Carbon monoxide releasing molecule A-1 attenuates acetaminophen-mediated hepatotoxicity and improves survival of mice by induction of Nrf2 and related genes.

Acute liver injury is frequently associated with oxidative stress. Here, we investigated the therapeutic potential of carbon monoxide releasing molecule A-1 (CORM A-1) in oxidative stress-mediated liver injury. Overnight-fasted mice were injected with acetaminophen (APAP; 300 mg/kg; intraperitoneally) and were sacrificed at 4 and 12 h. They showed elevated levels of serum transaminases, depleted hepatic glutathione (GSH) and hepatocyte necrosis. Mice injected with CORM A-1 (20 mg/kg) 1 h after APAP administration, had reduced serum transaminases, preserved hepatic GSH and reduced hepatocyte necrosis. Mice that received a lethal dose of APAP (600 mg/kg), died by 10 h; but those co-treated with CORM A-1 showed a 50% survival. Compared to APAP-treated mice, livers from those co-treated with CORM A-1, had upregulation of Nrf2 and ARE genes (HO-1, GCLM and NQO-1). APAP-treated mice had elevated hepatic mRNA levels of inflammatory genes (Nf-κB, TNF-α, IL1-ß and IL-6), an effect blunted in those co-treated with CORM A-1. In tert-butyl hydroperoxide (t-BHP)-treated HepG2 cells, CORM A-1 augmented cell viability, reduced oxidative stress, activated the nuclear factor erythroid 2-related factor 2 (Nrf2) and anti-oxidant response element (ARE) genes. The molecular docking profile of CO in the kelch domain of Keap1 protein suggested that CO released from CORM A-1 mediated Nrf2 activation. Collectively, these data indicate that CORM A-1 reduces oxidative stress by upregulating Nrf2 and related genes, and restoring hepatic GSH, to reduce hepatocyte necrosis and thus minimize liver injury that contributes to an overall improved survival rate.

Effect of Fermented Papaya Preparation on Doxorubicin Induced Myocardial Toxicity.

Many antitumor drugs cause “on treatment” cardio toxicity or introduce a measurable risk of delayed cardiovascular events. The problem of anthracycline-induced cardio toxicity has been around for some 40 years. Doxorubicin (DOX) is an anthracycline derivative used as an anticancer agent. However, its clinical use is limited due to its severe cardio toxic manifestations. The present aim is to evaluate the protective role of Fermented Papaya Preparation (FPP) in combating doxorubicin induced cardio-toxicity/oxidative stress. Female Wistar rats were pretreated with FPP (100 mg/kgbw or 250 mg/kgbw) or saline daily for 28 consecutive days followed by doxorubicin (10 mg/kgbw) induction for next 2 days. Results indicated that pretreatment with FPP significantly decreased serum levels of CK-MB and LDH cardiac marker enzymes. Further, FPP supplementation significantly increased SOD, GSH-Px and GSH (p<0.05) while decreased Malondialdehyes and Catalase levels in heart. Histological observations demonstrated that FPP pretreatment attenuated DOX induced myofribillar derangement and vascular congestion in heart tissue. Thus our results suggest that FPP exhibits significant preclinical potential in combating DOX induced oxidative stress.