163 research outputs found

    Estrogen Prevents Oxidative Damage to the Mitochondria in Friedreich's Ataxia Skin Fibroblasts

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    Estrogen and estrogen-related compounds have been shown to have very potent cytoprotective properties in a wide range of disease models, including an in vitro model of Friedreich's ataxia (FRDA). This study describes a potential estrogen receptor (ER)-independent mechanism by which estrogens act to protect human FRDA skin fibroblasts from a BSO-induced oxidative insult resulting from inhibition of de novo glutathione (GSH) synthesis. We demonstrate that phenolic estrogens, independent of any known ER, are able to prevent lipid peroxidation and mitochondrial membrane potential (ΔΨm) collapse, maintain ATP at near control levels, increase oxidative phosphorylation and maintain activity of aconitase. Estrogens did not, however, prevent BSO from depleting GSH or induce an increased expression level of GSH. The cytoprotective effects of estrogen appear to be due to a direct overall reduction in oxidative damage to the mitochondria, enabling the FRDA fibroblast mitochondria to generate sufficient ATP for energy requirements and better survive oxidative stress. These data support the hypothesis that phenol ring containing estrogens are possible candidate drugs for the delay and/or prevention of FRDA symptoms

    Proteomics of synapse

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    Large-scale phosphoproteome analysis on synaptosome and preparation of post-synaptic density (PSD) were investigated. It was found that protein phosphor is a common event in the synapse, which is consistent with the presence of diverse classes of kinases and phosphatases in the synapse. Synaptic proteomics analysis required the purification of subcellular organelles from the brain regions of interest. Multiple steps of discontinuous density gradient ultra-centrifugation were employed to enrich the distinct organelles. Two-dimensional gel electrophoresis was used to separate and quantify proteins, including post-translational modified forms, from synaptic structures. It was observed that proteomic analysis of the synaptic vesicle identified 36 proteins, including seven integral membrane proteins and vesicle regulatory proteins

    Breakthroughs in Medicinal Chemistry: New targets and mechanisms, new drugs, new hopes

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    The Editorial Board of the Medicinal Chemistry section of the journal Molecules publishes here its first Editorial, which has been prepared by highlighting, in sub-editorials of about one hundred words, some selected recently published articles that may have a profound impact on drug discovery and therapy. In particular, this editorial highlights new drug targets and mechanisms of action and new classes of drugs, as well as new therapeutic uses for known drugs or the involvement of known biological targets in new diseases. We also discuss some structural biology studies and new computational tools that may pave the way for the rational design or identification of more efficacious and safer drugs. Overall, the findings reported in these highlighted papers raise our hopes for the management of difficult-to-treat diseases that are posing a growing health threat, with new or repurposed drugs that overcome the limitations of currently applied therapies

    Constant activity of glutamine synthetase after morphine administration versus proteomic results

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    Glutamine synthetase is a key enzyme which has a regulatory role in the brain glutamate pool. According to previously published proteomic analysis, it was shown that the expression level of this enzyme is affected by morphine administration. In our study, we examined the activity of glutamine synthetase in various structures of rat brain (cortex, striatum, hippocampus and spinal cord) that are biochemically and functionally involved in drug addiction and antinociception caused by morphine. We were not able to observe any significant changes in the enzyme activity between morphine-treated and control samples despite previously reported changes in the expression levels of this enzyme. These findings stressed the fact that changes observed in the expression of particular proteins during proteomic studies may not be correlated with its activity

    Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–4

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    Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials, which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules. In these Editorials, we highlight in brief reports (of about one hundred words) a number of recently published articles that describe crucial findings, such as the discovery of novel drug targets and mechanisms of action, or novel classes of drugs, which may inspire future medicinal chemistry endeavours devoted to addressing prime unmet medical needs

    Secular Trends in the Prevalence of Overweight and Obesity in Sicilian Schoolchildren Aged 11–13 Years During the Last Decade

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    The present study evaluates trends in the prevalence of overweight and obesity in relation to gender and area of residence between two cohorts of students aged 11–13 years in Sicily. The analysis was performed on 1,839 schoolchildren, with 924 and 915 children being studied in 1999–2001 and 2009–2010, respectively. The children who were enrolled during 2009–2010 had significantly higher body mass indexes (BMI), BMI z-scores, and waist circumferences than the children who were studied during 1999–2001 (p<0.0001 for all); these differences was also observed when the cohort was subdivided according to gender or residence area The prevalence of obesity increased significantly from 7.9% in 1999–2001 to 13.7% in 2009–2010 (p<0.0001), whereas thinness decreased significantly from 10.1% to 2.3% (p<0.0001) in the same periods. The increase of trends in the prevalence of obesity was significantly higher in males (9.7% vs. 17.6%, p = 0.0006) than in females (6.3% vs. 9.8%, p = 0.04) and was slightly higher in urban areas (8.8% vs. 14.3%, p = 0.002) than in rural areas (7.8% vs. 13.0%, p = 0.012). The male gender was associated with a higher risk of being overweight or obese (odds ratio: 1.63; 95% confidence intervals: 1.24–2.15; p = 0.0005) in 2009–2010 than in 1999–2001, after adjusting for age and the residence area. In conclusion, this study showed an increasing trend in the prevalence of overweight and obesity in Sicilian schoolchildren during the last decade and that this trend was related to gender, age and the area of residence. More specifically, our data indicated that the prevalence of obesity increased by 5.8%, the prevalence of thinness decreased by 7.8% and the prevalence of normal-weight children did not change over the course of a decade. These results suggest a shift in the body weights of Sicilian children toward the upper percentiles

    Effect of Sex and Prior Exposure to a Cafeteria Diet on the Distribution of Sex Hormones between Plasma and Blood Cells

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    It is generally assumed that steroid hormones are carried in the blood free and/or bound to plasma proteins. We investigated whether blood cells were also able to bind/carry sex-related hormones: estrone, estradiol, DHEA and testosterone. Wistar male and female rats were fed a cafeteria diet for 30 days, which induced overweight. The rats were fed the standard rat diet for 15 additional days to minimize the immediate effects of excess ingested energy. Controls were always kept on standard diet. After the rats were killed, their blood was used for 1) measuring plasma hormone levels, 2) determining the binding of labeled hormones to washed red blood cells (RBC), 3) incubating whole blood with labeled hormones and determining the distribution of label between plasma and packed cells, discounting the trapped plasma volume, 4) determining free plasma hormone using labeled hormones, both through membrane ultrafiltration and dextran-charcoal removal. The results were computed individually for each rat. Cells retained up to 32% estrone, and down to 10% of testosterone, with marked differences due to sex and diet (the latter only for estrogens, not for DHEA and testosterone). Sex and diet also affected the concentrations of all hormones, with no significant diet effects for estradiol and DHEA, but with considerable interaction between both factors. Binding to RBC was non-specific for all hormones. Estrogen distribution in plasma compartments was affected by sex and diet. In conclusion: a) there is a large non-specific RBC-carried compartment for estrone, estradiol, DHEA and testosterone deeply affected by sex; b) Prior exposure to a cafeteria (hyperlipidic) diet induced hormone distribution changes, affected by sex, which hint at sex-related structural differences in RBC membranes; c) We postulate that the RBC compartment may contribute to maintain free (i.e., fully active) sex hormone levels in a way similar to plasma proteins non-specific binding

    Effect of Sex and Prior Exposure to a Cafeteria Diet on the Distribution of Sex Hormones between Plasma and Blood Cells

    Get PDF
    It is generally assumed that steroid hormones are carried in the blood free and/or bound to plasma proteins. We investigated whether blood cells were also able to bind/carry sex-related hormones: estrone, estradiol, DHEA and testosterone. Wistar male and female rats were fed a cafeteria diet for 30 days, which induced overweight. The rats were fed the standard rat diet for 15 additional days to minimize the immediate effects of excess ingested energy. Controls were always kept on standard diet. After the rats were killed, their blood was used for 1) measuring plasma hormone levels, 2) determining the binding of labeled hormones to washed red blood cells (RBC), 3) incubating whole blood with labeled hormones and determining the distribution of label between plasma and packed cells, discounting the trapped plasma volume, 4) determining free plasma hormone using labeled hormones, both through membrane ultrafiltration and dextran-charcoal removal. The results were computed individually for each rat. Cells retained up to 32% estrone, and down to 10% of testosterone, with marked differences due to sex and diet (the latter only for estrogens, not for DHEA and testosterone). Sex and diet also affected the concentrations of all hormones, with no significant diet effects for estradiol and DHEA, but with considerable interaction between both factors. Binding to RBC was non-specific for all hormones. Estrogen distribution in plasma compartments was affected by sex and diet. In conclusion: a) there is a large non-specific RBC-carried compartment for estrone, estradiol, DHEA and testosterone deeply affected by sex; b) Prior exposure to a cafeteria (hyperlipidic) diet induced hormone distribution changes, affected by sex, which hint at sex-related structural differences in RBC membranes; c) We postulate that the RBC compartment may contribute to maintain free (i.e., fully active) sex hormone levels in a way similar to plasma proteins non-specific binding

    Aldosterone Antagonists in Monotherapy Are Protective against Streptozotocin-Induced Diabetic Nephropathy in Rats

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    Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers
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