Trends on deaths from acute pesticide poisoning in Mexico, 2000-2021.

OBJETIVE: To provide a comprehensive analysis of mortality trends from acute pesticide poisoning in Mexico from 2000 through 2021. METHODS: The governmental records of deaths from acute pesticide poisoning were used. The age-standardized years of life lost and aged-standardized mortality rates were estimated. Significant changes in trends of annual percentage change were identified using Joinpoint regression. RESULTS: Between 2000 and 2021, mortality was primarily observed in individuals aged 15 to 19 years. Males were the most affected. Self-inflicted pesticide poisoning was the primary registered reason for death. The age-standardized mortality rate from acute pesticide poisoning was reduced from 2012 to 2021 (APC: -4.4; p=0.003). CONCLUSION: This report is the first study about the mortality rate from acute pesticide poisoning in Mexico. The results provided evidence to consider in developing laws to prevent acute pesticide poisoning.

Trends on deaths from acute pesticide poisoning in Mexico, 2000-2021 / Tendências das mortes por intoxicação aguda por pesticidas no México, 2000-2021

ABSTRACT Objetive: To provide a comprehensive analysis of mortality trends from acute pesticide poisoning in Mexico from 2000 through 2021. Methods: The governmental records of deaths from acute pesticide poisoning were used. The age-standardized years of life lost and aged-standardized mortality rates were estimated. Significant changes in trends of annual percentage change were identified using Joinpoint regression. Results: Between 2000 and 2021, mortality was primarily observed in individuals aged 15 to 19 years. Males were the most affected. Self-inflicted pesticide poisoning was the primary registered reason for death. The age-standardized mortality rate from acute pesticide poisoning was reduced from 2012 to 2021 (APC: -4.4; p=0.003). Conclusion: This report is the first study about the mortality rate from acute pesticide poisoning in Mexico. The results provided evidence to consider in developing laws to prevent acute pesticide poisoning.

RESUMO Objetivo: Fornecer uma análise abrangente das tendências de mortalidade por envenenamento agudo por pesticidas no México de 2000 a 2021. Métodos: Foram usados os registros governamentais de mortes por envenenamento agudo por pesticidas. Foram estimados os anos de vida perdidos estandardizados por idade e as taxas de mortalidade estandardizados por idade. Modificações significativas nas tendências de variação percentual anual foram identificadas usando a regressão Joinpoint. Resultados: Entre 2000 e 2021, a mortalidade foi observada principalmente em indivíduos na faixa etária de 15 a 19 anos. Os homens foram os mais afetados. O envenenamento por pesticida autoinfligido foi o principal motivo de morte registrado. A taxa de mortalidade estandardizada por idade por intoxicação aguda por pesticidas foi reduzida de 2012 a 2021 (Annual Percent Change — APC: -4,4; p=0,003). Conclusão: Este relatório é o primeiro estudo sobre a taxa de mortalidade por intoxicação aguda por pesticidas no México. Os resultados forneceram evidências a serem consideradas no desenvolvimento de leis para prevenir o envenenamento agudo por pesticidas.

[Foreign capital and structural change in the Brazilian private health services market]. / Capital estrangeiro e mudança estrutural no mercado privado de serviços de saúde brasileiro.

This article analyzes the process of structural transformation within the Brazilian private health services market since the 2000s, with emphasis on the growing participation of financial funds and foreign capital in the process of expansion and consolidation of the sector. The analysis of the movement of foreign capital into health services and plans in Brazil was developed from the construction of a database with a total of 297 equity operations involving companies with activities in health services, including companies operating health plans and insurance and companies administering health benefits. The analysis of these operations shows that the influx of foreign capital was fundamental to enable the centralization of capital in certain companies and catalyze the process of concentration and structural transformation of the health services sector over the last two decades. We concluded that the intensification of the intercapitalist dispute within the health services market led to the emergence of large corporations and new business models, with special emphasis on the emergence of verticalized care networks (operation of plans, hospital services, outpatient services, diagnosis and treatment, and primary care).

Este artigo analisa o processo de transformação estrutural no mercado privado de serviços de saúde brasileiro a partir dos anos 2000, com ênfase na crescente participação de fundos financeiros e do capital estrangeiro no processo de expansão e consolidação do setor. A análise do movimento de ingresso do capital estrangeiro nos serviços e planos de saúde no Brasil foi desenvolvida a partir da construção de uma base dados com um total de 297 operações patrimoniais envolvendo empresas com atividades em serviços de saúde, inclusive operadoras de planos e seguros de saúde e administradoras de benefícios em saúde. A análise dessas operações evidencia que o afluxo de capital estrangeiro foi fundamental para viabilizar a centralização de capital em determinadas empresas e catalisar o processo de concentração e transformação estrutural do setor de serviços de saúde ao longo das últimas duas décadas. Conclui-se que o acirramento da disputa intercapitalista no mercado de serviços de saúde levou à emergência de grandes corporações no mercado e a novos modelos de negócio, com destaque especial para o surgimento de redes verticalizadas de atendimento (operação de planos, serviços hospitalares, ambulatoriais, de diagnóstico e tratamento e de atenção básica).

Este artículo analiza el proceso de transformación estructural en el mercado privado de servicios de salud brasileño, a partir de los años 2000, con énfasis en la creciente participación de fondos financieros y del capital extranjero en el proceso de expansión y consolidación del sector. El análisis del movimiento de ingreso del capital extranjero en los servicios y planes de salud en Brasil fue desarrollado a partir de la construcción de una base datos con un total de 297 operaciones de capital de empresas con actividades en servicios de salud; inclusive las empresas operadoras de planes y seguros de salud y las empresas administradoras de beneficios en salud. El análisis de esas operaciones muestra que la entrada de capital extranjero fue fundamental para viabilizar la centralización de capital en determinadas empresas y catalizar el proceso de concentración y transformación estructural del sector de servicios de salud a lo largo de las últimas dos décadas. La conclusión que el recrudecimiento de la disputa intercapitalista dentro del mercado de servicios de salud llevó a la emergencia de grandes corporaciones en el mercado y nuevos modelos de negocio, con destaque especial para surgimiento de redes verticalizadas de atención (operación de planes, servicios hospitalarios, ambulatorios, de diagnóstico y tratamiento y de atención básica).

ß-glucuronidase as a biomarker for assessing the exposure to anticholinergic pesticides: A meta-analysis.

INTRODUCTION: The human exposure to anticholinergic pesticides has been associated with the development of various diseases. Therefore, several biomarkers have been proposed for biomonitoring human exposure to anticholinergic pesticides. OBJECTIVE: This work evaluated the effect of human exposure to anticholinergic pesticides on ß-glucuronidase (GUSB) levels. METHODS: A systematic review was performed using PubMed, Web of Science, Scopus, and EBSCO databases up to December 2021. The statistical analysis employed standardized mean differences and meta-regression. And the trial sequential analysis was performed. RESULTS: Nine studies were included. A monotonic relationship was observed between poisoning severity and GUSB. Furthermore, BuChE levels were correlated with GUSB levels. CONCLUSIONS: The results indicated that GUSB levels could be used as a possible diagnosis biomarker in poisoning related to anticholinergic pesticide exposure. However, the use of GUSB to assess the chronic exposure to anticholinergic pesticides could be only performed in recent exposure (≈ 7 days after last exposure).

Evaluation of the cytotoxicity and genotoxicity of glufosinate-ammonium at technical and commercial grades in HepG2 cells.

Exposure to genotoxic agents is associated with the development of cancer and related diseases. For this reason, assessing the genotoxicity of chemical compounds is necessary. In this line, information about the genotoxic effect of glufosinate-ammonium (GLA) has been reported only for the technical grade. However, humans are frequently exposed to commercial formulations of pesticides. Commercial formulations are characterized by using inner agents that increase toxicity compared to pesticides in technical grade. This study aimed to determine the cytotoxic and genotoxic effects of GLA on HepG2 cells. MTT and comet assays were performed to evaluate cell viability and DNA damage, respectively. HepG2 cells were exposed for 24 h to different concentrations of GLA (at 0.01 µg/mL; 0.04 µg/mL; 0.1 µg/mL; 0.24 µg/mL; 0.52 µg/mL; 1.25 µg/mL; 2.62 µg/mL and 13.12 µg/mL) in commercial- (Finale Ultra®) or technical-grade (GLAT). The results indicated that only Finale Ultra® induced a reduction in cell viability at 13.12 µg/mL. Furthermore, exposure to Finale Ultra® or GLAT was associated with increased DNA damage at concentrations from 0.52-13.12- µg/mL. This study shows the genotoxic effect of GLA on HepG2 cells.

The burden of physical inactivity for the public health care system in Brazil.

OBJECTIVE: To update the estimated cost of physical inactivity for the Brazilian Unified Health System (SUS). METHODS: The hospitalization costs were accessed via a database of the Ministry of Health - Informatics Department of the Brazilian SUS. Physical inactivity for the year 2017 was accessed via the Sistema de Vigilância de Fatores de Risco e Proteção para Doenças Crônicas por Inquérito Telefônico (Vigitel - Surveillance System for Risk and Protective Factors for Chronic Diseases by Telephone Survey). Seven chronic non-communicable diseases (NCD) were selected via the international classification of disease (ICD-10). The population fraction attributable to physical inactivity was calculated based on relative risk reported in previous studies and the prevalence of physical inactivity. RESULTS: In 2017, the seven NCD considered in the analysis were responsible for 154,017 hospital admissions in adults older than 40 years old, residing in the state capitals and the Federal District, which corresponded to 6.5% of hospitalizations and 10.6% of SUS costs at an estimated US$ 112,524,914.47. Considering the group of individuals with insufficient physical activity in their leisure time, the percentage cost attributed to physical inactivity reached 17.4% of the estimated costs with NCD. At a national level, NCD were responsible for approximately 740 thousand hospitalizations, costing US$ 482 million, from which 17.4%, US$ 83 million were attributed to physical inactivity. CONCLUSION: This study provides evidence to conclude that physical inactivity exerts an economic impact on the SUS due to NCD hospitalization. Physical inactivity is a modifiable lifestyle and compelling evidence, including that of this article, supports the promotion of a more active community as one of the major targets of public health care policies.

Capital estrangeiro e mudança estrutural no mercado privado de serviços de saúde brasileiro / Foreign capital and structural change in the Brazilian private health services market / Capital extranjero y cambio estructural en el mercado privado de servicios de salud brasileño

Resumo: Este artigo analisa o processo de transformação estrutural no mercado privado de serviços de saúde brasileiro a partir dos anos 2000, com ênfase na crescente participação de fundos financeiros e do capital estrangeiro no processo de expansão e consolidação do setor. A análise do movimento de ingresso do capital estrangeiro nos serviços e planos de saúde no Brasil foi desenvolvida a partir da construção de uma base dados com um total de 297 operações patrimoniais envolvendo empresas com atividades em serviços de saúde, inclusive operadoras de planos e seguros de saúde e administradoras de benefícios em saúde. A análise dessas operações evidencia que o afluxo de capital estrangeiro foi fundamental para viabilizar a centralização de capital em determinadas empresas e catalisar o processo de concentração e transformação estrutural do setor de serviços de saúde ao longo das últimas duas décadas. Conclui-se que o acirramento da disputa intercapitalista no mercado de serviços de saúde levou à emergência de grandes corporações no mercado e a novos modelos de negócio, com destaque especial para o surgimento de redes verticalizadas de atendimento (operação de planos, serviços hospitalares, ambulatoriais, de diagnóstico e tratamento e de atenção básica).

Abstract: This article analyzes the process of structural transformation within the Brazilian private health services market since the 2000s, with emphasis on the growing participation of financial funds and foreign capital in the process of expansion and consolidation of the sector. The analysis of the movement of foreign capital into health services and plans in Brazil was developed from the construction of a database with a total of 297 equity operations involving companies with activities in health services, including companies operating health plans and insurance and companies administering health benefits. The analysis of these operations shows that the influx of foreign capital was fundamental to enable the centralization of capital in certain companies and catalyze the process of concentration and structural transformation of the health services sector over the last two decades. We concluded that the intensification of the intercapitalist dispute within the health services market led to the emergence of large corporations and new business models, with special emphasis on the emergence of verticalized care networks (operation of plans, hospital services, outpatient services, diagnosis and treatment, and primary care).

Resumen: Este artículo analiza el proceso de transformación estructural en el mercado privado de servicios de salud brasileño, a partir de los años 2000, con énfasis en la creciente participación de fondos financieros y del capital extranjero en el proceso de expansión y consolidación del sector. El análisis del movimiento de ingreso del capital extranjero en los servicios y planes de salud en Brasil fue desarrollado a partir de la construcción de una base datos con un total de 297 operaciones de capital de empresas con actividades en servicios de salud; inclusive las empresas operadoras de planes y seguros de salud y las empresas administradoras de beneficios en salud. El análisis de esas operaciones muestra que la entrada de capital extranjero fue fundamental para viabilizar la centralización de capital en determinadas empresas y catalizar el proceso de concentración y transformación estructural del sector de servicios de salud a lo largo de las últimas dos décadas. La conclusión que el recrudecimiento de la disputa intercapitalista dentro del mercado de servicios de salud llevó a la emergencia de grandes corporaciones en el mercado y nuevos modelos de negocio, con destaque especial para surgimiento de redes verticalizadas de atención (operación de planes, servicios hospitalarios, ambulatorios, de diagnóstico y tratamiento y de atención básica).

The burden of physical inactivity for the public health care system in Brazil

ABSTRACT OBJECTIVE To update the estimated cost of physical inactivity for the Brazilian Unified Health System (SUS). METHODS The hospitalization costs were accessed via a database of the Ministry of Health - Informatics Department of the Brazilian SUS. Physical inactivity for the year 2017 was accessed via the Sistema de Vigilância de Fatores de Risco e Proteção para Doenças Crônicas por Inquérito Telefônico (Vigitel - Surveillance System for Risk and Protective Factors for Chronic Diseases by Telephone Survey). Seven chronic non-communicable diseases (NCD) were selected via the international classification of disease (ICD-10). The population fraction attributable to physical inactivity was calculated based on relative risk reported in previous studies and the prevalence of physical inactivity. RESULTS In 2017, the seven NCD considered in the analysis were responsible for 154,017 hospital admissions in adults older than 40 years old, residing in the state capitals and the Federal District, which corresponded to 6.5% of hospitalizations and 10.6% of SUS costs at an estimated US$ 112,524,914.47. Considering the group of individuals with insufficient physical activity in their leisure time, the percentage cost attributed to physical inactivity reached 17.4% of the estimated costs with NCD. At a national level, NCD were responsible for approximately 740 thousand hospitalizations, costing US$ 482 million, from which 17.4%, US$ 83 million were attributed to physical inactivity. CONCLUSION This study provides evidence to conclude that physical inactivity exerts an economic impact on the SUS due to NCD hospitalization. Physical inactivity is a modifiable lifestyle and compelling evidence, including that of this article, supports the promotion of a more active community as one of the major targets of public health care policies.

Desenvolvimento de novos medicamentos para doenças negligenciadas: uma análise bibliométrica / New drug development for neglected diseases: a bibliometric analysis / Desarrollo de nuevos fármacos para enfermedades desatendidas: un análisis bibliométrico

Doenças negligenciadas impõem um fardo humano, social e econômico devastador a mais de um bilhão de pessoas em todo o mundo. Embora existam ferramentas para controlar e até mesmo eliminar muitas dessas doenças, novos produtos terapêuticos precisam urgentemente ser desenvolvidos. Este artigo se baseia em um estudo que buscou quantificar e caracterizar a produção científica global sobre desenvolvimento de novos medicamentos para doenças negligenciadas, por meio de uma análise bibliométrica. De modo a investigar a pesquisa relacionada ao desenvolvimento de novos medicamentos para as doenças negligenciadas em âmbito global na última década, foi utilizada a base de dados Scopus. Observou-se aumento da produção de conhecimento sobre o tema, com relevante participação de autores, instituições e financiamento brasileiros, sobretudo de instituições públicas. Contudo, os esforços realizados têm sido insuficientes, sendo necessária a implementação de estratégias futuras de pesquisa e de financiamento que propiciem maior produção científica e uma tradução da pesquisa básica para a prática clínica.

Neglected diseases impose a devastating human, social, and economic burden on more than one billion people worldwide. While tools exist to control and even eliminate many of these diseases, new therapeutic products urgently need to be developed. This article is based on a study that sought to quantify and characterize the global scientific production on new drug development for neglected diseases through a bibliometric analysis. The Scopus database was used to investigate the research related to the development of new drugs for neglected diseases globally in the last decade. An increase in the production of knowledge about the theme and the relevant participation of Brazilian authors, institutions and funding, especially from public institutions were observed. However, their efforts have been insufficient, and the implementation of future research and funding strategies that provide greater scientific production and a translation of basic research into clinical practice is necessary.

Las enfermedades desatendidas imponen una carga humana, social y económica devastadora a más de mil millones de personas en todo el mundo. A pesar de haber herramientas para controlar y incluso eliminar muchas de estas enfermedades, es necesario desarrollar con urgencia nuevos productos terapéuticos. Este artículo se basa en un estudio lo cual ha buscado cuantificar y caracterizar la producción científica global sobre el desarrollo de nuevos fármacos para enfermedades desatendidas, a través de un análisis bibliométrico. Para inspeccionar investigaciones relacionadas con el desarrollo de nuevos medicamentos para enfermedades desatendidas en ámbito mundial durante la última década se utilizó la base de datos Scopus. Hubo un aumento de la producción de conocimiento sobre el tema, con una participación relevante de autores, instituciones y financiamiento brasileños, especialmente de instituciones públicas. Sin embargo, los esfuerzos realizados siguen siendo insuficientes, requiriendo la implementación de futuras estrategias de investigación y financiamiento que propicien una mayor producción científica y una traducción de la investigación básica a la práctica clínica.

Diverse Cell Death Mechanisms Are Simultaneously Activated in Macrophages Infected by Virulent Mycobacterium tuberculosis.

Macrophages are necessary to eliminate pathogens. However, some pathogens have developed mechanisms to avoid the immune response. One of them is modulating the cell death mechanism to favor pathogen survival. In this study, we evaluated if virulent Mycobacterium tuberculosis (M. tb) can simultaneously activate more than one cell death mechanism. We infected human monocyte-derived macrophages (MDM) in vitro with avirulent (H37Ra) and virulent (H37Rv) strains, and then we measured molecules involved in apoptosis, necroptosis, and pyroptosis. Our data showed that H37Rv infection increased the BCL-2 transcript and protein, decreased the BAX transcript, and increased phosphorylated BCL-2 at the protein level. Moreover, H37Rv infection increased the expression of the molecules involved in the necroptotic pathway, such as ASK1, p-38, RIPK1, RIPK3, and caspase-8, while H37Ra increased caspase-8 and decreased RIPK3 at the transcriptional level. In addition, NLRP3 and CASP1 expression was increased at low MOI in both strains, while IL-1ß was independent of virulence but dependent on infection MOI, suggesting the activation of pyroptosis. These findings suggest that virulent M. tb inhibits the apoptosis mediated by BCL-2 family molecules but, at the same time, increases the expression of molecules involved in apoptosis, necroptosis, and pyroptosis at the transcriptional and protein levels, probably as a mechanism to avoid the immune response and guarantee its survival.

Effects of exposure to environmental pollutants on mitochondrial DNA copy number: a meta-analysis.

Exposure to environmental pollutants has been associated with alteration on relative levels of mitochondrial DNA copy number (mtDNAcn). However, the results obtained from epidemiological studies are inconsistent. This meta-analysis aimed to evaluate whether environmental pollutant exposure can modify the relative levels of mtDNAcn in humans. We performed a literature search using PubMed, Scopus, and Web of Science databases. We selected and reviewed original articles performed in humans that analyzed the relationship between environmental pollutant exposure and the relative levels of mtDNAcn; the selection of the included studies was based on inclusion and exclusion criteria. Only twenty-two studies fulfilled our inclusion criteria. A total of 6011 study participants were included in this systematic review and meta-analysis. We grouped the included studies into four main categories according to the type of environmental pollutant: (1) heavy metals, (2) polycyclic aromatic hydrocarbons (PAHs), (3) particulate matter (PM), and (4) cigarette smoking. Inconclusive results were observed in all categories; the pooled analysis shows a marginal increase of relative levels of mtDNAcn in response to environmental pollutant exposure. The trial sequential analysis and rate confidence in body evidence showed the need to perform new studies. Therefore, a large-scale cohort and mechanistic studies in this area are required to probe the possible use of relative levels of mtDNAcn as biomarkers linked to environmental pollution exposure.

Genetic variants in SLC22A1 are related to serum lipid levels in Mexican women.

Dyslipidemia is the main risk factor for coronary artery disease and is characterized by alterations in concentrations of lipids, including low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triacylglycerols. The participation of several genes in the development of dyslipidemia has been evidenced. Genetic variants in SLC22A1 have been associated with elevated cholesterol and LDL-c levels. The aim of this study was to evaluate the association between single-nucleotide polymorphisms (SNPs) in the SLC22A1 gene with atherogenic risk lipid levels in Mexican women. Anthropometric and biochemical measurements were performed, and four SNPs in SLC22A1 were genotyped by real-time polymerase chain reaction. The Hardy-Weinberg equilibrium was verified, and haplotype frequencies were calculated. We found significant differences between the allele frequencies of the SNPs analyzed with those reported in Mexico and in the world, which could be due to differences in the historical admixture of the women studied. Generalized linear models were evaluated to determine the association between genotypes and haplotypes with lipids levels. We identified a significant increase in total cholesterol and LDL-c levels in women who were carriers of the GA and AG genotypes of the polymorphisms rs628031 and rs594709, respectively, significant effect that is also shown in a dominant inheritance model. Interestingly, we identified an important relationship of the AGC-GAT haplotype with the elevation in LDL-c levels and AGA-GAT haplotype with the elevation in HDL-c levels. On the other hand, we found a strong linkage disequilibrium between the polymorphisms studied. Our results show that variants in the SLC22A1 gene influence serum levels of atherogenic risk lipids, suggesting that these variants probably affect the function of organic cation transporter-1 and therefore, on the regulation of lipid metabolism.

Role of Long Non-Coding RNAs and the Molecular Mechanisms Involved in Insulin Resistance.

Long non-coding RNAs (lncRNAs) are single-stranded RNA biomolecules with a length of >200 nt, and they are currently considered to be master regulators of many pathological processes. Recent publications have shown that lncRNAs play important roles in the pathogenesis and progression of insulin resistance (IR) and glucose homeostasis by regulating inflammatory and lipogenic processes. lncRNAs regulate gene expression by binding to other non-coding RNAs, mRNAs, proteins, and DNA. In recent years, several mechanisms have been reported to explain the key roles of lncRNAs in the development of IR, including metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), imprinted maternal-ly expressed transcript (H19), maternally expressed gene 3 (MEG3), myocardial infarction-associated transcript (MIAT), and steroid receptor RNA activator (SRA), HOX transcript antisense RNA (HOTAIR), and downregulated Expression-Related Hexose/Glucose Transport Enhancer (DREH). LncRNAs participate in the regulation of lipid and carbohydrate metabolism, the inflammatory process, and oxidative stress through different pathways, such as cyclic adenosine monophosphate/protein kinase A (cAMP/PKA), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), polypyrimidine tract-binding protein 1/element-binding transcription factor 1c (PTBP1/SREBP-1c), AKT/nitric oxide synthase (eNOS), AKT/forkhead box O1 (FoxO1), and tumor necrosis factor-alpha (TNF-α)/c-Jun-N-terminal kinases (JNK). On the other hand, the mechanisms linked to the molecular, cellular, and biochemical actions of lncRNAs vary according to the tissue, biological species, and the severity of IR. Therefore, it is essential to elucidate the role of lncRNAs in the insulin signaling pathway and glucose and lipid metabolism. This review analyzes the function and molecular mechanisms of lncRNAs involved in the development of IR.

Characterization of Huh7 cells after the induction of insulin resistance and post-treatment with metformin.

Liver-specific insulin resistance is associated with the development of the main challenges in metabolism, resulting in dyslipidemia, hyperinsulinemia and hyperglycemia. In vitro models developed for researching hepatic insulin resistance are limited and employed cell lines without similar characteristics to primary human hepatocytes. The Huh7 cell line has been established as a model with similar characteristics to primary human hepatocytes. In addition, it has been identified in the Huh7 cell line that infection with the hepatitis C virus induces insulin resistance. Therefore, we analyzed the induction of insulin resistance (IR) in the Huh7 cell line using an overdosage of insulin and treatment with metformin for its reversal, with the purpose of establishing an insulin resistance model useful for metabolic and pharmacological studies. Insulin-resistant Huh7 (Huh7-IR) showed a reduction in Glut2, glycogen levels, and glucose uptake stimulated by insulin or tyrosine phosphorylation from the ß-fraction of insulin receptor post-insulin stimulation, with an increase of glucose production and lipid intracellular content. These biomarkers are frequently observed in insulin-resistant hepatic cells. Moreover, treatment of Huh7-IR with 0.5, 1 or 2 mM of metformin by 24 h decreased the biomarkers associated with an insulin-resistant state. These results suggest that Huh7-IR could be used as an in vitro system to research hepatic insulin resistance in metabolic and pharmacological studies.

Altered levels of MALAT1 and H19 derived from serum or serum exosomes associated with type-2 diabetes.

Environmental, genetic and epigenetic risk factors have been closely related to the development of type-2 diabetes (T2D). It has been reported that the expression in H19 and MALAT1 are related to metabolic diseases. To analyze the relationship between the expression of H19 and MALAT1 lncRNAs with diabetic patients. A study was conducted in subjects with T2D and nondiabetic controls, residents of Mexico City. Anthropometric measurements were made, and serum concentrations of glucose, glycosylated hemoglobin, total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol were analyzed. Total RNA was extracted from serum and serum exosomes. The H19 and MALAT1 expression levels were quantified by RT-qPCR. A significant reduction in the expression of MALAT1 from serum or serum exosomes were found in patients with T2D, metabolic syndrome and low levels of HDL-c. Significant increase in H19 levels was found in diabetic subjects with poor glycemic control. Additionally, the principal component analyzes showed that serum MALAT1 expression was associated with total cholesterol and HDL-c levels, and the exosomes H19 expression was associated with waist circumference. The results obtained suggest that MALAT1 expression levels could be an epigenetic biomarker of diabetes risk or of its comorbidities.

Pesquisa translacional e sistemas de inovação na saúde: implicações para o segmento biofarmacêutico / Translational research and innovation systems in health: implications on the biopharmaceutical segment

RESUMO A análise desenvolvida sobre a dinâmica de inovação em saúde no contexto do Sistema Nacional de Inovação em Saúde revela as potencialidades da articulação das instituições de Ciência, Tecnologia e Inovação (CT&I) com o Complexo Econômico-Industrial da Saúde (Ceis), a partir da interação entre as universidades e os institutos de pesquisa com o setor produtivo. A translação em saúde depende fortemente da dinâmica e da situação relativa do Ceis no Brasil ante o contexto internacional. O estudo faz uma análise das interações entre empresas farmacêuticas e grupos de pesquisa em saúde no País dos microdados da base de dados do Diretório de Grupos de Pesquisa do Conselho Nacional de Desenvolvimento Científico e Tecnológico (DGP-CNPq), utilizando uma abordagem metodológica apropriada aos estudos de redes de colaboração. Ademais, mostra o potencial de diversas instituições de CT&I brasileiras, revelando a presença de uma rede de interações com o setor produtivo na área biofarmacêutica, com potencial para o desenvolvimento do sistema de inovação em saúde. Essa interação poderá adquirir, de fato, uma perspectiva translacional para a utilização do conhecimento tecnológico pela sociedade brasileira na medida em que seja articulada com o desenvolvimento do Ceis no Brasil, como elo crítico no qual a pesquisa se transforma em produção de bens e serviços para atender às demandas do Sistema Único de Saúde.

ABSTRACT The analysis of the dynamics of innovation in health in the context of the National System of Innovation in Health reveals the potential of the articulation of Science, Technology and Innovation (ST&I) institutions with the Health Economic-Industrial Complex (HEIC), in view of the interactions between universities and research institutes with the productive sector. Translational health research depends heavily on the dynamics and relative situation of the HEIC in Brazil regarding the international context. The study analyzes the interactions between pharmaceutical companies and health research groups in the country, using microdata from the CNPq Research Group Directory database (DGP-CNPq), in a methodological approach appropriate to collaborative network studies. Furthermore, it shows the presence of a network of interactions with the productive sector in the biopharmaceutical area and highlights the potential of several Brazilian ST&I institutions to foster the development of the health innovation system. This interaction may acquire a translational perspective for the use of technological knowledge by the Brazilian society insofar as it is articulated with the development of the HEIC in Brazil as a critical link to meet the demands of the Unified Health System.

[Interchangeability of biological products in the Brazilian Unified National Health System (SUS): the main regulatory challenges]. / Intercambialidade de produtos biológicos no Sistema Único de Saúde (SUS): principais desafios regulatórios.

Biological products have sparked a worldwide therapeutic revolution. However, the high cost of these products threatens health systems' sustainability. The development of copies is considered an economic alternative, but due to the products' complexity, many concepts used in generic drugs do not apply. Interchangeability between biologicals poses a regulatory challenge. This essay discusses the main regulatory challenges for establishing criteria for interchangeability between new biologicals and their copies in the scope of the Brazilian Unified National Health System (SUS), considering the guidelines adopted by the world's main drug regulatory agencies concerning interchangeability and the prevailing Brazilian regulatory framework on this issue. Concerns related to the interchangeability of biologicals include automatic substitution, nomenclature, pharmacovigilance, immunogenicity, and extrapolation of therapeutic indications and clinical data from new biologicals to their copies. While the clinical success and economic benefits of switching from new biologicals to their biosimilars have already been observed, the heterogeneity between countries in the regulatory barriers to the approval of copies of biologicals should be taken into consideration during the regulation of interchangeability of biologicals in Brazil.

Produtos biológicos revolucionaram a terapêutica mundial. O alto custo desses medicamentos, no entanto, ameaça a sustentabilidade dos sistemas de saúde. O desenvolvimento de cópias é tido como uma alternativa econômica, mas devido à complexidade desses produtos, muitos conceitos utilizados para os medicamentos genéricos não se aplicam. A intercambialidade entre produtos biológicos representa um desafio regulatório a ser superado. Este ensaio discute os principais desafios regulatórios relacionados ao estabelecimento de critérios para intercambialidade entre produtos biológicos novos e suas cópias no âmbito do Sistema Único de Saúde (SUS), considerando as diretrizes adotadas pelas principais agências reguladoras de medicamentos do mundo sobre a intercambialidade e o arcabouço regulatório vigente no Brasil para esta questão. Preocupações relacionadas à intercambialidade de produtos biológicos incluem substituição automática, nomenclatura, farmacovigilância, imunogenicidade e extrapolação das indicações terapêuticas e dos dados clínicos de produtos biológicos novos para suas cópias. Embora o sucesso clínico e os benefícios econômicos da alternância entre alguns produtos biológicos novos e seus biossimilares já tenham sido observados, a heterogeneidade das barreiras regulatórias para aprovação das cópias de produtos biológicos entre diferentes países deve ser considerada para a regulamentação da intercambialidade de produtos biológicos no Brasil.

Los productos biológicos revolucionaron la terapéutica mundial. El alto coste de estos medicamentos, no obstante, amenaza la sostenibilidad de los sistemas de salud. El desarrollo de copias se considera como una alternativa económica, pero debido a la complejidad de estos productos, muchos conceptos utilizados para los medicamentos genéricos no se aplican a los mismos. La intercambiabilidad entre productos biológicos representa un desafío regulatorio que se debe superar. Este trabajo discute los principales desafíos regulatorios, relacionados con el establecimiento de criterios para la intercambiabilidad entre productos biológicos nuevos y sus copias en el ámbito del Sistema Único de Salud (SUS), considerando las directrices adoptadas por las principales agencias regulatorias de medicamentos del mundo sobre la intercambiabilidad y el armazón regulatorio vigente en Brasil para esta cuestión. Las preocupaciones relacionadas con la intercambiabilidad de productos biológicos incluyen la sustitución automática, nomenclatura, farmacovigilancia, inmunogenicidad y extrapolación de las indicaciones terapéuticas, así como de los datos clínicos de productos biológicos nuevos para sus copias. A pesar de que el éxito clínico y los beneficios económicos de la alternancia entre algunos productos biológicos nuevos y sus biosimilares, ya se han observados, la heterogeneidad de las barreras regulatorias para la aprobación de las copias de productos biológicos entre los diferentes países debe ser considerada para la regulación de la intercambiabilidad de productos biológicos en Brasil.

Intercambialidade de produtos biológicos no Sistema Único de Saúde (SUS): principais desafios regulatórios / Interchangeability of biological products in the Brazilian Unified National Health System (SUS): the main regulatory challenges / Intercambiabilidad de productos biológicos en el Sistema Único de Salud (SUS): principales desafíos regulatorios

Resumo: Produtos biológicos revolucionaram a terapêutica mundial. O alto custo desses medicamentos, no entanto, ameaça a sustentabilidade dos sistemas de saúde. O desenvolvimento de cópias é tido como uma alternativa econômica, mas devido à complexidade desses produtos, muitos conceitos utilizados para os medicamentos genéricos não se aplicam. A intercambialidade entre produtos biológicos representa um desafio regulatório a ser superado. Este ensaio discute os principais desafios regulatórios relacionados ao estabelecimento de critérios para intercambialidade entre produtos biológicos novos e suas cópias no âmbito do Sistema Único de Saúde (SUS), considerando as diretrizes adotadas pelas principais agências reguladoras de medicamentos do mundo sobre a intercambialidade e o arcabouço regulatório vigente no Brasil para esta questão. Preocupações relacionadas à intercambialidade de produtos biológicos incluem substituição automática, nomenclatura, farmacovigilância, imunogenicidade e extrapolação das indicações terapêuticas e dos dados clínicos de produtos biológicos novos para suas cópias. Embora o sucesso clínico e os benefícios econômicos da alternância entre alguns produtos biológicos novos e seus biossimilares já tenham sido observados, a heterogeneidade das barreiras regulatórias para aprovação das cópias de produtos biológicos entre diferentes países deve ser considerada para a regulamentação da intercambialidade de produtos biológicos no Brasil.

Abstract: Biological products have sparked a worldwide therapeutic revolution. However, the high cost of these products threatens health systems' sustainability. The development of copies is considered an economic alternative, but due to the products' complexity, many concepts used in generic drugs do not apply. Interchangeability between biologicals poses a regulatory challenge. This essay discusses the main regulatory challenges for establishing criteria for interchangeability between new biologicals and their copies in the scope of the Brazilian Unified National Health System (SUS), considering the guidelines adopted by the world's main drug regulatory agencies concerning interchangeability and the prevailing Brazilian regulatory framework on this issue. Concerns related to the interchangeability of biologicals include automatic substitution, nomenclature, pharmacovigilance, immunogenicity, and extrapolation of therapeutic indications and clinical data from new biologicals to their copies. While the clinical success and economic benefits of switching from new biologicals to their biosimilars have already been observed, the heterogeneity between countries in the regulatory barriers to the approval of copies of biologicals should be taken into consideration during the regulation of interchangeability of biologicals in Brazil.

Resumen: Los productos biológicos revolucionaron la terapéutica mundial. El alto coste de estos medicamentos, no obstante, amenaza la sostenibilidad de los sistemas de salud. El desarrollo de copias se considera como una alternativa económica, pero debido a la complejidad de estos productos, muchos conceptos utilizados para los medicamentos genéricos no se aplican a los mismos. La intercambiabilidad entre productos biológicos representa un desafío regulatorio que se debe superar. Este trabajo discute los principales desafíos regulatorios, relacionados con el establecimiento de criterios para la intercambiabilidad entre productos biológicos nuevos y sus copias en el ámbito del Sistema Único de Salud (SUS), considerando las directrices adoptadas por las principales agencias regulatorias de medicamentos del mundo sobre la intercambiabilidad y el armazón regulatorio vigente en Brasil para esta cuestión. Las preocupaciones relacionadas con la intercambiabilidad de productos biológicos incluyen la sustitución automática, nomenclatura, farmacovigilancia, inmunogenicidad y extrapolación de las indicaciones terapéuticas, así como de los datos clínicos de productos biológicos nuevos para sus copias. A pesar de que el éxito clínico y los beneficios económicos de la alternancia entre algunos productos biológicos nuevos y sus biosimilares, ya se han observados, la heterogeneidad de las barreras regulatorias para la aprobación de las copias de productos biológicos entre los diferentes países debe ser considerada para la regulación de la intercambiabilidad de productos biológicos en Brasil.

Effects of exposure to malathion on blood glucose concentration: a meta-analysis.

Exposure to malathion (an organophosphate pesticide widely used around the world) has been associated with alterations in blood glucose concentration in animal models. However, the results are inconsistent. The aim of this meta-analysis was to evaluate whether malathion exposure can disturb the concentrations of blood glucose in exposed rats. We performed a literature search of online databases including PubMed, EBSCO, and Google Scholar and reviewed original articles that analyzed the relation between malathion exposure and glucose levels in animal models. The selection of articles was based on inclusion and exclusion criteria. The database search identified thirty-five possible articles, but only eight fulfilled our inclusion criteria, and these studies were included in the meta-analysis. The effect of malathion on blood glucose concentration showed a non-monotonic dose-response curve. In addition, pooled analysis showed that blood glucose concentrations were 3.3-fold higher in exposed rats than in the control group (95% CI, 2-5; Z = 3.9; p < 0.0001) in a random-effect model. This result suggested that alteration of glucose homeostasis is a possible mechanism of toxicity associated with exposure to malathion.

Genotypes of Common Polymorphisms in the PON1 Gene Associated with Paraoxonase Activity as Cardiovascular Risk Factor.

BACKGROUND: Paraoxonase-1(PON1) exhibits hydrolytic activity and prevents the oxidation of high and low-density lipoproteins. Polymorphisms in the PON1 gene have been associated with variations in paraoxonase activity and with the risk of coronary artery disease (CAD). AIM OF THE STUDY: This study analyzed the association between the frequencies of genotypes of the L55 M and Q192 R SNPs in the PON1 gene with the PON1 activity and with CAD risk factors. METHODS: Women, determined by body composition, biochemical markers, and arylesterase (AREase) and paraoxonase (CMPase) activities were studied. Genotyping of L55 M and Q192 R polymorphisms was performed by TaqMan. Seventeen studies were used in the meta-analysis. RESULTS: A significant decrease in PON1 activity in carrying the LM/MM and QQ genotypes is identified, correlations are found between the AREase activity with glucose, cholesterol and atherogenic risk index. Carriers of the LM or MM genotype were related with obesity (OR = 1.6; p = 0.039), and the MQ haplotype has an effect on the decrease in AREase (ß = â€’22.4; p <0.001) and CMPase (ß = â€’3.8; p <0.001). In addition, a lower proportion of Native American admixture was observed in women with LM or MM genotype, while it was higher for the European proportion compared with the LL genotype (p <0.001). CONCLUSIONS: The LL-L55 M and QR-Q192 R genotypes are identified as the most frequently in the different states or cities of the country, and genotypic proportions are different, probably depending on the genetic structure of the populations. The association that is reported more frequently in the different studies is with enzymatic activity.