RESUMO
In this study, we focused on confirming the steroid hormone receptor-mediated endocrine-disrupting potential of the pyrethroid insecticide fenvalerate and unraveling the underlying mechanisms. Therefore, we assessed estrogen receptor-α (ERα)- and androgen receptor (AR)-mediated responses in vitro using a hormone response element-dependent transcription activation assay with a luciferase reporter following the Organization for Economic Cooperation and Development (OECD) test guidelines. We observed that fenvalerate acted as estrogen by inducing the translocation of cytosolic ERα to the nucleus via ERα dimerization, whereas it exhibited no AR-mediated androgen response element-dependent luciferase activity. Furthermore, we confirmed that fenvalerate-induced activation of ERα caused lipid accumulation, promoted in a fenvalerate-dependent manner in 3 T3-L1 adipocytes. Moreover, fenvalerate-induced lipid accumulation was inhibited in the presence of an ERα-selective antagonist, whereas it remained unaffected in the presence of a glucocorticoid receptor (GR)-specific inhibitor. In addition, fenvalerate was found to stimulate the expression of transcription factors that promote lipid accumulation in 3 T1-L1 adipocytes, and co-treatment with an ERα-selective antagonist suppressed adipogenic/ lipogenic transcription factors at both mRNA and protein levels. These findings suggest that fenvalerate exposure may lead to lipid accumulation by interfering with ERα activation-dependent processes, thus causing an ERα-mediated endocrine-disrupting effect.
Assuntos
Células 3T3-L1 , Disruptores Endócrinos , Receptor alfa de Estrogênio , Nitrilas , Piretrinas , Piretrinas/toxicidade , Animais , Nitrilas/toxicidade , Camundongos , Disruptores Endócrinos/toxicidade , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Inseticidas/toxicidade , Organização para a Cooperação e Desenvolvimento EconômicoRESUMO
Tetrabromobisphenol A (TBBPA), a widely-used brominated flame retardant, has been revealed to exert endocrine disrupting effects and induce adipogenesis. Given the high structural similarities of TBBPA analogues and their increasing exposure risks, their effects on lipid metabolism are necessary to be explored. Herein, 9 representative TBBPA analogues were screened for their interference on 3T3-L1 preadipocyte adipogenesis, differentiation of C3H10T1/2 mesenchymal stem cells (MSCs) to brown adipocytes, and lipid accumulation of HepG2 cells. TBBPA bis(2-hydroxyethyl ether) (TBBPA-BHEE), TBBPA mono(2-hydroxyethyl ether) (TBBPA-MHEE), TBBPA bis(glycidyl ether) (TBBPA-BGE), and TBBPA mono(glycidyl ether) (TBBPA-MGE) were found to induce adipogenesis in 3T3-L1 preadipocytes to different extends, as evidenced by the upregulated intracellular lipid generation and expressions of adipogenesis-related biomarkers. TBBPA-BHEE exhibited a stronger obesogenic effect than did TBBPA. In contrast, the test chemicals had a weak impact on the differentiation process of C3H10T1/2 MSCs to brown adipocytes. As for hepatic lipid formation test, only TBBPA mono(allyl ether) (TBBPA-MAE) was found to significantly promote triglyceride (TG) accumulation in HepG2 cells, and the effective exposure concentration of the chemical under oleic acid (OA) co-exposure was lower than that without OA co-exposure. Collectively, TBBPA analogues may perturb lipid metabolism in multiple tissues, which varies with the test tissues. The findings highlight the potential health risks of this kind of emerging chemicals in inducing obesity, non-alcoholic fatty liver disease (NAFLD) and other lipid metabolism disorders, especially under the conditions in conjunction with high-fat diets.
Assuntos
Células 3T3-L1 , Adipogenia , Retardadores de Chama , Metabolismo dos Lipídeos , Bifenil Polibromatos , Bifenil Polibromatos/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Animais , Camundongos , Adipogenia/efeitos dos fármacos , Humanos , Retardadores de Chama/toxicidade , Células Hep G2 , Diferenciação Celular/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismoRESUMO
Obesity is primarily exacerbated by excessive lipid accumulation during adipogenesis, with triacylglycerol (TG) as a major lipid marker. However, as the association between numerous lipid markers and various health conditions has recently been revealed, investigating the lipid metabolism in detail has become necessary. This study investigates the lipid metabolic effects of Hydrangea serrata (Thunb.) Ser. hot water leaf extract (WHS) on adipogenesis using LC-MS-based lipidomics analysis of undifferentiated, differentiated, and WHS-treated differentiated 3T3-L1 cells. WHS treatment effectively suppressed the elevation of glycerolipids, including TG and DG, and prevented a molecular shift in fatty acyl composition towards long-chain unsaturated fatty acids. This shift also impacted glycerophospholipid metabolism. Additionally, WHS stabilized significant lipid markers such as the PC/PE and LPC/PE ratios, SM, and Cer, which are associated with obesity and related comorbidities. This study suggests that WHS could reduce obesity-related risk factors by regulating lipid markers during adipogenesis. This study is the first to assess the underlying lipidomic mechanisms of the adipogenesis-inhibitory effect of WHS, highlighting its potential in developing natural products for treating obesity and related conditions. Our study provides a new strategy for the development of natural products for the treatment of obesity and related diseases.
Assuntos
Células 3T3-L1 , Adipogenia , Hydrangea , Metabolismo dos Lipídeos , Lipidômica , Extratos Vegetais , Folhas de Planta , Adipogenia/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Animais , Camundongos , Hydrangea/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Água/química , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Triglicerídeos/metabolismo , Obesidade/prevenção & controleRESUMO
Cyhalofop-butyl (CB) poses a significant threat to aquatic organisms, but there is a discrepancy in evidence about hepatotoxicity after prolonged exposure to environmental levels. The aim of this study was to investigate long-term hepatotoxicity and its effects on the gut-liver axis through the exposure of zebrafish to environmental concentrations of CB (0.1,1,10 µg/L) throughout their life cycle. Zebrafish experienced abnormal obesity symptoms and organ index after a prolonged exposure of 120 days. The gut-liver axis was found to be damaged both morphologically and functionally through an analysis of histology, electron microscopy subcellular structure, and liver function. The disruption of the gut-liver axis inflammatory process by CB is suggested by the rise in inflammatory factors and the alteration of inflammatory genes. Furthermore, there was a noticeable alteration in the blood and gut-liver axis biochemical parameters as well as gene expression linked to lipid metabolism, which may led to an imbalance in the gut flora. In conclusion, the connection between the gut-liver axis, intestinal microbiota, and liver leads to the metabolic dysfunction of zebrafish exposed to long-term ambient concentrations of CB, and damaged immune system and liver lipid metabolism. This study gives another knowledge into the hepatotoxicity component of long haul openness to ecological centralization of CB, and might be useful to assess the potential natural and wellbeing dangers of aryloxyphenoxypropionate herbicides.
Assuntos
Fígado , Poluentes Químicos da Água , Peixe-Zebra , Animais , Fígado/efeitos dos fármacos , Fígado/patologia , Poluentes Químicos da Água/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacosRESUMO
Microplastics (MP) and nanoplastics (NP) pollutions pose a rising environmental threat to humans and other living species, given their escalating presence in essential resources that living subjects ingest and/or inhale. Herein, to elucidate the potential health implications of MP/NP, we report for the first time by using label-free hyperspectral stimulated Raman scattering (SRS) imaging technique developed to quantitatively monitor the bioaccumulation and metabolic toxicity of MP/NP within live zebrafish larvae during their early developmental stages. Zebrafish embryos are exposed to environmentally related concentrations (3-60 µg/ml) of polystyrene (PS) beads with two typical sizes (2 µm and 50 nm). Zebrafish are administered isotope-tagged fatty acids through microinjection and dietary intake for in vivo tracking of lipid metabolism dynamics. In vivo 3D quantitative vibrational imaging of PS beads and intrinsic biomolecules across key zebrafish organs reveals that gut and liver are the primary target organs of MP/NP, while only 50 nm PS beads readily aggregate and adhere to the brain and blood vessels. The 50 nm PS beads are also found to induce more pronounced hepatic inflammatory response compared to 2 µm counterparts, characterized by increased biogenesis of lipid droplets and upregulation of arachidonic acid detected in zebrafish liver. Furthermore, Raman-tagged SRS imaging of fatty acids uncovers that MP/NP exposure significantly reduces yolk lipid utilization and promotes dietary lipid storage in zebrafish, possibly associated with developmental delays and more pronounced food dilution effects in zebrafish larvae exposed to 2 µm PS beads. The hyperspectral SRS imaging in this work shows that MP/NP exposure perturbs the development and lipid metabolism in zebrafish larvae, furthering the understanding of MP/NP ingestions and consequent toxicity in different organs in living species.
Assuntos
Metabolismo dos Lipídeos , Microplásticos , Peixe-Zebra , Animais , Microplásticos/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Larva/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Microscopia Óptica não Linear/métodos , Análise Espectral Raman/métodos , Monitoramento Ambiental/métodos , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Poliestirenos/toxicidadeRESUMO
Vitamin D deficiency is associated with poor mental health and dysmetabolism. Several metabolic abnormalities are associated with psychotic diseases, which can be compounded by atypical antipsychotics that induce weight gain and insulin resistance. These side-effects may be affected by vitamin D levels. The gut microbiota and endocannabinoidome (eCBome) are significant regulators of both metabolism and mental health, but their role in the development of atypical antipsychotic drug metabolic side-effects and their interaction with vitamin D status is unknown. We studied the effects of different combinations of vitamin D levels and atypical antipsychotic drug (olanzapine) exposure on whole-body metabolism and the eCBome-gut microbiota axis in female C57BL/6J mice under a high fat/high sucrose (HFHS) diet in an attempt to identify a link between the latter and the different metabolic outputs induced by the treatments. Olanzapine exerted a protective effect against diet-induced obesity and insulin resistance, largely independent of dietary vitamin D status. These changes were concomitant with olanzapine-mediated decreases in Trpv1 expression and increases in the levels of its agonists, including various N-acylethanolamines and 2-monoacylglycerols, which are consistent with the observed improvement in adiposity and metabolic status. Furthermore, while global gut bacteria community architecture was not altered by olanzapine, we identified changes in the relative abundances of various commensal bacterial families. Taken together, changes of eCBome and gut microbiota families under our experimental conditions might contribute to olanzapine and vitamin D-mediated inhibition of weight gain in mice on a HFHS diet.
Assuntos
Antipsicóticos/farmacologia , Endocanabinoides/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/tratamento farmacológico , Olanzapina/farmacologia , Vitamina D/farmacologia , Aldo-Ceto Redutases/genética , Aldo-Ceto Redutases/metabolismo , Amidoidrolases/genética , Amidoidrolases/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Sacarose Alimentar/efeitos adversos , Etanolaminas/metabolismo , Feminino , Regulação da Expressão Gênica , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Monoacilglicerol Lipases/genética , Monoacilglicerol Lipases/metabolismo , Monoglicerídeos/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Aumento de Peso/efeitos dos fármacosRESUMO
Obesity and associated metabolic disorders are heading up with an alarming rate in developing nations. One of highly sought solution for metabolic disorders is to identify natural molecule with an ability to reduce obesity and increase insulin sensitivity. Coelogin (CLN) is a phenanthrene derivative isolated from the ethanolic extract of Coelogyne cristata. In our constant efforts to identify novel anti-dyslipidemic and anti-adipogenic compounds using CFPMA (common feature pharmacophore model using known anti-adipogenic compounds) model, predicted possible anti-adipogenic activity of CLN. In vitro results showed significant inhibition of adipogenesis in 3T3-L1 and C3H10T1/2 cell by CLN. It arrests the cell cycle in G1 phase of interphase and inhibits mitotic clonal expansion to regulate adipogenesis. CLN elicits insulin sensitizing effect in mature adipocytes. During extracellular flux assessment studies, it increases oxidative respiration and energy expenditure in adipocytes. In vivo, CLN reversed HFD-induced dyslipidemia as well as insulin resistance in C57BL/6 mice. It promoted the expression of genes involved in improved mitochondrial function and fatty acid oxidation in eWAT. CLN restored energy expenditure and increased the capacity of energy utilization in HFD fed mice. Taken together, the study indicated beneficial effects of CLN in combating obesity-associated metabolic complications.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Obesidade/tratamento farmacológico , Fenantrenos/uso terapêutico , Piranos/uso terapêutico , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Fármacos Antiobesidade/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glicerol/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/metabolismo , Oxigênio/metabolismo , Fenantrenos/farmacologia , Piranos/farmacologiaRESUMO
P5 (LILPKHSDAD) is a hypocholesterolemic peptide from lupin protein with a multi-target activity, since it inhibits both 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) and proprotein convertase subtilisin/kexin type-9 (PCSK9). This work shows that, during epithelial transport experiments, the metabolic transformation mediated by intestinal peptidases produces two main detected peptides, ILPKHSDAD (P5-frag) and LPKHSDAD (P5-met), and that both P5 and P5-met are linearly absorbed by differentiated human intestinal Caco-2 cells. Extensive comparative structural, biochemical, and cellular characterizations of P5-met and the parent peptide P5 demonstrate that both peptides have unique characteristics and share the same mechanisms of action. In fact, they exert an intrinsically multi-target behavior being able to regulate cholesterol metabolism by modulating different pathways. The results of this study also highlight the dynamic nature of bioactive peptides that may be modulated by the biological systems they get in contact with.
Assuntos
Transporte Biológico/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lupinus/química , Peptídeos/farmacocinética , Proteínas de Plantas/farmacocinética , Células CACO-2 , Células Hep G2 , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Mucosa Intestinal/metabolismo , Pró-Proteína Convertase 9/metabolismoRESUMO
Luteolin (LU) is a flavonoid compound and metformin hydrochloride (MH) is a kind of drug. Studies have shown that both LU and MH have the function of hypoglycemic effect. However, there are few reports indicating that LU cooperated with MH (LU·MH) can relieve lipid metabolism disorders and optimize intestinal flora compositions of high-fat diet mice. In this research, we investigated the effects of LU, MH and LU·MH on lipid metabolism disorders and intestinal flora composition in high-fat diet mice. The study found that compared with high-fat diet (HFD) alone, LU, MH and LU·MH could significantly reduce the lipid metabolism disorder. Furthermore, compared with LU or MH alone, the biochemical indicators of LU·MH were significantly improved and the results of the histopathological section also showed that LU·MH has stronger liver repair ability. It revealed that the potential mechanisms of the LU·MH alleviating lipid metabolism disorders were involved in the simultaneous regulation of SREBP-1c/FAS and SREBP-1c/ACC/Cpt-1. In addition, LU·MH could regulate the intestinal flora compositions. This includes significantly reducing the ratio of Firmicutes and Bacteroidetes(F/B) and at the family level, increasing the relative abundance of Lachnospiraceae, Helicobacteraceae, Marinifilaceae and Peptococcaceae to relieve lipid metabolism disorders. In conclusion, the work found that LU·MH regulates the signal pathway of SREBP-1c/FAS and SREBP-1c/ACC/Cpt-1 simultaneously and decreases the ratio of F/B, as well as increases the relative abundance of certain microbiota to alleviate the lipid metabolism disorders of HFD-fed mice.
Assuntos
Transtornos do Metabolismo dos Lipídeos/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Luteolina/administração & dosagem , Metformina/administração & dosagem , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Dieta Hiperlipídica/efeitos adversos , Quimioterapia Combinada , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Transtornos do Metabolismo dos Lipídeos/etiologia , Transtornos do Metabolismo dos Lipídeos/metabolismo , Transtornos do Metabolismo dos Lipídeos/microbiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
Indiscriminate overuse or occupational exposure to agricultural chemicals can lead to neurotoxicity. Many pesticides act to impair mitochondrial function which can lead to exacerbation of neurodegeneration. Triazole fungicides are applied to grain, fruit, and vegetable crops to combat mold and fungi and their use is increasing worldwide. Here, we assessed the in vitro toxicity of two widely used triazole fungicides, propiconazole and tebuconazole, to mitochondria using differentiated SH-SY5Y neuroblastoma cells as an in vitro cell model used in Parkinson's disease research. Cell viability (based on ATP levels), mitochondrial membrane potential, oxidative respiration, and reactive oxygen species (ROS) were measured following fungicide treatments. Cell viability was decreased with 100 µM propiconazole after 24 and 48 h, while tebuconazole required higher doses to affect viability (-200 µM at 24 h). Mitochondrial membrane potential (MMP) was reduced with 50 µM propiconazole after 24 h while 200 µM tebuconazole reduced MMP. Oxidative respiration of SH-SY5Y cells was then measured using a XFe24 Flux analyzer and 100 µM propiconazole reduced basal respiration, oligomycin-induced ATP production, and FCCP-induced maximum respiration by -40-50%, while tebuconazole did not affect mitochondrial bioenergetics at the concentrations tested. Acute exposure to 100 µM propiconazole over 4 h did not immediately affect oxidative respiration in SH-SY5Y cells. ROS were not induced by propiconazole and tebuconazole up to 100 and 300 µM respectively. Based on these results, we focused our lipidomics investigations on SH-SY5Y exposed only to propiconazole, as lipid dysregulation is associated with mitochondrial dysfunction. Both 50 and 100 µM propiconazole altered the abundance of some ceramides, specifically reducing glucosylceramide non-hydroxyfatty acid-sphingosine (HexCer-NS) and increasing N-stearoyl-phytosphingosine (CerNP). Moreover, a recently discovered bioactive lipid called fatty acid ester of hydroxy fatty acid (FAHFA) was increased 5-fold, hypothesized to be a neuroprotective mechanism that has been demonstrated in other studies of human diseases. Additional lipids reduced in abundance included oxidized phosphatidylcholine (OxPC) and oxidized phosphatidylethanolamine (OxPE). There were no changes in cellular triacylglycerols nor total lipids with exposure to propiconazole. Taken together, this study provides insight into the toxicity of triazole fungicides in neuronal cells, which has implications for neurodegenerative diseases that involve the mitochondria such as Parkinson's disease.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Triazóis/toxicidade , Linhagem Celular Tumoral , Humanos , Lipidômica , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , OxirreduçãoRESUMO
Significant attention has been given to the potential of environmental chemicals to disrupt lipid homeostasis at the cellular level. These chemicals, classified as obesogens, are abundantly used in a wide variety of consumer products. However, there is a significant lack of information regarding the mechanisms by which environmental exposure can contribute to the onset of obesity and non-alcoholic fatty liver disease (NAFLD). Several studies have described the interaction of potential obesogens with lipid-related peroxisome proliferator-activated receptors (PPAR). However, no studies have quantified the degree of modification to lipidomic profiles in relevant human models, making it difficult to directly link PPAR agonists to the onset of lipid-related diseases. A quantitative metabolomic approach was used to examine the dysregulation of lipid metabolism in human liver cells upon exposure to potential obesogenic compounds. The chemicals rosiglitazone, perfluorooctanoic acid, di-2-ethylexylphthalate, and tributyltin significantly increased total lipids in liver cells, being diglycerides, triglycerides and phosphatidylcholines the most prominent. Contrarily, perfluorooctane sulfonic acid and the pharmaceutical fenofibrate appeared to lower total lipid concentrations, especially those belonging to the acylcarnitine, ceramide, triglyceride, and phosphatidylcholine groups. Fluorescence microscopy analysis for cellular neutral lipids revealed significant lipid bioaccumulation upon exposure to obesogens at environmentally relevant concentrations. This integrated omics analysis provides unique mechanistic insight into the potential of these environmental pollutants to promote diseases like obesity and NAFLD. Furthermore, this study provides a significant contribution to advance the understanding of molecular signatures related to obesogenic chemicals and to the development of alternatives to in vivo experimentation.
Assuntos
Exposição Ambiental/efeitos adversos , Poluentes Ambientais/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Obesidade/induzido quimicamente , Obesidade/metabolismo , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolômica/métodos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR gama/metabolismoRESUMO
Withania somnifera (WS), commonly known as ashwagandha, possesses diverse biological functions. WS root has mainly been used as an herbal medicine to treat anxiety and was recently reported to have an anti-obesity effect, however, the mechanisms underlying its action remain to be explored. We hypothesized that WS exerts its anti-obesity effect by enhancing energy expenditure through improving the mitochondrial function of brown/beige adipocytes and skeletal muscle. Male C57BL/6J mice were fed a high-fat diet (HFD) containing 0.25% or 0.5% WS 70% ethanol extract (WSE) for 10 weeks. WSE (0.5%) supplementation significantly suppressed the increases in body weight and serum lipids, and lipid accumulation in the liver and adipose tissue induced by HFD. WSE supplementation increased oxygen consumption and enhanced mitochondrial activity in brown fat and skeletal muscle in the HFD-fed mice. In addition, it promoted browning of subcutaneous fat by increasing mitochondrial uncoupling protein 1 (UCP1) expression. Withaferin A (WFA), a major compound of WS, enhanced the differentiation of pre-adipocytes into beige adipocytes and oxygen consumption in C2C12 murine myoblasts. These results suggest that WSE ameliorates diet-induced obesity by enhancing energy expenditure via promoting mitochondrial function in adipose tissue and skeletal muscle, and WFA is a key regulator in this function.
Assuntos
Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Fármacos Antiobesidade , Suplementos Nutricionais , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Obesidade/tratamento farmacológico , Fitoterapia , Extratos Vegetais/farmacologia , Withania/química , Vitanolídeos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Consumo de Oxigênio/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Vitanolídeos/administração & dosagem , Vitanolídeos/isolamento & purificaçãoRESUMO
The evaluation of bioconcentration, toxicity, and hazard (BTH) of persistent lipophilic organic compounds (LOCs) are generally performed as separate rather than integrated assessments. There are adequate data sets in the literature for chlorobenzenes (CBs) consisting of (a) concentrations in aquatic biota (CB) and water (Cw) in the natural environment, (b) laboratory-derived bioconcentration factors (KB) and field concentration ratios (CR), the field equivalent factor of KB, (c) measured internal lethal concentrations (ILC50) and model estimated ILC50 calculated from KB and lethal concentrations (LC50), and (d) calculated hazard quotients in aquatic biota (HQB) and in water (HQW). However, there have been no integrated studies of those parameter values based on the respective lipid-based parameters (CBL, KBL, CRL, ILC50L, HQBL) performed. This study utilized the lipid-based parameters for CBs; a group of widely occuring, bioaccumulative, and toxic LOCs, and integrated those parameters into a bioconcentration-toxicity-hazard (BTHL) index. The values of the parameters were obtained from selected literature with known lipid contents of the aquatic biota. The results showed that the laboratory derived bioconcentration factors, KBLs, were comparable to the corresponding field based factors, CRLs, and the measured internal lethal concentrations, ILC50L, showed comparable values with the estimated ones. The integrated BTHL index was less than an order of magnitude or moderately acceptable for the assessment of variability, uncertainty, and predictive power of the index. This integrated assessment can be used to support decision making dealing with CBs in specific and LOCs in general, both in regional and global aquatic environments.
Assuntos
Clorobenzenos/análise , Clorobenzenos/toxicidade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade , Animais , Bioacumulação , Clorobenzenos/farmacocinética , Ecotoxicologia/métodos , Dose Letal Mediana , Metabolismo dos Lipídeos/efeitos dos fármacos , Poluentes Químicos da Água/farmacocinéticaRESUMO
Acetamide (CAS 60-35-5) is detected in common foods. Chronic rodent bioassays led to its classification as a group 2B possible human carcinogen due to the induction of liver tumors in rats. We used a toxicogenomics approach in Wistar rats gavaged daily for 7 or 28 days at doses of 300 to 1500 mg/kg/day (mkd) to determine a point of departure (POD) and investigate its mode of action (MoA). Ki67 labeling was increased at doses ≥750 mkd up to 3.3-fold representing the most sensitive apical endpoint. Differential gene expression analysis by RNA-Seq identified 1110 and 1814 differentially expressed genes in male and female rats, respectively, following 28 days of treatment. Down-regulated genes were associated with lipid metabolism while up-regulated genes included cell signaling, immune response, and cell cycle functions. Benchmark dose (BMD) modeling of the Ki67 labeling index determined the BMD10 lower confidence limit (BMDL10) as 190 mkd. Transcriptional BMD modeling revealed excellent concordance between transcriptional POD and apical endpoints. Collectively, these results indicate that acetamide is most likely acting through a mitogenic MoA, though specific key initiating molecular events could not be elucidated. A POD value of 190 mkd determined for cell proliferation is suggested for risk assessment purposes.
Assuntos
Acetamidas/toxicidade , Carcinógenos/toxicidade , Contaminação de Alimentos , Neoplasias Hepáticas/genética , Modelos Biológicos , Animais , Carcinogênese/induzido quimicamente , Carcinogênese/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunidade/efeitos dos fármacos , Imunidade/genética , Antígeno Ki-67/análise , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Masculino , RNA-Seq , Ratos , Ratos Wistar , Medição de Risco/métodos , Testes de Toxicidade Crônica/métodos , Regulação para Cima/efeitos dos fármacosRESUMO
Objectives: To examine metabolic monitoring rates in commercially insured children and adolescents treated with a second-generation antipsychotic (SGA) during calendar years (CYs) 2016 and 2017. Methods: In this retrospective study, data were collected from a large national commercial health plan for the period covering January 1, 2016 to December 31, 2017. Commercially insured children and adolescents, aged 8-19 years with ≥2 SGA prescription claims during the CY, were identified for the CY2016 and CY2017 cohorts. The primary outcome of interest was the percentage of subjects with any glucose or lipid metabolism parameter monitoring. Other calculated metabolic testing rates included glucose, hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), other cholesterol (including triglycerides), and combined glucose and lipid metabolism testing (≥1 test for blood glucose or HbA1c and ≥1 test for LDL-C or other cholesterol). Results: In CY2016 and CY2017, 1502 and 1239 subjects, respectively, were identified for this study. The most common psychiatric diagnoses in CY2016 and CY2017 were major depressive disorder (57.1%, 56.5%, respectively), anxiety disorders (42.9%, 47.5%), attention-deficit/hyperactivity disorder (41.6%, 45.8%), and bipolar disorder (24.1%, 25.9%). The rate of any metabolic testing was 53.5% in CY2016 and 51.3% in CY2017. Glucose testing (50.3%, 46.9%, respectively) was most common in both CYs, followed by LDL-C testing (31.2%, 28.5%). Rates of combined glucose and lipid metabolism testing were 30.7% in CY2016 and 26.9% in CY2017. Conclusions: Given the known potential for adverse cardiometabolic effects, rates of metabolic monitoring associated with SGA use in children and adolescents urgently need to be improved. There is a critical need for understanding barriers to routine monitoring, particularly of lipids, and developing interventions to enhance metabolic monitoring.
Assuntos
Antipsicóticos/efeitos adversos , Glicemia/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Adolescente , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacologia , Criança , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Estudos Retrospectivos , Estados Unidos , Adulto JovemRESUMO
Rhizoma Paridis hepatotoxicity is a risk factor limiting its extensive use in clinic, there is limited information available regarding the mechanism by which typical environmental levels of exposure can contribute to the onset of this disease. The adult zebrafish were exposed to Rhizoma Paridis at a sub-lethal concentration. The alterations in protein expression profiles and metabolite levels in the adult zebrafish liver, a popular model for toxicity assessment, exposed to the Rhizoma Paridis were observed. The result showed that Rhizoma Paridis exposure treatment caused an obvious toxic effect on the zebrafish liver, resulting in a significant change of the liver organization structure and various biochemical parameters. The hepatotoxicity of adult zebrafish liver induced by Rhizoma Paridis was mainly associated with lipid metabolism and energy metabolism disorder. Furthermore, oxidative stress injury, inflammation, and endoplasmic reticulum stress might also be involved in the hepatotoxicity. Our study facilitated the understanding of molecular signatures of toxic effects of Rhizoma Paridis causing liver injury to move away from the risk assessment based on in vivo animal experiments.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Melanthiaceae/química , Metabolômica , Proteômica , Animais , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Medicina Tradicional Chinesa , Estresse Oxidativo/efeitos dos fármacos , Rizoma , Peixe-ZebraRESUMO
During early postnatal development, biomolecules are particularly exposed to the detrimental actions of unneutralized reactive oxygen species. These prooxidant molecules have been claimed to mediate the trade-off between growth and somatic maintenance. Vitamin E is a key exogenous antioxidant that plays an important role in protecting biological membranes against oxidative damage. However, evidence of the effect of vitamin E supplementation during early life on growth and oxidative status in wild populations is equivocal. We tested the effect of supplementing western bluebird nestlings (Sialia mexicana) with vitamin E on growth rate, antioxidant capacity, and oxidative damage to lipids. During the period of accelerated growth (5-8 d), bill growth rate was 21% higher in supplemented nestlings from nests with breeding helpers than in supplemented nestlings from unassisted nests. Vitamin E also boosted tarsus growth rate during the period of slow growth (11-18 d), and this effect was independent of the presence of breeding helpers. Differences in body size and mass, oxidative damage to lipids, and antioxidant capacity were not evident between supplemented and control nestlings at 18 d. Therefore, we conclude that vitamin E promoted faster bill and tarsus growth, but this transient effect disappeared as soon as the supplementation ceased. Our experimental study also supports the idea that tocopherols are rapidly metabolized, since we failed to detect any evident increase of vitamin E in supplemented nestlings at age 18 d. These results provide partial support for the hypothesis that growth rate is constrained by its costs in terms of increased susceptibility to oxidative stress.
Assuntos
Antioxidantes/metabolismo , Metabolismo dos Lipídeos , Micronutrientes/farmacologia , Estresse Oxidativo , Aves Canoras/fisiologia , Vitamina E/farmacologia , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Micronutrientes/administração & dosagem , Comportamento de Nidação , Aves Canoras/crescimento & desenvolvimento , Vitamina E/administração & dosagemRESUMO
Trophodynamics and risks of polychlorinated biphenyls (PCBs) in organisms from the Zhoushan fishing ground (ZFG), China were studied. Σ22PCBs varied from 1.36 to 36.75â¯ng/g wet weight, which were far below the maximum residue levels allowed in fishery products. However, estimated daily intake and hazard ratio calculations present possible adverse effects due to PCB pollution. Significantly positive correlations appeared between wet-weighted concentrations of target chemicals and trophic levels (TLs) of the organisms, with trophic magnification factors (TMFs) from 1.15 to 9.72. The TMF values first increased with an increase of compound's KOW values, and then decreased, with log KOW around 7.0 as an inflection point. TL is suggested as the key factor controlling contaminant burden among the species for only PCBs 105, 138, 153, and 171. For the remaining PCBs, lipid content of the organism or metabolite capacity of the compound may be more important influence on their bioaccumulation.
Assuntos
Cadeia Alimentar , Bifenilos Policlorados/análise , Poluentes Químicos da Água/análise , Animais , Biotransformação , China , Monitoramento Ambiental , Contaminação de Alimentos/análise , Metabolismo dos Lipídeos/efeitos dos fármacos , Bifenilos Policlorados/metabolismo , Medição de Risco , Alimentos Marinhos/análise , Poluentes Químicos da Água/metabolismoRESUMO
Lipids from trabecular meshwork (TM) cells are of particular interest to ophthalmological researchers as a therapeutic target for lowering intraocular pressure (IOP) in glaucomatous eyes. Fluorescence-based lipid transport assays (FBLTA) and immunocytochemistry (ICC) are dynamic fluorescence analysis techniques that allow for quantitative and qualitative comparisons, respectively, between multiple samples. Here we describe methods for FBLTA, ICC, and mass spectroscopy designed to measure the kinetics and localization of lipid metabolites within the trabecular meshwork.
Assuntos
Lipidômica/métodos , Lipídeos/isolamento & purificação , Malha Trabecular/metabolismo , Células Cultivadas , Fluorescência , Glaucoma/tratamento farmacológico , Glaucoma/patologia , Humanos , Imuno-Histoquímica/métodos , Pressão Intraocular/efeitos dos fármacos , Cinética , Metabolismo dos Lipídeos/efeitos dos fármacos , Espectrometria de Massas/métodos , Cultura Primária de Células , Malha Trabecular/citologia , Malha Trabecular/efeitos dos fármacosRESUMO
In this study, the antihypertensive activity of Purafect®-smooth hound viscera protein hydrolysate (VPH) and its peptide fraction with molecular weight (MW) below 1 kDa (VPH-I) was investigated. In addition, the lipase inhibitory activity, as well the anticoagulant potential, in vitro, were assessed. The antihypertensive effects of VPH and VPH-I were studied during 24 h (short-term effect) and 30 days (long-term effect) using high-salt (18% NaCl) and -fructose (10%) diet (HSFD)-induced hypertension. Data showed that, 4 h post-administration of VPH and VPH-I (200 mg/kg BW), the systolic blood pressure of rats was reduced by about 6 and 9 mmHg, respectively. These effects were similar to that obtained with Captopril (~9 mmHg at t = 4 h). On the other hand, exposing the rats to daily to HSFD, coupled to the administration of viscera peptides, was found to attenuate hypertension. In addition, the proteins' treatments were able to correct lipid and glycemic disorders, by reducing the total cholesterol and triglyceride contents and resorting to the plasma glucose level, compared to the HSFD group. Overall, the present findings demonstrated the preventive effect of VPH-peptides from hypertension complications, as a result of their biological properties.