*3.6. Hepatoprotective Activity*

Sepsis, shock, and renal artery stenosis are the major clinical problems of acute renal failure, usually associated with high morbimortality rates. Ischemia-reperfusion (I-R) injury provokes cell damage, cell death, tissue necrosis, multiorgan dysfunction and increases vascular permeability. These types of physiopathological processes include RNS, ROS, neutrophils, cytokines, platelets, coagulation system, endothelium, and xanthine oxidoreductase enzyme system activation. During I-R injury, cell death occurs as a result of both apoptosis and necrosis [77–79]. RA modulates lipid peroxidation, production of ROS, peroxynitrite formation, complement factors and proinflammatory mediators, such as cytokines and chemokines. These processes are involved in hepatic diseases [80].

On the other hand, RA at dose of 150 mg/kg was able to treat rats with I-R, lowered lipid peroxidation and nitro tyrosine levels, enhanced GSH contents, and reduced neutrophil infiltration, hepatocellular damage, and all oxidative or nitrative stress markers. It also exerted anti-inflammatory and antioxidant effects in the ischemic liver, protecting hepatocytes from ischemic injury [81,82]. Moreover, it also conferred marked protection against oxidative stress through increasing CAT and GPx contents, thus preventing hepatic steatosis. Different RA derivatives have also been reported as having anti-secretory and antiulcer effects in epithelial tissues, being able to heal gastric ulceration [83]. Indeed, RA led to a significant reduction in hepatic toxicity, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipid peroxidation, and oxidized glutathione levels and improved antioxidant effects of GPx, CAT, and SOD enzymes [26]. A marked improvement in liver serum markers and histology and inflammatory process decrease were also stated after RA administration at a dose of 10, 25, and 50 mg/kg by gavage once daily for two consecutive days against CCl4-induced hepatic necrosis. Furthermore, RA prevented α-smooth muscle actin ( α-SMA) and transforming growth factor β1 (TGF-β1) expression, suggesting profibrotic response suppression [84].

Peroxisome proliferator-activated receptor γ (PPARγ) is required for HSCs di fferentiation, and its epigenetic repression carries on the HSCs activation. RA inhibits HSCs signaling and expression by canonical Wnts as well as suppresses liver fibrosis progression and activation [85–87]. In CCl4-induced rat liver fibrosis model, RA inhibited HSCs proliferation and TGF-βl, connective transforming growth factor (CTGF), and α-SMA expression. Much evidence has shown that RA can decrease fibrosis grade and ameliorate biochemical and histopathological morphology in CCl4-induced liver fibrosis [88].

In lipopolysaccharide (LPS)-activated RAW164.7 cells, RA concentration-dependently downregulated IL-6, TNFα, and high mobility group box1 protein levels. RA also inhibited I kappa B kinase pathway and modulated NF-κB. RA intravenous injection also decreased puncture-induced lethality and cecal ligation in rats. Additionally, RA down-regulated serum IL-6 and TNFα levels, triggering receptor expressed on myeloid cells, high mobility group box1 protein, and endotoxin whilst up-regulating the serum IL-6 level. Moreover, post-RA injection, a marked decrease in serum enzyme activities was observed, along with amelioration of liver, lungs, and small intestine hemodynamics; this anti-inflammatory mechanism may be explained through inhibition of NF-κB pathway activation by inhibiting I kappa B kinase activity [89]. RA also decreased ROS production and protein and DNA synthesis inhibition in a dose-dependent manner [90].

In extrahepatic cholestasis rat model by bile-duct ligation, RA showed hepatoprotective e ffect via mechanisms involving resolution of oxidative burden and down-regulation of HMGB1/TLR4, NF-κB, AP-1, and TGF-β1/Smad signaling [91].
