Angiotensin {II}-induced redox-sensitive {SGLT}1 and 2 expression promotes high glucose-induced endothelial cell senescence

High glucose (HG)-induced endothelial senescence and dysfunction contribute to the increased cardiovascular risk in diabetes. Empagliflozin, a selective sodium glucose co-transporter2 (SGLT2) inhibitor, reduced the risk of cardiovascular mortality in type 2 diabetic patients but the protective mechanism remains unclear. This study examines the role of SGLT2 in HG-induced endothelial senescence and dysfunction. Porcine coronary artery cultured endothelial cells (ECs) or segments were exposed to HG (25 mmol/L) before determination of senescence-associated beta-galactosidase activity, protein level by Western blot and immunofluorescence staining, mRNA by RT-PCR, nitric oxide (NO) by electron paramagnetic resonance, oxidative stress using dihydroethidium and glucose uptake using 2-NBD-glucose. HG increased ECs senescence markers and oxidative stress, down-regulated eNOS expression and NO formation, and induced the expression of VCAM-1, tissue factor, and the local angiotensin system, all these effects were prevented by empagliflozin. Empagliflozin and LX-4211 (dual SGLT1/2 inhibitor) reduced glucose uptake stimulated by HG and H2O2 in ECs. HG increased SGLT1 and 2 protein levels in cultured ECs and native endothelium. Inhibition of the angiotensin system prevented HG-induced ECs senescence and SGLT1 and 2 expression. Thus, HG-induced ECs ageing is driven by the local angiotensin system via the redox-sensitive up-regulation of SGLT1 and 2, and, in turn, enhanced glucotoxicity

Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling

SummaryMany signals must be integrated to maintain self-renewal and pluripotency in embryonic stem cells (ESCs) and to enable induced pluripotent stem cell (iPSC) reprogramming. However, the exact molecular regulatory mechanisms remain elusive. To unravel the essential internal and external signals required for sustaining the ESC state, we conducted a short hairpin (sh) RNA screen of 104 ESC-associated phosphoregulators. Depletion of one such molecule, aurora kinase A (Aurka), resulted in compromised self-renewal and consequent differentiation. By integrating global gene expression and computational analyses, we discovered that loss of Aurka leads to upregulated p53 activity that triggers ESC differentiation. Specifically, Aurka regulates pluripotency through phosphorylation-mediated inhibition of p53-directed ectodermal and mesodermal gene expression. Phosphorylation of p53 not only impairs p53-induced ESC differentiation but also p53-mediated suppression of iPSC reprogramming. Our studies demonstrate an essential role for Aurka-p53 signaling in the regulation of self-renewal, differentiation, and somatic cell reprogramming

All-sky Medium Energy Gamma-ray Observatory: Exploring the Extreme Multimessenger Universe

The All-sky Medium Energy Gamma-ray Observatory (AMEGO) is a probe class mission concept that will provide essential contributions to multimessenger astrophysics in the late 2020s and beyond. AMEGO combines high sensitivity in the 200 keV to 10 GeV energy range with a wide field of view, good spectral resolution, and polarization sensitivity. Therefore, AMEGO is key in the study of multimessenger astrophysical objects that have unique signatures in the gamma-ray regime, such as neutron star mergers, supernovae, and flaring active galactic nuclei. The order-of-magnitude improvement compared to previous MeV missions also enables discoveries of a wide range of phenomena whose energy output peaks in the relatively unexplored medium-energy gamma-ray band

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Avaliação da toxicidade do extrato aquoso liofilizado de chapéu-de-couro (Echinodorus grandiflorus) em ratas prenhes

In Brazil, there are countless species that are used as phytotherapics, and among them there is E. grandiflorus, an Alismatacea aquatic or semi-aquatic herb, popularly known as chapéu-de-couro, commonly used in folk medicine as diuretic and anti-inflammatory and also in the treatment of kidney diseases, rheumatism, skin conditions and liver disorders. Several studies have confirmed its diuretic, anti-inflammatory and antinociceptive, hypotensive, antihypertensive and vasodilatory, antimicrobial, in vitro trypanocidal, leishmanicidal, antineoplastic, immunosuppressive and hypocholesterolemic pharmacological properties, though its toxicity was not evaluated during pregnancy. Numerous agents can interfere with the female reproductive system functionality and with one or more stages of embryo development, but the drugs, due to the frequency that they are used, are on the list of the most concerning factors. Considering the therapeutic potential of E. grandiflorus and the widespread utilization of its tea with curative purposes by the population and the lack of studies about this herb toxicity during pregnancy, its necessary to evaluate its toxicity and the aim of this study was to evaluate this effect on Wistar rats. During 15 days, vaginal smears were performed to observe the regularity of the estrous cycle. Rats with regular estrous cycle were separated into four experimental groups (n=16): C, control group that received saline solution by gavage, during 15 days, and T-250, T-500 and T-1000 which were treatment groups that received doses of 250, 500 and 1000 mg/kg/day of the extract, respectively, during this same period the vaginal smear was also performed. The rats were mated and the pregnant ones were treated up to the 14th day. On the 15th day they were euthanized by the method of exsanguination under full anesthesia and, then, laparotomyzed for examination, the organs were removed and weighed and the maternal, litter and placenta variables were recorded. Blood tests were made and the plasmatic concentrations of urea, creatinine, cholesterol, triglycerides, alanine transaminase and aspartate transaminase were determined. The liver, kidneys, spleen, ovaries and adrenal glands were removed and weighed. The number of corpora lutea, implants, resorptions, and live and dead fetuses were counted. The liver, the spleen, and the kidneys of pregnant rats were processed for histopathological analysis. There were no detectable signs of maternal toxicity, as measured by piloerection, diarrhea, change in ambulation in the cage and death. A reduction in the proportion of the estrous phases was observed after the treatment in the T-1000 group. In all treatment groups the average number of corpora lutea, implantations and reabsorption per dam was similar, as well as the post-implantation loss rate, the proportion of implantation and reabsorption. There were records of anemia and increased aspartate transaminase in all three treatment groups, in the highest dosage it was registered increase of cholesterol and leukocytosis, and histopathological alterations in the kidneys, liver and spleen of the dams. Taken together, this study data indicate that the administration of lyophilized aqueous extract of E. grandiflorus to pregnant rats at the dosages of 250, 500 and 1000 mg/kg/day, under this experiment conditions, was toxic to the dams, but did not affect the reproductive performance and no external malformation was observed in the fetuses.No Brasil, existem inúmeras espécies de plantas que são utilizadas como fitoterápicos, e, dentre elas, encontra-se E. grandiflorus, uma Alismatacea herbácea, aquática ou semi-aquática, conhecida popularmente como chapéu-de-couro, muito utilizada na medicina popular como diurética e anti-inflamatória e no tratamento de doenças renais, reumatismo, afecções cutâneas e problemas do fígado. Diversos trabalhos confirmaram suas ações farmacológicas como diurética, anti-inflamatória e antinociceptiva, hipotensora, anti-hipertensiva e vasodilatadora, antimicrobiana, tripanocida in vitro, leishmanicida, antineoplásica, hipocolesterolêmica e imunossupressora, entretanto sua toxicidade ainda não foi avaliada na gestação. Inúmeros agentes podem interferir com a funcionalidade do sistema reprodutor feminino e com uma ou mais fases do desenvolvimento embriofetal, mas os fármacos e os fitofármacos, pela freqüência com que são utilizados durante o período gestacional estão na lista dos fatores mais preocupantes. Considerando que o chapéu-de-couro é componente de refrigerante de grande aceitação popular e a grande utilização do chá pela população dado ao seu potencial terapêutico, e considerando a inexistência de estudos sobre a toxicidade da planta no período gestacional torna-se necessário avaliar sua toxicidade e, no presente trabalho, pretendeu-se avaliar tal efeito em fêmeas de ratas Wistar. Durante 15 dias foram feitos esfregaços vaginais para observação da regularidade do ciclo estral. Ratas com ciclo estral regular foram distribuídas em quatro grupos experimentais (n=16): C, grupo controle, que recebeu solução salina por gavagem, durante 15 dias, e T-250, T-500 e T-1000, grupos tratados, que receberam o extrato nas doses de 250, 500 e 1000mg/kg/dia, respectivamente, período no qual também foi feito esfregaço vaginal. As ratas foram acasaladas e as gestantes foram tratadas até o 14º dia. No 15º dia foram eutanasiadas por exsanguinação total sob anestesia e laparotomizadas para exame, remoção e pesagem dos órgãos e registro das variáveis maternas, ninhadas e placentas. O sangue colhido serviu para realização de hemograma e determinação das concentrações plasmáticas de uréia, creatinina, colesterol, triglicérides, alanina transaminase e aspartato transaminase. Fígado, rins, baço, ovários e adrenais foram removidos e pesados, sendo processados para análise histopatológica fígado, rim e baço. O número de corpos lúteos, implantes, reabsorções, fetos vivos e mortos foi contado. Não foram observados sinais detectáveis de toxicidade materna, aferidos por piloereção, diarréia, alteração na deambulação no interior da gaiola e mortes. Observou-se redução da proporção de fases estrais depois do tratamento no grupo T-1000. Em todos os grupos tratados a média de corpos lúteos, implantes e reabsorções por mãe foi semelhante, assim como o índice de perda pós-implantação, proporção de implantação e reabsorção. Foram registrados anemia e aumento na concentração de aspartato transaminase nos três grupos tratados, aumento de colesterol e leucocitose na maior dose, e alterações histopatológicas no fígado nas três doses testadas, no rim, nas doses de 500 e 1000mg/kg/dia e no baço de animais tratados com 1000mg/kg/dia. Analisados em conjunto, os dados do presente trabalho são indicativos de que o extrato aquoso liofilizado de E. grandiflorus administrado a ratas prenhes nas doses de 250, 500 e 1000mg/kg/dia e nas condições deste experimento foi tóxico para as mães, mas não alterou a performance reprodutiva e nenhuma malformação externa foi observada nos fetos