Journal of Biomedical Research最新文献

Hepatocellular carcinoma (HCC) remains the third leading cause of cancer-related deaths worldwide; however, its therapeutic options are limited. Understanding the molecular mechanisms of HCC could provide insight into new therapies. Emerging studies indicate the important role of long-noncoding RNAs (lncRNAs) in the pathogenesis of HCC. The expression of the well-studied lncRNA taurine upregulated gene 1 ( TUG1) is upregulated in HCC tissues, but its transcriptomic effects in HCC cells remain unexplored. We established TUG1-knockdown and control HCC cells for RNA-seq experiments. KEGG analysis revealed glycolysis as the top enriched pathway upon TUG1 silencing. Accordingly, TUG1-depleted HCC cells showed impairments in glucose uptake, ATP synthesis, and lactate production. Clinical HCC tissue data revealed positive gene expression correlations between TUG1 and several glycolysis-related genes. To identify a molecular function of TUG1 in glycolysis, we explored the competing endogenous model and used bioinformatic tools to find the five microRNAs (miRNAs) that had the most binding sites for TUG1. Among these miRNAs, miR-122-5p exhibited an inverse correlation in gene expression with most TUG1-regulated glycolysis genes, including PKM, ALDOA, ENO2, and PFKM. Dual-luciferase assays demonstrated the direct interaction between TUG1 and miR-122-5p and between miR-122-5p and the 3' untranslated regions of both PKM and ALDOA. We further showed that inhibition of miR-122-5p alleviated the suppression of glycolysis induced by TUG1 depletion. Together, our RNA-seq analysis of TUG1-depleted HCC cells, combined with clinical data, reveals a critical role of TUG1 in regulating glycolysis and provides new insight into its oncogenic function in HCC.

This study investigated differences in reproductive outcomes and vaginal microbiota profiles between two endometrial preparation protocols-letrozole (LE) combined with human menopausal gonadotropin (HMG) and hormone replacement therapy (HRT) with GnRH-a pretreatment-in women with endometriosis (EMs) undergoing frozen embryo transfer (FET). Following 1∶1 propensity score matching, a total of 770 FET cycles were analyzed. No statistically significant differences were observed in live birth rates or clinical pregnancy rates between the two groups. However, the LE + HMG group showed a lower miscarriage trend (13.7% vs. 19.8%, P = 0.070) and significantly fewer cesarean deliveries (64.9% vs. 75.4%, P = 0.020) and hypertensive disorders of pregnancy (4.8% vs. 10.1%, P = 0.039). Recent evidence suggests that GnRH-a treatment may disrupt reproductive tract microbiota. Given ethical constraints on endometrial sampling during FET, vaginal microbiota was used as a surrogate to explore microbial differences between protocols. In the prospective arm, vaginal samples from 55 women in the LE + HMG group and 50 in the GnRH-a HRT group were analyzed using 16S rRNA sequencing and droplet digital PCR. While no significant differences were observed in Lactobacillus or Gardnerella abundance, the GnRH-a HRT group exhibited enrichment of potential pathogens, such as Escherichia-Shigella and Staphylococcus. In conclusion, although both protocols achieved comparable live birth outcomes, the LE + HMG regimen was associated with fewer obstetric complications and a more favorable vaginal microbiota profile compared to GnRH-a HRT.

Gastric cancer (GC) is a prevalent and devastating disease with a poor prognosis. The lack of biomarkers for early detection and effective targeted therapeutics for GC patients represents two major challenges. Through isobaric tags for relative and absolute quantitation (iTRAQ) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) phosphoproteomic analysis of 14 GC and gastric epithelial cell lines, we discovered the discoidin domain receptor tyrosine kinase 1 (DDR1) as a top potential drug target out of 40 tyrosine kinases detected along with over 1000 phosphoproteins profiled. The DDR1 protein and mRNA levels were upregulated in GC cells concurrent with DDR1 gene amplification. Immunohistochemistry staining of more than 200 clinical samples revealed that DDR1 was overexpressed in approximately 41% and 48% of the intestinal and diffuse types of GC cases, respectively, compared with only 3.5% in normal tissues. Higher DDR1 expression was associated with poor prognosis. In cellular models, DDR1 overexpression led to accelerated proliferation, invasion, and malignant transformation, putatively via inhibition of the Hippo pathway and consequent activation of YAP-TEAD target gene expression. Notably, DDR1-overexpressing GC cells exhibited high vulnerability to selective DDR1 inhibitors. The present study provides preclinical support for the application of DDR1-selective inhibitors in DDR1-overexpressing GC.

The comorbidity of skin and gastrointestinal tract (GIT) diseases, primarily driven by the gut-skin axis (GSA), is well-known. However, the genetic contribution to the GSA remains unclear. Here, using genome-wide association study (GWAS) summary statistics from European populations, we performed genome-wide pleiotropic analysis to investigate the shared genetic basis and causal associations between skin and GIT diseases. We observed extensive genetic correlations and overlaps between skin and GIT diseases. A total of 298 pleiotropic loci were identified, 75 of which were colocalized, and 61 exhibited pleiotropic effects across multiple trait pairs, including 2p16.1 ( PUS10), 6p21.32 ( HLA-DRB1), 10q21.2 ( ZNF365), and 19q13.11 ( SLC7A10). Additionally, five novel loci were identified based on the pleiotropic analysis, with RORA at 15q22.2 validated by the latest inflammatory bowel disease GWAS. Gene-based analysis found 394 unique pleiotropic genes, which were enriched in GSA-associated tissues and immune system, whereas protein-protein interaction analysis further revealed the GPCR-cAMP, chromatin remodeling, JAK-STAT, and HLA-mediated immunity pathways coregulate GSA comorbidity. Notably, the JAK-STAT pathway showed strong potential in drug repurposing, with Adalimumab targeting TNF and Ustekinumab targeting IL-12B already used to treat both skin and GIT diseases. Finally, Mendelian randomization analysis suggested five significant causal associations, and subsequent mediation analysis introduced three potential microbiota-GIT-skin pathways. Taken together, our study suggested that the shared genetic factors between skin and GIT diseases are widely distributed across the genome. These findings will improve our understanding of the genetic basis of GSA and offer significant implications for simultaneously treating skin and GIT diseases.

Mosquito-borne diseases pose a significant global health threat, necessitating novel vector control strategies. This study explores the potential of harnessing the host immunity against mosquitoes through vaccination. Using Culex pipiens ( C. pipiens) as the study model, we found polyclonal antibodies against C. pipiens abdomen significantly compromised the mosquito oviposition and increased mosquito mortality, primarily through the classical complement activation pathway. However, repeated exposure led to resistance, indicating potential adaptation. Proteomic analysis identified metabolic proteins as key targets, with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses highlighting their roles in carboxylic acid metabolism, tyrosine degradation, and proteasome pathways. Intriguingly, cross-species reactivity was confirmed via Western blot, showing strong binding of Culex-specific antibodies to Anopheles and Aedes abdominal proteins. This study provides mechanistic insights into antibody-based mosquito suppression, highlighting its feasibility as a novel vector control strategy while underscoring the need for further research on resistance management and ecological impacts.

Neuromuscular electrical stimulation (NMES) is a well-established therapeutic approach for chronic wounds. Conventionally, NMES involves direct electrode contact with wounds or adjacent healthy skin; however, it is limited by the need for wound exposure and increased pain. Our preliminary study demonstrated the innovative application of remote NMES (rNMES) to the skeletal muscle of the distal calf, demonstrating the potential to accelerate wound healing in remote areas. rNMES is effective in human clinical trials in our previous work, although the underlying mechanisms remain unclear. As rNMES is often used to stimulate muscle contraction in long-term bedridden patients, we analyzed GEO database data and found that exercise promotes midkine (MDK) expression in muscle, a small secreted heparin-binding protein that interacts with multiple cell surface receptors to promote growth. MDK significantly enhanced macrophage efferocytosis in a low-density lipoprotein receptor-related protein 1 (LRP1)-dependent manner. Our findings demonstrate that rNMES upregulates MDK expression in skeletal muscles through the AMPK-ERK axis, facilitating its delivery to wounds through the circulatory system and promoting LRP1-mediated efferocytosis of apoptotic cells, thereby expediting wound healing.

As the prevalence of obesity increases dramatically, obesity-associated cardiac dysfunction constitutes a considerable challenge to human health. This study aimed to identify more useful lipid/inflammatory markers to predict the risk of obesity-associated cardiac dysfunction. By retrospectively analyzing the clinical characteristics of 5648 cardiac disease patients, we found that both the plasma level of high-density lipoprotein cholesterol (HDL-C) and the blood monocyte count were significantly associated with impairment of the left ventricular ejection fraction (LVEF). Univariate and multivariate regression analyses revealed that the monocyte to HDL-C ratio (MHR) was a more powerful predictor of the risk of LVEF decline than either HDL-C or monocyte alone. Mediation analysis further revealed a mediating effect of a high MHR on the decline in obesity-associated cardiac systolic function. Collectively, our results demonstrate a superior role of MHR in predicting the risk of an obesity-associated decline in cardiac systolic function among routine metabolic/inflammatory markers.

Acute kidney injury (AKI) is a critical condition with limited effective therapies. Akkermansia muciniphila ( A. muciniphila) is a probiotic with multiple beneficial effects, including the regulation of epithelial cell tight junctions. Since renal pathophysiology is associated with gut barrier integrity, we hypothesized that A. muciniphila may have preventive effects on AKI. We established a lipopolysaccharide (LPS)-induced AKI mouse model to evaluate the effects of A. muciniphila. Our findings showed that pretreatment with A. muciniphila significantly attenuated kidney injury, as evidenced by reduced serum creatinine and urea nitrogen levels, alongside decreased tubular necrosis and apoptosis. A. muciniphila preserved intestinal barrier integrity and induced marked shifts in gut microbial ecology and the metabolome. A. muciniphila notably induced an increase in the relative abundance of the phylum Proteobacteria while decreasing in that of the phylum Bacteroidetes. At the genus level, Prevotella, Faecalibaculum, Moraxella, and Lactobacillus were more abundant in A. muciniphila-pretreated mice. Metabolomic analysis revealed that A. muciniphila altered the gut metabolome, with changes involving pathways such as tyrosine metabolism, alanine/aspartate/glutamate homeostasis, cancer-related carbon flux, and GABAergic synaptic signaling. In conclusion, our findings indicate that A. muciniphila exerts renoprotective effects by modulating the gut-kidney axis, thereby establishing a foundation for future studies to explore the connection between gut microbiota and AKI.