AGING CELL
·
2026
·Vol. 25
·期 10
·e70732
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IF 7.7
Lixing Zhou,Ying Cheng,Wanyu Zhao,Xuelian Sun,Fengjuan Hu,Meiling Ge,Yan Zhang,Gongchang Zhang,Birong Dong,Xiaolei Liu
Cognitive impairment (CI) associated with aging and immunosenescence is linked to metabolic alterations. Microglial senescence and dysregulated autophagy have been implicated as major contributors to this process, but the underlying metabolic regulators remain unclear. This study aimed to identify key metabolic regulators of CI and elucidate their underlying mechanisms. Human cohort analyses, older and D‐galactose (D‐gal)‐induced mouse models, and microglial cell models were integrated to investigate the metabolic regulation of CI. Clinical analyses identified ghrelin as the factor most strongly associated with CI. Older and D‐gal mice exhibited CI, microglial senescence, enhanced inflammation, and elevated ghrelin. Ghrelin treatment improved cognitive function, attenuated microglial senescence, and suppressed inflammation, whereas high‐dose ghrelin induced growth hormone secretagogue receptor (GHSR) desensitization. Sex hormone‐binding globulin (SHBG) showed mainly cytoplasmic localization, was identified as a potential mediator of ghrelin signaling in microglia, and its expression was downregulated following ghrelin treatment. Transcriptomic profiling revealed significant enrichment of autophagy‐related pathways in ghrelin‐treated microglia. Ghrelin altered autophagy‐related markers, as indicated by increased Beclin1 and LC3 and decreased p62. SHBG overexpression or JNK1 inhibition attenuated the ghrelin‐induced alterations in autophagy‐related markers and anti‐senescent effects, whereas Beclin1 overexpression partially rescued these inhibitory effects caused by SHBG overexpression. In conclusion, ghrelin alleviated aging‐related CI, with mechanistic evidence indicating that the modulation of microglial autophagy‐related mechanisms through the SHBG/JNK1/Beclin1 axis may contribute to its protective effects, thereby providing a potential therapeutic strategy for aging‐related CI. This study found that aging‐related cognitive impairment is accompanied by hippocampal microglial senescence. Ghrelin suppresses microglial senescence by promoting autophagy through the SHBG/JNK1/Beclin1 axis, thereby alleviating aging‐related cognitive impairment. The graphical abstract was drawn using the Figdraw.
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DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2023
·Vol. 21
·期 1
·1-14
·
IF 7.4
Chen Shengnan,Li Bo,Chen Lei,Jiang Hongli
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.Conclusion sRES 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.
研究领域:
药理学
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分子生物学
·
糖尿病
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肾病学
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DOI
PubMed
高影响因子
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