Evaluation of notch and hypoxia signaling pathways in chemically induced hepatocelluar carcinoma in rats

Hepatocellular carcinoma [HCC] is a common worldwide malignancy. Notch signaling pathway contributes to the genesis of diverse cancers, however, its role in HCC is unclear. Hypoxia is a common feature of HCC. Signal integration between Nothc and hypoxia may be involved in HCC. The aim of this study was to evaluate the expression of some Notch pathway genes, in addition to hypoxia inducible factor-1 alpha [HIF-l alpha] during rat hepatocellular carcinogenesis. The study aimed also, to identify any crosstalk between Notch signaling and hypoxia throughout hepatocellular oncogenesis in rats. Hepatocellular carcinogenesis was chemically induced in rats. Tissue specimens were examined histopathologically and classified into early preneoplastic group, advanced preneoplastic group, and control group. The expression of Notch-l, Dll-4, and HIF-l alpha was evaluated in tissue samples by total RNA extraction and RT-PCR. The expression of target genes were significantly increased in the diseased group. There was a significant correlation between the expression of Notch-l, Dll4, and HIF-l alpha. These results indicate that overexpression of Notch-l, Dll-4, and HIF-l alpha may be associated with the malignant transformation of hepatocytes with a possible Notch-hypoxia cross talk during hepatocellular oncogenecity

Adiponectin levels and some risk factors for atheroscelerosis in rats with experimental hypo-and hyperthyroidism

Adiponectin, an adipocyte-derived hormone, has been reported to decrease body weight by increasing thermogenesis and lipid oxidation. Also, has been reported to have anti-inflammatory and anti-atherogenic effects. Its relation to the metabolic changes and some cardiovascular risk factors in thyroid dysfunction states is still unclear. The aim of the present study was to evaluate adiponectin levels and its relation to metabolic and cardiovascular risk factors in rats with thyroid dysfunction. The study was carried out on 32 adult male Wi-star rats that were divided into 4 groups [8 rats each]. Group 1 included normal rats [Euthyroid], group 2 included rats treated with 0.03% methimazole in the drinking water for 28 days [hypothyroid rats], group Ill included rats injected subcutaneously with thyroxine [50 microg/100 g body weight] for 10 days [hyperthyroid rats], group IV included hypothyroid rats injected intraperitoneal with adiponectin [1.5 mg/kg body weight] for 7 days. Blood samples were collected at the end of experiments by decapitating the rats. The following parameters were measured: serum adiponectin, serum T3, T4 and TSH levels, insulin level, fasting blood glucose, atherogenic indices [serum cholesterol, serum triglycerides, HDL-C, LDL-C, fibrinogen] and C-reactive protein. Insulin sensitivity was determined using the Homoestasis Model Assessment [HOMA-IR]. Serum adiponectin level in hyperthyroid rats was 2.9 fold higher than that of euthyroid [P<0.0001], while that in hypothyroid rats tended to be lower [20%] but without statistical significance. Serum adiponectin had a positive correlation with serum thyroxine and negative association with serum TSH [P<0.05]. Also, adiponectin levels correlated negatively with body weight. In the hypothyroid group adiponectin level correlated negatively with HOMA-IR [P<0.05]. There was a significant correlation between adiponectin and HDL-C, and CRP in both hypo- and hyperthyroid rats. Adiponectin administration produced significant decrease in cholesterol, triglycerides and low density lipoprotein cholesterol [LDL-C] and significant increase in HDL-C in hypothyroid rats. The results of our study demonstrated that, in rats; thyroid hormone disturbances modified serum adiponectin concentration and there was a significant relationship between adiponectin level and high density lipoprotein-cholesterol. Also, there is a possible role for adiponectin in cardiovascular protection through its effects on low grade inflammation and insulin resistance in cases of thyroid disorders

Biochemical evaluation of some indices of oxidative stress in patients with hyperthyrodism before and after treatment

This study aimed to evaluate changes in plasma malondialdehyde, total thiol concentration and total antioxidant activity in newly diagnosed Graves' disease and toxic multinodular goiter patients prior to antithyroid treatment and after restoration of stable euthyroid state. Forty subjects were included in this study. Thirty patients with hyperthyroidism, which were classified into two groups, the first [group I] Comprised 15 patients with hyperthyroidism due to untreated Graves' disease, and the second [group II] Comprised 15 patients with hyperthyroidism due to untreated toxic multinodular goiter. Ten patients of each group were treated pharmacologically with antithyroid drug carbimazol [30 mg/day for 8 weeks]. Total thyroxin [T4], total triiodothyronine [T3], TSH, malondialdehyde, total thiol concentration and total antioxidant activity were estimated before initiation of treatment. After apparent attainment of euthyroid state, all tests were repeated for ten of the patients with Graves' disease and ten of the patients with toxic multinodular goiter. The results of this study revealed that there were a statistically highly significant increase in plasma malandialdehyde [MDA], a significant decrease in plasma thiol and very highly significant decrease in total antioxidant activity in both patient groups when compared to healthy controls. After treatment, plasma MDA levels were highly significantly decreased and total antioxidant activity was very highly significantly increased in both patient groups when compared to control one. As regard thiol, it was significantly increased in group I only. From this study it could be conclude that, intensification of lipid and protein peroxidation process and the impairment of plasma antioxidant activity in patients with hyperthyroidism due to Graves' disease or toxic multinodular goiter confirm the presence of oxidative stress and the disturbances in the antioxidant systems might be an indicator of patients' susceptibility to free radical damage. So, supplementation of antioxidants as an adjuvant to medical antithyroid treatment could help to prevent oxidative damage in hyperthyroid patients. Also, we suggest that measuring oxidative stress parameters could be a better way of follow up of thyroid state improvement both from the chemical and economic point of view

Evaluation of soluble Fas as an apoptotic marker in male infertility

Inappropriate male germ cell apoptosis is associated with pathological conditions such as infertility Apoptosis is a key phenomenon in the control of sperm production. Fas is widely expressed glycosylated type transmembrane protein which has been suggested to play a role in regulating testicular germ cell apoptosis. A soluble isoforms of Fas [SFas/CD95] are lacking parts of the transmembrane domain generated by alternative mRNA splicing. These soluble molecules may regulate Fas mediated apoptosis. Our aim was to investigate the possible role of s Fas in regulation of germ cell apoptosis and its significance in male infertility. The seminal plasma levels of sFas and alpha glucosidase were measured using ELISA, and spectrophotometer respectively in 75 semen samples which were grouped into 6 groups [one fertile and five infertile] according to the criteria of WHO. There were a statistically significant [p < 0.001] increases in the levels of sFas in all studied infertile groups, while there were significant decreases [p<0.001] in alpha-glucosidase levels in the same infertile groups when compared with normozoospermia. There were significant negative correlations between sFas and sperm concentration, grade [A] motility, velocity, linear velocity, linearity index, normal morphology and alpha glucosidase activity. There were significant positive correlation between sFas and grade [D] motility. Receiver operating characteristic [ROC] curve was done to use sFas as a discrimination marker between fertile and infertile groups. From this study we concluded that the detection of sFas in seminal plasma could pro- vide additional information about the biochemical integrity of sperm and may be used in future studies from assessment of fertilization failures particularly in round head syndrome. In fact, these new hypotheses as regards apoptosis in male infertility need to be fatherly investigated to determine whether the opportunities of fered by modulation of apoptotic cell death will lead to new treatment approaches

impact of hypothyroidism on thrombophilic state in hypercholesterolemic patients

Hypercholesterolemia has been linked to an increase in coagulation factors. Hypercholesterolemia could be either primary or secondary to other diseases e.g. hypothyroidism that could also affect hemostasis. There fore, we studied the impact of hypothyroidism on thrombophilic state that accompanies hypercholesterolemia. 68 hypercholesterolemic patients were included into this study [40 with primary hypercholesterolemia and 28 with associated primary hypothyroidism]. 30 healthy subjects matched for age, sex, BMI and WHR were recruited as a control group. Both primary hypercholesterolemic and hypothyroid groups have higher levels of fibrinogen [304.1 +/- 44.9 and 297.4 +/- 37.6 mg% respectively] and increased coagulant activity of factor VII and VIII, together with significant shortening of PT and APTT in comparison to control group. Plasminogen and antithrombin Ill activity was significantly increased in both hypercholesterolemic groups, with higher levels found in hypothyroid group in comparison to primary hypercholesterolemic group [p<0. 05]. Primary hypercholesterolemic group had increased plasma levels of fibronectin [41.8 +/- 12 mg/ dl], whereas, hypothyroid group had decreased levels [23.96 +/- 6.17 mg/dl] in comparison to the control group [30.32 +/- 7.99 mg/dl]. Gender differences of fibronectin, FVII[c] and FVIII[c] are only evident in primary hypercholesterolemic group. From this study, it is concluded that, hemostasis may be affected by thyroid dysfunction in various ways. First: hypothyroidism will increase plasminogen and antithrombin III that render patients less prone to hypercoagulability that accompanies hypercholesterolemia. Second: gender differences in blood thrombogenicity that is evident in primary hypercholesterolemic patients is not manifest in hypothyroid patients. Third: decreased plasma level of fibronectin in hypothyroid patients in comparison to primary hypercholesterolemic patients