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.

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Rheumatoid arthritis (RA) is a disorder triggered by autoimmune reactions and related with chronic inflammation and severe disability. Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs) have shown a hopeful immunomodulatory effect towards repairing cartilage and restoring joint function. Additionally, indomethacin (IMC), a nonsteroidal compound, has been considered as a potent therapeutic agent that exhibits significant antipyretic properties and analgesic effects. The target of the current research is to assess the antiarthritic efficacy of BM-MSCs (106 cells/rat at 1, 6, 12 and 18 days) and IMC (2 mg/kg body weight/day for 3 weeks) either alone or concurrently administered against complete Freund’s adjuvant-induced arthritic rats. Changes in paw volume, body weight, gross lesions, and antioxidant defense system, as well as oxidative stress, were assessed. The Th1 cytokine (IL-1β) serum level and Th2 cytokine (IL-4) and Nrf-2 ankle joint expression were detected. In comparison to normal rats, it was found that the CFA-induced arthritic rats exhibited significant leukocytosis and increase in paw volume, LPO level, RF, and IL-1β serum levels. In parallel, arthritic rats that received BM-MSCs and/or IMC efficiently exhibited decrease in paw edema, leukocytosis, and enhancement in the antioxidant enzymatic levels of SOD, GPx, GST, and GSH in serum besides upregulation of Nrf-2 and anti-inflammatory IL-4 expression levels in the ankle articular joint. Likewise, these analyses were more evidenced by the histopathological sections and histological score. The data also revealed that the combined administration of BM-MSC and IMC was more potent in suppressing inflammation and enhancing the anti-inflammatory pathway than each agent alone. Thus, it can be concluded that the combined therapy with BM-MSC and IMC may be used as a promising therapeutic choice after assessing their efficacy and safety in human beings with RA, and the antiarthritic effects may be mediated via modulatory effects on Th1/Th2 cytokines, ozidative stress, and Nrf-2.

This study aims to assess the preventive effects of rutin and/or quercetin on doxorubicin-induced kidney and heart injuries and oxidative stress in male Wistar rats. The male Wistar rats, injected with doxorubicin at an intraperitoneal dose 2 mg/kg b.w. 2 days per week for 5 weeks, were orally treated with rutin and/or quercetin with dose level 50 mg /kg b.w. every other day for 5weeks. The treatments of doxorubicin-injected rats with rutin, quercetin and their combination resulted in a significant decrease in the elevated serum creatinine and urea levels reflecting an improvement in kidney function. Similarly, the elevated serum CK-MB and LDH activities were significantly ameliorated as a result of treatments of doxorubicin-injected rats, thereby manifesting an amendment of heart function. The treatments also led to the prevention of the elevated lipid peroxidation and amelioration of the lowered GPx, GST and SOD activities as well as GSH content in kidney and heart as a result of treatment of doxorubicin-injected rats with rutin and quercetin. Also, the treatments remarkably improved doxorubicin-induced deleterious histological alterations in kidney and heart. In conclusion, rutin and/or quercetin may have chemopreventive potentials against doxorubicin-induced nephrocardiotoxicity via suppression of oxidative stress and enhancement of antioxidant defense system.

The presented study was performed to verify whether rutin and/or quercetin can inhibit liver injury induced by doxorubicin (DXR) in male Wistar rats. In this study, male Wistar rats were treated via the oral route with rutin and quercetin (50 mg/kg) either alone or in combination every other day for five weeks concomitant with receiving intraperitoneal DXR (2 mg/kg) two times a week for five successive weeks. Quercetin, rutin, and their combination significantly improved the deteriorated serum AST, ALT, and ALP activities and total bilirubin level, as well as albumin, AFP, and CA 19.9 levels in DXR-injected rats. Treatments of the DXR-injected group with quercetin and rutin prevented the elevation in liver lipid peroxidation and the reduction in superoxide dismutase, glutathione-S-transferase and glutathione peroxidase activities, and glutathione content. Treatments with quercetin and rutin significantly repressed the elevated expression of liver p53 and TNF-α and enhanced Nrf2 expression. Furthermore, the treatments significantly reduced DXR-induced liver histological changes. In conclusion, rutin and quercetin either alone or in combination may have potential preventive effects against DXR-induced hepatotoxicity through inhibiting oxidative stress, inflammation, and apoptosis as well as modulating the Nrf2 expression.