ABSTRACT
Acute kidney injury (AKI) caused by Cis is considered one of the most severe adverse effects, which restricts its use and efficacy. This study seeks to examine the potential reno-protective impact of phenolic compound Hydroxytyrosol (HT) against Cis-induced AKI and the possible involvement of the mi-RNA25/Ox-LDL/NOX4 pathway elucidating the probable implicated molecular mechanisms. Forty rats were placed into 5 groups. Group I received saline only. Group II received Cis only. Group III, IV, and V received 20, 50, and 100 mg/kg b.w, of HT, respectively, with Cis delivery. NOX4, Ox-LDL, and gene expression of mi-RNA 25, TNF-α, and HO-1 in renal tissue were detected. HT showed reno-protective effect and significantly upregulated mi-RNA 25 and HO-1 as well as decreased the expression of NOX4, Ox-LDL, and TNF-α. In conclusion, HT may be promising in the fight against Cis-induced AKI through modulation of mi-RNA25/Ox-LDL/NOX4 pathway.
ABSTRACT
AIM: Liver fibrosis is a serious health problem which is a critical cause of morbidity and mortality worldwide. It is the main complication of untreated chronic inflammatory liver diseases which can progress to liver cirrhosis, hepatocellular carcinoma, and finally death. Coagulation cascade plays a mechanistic role in the pathogenesis of different chronic inflammatory disease including atherosclerosis, stroke, and tissue fibrosis. The current study was designed to investigate the effect of inhibition of coagulation cascade on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. MATERIAL AND METHODS: The study was conducted in rats. Rats were treated with CCl4 subcutaneously for 6 consecutive weeks to determine the onset of coagulation system activation in relation to development of fibrosis. To investigate the effects of coagulation system inhibition in CCl4-induced liver fibrosis, the anticoagulants drugs dabigatran and clopidogrel were administrated orally concurrently with CCl4 treatment. KEY FINDINGS: The results of our study revealed that during the first week, there were significant elevations of fibrin, tissue factor expressions, and prothrombin time (PT) coupled with neutropenia without significant changes in liver fibrosis markers such as TGF-ß, α-SMA and collagen deposition. Starting from the second week, tissue injury markers including the oxidative, inflammatory and fibrosis markers as well as histopathological changes became evident progressively. Intriguingly, dabigatran and clopidogrel significantly normalized the biochemical and pathological changes. SIGNIFICANCE: In conclusion, activation of coagulation cascade is a triggering stimulus in the initiation of CCl4-induced liver fibrosis and the anticoagulant drugs may exert promising anti-fibrotic effect.
Subject(s)
Clopidogrel/pharmacology , Dabigatran/pharmacology , Liver Cirrhosis/drug therapy , Animals , Anticoagulants/metabolism , Anticoagulants/pharmacology , Biomarkers/metabolism , Blood Platelets/drug effects , Blood Platelets/metabolism , Carbon Tetrachloride/pharmacology , Clopidogrel/metabolism , Dabigatran/metabolism , Liver/metabolism , Liver Cirrhosis/metabolism , Liver Cirrhosis/physiopathology , Male , Oxidative Stress/drug effects , Rats , Thrombin/drug effects , Thrombin/metabolismABSTRACT
Activated factor X has a central role in the coagulation activation and also contributes to chronic inflammation and tissue fibrosis. In this study, rivaroxaban, a direct factor X inhibitor, attenuates liver fibrosis induced by carbon tetrachloride (CCl4 ). Male rats were randomly allocated into three groups: a control group, CCl 4 fibrotic group, and CCl 4 +rivaroxaban (5 mg/kg) group. Liver fibrosis was induced by subcutaneous injection of CCl 4 twice a week for 6 weeks. Rivaroxaban significantly restored the biochemical parameter including inflammatory and fibrosis markers with histopathological evidence using routine and Masson trichrome staining. It reduced also the expression of tissue factor, fibrin, transforming growth factor and α-smooth muscle actin in the liver tissues. This concludes that rivaroxaban attenuates liver injury caused by CCl 4 , at least in part by inhibiting coagulation and proinflammatory activation. In conclusion, rivaroxaban may be used for the management of liver fibrosis.
