RESUMEN

Methylisothiazolinone (MIT) is a widely used preservative and biocide to prevent product degradation, yet its potential impact on plant growth remains poorly understood. In this study, we investigated MIT's toxic effects on Arabidopsis thaliana root growth. Exposure to MIT significantly inhibited Arabidopsis root growth, associated with reduced root meristem size and root meristem cell numbers. We explored the polar auxin transport pathway and stem cell regulation as key factors in root meristem function. Our findings demonstrated that MIT suppressed the expression of the auxin efflux carrier PIN1 and major root stem cell regulators (PLT1, PLT2, SHR, and SCR). Additionally, MIT hindered root regeneration by downregulating the quiescent center (QC) marker WOX5. Transcriptome analysis revealed MIT-induced alterations in gene expression related to oxidative stress, with physiological experiments confirming elevated reactive oxygen species (ROS) levels and increased cell death in root tips at concentrations exceeding 50 µM. In summary, this study provides critical insights into MIT's toxicity on plant root development and regeneration, primarily linked to modifications in polar auxin transport and downregulation of genes associated with root stem cell regulation.

Asunto(s)

Proteínas de Arabidopsis , Arabidopsis , Ácidos Indolacéticos , Raíces de Plantas , Arabidopsis/efectos de los fármacos , Arabidopsis/metabolismo , Arabidopsis/genética , Ácidos Indolacéticos/metabolismo , Raíces de Plantas/efectos de los fármacos , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Transporte Biológico/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Regeneración/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Meristema/efectos de los fármacos , Tiazoles/toxicidad

RESUMEN

BACKGROUND: Sleep problem among undergraduate students has become one of the most pressing public health problems. This study aimed to explore the latent class of sleep patterns and the factors affecting sleep in Chinese students of medical university. METHODS: 3423 students participated in the cross-sectional study. The survey consisted of the reduced Morningness-Evening Questionnaire, the Pittsburgh Sleep Quality Index, and Health-Promoting Lifestyle Profile-II. Latent profile analysis and multinominal logistic regression analysis were performed. RESULTS: Three potential sleep categories were identified: "sleep disorder group" (1.87 %), "daytime dysfunction group" (24.42 %), and "good sleep group" (73.71 %). Compared with the "good sleep group," the "sleep disorder group" showed monthly living expenses (RMB) ≥ 3000 yuan (OR) = 13.04), interpersonal relationships as poor (OR = 3.71), health status as poor (OR = 45.09), circadian rhythm as eveningness (OR = 6.17), and poor health-promoting lifestyles (OR = 2.090) as its risk factors (all p < 0.05). Meanwhile, sophomore (OR = 1.75), junior (OR = 1.52), interpersonal relationships as poor (OR = 1.88), health status as poor (OR = 4.62), intermediate-chronotype (OR = 2.19), eveningness chronotype (OR = 5.66), and health-promoting lifestyles as poor (OR = 1.55) were identified as risk factors for the "daytime dysfunction group" (all p < 0.05). LIMITATIONS: Causal conclusions can not be drawn and recall bias in data collection. CONCLUSIONS: Significant population heterogeneity was found in the sleep quality. Implementing targeted interventions focusing on circadian rhythm and lifestyle is crucial to improve the sleep quality of students with different conditions.

Asunto(s)

Calidad del Sueño , Trastornos del Sueño-Vigilia , Humanos , Universidades , Estudios Transversales , Análisis de Clases Latentes , Sueño , Ritmo Circadiano , Estudiantes , Trastornos del Sueño-Vigilia/epidemiología , Encuestas y Cuestionarios

RESUMEN

BACKGROUND: Nickel is considered an essential nutrient for certain microbial, plant, and animal species, but its role in human health remains controversial. Some studies have reported the relationship between nickel and type 2 diabetes mellitus (T2DM), but the results are not consistent and the mechanism is not clear, which needs further exploration. AIM: To investigate the possible correlation between nickel and T2DM. METHODS: We conducted a case-control study of 192 patients with T2DM and 189 healthy controls at a hospital in central China. Plasma concentrations of nickel and six other trace elements were measured with inductively coupled plasma mass spectrometry. Logistic regression models, restricted cubic spline models (RCS), and Bayesian kernel machine regression (BKMR) were used to evaluate the relationship between plasma nickel and T2DM and its metabolic risk factors, as well as the presence or absence of interactions between nickel and other elements. RESULTS: The T2DM group exhibited considerably lower plasma nickel levels than the control group (P < 0.001). Whether using a crude or adjusted model, logistic regression analysis finds a negative correlation between nickel levels and the risk of T2DM (P trend < 0.001). According to the RCS, the risk of T2DM reduces with rising nickel levels when the value is below 6.1 µg/L; nickel has a negative linear correlation with fasting plasma glucose (FPG), an inverse U-shaped connection with superoxide dismutase (SOD), and a positive linear correlation with malondialdehyde (MDA) (all P overall < 0.05). The plasma nickel concentration was positively correlated with zinc, vanadium, and chromium (r = 0.23, 0.11, and 0.19, respectively; all P < 0.05) and negatively correlated with copper (r = - 0.11, P < 0.05). In the BKMR model, interactions of nickel with zinc on T2DM and SOD, nickel with chromium on T2DM and homeostasis model assessment of ß cell (HOMA-ß), and nickel with copper on FPG, homeostasis model assessment of insulin (HOMA-IR), and MDA were observed. CONCLUSION: Nickel may have a dual effect on the risk of T2DM, with a protective range of less than 6.1 µg/L. Potential interactions between nickel, copper, zinc, and chromium existed in their associations with T2DM and its metabolic risk factors.

Asunto(s)

Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Humanos , Níquel , Cobre , Estudios de Casos y Controles , Teorema de Bayes , Zinc , Cromo , Superóxido Dismutasa , Glucemia/análisis

RESUMEN

BACKGROUND: Poor sleep quality have become one of the most pressing public health problems for undergraduate students. The aim of this cross-sectional study was to investigate the relationship between circadian rhythms and sleep quality and the meditating role of health-promoting lifestyles in the relationship of Chinese undergraduate students. METHODS: A total of 3423 students participated. The online survey consisted of the reduced Morningness-Evening Questionnaire (rMEQ), the Pittsburgh Sleep Quality Index (PSQI) and Health-Promoting Lifestyle Profile-II (HPLP-II). Logistic regression models were employed. RESULTS: The prevalence of poor sleep quality is 43.03 %. The total mean scores of HPLP - II, PSQI, and rMEQ are 96.94 ± 17.26, 5.20 ± 2.70 and 14.83 ± 2.10, respectively. A significant negative correlation exists between the rMEQ and PSQI scores (r = -0.262, p < 0.001), but a positive correlation exists between the rMEQ and HPLP scores (r = 0.232, p < 0.001). The total and sub-domain scores of HPLP are also negatively correlated with the PSQI scores (r = -[0.166, 0.291], p < 0.001). Mediation analysis demonstrates the mediation of HPLP (indirect effect = -0.036, p < 0.001) on the effect of the rMEQ on PSQI scores that accounts for 13.30 % of the total effect. LIMITATIONS: Cross-sectional design and recall bias in data collection. CONCLUSIONS: The effect of circadian rhythm on sleep quality is partially mediated by the health-promoting lifestyle. In addition to maintaining a normal circadian rhythm, helping undergraduate students develop a healthy lifestyle is also an effective measure to improve sleep quality.

Asunto(s)

Trastornos del Inicio y del Mantenimiento del Sueño , Sueño , Humanos , Estudios Transversales , Calidad del Sueño , Ritmo Circadiano , Estilo de Vida , Estudiantes , Encuestas y Cuestionarios , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , China/epidemiología

RESUMEN

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. In this study, we conducted a comparative analysis of the structural genes of SARS-CoV-2 and other CoVs. We found that the sequence of the E gene was the most evolutionarily conserved across 200 SARS-CoV-2 isolates. The E gene and M gene sequences of SARS-CoV-2 and NC014470 CoV were closely related and fell within the same branch of a phylogenetic tree. The absolute diversity of E gene and M gene sequences of SARS-CoV-2 isolates was similar to that of common CoVs (C-CoVs) infecting other organisms. The absolute diversity of the M gene sequence of the KJ481931 CoV that can infect humans was similar to that of SARS-CoV-2 and C-CoVs infecting other organisms. The M gene sequence of KJ481931 CoV (infecting humans), SARS-CoV-2 and NC014470 CoV (infecting other organisms) were closely related, falling within the same branch of a phylogenetic tree. Patterns of variation and evolutionary characteristics of the N gene and S gene were very similar. These data may be of value for understanding the origins and intermediate hosts of SARS-CoV-2.

RESUMEN

OBJECTIVES: To identify the general features of acquisition of drug-resistance genes in two multi-drug resistant Enterobacteriaceae strains isolated from a single patient in China. METHODS: The whole-plasmid was sequenced by Illumina Hiseq 4000 and Pacbio RSII procedures. The plasmid conjugation transfer experiment were performed by the mating-out assay. Drug-resistance genes were amplified by PCR assay. RESULTS: We identified two New Delhi metallo-ß-lactamase type 1(NDM-1)-producing isolates, named Raoultella ornithinolytica B1645-1 and Enterobacter cloacae B1645-2, which shared the same sulfonamide-resistant dihydropteroate synthase sul2 gene and aminoglycoside O-phosphotransferase aph(3'')-Ib gene. A novel antimicrobial resistance plasmid pCYNDM01 was first discovered from the multi-drug resistant R. ornithinolytica B1645-1. Interestingly, plasmid pCYNDM01 carried a Gifsy-2 prophage gene. The blaNDM-1 gene was located on a novel complex class 1 integron with a structure of sul1-qacEΔ1-ΔISAba125-blaNDM-1-blaMBL-trpC-ISCR1-catb8-aacA4-IS1-IS6100-dfrA14-intI1. The carrying the blaNDM-1 gene plasmid pCYNDM01 was transferred to the E. cloacae B1645-2 recipient strain. This 149.44 kb plasmid pCYNDM01 belonged to the IncFII type. CONCLUSIONS: A novel antimicrobial resistance plasmid pCYNDM01 was first recovered from a multi-drug resistance R. ornithinolytica B1645-1 isolated from China. The novel complex sul1-type class 1 integron might play an essential role in the mobilization of the blaNDM-1 gene among different enterobacterial species. The occurrence of plasmid pCYNDM01 transfer from R. ornithinolytica to E. cloacae in vitro by conjugation showed that plasmid pCYNDM01 was a self-conjugative plasmid and might cause dissemination of drug-resistance genes within different enterobacterial species from a single patient in vivo by conjugation. The novel variant F-like T4SS of plasmid pCYNDM01 might be as a tool of R. ornithinolytica B1645-1 for resistance genes transfer. The emergence of the two NDM-1-producing Enterobacteriaceae strains should be attracted China attentions and required to prevent its future prevalence.

Asunto(s)

Antibacterianos , Enterobacter cloacae , beta-Lactamasas , Antibacterianos/farmacología , China , Farmacorresistencia Bacteriana/efectos de los fármacos , Enterobacter cloacae/efectos de los fármacos , Enterobacter cloacae/genética , Enterobacter cloacae/metabolismo , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/genética , Humanos , Pruebas de Sensibilidad Microbiana , Plásmidos/genética

RESUMEN

BACKGROUND: 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) is an active compound derived from Polygonum multiflorum Thunb., a Chinese Taoist herbal medicine, which exerts lipid lowering, anti-cancer, anti-aging, anti-inflammatory and hepatoprotective effects. However, its role in protecting hepatocytes under pre-diabetic condition remains unclear. METHODS: In this study, we developed prediabetic SD rats by feeding high-fat and high-sugar diet. The body weight, blood lipid, blood glucose, and fasting insulin (FINS) and insulin resistance index (HOMA-IR) were detected and calculated to assess the potential risk of prediabetes. HE and Oil Red O staining was used, and blood level of biochemical index was detected to observe the liver injury. The autophagic cell death-associated signaling proteins, and the potential signaling factors p-Akt/Akt and p-Erk/Erk were detected using western blot to explore the potential effects of TSG on pre-diabetic liver and the underlying mechanisms. RESULTS: The results showed that the body weight in TSG-treated group was significantly decreased vs. the model group. The blood glucose, the level of FINS and HOMA-IR, TC and TG were decreased in TSG-treated group as well. Furthermore, TSG treatment significantly ameliorated lipid droplet accumulation, enhanced liver anti-oxidative response which may be associated with an increased activity of SOD and GSH-Px, and a decrease of LDLC and MDA. The autophagic cell death-associated proteins, p-AMPK, ATG12, LC3 II, and Beclin 1 were up-regulated in the TSG-treated group, while the upstream signaling pathway, PI3K/Akt and Erk, were activated. CONCLUSIONS: TSG induced liver autophagic cell death to protect liver from prediabetic injury by activating PI3K/Akt and Erk.

Asunto(s)

Autofagia/efectos de los fármacos , Glucósidos/farmacología , Hígado/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Estado Prediabético/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Estilbenos/farmacología , Animales , Fallopia multiflora/química , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley

RESUMEN

OBJECTIVE: To explore the influences of iodine excess on insulin secret function of mouse insulinoma cells ß-TC-6 and the mechanism. METHODS: ß-TC-6 cells were treated with excessive iodine( Na I) in vitro. After 24 hour of exposure, the MTT assay was used to measure the cell viabilities. ß-TC-6 cells, after 24 hour of exposure in excessive iodine, were stimulated with Krebs-Ringer bicarbonate buffer containing 5. 6mmol/L glucose for 1 hour at 37 ℃, then the supernatant was collected for insulin determination by ELISA kit. Western blot was used to detect the expression of Bcl-2, Bax, GRP78 and IRE1α. RESULTS: The rate of cell viability decreased from 1 mmol/L to 100mmol/L iodine excess group by a dose-dependent manner and was significantly lower than the control group and as follow by 73. 3%, 71. 2% and 55. 8% of that of control group. Iodine excess impaired the insulin secret function of ß-TC-6 cells in 1 mmol/L and 100 mmol/L iodine excess groups. The expression of Bcl-2 decreased while the expressionof Bax increased significantly when compared with control group( P < 0. 05). From 1mmol/L iodine excess group, the expression of GRP78 and IRE1α were increased significantly when compared with control group( P < 0. 05). CONCLUSION: Iodine excess decreased the cell viabilities and impaired insulin secret function, which might be related to endoplasmic reticulum stress and Bcl-2 families.

Asunto(s)

Células Secretoras de Insulina/efectos de los fármacos , Yodo/farmacología , Animales , Apoptosis , Chaperón BiP del Retículo Endoplásmico , Insulina , Yoduros , Ratones

RESUMEN

Both dietary fat and carbohydrates (Carbs) may play important roles in the development of insulin resistance. The main goal of this study was to further define the roles for fat and dietary carbs in insulin resistance. C57BL/6 mice were fed normal chow diet (CD) or HFD containing 0.1-25.5% carbs for 5 weeks, followed by evaluations of calorie consumption, body weight and fat gains, insulin sensitivity, intratissue insulin signaling, ectopic fat, and oxidative stress in liver and skeletal muscle. The role of hepatic gluconeogenesis in the HFD-induced insulin resistance was determined in mice. The role of fat in insulin resistance was also examined in cultured cells. HFD with little carbs (0.1%) induced severe insulin resistance. Addition of 5% carbs to HFD dramatically elevated insulin resistance and 10% carbs in HFD was sufficient to induce a maximal level of insulin resistance. HFD with little carbs induced ectopic fat accumulation and oxidative stress in liver and skeletal muscle and addition of carbs to HFD dramatically enhanced ectopic fat and oxidative stress. HFD increased hepatic expression of key gluconeogenic genes and the increase was most dramatic by HFD with little carbs, and inhibition of hepatic gluconeogenesis prevented the HFD-induced insulin resistance. In cultured cells, development of insulin resistance induced by a pathological level of insulin was prevented in the absence of fat. Together, fat is essential for development of insulin resistance and dietary carb is not necessary for HFD-induced insulin resistance due to the presence of hepatic gluconeogenesis but a very small amount of it can promote HFD-induced insulin resistance to a maximal level.

Asunto(s)

Dieta Alta en Grasa/efectos adversos , Carbohidratos de la Dieta/administración & dosificación , Resistencia a la Insulina , Obesidad/fisiopatología , Animales , Línea Celular , Línea Celular Tumoral , Colesterol/sangre , Relación Dosis-Respuesta a Droga , Ácidos Grasos no Esterificados/sangre , Furanos/farmacología , Gluconeogénesis/efectos de los fármacos , Hipoglucemiantes/farmacología , Immunoblotting , Insulina/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Músculo Esquelético/citología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Obesidad/sangre , Obesidad/etiología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Triglicéridos/sangre , Aumento de Peso/efectos de los fármacos , Aumento de Peso/fisiología

RESUMEN

Leucine, a branched-chain amino acid, has been shown to promote glucose uptake and increase insulin sensitivity in skeletal muscle, but the exact mechanism remains unestablished. We addressed this issue in cultured skeletal muscle cells in this study. Our results showed that leucine alone did not have an effect on glucose uptake or phosphorylation of protein kinase B (AKT), but facilitated the insulin-induced glucose uptake and AKT phosphorylation. The insulin-stimulated glucose uptake and AKT phosphorylation were inhibited by the phosphatidylinositol 3-kinase inhibitor, wortmannin, but the inhibition was partially reversed by leucine. The inhibitor of mammalian target of rapamycin complex 1 (mTORC1), rapamycin, had no effect on the insulin-stimulated glucose uptake, but eliminated the facilitating effect of leucine in the insulin-stimulated glucose uptake and AKT phosphorylation. In addition, leucine facilitation of the insulin-induced AKT phosphorylation was neutralized by knocking down the core component of the mammalian target of rapamycin complex 2 (mTORC2) with specific siRNA. Together, these findings show that leucine can facilitate the insulin-induced insulin signaling and glucose uptake in skeletal muscle cells through both mTORC1 and mTORC2, implicating the potential importance of this amino acid in glucose homeostasis and providing new mechanistic insights.

Asunto(s)

Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Leucina/metabolismo , Músculo Esquelético/metabolismo , Androstadienos/farmacología , Animales , Transporte Biológico , Proteínas Portadoras/genética , Células Cultivadas , Antagonistas de Insulina/farmacología , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Complejos Multiproteicos/antagonistas & inhibidores , Complejos Multiproteicos/genética , Músculo Esquelético/citología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Proteína Asociada al mTOR Insensible a la Rapamicina , Ratas , Transducción de Señal , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genética , Wortmanina

RESUMEN

We have previously shown that insulin plays an important role in the nutrient-induced insulin resistance. In this study, we tested the hypothesis that chronic exposure to excess long-acting insulin (glargine) can cause typical type 2 diabetes mellitus (T2DM) in normal mice fed on a chow diet. C57BL/6 mice were treated with glargine once a day for 8 weeks, followed by evaluations of food intake, body weight, blood levels of glucose, insulin, lipids, and cytokines, insulin signaling, histology of pancreas, ectopic fat accumulation, oxidative stress level, and cholesterol content in mitochondria in tissues. Cholesterol content in mitochondria and its association with oxidative stress in cultured hepatocytes and ß-cells were also examined. Results show that chronic exposure to glargine caused insulin resistance, hyperinsulinemia, and relative insulin deficiency (T2DM). Treatment with excess glargine led to loss of pancreatic islets, ectopic fat accumulation in liver, oxidative stress in liver and pancreas, and increased cholesterol content in mitochondria of liver and pancreas. Prolonged exposure of cultured primary hepatocytes and HIT-TI5 ß-cells to insulin induced oxidative stress in a cholesterol synthesis-dependent manner. Together, our results show that chronic exposure to excess insulin can induce typical T2DM in normal mice fed on a chow diet.

Asunto(s)

Diabetes Mellitus Tipo 2/fisiopatología , Dieta , Resistencia a la Insulina/fisiología , Insulina de Acción Prolongada/administración & dosificación , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Línea Celular Tumoral , Células Cultivadas , Colesterol/metabolismo , Cricetinae , Citocinas/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/inducido químicamente , Grasas/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/toxicidad , Insulina Glargina , Insulina de Acción Prolongada/sangre , Insulina de Acción Prolongada/toxicidad , Insulinoma/metabolismo , Insulinoma/patología , Lípidos/sangre , Lipogénesis/efectos de los fármacos , Lipogénesis/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

SCOPE: This study investigated the effect of chronic leucine supplementation on insulin sensitivity and the associated mechanisms in rats on high-fat diet (HFD). METHODS AND RESULTS: Male Sprague-Dawley rats were fed either normal chow diet or HFD supplemented with 0, 1.5, 3.0, and 4.5% leucine for 24 weeks. We found that chronic leucine supplementation increased insulin sensitivity together with increased body weight in rats on HFD, but had no effect on insulin sensitivity in rats on normal chow diet. The increased insulin sensitivity by leucine supplementation was not associated with altered ectopic fat accumulation in liver and muscle, plasma levels of lipids and cytokines, but is associated with reduced oxidative stress and improved insulin signaling. Chronic leucine supplementation did not enhance insulin receptor substract-1 (IRS-1) phosphorylation on serine 302, but elevated basal IRS-1 phosphorylation on tyrosine 632 and improved insulin-stimulated protein kinase B (Akt) and mammalian target of rapamycin (mTOR) phosphorylation in liver, skeletal muscle, and adipose tissue of rats on HFD rats, indicating leucine supplementation prevented HFD-induced insulin resistance in insulin-target tissues. CONCLUSION: Chronic leucine supplementation can increase insulin sensitivity and body weight likely by reducing oxidative stress and improving insulin signaling pathway in rats on HFD.

Asunto(s)

Peso Corporal/efectos de los fármacos , Resistencia a la Insulina , Insulina/metabolismo , Leucina/administración & dosificación , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Citocinas/sangre , Citocinas/metabolismo , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Ingestión de Energía/efectos de los fármacos , Gluconeogénesis/efectos de los fármacos , Gluconeogénesis/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Leucina/farmacología , Hígado/efectos de los fármacos , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Tirosina/metabolismo

RESUMEN

We addressed the link between excessive exposure to insulin and mitochondrion-derived oxidative stress in this study and found that prolonged exposure to insulin increased mitochondrial cholesterol in cultured hepatocytes and in mice and stimulated production of reactive oxygen species (ROS) and decreased the reduced glutathione to glutathione disulfide ratio in cultured hepatocytes. Exposure of isolated hepatic mitochondria to cholesterol alone promoted ROS emission. The oxidative stress induced by the prolonged exposure to insulin was prevented by inhibition of cholesterol synthesis with simvastatin. We further found that prolonged exposure to insulin decreased mitochondrial membrane potential and the increased ROS production came from mitochondrial respiration complex I. Finally, we observed that prolonged exposure to insulin decreased mitochondrial membrane fluidity in a cholesterol synthesis-dependent manner. Together our results demonstrate that excess exposure to insulin causes mitochondrion-derived oxidative stress through cholesterol synthesis in hepatocytes.

Asunto(s)

Colesterol/metabolismo , Hepatocitos/efectos de los fármacos , Insulina/farmacología , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Línea Celular , Hepatocitos/metabolismo , Hipoglucemiantes/farmacología , Insulina Glargina , Insulina de Acción Prolongada/farmacología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

p38 MAPK has been strongly implicated in the development of atherosclerosis, but its role in cholesterol ester accumulation in macrophages and formation of foam cells, an early step in the development of atherosclerosis, has not been investigated. We addressed this issue and made some brand new observations. First, elevated intracellular cholesterol level induced by the exposure to LDL-activated p38 MAPK and activation of p38 MAPK with anisomycin increased the ratio of cholesterol esters over free cholesterol, whereas inhibition of p38 MAPK with SB203580 or siRNA reduced the LDL loading-induced intracellular accumulation of free cholesterol and cholesterol esters in macrophages. Second, exposure to LDL cholesterol inhibited autophagy in macrophages, and inhibition of autophagy with 3-methyladenine increased intracellular accumulation of cholesterol (free cholesterol and cholesterol esters), whereas activation of autophagy with rapamycin decreased intracellular accumulation of free cholesterol and cholesterol esters induced by the exposure to LDL cholesterol. Third, LDL cholesterol loading-induced inhibition of autophagy was prevented by blockade of p38 MAPK with SB203580 or siRNA. Neutral cholesterol ester hydrolase was co-localized with autophagosomes. Finally, LDL cholesterol loading and p38 activation suppressed expression of the key autophagy gene, ulk1, in macrophages. Together, our results provide brand new insight about cholesterol ester accumulation in macrophages and foam cell formation.

Asunto(s)

Ésteres del Colesterol/metabolismo , Macrófagos/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología , Anisomicina/farmacología , Autofagia , Homólogo de la Proteína 1 Relacionada con la Autofagia , Línea Celular , Activación Enzimática , Activadores de Enzimas/farmacología , Regulación de la Expresión Génica , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Imidazoles/farmacología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Movilización Lipídica , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/fisiología , Lisosomas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Macrófagos/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Piridinas/farmacología , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo

RESUMEN

As excessive iodine intake is associated with a decrease of the activities of selenocysteine-containing enzymes, supplemental selenium was hypothesized to alleviate the toxic effects of excessive iodine. In order to verify this hypothesis, Balb/C mice were tested by giving tap water with or without potassium iodate and/or sodium selenite for 16 weeks, and the levels of iodine in urine and thyroid, the hepatic selenium level, the activities of glutathione peroxidase (GSHPx), type 1 deiodinase (D1), and thyroid peroxidase (TPO) were assayed. It had been observed in excessive iodine group that hepatic selenium, the activities of GSHPx, D1, and TPO decreased, while in the groups of 0.2 mg/L, 0.3 mg/L and 0.4 mg/L supplemental selenium, the urinary iodine increased significantly. Compared with the group of excessive iodine intake alone, supplemental selenium groups had higher activities of GSHPx, D1, and TPO. We could draw the conclusion that supplemental selenium could alleviate toxic effect of excessive iodine on thyroid. The optimal dosage of selenium ranges from 0.2 to 0.3 mg/L which can protect against thyroid hormone dysfunction induced by excessive iodine intake.

Asunto(s)

Yodatos/toxicidad , Compuestos de Potasio/toxicidad , Selenito de Sodio/farmacología , Glándula Tiroides/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Femenino , Glutatión Peroxidasa/metabolismo , Yodatos/administración & dosificación , Yoduro Peroxidasa/metabolismo , Ratones , Ratones Endogámicos BALB C , Compuestos de Potasio/administración & dosificación , Selenito de Sodio/administración & dosificación , Glándula Tiroides/enzimología , Glándula Tiroides/patología , Agua

RESUMEN

OBJECTIVE: To study the mechanism of the disorder of thyroid hormone metabolism resulted from iodine excess in order to seek suitable selenium intervention dosage. METHODS: 140 Balb/c mice were randomly divided into seven groups, the normal control group, the excessive iodine group (drank the water containing potassium iodate 3000 microg/L) and five selenium intervention groups (drank the water containing 3000 microg/L of potassium iodate and 0.1, 0.2, 0.3, 0.4 and 0.5 mg/L of selenium). All of the mice were cultivated for 16 weeks and the thyroid hormone in plasma were assayed by radioimmunoassay. The iodine in urine and thyroid were analyzed by Cer-Arsenite colormetric method. The activities of glutathione peroxidase, superoxide dismutase and thyroid peroxidase and the level of malondialdehyde in thyroid were analyzed. RESULTS: The level of thyroid hormone of selenium intervention groups had no significant difference with that of normal control group (P > 0.05). Compared with excessive iodine group, the iodine in thyroid of 0.2 mg/L selenium intervention group increased significantly (P < 0.05). Compared with the normal control group, the activities of glutathione peroxidase and superoxide dismutase and the level of malondialdehyde of 0.2-0.3 mg/L selenium intervention groups in thyroid were not significantly different. Compared with the normal control group, the activity of thyroid peroxidase of 0.1-0.3 mg/L selenium intervention groups were not significantly different. CONCLUSION: The results indicated that the optimal dose of selenium could restrain the disorder of thyroid hormone metabolism induced by excessive iodine in mice.

Asunto(s)

Yodo/administración & dosificación , Yodo/efectos adversos , Selenio/farmacología , Hormonas Tiroideas/sangre , Animales , Femenino , Yoduro Peroxidasa/metabolismo , Yodo/metabolismo , Ratones , Ratones Endogámicos BALB C , Distribución Aleatoria , Glándula Tiroides/metabolismo

RESUMEN

OBJECTIVE: To study the mechanism of the damage resulted from iodine excess and to seek suitable selenium intervention dosage. METHOD: 160 BALB/c mice were divided into eight groups, the normal control group, the excessive iodine group (drunk the water containing potassium iodate 3000 microg/L) and six selenium groups (drunk the water containing potassium iodate 3000 microg/L and selenium 0.1, 0.2, 0.3, 0.4, 0.5 and 0.75 mg/L). The type 1 deiodinase (D1) activities and the levels of mRNA in liver, kidney and thyroid were determined by RT-PCR. RESULTS: The mRNA levels of D1 restored to normal levels in all of the IS groups, while only 0.1-0.4 mg/L selenium supplement groups had normal activities of D1 in liver, kidney and thyroid. CONCLUSION: Decline of D1 activities in liver, kidney and thyroid seems to be one of the reasons of the damage and should be chosen for effective intervention.

Asunto(s)

Yoduro Peroxidasa/metabolismo , Yodo/administración & dosificación , Yodo/efectos adversos , Selenio/farmacología , Animales , Femenino , Yoduro Peroxidasa/genética , Yodo/metabolismo , Hígado/enzimología , Ratones , Ratones Endogámicos BALB C , ARN Mensajero/genética , ARN Mensajero/metabolismo , Distribución Aleatoria , Selenio/administración & dosificación , Glándula Tiroides/enzimología

RESUMEN

OBJECTIVE: To study effects of iodine excess on the levels of serum T4 and T3 and TRalpha1 and TRbeta1 expression in the cerebrum of filial mice and the supplement of selenium. METHODS: Sixty BALB/c mice were divided randomly into four groups: control group (tap water, NC), iodine excess group (3000 microg/L I, EI +), selenium supplement group (200 microg/L Se, Se +) and iodine excess plus selenium (3000 microg/L + I 200 microg/L Se, EI + Se +) group. The mice were mated at the end of the fourth month. Serum T4 and T3 were determined on postnatal day 14 and 28. The expression levels of TRalpha1 and TRbeta1 mRNA in filial mice cerebrum were detected by fluor scent real time PCR. RESULTS: Serum T4 level in EI + was lower significantly than that in NC and EI + Se + on postnatal day 14. mRNA levels of TRalpha1 and TRbeta1 in EI + were higher than those in other groups on postnatal day 0 and 28. No significant difference in serum T4 level and TRalpha1 and TRbeta1 mRNA expression level between four group on postnatal day 28. CONCLUSION: The expression of TRalpha1 and TRbeta1 infilial mice cerebrum could be up-regulated by iodine excess intake and could be alleviated by selenium supplement.

Asunto(s)

Cerebro/metabolismo , Yodo/administración & dosificación , Efectos Tardíos de la Exposición Prenatal , Receptores de Hormona Tiroidea/metabolismo , Selenio/farmacología , Hormonas Tiroideas/sangre , Animales , Animales Recién Nacidos , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Embarazo , Tiroxina/sangre , Triyodotironina/sangre

RESUMEN

OBJECTIVE: To study the effects of excess iodine intake on neurogranin expression in cerebrum of filial mice and the intervention of selenium. METHODS: Sixty BALB/c mice were divided randomly into four groups with different drinking water: control group (tap water, NC), excess iodine group (3000 microg/L I, EL +), supplementing selenium group (200 microg/L Se, Se +) and the excess iodine plus selenium (3000 microg/L + I 200 microg/L Se, EI + Se +) group. The mice were mated at the end of the fourth month. Serum T4 and T3 were determined on postnatal day 14 and 28. The expression level of neurogranin in filial cerebrum was measured by immunohistochemistry and Western blot. RESULTS: Serum T4 level in EI (68.78 +/- 11.10 nmol/ L) + was lower significantly than that in NC (100.85 +/- 11.47 nmol/ L) and EI + Se + (93.15 +/- 12.10 nmol/ L) on postnatal day 14. Western blot analysis showed that the relative level of neurogranin in EI + (0.621 +/- 0.041) was lower than that in NC (0.841 +/- 0.039) and EI + Se + (0.781 +/- 0.029) on postnatal day 14 (P < 0.05). No significant difference in serum T4 and neurogranin level between four groups on postnatal day 28. CONCLUSION: Excess iodine intake might change the expression of neurogranin in filial cerebrum and the selenium supplementation might alleviate it.

Asunto(s)

Yodo/efectos adversos , Neurogranina/biosíntesis , Selenio/farmacología , Telencéfalo/metabolismo , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Tiroxina/sangre , Triyodotironina/sangre

RESUMEN

The effects of supplementing selenium on thyroid hormone metabolism were studied on mice with excessive iodine exposure. The serum concentrations of thyroxine (T4) and triiodothyronine (T3) and the activities of iodothyronine 5\' and 5-deiodinase (D2, D3) were measured in the brain of filial mice to study the influence of selenium on thyroid hormone metabolism. Measurements were carried out on postnatal day 0, 14, and 28. It was found that selenium supplementation alleviated the adverse effects of excessive iodine on progeny. The serum TT4 level as well as TT4 and TT3 concentrations and D3 activity in cerebrum of progeny decreased, whereas D2 activity increased in the cerebrum of progeny on postnatal day 0 and 14. Selenium supplementation exerted some favorable effects on thyroid hormone metabolism in cerebrum of progeny of dam with excessive iodine intake.

Asunto(s)

Yodo/farmacología , Yodo/toxicidad , Selenio/farmacología , Selenio/toxicidad , Telencéfalo/efectos de los fármacos , Hormonas Tiroideas/metabolismo , Animales , Animales Recién Nacidos , Femenino , Yodo/metabolismo , Masculino , Exposición Materna , Ratones , Ratones Endogámicos BALB C , Tiroxina/metabolismo , Factores de Tiempo , Triyodotironina/metabolismo