Tissue inhibitor of metalloproteinases-1 protects human neurons from staurosporine and HIV-1-induced apoptosis: mechanisms and relevance to HIV-1-associated dementia

HIV-1-associated dementia (HAD)-relevant proinflammatory cytokines robustly induce astrocyte tissue inhibitor of metalloproteinases-1 (TIMP-1). As TIMP-1 displays pleotropic functions, we hypothesized that TIMP-1 expression may serve as a neuroprotective response of astrocytes. Previously, we reported that chronically activated astrocytes fail to maintain elevated TIMP-1 expression, and TIMP-1 levels are lower in the brain of HAD patients; a phenomenon that may contribute to central nervous system pathogenesis. Further, the role of TIMP-1 as a neurotrophic factor is incompletely understood. In this study, we report that staurosporine (STS) and HIV-1ADA virus, both led to induction of apoptosis in cultured primary human neurons. Interestingly, cotreatment with TIMP-1 protects neurons from apoptosis and reverses neuronal morphological changes induced by these toxins. Further, the anti-apoptotic effect was not observed with TIMP-2 or -3, but was retained in a mutant of the N-terminal TIMP-1 protein with threonine-2 mutated to glycine (T2G) that is deficient in matrix metalloproteinase (MMP)-1, -2 and -3 inhibitory activity. Therefore, the mechanism is specific to TIMP-1 and partially independent of MMP-inhibition. Additionally, TIMP-1 modulates the Bcl-2 family of proteins and inhibits opening of mitochondrial permeability transition pores induced by HIV-1 or STS. Together, these findings describe a novel function, mechanism and direct role of TIMP-1 in neuroprotection, suggesting its therapeutic potential in HAD and possibly in other neurodegenerative diseases

Culturing Pancreatic Islets in Microfluidic Flow Enhances Morphology of the Associated Endothelial Cells

Pancreatic islets are heavily vascularized in vivo with each insulin secreting beta-cell associated with at least one endothelial cell (EC). This structure is maintained immediately post-isolation; however, in culture the ECs slowly deteriorate, losing density and branched morphology. We postulate that this deterioration occurs in the absence of blood flow due to limited diffusion of media inside the tissue. To improve exchange of media inside the tissue, we created a microfluidic device to culture islets in a range of flow-rates. Culturing the islets from C57BL6 mice in this device with media flowing between 1 and 7 ml/24 hr resulted in twice the EC-density and -connected length compared to classically cultured islets. Media containing fluorescent dextran reached the center of islets in the device in a flow-rate-dependant manner consistent with improved penetration. We also observed deterioration of EC morphology using serum free media that was rescued by addition of bovine serum albumin, a known anti-apoptotic signal with limited diffusion in tissue. We further examined the effect of flow on beta-cells showing dampened glucose-stimulated Ca2+-response from cells at the periphery of the islet where fluid shear-stress is greatest. However, we observed normal two-photon NAD(P)H response and insulin secretion from the remainder of the islet. These data reveal the deterioration of islet EC-morphology is in part due to restricted diffusion of serum albumin within the tissue. These data further reveal microfluidic devices as unique platforms to optimize islet culture by introducing intercellular flow to overcome the restricted diffusion of media components

Early life factors and being overweight at 4 years of age among children in Malmö, Sweden

<p>Abstract</p> <p>Background</p> <p>Rising rates of obesity and overweight is an increasing public health problem all over the world. Recent research has shown the importance of early life factors in the development of child overweight. However, to the best of our knowledge there are no studies investigating the potential synergistic effect of early life factors and presence of parental overweight on the development of child overweight.</p> <p>Methods</p> <p>The study was population-based and cross-sectional. The study population consisted of children who visited the Child Health Care (CHC) centers in Malmö for their 4-year health check during 2003-2008 and whose parents answered a self-administered questionnaire (n = 9009 children).</p> <p>Results</p> <p>The results showed that having overweight/obese parents was strongly associated with the child being overweight or obese. Furthermore, there was an association between unfavorable early life factors (i.e., mother smoking during pregnancy, presence of secondhand tobacco smoke early in life, high birth weight) and the development of child overweight/obesity at four years of age, while breastfeeding seemed to have a protective role. For example, maternal smoking during pregnancy was associated with an odds ratio (OR) of 1.47 (95% CI: 1.22, 1.76) for overweight and 2.31 (95% CI: 1.68, 3.17) for obesity. The results further showed synergistic effects between parental overweight and exposure to unfavourable early life factors in the development of child overweight.</p> <p>Conclusions</p> <p>The present study shows the importance of early life factors in the development of child overweight and obesity, and thus puts focus on the importance of early targeted interventions.</p

Offspring Hormones Reflect the Maternal Prenatal Social Environment: Potential for Foetal Programming?

Females of many species adaptively program their offspring to predictable environmental conditions, a process that is often mediated by hormones. Laboratory studies have shown, for instance, that social density affects levels of maternal cortisol and testosterone, leading to fitness-relevant changes in offspring physiology and behaviour. However, the effects of social density remain poorly understood in natural populations due to the difficulty of disentangling confounding influences such as climatic variation and food availability. Colonially breeding marine mammals offer a unique opportunity to study maternal effects in response to variable colony densities under similar ecological conditions. We therefore quantified maternal and offspring hormone levels in 84 Antarctic fur seals (Arctocephalus gazella) from two closely neighbouring colonies of contrasting density. Hair samples were used as they integrate hormone levels over several weeks or months and therefore represent in utero conditions during foetal development. We found significantly higher levels of cortisol and testosterone (both P < 0.001) in mothers from the high density colony, reflecting a more stressful and competitive environment. In addition, offspring testosterone showed a significant positive correlation with maternal cortisol (P < 0.05). Although further work is needed to elucidate the potential consequences for offspring fitness, these findings raise the intriguing possibility that adaptive foetal programming might occur in fur seals in response to the maternal social environment. They also lend support to the idea that hormonally mediated maternal effects may depend more strongly on the maternal regulation of androgen rather than cortisol levels

Amelioration of galactosamine-induced nephrotoxicity by a protein isolated from the leaves of the herb, Cajanus indicus L

<p>Abstract</p> <p>Background</p> <p>Galactosamine (GalN), an established experimental toxin, mainly causes liver injury via the generation of free radicals and depletion of UTP nucleotides. Renal failure is often associated with end stage liver damage. GalN intoxication also induces renal dysfunction in connection with hepatic disorders. Present study was designed to find out the effect of a protein isolated from the leaves of the herb <it>Cajanus indicus </it>against GalN induced renal damage.</p> <p>Methods</p> <p>Both preventive as well as curative effect of the protein was investigated in the study. GalN was administered intraperitoneally at a dose of 800 mg/kg body weight for 3 days pre and post to protein treatment at an intraperitoneal dose of 2 mg/kg body weight for 4 days. The activities of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione-S-transferase (GST), levels of cellular metabolites, reduced glutathione (GSH), total thiols, oxidized glutathione (GSSG) and lipid peroxidation end products were determined to estimate the status of the antioxidative defense system. In addition, serum creatinine and urea nitrogen (UN) levels were also measured as a marker of nephrotoxicity.</p> <p>Results</p> <p>Results showed that GalN treatment significantly increased the serum creatinine and UN levels compared to the normal group of mice. The extent of lipid peroxidation and the level of GSSG were also enhanced by the GalN intoxication whereas the activities of antioxidant enzymes SOD, CAT, GR and GST as well as the levels of total thiols and GSH were decreased in the kidney tissue homogenates. Protein treatment both prior and post to the toxin administration successfully altered the effects in the experimental mice.</p> <p>Conclusion</p> <p>Our study revealed that GalN caused a severe oxidative insult in the kidney. Protein treatment both pre and post to the GalN intoxication could protect the kidney tissue against GalN induced oxidative stress. As GalN induced severe hepatotoxicity followed by renal failure, the protective role of the protein against GalN induced renal damages is likely to be an indirect effect. Since the protein possess hepatoprotective activity, it may first ameliorate GalN-induced liver damage and consequently the renal disorders are reduced. To the best of our knowledge, this is probably the first report describing GalN-induced oxidative stress in renal damages and the protective role of a plant protein molecule against it.</p

Monitoring activities of teenagers to comprehend their habits: study protocol for a mixed-methods cohort study

Abstract: Background: Efforts to increase physical activity in youth need to consider which activities are most likely to be sustained over time in order to promote lifelong participation in physical activity. The Monitoring Activities of Teenagers to Comprehend their Habits (MATCH) study is a prospective cohort study that uses quantitative and qualitative methods to develop new knowledge on the sustainability of specific physical activities. Methods/design: Eight hundred and forty-three grade 5 and 6 students recruited from 17 elementary schools in New Brunswick, Canada, are followed-up three times per year. At each survey cycle, participants complete self-report questionnaires in their classroom under the supervision of trained data collectors. A sub-sample of 24 physically active students is interviewed annually using a semi-structured interview protocol. Parents (or guardians) complete telephone administered questionnaires every two years, and a health and wellness school audit is completed for each school. Discussion: MATCH will provide a description of the patterns of participation in specific physical activities in youth, and enable identification of the determinants of maintenance, decline, and uptake of participation in each activity. These data will inform the development of interventions that take into account which activities are the most likely to be maintained and why activities are maintained or dropped

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference