Mast cell-derived chymase is implicated in myocardial fibrosis (MF), but the underlying mechanism of intracellular signaling remains unclear. Transforming growth factor-beta 1 (TGF-beta1) is identified as the most important profibrotic cytokine, and Smad proteins are essential, but not exclusive downstream components of TGF-beta 1 signaling. Moreover, novel evidence indicates that there is a cross talk between Smad and mitogen-activated protein kinase (MAPK) signaling cascade. We investigated whether chymase activated TGF-beta 1/Smad pathway and its potential role in MF by evaluating cardiac fibroblasts (CFs) proliferation and collagen synthesis in neonatal rats. MTT assay and 3H-Proline incorporation revealed that chymase induced CFs proliferation and collagen synthesis in a dose-dependent manner. RT-PCR and Western blot assay demonstrated that chymase not only increased TGF-beta1 expression but also upregulated phosphorylated-Smad2/3 protein. Furthermore, pretreatment with TGF-beta 1 neutralizing antibody suppressed chymase-induced cell growth, collagen production, and Smad activation. In contrast, the blockade of angiotensin II receptor had no effects on chymase-induced production of TGF-beta 1 and profibrotic action. Additionally, the inhibition of MAPK signaling had no effect on Smad activation elicited by chymase. These results suggest that chymase can promote CFs proliferation and collagen synthesis via TGF-beta 1/Smad pathway rather than angiotensin II, which is implicated in the process of MF.

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Inflammatory damage plays a pivotal, mainly detrimental role in cerebral ischemic pathogenesis and may represent a promising target for treatment. Naringenin (NG) has gained growing appreciation for its beneficial biological effects through its anti-inflammatory property. Whether this protective effect applies to cerebral ischemic injury, we therefore investigate the potential neuroprotective role of NG and the underlying mechanisms. Focal cerebral ischemia in male Sprague-Dawley rats was induced by permanent middle cerebral artery occlusion (pMCAO) and NG was pre-administered intragastrically once daily for four consecutive days before surgery. Neurological deficit, brain water content and infarct volume were measured at 24 h after stroke. Immunohistochemistry, Western blot and RT-qPCR were used to explore the anti-inflammatory potential of NG in the regulation of NOD2, RIP2 and NF-κB in ischemic cerebral cortex. Additionally, the activities of MMP-9 and claudin-5 were analyzed to detect NG's influence on blood-brain barrier. Compared with pMCAO and Vehicle groups, NG noticeably improved neurological deficit, decreased infarct volume and edema at 24 h after ischemic insult. Consistent with these results, our data also indicated that NG significantly downregulated the expression of NOD2, RIP2, NF-κB and MMP-9, and upregulated the expression of claudin-5 (P < 0.05). The results provided a neuroprotective profile of NG in cerebral ischemia, this effect was likely exerted by down-regulated NOD2, RIP2, NF-κB, MMP-9 and up-regulated claudin-5 expression.

N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic mRNA and potential regulatory functions of m6A have been shown by mapping the RNA m6A modification landscape. m6A modification in active gene regulation manifests itself as altered methylation profiles. The number of reports regarding to the profiling of m6A modification and its potential role in the placenta of preeclampsia (PE) is small. In this work, placental samples were collected from PE and control patients. Expression of m6A-related genes was investigated using quantitative real-time PCR. MeRIP-seq and RNA-seq were performed to detect m6A methylation and mRNA expression profiles. Gene ontology (GO) functional and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were also conducted to explore the modified genes and their clinical significance. Our findings show that METTL3 and METTL14 were up-regulated in PE. In total, 685 m6A peaks were differentially expressed as determined by MeRIP-seq. Altered peaks of m6A-modified transcripts were primarily associated with nitrogen compound metabolic process, positive regulation of vascular-associated smooth muscle cell migration, and endoplasmic reticulum organisation. The m6A hyper-methylated genes of Wnt/β-catenin signalling pathway, mTOR signalling pathway, and several cancer-related pathways may contribute to PE. We also verified that the significant increase of HSPA1A mRNA and protein expression was regulated by m6A modification, suggesting m6A plays a key role in the regulation of gene expression. Our data provide novel information regarding m6A modification alterations in PE and help our understanding of the pathogenesis of PE.

Population admixture results in genome-wide combinations of genetic variants derived from different ancestral populations of distinct ancestry, thus providing a unique opportunity for understanding the genetic determinants of phenotypic variation in humans. Here, we used whole-genome sequencing of 92 individuals with high coverage (30–60×) to systematically investigate genomic diversity in the Uyghurs living in Xinjiang, China (XJU), an admixed population of both European-like and East-Asian-like ancestry. The XJU population shows greater genetic diversity, especially a higher proportion of rare variants, compared with their ancestral source populations, corresponding to greater phenotypic diversity of XJU. Admixture-induced functional variants in EDAR were associated with the diversity of facial morphology in XJU. Interestingly, the interaction of functional variants between SLC24A5 and OCA2 likely influences the diversity of skin pigmentation. Notably, selection has seemingly been relaxed or canceled in several genes with significantly biased ancestry, such as HERC2 – OCA2 . Moreover, signatures of post-admixture adaptation in XJU were identified, including genes related to metabolism (e.g. CYP2D6 ), digestion (e.g. COL11A1 ), olfactory perception (e.g. ANO2 ) and immunity (e.g. HLA ). Our results demonstrated population admixture as a driving force, locally or globally, in shaping human genetic and phenotypic diversity as well as in adaptive evolution.

<b><i>Introduction:</i></b> This study aimed to assess the efficacy of acupuncture in patients with herpes zoster (HZ) based on current randomized clinical trials (RCTs). <b><i>Methods:</i></b> Five databases were screened for RCTs published until August 2019. Studies that assessed the efficacy of acupuncture when used as an independent intervention for HZ were included. The outcomes of interest were pain intensity, as assessed using the visual analog scale (VAS), incrustation time, decrustation time, and incidence of post-herpetic neuralgia (PHN). <b><i>Results:</i></b> In total, 21 RCTs were included in this research. Compared with antiviral therapy, acupuncture was associated with a reduction in VAS score by 16.13, incrustation time by 1.86 days, decrustation time by 2.19 days, and incidence of PHN by 83%. According to a meta-regression analysis, the main sources of heterogeneity were sample size and duration of treatment. There was no publication bias except on decrustation time. A sensitivity analysis showed that the outcomes were relatively stable and reliable. <b><i>Conclusion:</i></b> Acupuncture may be effective for patients with HZ. Nevertheless, this finding should be validated by conducting high-quality trials with a larger sample size.