Preventive Effects of Mandarin Fruit Peel Hydroethanolic Extract, Hesperidin, and Quercetin on Acetaminophen-Induced Hepatonephrotoxicity in Wistar Rats.

Acetaminophen, also known as N-acetyl-para-aminophenol (NAPAP), is a traditional antipyretic and analgesic that is used extensively around the world to treat colds and fevers. However, a NAPAP excess causes rapid, severe liver and kidney damage. The goal of the study was to examine the protective effects and determine the mechanisms of action of MPHE, hesperidin, and quercetin in NAPAP-induced hepatorenal damage in Wistar rats. Male Wistar rats received a 0.5 g/kg oral supplement of NAPAP every other day for a period of four weeks. During the same period of NAPAP supplementation, MPHE (50 mg/kg), quercetin (20 mg/kg), and hesperidin (20 mg/kg) were administered to rats receiving NAPAP. MPHE, quercetin, and hesperidin treatments significantly improved liver function in NAPAP-supplemented rats. The high serum levels of aminotransferases, alkaline phosphatase, lactate dehydrogenase, and γ-glutamyl transferase as well as total bilirubin were significantly reduced, while the levels of suppressed serum albumin were significantly increased, demonstrating this improvement. Treatments utilizing these natural substances significantly enhanced kidney function as seen by a considerable decline in the increased blood levels of urea, uric acid, and creatinine. Additionally, the injection of MPHE, hesperidin, and quercetin resulted in a decrease in the quantity of lipid peroxides while increasing the activities of superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase in the liver and kidneys. The treatments markedly abated the NAPAP-induced liver and kidney histological perturbations and reduced the NAPAP-induced serum tumor necrosis factor-α level and liver and kidney proapoptotic protein 53 and caspase 3 expressions. Otherwise, serum interleukin-4 level significantly increased by treatments. The MPHE, hesperidin, and quercetin treatments resulted in marked decrease in liver and kidney histopathological scores including inflammation, necrosis, apoptosis, and congestion. In conclusion, the MPHE, quercetin, and hesperidin may induce hepatonephropreventive impacts in NAPAP-supplemented rats via enhancing the antioxidant defense system, anti-inflammatory activity, and antiapoptotic action.

The Preventive Effects and the Mechanisms of Action of Navel Orange Peel Hydroethanolic Extract, Naringin, and Naringenin in N-Acetyl-p-aminophenol-Induced Liver Injury in Wistar Rats.

N-Acetyl-p-aminophenol (APAP) or acetaminophen is the most common drug ingredient worldwide. It is found in more than 600 different over-the-counter and prescription medicines. Its long-term and overdose use is highly toxic and may result in liver injury. Thus, this study was designed to assess the preventive effects and to suggest the mechanisms of action of the navel orange peel hydroethanolic extract, naringin, and naringenin in APAP-induced hepatotoxicity in male Wistar rats. APAP was administered to male Wistar rats at a dose level of 0.5 g/kg body weight (b.w.) by oral gavage every other day for 4 weeks. APAP-administered rats were treated with the navel orange peel hydroethanolic extract (50 mg/kg b.w.), naringin (20 mg/kg b.w.), and naringenin (20 mg/kg b.w.) by oral gavage every other day during the same period of APAP administration. The treatments of APAP-administered rats with the peel extract, naringin, and naringenin produced a significant decrease in the elevated serum AST, ALT, ALP, LDH, and GGT activities as well as total bilirubin and TNF-α levels while they induced a significant increase in the lowered serum albumin and IL-4 levels. The treatments also resulted in a significant decrease in the elevated liver lipid peroxidation and enhanced the liver GSH content and SOD, GST, and GPx activities as compared with APAP-administered control; the peel extract was the most potent in improving the liver LPO, GSH content, and GPx activity. In addition, the three treatments significantly downregulated the elevated hepatic proapoptotic mediators p53, Bax, and caspase-3 and significantly upregulated the suppressed antiapoptotic protein, Bcl-2, in APAP-administered rats. In association, the treatments markedly amended the APAP-induced liver histopathological deteriorations that include hepatocyte steatosis, cytoplasmic vacuolization, hydropic degeneration, and necrosis together with mononuclear leucocytic and fibroblastic inflammatory cells' infiltration. In conclusion, the navel orange peel hydroethanolic extract, naringin, and naringenin may exert their hepatopreventive effects in APAP-administered rats via enhancement of the antioxidant defense system and suppression of inflammation and apoptosis.

Cardiac and testicular toxicity effects of the latex and ethanolic leaf extract of Calotropis procera on male albino rats in comparison to abamectin.

The present study aims to assess the toxic effect of latex and ethanolic leaf extract of Calotropis procera (C. procera), in comparison to abamectin, on serum biomarkers of function and histological integrity of heart and testis in male albino rats. To achieve this aim, the albino rats were separately administered 1/20 and 1/10 of LD50 of C. procera latex, ethanolic C. procera leaf extract and abamectin respectively by oral gavage for 4 and 8 weeks. C. procera latex and leaf extract as well as abamectin markedly elevated the activities of serum CK-MB, AST and LDH at the two tested periods in a dose dependent manner. Lipid peroxidation was significantly increased while GSH level and GPx, GST and SOD activities were significantly depleted in heart and testis of all treated rats. All treatments also induced a marked increase in serum TNF-α and decrease in serum IL-4, testosterone, FSH and LH levels in a dose dependent manner. The latex seemed to be more effective in deteriorating the testicular function and sex hormones' levels while the ethanolic leaf extract produced more deleterious effects on oxidative stress and antioxidant defense system in both heart and testis. The normal histological architecture and integrity of the heart and testis were perturbed after treatments and the severity of lesions, which include odema, inflammatory cell infiltration, necrosis and degeneration, is dose and time dependent. In conclusion, the findings of this study indicated that C. procera latex and ethanolic extract of leaves could induce marked toxicity in heart and testis and these toxic effects may be more or less similar to those of abamectin. The cardiotoxicity and testicular toxicity may be mediated via stimulation of inflammation, increased oxidative stress and suppression of antioxidant defense system.