Galangin Activates Nrf2 Signaling and Attenuates Oxidative Damage, Inflammation, and Apoptosis in a Rat Model of Cyclophosphamide-Induced Hepatotoxicity

Abstract

Cyclophosphamide (CP) is a widely used chemotherapeutic agent; however, its clinical application is limited because of its multi-organ toxicity. Galangin (Gal) is a bioactive flavonoid with promising biological activities. This study investigated the hepatoprotective effect of Gal in CP-induced rats. Rats received Gal (15, 30 and 60 mg/kg/day) for 15 days followed by a single dose of CP at day 16. Cyclophosphamide triggered liver injury characterized by elevated serum transaminases, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), and histopathological manifestations. Increased hepatic reactive oxygen species, malondialdehyde, nitric oxide, and oxidative DNA damage along with declined glutathione and antioxidant enzymes were demonstrated in CP-administered rats. CP provoked hepatic nuclear factor-kappaB (NF-κB) phosphorylation and increased mRNA abundance of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) both expression and serum levels. Gal prevented CP-induced liver injury, boosted antioxidants and suppressed oxidative stress, DNA damage, NF-κB phosphorylation and pro-inflammatory mediators. Gal diminished Bax and caspase-3, and increased B-cell lymphoma-2 (Bcl-2) in liver of CP-administered rats. In addition, Gal increased peroxisome proliferator-activated receptor gamma (PPARγ) expression and activated hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) signaling showed by the increase in Nrf2, NAD(P)H: quinone acceptor oxidoreductase-1 (NQO-1) and heme oxygenase 1 (HO-1) in CP-administered rats. These findings suggest that Gal prevents CP hepatotoxicity through activation of Nrf2/HO-1 signaling and attenuation of oxidative damage, inflammation and cell death. Therefore, Gal might represent a promising adjuvant therapy to prevent hepatotoxicity in patients on CP treatment.

Consumption of Terpenoids-Rich Padina pavonia Extract Attenuates Hyperglycemia, Insulin Resistance and Oxidative Stress, and Upregulates PPARγ in a Rat Model of Type 2 Diabetes

“…Hyperglycemia and hyperlipidemia were associated with increased generation of ROS, oxidative stress, and inflammation [15,86]. The role of ROS in liver injury has been established by studies showing that reduction of ROS can protect against hepatocyte damage induced by several insults [87][88][89]. HFD/STZ diabetic rats in this study showed excessive production of ROS associated with increased MDA and NO.…”

Curcumin Prevents Cyclophosphamide-Induced Lung Injury in Rats by Suppressing Oxidative Stress and Apoptosis

“…Here, MDA and PCO were significantly increased in the lung of CP-induced rats, demonstrating lipid and protein damage, respectively. In the same context, CP has been recently reported to increase ROS generation and DNA damage in the liver of rats [51].…”

“…Therefore, oxidative stress and apoptosis are implicated in CP-induced lung injury. In this context, apoptosis and oxidative injury induced by CP have been reported in different tissues, including lung, liver, and kidney [6,7,[43][44][45][46][50][51][52][53][54].…”

Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway

“…The crosstalk between Nrf2 and NF-κB has been reviewed by Wardyn et al [51]. The lack of Nrf2 can aggravate NF-κB activity leading to increased inflammatory cytokine release [52], whereas Nrf2 upregulation resulted in diminished inflammatory responses in rodent models of liver and kidney injury [53][54][55][56][57][58][59][60]. The Nrf2 target gene HO-1 has been demonstrated to inhibit NF-κB-mediated transcription of adhesion molecules possibly through decreasing free intracellular iron in endothelial cells [61].…”