Stevioside modulates oxidative damage in the liver and kidney of high fat/low streptozocin diabetic rats

This study investigated the potential of stevioside to prevent oxidative DNA damage in the liver and kidney of type 2 diabetes mellitus (T2DM) using high fat-low streptozocin rat model. Rats were treated daily with 12.5, 25 and 50 mg/kg stevioside orally for 21 days. Levels of biomarkers of T2DM, lipid profile and oxidative stress were assayed spectrophotometrically. The DNA ladder assay method was used to assess DNA fragmentation in the liver and kidney while computational analysis was used to predict the mechanisms of antidiabetic properties of stevioside. Stevioside significantly (p < 0.05) decreased the levels of plasma glucose, insulin, dipeptidyl peptidase IV and activities of kidney angiotensin converting enzyme. Stevioside significantly reduced oxidative stress by decreasing the levels of lipid peroxidation and nitric oxide in the liver and kidney; thereby, reducing the extent of DNA fragmentation in the liver and kidney of the diabetic rats. The in silico analysis showed that the ability of stevioside to exert these effects is linked to its inhibition of beta-adrenergic receptor kinase and G-protein-coupled receptor kinase. The results of this study suggest that the prevention of DNA fragmentation may be an additional benefit of the use of stevioside in the management of T2DM

Effects of Stevioside on oxidative DNA damage in liver and kidney of High Fat Diet Induced type 2 diabetes in Rats

Type 2 diabetes mellitus (T2DM) is the most prevalent form of diabetes and it has been reported to be associated with oxidative stress-induced cellular dysfunction including diabetic nephropathy. Stevioside (STV), a natural non-caloric sweetener refined from the leaves of Stevia rebaudiana Bertoni, has been reported for its insulinotropic and antihyperlipemic effects. In order to investigate the influence of STV on oxidative stress and oxidative DNA damage, high fat-low streptozocin rat model of T2DM were treated orally with 0.125mg/Kg, 0.25mg/Kg and 0.50mg/Kg body weight of STV for 21days. The levels of plasma insulin and dipeptidyl peptidase-4 (DPP IV) were determined using enzyme-linked immunosorbent assay while other biomarkers of T2DM, organ function, oxidative stress and lipid profile were assayed spectrophotometrically. DNA damage in the liver and kidney was determined by assessing the internucleosomal DNA fragmentation pattern on agarose gel electrophoresis. STV treatment resulted in decrease in the levels of fasting plasma glucose, insulin and DPP IV as well as in the activities of plasma amylase and kidney angiotensin-converting enzyme. STV also significantly (p<0.05) improved plasma lipid profile and oxidative stress in the liver and kidney of the diabetic rats, with rats treated with 0.50mg/kg STV having the lowest levels of malondialdehyde and nitric oxide in liver and kidney. There was also a concomitant decrease in the fragmentation of genomic DNA in the liver and kidney of the diabetic rats. This ability of STV, administered orally, to prevent oxidative DNA damage in the liver and kidney of type 2 diabetic rats should contribute to its use in the management of T2DM

Early Life Exposure to Aflatoxin B1 in Rats: Alterations in Lipids, Hormones, and DNA Methylation among the Offspring

Aflatoxins are toxic compounds produced by molds of the Aspergillus species that contaminate food primarily in tropical countries. The most toxic aflatoxin, aflatoxin B1 (AFB1), is a major cause of hepatocellular carcinoma (HCC) in these countries. In sub-Saharan Africa, aflatoxin contamination is common, and perinatal AFB1 exposure has been linked to the early onset of HCC. Epigenetic programming, including changes to DNA methylation, is one mechanism by which early life exposures can lead to adult disease. This study aims to elucidate whether perinatal AFB1 exposure alters markers of offspring health including weight, lipid, and hormone profiles as well as epigenetic regulation that may later influence cancer risk. Pregnant rats were exposed to two doses of AFB1 (low 0.5 and high 5 mg/kg) before conception, throughout pregnancy, and while weaning and compared to an unexposed group. Offspring from each group were followed to 3 weeks or 3 months of age, and their blood and liver samples were collected. Body weights and lipids were assessed at 3 weeks and 3 months while reproductive, gonadotropic, and thyroid hormones were assessed at 3 months. Prenatal AFB1 (high dose) exposure resulted in significant 16.3%, 31.6%, and 7.5% decreases in weight of the offspring at birth, 3 weeks, and 3 months, respectively. Both doses of exposure altered lipid and hormone profiles. Pyrosequencing was used to quantify percent DNA methylation at tumor suppressor gene Tp53 and growth-regulator H19 in DNA from liver and blood. Results were compared between the control and AFB1 exposure groups in 3-week liver samples and 3-week and 3-month blood samples. Relative to controls, Tp53 DNA methylation in both low- and high-dose exposed rats was significantly decreased in liver samples and increased in the blood (p &lt; 0.05 in linear mixed models). H19 methylation was higher in the liver from low- and high-exposed rats and decreased in 3-month blood samples from the high exposure group (p &lt; 0.05). Further research is warranted to determine whether such hormone, lipid, and epigenetic alterations from AFB1 exposure early in life play a role in the development of early-onset HCC

Novel DNA methylation changes in mouse lungs associated with chronic smoking

ABSTRACTSmoking is a potent cause of asthma exacerbations, chronic obstructive pulmonary disease (COPD) and many other health defects, and changes in DNA methylation (DNAm) have been identified as a potential link between smoking and these health outcomes. However, most studies of smoking and DNAm have been done using blood and other easily accessible tissues in humans, while evidence from more directly affected tissues such as the lungs is lacking. Here, we identified DNAm patterns in the lungs that are altered by smoking. We used an established mouse model to measure the effects of chronic smoke exposure first on lung phenotype immediately after smoking and then after a period of smoking cessation. Next, we determined whether our mouse model recapitulates previous DNAm patterns observed in smoking humans, specifically measuring DNAm at a candidate gene responsive to cigarette smoke, Cyp1a1. Finally, we carried out epigenome-wide DNAm analyses using the newly released Illumina mouse methylation microarrays. Our results recapitulate some of the phenotypes and DNAm patterns observed in human studies but reveal 32 differentially methylated genes specific to the lungs which have not been previously associated with smoking. The affected genes are associated with nicotine dependency, tumorigenesis and metastasis, immune cell dysfunction, lung function decline, and COPD. This research emphasizes the need to study CS-mediated DNAm signatures in directly affected tissues like the lungs, to fully understand mechanisms underlying CS-mediated health outcomes

Novel DNA methylation changes in mouse lungs associated with chronic smoking

Smoking is a potent cause of asthma exacerbations, chronic obstructive pulmonary disease (COPD) and many other health defects, and changes in DNA methylation (DNAm) have been identified as a potential link between smoking and these health outcomes. However, most studies of smoking and DNAm have been done using blood and other easily accessible tissues in humans, while evidence from more directly affected tissues such as the lungs is lacking. Here, we identified DNAm patterns in the lungs that are altered by smoking. We used an established mouse model to measure the effects of chronic smoke exposure first on lung phenotype immediately after smoking and then after a period of smoking cessation. Next, we determined whether our mouse model recapitulates previous DNAm patterns observed in smoking humans, specifically measuring DNAm at a candidate gene responsive to cigarette smoke, Cyp1a1. Finally, we carried out epigenome-wide DNAm analyses using the newly released Illumina mouse methylation microarrays. Our results recapitulate some of the phenotypes and DNAm patterns observed in human studies but reveal 32 differentially methylated genes specific to the lungs which have not been previously associated with smoking. The affected genes are associated with nicotine dependency, tumorigenesis and metastasis, immune cell dysfunction, lung function decline, and COPD. This research emphasizes the need to study CS-mediated DNAm signatures in directly affected tissues like the lungs, to fully understand mechanisms underlying CS-mediated health outcomes.</p