fumarates and Sepsis

Sepsis is a potentially fatal illness that can lead to impairment of multiple organs such as liver. The condition is deeply associated with oxidative stress and inflammation. Monomethyl fumarate (MMF) has manifested antioxidant and immunomodulatory properties. The aim of current study was to evaluate protective effects of MMF in sepsis-induced hepatic dysfunction.. Sepsis was induced by cecal ligation and puncture (CLP). Wistar rats were assigned to one of sham, CLP, CLP + dexamethasone (as positive control of inflammation) and CLP + MMF groups. Levels of serum IL-1β, IL-6, IL-10, AST, ALT and γ‑GT were quantified. Furthermore, Hepatic levels of GSH and MDA and mRNA expression of TNF and NFKBIA along with hepatic protein level of TLR-4 were assessed. Also, histopathological study of liver was carried out to evaluate hepatic injuries.. Septic rats demonstrated risen levels of IL-1β, IL-6, IL-10, AST, ALT and γ‑GT, while treatment with dexamethasone or MMF attenuated these levels. Moreover, enhancements in protein level of TLR-4 and mRNA levels of TNF and NFKBIA were observed in CLP rats. These elevations were mitigated in CLP-induced rats that were treated with either dexamethasone or MMF. Treatment with dexamethasone or MMF also shifted sepsis-induced disturbance in the levels of GSH and MDA towards sham levels. Hepato-protective effects of dexamethasone and MMF were further confirmed by histopathological observations.. Our findings imply that MMF alleviates sepsis-induced hepatic dysfunction by mitigating the inflammatory and oxidative state and this effect is at least partly mediated by the inhibition of TLR-4/NF-κB signalling pathway.

Topics: Animals; Antioxidants; Dexamethasone; Disease Models, Animal; Fumarates; Inflammation; Liver Diseases; Male; Maleates; NF-kappa B; NF-KappaB Inhibitor alpha; Oxidative Stress; Rats; Rats, Wistar; RNA, Messenger; Sepsis; Signal Transduction; Toll-Like Receptor 4

The sepsis caused by Vibrio vulnificus is characterized by an average incubation period of 26 h and a high mortality rate exceeding 50%. The fast growth and dissemination of V. vulnificus in vivo lead to poor clinical outcomes in patients. Therefore, elucidation of the proliferation mechanisms of this organism in vivo may lead to the development of an effective therapeutic strategy. In this study, we focused on the low oxygen concentration in the intestinal milieu because of its drastic difference from that in air. Fumarate and nitrate reduction regulatory protein (FNR) is known to be a global transcriptional regulator for adaptation to anaerobic conditions in various bacteria. We generated a strain of V. vulnificus in which the fnr gene was replaced with an erythromycin resistance gene (fnr::erm mutant). When the fnr::erm mutant was tested in a growth competition assay against the wild-type (WT) in vivo, the competitive index of fnr::erm mutant to WT in the intestinal loop and liver was 0.378 ± 0.192 (mean ± SD) and 0.243 ± 0.123, respectively. These data suggested that FNR is important for the proliferation of V. vulnificus in the intestine to achieve a critical mass to be able to invade the systemic circulation.

Topics: Anaerobiosis; Animals; Bacterial Proteins; Cell Division; Escherichia coli; Fumarates; Gene Deletion; Humans; Intestines; Mice; Mutation; Nitrates; Oxidation-Reduction; Sepsis; Transcription Factors; Vibrio vulnificus

Sepsis and sepsis-related acute lung injuries (ALIs) are one of the main causes of death among hospitalized patients. Renin-angiotensin-aldosterone system (RAAS) has been reported to have role in sepsis. However, there is no study on aliskiren, a renin inhibitor, on sepsis-induced ALI. We aimed to investigate the potential protective effects of aliskiren in a model of cecal ligation and puncture (CLP)-induced lung injury. The rats were separated into five groups: sham, CLP, CLP + aliskiren 50 mg/kg (per orem (p.o.)), CLP + aliskiren 100 mg/kg (p.o.), and sham + aliskiren 100 mg/kg (p.o.). CLP model was applied via ligation of cecum and two punctures. After experiment, biochemical, molecular, and pathologic examinations were performed on lung and serum samples of rats. In our study, sepsis decreased superoxide dismutase (SOD) and glutathione (GSH) and increased malondialdehyde (MDA) in lung tissues of rats while aliskiren increased the SOD and GSH and decreased MDA. Also, sepsis caused a significant increase in pro-inflammatory cytokine levels (TNF-α, IL-1β, and IL-6) while aliskiren administration decreased these cytokines. Also, aliskiren administration at high dose protected lungs in pathologic evaluation. As a result of RAAS inhibition, aliskiren caused a decrease in serum angiotensin II level and increase in serum renin level. In light of these observations, we can suggest that the therapeutic administration of aliskiren prevented oxidative stress changes and cytokine changes and also protected lung tissues during CLP-induced sepsis by changing status of RAAS.

Topics: Amides; Angiotensin II; Animals; Fumarates; Glutathione; Lipid Peroxidation; Lung Injury; Male; Oxidative Stress; Rats; Rats, Wistar; Renin; Sepsis; Treatment Outcome