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1.
Chem Commun (Camb) ; 55(78): 11802-11805, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31524901

RESUMO

Introduction of a heteroatom into a fluorophore was carried out for coumarin through a replacement of its bridging oxygen atom with a silicon atom. The maximum-emission wavelength of Si-coumarin (SiC B) bathochromically shifted from 426 nm in cyclohexane to 626 nm in water. The adipogenic differentiation processes in mesenchymal stem cells were monitored using SiC B.


Assuntos
Cumarínicos/química , Silício/química , Adipogenia/efeitos dos fármacos , Animais , Linhagem Celular , Teoria da Densidade Funcional , Ligações de Hidrogênio , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Microscopia Confocal
2.
Chem Biol Interact ; 311: 108755, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31319077

RESUMO

Effective control of white adipose tissue accumulation would provide a therapeutic strategy for obesity, which poses a growing global problem. The plant chemical mangiferin stimulates adenosine monophosphate-activated protein kinase (AMPK), which inhibits adipogenesis and has therefore been considered a therapeutic target for obesity and related diseases. We previously reported the anti-inflammatory properties of 6'-O-acetyl mangiferin (OAM). In this study, we evaluated the potential of OAM as an AMPK activator in vitro in 3T3-L1 preadipocytes. OAM inhibited adipogenesis as indicated by lower intracellular lipid and triglyceride accumulation as well as reduced adipogenic gene and protein expression upon treatment. OAM-treated 3T3-L1 cells excreted more glycerol, indicating increased lipolysis, which was supported by increased expression of lipolysis-related genes, including adipose triglyceride lipase and hormone-sensitive lipase. We determined that OAM upregulates lipolysis via phosphorylation-dependent activation of AMPK. Further, OAM upregulated the ß-oxidation pathway as indicated by enhanced expression of phosphorylated acetyl-CoA-carboxylase and long-chain acyl-CoA synthetase 1. In conclusion, OAM markedly decreased intracellular lipid accumulation by enhancing lipolysis via AMPK activation and by upregulating ß-oxidation. Thus, OAM has potential as a drug for the prevention and/or improvement of obesity and related diseases and deserves further study.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia/efeitos dos fármacos , Iris (Planta)/química , Lipólise/efeitos dos fármacos , Xantonas/farmacologia , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Iris (Planta)/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Triglicerídeos/metabolismo
3.
Food Chem Toxicol ; 131: 110543, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31154084

RESUMO

A dual role of hydrogen sulfide (H2S) in inflammation is well-reported and recent studies demonstrated adipogenic effects of H2S in 3T3-L1 cells. Here, we aimed to investigate the effects of H2S on adipocyte differentiation and inflammation. H2S concentration in 3T3-L1 culture media was increased during adipocyte differentiation in parallel to adipogenic and Cth gene expression, and its inhibition using DL-Propargyl Glycine (PPG) impaired 3T3-L1 differentiation. GYY4137 and Na2S administration only in the first or in the last stage of adipocyte differentiation resulted in a significant increased expression of adipogenic genes. However, when GYY4137 or Na2S were administrated during all process no significant effects on adipogenic gene expression were found, suggesting that excessive H2S administration might exert negative effects on adipogenesis. In fact, continuous addition of Na2S, which resulted in Na2S excess, inhibited adipogenesis, whereas time-expired Na2S had no effect. In inflammatory conditions, GYY4137, but not Na2S, administration attenuated the negative effects of inflammation on adipogenesis and insulin signaling-related gene expression during adipocyte differentiation. In inflamed adipocytes, Na2S administration enhanced the negative effects of inflammatory process. Altogether these data showed that slow-releasing H2S improved adipocyte differentiation in inflammatory conditions, and that H2S proadipogenic effects depend on dose, donor and exposure time.


Assuntos
Adipócitos/efeitos dos fármacos , Sulfeto de Hidrogênio/metabolismo , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Sulfetos/farmacologia , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Adipogenia/fisiologia , Alquinos/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Glicina/análogos & derivados , Glicina/farmacologia , Inflamação/fisiopatologia , Camundongos
4.
J Agric Food Chem ; 67(25): 7136-7146, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31240929

RESUMO

Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) are organosulfur phytochemicals rich in cruciferous vegetables. We investigated the antiobesity and antihepatosteatosis activities of BITC and PEITC and the working mechanisms involved. C57BL/6J mice were fed a low-fat diet (LFD), a high-fat diet (HFD), or a HFD supplemented with 0.5 (L) or 1 g/kg (H) BITC or PEITC for 18 weeks. Compared with the HFD group, BITC or PEITC decreased the final body weight of mice in a dose-dependent manner [39.0 ± 3.1 (HFD), 34.4 ± 3.2 (BITC-L), 32.4 ± 2.8 (BITC-H), 36.2 ± 4.4 (PEITC-L), and 32.8 ± 2.9 (PEITC-H) g, p < 0.05], relative weight of epididymal fat [5.7 ± 0.4 (HFD), 4.7 ± 0.7 (BITC-L), 3.7 ± 0.3 (BITC-H), 4.4 ± 1.0 (PEITC-L), and 3.2 ± 0.6 (PEITC-H) %, p < 0.05], hepatic triglycerides [98.4 ± 6.0 (HFD), 81.0 ± 8.9 (BITC-L), 63.5 ± 5.6 (BITC-H), 69.3 ± 5.6 (PEITC-L), and 49.4 ± 2.9 (PEITC-H) mg/g, p < 0.05], and plasma total cholesterol [140 ± 21.3 (HFD), 109 ± 5.6 (BITC-L), 101 ± 11.3 (BITC-H), 126 ± 8.3 (PEITC-L), and 91.8 ± 12.7 (PEITC-H) mg/dL, p < 0.05]. Q-PCR and immunoblotting assays revealed that BITC and PEITC suppressed the expression of liver X receptor α, sterol regulatory element-binding protein 1c, stearoyl-CoA desaturase 1, fatty acid synthase, and acetyl-CoA carboxylase in both epididymal adipose and liver tissues. After a single oral administration of 85 mg/kg BITC or PEITC, the maximum plasma concentrations ( Cmax) of BITC and PEITC were 5.8 ± 2.0 µg/mL and 4.3 ± 1.9 µg/mL, respectively. In 3T3-L1 adipocytes, BITC and PEITC dose-dependently reduced adipocyte differentiation and cell cycle was arrested in G0/G1 phase. These findings indicate that BITC and PEITC ameliorate HFD-induced obesity and fatty liver by down-regulating adipocyte differentiation and the expression of lipogenic transcription factors and enzymes.


Assuntos
Adipogenia/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Isotiocianatos/administração & dosagem , Obesidade/tratamento farmacológico , Animais , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/fisiopatologia
5.
Nat Commun ; 10(1): 2430, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160583

RESUMO

Muscle loss due to fibrotic or adipogenic replacement of myofibers is common in muscle diseases and muscle-resident fibro/adipogenic precursors (FAPs) are implicated in this process. While FAP-mediated muscle fibrosis is widely studied in muscle diseases, the role of FAPs in adipogenic muscle loss is not well understood. Adipogenic muscle loss is a feature of limb girdle muscular dystrophy 2B (LGMD2B) - a disease caused by mutations in dysferlin. Here we show that FAPs cause the adipogenic loss of dysferlin deficient muscle. Progressive accumulation of Annexin A2 (AnxA2) in the myofiber matrix causes FAP differentiation into adipocytes. Lack of AnxA2 prevents FAP adipogenesis, protecting against adipogenic loss of dysferlinopathic muscle while exogenous AnxA2 enhances muscle loss. Pharmacological inhibition of FAP adipogenesis arrests adipogenic replacement and degeneration of dysferlin-deficient muscle. These results demonstrate the pathogenic role of FAPs in LGMD2B and establish these cells as therapeutic targets to ameliorate muscle loss in patients.


Assuntos
Tecido Adiposo/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Células-Tronco/citologia , Adipócitos/patologia , Adipogenia/efeitos dos fármacos , Tecido Adiposo/patologia , Adolescente , Idade de Início , Animais , Anexina A2/metabolismo , Estudos de Casos e Controles , Disferlina/genética , Venenos Elapídicos/toxicidade , Feminino , Fibrose , Humanos , Técnicas In Vitro , Masculino , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologia , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Inibidores de Proteases/farmacologia , Índice de Gravidade de Doença , Células-Tronco/efeitos dos fármacos , Tiofenos/farmacologia , Adulto Jovem
6.
Food Chem Toxicol ; 131: 110576, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31199990

RESUMO

Ivermectin, a member of the avermectins, is one of the most used anti-parasitic agents, and acts by binding to glutamate-gated chloride channels in invertebrate nerve cells. There is limited information, however, on the effects of ivermectin in non-neural cell, such as adipocytes. The present work aimed to investigate the role of ivermectin in adipogenesis using 3T3-L1 preadipocytes. Ivermectin inhibited the differentiation of preadipocytes and triglyceride (TG) accumulation. In particular, the treatment of ivermectin at the middle to late adipogenic differentiation period (day 2-8) was correlated with the inhibition of fat accumulation. Ivermectin treatment also significantly modulated the mRNA expression of key markers in adipogenesis, fatty acid synthesis, uptake, and oxidation, and enhanced the gene expression of two subunits of the glycine receptor (GlyR). Specifically, the protein levels of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and acetyl-CoA carboxylase (ACC) were reduced. Interestingly, the suppression of TG accumulation by ivermectin was partially abolished by rosiglitazone, a specific PPARγ agonist, but Z-guggulsterone, a selective FXR antagonist, failed to rescue the ivermectin-induced effect on adipogenesis. Lastly, ivermectin prevented adipogenesis induced by permethrin and fipronil. In conclusion, ivermectin inhibits adipogenesis of 3T3-L1 preadipocytes partially via PPARγ & GlyR-dependent, but not FXR-dependent, pathway.


Assuntos
Adipogenia/efeitos dos fármacos , Antiparasitários/farmacologia , Ivermectina/farmacologia , Triglicerídeos/metabolismo , Células 3T3-L1 , Animais , Diferenciação Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Camundongos , PPAR gama/metabolismo , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores da Glicina/metabolismo
7.
Yakugaku Zasshi ; 139(6): 861-866, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31155526

RESUMO

Brown adipose tissue is a critical regulator of metabolic health, and contributes to thermogenesis by uncoupling oxidative phosphorylation through the action of mitochondrial uncoupling protein 1 (Ucp1). Recent studies have shown that cold exposure and the stimulation of ß3-adrenergic receptors induce the development of brown cell-like "beige" adipocytes in white adipose tissue. Brown and/or beige adipocyte-mediated thermogenesis suppresses high-fat diet-associated obesity. Therefore, the development of brown/beige adipocytes may prevent obesity and metabolic diseases. In the present study, we elucidated whether naturally occurring compounds contribute to regulating the cellular differentiation of brown/beige adipocytes. We screened for the up-regulated expression of Ucp1 during beige adipogenesis using extracts of crude herbal drugs frequently used in Kampo prescriptions (therapeutic drugs in Japanese traditional medicine). This screening revealed that the extract prepared from Citri Unshiu Pericarpium [the peel of Citrus unshiu (Swingle) Marcov.] increased the expression of Ucp1 in beige adipocytes. We also focused on the function of clock genes in regulating brown/beige adipogenesis. Therefore, another aim of the present study was to evaluate naturally occurring compounds that regulate brain and muscle Arnt-like 1 (Bmal1) gene expression. In this review, we focus on naturally occurring compounds that affect regulatory processes in brown/beige adipogenesis, and discuss better preventive strategies for the management of obesity and other metabolic disorders.


Assuntos
Fatores de Transcrição ARNTL , Adipócitos Bege/fisiologia , Adipócitos Marrons/fisiologia , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Diferenciação Celular , Medicamentos de Ervas Chinesas/farmacologia , Proteína Desacopladora 1 , Fatores de Transcrição ARNTL/metabolismo , Fatores de Transcrição ARNTL/fisiologia , Animais , Relógios Biológicos/genética , Temperatura Baixa , Dieta Hiperlipídica/efeitos adversos , Expressão Gênica , Humanos , Medicina Kampo , Doenças Metabólicas/prevenção & controle , Obesidade/etiologia , Obesidade/prevenção & controle , Fosforilação Oxidativa , Receptores Adrenérgicos beta 3/metabolismo , Termogênese , Proteína Desacopladora 1/metabolismo
8.
Mar Drugs ; 17(5)2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31137922

RESUMO

Fucoxanthin (FX), a marine carotenoid found in macroalgae and microalgae, exhibits several beneficial effects to health. The anti-obesity activity of FX is well documented, but FX has not been mass-produced or applied extensively or commercially because of limited availability of raw materials and complex extraction techniques. In this study, we investigated the anti-obesity effect of standardized FX powder (Phaeodactylum extract (PE)) developed from microalga Phaeodactylum tricornutum as a commercial functional food. The effects of PE on adipogenesis inhibition in 3T3-L1 adipocytes and anti-obesity in high-fat diet (HFD)-fed C57BL/6J mice were evaluated. PE and FX dose-dependently decreased intracellular lipid contents in adipocytes without cytotoxicity. In HFD-fed obese mice, PE supplementation for six weeks decreased body weight, organ weight, and adipocyte size. In the serum parameter analysis, the PE-treated groups showed attenuation of lipid metabolism dysfunction and liver damage induced by HFD. In the liver, uncoupling protein-1 (UCP1) upregulation and peroxisome proliferator activated receptor γ (PPARγ) downregulation were detected in the PE-treated groups. Additionally, micro computed tomography revealed lower fat accumulation in PE-treated groups compared to that in the HFD group. These results indicate that PE exerts anti-obesity effects by inhibiting adipocytic lipogenesis, inducing fat mass reduction and decreasing intracellular lipid content, adipocyte size, and adipose weight.


Assuntos
Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Produtos Biológicos/farmacologia , Estramenópilas/química , Xantofilas/farmacologia , Adipócitos/efeitos dos fármacos , Animais , Fármacos Antiobesidade/isolamento & purificação , Dieta Hiperlipídica , Alimento Funcional/análise , Camundongos Endogâmicos C57BL , Microalgas/química
9.
J Agric Food Chem ; 67(24): 6785-6791, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31141356

RESUMO

Obesity is a worldwide epidemic contributing to a higher risk of developing maladies such as type 2 diabetes, heart disease, and cancer. Shiya tea (leaves of Adinandra nitida), a traditional Chinese tea, is widely consumed due to its palatable flavor and various curative effects, such as reducing blood pressure and blood lipids, as well as anti-inflammation, etc. However, no relevant research on the antiobesity effects of Shiya tea has been reported. In particular, no health-benefiting compounds, other than flavonoids, in Shiya tea have been reported. Thus, 3T3-L1 preadipocytes have been used as a bioactivity-guided identification model to verify the inhibitory effects of Shiya tea on adipogenesis, as well as to identify antiadipogenic compounds. Four triterpenoid saponins (1-4), including one new compound (2α,3α-dihydroxyursolic acid 28- O-ß-d-glucopyranosyl ester, compound 1), and a flavonoid (5) have been identified using NMR (1D and 2D NMR) and liquid chromatography (LC)-MS techniques. Compound 1, the major antiadipogenic constituent with an IC50 value of 27.6 µg/mL, has been identified for the first time in Shiya tea. To understand the structure-activity relationship, three hydrolytic compounds (1s, 2s, and 5s) were obtained to provide an inhibitory effect on lipid accumulation during 3T3-L1 adipocyte differentiation. The inhibitory effect of the triterpenoid (1s) possessing no sugar group decreased significantly, while the flavonoid (5s) also without a sugar group showed increased activity. In addition, the hydroxyl group position may also play a role in inhibitory efficacy.


Assuntos
Adipócitos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Ericales/química , Folhas de Planta/química , Células 3T3-L1 , Adipócitos/citologia , Adipogenia/efeitos dos fármacos , Animais , Medicamentos de Ervas Chinesas/isolamento & purificação , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos
10.
Molecules ; 24(9)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035366

RESUMO

Limonoids are phytochemicals with a variety of biological properties. In the present study, we elucidated the molecular mechanism of suppression of adipogenesis in adipocytes by a limonoid, 7-deacetoxy-7-oxogedunin (CG-1) from Carapa guianensis (Meliaceae), known as andiroba. CG-1 reduced the accumulation of intracellular triglycerides in a concentration-dependent manner. The expression levels of the adipogenic, lipogenic, and lipolytic genes were decreased by CG-1 treatment, whereas the glycerol release level was not affected. When CG-1 was added into the medium during days 0-2 of 6-days-adipogenesis, the accumulation of intracellular lipids and the mRNA levels of the adipogenesis-related genes were decreased. In addition, the phosphorylation level of insulin receptor substrate-1 (IRS-1) and Akt in the early phase of adipocyte differentiation (within 1 day after initiating adipocyte differentiation) was reduced by CG-1. Furthermore, insulin-activated translocation of glucose transporter 4 to the plasma membranes in adipocytes was suppressed by CG-1, followed by decreased glucose uptake into the cells. These results indicate that an andiroba limonoid CG-1 suppressed the accumulation of intracellular lipids in the early phase of adipocyte differentiation through repression of IRS-1/Akt-mediated glucose uptake in adipocytes.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Transportador de Glucose Tipo 4/genética , Glucose/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Limoninas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Transportador de Glucose Tipo 4/metabolismo , Limoninas/química , Meliaceae/química , Camundongos , Estrutura Molecular
11.
Cancer Sci ; 110(8): 2676-2683, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31069877

RESUMO

Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are the most common types of liposarcoma. Although WDLPS and DDLPS patients receive intensive treatment including radical surgery and systemic therapy, their overall 5-year survival rates are 90% and 30%, respectively, indicating that DDLPS is clinically more aggressive. We examined whether adipogenic stimulation induces adipogenesis in human WDLPS/DDLPS cells by using dexamethasone, indomethacin, insulin, and 3-isobutyl-1-methylxanthine (IBMX), all putative medications or drugs. Functional in vitro experiments showed that treatment with these four compounds induced adipogenic potency by transcriptional and translational upregulation of genes related to the maintenance of stemness and adipogenic differentiation. Using in vivo xenograft models, we found that the induction of stemness and adipogenesis inhibited the tumorigenic potency of DDLPS. This study suggests a potential application of drug repositioning in which adipogenesis-inducing compounds could be used to treat DDLPS patients in a clinical setting.


Assuntos
Adipogenia/genética , Desdiferenciação Celular/genética , Proliferação de Células/genética , Lipossarcoma/genética , 1-Metil-3-Isobutilxantina/farmacologia , Adipogenia/efeitos dos fármacos , Desdiferenciação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular Tumoral , Dexametasona/farmacologia , Humanos , Indometacina/farmacologia , Insulina/farmacologia , Lipossarcoma/tratamento farmacológico , Lipossarcoma/patologia , Biossíntese de Proteínas/efeitos dos fármacos , Biossíntese de Proteínas/genética , Transcrição Genética/efeitos dos fármacos , Transcrição Genética/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
12.
Transl Res ; 210: 26-42, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31121128

RESUMO

Obesity is a major cause of metabolic syndrome and type II diabetes, and it presents with metabolic disorders, such as hyperglycemia, hyperlipidemia, and insulin resistance. Pigment epithelium-derived factor (PEDF), a protein isolated from retinal pigment epithelial cells, has multiple functions, including neuronal protection, antineoplastic effects, and anti-inflammatory activity. The aim of this study is to investigate the antiobesity effects of PEDF. The antiobesity effects of PEDF on fat accumulation, inflammation, energy expenditure, insulin resistance, and obesity-related physiological parameters and protein levels were assessed in high-fat diet (HFD)-induced obese mice in vivo and in 3T3-L1 adipocytes, palmitate (PA)-treated HepG2 cells, and C2C12 myotubes in vitro. In an in vivo assay, PEDF effectively decreased body weight gain, white adipose tissue mass, and inflammation and improved insulin resistance, dyslipidemia, and hyperglycemia in HFD-induced mice. In liver tissue, PEDF decreased lipid accumulation and fibrosis. In an in vitro assay, PEDF diminished the differentiation of 3T3-L1 preadipocytes. We also determined that PEDF promoted lipolysis and prolonged cell cycle progression, through the mTOR-S6K pathway and downstream transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein α (CEBP-α), and CEBP-ß. In addition, PEDF decreased reactive oxygen species production in PA-induced HepG2 cells and improved glucose uptake ability in PA-induced HepG2 cells and C2C12 myotubes. In the present study, PEDF protected against HFD-induced obesity and metabolic disorders in mice, inhibited adipogenesis, and improved insulin resistance. These results provide a new potential treatment for obesity in the future.


Assuntos
Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Proteínas do Olho/farmacologia , Doenças Metabólicas/patologia , Fatores de Crescimento Neural/farmacologia , Obesidade/patologia , Obesidade/prevenção & controle , Serpinas/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Clonais , Dieta Hiperlipídica , Fígado Gorduroso/sangue , Fígado Gorduroso/complicações , Fígado Gorduroso/patologia , Células Hep G2 , Humanos , Inflamação/patologia , Resistência à Insulina , Masculino , Doenças Metabólicas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Obesidade/sangue , Obesidade/complicações , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
13.
BMC Complement Altern Med ; 19(1): 100, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068163

RESUMO

BACKGROUND: Obesity is a risk factor for many diseases including diabetes, cancer, arthritis, and cardiovascular diseases. Angiogenesis nourishes adipose tissues and contributes to obesity; it can be prevented by suppressing the expression of associated signaling molecules. Natural products have garnered attention owing to their safety and efficacy in treating several diseases, including obesity. METHODS: Crude Microcystins were extracted from the blooming Microcystis aeruginosa under stress conditions, by ultrasonication following by solvent extraction. The microcystin extract was evaluated for its potential of inhibiting angiogenesis and adipogenesis. The antiangiogenic activity of the microcystins extract was investigated using human umbilical vein endothelial cells (HUVECs), and its anti-obesity activity was determined in vitro by quantification of the accumulated lipids in mouse 3 T3-L1 cells via Oil Red O staining method. RESULTS: The microcystin extract suppressed HUVECs proliferation and tubes formation in Matrigel in a dose-dependent manner. RT-PCR analysis revealed the downregulation of the mRNA expression of angiogenesis-related signaling molecules, such as PI3K, ß-catenin, vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial-cadherin, Akt1, and NF-κB. Additionally, it inhibited the differentiation of premature 3 T3 cells and lipid accumulation in a dose-dependent manner. It suppressed adipogenesis and lipogenesis by reducing the expression level of peroxisome proliferator-activated receptor γ, CCAAT/enhancer binding protein α, and sterol regulatory element-binding protein. CONCLUSIONS: Crude microcystin exerts anti-angiogenic and anti-obesity effects due to the inhibitory effects on the genes expression of associated signaling molecules and transcriptional factors.


Assuntos
Adipogenia/efeitos dos fármacos , Inibidores da Angiogênese/farmacologia , Fármacos Antiobesidade/farmacologia , Microcistinas/farmacologia , Microcystis/química , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Camundongos , Neovascularização Patológica/metabolismo
14.
Cell Prolif ; 52(4): e12624, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31038249

RESUMO

OBJECTIVES: Excessive oxidative stress and diminished antioxidant defences could contribute to age-related tissue damage and various diseases including age-related osteoporosis. Dendrobium officinale polysaccharides (DOPs), a major ingredient from a traditional Chinese medicine, have a great potential of antioxidative activity. In this study, we explore the role of DOP in age-related osteoporosis that remains elusive. MATERIALS AND METHODS: Oxidative stimulation and DOP were used to treat bone marrow mesenchymal stem cells (BMSCs), whose lineage commitment was measured by adipogenic- and osteoblastic-induced differentiation analysis. The oxidative stress and antioxidant capacity of BMSCs under the treatment of DOP were analysed by the level of MDA, SOD. Related mechanism studies were confirmed by qRT-PCR, Western blotting and siRNA transfection. DOP was orally administrated in aged mice whose phenotype was confirmed by micro-CT, immunofluorescence, immunochemistry and calcein double-labelling analysis. RESULTS: Dendrobium officinale polysaccharide treatment markedly increased osteogenic differentiation of BMSCs, while inhibiting adipogenic differentiation. In vitro, DOP could rescue H2O2-induced switch of BMSCs differentiation fate. However, this effect was abolished in BMSCs when interfered with Nrf2 siRNA. Furthermore, administration of DOP to aged mice significantly increased the bone mass and reduced the marrow adipose tissue (MAT) accompanied with decreased oxidative stress of BMSCs. CONCLUSIONS: Our study reveals that DOP can attenuate bone loss and MAT accumulation through NRF2 antioxidant signalling, which may represent as potential therapeutic agent for age-related osteoporosis.


Assuntos
Adipogenia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Dendrobium/química , Osteogênese/efeitos dos fármacos , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Adulto , Idoso , Animais , Antioxidantes/farmacologia , Humanos , Peróxido de Hidrogênio/farmacologia , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
15.
Anal Bioanal Chem ; 411(15): 3257-3268, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31089788

RESUMO

It has been demonstrated that triterpenes in Alismatis rhizoma (Zexie in Chinese, ZX) contributed to the lipid-lowering effect on high-fat diet-induced hyperlipidemia. Alisol B 23-acetate, one of the abundant triterpenes in ZX, was used as the marker of quality control for ZX in Chinese Pharmacopoeia, while it could not reflect the lipid-lowering effect because other triterpenes in ZX also had prominent medicinal efficacy. To identify the significantly bioactive triterpenes in ZX, a multiple reaction monitoring (MRM)-based characteristic chemical profile (CCP)-support vector machine (SVM) model was used to explore the relationship between triterpenes and lipid-lowering effect of ZX. Firstly, the content of 87 targeted triterpenes was quantified by the MRM-based CCP using UHPLC-QTRAP-MS/MS. Secondly, the lipid-lowering effect of 30 ZX samples was assessed by 3T3-L1 preadipocytes. Thirdly, 9 of the 87 triterpenes possessing high mean impact value were identified to have significant lipid-lowering effect via the particle swarm-optimized SVM model. The new SVM model constructed by the 9 triterpenes showed good prediction performance and the overall prediction accuracy reached 81.94%. Finally, the real activity of these triterpenes was partly confirmed and was consistent with the prediction of SVM. These results showed that the method for discovery of triterpenes with prominent lipid-lowering activity in ZX was reliable. The proposed method is expected to provide an efficient and rapid approach for screening of active component and drug discovery in traditional herbs. Graphical abstract.


Assuntos
Alismataceae/química , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Rizoma/química , Máquina de Vetores de Suporte , Triterpenos/química , Triterpenos/farmacologia , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Cromatografia Líquida de Alta Pressão , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Hiperlipidemias/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/análise , Camundongos , Espectrometria de Massas em Tandem
16.
BMC Bioinformatics ; 20(Suppl 7): 201, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31074378

RESUMO

BACKGROUND: A key problem in systems biology is the determination of the regulatory mechanism corresponding to a phenotype. An empirical approach in this regard is to compare the expression profiles of cells under two conditions or tissues from two phenotypes and to unravel the underlying transcriptional regulation. We have proposed the method BASE to statistically infer the effective regulatory factors that are responsible for the gene expression differentiation with the help from the binding data between factors and genes. Usually the protein-DNA binding data are obtained by ChIP-seq experiments, which could be costly and are condition-specific. RESULTS: Here we report a definition of binding strength based on a probability model. Using this condition-free definition, the BASE method needs only the frequencies of cis-motifs in regulatory regions, thereby the inferences can be carried out in silico. The directional regulation can be inferred by considering down- and up-regulation separately. We showed the effectiveness of the approach by one case study. In the study of the effects of polyunsaturated fatty acids (PUFA), namely, docosahexaenoic (DHA) and eicosapentaenoic (EPA) diets on mouse small intestine cells, the inferences of regulations are consistent with those reported in the literature, including PPARα and NFκB, respectively corresponding to enhanced adipogenesis and reduced inflammation. Moreover, we discovered enhanced RORA regulation of circadian rhythm, and reduced ETS1 regulation of angiogenesis. CONCLUSIONS: With the probabilistic definition of cis-trans binding affinity, the BASE method could obtain the significances of TF regulation changes corresponding to a gene expression differentiation profile between treatment and control samples. The landscape of the inferred cis-trans regulations is helpful for revealing the underlying molecular mechanisms. Particularly we reported a more comprehensive regulation induced by EPA&DHA diet.


Assuntos
Indutores da Angiogênese/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Regulação da Expressão Gênica , Hiperlipidemias/genética , Motivos de Nucleotídeos , Transcrição Genética , Adipogenia/efeitos dos fármacos , Animais , Hiperlipidemias/tratamento farmacológico , Intestino Delgado/metabolismo , Camundongos , Regiões Promotoras Genéticas
17.
In Vivo ; 33(3): 707-715, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31028187

RESUMO

BACKGROUND/AIM: The rapid increase in the number of people who are overweight or obese, which increases the risk of diseases and health problems, is becoming an important issue. Herein, we investigated whether olive leaf extract (OLE) has potent anti-obesity effects in high-fat induced mouse models. MATERIALS AND METHODS: C57BL/6 mice were randomized into normal control, high-fat diet (HFD), HFD with OLE, and HFD with garcinia groups and administered experimental diets for 12 weeks. Body weight and food intake were measured once per week and obesity-related biomarkers were evaluated in the serum and adipose tissue. RESULTS: OLE significantly suppressed weight gain, food efficiency ratio, visceral fat accumulation, and serum lipid composition in HFD-induced mice. Furthermore, the expression of adipogenesis- and thermogenesis-related molecules was decreased in the OLE-treated group. CONCLUSION: OLE prevents obesity development by regulating the expression of molecules involved in adipogenesis and thermogenesis.


Assuntos
Fármacos Antiobesidade/farmacologia , Olea/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Fármacos Antiobesidade/química , Biomarcadores , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Metabolismo dos Lipídeos , Masculino , Camundongos , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo , Extratos Vegetais/química , Termogênese/efeitos dos fármacos
18.
Biomed Pharmacother ; 114: 108853, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30986624

RESUMO

It is known that users of psychotropic drugs often have weight gain, adverse effects on bone mineral density and osteoporosis, but the molecular basis for these side effects is poorly understood. The aim of this study is to evaluate the effects in vitro of duloxetine (a serotonin and norepinephrine reuptake inhibitor) and fluoxetine (a selective serotonin reuptake inhibitor) on the physiology of human adult stem cells. Adipose-derived stem cells (ADSCs) were isolated and characterized investigating phenotype morphology, expression and frequency of surface markers. Then, a non-toxic concentration of duloxetine and fluoxetine was selected to treat cells during adipogenic and osteogenic differentiation. Stemness properties and the differentiation potential of drug-treated cells were investigated by the quantification of adipogenic and osteogenic markers gene expression and histological staining. The collected data showed that the administration of a daily non-toxic dose of duloxetine and fluoxetine has not directly influenced ADSCs proliferation and their stemness properties. The treatment with duloxetine or fluoxetine did not lead to morphological alterations during adipogenic or osteogenic commitment. However, treatments with the antidepressant showed a slight difference in adipogenic gene expression timing. Furthermore, duloxetine treatment caused an advance in gene expression of early and late osteogenic markers. Fluoxetine instead caused an increase in expression of osteogenic genes compared to untreated cells. In contrast, in pre-differentiated cells, the daily treatment with duloxetine or fluoxetine did not alter the expression profile of adipogenic and osteogenic differentiation. In conclusion, a non-toxic concentration of duloxetine and fluoxetine does not alter the stemness properties of ADSCs and does not prevent the commitment of pre-differentiated ADSCs in adipocytes or osteocyte. Probably, the weight gain and osteoporotic effects associated with the use of psychotropic drugs could be closely related to the direct action of serotonin.


Assuntos
Antidepressivos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Adulto , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cloridrato de Duloxetina/farmacologia , Fluoxetina/farmacologia , Expressão Gênica/efeitos dos fármacos , Humanos , Osteócitos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Inibidores de Captação de Serotonina/farmacologia , Adulto Jovem
19.
Int J Mol Sci ; 20(8)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991711

RESUMO

Adiponectin (APN), released mainly from adipose tissue, is a well-known homeostatic factor for regulating glucose levels, lipid metabolism, and insulin sensitivity. A recent study showed that human hair follicles express APN receptors and the presence of APN-mediated hair growth signaling, thereby suggesting that APN is a potent hair growth-promoting adipokine. Previously, kojyl cinnamate ester derivatives (KCEDs) were synthesized in our institute as new anti-aging or adiponectin-/adipogenesis-inducing compounds. Here, we tested the activity of these derivatives to induce endogenous APN secretion. Among the derivatives, KCED-1 and KCED-2 showed improved activity in inducing APN mRNA expression, secretion of APN protein, and adipogenesis in human subcutaneous fat cells (hSCFs) when compared with the effects of Seletinoid G, a verified APN inducer. When human follicular dermal papilla cells were treated with the culture supernatant of KCED-1- or KCED-2-treated hSCFs, the mRNA expression of APN-induced hair growth factors such as insulin-like growth factor, hepatocyte growth factor, and vascular endothelial growth factor was upregulated compared with that in the control. Taken together, our study shows that among kojyl cinnamate ester derivatives, KCED-1, KCED-2, as well as Seletinoid G are effective inducers of endogenous APN production in subcutaneous fat tissues, which may in turn contribute to the promotion of hair growth in the human scalp.


Assuntos
Adiponectina/genética , Cinamatos/farmacologia , Folículo Piloso/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Adiponectina/metabolismo , Linhagem Celular , Cinamatos/química , Ésteres/química , Ésteres/farmacologia , Cabelo/citologia , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Cabelo/metabolismo , Folículo Piloso/citologia , Folículo Piloso/crescimento & desenvolvimento , Folículo Piloso/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
20.
Int J Mol Sci ; 20(8)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027178

RESUMO

Skin provides the first defense line against the environment while preserving physiological homeostasis. Subcutaneous tissues including fat depots that are important for maintaining skin structure and alleviating senescence are altered during aging. This study investigated whether theaflavin (TF) in green tea (GT) has skin rejuvenation effects. Specifically, we examined whether high ratio of TF contents can induce the subcutaneous adipogenesis supporting skin structure by modulating lipid metabolism. The co-fermented GT (CoF-GT) fraction containing a high level of TF was obtained by co-fermentation with garland chrysanthemum (Chrysanthemum coronarium) and the conventionally fermented GT (F-GT) fraction was also obtained. The effects of the CoF- or F-GT fractions on adipogenesis were assessed using primary human subcutaneous fat cells (hSCF). Adipogenesis was evaluated based on lipid droplet (LD) formation, as visualized by Oil Red O staining; by analyzing of adipogenesis-related factors by real-time quantitative polyperase chain reaction (RT-qPCR); and by measuring the concentration of adiponectin released into the culture medium by enzyme-linked immunosorbent assay. TF-enriched CoF-GT fraction did not adversely affect hSCF cell viability but induced their adipogenic differentiation, as evidenced by LD formation, upregulation of adipogenesis-related genes, and adiponectin secretion. TF and TF-enriched CoF-GT fraction promoted differentiation of hSCFs and can therefore be used as an ingredient in rejuvenating agents.


Assuntos
Adipócitos/citologia , Adipogenia/efeitos dos fármacos , Biflavonoides/farmacologia , Catequina/farmacologia , Gordura Subcutânea/citologia , Adipócitos/efeitos dos fármacos , Adipogenia/genética , Adiponectina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Chrysanthemum/química , Fermentação/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Modelos Biológicos
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