Bioactive glass in the treatment of ulcerative colitis to regulate the TLR4 / MyD88 / NF-κB pathway.

Ulcerative colitis (UC) is a chronic and recurrent intestinal disease of unknown aetiology, and the few treatments approved for UC have serious side effects. In this study, a new type of uniformly monodispersed calcium-enhanced radial mesoporous micro-nano bioactive glass (HCa-MBG) was prepared for UC treatment. We established cellular and rat UC models to explore the effects and mechanism of HCa-MBG and traditional BGs (45S5, 58S) on UC. The results showed that BGs significantly reduced the cellular expression of several inflammatory factors, such as IL-1ß, IL-6, TNF-α and NO. In the animal experiments, BGs were shown to repair the DSS-damaged colonic mucosa. Moreover, BGs downregulated the mRNA levels of the inflammatory factors IL-1ß, IL-6, TNF-α and iNOS, which were stimulated by DSS. BGs were also found to manage the expression of key proteins in NF-kB signal pathway. However, HCa-MBG was more effective than traditional BGs in terms of improving UC clinical manifestations and reducing the expression of inflammatory factors in rats. This study confirmed for the first time that BGs can be used as an adjuvant drug in UC treatment, thereby preventing UC progression.

[Enterovirus 71 induces apoptosis in a Bax dependent manner].

OBJECTIVE: To explore the molecular mechanism of apoptosis induced by enterovirus 71 (EV71) infection. METHODS: The effects of EV71 on Rhabdomyosarcoma (RD) cell viability were detected by CCK8 assay. EV71-induced apoptosis on RD cells were detected by Hoechst 33342 staining and Western blot targeting Caspase 3, 8 and PARP. Bax conformational change was detected by immunoprecipitation with Bax 6A7 antibody. RESULTS: EV71 decreased the viability of RD cells and induces the activation of Caspase 3, 8 and PARP. Bax expression increases in RD cells after EV71 infection, and Bax conformational change also can be detected after EV71 infection. CONCLUSION: Our study reveals that EV71 induces Caspase-dependent apoptosis by Bax conformational change.

Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by Toll-like receptor 3.

Enterovirus 71 (EV71) causes hand-foot-and-mouth disease and neurological complications in young children. Although the underlying mechanisms remain obscure, impaired or aberrant immunity is thought to play a role. In infected cells, EV71 suppresses type I interferon responses mediated by retinoid acid-inducible gene I (RIG-I). This involves the EV71 3C protein, which disrupts the formation of a functional RIG-I complex. In the present study, we report that EV71 inhibits the induction of innate immunity by Toll-like receptor 3 (TLR3) via a distinct mechanism. In HeLa cells stimulated with poly(I · C), EV71 inactivates interferon regulatory factor 3 and drastically suppresses interferon-stimulated gene expression. Notably, EV71 specifically downregulates a TRIF, TIR domain-containing adaptor inducing beta interferon (IFN-ß). When expressed alone in mammalian cells, EV71 3C is capable of exhibiting these activities. EV71 3C associates with and induces TRIF cleavage in the presence of Z-VAD-FMK, a caspase inhibitor. TRIF cleavage depends on its amino acid pair Q312-S313, which resembles a proteolytic site of picornavirus 3C proteases. Further, site-specific 3C mutants with a defective protease activity bind TRIF but fail to mediate TRIF cleavage. Consequently, these 3C mutants are unable to inhibit NF-κB and IFN-ß promoter activation. TRIF cleavage mediated by EV71 may be a mechanism to impair type I IFN production in response to Toll-like receptor 3 (TLR3) activation.

Enterovirus 71 induces degradation of TRIM38, a potential E3 ubiquitin ligase.

BACKGROUND: The tripartite motif (TRIM) proteins are a family of more than 70 members in human. However, only a few of them have been well studied. The TRIM proteins contain the conserved RING, B-box, coiled-coil, and SPRY domains, most of which are involved in protein ubiquitination. TRIM38 is a member of the TRIM protein family, which we studied in more detail here as its functions are largely unknown. RESULTS: Our study shows that, similar to other TRIM family members, TRIM38 is localized in the cytoplasm. TRIM38 increases ubiquitination of other cellular proteins and catalyzes self-ubiquitination. TRIM38 also promotes K63- and K48-linked ubiquitination of cellular proteins. An intact RING domain is important for the functions of TRIM38. In addition, enterovirus 71 infection induces TRIM38 degradation. CONCLUSIONS: Our observations demonstrate that TRIM38 has E3 ubiquitin ligase activity and can be degraded during virus infection. These findings may provide insight into innate immune signaling pathways.

The 3C protein of enterovirus 71 inhibits retinoid acid-inducible gene I-mediated interferon regulatory factor 3 activation and type I interferon responses.

Enterovirus 71 (EV71) is a human pathogen that induces hand, foot, and mouth disease and fatal neurological diseases. Immature or impaired immunity is thought to associate with increased morbidity and mortality. In a murine model, EV71 does not facilitate the production of type I interferon (IFN) that plays a critical role in the first-line defense against viral infection. Administration of a neutralizing antibody to IFN-alpha/beta exacerbates the virus-induced disease. However, the molecular events governing this process remain elusive. Here, we report that EV71 suppresses the induction of antiviral immunity by targeting the cytosolic receptor retinoid acid-inducible gene I (RIG-I). In infected cells, EV71 inhibits the expression of IFN-beta, IFN-stimulated gene 54 (ISG54), ISG56, and tumor necrosis factor alpha. Among structural and nonstructural proteins encoded by EV71, the 3C protein is capable of inhibiting IFN-beta activation by virus and RIG-I. Nevertheless, EV71 3C exhibits no inhibitory activity on MDA5. Remarkably, when expressed in mammalian cells, EV71 3C associates with RIG-I via the caspase recruitment domain. This precludes the recruitment of an adaptor IPS-1 by RIG-I and subsequent nuclear translocation of interferon regulatory factor 3. An R84Q or V154S substitution in the RNA binding motifs has no effect. An H40D substitution is detrimental, but the protease activity associated with 3C is dispensable. Together, these results suggest that inhibition of RIG-I-mediated type I IFN responses by the 3C protein may contribute to the pathogenesis of EV71 infection.