Berberine ameliorates CCl4‑induced liver injury in rats through regulation of the Nrf2‑Keap1‑ARE and p53 signaling pathways

Abstract

Berberine (BBR) is an isoquinoline alkaloid, reported to have multiple pharmacological functions. However, its effects against CCl4-induced oxidative damage remain poorly studied. Therefore, the present study investigated the protective action of BBR, and its antioxidant mechanisms, against CCl4-induced liver injury in rats. A total of 48 rats were randomly arranged into six groups: Control; model; positive control (PC); BBR low-dose (BL); BBR middle-dose (BM); and BBR high-dose (BH). The BL, BM and BH animals received BBR (5, 10 and 15 mg/kg by weight, respectively) orally for 7 consecutive days. Rats in the PC group were given silymarin (150 mg/kg), and the control and model groups were administered distilled water orally. At the end of the experiment, blood samples and livers were collected. To measure the liver biochemical indices, the reactive oxygen species (ROS) generation and the expression levels of related genes and protein, the following methods were used: An automatic biochemical analyzer; flow cytometry; spectrophotometry; reverse transcription-quantitative PCR; western blotting; and hematoxylin and eosin staining. The results revealed that BBR significantly decreased the serum levels of alanine transaminase, aspartate transaminase and alkaline phosphatase, and increased those of glutathione and superoxide dismutase, but decreased malondialdehyde activity in hepatic tissue, and significantly decreased the reactive oxygen species level in hepatocytes. In hepatic tissue, the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), kelch-like ECH-associated protein 1 (Keap-1), NAD(P)H quinone dehydrogenase 1 (NQO-1), heme oxygenase 1 (HO-1), Bcl-2 and Bcl-xL mRNA, and HO-1 protein were elevated, and the expression of p53 mRNA was decreased, particularly in the BH group (15 mg/kg). In conclusion, BBR exerts a protective action against CCl4-induced acute liver injury in rats via effectively regulating the expression of Nrf2-Keap1-antioxidant responsive element-related genes and proteins, and inhibiting p53 pathway-mediated hepatocyte apoptosis.

Protective effect of Moringa oleifera Lam. leaf extract against carbon tetrachloride-induced neuroinflammation in a mouse model of hepatic encephalopathy

“…Moreover, the decline of GSH and SOD levels was reportedly due to ROS release in the CCl 4 mouse model of encephalopathy 29 . The dysregulated antioxidant mechanism in the current model was in line with previous reports 1,30 , in which an elevated MDA and reduced antioxidant mechanism in different brain regions were observed following CCl 4 intoxication. MOLE pretreatment successfully restored the antioxidative power in HC and CC through the reduction of MDA and restoration of antioxidative mechanisms which was in agreement with Idoga et al, (2018) 31 .…”

The antioxidant and anti-inflammatory effects of Carica Papaya Linn. seeds extract on CCl4-induced liver injury in male rats

“…These results are in agreement with the biochemical results where CCl 4 administration caused a significant elevation in MDA and NO levels beside GSR activity, with significant declines in GSH level and the activities of SOD, t-GPx and GST as compared to the control group. This indicates that CCl 4 induced OS where it increased LP and disrupted the antioxidant system in the liver [ 56 , 57 ]. In the liver, CCl 4 is bio-transformed into active metabolites (CCl 3 • and CCl 3 OO•) which are responsible for the increment of the MDA level through the enhancement of LP of the polyunsaturated fatty acids of the cell membrane [ 58 – 60 ].…”

“…6 ” indicating that CCl 4 induces hepatocytes apoptosis. Where, p53 triggers the apoptosis by increasing the pro-apoptotic gene expression and decreasing the anti-apoptotic genes [ 57 , 75 ]. Previous studies reported that the promoter of the p53 gene has different binding sites one of them for p53 itself and another one for NF-κB since, the activation of NF-κB lead to up-regulation of p53 gene expression [ 60 ].…”

“…Previous studies reported that the promoter of the p53 gene has different binding sites one of them for p53 itself and another one for NF-κB since, the activation of NF-κB lead to up-regulation of p53 gene expression [ 60 ]. Moreover, the elevation of OS induced by CCl 4 stimulates apoptosis via the elevation of gene expression of p53 and Bax and decreasing the gene expression of Bcl-2 and Bcl-xL [ 57 , 75 ].…”

Dietary Flavonoids in p53—Mediated Immune Dysfunctions Linking to Cancer Prevention

“…Pretreatment with quercetin further activates the Keap1/Nrf2/ARE-anti-oxidant pathway, which induces cellular defenses against various oxidative stress [128]. Recent reports have shown that p53 can activate the Keap1/Nrf2/ARE-anti-oxidant pathway and can act as the main regulator of the cells anti-oxidant response [129,130]. This effect of p53 largely depends on the intensity and degree of oxidative stress imposed.…”