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1.
AAPS PharmSciTech ; 21(2): 64, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932990

RESUMO

In our previously studies, we confirmed that ergosterol could ameliorate diabetic nephropathy by suppressing the proliferation of mesangial cells and the accumulation of extracellular matrix (ECM). However, the therapeutic application of ergosterol may be confined due to poor aqueous solubility and low oral bioavailability. We aim to prepare ergosterol-loaded nanostructured lipid carriers (ERG-NLCs) to enhance the solubility and oral bioavailability of ergosterol. ERG-NLCs were prepared using glyceryl monostearate and decanoyl/octanoyl-glycerides by hot emulsification-ultrasonication method and characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) analysis, entrapment efficiency (EE), and drug loading (DL) capacity studies. The prepared ERG-NLCs were spherical, with particle size of 81.39 nm and negative zeta potential of 30.77 mV. Ergosterol was successfully encapsulated in NLCs with a high EE of 92.95% and a DL capacity of 6.51%. In pharmacokinetic study, Cmax and AUC0-∞ of ergosterol in ERG-NLCs were obviously enhanced, and the relative oral bioavailability of ERG-NLCs was 277.56% higher than that of raw ergosterol. Moreover, the in vitro pharmacodynamic study indicated that ERG-NLCs inhibited high-glucose-stimulated mesangial cells over proliferation and ECM accumulation more effectively compared to raw ergosterol. In conclusion, the validated ERG-NLCs showed that NLCs mediated delivery could be used as potential vehicle to enhance solubility, oral bioavailability and therapeutic efficacy of ergosterol.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Ergosterol/administração & dosagem , Hipoglicemiantes/administração & dosagem , Nanoestruturas/química , Administração Oral , Animais , Disponibilidade Biológica , Portadores de Fármacos/química , Ergosterol/química , Ergosterol/farmacocinética , Lipídeos/química , Masculino , Ratos , Ratos Sprague-Dawley
2.
Food Funct ; 10(8): 4725-4738, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31304955

RESUMO

Antrodia camphorata is a well-known traditional Chinese mushroom used as a functional food and nutraceutical in Taiwan and China. The aim of this study was to explore the protective effects and mechanism(s) of the ethyl acetate crude extract of A. camphorata (EtOAc-AC) and its active constituent ergostatrien-7,9(11),22-trien-3ß-ol (EK100) in an acute ischemic stroke (AIS) murine model. Treating mice with induced AIS injury by using EtOAc-AC (0.3-0.6 g kg-1, p.o.) and EK100 (60 and 120 mg kg-1, p.o.) 2 h after AIS induction significantly increased the tracking distance and reduced brain infarction. Both EtOAc-AC and EK-100 reduced the expression levels of p65NF-κB and caspase 3 near the peri-infarct cortex and promoted the expression of neurogenesis-associated protein doublecortin (DCX) near the hippocampus, accompanied by glycogen synthase kinase 3 (GSK-3) inhibition and ß-catenin upregulation. Signaling pathway analysis revealed that the advantageous effects of EtOAc-AC and EK-100 involved triggering the activation of PI3K/Akt and inhibition of GSK-3. Our findings suggest that EtOAc-AC and its active constituent EK100 display anti-inflammatory and anti-apoptotic activities. Both EtOAc-AC and EK100 reduce ischemic brain injury by decreasing p65NF-κB and caspase 3 expression, and they promote neurogenesis (DCX) and neuroprotection (Bcl2) by activating the PI3k/Akt-associated GSK3 inhibition and ß-catenin activation.


Assuntos
Antrodia/química , Isquemia Encefálica/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Ergosterol/análogos & derivados , Neurogênese/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Apoptose/efeitos dos fármacos , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Caspase 3/genética , Caspase 3/metabolismo , Cateninas/genética , Cateninas/metabolismo , Proteína Duplacortina , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Ergosterol/administração & dosagem , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
3.
Food Funct ; 10(6): 3386-3395, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31112178

RESUMO

3-Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first rate-limiting step for the synthesis of glucose-derived serine by converting 3-phosphoglycerate (3-PG) to phosphohydroxypyruvate (p-Pyr), which has been reported to associate with tumorigenesis in many cancers. Iox A, a natural withanolide obtained from dietary tomatillo (Physalis ixocarpa), showed significant PHGDH inhibitory activity with an IC50 value of 1.66 ± 0.28 µM, and it was further confirmed to bind directly to PHGDH by the MST assay. Molecular docking demonstrated that Iox A coordinated at the allosteric site of PHGDH, which was consistent with the non-competitive kinetics. Meanwhile, Iox A selectively inhibited the proliferation of high PHGDH-expressing cancer cell lines (SW1990, MCF-7 and HeLa) and showed no obvious cytotoxicities on normal human cells (LO2, L929 and HPDE6-C7). In particular, Iox A showed a dose-dependent proapoptotic activity against SW1990 cells in a micromolar concentration as detected by flow cytometry and western blot analysis. DARTS and siRNA assays further demonstrated that Iox A directly targets at PHGDH to inhibit the proliferation of SW1990 cells. Furthermore, Iox A significantly inhibited the tumor growth in a SW1990 xenograft mouse model with low toxicities, suggesting its potential therapeutic application in pancreatic cancer treatment. Therefore, Iox A was identified as a novel natural PHGDH inhibitor with high targeting and low toxicities for the treatment of pancreatic cancers.


Assuntos
Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Ergosterol/análogos & derivados , Neoplasias Pancreáticas/fisiopatologia , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Physalis/química , Extratos Vegetais/análise , Animais , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Ergosterol/administração & dosagem , Ergosterol/química , Frutas/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos SCID , Simulação de Acoplamento Molecular , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Fosfoglicerato Desidrogenase/genética , Fosfoglicerato Desidrogenase/metabolismo , Extratos Vegetais/química
4.
Nutrients ; 11(2)2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30823598

RESUMO

(1) Background: Diabetic nephropathy, a microvascular complication of diabetes, is one of the principal causes of end-stage renal disease worldwide. The aim of this study was to explore the therapeutic effects of ergosterol on diabetic nephropathy. (2) Methods: Streptozotocin (STZ)-induced C57BL/6 diabetic mice were treated with ergosterol (10, 20, 40 mg/kg/day) for 8 weeks by oral gavage. The in vitro study employed rat mesangial cells exposed to 30 mM glucose for 48 h in the presence of 10 or 20 µM ergosterol. (3) Results: Ergosterol treatment improved body weights, ameliorated the majority of biochemical and renal functional parameters and histopathological changes, and reduced extracellular matrix (ECM) deposition in diabetic mice. In vitro, ergosterol suppressed proliferation, reduced the levels of ECM proteins, and increased the expression of matrix metalloproteinase-2 and -9 in high glucose-induced mesangial cells; Furthermore, ergosterol markedly improved transforming growth factor-ß1 (TGF-ß1) expression, enhanced phosphorylation levels of drosophila mothers against decapentaplegic 2 (Smad2), and regulated the downstream factors in vivo and in vitro. (4) Conclusions: Ergosterol alleviated mesangial cell proliferation and the subsequent ECM deposition by regulating the TGF-ß1/Smad2 signaling pathway.


Assuntos
Proliferação de Células/efeitos dos fármacos , Nefropatias Diabéticas/tratamento farmacológico , Ergosterol/farmacologia , Células Mesangiais/efeitos dos fármacos , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/complicações , Relação Dose-Resposta a Droga , Ergosterol/administração & dosagem , Ergosterol/química , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Células Mesangiais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos , Proteína Smad2/genética , Fator de Crescimento Transformador beta1/genética
5.
Medicine (Baltimore) ; 97(33): e11916, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30113492

RESUMO

BACKGROUND: Lung cancer is one of the most important diseases threatening human health, and targeted therapy has become the main research direction. This work, therefore, aimed to develop cyclic arginine-glycine-aspartic (RGD) and octa-arginine (R8) peptide-modified ergosterol (ERG)-combined cisplatin (diamminedichloridoplatinum(II) [DDP]) liposomes (LIP) as a drug delivery system. METHODS: Soybean phospholipids (SPC) and cholesterol (Chol) were selected to prepare different LIPs: ERG-loaded LIP (ERG-LIP), DDP and ERG-LIP (DDP/ERG-LIP), R8 peptide-modified DDP and ERG-LIP (R8-DDP/ERG-LIP), and cyclic RGD and R8-DDP/ERG-LIP (RGD/R8-DDP/ERG-LIP). The quality, tumor sphere penetrating ability, in vitro cellular uptake, mechanism of cellular uptake, and in vitro cytotoxicity of RGD/R8-DDP/ERG-LIP were evaluated. RESULTS: The LIP quality evaluation revealed that RGD/R8-DDP/ERG-LIP is round with a double-layer structure. The average particle size, dispersion coefficient of the polydispersity index (PDI), and zeta potential of RGD/R8-DDP/ERG-LIP were 155.2 ±â€Š8.7 nm, 0.102, and 4.74 ±â€Š0.7 mV, respectively. Furthermore, the LIPs were stable in the serum, and obviously inhibited the growth of A549 lung cancer cells with RGD/R8-DDP/ERG-LIP exhibiting the strongest inhibitory effect. The highest cellular uptake rate, which was at 4 hours, was exhibited by RGD/R8-DDP/ERG-LIP in a concentration-dependent manner. CONCLUSION: The results showed that LIP uptake by A549 cells was mainly by the clathrin-mediated endocytosis pathway (chlorpromazine). The results also suggest that RGD/R8-DDP/ERG-LIP might be a promising drug delivery system to improve antilung cancer drug effect and tumor-targeting in vitro.


Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Ergosterol/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Lipossomos , Oligopeptídeos , Tamanho da Partícula , Peptídeos Cíclicos
6.
Acta Pharmacol Sin ; 37(6): 834-44, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27133301

RESUMO

AIM: Ergosterol is a plant sterol with anti-tumor and anti-angiogenic activities, but is poorly soluble. In this study, we attempted to enhance its anti-tumor action and oral bioavailability via poly(lactide-co-glycolide) (PLGA) nanoparticle encapsulation. METHODS: Ergosterol-loaded PLGA nanoparticles (NPs/Erg) were prepared using the emulsion/solvent evaporation technique. Their physicochemical properties were characterized, and their cytotoxicity against human cancer cell lines was evaluated with MTT assay. The pharmacokinetics and tissue distribution of NPs/Erg were investigated in rats and mice, respectively. RESULTS: NPs/Erg were spherical in shape with a particle size of 156.9±4.8 nm and a Zeta potential of -19.27±1.13 mV, and had acceptable encapsulation efficiency and loading capacity. NPs/Erg exerted much stronger cytotoxicity against human cancer cells than the free ergosterol, and showed significantly reduced IC50 values (14.69±0.48 µg/mL in glioma U251 cells; 9.43±0.52 µg/mL in breast cancer MCF-7 cells; 4.70±0.41 µg/mL in hepatoma HepG2 cells). After oral administration of a single dose in rats, NPs/Erg displayed a prolonged plasma circulation with a 4.9-fold increase of oral bioavailability compared with the free ergosterol. After mice received NPs/Erg, the ergosterol in NPs/Erg was rapidly distributed in stomach, kidneys, liver, brain, spleen, and virtually non-existent in heart and lungs. The presence of NPs/Erg in brain was particularly improved compared with the free ergosterol. CONCLUSION: The PLGA nanoparticles serve as a promising carrier for the poorly soluble ergosterol and significantly improve its bioavailability, biodistribution and in vitro anti-tumor activities.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Portadores de Fármacos/química , Ergosterol/administração & dosagem , Ergosterol/farmacocinética , Nanopartículas/química , Poliglactina 910/química , Administração Oral , Animais , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ergosterol/farmacologia , Humanos , Masculino , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Ratos Sprague-Dawley
7.
Food Funct ; 7(4): 1915-23, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27040153

RESUMO

Advanced glycation endproducts (AGEs) were shown to play an important role in metabolic syndrome and were suggested to contribute to the development of hepatic fibrosis. Evidence indicates that AGEs resulted in hepatic fibrosis coupled to the activation of the receptor for AGEs (RAGE) in hepatic stellate cells (HSCs). NADPH oxidase is downstream of the RAGE signaling pathway, resulting in an increase in reactive oxygen species (ROS), alpha-smooth muscle actin (alpha-SMA), RAGE, and matrix metalloproteinase-9 (MMP-9). This study was designed to evaluate the effects of ergosterol on RAGE signaling in HSC-T6 cells. Ergosterol suppressed the activation of HSC-T6 cells induced by AGEs, and attenuated overexpressions of alpha-SMA, MMP-9, and epithelial-mesenchymal transition (EMT) markers, including N-cadherin and vimentin. We also found that these inhibitory effects of ergosterol on the activation of HSCs were dependent on peroxisome proliferator-activated receptor-gamma (PPARgamma) confirmed by PPARgamma reporter assay and PPARgamma knockdown. In addition, ergosterol also showed an inhibitory effect on the generation of AGEs, fructosamine, and α-dicarbonyl compounds in this study. Our results show that ergosterol can be used as a protective agent against hepatic fibrosis caused by induction of AGEs.


Assuntos
Ergosterol/administração & dosagem , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/metabolismo , PPAR gama/genética , Caderinas/genética , Caderinas/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , PPAR gama/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
8.
Int J Oncol ; 48(4): 1670-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26893131

RESUMO

Agaricus blazei (A. blazei) is a mushroom with many biological effects and active ingredients. We purified a tumoricidal substance from A. blazei, an ergosterol derivative, and named it 'Agarol'. Cytotoxic effects of Agarol were determined by the MTT assay using A549, MKN45, HSC-3, and HSC-4 human carcinoma cell lines treated with Agarol. Apoptosis was detected by flow cytometry analysis. Reactive oxygen species (ROS) levels and mitochondria membrane potential (∆ψm) were also determined by flow cytometry. Western blot analysis was used to quantify the expression of apoptosis-related proteins. Agarol predominantly induced apoptosis in two p53-wild cell lines (A549 and MKN45) compared to the other p53-mutant cell lines (HSC-3 and HSC-4). Further mechanistic studies revealed that induction of apoptosis is associated with increased generation of ROS, reduced ∆ψm, release of apoptosis-inducing factor (AIF) from the mitochondria to the cytosol, upregulation of Bax, and downregulation of Bcl-2. Caspase-3 activities did not increase, and z-VAD-fmk, a caspase inhibitor, did not inhibit the Agarol-induced apoptosis. These findings indicate that Agarol induces caspase-independent apoptosis in human carcinoma cells through a mitochondrial pathway. The in vivo anticancer activity of Agarol was confirmed in a xenograft murine model. This study suggests a molecular mechanism by which Agarol induces apoptosis in human carcinoma cells and indicates the potential use of Agarol as an anticancer agent.


Assuntos
Agaricus/química , Antineoplásicos/administração & dosagem , Ergosterol/administração & dosagem , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ergosterol/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Nat Prod Res ; 30(16): 1862-5, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26382563

RESUMO

The fruit body of Lasiosphaera fenzlii was found to show cytotoxicity on cancer cells during a preliminary screening. Repeated column chromatography of the fungal methanol extract resulted in the isolation of six compounds identified as 5α,8α-epidioxy-ergosta-6,22-dien-3ß-ol (1), 5α,8α-epidioxy-ergosta-6,9(11),22-trien-3ß-ol (2), 5α-ergosta-7,22-dien-3ß-ol (3), 5α-ergosta-7,22-dien-3-one (4), ergosta-7,22-dien-3ß,5α,6ß-triol (5) and 6-dihydroxy-2,3-dihydro-1H-isoindol-1-one (6). The two peroxide compounds, 1 and 2, showed cytotoxic activity and compound 1 was selectively cytotoxic to cancer cells. Furthermore, compound 1 synergised the cytotoxicity of paclitaxel on Hela cells by increasing intracellular accumulation of paclitaxel in cancer cells but not in normal cells.


Assuntos
Agaricales/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Ergosterol/administração & dosagem , Ergosterol/análogos & derivados , Ergosterol/farmacologia , Células HeLa/efeitos dos fármacos , Humanos , Isoindóis/administração & dosagem , Isoindóis/farmacologia , Paclitaxel/administração & dosagem
10.
Int J Pharm ; 489(1-2): 277-84, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25957702

RESUMO

In fear of animal-associated diseases, there is a trend in searching for non-animal derived substitutes for existing excipients in the pharmaceutical industries. This paper aimed to screen cholesterol analogues as membrane stabilizers of liposomes from botanical sterols, including ß-sitosterol, stigmasterol, ergosterol and lanosterol. Liposomes containing four kinds of sterols were prepared and evaluated in vitro and in vivo as oral delivery system of insulin. Liposomes containing ß-sitosterol (Si-Lip), stigmasterol (St-Lip) and lanosterol (La-Lip) was found not to protect insulin against degradation. Only 10% of the initial insulin in liposomes was preserved after a 30 min exposure to simulated gastric fluids. However, the protective ability of liposomes containing ergosterol (Er-Lip) was similar to that of liposomes containing sodium glycocholate (Sgc-Lip) and superior to that of liposomes containing cholesterol (Ch-Lip). In addition, the blood glucose level can decrease to about 50% of initial level after oral Er-Lip which was significantly superior to the in vivo performance of Si-Lip and Ch-Lip and similar to Sgc-Lip. Er-Lips of ergosterol/phospholipids ratios of 1:4 or 1:6 exerts more pronounced protective ability of insulin in simulated gastrointestinal fluids and hypoglycemic effects in rats than other formulations. Furthermore, Er-Lips exerted low toxicity to Caco-2 cells through a cell viability study. Meahwhile, insulin permeability was significantly increased across Caco-2 monolayers by encapsulating in Er-Lip. It was concluded that ergosterol could be used as a substitute for cholesterol and bile salt derivatives in liposomes to enhance oral bioavailability of insulin.


Assuntos
Ergosterol/administração & dosagem , Insulina/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Transporte Biológico , Glicemia/análise , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Colesterol/análogos & derivados , Ergosterol/química , Ergosterol/farmacologia , Humanos , Insulina/química , Insulina/farmacologia , Lipossomos , Tamanho da Partícula , Ratos Wistar
11.
J Agric Food Chem ; 63(9): 2479-89, 2015 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-25693659

RESUMO

This study was designed to explore the effects and mechanism of ergostatrien-3ß-ol (EK100) from the submerged whole broth of Antrodia camphorata on diabetes and dyslipidemia in high fat diet (HFD)-fed mice for 12 weeks. The C57BL/6J mouse fed with a high fat diet (HFD) could induce insulin resistance and hyperlipidemia. After 8 week of induction, mice were receiving EK100 (at three dosages) or fenofibrate (Feno) or rosiglitazone (Rosi) or vehicle by oral gavage 4 weeks afterward. HFD-fed mice display increased blood glucose, glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), insulin, and leptin levels. These blood markers were significantly lower in EK100-treated mice, and finally ameliorated insulin resistance. EK100 treatment exhibited reduced hepatic ballooning degeneration and size of visceral adipocytes. Glucose transporter 4 (GLUT4) proteins and phosphorylation of Akt in skeletal muscle were significantly increased in EK100- and Rosi-treated mice. EK100, Feno, and Rosi treatment led to significant increases in phosphorylation of AMP-activated protein kinase (phospho-AMPK) protein in both skeletal muscle and liver. Moreover, EK100 caused a decrease in hepatic expressions of phosphenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6 Pase), and decreased glucose production. EK100 lowered blood TG level by inhibition of hepatic fatty acid synthesis by dampening sterol response element binding protein-1c (SREBP-1c) but increasing expression of peroxisome proliferator activated receptor α (PPARα). Moreover, EK100-treated mice reduced blood TC levels by decreased hepatic expressions of SREBP2, which plays a major role in the regulation of cholesterol synthesis. EK100 increased high-density lipoprotein cholesterol (HDL-C) concentrations by increasing expressions of apolipoprotein A-I (apo A-I) in liver tissue. Our findings manifest that EK100 may have therapeutic potential in treating type 2 diabetes associated with hyperlipidemia in HFD-fed mice by regulation of GLUT4, PEPCK, G6 Pase, SREBP1c, SREBP2, apo A-I, and AMPK phosphorylation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antrodia/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Ergosterol/análogos & derivados , Transportador de Glucose Tipo 4/metabolismo , Hiperlipidemias/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/genética , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ergosterol/administração & dosagem , Transportador de Glucose Tipo 4/genética , Humanos , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Triglicerídeos/metabolismo
12.
Pharmacol Rep ; 61(4): 719-26, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19815955

RESUMO

Circadian time-dependent treatment with chemotherapeutic drugs (chronotherapy) optimizes the therapeutic index by maximizing treatment efficacy and minimizing toxicity. The circadian time-dependent chemopreventive and anti-lipid peroxidative efficacy of withaferin-A in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis was investigated in the present study. We induced oral squamous cell carcinoma in the buccal pouches of golden Syrian hamsters during the day (4:00, 8:00, 12:00, 16:00, 20:00 and 24:00) by application of DMBA three times per week for 14 weeks. The circadian time-dependent tumor incidence, volume and burden were observed in hamsters treated with either DMBA alone or DMBA + withaferin-A. The circadian pattern of lipid peroxidation by-products, as measured by the formation of thiobarbituric acid reactive substances (TBARS) and enzymatic antioxidants [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)], was also analyzed in the buccal mucosa of DMBA-treated hamsters. We found the highest incidence of tumor formation at 24.00 h in hamsters treated with DMBA alone as compared to other experimental groups. Circadian dysregulation of lipid peroxidation and antioxidant status was observed in DMBA-treated animals as compared to control animals. Oral (po) administration of withaferin-A (20 mg/kg) completely prevented the formation of tumors between 8.00 h and 12.00 h and synchronized the status of lipid peroxidation and antioxidants in the buccal mucosa of hamsters treated with DMBA alone. Also, oral administration of withaferin-A to DMBA-treated animals significantly reduced the formation of tumors and synchronized the status of lipid peroxidation and antioxidants in the rest of the time intervals. Our study thus suggests that withaferin-A has significant chemopreventive and anti-lipid peroxidative potential in DMBA-induced oral carcinogenesis, probably by interfering with DMBA-induced abnormal cell proliferation in the buccal mucosa.


Assuntos
9,10-Dimetil-1,2-benzantraceno/toxicidade , Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Ritmo Circadiano/efeitos dos fármacos , Ergosterol/análogos & derivados , Neoplasias Bucais/tratamento farmacológico , 9,10-Dimetil-1,2-benzantraceno/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/fisiopatologia , Ritmo Circadiano/fisiologia , Cricetinae , Ergosterol/administração & dosagem , Ergosterol/isolamento & purificação , Ergosterol/uso terapêutico , Masculino , Mesocricetus , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/fisiopatologia , Fitoterapia/métodos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Raízes de Plantas , Vitanolídeos
13.
Int Immunopharmacol ; 9(10): 1137-44, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19524704

RESUMO

This study was taken up to see the effect of Withanolide A (WS-1), a compound isolated from Withania somnifera root extract on chronic stress-induced alterations on T lymphocyte subset distribution and corresponding cytokine secretion patterns in experimental Swiss albino mice. Stress disturbs the homeostatic state of the organism and brings about behavioral, endocrine and immunological changes. The chronic suppression induced by stress depresses the immune functioning and increases susceptibility to diseases. Oral administration of WS-1 once daily at the graded doses of 0.25, 0.5, 1 and 2 mg/kg p.o. caused significant recovery of stress-induced depleted T cell population causing an increase in the expression of IL-2 and IFN-gamma (a signature cytokine of Th1 helper cells) and a decrease in the concentration of corticosterone in stressed experimental animals. It also reversed the restraint stress-induced increase in plasma alanine aminotransferase (ALT), aspartate aminotransferase(AST) and hepatic lipid peroxidation (LP) levels and improved the restraint stress-induced decrease in hepatic glutathione (GSH), and glycogen levels, thus showing the significant antistress potential of the test drug.


Assuntos
Ergosterol/análogos & derivados , Hepatócitos/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/imunologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Withania , Administração Oral , Alanina Transaminase/biossíntese , Alanina Transaminase/sangue , Alanina Transaminase/genética , Animais , Aspartato Aminotransferases/biossíntese , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/genética , Corticosterona/genética , Corticosterona/metabolismo , Ergosterol/administração & dosagem , Hepatócitos/imunologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Imunofenotipagem , Interferon gama/metabolismo , Interleucina-2/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Restrição Física , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Vitanolídeos
14.
Eur J Pharmacol ; 599(1-3): 11-7, 2008 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-18838070

RESUMO

Induction of inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production is thought to have beneficial immunomodulatory effects in acute and chronic inflammatory disorders. In Raw 264.7 cells stimulated with lipopolysaccharide (LPS) to mimic inflammation, withaferin A inhibited LPS-induced expression of both iNOS protein and mRNA in a dose-dependent manner. To investigate the mechanism by which withaferin A inhibits iNOS gene expression, we examined activation of mitogen-activated protein kinases (MAPKs) and Akt in Raw 264.7 cells. We did not observe any significant changes in the phosphorylation of p38 MAPK in cells treated with LPS alone or LPS plus withaferin A. However, LPS-induced Akt phosphorylation was markedly inhibited by withaferin A, while the phosphorylation of p42/p44 extracellular signal-regulated kinases (ERKs) was slightly inhibited by withaferin A treatment. Withaferin A prevented IkappaB phosphorylation, blocking the subsequent nuclear translocation of nuclear factor-kappaB (NF-kappaB) and inhibiting its DNA binding activity. LPS-induced p65 phosphorylation, which is mediated by extracellular signal-regulated kinase (ERK) and Akt pathways, was attenuated by withaferin A treatment. Moreover, LPS-induced NO production and NF-kappaB activation were inhibited by SH-6, a specific inhibitor of Akt. Taken together, these results suggest that withaferin A inhibits inflammation through inhibition of NO production and iNOS expression, at least in part, by blocking Akt and subsequently down-regulating NF-kappaB activity.


Assuntos
Ergosterol/análogos & derivados , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico/biossíntese , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ergosterol/administração & dosagem , Ergosterol/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Fator de Transcrição RelA/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Vitanolídeos , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Planta Med ; 73(11): 1208-13, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17764065

RESUMO

Three new anti-oxidative ergostanes, methyl antcinate L (1), antcin M (2), and methyl antcinate K (3), together with nine additional known compounds, 3-ketodehydrosulphurenic acid, sulphurenic acid, dehydrosulphurenic acid, 3beta,15alpha-dihydroxylanosta-7,9(11),24-trien-21-oic acid, zhankuic acid A, zhankuic acid B, zhankuic acid C, antcin C, and antcin K were isolated from the basidiomata of Antrodia salmonea, a newly identified species of Antrodia (Polyporaceae) in Taiwan. These three new compounds were identified as methyl 3alpha,7alpha,12alpha-trihydroxy-4alpha-methylergosta-8,24(29)-dien-11-on-26-oate (1), 3alpha,12alpha-dihydroxy-4alpha-methylergosta-8,24(29)-dien-11-on-26-oic acid (2), and methyl 3alpha,4beta,7beta-trihydroxy-4alpha-methylergosta-8,24(29)-dien-11-on-26-oate (3) by spectroscopic analysis. We studied their antioxidative potential on the production of reactive oxygen species and nitric oxide (NO) in neutrophils and microglial cells, respectively. Compounds 1-3 displayed potent antioxidative activity with IC50 values of around 2.0-8.8 microM that was partially due to inhibition (6-67%) of NADPH oxidase activity but not through direct radical-scavenging properties. Compounds 1-3 also inhibited NO production with IC50 values of around 1.7-16.5 microM and were more potent than a non-specific NOS inhibitor. We conclude that these three new compounds 1, 2, and 3 exhibit anti-inflammatory activities in activated inflammatory cells.


Assuntos
Anti-Inflamatórios/farmacologia , Fitoterapia , Extratos Vegetais/farmacologia , Polyporales , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Compostos de Bifenilo , Ergosterol/administração & dosagem , Ergosterol/análogos & derivados , Ergosterol/farmacologia , Ergosterol/uso terapêutico , Humanos , Concentração Inibidora 50 , Camundongos , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Óxido Nítrico/metabolismo , Picratos/química , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
16.
Phytother Res ; 21(7): 601-4, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17357175

RESUMO

Ergosterol peroxide, cycloart-23-en-3beta,25-diol, vanillin and 4-hydroxybenzaldehyde have been isolated and characterized from a crude methanol extract of Euphorbia lagascae. Previous studies have shown contradictory results about the antibacterial activity of ergosterol peroxide against Mycobacterium tuberculosis. In order to clarify this question, the activity of this compound was tested against Mycobacterium tuberculosis H37Rv ATCC 27294 strain using two different systems: BACTEC 460TB (Bactec 460) and BACTEC MGIT 960 system (Bactec 960). The results obtained show that significant activity was demonstrable only with the Bactec 460 system. The lack of activity noted with the Bactec 960 system appears to be due to the much faster growth rate of the organism in the medium of this system as opposed to that of the Bactec 460 system. Ergosterol peroxide is also shown by the current study to be devoid of any activity against an antibiotic sensitive ATCC strain of Staphylococcus aureus.


Assuntos
Antituberculosos/farmacologia , Ergosterol/análogos & derivados , Euphorbia , Mycobacterium tuberculosis/efeitos dos fármacos , Fitoterapia , Antituberculosos/administração & dosagem , Antituberculosos/uso terapêutico , Resistência a Múltiplos Medicamentos , Ergosterol/administração & dosagem , Ergosterol/farmacologia , Ergosterol/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/classificação , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
17.
Planta Med ; 71(1): 77-9, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15678378

RESUMO

Recently, we found that the MeOH extract of Penicillium oxalicum showed inhibitory activity towards DNA topoisomerase I. Subsequently, ergosterol peroxide, ergosterol, palmitoleic acid, and linoleic acid were isolated from the cultured mycelia of P. oxalicum. The structural determinations were based on physical and spectral analyses. Biological evaluation revealed that ergosterol peroxide inhibited the relaxation of supercoiled DNA (pBR322) induced by DNA topoisomerase I, and also showed marginal, selective cytotoxic activity against human colon tumor cells [COLO-205 (ED50=8.56 microg/mL].


Assuntos
Inibidores da Aromatase/farmacologia , Ergosterol/análogos & derivados , Ergosterol/farmacologia , Penicillium , Fitoterapia , Inibidores da Topoisomerase I , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/uso terapêutico , DNA Topoisomerases Tipo I/efeitos dos fármacos , Ergosterol/administração & dosagem , Ergosterol/uso terapêutico , Humanos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
18.
Phytomedicine ; 11(5): 452-60, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15330502

RESUMO

Histopathological studies of the cutaneous tissues of Wistar rats exposed to UV B radiation (294 nm) for 20 days and rats exposed to UV B radiation for 20 days, followed by topical treatment with benzoyl peroxide, a tumor promoter (20 mg/animal/0.2 ml acetone) twice a week for 1 month, and kept under observation for 12 weeks, demonstrate the development of malignancy. Pretreatment of the animals with 1-oxo-5beta, 6beta-epoxy-witha-2-enolide (20 mg/kg bwt.), isolated from the roots of Withania somnifera, prior to exposing the animals to UV B radiation, prevents the incidence of skin carcinoma. The administration of 1-oxo-5beta, 6beta-epoxy-witha-2-enolide, to the animals after exposing them to UV B radiation/UV B radiation and benzoyl peroxide also prevents the occurrence of malignancy in the cutaneous tissue. Immunohistochemical staining of the cutaneous tissues of rats exposed to UV B radiation show the presence of p53 + foci (clusters of cells containing the mutated p53 protein), whereas an absence of p53 + foci is observed in animals pretreated with 1-oxo-5beta, 6beta-epoxy-witha-2-enolide. These results prove that 1-oxo-5beta, 6beta-epoxy-witha-2-enolide has the potential for acting as an effective agent to prevent the incidence of skin carcinoma induced by UV B radiation.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ergosterol/farmacologia , Fitoterapia , Neoplasias Cutâneas/tratamento farmacológico , Withania , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Modelos Animais de Doenças , Ergosterol/administração & dosagem , Ergosterol/análogos & derivados , Ergosterol/uso terapêutico , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Raízes de Plantas , Ratos , Ratos Wistar , Raios Ultravioleta
19.
J Econ Entomol ; 97(3): 1025-35, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15279287

RESUMO

The feeding preferences of the Formosan subterranean termite, Coptotermes formosanus Shiraki, for commercial lumber Alaska yellow cedar, Chamaecyparis nootkatensis (D. Don) Spach; yellow birch, Betula alleghaniensis Britton; northern red oak, Quercus rubra L.; redwood, Sequoia sempervirers (D. Don) Endl; and spruce (Picea spp.) were examined to determine whether the presence of the lignin-degrading basidiomycete Marasmiellus troyanus (Murrill) Singer could alter the relative preference of termites for these wood species. In paired choice tests with fungus-inoculated sawdust versus control sawdust, termites showed a strong preference for the fungus-inoculated sawdust for all wood species tested, except for Alaska yellow cedar. In a multiple-choice test using sawdust without fungus, termites showed a very strong preference for red oak sawdust over the other three species. In a paired choice test using fungus-inoculated sawdust, termites showed a preference for redwood over red oak sawdust. In a feeding test using autoclaved wood blocks without fungal decay, there was no difference in termite consumption of birch, red oak, or redwood. The relative preference of termites for redwood increased when blocks were decayed by M. troyanus for 3 and 8 wk. These results indicate that chemical modifications due to fungal decay affected the feeding preference of termites for different commercial lumber.


Assuntos
Basidiomycota/metabolismo , Comportamento Animal , Isópteros/fisiologia , Lignina/metabolismo , Madeira , Animais , Ergosterol/administração & dosagem , Comportamento Alimentar , Preferências Alimentares
20.
Planta Med ; 70(4): 310-4, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15095145

RESUMO

We have previously shown that a concentrated ethanol extract of the fruiting bodies of Antrodia camphorata exhibited immunomodulating effects in human leukocytes and fourteen compounds including zhankuic acids A, B, C, and antcin K were identified in the extract. In this study, an acute cellular model in isolated peripheral human neutrophils was established to elucidate the anti-inflammatory effects of these compounds. Reactive oxygen species (ROS) production and firm adhesion by neutrophils display two important responses during inflammation. To evaluate whether these compounds could prevent inflammatory responses by neutrophils, their effects on N-formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol 12-myristate-13-acetate (PMA)-activated peripheral human neutrophils were examined. Pretreatment with 1 - 25 microM of zhankuic acids A, B, C, or antcin K concentration-dependently diminished fMLP- or PMA-induced ROS production, as measured by a lucigenin-amplified chemiluminescence, with IC (50) (microM) around 5 - 20 microM. Zhankuic acids A, B, C, or antcin K also effectively inhibited the fMLP- or PMA-induced firm adhesion without interfering with the up-expression of surface Mac-1 (CD11b/CD18), a beta2 integrin mediating the firm adhesion of neutrophils to endothelium. The anti-inflammatory actions of these drugs were not due to cytotoxic effects because no significant difference in cell viability was observed compared to vehicle control. These data suggest that inhibition of both ROS production and firm adhesion by neutrophils has no significant cytotoxic effect that could give these drugs the potential to be anti-inflammatory agents for the clinical treatment.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Colestenos/farmacologia , Ergosterol/análogos & derivados , Neutrófilos/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Polyporaceae , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Colestenos/administração & dosagem , Colestenos/uso terapêutico , Ergosterol/administração & dosagem , Ergosterol/farmacologia , Ergosterol/uso terapêutico , Frutas , Humanos , Concentração Inibidora 50 , Neutrófilos/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
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