1,171 research outputs found

    Small molecules targeting endocytic uptake and recycling pathways

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    Over the past years a growing number of studies highlighted the pivotal role of intracellular trafficking in cell physiology. Among the distinct transport itineraries connecting the endocytic system, both internalization (endocytosis) and recycling (endocytic recycling) pathways were found fundamental to ensure cellular sensing, cell-to-cell communication, cellular division, and collective cell migration in tissue specific-contexts. Consistently, the dysregulation of endocytic trafficking pathways is correlated with several human diseases including both cancers and neurodegeneration. Aimed at suppress specific intracellular trafficking routes involved in disease onset and progression, huge efforts have been made to identify small molecule inhibitors with suitable pharmacological properties for in vivo administration. Here, we review most used drugs and recently discovered small molecules able to block endocytosis and endocytic recycling pathways. We characterize such pharmacological inhibitors by emphasizing their target specificity, molecular affinity, biological activity and efficacy in both in vitro and in vivo experimental models

    Methylglyoxal-dependent glycative stress and deregulation of SIRT1 functional network in the ovary of PCOS mice

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    Advanced glycation end-products (AGEs) are involved in the pathogenesis and consequences of polycystic ovary syndrome (PCOS), a complex metabolic disorder associated with female infertility. The most powerful AGE precursor is methylglyoxal (MG), a byproduct of glycolysis, that is detoxified by the glyoxalase system. By using a PCOS mouse model induced by administration of dehydroepiandrosterone (DHEA), we investigated whether MG-dependent glycative stress contributes to ovarian PCOS phenotype and explored changes in the Sirtuin 1 (SIRT1) functional network regulating mitochondrial functions and cell survival. In addition to anovulation and reduced oocyte quality, DHEA ovaries revealed altered collagen deposition, increased vascularization, lipid droplets accumulation and altered steroidogenesis. Here we observed increased intraovarian MG-AGE levels in association with enhanced expression of receptor for AGEs (RAGEs) and deregulation of the glyoxalase system, hallmarks of glycative stress. Moreover, DHEA mice exhibited enhanced ovarian expression of SIRT1 along with increased protein levels of SIRT3 and superoxide dismutase 2 (SOD2), and decreased peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC1 alpha), mitochondrial transcriptional factor A (mtTFA) and translocase of outer mitochondrial membrane 20 (TOMM20). Finally, the presence of autophagy protein markers and increased AMP-activated protein kinase (AMPK) suggested the involvement of SIRT1/AMPK axis in autophagy activation. Overall, present findings demonstrate that MG-dependent glycative stress is involved in ovarian dysfunctions associated to PCOS and support the hypothesis of a SIRT1-dependent adaptive response

    L’Auréomycine, traitement efficace et rapide des « Infections Pulmonaires Mixtes » du Porc

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    Placidi Louis, Charbit Claude. L’Auréomycine, traitement efficace et rapide des «Infections Pulmonaires Mixtes» du Porc. In: Bulletin de l'Académie Vétérinaire de France tome 108 n°10, 1955. pp. 497-501

    Reflectance anisotropy spectroscopy of strain-engineered GaAsBi alloys

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    In this paper, we present results obtained by an optical technique, namely, reflectance anisotropy spectroscopy (RAS), applied to a series of GaAs1-xBix samples grown by molecular beam epitaxy (MBE) under different strain conditions with the increasing concentration of Bi, up to the higher value of about 7%. The epitaxial buffer layers for the growing GaAs1-xBix layer were prepared with either a compressive strain (as it is commonly done) or a tensile strain: The latter case has been proven to be a strategy that allows us to obtain a better crystalline quality [Tisbi et al., Phys. Rev. Appl. 14, 014028 (2020)]. A characteristic, well defined anisotropy signal below 2.5 eV is demonstrated to be connected to the presence of Bi and, in particular, to the strain produced in the sub-surface region by the voluminous Bi atoms. The amplitude of this signal directly relates to the Bi quantity, while its sign gives information about the local clustering/ordering of Bi atoms in the grown sample. We conclude that the detailed interpretation of RAS signatures and the knowledge of their origin offer the opportunity to utilize this technique to follow in real time the GaAsBi growth either in MBE or in metal organic vapor phase epitaxy processes

    Small molecules targeting endocytic uptake and recycling pathways

    Get PDF
    Over the past years a growing number of studies highlighted the pivotal role of intracellular trafficking in cell physiology. Among the distinct transport itineraries connecting the endocytic system, both internalization (endocytosis) and recycling (endocytic recycling) pathways were found fundamental to ensure cellular sensing, cell-to-cell communication, cellular division, and collective cell migration in tissue specific-contexts. Consistently, the dysregulation of endocytic trafficking pathways is correlated with several human diseases including both cancers and neurodegeneration. Aimed at suppress specific intracellular trafficking routes involved in disease onset and progression, huge efforts have been made to identify small molecule inhibitors with suitable pharmacological properties for in vivo administration. Here, we review most used drugs and recently discovered small molecules able to block endocytosis and endocytic recycling pathways. We characterize such pharmacological inhibitors by emphasizing their target specificity, molecular affinity, biological activity and efficacy in both in vitro and in vivo experimental models

    Protective effects of a SIRT1 inhibitor on primordial follicle activation and growth induced by cyclophosphamide: insights from a bovine in vitro folliculogenesis system

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    Purpose: Although oncological advances have improved survival rates of female cancer patients, they often suffer a reduced fertility due to treatment side effects. In the present study, we evaluated the potential fertoprotective effects of the specific inhibitor of SIRT1, EX-527, on the gonadotoxic action exerted by cyclophosphamide (CPM) on loss of primordial follicles (PFs). Methods: The effects of the CPM metabolite phosphoramide mustard (PM) on follicle activation, growth and viability and the protective action of EX-527 against PM effects were evaluated on bovine ovarian cortical strips in vitro cultured for 1 or 6 days. To understand whether PFs exposed to PM plus EX-527 were able to activate and grow to the secondary stage after suspension of the treatment, strips cultured for 3 days in PM plus EX-527 for 3 days were transferred to plain medium until day 6. Follicle growth and health were evaluated through histology and viability assay at a confocal microscope. In order to investigate the molecular pathways underlying the ovarian response to PM in the presence of EX-527, we analysed the protein level of SIRT1, HuR, PARP1 and SOD2 after 1 day of in vitro culture. Results: We found that (1) PM, the main CPM active metabolite, promotes PF activation; (2) the ovarian stress response induced by PM includes a SIRT1-dependent pathway; and (3) EX-527 reduces PF activation and growth induced by PM. Conclusion: SIRT1 can represent a candidate molecule to be targeted to protect ovarian follicles from alkylating agents and EX-527 could represent a potential fertoprotective agent for cancer patients
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