Microbiota-host interactions in irritable bowel syndrome: Epithelial barrier, immune regulation and brain-gut interactions

Irritable bowel syndrome(IBS) is a common, sometimes debilitating, gastrointestinal disorder worldwide. While altered gut motility and sensation, as well as aberrant brain perception of visceral events, are thought to contribute to the genesis of symptoms in IBS, a search for an underlying aetiology has, to date, proven unsuccessful. Recently, attention has been focused on the microbiota as a possible factor in the pathogenesis of IBS. Prompted by a number of clinical observations, such as the recognition of the de novo development of IBS following enteric infections, as well as descriptions of changes in colonic bacterial populations in IBS and supported by clinical responses to interventions, such as antibiotics and probiotics, that modify the microbiota, various approaches have been taken to investigating the microbiota-host response in IBS, as well as in animal models thereof. From such studies a considerable body of evidence has accumulated to indicate the activation or upregulation of both factors involved in bacterial engagement with the host as well host defence mechanisms against bacteria. Alterations in gut barrier function, occurring in response, or in parallel, to changes in the microbiota, have also been widely described and can be seen to play a pivotal role in generating and sustaining host immune responses both within and beyond the gut. In this manner a plausible hypothesis, based on an altered microbiota and/or an aberrant host response, for the pathogenesis, of at least some instances of IBS, can be generated.

Tenascin C upregulates interleukin-6 expression in human cardiac myofibroblasts via toll-like receptor 4

AIM:To investigate the effect of Tenascin C(TNC)on the expression of pro-inflammatory cytokines and matrixmetalloproteinases in human cardiac myofibroblasts(CMF).METHODS:CMF were isolated and cultured from patients undergoing coronary artery bypass grafting.Cultured cells were treated with either TNC(0.1μmol/L,24 h)or a recombinant protein corresponding to different domains of the TNC protein;fibrinogen-like globe(FBG)and fibronectin typeⅢ-like repeats(TNⅢ5-7)(both 1μmol/L,24 h).The expression of the proinflammatory cytokines;interleukin(IL)-6,IL-1β,TNFαand the matrix metalloproteinases;MMPs(MMP1,2,3,9,10,MT1-MMP)was assessed using real time RT-PCR and western blot analysis.RESULTS:TNC increased both IL-6 and MMP3(P<0.01)mR NA levels in cultured human CMF but had no significant effect on the other markers studied.The increase in IL-6 mR NA expression was mirrored by an increase in protein secretion as assessed by enzymelinked immunosorbant assay(P<0.01).Treating CMF with the recombinant protein FBG increased IL-6mR NA and protein(P<0.01)whereas the recombinant protein TNⅢ5-7 had no effect.Neither FBG nor TNⅢ5-7 had any significant effect on MMP3 expression.The expression of toll-like receptor 4(TLR4)in human CMF was confirmed by real time RT-PCR,western blot and immunohistochemistry.Pre-incubation of cells with TLR4neutralising antisera attenuated the effect of both TNC and FBG on IL-6 mR NA and protein expression.CONCLUSION:TNC up-regulates IL-6 expression in human CMF,an effect mediated through the FBG domain of TNC and via the TLR4 receptor.

Innate immune receptors in heart failure: Side effect or potential therapeutic target?

Heart failure(HF) is a leading cause of mortality and morbidity in western countries and occasions major expenses for public health systems. Although optimal medical treatment is widely available according to current guidelines, the prognosis of patients with HF is still poor. Despite the etiology of the disease, increased systemic or cardiac activation of the innate immune system is well documented in several types of HF. In some cases there is evidence of an association between innate immune activation and clinical outcome of patients with this disease. However, the few large trials conducted with the use of anti-inflammatory medication in HF have not revealed its benefits. Thus, greater understanding of the relationship between alteration in the immune system and development and progression of HF is urgently necessary: prior to designing therapeutic interventions that target pathological inflammatory processes in preventing harmful cardiac effects of immune modulatory therapy. In this regard, relatively recently discovered receptors of the innate immune system, i.e., namely toll-like receptors(TLRs) and nodlike receptors(NLRs)-are the focus of intense cardiovascular research. These receptors are main up-stream regulators of cytokine activation. This review will focus on current knowledge of the role of TLRs and NLRs, as well as on downstream cytokine activation, and will discuss potential therapeutic implications.

Taohong Siwu decoction(桃红四物汤)ameliorates atherosclerosis in rats possibly through toll-like receptor 4/myeloid differentiation primary response protein 88/nuclear factor-κB signal pathway

OBJECTIVE:To investigate the effect of Taohong Siwu decoction(桃红四物汤,TSD)on atherosclerosis in rats as well as investigate the underlying mechanism based on molecular docking.METHODS:Sixty healthy male Sprague-Dawley rats were randomly divided into 6 groups with 10 rats in each group:control group,model group,atorvastatin group(AT,2.0 mg/kg),and TSD groups(20,10,5 g/kg)after 7 d of acclimation.The model of atherosclerosis was successfully established except the control group by high fat diet(HFD)and vitamin D2.Biochemical analyzers were used to detect the levels of triglyceride(TG),total cholestero(TC),low density lipoprotein-cholesterol(LDLC)and high density lipid-cholesterol(HDL-C)in blood lipid.The levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and interleukin-1β(IL-1β)were determined by enzyme-linked immunosorbent assay.Sudan IV staining and Hematoxylin and eosin staining(HE staining)were performed to observe the pathological changes in aortic tissue.Molecular docking technology was used to predict the best matching between the main components of TSD and the target proteins.The expression of target proteins was further detected by quantitative real time polymerase chain reaction(q RTPCR)and Western blot analysis.RESULTS:The results showed that TSD restricted atherosclerosis development and decreased the inflammatory cytokines in plasma.Molecular docking results predicted that the main components of TSD showed a strong binding ability with toll-like receptor(TLR4),myeloid differentiation primary response protein 88(My D88),and nuclear factor kappa-B(NF-κB).The results of q RT-PCR and Western blot analysis showed that the m RNA and protein expressions of TLR4,My D88 and NF-κB p65 in the aorta were reduced in atorvastatin group and TSD group.CONCLUSIONS:TSD can ameliorate atherosclerosis in rats,and the underlying mechanism is supposed be related to the suppression of inflammatory response by regulating TLR4/My D88/NF-κB signal pathway.