Febuxostat mitigates concanavalin A-induced acute liver injury via modulation of MCP-1, IL-1ß, TNF-α, neutrophil infiltration, and apoptosis in mice.

AIM: Liver plays a crucial role in innate immunity reactions. This role predisposes the liver to innate-mediated liver injury when uncontrolled inflammation occurs. In this study, the effect of febuxostat administration on acute liver injury induced by concanavalin A (Con A) injection into mouse eye orbital sinus was studied. MATERIALS AND METHODS: Two doses of febuxostat (10 and 20 mg/kg, orally) were administered either 1 h before or 30 min after the administration of Con A. Febuxostat at a low dose (10 mg/kg) before and after Con A modulated the elevation of serum ALT, liver uric acid, liver myeloperoxidase (MPO), and interleukin-1ß (IL-1ß) induced by Con A. The same dose of febuxostat before Con A also decreased serum total bilirubin and neutrophil infiltration, as evidenced by flow cytometry and histopathological analysis. KEY FINDINGS: Febuxostat at a high dose (20 mg/kg) significantly improved serum ALT, AST, albumin, total bilirubin, liver uric acid, MPO, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-4 (IL-4), IL-1ß, and neutrophil infiltration induced by Con A administration. The results of histopathological examination of liver cells paralleled the observed biochemical improvements. Hepatocyte apoptosis as evidenced by immunohistochemical examination of cleaved caspase-3 was markedly decreased in the febuxostat protection and treatment groups, in a dose-dependent manner SIGNIFICANCE: These results indicate that febuxostat, especially at the higher dose, may be an effective inhibitor of immune reactions evoked by Con A administration.

Effect of tranilast in comparison with beclomethasone in chronic murine model of asthma.

AIM OF THE STUDY: The current investigation was taken to scrutinize the action of tranilast on the airway remodeling in chronic asthma in mice. MATERIALS AND METHODS: Intraperitoneal injection of ovalbumin was applied to mice for sensitization and subsequent inhalation of 1% ovalbumin three times week for 10 weeks for challenge. Beclomethasone or tranilast were given daily for the 10 week challenge period. At the end of the study, lung weight index, total collagen content, bronchoalveolar lavage level of total and differential cell counts, interleukin-13, in addition to lung tissue nitrate/nitrite and transforming growth beta-1 were measured. Also, histological analysis was done. RESULTS: Asthmatic mice demonstrated apparent fibrotic changes. Significant airway fibrosis was demonstrated by hyperplasia of goblet cells and thickening of airway epithelium, increased content of lung collagen, lung and bronchoalveolar lavage of transforming growth factor beta-1 and interleukin-13 mutually accompanied by reduction in nitrate/nitrite generation. CONCLUSIONS: Beclomethasone influence on airway remodeling was mediated mainly via suppression of eosinophilic recruitment into the airways and reduction of interleukin-13 cytokine levels. Whereas, tranilast effects on airway remodeling was found to be mainly mediated via its inhibitory effect on transforming growth beta-1. Both beclomethasone and tranilast influence airway remodeling by different degrees and mechanisms.

Pomegranate protects liver against cecal ligation and puncture-induced oxidative stress and inflammation in rats through TLR4/NF-κB pathway inhibition.

Acute liver injury secondary to sepsis is a major challenge in intensive care unit. This study was designed to investigate potential protective effects of pomegranate against sepsis-induced acute liver injury in rats and possible underlying mechanisms. Pomegranate was orally given (800mg/kg/day) for two weeks before sepsis induction by cecal ligation and puncture (CLP). Pomegranate improved survival and attenuated liver inflammatory response, likely related to downregulation of mRNA expression of toll like recptor-4, reduced nuclear translocation and DNA binding activity of proinflammatory transcription factor NF-κB subunit p65, decreased mRNA and protein expression of tumor necrosis factor-alpha and reduction in myeloperoxidase activity and mRNA expression. Pomegranate also decreased CLP-induced oxidative stress as reflected by decreased malondialdehyde content, and increased reduced glutathione level and superoxide dismutase activity. These results confirm the antiinflammatory and antioxidant effects of pomegranate in CLP-induced acute liver injury mediated through inhibiting TLR4/NF-κB pathway, lipid peroxidation and neutrophil infiltration.