Involvement of PI3K/Akt pathway in the protective effect of hesperidin against a chemically induced liver cancer in rats

Abstract

Hesperidin is a flavanone glycoside that is found in the Citrus species and showed antioxidant, hepatoprotective as well as anticancer activity. This study investigated the effect of hesperidin on the PI3K/Akt pathway as a possible mechanism for its protective effect against diethylnitrosamine (DEN)‐induced hepatocellular carcinoma (HCC). Adult Wistar rats were divided into Control group (received drug vehicle); DEN group (received 100 mg/L of DEN solution for 8 weeks), and hesperidin + DEN group (received 200 mg/kg body weight of hesperidin/day orally for 16 weeks + DEN solution as DEN group). Our findings showed that the administration of hesperidin significantly decreased the elevation in liver function enzymes, serum AFP level, and oxidative stress markers. Moreover, hesperidin administration suppressed DEN‐induced upregulation of PI3K, Akt, CDK‐2 protein expression, and preserved the integrity of the liver tissues from HCC formation. In conclusion, the hepatoprotective activity of hesperidin is mediated via its antioxidation and downregulation of the PI3K/Akt pathway.

Hesperidin ameliorates liver ischemia/reperfusion injury via activation of the Akt pathway

“…HDN is a compound that is extracted from citrus fruits (13), that has been demonstrated to have potent pharmacological effects against oxidative stress, inflammation, microbes and cancer (13)(14)(15)(16). However, the exact role and mechanisms of HDN in liver I/R injury remains unknown.…”

“…It has been confirmed that HDN has hydrogen radical-and hydrogen peroxide-removal activities (13,14). Additionally, it has been reported that HDN has numerous beneficial effects, such as anti-inflammatory, antibacterial, anticancer and anti-edema properties (13)(14)(15)(16). Thus, HDN has a protective effect on sterile organ injuries, including ischemic stroke and arthritis, and infectious diseases such as lipopolysaccharide-induced inflammation (17)(18)(19)(20).…”

“…Having determined that HDN ameliorates liver I/R injury, the mechanisms underlying the modulation of cellular functions by HDN were next examined. Akt serves a key role in protecting against liver I/R injury (11,12), and several previous studies indicated that HDN induces Akt phosphorylation and influences apoptosis (16,18,21,22). Thus, the relationship between HDN and the Akt pathway in liver I/R injury was investigated.…”

“…Thus, HDN has a protective effect on sterile organ injuries, including ischemic stroke and arthritis, and infectious diseases such as lipopolysaccharide-induced inflammation (17)(18)(19)(20). A number of studies reveal that the activation of PI3K/Akt pathway is one of the most important mechanisms for the biological effects of HDN (16,18,21,22).…”

Flavonoids from Aurantii Fructus Immaturus and Aurantii Fructus: promising phytomedicines for the treatment of liver diseases

“…It has been documented that HD (50 mg/kg) suppresses cell proliferation, collagen deposition and further inhibits hepatocarcinogenesis by suppressing NF-κB, TGF-β1/Smad3 signaling and activating Nrf2/ARE/HO-1 and PPARγ pathways in diethylnitrosamine (DEN)/CCl 4 -induced rats model [73]. Evidence also suggested that HD (200 mg/ kg) inhibited the DEN-induced liver fibrosis and tumor growth through the upregulation of phosphatidylinositide 3-kinases (PI3K), serine/threonine kinase (AKT), cyclin-dependent kinase 2 (CDK-2) signaling pathway [74]. Most recently, emerging evidence has emphasized the role of long noncoding RNA (lncRNA) and exosomes in the progression of liver fibrosis and HCC.…”