NKG2C+CD57+ natural killer cells with senescent features are induced during cutaneous leishmaniasis and accumulate in patients with lesional healing impairment.

Natural killer (NK) cells include different subsets with diverse effector capacities that are poorly understood in the context of parasitic diseases. Here, we investigated inhibitory and activating receptor expression on NK cells in patients with cutaneous leishmaniasis (CL) and explored their phenotypic and functional heterogeneity based on CD57 and NKG2C expression. The expression of CD57 identified NK cells that accumulated in CL patients and exhibited features of senescence. The CD57+ cells exhibited heightened levels of the activating receptor NKG2C and diminished expression of the inhibitory receptor NKG2A. RNA sequencing analyses based on NKG2C transcriptome have revealed two distinct profiles among CL patients associated with cytotoxic and functional genes. The CD57+NKG2C+ subset accumulated in the blood of patients and presented conspicuous features of senescence, including the expression of markers such as p16, yH2ax, and p38, as well as reduced proliferative capacity. In addition, they positively correlated with the number of days until lesion resolution. This study provides a broad understanding of the NK cell biology during Leishmania infection and reinforces the role of senescent cells in the adverse clinical outcomes of CL.

Oral formulation of DPP-4 inhibitor plus Quercetin improves metabolic homeostasis in type 1 diabetic rats.

This study aimed to investigate the potential of an oral formulation (QV formulation) containing Quercetin and a Dipeptidyl Peptidase-4 Inhibitor (DPP-4 inhibitor), Vildagliptin, in improving metabolic homeostasis in type 1 diabetes model. Female albino Fischer rats were divided into four groups: untreated control animals (C), untreated diabetic animals (D), diabetic animals treated with QV formulation (DQV), and diabetic animals treated with insulin (DI). Diabetes was induced by injection of alloxan (135 mg kg body mass)-1 and confirmed by glycemic test. After the 30-day treatment period, biochemical parameters were analyzed in the pancreas, liver, and serum. Histopathological changes in pancreatic tissue were examined by Hematoxyline & Eosin staining and the insulin content in the islet measured by immunohistochemistry with anti-insulin antibody. The glycogen content in the hepatocytes was quantified by Periodic Schiff Acid staining. The QV formulation reduced the glycemia, preserved the pancreatic architecture, increased insulin levels, furthermore ameliorated lipid profile and to promote higher survival rate of animals. Together, our data suggest that the QV formulation treatment was able to normalize metabolic homeostasis in type 1 diabetic rats.

Baccharis trimera protects against ethanol induced hepatotoxicity in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Baccharis trimera has been traditionally used in Brazil to treat liver diseases. AIM OF THE STUDY: To evaluate the protective effect of Baccharis trimera in an ethanol induced hepatotoxicity model. MATERIALS AND METHODS: The antioxidant capacity was evaluated in vitro by the ability to scavenged the DPPH radical, by the quantification of ROS, NO and the transcription factor Nrf2. Hepatotoxicity was induced in animals by administration of absolute ethanol for 2 days (acute) or with ethanol diluted for 28 days (chronic). The biochemical parameters of hepatic function (ALT and AST), renal function (urea and creatinine) and lipid profile (total cholesterol, triglycerides and HDL) were evaluated. In addition to antioxidant defense (SOD, catalase, glutathione), oxidative damage markers (TBARS and carbonylated protein), MMP-2 activity and liver histology. RESULTS: Baccharis trimera promoted a decrease in ROS and NO, and at low concentrations promoted increased transcription of Nrf2. In the acute experiment it promoted increase of HDL, in the activity of SOD and GPx, besides diminishing TBARS and microesteatosis. Already in the chronic experiment B. trimera improved the hepatic and renal profile, decreased triglycerides and MMP-2 activity, in addition to diminishing microesteatosis. CONCLUSION: We believe that B. trimera action is possibly more associated with direct neutralizing effects or inhibition of reactive species production pathways rather than the modulation of the antioxidant enzymes activity. Thus it is possible to infer that the biological effects triggered by adaptive responses are complex and multifactorial depending on the dose, the time and the compounds used.

Vildagliptin ameliorates oxidative stress and pancreatic beta cell destruction in type 1 diabetic rats.

BACKGROUND AND AIMS: It is believed that oxidative stress plays a role in the pathogenesis of diabetes mellitus. Several strategies have been developed with the objective of minimizing diabetic complications. Among these, inhibitors of dipeptidyl peptidase-IV (DPP-IV), which act by blocking degradation of incretin hormones, glucagon-like peptide hormone (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), have been the focus of many studies. It is known that, among the effects of incretins, we highlight its insulinotropic and cytoprotective effects on pancreatic ß-cells. The objective of this study was to evaluate the possible protective effects of treatment with vildagliptin, a DPP-IV inhibitor, in ß-cells in an experimental model of type 1 diabetes induced by streptozotocin (STZ). METHODS: Rats were treated for 4 weeks with vildagliptin at concentrations of 5 and 10 mg/kg. In order to observe the pancreatic damage and the possible protective effects of vildagliptin treatment, we measured stress markers TBARS and protein carbonyl, antioxidant enzymes SOD and catalase, and analyzed pancreatic histology. RESULTS: The treatment was effective in modulating stress in pancreatic tissue, both by reducing levels of stress markers as well as by increasing activity of SOD and catalase. After analyzing the pancreatic histology, we found that vildagliptin was also able to preserve islets and pancreatic ß-cells, especially at the concentration of 5 mg/kg. CONCLUSION: Thus, our results suggest that vildagliptin ameliorates oxidative stress and pancreatic beta cell destruction in type 1 diabetic rats. However, to evaluate the real potential of this medication in type 1 diabetes, further studies are needed.

Da saúde internacional à saúde global: trajetórias históricas e geográficas do conceito de medicamentos essenciais / From international health to global health: historical and geographical trajectories of the essential medicines concept

As questões que envolvem o lugar que os medicamentos ocupam no âmbito da saúde pública têm sido foco de importantes debates. A partir dos anos 1970, estados terceiro-mundistas levaram a Organização Mundial de Saúde (OMS) a se debruçar sobre o tema, o que deu origem à primeira lista de medicamentos essenciais, num arranjo de governança em saúde marcadamente estadocêntrico e multilateral. Com a assinatura do Acordo TRIPS e a consolidação da epidemia de HIV como um problema de proporções mundiais, nos anos 1990, o conceito de medicamento essencial assume novos contornos, passando a ser disputado na governança da saúde global, sob a égide do multi-institucionalismo. O objetivo desta tese é estudar as trajetórias históricas e geográficas do conceito de medicamentos essenciais (ME), na transição da saúde internacional para a saúde global. Utilizamos os conceitos de "governança" e "governança em saúde", bem como os estudos do chamado campo da "saúde internacional/global" e a Teoria Crítica das Relações Internacionais para delinear os contextos políticos e econômicos que dão sustentação aos processos de deslocamento do conceito em análise. Partimos de literatura especializada, à qual agregamos o resultado de entrevistas informativas com atores chave, além de pesquisa documental nos arquivos da OMS, em Genebra. No primeiro capítulo, caracterizamos a Saúde Internacional, estudamos o nascimento da lista de medicamentos essenciais da OMS, calcada no multilateralismo e no estadocentrismo e apontamos os sinais que indicam a transição para a Saúde Global. No segundo, descrevemos a ascensão do neoliberalismo, a crise do Estado nacional e da própria OMS para caracterizar a Saúde Global como multi-institucional, formada por uma profusão de "atores". Discutimos os diversos sentidos atribuídos ao conceito de medicamentos essenciais e analisamos a atuação de organizações da sociedade civil, num movimento de repolitização do conceito. O terceiro capítulo estuda o caso do sofosbuvir, medicamento para tratar a Hepatite C, com seus desdobramentos para a governança em saúde e para os medicamentos essenciais. O estudo permitiu concluir que a inclusão do sofosbuvir na lista de ME da OMS, em 2015, tem origem nos processos políticos desencadeados em 2001. Argumentamos que o caso em análise determinou deslocamentos históricos e desencadeou rearranjos geográficos na dinâmica Norte-Sul, afetando de maneira emblemática a questão do acesso a medicamentos

The issues surrounding the place of medicines in public health have been the focus of important discussions. Since the 1970s, third-world states have led the World Health Organization (WHO) to address the issue, which has given rise to the first list of essential drugs in a markedly state-centric and multilateral health governance arrangement. With the signing of the TRIPs Agreement and the consolidation of the HIV epidemic as a problem of worldwide proportions, in the 1990s the concept of essential medicine takes on new shapes, and is challenged in global health governance under the aegis of multistakeholderism. The objective of this thesis is to study the historical and geographical trajectories of the essential drugs concept, in the transition from international health to global health. We use the concepts of "governance" and "health governance" as well as studies of the so-called "international / global health" field and the Critical Theory of International Relations to delineate the political and economic contexts that underpin the concept under analysis. We started with specialized literature, to which we aggregated the information withdrawn from interviews with key actors, as well as research in the WHO archives Headquarters in Geneva. In the first chapter, we characterize International Health, we study the birth of the essential medicines list of the WHO, based on multilateralism and the state-centric, and point out the signs that indicate the transition to Global Health. In the second chapter, we describe the rise of neoliberalism, the crisis of the State and of the WHO's itself to characterize Global Health as multistakeholder environment, formed by an assemblage of "actors". We discuss the different meanings attributed to the concept of essential drugs and analyze the performance of civil society organizations in re-politicizing the concept. The third chapter looks at the case of sofosbuvir, a drug to treat Hepatitis C, and its implications for health governance and essential medicines. The study allowed us to conclude that the inclusion of sofosbuvir in the WHO essential medicines list in 2015 derives from the political processes initiated in 2001. We argue that the case in question determined historical displacements and triggered geographic rearrangements in the North-South dynamics, regarding the issue of access to medicines

Acordo TRIPS e Saúde Pública :: o papel da sociedade civil a ampliação do acesso ao tratamento para HIV/AIDS no Brasil /

Resumo: Nos anos 1990, o mundo assistiu a inúmeros eventos importantes. Para o campo da saúde pública e acesso a medicamentos, a assinatura do Acordo TRIPS foi um marco. No Brasil, o Acordo foi incorporado à legislação nacional no mesmo ano em que foi promulgada a lei que obrigaria o Estado brasileiro a fornecer gratuitamente terapia ARV para todos os pacientes que dela necessitassem. Desta forma, o Estado passou a conceder patentes para medicamentos e se comprometer com o tratamento de todas as pessoas vivendo com HIV/AIDS no país. O Acordo TRIPS, do ponto de vista institucional, levou o neoliberalismo para a saúde pública e, do ponto de vista da práxis, transformou-a em uma commodity. Entre 1990 e 2000 a Lei teve sua sustentabilidade ameaçada freqüentemente por causa dos altos preços praticados por empresas multinacionais detentoras das patentes dos medicamentos ARVs. Nesse cenário, foi e é importantíssima a atuação das ONGs/ AIDS para buscar a manutenção do programa brasileiro, bem como atuar internacionalmente, fortalecendo a cooperação sul-sul, a fim de. ampliar o acesso a medicamentos em outros países em desenvolvimento. As ONGs/ AIDS são peça fundamental na luta pela construção de uma alternativa contra-hegemônica à perspectiva neoliberal e "desmercantilizar" a saúde

Abstract: In the 1990s, the world witnessed countless important events. For the field of public health and access to medicines, the signing of the TRIPS Agreement was a milestone. In Brazil, the Agreement was incorporated into national legislation in the same year in which the law was promulgated, which would oblige the Brazilian State to provide ARV therapy free of charge for all patients who needed it. In this way, the state started granting patents for medicines and committed to the treatment of all people living with HIV / AIDS in the country. The TRIPS Agreement, from the institutional point of view, has led neoliberalism to public health and, from the point of view of praxis, has turned it into a commodity. Between 1990 and 2000 the Law had its sustainability often threatened because of the high prices practiced by multinational companies that hold the patents of ARV drugs. In this scenario, it was and is very important the NGO / AIDS action to seek the maintenance of the Brazilian program, as well as to act internationally, strengthening South-South cooperation in order to. access to medicines in other developing countries. NGOs / AIDS are a key element in the struggle to build a counter-hegemonic alternative to the neoliberal perspective and to "de-commodify" health