Introductionwe also investigated the prognostic correlation between the expression level of lncRNA HOTAIR in tumor tissues and peripheral blood of patients with advanced HCC and sunitinib monotherapy.Material and methodsA total of 60 patients with advanced HCC who received sunitinib monotherapy and another 60 healthy individuals who were examined at the physical examination center during the same period were included in the study. Real-time quantitative PCR (RT-QPCR) was used to determine the relative expression of lncRNA HOTAIR in tumor tissue, adjacent tissue and peripheral blood of HCC patients as well as peripheral blood of healthy controls.ResultsPatients with low lncRNA HOTAIR expression in tumor tissues harbored significantly longer OS (13.4 vs. 9.5, P <0.001) and PFS (8.4 vs6.2, P <0.001) compared to those with high expression. Consistently, patients with low lncRNA HOTAIR expression in peripheral blood had significantly prolonged OS (12.8 vs9.1, P<0.001) and PFS (8.9 vs6.4, P<0.001) compared to those with high expression.Cox regression analysis indicated that the expression level of lncRNA HOTAIR in tumor tissue and peripheral blood was an independent predictive factor of OS and PFS in patients with advanced HCC treated by sunitinib.ConclusionsThe expression of lncRNA HOTAIR was up-regulated in tumor tissue and peripheral blood in patients with advanced HCC. In addition, the expression level of lncRNA HOTAIR was one of the indicator in predicting the effectiveness of sunitinib therapy.
ObjectiveIn this study, we mainly explored the mechanism and target of the anti-inflammatory effects of Aureusidin (Aur) in acute liver injury.MethodsLipopolysaccharide (LPS) was used to induce inflammatory injury in Kupffer cells (KCs) in vitro. After Aur treatment with gradient concentration, flow cytometry, propidium iodide (PI) staining, and Hoechst 33342 staining were used to detect the apoptotic level of KCs, and an enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of inflammatory factors, including Interleukin-1β (IL-1β), Interleukin-18 (IL-18), and tumor necrosis factor alpha (TNF-α). Western blot was used to detect the expression of toll-like receptor 4 (TLR4), myeloid differentiation protein-2 (MD2), MyD88, and p-P65. Aur was labeled with biotin, followed by a pull-down assay to detect its binding with MD2. Moreover, D-GalN/LPS was used to induce acute liver injury in mice in vitro, followed by Aur treatment by gavage. H&E staining was used to detect the pathological changes of liver tissue, an IF assay was used to detect the expression of MD2, Western blot was used to detect the expression of relevant proteins.ResultsAur pretreatment could significantly inhibit LPS-induced KC injury, downregulate the apoptotic level, inhibit the expression of inflammatory factors, decrease the level of MDA, and downregulate the expression of MD2 in cells. Aur could inhibit the activation level of TLR4/MD2-NF-κB in a dose-dependent pattern, a high dose of Aur had a superior effect compared to low-dose Aur. In the case of MD2 deletion, the effects of Aur were suppressed. Additionally, pull-down and co-immunoprecipitation assays show that Aur can bind with the MD2 protein to inhibit the activation of TLR4/MD2-NF-κB. Results of mice experiments also showed that Aur could relieve liver injury, decrease the levels of ALT and AST, and simultaneously downregulate the levels of inflammatory factors in tissues and peripheral blood.ConclusionWe found that Aur exerted an anti-inflammatory effect by directly targeting the MD2 protein, further inhibiting the expression of TLR4/MD2-NF-κB, thereby relieving acute liver injury. Therefore, Aur might be a potential inhibitor for MD2.
PIP has a broad market and considerable economic benefits in China.Extraction of pepper is the main way to obtain PIP. There are three main types of extraction methods, including acid extraction method (PIP is a basic substance 2,3 ). Pharmacological studies have confirmed that PIP has a series of functions, including analgesia, antipyresis, anti-oxidation, anti-tumour, immune regulation, etc. 4,5 In the study of the anti-tumour activity of piperine, several cancer models showed cytotoxic and inhibitory effects on a variety of cancer cell lines, including colon cancer, lung cancer, breast cancer, pancreatic cancer, kidney cancer and prostate cancer. 6 In addition, anti-tumour activity has also been found in various animal models. Piperine triggers cell death by causing cell apoptosis and necrosis. The molecular apoptotic effects of piperine activity include reduction of cell lymphoma, caspase-3, poly(ADP-ribose) polymerase(PARP) activation, oncogene and NH2-terminal kinase activation are involved. In addition, piperoning was found to restore the normal function of the
Short-chain fatty acids (SCFAs) are a product of intestinal bacteria metabolism. Our previous study has found that intestinal bacteria in patients with Alzheimer’s disease (AD) can promote the activation of NLRP3 inflammasome and mediate neuroinflammation. In this study, we mainly explored the regulation of intestinal microenvironmental immunity by intestinal bacterial metabolite SCFAs and the mechanism of NLRP3 activation. First, wild-type (WT) and APP/PS1 mice were intervened with SCFAs. As a result, the proportion of double-negative T cells (CD3 + CD4 − CD8 − , DNTs) in the intestine was increased, SCFAs could promote the expression of intestinal NLRP3 and inflammatory factors (IL-18, IL-6 and TNF-α). Moreover, SCAFs could also promote the level of inflammatory factors in the cerebrospinal fluid (CSF) of mice and aggravate the cognitive impairment in AD mice. CD3 + T cells isolated from the spleen were pre-treated with SCFAs, followed by detection of the proportion of DNTs. Consequently, SCFAs could promote the formation of DNTs, activate OX40 signal and simultaneously up-regulate the protein expression of Bcl-2, Bcl-xl and Survivin. Knockdown of OX40 could inhibit SCFAs-induced differentiation of DNTs. The co-culture of DNTs and intestinal macrophages showed that DNTs could activate Fas/FasL-TNF-α signal and induce the activation of NLRP3 inflammasome. In AD mouse models, treatment with Fas and TNFR1 inhibitors could significantly inhibit SCFAs-induced NLRP3 activation and inflammatory factors, while attenuate the inflammatory response in the brain tissue of mice and improve the cognitive ability of mice, however, without significant effect on the level of DNTs. The present study showed that SCFAs can promote the formation of DNTs through OX40. DNTs could induce the activation of NLRP3 inflammasome and the release of inflammatory factors in macrophages through Fas/FasL-TNF-α signals, thereby increasing the level of inflammatory factors in the central nervous system. When Fas and TNFR1 were inhibited by suppressing the functions of DNTs and macrophages, the activation of NLRP3 was inhibited. DNTs are affected by SCFAs, which is a new mechanism of neuroinflammation in AD.
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