312 research outputs found
Updating the dual role of brain nitric oxide in neurodegeneration/neuroprotection: understanding molecular mechanisms to devise drug approaches.
No full textIn the framework of articles dealing with central nervous system disorders, the paper addresses the multiple roles of the diffusible messenger, Nitric oxide
Building a bridge between clinical and basic research: the phenotypic elements of familial predisposition to type 1 diabetes
No full textImmunophilin chaperones in steroid receptor signalling
No full textThe immunophilin cochaperones, cyclophilin 40 (CyP40), FKBP51 and FKBP52 and PP5, a serine/threonine protein phosphatase, have been implicated as modulators of steroid receptor function through their association with Hsp90, a molecular chaperone with a key role in steroid hormone signalling. Although progress towards a satisfying definition for the role of these components in steroid receptor complexes has been slow, recent developments arising from novel approaches in both yeast and mammalian systems, together with available crystal structures for Hsp90 and some of these cochaperones, are beginning to provide important clues about their function. Hsp90, recently identified as a member of the GHKL superfamily of ATPases, is the central player in receptor assembly, an energy-driven process that allows receptor and the immunophilins to be proximally located, or to interact directly, on a Hsp90 scaffold. Immunophilin structure, relative abundance, their binding affinity for Hsp90 and their ability to interact with specific receptors may all contribute to a selective preference of the immunophilins for individual receptors. Association of receptors with different immunophilins leads to differential functional consequences for receptor activity. Observations of glucocorticoid resistance in New World primates, attributed to FKBP51 overexpression and incorporation into glucocorticoid receptor complexes, have provided the first evidence that these cochaperones can control hormone-binding affinity. Application of a yeast model to FKBP52 function in the glucocorticoid receptor system has now provided crucial evidence that this immunophilin enhances receptor transcriptional activity by increasing receptor avidity for hormone through PPIase-mediated conformational changes in the ligand-binding domain. A recent novel finding suggests that hormone binding may induce a functional exchange of immunophilins in receptor complexes and that the modified complex directs receptor to the nucleus
Endothelial Dysfunction in Diabetes: An Update on Mechanisms and Therapeutic Targets
No full textOver recent years, the explosive increase in the worldwideprevalence of type 2 diabetes has transformed this disease into a major public health concern. Cardiovascular complications are the leading causes of morbidity in diabetic patients, whose cardiovascular mortality risk is up to four times higher than in non-diabetic subjects. Morphological and structural changes in large and small vessels are usually preceded by alterations in endothelial function, resulting from the unbalanced production of endothelial-derived vascular mediators. Metabolic disturbances including hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia all contribute to endothelial dysfunction via both distinct and overlapping mechanisms. In turn, abnormal synthesis and release of endothelial mediators may contribute to exacerbate the impaired function of metabolic tissues, thus creating a vicious circle where these conditions reciprocally reinforce and worsen each other. Increasing understanding on mechanisms underlying endothelial dysfunction in diabetes may serve to identify potential therapeutic targets, and help to develop novel therapeutic approaches for reducing cardiovascular risk rate in diabetic patients. This chapter summarizes the current knowledge on the most recently identified targets and therapies for the treatment of diabetes and its cardiovascular complications
The medicinal chemistry of novel iron chelators for the treatment of cancer
No full textCancer is one of the leading causes of death worldwide and there is an increasing need for novel anti-tumor therapeutics with greater selectivity and potency. A new strategy in the treatment of cancer has focused on targeting an essential cell metabolite, iron (Fe). Iron is vital for cell growth and metabolism, forming a crucial component of the active site of ribonucleotide reductase (RR), the rate-limiting enzyme in DNA synthesis. Cancer cells in particular require large amounts of Fe to proliferate, making them more susceptible to the Fe deficiency caused by Fe chelators. Beginning with primordial siderophores, Fe chelators have since evolved to a new generation of potent and efficient anti-cancer agents. Recently, investigations have led to the generation of novel di-2-pyridylketone thiosemicarbazone (DpT) and 2-benzoylpyridine thiosemicarbazone (BpT) ligands that demonstrate marked and selective anti-tumor activity both in vitro and in vivo against a wide spectrum of tumors. The mechanism of action of these novel ligands includes alterations in the expression of key regulatory molecules as well as the generation of redox active Fe complexes. Interestingly, nonsynthetic Fe chelators including silybin and curcumin, both of which are derived from plants, also have a high potential in the treatment of cancer. This review explores the development of novel Fe chelators for the treatment of cancer and their mechanisms of action
Histone deacetylase inhibitors in inflammatory disease
No full textLysine acetylation is becoming increasingly appreciated as a key post-translational modification in the endogenous regulation of protein function. The so-called histone acetyl transferases (HATs) and histone deacetylases (HDACs), best known for their roles in controlling chromatin remodeling via histone acetylation/deacetylation, are now known to modify a large number of non-histone proteins to control diverse cell processes. In relation to inflammation, acetylation modulates the activity or function of cytokine receptors, nuclear hormone receptors, intracellular signaling molecules and transcription factors. Small molecule inhibitors of HDACs have been found to trigger both pro- and antiinflammatory effects in a range of inflammation-relevant cell types. Although their inflammatory profiles have only just begun to be elucidated, some HDAC inhibitors are already showing therapeutic promise in animal models of inflammatory diseases such as arthritis, inflammatory bowel diseases, septic shock, ischemia-reperfusion injury, airways inflammation and asthma, diabetes, age-related macular degeneration, cardiovascular diseases, multiple sclerosis and other CNS and neurodegenerative diseases. This article describes those HDAC inhibitors which have been most examined to date for their potentially beneficial effects on inflammatory cells or in animal models of inflammatory disease
Caracterização reprodutiva de Dyckia ibiramensis Reitz, uma bromélia endêmica ao Alto Vale do Itajaí, SC
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em Biologia VegetalDyckia ibiramensis Reitz (Bromeliaceae) é uma espécie endêmica do município de Ibirama/SC, cuja distribuição se restringe a aproximadamente 4 km de extensão nas margens do Rio Itajaí do Norte. Desde 1992, consta na "Lista de Espécies da Flora Ameaçadas de Extinção" na categoria "Em perigo", e no ano de 2005, no Workshop "Revisão da Lista da Flora Brasileira Ameaçada de Extinção" foi incluída na categoria "Criticamente em perigo". Neste contexto, o objetivo deste estudo foi elucidar o modo de reprodução de D. ibiramensis, empregando-se experimentos de polinização manual e análise genética, bem como seu sistema de polinização e sua diversidade e estrutura genética, visando obter informações que auxiliem na elaboração de estratégias de conservação para a espécie. D. ibiramensis possui inflorescências simples e ramificadas com, em média, 58 e 137 flores, respectivamente. Suas flores apresentam formato de sino, corola amarela e sépalas variando de verdes a alaranjadas, e eixo da inflorescência variando de verde até avermelhado. Ocorre a abertura de uma a três flores por dia por indivíduo. A antese se inicia em torno de 7h00 e as flores têm duração de um dia e meio. O volume de néctar acumulado é de 27,75 L flor-1, com pico de produção no início da antese da flor, e a concentração de açúcares totais média é 22,38%. A mamangava Xylocopa (Neoxylocopa) brasilianorum juntamente com o beija-flor Thalurania glaucopis são os principais polinizadores de D. ibiramensis. Os experimentos de sistema reprodutivo indicaram que a espécie possui auto-incompatibilidade, a julgar pela inviabilidade de sementes provenientes dos tratamentos de autopolinização (manual e espontânea) e agamospermia. As estimativas de diversidade e estrutura genética, obtidas a partir de progênies e empregando-se nove locos alozímicos, mostraram que D. ibiramensis possui alta diversidade gênica, baixa endogamia e forte estruturação. A grande quantidade de alelos muito raros e a detecção de alelos fixados sugerem fortes efeitos de deriva genética. As populações que se situam a montante no Rio Itajaí do Norte são as que apresentam maiores índices de variabilidade genética e, possivelmente, constituam o centro de diversidade genética da espécie. As estimativas de taxa de cruzamento multilocos atribuem à espécie sistema misto de reprodução, com predominância de cruzamentos. Somando-se este resultado ao obtido pelos experimentos de biologia reprodutiva, sugere-se que D. ibiramensis apresenta sistema de auto-incompatibilidade parcial. Muitos cruzamentos ocorrem entre rosetas próximas, implicando em cruzamentos biparentais e coeficientes de coancestria, em geral, maiores ou próximos aos esperados para irmãos-completos. A manutenção in loco de todas as populações existentes de D. ibiramensis é extremamente necessária para sua conservação em longo prazo, enquanto a conservação ex situ da espécie deve ser encarada apenas como uma forma complementar àquela in situ
Borne Lecturer to Discuss Potential Treatments for Alzheimer\u27s Disease
No full textOXFORD, Miss. - Allen B. Reitz, senior research fellow at Johnson & Johnson Pharmaceutical Research and Development, discusses his work Tuesday (April 18) in the annual Ronald F. Borne Distinguished Lecture in Medicinal Chemistry
Thesaurus nummorum Sueo-Gothicorum : studio indefesso Eliae Brenneri L. annorum spatio collectus, secundum seriem temporum dispositus, atque e tenebris, cum commentatione in apricum prolatus ; accessit ejusdem auctoris Libellus de nummophylaciis Sveciae : de scriptoribus rei nummariae Svethicae, atque de thesauris, seu variis vetustorum nummorum cumulis, passim per Sveoniam fortuito casu repertis.
No full textAdded engraved t.p.CicognaraEdited by Nils Keder. Cf. Cat. of Biblioth eque Nationale.In addition to Elias Brenner, some plates engraved by Sartorius, Iuo. Scheffer, E. Reitz, W. Swidde.Portrait of author, engraved; devices.Libellus de nummophylaciis Sveciae.Dekesel, C.E. Bibliography of 18th century numismatic books; B 527 (Cat. 1), vol. 1, p. 888-889.Lipsius, J.G. Bibliotheca numaria ; p. 57.Europeana-GoogleBook
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