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.

Rheumatoid arthritis (RA) is an autoimmune syndrome affecting joint spaces, leading to the disabled state. Currently, there is no optimal therapy for RA except for systemic immunosuppressants that have variable undesirable effects after long-term use. Hence, the need for other treatment modalities has emerged in an attempt to develop a treating agent that is effective but without bad effects. Bone marrow-derived mesenchymal stem cells (BM-MSCs) may be an alternative medicine since they may differentiate into a variety of mesenchymal tissues including bone and cartilage. Indomethacin (IMC) could be suggested as an analgesic, anti-inflammatory, and antirheumatic potential agent against the course of RA since it possesses significant palliative effects and antipyretic properties. Therefore, our target of this study was to explore and compare the effect of BM-MSCs ( 1 × 10 6 cells/rat at the 1st, 6th, 12th, and 18th days) and IMC (2 mg/kg b.w./day for 3 weeks) either alone or in combination on arthritic rats. The model of rheumatoid arthritis in rats was induced by subcutaneous injection of 0.1 mL/rat CFA into the footpad of the right hind paw. The BM-MSC intravenous injection and IMC oral administration significantly reduced the elevated right hind leg paw diameter and circumference, serum anti-CCP, and ankle joint articular tissue expressions of TNF-α, iNOS, MMP-9, and TGF-β1 while they significantly increased the lowered articular IL-10 expression in CFA-induced arthritic rats. The combinatory effect of the two treatments was the most potent. In conclusion, the treatment of RA with BM-MSCs and IMC together is more effective than the treatment with either BM-MSCs or IMC. The Th1 cytokine (TNF-α), Th2 cytokine (IL-10), iNOS, MMP-9, and TGF-β1 are important targets for mediating the antiarthritic effects of BM-MSCs and IMC in CFA-induced arthritis in rats.

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.

The purpose of present study was to assess the nephropreventive and antioxidant effects of navel orange peel hydroethanolic extract, naringin and naringenin in N-acetyl-p-aminophenol (APAP)-administered male Wistar rats. APAP was administered at dose 0.5 g/kg/b.w. every other day by oral gavage for 4 weeks to male Wistar rats. APAPadministered rats were treated with navel orange peel hydroethanolic extract (50 mg/kg b.w.), naringin (20 mg/kg b.w.) and naringenin (20 mg/kg b.w.) every other day by oral gavage during the same period of APAP administration. The treatment of APAP-administered rats with navel orange peel extract, naringin and naringenin significantly improved the kidney function manifested by a significant decrease in the elevated serum urea, uric acid and creatinine levels. In association, the deteriorated kidney histological changes represented by congestion, hypertrophied glomerulus, vacuolization of the endothelial cells lining the glomerular tuft and interstitial nephritis in APAP-administered rats were remarkably amended. The elevated kidney lipid peroxidation and the lowered glutathione content as well as the suppressed antioxidant enzymes activities were significantly ameliorated. In conclusion, the navel orange peel hydroethanolic extract, naringin and naringenin have improvement effects on kidney function and structural integrity which may be mediated at least in part to via their antioxidant efficiencies.