Effects of bisphenol A and bisphenol analogs on the nervous system / 中华医学杂志(英文版)

Estrogen impacts neural development; meanwhile, it has a protective effect on the brain. Bisphenols, primarily bisphenol A (BPA), can exert estrogen-like or estrogen-interfering effects by binding with estrogen receptors. Extensive studies have suggested that neurobehavioral problems, such as anxiety and depression, can be caused by exposure to BPA during neural development. Increasing attention has been paid to the effects on learning and memory of BPA exposure at different developmental stages and in adulthood. Further research is required to elucidate whether BPA increases the risk of neurodegenerative diseases and the underlying mechanisms, as well as to assess whether BPA analogs, such as bisphenol S and bisphenol F, influence the nervous system.

The association between bisphenol A exposure and obesity/overweight in children and adolescents: dose-response Meta analysis / 中华预防医学杂志

Objective: To explore the relationship between bisphenol A (BPA) exposure and obesity/overweight in children and adolescents through Dose-response Meta analysis. Methods: Articles published up to September 1st 2021 were systematically searched in PubMed, Web of science, Scopus, Embase, Cochrane library, CNKI, Wanfang databases and VIP Chinese Science and Technology Journal by using "bisphenol A" "BPA" "obesity" "weight" "fat""overweight" "body mass index" "BMI" "waist circumference" (both in English and in Chinese) as keywords. Use Stata 15.1 software to calculate the pooled OR (95%CI), perform heterogeneity test, subgroup analysis, sensitivity analysis, publication bias and the exposure-response relationship fitting. Results: A total of 9 English articles were included from 1 948 articles retrieved, including 8 articles from American and 1 article from China. 15 614 children/adolescents and 3 446 obese/overweight cases were further used for Meta-analysis of dose-response relationship. Meta-analysis results showed that there was heterogeneity among the highest dose groups in different studies(I2=52.1%, P=0.033). The random effect model-analysis found that compared with those in the lowest group, the OR(95%CI) for those in the highest group of urine BPA was 1.56(1.18-1.94)for the risk of obesity/overweight in children and adolescents, but there was no linear or nonlinear dose-response relationship. Sensitivity analyses showed that the results were robust, Egger's test(P=0.263) and Begg's test(P=0.348) showed that there was no publication bias. Conclusion: Bisphenol A exposure may increase the risk of obesity/overweight epidemics in children and adolescent.

Impact of empagliflozin on peak oxygen uptake in HFmrEF patients: a randomized controlled trial / 中华心血管病杂志

Objective: To evaluate the impact of empagliflozin on peak oxygen uptake (VO2peak) in patients with heart failure with mildly reduced ejection fraction (HFmrEF). Methods: In this randomized controlled trial, consecutive HFmrEF patients admitted to the Department of Cardiology of China-Japan Friendship Hospital from September 2019 to October 2020 were screened, and randomly assigned to empagliflozin group (EG) or conventional group (CG) using a random number table. The enrolled patients were treated according to the guidelines, and patients in the empagliflozin group received additional empagliflozin (10 mg, once a day, orally) on top of the conventional treatment. The primary end points were VO2peak at 6 months after treatment, and the secondary end points included other parameters of cardiopulmonary exercise test (CPET), 6-minute walking distance, N-terminal B-type pro-natriuretic peptide (NT-proBNP) level, and Kansas City Cardiomyopathy Questionnaire (KCCQ) score. Results: A total of 112 patients were included (mean age 69 (57, 78) years, 84 male (75.0%)). There were 55 cases in CG group and 57 cases in EG group. There were no significant differences in baseline data including age, sex, body mass index, left ventricular ejection fraction, systolic blood pressure, heart rate, estimated glomerular filtration rate, glycosylated hemoglobin, hemoglobin, NT-proBNP, daily dose of tolasemi, combined medication, CPET parameters, the proportion of New York Heart Association heart function Ⅲ/Ⅳ, history of coronary heart disease, history of hypertension, history of diabetes (all P>0.05). At 6 months after treatment, VO2peak was significantly higher in EG group than in CG group(P=0.023). VE/VCO2 slope was significantly lower in EG group than in CG group(P=0.034). Oxygen uptake efficiency slope was significantly higher in EG group than in CG group(P=0.038). The level of NT-proBNP was significantly lower in EG group than in CG group(P=0.020). Six-minute walking distance was significantly higher in EG group than in CG group(P=0.037). KCCQ score was significantly higher in EG group than in CG group(P=0.048). Exercise oscillatory ventilation decreased in both groups (1 case in each group, P>0.05). Conclusion: Empagliflozin can significantly improve VO2peak in patients with HFmrEF.

Effectiveness of triple therapy with dapagliflozin add-on to dual therapy over 52 weeks in patients with uncontrolled type 2 diabetes mellitus in a centre of high complexity, Cali-Colombia

ABSTRACT Objectives: To evaluate the effectiveness of adding dapagliflozin as an intensification strategy for the treatment of patients with uncontrolled type 2 diabetes mellitus (T2DM). Materials and methods: A historical cohort study was conducted in 123 adult patients over 18 years old who were diagnosed with uncontrolled T2DM, who received dapagliflozin add-on to their dual base treatment: metformin plus glibenclamide (n = 32), metformin plus saxagliptin (n = 29), metformin plus exenatide (n = 28), or metformin plus insulin (n = 34). The endpoints were evaluated using analysis of variance. Results: All the patients completed a 52-week follow-up. Overall, 52.85% of patients were female, the Hispanic population represented the largest proportion of patients in all groups (60.98%), and the mean ± SD patient age and body weight were 55.05 ± 7.58 years and 83.55 ± 9.65 kg, respectively. The mean ± SD duration of T2DM, glycated hemoglobin (HbA1c), and fasting plasma glucose (FPG) were 5.93 ± 2.98 years, 8.1 ± 0.53%, and 166.03 ± 26.80 mg/dL, respectively. The grand mean changes of HbA1c, FPG, body weight and blood pressure showed a decreasing trend during the study period and it was statistically significant in all groups (p-value = <0.001). The proportion of patients achieving HbA1c target (<7%) was highest in the group that used a dapagliflozin add-on to metformin plus saxagliptin. Conclusion: The addition of dapagliflozin as an alternative for intensification of dual therapy consistently improved, not only FPG and HbA1c, but also body weight and blood pressure, with statistically significant results.

Effects of bisphenol A on apoptosis of ovarian preantral follicular granulosa cells and ovarian development in mice / 南方医科大学学报

OBJECTIVE@#To investigate the effect of environmental estrogen bisphenol A (BPA) exposure on apoptosis of mouse ovarian preantral follicular granulosa cells and ovarian development and explore the underlying mechanism.@*METHODS@#Mouse ovarian preantral follicular granulosa cells were isolated from female ICR mice at postnatal day (PND) 10 and cultured @*RESULTS@#Compared with the control cells group, the isolated cells exposed to a low concentration of BPA (50 μmol/L) showed a significantly lowered apoptosis rate, increased mitochondrial membrane potential, and enhanced cellular proliferation (@*CONCLUSIONS@#BPA can concentration-dependently regulate the function of ovarian preantral follicular granulosa cells in mice and potentially affects both the pregnant mice and the offspring female mice in light of early ovarian development.

Population diversity of cardiovascular outcome trials and real-world patients with diabetes in a Chinese tertiary hospital / 中华医学杂志(英文版)

BACKGROUND@#Recent cardiovascular outcome trials (CVOTs) changed the therapeutic strategy of guidelines for type 2 diabetes. We compared the characteristics of patients from real-world hospital settings with those of participants in recent pragmatic randomized trials.@*METHODS@#This electronic medical record (EMR)-based retrospective observational study investigated the data of patients with diabetes from inpatient and outpatient settings in West China Hospital of Sichuan University from January 1, 2011, to June 30, 2019. We identified patients meeting the inclusion criteria of a pragmatic randomized trial (EMPA-REG OUTCOME) based on EMRs and compared their baseline characteristics with those of the trial participants. The cutoff for the clinical significance of each characteristic was set as its minimal clinically important difference based on expert consultation.@*RESULTS@#We included 48,257 inpatients and 36,857 outpatients with diabetes and found that 8389 (17.4%) inpatients and 2646 (7.2%) outpatients met the inclusion criteria for the EMPA-REG OUTCOME trial. Compared with the trial population, the real-world inpatients meeting the eligibility criteria of the EMPA-REG OUTCOME had similar age, blood pressure, and lipid profiles but comprised of fewer males, metformin users, anti-hypertensive drug users, and aspirin users, and had a lower body mass index. The group of outpatients meeting the eligibility criteria had fewer males, similar age, fewer metformin users, fewer insulin users, fewer anti-hypertensive drug users, and fewer aspirin users compared with the trial population.@*CONCLUSIONS@#The trial population in EMPA-REG OUTCOME represents only a small portion of patients with diabetes from the inpatient and outpatient departments of a Chinese tertiary medical center. Evidence localization in different clinical settings and validation are essential to enabling extrapolation of the results from CVOTs in patients with diabetes to Chinese clinical practice.

The association between urinary bisphenol A levels and nonalcoholic fatty liver disease in Korean adults: Korean National Environmental Health Survey (KoNEHS) 2015-2017

BACKGROUND@#Nonalcoholic fatty liver disease (NAFLD) is becoming a global health problem. Bisphenol A (BPA), one of most widely used environmental chemicals, is suspected to be a contributor to the development NAFLD. This study was performed to examine the relationship between human BPA levels and risk of NAFLD.@*METHODS@#The data (n = 3476 adults: 1474 men and 2002 women) used in this study were obtained from the Korean National Environmental Health Survey III (2015-2017). BPA levels were measured in urine samples. NAFLD was defined using hepatic steatosis index after exclusion of other causes of hepatic diseases.@*RESULTS@#There was a significant linear relationship between the elevated urinary BPA concentrations and risk of NAFLD. In a univariate analysis, odds ratio (OR) of the highest quartile of urinary BPA level was 1.47 [95% confidence interval (CI) 1.11-1.94] compared to the lowest quartile. After adjusted with covariates, the ORs for NAFLD in the third and fourth quartiles were 1.31 [95% CI 1.03-1.67] and 1.32 [95% CI 1.03-1.70], respectively.@*CONCLUSIONS@#Urinary BPA levels are positively associated with the risk of NAFLD in adults. Further experimental studies are needed to understand the molecular mechanisms of BPA on NAFLD prevalence.

BPA toxicity during development of zebrafish embryo / Toxicidade do BPA durante o desenvolvimento de embriões de Zebrafish

Bisphenol A (BPA) is a monomer used in the production of polycarbonate, a polymer commonly found in plastics, epoxy resins and thermal papers. The presence of BPA in food, water, air and dust has been of great concern in recent years not only due to environmental and ecological issues but also because of its supposed risk to public health related to its mutagenic and carcinogenic potential. In this study we evaluated the toxicity of bisphenol A in zebrafish embryos (Danio rerio) and determined the 50% lethal concentration (LC50) of this chemical. BPA was used at concentrations ranging from 1 µM to 100 µM in E3 medium/0.5% dimethylsulfoxide (DMSO) from previously prepared stock solutions in 100% DMSO. Controls included embryos exposed only to E3 medium or supplemented with 0.5% DMSO. Camptothecin (CPT), a known inhibitor of cell proliferation was used as positive control at a concentration of 0.001 µM in E3 medium/0.5% DMSO. Adults zebrafish were placed for breeding a day before the experimental set up, then, viable embryos were collected and selected for use. Experiments were carried out in triplicates, according to specifications from Organization for Economic Cooperation and Development (OECD). One embryo/well (25 embryos per concentration) was distributed in 96 well microplates in presence or absence of the chemicals. The plates were kept in BOD incubators with a controlled temperature of 28.5 ºC and with photoperiod of 14 h light:10 h dark. After 24h, 48h, 72h and 96h exposure, the exposed embryos were evaluated according to the following parameters: mortality, coagulation, rate of heartbeat, hatching and presence of morphological abnormalities. Photography was obtained by photomicroscopy. Apoptosis was evaluated by DNA ladder assay. DNA was extracted by phenol:chloroform method and analyzed by 2% agarose gel electrophoresis. DNA fragments were visualized after ethidium bromide staining in ultraviolet transilluminator. The LC50 determined for BPA was 70 µM after 24 hours, 72 µM after 48 hours, 47 µM after 72 hours and 31 µM after 96 hours exposure. BPA induced morphological and physiological alterations such as yolk sac and pericardial edema, hatching delay or inhibition, spine deformation, decreasing in heartbeat rate and mortality. In conclusion, this study demonstrated that BPA induced marked malformations in zebrafish embryos at concentrations above 25 µM corroborating the current concerns related to the widespread presence of BPA in the air, food and water used by humans as well as in the bodily fluids and tissues.

Bisfenol A (BPA) é um monômero utilizado na produção de policarbonato, um polímero comumente encontrado em plásticos, resinas epóxi e papéis térmicos. A presença de BPA em alimentos, água, ar e poeira tem sido motivo de grande preocupação nos últimos anos, não só devido a questões ambientais e ecológicas, mas também ao suposto risco para a saúde pública relacionado ao seu potencial mutagênico e carcinogênico. Neste estudo avaliamos a toxicidade do bisfenol A em embriões de peixe-zebra (Danio rerio) e determinamos a concentração letal 50% (LC50) deste composto químico. O BPA foi usado na faixa de concentração entre 1 µM e 100µM em meio E3/0,5% de dimetilsulfóxido (DMSO), preparado a partir de soluções estoques em 100% DMSO. Os controles negativos incluíram embriões expostos apenas ao meio E3 ou suplementado com 0,5% DMSO. Camptotecina (CPT), um conhecido inibidor da proliferação celular, foi usado como controle positivo a uma concentração de 0,001 µM em meio E3/0,5% DMSO. Peixes-zebra adultos foram colocados para reprodução um dia antes da montagem experimental, em seguida, embriões viáveis foram coletados e selecionados para uso. Os experimentos foram realizados em triplicata, de acordo com as especificações da Organização para Cooperação e Desenvolvimento Econômico (OCDE). Um embrião/ poço (25 embriões por concentração) foi distribuído em microplacas de 96 poços na presença ou ausência dos compostos químicos. As placas foram mantidas em incubadoras BOD com temperatura controlada de 28,5 ºC e com fotoperíodo de 14h claro:10h escuro. Após 24h, 48h, 72h e 96h, os embriões expostos foram avaliados de acordo com os seguintes parâmetros: mortalidade, presença de coagulação, taxa do batimento cardíaco, eclosão e presença de anormalidades morfológicas. Fotografias foram obtidas por fotomicroscopia. A apoptose foi avaliada pelo ensaio de DNA ladder. O DNA foi extraído pelo método fenol:clorofórmio e analisado por eletroforese em gel de agarose a 2%. Fragmentos de DNA foram visualizadas após coloração com brometo de etídio em um transiluminador ultravioleta. A LC50 determinada para o BPA foi 70 µM após 24 horas, 72 µM após 48 horas, 47 µM após 72 horas e 31 µM após exposição por 96 horas. O BPA induziu alterações morfológicas e fisiológicas como edema de saco vitelino e edema pericárdico, atraso no tempo ou inibição da eclosão, deformação da coluna vertebral, diminuição da taxa de batimentos cardíacos e mortalidade. Em conclusão, este estudo demonstrou que o BPA induziu grande número de malformações em embriões de peixe-zebra em concentrações acima de 25 µM, corroborando as preocupações atuais relacionadas a presença generalizada do BPA no ar, alimento e água usados pelos seres humanos bem como nos fluidos e tecidos corporais.

Antioxidant activity of selenium on bisphenol-induced apoptosis and testicular toxicity of Albino rats / Actividad antioxidante el selenio sobre la apoptosis inducid por bisfenol y toxicidad testicular en ratas albinas

SUMMARY: Bisphenol A (BPA) is an industrial chemical widely used to make polycarbonate plastics for packaging and epoxy resins. This study sought to examine how selenium (Se) affects BPA toxicity in terms of albino rats' histological structure, antioxidant enzymes and reproductive organs (seminiferous tubules). Twenty-four adult male rats were divided into four experimental groups: Group 1: Control; Group 2: Orally administered BPA; Group 3: Orally administered sodium selenite; Group 4: Treated daily with BPA followed by selenium (Se). All experiment done for 4 weeks. BPA exposure caused changes in the testicular histological structure, which consists apoptosis, and led to changes in several biochemical markers: Malondialdehyde, catalase, superoxide dismutase, and glutathione peroxidase. However, these BPA side effects may be ameliorated in rats treated with BPA-plus-Se. These protective effects of Se may attributable to its ability to remove potentially damaging oxidizing agents in living organisms. The results may confirm that Se countered the oxidant effects and increased the BPA-induced stress response in rats. So, Se promotes the healthy growth and development of mammals by protecting them from oxidative stress. As human are greatly exposed to BPA and it can accumulate in tissues, there is concern about human reproductive functions particularly for occupational workers exposed usually to greater levels of BPA. Thus, the use of BPA in multiple industries must be restricted and the inaccurate usage of plastic containers should be avoided to decrease the health hazards. Administration of Se may protect against the adverse effects of BPA on reproductive functions and structures.

RESUMEN: El bisfenol A (BPA) es un químico industrial ampliamente utilizado para fabricar plásticos de policarbonato para envases y resinas epoxi. Este estudio examinó el efecto de selenio (Se) en la toxicidad del BPA en términos de la estructura histológica, enzimas antioxidantes y los órganos reproductivos (túbulos seminíferos) de ratas albinas. Se dividieron veinticuatro ratas macho adultas en cuatro grupos experimentales: Grupo 1: control; Grupo 2: BPA administrado por vía oral; Grupo 3: BPA administrado por vía oral para; Grupo 4: tratado diariamente con BPA seguido de selenio (Se). El experimento se realizó durante cuatro semanas y se observó que la exposición al BPA provocó cambios en la estructura histológica testicular, incluyendo apoptosis, y alteraciones en varios marcadores bioquímicos:malondialdehído, catalasa, superóxido dismutasa y glutatión peroxidasa. Sin embargo, estos efectos secundarios del BPA pueden mejorar en ratas tratadas con BPA-plus-Se. Estos efectos protectores del Se pueden ser atribuidos a la capacidad de eliminar agentes oxidantes potencialmente dañinos en organismos vivos. Los resultados indicaron que se contrarrestaron los efectos oxidantes y aumentó la respuesta al estrés inducido por BPA en ratas, y favorece el crecimiento y desarrollo en los mamíferos al protegerlos del estrés oxidativo. Debido a la exposición al BPA en el ser humano, se puede acumular en los tejidos, por lo que existe una preocupación por el daño a las funciones reproductivas en particular de los trabajadores que generalmente están expuestos a niveles más altos de BPA. Por lo tanto, se debe restringir el uso de BPA en las industrias y evitar el uso incorrecto de envases de plástico para así disminuir los riesgos para la salud. La administración correcta de Se puede proteger contra los efectos adversos del BPA en las funciones y estructuras reproductivas.

Contaminação em larga escala por Bisfenol-A: estamos conscientes do risco e formas de exposição? / Large-scale contamination by Bisphenol A: are we aware of the risk and forms of exposure?

Resumo O Bisfenol-A (BFA) é uma substância amplamente empregada no cotidiano, principalmente nos materiais plásticos. Este estudo avaliou a exposição de universitários ao disruptor endócrino BFA, o conhecimento dos mesmos acerca dessa substância e dos seus danos à saúde humana. Trata-se de um estudo transversal descritivo realizado com 500 estudantes de uma Universidade de Curitiba. A amostra foi selecionada de forma proporcional as três grandes áreas do conhecimento, sendo que os cursos entrevistados foram sorteados. Aos estudantes aplicou-se um questionário objetivo composto por três partes: socioeconômica, avaliação da exposição e testes de conhecimento. Dos respondentes, 91,3% consomem alimentos armazenados em embalagens plásticas, 90,06% utilizam bebidas nesse tipo de recipiente e 84,8% consomem bebidas/alimentos enlatados. Entretanto, apenas 19,8% já ouviram falar em BFA e 97,2% não sabem sobre a relação entre a exposição ao BFA e alterações endócrinas. Observou-se uma alta taxa de exposição ao BFA e um baixo nível de conhecimento sobre o assunto. Essa desproporção evidencia a necessidade de pesquisas mais aprofundadas sobre o tema na população brasileira, além da ampliação de medidas informativas.

Abstract Bisphenol A (BPA) is a substance extensively used in daily life, mainly in plastic materials. This study assessed the exposure of university students to endocrine disruptor BPA, their knowledge about this substance and the damage it causes to human health. This is a cross-sectional descriptive study carried out with 500 students from a University in Curitiba. The sample was selected proportionally to the three major areas of knowledge, and the courses interviewed were drawn at random. Students were asked to fill out an objective questionnaire consisting of three parts: socioeconomic, assessment of exposure and knowledge tests. Of the respondents, 91.3% consume food stored in plastic packaging, 90.06% use drinks in this type of container and 84.8% consume canned food/drinks. However, only 19.8% have heard of BPA and 97.2% do not know about the relationship between exposure to BPA and endocrine changes. A high rate of exposure to BPA and a low level of knowledge on the subject was detected. This disproportion highlights the need for more in-depth research on the topic among the Brazilian population, in addition to broadening dissemination of information measures on the issue.

Long-term efficacy of gliflozins versus gliptins for Type 2 Diabetes after metformin failure: a systematic review and network meta-analysis

SUMMARY After metformin failure in treatment for diabetes type 2, there is no trivial option for adjuvant medication. The last two oral class medications, gliflozins and gliptins, have different mechanisms of action but have never been compared in long run studies. The aim of the present meta-analysis is to assess the overall long-term efficacy of these drugs after metformin failure. A systematic review and meta-analysis were performed, including all trials with a duration of over 2 years, comparing gliflozins or gliptins after metformin failure in type 2 diabetes. Data Sources: Pubmed (Medline), Embase, Lilacs, and the Cochrane Library from inception through July 2016 without language restrictions. The longest study period found in the literature was 4 years. We selected 1 article on empagliflozin, 1 on dapagliflozin, and 1 on saxagliptin with missing data. After one year of treatment, over 50% of the patients presented HbA1c > 7%. Efficacy rate after 4 years of empagliflozin (23%) was better than dapagliflozin (5%) and saxagliptin (7%); however, it presented statistically non-significant values for HbA1c (7.4 and 7.3% between gliflozins), and missing data for saxaglifozin. Nonetheless, empagliflozin performed better than glimepiride in the 4-year period (standardized mean difference SMD 0.4, confidence interval CI 95% 0.23 to 0.56). The failure of the secondary treatment using gliflozins occurs in less than one year of treatment (less than 50% of the patients presenting HbA1c > 7 %). Empagliflozin offered better glycemic control compared to sulfonylureas but was similar to dapagliflozin.

RESUMO Após a falha da metformina no tratamento do diabetes tipo 2, não existe uma opção trivial para a medicação adicional. Os dois últimos medicamentos de classe oral, gliflozinas e gliptinas, têm mecanismos de ação diferentes, mas nunca foram comparados em estudos de longo prazo. O objetivo da presente meta-análise é a avaliação da eficácia global em longo prazo desses medicamentos após a falha da metformina. Uma revisão sistemática e meta-análise foram realizadas, incluindo todos os ensaios com uma duração de mais de dois anos, comparando gliflozinas ou gliptinas após a insuficiência de metformina no diabetes tipo 2. Fontes de dados: PubMed (Medline), Embase, Lilacs e a Biblioteca Cochrane desde o início até julho de 2016, sem restrições de idioma. O período mais longo de estudo encontrado na literatura foi de quatro anos. Foi selecionado um artigo sobre empagliflozina, um artigo sobre dapagliflozina e um artigo sobre saxagliptina com dados faltantes. Após um ano de tratamento, mais de 50% dos pacientes apresentavam HbA1c >7%. A taxa de eficácia em quatro anos de empagliflozina (23%) foi melhor que dapagliflozina (5%) e saxagliptina (7%), porém com valores estatisticamente não significativos para HbA1c (7,4% e 7,3% entre gliflozinas) e dados ausentes para a saxaglifozina. No entanto, a empagliflozina teve um desempenho melhor do que a glimepirida no período de quatro anos (diferença média padronizada SMD 0,4, intervalo de confiança IC 95% 0,23 a 0,56). A falha do tratamento secundário com gliflozinas ocorre em menos de um ano de tratamento (menos de 50% dos pacientes com HbA1c >7%). A empagliflozina ofereceu melhor controle glicêmico em comparação com as sulfonilureias, mas semelhante à dapagliflozina.

SGLT-2 inhibitors in diabetes: a focus on renoprotection

SUMMARY Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for chronic kidney disease. Various hypoglycemic therapies have proved to be beneficial to clinical outcomes, while others have failed to provide an improvement in cardiovascular and renal failure, only reducing blood glucose levels. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, represented by the empagliflozin, dapagliflozin, and canagliflozin, have been showing satisfactory and strong results in several clinical trials, especially regarding the reduction of cardiovascular mortality, reduction of hospitalization due to heart failure, reduction of albuminuria, and long-term maintenance of the glomerular filtration rate. The benefit from SGLT2 inhibitors stems from its main mechanism of action, which occurs in the proximal tubule of the nephron, causing glycosuria, and a consequent increase in natriuresis. This leads to increased sodium intake by the juxtaglomerular apparatus, activating the tubule glomerular-feedback and, finally, reducing intraglomerular hypertension, a frequent physiopathological condition in kidney disease caused by diabetes. In addition, this class of medication presents an appropriate safety profile, and its most frequently reported complication is an increase in the incidence of genital infections. Thus, these hypoglycemic agents gained space in practical recommendations for the management of type 2 diabetes mellitus and should be part of the initial therapeutic approach to provide, in addition to glycemic control, cardiovascular outcomes, and the renoprotection in the long term.

Ecotoxicological risk assessment due to the presence of bisphenol A and caffeine in surface waters in the Sinos River Basin - Rio Grande do Sul - Brazil / Risco ecotoxicológico devido à presença de bisfenol A e cafeína nas águas superficiais na Bacia do Rio Sinos - Rio Grande do Sul - Brasil

Abstract Bisphenol A (BPA) is an emerging contaminant, regularly detected in aquatic ecosystems, considered as an endocrine disrupting compound (EDC). Caffeine is another chemical related to human activity, often found in surface waters. The objective of this study was to evaluate the ecotoxicological risk due to BPA and caffeine in water samples from the Sinos River basin, Rio Grande do Sul, Brazil. Water samples were collected at three sites monthly from May 9 th, 2016 to April 11th, 2017 (n = 36). BPA concentrations in water samples collected were in the range of not detected to 517 ng L-1 and caffeine concentrations in the range of 41.7 to 28,439.6 ng L-1. The concentration of BPA in the analyzed samples had a moderate correlation with caffeine (rs = 0.402). High ecotoxicological risk for BPA was characterized in 77.77% of samples, with 11.11% presenting medium and 11.1% presenting low risk. For caffeine 13.9%, 50% and 36.11% of the samples presented high, medium and low risk, respectively. Caffeine concentrations in water can be used as predictors of BPA concentrations above 10 ng L-1, the lower concentration of ecotoxicological risk, with specificity of 66.7% and sensitivity of 70.4%. The assessment of aquatic risks has shown that both investigated compounds pose risks to organisms in the studied surface waters, mouth of the Pampa stream, mouth of the Luiz Rau stream and catchment point for public supply in Lomba Grande.

Resumo Bisfenol A (BPA) é um contaminante emergente regularmente detectado em ecossistemas aquáticos, é considerado um agente modificador endócrino (EDC). Além disso, outro produto químico relacionado com atividade humana, encontrado com frequência nas águas superficiais, é a cafeína. O objetivo deste estudo foi avaliar a ocorrência de risco ecotoxicológico devido a BPA e cafeína em amostras de água da Bacia Hidrográfica do Rio Sinos, Rio Grande do Sul, Brasil. Foram coletadas amostras de água em três locais mensalmente no período de 9 de maio de 2016 a 11 de abril de 2017 (n = 36). As concentrações de BPA em amostras de água coletadas estavam na faixa de não detectada a 517 ng L-1 e concentrações de cafeína na faixa de 41,7 a 28,439,6 ng L-1. A concentração de BPA nas amostras analisadas apresentou correlação moderada com a cafeína (rs = 0,402). Alto risco ecotoxicológico para BPA foi caracterizado em 77,77% das amostras, com 11,11% apresentando médio e 11,1% apresentando baixo risco. Para cafeína 13,9%, 50% e 36,11% das amostras apresentaram risco alto, médio e baixo, respectivamente. Concentrações de cafeína em água podem ser utilizadas como preditoras de concentrações de BPA acima de 10 ng L-1, menor concentração de risco ecotoxicológico, com especificidade de 66,7% e sensibilidade de 70,4%. A avaliação dos riscos aquáticos revelou que ambos os compostos investigados representam risco para os organismos nas águas superficiais estudadas, foz do arroio Pampa, foz do arroio Luiz Rau e ponto de captação para abastecimento público em Lomba Grande.

Challenges to regulate products containing bisphenol A: Implications for policy / Desafíos para regular los productos que contienen bisfenol A: implicaciones para la política

Abstract: Bisphenol A (BPA), found in plastics and epoxy resins, is one of the most studied chemicals. BPA is regarded as an endocrine disruptor and has been related to adverse health effects in humans. However, some regulatory agencies around the world have concluded that BPA is safe at current human exposure levels. As the scientific community attempts to settle the debate on BPA's health effects, regulatory agencies have been put into a challenging public health policy situation. The United States has implemented no regulatory actions due to safety concerns, while Europe has used the precautionary principle to guide its regulation in the face of scientific uncertainty. In this paper, we explore the debate surrounding BPA regulation and the possibility for countries to introduce guidelines, using Mexico as an example. Policy change determinants analysis suggest that countries can and should impose regulations on BPA.

Resumen: El bisfenol A (BPA), presente en plásticos y resinas epoxi, es uno de los químicos más estudiados. Se considera un disruptor endocrino y se ha relacionado con efectos adversos para la salud humana. Algunas agencias regulatorias en el mundo han concluido que el BPA es seguro a los niveles de exposición humana actuales. Mientas la comunidad científica intenta resolver el debate sobre dichos efectos, las agencias regulatorias enfrentan una difícil situación de política pública. Los Estados Unidos de América no han implementado acciones reglamentarias por razones precautorias, mientras que Europa ha utilizado el principio precautorio para guiar su regulación ante la incertidumbre científica. En este documento exploramos el debate que rodea la regulación del BPA y la posibilidad de que los países introduzcan directrices, usando a México como ejemplo. El análisis de los determinantes del cambio de políticas sugiere que los países pueden y deben regular el BPA.

Use of sodium-glucose cotransporter-2 inhibitors and urinary tract infections in type 2 diabetes patients: a systematic review

SUMMARY Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are drugs that act by maintaining glycosuria. Recent studies have shown promising effects of these in the treatment of type 2 diabetes mellitus (DM2). However, there may be an increased risk of developing urinary tract infections (UTIs) in patients treated with these. Our study aims to analyze the association between the risk of UTI in patients treated with SGLT2i. A systematic review of the literature was carried out by randomized clinical trials, totalizing at the end of the selection 23 articles that were statistically evaluated. The incidence of UTI was generally demonstrated in articles and in different subgroups: patients on SGLT2i monotherapy or on combination therapy; according to specific comorbidities of each sample or according to the drug used. They noticed an increase in the chance of UTI in the SGLT2i groups compared to the control groups on placebo or other oral antidiabetic agents. This increased chance was found predominantly with the use of Dapagliflozin, Canagliflozin, and Tofogliflozin, regardless of the dosing. Lastly, stands out that the dimension of UTI chances for DM2 patients who use SGLT2i remains to be more strictly determined.

RESUMO Os inibidores do cotransportador de sódio-glicose do tipo 2 (SGLT2i) são medicamentos que atuam mantendo a glicosúria. Estudos recentes têm demonstrado efeitos promissores desses no tratamento de diabetes mellitus tipo 2 (DM2). No entanto, pode haver um risco aumentado de desenvolver infecções do trato urinário (UTI) em pacientes tratados com essa classe de medicação. Nosso estudo tem como objetivo analisar a associação entre o risco de desenvolver UTI em pacientes tratados com SGLT2i. Uma revisão sistemática da literatura foi realizada por ensaios clínicos randomizados, totalizando, ao final da seleção, 23 artigos que foram avaliados estatisticamente. A incidência de UTI foi demonstrada genericamente de acordo com os dados dos artigos e em diferentes subgrupos: pacientes em monoterapia com SGLT2i ou em terapia combinada, de acordo com as comorbidades específicas de cada amostra ou de acordo com a droga utilizada. Verificou-se um aumento na chance de UTI nos grupos SGLT2i em comparação com os grupos de controle em placebo ou outros agentes antidiabéticos orais. Essa chance aumentada foi encontrada predominantemente com uso de Dapagliflozina, Canagliflozina e Tofoglifozina, independentemente da dosagem. Por fim, ressaltou-se que as chances de UTI em pacientes com DM2 em uso de SGLT2i ainda precisam ser mais bem determinadas.

Analysis of individual and combined estrogenic effects of bisphenol, nonylphenol and diethylstilbestrol in immature rats with mathematical models

BACKGROUND@#Traditional toxicological studies focus on individual compounds. However, this single-compound approach neglects the fact that the mixture exposed to human may act additively or synergistically to induce greater toxicity than the single compounds exposure due to their similarities in the mode of action and targets. Mixture effects can occur even when all mixture components are present at levels that individually do not produce observable effects. So the individual chemical effect thresholds do not necessarily protect against combination effects, an understanding of the rules governing the interactive effects in mixtures is needed. The aim of the study was to test and analyze the individual and combined estrogenic effects of a mixture of three endocrine disrupting chemicals (EDCs), bisphenol A (BPA), nonylphenol (NP) and diethylstilbestrol (DES) in immature rats with mathematical models.@*METHOD@#In the present study, the data of individual estrogenic effects of BPA, NP and DES were obtained in uterotrophic bioassay respectively, the reference points for BPA, NP and DES were derived from the dose-response ralationship by using the traditional no observed adverse effect (NOAEL) or lowest observed adverse effect level (LOAEL) methods, and the benchmark dose (BMD) method. Then LOAEL values and the benchmark dose lower confidence limit (BMDL) of single EDCs as the dose design basis for the study of the combined action pattern. Mixed prediction models, the 3 × 2 factorial design model and the concentration addition (CA) model, were employed to analyze the combined estrogenic effect of the three EDCs.@*RESULTS@#From the dose-response relationship of estrogenic effects of BPA, NP and DES in the model of the prepuberty rats, the BMDL(NOAEL) of the estrogenic effects of BPA, NP and DES were 90(120) mg/kg body weight, 6 mg/kg body weight and 0.10(0.25) μg/kg body weight, and the LOAEL of the the estrogenic effects of three EDCs were 240 mg/kg body weight, 15 mg/kg body weight and 0.50 μg/kg body weight, respectively. At BMDL doses based on the CA concept and the factorial analysis, the mode of combined effects of the three EDCs were dose addition. Mixtures in LOAEL doses, NP and DES combined effects on rat uterine/body weight ratio indicates antagonistic based on the CA concept but additive based on the factorial analysis. Combined effects of other mixtures are all additive by using the two models.@*CONCLUSION@#Our results showed that CA model provide more accurate results than the factorial analysis, the mode of combined effects of the three EDCs were dose addition, except mixtures in LOAEL doses, NP and DES combined effects indicates antagonistic effects based on the CA model but additive based on the factorial analysis. In particular, BPA and NP produced combination effects that are larger than the effect of each mixture component applied separately at BMDL doses, which show that additivity is important in the assessment of chemicals with estrogenic effects. The use of BMDL as point of departure in risk assessment may lead to underestimation of risk, and a more balanced approach should be considered in risk assessment.

Effect of bisphenol F, an analog of bisphenol A, on the reproductive functions of male rats

OBJECTIVE@#Bisphenol A (BPA) is a monomer primarily used in the production of polycarbonate plastic and epoxy resins. Bisphenol F (BPF) is apparently the main BPA replacement that is used increasingly. BPF has been detected in canned food, thermal paper receipts, and soft drinks. In the present experiment, we did both in vitro and in vivo studies to evaluate the effect of low and high-dose BPF exposures on testosterone concentration, oxidative stress, and antioxidants activity in reproductive tissues of male rats.@*METHODS@#Adult (80-90 days old) male Sprague Dawley rats (n = 36) obtained from the rodent colony of Animal Sciences Department of Quaid-i-Azam University. The direct effects of BPF on the antioxidant enzymes and testosterone secretion were measured in vitro and in vivo studies. In an in vivo experiment, adult male Sprague Dawley rats (n = 42) were exposed to different concentrations of bisphenol F (1, 5, 25, and 50 mg/kg/d) for 28 days. Various biochemical parameters were analyzed including the level of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), reactive oxygen species (ROS), and lipid peroxidation (LPO). Moreover, sperm motility, daily sperm production (DSP), comet assay, and histological analysis were performed.@*RESULTS@#In vitro study showed that BPF exposure significantly (p < 0.05) induced oxidative stress biomarkers, i.e., ROS and LPO, while it did not change antioxidant enzyme and testicular testosterone concentration. Whereas, an in vivo study revealed that BPF induced dose-dependent effect and high-dose (100 mg/kg) exposure of BPF significantly reduced tissue protein (p < 0.05) content, CAT (p < 0.001), SOD (p < 0.05), and POD (p < 0.05) levels while significantly (p < 0.05) augmented ROS and lipid peroxidation. Furthermore, BPF reduces testosterone, LH, and FSH secretion in a dose-dependent manner. Significant (p < 0.001) reduction in plasma and intra-testicular testosterone, LH, and FSH was noticed at 100 mg/kg BFP dose. High-dose exposure reduces spermatogenesis.@*CONCLUSION@#BPF showed an antagonistic effect on male reproductive hormones and induce alterations in testicular morphology. Increased oxidative stress and decreased testicular antioxidant status might be the underlying mechanism of BFP-induced testicular toxicity.

Dapagliflozin versus saxagliptin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin

ABSTRACT Objective: This analysis compared the efficacy and safety of the sodium-glucose cotransporter-2 (SGLT2) inhibitor, dapagliflozin, and the dipeptidyl peptidase-4 (DPP4) inhibitor, saxagliptin, both added on to metformin. Materials and methods: This was a post-hoc analysis from a double-blind, randomized, 24-week clinical trial (NCT01606007) of patients with type 2 diabetes (T2D) inadequately controlled with metformin. We compared the dapagliflozin 10 mg (n = 179) and saxagliptin 5 mg (n = 176) treatment arms. Results: Dapagliflozin showed significantly greater mean reductions versus saxagliptin in HbA1c (difference versus saxagliptin [95% CI]: −0.32% [-0.54, −0.10]; p < 0.005), fasting plasma glucose (-0.98 [-1.42, −0.54] mmol/L; p < 0.0001), body weight (-2.39 [-3.08, −1.71] kg; p < 0.0001) and systolic blood pressure (SBP) (-3.89 [-6.15, −1.63] mmHg; p < 0.001). More dapagliflozintreated than saxagliptin-treated patients achieved the composite endpoint of HbA1c reduction ≥ 0.5%, weight loss ≥ 2 kg, SBP reduction ≥ 2 mmHg and no major/minor hypoglycemia (24% versus 7%). No major events of hypoglycemia were reported. More patients on dapagliflozin (6%) versus saxagliptin (0.6%) experienced genital infections. Conclusion: Dapagliflozin demonstrated greater glycemic efficacy than saxagliptin with additional benefits on weight and SBP, and the safety profile was consistent with previous studies.