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Whole exome sequencing (WES) was used in the research of familial pulmonary arterial hypertension (FPAH). CAV1 and KCNK3 were found as two novel candidate genes of FPAH. However, few pathogenic genes were identified in idiopathic pulmonary arterial hypertension (IPAH). We conducted WES in 20 unrelated IPAH patients that did not carry the known PAH-pathogenic variants among BMPR2, CAV1, KCNK3, SMAD9, ALK1 and ENG. We found a total of 4950 variants in 3534 genes including 4444 SNPs and 506 InDels. Through the comprehensive and multi-level analysis, we disclosed several novel signaling cascades significantly connected to IPAH, including variants related to cadherin signaling pathway, dilated cardiomyopathy, glucose metabolism, immune response, mucin-type O-glycosylation, PLC-activating GPCR signaling pathway, vascular contraction and generation, and voltage-dependent Ca2+ channels. We also conducted validation studies in five mutant genes related to PLC-activating GPCR signaling pathway potentially involved in intracellular calcium regulation through Sanger sequencing for mutation accuracy, qRT-PCR for mRNA stability, immunofluorescence for subcellular localization, western blot for protein level, fura-2 imaging for intracellular calcium and proliferation analysis for cell function. The validation experiments showed that those variants in CCR5 and C3AR1 significantly increased the rise of intracellular calcium and the variant in CCR5 profoundly enhanced proliferative capacity of human pulmonary artery smooth muscle cells. Thus, our study suggests that multiple genetically-affected signaling pathways take effect together to cause IPAH and right heart failure, and may further provide new therapy targets or putative clues for the current treatments such as limited therapeutic effectiveness of Ca2+ channel blockers.Prostate cancer (PCa) is a leading cause of cancer death in men. Despite the anti-proliferation effects of 1α,25-dihydroxyvitamin D3 (1,25-VD) on PCa, accumulating evidence indicates that 1,25-VD promotes cancer progression by increasing genome plasticity. Our investigation of epigenetic changes associated with vitamin D insensitivity found that 1,25-VD treatment reduced the expression levels and activities of DNA methyltransferases 1 and 3B (DNMT1 and DNMT3B). In-silico analysis and reporter assay confirmed that 1,25-VD downregulated transcriptional activation of the DNMT3B promoter and upregulated miRNAs targeting the 3'-UTR regions of DNMT3B. We then profiled DNA methylation in the vitamin D resistant PC-3 cells and a resistant PCa cell model generated by long-term 1,25-VD exposure. Several candidate genes were found to be hypomethylated and overexpressed in vitamin D resistant PCa cells compared to vitamin D sensitive cells. Most of the identified genes were associated with mTOR signaling activation, which is known to promote cancer progression. Among them, we found that inhibition of RPS6KA1 promoted vitamin D sensitivity in PC-3 cells. Furthermore, TCGA prostate cancer dataset demonstrated that MID1 expression is positively correlated with tumor stage. Overall, our study reveals that inhibitory mechanism of 1,25-VD on DNMT3B, which may contribute to vitamin D resistance in PCa.Danger sensing is one of the most fundamental evolutionary features enabling multicellular organisms to perceive potential threats, escape from risky situations, fight actual intruders and repair damage. Several endogenous molecules are used to "signal damage", currently referred to as "alarmins" or "Damage-Associated Molecular Patterns" (DAMPs), most being already present within all cells (pre-formed DAMPs), and thus ready to be released, and others neo-synthesized following injury. Over recent years it has become overwhelmingly clear that adenosine 5'-triphosphate (ATP) is a ubiquitous and extremely efficient DAMP (thus promoting inflammation) and its main metabolite, adenosine, is a strong immunosuppressant (thus dampening inflammation). Extracellular ATP ligates and activates the P2 purinergic receptors (P2Rs) and is then degraded by soluble and plasma membrane ecto-nucleotidases to generate adenosine acting at P1 purinergic receptors (P1Rs). Extracellular ATP, P2Rs, ecto-nucleotidases, adenosine and P1Rs are basic elements of the purinergic signalling network and fundamental pillars of inflammation.More and more evidences advise that circular RNAs (circRNAs) function critically in regulating different disease microenvironments. Our previous study found that autotransplantation of adipose-derived mesenchymal stem cells (ADSCs) promotes diabetes wound healing. Exosomes derived in ADSCs play an important regulatory role. This study aimed to characterize if mmu_circ_0000250 played a role in ADSC-exosomes-mediated full-thickness skin wound repair in diabetic rats. Endothelial progenitor cell (EPCs) were selected to study the therapeutic mechanism of exosomes in high glucose (HG)-induced cell damage and dysfunction. Analysis and luciferase reporter assay were utilized to explore the interaction among mmu_circ_0000250, miRNA (miR)-128-3p and sirtuin (SIRT)1. The diabetic rats were used to confirm the therapeutic effect of mmu_circ_0000250 against exosomes-mediated wound healing. Exosomes containing a high concentration of mmu_circ_0000250 had a greater therapeutic effect on restoration of the function of EPCs by promotion autophagy activation under HG conditions. Expression of mmu_circ_0000250 promoted SIRT1 expression by miR-128-3p adsorption, which was confirmed via luciferase reporter assay and bioinformatics analysis. In vivo, exosomes containing a high concentration of mmu_circ_0000250 had more therapeutic effect on wound healing when compared with wild-type exosomes from ADSCs. Immunohistochemistry and immunofluorescence detection showed that mmu_circ_0000250 increased angiopoiesis with exosome treatment in wound skin and suppressed apoptosis by autophagy activation. https://www.selleckchem.com/products/apcin.html In conclusion, we verified that mmu_circ_0000250 enhanced the therapeutic effect of ADSCs-exosomes to promote wound healing in diabetes by absorption of miR-128-3p and upregulation of SIRT1. Therefore, these findings advocate targeting the mmu_circ_0000250/miR-128-3p/SIRT1 axis as a candidate therapeutic option for diabetic ulcers.
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