Moxibustion attenuates inflammation in intestinal mucosal by regulating RAGE-mediated TLR4-NF-κBp65 signaling pathway in vivo and in vitro.
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ABSTRACT:
SUBMITTER: Li B
PROVIDER: S-EPMC9274590 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Resveratrol (RSV) is a natural compound exhibiting anti-inflammatory effect, but the anti-inflammatory mechanism has not been fully understood. This study is aimed to evaluate the anti-inflammatory activity and mechanism of RSV in lipopolysaccharides-induced rats' model. The visceral wet/dry weight ratios and the changes of hematologic and biochemical indices indicated that LPS- stimulation mainly caused damages to liver and lung, while pretreatment with RSV could alleviate the lesions. The cytokine assays showed that RSV could markedly decrease the production of proinflammatory mediators and cytokines (IL-1, IL-1β, IL-6, NO, iNOS and COX-2), and increase the expression of anti-inflammatory mediator (IL-10). RSV could inhibit TLR4 signaling pathway by down-regulating the mRNA levels of MyD88 and TRAF6, and suppressing the TLR4 protein. RSV could inhibit the signaling cascades of NF-κBp65 and MAPKs through down-regulating the mRNA levels of IκBα, p38MAPK, JNK, ERK1, ERK2 and ERK5 in liver and lung, and suppressing the dynamic changes of proteins and phosphorylated proteins including IκBα, NF-κBp65, p38MAPK, JNK, ERK1/2 and ERK5 from tissue's cytoplasm to nucleus. In conclusion, RSV possessed a therapeutic effect on LPS-induced inflammation in rats and the mechanism mainly attributed to suppressing the signaling cascades of NF-κBp65 and MAPKs by inhibiting the TLR4 signaling pathway.
| S-EPMC5359552 | biostudies-literature
Project description:Atherosclerosis is a leading cause of death worldwide and is characterized by lipid-laden foam cell formation. Recently, pycnogenol (PYC) has drawn much attention because of its prominent effect on cardiovascular disease (CVD). However, its protective effect against atherosclerosis and the underlying mechanism remains undefined. Here PYC treatment reduced areas of plaque and lipid deposition in atherosclerotic mice, concomitant with decreases in total cholesterol and triglyceride levels and increases in HDL cholesterol levels, indicating a potential antiatherosclerotic effect of PYC through the regulation of lipid levels. Additionally, PYC preconditioning markedly decreased foam cell formation and lipid accumulation in lipopolysaccharide (LPS)-stimulated human THP-1 monocytes. A mechanistic analysis indicated that PYC decreased the lipid-related protein expression of adipose differentiation-related protein (ADRP) and adipocyte lipid-binding protein (ALBP/aP2) in a dose-dependent manner. Further analysis confirmed that PYC attenuated LPS-induced lipid droplet formation via ADRP and ALBP expression through the Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) pathway, because pretreatment with anti-TLR4 antibody or a specific inhibitor of NF-κB (PDTC) strikingly mitigated the LPS-induced increase in ADRP and ALBP. Together, our results provide insight into the ability of PYC to attenuate bacterial infection-triggered pathological processes associated with atherosclerosis. Thus PYC may be a potential lead compound for the future development of antiatherosclerotic CVD therapy.
| S-EPMC4673476 | biostudies-other
Project description:BackgroundAfter traumatic brain injury (TBI), an acute, robust inflammatory cascade occurs that is characterized by the activation of resident cells such as microglia, the migration and recruitment of peripheral immune cells and the release of inflammatory mediators that induce secondary cell death and impede neurological recovery. In addition, neuroinflammation can alter blood-brain barrier (BBB) permeability. Controlling inflammatory responses is considered a promising therapeutic approach for TBI. Hydroxychloroquine (HCQ) has already been used clinically for decades, and it is still widely used to treat various autoimmune diseases. However, the effects of HCQ on inflammation and the potential mechanism after TBI remain to be defined. The aim of the current study was to elucidate whether HCQ could improve the neurological recovery of mice post-TBI by inhibiting the inflammatory response via the TLR4/NF-κB signaling pathway.MethodsC57BL/6 mice were subjected to controlled cortical impact (CCI) and randomly divided into groups that received intraperitoneal HCQ or vehicle daily after TBI. TAK-242 (3.0 mg/kg), an exogenous TLR4 antagonist, was injected intraperitoneally 1 h before TBI. Behavioral assessments were performed on days 1 and 3 post-TBI, and the gene expression levels of inflammatory cytokines were analyzed by qRT-PCR. The presence of infiltrated immune cells was examined by flow cytometry and immunostaining. In addition, BBB permeability, tight junction expression and brain edema were investigated.ResultsHCQ administration significantly ameliorated TBI-induced neurological deficits. HCQ alleviated neuroinflammation, the activation and accumulation of microglia and immune cell infiltration in the brain, attenuated BBB disruption and brain edema, and upregulated tight junction expression. Combined administration of HCQ and TAK-242 did not enhance the neuroprotective effects of HCQ.ConclusionsHCQ reduced proinflammatory cytokine expression, and the underlying mechanism may involve suppressing the TLR4/NF-κB signaling pathway, suggesting that HCQ is a potential therapeutic agent for TBI treatment.
| S-EPMC8961949 | biostudies-literature
Project description:Balanced control of innate immune signaling in the intestine represents an important host defense mechanism to avoid inappropriate responses that may exacerbate mucosal injury in acute inflammation. In this study, we report that TRIM58, a RING E3-ubiquitin ligase, associates with TLR2. The interaction was found in a yeast two-hybrid screen (human leukocyte and mononuclear library) and confirmed by coimmunoprecipitation of tagged and endogenous proteins. TRIM58 was predominantly expressed by murine and human myeloid-derived cells. Stimulation with a TLR2 ligand modulated TRIM58 synthesis in myeloid cells. Overexpression of TRIM58, but only in presence of the RING domain, promoted proteasome-dependent degradation of TLR2, inhibiting its signaling activity. Genetic deletion of Trim58 in mice (Trim58 -/-) led to impaired resolution of acute dextran sodium sulfate-induced colitis, which was characterized by delayed recovery from colonic injury and associated with enhanced expression of TLR2 protein and proinflammatory cyto/chemokine production in inflamed colons. Using myeloid cell-specific deletion of Trim58 in mice, we demonstrated that the myeloid cell compartment was responsible for early colitis acceleration in Trim58 deficiency. In vitro studies revealed that Trim58 -/- myeloid cells, which showed constitutive upregulation of TLR2 protein, overreacted to a proinflammatory milieu (TNF-α and IFN-γ) with increased IL-1β protein production, which mechanistically depended on Tlr2 Finally, we found that TRIM58 mRNA and protein expression levels were reduced in colonic specimens from patients with ulcerative colitis. In conclusion, we identify TRIM58 as a novel negative mediator of innate immune control and mucosal homeostasis via TLR2 signaling. Dysfunction of TRIM58 in myeloid cells may contribute to ulcerative colitis pathogenesis.
| S-EPMC6731451 | biostudies-literature
Project description:Ulcerative colitis (UC) is a chronic, relapsing, and nonspecific inflammatory bowel disease (IBD). Phillygenin (PHI), a natural bioactive ingredient, isolated from Forsythiae Fructus, exhibits anti-inflammatory, anti-oxidative, and hepatoprotective activities. However, few reports provide direct evidence on the efficacy of PHI in improving colitis mice. The present study elucidated that the symptoms of DSS-induced colitis mice were alleviated after PHI administration, including body weight loss, the disease activity index, colon length shortening, colonic pathological damage, splenomegaly, and hepatomegaly. PHI treatment improved the intestinal mucosal barrier by protecting goblet cells, promoting gene expressions of Clca1, Slc26a3, and Aqp8, increasing tight junction proteins (TJs), and reducing epithelial cell apoptosis. In addition, the levels of oxidative stress (MPO, SOD, and MDA) and inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-10) were reversed by PHI in colitis mice. According to transcriptome and network pharmacology analysis, inflammatory pathway might be an important mechanism for PHI to improve colitis. Western blotting displayed that the PHI inhibited the activation of tyrosine kinase Src mediated by TLR4, and then reduced the phosphorylation of downstream proteins p38, JNK, and NF-κB in colitis mice. In summary, our results suggested that PHI might be an appropriate and effective drug candidate to protect colitis.
| S-EPMC9917337 | biostudies-literature
Project description:To investigate the potential protective effect of prior cold stimulation on broiler intestine induced by acute cold stress (ACS). A total of 384 one-day-old broilers were divided into control (CON), ACS, cold stimulation Ⅰ (CS3+ACS), and cold stimulation Ⅱ (CS9+ACS) groups. Broilers in CON and ACS groups were reared normally, and birds in CS3+ACS and CS9+ACS groups were reared at 3℃ and 9℃ below CON group for 5 h, respectively, on alternate days from d 15 to 35. Broilers in ACS, CS3+ACS, and CS9+ACS groups were subjected to 10℃ for 24 h on d 43. Eventually, small intestine tissues were collected for histopathological observation and indexes detection. The results showed that intestinal tissues in all ACS-broilers exhibited inflammatory cell infiltrates, microvilli disruption, reduced villus length in jejunum and increased crypt depth in jejunum and ileum. Whereas these phenomena were relatively light in CS3+ACS group. Compared to CON group, mRNA expression of the TLR4/MyD88/NF-κB pathway-related genes (TLR4, MyD88, NF-κBp65, COX-2, iNOS, PTGEs, TNF-α), Th1/Th17-derived cytokines (IL-1β, IL-2, IL-8, IL-12, IFN-γ, IL-17), and HSPs (HSP40, HSP60, HSP70, HSP90) was upregulated (P < 0.05), and that of Th2-deviated cytokines (IL-4, IL-6, IL-10, IL-13) and IκBα was downregulated (P < 0.05) in small intestine in almost all ACS-broilers. Compared to ACS group, mRNA expression of most of the TLR4/MyD88/NF-κB pathway-related genes, Th1/Th17-derived cytokines, and HSPs was downregulated and that of Th2-derived cytokines was upregulated in CS3+ACS group (P < 0.05). Protein expression levels of TLR4, MyD88, p-p65/p65, p-IκBα/IκBα, IKK, TNF-α, IL-1β, IL-10, and HSPs were similar to their mRNA expression. The concentration of sIgA and activities of CAT, SOD, and GSH-px were decreased and MDA and H2O2 were increased in ACS and CS9+ACS groups compared to CON group (P < 0.05). Therefore, cold stress caused oxidative stress and inflammation, leading to gut immune dysfunction; while mild cold stimulation at 3℃ below normal rearing temperature alleviated cold stress-induced intestinal injure and dysfunction by modulating the TLR4/MyD88/NF-κB pathway in broilers.
| S-EPMC10978541 | biostudies-literature
Project description:Aims: The inflammatory response and apoptosis are the major pathological features of myocardial ischemia/reperfusion injury (MI/RI). Maslinic acid (MA), a natural pentacyclic triterpene with various bioactivities, plays critical roles in the multiple cellular biological processes, but its protective effects on the pathophysiological processes of MI/RI have not been extensively investigated. Our study aimed to determine whether MA treatment alleviate ischemia/reperfusion (I/R)-induced myocardial inflammation and apoptosis both in vitro and in vivo, and further reveal the underlying mechanisms. Methods and results: An MI/RI rat model was successfully established by ligating the left anterior descending coronary artery and H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to mimic I/R injury. In addition, prior to H/R stimulation or myocardial I/R operation, the H9c2 cells or rats were treated with varying concentrations of MA or vehicle for 24 h and two consecutive days, respectively. In this study, our results showed that MA could obviously increase the cell viability and decrease the cardiac enzymes release after H/R in vitro. MA could significantly improve the H/R-induced cardiomyocyte injury and I/R-induced myocardial injury in a dose-dependent manner. Moreover, MA suppressed the expression of inflammatory cytokines (tumor necrosis factor alpha [TNF-α, interleukin-1β [IL-1β and interleukin-6 [IL-6]) and the expressions of apoptosis-related proteins (cleaved caspase-3 and Bax) as well as increased the levels of anti-apoptotic protein Bcl-2 expression both in vitro and in vivo. Mechanistically, MA significantly inhibited nuclear translocation of nuclear factor-κB (NF-κB) p65 after H/R via regulating high mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) axis. Conclusion: Taken together, MA treatment may alleviate MI/RI by suppressing both the inflammation and apoptosis in a dose-dependent manner, and the cardioprotective effect of MA may be partly attributable to the inactivation of HMGB1/TLR4/NF-κB pathway, which offers a new therapeutic strategy for MI/RI.
| S-EPMC8631436 | biostudies-literature
Project description:Neonatal necrotizing enterocolitis (NEC) is an inflammatory disease that occurs in premature infants and has a high mortality rate; however, the mechanisms behind this disease remain unclear. The TLR4 signaling pathway in intestinal epithelial cells, mediated by TLR4, is important for the activation of the inflammatory storm in NEC infants. Myeloid differentiation protein 2 (MD2) is a key auxiliary component of the TLR4 signaling pathway. In this study, MD2 was found to be significantly increased in intestinal tissues of NEC patients at the acute stage. We further confirmed that MD2 was upregulated in NEC rats. MD2 inhibitor (MI) pretreatment reduced the occurrence and severity of NEC in neonatal rats, inhibited the activation of NF-κB and the release of inflammatory molecules (TNF-α and IL-6), and reduced the severity of intestinal injury. MI pretreatment significantly reduced enterocyte apoptosis while also maintaining tight junction proteins, including occludin and claudin-1, and protecting intestinal mucosal permeability in NEC rats. In addition, an NEC in vitro model was established by stimulating IEC-6 enterocytes with LPS. MD2 overexpression in IEC-6 enterocytes significantly activated NF-κB. Further, both MD2 silencing and MI pretreatment inhibited the inflammatory response. Overexpression of MD2 increased damage to the IEC-6 monolayer cell barrier, while both MD2 silencing and MI pretreatment played a protective role. In conclusion, MD2 triggers an inflammatory response through the TLR4 signaling pathway, leading to intestinal mucosal injury in NEC. In addition, MI alleviates inflammation and reduces intestinal mucosal injury caused by the inflammatory response by blocking the TLR4-MD2/NF-κB signaling axis. These results suggest that inhibiting MD2 may be an important way to prevent NEC.
| S-EPMC9663461 | biostudies-literature
Project description:Inosine is a type of purine nucleoside, which is considered to a physiological energy source, and exerts a widely range of anti-inflammatory efficacy. The TLR4/MyD88/NF-κB signaling pathway is essential for preventing host oxidative stresses and inflammation, and represents a promising target for host-directed strategies to improve some forms of disease-related inflammation. In the present study, the results showed that inosine pre-intervention significantly suppressed the pulmonary elevation of pro-inflammatory cytokines (including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)), malondialdehyde (MDA), nitric oxide (NO), and reactive oxygen species (ROS) levels, and restored the pulmonary catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and myeloperoxidase (MPO) activities (p < 0.05) in lipopolysaccharide (LPS)-treated mice. Simultaneously, inosine pre-intervention shifted the composition of the intestinal microbiota by decreasing the ratio of Firmicutes/Bacteroidetes, elevating the relative abundance of Tenericutes and Deferribacteres. Moreover, inosine pretreatment affected the TLR4/MyD88/NF-κB signaling pathway in the pulmonary inflammatory response, and then regulated the expression of pulmonary iNOS, COX2, Nrf2, HO-1, TNF-α, IL-1β, and IL-6 levels. These findings suggest that oral administration of inosine pretreatment attenuates LPS-induced pulmonary inflammatory response by regulating the TLR4/MyD88/NF-κB signaling pathway, and ameliorates intestinal microbiota disorder.
| S-EPMC9318366 | biostudies-literature
Project description:BackgroundNuclear factor-κB (NF-κB) plays a vital role in hepatocellular carcinoma (HCC). β-arrestin1 (ARRB1) has been proved to enhance the activity of NF-κBp65, and our previous study indicated that ARRB1 promotes hepatocellular carcinogenesis and development of HCC. However, it remains unknown whether p65 is involved in hepatocellular carcinogenesis through the ARRB1-mediated pathway.MethodsThe levels of NF-κBp65 and NF-κBp65 phosphorylation (p-p65) were assessed in including normal liver, primary HCC and paired paracancerous tissues. Liver-specific p65 knockout mice were used to examine the role of p65 and p-p65 in hepatocarcinogenesis. The mechanism of NF-κBp65 and p-p65 in hepatocarcinogenesis via ARRB1 was also studied both in vitro and in vivo.ResultsPhosphorylation of NF-κBp65 was markedly upregulated in inflammation-related HCC patients and was significantly increased in mouse hepatic inflammation models, which were induced by tetrachloromethane (CCl4), diethylnitrosamine (DEN), TNF-α, as well as DEN-induced HCC. Hepatocyte-specific p65-deficient mice markedly decreased in the HCC incidence and size of tumours by the repressing of the proliferation of malignant cells in a DEN-induced HCC model. Furthermore, ARRB1 directly bounds p65 to promote the phosphorylation of NF-κBp65 at ser536, resulted in cell malignant proliferation through GSK3β/mTOR signalling.ConclusionThe data demonstrated that phosphorylation of NF-κBp65 drives hepatocellular carcinogenesis in response to inflammation-mediated ARRB1, and that inhibition of the phosphorylation of NF-κBp65 restrains the hepatocellular carcinogenesis. The results indicate that phosphorylation of NF-κBp65 is a novel therapeutic target for HCC.
| S-EPMC8359590 | biostudies-literature