Discovering small-molecule senolytics with deep neural networks

Nature Aging, Год журнала: 2023, Номер 3(6), С. 734 - 750

Опубликована: Май 4, 2023

Язык: Английский

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Oxidative Stress and Cellular Senescence Are Involved in the Aging Kidney

Antioxidants, Год журнала: 2022, Номер 11(2), С. 301 - 301

Опубликована: Янв. 31, 2022

Chronic kidney disease (CKD) can be considered as a clinical model for premature aging. However, non-invasive biomarkers to detect early damage and the onset of senescent phenotype are lacking. Most preclinical senescence studies in aging have been done very old mice. Furthermore, precise characterization over-time development age-related remain unclear. To address these limitations, activation cellular senescence-associated mechanisms their correlation with structural changes were investigated 3- 18-month-old C57BL6 Inflammatory cell infiltration was observed by 12 months, whereas tubular collagen accumulation occurred later. Early cellular-senescence-associated found 12-month-old mice, characterized DNA-damage-response (DDR), mainly cells; antioxidant NRF2 pathway; klotho downregulation. induction tubular-cell-cycle-arrest (CCA) overexpression renal senescent-associated secretory (SASP) components only In both inflammation oxidative stress (marked elevated lipid peroxidation inactivation) remained increased. These findings support hypothesis that prolonged DDR CCA, loss nephroprotective factors (klotho), dysfunctional redox regulatory (NRF2/antioxidant defense) drivers kidney-damage progression.

Язык: Английский

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Screening of immune-related secretory proteins linking chronic kidney disease with calcific aortic valve disease based on comprehensive bioinformatics analysis and machine learning

Journal of Translational Medicine, Год журнала: 2023, Номер 21(1)

Опубликована: Июнь 1, 2023

Chronic kidney disease (CKD) is one of the most significant cardiovascular risk factors, playing vital roles in various diseases such as calcific aortic valve (CAVD). We aim to explore CKD-associated genes potentially involving CAVD pathogenesis, and discover candidate biomarkers for diagnosis CKD with CAVD.Three CAVD, CKD-PBMC CKD-Kidney datasets expression profiles were obtained from GEO database. Firstly, detect key secretory proteins, differentially expressed analysis WGCNA carried out. Protein-protein interaction (PPI), functional enrichment cMAP analyses employed reveal CKD-related pathogenic underlying mechanisms well potential drugs treatment. Then, machine learning algorithms including LASSO regression random forest adopted screening constructing diagnostic nomogram predicting CAVD. Moreover, ROC curve, calibration curve decision applied evaluate performance nomogram. Finally, CIBERSORT algorithm was used immune cell infiltration CAVD.The integrated dataset identified 124 by intersecting differential analyses. Totally 983 proteins screened CKD-PBMC/Kidney datasets. PPI two modules containing 76 nodes, regarded which mostly enriched inflammatory regulation analysis. The exposed metyrapone a more drug 17 overlapped between hub chosen developing ideal through learning. Furthermore, SLPI/MMP9 patterns confirmed our external cohort could serve novel models distinguishing results uncovered dysregulation significantly associated invasive cells.We revealed inflammatory-immune pathways developed SLPI/MMP9-based nomogram, offered insights into future serum-based therapeutic intervention

Язык: Английский

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Cellular Senescence and the Kidney: Potential Therapeutic Targets and Tools

Frontiers in Pharmacology, Год журнала: 2019, Номер 10

Опубликована: Июль 12, 2019

Chronic kidney disease is an increasing health burden (affecting approximately 13.4% of the population). Currently, no curative treatment options are available and focused on limiting progression. Accumulation senescent cells has been implicated in development fibrosis by tissue rejuvenation through secretion pro-fibrotic pro-inflammatory mediators termed senescence-associated secretory phenotype. Clearance aging models results improved function, which shows promise for targeting chronic disease. There several approaches 'senotherapies', most rigorous elimination so called senolytic drugs either newly developed or repurposed off-target effects terms selectively inducing apoptosis cells. Several chemotherapeutics checkpoint inhibitors currently used daily oncological practice show properties. However, applicability such compounds renal diseases hardly investigated. A serious concern that systemic side will limit use senolytics fibrosis. Specifically and/or targeted drug delivery to might circumvent these effects. In this review we discuss connection between senescence, pharmacological cells, means specifically target kidney.

Язык: Английский

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Cellular senescence is associated with reorganization of the microtubule cytoskeleton

Cellular and Molecular Life Sciences, Год журнала: 2018, Номер 76(6), С. 1169 - 1183

Опубликована: Дек. 31, 2018

Язык: Английский

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