An in silico analysis of Ibuprofen enantiomers in high concentrations of sodium chloride with SARS-CoV-2 main protease.

2020 will be remembered worldwide for the outbreak of Coronavirus disease (COVID-19), which quickly spread until it was declared as a global pandemic. The main protease (Mpro) of SARS-CoV-2, a key enzyme in coronavirus, represents an attractive pharmacological target for inhibition of SARS-CoV-2 replication. Here, we evaluated whether the anti-inflammatory drug Ibuprofen, may act as a potential SARS-CoV-2 Mpro inhibitor, using an in silico study. From molecular dynamics (MD) simulations, we also evaluated the influence of ionic strength on the affinity and stability of the Ibuprofen-Mpro complexes. The docking analysis shows that R(-)Ibuprofen and S(+)Ibuprofen isomers can interact with multiple key residues of the main protease, through hydrophobic interactions and hydrogen bonds, with favourable binding energies (-6.2 and -5.7 kcal/mol, respectively). MM-GBSA and MM-PBSA calculations confirm the affinity of these complexes, in terms of binding energies. It also demonstrates that the ionic strength modifies significantly their binding affinities. Different structural parameters calculated from the MD simulations (120 ns) reveal that these complexes are conformational stable in the different conditions analysed. In this context, the results suggest that the condition 2 (0.25 NaCl) bind more tightly the Ibuprofen to Mpro than the others conditions. From the frustration analysis, we could characterize two important regions (Cys44-Pro52 and Linker loop) of this protein involved in the interaction with Ibuprofen. In conclusion, our findings allow us to propose that racemic mixtures of the Ibuprofen enantiomers might be a potential treatment option against SARS-CoV-2 Mpro. However, further research is necessary to determinate their possible medicinal use.Communicated by Ramaswamy H. Sarma.

Focal adhesion kinase governs cardiac concentric hypertrophic growth by activating the AKT and mTOR pathways.

The heart responds to sustained overload by hypertrophic growth in which the myocytes distinctly thicken or elongate on increases in systolic or diastolic stress. Though potentially adaptive, hypertrophy itself may predispose to cardiac dysfunction in pathological settings. The mechanisms underlying the diverse morphology and outcomes of hypertrophy are uncertain. Here we used a focal adhesion kinase (FAK) cardiac-specific transgenic mice model (FAK-Tg) to explore the function of this non-receptor tyrosine kinase on the regulation of myocyte growth. FAK-Tg mice displayed a phenocopy of concentric cardiac hypertrophy, reflecting the relative thickening of the individual myocytes. Moreover, FAK-Tg mice showed structural, functional and molecular features of a compensated hypertrophic growth, and preserved responses to chronic pressure overload. Mechanistically, FAK overexpression resulted in enhanced myocardial FAK activity, which was proven by treatment with a selective FAK inhibitor to be required for the cardiac hypertrophy in this model. Our results indicate that upregulation of FAK does not affect the activity of Src/ERK1/2 pathway, but stimulated signaling by a cascade that encompasses PI3K, AKT, mTOR, S6K and rpS6. Moreover, inhibition of the mTOR complex by rapamycin extinguished the cardiac hypertrophy of the transgenic FAK mice. These findings uncover a unique role for FAK in regulating the signaling mechanisms that governs the selective myocyte growth in width, likely controlling the activity of PI3K/AKT/mTOR pathway, and suggest that FAK activation could be important for the adaptive response to increases in cardiac afterload. This article is part of a Special Issue entitled "Local Signaling in Myocytes".

Focal adhesion kinase signaling in cardiac hypertrophy and failure.

Focal adhesion kinase (FAK) is a broadly expressed tyrosine kinase implicated in cellular functions such as migration, growth and survival. Emerging data support a role for FAK in cardiac development, reactive hypertrophy and failure. Data reviewed here indicate that FAK plays a critical role at the cellular level in the responses of cardiomyocytes and cardiac fibroblasts to biomechanical stress and to hypertrophic agonists such as angiotensin II and endothelin. The signaling mechanisms regulated by FAK are discussed to provide insight into its role in the pathophysiology of cardiac hypertrophy and failure.

Focal adhesion kinase signaling in cardiac hypertrophy and failure

Focal adhesion kinase (FAK) is a broadly expressed tyrosine kinase implicated in cellular functions such as migration, growth and survival. Emerging data support a role for FAK in cardiac development, reactive hypertrophy and failure. Data reviewed here indicate that FAK plays a critical role at the cellular level in the responses of cardiomyocytes and cardiac fibroblasts to biomechanical stress and to hypertrophic agonists such as angiotensin II and endothelin. The signaling mechanisms regulated by FAK are discussed to provide insight into its role in the pathophysiology of cardiac hypertrophy and failure.

Effect of maternal heat-stress on follicular growth and oocyte competence in Bos indicus cattle.

The objective was to determine whether exposure of Gir (Bos indicus) cows to heat-stress (HS) causes immediate and delayed deleterious effect on follicular dynamics, hormonal profile and oocyte competence. The cows were kept in tie-stalls for an adaptive thermoneutral period of 28 days (Phase I, Days -28 to -1). In Phase II (Days 0-28) cows were randomly allocated into control (CG, n=5) and HS (HS, n=5) treatments. The HS cows were placed in an environmental chamber at 38 degrees C and 80% relative humidity (RH) during the day and 30 degrees C, 80% RH during the night for 28 days. The CG group was maintained in shaded tie-stalls (ambient temperature) for 28 days. During Phase III (Days 28-147) animals were placed in tie-stalls (Days 28-42) followed by pasture (Days 42-147) under thermoneutrality. In each phase, weekly ovum pick up (OPU) sessions were to evaluate follicular development, morphology of cumulus-oocyte complexes (COCs), and developmental competence after in vitro maturation, fertilization, and culture. Serum concentrations of progesterone (P(4)) and cortisol were evaluated by radioimmunoassay. Exposure of Gir cows to HS had no immediate effect on reproductive function, but exerted a delayed deleterious effect on ovarian follicular growth, hormone concentrations, and oocyte competence. Heat-stress increased the diameter of the first and second largest follicles from Days 28 to 49. Indeed, HS increased the number of >9 mm follicles (characterized as follicular codominance) during this phase. Cows exposed to HS had longer periods of non-cyclic activity (P(4)<1 ng/mL), as well as shorter estrous cycles. However, HS did not affect cortisol concentration as compared to CG. Although HS had no significant effect on cleavage rate, it reduced blastocyst development during Phase III. In conclusion, long-term exposure of B. indicus cattle to HS had a delayed deleterious effect on ovarian follicular dynamics and oocyte competence.

Phenotypic expression of familial amyloid polyneuropathy in Brazil.

Familial amyloid polyneuropathy (FAP) is an inherited amyloidosis mainly associated with transthyretin Val30Met variant. Clinical heterogeneity has been reported in different populations with FAP and Va130Met variant. In order to characterize FAP expression in Brazilians and to compare its features to those reported in other cohorts, 44 Brazilian patients (27 females, median age 36 [23-53] years) with FAP and the Val30Met variant were investigated. Approximately 40% of their family members, with the exception, of parents and siblings, had FAP. Most of the patients had symptoms of peripheral neuropathy at onset. Median age at onset was 32 [20-44] years. Earlier onset was observed in males (27 [20-43] years in males vs. 33 [20-44] years in females, P = 0.02) and in patients whose parents had FAP (31 [20-44] years vs. 40 [37-43] years in patients, respectively with and without affected parents, P = 0.03). Phenotypic expression of FAP in Brazil is similar to the one reported in Portugal, characterized by high disease penetrance, early onset, particularly in males and in subjects with affected parents, and major symptoms of peripheral neuropathy. These data highlight the influence of common genetic factors, shared by both groups of patients, in disease expression.

Epidemiology of hepatitis A and E virus infection in Brazil.

This review has the objective to discuss the epidemiological aspects of the enterically transmitted hepatitis A and E in Brazil. The prevalence of hepatitis A varies greatly in different Brazilian regions, from 56% in South and Southeast to 93% in North region (Manaus, Amazon). Such differences are also found in different socioeconomic levels among age groups. A significantly higher prevalence was seen in the low socioeconomic group between 1-30 years. This difference is most striking in the first 10 years of age (23.5% vs 60.0%, high/middle vs low, respectively). Despite the improvements in sanitary conditions, hepatitis A is still endemic and outbreaks may occur. As an increasing proportion of the population is becoming susceptible to hepatitis A virus infection and as adult individuals may present more severe forms of the disease, the authors conclude that the implement of hepatitis A vaccination should be considered. Some Brazilian data have shown that the genotype found in our country were IA and IB. Isolates from this study were closely related genetically (or even identical) to isolates originating in other South American countries and overseas, providing firm evidence for epidemiological links between persons who travel to endemic areas. In spite of favorable environmental conditions, outbreaks of hepatitis E have never been reported in Brazil. Nevertheless, reports have demonstrated the evidence of anti-hepatitis E virus antibodies in some Brazilian regions. The seroprevalence of IgG anti-hepatitis E virus among normal populations shows positivities of 6.1% in gold-miners, 3.3% in general population, 2.0-7.5% in blood donors, 1.0% in pregnant women, and 4.5% in children, with no differences among regions. In populations at risk the prevalence of anti-hepatits E virus varies greatly. Among patients with acute non-A, non-B, non-C hepatitis 2.1% was detected in the Southeast to 29% in the Northeast, in 10.6% of acute non-A, non-B, non-C hepatitis relatives in the Amazon basin, in 12% of acute sporadic non-A non-B hepatitis patients in the Northeast, a co-infection with acute hepatitis A in 25 to 38% in the Northeast, in 14 to 18% among prostitutes and women considered at risk for human immunodeficiency virus in the Southeast, and in 12% of the intravenous drug users in the Southeast.

Gastric cryptosporidiosis as a clue for the diagnosis of the acquired immunodeficiency syndrome.

Cryptosporidium parvum has been detected with increasing frequency in the gastrointestinal tract, but involvement of the stomach is rarely reported. Whenever found in the histologic examination of the gastrointestinal mucosa, it should raise the suspicion of an immunocompromised host. We report a case of Cryptosporidium-associated erosive gastritis in a 64-year-old woman, who was found later to have the acquired immunodeficiency syndrome. Gastroduodenoendoscopy and biopsy of the gastric mucosa played an invaluable role in the diagnosis of cryptosporidiosis and to disclose the underlying immunodeficiency state.

Curso: Tópicos de Medicina Interna: Hemorragia digestiva alta não-varicosa: avaliação da gravidade e conduta terapêutica / Course: Internal Medicine topics: Nonvariceal upper gastrointestinal bleeding: Gravity evaluation and therapeutical approach

A hemorragia digestiva alta (HDA) continua sendo uma das principais causas de atendimento hospitalar emergencial

Mineralogia e mobilidade de cations de uma alteração intempérica de diabásio

The mobility of the main cátions and the mineralógical evolution are studied for a weathering sequence of a diabase, from unaltered rock to the rock-derived soil. The diabase is located in conditions of subhumid and subtropical weather, having good drainage, located in Capivari (SP), Brazil. The mineralogy of diabase, essentialy constitued of plagioclases and pyroxenes, developed to a simple mineralogy, in which the clay fraction of the soil consists only of kaolinite, associated to non determined iron oxides. Vermiculite occurs in the intermediary stages, as the only 2:1 clay mineral. The leaching of soluble cátions occurs rapidly in the first stages of the process, followed by silica, also with rapid removal, however due to its high concentration in the original rock, it remains longer time in the system, in the structure of kaolinite and also as quartz in small quantity. Aluminium and iron are immobilized in the system, aluminium in the structure of kaolinite and iron as oxide.

Em uma seqüência de alteração intempérica de diabásio, situada no município de Capivari, SP, foram estudadas a mobilidade de cátions liberados no processo e a evolução mineralógica ocorrida. A seqüência situa-se em condições de clima sub-tropical semi-úmido e de boa drenagem. A mineralogia do diabásio, constituída essencialmente de plagioclásios e piroxênios, evoluiu para uma mineralogia simples, onde na fração argila do solo ocorre apenas a caulinita, associada a óxidos de ferro, que não foram determinados. Vermiculita ocorre nas fases intermediárias, como o único argilomineral 2:1. A lixiviação de cátions solúveis ocorre já nos primeiros estágios do processo, seguidos da sílica, também com remoção rápida, mas que, em face de seu elevado teor na rocha de origem, permanece maior tempo no sistema, permitindo a gênese da caulinita e també, de quartzo em pequena quantidade. Alumínio e ferro são imobilizados no sistema, o alumínio como constituinte de caulinita e o ferro como óxido.

Mineralogia e mobilidade de cations de uma alteração intempérica de diabásio

The mobility of the main cátions and the mineralógical evolution are studied for a weathering sequence of a diabase, from unaltered rock to the rock-derived soil. The diabase is located in conditions of subhumid and subtropical weather, having good drainage, located in Capivari (SP), Brazil. The mineralogy of diabase, essentialy constitued of plagioclases and pyroxenes, developed to a simple mineralogy, in which the clay fraction of the soil consists only of kaolinite, associated to non determined iron oxides. Vermiculite occurs in the intermediary stages, as the only 2:1 clay mineral. The leaching of soluble cátions occurs rapidly in the first stages of the process, followed by silica, also with rapid removal, however due to its high concentration in the original rock, it remains longer time in the system, in the structure of kaolinite and also as quartz in small quantity. Aluminium and iron are immobilized in the system, aluminium in the structure of kaolinite and iron as oxide.

Em uma seqüência de alteração intempérica de diabásio, situada no município de Capivari, SP, foram estudadas a mobilidade de cátions liberados no processo e a evolução mineralógica ocorrida. A seqüência situa-se em condições de clima sub-tropical semi-úmido e de boa drenagem. A mineralogia do diabásio, constituída essencialmente de plagioclásios e piroxênios, evoluiu para uma mineralogia simples, onde na fração argila do solo ocorre apenas a caulinita, associada a óxidos de ferro, que não foram determinados. Vermiculita ocorre nas fases intermediárias, como o único argilomineral 2:1. A lixiviação de cátions solúveis ocorre já nos primeiros estágios do processo, seguidos da sílica, também com remoção rápida, mas que, em face de seu elevado teor na rocha de origem, permanece maior tempo no sistema, permitindo a gênese da caulinita e també, de quartzo em pequena quantidade. Alumínio e ferro são imobilizados no sistema, o alumínio como constituinte de caulinita e o ferro como óxido.

Moduladores biológicos de la respuesta inmune en la terapia del cáncer / Immune response biological modulators in cancer therapy

Los modificadores de la respuesta biológica o inmunomoduladas, son un conjunto de compuestos que de alguna manera tienden a modificar el sistema inmune del huésped. Sus efectos potenciales no estan lejos de brindar frutos sólidos al armamentario terapéutico contra el cáncer. Estos inmunomoduladores representan una gran variedad de agentes; algunos de ellos pueden variar las estructuras inmunológicas del huésped, con lo que el paciente oncológico puede tolerar con menor morbiletalidad, la terapia convencional contra el cancer. Por otro lado, existen compuestos como el interferón que son verdaderas armas terapéuticas aceptadas ampliamente contra algunas neoplasias, y con el cual se han obtenido respuestas favorables, como en el caso de remisiones prolongadas en leucemias mielocíticas crónicas. Otros, como la interleucina 2, se encuentran en fase muy preliminar de experimentación como para concluir acerca de sus resultados. Consideramos que la investigación bien fundamentada con estos agentes podrá producir una opción más en el tratamiento del niño con cáncer.