Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration

Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy

Tannins, Peptic Ulcers and Related Mechanisms

This review of the current literature aims to study correlations between the chemical structure and gastric anti-ulcer activity of tannins. Tannins are used in medicine primarily because of their astringent properties. These properties are due to the fact that tannins react with the tissue proteins with which they come into contact. In gastric ulcers, this tannin-protein complex layer protects the stomach by promoting greater resistance to chemical and mechanical injury or irritation. Moreover, in several experimental models of gastric ulcer, tannins have been shown to present antioxidant activity, promote tissue repair, exhibit anti Helicobacter pylori effects, and they are involved in gastrointestinal tract anti-inflammatory processes. The presence of tannins explains the anti-ulcer effects of many natural products

Valores em serviços de policiamento comunitário: o Programa Ronda do Quarteirão sob a ótica da teoria da cadeia de meios e fins

O crescimento da violência, a preocupação mais intensa dos cidadãos pela busca da segurança e as estratégias gerenciais adotadas por organizações privadas contribuíram para que as organizações policiais adotassem um novo modelo de policiamento - "o policiamento comunitário", com foco na parceria entre a sociedade e a polícia para juntos melhorarem a sensação de bem-estar das pessoas. Este artigo tem como objetivo analisar, sob a ótica da teoria da cadeia de meios e fins, a estrutura de valores dos usuários dos serviços de policiamento comunitário: o Ronda do Quarteirão na cidade de Fortaleza (CE), tomando como base a identificação de atributos do serviço percebidos por estes usuários e das relações entre os atributos e suas consequências na utilização do serviço com os valores pessoais dos indivíduos. Utilizou-se a técnica de laddering que permite a construção do mapa hierárquico de valor, evidenciando os elementos que caracterizam o comportamento dos consumidores ao utilizarem tal serviço. Os resultados mostram a preocupação dos usuários dos seviços do Ronda do Quarteirão em atingir o bem-estar que poderá ser adquirido na realização dos valores: amar o que faz, amizade, cidadania, defender a pátria, felicidade, honestidade, satisfação, segurança e sentir-se útil à sociedade

Valores Associados à Compra de Automóvel por Jovens no Ceará: Um Estudo sob a Ótica da Cadeia de Meios-Fim

O setor automotivo enfrenta um ambiente competitivo e, por isso, precisa implementar estrat&eacute;gias de diferencia&ccedil;&atilde;o para que o consumidor prefira uma empresa em detrimento a outra. A fim de alcan&ccedil;ar atingir o seu objetivo, as organiza&ccedil;&otilde;es devem criar estrat&eacute;gias que podem ser tra&ccedil;adas atrav&eacute;s da conquista de um p&uacute;blico espec&iacute;fico, o jovem. Para conquistar esse p&uacute;blico, por&eacute;m, deve-se buscar entender o que os motiva a adquirir um ve&iacute;culo, quais s&atilde;o os valores por tr&aacute;s da compra de um determinado autom&oacute;vel, para que a empresa possa oferecer realmente um carro que o cliente procura. Esse, portanto, &eacute; o objetivo desta pesquisa, que &eacute; analisada sob a &oacute;tica da teoria de meios-fim, t&atilde;o importante para a identifica&ccedil;&atilde;o de atributos, consequ&ecirc;ncias e valores envolvidos na rela&ccedil;&atilde;o do jovem e o autom&oacute;vel. DOI: 10.5585/remark.v11i3.2298</strong

Nucleoside/nucleotide reverse transcriptase inhibitors attenuate angiogenesis and lymphangiogenesis by impairing receptor tyrosine kinases signalling in endothelial cells

Background and purposeCardiovascular disease associated with antiretroviral therapy (ART) has become a major clinical challenge for HIV-positive patients. However, the role of ART in blood vessel growth is largely unknown. Here, we examined an integral component of ART, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and investigated their effects on key microvascular functions, including angiogenesis and lymphangiogenesis.Experimental approachThe angiogenesis/lymphangiogenesis capability of endothelial cells (ECs) was evaluated using migration, proliferation and tube formation assays in vitro, and mouse ear and Matrigel plug assays in vivo. Expressions of signalling molecules and mitochondrial antioxidant catalases were determined using Western blotting. Receptor tyrosine kinase (RTK) internalization and endocytosis were examined using flow cytometry and confocal immunofluorescence microscopy respectively. Mitochondrial DNA copy number and ROS were determined using quantitative real-time PCR and MitoSOX staining respectively.Key resultsPharmaceutical doses of NRTIs [azidothymidine (AZT), tenofovir disoproxil fumarate (TDF) and lamivudine (3TC)] inhibited angiogenesis and lymphangiogenesis both in vivo and in vitro by affecting the proliferation and migration of ECs. Correspondingly, NRTIs selectively attenuated the activation and transduction of endothelial RTK signals, VEGFR2 and FGFR1 pathways, in vascular ECs and the VEGFR3 pathway in lymphatic ECs. Both TDF and 3TC restrained RTKs' endocytosis into early endosomes but not internalization, while AZT blocked the protein maturation of RTKs. Excessive ROS levels were detected in NRTI-treated ECs, and the MnSOD mimic MnTMPyP alleviated the angiogenic/lymphangiogenic defects induced by NRTIs.Conclusions and implicationsNRTIs negatively regulate angiogenesis and lymphangiogenesis by inducing mitochondrial oxidative stress and subsequently impairing RTK signalling in ECs.Linked articlesThis article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc