RESUMO
Since the removal of thiazolidinediones (TZDs) from the market, researchers have been exploring alternative anti-diabetic drugs that target PPARγ without causing adverse effects while promoting insulin sensitization by blocking serine 273 phosphorylation (Ser273 or S273). Nonetheless, the underlying mechanisms of the relationship between insulin resistance and S273 phosphorylation are still largely unknown, except for the involvement of growth differentiation factor (GDF3) regulation in the process. To further investigate potential pathways, we generated a whole organism knockin mouse line with a single S273A mutation (KI) that blocks the occurrence of its phosphorylation. Our observations of KI mice on different diets and feeding schedules revealed that they were hyperglycemic, hypoinsulinemic, presented more body fat at weaning, and presented an altered plasma and hepatic lipid profile, distinctive liver morphology and gene expression. These results suggest that total blockage of S273 phosphorylation may have unforeseen effects that, in addition to promoting insulin sensitivity, could lead to metabolic disturbances, particularly in the liver. Therefore, our findings demonstrate both the beneficial and detrimental effects of PPAR S273 phosphorylation and suggest selective modulation of this post translational modification is a viable strategy to treat type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Camundongos , Animais , PPAR gama/genética , PPAR gama/metabolismo , Insulina/metabolismo , Fosforilação , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/metabolismo , Fígado/metabolismoRESUMO
Salmon aquaculture is constantly threatened by pathogens that impact fish health, welfare, and productivity, including the sea louse Caligus rogercresseyi. This marine ectoparasite is mainly controlled through delousing drug treatments that have lost efficacy. Therein, strategies such as salmon breeding selection represent a sustainable alternative to produce fish with resistance to sea lice. This study explored the whole-transcriptome changes in Atlantic salmon families with contrasting resistance phenotypes against lice infestation. In total, 121 Atlantic salmon families were challenged with 35 copepodites per fish and ranked after 14 infestation days. Skin and head kidney tissue from the top two lowest (R) and highest (S) infested families were sequenced by the Illumina platform. Genome-scale transcriptome analysis showed different expression profiles between the phenotypes. Significant differences in chromosome modulation between the R and S families were observed in skin tissue. Notably, the upregulation of genes associated with tissue repairs, such as collagen and myosin, was found in R families. Furthermore, skin tissue of resistant families showed the highest number of genes associated with molecular functions such as ion binding, transferase, and cytokine activity, compared with the susceptible. Interestingly, lncRNAs differentially modulated in the R/S families are located near genes associated with immune response, which are upregulated in the R family. Finally, SNPs variations were identified in both salmon families, where the resistant ones showed the highest number of SNPs variations. Remarkably, among the genes with SPNs, genes associated with the tissue repair process were identified. This study reported Atlantic salmon chromosome regions exclusively expressed in R or S Atlantic salmon families' phenotypes. Furthermore, due to the presence of SNPs and high expression of tissue repair genes in the resistant families, it is possible to suggest mucosal immune activation associated with the Atlantic salmon resistance to sea louse infestation.
Assuntos
Infestações por Piolhos , Salmo salar , Animais , Transcriptoma/genética , Salmo salar/genética , Pele/parasitologia , FenótipoRESUMO
Throughout the 20th and 21st centuries, the incidence of non-communicable diseases (NCDs), also known as chronic diseases, has been increasing worldwide. Changes in dietary and physical activity patterns, along with genetic conditions, are the main factors that modulate the metabolism of individuals, leading to the development of NCDs. Obesity, diabetes, metabolic associated fatty liver disease (MAFLD), and cardiovascular diseases (CVDs) are classified in this group of chronic diseases. Therefore, understanding the underlying molecular mechanisms of these diseases leads us to develop more accurate and effective treatments to reduce or mitigate their prevalence in the population. Given the global relevance of NCDs and ongoing research progress, this article reviews the current understanding about NCDs and their related risk factors, with a focus on obesity, diabetes, MAFLD, and CVDs, summarizing the knowledge about their pathophysiology and highlighting the currently available and emerging therapeutic strategies, especially pharmacological interventions. All of these diseases play an important role in the contamination by the SARS-CoV-2 virus, as well as in the progression and severity of the symptoms of the coronavirus disease 2019 (COVID-19). Therefore, we briefly explore the relationship between NCDs and COVID-19.
Assuntos
COVID-19/terapia , Doenças Metabólicas/terapia , Animais , COVID-19/epidemiologia , COVID-19/metabolismo , COVID-19/fisiopatologia , Doença Crônica , Humanos , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/fisiopatologia , Doenças não Transmissíveis/epidemiologia , Doenças não Transmissíveis/terapia , Prevalência , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de DoençaRESUMO
Bisphenol-A (BPA) is an endocrine disruptor associated with higher risk of insulin resistance, type 2 diabetes, and cardiovascular diseases especially in susceptible populations. Because malnutrition is a nutritional disorder associated with high cardiovascular risk, we sought to compare the effects of short-term BPA exposure on cardiovascular parameters of healthy and protein-malnourished mice. Postweaned male mice were fed a normo- (control) or low-protein (LP) diet for 8 weeks and then exposed or not to BPA (50 µg kg-1 day-1) for the last 9 days. Systolic blood pressure was higher in BPA or LP groups compared with the control group. However, diastolic blood pressure was enhanced by BPA only in malnourished mice. Left ventricle (LV) end diastolic pressure (EDP), collagen deposition, and CTGF mRNA expression were higher in the control or malnourished mice exposed to BPA than in the respective nonexposed groups. Nevertheless, mice fed LP diet exposed to BPA exhibited higher angiotensinogen and cardiac TGF-ß1 mRNA expression than mice treated with LP or BPA alone. Wall:lumen ratio and cross-sectional area of intramyocardial arteries were higher either in the LP or BPA group compared with the control mice. Taken together, our data suggest that short-term BPA exposure results in LV diastolic dysfunction and fibrosis, and intramyocardial arteries inward remodeling, besides potentiate protein malnutrition-induced hypertension and cardiovascular risk.
RESUMO
BACKGROUND: HMG-CoA reductase inhibitors (statins) are cholesterol-lowering drugs widely used to treat hypercholesterolemia and prevent cardiovascular disease. Statins are generally well tolerated, but adverse reactions may occur, particularly myopathy and new onset of diabetes. The exact mechanism of statin-induced myopathy and diabetes has not been fully elucidated. We have previously shown that treatment of hypercholesterolemic (LDLr-/-) mice with pravastatin for 2 months decreased pancreatic islet insulin secretion and increased oxidative stress and cell death, but no glucose intolerance was observed. The purpose of the current work was to study long-term pravastatin effects on glucose homeostasis, insulin sensitivity, muscle protein turnover and cell viability. METHODS: LDLr-/- mice were treated with pravastatin for 3, 6 and 10 months. Glucose tolerance, insulin resistance and glucose-stimulated insulin secretion were evaluated. The rates of protein synthesis and degradation were determined in gastrocnemius muscle after 10 months of treatment. Insulin signalling, oxidative stress and cell death were analysed in vitro using C2C12 myotubes. RESULTS: After 6 and 10 months of treatment, these mice became glucose intolerant, and after 10 months, they exhibited marked insulin resistance. Reduced islet glucose-stimulated insulin secretion was observed after the 3rd month of treatment. Mice treated for 10 months showed significantly decreased body weight and increased muscle protein degradation. In addition, muscle chymotrypsin-like proteasomal activity and lysosomal cathepsin were markedly elevated. C2C12 myotubes exposed to increasing concentrations of pravastatin presented dose-dependent impairment of insulin-induced Akt phosphorylation, increased apoptotic markers (Bax protein and cleaved caspase-3) and augmented superoxide anion production. CONCLUSIONS: In addition to reduced insulin secretion, long-term pravastatin treatment induces insulin resistance and muscle wasting. These results suggest that the diabetogenic effect of statins is linked to the appearance of myotoxicity induced by oxidative stress, impaired insulin signalling, proteolysis and apoptosis.
Assuntos
Diabetes Mellitus Experimental/complicações , Hipercolesterolemia/complicações , Resistência à Insulina , Miotoxicidade/complicações , Pravastatina/efeitos adversos , Animais , Apoptose , Glicemia/metabolismo , Peso Corporal , Linhagem Celular , Diabetes Mellitus Experimental/sangue , Jejum/sangue , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/complicações , Homeostase , Hipercolesterolemia/sangue , Insulina/sangue , Secreção de Insulina , Camundongos Endogâmicos C57BL , Modelos Biológicos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/metabolismo , Miotoxicidade/sangue , Estresse Oxidativo , Fosforilação , Proteólise , Receptores de LDL/deficiência , Receptores de LDL/metabolismo , Transdução de Sinais , Superóxidos/metabolismoRESUMO
New onset of diabetes is associated with the use of statins. We have recently demonstrated that pravastatin-treated hypercholesterolemic LDL receptor knockout (LDLr-/- ) mice exhibit reductions in insulin secretion and increased islet cell death and oxidative stress. Here, we hypothesized that these diabetogenic effects of pravastatin could be counteracted by treatment with the antioxidant coenzyme Q 10 (CoQ 10 ), an intermediate generated in the cholesterol synthesis pathway. LDLr -/- mice were treated with pravastatin and/or CoQ 10 for 2 months. Pravastatin treatment resulted in a 75% decrease of liver CoQ 10 content. Dietary CoQ 10 supplementation of pravastatin-treated mice reversed fasting hyperglycemia, improved glucose tolerance (20%) and insulin sensitivity (>2-fold), and fully restored islet glucose-stimulated insulin secretion impaired by pravastatin (40%). Pravastatin had no effect on insulin secretion of wild-type mice. In vitro, insulin-secreting INS1E cells cotreated with CoQ 10 were protected from cell death and oxidative stress induced by pravastatin. Simvastatin and atorvastatin were more potent in inducing dose-dependent INS1E cell death (10-15-fold), which were also attenuated by CoQ 10 cotreatment. Together, these results demonstrate that statins impair ß-cell redox balance, function and viability. However, CoQ 10 supplementation can protect the statins detrimental effects on the endocrine pancreas.
Assuntos
Hipercolesterolemia/tratamento farmacológico , Células Secretoras de Insulina/efeitos dos fármacos , Pravastatina/efeitos adversos , Receptores de LDL/metabolismo , Ubiquinona/análogos & derivados , Animais , Linhagem Celular , Sobrevivência Celular , Diabetes Mellitus/induzido quimicamente , Suplementos Nutricionais , Feminino , Teste de Tolerância a Glucose , Peróxido de Hidrogênio , Insulina , Fígado/metabolismo , Camundongos , Camundongos Knockout , Pravastatina/uso terapêutico , Receptores de LDL/genética , Ubiquinona/farmacologiaRESUMO
Low levels of estrogens are associated with obesity-related comorbidities. Mice with lower levels of estrogens are thereby more sensitive to the effects of a high-fat-diet (HFD) for the development of glucose intolerance and insulin resistance. Studies in vivo have demonstrated that taurine (TAU) supplementation prevents glucose and insulin resistance. Thus, we aimed to investigate the potential beneficial effects of TAU supplementation on glucose homeostasis of mice with low levels of estrogens fed with a HFD. 3-month-old female C57BL/6J mice underwent bilateral ovariectomy (OVX). After 1 week of recovery, mice were divided into 4 groups and either received: a standard chow diet (OVXC), chow diet plus drinking water enriched with 3% of TAU (OVXCT), HFD (OVXH), and HFD plus supplementation of TAU (OVXHT) for 14 weeks. Exposure to the HFD increased adiposity and plasma levels of glucose and insulin. Contrary to our prediction, the addition of TAU enhanced the deleterious effects of the HFD. Glucose and insulin tolerance tests (ipGTT and ipITT) indicated that mice maintained on the HFD + TAU had worse glucose intolerance and insulin resistance that was linked to lower insulin signaling in skeletal muscle and liver. Insulin secretion of isolated pancreatic islets of OVXH mice was higher than OVXC, and the addition of TAU associated with a HFD did not modulate insulin secretion, suggesting a failure of pancreatic ß cells of OVXHT mice. These results suggest that despite the beneficial reports of TAU, it should be used cautiously in situations where the levels of estrogens are low.
Assuntos
Suplementos Nutricionais , Glucose/metabolismo , Obesidade/tratamento farmacológico , Taurina/administração & dosagem , Animais , Glicemia/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Estrogênios/metabolismo , Homeostase , Humanos , Insulina/metabolismo , Resistência à Insulina/genética , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Camundongos , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , OvariectomiaRESUMO
El objetivo general por el que se lleva a cabo este estudio; donde específicamente se busca determinar la longitud de trabajo de treinta piezas dentales indicadas para extracción, de pacientes que asisten a las instalaciones de dicha institución; primero, utilizando una radiografía preoperatoria se determinó la longitud del diente midiendo con una regla milimetrada el órgano dental en dicha radiografía, para establecer una medida provisional; y segundo haciendo uso de un Localizador Electrónico Apical, el cual permite obtener la longitud de trabajo de manera electrónica. Posteriormente, se extrajeron estas piezas, en su mayoría por problemas periodontales, y razones ortodónticas; para poder así determinar la posición de la lima dentro del conducto radicular en ambas técnicas, realizando cortes por desgaste siguiendo el eje longitudinal del diente, y así establecer una comparación entre los datos obtenidos en ambas técnicas. Del total de piezas multiradiculares analizadas se obtuvo un 69.23% con medida longitudinal adecuada utilizando Localizador Electrónico Apical, y un 21.74% con Longitud Radiográfica Estimada. Además, en las piezas monoradiculares analizadas el 80% presentó medida de trabajo adecuada utilizando Localizador Electrónico Apical y un 28.57% con Longitud Radiográfica Estimada. Dichos resultados fueron analizados por medio de cuadros de frecuencias. En base a los resultados antes mencionados se concluye que al utilizar correctamente el Localizador Electrónico Apical se pueden obtener medidas más exactas en la toma de la conductometria para garantizar mejores resultados en los tratamientos de conductos radiculares.
The general objective for which this study is carried out; where it is specifically sought to determine the working length of thirty dental pieces indicated for extraction, of patients who attend the facilities of said institution; First, using a preoperative X-ray, the length of the tooth was determined by measuring the dental organ in said X-ray with a millimeter ruler, to establish a provisional measurement; and second by making use of an Apical Electronic Locator, which allows to obtain the working length electronically. Later, these pieces were extracted, mostly due to periodontal problems and orthodontic reasons; in order to thus determine the position of the file within the root canal in both techniques, making wear cuts following the longitudinal axis of the tooth, and thus establish a comparison between the data obtained in both techniques. Of the total multiradicular pieces analyzed, 69.23% were obtained with adequate longitudinal measurement using the Electronic Apical Locator, and 21.74% with Estimated Radiographic Length. In addition, in the single-rooted pieces analyzed, 80% presented adequate work measurement using the Electronic Apical Locator and 28.57% with Estimated Radiographic Length. Said results were analyzed by means of frequency tables. Based on the aforementioned results, it is concluded that by using the Electronic Apical Locator correctly, more exact measurements can be obtained in taking the conductometry to guarantee better results in root canal treatments.