing attention. In addition, although EZH2 inhibitors have been approved for clinical use, whether they can be repurposed for the treatment of degenerative musculoskeletal diseases needs to be considered. Here, we reviewed the role of EZH2 in the development of degenerative musculoskeletal diseases and brought forward prospects of its pharmacological inhibitors in the improvement of the treatment of the diseases.
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Affiliation(s)
- Zetao Ma
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, People's Republic of China
| | - Lei Chen
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, People's Republic of China; Shantou University Medical College, Shantou 515031, People's Republic of China
| | - Yushun Wang
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, People's Republic of China
| | - Sheng Zhang
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, People's Republic of China
| | - Jianrui Zheng
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, People's Republic of China
| | - Yuhong Luo
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, People's Republic of China
| | - Chao Wang
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, People's Republic of China
| | - Hui Zeng
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, People's Republic of China
| | - Lixiang Xue
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, People's Republic of China.
| | - Zhen Tan
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, People's Republic of China.
| | - Deli Wang
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, People's Republic of China.
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Fei J, Wang H, Han J, Zhang X, Ma H, Qin X, Yu C, Jiang J. TXNIP activates NLRP3/IL-1β and participate in inflammatory response and oxidative stress to promote deep venous thrombosis. Exp Biol Med (Maywood) 2023; 248:1588-1597. [PMID: 37749991 PMCID: PMC10676131 DOI: 10.1177/15353702231191124] [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: 09/11/2022] [Accepted: 04/12/2023] [Indexed: 09/27/2023] Open
Abstract
Increasing evidence indicates that deep venous thrombosis (DVT) is a common peripheral vascular disease. This study aims to investigate the mechanisms of thioredoxin-interacting protein (TXNIP) and nod-like receptor protein 3 (NLRP3) inflammasome in deep venous thrombosis (DVT). A total of 66 Sprague-Dawley (SD) rats were employed to conduct DVT model. DVT rat was treated with silenced TXNIP (si-TXNIP) lentivirus and MCC950 (a NLRP3 inhibitor). The thrombosis weight and weight/length ratio, tissue factor, inflammatory factors, superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) were measured. Hematoxylin-eosin (H&E) staining was used to investigate the pathological change. Western blotting was used to determine the protein expression level. The expression level of thioredoxin (TRx) was suppressed, whereas TXNIP and NLRP3 were elevated in DVT rat. Si-TXNIP or MCC950 could reduce the thrombosis weight and weight/length ratio, ameliorate the pathological change, and decrease inflammatory reaction. Mechanistically, si-TXNIP or MCC950 inhibited the expression levels of TXNIP, NLRP3, and interleukin (IL)-1β while elevating the TRx level, thereby suppressing the DVT. Our study indicated that si-TXNIP or MCC950 injection rescued the injury of vein induced by DVT. The possible mechanisms connected with the inhibition of TXNIP and NLRP3. TXNIP is a possible therapeutic target for DVT.
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Affiliation(s)
- Jianwen Fei
- Department of Pulmonary and Critical Care Medicine, Yantaishan Hospital, Yantai 264000, China
| | - Haixia Wang
- Department of Pulmonary and Critical Care Medicine, Yantaishan Hospital, Yantai 264000, China
| | - Jin Han
- Department of Pulmonary and Critical Care Medicine, Yantaishan Hospital, Yantai 264000, China
| | - Xuefeng Zhang
- Department of Pulmonary and Critical Care Medicine, Yantaishan Hospital, Yantai 264000, China
| | - Hongfu Ma
- Department of Pulmonary and Critical Care Medicine, Yantaishan Hospital, Yantai 264000, China
| | - Xiao Qin
- Department of Pulmonary and Critical Care Medicine, Yantaishan Hospital, Yantai 264000, China
| | - Chaoxiao Yu
- Department of Pulmonary and Critical Care Medicine, Yantaishan Hospital, Yantai 264000, China
| | - Junjie Jiang
- Department of Orthopedics, Yantaishan Hospital, Yantai 264000, China
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Zou K, Zeng Z. Role of early growth response 1 in inflammation-associated lung diseases. Am J Physiol Lung Cell Mol Physiol 2023; 325:L143-L154. [PMID: 37401387 PMCID: PMC10511164 DOI: 10.1152/ajplung.00413.2022] [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: 01/04/2023] [Revised: 05/03/2023] [Accepted: 06/27/2023] [Indexed: 07/05/2023] Open
Abstract
Early growth response 1 (EGR1), which is involved in cell proliferation, differentiation, apoptosis, adhesion, migration, and immune and inflammatory responses, is a zinc finger transcription factor. EGR1 is a member of the EGR family of early response genes and can be activated by external stimuli such as neurotransmitters, cytokines, hormones, endotoxins, hypoxia, and oxidative stress. EGR1 expression is upregulated during several common respiratory diseases, such as acute lung injury/acute respiratory distress syndrome, chronic obstructive pulmonary disease, asthma, pneumonia, and novel coronavirus disease 2019. Inflammatory response is the common pathophysiological basis of these common respiratory diseases. EGR1 is highly expressed early in the disease, amplifying pathological signals from the extracellular environment and driving disease progression. Thus, EGR1 may be a target for early and effective intervention in these inflammation-associated lung diseases.
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Affiliation(s)
- Kang Zou
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical College, Ganzhou, People's Republic of China
- Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
| | - Zhenguo Zeng
- Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
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Zhu HM, Liu N, Sun DX, Luo L. Machine-learning algorithm-based prediction of a diagnostic model based on oxidative stress-related genes involved in immune infiltration in diabetic nephropathy patients. Front Immunol 2023; 14:1202298. [PMID: 37554330 PMCID: PMC10406381 DOI: 10.3389/fimmu.2023.1202298] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 06/29/2023] [Indexed: 08/10/2023] Open
Abstract
Diabetic nephropathy (DN) is the most prevalent microvascular consequence of diabetes and has recently risen to the position of the world's second biggest cause of end-stage renal diseases. Growing studies suggest that oxidative stress (OS) responses are connected to the advancement of DN. This study aimed to developed a novel diagnostic model based on OS-related genes. The differentially expressed oxidative stress-related genes (DE-OSRGs) experiments required two human gene expression datasets, which were given by the GEO database (GSE30528 and GSE96804, respectively). The potential diagnostic genes were identified using the SVM-RFE assays and the LASSO regression model. CIBERSORT was used to determine the compositional patterns of the 22 different kinds of immune cell fraction seen in DN. These estimates were based on the combined cohorts. DN serum samples and normal samples were both subjected to RT-PCR in order to investigate the degree to which certain genes were expressed. In this study, we were able to locate 774 DE-OSRGs in DN. The three marker genes (DUSP1, PRDX6 and S100A8) were discovered via machine learning on two different machines. The high diagnostic value was validated by ROC tests, which focused on distinguishing DN samples from normal samples. The results of the CIBERSORT study suggested that DUSP1, PRDX6, and S100A8 may be associated to the alterations that occur in the immunological microenvironment of DN patients. Besides, the results of RT-PCR indicated that the expression of DUSP1, PRDX6, and S100A8 was much lower in DN serum samples compared normal serum samples. The diagnostic value of the proposed model was likewise verified in our cohort, with an area under the curve of 9.946. Overall, DUSP1, PRDX6, and S100A8 were identified to be the three diagnostic characteristic genes of DN. It's possible that combining these genes will be effective in diagnosing DN and determining the extent of immune cell infiltration.
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Affiliation(s)
- Heng-Mei Zhu
- Department of Nephrology, South China Hospital, Medical School, Shenzhen University, Shenzhen, Guangdong, China
- Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Department of Nephrology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Na Liu
- Department of Nephrology, the Third Hospital of Nanchang, Nanchang, Jiangxi, China
| | - Dong-Xuan Sun
- Department of Nephrology, South China Hospital, Medical School, Shenzhen University, Shenzhen, Guangdong, China
| | - Liang Luo
- Department of Cardiology, Ganzhou People’s Hospital, Ganzhou, China
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Kaverina N, Schweickart RA, Chan GC, Maggiore JC, Eng DG, Zeng Y, McKinzie SR, Perry HS, Ali A, O’Connor C, Pereira BMV, Theberge AB, Vaughan JC, Loretz CJ, Chang A, Hukriede NA, Bitzer M, Pippin JW, Wessely O, Shankland SJ. Inhibiting NLRP3 signaling in aging podocytes improves their life- and health-span. Aging (Albany NY) 2023; 15:6658-6689. [PMID: 37487005 PMCID: PMC10415579 DOI: 10.18632/aging.204897] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 07/06/2023] [Indexed: 07/26/2023]
Abstract
The decrease in the podocyte's lifespan and health-span that typify healthy kidney aging cause a decrease in their normal structure, physiology and function. The ability to halt and even reverse these changes becomes clinically relevant when disease is superimposed on an aged kidney. RNA-sequencing of podocytes from middle-aged mice showed an inflammatory phenotype with increases in the NLRP3 inflammasome, signaling for IL2/Stat5, IL6 and TNF, interferon gamma response, allograft rejection and complement, consistent with inflammaging. Furthermore, injury-induced NLRP3 signaling in podocytes was further augmented in aged mice compared to young ones. The NLRP3 inflammasome (NLRP3, Caspase-1, IL1β IL-18) was also increased in podocytes of middle-aged humans. Higher transcript expression for NLRP3 in human glomeruli was accompanied by reduced podocyte density and increased global glomerulosclerosis and glomerular volume. Pharmacological inhibition of NLRP3 with MCC950, or gene deletion, reduced podocyte senescence and the genes typifying aging in middle-aged mice, which was accompanied by an improved podocyte lifespan and health-span. Moreover, modeling the injury-dependent increase in NLRP3 signaling in human kidney organoids confirmed the anti-senescence effect of MC9950. Finally, NLRP3 also impacted liver aging. Together, these results suggest a critical role for the NLRP3 inflammasome in podocyte and liver aging.
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Affiliation(s)
- Natalya Kaverina
- Division of Nephrology, University of Washington, Seattle, WA 98109, USA
| | - R. Allen Schweickart
- Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA
| | - Gek Cher Chan
- Department of Medicine, Division of Nephrology, National University Hospital, Singapore
| | - Joseph C. Maggiore
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Diana G. Eng
- Division of Nephrology, University of Washington, Seattle, WA 98109, USA
| | - Yuting Zeng
- Department of Chemistry, University of Washington, Seattle, WA 98109, USA
| | - Sierra R. McKinzie
- Division of Nephrology, University of Washington, Seattle, WA 98109, USA
| | - Hannah S. Perry
- Department of Chemistry, University of Washington, Seattle, WA 98109, USA
| | - Adilijiang Ali
- Department of Chemistry, University of Washington, Seattle, WA 98109, USA
| | | | | | | | - Joshua C. Vaughan
- Department of Chemistry, University of Washington, Seattle, WA 98109, USA
- Department of Physiology and Biophysics, University of Washington, Seattle, WA 98109, USA
| | - Carol J. Loretz
- Division of Nephrology, University of Washington, Seattle, WA 98109, USA
| | - Anthony Chang
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA
| | - Neil A. Hukriede
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Markus Bitzer
- Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jeffrey W. Pippin
- Division of Nephrology, University of Washington, Seattle, WA 98109, USA
| | - Oliver Wessely
- Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA
| | - Stuart J. Shankland
- Division of Nephrology, University of Washington, Seattle, WA 98109, USA
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
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Sarwar MS, Cheng D, Peter RM, Shannar A, Chou P, Wang L, Wu R, Sargsyan D, Goedken M, Wang Y, Su X, Hart RP, Kong AN. Metabolic rewiring and epigenetic reprogramming in leptin receptor-deficient db/db diabetic nephropathy mice. Eur J Pharmacol 2023:175866. [PMID: 37331680 DOI: 10.1016/j.ejphar.2023.175866] [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: 07/28/2022] [Revised: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 06/20/2023]
Abstract
BACKGROUND Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the United States. Emerging evidence suggests that mitochondrial metabolism and epigenetics play an important role in the development and progression of DN and its complications. For the first time, we investigated the regulation of cellular metabolism, DNA methylation, and transcriptome status by high glucose (HG) in the kidney of leptin receptor-deficient db/db mice using multi-omics approaches. METHODS The metabolomics was performed by liquid-chromatography-mass spectrometry (LC-MS), while epigenomic CpG methylation coupled with transcriptomic gene expression was analyzed by next-generation sequencing. RESULTS LC-MS analysis of glomerular and cortex tissue samples of db/db mice showed that HG regulated several cellular metabolites and metabolism-related signaling pathways, including S-adenosylmethionine, S-adenosylhomocysteine, methionine, glutamine, and glutamate. Gene expression study by RNA-seq analysis suggests transforming growth factor beta 1 (TGFβ1) and pro-inflammatory pathways play important roles in early DN. Epigenomic CpG methyl-seq showed HG revoked a list of differentially methylated regions in the promoter region of the genes. Integrated analysis of DNA methylation in the promoter regions of genes and gene expression changes across time points identified several genes persistently altered in DNA methylation and gene expression. Cyp2d22, Slc1a4, and Ddah1 are some identified genes that could reflect dysregulated genes involved in renal function and DN. CONCLUSION Our results suggest that leptin receptor deficiency leading to HG regulates metabolic rewiring, including SAM potentially driving DNA methylation and transcriptomic signaling that could be involved in the progression of DN.
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Affiliation(s)
- Md Shahid Sarwar
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - David Cheng
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Rebecca Mary Peter
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Ahmad Shannar
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Pochung Chou
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Lujing Wang
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Renyi Wu
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Davit Sargsyan
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Graduate Program in Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Michael Goedken
- Office of Translational Science, Research Pathology Services, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Yujue Wang
- Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA
| | - Xiaoyang Su
- Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA
| | - Ronald P Hart
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Ah-Ng Kong
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.
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Sklifasovskaya A, Blagonravov M, Azova M, Goryachev V. Myocardial Glutathione Synthase and TRXIP Expression Are Significantly Elevated in Hypertension and Diabetes: Influence of Stress on Antioxidant Pathways. PATHOPHYSIOLOGY 2023; 30:248-259. [PMID: 37368371 DOI: 10.3390/pathophysiology30020021] [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: 05/04/2023] [Revised: 06/01/2023] [Accepted: 06/09/2023] [Indexed: 06/28/2023] Open
Abstract
Antioxidant protection is one of the key reactions of cardiomyocytes (CMCs) in response to myocardial damage of various origins. The thioredoxin interacting protein (TXNIP) is an inhibitor of thioredoxin (TXN). Over the recent few years, TXNIP has received significant attention due to its wide range of functions in energy metabolism. In the present work, we studied the features of the redox-thiol systems, in particular, the amount of TXNIP and glutathione synthetase (GS) as markers of oxidative damage to CMCs and antioxidant protection, respectively. This study was carried out on 38-week-old Wistar-Kyoto rats with insulin-dependent diabetes mellitus (DM) induced by streptozotocin, on 38- and 57-week-old hypertensive SHR rats and on a model of combined hypertension and DM (38-week-old SHR rats with DM). It was found that the amount of TXNIP increased in 57-week-old SHR rats, in diabetic rats and in SHR rats with DM. In 38-week-old SHR rats, the expression of TXNIP significantly decreased. The expression of GS was significantly higher compared with the controls in 57-week-old SHR rats, in DM rats and in the case of the combination of hypertension and DM. The obtained data show that myocardial damage caused by DM and hypertension are accompanied by the activation of oxidative stress and antioxidant protection.
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Affiliation(s)
| | - Mikhail Blagonravov
- Institute of Medicine, RUDN University, 6 Miklukho-Maklaya St., 117198 Moscow, Russia
| | - Madina Azova
- Institute of Medicine, RUDN University, 6 Miklukho-Maklaya St., 117198 Moscow, Russia
| | - Vyacheslav Goryachev
- Institute of Medicine, RUDN University, 6 Miklukho-Maklaya St., 117198 Moscow, Russia
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Chen S, Li B, Chen L, Jiang H. Uncovering the mechanism of resveratrol in the treatment of diabetic kidney disease based on network pharmacology, molecular docking, and experimental validation. J Transl Med 2023; 21:380. [PMID: 37308949 DOI: 10.1186/s12967-023-04233-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/28/2023] [Indexed: 06/14/2023] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD) has been the leading cause of chronic kidney disease in developed countries. Evidence of the benefits of resveratrol (RES) for the treatment of DKD is accumulating. However, comprehensive therapeutic targets and underlying mechanisms through which RES exerts its effects against DKD are limited. METHODS Drug targets of RES were obtained from Drugbank and SwissTargetPrediction Databases. Disease targets of DKD were obtained from DisGeNET, Genecards, and Therapeutic Target Database. Therapeutic targets for RES against DKD were identified by intersecting the drug targets and disease targets. GO functional enrichment analysis, KEGG pathway analysis, and disease association analysis were performed using the DAVID database and visualized by Cytoscape software. Molecular docking validation of the binding capacity between RES and targets was performed by UCSF Chimera software and SwissDock webserver. The high glucose (HG)-induced podocyte injury model, RT-qPCR, and western blot were used to verify the reliability of the effects of RES on target proteins. RESULTS After the intersection of the 86 drug targets and 566 disease targets, 25 therapeutic targets for RES against DKD were obtained. And the target proteins were classified into 6 functional categories. A total of 11 cellular components terms and 27 diseases, and the top 20 enriched biological processes, molecular functions, and KEGG pathways potentially involved in the RES action against DKD were recorded. Molecular docking studies showed that RES had a strong binding affinity toward PPARA, ESR1, SLC2A1, SHBG, AR, AKR1B1, PPARG, IGF1R, RELA, PIK3CA, MMP9, AKT1, INSR, MMP2, TTR, and CYP2C9 domains. The HG-induced podocyte injury model was successfully constructed and validated by RT-qPCR and western blot. RES treatment was able to reverse the abnormal gene expression of PPARA, SHBG, AKR1B1, PPARG, IGF1R, MMP9, AKT1, and INSR. CONCLUSIONS RES may target PPARA, SHBG, AKR1B1, PPARG, IGF1R, MMP9, AKT1, and INSR domains to act as a therapeutic agent for DKD. These findings comprehensively reveal the potential therapeutic targets for RES against DKD and provide theoretical bases for the clinical application of RES in the treatment of DKD.
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Affiliation(s)
- Shengnan Chen
- Department of Critical Care Nephrology and Blood Purification, The First Affiliated Hospital of Xi'an Jiaotong University, West Yanta Road No.277, Xi'an, 710061, Shaanxi, China
| | - Bo Li
- Department of Nephrology, Ningxia Medical University Affiliated People's Hospital of Autonomous Region of Ningxia, Yinchuan, 750002, Ningxia, China
| | - Lei Chen
- Department of Critical Care Nephrology and Blood Purification, The First Affiliated Hospital of Xi'an Jiaotong University, West Yanta Road No.277, Xi'an, 710061, Shaanxi, China
| | - Hongli Jiang
- Department of Critical Care Nephrology and Blood Purification, The First Affiliated Hospital of Xi'an Jiaotong University, West Yanta Road No.277, Xi'an, 710061, Shaanxi, China.
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Kim D, Ban KY, Lee GH, Jun HS. Lysophosphatidic Acid Induces Podocyte Pyroptosis in Diabetic Nephropathy by an Increase of Egr1 Expression via Downregulation of EzH2. Int J Mol Sci 2023; 24:9968. [PMID: 37373116 DOI: 10.3390/ijms24129968] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/04/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Podocyte damage and renal inflammation are the main features and pathogenesis of diabetic nephropathy (DN). Inhibition of lysophosphatidic acid (LPA) receptor 1 (LPAR1) suppresses glomerular inflammation and improves DN. Herein, we investigated LPA-induced podocyte damage and its underlying mechanisms in DN. We investigated the effects of AM095, a specific LPAR1 inhibitor, on podocytes from streptozotocin (STZ)-induced diabetic mice. E11 cells were treated with LPA in the presence or absence of AM095, and the expression of NLRP3 inflammasome factors and pyroptosis were measured. A chromatin immunoprecipitation assay and Western blotting were performed to elucidate underlying molecular mechanisms. Gene knockdown by transfecting small interfering RNA was used to determine the role of the transcription factor Egr1 (early growth response protein 1) and histone methyltransferase EzH2 (Enhancer of Zeste Homolog 2) in LPA-induced podocyte injury. AM095 administration inhibited podocyte loss, NLRP3 inflammasome factor expression, and cell death in STZ-induced diabetic mice. In E11 cells, LPA increased NLRP3 inflammasome activation and pyroptosis via LPAR1. Egr1 mediated NLRP3 inflammasome activation and pyroptosis in LPA-treated E11 cells. LPA decreased H3K27me3 enrichment at the Egr1 promoter in E11 cells by downregulating EzH2 expression. EzH2 knockdown further increased LPA-induced Egr1 expression. In podocytes from STZ-induced diabetic mice, AM095 suppressed Egr1 expression increase and EzH2/H3K27me3 expression reduction. Collectively, these results demonstrate that LPA induces NLRP3 inflammasome activation by downregulating EzH2/H3K27me3 and upregulating Egr1 expression, resulting in podocyte damage and pyroptosis, which may be a potential mechanism of DN progression.
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Affiliation(s)
- Donghee Kim
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Ka-Yun Ban
- College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Republic of Korea
| | - Geon-Ho Lee
- College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Republic of Korea
| | - Hee-Sook Jun
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
- College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Republic of Korea
- Gachon Medical Research Institute, Gil Hospital, Incheon 21565, Republic of Korea
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