Renoprotective effect of a novel combination of 6-gingerol and metformin in high-fat diet/streptozotocin-induced diabetic nephropathy in rats via targeting miRNA-146a, miRNA-223, TLR4/TRAF6/NLRP3 inflammasome pathway and HIF-1α

被引:5
作者
Aboismaiel, Merna G. [1 ]
Amin, Mohamed N. [1 ]
Eissa, Laila A. [1 ]
机构
[1] Mansoura Univ, Fac Pharm, Dept Biochem, Mansoura 35516, Egypt
关键词
6-Gingerol; Diabetic nephropathy; MiRNA-146a; MiRNA-223; NLRP3; inflammasome; TLR4; NF-KAPPA-B; RENAL FIBROSIS; EPIDEMIOLOGY; EXPRESSION; TISSUE;
D O I
10.1186/s40659-024-00527-9
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
BackgroundMiRNA-146a and miRNA-223 are key epigenetic regulators of toll-like receptor 4 (TLR4)/tumor necrosis factor-receptor-associated factor 6 (TRAF6)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway, which is involved in diabetic nephropathy (DN) pathogenesis. The currently available oral anti-diabetic treatments have been insufficient to halt DN development and progression. Therefore, this work aimed to assess the renoprotective effect of the natural compound 6-gingerol (GR) either alone or in combination with metformin (MET) in high-fat diet/streptozotocin-induced DN in rats. The proposed molecular mechanisms were also investigated.MethodsOral gavage of 6-gingerol (100 mg/kg) and metformin (300 mg/kg) were administered to rats daily for eight weeks. MiRNA-146a, miRNA-223, TLR4, TRAF6, nuclear factor-kappa B (NF-kappa B) (p65), NLRP3, caspase-1, and hypoxia-inducible factor-1 alpha (HIF-1 alpha) mRNA expressions were measured using real-time PCR. ELISA was used to measure TLR4, TRAF6, NLRP3, caspase-1, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1-beta (IL-1 beta) renal tissue levels. Renal tissue histopathology and immunohistochemical examination of fibronectin and NF-kappa B (p65) were performed.Results6-Gingerol treatment significantly reduced kidney tissue damage and fibrosis. 6-Gingerol up-regulated miRNA-146a and miRNA-223 and reduced TLR4, TRAF6, NF-kappa B (p65), NLRP3, caspase-1, TNF-alpha, IL-1 beta, HIF-1 alpha and fibronectin renal expressions. 6-Gingerol improved lipid profile and renal functions, attenuated renal hypertrophy, increased reduced glutathione, and decreased blood glucose and malondialdehyde levels. 6-Gingerol and metformin combination showed superior renoprotective effects than either alone.Conclusion6-Gingerol demonstrated a key protective role in DN by induction of miRNA-146a and miRNA-223 expression and inhibition of TLR4/TRAF6/NLRP3 inflammasome signaling. 6-Gingerol, a safe, affordable, and abundant natural compound, holds promise for use as an adjuvant therapy with metformin in diabetic patients to attenuate renal damage and stop the progression of DN.
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共 106 条
  • [31] [6]-Gingerol Ameliorates ISO-Induced Myocardial Fibrosis by Reducing Oxidative Stress, Inflammation, and Apoptosis through Inhibition of TLR4/MAPKs/NF-κB Pathway
    Han, Xue
    Liu, Panpan
    Liu, Miaomiao
    Wei, Ziheng
    Fan, Sen
    Wang, Xiangting
    Sun, Shijiang
    Chu, Li
    [J]. MOLECULAR NUTRITION & FOOD RESEARCH, 2020, 64 (13)
  • [32] Mesenchymal Stem Cell-Derived Exosomes Carry MicroRNA-125a to Protect Against Diabetic Nephropathy by Targeting Histone Deacetylase 1 and Downregulating Endothelin-1
    Hao, Yan
    Miao, Jie
    Liu, Wenjia
    Cai, Kangqin
    Huang, Xianli
    Peng, Li
    [J]. DIABETES METABOLIC SYNDROME AND OBESITY-TARGETS AND THERAPY, 2021, 14 : 1405 - 1418
  • [33] Hassaballa M, 2022, Egyptian renal data system (ERDS) 2020: an annual report of end-stage kidney disease patients on regular hemodialysis, V22, P1
  • [34] MicroRNA-146 attenuates lipopolysaccharide induced ovarian dysfunction by inhibiting the TLR4/NF- κB signaling pathway
    He, Fengping
    Liu, Yanhui
    Li, Tang
    Ma, Qiulin
    Yongmei, Zhang
    He, Peiqing
    Xiong, Chuanyin
    [J]. BIOENGINEERED, 2022, 13 (05) : 11611 - 11623
  • [35] Epidemiology of and Risk Factors for Type 2 Diabetes in Egypt
    Hegazi, Refaat
    El-Gamal, Mohamed
    Abdel-Hady, Nagy
    Hamdy, Osama
    [J]. ANNALS OF GLOBAL HEALTH, 2015, 81 (06): : 814 - 820
  • [36] 6-gingerol ameliorates gentamicin induced renal cortex oxidative stress and apoptosis in adult male albino rats
    Hegazy, Ahmed M. S.
    Mosaed, Mohammed M.
    Elshafey, Saad H.
    Bayomy, Naglaa A.
    [J]. TISSUE & CELL, 2016, 48 (03) : 208 - 216
  • [37] 6-Gingerol ameliorates sepsis-induced liver injury through the Nrf2 pathway
    Hong, Mu-Keng
    Hu, Lan-Lan
    Zhang, Ya-Xin
    Xu, Yu-Ling
    Liu, Xiao-Yu
    He, Pei-Kun
    Jia, Yu-Hua
    [J]. INTERNATIONAL IMMUNOPHARMACOLOGY, 2020, 80
  • [38] 6-Gingerol attenuates ventilator-induced lung injury via anti-inflammation and antioxidative stress by modulating the PPARγ/NF- κB signalling pathway in rats
    Hong, Wei
    Zhi, Fang Xiang
    Kun, Tu Han
    Hua, Feng Jie
    Ling, Li Huan
    Fang, Fang
    Wen, Chen
    Jie, Wang
    Yang, Li Chao
    [J]. INTERNATIONAL IMMUNOPHARMACOLOGY, 2021, 92
  • [39] Hoogeveen EK., 2022, Epidemiol Diabet Kidney Disease, V2, P433
  • [40] Hyun Bobae, 2013, Immune Netw, V13, P123, DOI 10.4110/in.2013.13.4.123