Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.090
Filtrar
1.
Nat Commun ; 12(1): 5323, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493722

RESUMO

The role of intestine clock in energy homeostasis remains elusive. Here we show that mice with Bmal1 specifically deleted in the intestine (Bmal1iKO mice) have a normal phenotype on a chow diet. However, on a high-fat diet (HFD), Bmal1iKO mice are protected against development of obesity and related abnormalities such as hyperlipidemia and fatty livers. These metabolic phenotypes are attributed to impaired lipid resynthesis in the intestine and reduced fat secretion. Consistently, wild-type mice fed a HFD during nighttime (with a lower BMAL1 expression) show alleviated obesity compared to mice fed ad libitum. Mechanistic studies uncover that BMAL1 transactivates the Dgat2 gene (encoding the triacylglycerol synthesis enzyme DGAT2) via direct binding to an E-box in the promoter, thereby promoting dietary fat absorption. Supporting these findings, intestinal deficiency of Rev-erbα, a known BMAL1 repressor, enhances dietary fat absorption and exacerbates HFD-induced obesity and comorbidities. Moreover, small-molecule targeting of REV-ERBα/BMAL1 by SR9009 ameliorates HFD-induced obesity in mice. Altogether, intestine clock functions as an accelerator in dietary fat absorption and targeting intestinal BMAL1 may be a promising approach for management of metabolic diseases induced by excess fat intake.


Assuntos
Fatores de Transcrição ARNTL/genética , Ritmo Circadiano/genética , Diacilglicerol O-Aciltransferase/genética , Fígado Gorduroso/genética , Hiperlipidemias/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Obesidade/genética , Fatores de Transcrição ARNTL/deficiência , Animais , Diacilglicerol O-Aciltransferase/metabolismo , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Regulação da Expressão Gênica , Homeostase/efeitos dos fármacos , Homeostase/genética , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Hiperlipidemias/prevenção & controle , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/prevenção & controle , Regiões Promotoras Genéticas , Ligação Proteica , Pirrolidinas/farmacologia , Transdução de Sinais , Tiofenos/farmacologia , Triglicerídeos/biossíntese
2.
Biomed Pharmacother ; 139: 111668, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243630

RESUMO

Metabolic Syndrome (MetS) is a complex and multifactorial condition often characterised by obesity, hypertension, hyperlipidaemia, insulin resistance, glucose intolerance and fasting hyperglycaemia. Collectively, MetS can increase the risk of atherosclerotic-cardiovascular disease, which is the leading cause of death worldwide. However, no animal model currently exists to study MetS in the context of atherosclerosis. In this study we developed a pre-clinical mouse model that recapitulates the spectrum of MetS features while developing atherosclerosis. When BPHx mice were placed on a western type diet for 16 weeks, all the classical characteristics of MetS were observed. Comprehensive metabolic analyses and atherosclerotic imaging revealed BPHx mice to be obese and hypertensive, with elevated total plasma cholesterol and triglyceride levels, that accelerated atherosclerosis. Altogether, we demonstrate that the BPHx mouse has all the major components of MetS, and accelerates the development of atherosclerosis.


Assuntos
Aterosclerose/patologia , Dieta/efeitos adversos , Hipertensão/patologia , Síndrome Metabólica/patologia , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Glicemia/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hipertensão/sangue , Hipertensão/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/metabolismo , Obesidade/patologia , Triglicerídeos/sangue
3.
Molecules ; 26(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34210097

RESUMO

Obesity and hyperlipidemia are metabolic dysregulations that arise from poor lifestyle and unhealthy dietary intakes. These co-morbidity conditions are risk factors for vascular diseases. Piper sarmentosum (PS) is a nutritious plant that has been shown to pose various phytochemicals and pharmacological actions. This study aimed to investigate the effect of PS on obesity and hyperlipidemia in an animal model. Forty male Wistar rats were randomly divided into five experimental groups. The groups were as follows: UG-Untreated group; CTRL-control; FDW-olive oil + 20% fructose; FDW-PS-PS (125 mg/kg) + 20% fructose; FDW-NGN-naringin (100 mg/kg) + 20% fructose. Fructose drinking water was administered daily for 12 weeks ad libitum to induce metabolic abnormality. Treatment was administered at week 8 for four weeks via oral gavage. The rats were sacrificed with anesthesia at the end of the experimental period. Blood, liver, and visceral fat were collected for further analysis. The consumption of 20% fructose water by Wistar rats for eight weeks displayed a tremendous increment in body weight, fat mass, percentage fat, LDL, TG, TC, HMG-CoA reductase, leptin, and reduced the levels of HDL and adiponectin as well as adipocyte hypertrophy. Following the treatment period, FDW-PS and FDW-NGN showed a significant reduction in body weight, fat mass, percentage fat, LDL, TG, TC, HMG-CoA reductase, and leptin with an increment in the levels of HDL and adiponectin compared to the FDW group. FDW-PS and FDW-NGN also showed adipocyte hypotrophy compared to the FDW group. In conclusion, oral administration of 125 mg/kg PS methanolic extract to fructose-induced obese rats led to significant amelioration of obesity and hyperlipidemia through suppressing the adipocytes and inhibiting HMG-CoA reductase. PS has the potential to be used as an alternative or adjunct therapy for obesity and hyperlipidemia.


Assuntos
Frutose/efeitos adversos , Hiperlipidemias , Síndrome Metabólica , Metanol/química , Obesidade , Piper/química , Extratos Vegetais , Animais , Frutose/farmacologia , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Masculino , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar
4.
Molecules ; 26(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299638

RESUMO

The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis is essential for cellular functions. Several pathophysiological conditions and pharmacological agents are known to disrupt ER homeostasis, thereby, causing ER stress. The cells react to ER stress by initiating an adaptive signaling process called the unfolded protein response (UPR). However, the ER initiates death signaling pathways when ER stress persists. ER stress is linked to several diseases, such as cancer, obesity, and diabetes. Thus, its regulation can provide possible therapeutic targets for these. Current evidence suggests that chronic hyperglycemia and hyperlipidemia linked to type II diabetes disrupt ER homeostasis, thereby, resulting in irreversible UPR activation and cell death. Despite progress in understanding the pathophysiology of the UPR and ER stress, to date, the mechanisms of ER stress in relation to type II diabetes remain unclear. This review provides up-to-date information regarding the UPR, ER stress mechanisms, insulin dysfunction, oxidative stress, and the therapeutic potential of targeting specific ER stress pathways.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Estresse do Retículo Endoplasmático , Estresse Oxidativo , Transdução de Sinais , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia
5.
Chem Biol Interact ; 347: 109601, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34324854

RESUMO

Exploration of long-term in vivo effects of nanomaterials, particularly those with potential biomedical applications, is quite important for better understanding and evaluating their biosafety. Selenium nanoparticles (SeNPs) has been considered as a good candidate in biomedical applications due to its high bioavailability, considerable biological activity, and low toxicity. However, its long-term biological effects and biosafety remain unknown. Our previous study demonstrated that 8-week supplementation with SeNPs (50 µg Se/kg/day) was safe and had an anti-atherosclerotic activity in apolipoprotein E-deficient (ApoE-/-) mice, a well-known animal model of atherosclerosis. As a chronic disease, atherosclerosis needs long-term drug therapy. The aim of this study is to investigate the long-term effects of SeNPs with different sizes on atherosclerotic lesions and their biosafety in ApoE-/- mice fed with a high fat diet. Unexpectedly, the results showed that 24-week administration of SeNPs even at a low dose (50 µg Se/kg/day) aggravated atherosclerotic lesions. Furthermore, SeNPs exacerbated oxidative stress by inhibiting the activities of antioxidant enzymes and the expression of antioxidant selenoenzymes. SeNPs also exacerbated hyperlipidaemia by inducing hepatic lipid metabolic disorder. In the meanwhile, SeNPs aggravated organ injury, especially liver and kidney injury. The above adverse effects of SeNPs were size dependent: SeNPs with the size of 40.4 nm showed the highest adverse effects among the SeNPs with three sizes (23.1 nm, 40.4 nm, and 86.8 nm). In conclusion, the present work shows that long-term administration of low-dose SeNPs aggravated atherosclerotic lesions by enhancing oxidative stress and hyperlipidaemia in ApoE-/- mice, indicative of cardiovascular toxicity. Moreover, long-term administration of SeNPs led to injury to liver and kidney. These results offer novel insights for better understanding the biosafety of SeNPs and other biomedical nanomaterials.


Assuntos
Aterosclerose/etiologia , Nanopartículas/toxicidade , Selênio/toxicidade , Animais , Apolipoproteínas E/deficiência , Aterosclerose/metabolismo , Aterosclerose/patologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Glutationa Peroxidase/metabolismo , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Fígado/patologia , Efeitos Adversos de Longa Duração , Masculino , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Selênio/administração & dosagem , Selênio/química , Tiorredoxina Redutase 1/metabolismo , Tiorredoxina Redutase 2/metabolismo
6.
Eur J Med Chem ; 221: 113522, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33984804

RESUMO

Statins play an important role in the treatment of hyperlipidemia, but drug resistance and adverse effects greatly limits their application. To discover new lipid-lowering drugs, three different series of tetrahydroprotoberberine derivatives (THPBs) were designed and synthesized. These compounds were first tested for their effects on viability of HepG2 cells and 21 compounds with the percent of cell viability over 90% were further screened to evaluate their ability to reduce total cholesterol (TC) and triglyceride (TG) levels. Among these derivatives, two compounds displayed significant down-regulation both intracellular of TC and TG content, especially compound 49 exhibited the greatest efficacy. Mechanistically, compound 49 promoted proteasomal degradation of SREBPs. Importantly, compound 49 displayed superior bioavailability (F = 65.1%) and obvious efficacy in the treatment of high fat diet induced obesity in vivo. Therefore, compound 49 is a promising candidate to develop new treatment of hyperlipidemia.


Assuntos
Antineoplásicos/farmacologia , Alcaloides de Berberina/farmacologia , Desenho de Fármacos , Hiperlipidemias/tratamento farmacológico , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 2/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Alcaloides de Berberina/síntese química , Alcaloides de Berberina/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Estrutura Molecular , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Relação Estrutura-Atividade
7.
Artigo em Inglês | MEDLINE | ID: mdl-34058527

RESUMO

Hyperlipidemia is a major risk factor and pathological basis for cardiovascular diseases. Polygonum cuspidatum (HZ), a famous traditional Chinese medicine, is frequently used to treat hyperlipidemia. However, little is known about its underlying mechanism. Herein, an integrated approach combining multiplatform-based metabonomics and network analysis was adopted to elucidate the ameliorative mechanism of HZ on hyperlipidemia. The global metabolomic characters of HZ on hyperlipidemia were investigated by GC-MS and LC-MS based metabonomics. Significant metabonomic alterations were observed in hyperlipidemic group, which could be restored by HZ supplementation. Furthermore, the drug-ingredients-target-metabolic pathway network was constructed, and the result indicated that HZ exhibited hypolipidemic efficacy through resveratrol, polydatin, torachrysone-8-O-ß-D-(6'-oxayl)-glucoside, physciondiglucoside, (+)-catechin, ß-sitosterol, quercetin, luteolin and physovenine acting on phospholipase A2, unspecific monooxygenase, arachidonate 15-lipoxygenase, aromatic-L-amino-acid decarboxylase, alcohol dehydrogenase and triacylglycerol lipase. In conclusion, this study explored potential mechanism of HZ on hyperlipidemia with the aid of the integrated approach combining multiplatform-based metabonomics and network analysis, which might provide a theoretical basis for the clinical application of HZ.


Assuntos
Fallopia japonica/química , Hiperlipidemias/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Animais , Cromatografia Líquida , Cricetinae , Modelos Animais de Doenças , Cromatografia Gasosa-Espectrometria de Massas , Lipídeos/sangue , Masculino , Mesocricetus , Metabolômica , Extratos Vegetais/farmacologia
8.
Comput Biol Chem ; 92: 107505, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34030115

RESUMO

Hyperlipidemia causes diseases like cardiovascular disease, cancer, Type II Diabetes and Alzheimer's disease. Drugs that specifically target HL associated diseases are required for treatment. 34 KEGG pathways targeted by lipid lowering drugs were used to construct a directed protein-protein interaction network and driver nodes were determined using CytoCtrlAnalyser plugin of Cytoscape 3.6. The involvement of driver nodes of HL in other diseases was verified using GWAS. The central nodes of the network and 34 overrepresented pathways had a critical role in Hyperlipidemia. The PI3K-AKT signalling pathway, non-essentiality, non-centrality and approved drug target status were the predominant features of the driver nodes. Next, a Random Forest classifier was trained on 1445 molecular descriptors calculated using PaDEL for 50 approved lipid lowering and 84 lipid raising drugs as the positive and negative training set respectively. The classifier showed average accuracy of 76.8 % during 5-fold cross validation with AUC of 0.79 ± 0.06 for the ROC curve. The classifier was applied to select molecules with favourable properties for lipid lowering from the 130 approved drugs interacting with the identified driver nodes. We have integrated diverse network data and machine learning to predict repurposing of nine drugs for treatment of HL associated diseases.


Assuntos
Biologia Computacional , Hiperlipidemias/tratamento farmacológico , Aprendizado de Máquina , Redes Neurais de Computação , Reposicionamento de Medicamentos , Humanos , Hiperlipidemias/metabolismo , Curva ROC
9.
Metabolism ; 120: 154800, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34051224

RESUMO

OBJECTIVE: Apolipoprotein C-III (Apoc3) is a key component of triglyceride-rich lipoproteins (TRL). The Apoc3-transgenic mice are characterized by high levels of plasma triglyceride and free fatty acids (FFAs). Apoc3 stimulates human monocytes via activation of the NLRP3 inflammasome. Considering the NK cell downregulation in obese individuals and the possible stimulatory-effects of macrophages, variations of NK cell functions and underlying mechanisms were investigated in mice with Apoc3-induced hyperlipidemia. METHODS: Variations of activities and glycolipid metabolism in NK cells of the Apoc3-transgenic mice with hyperlipidemia were detected. Molecular mechanisms of lipid-induced metabolic-reprogramming in NK cells were analyzed based on the transcriptome sequencing. Finally, effects of DCs in mice with hyperlipidemia on NK cell functions were determined. RESULTS: Impaired number and function of NK cells in Apoc3TG mice was involved with the increased fatty acid oxidation and decreased glycolysis. Increased uptake of FFAs in Apoc3TG-NK cells contributed to the peroxisome proliferator-activated receptor (PPAR) activation and the downstream PTEN-AKT-mTOR/FOXO1 signaling pathway. Inhibition of PPAR or CPT1α only partly reversed the IFN-γ production of Apoc3TG-NK cells, but completely restored IFN-γ secretion by palmitic acid-treated NK cells ex vivo, indicating that other factors contributed to the Apoc3TG-NK cell downregulation. Meanwhile, Apoc3TG-DCs, which contained more lipids in the cytoplasm, depended on reactive oxygen species (ROS) to increase the expressions PD-L1, TGF-ß1, and NKG2D ligands and suppress NK cell activities. DCs of the Apoc3TG-CD36-/+ hybrid mice with less intracellular lipids and ROS production could not inhibit NK cells, indicating that intracellular FFAs promoted the immune-modulatory function of DCs. CONCLUSIONS: The downregulation of NK cell activities in individuals with Apoc3-induced hyperlipidemia was due to the increased fatty acid oxidation in NK cells and the bystander suppression caused by lipid-laden DCs. The dual recovery function of NK cells and DCs would improve the prognosis of patients with metabolic syndrome.


Assuntos
Células Dendríticas/fisiologia , Hiperlipidemias/imunologia , Células Matadoras Naturais/fisiologia , Animais , Apolipoproteína C-III/genética , Efeito Espectador/genética , Comunicação Celular/imunologia , Reprogramação Celular/genética , Células Dendríticas/metabolismo , Regulação para Baixo , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Metabolismo dos Lipídeos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Triglicerídeos/metabolismo
10.
Zhongguo Zhong Yao Za Zhi ; 46(7): 1795-1802, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33982484

RESUMO

This article aims to investigate the ameliorative effect of Linderae Radix ethanol extract on hyperlipidemia rats induced by high-fat diet and to explore its possible mechanism from the perspective of reverse cholesterol transport(RCT). SD rats were divided into normal group, model group, atorvastatin group, Linderae Radix ethanol extract(LREE) of high, medium, low dose groups. Except for the normal group, the other groups were fed with a high-fat diet to establish hyperlipidemia rat models; the normal group and the model group were given pure water, while each administration group was given corresponding drugs by gavage once a day for five weeks. Serum total cholesterol(TC), triglyceride(TG), high density lipoprotein-cholesterol(HDL-c), low density lipoprotein-cholesterol(LDL-c), alanine aminotransferase(ALT), and aspartate aminotransferase(AST) levels were measured by automatic blood biochemistry analyzer; the contents of TC, TG, total bile acid(TBA) in liver and TC and TBA in feces of rats were detected by enzyme colorimetry. HE staining was used to observe the liver tissue lesions; immunohistochemistry was used to detect the expression of ATP-binding cassette G8(ABCG8) in small intestine; Western blot and immunohistochemistry were used to detect the expression of peroxisome proliferator-activated receptor gamma/aerfa(PPARγ/α), liver X receptor-α(LXRα), ATP-binding cassette A1(ABCA1) pathway protein and scavenger receptor class B type Ⅰ(SR-BⅠ) in liver. The results showed that LREE could effectively reduce serum and liver TC, TG levels, serum LDL-c levels and AST activity, and increase HDL-c levels, but did not significant improve ALT activity and liver index; HE staining results showed that LREE could reduce liver lipid deposition and inflammatory cell infiltration. In addition, LREE also increased the contents of fecal TC and TBA, and up-regulated the protein expressions of ABCG8 in small intestine and PPARγ/α, SR-BⅠ, LXRα, and ABCA1 in liver. LREE served as a positive role on hyperlipidemia model rats induced by high-fat diet, which might be related to the regulation of RCT, the promotion of the conversion of cholesterol to the liver and bile acids, and the intestinal excretion of cholesterol and bile acids. RCT regulation might be a potential mechanism of LREE against hyperlipidemia.


Assuntos
Hiperlipidemias , Animais , Transporte Biológico , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Fígado/metabolismo , Ratos , Ratos Sprague-Dawley , Triglicerídeos/metabolismo
11.
Int J Mol Sci ; 22(7)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801684

RESUMO

Metabolic dysfunction is a comorbidity of many types of cancers. Disruption of glucose metabolism is of concern, as it is associated with higher cancer recurrence rates and reduced survival. Current evidence suggests many health benefits from exercise during and after cancer treatment, yet only a limited number of studies have addressed the effect of exercise on cancer-associated disruption of metabolism. In this review, we draw on studies in cells, rodents, and humans to describe the metabolic dysfunctions observed in cancer and the tissues involved. We discuss how the known effects of acute exercise and exercise training observed in healthy subjects could have a positive outcome on mechanisms in people with cancer, namely: insulin resistance, hyperlipidemia, mitochondrial dysfunction, inflammation, and cachexia. Finally, we compile the current limited knowledge of how exercise corrects metabolic control in cancer and identify unanswered questions for future research.


Assuntos
Terapia por Exercício/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias/metabolismo , Neoplasias/terapia , Tecido Adiposo/metabolismo , Animais , Caquexia/metabolismo , Exercício Físico/fisiologia , Humanos , Hiperlipidemias/metabolismo , Inflamação , Resistência à Insulina , Doenças Metabólicas/metabolismo , Camundongos , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Neoplasias/fisiopatologia , Ratos , Regulação para Cima
12.
Life Sci ; 278: 119562, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915130

RESUMO

AIMS: To investigate the nuclear receptor subfamily 2 group E member 1 (Nr2e1) expression in adipose tissues of obese mice and assess the role of Nr2e1 in insulin resistance and chronic inflammation of the adipose tissues. MAIN METHODS: An obese model was established in Nr2e1 knockout (KO) mice and their wild type (WT) littermates through a long-term high-fat diet (HFD) feeding regime. The epididymal fat weight, body weight, and daily food intake were recorded. The blood lipid profile, blood inflammatory factors, and the levels of fasting blood glucose (FBG) and fasting insulin were determined. We estimated insulin resistance by the homeostasis model assessment (HOMA). The expression of inflammatory factors and F4/80 was examined by polymerase chain reaction (PCR) and western blotting to assess adipose tissues inflammation. We also determined the molecules of insulin signaling and the nuclear factor kappa B (NF-κB) pathway by western blotting. KEY FINDINGS: The Nr2e1 expression was upregulated in WT obese mice when compared with that in control mice. Despite a lower body weight and epididymal fat mass in Nr2e1-/- mice, these rats showed increased inflammatory cytokines secretion, more pronounced hyperlipidemia, and impaired insulin sensitivity after HFD treatment. Further investigation revealed that Nr2e1 deletion affected the expression of insulin signaling and NF-κB pathway-related molecules in visceral adipose tissues. SIGNIFICANCE: Nr2e1 may act as a potential target to improve insulin sensitivity and inflammation in obesity and related complications.


Assuntos
Resistência à Insulina , Gordura Intra-Abdominal/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Ração Animal , Animais , Glicemia/metabolismo , Peso Corporal , Doença Crônica , Cruzamentos Genéticos , Modelos Animais de Doenças , Intolerância à Glucose , Teste de Tolerância a Glucose , Homeostase , Hiperlipidemias/metabolismo , Inflamação , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Subunidade p50 de NF-kappa B/metabolismo , Obesidade/metabolismo , Transdução de Sinais
13.
Molecules ; 26(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803259

RESUMO

Ezetimibe (EZE) possesses low aqueous solubility and poor bioavailability and in addition, its extensive hepatic metabolism supports the notion of developing a novel carrier system for EZE. Ezetimibe was encapsulated into nanostructured lipid carriers (EZE-NLCs) via a high pressure homogenization technique (HPH). A three factor, two level (23) full factorial design was employed to study the effect of amount of poloxamer 188 (X1), pressure of HPH (X2) and number of HPH cycle (X3) on dependent variables. Particle size, polydispersity index (PDI), % entrapment efficiency (%EE), zeta potential, drug content and in-vitro drug release were evaluated. The optimized formulation displays pragmatic inferences associated with particle size of 134.5 nm; polydispersity index (PDI) of 0.244 ± 0.03; zeta potential of -28.1 ± 0.3 mV; % EE of 91.32 ± 1.8% and % CDR at 24-h of 97.11%. No interaction was observed after X-ray diffraction (XRD) and differential scanning calorimetry (DSC) studies. EZE-NLCs (6 mg/kg/day p.o.) were evaluated in the high fat diet fed rats induced hyperlipidemia in comparison with EZE (10 mg/kg/day p.o.). Triglyceride, HDL-c, LDL-c and cholesterol were significantly normalized and histopathological evaluation showed normal structure and architecture of the hepatocytes. The results demonstrated the superiority of EZE-NLCs in regard to bioavailability enhancement, dose reduction and dose-dependent side effects.


Assuntos
Ezetimiba/farmacologia , Hiperlipidemias/tratamento farmacológico , Nanotecnologia/métodos , Animais , Disponibilidade Biológica , Dieta Hiperlipídica/efeitos adversos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Ezetimiba/administração & dosagem , Hiperlipidemias/metabolismo , Lipídeos/química , Lipídeos/farmacologia , Masculino , Nanopartículas/química , Nanoestruturas/química , Tamanho da Partícula , Ratos , Ratos Wistar , Solubilidade , Triglicerídeos , Difração de Raios X
14.
Int J Mol Sci ; 22(8)2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33919597

RESUMO

Inappropriate nutrition and a sedentary lifestyle can lead to obesity, one of the most common risk factors for several chronic diseases. Although regular physical exercise is an efficient approach to improve cardiometabolic health, the exact cellular processes are still not fully understood. We aimed to analyze the morphological, gene expression, and lipidomic patterns in the liver and adipose tissues in response to regular exercise. Healthy (wild type on a normal diet) and hyperlipidemic, high-fat diet-fed (HFD-fed) apolipoprotein B-100 (APOB-100)-overexpressing mice were trained by treadmill running for 7 months. The serum concentrations of triglyceride and tumor necrosis factor α (TNFα), as well as the level of lipid accumulation in the liver, were significantly higher in HFD-fed APOB-100 males compared to females. However, regular exercise almost completely abolished lipid accumulation in the liver of hyperlipidemic animals. The expression level of the thermogenesis marker, uncoupling protein-1 (Ucp1), was significantly higher in the subcutaneous white adipose tissue of healthy females, as well as in the brown adipose tissue of HFD-fed APOB-100 females, compared to males. Lipidomic analyses revealed that hyperlipidemia essentially remodeled the lipidome of brown adipose tissue, affecting both the membrane and storage lipid fractions, which was partially restored by exercise in both sexes. Our results revealed more severe metabolic disturbances in HFD-fed APOB-100 males compared to females. However, exercise efficiently reduced the body weight, serum triglyceride levels, expression of pro-inflammatory factors, and hepatic lipid accumulation in our model.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Hiperlipidemias/metabolismo , Hiperlipidemias/fisiopatologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Condicionamento Físico Animal/fisiologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Metabolismo Energético/fisiologia , Feminino , Fígado/metabolismo , Masculino , Camundongos , Camundongos Transgênicos
15.
Int J Mol Sci ; 22(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921777

RESUMO

Obesity and hyperlipidemia are major risk factors for developing vascular diseases. Bee bread (BB) has been reported to exhibit some biological actions, including anti-obesity and anti-hyperlipidemic. This study aims to investigate whether bee bread can ameliorate vascular inflammation and impaired vasorelaxation activity through eNOS/NO/cGMP pathway in obese rats. Forty male Sprague-Dawley rats were randomly divided into four groups (n = 10/group), namely: control (normal group), obese rats (OB group), obese rats treated with bee bread (0.5 g/kg/day, OB/BB group) and obese rats treated with orlistat (10 mg/kg/day, OB/OR group). The latter three groups were given a high-fat diet (HFD) for 6 weeks to induced obesity before being administered with their respective treatments for another 6 weeks. After 12 weeks of the total experimental period, rats in the OB group demonstrated significantly higher Lee obesity index, lipid profile (total cholesterol, triglyceride, low-density lipoprotein), aortic proinflammatory markers (tumor necrosis factor-α, nuclear factor-κß), aortic structural damage and impairment in vasorelaxation response to acetylcholine (ACh). Bee bread significantly ameliorated the obesity-induced vascular damage manifested by improvements in the lipid profile, aortic inflammatory markers, and the impaired vasorelaxation activity by significantly enhancing nitric oxide release, promoting endothelial nitric oxide synthase (eNOS) and cyclic guanosine monophosphate (cGMP) immunoexpression. These findings suggest that the administration of bee bread ameliorates the impaired vasorelaxation response to ACh by improving eNOS/NO/cGMP-signaling pathway in obese rats, suggesting its vascular therapeutic role.


Assuntos
GMP Cíclico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Nucleotídeos Cíclicos/metabolismo , Obesidade/complicações , Própole/uso terapêutico , Animais , Dieta Hiperlipídica/efeitos adversos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Orlistate/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
16.
Aging (Albany NY) ; 13(7): 9732-9747, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33744860

RESUMO

We analyzed the effects of ginsenoside Rb1 on hyperlipidemic in model mice. Using stool, plasma and hepatic tissue samples, we observed that the genera Blautia and Allobaculum were increased and Turicibacter was decrease in Rb1-treated mice as compared to untreated model mice. Ether lipid metabolism, glycerolipid metabolism, and glyoxylate and dicarboxylate metabolism were differentially enriched between the Rb1 and model groups. Lipidomics revealed 169 metabolites differentially expressed between the model and Rb1 groups in a positive ion model and 58 in a negative ion model. These metabolites mainly participate in glycerophospholipid, linoleic acid, and alpha-linolenic acid metabolism. The main metabolites enriched in these three pathways were phosphatidylcholine, diacylglycerol and ceramide, respectively. In a transcriptome analysis, 766 transcripts were differentially expressed between the Rb1 and model groups. KEGG analysis revealed lysine degradation, inositol phosphate metabolism, and glycerophospholipid metabolism to be the main enriched pathways. Multiomics analysis revealed glycerophospholipid metabolism to be a common pathway and phosphatidylcholine the main metabolite differentially enriched between the Rb1 and model groups. Results from fecal transplanted germ-free mice suggest that to suppress hyperlipidemia, Rb1 regulates gut microbiota by regulating the synthesis and decomposition of phosphatidylcholine in glycerophospholipid metabolism, which in turn decreases serum total cholesterol.


Assuntos
Ginsenosídeos/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Ginsenosídeos/farmacologia , Hiperlipidemias/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Proteômica
17.
J Cell Mol Med ; 25(7): 3585-3600, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33751819

RESUMO

Obesity is associated with biological dysfunction in skeletal muscle. As a condition of obesity accompanied by muscle mass loss and physical dysfunction, sarcopenic obesity (SO) has become a novel public health problem. Human fibroblast growth factor 19 (FGF19) plays a therapeutic role in metabolic diseases. However, the protective effects of FGF19 on skeletal muscle in obesity and SO are still not completely understood. Our results showed that FGF19 administration improved muscle loss and grip strength in young and aged mice fed a high-fat diet (HFD). Increases in muscle atrophy markers (FOXO-3, Atrogin-1, MuRF-1) were abrogated by FGF19 in palmitic acid (PA)-treated C2C12 myotubes and in the skeletal muscle of HFD-fed mice. FGF19 not only reduced HFD-induced body weight gain, excessive lipid accumulation and hyperlipidaemia but also promoted energy expenditure (PGC-1α, UCP-1, PPAR-γ) in brown adipose tissue (BAT). FGF19 treatment restored PA- and HFD-induced hyperglycaemia, impaired glucose tolerance and insulin resistance (IRS-1, GLUT-4) and mitigated the PA- and HFD-induced decrease in FNDC-5/irisin expression. However, these beneficial effects of FGF19 on skeletal muscle were abolished by inhibiting AMPK, SIRT-1 and PGC-1α expression. Taken together, this study suggests that FGF19 protects skeletal muscle against obesity-induced muscle atrophy, metabolic derangement and abnormal irisin secretion partially through the AMPK/SIRT-1/PGC-α signalling pathway, which might be a potential therapeutic target for obesity and SO.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fatores de Crescimento de Fibroblastos/fisiologia , Fibronectinas/metabolismo , Atrofia Muscular/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Linhagem Celular , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos/farmacologia , Hiperglicemia/metabolismo , Hiperlipidemias/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Transdução de Sinais
18.
PLoS One ; 16(3): e0247638, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33764994

RESUMO

CONTEXT: Obesity, is a state of chronic inflammation, characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism. We have defined the accompanying decreased Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), ovarian steroids and reduced pituitary response to Gonadotropin-releasing Hormone (GnRH) as Reprometabolic syndrome, a phenotype that can be induced in healthy normal weight women (NWW) by acute infusion of free fatty acids and insulin. OBJECTIVE: To identify potential mediators of insulin and lipid-related reproductive endocrine dysfunction. DESIGN, SETTING, PARTICIPANTS: Secondary analysis of crossover study of eumenorrheic reproductive aged women of normal Body Mass Index (BMI) (<25 kg/m2) at an academic medical center. INTERVENTION: Participants underwent 6-hour infusions of either saline/heparin or insulin plus fatty acids (Intralipid plus heparin), in the early follicular phase of sequential menstrual cycles, in random order. Euglycemia was maintained by glucose infusion. Frequent blood samples were obtained. MAIN OUTCOME MEASURES: Pooled serum from each woman was analyzed for cytokines, interleukins, chemokines, adipokines, Fibroblast Growth Factor-21 (FGF-21) and markers of endoplasmic reticulum (ER) stress (CHOP and GRP78). Wilcoxon signed-rank tests were used to compare results across experimental conditions. RESULTS: Except for Macrophage Inflammatory Protein-1ß (MIP-1ß), no significant differences were observed in serum levels of any of the inflammatory signaling or ER stress markers tested. CONCLUSION: Acute infusion of lipid and insulin, to mimic the metabolic syndrome of obesity, was not associated with an increase in inflammatory markers. These results imply that the endocrine disruption and adverse reproductive outcomes of obesity are not a consequence of the ambient inflammatory environment but may be mediated by direct lipotoxic effects on the hypothalamic-pituitary-ovarian (HPO) axis.


Assuntos
Ácidos Graxos não Esterificados/administração & dosagem , Hiperinsulinismo/metabolismo , Hiperlipidemias/metabolismo , Insulina/administração & dosagem , Síndrome Metabólica/metabolismo , Transdução de Sinais , Centros Médicos Acadêmicos , Adolescente , Adulto , Índice de Massa Corporal , Estudos Cross-Over , Citocinas/genética , Citocinas/metabolismo , Estresse do Retículo Endoplasmático , Emulsões Gordurosas Intravenosas/administração & dosagem , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Hormônio Foliculoestimulante/genética , Hormônio Foliculoestimulante/metabolismo , Expressão Gênica , Aptidão Genética/efeitos dos fármacos , Aptidão Genética/genética , Técnica Clamp de Glucose , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/genética , Hiperinsulinismo/patologia , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/genética , Hiperlipidemias/patologia , Hormônio Luteinizante/genética , Hormônio Luteinizante/metabolismo , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo
19.
Food Funct ; 12(6): 2726-2740, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33681875

RESUMO

Obesity is an increasingly concerning global health issue, which is accompanied by disruption of glucose and lipid metabolisms. The aim of this study was to uncover the potential and molecular actions of puerarin, a phytochemical, for alleviating metabolic dysfunctions of glucose and lipid metabolisms. A rat model fed a high fat and high fructose diet and a HepG2 cell model challenged with fructose combined with free fatty acid were utilized to identify the effects of puerarin on obesity-associated insulin resistance and hepatic steatosis. The molecular mechanisms underlying puerarin treatment effects were further investigated using qRT-PCR and western blotting. Results show that puerarin significantly ameliorated features of obesity in rats, including bodyweight, hyperlipidemia, hyperglycemia, glucose/insulin intolerance, insulin resistance, hepatic steatosis, and oxidative stress, which are related to the activation of AMPK and PI3K/Akt pathways in the liver. Puerarin reduced lipid accumulation and caused a reduction of the mRNA expression of lipogenic genes such as SREBP-1c, FAS, SCD-1, and HMGCR, and an increment in the phosphorylation of AMPK and ACC in HepG2 cells. Moreover, puerarin ameliorated insulin resistance by increasing GLUT4 mRNA expression and activating the PI3K/Akt pathway. Treatment with the AMPK inhibitor compound C partially abolished the beneficial effects of puerarin on lipid accumulation and insulin resistance in HepG2 cells, which indicated that the protective effects of puerarin partially depend on the AMPK pathway. The present study indicates that puerarin shows potential as a functional food therapeutic for the treatment of obesity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Glicemia , Isoflavonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica , Fígado Gorduroso/metabolismo , Células Hep G2 , Humanos , Hiperlipidemias/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Obesidade , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
20.
Food Funct ; 12(5): 2044-2057, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33532813

RESUMO

This study aimed to investigate the effects and mechanism of selenium-enriched kiwifruit (Se-Kiwi) on lipid-lowering and liver protection in hyperlipidaemic mice induced by consuming a long-term high-fat diet. Selenium-enriched cultivation can significantly improve the contents of vitamins and functional elements in kiwifruits, especially vitamin C, selenium, and manganese, thus enhancing the activity of antioxidant enzymes in Se-Kiwi. Se-Kiwi can significantly improve the activity of antioxidant enzymes in the liver of hyperlipidaemic mice, restore the liver morphology of mice close to normal, reduce the fat content in the liver, and inhibit the accumulation of abdominal fat cells. Meanwhile, the expression levels of inflammation-related factors (TNF-α and NF-κB) and lipid synthesis related genes (SREBP-1c and FAS) are inhibited at the gene transcription and protein expression levels, and the expression levels of energy expenditure related genes (PPAR-α and CPT1) are increased, resulting in lipid reductions and liver protection. In conclusion, our results indicate that the protective mechanism of Se-Kiwi on high-fat diet mice is associated with enhancing the activity of antioxidant enzymes, reducing the degree of the inflammatory reaction, inhibiting the fat synthesis, and accelerating body energy consumption.


Assuntos
Actinidia/química , Tecido Adiposo/efeitos dos fármacos , Hiperlipidemias , Fígado/efeitos dos fármacos , Selênio/farmacologia , Animais , Linhagem Celular , Dieta Hiperlipídica , Frutas/química , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Camundongos , Substâncias Protetoras/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...