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As the major component in the cell wall of brown algae, alginates are degradable by alginate lyases via ß-elimination. Alginate lyases can be categorized into various polysaccharide lyase (PL) families, and PL7 family alginate lyases are the largest group and can be divided into six subfamilies. However, the major difference among different PL7 subfamilies is not fully understood. In this work, a marine alginate lyase, VaAly2, from Vibrio alginolyticus ATCC 17749 belonging to the PL7_5 subfamily was identified and characterized. It displayed comparatively high alginolytic activities toward different alginate substrates and functions as a bifunctional lyase. Molecular docking and biochemical analysis suggested that VaAly2 not only contains a key catalyzing motif (HQY) conserved in the PL7 family but also exhibits some specific characters limited in the PL7_5 subfamily members, such as the key residues and a long loop1 structure around the active center. Our work provides insight into a loop structure around the center site which plays an important role in the activity and substrate binding of alginate lyases belonging to the PL7_5 subfamily.
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BACKGROUND: Follow-up study of coronavirus disease 2019 (COVID-19) survivors has rarely been reported. We aimed to investigate longitudinal changes in the characteristics of COVID-19 survivors after discharge. METHODS: A total of 594 COVID-19 survivors discharged from Tongji Hospital in Wuhan from February 10 to April 30, 2020 were included and followed up until May 17, 2021. Laboratory and radiological findings, pulmonary function tests, electrocardiogram, symptoms and signs were analyzed. RESULTS: 257 (51.2%) patients had at least one symptom at 3 months post-discharge, which decreased to 169 (40.0%) and 138 (28.4%) at 6-month and 12-month visit respectively. During follow-up period, insomnia, chest tightness, and fatigue were the most prevalent symptoms. Most laboratory parameters returned to normal, whereas increased incidence of abnormal liver and renal function and cardiovascular injury was evidenced after discharge. Fibrous stripes (213; 42.4%), pleural thickening and adhesions (188; 37.5%) and enlarged lymph nodes (120; 23.9%) were the most common radiographical findings at 3 months post-discharge. The abnormalities of pulmonary function included obstructive, restrictive, and mixed, which were 5.5%, 4.0%, 0.9% at 6 months post, and 1.9%, 4.7%, 0.2% at 12 months. Electrocardiogram abnormalities occurred in 256 (51.0%) patients at 3 months post-discharge, including arrhythmia, ST-T change and conduction block, which increased to 258 (61.1%) cases at 6-month visit and were maintained at high frequency (242;49.8%) at 12-month visit. CONCLUSIONS: Physiological, laboratory, radiological, or electrocardiogram abnormalities, particularly those related to renal, cardiovascular, and liver functions are common in patients who recovered from coronavirus disease 2019 (COVID-19) up to 12 months post-discharge.
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COVID-19 , Cuidados Posteriores , China/epidemiología , Estudios de Seguimiento , Hospitales , Humanos , Alta del Paciente , Estudios Prospectivos , SARS-CoV-2RESUMEN
Since the voluntary phaseout of perfluorooctanesulfonic acid (PFOS), smaller congeners, such as perfluorobutanesulfonic acid (PFBS) have served as industrial replacements and been detected in contaminated aquifers. This study sought to examine the effects of a maternal preconception PFBS exposure on the development of eggs and healthy offspring. Adult female zebrafish received a one-week waterborne exposure of 0.08, 0.14, and 0.25 mg/L PFBS. After which, females were bred with non-exposed males and embryos collected over 5 successful breeding events. PFBS concentrations were detected in levels ranging from 99 to 253 pg/embryo in the first collection but were below the limit of quantitation by fourth and fifth clutches. Therefore, data were subsequently binned into early collection embryos in which PFBS was detected and late collections, in which PFBS was below quantitation. In the early collection, embryo 24 h survival was significantly reduced. In the late collection, embryo development was impacted with unique patterns emerging between Nrf2a wildtype and mutant larvae. Additionally, the impact of nutrient loading into the embryos was assessed through measurement of fatty acid profiles, total cholesterol, and triglyceride content. There were no clear dose-dependent effects, but again unique patterns were observed between the genotypes. Preconception PFBS exposures were found to alter egg and embryo development, which is mediated by direct toxicant loading in the eggs, nutrient loading into eggs, and the function of Nrf2a. These findings provide insight into the reproductive and developmental effects of PFBS and identify maternal preconception as a novel critical window of exposure.
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Fluorocarburos , Pez Cebra , Animales , Desarrollo Embrionario , Femenino , Fluorocarburos/toxicidad , Humanos , Masculino , Exposición Materna , Ácidos Sulfónicos/toxicidad , Pez Cebra/genéticaRESUMEN
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has posed a serious threat to global public health security. With the increase in the number of confirmed cases globally, the World Health Organization has declared the outbreak of COVID-19 an international public health emergency. Despite atypical pneumonia as the primary symptom, liver dysfunction has also been observed in many clinical cases and is associated with the mortality risk in patients with COVID-19, like severe acute respiratory syndrome and Middle East respiratory syndrome. Here we will provide a schematic overview of the clinical characteristics and the possible mechanisms of liver injury caused by severe acute respiratory syndrome coronavirus 2 infection, which may provide help for optimizing the management of liver injury and reducing mortality in COVID-19 patients.
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Background: Coronavirus disease 2019 (COVID-19) is a serious and even lethal respiratory illness. The mortality of critically ill patients with COVID-19, especially short term mortality, is considerable. It is crucial and urgent to develop risk models that can predict the mortality risks of patients with COVID-19 at an early stage, which is helpful to guide clinicians in making appropriate decisions and optimizing the allocation of hospital resoureces. Methods: In this retrospective observational study, we enrolled 949 adult patients with laboratory-confirmed COVID-19 admitted to Tongji Hospital in Wuhan between January 28 and February 12, 2020. Demographic, clinical and laboratory data were collected and analyzed. A multivariable Cox proportional hazard regression analysis was performed to calculate hazard ratios and 95% confidence interval for assessing the risk factors for 30-day mortality. Results: The 30-day mortality was 11.8% (112 of 949 patients). Forty-nine point nine percent (474) patients had one or more comorbidities, with hypertension being the most common (359 [37.8%] patients), followed by diabetes (169 [17.8%] patients) and coronary heart disease (89 [9.4%] patients). Age above 50âyears, respiratory rate above 30 beats per minute, white blood cell count of more than10â×â109/L, neutrophil count of more than 7â×â109/L, lymphocyte count of less than 0.8â×â109/L, platelet count of less than 100â×â109/L, lactate dehydrogenase of more than 400âU/L and high-sensitivity C-reactive protein of more than 50âmg/L were independent risk factors associated with 30-day mortality in patients with COVID-19. A predictive CAPRL score was proposed integrating independent risk factors. The 30-day mortality were 0% (0 of 156), 1.8% (8 of 434), 12.9% (26 of 201), 43.0% (55 of 128), and 76.7% (23 of 30) for patients with 0, 1, 2, 3, ≥4 points, respectively. Conclusions: We designed an easy-to-use clinically predictive tool for assessing 30-day mortality risk of COVID-19. It can accurately stratify hospitalized patients with COVID-19 into relevant risk categories and could provide guidance to make further clinical decisions.
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Per- and polyfluoroalkyl substances, a group of fluoro-surfactants widely detected in the environment, wildlife and humans, have been linked to adverse health effects. A growing body of literature has addressed their effects on obesity, diabetes and non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis. This review summarizes the brief historical use and chemistry of per- and polyfluoroalkyl substances, routes of human exposure, as well as the epidemiologic evidence for associations between exposure to per- and polyfluoroalkyl substances and the development of obesity, diabetes and non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis. We identified 22 studies on obesity and 32 studies on diabetes, while only 1 study was found for non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis by searching PubMed for human studies. Approximately 2/3 of studies reported positive associations between per- and polyfluoroalkyl substances exposure and the prevalence of obesity and/or type 2 diabetes. Causal links between per- and polyfluoroalkyl substances and obesity, diabetes and non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis, however, require further large-scale prospective cohort studies combined with mechanistic laboratory studies to better assess these associations.
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BACKGROUND: Coronavirus disease 2019 (COVID-19) has rapidly become a major international public health concern. This study was designed to evaluate the clinical characteristics and risk factors of COVID-19-associated liver injury. METHODS: A fraction of 657 COVID-19 patients were retrospectively analyzed. Clinical and laboratory data were derived from electronic medical records and compared between patients with or without liver injury. Multivariate logistic regression method was used to analyze the risk factors for liver injury. RESULTS: Among 657 patients, 303 (46.1%) patients had liver injury with higher rate in severe/critically ill patients [148/257 (57.6%)] than those in moderate cases [155/400 (38.8%)]. The incidence of liver injury was much higher in male [192/303 (63.4%)] than female [111/303 (36.6%)], and in severe/critical patients [148/303 (48.8%)] with percutaneous oxygen saturation ≤ 93% [89/279 (31.9%)] or peak body temperature ≥ 38.5 °C [185/301 (61.5%)] on admission. Liver injury-related inflammations included increased white blood cells, neutrophils and decreased lymphocytes. More patients with liver injury than without had increased serum IL-2R, TNFα, ferritin, hsCRP, PCT, ESR, γ-GT, and LDH. Multivariate regression analysis revealed that increasing odds of liver injury were related to male, higher serum hsCRP (≥ 10 mg/L), and neutrophil-to-lymphocyte ratio (NLR) (≥ 5). Moreover, more deceased patients (14/82 (17%)) had significantly elevated serum TBIL than discharged patients [25/532 (4.7%)]. CONCLUSION: Liver injury is a common complication in COVID-19 patients. The potential risk factors of liver injury include male, hsCRP and NLR score. A close monitor of liver function should be warned in COVID-19 patients, especially in severe/critical individuals.
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Infecciones por Coronavirus , Citocinas/sangre , Insuficiencia Hepática , Recuento de Leucocitos/métodos , Pruebas de Función Hepática , Pandemias , Neumonía Viral , Betacoronavirus/aislamiento & purificación , COVID-19 , China/epidemiología , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/terapia , Enfermedad Crítica/epidemiología , Enfermedad Crítica/terapia , Femenino , Insuficiencia Hepática/sangre , Insuficiencia Hepática/epidemiología , Insuficiencia Hepática/virología , Humanos , Incidencia , Pruebas de Función Hepática/métodos , Pruebas de Función Hepática/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Neumonía Viral/complicaciones , Neumonía Viral/mortalidad , Neumonía Viral/fisiopatología , Neumonía Viral/terapia , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2 , Factores SexualesRESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) is a newly emerging infectious disease and rapidly escalating epidemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The pathogenesis of COVID-19 remains to be elucidated. We aimed to clarify correlation of systemic inflammation with disease severity and outcomes in COVID-19 patients. METHODS: In this retrospective study, baseline characteristics, laboratory findings, and treatments were compared among 317 laboratory-confirmed COVID-19 patients with moderate, severe, or critically ill form of the disease. Moreover, the longitudinal changes of serum cytokines, lactate dehydrogenase (LDH), high-sensitivity C-reactive protein (hsCRP), and hsCRP to lymphocyte count ratio (hsCRP/L) as well as their associations with disease severity and outcomes were investigated in 68 COVID-19 patients. RESULTS: Within 24 h of admission, the critically ill patients showed higher concentrations of inflammatory markers including serum soluble interleukin (IL)-2 receptor, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), ferritin, procalcitonin, LDH, hsCRP, and hsCRP/L than patients with severe or moderate disease. The severe cases displayed the similar response patterns when compared with moderate cases. The longitudinal assays showed the levels of pro-inflammatory cytokines, LDH, hsCRP, and hsCRP/L gradually declined within 10 days post admission in moderate, severe cases or those who survived. However, there was no significant reduction in cytokines, LDH, hsCRP, and hsCRP/L levels in critically ill or deceased patients throughout the course of illness. Compared with female patients, male cases showed higher serum concentrations of soluble IL-2R, IL-6, ferritin, procalcitonin, LDH, and hsCRP. Multivariate logistic regression analysis revealed that IL-6 > 50 pg/mL and LDH > 400 U/L on admission were independently associated with disease severity in patients with COVID-19. CONCLUSION: Exuberant inflammatory responses within 24 h of admission in patients with COVID-19 may correlate with disease severity. SARS-CoV-2 infection appears to elicit a sex-based differential immune response. IL-6 and LDH were independent predictive parameters for assessing the severity of COVID-19. An early decline of these inflammation markers may be associated with better outcomes.
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Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/terapia , Citocinas/sangre , Inflamación/sangre , Neumonía Viral/sangre , Neumonía Viral/terapia , Anciano , COVID-19 , China/epidemiología , Infecciones por Coronavirus/epidemiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Per- and poly-fluoroalkyl substances, especially perfluorooctanesulfonic acid, have been extensively used for over 50 years. A growing body of evidence has emerged demonstrating the potential adverse effects of these substances, including its effect on the development of non-alcoholic fatty liver disease, as one of the most prevalent chronic liver diseases. Nonetheless, there is no report of effects of perfluorobutanesulfonic acid, the major replacement for perfluorooctanesulfonic acid, on non-alcoholic fatty liver disease. Therefore, the effects of perfluorobutanesulfonic acid exposure on fat accumulation in a human hepatoma cell line were examined. Cells were exposed to perfluorobutanesulfonic acid with or without 300 µmol/L fatty acid mixture (oleic acid:palmitic acid = 2:1) conjugated by bovine serum albumin as an inducer of steatosis for 48 hours. Perfluorobutanesulfonic acid at 200 µmol/L significantly increased the triglyceride level in the presence of fatty acid compared to the control, but not without fatty acid, which was abolished by a specific peroxisome proliferator-activated receptor gamma antagonist. Perfluorobutanesulfonic acid upregulated key genes controlling lipogenesis and fatty acid uptake. Perfluorobutanesulfonic acid treatment also promoted the production of reactive oxygen species, an endoplasmic reticulum stress marker and cytosolic calcium. In conclusion, perfluorobutanesulfonic acid increased fat accumulation, in part, via peroxisome proliferator-activated receptor gamma-mediated pathway in hepatoma cells.
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Frying in vegetable oil is a popular cooking and food processing method worldwide; as a result, the oils used for frying are widely consumed by the general public and it is of practical importance to better understand their health impacts. To date, the effects of frying oil consumption on human health are inconclusive, making it difficult to establish dietary recommendations or guidelines. Here we show that dietary administration of frying oil, which was prepared under the conditions of good commercial practice, exaggerated dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colon tumorigenesis in mice. In addition, dietary administration of frying oil impaired intestinal barrier function, enhanced translocation of lipopolysaccharide (LPS) and bacteria from the gut into the systemic circulation, and increased tissue inflammation. Finally, to explore the potential compounds involved in the actions of the frying oil, we isolated polar compounds from the frying oil and found that administration of the polar compounds exacerbated DSS-induced colitis in mice. Together, our results showed that dietary administration of frying oil exaggerated development of inflammatory bowel disease (IBD) and IBD-associated colon tumorigenesis in mice, and these effects could be mediated by the polar compounds in the frying oil.
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Azoximetano/toxicidad , Transformación Celular Neoplásica/patología , Colitis/patología , Neoplasias del Colon/patología , Sulfato de Dextran/toxicidad , Inflamación/patología , Aceites/efectos adversos , Animales , Carcinógenos/toxicidad , Transformación Celular Neoplásica/inducido químicamente , Colitis/inducido químicamente , Colitis/complicaciones , Neoplasias del Colon/etiología , Modelos Animales de Enfermedad , Calor/efectos adversos , Humanos , Inflamación/inducido químicamente , Inflamación/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Aceites/administración & dosificaciónRESUMEN
trans-Trismethoxy resveratrol (TMR) is a methyl analog of resveratrol. It is found to exhibit enhanced biological effects compared to resveratrol, such as inhibition of cancer cell growth and pro-apoptotic activities. However, the role of TMR in lipid metabolism is not fully understood. In this study, we used Caenorhabditis elegans, an in vivo nematode model which has been widely applied in disease research, including research on obesity, to investigate the effect of TMR on lipid metabolism. Treatment with TMR (100 and 200 µM) for 4 days significantly reduced triglyceride accumulation (14% and 20% reduction over the control, respectively) of C. elegans, without affecting nematode growth, food intake and reproduction. Treatment with TMR significantly downregulated stearoyl-CoA desaturase genes, fat-6 and fat-7, accompanied by a decrease in the desaturation index of fatty acids, the ratio of oleic acid to stearic acid. These results suggest that TMR inhibits fat accumulation by downregulating stearoyl-CoA desaturase in C. elegans.
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Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/metabolismo , Grasas/metabolismo , Ácido Graso Desaturasas/metabolismo , Resveratrol/farmacología , Estearoil-CoA Desaturasa/metabolismo , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Ácido Graso Desaturasas/genética , Resveratrol/química , Estearoil-CoA Desaturasa/genética , Triglicéridos/metabolismoRESUMEN
Ivermectin, a member of the avermectins, is one of the most used anti-parasitic agents, and acts by binding to glutamate-gated chloride channels in invertebrate nerve cells. There is limited information, however, on the effects of ivermectin in non-neural cell, such as adipocytes. The present work aimed to investigate the role of ivermectin in adipogenesis using 3T3-L1 preadipocytes. Ivermectin inhibited the differentiation of preadipocytes and triglyceride (TG) accumulation. In particular, the treatment of ivermectin at the middle to late adipogenic differentiation period (day 2-8) was correlated with the inhibition of fat accumulation. Ivermectin treatment also significantly modulated the mRNA expression of key markers in adipogenesis, fatty acid synthesis, uptake, and oxidation, and enhanced the gene expression of two subunits of the glycine receptor (GlyR). Specifically, the protein levels of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and acetyl-CoA carboxylase (ACC) were reduced. Interestingly, the suppression of TG accumulation by ivermectin was partially abolished by rosiglitazone, a specific PPARγ agonist, but Z-guggulsterone, a selective FXR antagonist, failed to rescue the ivermectin-induced effect on adipogenesis. Lastly, ivermectin prevented adipogenesis induced by permethrin and fipronil. In conclusion, ivermectin inhibits adipogenesis of 3T3-L1 preadipocytes partially via PPARγ & GlyR-dependent, but not FXR-dependent, pathway.
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Adipogénesis/efectos de los fármacos , Antiparasitarios/farmacología , Ivermectina/farmacología , Triglicéridos/metabolismo , Células 3T3-L1 , Animales , Diferenciación Celular/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Ratones , PPAR gamma/metabolismo , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Glicina/metabolismoRESUMEN
Recent studies have reported the positive association between exposure to insecticides and increased risk of obesity and type 2 diabetes, which are closely associated with non-alcoholic fatty liver disease (NAFLD). However, it is not known if insecticide exposure can contribute to NAFLD. Thus, the goal of the current study was to determine if insecticide exposures can exacerbate the physiological conditions of NAFLD by modulating hepatic lipid metabolism. The effects of 12 insecticides on triglycerides (TG) accumulation were tested using palmitic acid (PA)-induced HepG2 hepatoma steatosis model. Results showed that among tested insecticides, permethrin and ivermectin significant interacted with palmitic acid to potentiate (permethrin) or decrease (ivermectin) TG accumulation. Further study showed that permethrin significantly promoted fatty acid synthesis, while suppressed lipid oxidation-related genes only under steatosis conditions. In comparison, ivermectin inhibited lipogenesis-related genes and promoted farnesoid X receptor, which upregulates fatty acid oxidation. Results in this study suggested that hepatic lipid metabolism may be more susceptible to insecticide exposure in the presence of excessive fatty acids, which can be associated with the development of NAFLD.
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Hepatocitos/efectos de los fármacos , Insecticidas/farmacología , Ivermectina/farmacología , Lipogénesis/efectos de los fármacos , Permetrina/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ácidos Grasos/química , Ácidos Grasos/metabolismo , Hígado Graso/inducido químicamente , Células Hep G2 , Humanos , Oxidación-Reducción , Ácido Palmítico , Triglicéridos/metabolismoRESUMEN
Perfluorobutanesulfonic acid (PFBS) is used as the replacement of perfluorooctanesulfonic acid (PFOS) since 2000 because of the concern on PFOS' persistence in the environment and the bioaccumulation in animals. Accumulating evidence has shown the correlation between the exposure to perfluorinated compounds and enhanced adipogenesis. There is no report, however, of the effect of PFBS on adipogenesis. Therefore, the present work aimed to investigate the role of PFBS in adipogenesis using 3T3-L1 adipocytes. PFBS treatment for 6 days extensively promoted the differentiation of 3T3-L1 preadipocytes to adipocytes, resulting in significantly increased triglyceride levels. In particular, the treatments of PFBS at the early adipogenic differentiation period (day 0-2) were positively correlated with increased the triglyceride accumulation on day 6. PFBS treatments significantly increased the protein and mRNA levels of the master transcription factors in adipocyte differentiation; CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor gamma (PPARγ), along with acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), the key proteins in lipogenesis. PFBS significantly activated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) after 4-h treatment, and PFBS' effect on triglyceride was abolished by U0126, a specific MAPK/ERK kinase (MEK) inhibitor. In conclusion, PFBS increased the adipogenesis of 3T3-L1 adipocytes, in part, via MEK/ERK-dependent pathway.
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Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Células 3T3-L1 , Adipocitos/enzimología , Animales , Butadienos/farmacología , Diferenciación Celular , Relación Dosis-Respuesta a Droga , Ratones , Nitrilos/farmacología , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Obesity is associated with enhanced colonic inflammation, which is a major risk factor for colorectal cancer. Considering the obesity epidemic in Western countries, it is important to identify novel therapeutic targets for obesity-induced colonic inflammation, to develop targeted strategies for prevention. Eicosanoids are endogenous lipid signaling molecules involved in regulating inflammation and immune responses. Using an LC-MS/MS-based lipidomics approach, we find that obesity-induced colonic inflammation is associated with increased expression of soluble epoxide hydrolase (sEH) and its eicosanoid metabolites, termed fatty acid diols, in colon tissue. Furthermore, we find that pharmacological inhibition or genetic ablation of sEH reduces colonic concentrations of fatty acid diols, attenuates obesity-induced colonic inflammation, and decreases obesity-induced activation of Wnt signaling in mice. Together, these results support that sEH could be a novel therapeutic target for obesity-induced colonic inflammation and associated diseases.
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Colitis/etiología , Dieta Alta en Grasa/efectos adversos , Epóxido Hidrolasas/fisiología , Inflamación/etiología , Lípidos/análisis , Metabolómica/métodos , Obesidad/complicaciones , Animales , Colitis/metabolismo , Colitis/patología , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de SeñalRESUMEN
Permethrin is a pyrethroid pesticide that was previously reported to promote fat accumulation and insulin resistance in vitro. A recent study in female mice also found that permethrin could promote high fat-induced insulin resistance. The effects of permethrin on glucose and lipid metabolisms in male mice, however, remain unknown. The purpose of this study was to investigate the effects and interactions of permethrin exposure (50, 500, and 5000 µg/kg body weight/day) and dietary fat (low fat, 4% w/w; high fat, 20% w/w) on development of obesity and insulin resistance in male C57BL/6J mice. Our results showed that permethrin treatment significantly increased body weight, fat mass, and insulin resistance with high fat diet, but not with low fat diet, without influencing energy intake. Permethrin treatment also significantly increased serum levels of insulin, glucose, leptin, triglycerides and cholesterol. Further results showed that permethrin inhibited AMP-activated protein kinase in white adipose tissue. These results suggest that permethrin interacts with dietary fat to alter lipid and glucose metabolisms in male C57BL/6J mice.
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Dieta Alta en Grasa/efectos adversos , Insecticidas/toxicidad , Resistencia a la Insulina , Permetrina/toxicidad , Animales , Relación Dosis-Respuesta a Droga , Glucosa/metabolismo , Homeostasis , Insecticidas/administración & dosificación , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Permetrina/administración & dosificaciónRESUMEN
Permethrin, a pyrethroid insecticide, was previously reported to promote adipogenesis in vitro and weight gain in vivo. The mechanism by which permethrin promotes adipogenesis/obesity, however, has not been fully explored. Intracellular calcium and endoplasmic reticulum (ER) stress have been reported to be linked with adipogenesis and obesity. Because pyrethroid insecticides have been determined to influence intracellular calcium and ER stress in vitro, the purpose of this current study was to investigate whether permethrin potentiates adipogenesis via a change in intracellular calcium, leading to endoplasmic reticulum (ER) stress in 3T3-L1 adipocytes. 3T3-L1 cells were exposed to four different concentrations of permethrin (0.01, 0.1, 1 & 10 µM) for 6 days during differentiation. Treatment of permethrin increased intracellular calcium level in a concentration-dependent manner. Similarly, permethrin treatment increased protein levels of ER stress markers in a concentration-dependent manner. These data suggest that intracellular calcium and ER stress may be involved in permethrin-induced adipogenesis of 3T3-L1 cells.
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Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Calcio/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Insecticidas/efectos adversos , Permetrina/efectos adversos , Células 3T3-L1 , Adipocitos/citología , Adipocitos/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Ratones , Permetrina/farmacologíaRESUMEN
Previously 10 µM permethrin (38.7% cis and 59.4% trans isomers), a pyrethroid insecticide widely used in agriculture and household products for pest control, was reported to reduce insulin-stimulated glucose uptake and phosphorylation of protein kinase B (p-AKT) in C2C12 mouse myotubes. The underlying mechanisms on how permethrin decreases insulin-stimulated AKT phosphorylation, however, are unknown. Thus, the goal of this study was to determine the possible mechanism(s) through which permethrin reduced insulin-stimulated AKT phosphorylation in C2C12 myotubes. Permethrin treatment, at 10 µM, decreased insulin-stimulated membrane glucose transporter type 4 (GLUT4) and AKT phosphorylation, and increased insulin receptor substrate 1 (IRS1) Ser307 phosphorylation in the presence of insulin. The inactivation of AKT by permethrin was independent of AMPKα. ERK inactivation by U0126, however, restored insulin-stimulated AKT phosphorylation, which was decreased by permethrin treatment. These results suggest that permethrin decreased insulin-stimulated AKT phosphorylation via ERK activation, but not by AMPKα inactivation.
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Proteínas Quinasas Activadas por AMP/metabolismo , Insecticidas/farmacología , Insulina/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fibras Musculares Esqueléticas/efectos de los fármacos , Permetrina/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Animales , Transportador de Glucosa de Tipo 4/metabolismo , Ratones , Proteína Quinasa 3 Activada por Mitógenos/genética , Fibras Musculares Esqueléticas/enzimología , Fibras Musculares Esqueléticas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Many studies have shown that dietary intake of ω-3 polyunsaturated fatty acids (PUFAs) reduces the risks of colorectal cancer; however, the underlying mechanisms are not well understood. Here we used a LC-MS/MS-based lipidomics to explore the role of eicosanoid signaling in the anti-colorectal cancer effects of ω-3 PUFAs. Our results showed that dietary feeding of ω-3 PUFAs-rich diets suppressed growth of MC38 colorectal tumor, and modulated profiles of fatty acids and eicosanoid metabolites in C57BL/6 mice. Notably, we found that dietary feeding of ω-3 PUFAs significantly increased levels of epoxydocosapentaenoic acids (EDPs, metabolites of ω-3 PUFA produced by cytochrome P450 enzymes) in plasma and tumor tissue of the treated mice. We further showed that systematic treatment with EDPs (dose=0.5 mg/kg per day) suppressed MC38 tumor growth in mice, with reduced expressions of pro-oncogenic genes such as C-myc, Axin2, and C-jun in tumor tissues. Together, these results support that formation of EDPs might contribute to the anti-colorectal cancer effects of ω-3 PUFAs.
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Neoplasias Colorrectales/dietoterapia , Sistema Enzimático del Citocromo P-450/metabolismo , Eicosanoides/metabolismo , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Insaturados/farmacología , Animales , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Eicosanoides/sangre , Humanos , Masculino , Ratones Endogámicos C57BL , Espectrometría de Masas en Tándem , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Imidacloprid, a neonicotinoid insecticide, was previously reported to enhance adipogenesis and resulted in insulin resistance in cell culture models. It was also reported to promote high fat diet-induced obesity and insulin resistance in male C57BL/6J mice. Thus, the goal of the present study was to determine the effects of imidacloprid and dietary fat interaction on the development of adiposity and insulin resistance in female C57BL/6J mice. Mice were fed with a low (4% w/w) or high fat (20% w/w) diet containing imidacloprid (0.06, 0.6, or 6 mg/kg bw/day) for 12 weeks. Mice fed with imidacloprid (0.6 mg/kg bw/day) significantly enhanced high fat diet-induced weight gain and adiposity. Treatment with imidacloprid significantly increased serum insulin levels with high fat diet without effects on other markers of glucose homeostasis. AMPKα activation was significantly inhibited by 0.6 and 6 mg imidacloprid/kg bw/day in white adipose tissue. Moreover, AMPKα activation with 5-aminoimidazole-4-carboxamide ribonucleotide abolished the effects of imidacloprid (10 µM) on enhanced adipogenesis in 3T3-L1 adipocytes. N-Acetyl cysteine also partially reversed the effects of imidacloprid on reduced phosphorylation of protein kinase B (AKT) in C2C12 myotubes. These results indicate that imidacloprid may potentiate high fat diet-induced adiposity in female C57BL/6J mice and enhance adipogenesis in 3T3-L1 adipocytes via the AMPKα-mediated pathway. Imidacloprid might also influence glucose homeostasis partially by inducing cellular oxidative stress in C2C12 myotubes.