Voluntary exercise protects against methamphetamine-induced oxidative stress in brain microvasculature and disruption of the blood--brain barrier

BACKGROUND: There is no effective therapeutic intervention developed targeting cerebrovascular toxicity of drugs of abuse, including methamphetamine (METH). We hypothesize that exercise protects against METH-induced disruption of the blood--brain barrier (BBB) by enhancing the antioxidant capacity of cerebral microvessels and modulating caveolae-associated signaling. Mice were subjected to voluntary wheel running for 5 weeks resembling the voluntary pattern of human exercise, followed by injection with METH (10 mg/kg). The frequency, duration, and intensity of each running session were monitored for each mouse via a direct data link to a computer and the running data are analyzed by Clock labTM Analysis software. Controls included mice sedentary that did not have access to running wheels and/or injections with saline. RESULTS: METH induced oxidative stress in brain microvessels, resulting in up regulation of caveolae-associated NAD(P)H oxidase subunits, and phosphorylation of mitochondrial protein 66Shc. Treatment with METH disrupted also the expression and colocalization of tight junction proteins. Importantly, exercise markedly attenuated these effects and protected against METH-induced disruption of the BBB integrity. CONCLUSIONS: The obtained results indicate that exercise is an important modifiable behavioral factor that can protect against METH-induced cerebrovascular toxicity. These findings may provide new strategies in preventing the toxicity of drug of abuse

Increased Birth Weight is Associated with Altered Gene Expression in Neonatal Foreskin

Elevated birth weight is linked to glucose intolerance and obesity health-related complications later in life. No studies have examined if infant birth weight is associated with gene expression markers of obesity and inflammation in a tissue that comes directly from the infant following birth. We evaluated the association between birth weight and gene expression on fetal programming of obesity. Foreskin samples were collected following circumcision, and gene expression analyzed comparing the 15% greatest birth weight infants (n = 7) v. the remainder of the cohort (n = 40). Multivariate linear regression models were fit to relate expression levels on differentially expressed genes to birth weight group with adjustment for variables selected from a list of maternal and infant characteristics. Glucose transporter type 4 (GLUT4), insulin receptor substrate 2 (IRS2), leptin receptor (LEPR), lipoprotein lipase (LPL), low-density lipoprotein receptor-related protein 1 (LRP1), matrix metalloproteinase 2 (MMP2), plasminogen activator inhibitor-1 (PAI-1) and transcription factor 7-like 2 (TCF7L2) were significantly upregulated and histone deacetylase 1 (HDAC1) and thioredoxin (TXN) downregulated in the larger birth weight neonates v. controls. Multivariate modeling revealed that the estimated adjusted birth weight group difference exceeded one standard deviation of the expression level for eight of the 10 genes. Between 25 and 50% of variation in expression level was explained by multivariate modeling for eight of the 10 genes. Gene expression related to glycemic control, appetite/energy balance, obesity and inflammation were altered in tissue from babies with elevated birth weight, and these genes may provide important information regarding fetal programming in macrosomic babies

Endothelial Cell Biology and HIV-1 Infection

An understanding of endothelial cell function both systemically and in the central nervous system is relevant to many aspects of HIV1 associated disease. Endothelial cells produce a variety of biologically active factors (e.g., NO, prostacyclin, chemokines) that control vascular permeability, vessel tone, coagulation, fibrinolysis, and inflammatory responses. These factors can be generated by other vascular cells, as well as nonvascular cells. Alterations of normal endothelial cell biology have critical significance in the development of vascular and neurovascular pathology during HIV1 infection. For example, such alterations can contribute to disruption of the BBB, to HIV1 entry into the brain, to the development of vasculopathies, and to atherosclerosis. The underlying mechanisms appear to be related to induction of oxidative stress and alterations of redoxrelated signaling. Vascular toxicity may be induced by HIV1 itself or it can be mediated by a variety of HIV1specific proteins, as well as by antiretroviral drugs.

Sex- and Dose-Specific Effects of Maternal Bisphenol A Exposure on Pancreatic Islets of First- and Second-Generation Adult Mice Offspring

BACKGROUND: Exposure to the environmental endocrine disruptor bisphenol A (BPA) is ubiquitous and associated with the increased risk of diabetes and obesity. However, the underlying mechanisms remain unknown. We recently demonstrated that perinatal BPA exposure is associated with higher body fat, impaired glucose tolerance, and reduced insulin secretion in first- (F1) and second-generation (F2) C57BL/6J male mice offspring. OBJECTIVE: We sought to determine the multigenerational effects of maternal bisphenol A exposure on mouse pancreatic islets. METHODS: Cellular and molecular mechanisms underlying these persistent changes were determined in F1 and F2 adult offspring of F0 mothers exposed to two relevant human exposure levels of BPA (10 mu g/kg/d-LowerB and 10 mg/kg/d-UpperB). RESULTS: Both doses of BM significantly impaired insulin secretion in male but not female F1 and F2 offspring. Surprisingly, LowerB and-UpperB induced islet inflammation in male 1 offspring that persisted into the next generation. We also observed close-specific effects of BPA on islets in males. UpperB exposure impaired mitochondrial function, whereas LowerB exposure significantly reduced beta-cell mass and increased beta-cell death that persisted in the F2 generation. Transcriptome analyses supported these physiologic findings and there were significant dose-specific changes in the expression of genes regulating inflammation and mitochondrial function. Previously we observed increased expression of the critically important beta-cell gene, Igf2 in whole F1 embryos. Surprisingly, increased Igf2 expression persisted in the islets of male F1 and F2 offspring and was associated with altered DNA methylation. CONCLUSION: These findings demonstrate that maternal BPA exposure has dose- and sex-specific effects on pancreatic islets of adult F1 and F2 mice offspring. The transmission of these changes across multiple generations may involve either mitochondrial dysfunction and/or epigenetic modifications