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1.
PLoS One ; 15(8): e0237665, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866166

RESUMO

AIMS: Inflammation plays a pivotal role in atherothrombosis. Colchicine is an anti-inflammatory drug that may attenuate this process. Cardiovascular protective effects of anti-inflammatory drugs, however, seem to be limited to patients with a biochemical response. We therefore investigated whether short-term exposure to colchicine reduced inflammatory markers and whether additional laboratory changes occur in patients with chronic coronary artery disease. METHODS & RESULTS: In 138 consecutive patients with chronic coronary artery disease and a high sensitivity C-reactive Protein (hs-CRP) ≥ 2 mg/L, inflammatory markers, lipids, haematologic parameters and renal function were measured at baseline and after 30 days exposure to colchicine 0.5mg once daily. Hs-CRP decreased from baseline 4.40 mg/L (interquartile range [IQR] 2.83-6.99 mg/L) to 2.33 mg/L (IQR 1.41-4.17, median of the differences -1.66 mg/L, 95% confidence interval [CI] -2.17 - -1.22 mg/L, p-value <0.01), corresponding to a median change from baseline of -40%. Interleukin-6 decreased from 2.51 ng/L (IQR 1.59-4.32 ng/L) to 2.22 ng/L (median of the differences -0.36 ng/L, 95%CI -0.70 - -0.01 ng/L, p-value 0.04), corresponding to a median change from baseline of -16%. No clinically relevant changes in lipid fractions were observed. Both leukocyte and thrombocyte count decreased (median change from baseline -7% and -4% respectively). Estimated glomerular filtration rate decreased with a mean change from baseline of -2%. CONCLUSION: In patients with chronic coronary artery disease and elevated hs-CRP, one-month exposure to colchicine 0.5 mg once daily was associated with a reduction of inflammatory markers. A small effect was seen on white blood cell count and platelet count, as well as a small decrease in estimated glomerular filtration rate.


Assuntos
Proteína C-Reativa/análise , Colchicina/administração & dosagem , Doença da Artéria Coronariana/tratamento farmacológico , Inflamação/tratamento farmacológico , Idoso , Biomarcadores/sangue , Doença Crônica/tratamento farmacológico , Colchicina/efeitos adversos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/imunologia , Esquema de Medicação , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/imunologia , Contagem de Leucócitos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Prospectivos , Resultado do Tratamento
2.
Aquat Toxicol ; 227: 105590, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32891021

RESUMO

The aim of the present study was to investigate effects of defined mixtures of polycyclic aromatic hydrocarbons (PAHs) and perfluoroalkyl substances (PFASs), at low, environmentally relevant (1× = L), or high (20× = H) doses, on biological responses in Atlantic cod (Gadus morhua). To this end, farmed juvenile cod were exposed at day 0 and day 7 via intraperitoneal (i.p.) injections, in a two-week in vivo experiment. In total, there were 10 groups of fish (n = 21-22): two control groups, four separate exposure groups of PAH and PFAS mixtures (L, H), and four groups combining PAH and PFAS mixtures (L/L, H/L, L/H, H/H). Body burden analyses confirmed a dose-dependent accumulation of PFASs in cod liver and PAH metabolites in bile. The hepatosomatic index (HSI) was significantly reduced for three of the combined PAH/PFAS exposure groups (L-PAH/H-PFAS, H-PAH/L-PFAS, H-PAH/H-PFAS). Analysis of the hepatic proteome identified that pathways related to lipid degradation were significantly affected by PFAS exposure, including upregulation of enzymes in fatty acid degradation pathways, such as fatty acid ß-oxidation. The increased abundances of enzymes in lipid catabolic pathways paralleled with decreasing levels of triacylglycerols (TGs) in the H-PFAS exposure group, suggest that PFAS increase lipid catabolism in Atlantic cod. Markers of oxidative stress, including catalase and glutathione S-transferase activities were also induced by PFAS exposure. Only minor and non-significant differences between exposure groups and control were found for cyp1a and acox1 gene expressions, vitellogenin concentrations in plasma, Cyp1a protein synthesis and DNA fragmentation. In summary, our combined proteomics and lipidomics analyses indicate that PFAS may disrupt lipid homeostasis in Atlantic cod.


Assuntos
Fluorcarbonetos/toxicidade , Gadus morhua/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Bile/metabolismo , Biomarcadores/metabolismo , Fluorcarbonetos/análise , Lipidômica , Fígado/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/análise , Proteoma/metabolismo , Proteômica , Vitelogeninas/metabolismo , Poluentes Químicos da Água/análise
3.
Ecotoxicol Environ Saf ; 203: 111044, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888613

RESUMO

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with various adverse health outcomes. Although several mechanisms have been proposed including oxidative stress and inflammatory responses, the exact mechanism is still unknown. Few studies have investigated the mechanism linking PM2.5 and blood pressure (BP). In this study, we measured urinary metabolites and BP -related renin-angiotensin-aldosterone system (RAAS) to investigate the associations between ambient PM2.5 exposure and BP in healthy C57BL/6 mice. METHODS: The C57BL/6 mice were exposed to ambient concentrated PM2.5 or filtered air (FA) for 16 weeks. Systolic BP and diastolic BP were measured by noninvasive BP system. The urine metabolites were quantified using the untargeted metabolomics approach. The expression of RAAS-related proteins angiotensin-converting enzyme (ACE)2, angiotensin (Ang) II, Ang (1-7) and aldosterone (ALD) were measured using Western blot and ELISA kits. RESULTS: The metabolomics analysis demonstrated that PM2.5 exposure induced significant changes of some metabolites in urine, including stress hormones, amino acids, fatty acids, and lipids. Furthermore, there was an elevation of BP, increase of serous Ang II and ALD, along with the decrease of ACE2 and Ang (1-7) in kidney in the PM2.5-exposed mice compared with FA-exposed mice. CONCLUSIONS: The results demonstrated that PM2.5 exposure-induced BP elevation might be associated with RAAS activation. Meanwhile, PM2.5 exposure-induced changes of stress hormone and lipid metabolism might mediate the activation of RAAS. The results suggested that the systemic stress hormone and lipid metabolism was associated with the development of hypertension.


Assuntos
Poluentes Atmosféricos/toxicidade , Angiotensina I/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Material Particulado/toxicidade , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Acetilglucosaminidase/urina , Angiotensina I/sangue , Animais , Biomarcadores/sangue , Biomarcadores/urina , Hipertensão/urina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metaboloma/efeitos dos fármacos , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , beta-Galactosidase/urina
4.
Anticancer Res ; 40(9): 4843-4856, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878772

RESUMO

Aberrant fatty acid (FA) metabolism has long been recognized in colorectal cancer (CRC) cells. Since de novo lipogenesis is required for CRC tumour growth and survival, the inhibition of FA metabolism is a promising potential therapeutic target. Inhibition of the opposite process, ß-oxidation of FAs, has also showed promising results in many CRC models. For patients with CRC, both FA synthesis and ß-oxidation inhibitors are promising potential therapeutic options as monotherapies or as combination therapies with other anticancer agents. In this review, we discuss recent reports concerning inhibitors of FA synthesis and ß-oxidation in various CRC models. The exact mechanisms of action of the selected compounds described in this review remain unknown and require precise evaluation before the development of new successful therapies for CRC is possible.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos
5.
Yakugaku Zasshi ; 140(8): 1051-1061, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741863

RESUMO

It has been reported that medium-chain triglyceride (MCT) have various physiological functions, such as anti-obesity and hypolipidemic effects. They can also elicit increased disaccharidase activity and intestinal cell proliferation. However, a meta-analysis of randomized controlled trials, comparing the effects of MCT on weight loss and body composition, detected commercial bias. Additional research on the physiological functions is needed in order to have conclusive evidence. Thus, we sought to evaluate the various functions of MCT by conducting a feeding study in rats. Rats fed a diet containing 15% (w/w) MCT, had significantly lower visceral fat weight, plasma and liver lipid concentrations; they had significantly higher intestinal maltase and glucoamylase activities; and they had a greater number of Ki-67 positive cells/crypt, compared to the rats fed a diet containing 15% (w/w) lard. The effects of a diet containing 5% (w/w) MCT was observed only for plasma cholesterol levels and the number of Ki-67 positive cells/crypt; in which some results were found to be inconsistent with previous reports. These results indicate that physiological functions of MCT are numerous and need to be confirmed by additional research.


Assuntos
Glucana 1,4-alfa-Glucosidase/metabolismo , Intestino Delgado/enzimologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Triglicerídeos/administração & dosagem , Triglicerídeos/farmacologia , alfa-Glucosidases/metabolismo , Animais , Fármacos Antiobesidade , Proliferação de Células/efeitos dos fármacos , Dieta , Hipolipemiantes , Intestino Delgado/citologia , Gordura Intra-Abdominal , Antígeno Ki-67/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Triglicerídeos/química
6.
Medicine (Baltimore) ; 99(34): e21744, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846797

RESUMO

BACKGROUND: In recent years, clinical studies about Yangxin Decoction combined acupuncture (YXDA) for the treatment of Qi Deficiency and Blood Stasis type of Chest Bi-Syndrome (CBS-QDBS) has been increased, but the results are different. The aim of this study is to investigate the effect of YXDA on blood lipid metabolism (BLMB) in patients with CBS-QDBS. METHODS: We will collect any randomized controlled trials that assess the effect of YXDA on BLMB in CBS-QDBS from PUBMED, EMBASE, Cochrane Library, PsycINFO, CINAHL, Allied and Complementary Medicine Database, and China National Knowledge Infrastructure. All of these databases will be searched from their initial time to the present. All language limitation will be imposed. Literature selection, information collection, and risk of bias assessment will be performed independently by two authors, respectively. All data analysis will be undertaken using RevMan 5.3 Software. RESULTS: This study will summarize the systematic nature of the literature search and its methods for assessing study quality and analyzing all relevant outcome data. Considering the inconsistent results, this study will improve the existing evidence on the effect of YXDA on BLMB in CBS-QDBS. CONCLUSION: The findings of this study will present the latest evidence of YXDA on BLMB in patients with CBS-QDBS. STUDY REGISTRATION: INPLASY202070047.


Assuntos
Terapia por Acupuntura/métodos , Dor no Peito/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Qi , Terapia Combinada , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
7.
Chem Biol Interact ; 329: 109213, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32739323

RESUMO

Phytoestrogens are plant-derived substances with a similar structure to 17-beta-estradiol, which have protective roles in estrogen-dependent diseases. Isoflavones, the most well-known subgroup of phytoestrogens, play protective roles against chemicals-induced liver injuries through several molecular mechanisms. Hepatoprotective effects of isoflavones are, partly, associated with their antioxidant, anti-inflammatory, immunomodulatory, and anti-fibrotic properties. Besides, isoflavones can reduce gut-derived endotoxins, accelerate alcohol metabolism, stimulate detoxification of hepatotoxic chemicals, suppress the bioactivation of these chemicals, inhibit hepatocytes apoptosis, and restore autophagy activity during chemicals-induced liver diseases. This review provides a summary of the molecular mechanisms underlying the hepatoprotective effects of isoflavones. It seems that further studies are needed to investigate the hepatoprotective potential of isoflavones in patients with different stages of chemicals-induced liver injuries.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Isoflavonas/metabolismo , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Inflamação/prevenção & controle , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia
8.
Life Sci ; 258: 118030, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739470

RESUMO

The risk of atherosclerosis (AS) ascends among post-menopausal women, while current hormone replacement therapy exerts several adverse effects. Alisol B 23-acetate (AB23A), a tetracyclic triterpenoid isolated from the rhizome of Alisma orientale, was reported to show multiple physiological activities, including regulating lipid metabolism. According to molecular docking analysis, it was predicted to bind with estrogen receptor α (ERα). In this study, we aimed to observe the effect of AB23A on preventing post-menopausal AS and explore whether the mechanism was mediated by ERα. In vitro, free fatty acid (FFA) was applied to induce the abnormal lipid metabolism of L02 cells. In vivo, the ApoE-/- mice were ovariectomized to mimic the cessation of estrogen. The high-fat diet was also given to induce post-menopausal AS. We demonstrated AB23A attenuated the accumulation of total cholesterol and triglyceride induced by free fatty acids in hepatocytes. In high-fat diet-ovariectomy-treated ApoE-/- mice, AB23A eliminated lipids in blood and liver. AB23A not only reduced the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) through sterol-regulatory element binding proteins (SREBPs) but also suppressed the secretion of PCSK9 through silent information regulator 1 (SIRT1). Notably, AB23A promoted the expression of ERα in vivo and in vitro. The both ERα inhibitor and ERα siRNA were also applied in confirming whether the hepatic protective effect of AB23A was mediated by ERα. We found that AB23A significantly promoted the expression of ERα. AB23A could inhibit the synthesis and secretion of PCSK9 through ERα, lower the accumulation of triglyceride and cholesterol, and prevent post-menopausal AS.


Assuntos
Aterosclerose/patologia , Colestenonas/farmacologia , Receptor alfa de Estrogênio/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Pós-Menopausa/efeitos dos fármacos , Animais , Aterosclerose/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colestenonas/química , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Feminino , Lipoproteínas LDL/metabolismo , Camundongos , Ovariectomia , Regiões Promotoras Genéticas/genética , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Sirtuína 1/metabolismo , Proteínas de Ligação a Elemento Regulador de Esterol/genética , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , Regulação para Cima/efeitos dos fármacos
9.
Toxicon ; 186: 109-119, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32805295

RESUMO

To investigate the effects of oral administration of probiotics consortium on lipid metabolism in aflatoxin B1 (AFB1) exposed rats, ninety female albino rats were first grouped into two: NC (control fed standard feed) and AF (fed AFB1-contaminated feed at 40 ppb). After eight weeks, baseline animals were sacrificed from both groups while the others further divided into four groups - NC treated with and without the probiotics consortium, aflatoxin treated with and without the probiotics consortium (NCT, NCC, AFT, and AFC respectively). Five animals from each group were sacrificed weekly for four weeks, with the collection of blood, liver, brain, and the small intestine. Administration of probiotics instigated significant (p < 0.05) reductions in the elevated plasma and organ lipids as well as HDL-TAG and VLDL + LDL CHO concentrations of animals exposed to AF. AF-induced hepatic lipogenesis and up-regulation of 3-hydroxy-3-methylglutaryl-CoA reductase activity were also significantly (p < 0.05) attenuated following treatment with probiotics in a time-dependent manner. Moreover, neither AF nor probiotics had any effect on glycerol-3-phosphate acyltransferase. Lipid peroxidation was significantly (p < 0.05) reduced in probiotics-treated AF groups, compared to the AF-control groups. This study indicates that the probiotic consortium used synergistically ameliorated the AFB1-induced disruptions in lipid metabolism.


Assuntos
Aflatoxina B1/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Probióticos , Administração Oral , Animais , Feminino , Peroxidação de Lipídeos , Fígado , Ratos
10.
Medicine (Baltimore) ; 99(29): e20735, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702819

RESUMO

BACKGROUND: Type 2 diabetes mellitus is one of the most common chronic diseases, which endangers peoples health and life qualities. Sodium-Glucose Transporter 2 (SGLT2) inhibitors have been widely recognized since their clinical application in blood glucose control. While, dyslipidemia caused by SGLT2 inhibitors has been identified that affected the prognosis of this disease. METHODS: We will retrieve 8 databases including English and Chinese. After multiple screening, all randomized controlled trials (RCTs) related to SGLT2 inhibitors will be included by the 2 authors and data will be extracted. After completion of the risk of bias assessment, we will use these effect values including risk ratio (RR), weighted mean difference (WMD) and 95% confidence interval (CI) to conduct data analysis. Chi-Squared test and I test will be used to assess heterogeneity between studies. The robustness of meta-analysis results will be determined by sensitivity analysis. It will be assessed that evidence quality of the outcomes on the GRADE. RESULTS: The results of our research will be published in a peer-reviewed journal. CONCLUSION: The purpose of this systematic review and meta-analysis is to evaluate the association and degree of association between different doses of SGLT2 inhibitors and changes on blood lipid levels in patients with type 2 diabetes mellitus, in order to provide a reliable basis for clinical medication. INPLASY REGISTRATION NUMBER: INPLASY202040201.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Glicemia/efeitos dos fármacos , Estudos de Casos e Controles , Protocolos Clínicos/normas , Feminino , Humanos , Masculino , Placebos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
11.
Life Sci ; 257: 118090, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679144

RESUMO

AIMS: This study aimed to investigate oxymatrine via regulating miR-182 improved the hepatic lipid accumulation in non-alcoholic fatty liver disease (NAFLD) model. MATERIALS AND METHODS: Wistar rats were fed high-fat and high-fructose diet (HFDHFr group) for 4 weeks and HepG2 cells were treated with palmitic acid (PA group), and then were given oxymatrine intervention. The expression profiles of miRNAs were accessed by RNA sequencing (RNA-Seq). Hematoxylin-eosin (HE) staining and Oil Red O staining were used to observe the inflammation and lipid accumulation in liver. The levels of sterol regulatory element binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty-acid synthase (FAS) and carnitine palmitoyltransferase 1A (CPT-1A) were detected by RT-qPCR and Western blotting, respectively. Cell viability was detected by Cell Counting Kit-8 (CCK-8). KEY FINDINGS: miR-182 was down-regulated in the HFDHFr group and PA group. Oxymatrine reduced body weight, and improved glucose tolerance and insulin resistance in the HFDHFr + OMT group compared with HFDHFr group. In addition, oxymatrine reduced the ratio (liver weight/body weight), the content of triglycerides (TG), hepatic lipid accumulation and steatosis. The levels of SREBP-1c, ACC, and FAS were significantly decreased, while the CPT-1A level was obviously elevated after oxymatrine intervention (P < 0.05). In vivo, miR-182 knockdown increased the levels of SREBP-1c, ACC and FAS, while reduced the CPT-1A level. Additionally, oxymatrine attenuated the effects of miR-182 inhibitor on lipid accumulation. SIGNIFICANCE: We presented a possible mechanism that oxymatrine alleviated hepatic lipid metabolism via regulating miR-182 in NAFLD model.


Assuntos
Alcaloides/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Quinolizinas/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Ácido Palmítico/administração & dosagem , Ratos , Ratos Wistar
12.
Food Chem ; 333: 127478, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663752

RESUMO

Moringa oleifera Lam. (M. oleifera) leaves have long been consumed as both nutritive vegetable and popular folk medicine for hyperglycemia and hyperlipidemia in Kenya communities. In the current study, in vitro inhibition by M. oleifera leaf extract (MOLE, 90% (v/v) ethanol) of α-glucosidase and pancreatic lipase was demonstrated, followed by determination of the effects of MOLE on both glucose consumption and lipid levels (TC, TG, HDL-C and LDL-C) in 3T3-L1 cells. Potential ligands in MOLE were fast screened using affinity ultrafiltration LC-MS, and 14 and 10 components displayed certain binding affinity to α-glucosidase and pancreatic lipase, respectively. Docking studies revealed the binding energies and hydrogen bonds between potential ligands and enzymes. This study suggests that M. oleifera leaves may be a promising natural source for the prevention and treatment of hyperglycemia and hyperlipidemia as well as a functional food or other product for health care in the near future.


Assuntos
Moringa oleifera/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Células 3T3-L1 , Animais , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Lipase/antagonistas & inibidores , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos
13.
Eur J Endocrinol ; 183(4): 439-452, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698159

RESUMO

Objective: Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. Design: Randomized, double-blind, crossover pilot trial with washout was conducted at Pennington Biomedical Research Center. Eight postmenopausal women (age 50-60 years, BMI 30-40 kg/m2) were randomized to 8 weeks CE/BZA or placebo. Primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp). Secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); serum inflammatory markers; and serum metabolome (LC/MS). Results: CE/BZA treatment produced no detectable effect on insulin sensitivity, body composition, ectopic fat, fat cell size, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: P = 0.06; high-dose clamp: P = 0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein (HDL)-cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs) and decreased long-chain acylcarnitines, possibly reflecting increased hepatic de novo FA synthesis and esterification into TAGs for export into very low-density lipoproteins, as well as decreased FA oxidation, respectively (P < 0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in serum lipoproteins (P < 0.05). Conclusions: A short treatment of obese postmenopausal women with CE/BZA does not alter insulin action or ectopic fat but increases serum markers of hepatic de novo lipogenesis and TAG production.


Assuntos
Metabolismo dos Carboidratos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Estrogênios Conjugados (USP)/farmacologia , Glucose/metabolismo , Indóis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/metabolismo , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Estrogênios Conjugados (USP)/uso terapêutico , Feminino , Humanos , Indóis/uso terapêutico , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Projetos Piloto , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/metabolismo
14.
Life Sci ; 257: 118036, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622949

RESUMO

AIMS: Anti-obesity effects and improved leptin sensitivity from n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported in diet-induced obese animals. This study sought to determine the beneficial central effects and mechanism of docosahexaenoic acid (DHA, 22:6 n-3) in high-fat (HF) diet fed mice. MAIN METHODS: Male C57BL/6J mice were given HF diet with or without intracerebroventricular (icv) injection of docosahexaenoic acid (DHA, 22:6 n-3) for two days. Central leptin sensitivity, hypothalamic inflammation, leptin signaling molecules and tyrosine hydroxylase (TH) were examined by central leptin sensitivity test and Western blot. Furthermore, the expression of hepatic genes involved in lipid metabolism was examined by RT-PCR. KEY FINDINGS: We found that icv administration of DHA not only reduced energy intake and body weight gain but also corrected the HF diet-induced hypothalamic inflammation. DHA decreased leptin signaling inhibitor SOCS3 and improved the leptin JAK2-Akt signaling pathways in the hypothalamus. Furthermore, icv administration of DHA improved the effects of leptin in the regulation of mRNA expression of enzymes related to lipogenesis, fatty acid ß-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus. SIGNIFICANCE: Therefore, increasing central DHA concentration may prevent the deficit of hypothalamic regulation, which is associated with disorders of energy homeostasis in the liver as a result of a high-fat diet.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Leptina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Toxicol Lett ; 332: 65-73, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32649966

RESUMO

Exposure to multi-walled carbon nanotubes (MWCNTs) might induce lipid droplet (LD) biogenesis, but the roles of physicochemical properties of MWCNTs, as well as the mechanisms, remain poorly understood. In this study, we investigated lipid laden foam formation in THP-1 macrophages exposed to MWCNTs of different diameters, and attempted transcriptomic analysis to study the possible mechanisms. We observed diameter-dependent cytotoxicity, lipid accumulation and intracellular reactive oxygen species production that were more pronounced for MWCNTs with smaller diameters compared with those with larger diameters. However, more MWCNTs with larger diameters were retained in macrophages after 24 h exposure. One possible explanation for the inverse relationship between MWCNT bio-effects and internalization is that macrophages altered the expression of exocytotic genes to export toxic MWCNTs. Transcriptomic data showed that MWCNTs with smaller diameters more effectively altered the expression of genes related with cytotoxicity and lipid metabolism, and KEGG pathway analysis suggested that MWCNTs with smaller diameters activated peroxisome proliferator-activated receptor (PPAR) signalling pathway (map03320), leading to over-expression of perilipin 2, the surface proteins of LDs. Western blot confirmed that MWCNTs effectively promoted CD36, PPARγ and perilipin 2, key components in map03320. Moreover, inhibition of PPARγ by chemicals or siRNA significantly inhibited lipid accumulation induced by MWCNTs with smaller diameters, and perilipin 2 proteins in MWCNT-exposed macrophages could be decreased by PPARγ siRNA. In conclusion, the results of this study revealed the induction of LDs by MWCNTs in a diameter-dependent manner through the activation of PPAR signalling pathway.


Assuntos
Gotículas Lipídicas/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Tamanho da Partícula , Receptores Ativados por Proliferador de Peroxissomo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos
16.
Food Chem ; 333: 127528, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32682231

RESUMO

Endogenous lipase and lipoxygenase play important roles in accelerating lipid oxidation. Polyphenols are a series of commonly used chemicals for preserving fish and seafood products, due to their positive inhibitory effects on lipid oxidation. However, the mechanism involved is still unknown. The inhibitory effects of chlorogenic acid (CGA) on lipase and lipoxygenase were investigated and explored with multi- spectroscopic and molecular docking approaches. Results showed that CGA could inhibit the activities of lipase and lipoxygenase with concentration increased in a highly dose-dependent manner. CGA quenched intrinsic fluorescence intensities of enzymes by static quenching and binding with CGA which led to changes in 3D structures of enzymes. Results of the molecular docking confirmed binding modes, binding sites and major interaction forces between CGA and enzymes, which reduced the corresponding activity. Thus, this study could provide basic mechanisms of the inhibitory effects of polyphenols on lipid oxidation during food preservation.


Assuntos
Ácido Clorogênico/metabolismo , Ácido Clorogênico/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/farmacologia , Simulação de Acoplamento Molecular , Animais , Sítios de Ligação , Conservação de Alimentos , Lipase/antagonistas & inibidores , Lipase/química , Lipase/metabolismo , Lipoxigenase/química , Lipoxigenase/metabolismo , Oxirredução/efeitos dos fármacos , Polifenóis/farmacologia , Espectrometria de Fluorescência
17.
Chemosphere ; 258: 127255, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32554004

RESUMO

Trifluoromethanesulfonic acid (TFMS) is the shortest chain perfluorinated compound. Recently, it has been identified as a persistent and mobile organic chemical with a maximum concentration of 1 µg/L in the environment. However, its toxicological mechanism remains unclear. In this study, to evaluate the liver and intestinal toxicity of TFMS in mammals, male mice were orally exposed to 0, 1, 10 and 100 µg/kg for 12 weeks. Our results showed that TFMS exposure reduced the epididymal fat weight in mice, caused the decrease of serum and liver triglyceride (TG) level and the increase of serum low density lipoprotein (LDL) level. Also, we observed the inflammatory cell infiltration in the liver of mice exposed to 10 µg/kg and 100 µg/kg TFMS, which was coupled with the increased mRNA expression levels of inflammatory factors such as COX2, TNF-α, IL-1ß in the liver. In addition, the mRNA expression levels of lipid metabolism-related genes (PPAR-α, ACOX, SCD1, PPAR-γ, etc.) were significantly decreased in the liver of mice after exposure to both doses of TFMS. We also found TFMS exposure caused the imbalance of cecal gut microbiota and change of cecal microbiota diversity. KEGG pathway predictions showed that the exposure of 100 µg/kg TFMS changed the synthesis and degradation of ketone bodies, benzoate degradation and several other metabolic pathways. Our findings indicated that TFMS exposure disturbed the liver lipid metabolism possibly via altering the gut microbiota.


Assuntos
Poluentes Ambientais/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Mesilatos/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Ceco/efeitos dos fármacos , Ceco/microbiologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Disbiose , Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Triglicerídeos/sangue
18.
Toxicol Lett ; 331: 167-177, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32535229

RESUMO

Prenatal ethanol exposure (PEE) could increase offspring's susceptibility to adult liver lipid-metabolism diseases. This study aimed to confirm intrauterine programming mechanism of glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis for liver dysfunction in offspring rats induced by PEE. The results showed that levels of hepatic IGF1, lipid metabolism-related enzymes (e.g. FASN and HMGCR) and serum phenotype (TG, TCH, HDL-C, and LDL-C) were low in fetal rats of PEE but high in adult offspring except for HDL-C, meanwhile, hepatic H3K9ac and expression levels of IGF1 were low in fetal rats but high in adult offspring. Furthermore, levels of serum corticosterone and hepatic glucocorticoid-activation system (mainly including expression of 11ß-HSD1, GR, and C/EBPα as well as 11ß-HSD1/11ß-HSD2 ratio) were high in fetal rats of PEE but low or unchanged in adult offspring. The adult F2 generation of PEE maintained the same GC-IGF1 axis programming alteration as the F1 generation despite gender differences. In vitro, cortisol was proved to activate hepatocyte glucocorticoid-activation system and decrease H3K9ac and expression levels of IGF1 by GR. Therefore, PEE has a long-term effect on the offspring's liver functional development, which may be mainly related to the epigenetic programming alteration of the GC-IGF1 axis mediated by the glucocorticoid-activation system.


Assuntos
Etanol/toxicidade , Glucocorticoides/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Peso Corporal , Corticosterona/sangue , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/metabolismo , Células Hep G2 , Humanos , Lipídeos/sangue , Fígado/embriologia , Fígado/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Ratos Wistar , Transdução de Sinais
19.
Sci Total Environ ; 740: 139917, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32563870

RESUMO

Ambient ammonia exposure has been known to perturb lipid metabolism in farm animals, but the underlying mechanism is unclear. The current study was conducted to investigate how ambient ammonia exposure influences lipid metabolism in the pig model. Twelve pigs were randomly divided into two groups, either exposed to 0 or 35 mg/m3 atmospheric ammonia for 25 days. Serum ammonia remained unchanged (p > 0.05), but increased serum urea concentration was found (p < 0.05) after ammonia exposure. Ammonia exposure also caused an increased C18:0, C18:2n6c, C18:3n6, C18:3n3, C20:0, C20:2, C20:3n6, C20:3n3, C22:0 concentrations and fat content in the longissimus dorsi muscle (p < 0.05), and also serum total triglyceride (p = 0.0294) and ApoB (p = 0.0061) contents. Analysis of serum free amino acids profile revealed that concentrations of ornithine, tyrosine, asparagine, histidine, phenylalanine, leucine, isoleucine, glutamine and valine were significantly increased in the pigs exposed to 35 mg/m3 ammonia (p < 0.05). RNA-Seq analysis showed that genes encoding enzymes involved in lipid synthesis (FASN, SCD and FADS1) and uptake (LDLR) were up-regulated, whereas genes related to lipolysis (PNPLA4, ANGPTL4 and CEL), transport (CPT1A, CPT1B and CPT2) and ß-oxidation (ACADL, ACADVL, UCP2 and UCP3) were down-regulated. Furthermore, exposure to 35 mg/m3 atmospheric ammonia increased expression of mTOR (p = 0.0377) and its downstream P70S6K (p = 0.0139) and p-P70S6K (p = 0.0431), but decreased AMPK (p < 0.0001) and p-AMPK (p = 0.0071) in the longissimus dorsi muscle. In conclusion, high concentration of atmospheric ammonia exposure greatly interferes with amino acid metabolism, resulting in increased BCAAs and aromatic amino acids. The increased BCAAs production can up-regulate lipid synthesis and down-regulate ß-oxidation by activating mTOR signaling and inhibiting AMPK signaling.


Assuntos
Amônia , Metabolismo dos Lipídeos , Músculo Esquelético/metabolismo , Suínos/metabolismo , Amônia/sangue , Amônia/farmacologia , Animais , Leucina , Metabolismo dos Lipídeos/efeitos dos fármacos , Serina-Treonina Quinases TOR
20.
Artigo em Inglês | MEDLINE | ID: mdl-32558618

RESUMO

Retene (1-methyl-7-isopropyl-phenanthrene, RET) is an alkyl polycyclic aromatic hydrocarbon (PAH) with environmental risk to aquatic animals. Takifugu obscurus is a migratory fish species with high economic and ecological value. To assess the toxic effects of RET on molecular metabolism, juvenile T. obscurus in this study were acutely exposed to 44.30 µg/L of RET for four days. The transcriptome profiles of livers were compared between RET treatment group and the control, and the results revealed that 1,897 genes were significantly differentially expressed (DEGs) after exposure to RET, which enriched 17 KEGG pathways. Among these, glycerolipid metabolism, glycerophospholipid metabolism, insulin signaling pathway, and FOXO signaling pathways were significantly activated. Further exploration indicated that RET exposure disrupted glucose metabolism, stimulated insulin metabolism, and activated cell proliferation genes. Overall, these findings help explain the molecular mechanisms underlying RET toxicity, and may offer evidence to support T. obscurus protection.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fenantrenos/toxicidade , Takifugu/genética , Transcriptoma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Perfilação da Expressão Gênica , Fígado/metabolismo , Takifugu/metabolismo
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