Sodium humate ameliorates LPS-induced liver injury in mice by inhibiting TLR4/NF-κB and activating NRF2/HO-1 signaling pathways.

BACKGROUND: Acute liver damage is a type of liver disease that has a significant global occurrence and a lack of successful treatment and prevention approaches. Sodium humate (HNa), a natural organic substance, has extensive applications in traditional Chinese medicine due to its antibacterial, anti-diarrheal, and anti-inflammatory characteristics. The purpose of this research was to examine the mitigating impacts of HNa on liver damage induced by lipopolysaccharide (LPS) in mice. METHODS AND RESULTS: A total of 30 female mice were randomly assigned into Con, Mod, L-HNa, M-HNa, and H-HNa groups. Mice in the Con and Mod groups were gavaged with PBS, whereas L-HNa, M-HNa, and H-HNa groups mice were gavaged with 0.1%, 0.3%, and 0.5% HNa, daily. On day 21, Mod, L-HNa, M-HNa, and H-HNa groups mice were challenged with LPS (10 mg/kg). We discovered that pretreatment with HNa improved liver pathological damage and inflammation by inhibiting the toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway, enhancing the polarization of liver M2 macrophages, and reducing the levels of inflammatory cytokines. Our further study found that pretreatment with HNa enhanced the liver ability to combat oxidative stress and reduced hepatocyte apoptosis by activating the nuclear factor erythroid-2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway and enhancing the activities of antioxidant enzymes. CONCLUSIONS: In conclusion, HNa could alleviate LPS-induced liver damage through inhibiting TLR4/NF-κB and activating NRF2/HO-1 signaling pathways. This study is the first to discover the therapeutic effects of HNa on liver damage induced by LPS.

Sodium humate alleviates LPS-induced intestinal barrier injury by improving intestinal immune function and regulating gut microbiota.

Sodium humate (HNa), known for its abundant functional active groups, is extensively utilized in food dietary supplements due to its versatile properties. Furthermore, HNa possesses notable anti-inflammatory, antioxidant, and anti-diarrheal properties. This research endeavor aimed to elucidate the protective effects of HNa against intestinal barrier injury induced by lipopolysaccharide (LPS). The findings of this study demonstrated that pretreatment with HNa effectively mitigated intestinal barrier injury in the jejunum. HNa exhibited inhibitory effects on the activation of the NLRP3 inflammasome and the production of inflammatory factors within the intestine. HNa supplementation also contributed to the upregulation of mucin and tight junctions (TJs) expression, consequently enhancing the integrity of the intestinal barrier. Notably, our investigation revealed that HNa shared comparable efficacy with the TLR4 inhibitor TAK-242 in inhibiting the TLR4/NFκB signaling pathway. Furthermore, an in-depth analysis of the gut microbiota demonstrated that HNa exerted a regulatory influence on LPS-induced microflora disturbance. In conclusion, these findings collectively indicate that HNa mitigates LPS-induced mucosal damage in the jejunum and preserves the integrity of the intestinal barrier by modulating intestinal immune function and regulating gut microbiota.

Sodium Humate-Derived Gut Microbiota Ameliorates Intestinal Dysfunction Induced by Salmonella Typhimurium in Mice.

Salmonella is a foodborne pathogen that is one of the main causes of gastroenteric disease in humans and animals. As a natural organic substance, sodium humate (HNa) possesses antibacterial, antidiarrheal, and anti-inflammatory properties. However, it is unclear whether the HNa and HNa-derived microbiota exert alleviative effects on Salmonella enterica serovar Typhimurium-induced enteritis. We found that treatment with HNa disrupted the cell wall of S. Typhimurium and decreased the virulence gene expression. Next, we explored the effect of HNa presupplementation on S. Typhimurium-induced murine enteritis. The results revealed that HNa ameliorated intestinal pathological damage. In addition, we observed that presupplementation with HNa enhanced intestinal barrier function via modulating gut microbiota, downregulating toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) and NOD-like receptor protein 3 (NLRP3) signaling pathways, regulating intestinal mucosal immunity, and enhancing tight junction protein expression. To further validate the effect of HNa-derived microbiota on S. Typhimurium-induced enteritis, we performed fecal microbiota transplantation and found that HNa-derived microbiota also alleviated S. Typhimurium-induced intestinal damage. It is noteworthy that both HNa and HNa-derived microbiota improved the liver injury caused by S. Typhimurium infection. Collectively, this is the first study to confirm that HNa could alleviate S. Typhimurium-induced enteritis in a gut microbiota-dependent manner. This study provides a new perspective on HNa as a potential drug to prevent and treat salmonellosis. IMPORTANCE Salmonella Typhimurium is an important zoonotic pathogen, widely distributed in nature. S. Typhimurium is one of the leading causes of foodborne illnesses worldwide, and more than 350,000 people died from Salmonella infection each year, which poses a substantial risk to public health and causes a considerable economic loss. Here, we found that the S. Typhimurium infection caused severe intestinal and liver damage. In addition, we first found that sodium humate (HNa) and HNa-derived gut microbiota can alleviate S. Typhimurium infection-induced intestinal damage. These findings extend the knowledge about the public health risk and pathogenic mechanisms of S. Typhimurium.

Dioscin ameliorates cisplatin-induced intestinal toxicity by mitigating oxidative stress and inflammation.

Cisplatin is the most widely prescribed drug in chemotherapy, but its gastrointestinal toxicity reduces therapeutic efficacy. Oxidative stress and inflammation are considered to be the main pathogenesis of cisplatin-induced intestinal toxicity. Dioscin is a steroidal saponin with potential anti-cancer, antioxidant, and anti-inflammatory activities. In this study, we established a rat model of intestinal injury by tail vein injection of cisplatin, and intragastrically administered dioscin to evaluate its effect on intestinal injury. Biochemical markers, western blotting, qRT-PCR and histopathological staining were used to analyze intestinal injury according to various molecular mechanisms. The results revealed that dioscin significantly inhibited cisplatin-induced intestinal mucosal damage and decreased DAO levels in rats. Furthermore, dioscin activated the Nrf2/HO-1 pathway to increase the level of antioxidant enzymes and reduce the levels of MDA and H2O2. In addition, dioscin pretreatment significantly reduced ileum epithelial NLRP3 inflammasome formation and decreased the levels of inflammatory factors compared with the cisplatin group. In parallel, Nrf2 inhibitor ML385 blocked the therapeutic effect of dioscin in rat with cisplatin-induced intestinal toxicity. In terms of mechanisms, dioscin reversed cisplatin-induced up-regulation of MAPKs and up-regulated p-PI3K and p-AKT levels. Meanwhile, dioscin potently promoted Wnt3A/ß-catenin signaling to relieve cisplatin-induced proliferation inhibition. In conclusion, our study suggests that dioscin could ameliorate the cisplatin-induced intestinal toxicity by reducing oxidative stress and inflammation.

Sodium Humate Alleviates Enterotoxigenic Escherichia coli-Induced Intestinal Dysfunction via Alteration of Intestinal Microbiota and Metabolites in Mice.

Enterotoxigenic Escherichia coli (ETEC) can damage intestinal epithelial barrier function and lead to serious intestinal diarrhea in newborns and young animals. Sodium humate (HNa) is natural organic bioactive compound possessing antibacterial, anti-inflammatory, and anti-diarrheal properties. This study investigated the alleviative potential of HNa on the impaired intestinal barrier and intestinal inflammation, and regulatory effects on gut microbiota and metabolites in ETEC K88 infected mice. A total of 30 female mice were randomly assigned into three groups. The mice in the control and ETEC groups were gavaged with 0.2 mL of sterile saline, while the mice in the ETEC + HNa group were gavaged with 0.2 mL of 5% HNa, daily. On day 8, the mice in ETEC and ETEC + HNa group were challenged with ETEC K88. The trial lasted for 12 days. HNa administration elevated ETEC K88-induced body weight loss and ameliorated jejunum and colon pathological injury. HNa also reduced the levels of pro-inflammatory cytokines in the serum, jejunum, and colon. Additionally, HNa reduced intestinal barrier damage by up-regulating the expression of tight junction proteins (TJPs) and mucosal repair factors. 16s rDNA gene sequencing results showed that HNa increased the abundance of beneficial bacteria Lactobacillus, Prevotella_9, and Odoribacter but decreased the abundance of pathogenic bacteria Escherichia and Gastranaerophilales in the feces of mice. Moreover, metabolomic analysis revealed that the concentrations of 15 metabolites, the pathways of protein digestion and absorption, and propanoic acid metabolism were changed by HNa administration. In conclusion, HNa could alleviate ETEC K88-induced intestinal dysfunction through restoring intestinal barrier integrity, modulating gut microbiota, and metabolites.