Uterine contraction is crucial for a successful labor and the prevention of postpartum hemorrhage. It is enhanced by hypoxia; however, its underlying mechanisms are yet to be elucidated. In this study, transcriptomes revealed that hypoxia-inducible factor (HIF)-1α was up-regulated in laboring myometrial biopsies, while blockade of HIF-1α decreased the contractility of the myometrium and myocytes in vitro via siRNA and the inhibitor, 2-methoxyestradiol. Chromatin immunoprecipitation sequencing revealed that HIF-1α directly binds to the genome of contraction-associated proteins: the promoter of GJA1 and PTGS2, and the intron of OXTR. Silencing the HIF-1α reduced the expression of PTGS2, GJA1, and OXTR. Furthermore, blockade of GJA1 or PTGS2 led to a significant decrease in myometrial contractions in the hypoxic tissue model, whereas atosiban did not remarkably influence contractility. Our study demonstrates that HIF-1α is essential for promoting myometrial contractility under hypoxia by directly targeting GJA1 and PTGS2, but not OXTR. These findings help us to better understand the regulation of myometrial contractions under hypoxia and provide a promising strategy for labor management and postpartum hemorrhage treatment.

Despite the expectation that retinoic acid receptor could be the potential therapeutic targets for pancreatic cancers, there has been the lack of information about the role and the impact of retinoic acid receptor gamma (RARγ, RARG) on pancreatic cancer, unlike other two RARs. Herein, we applied TCGA and GEO database to show that the expression and prognosis of RARG is closely related to pancreatic cancer, which demonstrates that RARG is commonly overexpressed in human pancreatic cancer and is an independent diagnostic marker predicting the poor prognosis of pancreatic cancer patients. In addition, we demonstrated that the reduction in the expression of RARG in human pancreatic cancer cells dramatically suppress their proliferation and tumor growth in vivo, partially attributable to the downregulation of tumor-supporting biological processes such as cell proliferation, antiapoptosis and metabolism and the decreased expression of various oncogenes like MYC and STAT3. Mechanistically, RARG binds on the promoters of MYC, STAT3, and SLC2A1 which is distinguished from well-known conventional Retinotic acid response elements (RAREs) and that the binding is likely to be responsible for the epigenetic activation in the level of chromatin, assessed by the measurement of deposition of the gene activation marker histone H3 K27 acetylation (H3K27ac) using ChIP-qPCR. In this study, we reveal that RARG plays important role in the tumorigenesis of pancreatic cancer and represents new therapeutic targets for human pancreatic cancer.

Background The transition of the myometrium from a quiescent to a contractile state during labour is known to involve inflammation, which is characterized by the infiltration of immune cells and the secretion of cytokines. However, the specific cellular mechanisms underlying inflammation in the myometrium during human parturition are not yet fully understood. Methods Through the analysis of transcriptomics, proteomics, and cytokine arrays, the inflammation in the human myometrium during labour was revealed. By performing single‐cell RNA sequencing (scRNA‐seq) and spatiotemporal transcriptomic (ST) analyses on human myometrium in term in labour (TIL) and term in non‐labour (TNL), we established a comprehensive landscape of immune cells, their transcriptional characteristics, distribution, function and intercellular communications during labour. Histological staining, flow cytometry, and western blotting were applied to validate some results from scRNA‐seq and ST. Results Our analysis identified immune cell types, including monocytes, neutrophils, T cells, natural killer (NK) cells and B cells, present in the myometrium. TIL myometrium had a higher proportion of monocytes and neutrophils than TNL myometrium. Furthermore, the scRNA‐seq analysis showed an increase in M1 macrophages in TIL myometrium. CXCL8 expression was mainly observed in neutrophils and increased in TIL myometrium. CCL3 and CCL4 were principally expressed in M2 macrophages and neutrophils‐6, and decreased during labour; XCL1 and XCL2 were specifically expressed in NK cells, and decreased during labour. Analysis of cytokine receptor expression revealed an increase in IL1R2, which primarily expressed in neutrophils. Finally, we visualized the spatial proximity of representative cytokines, contraction‐associated genes, and corresponding receptors in ST to demonstrate their location within the myometrium. Conclusions Our analysis comprehensively revealed changes in immune cells, cytokines, and cytokine receptors during labour. It provided a valuable resource to detect and characterize inflammatory changes, yielding insights into the immune mechanisms underlying labour.

Myometrial contraction is essential for successful delivery. Recent studies have highlighted the vital roles of tissue-derived exosomes in disease diagnostic, prognostic, and therapeutic applications; however, the characteristics of uterine myometrium-derived exosomes are unclear. Here, we successfully isolated exosomes from myometrial tissues, human myometrial smooth muscle cells (HMSMCs), and human umbilical vein endothelial cells (HUVECs), then performed quantitative liquid chromatography-tandem mass spectrometry and miRNA sequencing to investigate the cargo of the exosomes. Fifty-two proteins and five miRNAs were differentially expressed (DE) in term non-labor and term labor myometrium-derived exosomes. Among them, seven proteins (SERPINE1, THBS1, MGAT1, VIM, FGB, FGG, and VWF) were differentially expressed both in the myometrial exosomes and tissues, three miRNAs (miR-363-3p, miR-203a-3p, and miR-205-5p) target 13 DE genes. The top three miRNA derived from HMSMCs (miR-125b-1-3p, miR-337-5p, and miR-503-5p) and HUVECs (miR-663a, miR-4463, and miR-3622a-5p) were identified. Two proteins, GJA1 and SLC39A14, exist in female blood exosomes and are highly expressed in HMSMCs exosomes, are also upregulated in the laboring myometrium, which verified increased in laboring blood samples, might be novel potential biomarkers for myometrial activation. The proteomic and miRNA profile of exosomes derived from laboring myometrium revealed some molecules in the exosomes that affect the intercellular communication and the function of the myometrium.

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