AUTHOR=Wu Kanglu , Zhao Xudong , Xiao Xian , Chen Miao , Wu Liang , Jiang Chao , Jin Jing , Li Lei , Ruan Qinli , Guo Jun 

TITLE=BuShen HuoXue decoction improves fertility through intestinal hsp-16.2-mediated heat-shock signaling pathway in Caenorhabditis elegans

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1210701

DOI=10.3389/fphar.2023.1210701

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> BuShen HuoXue (BSHX) decoction is commonly used in the clinical treatment of premature ovarian failure because it can increase estradiol level and decrease follicle-stimulating hormone level. In this study, we determined the potential therapeutic effects of BSHX decoction <italic>via</italic> anti-stress pathway and the underlying mechanism by using the nematode <italic>Caenorhabditis elegans</italic> as an assay system.</p><p><bold>Methods:</bold> Bisphenol A (BPA, 175 μg/mL) was used to establish a fertility-defective <italic>C. elegans</italic> model. Nematodes were cultivated according to standard methods. Brood size, DTC, the number of apoptotic cells and oocytes were used to evaluate the fertility of nematodes. Nematodes were cultivated at 35°C as heat stress. RNA isolation and RT-qPCR were used to detect the mRNA expression level of genes. Intestinal ROS and intestinal permeability were used to evaluate the function of intestinal barrier. BSHX decoction was extracted with water and analyzed by LC/Q-TOF.</p><p><bold>Results and Discussion:</bold> In BPA-treated N2 nematodes, 62.5 mg/mL BSHX decoction significantly improved the brood size and the oocytes quality at different developmental stages. BSHX decoction improved resistance to heat stress through the <italic>hsf-1</italic>-mediated heat-shock signaling pathway. Further analysis showed that the decoction significantly improved the transcriptional levels of <italic>hsf-1</italic> downstream target genes, such as <italic>hsp-16.1</italic>, <italic>hsp-16.2</italic>, <italic>hsp-16.41</italic>, and <italic>hsp-16.48</italic>. Other than <italic>hsp-16.2</italic> expression in the gonad, the decoction also affected intestinal <italic>hsp-16.2</italic> expression and significantly reversed the adverse effects induced by BPA. Moreover, the decoction ameliorated intestinal ROS and permeability. Thus, BSHX decoction can improve fertility by increasing intestinal barrier function via <italic>hsp-16.2</italic>-mediated heat-shock signaling pathway in <italic>C. elegans</italic>. These findings reveal the underlying regulatory mechanisms of <italic>hsp-16.2</italic>-mediated heat resistance against fertility defect.</p>