Commensal bacteria promote azathioprine therapy failure in inflammatory bowel disease via decreasing 6-mercaptopurine bioavailability.

Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD.

Advanced and Readily-Available Wireless-Powered Blue-Light-Implant for Non-Invasive Peri-Implant Disinfection.

Non-invasive light-based antibacterial therapy has a good prospect in non-surgical treatment of peri-implant infections. However, its applications are severely limited by poor penetration of light into human tissues, leading to unsatisfying outcomes. Moreover, as an essential prerequisite for traditional light therapy, lasers can no longer meet the patients' needs for convenient treatment at any time. To break through the spatial and temporal limitations of traditional light therapy, a wireless-powered blue-light zirconia implant for readily available treatment of peri-implant infection is proposed. In space, complete irradiation to complex peri-implant structure is realized by the built-in wireless-powered light source, thus improving the efficacy. In time, wireless-powering allows timely and controllable anti-infection treatment. Blue micro-light emitting diodes are used as therapeutic light sources, which effectively kill peri-implant infection-related bacteria without exogenous photosensitive agents. Porphyromonas gingivalis biofilm on implant surface can be completely killed after 20 min irradiation in vitro. The bactericidal rate of peri-implant methicillin-resistant Staphylococcus aureus infection reaches 99.96 ± 0.03% under 30 min per day blue light exposure in vivo. Within the scope of this study, the treatment of peri-implant infection with blue-light implant has preliminary feasibility, giving a new approach to non-invasive treatment of deep oral infections, including peri-implant infections.

Network pharmacology approach to investigate the multitarget mechanisms of Zhishi Rhubarb Soup on acute cerebral infarction.

CONTEXT: Zhishi Rhubarb Soup (ZRS) is a traditional Chinese medicine formula used in the clinic to treat acute cerebral infarction (ACI) for many years. However, the exact mechanism of the treatment remains unclear. OBJECTIVE: This study elucidates the multitarget mechanisms underlying the effects of ZRS on ACI using network pharmacology analysis and verify its effect by performing animal experiments. MATERIALS AND METHODS: Using the network pharmacology approach, the multiple components, critical targets and potential mechanisms of ZRS against ACI were investigated. Six herbal names of ZRS and 'acute cerebral infarction' were used as keywords to search the relevant databases. In addition, we established the MCAO model to verify the results of network pharmacology enrichment analysis. ZRS (10 g crude drug/kg) was gavaged once per day for 7 consecutive days beginning 3 h after model establishment. After ZRS treatment, TTC staining, Western blot analysis, IHC and ELISA were conducted to further explore the mechanism of ZRS intervention in ACI. RESULTS: The network pharmacology approach identified 69 key targets, 10 core genes and 169 signalling pathways involved in the treatment of ACI with ZRS. In vivo experiment showed that ZRS treatment significantly reduced cerebral infarction volume (42.76%). It also reduced the expression level of AGE, RAGE and P65; and inhibited the expression of inflammatory MMP-9 and IFN-γ. CONCLUSIONS: This study demonstrated that ZRS improved cerebral ischaemic injury by inhibiting neuroinflammation partly via the AGE-RAGE signalling pathway. It provides a theoretical basis for the clinical application of ZRS in the treatment of ACI.

Lactic Acid and Peroxyacetic Acid Inhibit Biofilm of Escherichia coli O157:H7 Formed in Beef Extract.

The objective of this study was to evaluate the inhibitory effect of lactic acid (LA) and peroxyacetic acid (PAA) on the biofilm formation of Escherichia coli O157:H7 in beef extract (BE). BE medium was used as the growth substrate in this study, to make the control effect closer to the situation of the factory. The biofilm inhibitory efficacy of LA and PAA was tested by using a crystal violet staining assay and microscopic examination. And then, extracellular polymeric substance (EPS) production, metabolic activity, and real-time polymerase chain reaction assay were used to reveal the biofilm inhibition mechanism of LA and PAA. The results showed that both LA and PAA significantly inhibited biofilm formation of E. coli O157:H7 at minimum inhibitory concentrations (MICs) (p < 0.05). At MIC, LA and PAA showed different effects on the biofilm metabolic activity and the EPS production of E. coli O157:H7. Supporting these findings, expression analysis showed that LA significantly suppressed quorum sensing genes (luxS and sdiA) and adhesion genes (flhC), while PAA downregulated the transcription of extracellular polysaccharide synthesis genes (adrB and adrA) and the global regulatory factor csgD. This result revealed that LA and PAA had different biofilm inhibitory mechanisms on E. coli O157:H7; LA inhibited the biofilm formation mainly by inhibiting metabolic activity, while PAA inhibited EPS production. This study provided a theoretical basis for the control of E. coli O157:H7 biofilm in the actual production process.

[Anti-inflammatory effect and mechanisms of Huangqi glycoprotein in treating experimental autoimmune encephalomyelitis].

Huangqi glycoprotein (HQGP) is prepared from Astragalus membranaceus by ammonium sulfate precipitation. It was indicated that HQGP has an immunoregulatory effect. In this study, we established a chronic experimental autoimmune encephalomyelitis (EAE) model and observed the therapeutic effect and possible mechanisms of HQGP (intraperitoneally at 1 mg/kg/day) on EAE. The results showed that HQGP delayed onset and ameliorated severity of EAE, and reduced the infiltration and accumulation of pathogenic T cells in the central nerves system (CNS). HQGP also reduced the production of IL-6, IL-17 and TNF-α and increased the level of IL-10. However, the level of IFN-γ production was also increased in HQGP-treated mice compared with EAE control mice. In brain, chemokines such as CCL2 and CCL5 were inhibited in HQGP-treated EAE compared with control mice. These results demonstrate that HQGP alleviates the pathogenesis of EAE possibly by suppressing the neuroinflammation and decreasing the secretion of chemokines and cell adhesion..