Causal relationship between blood metabolites and risk of five infections: a Mendelian randomization study.

OBJECTIVE: Infectious diseases continue to pose a significant threat in the field of global public health, and our understanding of their metabolic pathogenesis remains limited. However, the advent of genome-wide association studies (GWAS) offers an unprecedented opportunity to unravel the relationship between metabolites and infections. METHODS: Univariable and multivariable Mendelian randomization (MR) was commandeered to elucidate the causal relationship between blood metabolism and five high-frequency infection phenotypes: sepsis, pneumonia, upper respiratory tract infections (URTI), urinary tract infections (UTI), and skin and subcutaneous tissue infection (SSTI). GWAS data for infections were derived from UK Biobank and the FinnGen consortium. The primary analysis was conducted using the inverse variance weighted method on the UK Biobank data, along with a series of sensitivity analyses. Subsequently, replication and meta-analysis were performed on the FinnGen consortium data. RESULTS: After primary analysis and a series of sensitivity analyses, 17 metabolites were identified from UK Biobank that have a causal relationship with five infections. Upon joint analysis with the FinGen cohort, 7 of these metabolites demonstrated consistent associations. Subsequently, we conducted a multivariable Mendelian randomization analysis to confirm the independent effects of these metabolites. Among known metabolites, genetically predicted 1-stearoylglycerol (1-SG) (odds ratio [OR] = 0.561, 95% confidence interval [CI]: 0.403-0.780, P < 0.001) and 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) (OR = 0.780, 95%CI: 0.689-0.883, P < 0.001) was causatively associated with a lower risk of sepsis, and genetically predicted phenylacetate (PA) (OR = 1.426, 95%CI: 1.152-1.765, P = 0.001) and cysteine (OR = 1.522, 95%CI: 1.170-1.980, P = 0.002) were associated with an increased risk of UTI. Ursodeoxycholate (UDCA) (OR = 0.906, 95%CI: 0.829-0.990, P = 0.029) is a protective factor against pneumonia. Two unknown metabolites, X-12407 (OR = 1.294, 95%CI: 1.131-1.481, P < 0.001), and X-12847 (OR = 1.344, 95%CI: 1.152-1.568, P < 0.001), were also identified as independent risk factors for sepsis. CONCLUSIONS: In this MR study, we demonstrated a causal relationship between blood metabolites and the risk of developing sepsis, pneumonia, and UTI. However, there was no evidence of a causal connection between blood metabolites and the risk of URTI or SSTI, indicating a need for larger-scale studies to further investigate susceptibility to certain infection phenotypes.

High expression of Ran binding protein 1 predicts poor outcomes in hepatocellular carcinoma patients: a Cancer Genome Atlas database analysis.

BACKGROUND: Ran-specific binding protein 1 (RANBP1) is involved in the regulation of the cell cycle, while its role in hepatocellular carcinoma (HCC) is unknown. Therefore, we aimed to demonstrate the association of RANBP1 with clinicopathologic features and potential biological functions in HCC based on The Cancer Genome Atlas (TCGA) data. METHODS: We assessed RANBP1 expression and its correlation with clinicopathologic features and evaluated the prognostic value of RANBP1 with Kaplan-Meier survival analysis and the MethSurv database. Univariate and multivariate Cox regression analyses were conducted to elucidate the factors responsible for prognosis. The identification of a co-expression network and the analysis of related biological events with RANBP1 in HCC were assessed using LinkedOmics. Moreover, gene set enrichment analysis (GSEA) was employed to annotate the biological function of RANBP1. We also explored the correlation between RANBP1 and tumor immune infiltrates using a single sample GSEA (ssGSEA). RESULTS: The expression of RANBP1 was found significantly elevated in HCC and linked to advanced T stage and histopathological grade. Up-regulated RANBP1 expression was linked to poor prognosis. High DNA methylation levels of RANBP1 were significantly linked to very poor overall survival (OS). Co-expression network analysis revealed that RANBP1 was involved in ribosome, spliceosome, deoxyribonucleic acid (DNA) replication, ribonucleic acid (RNA) transport, and cell cycle. GSEA showed enrichment of G2M-checkpoint, Wingless and Int-1 (Wnt) cell signaling, and DNA repair in the RANBP1 high-expression phenotype. By using ssGSEA analysis, the increased RANBP1 expression was positively linked to the immune infiltration level of T helper cell type-1 (Th1) and negatively linked to the immune infiltration levels of T helper cell type-17 (Th17). CONCLUSIONS: Findings suggest that RANBP1 may play a pivotal role in HCC prognosis and can potentially serve as a candidate biosignature and as a therapeutic target for HCC.

The microRNA miR-19a-3p suppresses cell growth, migration, and invasion in multiple myeloma via the Wnt/ß-catenin pathway.

BACKGROUND: MicroRNAs have been suggested as potential regulators in the development of multiple myeloma (MM) through affecting the expression of their target genes. This study aimed to investigate the effects of miR-19a-3p in MM, and its underlying mechanisms in regulating cell proliferation and invasion. METHODS: Bone marrow samples from 25 MM patients and 12 healthy donors were collected and miR-19a-3p and Wnt1 mRNA expression was assessed. The effects of miR-19a-3p on cell proliferation, migration, and invasion in U226 and RPMI-8226 MM cells were evaluated by miR-19a-3p overexpression. Luciferase assays were performed to explore the potential target genes. Knock down or overexpression of Wnt1 was used to explore the effects of miR-19a-3p on cell growth, migration, and invasion. RESULTS: The expression of miR-19a-3p was downregulated in MM and cell lines, while Wnt1 mRNA levels were increased. Overexpression of miR-19a-3p inhibited cell proliferation, migration, and invasion in U226 and RPMI-8226 cells. Additionally, western blot assays revealed that miR-19a-3p could suppress Wnt1, ß-catenin, cyclin D1, and c-Myc expression. Knockdown of Wnt1 also inhibited cell growth, migration, and invasion. Moreover, luciferase reporter assay revealed direct binding between Wnt1 and miR-19a-3p. Wnt1 overexpression partially reversed the suppressive effects of miR-19a-3p on cell proliferation, migration, and invasion in U266 cells. CONCLUSIONS: The expression of miR-19a-3p was downregulated in MM patients and MM cell lines. Overexpression of miR-19a-3p inhibited proliferation, migration, and invasion by targeting Wnt1 via the Wnt/ß-catenin signaling pathway.