Rutin and Quercetin Counter Doxorubicin-Induced Liver Toxicity in Wistar Rats via Their Modulatory Effects on Inflammation, Oxidative Stress, Apoptosis, and Nrf2.

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.

New insights into the in vitro, in situ and in vivo antihyperglycemic mechanisms of gallic acid and p-coumaric acid.

Objective: To explore the probable in vitro, in situ and in vivo mechanisms of gallic acid (GA) and p-coumaric acid (PCA) as anti-hyperglycemic agents.Animals and methods: Male albino rats were allocated into four groups, group1 was used as normal control. Group 2 was established as a diabetic control and group3 and 4 were treated with an oral dose of GA and PCA, respectively.Results: GA and PCA revealed a significant decrease in the activity of α-amylase, a noticeable rise in glucose induced-insulin secretion and glucose-uptake in peripheral glucose-uptake in vitro, increase also liver glycogen and serum insulin levels in vivo. Further, GA and PCA exhibited a significant reduction in intestinal glucose absorption in situ compared to blank.Conclusion: The antihyperglycemic activities of GA and PCA can be mediated through delaying intestinal glucose absorption, enhancing ß-cell activity and promoting glucose uptake by peripheral tissue via enhancing insulin sensitivity.

Potency of Bone Marrow-Derived Mesenchymal Stem Cells and Indomethacin in Complete Freund's Adjuvant-Induced Arthritic Rats: Roles of TNF-α, IL-10, iNOS, MMP-9, and TGF-ß1.

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 × 106 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-ß1 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-ß1 are important targets for mediating the antiarthritic effects of BM-MSCs and IMC in CFA-induced arthritis in rats.

Combinatory Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Indomethacin on Adjuvant-Induced Arthritis in Wistar Rats: Roles of IL-1ß, IL-4, Nrf-2, and Oxidative Stress.

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-1ß) 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-1ß 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.

Modulation of hyperglycemia and dyslipidemia in experimental type 2 diabetes by gallic acid and p-coumaric acid: The role of adipocytokines and PPARγ.

There are many indications that confirm the vital role of adipocytokines and PPARγ in diabetics. Hence, the current investigation aimed to study the modulatory effects of gallic acid and p-coumaric acid on adipocytokines secretion and PPARγ mRNA expression in type 2 diabetic rats. After induction of type 2 diabetes, diabetic rats were orally treated with 20 mg/kg body mass gallic acid and 40 mg/kg body mass p-coumaric acid for six weeks. Among treatment diabetic rats, glucose and glycosylated hemoglobin levels significantly declined in diabetic rats, while insulin level and body weight significantly increased as compared to control group. Gallic acid and p-coumaric acid markedly decreased the level of TNF-α and increased the levels of PPARγ mRNA and adiponectin. In addition, the tested agents improved markedly lipid profile parameters, cardiovascular indices 1 and 2 and anti-atherogenic index. In conclusion, gallic acid and p-coumaric acid exhibited marked antidiabetic action that could be mediated via modulation of TNF-α and adipocytokines secretions as well as upregulation of PPARγ mRNA expression.

Gallic acid and p-coumaric acid attenuate type 2 diabetes-induced neurodegeneration in rats.

The brain of diabetics revealed deterioration in many regions, especially the hippocampus. Hence, the present study aimed to evaluate the effects of gallic acid and p-coumaric acid against the hippocampal neurodegeneration in type 2 diabetic rats. Adult male albino rats were randomly allocated into four groups: Group 1 served as control ones and others were induced with diabetes. Group 2 considered as diabetic, and groups 3 and 4 were further orally treated with gallic acid (20 mg/kg b.wt./day) and p-coumaric acid (40 mg/kg b.wt./day) for six weeks. Diabetic rats revealed significant elevation in the levels of serum glucose, blood glycosylated hemoglobin and serum tumor necrosis factor-α, while the level of serum insulin was significantly declined. Furthermore, the brain of diabetic rats showed a marked increase in oxidative stress and a decrease of antioxidant parameters as well as upregulation the protein expression of Bax and downregulation the protein expression of Bcl-2 in the hippocampus. Treatment of diabetic rats with gallic acid and p-coumaric acid significantly ameliorated glucose tolerance, diminished the brain oxidative stress and improved antioxidant status, declined inflammation and inhibited apoptosis in the hippocampus. The overall results suggested that gallic acid and p-coumaric acid may inhibit hippocampal neurodegeneration via their potent antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, both compounds can be recommended as hopeful adjuvant agents against brain neurodegeneration in diabetics.

Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats.

Abnormal regulation of glucose and impaired carbohydrate utilization that result from a defective or deficient insulin are the key pathogenic events in type 2 diabetes mellitus (T2DM). The present study was hypothesized to investigate the beneficial effects of hesperidin and naringin on hyperglycemia-induced oxidative damage in HFD/STZ-induced diabetic rats. Diabetes was induced by feeding rats with an HFD for 2 weeks followed by an intraperitoneal injection of STZ (35 mg/kg body weight). An oral dose of 50mg/kg hesperidin or naringin was daily given for 4 weeks after diabetes induction. At the end of the experimental period, blood was obtained from jugular vein and livers were rapidly excised and homogenized for biochemical assays. In the diabetic control group, levels of glucose, glycosylated hemoglobin (HbA1c%), MDA, NO, TNF-α and IL-6 were significantly increased, while serum insulin, GSH, vitamin C, and vitamin E levels were decreased. Both hesperidin and naringin administration significantly reversed these alterations. Moreover, supplementation with either compound significantly ameliorated serum and liver MDA, NO and glutathione, and liver antioxidant enzymes. Although detailed studies are required for the evaluation of the exact mechanism of the ameliorative effects of hesperidin and naringin against diabetic complications, these preliminary experimental findings demonstrate that both hesperidin and naringin exhibit antidiabetic effects in a rat model of T2DM by potentiating the antioxidant defense system and suppressing proinflammatory cytokine production.