17 research outputs found
Designed Inhibitors of Insulin-Degrading Enzyme Regulate the Catabolism and Activity of Insulin
Background: Insulin is a vital peptide hormone that is a central regulator of glucose homeostasis, and impairments in insulin signaling cause diabetes mellitus. In principle, it should be possible to enhance the activity of insulin by inhibiting its catabolism, which is mediated primarily by insulin-degrading enzyme (IDE), a structurally and evolutionarily distinctive zinc-metalloprotease. Despite interest in pharmacological inhibition of IDE as an attractive anti-diabetic approach dating to the 1950s, potent and selective inhibitors of IDE have not yet emerged. Methodology/Principal Findings: We used a rational design approach based on analysis of combinatorial peptide mixtures and focused compound libraries to develop novel peptide hydroxamic acid inhibitors of IDE. The resulting compounds are ∼106 times more potent than existing inhibitors, non-toxic, and surprisingly selective for IDE vis-à-vis conventional zinc-metalloproteases. Crystallographic analysis of an IDE-inhibitor complex reveals a novel mode of inhibition based on stabilization of IDE's “closed,” inactive conformation. We show further that pharmacological inhibition of IDE potentiates insulin signaling by a mechanism involving reduced catabolism of internalized insulin. Conclusions/Significance: The inhibitors we describe are the first to potently and selectively inhibit IDE or indeed any member of this atypical zinc-metalloprotease superfamily. The distinctive structure of IDE's active site, and the mode of action of our inhibitors, suggests that it may be possible to develop inhibitors that cross-react minimally with conventional zinc-metalloproteases. Significantly, our results reveal that insulin signaling is normally regulated by IDE activity not only extracellularly but also within cells, supporting the longstanding view that IDE inhibitors could hold therapeutic value for the treatment of diabetes
Risk factors for hepatitis C virus infection among blood donors in southern Brazil: a case-control study
BACKGROUND: In Brazil, it is estimated that between 2.5 and 4.9% of the general population present anti-hepatitis C virus (HCV) antibodies, which corresponds to as many as 3.9 to 7.6 million chronic carriers. Chronic liver disease is associated with HCV infection in 20% to 58% of the Brazilian patients. The objective of this case-control study was to investigate the risk factors for presence of anti-HCV antibody in blood donors in southern Brazil. METHODS: One hundred and seventy eight blood donors with two positive ELISA results for anti-HCV were cases, and 356 controls tested negative. A standardized questionnaire was used to collect data concerning demographic and socioeconomic aspects, history of previous hepatitis infection, social and sexual behaviors, and number of donations. Variables were grouped into sets of hierarchical categories. Cases and controls were compared using logistic regression, odds ratios, and 95% confidence intervals. The statistical significance of the associations was assessed through likelihood ratio tests based on a P value < 0.05. RESULTS: The prevalence of anti-HCV among blood donors was 1.1%. Most of the donors were white and males. In the multivariate analysis, independent predictors of anti-HCV positivity were: intravenous drug use, blood transfusion >10 years earlier, having had two to four sexually transmitted diseases, incarceration, tattooing, sex with a hepatitis B or C virus carrier or with intravenous drug users. CONCLUSION: Intravenous drug use, blood transfusion, and tattooing were the main risk factors for anti-HCV positivity among blood donors from southern Brazil, but sexual HCV transmission should also be considered
Sustainable Sources of Biomass for Bioremediation of Heavy Metals in Waste Water Derived from Coal-Fired Power Generation
Biosorption of heavy metals using dried algal biomass has been extensively described but rarely implemented. We contend this is because available algal biomass is a valuable product with a ready market. Therefore, we considered an alternative and practical approach to algal bioremediation in which algae were cultured directly in the waste water stream. We cultured three species of algae with and without nutrient addition in water that was contaminated with heavy metals from an Ash Dam associated with coal-fired power generation and tested metal uptake and bioremediation potential. All species achieved high concentrations of heavy metals (to 8% dry mass). Two key elements, V and As, reached concentrations in the biomass of 1543 mg.kg−1 DW and 137 mg.kg−1 DW. Growth rates were reduced by more than half in neat Ash Dam water than when nutrients were supplied in excess. Growth rate and bioconcentration were positively correlated for most elements, but some elements (e.g. Cd, Zn) were concentrated more when growth rates were lower, indicating the potential to tailor bioremediation depending on the pollutant. The cosmopolitan nature of the macroalgae studied, and their ability to grow and concentrate a suite of heavy metals from industrial wastes, highlights a clear benefit in the practical application of waste water bioremediation
Spt6 is a maintenance factor for centromeric CENP-A
Replication and transcription of genomic DNA requires partial disassembly of nucleosomes to allow progression of polymerases. This presents both an opportunity to remodel the underlying chromatin and a danger of losing epigenetic information. Centromeric transcription is required for stable incorporation of the centromere-specific histone dCENP-A in M/G1 phase, which depends on the eviction of previously deposited H3/H3.3-placeholder nucleosomes. Here we demonstrate that the histone chaperone and transcription elongation factor Spt6 spatially and temporarily coincides with centromeric transcription and prevents the loss of old CENP-A nucleosomes in both Drosophila and human cells. Spt6 binds directly to dCENP-A and dCENP-A mutants carrying phosphomimetic residues alleviate this association. Retention of phosphomimetic dCENP-A mutants is reduced relative to wildtype, while non-phosphorylatable dCENP-A retention is increased and accumulates at the centromere. We conclude that Spt6 acts as a conserved CENP-A maintenance factor that ensures long-term stability of epigenetic centromere identity during transcription-mediated chromatin remodeling
La microscopie électronique à balayage environnementale équipée en micro-analyse X : son utilisation en pathologie osseuse humaine. Perspectives et limites
Dans une étude récemment publiée, nous avons montré l'intérêt de l'utilisation des techniques physiques telles que la diffraction des rayons X, la fluorescence X et la microscopie électronique à balayage environnementale (MEBE) équipée en microanalyse X dans l'identification de la tuberculose ostéo-articulaire sur du matériel ostéo-archéologique.
L'objectif de l'étude actuelle est l'application du MEB environnemental dans l'identification de la maladie tuberculeuse dans des os provenant de biopsie. Nous avons étudié d'abord l'effet d'un traitement à la potasse sur le carbonate de calcium, composant dont la présence au sein de la lésion osseuse serait spécifique de la tuberculose. Une attaque dans une solution de potasse KOH 2M à 105 °C pendant 2 heures, a été retenue comme condition de traitement. Le traitement a été appliqué ensuite à un os sain frais pour en apprécier l'efficacité sur le collagène dont la présence pourrait gêner la lecture du carbonate de calcium au MEB. Enfin, le même traitement est appliqué à un os tuberculeux. Nous avons montré une conservation de la structure apatitique de l'os après traitement et une destruction partielle du collagène. Dans l'os tuberculeux, nous avons mis en évidence la conservation partielle du dépôt de carbonate de calcium dont une partie n'a pas résisté au traitement. Ces résultats permettent de définir les termes d'une nouvelle méthode de traitement à la fois plus agressive pour le collagène et moins agressive pour le carbonate de calcium et confirment, par la qualité des images et la précision des analyses, les potentialités des applications du MEB environnemental dans la recherche médicale.In a recently published study, we have shown the utility of X-ray diffraction, X-ray fluorescence and environmental SEM equipped with micro-analysis in the identification of bone tuberculosis from osteo-archaeological origin. The goal of the present study is the application of environmental SEM in the identification of bone tuberculosis from bone harvested at autopsy. First we studied the effects of potash on calcie, the presence of which signals tuberculosis. The condition under which the calcite remains practically unaffected was KOH 2M at 105° C for two hours. The treatment was applied to a fresh bone sample in order to know the effect on the bone collagen, so that no overlap occurred between the calcium carbonate and the collagen of bone. Finally the same treatment was applied to a bone from a known tuberculous sample. We have noted no destruction of the apatitic structure of the bone with only partial destruction of the collagen. For the tuberculous bone, we have shown the partial conservation of the calcium carbonate deposit. These results allow us to define a new treatment method, which is at the same time more destructive to the collagen and less destructive for the calcium carbonate component. This paper presents a new application of a nineteenth century method of extracting collagen. These results confirm, by the fine quality of the environmental SEM images and the precision analyses, the great potential of environmental SEM in medical research
Minimising the risk posed by TiO2 nanomaterials used in sunscreen throughout the entire product lifecycle
Sunscreens are of emerging concern regarding both human and environmental health. While TiO2 nanoparticles used as UV-blockers may offer a safer alternative to organic filters, their fate and impact and resulting regulation are still under consideration, largely related to the potential risk of nanotechnology-based products. After leaving the skin either through bathing or cleaning, the TiO2 nanomaterials contained in the sunscreen can be released into rivers, lakes, sea shores, and/or sewage treatment plants. Their fate and impact in these different systems is largely determined by the surface properties, i.e. the coating type and lifetime. This project aims to develop the eco-design of sunscreens through the minimization of risks associated with nanomaterials incorporated into the formulation. All stages of the cream life cycle must be considered in this light, from its manufacture to its end of life, through its use by the consumer and its impact on the exposed environment. By considering each development stage of the sunscreen, from the choice of UV-blocker and its integration into a cosmetic formulation, to the knowledge of the risk involved in this choice all along the product lifecycle, an eco-design approach can be achieved and risk can be minimized. The present work combines industrial companies specialising in cosmetic formulation with academic research experts in the fields of exposure, toxicity and lifecycle assessment. Sunscreen fabrication, risk for the consumer by dermal exposure, risk for the direct aquatic environment and risk related to the end of life of the product are as many key steps of the sunscreen lifecycle that were investigated in this project
Contrasting patterns of mortality in Polynesian coral reefs following the third global coral bleaching event in 2016
In 2016, many tropical corals worldwide were exposed to anomalously high temperatures due to one of the strongest El Nino events ever recorded. Bleaching impacts were reported on 23 islands within three archipelagos of French Polynesia (Tuamotu, Society and Marquesas archipelagos). A detailed study on the effects of elevated temperatures on corals was performed on five islands (Mo'orea, Makemo, Hikueru, Marutea and Katiu) and revealed contrasting patterns of coral bleaching responses between Mo'orea (Society Archipelago) and the four islands of the Tuamotu Archipelago. While some reefs from the Tuamotu lost more than half of their coral cover, in Mo'orea, less than 1% mortality was recorded 6 months after bleaching. During the 2016 bleaching event, certain reefs at 12 m depth in the outer reef habitats were not exposed to sufficiently long high-temperature periods (heat stress not exceeding 1.1 degrees C weeks in Mo'orea) to cause large-scale bleaching-related coral mortality. In contrast, other reefs in the Tuamotu Archipelago had DHW reaching up to 9.2 degrees C weeks and experienced severe mortality (up to 71%). Our study showed how differential heat stress exposure across reefs of French Polynesia led to different impacts on corals. Until now, Mo'orea reefs have been spared abnormally high temperatures leading to mortality and should be considered an important source of larvae to help maintain reefs on the surrounding islands
Eco-SUN for Eco-design of sunscreen using titanium dioxide nanoparticles
Among cosmetics and personal care products, sunscreen products are of emerging concern regarding both human and environmental health. The fate and impact of mineral nanoparticulate UV-blockers, such as TiO2 nanomaterials, is under consideration from a regulatory perspective due to their potential impact. Once leaving the skin either through bathing or everyday usage and cleaning, the nanomaterials contained in the sunscreen can be released into rivers, lakes, sea shores, and/or sewage treatment plants. The nanomaterial behaviour, fate and impact in these different systems is largely determined by its surface properties, (e.g. the nanomaterial coating type) and lifetime. Here we present the first result of the Eco-SUN research program aimed at developing the eco-design of sunscreens through the minimization of risks associated with nanomaterials incorporated into the formulation. Different stages of the cream lifecycle are considered from its manufacture to its end of life, through its use by the consumer and its impact on the exposed environments. Reducing the potential release and / or toxicity of the nanomaterial from the cream is a decisive criterion for its eco-design. Different relevant TiO2 UV-blockers have been selected to integrate a typical o/w formulation as case studies. The resulting sunscreen were characterised in terms of nanomaterial localisation, sun protection factor and photo-passivation. The risk for the consumer by dermal exposure was assessed using skin biopsies. Inflammation and skin penetration were evaluated. The risk for the aquatic environment directly expose was assessed both in terms of exposure and hazard. The release of nanomaterials from the sunscreen upon normal usage was studied in laboratory through simulated aging procedure. Two biological models, sea urchin and coral colonies, were selected as relevant endpoints to assess the marine ecotoxicity of the byproducts formed. Finally, the risk related to the end of life of the sunscreen through the removal with cleaning water followed by drainage to sewage treatment plants was evaluated by considering two opposite fate scenarios: (i) nanomaterial concentration in sewadge sludge later spread as fertilizer in agriculture, and (ii) nanomaterial suspension maintained in the treated water and released in river water. Thus, fate and impact in soil and river ecosystems were also studied
Lifecycle and ompact of sunscreens using TiO2 nanomaterials
Among cosmetics and personal care products, sunscreen products are of emerging concern regarding both human and environmental health. The fate and impact of mineral nanoparticulate UV-blockers, such as TiO2 nanomaterials, is under consideration from a regulatory perspective due to their potential impact. Once leaving the skin either through bathing or everyday usage and cleaning, the nanomaterials contained in the sunscreen can be released into rivers, lakes, sea shores, and/or sewage treatment plants. The nanomaterial behaviour, fate and impact in these different systems is largely determined by its surface properties, (e.g. the nanomaterial coating type) and lifetime. Here we present the first result of the Eco-SUN research program aimed at developing the eco-design of sunscreens through the minimization of risks associated with nanomaterials incorporated into the formulation. Different stages of the cream lifecycle are considered from its manufacture to its end of life, through its use by the consumer and its impact on the exposed environments. Reducing the potential release and / or toxicity of the nanomaterial from the cream is a decisive criterion for its eco-design. Different relevant TiO2 UV-blockers have been selected to integrate a typical o/w formulation as case studies. The resulting sunscreen were characterised in terms of nanomaterial localisation, sun protection factor and photo-passivation. The risk for the consumer by dermal exposure was assessed using skin biopsies. Inflammation and skin penetration were evaluated. The risk for the aquatic environment directly expose was assessed both in terms of exposure and hazard. The release of nanomaterials from the sunscreen upon normal usage was studied in laboratory through simulated aging procedure. Two biological models, sea urchin and coral colonies, were selected as relevant endpoints to assess the marine ecotoxicity of the byproducts formed. Finally, the risk related to the end of life of the sunscreen through the removal with cleaning water followed by drainage to sewage treatment plants was evaluated by considering two opposite fate scenarios: (i) nanomaterial concentration in sewadge sludge later spread as fertilizer in agriculture, and (ii) nanomaterial suspension maintained in the treated water and released in river water. Thus, fate and impact in soil and river ecosystems were also studied
Safer by design sunscreen using titanium dioxide nanoparticles
Among cosmetics and personal care products, sunscreen products are of emerging concern regarding both human and environmental health. The fate and impact of mineral nanoparticulate UV-blockers, such as TiO2 nanomaterials, is under consideration from a regulatory perspective due to their potential impact. Here we present the first result of the Eco-SUN research program aimed at developing the eco-design of sunscreens through the minimization of risks associated with nanomaterials incorporated into the formulation. Different stages of the cream lifecycle are considered from its manufacture to its end of life, through its use by the consumer and its impact on the exposed environments. Reducing the potential release and / or toxicity of the nanomaterial from the cream is a decisive criterion for its ecodesign. Different relevant TiO2 UV-blockers have been selected to integrate a typical w/o formulation as case studies. The resulting sunscreens were characterised in terms of nanomaterial localisation, sun protection factor and photo-passivation. The risk for the consumer by dermal exposure will be assessed using skin biopsies, and evaluating inflammation and skin penetration. The risk for the aquatic environment directly exposed will be assessed both in terms of exposure and hazard. The release of nanomaterials from the sunscreen upon normal usage was studied in the laboratory through a simulated aging procedure. Two biological models, sea urchin and coral colonies, were selected as relevant endpoints to assess the marine ecotoxicity of the by-products formed. Finally, the risk related to the end of life of the sunscreen through the removal with cleaning water followed by drainage to sewage treatment plants will be evaluated by considering the scenarios of nanomaterial concentration in sewage sludge later spread as fertilizer in agriculture