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Sepsis-associated encephalopathy (SAE) is a common and severe complication of sepsis. The cognitive dysfunction that ensues during SAE has been reported to be caused by impairments of the hippocampus. Microglia serves a key role in neuroinflammation during SAE through migration. Forkhead box C1 (Foxc1) is a member of the forkhead transcription factor family that has been found to regulate in cell migration. However, the role of Foxc1 in neuroinflammation during SAE remains unknown. In the present study, the mechanistic role of Foxc1 on microglial migration, neuroinflammation and neuronal apoptosis during the occurrence of cognitive dysfunction in SAE was investigated. A microglia-mediated inflammation model was induced by LPS in BV-2 microglial cells in vitro, whilst a SAE-related cognitive impairment model was established in mice using cecal ligation and perforation (CLP) surgery. Cognitive function in mice was evaluated using the Morris Water Maze (MWM) trial. Lipopolysaccharide (LPS) treatment was found to trigger BV-2 cell migration, inflammation and neuronal apoptosis. In addition, CLP surgery induced cognitive injury, which was indicated by longer latencies and shorter dwell times in the goal quadrant compared with those in the Sham group in the MWM trial. LPS treatment or CLP induction decreased the expression of Foxc1 and inhibitor of NF-κB (IκΒα) whilst increasing that of p65, IL-1β and TNF-α. After Foxc1 was overexpressed, the cognitive dysfunction of mice that underwent CLP surgery was improved, with the expression of IκBα also increased, microglial cell migration, the expression of p65, IL-1β and TNF-α and neuronal apoptosis were all decreased in vivo and in vitro, which were in turn reversed by the inhibition of IκBα in vitro. Overall, these results suggest that the overexpression of Foxc1 inhibited microglial migration whilst suppressing the inflammatory response and neuronal apoptosis by regulating the IκBα/NF-κB pathway, thereby improving cognitive dysfunction during SAE.

Viral myocarditis (VMC) commonly triggers heart failure, for which no specific treatments are available. This study aims to explore the specific role of long non‐coding RNA (lncRNA) maternally expressed 3 (MEG3) in VMC. A VMC mouse model was induced by Coxsackievirus B3 (CVB3). Then, MEG3 and TNF receptor‐associated factor 6 (TRAF6) were silenced and microRNA‐223 (miR‐223) was over‐expressed in the VMC mice, followed by determination of ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS). Dual‐luciferase reporter assay was introduced to test the interaction among MEG3, TRAF6 and miR‐223. Macrophages were isolated from cardiac tissues and bone marrow, and polarization of M1 or M2 macrophages was induced. Then, the expressions of components of NLRP3 inflammatory body (NLRP3, ASC, Caspase‐1), M1 markers (CD86, iNOS and TNF‐α) and M2 markers (CD206, Arginase‐1 and Fizz‐1) were measured following MEG3 silencing. In the VMC mouse model, MEG3 and TRAF6 levels were obviously increased, while miR‐223 expression was significantly reduced. Down‐regulation of MEG3 resulted in the inhibition of TRAF6 by promoting miR‐223. TRAF6 was negatively correlated with miR‐223, but positively correlated with MEG3 expression. Down‐regulations of MEG3 or TRAF6 or up‐regulation of miR‐223 was observed to increase mouse weight, survival rate, LVEF and LVFS, while inhibiting myocarditis and inflammation via the NF‐κB pathway inactivation in VMC mice. Down‐regulation of MEG3 decreased M1 macrophage polarization and elevated M2 macrophage polarization by up‐regulating miR‐223. Collectively, down‐regulation of MEG3 leads to the inhibition of inflammation and induces M2 macrophage polarization via miR‐223/TRAF6/NF‐κB axis, thus alleviating VMC.

Objectives The correlations between long non‐coding RNAs (lncRNAs) and diverse mammal diseases have been clarified by many researches, but the cognition about bovine mastitis‐related lncRNAs remains limited. This study aimed to investigate the potential role of lncRNA X‐inactive specific transcript (XIST) in the inflammatory response of bovine mammary epithelial cells. Materials and methods Two inflammatory bovine mammary alveolar cell‐T (MAC‐T) models were established by infecting the cells with Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The expressions of pro‐inflammatory cytokines were measured, and the proliferation, viability and apoptosis of the inflammatory cells were evaluated after XIST was knocked down by an siRNA. The relationship among XIST, NF‐κB pathway and NOD‐like receptor protein 3 (NLRP3) inflammasome was investigated using an inhibitor of NF‐κB signal pathway. Results The expression of XIST was abnormally increased in bovine mastitic tissues and inflammatory MAC‐T cells. Silencing of XIST significantly increased the expression of E. coli or S. aureus‐induced pro‐inflammatory cytokines. Additionally, knockdown of XIST could inhibit cell proliferation, suppress cell viability and promote cell apoptosis under inflammatory conditions. Furthermore, XIST inhibited E. coli or S. aureus‐induced NF‐κB phosphorylation and the production of NLRP3 inflammasome. Conclusions The expression of XIST was promoted by activated NF‐κB pathway and, in turn, XIST generated a negative feedback loop to regulate NF‐κB/NLRP3 inflammasome pathway for mediating the process of inflammation.

Ovarian cancer is the leading cause of death in gynecological malignancies worldwide. Our previous studies have proved that metformin inhibited the proliferation and invasion of ovarian cancer in vitro and in vivo. However, the underlying mechanisms have not been fully elucidated. Immunohistochemistry was carried out to detect the expression of tripartite motif‐containing 37 (TRIM37), Ki‐67, and MMP‐9 in ovarian cancer and normal tissues. The influence of TRIM37 on the proliferation and invasion of ovarian cancer cells was verified by the real‐time cellular analysis proliferation test, colony formation test, and Transwell assay. Western blot analysis and immunoprecipitation were used to detect the expression of the nuclear factor‐κB (NF‐κB) pathway and the interaction between TRIM37 and tumor necrosis factor receptor‐associated factor 2 (TRAF2). Ubiquitination detection was carried out to detect the ubiquitination level of TRAF2. The present study revealed that TRIM37 expression was significantly increased in ovarian cancer tissues compared with normal control tissues, and its overexpression was closely associated with proliferation and metastasis. Metformin inhibited the NF‐κB signaling pathway by downregulating TRIM37. Metformin also inhibited the ubiquitination of TRAF2 induced by TRIM37 overexpression. Metformin inhibits the proliferation and invasion of ovarian cancer cells by suppressing TRIM37‐induced TRAF2 ubiquitination. We found that metformin inhibited the NF‐kB signaling pathway via downregulating TRIM37. Metformin inhibited the ubiquitination of TRAF2 induced by TRIM37‐overexpression.

The aim of this study is to investigate the effects of POSTN on IL‐1β induced inflammation, apoptosis, NF‐κB pathway and intervertebral disc degeneration (IVDD) in Nucleus pulposus (NP) cells (NPCs). NP tissue samples with different Pfirrmann grades were collected from patients with different degrees of IVDD. Western blot and immunohistochemical staining were used to compare the expression of POSTN protein in NP tissues. Using the IL‐1β‐induced IVDD model, NPCs were transfected with lentivirus‐coated si‐POSTN to down‐regulate the expression of POSTN and treated with CU‐T12‐9 to evaluate the involvement of NF‐κB pathway. Western blot, immunofluorescence, and TUNEL staining were used to detect the expression changes of inflammation, apoptosis and NF‐κB pathway‐related proteins in NPCs. To investigate the role of POSTN in vivo, a rat IVDD model was established by needle puncture of the intervertebral disc. Rats were injected with lentivirus‐coated si‐POSTN, and H&E staining and immunohistochemical staining were performed. POSTN expression is positively correlated with the severity of IVDD in human. POSTN expression was significantly increased in the IL‐1β‐induced NPCs degeneration model. Downregulation of POSTN protects NPCs from IL‐1β‐induced inflammation and apoptosis. CU‐T12‐9 treatment reversed the protective effect of si‐POSTN on NPCs. Furthermore, lentivirus‐coated si‐POSTN injection partially reversed NP tissue damage in the IVDD model in vivo. POSTN knockdown reduces inflammation and apoptosis of NPCs by inhibiting NF‐κB pathway, and ultimately prevents IVDD. Therefore, POSTN may be an effective target for the treatment of IVDD. In the present experiment, the mechanism of action of POSTN on IL‐1β‐induced nucleus pulposus cells was investigated. Inhibition of POSTN expression can alleviate the inflammatory response and apoptosis of nucleus pulposus cells, and this effect is mediated by inhibiting the activity of NF‐κB pathway. It is believed that our study contributes to the elucidation of the pathogenesis of intervertebral disc degeneration and raises the awareness of the role of POSTN in intervertebral disc degeneration. At the same time, a new perspective on the potential treatment of intervertebral disc degeneration is presented.

Non‐alcoholic steatohepatitis (NASH) is a severe form of fatty liver disease. If not treated, it can lead to liver damage, cirrhosis and even liver cancer. However, advances in treatment have remained relatively slow, and there is thus an urgent need to develop appropriate treatments. Hedan tablet (HDP) is used to treat metabolic syndrome. However, scientific understanding of the therapeutic effect of HDP on NASH remains limited. We used HDP to treat a methionine/choline‐deficient diet‐induced model of NASH in rats to elucidate the therapeutic effects of HDP on liver injury. In addition, we used untargeted metabolomics to investigate the effects of HDP on metabolites in liver of NASH rats, and further validated its effects on inflammation and lipid metabolism following screening for potential target pathways. HDP had considerable therapeutic, anti‐oxidant, and anti‐inflammatory effects on NASH. HDP could also alter the hepatic metabolites changed by NASH. Moreover, HDP considerable moderated NF‐κB and lipid metabolism‐related pathways. The present study found that HDP had remarkable therapeutic effects in NASH rats. The therapeutic efficacy of HDP in NASH mainly associated with regulation of NF‐κB and lipid metabolism‐related pathways via arachidonic acid metabolism, glycine‐serine‐threonine metabolism, as well as steroid hormone biosynthesis.

Turmeric (Curcuma longa) contains various compounds that potentially improve health. Bisacurone is a turmeric-derived compound but has been less studied compared to other compounds, such as curcumin. In this study, we aimed to evaluate the anti-inflammatory and lipid-lowering effects of bisacurone in high-fat diet (HFD)-fed mice. Mice were fed HFD to induce lipidemia and orally administered bisacurone daily for two weeks. Bisacurone reduced liver weight, serum cholesterol and triglyceride levels, and blood viscosity in mice. Splenocytes from bisacurone-treated mice produced lower levels of the pro-inflammatory cytokines IL-6 and TNF-α upon stimulation with a toll-like receptor (TLR) 4 ligand, lipopolysaccharide (LPS), and TLR1/2 ligand, Pam3CSK4, than those from untreated mice. Bisacurone also inhibited LPS-induced IL-6 and TNF-α production in the murine macrophage cell line, RAW264.7. Western blot analysis revealed that bisacurone inhibited the phosphorylation of IKKα/β and NF-κB p65 subunit, but not of the mitogen-activated protein kinases, p38 kinase and p42/44 kinases, and c-Jun N-terminal kinase in the cells. Collectively, these results suggest that bisacurone has the potential to reduce serum lipid levels and blood viscosity in mice with high-fat diet-induced lipidemia and modulate inflammation via inhibition of NF-κB-mediated pathways.

This study was designed to observe the effect of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway activity on sepsis-associated acute kidney injury (SA-AKI), thereby providing new considerations for the prevention and treatment of SA-AKI. The rats were divided into Sham, cecal ligation and puncture (CLP), CLP + vehicle, and CLP + TAK-242 groups. Except the Sham group, a model of CLP-induced sepsis was established in other groups. After 24 h, the indicators related to kidney injury in blood samples were detected. The pathological changes in the kidneys were observed by hematoxylin-eosin staining, and tubular damage was scored. Oxidative stress-related factors, mitochondrial dysfunction-related indicators in each group were measured; the levels of inflammatory factors in serum and kidney tissue of rats were examined. Finally, the expression of proteins related to the TLR4/NF-κB signaling pathway was observed by western blot. Compared with the CLP + vehicle and CLP + TAK-242 groups, the CLP + TAK-242 group reduced blood urea nitrogen (BUN), creatinine (Cr), cystatin-C (Cys-C), reactive oxygen species (ROS), malondialdehyde (MDA), and inflammatory factors levels (  < 0.01), as well as increased superoxide dismutase (SOD) activity of CLP rats (  < 0.01). Additionally, TAK-242 treatment improved the condition of CLP rats that had glomerular and tubular injuries and mitochondrial disorders (  < 0.01). Further mechanism research revealed that TAK-242 can inhibit the TLR4/NF-κB signaling pathway activated by CLP (  < 0.01). Above indicators after TAK-242 treatment were close to those of the Sham group. TAK-242 can improve oxidative stress, mitochondrial dysfunction, and inflammatory response by inhibiting the activity of TLR4/NF-κB signaling pathway, thereby preventing rats from SA-AKI.

Interleukin (IL)‐1β plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. The production of IL‐1β is dependent upon caspase‐1‐containing multiprotein complexes called inflammasomes and IL‐1R1/MyD88/NF‐κB pathway. In this study, we explored whether a potential anti‐fibrotic agent fluorofenidone (FD) exerts its anti‐inflammatory and anti‐fibrotic effects through suppressing activation of NACHT, LRR and PYD domains‐containing protein 3 (NALP3) inflammasome and the IL‐1β/IL‐1R1/MyD88/NF‐κB pathway in vivo and in vitro. Male C57BL/6J mice were intratracheally injected with Bleomycin (BLM) or saline. Fluorofenidone was administered throughout the course of the experiment. Lung tissue sections were stained with haemotoxylin and eosin and Masson's trichrome. Cytokines were measured by ELISA, and α‐smooth muscle actin (α‐SMA), fibronectin, collagen I, caspase‐1, IL‐1R1, MyD88 were measured by Western blot and/or RT‐PCR. The human actue monocytic leukaemia cell line (THP‐1) were incubated with monosodium urate (MSU), with or without FD pre‐treatment. The expression of caspase‐1, IL‐1β, NALP3, apoptosis‐associated speck‐like protein containing (ASC) and pro‐caspase‐1 were measured by Western blot, the reactive oxygen species (ROS) generation was detected using the Flow Cytometry, and the interaction of NALP3 inflammasome‐associated molecules were measured by Co‐immunoprecipitation. RLE‐6TN (rat lung epithelial‐T‐antigen negative) cells were incubated with IL‐1β, with or without FD pre‐treatment. The expression of nuclear protein p65 was measured by Western blot. Results showed that FD markedly reduced the expressions of IL‐1β, IL‐6, monocyte chemotactic protein‐1 (MCP‐1), myeloperoxidase (MPO), α‐SMA, fibronectin, collagen I, caspase‐1, IL‐1R1 and MyD88 in mice lung tissues. And FD inhibited MSU‐induced the accumulation of ROS, blocked the interaction of NALP3 inflammasome‐associated molecules, decreased the level of caspase‐1 and IL‐1β in THP‐1 cells. Besides, FD inhibited IL‐1β‐induced the expression of nuclear protein p65. This study demonstrated that FD, attenuates BLM‐induced pulmonary inflammation and fibrosis in mice via inhibiting the activation of NALP3 inflammasome and the IL‐1β/IL‐1R1/MyD88/ NF‐κB pathway.

ABSTRACT As a multifunctional scavenger receptor, stabilin‐1 (STAB1) has been identified to induce chronic inflammation and promote cancer progression. Although in silico studies from multiple data sets showed that STAB1 might facilitate the progression of acute myeloid leukemia (AML) and drug resistance, the real impacts of STAB1 expression on AML patients and the detailed mechanisms remain unclear. Herein, we found that a higher expression of STAB1 is associated with a worse prognosis in AML patients. Subsequent in vitro experiments demonstrated that STAB1 knockdown suppressed proliferation and promoted apoptosis through regulating the IKK/NF‐κB pathway in human AML cell lines HEL and NB4. In addition, in vivo studies showed that STAB1 silencing prolonged survival, reduced proliferation, and inhibited aggressiveness of AML cells in xenograft mouse models. Moreover, we investigated the impact of STAB1 expression in AML cells on macrophage differentiation and found that co‐culture of macrophages with conditioned medium from STAB1‐knockdown AML cells reduced M2 polarization of macrophages. Taken together, our study suggests that STAB1 promotes growth and aggressiveness of AML cells through activating the IKK/NF‐κB pathway while also regulating M2 macrophage polarization within the chronic inflammatory environment. Therefore, targeting STAB1 could be a potential therapeutic strategy for treating AML. In this study, we explored the effects of silenced STAB1 expression in AML cells on the polarization of M2‐like macrophages, as well as the involvement of nuclear factor‐kappa B (NF‐κB) signaling pathways in the pro‐oncogenic roles of STAB1. By investigating the expression pattern of STAB1 along with its regulatory mechanisms in AML patients, we aimed to shed new light on potential novel strategies for improving the efficacy of AML treatments.