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Ulcerative colitis （UC） is a disease that affects the mucosal and submucosal layers of the colon and is characterized by inflammation of the intestinal mucosa. The incidence of UC is increasing year by year， and it is complex and refractory， severely impacting the physical and mental health of patients. The pathological mechanism of this disease is complex， with immune responses and uncontrollable inflammatory reactions in the intestine being important physiopathologic mechanisms. Toll-like receptor 4 （TLR4）， as a transmembrane signaling receptor， plays a key role in mediating immune responses and inflammatory reactions in the development of UC. Currently， the treatment of UC mainly relies on salicylic acids， glucocorticoids， and other agents to reduce intestinal inflammation. While these drugs can partially inhibit the progression of the disease， they often come with significant adverse effects and the potential for relapse upon discontinuation. Traditional Chinese medicine （TCM） offers multiple pathways， effects， and targets for regulating the TLR4 pathway， suppressing inflammatory responses， and effectively intervening in the progression of UC. This approach has become a hot topic in the prevention and treatment of UC. Numerous studies have shown that TCM treatment of UC has unique advantages. TCM can enhance immune defenses， suppress inflammatory responses， promote intestinal mucosal healing， and maintain the balance of the intestinal microbiota by regulating the TLR4 signaling pathway， thereby effectively treating UC， with substantial progress achieved. However， there is currently a lack of comprehensive reviews on the role of TCM in regulating the TLR4 signaling pathway for the treatment of UC. Therefore， this article systematically summarized the relationship between the TLR4 signaling pathway and UC， as well as the role of TCM in this context， by reviewing relevant literature from recent years， aiming to provide new insights into the potential treatment and new drug development for UC.
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Objective:To investigate the effect of low molecular weight heparin (LMWH) on the inflammatory response of PC12 cells induced by oxygen glucose deprivation (OGD) and its related mechanism.Methods:The PC12 cells were cultured in vitro were randomly divided into sham(control) group, OGD group, LMWH group and blocking agent group. The latter group was divided into six groups: Eritoran+ OGD group, LMWH+ Eritoran+ OGD group, ST2825+ OGD group, LMWH+ ST2825+ OGD group, pyrrolidinedithiocarbamate (PDTC)+ OGD group and LMWH+ PDTC+ OGD group. OGD cell model was established. Cell counting kit-8 (CCK-8) assay was used to detect cell activity. The expressions of toll-like receptor 4 (TLR4), MyD88 and nuclear factor κB (NF-κB) mRNA and protein were detected by real time polymerase chain reaction (qRT-PCR) and Western blot. The concentration of interleukin (IL)-1β, IL-6, tumor necrosis factor-α(TNF-α) and S100β were determined by enzyme linked immunosorbent assay (ELISA). Results:The cell activity of OGD group was significantly lower than that of control group on the first, second, third day ( P<0.05). Compared with OGD group, the activity of LMWH group was increased on the second, third day ( P<0.05), but lower than that of control group ( P<0.01). The mRNA expression of TLR4, MyD88 and NF-κB was significantly increased in OGD group compared with the control group ( F=144.9, F=710.5, 79.51, P<0.01). Compared with OGD group, the mRNA expression of TLR4, MyD88 and NF-κB were significantly decreased after treatment with LMWH ( P<0.01), and the specific inhibitor of TLR4, MyD88 and NF-κB enhanced the anti-inflammatory effect of LMWH. The protein expression of this pathway was consistent with that of the gene. The concentration of IL-1β, IL-6, TNF-α and S100β in OGD group was significantly higher than control group ( P<0.05). After treatment with LMWH, the concentrations of inflammatory factors and S100β were significantly decreased compared with OGD group ( P<0.01). When hinder TLR4, MyD88 and NF-κB respectively by Eritoran, ST2825 and PDTC, the concentrations of inflammatory factors and S100β were significantly decreased, but it was still higher than control group ( P<0.05). Conclusions:OGD can cause pathological damage of PC12 cells, including high expression level of S100β and aggravation of inflammatory reaction. LMWH can improve cell activity, down-regulate inflammatory reaction degree and protect the cells. Using inhibitors of TLR4/MyD88/NF-κB pathway to inhibit the corresponding target, the up-regulation of inflammatory factors by OGD can be inhibited in varying degrees. These suggested that LMWH may regulate inflammatory reaction of PC12 cells induced by OGD through TLR4/MyD88/NF-κB pathway.
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Objective The TLR4 signaling pathway may be involved in the development and progression of hepatocarcinoma . This study aimed to investigate the effect of inhibiting the TLR 4 signaling pathway on the orthotopic implanted liver tumor (OILT) in mice. Methods A TLR4-silencing siRNA lentiviral vector was constructed and transfected into mouse hepatoma H 22 cells.Mouse hepatoma H22 cells were divided into groups A (blank control), B (empty vector) and C (siRNA lentiviral vector), those in group A left untreated and those in groups B and C infected with an empty vector and the TLR 4-silencing siRNA lentiviral vector , respectively. The volumes of the OILTs in different groups measured and the expressions of TLR 4, MyD88, NF-κB and TRAM in the tumor cells de-termined by immunohistochemistry and Western blot . Results The OILT volume was significantly reduced in group C than in A and B ([568.3±90.3] vs [1303.0±194.1] and [1385.0±137.0] mm3 , P<0.05), and so were the expressions of TLR4, MyD88, NF-κB and TRAM in the tumor cells (P<0.05). Conclusion Down-regula-ting the TLR4 signaling pathway can suppress the growth of the ortho -topic implanted liver tumor in mice, which may be associated with the activation of NF-κB by the MyD88-dependent signaling pathway and that of TRAM by the MyD88-independent signaling pathway .
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Objective:To investigate the effects of Acanthopanax Senticosus polysaccharides (ASPS) on TLR4 signaling pathway in Lewis tumor-bearing mice,and to explore the immunomodulatory mechanism of ASPS.Methods:Lewis lung carcinoma cells and C57BL/6 mice were used to establish the animal model for solid tumor.The tumor-bearing mice were divided into five groups:normal saline (NS) group,Adriamycin (ADM) group,ASPS low-dose group,ASPS middle-dose group and ASPS high-dose group.Mter 25 d treatment,the weight of tumor,tumor inhibition rate and immune organ index were measured.ELISA were applied to detected the cytokines in peripheral blood of tumor-bearing mice.Quantitative real-time PCR (Q-PCR) and Western blot were selectively used to detect the gene and protein expression of TLR4 signaling pathway in splenocytes.Results:The tumor inhibition rate,immune organ index and the secretion of TNF-α,IL-1β and IL-6 were increased by ASPS,compared with NS group (P＜0.05).The gene and protein expression of TLR4,MyD88,TRAF6,NF-κB p65 and AP-1 were also induced by ASPS (P＜0.05).Meanwhile,ASPS had no obvious effects on the secretion of IL-12p70 and the expression of TRAM (P＞0.05).Conclusion:TLR4 signaling pathway may be involved in the immunomodulatory effects of ASPS on Lewis tumor-bearing mice.
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TLR4 signaling pathway plays an important role in regulation of the innate immune response and the adaptive immune response.Studies have shown that TLR4 signaling pathway is closely associated with the immune inflammatory process in major depressive disorder,but the underlying mechanisms are not clear.The pathophysiological process of depression involves multiple molecule mechanisms and signal pathways.The change of TLR4 signaling pathways exists in the peripheral circulation system or the central nervous system of depressive patients and depression animal models.The activation of TLR4 signaling pathways is associated with stress-inflammation-depression approach and leaky gut hypothesis,however,the relationship of peripheral and central TLR4 signaling pathways is not clear yet.TLR4 signaling pathway may be potential targets for the anti-inflammatory treatment of depression.
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Objective To discuss the mechanism of rabbit plaque formation of carotid atherosclerosis (CAS) and inhibition of the expression of inflammatory factors. Methods Ten white rabbit randomly selected from 84 white rabbits were set as blank group, and the rest rabbits were fed with high-fat diet for the establishment of CAS models. 48 CAS model rabbits were randomly divided into model group, the natural healing group, simvastatin group, and Huoxue Tongmai Granule low-, medium- and high-dose groups, 8 rabbits in each group. Each medication group was given relevant medicine for gavage, once a day for 5 weeks. Carotid artery tissue routine HE staining was used to observe the pathological changes. Immunohistochemical detection was used for the activity of TLR4 expression in rabbit carotid artery. Fluorescence quantitative PCR was used to detect the TLR4 and the inflammation factor MCP-1, NF-κB mRNA expression. Results The rabbit endometria in model group were obvious thickening; atherosclerosis was widely distributed; a large number of foam cells in plaque were observed. Immunohistochemical in treatment groups showed that TLR4 positive staining area percentage significantly smaller than the natural healing group (P<0.01). There were relatively few differences between Huoxue Tongma Granule high-dose group and simvastatin group. The expressions of TLR4, NF-κB, MCP-1 mRNA in the treatment group were lower than the natural healing group by Fluorescence quantitative PCR detection (P<0.05). Conclusion Huoxue Tongmai Granules achieve therapeutical effect by intervening CAS rabbit plaque formation and inhibiting the expression of inflammatory factors through TLR4 signaling pathways.
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Objective To study the function of the toll-like receptor-4 (TLR-4) signaling pathway in the synthesis and secretion of pulmonary artery smooth muscle cells of rats with COPD. Methods The primary pulmonary artery smooth muscle cells (PASMCs) of rats with COPD were digested, separated and purified. Then they were randomly divided into control group, LPS group, TLR4 inhibitor group (TAK242) and LPS + TLR4 inhibitor group. RT-PCR, Western blot were used to detect the expression level of TLR-4 and NF-κB among groups. The levels of IFN-γ and PDGF-AB in supernatant with PASMCs in each group were detected by ELISA. Results LPS increased the expression of TLR-4、 NF-κB and the levels of IFN-γ and PDGF-AB. The expression of TLR4, NF-κB and the levels of IFN-γ and PDGF-AB were significantly reduced after inhibiting the expression of TLR4(P < 0.05). Conclusion TLR-4 signaling pathway involved in the inflammatory response and pulmonary vascular remodeling which increased the synthesis and secretion of IFN-γ and PDGF-AB in PASMCs. It provides a theoretical approach for the early intervention of clinical with COPD.
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BACKGROUND/OBJECTIVES: Inflammation is associated with various types of acute and chronic alcohol liver diseases. In this study, we examined whether umbelliferone (7-hydroxycoumarin, UF) ameliorates chronic alcohol-induced liver damage by modulating inflammatory response and the antioxidant system. METHODS: Rats were fed a Liber-Decarli liquid diet containing 5% alcohol with or without UF (0.05 g/L) for 8 weeks, while normal rats received an isocaloric carbohydrate liquid diet. RESULTS: Chronic alcohol intake significantly increased serum tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 levels and decreased interleukin 10 level; however, UF supplementation reversed the cytokines related to liver damage. UF significantly suppressed hepatic lipopolysaccharide binding protein, toll-like receptor 4 (TLR4), nuclear factor kappa B, and TNF-alpha gene expression increases in response to chronic alcohol intake. Masson's trichrome staining revealed that UF improved mild hepatic fibrosis caused by alcohol, and UF also significantly increased the mRNA expressions and activities of superoxide dismutase and catalase in liver, and thus, decreased lipid peroxide and mitochondrial hydrogen peroxide levels. CONCLUSIONS: The findings of this study indicate that UF protects against alcohol-induced liver damage by inhibiting the TLR4 signaling pathway and activating the antioxidant system.
Subject(s)
Animals , Rats , Antioxidants , Carrier Proteins , Catalase , Cytokines , Diet , Fibrosis , Gene Expression , Hydrogen Peroxide , Inflammation , Interleukin-10 , Interleukin-6 , Liver , Liver Diseases , NF-kappa B , RNA, Messenger , Superoxide Dismutase , Toll-Like Receptor 4 , Tumor Necrosis Factor-alphaABSTRACT
Objective To observe the expression of toll like receptor 4(TLR4) Signaling and the release of inflammation factors in rat tubular epithelial cell(NRK-52E) under high glucose condition after TLR4-siRNA transfection.Methods Three TLR4-siRNA sequences were designed and synthesized.The transfection efficiency was observed by fluorescence microscope after transfection,and the expression of TLR4 mRNA was detected by real time PCR.The most effective siRNA was selected to be used for forward experiments.After transfection for 24 h,cells were stimulated with 25 mmol/L glucose and/or 10-7 mmol/L Angiotension Ⅱ (Ang Ⅱ) for 12 h,24 h; cells without stimulation were as normal control.Real-time PCR was used to analyze TLR4 and myeloid differentiation factor 88 (MyD88) mRNA expression; Western blot was used to observe TLR4/MyD88 and NF-κB protein expression.ELISA assay was used to detect the concentration of monocyte chemoattractant protein-1 (MCP-1),interleukin-6(IL-6) in cell supernatant after cells were stimulated for 24 h.Results TLR4/ MyD88 mRNA and TLR4/MyD88/NF-κB protein were highly expressed under high glucose or Ang Ⅱ co -incubated NRK-52E(P ＜ 0.01),the MCP-1 and IL-6 levels were also increased markedly compared with normal control group (P ＜ 0.01).TLR4/MyD88 mRNA and TLR4/MyD88/NF-kB protein expressions were obviously inhibited in cells that were transfected with TLR4-siRNA compared with high glucose group(P ＜ 0.01),MCP-1 and IL-6 production decreased remarkably compared with high glucose or Ang Ⅱ co-stimulated group(P ＜ 0.01).Conclusions High glucose can lead to the activation of TLR4/ MyD88/NF-kB signaling and the secretion of inflammation factors in NRK-52E,Ang Ⅱ further augments these effects.The effect can be blocked efficiently by specific siRNA gene silence.TLR4 signaling plays a pivotal role in the innate-immune inflammatory reaction in NRK-52E.