Dictyophora indusiata polysaccharide attenuated LPS-induced intestinal inflammation of mice via the TLR4/JNK signaling pathway.

BACKGROUND: Dictyophora indusiata polysaccharide is an important bioactive component of D. indusiata, playing an important role in alleviating inflammation. The present study aimed to investigate the anti-inflammatory effect and mechanism of D. indusiata polysaccharide on lipopolysaccharide (LPS)-induced intestinal inflammation in mice. RESULTS: Our results indicated that D. indusiata polysaccharide ameliorated intestinal inflammation of mice by increasing the body weight, the number of goblet cells and decreasing inflammatory cell infiltration. In addition, D. indusiata polysaccharide significantly up-regulated expression of ZO-1, Occuldin mRNA, which were 2.55-fold and 2.28-fold higher than the LPS group, respectively. In particular, D. indusiata polysaccharide effectively inhibited the Toll-like receptor 4 (TLR4)/ c-Jun NH2-terminal kinase (JNK) signalling pathway which was 0.34-fold and 0.49-fold of gene expression and 0.41-fold and 0.39-fold of protein expression in the LPS group, respectively. CONCLUSION: The results of the present study suggested that D. indusiata polysaccharide exerted anti-inflammatory and intestinal protective effects by inhibiting the TLR4/JNK signaling pathway, which will provide a basis for the potential value of D. indusiata polysaccharide as prebiotics in food applications. © 2024 Society of Chemical Industry.

Ebselen improves lipid metabolism by activating PI3K/Akt and inhibiting TLR4/JNK signaling pathway to alleviate nonalcoholic fatty liver.

Nonalcoholic fatty liver disease (NAFLD), a metabolic disease associated with obesity and type 2 diabetes. Due to its complex pathogenesis, there are still limitations in the knowledge of the disease. To date, no drug has been approved to treat NAFLD. This study aims to explore the role and mechanism of Ebselen (EbSe) in NAFLD. A high-fat diet-induced mouse model of NAFLD was employed to investigate EbSe function in NAFLD mice by EbSe gavage and to regularly monitor the mouse body weight. HE and oil red O staining were performed, respectively, to detect the pathological damage and lipid accumulation in mouse liver tissues. The biochemical and ELISA kits were employed to measure the levels of ALT, AST, TG, TC, LDL-C, HDL-C and pro-inflammatory cytokines within mouse serum or liver tissue. The expression of key proteins of PPARα, fatty acid ß oxidation-related protein, PI3K/Akt and TLR4/JNK signaling pathway was detected by western blot. EbSe significantly downregulated body weight, liver weight and liver lipid accumulation in NAFLD mice and downregulated ALT, AST, TG, TC, LDL-C and increased HDL-C serum levels. EbSe upregulated the expression levels of PPARα and fatty acid ß oxidation-associated proteins CPT1α, ACOX1, UCP2 and PGC1α. EbSe promoted Akt and PI3K phosphorylation, and inhibited TLR4 expression and JNK phosphorylation. EbSe can upregulate PPARα to promote fatty acid ß-oxidation and improve hepatic lipid metabolism. Meanwhile, EbSe also activated PI3K/Akt and inhibited TLR4/JNK signaling pathway. EbSe is predicted to be an effective therapeutic drug for treating NAFLD.

Auricularia auricula-judae (Bull.) polysaccharides improve obesity in mice by regulating gut microbiota and TLR4/JNK signaling pathway.

Obesity has emerged as a crucial factor impacting people's lives, and gut microbiota disorders contribute to its development and progression. Auricularia auricula-judae (Bull.) polysaccharides (AAPs), a traditional functional food in Asia, exhibit potential anti-obesity effects. However, the specific mechanism still needs to be further confirmed. This study investigated the beneficial effects and specific mechanisms of AAPs on obesity. Firstly, AAPs showed significant improvements in overweight, insulin resistance, glucose and lipid metabolism disorders, and liver damage in obese mice. Additionally, AAPs ameliorated gut microbiota disorders, promoting the proliferation of beneficial bacteria like Lactobacillus and Roseburia, resulting in increased levels of SCFAs, folate, and cobalamin. Simultaneously, AAPs inhibited the growth of harmful bacteria, thereby protecting intestinal barrier function, improving endotoxemia, and decreasing the levels of inflammatory factors such as TNF-α and IL-6. Furthermore, AAPs can inhibit the TLR4/JNK signaling pathway while promoting the activation of AKT and AMPK. Importantly, our study underscored the pivotal role of gut microbiota in the anti-obesity effects of AAPs, as evidenced by fecal microbiota transplantation experiments. In conclusion, our findings elucidated that AAPs improve obesity by regulating gut microbiota and TLR4/JNK signaling pathway, offering novel perspectives for further conclusion the anti-obesity potential of AAPs.

Astragalus polysaccharide alleviates alcoholic-induced hepatic fibrosis by inhibiting polymerase I and transcript release factor and the TLR4/JNK/NF-κB/MyD88 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragali Radix (AR), the root of Astragalus membranaceus (Fisch.) Bge. or Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, known as Huangqi in traditional Chinese medicine, has been widely used in traditional Chinese medicine prescriptions for acute and chronic liver injury. AR was the most important medicine in a Chinese traditional prescription called Huangqi Decoction (HQD), has been used to treat chronic liver diseases since the 11th century. In particular, its major active ingredient, Astragalus polysaccharide (APS), has demonstrated promising effects on inhibiting hepatic fibrosis. However, to date, the effect of APS against alcohol-induced hepatic fibrosis and its underlying molecular mechanisms remains unknown. AIMS OF THE STUDY: This study aimed to explore the effect and potential molecular mechanisms of APS against alcohol-induced hepatic fibrosis by using network pharmacology and experimental validation. MATERIALS AND METHODS: The potential targets and underling mechanism of AR in alcoholic liver fibrosis were first predicted using network pharmacology, followed by experimental validation using SD rat model with alcohol-induced hepatic fibrosis. Further, the predicted candidate signaling pathways and potential target polymerase I and transcript release factor (PTRF) were combined to explore the multifaceted mechanism of APS against alcohol-induced hepatic fibrosis. Finally, overexpression of PTRF was explored to reveal the role of PTRF in the mechanism of APS against alcohol-induced hepatic fibrosis. RESULT: APS exerted potent anti-hepatic fibrosis effects by downregulating genes involved in the Toll-like receptor 4 (TLR4)/JNK/NF-κB/MyD88 pathway. Notably, APS treatment ameliorated the hepatic damage by inhibiting the overexpression of PTRF and decreasing the co-localisation of TLR4/PTRF. Overexpression of PTRF induced reversal of the protective effects of APS on alcohol-induced hepatic fibrosis. CONCLUSION: This study indicated that APS may alleviate alcohol-induced hepatic fibrosis by inhibiting the activation of PTRF and TLR4/JNK/NF-κB/MyD88 pathway, which provides a scientific elucidation for the mechanisms of APS on the anti-hepatic fibrosis activity and presents a promising therapeutic approach for treating hepatic fibrosis.

Inhibitory effects of fluoxetine on the secretion of inflammatory mediators and JAK/STAT3 and JNK/TLR4 gene expression.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the most common class of medicines used for the treatment of major depression. Recent studies have reported an association between depression and inflammation and suggested the significant effects of SSRIs on inflammatory processes. METHODS: The current study aimed to evaluate the effects of fluoxetine, an SSRI, on the level of inflammatory cytokines, including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), in the rat serum and RAW264.7 mouse macrophage cell line, using ELISA sandwich assays. Also, the expression of inflammatory genes, including JAK/STAT3 and TLR4/JNK, was examined in macrophages, using real-time quantitative reverse transcription PCR to determine the potential mechanism of fluoxetine in inflammation. The rats received fluoxetine (10, 20, and 40 mg/kg) 30 min before lipopolysaccharide (LPS) treatment for 90 min. The cells received different doses of fluoxetine (5, 10, and 20 µg/mL) before stimulation with LPS for 24 or 48 h. RESULTS: The serum concentrations of IL-1ß, IL-6, and TNF-α were reduced in rats and cells treated with fluoxetine. Following fluoxetine administration, the expression of JAK/STAT3 and TLR4/JNK genes was significantly decreased in the RAW264.7 cells treated with LPS for 24 h. However, after 48 h of treatment with LPS, fluoxetine failed to diminish the elevated expression of JAK and JNK genes, while it significantly decreased the expression of STAT3 and TLR4 genes. CONCLUSION: The findings revealed that fluoxetine has anti-inflammatory properties, mainly due to the reduction of inflammatory cytokines and inhibition of JAK/STAT3 and TLR4/JNK gene expression in macrophages.

Anfibatide protects against rat cerebral ischemia/reperfusion injury via TLR4/JNK/caspase-3 pathway.

Anfibatide (ANF) is a GPIb antagonist derived from the protein complex agglucetin. Previous studies have showed that it has protective effect on cerebral ischemia/reperfusion injury, the mechanism of which is still unclear, however. The present study was designed to investigate the protective effect of ANF on cerebral I/R injury in rats and the possible mechanisms. Focal cerebral ischemia was induced by 90min of transient middle cerebral artery occlusion (MCAO). ANF (1, 2, 4µg/kg) was achieved by intravenous injection after 120min of MCAO followed by 1h, 24h ,48h and 72h reperfusion. Neurological deficit, infarct volume, histopathology, neuronal apoptosis, NeuN and the expression of TLR4, total and phosphorylated c-Jun NH2-terminal kinase (JNK/p-JNK), Bcl-2, Bax, caspase-3, NF-κB protein in rat brain, the levels of IL-1ß, IL-6 and TNF-α in serum were evaluated 72h after reperfusion. ANF could significantly decrease neurological score, reduce the infarct volumes, ameliorate the histopathological alteration, attenuate the neuronal apoptosis and increase the fluorescence density of NeuN in the rat brain. Furthermore, ANF could obviously decrease the expression of TLR4, p-JNK, caspase-3, NF-κB , relative ratio of Bax/Bcl-2 in brain and the levels of IL-1ß, IL-6 and TNF-α in serum. The results indicate that ANF has protective effect against cerebral I/R injury in rats and the underlying mechanism may be associated with the suppression of apoptosis through inhibiting TLR4/JNK/caspase-3 signaling pathway.

Discovery of novel sesquistilbene indanone analogues as potent anti-inflammatory agents.

To develop novel anti-inflammatory agents with improved pharmaceutical profiles, twenty-eight novel sesquistilbene indanone analogues were synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. Among these compounds, compound 11k was found to be one of the most potent analogues in inhibiting NO production in LPS-stimulated RAW264.7 cells. Furthermore, it could also significantly suppress LPS-induced iNOS and COX-2 expression and NO production through TLR4/JNK/NF-κB signaling pathway in a concentration dependent manner.