Protective effects of combined Losartan and Nilotinib on carbon tetrachloride (CCl4)-induced liver fibrosis in rats.

Tyrosine kinase inhibitors (TKIs) have been developed as therapeutic compounds for inhibiting the progression of liver fibrosis. In the present study, the simultaneous treatment of Nilotinib (TKIs) and Losartan was studied. Forty rats were divided into eight groups of fibrosis induced by carbon tetrachloride (CCl4) and therapeutics (Nilotinib, Losartan, and combination therapy). In the end, serum parameters of the liver and gene expression analysis of transforming growth factor-ß1, its receptors (TßRII), platelet-derived growth factor, its receptors (PDGFRß), matrix metalloproteinases (MMP-2 and MMP-9), tumor necrosis factor-α, cytochrome P450 2E1, and collagen1 type 1 were performed. The oxidant/antioxidant factors were also analyzed. Histopathology analysis along with α-SMA immunohistochemistry and hydroxyproline evaluation was also conducted for a more in-depth study. The overall results indicated a better therapeutic effect of co-treatment of Nilotinib-Losartan in comparison with the treatment of each of them alone. Interestingly, some gene and protein factors and fibrotic indices were reduced even to the normal levels of the control group. The results of this study suggest that co-administration of these two combinations, strengthens their anti-fibrotic properties and, due to the routine use of these compounds against AML and blood pressure, these compounds can be used with caution against human liver fibrosis.

Hepatoprotective effect of parthenolide in rat model of nonalcoholic fatty liver disease.

CONTEXT: The active ingredients of traditional medical herbs have been the focus of scientific interests. OBJECTIVE: This study was designed to explore the mechanisms of actions of parthenolide on nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: Thirty-five male Wistar rats were fed high-fat diet (HFD) for eight weeks with or without an intraperitoneal injection of parthenolide to develop NAFLD. Liver triacylglycerol (TG), total antioxidant capacity (TAC), total oxidative status (TOS), thiobarbituric acid reactant substances (TBARs), total thiol groups and tumor necrosis factor alpha (TNF-α) and cytochrome P4502E1 (CYP2E1) levels as well as liver ALT, AST and catalase activities were determined. In addition, quantitative real-time PCR was performed to obtain hepatic gene expression levels of TNF-α, CYP2E1 and nuclear factor-κB (NF-κB). RESULTS: HFD caused a significant weight gain and increased liver TG content as well as alteration in ALT and AST activities, which were attenuated after administration of parthenoide (p < .05). Weakened liver antioxidant system (TAC, total thiol groups and catalase activity) and increased oxidative stress markers (TBARs and TOS) were mainly ameliorated by parthenolide treatment (p < .05). Increased hepatic TNF-α, NF-κB and CYP2E1 at the both gene expression and protein levels were found associated with necroinflammatory changes in histopathological observations and were abrogated almost completely after parthenolide treatment. Oxidative and inflammatory changes observed in HFD fed rats were indicative of NAFLD, which were suppressed with parthenolide treatment. CONCLUSIONS: Based on these results, parthenolide might be a candidate agent for preventing NAFLD due to its anti-inflammatory and anti-oxidative potency.

Leuprolide Acetate Release Study from γ-Irradiated PLGA-based In Situ Forming System.

BACKGROUND: It is well known that the properties of polymers can be altered by exposure to γ- ray. γ-irradiation has been used as a sterilization method for polymeric drug delivery devices, and its drug release profile must not be significantly changed. In this study, the effect of γ-irradiation on the release profile of leuprolide acetate from PLGA-based in situ forming system was investigated. METHODS: Poly(lactide-co-glycolide) (PLGA) was dissolved in N-methylpyrrolidinone (NMP) and irradiated with a total dose of 8 kGy γ-ray emitted by a 60Co source. Then, leuprolide acetate was added to the polymer solution. PLGA-based in situ forming systems were prepared by injecting some specific amount of prepared solution into a buffer phosphate pH 7.4 at 37 °C. The effects of γ-ray on drug release profiles, morphology of matrices and thermal properties as well as stability of polymer were evaluated. RESULTS: The results showed that γ-irradiation causes a decrease in glass transition temperature (Tg) of PLGA from 43.4 to 38.1°C. A reduction in molecular weight of PLGA by about 17.8 % was found as consequence of radiolytic degradation. The morphological studies of PLGA matrices confirmed that the irradiated sample had higher porosity than the non-irradiated sample. It is found that the amount of released leuprolide acetate from irradiated matrix was increased by about 1.6 times after 33 days compared to the nonirradiated ones. In vitro drug release experimental data were fitted using the Gallagher- Corrigan model which indicated that diffusion and degradation were the predominant mechanisms of drug release. CONCLUSION: Accordingly, leuprolide acetate was released faster from the irradiated matrix compared to the non- irradiated matrix.

Dasatinib prevent hepatic fibrosis induced by carbon tetrachloride (CCl4) via anti-inflammatory and antioxidant mechanism.

OBJECTIVES: Dasatinib, a potent and broad-spectrum tyrosine kinase inhibitor, is approved for the treatment of imatinib-resistant chronic myelogenous leukemia. The aim of this study was to evaluate the anti-fibrotic, anti-inflammatory and antioxidant effects of this agent against CCl4-induced hepatic fibrosis and oxidative status. MATERIALS AND METHODS: Experimental fibrosis was induced in Wistar male rats by 12 weeks of CCl4 administration (i.p.). During the last 8 weeks of injection, rats were gavaged daily with Dasatinib (10 mg/kg). To evaluate anti-inflammatory and anti-fibrotic effects of Dasatinib, histopathological examination of liver tissue was performed and serum ALT and AST activities, oxidant, antioxidant parameters and hepatic tumor necrosis factor alpha (TNF-α) were examined. Moreover, transforming growth factor (TGF-ß1), platelet derived growth factor (PDGF) and TNF-α mRNA expressions were also evaluated by real time polymerase chain reaction. RESULTS: Dasatinib administration induced a significant reduction of ALT and AST activities (p < .001) and Malondialdehyde (MDA) content in CCl4 injected rats (p < .05). Concomitantly hepatic protein and mRNA expression of TNF-α, mRNA expression of TGF-ß1 and PDGF were increased due to CCl4 intoxication (p < .001), but Dasatinib treatment could significantly ameliorate these mediators at the level of gene expression (p < .01) and protein level of TNF-α (p < .001). The necro-inflammatory changes in histopathological finding, nitric oxide and hydroxyproline level were also increased during 12 weeks of CCl4 administration which was significantly attenuated by Dasatinib (p < .01). DISCUSSION AND CONCLUSION: Our findings indicate that Dasatinib can be cautiously an anti-fibrotic, anti-inflammatory and anti-oxidative agent in clinical setting.

Lipid Peroxidation and Antioxidant Status in Patients with Medullary Thyroid Carcinoma: A Case-Control Study.

INTRODUCTION: Oxidative stress or oxidant/antioxidant imbalance has a crucial role in the pathogenesis of some diseases like cancer. Medullary thyroid carcinoma (MTC) originates in the thyroid parafollicular cells and includes 3-4% of the malignant neoplasms that have an effect on this gland. The aetiology of MTC has not been clarified. However, oxidative stress may be one of the factors involved. AIM: The aim of the current study was to evaluate the antioxidant enzyme activity of catalase (CAT), Glutathione (GSH), total antioxidant capacity (TAC) and the levels of the lipid peroxidation product malondialdehyde (MDA) in blood samples of MTC patients as compared to healthy controls. MATERIALS AND METHODS: A case-control study was designed enrolling patients with confirmed MTC diagnosis and age-and sex group matched healthy volunteers referred to the clinic of the Research Institute for Endocrine Sciences, Tehran, Iran from April 2013 to July 2015. Fasting blood samples were taken for study. Catalase, GSH, MDA and TAC levels were measured by colorimetry using commercial kits (ZellBio GmbH, Germany). Data were analysed using SPSS 17 software, comparing mean±SD through t-test and difference between proportions through chi-square. RESULTS: No statistical difference was observed in the demographic characteristic between cases and controls. The final MTC group included 40 males and 45 females with a mean age of 30±12.9 year, and the control group 40 males and 47 females, with a mean age of 31.2±12.3 year. Anthropometric parameters, dietary and thyroid hormones levels (T3, T4 and TSH) were similar. Serum TAC (p=0.015), GSH (p=0.029) and CAT (p<0.001) levels were found to be significantly lower in the MTC patients, while serum MDA levels were significantly higher in MTC patients than controls (p<0.001). CONCLUSION: These preliminary findings suggest that oxidant/antioxidant imbalance may be associated with or possibly indicate an increased risk to medullary thyroid carcinoma. Further studies are needed to explore these findings.

Relationship between estradiol and antioxidant enzymes activity of ischemic stroke.

Some evidence suggests the neuroprotection of estrogen provided by the antioxidant activity of this compound. The main objective of this study was to determine the level of estradiol and its correlation with the activity of antioxidant enzymes, total antioxidant status and ferritin from ischemic stroke subjects. The study population consisted of 30 patients with acute ischemic stroke and 30 controls. There was no significant difference between estradiol in stroke and control group. The activity of superoxide dismutase and level of ferritin was higher in stroke compared with control group (P < .05, P < .001, resp.). There was no significant correlation between estradiol and glutathione peroxidase, glutathione reductase, catalase, total antioxidant status, and ferritin in stroke and control groups. We observed inverse correlation between estradiol with superoxide dismutase in males of stroke patients (r = -0.54, P = .029). Our results supported that endogenous estradiol of elderly men and women of stroke or control group has no antioxidant activity.

Sex differences in adenosine deaminase activity of stroke patients.

BACKGROUND: Adenosine deaminase (ADA) catalyzes the irreversible hydrolytic deamination of adenosine to inosine. The purpose of this study was to determine the plasma activities of total adenosine deaminase (ADA T), and its isoenzymes, ADA1 and ADA2, and ADA1/ADA2 ratio of male and female ischemic stroke patients. METHODS: We determined activities of plasma ADA T, ADA1, ADA2 and ADA1/ADA2 ratio in 30 patients (15 men and 15 women) with acute ischemic stroke within 12 h of the onset of the attack, as well as in 30 control subjects (15 men and 15 women) of comparable age. RESULTS: There were significant differences between the ADA1 activity and ADA1/ADA2 ratio in male and female stroke patients (p<0.05). Compared with male stroke subjects, females had higher ADA1 activity and ADA1/ADA2 ratios. There were no significant differences between activities of ADA T and ADA2 in men and women of the stroke and control groups. In addition, the Canadian Neurological Scale in men was significantly higher than that of women in the stroke group (p<0.05). CONCLUSIONS: Our results suggest that the primary mechanism in men with ischemic stroke might involve the reduction of ADA1 activity. The reduction is probably an adaptation mechanism for induced increase in adenosine availability and protection of brain to ischemic injury.