Betaine protects against sodium arsenite-induced diabetes and hepatotoxicity in mice.

Epidemiological evidence has associated chronic exposure to inorganic arsenic with an increased occurrence of glucose intolerance and diabetes mellitus. Furthermore, inorganic arsenic induces oxidative stress in organs such as the liver. Betaine, as a methyl donor, plays a pivotal role in homocysteine metabolism. Betaine has antioxidant and anti-inflammatory properties. Therefore, the aim of this study was to evaluate the effects of betaine against sodium arsenite-induced diabetes and hepatotoxicity in mice. Forty-eight male mice were divided into 6 groups of 8. Group 1, received distilled water every day for 4 weeks by gavage. Group 2 received 500 mg/kg betaine every day for 4 weeks by gavage. Group 3 was given 10 mg/kg NaAsO2 every day for 4 weeks by gavage. Groups 4, 5, and 6 were co-treated with 125, 250, and 500 mg/kg betaine half an hour before NaAsO2 (10 mg/kg), respectively, daily for up to 4 weeks by gavage. After 28 days of the study, the mice were fasted overnight and on day 29, fasting blood glucose was measured and glucose tolerance test was performed. On day 30, the mice were anesthetized and a blood sample was taken from the heart. Serum factors (alanine aminotransferase, aspartate transaminase, and alkaline phosphatase activities), oxidative stress factors (malondialdehyde and glutathione levels, and the activity of superoxide dismutase, glutathione peroxidase, and catalase enzymes) and hepatic inflammatory factors (nitric oxide and tumor necrosis factor α) were measured. Histopathological studies were also performed on the liver and pancreas. In this study, it was shown that arsenic causes glucose intolerance, and oxidative/inflammatory hepatic damage. Co-administration of betaine prevents hepatotoxicity and glucose intolerance induced by arsenic in mice. Co-treatment of betaine with arsenic improved glucose intolerance and protected the liver against arsenic induced-oxidative damage and inflammation. Betaine at the dose of 500 mg/kg showed better results than the other doses. Accordingly, betaine can be suggested as a therapeutic agent against diabetogenic and hepatotoxic effects of arsenic.

The combined effect of dichloroacetate and 3-bromopyruvate on glucose metabolism in colorectal cancer cell line, HT-29; the mitochondrial pathway apoptosis.

BACKGROUND: 5-Fluorouracil (5-FU) is regarded as the first line treatment for colorectal cancer; however, its effectiveness is limited by drug resistance. The ultimate goal of cancer therapy is induction of cancer cell death to achieve an effective outcome with minimal side effects. The present work aimed to assess the anti-cancer activities of mitocans which can be considered as an effective anticancer drug due to high specificity in targeting cancer cells. METHODS: MTT (3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay was performed to determine the effects of our mitocans on cell viability and cell death. Apoptosis and necrosis, caspase 3 activity, mitochondrial membrane potential and ROS production in HT29 cell lines were analyzed by ApopNexin™ FITC/PI Kit, Caspase- 3 Assay Kit, MitoTracker Green and DCFH-DA, respectively. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) genes in HT29 cell lines. RESULTS: Treatment with mitocans (3Br-P + DCA) inhibited the growth of HT29. Moreover, 3Br-P + DCA significantly induced apoptosis and necrosis, activation of caspase 3 activity, depolarize the mitochondrial membrane potential, and ROS production. At a molecular level, 3Br-P + DCA treatment remarkably down-regulated the expression of Bcl-2, while up-regulated the expression of Bax. CONCLUSION: Mitocans, in particular the combined drug, 3Br-P + DCA, could be regarded and more evaluated as a safe and effective compound for CRC treatment. Targeting hexokinase and pyruvate dehydrogenase kinase enzymes may be an option to overcome 5-FU -mediated chemo-resistant in colorectal cancer.

The roles of FOX proteins in virus-associated cancers.

Forkhead box (FOX) proteins play a crucial role in regulating the expression of genes involved in multiple biological processes, such as metabolism, development, differentiation, proliferation, apoptosis, migration, invasion, and longevity. Deregulation of FOX proteins is commonly associated with cancer initiation, progression, and chemotherapeutic drug resistance in many human tumors. FOX proteins deregulate through genetic events and the perturbation of posttranslational modification. The purpose of the present review is to describe the deregulation of FOX proteins by oncoviruses. Oncoviruses utilize various mechanisms to deregulate FOX proteins, including alterations in posttranslational modifications, cellular localization independently of posttranslational modifications, virus-encoded miRNAs, activation or suppression of a series of cell signaling pathways. This deregulation can affect proliferation, metastasis, chemotherapy resistance, and immunosuppression in virus-induced cancers and help to chronic viral infection, development of gluconeogenic responses, and inflammation. Since the PI3K/Akt/mTOR signaling pathway is the upstream FOXO, suppressing it can cause FOXO function to return, and this can be one of the reasons for patients to recover from the infection of the viruses used to treat these inhibitors. Hence, FOX proteins could serve as prognosis markers and target therapy specifically in cancers caused by oncoviruses.

Protective Effect of Gemfibrozil on Hepatotoxicity Induced by Acetaminophen in Mice: the Importance of Oxidative Stress Suppression.

Purpose: Gemfibrozil (GEM) apart from agonist activity at peroxisome proliferator-activated receptor-alpha (PPAR-α) has antioxidant and anti-inflammatory properties. Accordingly, the present study was designed to investigate the protective effect of GEM on acute liver toxicity induced by acetaminophen (APAP) in mice. Methods: In this study, mice divided in seven groups include, control group, APAP group, GEM group, three APAP groups pretreated with GEM at the doses of 25, 50 and 100 mg/kg respectively and APAP group pretreated with N-Acetyl cysteine. GEM, NAC or vehicle were administered for 10 days. In last day, GEM and NAC were gavaged 1 h before and 1 h after APAP injection. Twenty four hours after APAP, mice were sacrificed. Serum parameters include alanine aminotransferase (ALT), aspartate aminotransferase (AST) and liver tissue markers including catalase enzyme activity, reactive oxygen species (ROS), malondialdehyde and reduced glutathione (GSH) levels determined and histopathological parameters measured. Results: GEM led to significant decrease in serum ALT and AST activities and increase in catalase activity and hepatic GSH level and reduces malondialdehyde and ROS levels in the liver tissue. In confirmation, histopathological findings revealed that GEM decrease degeneration, vacuolation and necrosis of hepatocytes and infiltration of inflammatory cells. Conclusion: Present data demonstrated that GEM has antioxidant properties and can protect the liver from APAP toxicity, just in the same pathway that toxicity occurs by toxic ROS and that GEM may be an alternative therapeutic agent to NAC in APAP toxicity.