Wenshu Zou,Minyong Zhong,Zerong Pei,Yuxin Chen,Wenwen Deng,Hui Li
Introduction Salmonella -induced colitis is a global health burden characterized by intestinal barrier disruption and deficient epithelial repair that involves a critical interplay between neutrophil dynamics and intestinal stem cell (ISC) regeneration. Current therapies do not target this interplay and do not adequately address therapeutic need. This study investigated the therapeutic mechanism of asiatic acid (AA) in a murine Salmonella typhimurium ( S.T ) infection model, focusing on its effects on the neutrophil-Notch-ISC axis. Methods Balb/c mice were administered S.T for 3 days to model S.T infection AA (10 mg/kg) was gavage administered to mice 6 h after the S.T infection. Neutrophil-deficient mice were generated by daily intraperitoneal injection of Ly6G for 3 days. Results Mouse colons were analyzed histologically, and transcriptomic, network pharmacology, western blotting, and immunohistochemistry investigations were performed. AA restored mucosal integrity by upregulating tight junction proteins (occludin and claudin 1) and acidic mucin granules levels, and by rescuing ISC proliferation through suppression of Notch2/Hes5/Hey1 signaling. Multiomics analyses further revealed the modulation of neutrophil chemotaxis and inflammatory pathways by AA. Strikingly, neutrophil ablation reduced the efficacy of AA, confirming that AA acts via neutrophil-mediated containment of bacterial invasion and epithelial shedding. Discussion By revealing the neutrophil-Notch2-ISC axis as a pivotal regulator of mucosal repair, our findings show AA to be a dual-action therapeutic agent that synergizes immune containment and regenerative pathways. These findings highlight an aspect of S.T pathogenesis and underscore the potential of natural compounds to harmonize host defense and tissue regeneration, offering a transformative strategy for infectious colitis beyond conventional anti-inflammatory approaches
Estrogen plays an essential role in the development of mammalian oocytes, and recent studies suggest that it also regulates primordial follicle assembly in the neonatal ovaries. During the last decade, potential exposure of humans and animals to estrogen-like endocrine disrupting chemicals has become a growing concern. In the present study, we focused on the effect of diethylhexyl phthalate (DEHP), a widespread plasticizer with estrogen-like activity, on germ-cell cyst breakdown and primordial follicle assembly in the early ovarian development of mouse. Neonatal mice injected with DEHP displayed impaired cyst breakdown. Using ovary organ cultures, we revealed that impairment was mediated through estrogen receptors (ERs), as ICI 182,780, an efficient antagonist of ER, reversed this DEHP-mediated effect. DEHP exposure reduced the expression of ERβ, progesterone receptor (PR), and Notch2 signaling components. Finally, DEHP reduced proliferation of pregranulosa precursor cells during the process of primordial folliculogenesis. Together, our results indicate that DEHP influences oocyte cyst breakdown and primordial follicle formation through several mechanisms. Therefore, exposure to estrogen-like chemicals during fetal or neonatal development may adversely influence early ovarian development.
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