Effects of aged garlic and ginkgo biloba extracts on the pharmacokinetics of sofosbuvir in rats.

Sofosbuvir is a direct acting antiviral (DAA) approved for the treatment of hepatitis C virus (HCV). Sofosbuvir is a substrate of P-glycoprotein (P-gp). For this reason, inhibitors, or inducers of intestinal P-gp may alter the plasma concentration of sofosbuvir and increase or decrease its efficacy causing a significant change in its pharmacokinetic parameters. The purpose of the study was to evaluate the pharmacokinetic interaction between either aged garlic or ginkgo biloba extracts with sofosbuvir through targeting P-gp as well as possible toxicities in rats. Rats were divided into four groups and treated for 14 days with saline, verapamil (15 mg/kg, PO), aged garlic extract (120 mg/kg, PO), or ginkgo biloba extract (25 mg/kg, PO) followed by a single oral dose of sofosbuvir (40 mg/kg). Validated LC-MS/MS was used to determine sofosbuvir and its metabolite GS-331007 in rat plasma. Aged garlic extract caused a significant decrease of sofosbuvir AUC(0-t) by 36%, while ginkgo biloba extract caused a significant increase of sofosbuvir AUC(0-t) by 11%. Ginkgo biloba extract exhibited a significant increase of the sofosbuvir t1/2 by 60%, while aged garlic extract significantly increased the clearance of sofosbuvir by 63%. The pharmacokinetic parameters of GS-331007 were not affected. The inhibitory action of ginkgo biloba on P-gp and the subsequent increase in the sofosbuvir plasma concentration did not show a significant risk of renal or hepatic toxicity. Conversely, although aged garlic extracts increased intestinal P-gp expression, they did not alter the Cmax and Tmax of sofosbuvir and did not induce significant hepatic or renal toxicities.

Non-alcoholic fatty liver disease: An overview of risk factors, pathophysiological mechanisms, diagnostic procedures, and therapeutic interventions.

Non-alcoholic fatty liver disease (NAFLD) is a disorder of excessive fat accumulation in the liver, known as steatosis, without alcohol overconsumption. NAFLD can either manifest as simple steatosis or steatohepatitis, known as non-alcoholic steatohepatitis (NASH), which is accompanied by inflammation and possibly fibrosis. Furthermore, NASH might progress to hepatocellular carcinoma. NAFLD and NASH prevalence is in a continuous state of growth, and by 2018, NAFLD became a devastating metabolic disease with a global pandemic prevalence. The pathophysiology of NAFLD and NASH is not fully elucidated, but is known to involve the complex interplay between different metabolic, environmental, and genetic factors. In addition, unhealthy dietary habits and pre-existing metabolic disturbances together with other risk factors predispose NAFLD development and progression from simple steatosis to steatohepatitis, and eventually to fibrosis. Despite their growing worldwide prevalence, to date, there is no FDA-approved treatment for NAFLD and NASH. Several off-label medications are used to target disease risk factors such as obesity and insulin resistance, and some medications are used for their hepatoprotective effects. Unfortunately, currently used medications are not sufficiently effective, and research is ongoing to investigate the beneficial effects of different drugs and phytochemicals in NASH. In this review article, we outline the different risk factors and pathophysiological mechanisms involved in NAFLD, diagnostic procedures, and currently used management techniques.

Phytoestrogen genistein hinders ovarian oxidative damage and apoptotic cell death-induced by ionizing radiation: co-operative role of ER-ß, TGF-ß, and FOXL-2.

Radiotherapy is a well-known cause of premature ovarian failure (POF). Therefore, we investigated the molecular influence of genistein (GEN) on the ovarian reserve of rats exposed to ϒ-radiation. Female Sprague Dawley rats were exposed to a 3.2 Gy γ-radiation to induce POF and/or treated with either GEN (5 mg/kg, i.p.) or Ethinyl estradiol (E2; 0.1 mg/kg, s.c.), once daily for 10 days. GEN was able to conserve primordial follicles stock and population of growing follicles accompanied with reduction in atretic follicles. GEN restored the circulating estradiol and anti-Müllerian hormone levels which were diminished after irradiation. GEN has potent antioxidant activity against radiation-mediated oxidative stress through upregulating endogenous glutathione levels and glutathione peroxidase activity. Mechanistically, GEN inhibited the intrinsic pathway of apoptosis by repressing Bax expression and augmenting Bcl-2 expression resulted in reduced Bax/Bcl-2 ratio with subsequent reduction in cytochrome c and caspase 3 expression. These promising effects of GEN are associated with improving granulosa cells proliferation. On the molecular basis, GEN reversed ovarian apoptosis through up-regulation of ER-ß and FOXL-2 with downregulation of TGF-ß expression, therefore inhibiting transition of primordial follicles to more growing follicles. GEN may constitute a novel therapeutic modality for safeguarding ovarian function of females' cancer survivors.

EVESOR, a model-based, multiparameter, Phase I trial to optimize the benefit/toxicity ratio of everolimus and sorafenib.

AIM: This novel multiparameter Phase I study aimed to optimize doses/dosing schedules of everolimus and sorafenib drug combination, based on modeling/simulation (NCT01932177). PATIENTS & METHODS: About 26 patients with solid tumors were treated in four different dosing schedules. Everolimus once daily + sorafenib twice daily were given continuously in arms A and B, and intermittently in arms C (alternating every other week) and D (everolimus continuous and sorafenib 3 days on/4 days off). RESULTS: Continuous schedules exhibited higher toxicity risks than intermittent schedules (64.1 vs 35.9%; p < 0.0001), and trends for lower disease control rates (80 vs 100%). No significant pharmacokinetic interaction was identified. CONCLUSION: Feasibility of EVESOR trial is demonstrated. Intermittent schedules might provide better tolerance and efficacy than continuous schedules.

Antifibrotic mechanism of deferoxamine in concanavalin A induced-liver fibrosis: Impact on interferon therapy.

Iron-overload is a well-known factor of hepatotoxicity and liver fibrosis, which found to be a common finding among hepatitis C virus patients and related to interferon resistance. We aimed to elucidate the potential antifibrotic effect of deferoxamine; the main iron chelator, and its additional usefulness to interferon-based therapy in concanavalin A-induced immunological model of liver fibrosis. Rats were treated with deferoxamine and/or pegylated interferon-α for 6 weeks. Hepatotoxicity indices, oxidative stress, inflammatory and liver fibrosis markers were assessed. Concanavalin A induced a significant increase in hepatotoxicity indices and lipid peroxidation accompanied with a significant depletion of total antioxidant capacity, glutathione level and superoxide dismutase activity. Besides, it increased CD4(+) T-cells content and the downstream inflammatory cascades, including NF-κB, TNF-α, iNOS, COX-2, IL-6 and IFN-γ. Furthermore, α-SMA, TGF-ß1 and hydroxyproline were increased markedly, which confirmed by histopathology. Treatment with either deferoxamine or pegylated interferon-α alone reduced liver fibrosis markers significantly and improved liver histology. However, some of the hepatotoxicity indices and oxidative stress markers did not improve upon pegylated interferon-α treatment alone, besides the remarkable increase in IL-6. Combination therapy of deferoxamine with pegylated interferon-α further improved all previous markers, ameliorated IL-6 elevation, as well as increased hepcidin expression. In conclusion, our study provides evidences for the potent antifibrotic effects of deferoxamine and the underlying mechanisms that involved attenuating oxidative stress and subsequent inflammatory cascade, as well as the production of profibrogenic factors. Addition of deferoxamine to interferon regimen for HCV patients may offer a promising adjuvant modality to enhance therapeutic response.

Epigallocatechin-3-gallate pretreatment attenuates doxorubicin-induced cardiotoxicity in rats: A mechanistic study.

Doxorubicin (DOX) is a widely used chemotherapeutic agent however its clinical use is limited by cumulative cardiotoxicity. Epigallocatechin-3-gallate (EGCG), a main catechin in green tea, possesses a potent antioxidant, anti-apoptotic and anticancer properties. The current study aimed to investigate the potential protective effect of EGCG against DOX-induced cardiotoxicity. Firstly the potential cardioprotective dose of EGCG was screened at different doses (10, 20 and 40 mg/kg/day) against a single dose of DOX (15 mg/kg; i.p.). EGCG protected against DOX-induced ECG changes, leakage of cardiac enzymes (creatine kinase isoenzyme-MB, and lactate dehydrogenase) and histopathological changes. The dose of 40 mg/kg EGCG was selected for further assessment to address the EGCG cardioprotective mechanisms. EGCG was given orally 3 times/week for 4 consecutive weeks and DOX (2.5 mg/kg; i.p.) 3 times/week on the last 2 weeks. EGCG significantly ameliorated oxidative stress injury evoked by DOX as evidenced by inhibition of reduced glutathione depletion and lipid peroxidation as well as elevation of antioxidant enzyme activities. DOX caused down-regulation of ErbB2 expression while EGCG pretreatment significantly increased ErbB2 expression indicating its effect on pro-survival pathway. Furthermore, DOX provoked apoptotic responses evidenced by increasing the expression of nuclear factor kappa-B, tumor suppressor protein p53, calpain 2, caspases 3 and 12. Additionally basal level of Hsp70 was reduced in DOX-intoxicated group. EGCG pretreatment significantly ameliorated these apoptotic signals indicating its anti-inflammatory and anti-apoptotic actions. In conclusion, EGCG possesses cardioprotective action against DOX-induced cardiotoxicity by suppressing oxidative stress, inflammation and apoptotic signals as well as activation of pro-survival pathways.

Targeting TNF-α and NF-κB activation by bee venom: role in suppressing adjuvant induced arthritis and methotrexate hepatotoxicity in rats.

UNLABELLED: Low dose methotrexate is the cornerstone for the treatment of rheumatoid arthritis. One of its major drawbacks is hepatotoxicity, resulting in poor compliance of therapy. Dissatisfied arthritis patients are likely to seek the option of complementary and alternative medicine such as bee venom. The combination of natural products with modern medicine poses the possibility of potential interaction between the two groups and needs investigation. The present study was aimed to investigate the modulatory effect of bee venom acupuncture on efficacy, toxicity, and pharmacokinetics and tissue disposition of methotrexate. Complete Freund's adjuvant induced arthritic rats were treated for 3 weeks with methotrexate and/or bee venom. Arthritic score, ankle diameter, paw volume and tissue expression of NF-κB and TNF-α were determined to assess anti-arthritic effects, while anti-nociceptive effects were assessed by gait score and thermal hyperalgesia. Methotrexate toxicity was assessed by measuring serum TNF-α, liver enzymes and expression of NF-κB in liver. Combination therapy of bee venom with methotrexate significantly improved arthritic parameters and analgesic effect as compared to methotrexate alone. Bee venom ameliorated serum TNF-α and liver enzymes elevations as well as over expression of NF-κB in liver induced by methotrexate. Histological examination supported the results. And for the first time bee venom acupuncture was approved to increase methotrexate bioavailability with a significant decrease in its elimination. CONCLUSION: bee venom potentiates the anti-arthritic effects of methotrexate, possibly by increasing its bioavailability. Also, it provides a potent anti-nociceptive effect. Furthermore, bee venom protects against methotrexate induced hepatotoxicity mostly due to its inhibitory effect on TNF-α and NF-κB.

Effect of taurine supplementation on hyperhomocysteinemia and markers of oxidative stress in high fructose diet induced insulin resistance.

BACKGROUND: High intake of dietary fructose is accused of being responsible for the development of the insulin resistance (IR) syndrome. Concern has arisen because of the realization that fructose, at elevated concentrations, can promote metabolic changes that are potentially deleterious. Among these changes is IR which manifests as a decreased biological response to normal levels of plasma insulin. METHODS: Oral glucose tolerance tests (OGTT) were carried out, homeostasis model assessment of insulin resistance (HOMA) was calculated, homocysteine (Hcy), lipid concentrations and markers of oxidative stress were measured in male Wistar rats weighing 170-190 g. The rats were divided into four groups, kept on either control diet or high fructose diet (HFD), and simultaneously supplemented with 300 mg/kg/day taurine via intra-peritoneal (i.p.) route for 35 days. RESULTS: Fructose-fed rats showed significantly impaired glucose tolerance, impaired insulin sensitivity, hypertriglyceridemia, hypercholesterolemia, hyperhomocysteinemia (HHcy), lower total antioxidant capacity (TAC), lower paraoxonase (PON) activity, and higher nitric oxide metabolites (NOx) concentration, when compared to rats fed on control diet. Supplementing the fructose-fed rats with taurine has ameliorated the rise in HOMA by 56%, triglycerides (TGs) by 22.5%, total cholesterol (T-Chol) by 11%, and low density lipoprotein cholesterol (LDL-C) by 21.4%. Taurine also abolished any significant difference of TAC, PON activity and NOx concentration among treated and control groups. TAC positively correlated with PON in both rats fed on the HFD and those received taurine in addition to the HFD. Fructose-fed rats showed 34.7% increase in Hcy level. Taurine administration failed to prevent the observed HHcy in the current dosage and duration. CONCLUSION: Our results indicate that HFD could induce IR which could further result in metabolic syndrome (MS), and that taurine has a protective role against the metabolic abnormalities induced by this diet model except for HHcy.

Rubus sanctus protects against carbon tetrachloride-induced toxicity in rat isolated hepatocytes: isolation and characterization of its galloylated flavonoids.

OBJECTIVES: Rubus sanctus Schreb., known from the Bible as 'holy thorn bush', grows wild in Egypt. Rubus sanctus aqueous alcoholic extract (RE) contains a complicated phenolic mixture (ellagitanins, flavonoids and caffeic acid derivatives). In this study, the phytochemical investigation of the plant was re-evaluated. Herein, we report on the isolation and identification of three galloylated flavonoids, namely kaempferol-3-O-(6''-O-galloyl)-(4)C(1)-beta-d-galactopyranoside, quercetin-3-O-(6''-O-galloyl)-(4)C(1)-beta-d-galactopyranoside and myricetin-3-O-(6''-O-galloyl)-(4)C(1)-beta-d-galactopyranoside for the first time from the Rubus genus. We further aimed at evaluating the potential protective effects of RE against carbon tetrachloride (CCl(4))-induced toxicity in isolated rat hepatocytes. METHODS: Based on an initial concentration-response experiment, a concentration of 100 mug/ml was selected to investigate the hepatoprotective activity of RE. KEY FINDINGS: Pretreatment with RE afforded protection as indicated by counteracting CCl(4)-induced cell death, and reduced glutathione depletion. In addition, RE ameliorated CCl(4)-induced enzyme leakage by 40% for lactate dehydrogenase, 30% for alanine aminotransferase and 20% for aspartate aminotransferase as compared with CCl(4)-treated cells. Moreover, RE counteracted CCl(4)-induced lipid peroxidation and inhibited spontaneous lipid peroxidation in the control group. CONCLUSIONS: In conclusion, RE protects against CCl(4)-induced toxicity in isolated rat hepatocytes.