Pinocembrin (PIN) is a natural flavonoid widely found in bee propolis with potent gastrointestinal protective effects. In consequence, PIN has great potential in preventing inflammatory bowel diseases (IBDs) while scant information is available. In this study, a dextran sulfate sodium (DSS)-induced rats ulcerative colitis model (3.5% DSS in drinking water for 7 days) was applied to explore the protective effects of PIN on macroscopic colitis symptoms, inflammation, intestinal epithelial barrier function, and gut microbiota homeostasis. While DSS-treated rats showed severe colitis clinical symptoms and histological changes (colonic pathological damages and intestinal goblet cells loss), pre-administration of PIN (5 and 10 mg/kg, p.o.) for a week alleviated these symptoms. Pre-administration of PIN also suppressed the pro-inflammatory gene expressions and improved tight junction functions of colonic epithelial cells. Additionally, PIN administration reversed DSS-induced short chain fatty acid loss, and improved the gut microbial diversity assessed by 16S rRNA phylogenetic sequencing. Overall, our results suggest a wide spectrum of protective effects of PIN in preventing IBDs.

Alternative splicing (AS) of mRNA is known to be involved in regulation of immune cell differentiation and activation. Elongation factor Tu GTP binding domain containing 2 (Eftud2) is an AS factor to potentially modulate innate immune response in macrophages. In this study, we investigate its involvement in the pathogenesis of colitis-associated cancer (CAC). Using an established mouse model of CAC, we show that Eftud2 is constantly overexpressed in the colonic tissues as well as infiltrating macrophages. Myeloid-specific knockout of Eftud2 remarkably suppresses chronic intestinal inflammation and tumorigenesis, which is associated with decreased production of inflammatory cytokines and tumorigenic factors. Repression of colonic inflammation and colorectal tumor development in Eftud2-deficient mice is due to the impaired activation of NF-κB signaling in LPS-challenged macrophages. Furthermore, the alteration of Eftud2-mediated AS involving the components of TLR4-NF-κB cascades underlies the impairment of NF-κB activation. Overall, these findings provide new insights into the tight link between inflammation and cancer and modulation of AS in innate immune signals may be a potentially therapeutic avenue for CAC treatment.

Coronary atherosclerosis (CA) is a chronic and evolving inflammatory disease characterized by the build-up of atherosclerotic plaque in the wall of coronary arteries. Guanxinning tablet (GXNT) is a novel Chinese medicine formula, which has been clinically used to treat coronary heart disease for many years. However, the potential mechanism for treating CA remains unclear. Thus, the study was aimed at investigating the therapeutic effect of GXNT on CA and further explore the underlying mechanisms from the perspective of gut microbiota. Following the establishment of a CA model in Tibetan minipigs, GXNT was orally administrated. We simultaneously detected blood lipid levels, observed ventricular function using ultrasound examination, measured platelet aggregation, and checked changes in inflammatory factors, oxidative stress factors, and vascular endothelial injury-related indexes applying ELISA assays. Histopathological changes of coronary artery tissue were subsequently evaluated using Sudan IV staining, HE staining, Oil red O staining, and immunohistochemistry assays. Finally, alterations of the gut microbiota and microbial metabolites were detected using metagenomic sequencing and targeted metabolomics, respectively. The results have suggested that GXNT could regulate dyslipidemia, improve heart function, and inhibit the levels of ox-LDL, CRP, TNF-α, IL-1β, SOD, MDA, vWF, and ET-1, as well as platelet aggregation. Additionally, histopathological findings revealed that GXNT could reduce lipid deposition, alleviate AS lesions, and restrain the expressions of NF-κB, TNF-α, and MMP-9. Furthermore, the composition of the gut microbiota was altered. Specifically, GXNT could upregulate the relative abundance of Prevotellaceae and Prevotella and downregulate the abundance of Proteobacteria, Enterobacteriaceae, and Escherichia. As for microbial metabolites, GXNT could increase fecal propionic acid, butyric acid, and LCA-3S and decrease fecal TMA-related metabolites, CDCA, and serum TMAO. In sum, the results showed that GXNT had a satisfactory anti-CA effect, and the mechanism was closely associated with modulating gut microbiota and related metabolites.

Background: Vaccination remains one of the most effective approaches to prevent the spread of infectious diseases. Immune responses to vaccination can be enhanced by inclusion of adjuvant in a vaccine. Paclitaxel extracted from the bark of the Pacific yew tree Taxus brevifola was previously demonstrated to have adjuvant property. Compared to paclitaxel, docetaxel is another member of taxane family, and is more soluble in water and easier to manipulate in medication. To investigate the adjuvant effect of this compound, we measured the immune responses induced by co-administration of a split inactivated influenza H1N1 vaccine antigen with docetaxel. Results: When co-administered with docetaxel, lower dose antigen (equivalent to 10 ng HA) induced similar levels of IgG and IgG isotypes as well as HI titers to those induced by higher dose antigen (equivalent to 100 ng HA). Docetaxel promoted splenocyte responses to H1N1 antigen, ConA and LPS, mRNA expressions of cytokines (IFN-gamma, IL-12, IL-4 and IL-10) and T-bet/GATA-3 by splenocytes. The enhanced immunity was associated with up-expressed microRNAs (miR-155, miR-150 and miR-146a) in docetaxel-stimulated RAW264.7 cells. Docetaxel promoted similar IgE level to but alum promoted significantly higher IgE level than the control. Conclusion: Docetaxel has adjuvant effect on the influenza H1N1 vaccine by up-regulation of Th1/Th2 immune responses. Considering its unique vaccine adjuvant property as well as the safe record as an anti-neoplastic agent clinically used in humans during a long period, docetaxel should be further studied for its use in influenza vaccine production.

Patients afflicted with Wilson’s disease (WD) may encounter hepatic and extraneous manifestations due to the progressive accumulation of copper in the liver and other subsequent organs. Copper-chelating agents, such as D-penicillamine (DPA), are commonly utilized in the medical treatment of copper overload in WD. Manipulating the composition of gut microbiota appropriately can enhance drug efficacy and safety. This study aims to investigate how targeted intervention on gut microbiota influences the effectiveness of copper removal in a WD model during DPA treatment. First, following a 4-week treatment of DPA, the liver copper concentration and gut microbial composition were assessed in the WD mice model to identify potential candidates for targeted regulation of gut microbiota. Second, after 8 weeks of manipulating the gut microbiota during DPA treatment, various parameters including blood liver function indicators, tissue copper load, hepatic histopathological features, and gut microbiota were investigated in WD mice. The findings demonstrated that the presence of Akkermansia significantly enhances the efficacy of DPA, leading to a more efficient elimination of copper from tissues and a greater improvement in liver injury, liver dysfunction, and gut dysbiosis. In contrast, Butyricimonas has an antagonistic effect. The results of gene function prediction analysis indicated that the altered gut microbial function by DPA and Akk is primarily linked to energy generation/utilization, amino acid, fatty acid, lipid, and nucleic acid metabolisms. To summarize, this study provides experimental evidence for the potential application of targeted regulation of gut microbiota in the adjunctive therapy of copper dysregulation disease. IMPORTANCE: Copper is an essential element in virtually all living organisms. Wilson’s disease (WD) is a representative disorder caused by the disruption of copper homeostasis. Oral-chelating agents are the first-line treatment for copper-overloaded diseases, with D-penicillamine (DPA) being the prototypical drug. However, the efficacy and adverse effects of DPA remain challenging in its use for WD treatment. In our study, the supplementation of Akkermansia muciniphila (Akk), a key gut microbe, along with DPA was demonstrated to enhance copper removal, ameliorate liver injury and dysfunction, and restore gut dysbiosis in a mouse model of WD. These findings highlight the significant potential applications of targeted modulation of gut microbiota as “pharmacomicrobiomics” in adjunctive therapy for disorders involving copper dysregulation.