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Calcium homeostasis plays a vital role in protecting against Alzheimer’s disease (AD). In this study, amyloid-β (Aβ)-induced C. elegans models of AD were used to elucidate the mechanisms underlying calcium homeostasis in AD. Calcium acetate increased the intracellular calcium content, exacerbated Aβ1–42 aggregation, which is closely associated with oxidative stress, aggravated neuronal degeneration and dysfunction, and shortened the lifespan of the C. elegans models. Ethylene glycol tetraacetic acid (EGTA) and nimodipine were used to decrease the intracellular calcium content. Both EGTA and nimodipine showed remarkable inhibitory effects on Aβ1–42 aggregations by increasing oxidative stress resistance. Moreover, both compounds significantly delayed the onset of Aβ-induced paralysis, rescued memory deficits, ameliorated behavioral dysfunction, decreased the vulnerability of two major (GABAergic and dopaminergic) neurons and synapses, and extended the lifespan of the C. elegans AD models. Furthermore, RNA sequencing of nimodipine-treated worms revealed numerous downstream differentially expressed genes related to calcium signaling. Nimodipine-induced inhibition of selective voltage-gated calcium channels was shown to activate other calcium channels of the plasma membrane (clhm-1) and endoplasmic reticulum (unc-68), in addition to sodium-calcium exchanger channels (ncx-1). These channels collaborated to activate downstream events to resist oxidative stress through glutathione S-transferase activity mediated by HPGD and skn-1, as verified by RNA interference. These results may be applied for the treatment of Alzheimer’s disease.

Introduction: 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 via anti-stress pathway and the underlying mechanism by using the nematode Caenorhabditis elegans as an assay system.Methods: Bisphenol A (BPA, 175 μg/mL) was used to establish a fertility-defective C. elegans 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.Results and Discussion: 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 hsf-1-mediated heat-shock signaling pathway. Further analysis showed that the decoction significantly improved the transcriptional levels of hsf-1 downstream target genes, such as hsp-16.1, hsp-16.2, hsp-16.41, and hsp-16.48. Other than hsp-16.2 expression in the gonad, the decoction also affected intestinal hsp-16.2 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 hsp-16.2-mediated heat-shock signaling pathway in C. elegans. These findings reveal the underlying regulatory mechanisms of hsp-16.2-mediated heat resistance against fertility defect.