Ischemia-reperfusion injuries (IRI) occur in different clinical conditions such as stroke, trauma, organ transplantation, and so on. Ischemia damages mainly arise from oxygen depletion in tissues. The lack of oxygen as the last acceptor of electron in the respiratory chain causes a decrease in ATP production and eventually leads to disruption of membrane transport, acidosis, cellular edema and membrane distortion of organelles, and cells. Reperfusion can intensify ischemic injuries by the infiltration of inflammatory cells and also oxygen and calcium overloading. Since the tissue antioxidant contents decreased due to increased generation of reactive oxygen species (ROS) during IRI, the application of antioxidants is considered an appropriate strategy to ameliorate IRI. Silymarin constitutes about 70–80% of silybum marianum dry extract and is known as a strong free radical scavenger with anti-inflammatory properties. In several studies, silibinin as a major component of Silymarin could provide protective effects in various tissue IRI by different mechanisms such as scavenging free radicals, decreasing inflammatory cytokines, inhibiting cellular death, and increasing the expression of antioxidant enzymes. To clarify functional mechanisms, the present article evaluates studies about silymarin effects in different tissues IRI.

This research examined silibinin's anti-inflammatory outcomes on the NOD-like receptor protein-3 (NLRP3) and NF-κB gene expression, which plays a notable role in inciting inflammatory pathways. Hepatic ischemia-reperfusion (I/R) is a common phenomenon in many clinical cases, including liver surgery and transplantation. Inflammatory mediators are vital contributors to the expansion of hepatic damage after I/R injury (I/RI), and therefore, targeting inflammation is a considerable candidate for the management of hepatic I/RI and its complications. Thirty-two male Wistar rats were divided equally into four groups: 1) Control (Vehicle) group, in which rats underwent laparotomy and received normal saline; 2) SILI group, in which rats underwent laparotomy, and 30 mg/kg silibinin was injected intraperitoneal (IP); 3) I/R group, in which rats underwent I/R and received normal saline; and 4) I/R + SILI group, who encountered I/R after laparotomy and received silibinin. After one hour of ischemia and three hours of reperfusion, blood and liver tissue samples were assembled for future biochemical, histological, and gene expression studies. In vivo analysis attested that serum AST and ALT activities were significantly lessened by silibinin in the SILI + I/R group (p <0.001). Silibinin ameliorated inflammatory liver tissue injuries, including neutrophil and macrophage infiltration, hepatocyte degeneration, cytoplasmic vacuolation, vascular endothelial damages, and sinusoid dilation observed in the I/R group. During I/R, NLRP3 and NF-κB gene expression showed a significant increment compared to the control group (p <0.001), which could be alleviated by silibinin (p <0.01). The results evidence that adjusting the expression of NLRP3 and NF-κB genes during I/R is probably one of the mechanisms of the anti-inflammatory effects of silibinin.

Introduction: Hepatic fat accumulation is a complication of non-alcoholic fatty liver disease (NAFLD). An AMP-activated protein kinase (AMPK) reduces the synthesis of fatty acids by inhibiting sterol regulatory element-binding transcription factor 1-c (SREBP1-C) and acetyl COA carboxylase (ACC). Objectives: We aimed to investigate the impress of galbanic acid (Gal) from the Ferula plant on AMPK and its inhibitory effect on lipogenic enzymes in HepG2 cells. Materials and Methods: In an applied-fundamental study, HepG2 cells were treated for 24 hours with Gal in palmitate (Pal). Resveratrol (RSV) was conducted as a positive control. Fatty acid synthase (FAS) and SREBP1-C gene expression were evaluated by reverse transcription polymerase chain reaction (RT-PCR). FAS, phospho-acetyl-CoA carboxylase (P-ACC), P-AMPK, AMPK, SREBP-1c, and ACC protein levels were measured by western blotting. Lipid accumulation was investigated qualitatively and semi-quantitatively with oil red. Results: The semi-quantitative results of oil revealed a substantial reduction (P<0.004) in lipid accumulation for treatment with Gal. The significant increase in the protein level of P-AMPK (P<0.001) and P-ACC (P=0.054) and significant decrease in FAS (P<0.003), SREBP-1c (P<0.001) and ACC (P<0.011) due to the effect galbanic acid was observed. FAS gene expression decreased significantly (P<0.009), while the decrease in SREBP-1c gene expression was not significant (P=0.303). Conclusion: These findings direct that galbanic acid can be a new regulator of AMPK. Hence, the present study may introduce galbanic acid as a new plan to positively regulate the AMPK pathway, which leads to the regulation of various cellular processes.

Objective(s): Signal transduction of mitogen-activated protein kinases (MAPKs) is activated during ischemia. In this study, c-Jun N-terminal Kinase (JNK) and p38 MAPK (p38) gene and protein expression were evaluated as two members of the MAPK family during liver ischemia-reperfusion in rats. Materials and Methods: Thirty-two male Wistar rats were divided into four groups of eight: Vehicle, ischemia-reperfusion (IR), ischemia-reperfusion+silibinin (IR+SILI), and SILI. The IR and IR+SILI groups differed from the other two groups in that they underwent one hour of ischemia followed by three hr of reperfusion. The Vehicle and IR groups received normal saline while the SILI and IR+SILI groups were treated with silibinin (50 mg/kg). At the end of the reperfusion time, blood and ischemic liver tissue were collected for further experiments. Results: The expression of JNK and p38 gene, the amount of serum hepatic injury indices, and malondialdehyde (MDA) in the IR group increased significantly compared with the vehicle group. The JNK and p38 gene expression decreased significantly in the IR + SILI group compared with the IR group. Glutathione peroxidase (GPx) and total antioxidant capacity (TAC) levels decreased in the IR group while increasing in the IR+SILI group. Histological examination showed that silibinin significantly reduced the severity of hepatocyte degradation. Western blot results were completely consistent with real-time PCR results. Conclusion: The possible pathways of the protective effect of silibinin against hepatic ischemia damages is to reduce the expression of the p38 and JNK gene and protein.