The SUR2B/Kir6.1 channel openers iptakalim and natakalim reverse cardiac remodeling and ameliorate endothelial dysfunction by re-establishing the balance between the nitric oxide and endothelin systems. In this study, we investigated the microRNAs (miRs) involved in the molecular mechanisms of SUR2B/Kir6.1 channel opening in chronic heart failure. Both iptakalim and natakalim significantly upregulated the expression of miR-1-3p, suggesting that this miR is closely associated with the therapeutic effects against chronic heart failure. Bioinformatic analysis showed that many of the 183 target genes of miR-1-3p are involved in cardiovascular diseases, suggesting that miR-1-3p plays a vital role in such diseases and vascular remodeling. Target gene prediction showed that miR-1-3p combines with the 3' untranslated region (UTR) of endothelin-1 (ET-1) mRNA. Iptakalim and natakalim upregulated miR-1-3p expression and downregulated ET-1 mRNA expression in vitro. The dual luciferase assay confirmed that there is a complementary binding sequence between miR-1-3p and the 3' UTR 158-165 sequence of ET-1 mRNA. To verify the effect of miR-1-3p on ET-1, lentiviral vectors overexpressing or inhibiting miR-1-3p were constructed for the transduction of rat primary cardiac microvascular endothelial cells. The results showed that natakalim enhanced the miR-1-3p level. miR-1-3p overexpression downregulated the expression of ET-1, whereas miR-1-3p inhibition had the opposite effect. Therefore, we verified that SUR2B/Kir6.1 channel openers could correct endothelial imbalance and ameliorate chronic heart failure through the miR-1-3p/ET-1 pathway in endothelial cells. Our study provides comprehensive insights into the molecular mechanisms behind the SUR2B/Kir6.1 channel's activity against chronic heart failure.

Long term heat exposure (HE) leads to estrous cycle disorder (ECD) in female rats and damages reproductive function. However, the regulation mechanism of vaginal microorganisms and serum metabolomics remains unclear. This study aimed to explore the effects of microbes on the vaginal secretions of rats with ECD and describe the serum metabolomics characteristics and their relationship with vaginal microorganisms. The alterations in the serum levels of neurotransmitters were used to verify the possible regulatory pathways. The relative abundance, composition, and colony interaction network of microorganisms in the vaginal secretions of rats with ECD changed significantly. The metabolomics analysis identified 22 potential biomarkers in the serum including lipid metabolism, amino acid metabolism, and mammalian target of rapamycin and gonadotropin-releasing hormone (GnRH) signaling pathways. Further, 52 pairs of vaginal microbiota–serum metabolites correlations (21 positive and 31 negative) were determined. The abundance of Gardnerella correlated positively with the metabolite L-arginine concentration and negatively with the oleic acid concentration. Further, a negative correlation was found between the abundance of Pseudomonas and the L-arginine concentration and between the metabolite benzoic acid concentration and the abundance of Adlercreutzia. These four bacteria–metabolite pairs had a direct or indirect relationship with the estrous cycle and reproduction. The glutamine, glutamate, and dopamine levels were significantly uncontrolled. The former two were closely related to GnRH signaling pathways involved in the development and regulation of HE-induced ECD in rats. Serum neurotransmitters partly reflected the regulatory effect of vaginal microorganisms on the host of HE-induced ECD, and glutamatergic neurotransmitters might be closely related to the alteration in vaginal microorganisms. These findings might help comprehend the mechanism of HE-induced ECD and propose a new intervention based on vaginal microorganisms.

Objective: Menstrual disorders induced by high-temperature environments, can seriously damage women’s reproductive health and workability. The regulation mechanism underlying it is not yet to be elucidated. Saliva is an information-rich biological fluid that can reflect systemic diseases. Here, we investigated the characteristics of menstrual cycle disorders and saliva metabolomics to provide a deeper insight of the regulation mechanism of young women in high-temperature environments.Methods: Women from high and normal temperature areas of China were selected and divided into two groups—high-temperature (H group) and control (C group). A questionnaire survey was conducted in summer (July) to investigate the incidence rate of menstrual disorders, characteristics of the disorders, and factors influencing the risk of these disorders in different regions. Metabolomics was applied to analyze the characteristics of the salivary metabolites and neurotransmitters in the two groups of women with menstrual disorders.Results: The incidence rate of menstrual disorders was significantly higher in the H group than that in the C group (p < 0.05). High-temperature environment, stress, and sleep quality were identified as critical factors associated with menstrual disorders. Non-targeted saliva metabolomics identified 64 significantly different metabolites between two groups, which mainly enriched in metabolic pathways such as carbohydrate metabolism, membrane transport, digestive system, and nucleotide metabolism (p < 0.05). N-acetylneuraminic acid, MYO, and tyramine may be candidate markers for early diagnosis of menstrual disorders in high temperature environments. Metabolites may be involving in the acute-phase response during an inflammatory process, to affecting the reproductive system by influencing the HPA axis loop. Regulations about oocyte membrane production and the luteal functions would be exerted in menstrual disorders. Targeted metabolomics of neurotransmitters revealed increased expression of histamine (HA) and glutamine and decreased expression of 5-hydroxyindole acetic acid (5-HIAA) (p < 0.05).Conclusion: Menstrual disorder characteristics induced by high temperature environments were specific. Anxiety, sleep quality and temperature feeling were the key factors to the menstrual disorder. endocrine regulation mechanism and inflammatory reactions might contribute to the development of menstrual disorders through influencing the formation of the follicular cell membrane.

High-temperature environments induce menstrual disorders, which can seriously damage women's reproductive health and workability. The regulation mechanism underlying the induction of these disorders at high temperature is yet to be elucidated. Saliva is an information-rich biological fluid that can reflect systemic diseases. Here, we investigated the characteristics of menstrual cycle disorders and saliva metabolomics. Women from high and normal temperature areas of China were selected and divided into two groups—high-temperature (H group) and control (C group). A questionnaire survey was conducted in summer (July) to investigate the incidence rate of menstrual disorders, characteristics of the disorders, and factors influencing the risk of these disorders in different regions. Metabolomics was applied to analyze the characteristics of the salivary metabolites and neurotransmitters in the two groups of women with menstrual disorders.The incidence rate of menstrual disorders was significantly higher in the H group than in the C group (P < 0.05). High-temperature environment, anxiety, pressure, and sleep quality were identified as critical factors associated with menstrual disorders. Non-targeted saliva metabolomics identified 64 significantly different metabolites, which mainly enriched in metabolic pathways such as carbohydrate metabolism, membrane transport, digestive system, and nucleotide metabolism(P < 0.05). Targeted metabolomics of neurotransmitters revealed increased expression of histamine (HA) and glutamine and decreased expression of 5-hydroxyindole acetic acid (5-HIAA) (P < 0.05). Therefore, the incidence rate of menstrual disorder was increased in the H group, which is significantly related to factors such as anxiety and pressure. Changes in metabolites and neurotransmitters indicated that besides mood, endocrine regulation mechanism, inflammatory reactions that affect the formation of the follicular, cell membrane might contribute to the development of menstrual disorders.