Background: Vonoprazan fumarate is a potassium-competitive acid blocker that was developed as a novel acid-suppressing drug for multiple indications. As a potential alternative to proton-pump inhibitors, the determination of the drug-drug interactions is vital for further applications. Probe drug cocktails are a type of rapid, economical, and efficient approach for evaluating cytochrome P450 enzyme activities. Since vonoprazan is metabolized partly by cytochrome P450, cocktails were used to study CYP-based drug-drug interactions. Methods: This study was conducted both in vitro and in vivo. In the in vitro study of rat liver microsomes, ultra-performance liquid chromatography coupled to tandem mass spectrometry was utilized to assess the reversible inhibition of cytochrome P450 by vonoprazan by determining the concentration of probe drugs (phenacetin, bupropion, tolbutamide, dextromethorphan, midazolam, chlorzoxazone). The differences in the levels of probe drugs between the rat groups with or without vonoprazan administration were also tested in the rats. Results: In vitro analysis revealed that the IC₅₀ values of midazolam, tolbutamide, dextromethorphan, and bupropion in rat microsomes were 22.48, 18.34, 3.62, and 3.68 μM, respectively, while chlorzoxazone and phenacetin displayed no inhibition. In vivo analysis revealed that midazolam, bupropion, dextromethorphan, and tolbutamide showed significant (P < 0.05) differences in distinct pharmacokinetic parameters after vonoprazan administration, while those of chlorzoxazone and phenacetin were not significantly different. Conclusion: The in vitro and in vivo results indicated that vonoprazan can inhibit CYP3A4, CYP2C9, CYP2D6, and CYP2B6, suggesting that the coadministration of vonoprazan with cytochrome P450 substrates should be performed cautiously in clinical settings.

Parkinson’s disease (PD) is the second most common neurodegenerative disease but still lacks a preclinical strategy to identify it. The diagnostic value of intestinal mucosal α-synuclein (αSyn) in PD has not drawn a uniform conclusion. The relationship between the alteration of intestinal mucosal αSyn expression and mucosal microbiota is unclear. Nineteen PD patients and twenty-two healthy controls were enrolled in our study from whom were collected, using gastrointestinal endoscopes, duodenal and sigmoid mucosal samples for biopsy. Multiplex immunohistochemistry was performed to detect total, phosphorylate, and oligomer α-synuclein. Next-generation 16S rRNA amplicon sequencing was applied for taxonomic analysis. The results implied that oligomer α-synuclein (OSyn) in sigmoid mucosa of PD patients was transferred from the intestinal epithelial cell membrane to the cytoplasm, acinar lumen, and stroma. Its distribution feature was significantly different between the two groups, especially the ratio of OSyn/αSyn. The microbiota composition in mucosa also differed. The relative abundances of Kiloniellales, Flavobacteriaceae, and CAG56 were lower, while those of Proteobacteria, Gammaproteobacteria, Burkholderiales, Burkholdriaceae, Oxalobacteraceae, Ralstonia, Massilla, and Lactoccus were higher in duodenal mucosa of PD patients. The relative abundances of Thermoactinomycetales and Thermoactinomycetaceae were lower, while those of Prevotellaceae and Bifidobacterium longum were higher in patients’ sigmoid mucosa. Further, the OSyn/αSyn level was positively correlated with the relative abundances of Proteobacteria, Gammaproteobacteria, Burkholderiales, Pseudomonadales, Burkholderiaceae, and Ralstonia in the duodenal mucosa, while it was negatively correlated with the Chao1 index and observed operational taxonomic units of microbiota in sigmoid mucosa. The intestinal mucosal microbiota composition of PD patients altered with the relative abundances of proinflammatory bacteria in the duodenal mucosa increased. The ratio of the OSyn/αSyn level in the sigmoid mucosa indicated a potential diagnostic value for PD, which also correlated with mucosal microbiota diversity and composition. Key points: • The distribution of OSyn in sigmoid mucosa differed between PD patients and healthy controls. • Significant alterations in the microbiome were found in PD patients’ gut mucosa. • OSyn/αSyn level in sigmoid mucosa indicated a potential diagnostic value for PD.

Autoimmune thyroiditis (AIT), also known as Hashimoto's thyroiditis (HT) or chronic lymphocytic thyroiditis, is a prevalent autoimmune disorder. Despite its high prevalence, the pathogenesis of AIT remains unclear. Previous studies have suggested a potential association between gut microbiota and AIT. However, whether this relationship is causal or coincidental remains uncertain. To address this gap in knowledge, our study aimed to investigate the potential causal association between gut microbiota and AIT using the two-sample Mendelian randomization (MR) method. Summary-level gut microbiota data comprising 211 taxa (131 genera, 35 families, 20 orders, 16 classes, and 9 phyla) were obtained from the comprehensive MiBioGen study. Genetic associations with 22 gastrointestinal diseases were extracted from the UK Biobank, FinnGen study, and various extensive GWAS studies. A meticulous MR analysis was conducted to evaluate the causal relationship between genetically predicted gut microbiota and these gastrointestinal diseases. Sensitivity analyses and tests for heterogeneity were systematically performed to validate the reliability of our findings. Six gut microbiota species showed significant associations with AIT according to the IVW method. Among them, the following exhibited negative associations with AIT: family Alcaligenaceae, family Pasteurellaceae (ID: 3689), family Peptococcaceae, genus Lachnospira, genus Victivallis, and order Pasteurellales (ID: 3688). No evidence of pleiotropy or heterogeneity was detected. The MR analysis uncovered a causal relationship at the genetic prediction level between specific gut microbiota and AIT. These findings offer novel insights into the mechanisms governing the development of AIT mediated by gut microbiota. This knowledge could inform the design of future interventions, potentially involving microbiome-related strategies, to address the mechanisms associated with AIT development.

Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown.To study the interaction mechanism and pharmacokinetics of poziotini...

The increasing incidence of multidrug-resistant (MDR) Salmonella enterica serovar Typhimurium (S. Tm), known for causing invasive enteric infections, presents a significant public health challenge. Given the diminishing efficacy of existing antibiotics, it is imperative to explore novel alternatives for the treatment of MDR S. Tm infections. Here, we identified esculetin (EST), a natural coumarin abundant in dietary foods and herbs, as a compound exhibiting broad-spectrum antibacterial properties against a range of MDR bacteria. Our findings demonstrate that EST effectively inhibited the proliferation and expansion of MDR S. Tm in both in vitro experiments and animal models. Specifically, EST significantly downregulated the type 3 secretion system-1 (T3SS-1) virulence expression of MDR S. Tm, thereby preventing its invasion into intestinal epithelial cells. In S. Tm-infected mice, we observed cecal injury characterized by the upregulation of inflammatory cytokines, a reduction in goblet cell numbers, a decreased expression of tight junction proteins, and microbial dysbiosis. Conversely, EST treatment ameliorated these pathological changes induced by S. Tm infection and reduced oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, thereby improving intestinal barrier function. These results suggest that dietary coumarins or a targeted plant-based diet may offer a promising strategy to counteract MDR bacteria-induced enteric diseases.

Biomarkers are important in the study of tumor processes for early detection and precise treatment. The biomarkers that have been previously detected are not useful for clinical application for primary colorectal carcinoma (PCRC). The aim of this study was to explore clinically valuable biomarkers of PCRC based on integrated bioinformatic analysis. Gene expression data were acquired from the GSE41258 dataset, and the differentially expressed genes were determined between PCRC and normal colorectal samples. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were implemented via Gene Set Enrichment Analysis. A protein-protein interaction (PPI) network was constructed. The significant modules and hub genes were screened and identified in the PPI network. A total of 202 DEGs were identified, including 58 upregulated and 144 downregulated genes in PCRC samples compared to those in normal colorectal samples. Enrichment analysis demonstrated that the gene sets enriched in PCRC were significantly related to bicarbonate transport, regulation of sodium ion transport, potassium ion homeostasis, regulation of telomere maintenance, and other processes. A total of 10 hub genes was identified by cytoHubba: PYY, CXCL3, CXCL11, CXCL8, CXCL12, CCL20, MMP3, P2RY14, NPY1R, and CXCL1. The hub genes, such as NPY1R, P2RY14, and CXCL12, and the electrolyte disequilibrium resulting from the differential expression of genes, especially bicarbonate imbalance, may provide novel insights and evidence for the future diagnosis and targeted therapy of PCRC.