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Sepsis, a systemic inflammatory response mediated by excessive production of diverse inflammatory cytokines, remains the vital cause of morality in the intensive care unit (ICU). TLR4-MD2 (toll-like receptor 4-myeloid differentiation factor 2) complex activated by LPS serves as an effective target to decrease the inflammation during sepsis. In this study, we evaluated the effects of a new small molecule Z20 structural based on (2S, 3R, 4S)-chromene-3-carboxamide on LPS-induced sepsis in mice. We found Z20 markedly improved the survival rate and attenuated the multiply organs injury after LPS administration in mice. In addition, Z20 significantly alleviated organ inflammation as characterized by diminished inflammatory factors expression in vivo. Furthermore, by employing surface plasmon resonance (SPR) experiment, we identified that TLR4-MD2 complex was the potential target for Z20. Finally, we performed the safety assessment experiment to confirm the safety of Z20 in vivo. In conclusion, Z20, as a potential TLR4-MD2 inhibitor, effectively attenuated LPS-induced organ injury and inflammation.

Acetaminophen (APAP) overdose–induced hepatotoxicity is the leading cause of drug-induced liver injury worldwide. The related injury pathogenesis is mainly focused on the liver. Here, the authors report that gut barrier disruption may also be involved in APAP hepatotoxicity. APAP administration led to gut leakiness and colonic epithelial chemokine (C-C motif) ligand 7 (CCL7) up-regulation. Intestinal epithelial cell (IEC)-specific CCL7 transgenic mice (CCL7(tgIEC) mice) showed markedly increased myosin light chain kinase phosphorylation, and elevated gut permeability and bacterial translocation into the liver compared to wild-type mice. Global transcriptome analysis revealed that the expression of hepatic proinflammatory genes was enhanced in CCL7(tgIEC) mice compared with wild-type animals. Moreover, CCL7 overexpression in intestinal epithelial cells significantly augmented APAP-induced acute liver injury. These data provide new evidence that dysfunction of CCL7-mediated gut barrier integrity may be an important contributor to APAP-induced hepatotoxicity.

Sepsis-induced liver injury is recognized as a key problem in intensive care units. The gut microbiota has been touted as an important mediator of liver disease development; however, the precise roles of gut microbiota in regulating sepsis-induced liver injury are unknown. Here, we aimed to investigate the role of the gut microbiota in sepsis-induced liver injury and the underlying mechanism. Cecal ligation and puncture (CLP) was used to induce polymicrobial sepsis and related liver injury. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota in these pathologies. Metabolomics analysis was performed to characterize the metabolic profile differences between sepsis-resistant (Res; survived to 7 days after CLP) and sepsis-sensitive (Sen; moribund before or approximately 24 hours after CLP) mice. Mice gavaged with feces from Sen mice displayed more-severe liver damage than did mice gavaged with feces from Res mice. The gut microbial metabolic profile between Sen and Res mice was different. In particular, the microbiota from Res mice generated more granisetron, a 5-hydroxytryptamine 3 (5-HT3 ) receptor antagonist, than the microbiota from Sen mice. Granisetron protected mice against CLP-induced death and liver injury. Moreover, proinflammatory cytokine expression by macrophages after lipopolysaccharide (LPS) challenge was markedly reduced in the presence of granisetron. Both treatment with granisetron and genetic knockdown of the 5-HT3A receptor in cells suppressed nuclear factor kappa B (NF-кB) transactivation and phosphorylated p38 (p-p38) accumulation in macrophages. Gut microbial granisetron levels showed a significantly negative correlation with plasma alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels in septic patients. Conclusion: Our study indicated that gut microbiota plays a key role in the sensitization of sepsis-induced liver injury and associates granisetron as a hepatoprotective compound during sepsis development.

Sepsis is a serious condition with a high mortality rate worldwide. Granisetron is an anti-nausea drug for patients undergoing chemotherapy. Here we aimed to identify the novel effect of granisetron on sepsis-induced acute lung injury (ALI). Our results showed that mice treated with granisetron displayed less severe lung damage than controls. Granisetron administration reduced pulmonary neutrophil recruitment after CLP. Moreover, the expressions of Cxcl1 and Cxcl2 were diminished in the presence of granisetron in THP-1 macrophages after lipopolysaccharide exposure. Additionally, granisetron could inhibit the activation of p38 MAPK and NLRP3 inflammasome both in vivo and in vitro. Collectively, granisetron protects against sepsis-induced ALI by suppressing macrophage Cxcl1/Cxcl2 expression and neutrophil recruitment in the lung.

Background l-Fucose (Fuc), a six-deoxy hexose monosaccharide, is present endogenously in humans and animals and has a wide range of biological functions. In the present study, we aimed to examine the effect of Fuc on obesity and hepatic steatosis in mice fed a high-fat diet (HFD). Methods C57BL/6 mice were fed a normal chow (NC) or HFD for 18 weeks to induce obesity and fatty liver. Fuc was administered intragastrically from the 8th week to the end of the experiment (18 weeks). Results Metagenomic analysis showed that HFD altered the genomic profile of gut microbiota in the mice; specifically, expression of alpha-l-fucosidase, the gene responsible for Fuc generation, was markedly reduced in the HFD group compared with that in the NC group. Fuc treatment decreased body weight gain, fat accumulation, and hepatic triglyceride elevation in HFD-fed mice. In addition, Fuc decreased the levels of endotoxin-producing bacteria of the Desulfovibrionaceae family and restored HFD-induced enteric dysbiosis at both compositional and functional levels. Conclusion Our findings suggest that Fuc might be a novel strategy to treat HFD-induced obesity and fatty liver.

Liver injury, one of the major side effects of diclofenac (DIC), plagues thousands of patients who treated with it. Although involvements of metabolic factors, oxidative stress, and mitochondrial injury have been characterized, the exact immunomolecular mechanism of the hepatotoxicity of DIC still remains ambiguous. In this study, we investigated the role of chemokine receptors CCR2 and CCR5 in this progression. Ccr2, Ccr5, and Tnfr1/2-deficient mice, as well as wild type littermates, were administrated DIC or vehicle for 24 h, receptively. Hepatic expression of CCR2, CCR5, and their ligands were upregulated after DIC treatment. DIC-induced liver injury was augmented in Ccr2+/+ mice than Ccr2−/− mice, a similar phenotype was observed in Ccr5-deficient mice. In addition, antagonists of CCR2 or CCR5 protected liver damage caused by diclofenac. Besides, the number of neutrophils present in the liver was gradually increased from 0 to 12 h after drug administration. However, the recruitment of neutrophils was dramatically lessened after blocking CCR2 or CCR5 signaling. Furthermore, TNF-α level in the liver was decreased in Ccr2−/− mice compared with Ccr2+/+ mice. Intriguingly, in line with this, TNF receptor 1 and 2 double knockout mice showed markedly attenuated hepatotoxicity of DIC. These suggested that CCR2 and CCR5 mediated hepatotoxicity induced by diclofenac, TNF-α was responsible, at least in part, for it, and the pharmacological inhibition of CCR2 or CCR5 might serve as a novel therapeutic approach for DIC-induced hepatotoxicity.