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Abstract DNA damage is considered to be a potentially unifying driver of ageing, and the stalling of DNA damage repair accelerates the cellular senescence. However, augmenting DNA repair has remained a great challenge due to the intricate repair mechanisms specific for multiple types of lesions. Herein, we miniaturized our modified detecting system for homologous recombination (HR) into a 96-well-based platform and performed a high-throughput chemical screen for FDA-approved drugs. We uncovered that amodiaquine could significantly augment HR repair at the noncytotoxic concentration. Further experiments demonstrated that amodiaquine remarkably suppressed stress-induced premature cellular senescence (SIPS), as evidenced by senescence-associated beta-galactosidase (SA-β-gal) staining or senescence‐related markers p21WAF1 and p16ink4a, and the expression of several cytokines. Mechanistic studies revealed that the stimulation of HR repair by amodiaquine might be mostly attributable to the promotion of SIRT1 at the transcriptional level. Additionally, SIRT1 depletion abolished the amodiaquine‐mediated effects on DNA repair and cellular senescence, indicating that amodiaquine delayed the onset of SIPS via a SIRT1-dependent pathway. Taken together, this experimental approach paved the way for the identification of compounds that augment HR activity, which could help to underscore the therapeutic potential of targeting DNA repair for treating aging-related diseases.

Abstract Background Bleomycin, a potent antitumor agent, is limited in clinical use due to the potential for fatal pulmonary toxicity. The accelerated DNA damage and senescence in alveolar epithelial cells (AECs) is considered a key factor in the development of lung pathology. Understanding the mechanisms for bleomycin-induced lung injury is crucial for mitigating its adverse effects. Methods Human lung epithelial (A549) cells were exposed to bleomycin and subsequently assessed for cellular senescence, DNA damage, and double-strand break (DSB) repair. The impact of Rad51 overexpression on DSB repair and senescence in AECs was evaluated in vitro. Additionally, bleomycin was intratracheally administered in C57BL/6 mice to establish a pulmonary fibrosis model. Results Bleomycin exposure induced dose- and time-dependent accumulation of senescence hallmarks and DNA lesions in AECs. These effects are probably due to the inhibition of Rad51 expression, consequently suppressing homologous recombination (HR) repair. Mechanistic studies revealed that bleomycin-mediated transcriptional inhibition of Rad51 might primarily result from E2F1 depletion. Furthermore, the genetic supplement of Rad51 substantially mitigated bleomycin-mediated effects on DSB repair and senescence in AECs. Notably, decreased Rad51 expression was also observed in the bleomycin‐induced mouse pulmonary fibrosis model. Conclusions Our works suggest that the inhibition of Rad51 plays a pivotal role in bleomycin-induced AECs senescence and lung injury, offering potential strategies to alleviate the pulmonary toxicity of bleomycin.

Objective: Seseli mairei Wolff extracts (SMWE) are widely used to treat psoriasis as a Chinese medicine, but their effect and mechanism are unclear. This study verified the effect of SMWE on psoriasis by regulating Th17 cells. Methods: HaCaT cells were treated with IL-17A in vitro to evaluate the effect of SMWE on psoriasis. In vivo, the mice psoriasis model was established using imiquimod (IMQ, 62.5 mg/d), and intragastrically treated with the different drugs for six days. The severity of skin inflammation was evaluated with Psoriasis Area and Severity Index (PASI) scores and pathology. The levels of inflammation cytokines were assessed with immunofluorescence, immunochemistry, ELISA, and real-time PCR. The number of Th17 cells was determined with flows. Results: SMWE inhibited the proliferation of HaCaT cells and reduced the IL-17A-induced IL-6 production in vitro. In vivo, SMWE deduced the levels of IL-1β, IL-6, IL-8, IL-17A, IL-17F, IL-22, IL-23, and TNF-α, while increasing the level of IL-10 compared to the model group. SMWE also inhibited the levels of NF-κB, JAK2, and STAT3 proteins, while declining the expressions of Gr-1, and MPO. Interestingly, SMWE significantly decreased the number of Th17 cells. Conclusion: SMWE inhibited the proliferation of HaCaT cells and attenuated the development of psoriasis lesions by inhibiting Th17 cells to regulate the levels of inflammation cytokines.