Background The clinical application of methotrexate (MTX), an efficacious cytotoxic drug, is restricted due to its associated liver toxicity. Ellagic acid (EA), a natural polyphenol, possesses hepatoprotective, antioxidant and anti-inflammatory properties.Objectives The present study seeks to address the hepatoprotective effects of Ellagic acid (EA) against MTX-mediated oxidative stress (OS) and widen our current knowledge of the underlying molecular mechanisms of MTX toxicity. Methods Wistar rats were orally given EA (5 mg/kg and 10 mg/kg) for 10 successive days and at the end of the third day they were administered a single dose of MTX (20 mg/kg i.p). Results After performing biochemical analysis, liver enzymes and malondialdehyde were significantly higher in the MTX group, indicating hepatic oxidative damage. MTX-induced OS was further confirmed with observation of events such as reactive oxygen species (ROS) overproduction, mitochondrial outer membrane potential decrease, mitochondrial swelling, cytochrome c release and caspase-3/9 increase, resulting in apoptosis. Furthermore, overexpression of pro-inflammatory factors such as nuclear factor kappa B (NF-ĸB) and interleukin 6 (IL-6) indicated the MTX-induced inflammation in MTX-treated group. Interestingly, EA was able to significantly prevent OS, mitochondrial dysfunction, apoptosis and inflammation induced by MTX. Also, EA-treated rats demonstrated significant upregulation of both nuclear factor erythroid 2-related factor 2 (Nrf2) and hemoxygenase-1 (HO-1), which were considerably downregulated in MTX-treated rats. Conclusions EA protects rats against MTX-induced apoptosis and mitochondrial dysfunction via up-Regulating Nrf2 and HO-1 expression and inhibiting the NF-κB signaling pathway. Therefore, EA may protect patients against MTX-induced hepatotoxicity and encourage its clinical application.
Background:The pattern of drug abuse in Iran has dramatically changed in recent years, turning from the traditional opioids [opium, opium dross, and refined opium dross (Shireh)] into drugs with newer forms. The present study is aimed at investigating the frequency of pathological changes in the lungs of bodies with positive postmortem toxicology results for narcotics and psychotropic substances autopsied in the forensic dissection hall of Tehran, Iran [the Iranian Legal Medicine Organization (LMO)]. Methods:The present study is a cross-sectional descriptive study. The sample consisted of 153 bodies, which had been referred to the LMO with positive results in postmortem toxicology for narcotics and psychotropic substances. Results:We found that narcotic drugs and psychotropic substances were used more in men than women. Moreover, the average age of death due to drug use was 36 years old. In addition, methamphetamine was the mostly-used type of substances, and smoking was the most widely used method to use the drugs. Besides, the dominant consistency and color of the lungs of half of the bodies investigated were elastic brown-gray. Moreover, the most common pathologic changes observed in the lungs of the bodies investigated were congestion and edema. Conclusion:Given the prevalence of pathological changes in the lungs of the examined bodies and congestion, edema, and pulmonary hemorrhage, the results of the present study can be particularly effective in determining the drug use and the resultant death in the absence of any previous records and/or a negative result of toxicology.
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