Hereditas最新文献

Background: Luoshi Neiyi prescription (LSNYP) is a traditional Chinese medicine that has a clinical effect on endometriosis (EMs). This study combined network pharmacology with experimental validation to explore its potential molecular mechanisms.

Methods: The primary components of LSNYP were identified based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and a Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). The possible target proteins were predicted using the SwissTargetPrediction online tool. The GeneCards and DisGeNET databases were used to identify targets associated with EMs. The protein-protein interaction (PPI) network, herb-component-target network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Molecular docking, molecular dynamics (MD) simulation and experimental verification were carried out.

Results: 217 potential therapeutic targets were identified. Enrichment analyses revealed involvement in key biological processes and pathways, including cell migration, inflammatory response, focal adhesion, and the VEGF signaling pathway, which are closely related to the adhesion-invasion-angiogenesis progression in EMs pathogenesis. Molecular docking and MD simulation results showed stable binding between corresponding components and typical targets (ICAM1, MMP9 and VEGFA) involved in the progression. Experimental results demonstrated that LSNYP could decrease typical targets of the progression in rats and inhibit the invasion, migration and adhesion capabilities of human endometriotic stromal cells (ESCs).

Conclusion: These findings suggest LSNYP may be a promising candidate for EMs, potentially through inhibiting the adhesion-invasion-angiogenesis progression.

Background: Epiphycan (EPYC) has been confirmed to play an oncogenic role in many cancers. However, its role and mechanism in gastric cancer (GC) progression has not been explored.

Methods: The levels of EPYC and NOP2/Sun domain 2 (NSUN2) were detected by qRT-PCR and western blot. Cell proliferation, apoptosis, migration and invasion were determined by cell counting kit 8 assay, colony formation assay, flow cytometry, wound healing assay and transwell assay. Fe²⁺ and iron levels were examined to assess cell ferroptosis. Actinomycin D assay was used to detect the effect of NSUN2 knockdown on EPYC mRNA stability, and methylated RNA immunoprecipitation (MeRIP) assay was performed to determine the effect of NSUN2 silencing on 5-methylcytosine (m5C) level of EPYC. Xenograft tumors were constructed to explore the regulation of NSUN2 knockdown on GC tumorigenesis in vivo.

Results: EPYC was abnormally higher expressed in GC tissues and cells. Knockdown of EPYC restrained GC cell proliferation, migration and invasion, while enhanced apoptosis and ferroptosis. NSUN2 had elevated expression in GC, which could increase the mRNA stability and expression of EPYC through m5C modification. NSUN2 silencing inhibited GC cell proliferation, metastasis, promoted apoptosis and ferroptosis, while these effects were reversed by EPYC overexpression. In vivo experiments revealed that NSUN2 downregulation reduced GC tumorigenesis by decreasing EPYC level in vivo.

Conclusion: NSUN2-mediated m5C modification of EPYC contributed to GC cell growth and metastasis, which provided a novel regulatory axis for understanding the pathogenesis of GC.

Background: The role of cholesterol metabolism in IgA nephropathy (IgAN) remains poorly understood.

Methods: We applied a multi-omics integrative framework to systematically identify key regulatory genes. This approach combined genome-wide association study (GWAS), summary-data-based mendelian randomization (SMR), conventional MR, Bayesian colocalization, single-cell RNA sequencing (scRNA-seq), bulk transcriptome validation, molecular docking, and molecular dynamics simulations.

Results: ACOX2 was identified as a protective hub gene. Genetic analyses revealed an inverse association between ACOX2 expression and IgAN risk (OR = 0.917, 95% CI: 0.879-0.957; PPH4 = 90.75%). scRNA-seq demonstrated the downregulation of ACOX2 in proximal tubular cells, which was further confirmed in external datasets. Molecular docking and molecular dynamics simulation suggested flavin adenine dinucleotide (FAD) as a potential therapeutic ligand targeting ACOX2.

Conclusion: This study uncovers a cholesterol metabolism-related regulatory axis in IgAN, establishes ACOX2 as a protective biomarker, and highlights a therapeutically actionable pathway; it provides mechanistic insights and translational opportunities for biomarker development and drug discovery.

Hepatic ischemia-reperfusion (I/R) injury is an unavoidable process in liver surgeries like transplantation and hepatectomy, and it greatly impairs postoperative liver function. Recent studies have shown that anesthetic agents, such as remifentanil, offer liver protection. However, the exact mechanisms of remifentanil's protective effects remain unclear. In this study, a rat hepatic I/R injury model and a hepatocyte BRL-3 A hypoxia/reoxygenation (H/R) model were successfully established, and remifentanil preconditioning (RPC) was administered. Liver function enzyme activities were measured using biochemical assays, and the extent of liver damage was assessed via HE staining as well as TUNEL staining. The survival rate and apoptosis rate of BRL-3 A cells were determined by CCK-8 assay and flow cytometry, respectively. Levels of proinflammatory cytokines were quantified using ELISA. qRT-PCR and Western blotting analysis were employed to evaluate the expression of α7 nicotinic acetylcholine receptor (α7nAChR) and the phosphorylation of NF-κB. Loss-of- function experiments of α7nAChR were conducted to further elucidate the underlying molecular mechanism by which remifentanil protects the liver against I/R injury. The findings demonstrated that RPC markedly mitigated liver dysfunction, decreased hepatic cell necrosis and apoptosis, and suppressed the inflammation in rats subjected to I/R. Furthermore, RPC provided protection for BRL-3 A cells against H/R-induced injury and inflammation. Notably, RPC upregulated α7nAChR expression in I/R liver tissue and H/R-exposed BRL-3 A cells while concurrently inhibiting NF-κB phosphorylation. However, the protective effects of RPC on hepatic I/R injury and H/R-induced BRL-3 A cells injury were abrogated by the administration of an α7nAChR antagonist or α7nAChR knockdown. Taken together, these data reveal a novel mechanism of remifentanil's hepatoprotective effect, which is that remifentanil alleviates hepatic I/R injury by upregulating α7nACh to inhibit inflammation mediated by NF-κB activation.

Background: The microRNA expression profile in the bodily fluids of individuals with acute pancreatitis (AP) undergoes considerable alterations; nevertheless, the precise mechanism requires more elucidation.

Methods: A dataset of 2083 human blood microRNAs (miRNAs) was obtained from the miRNA expression quantitative loci data. The genome-wide association study data for AP was obtained from the FinnGen Consortium. The causal association between miRNA and susceptibility to AP was evaluated using the Mendelian randomization (MR) method. Receiver operating characteristic (ROC) curve analyses were implemented to assess the miRNA's clinical usefulness. The GSE188819 and GSE249349 datasets were analyzed to determine changes in cell subset amounts and differentially expressed genes during the advancement and regression of AP mice. We assessed the inhibitory impact of miR-27b-3p and miR-193a-5p overexpression on AR42J cell and RAW 264.7 cell inflammation using western blot.

Results: Following a thorough process of genetic variation selection, MR analysis, and sensitivity analysis, we identified 66 miRNAs with suggestive causality to AP susceptibility. We conducted ROC curve analysis on 66 variables, identifying 6 miRNAs that have the potential to diagnose AP. Six and twelve cell subsets were identified from the GSE249349 and GSE188819 datasets, respectively. In the inflammatory advancement stage, the percentage of acinar cells in the AP group decreased relative to the control group samples. In the inflammatory regression phase, the percentage of monocytes in the AP (96 h) group decreased relative to the AP (12 h) group. In vitro, experiments have found that the overexpression of miR-27b-3p and miR-193a-5p in RAW 264.7 cells AR42J cells significantly inhibited the protein expression of p-P65.

Conclusion: Our research identified novel miRNAs associated with the pathogenesis of AP. In vitro experiments have confirmed that miR-27b-3p and miR-193a-5p can inhibit the inflammatory response in RAW 264.7 cells and AR42J cells.