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1.
Front Nutr ; 9: 865257, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35571927

RESUMO

Atractylodes macrocephala rhizome (called Bái-zhú in China) has a long history as a functional food and herbal medicine in East Asia, especially China. Sesquiterpenoids are one of the main active compounds of Atractylodes macrocephala rhizome. This study aimed to explore the unknown sesquiterpenoids of A. macrocephala rhizome using a molecular networking strategy. Two new nitrogen-containing sesquiterpenoids, atractylenolactam A (1) and atractylenolactam B (2), and 2 new sesquiterpene lactones, 8-methoxy-atractylenolide V (6) and 15-acetoxyl atractylenolide III (7), along with 12 known analogs (3-5 and 8-16) were discovered and isolated. All the structures were assigned based on detailed spectroscopic analyses. The absolute configurations of 1, 2, 6, and 7 were established by time-dependent density functional theory ECD (TDDFT-ECD) calculations. All these compounds had different degrees of concentration-dependent activating effects on nuclear-factor-E2-related factor-2 (Nrf2).

2.
Zhongguo Zhong Yao Za Zhi ; 47(2): 428-432, 2022 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-35178985

RESUMO

Three sesquiterpenoids were isolated and purified from the 95% ethanol extract of Atractylodis Macrocephalae Rhizoma by column chromatography on silica gel, Sephadex LH-20, ODS, and high-performance liquid chromatography(HPLC). Their chemical structures were identified on the basis of spectroscopic analysis and physiochemical properties as(7Z)-8ß,13-diacetoxy-eudesma-4(15),7(11)-diene(1), 7-oxo-7,8-secoeudesma-4(15),11-dien-8-oic acid(2), and guai-10(14)-en-11-ol(3). Compounds 1 and 2 are new compounds and compound 3 was obtained from Compositae family for the first time. Compounds 1, 2, and 3 showed weak inhibitory activities against sterol regulatory element-binding proteins(SREBPs).


Assuntos
Atractylodes , Medicamentos de Ervas Chinesas , Sesquiterpenos de Eudesmano , Proteínas de Ligação a Elemento Regulador de Esterol/antagonistas & inibidores , Atractylodes/química , Medicamentos de Ervas Chinesas/química , Rizoma/química , Sesquiterpenos de Eudesmano/análise , Sesquiterpenos de Eudesmano/farmacologia
3.
Zhongguo Zhong Yao Za Zhi ; 47(2): 453-460, 2022 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-35178989

RESUMO

The present study investigated the pharmaceutical effect and underlying mechanism of Zexie Decoction(ZXD) on nonalcoholic fatty liver disease(NAFLD) in vitro and in vivo via the LKB1/AMPK/PGC-1α pathway based on palmitic acid(PA)-induced lipid accumulation model and high-fat diet(HFD)-induced NAFLD model in mice. As revealed by the MTT assay, ZXD had no effect on HepG2 activity, but dose-dependently down-regulated alanine aminotransferase(ALT) and aspartate aminotransferase(AST) in the liver cell medium induced by PA, and decreased the plasma levels of ALT and AST, and total cholesterol(TC) and triglyceride(TG) levels in the liver. Nile red staining showed PA-induced intracellular lipid accumulation, significantly increased lipid accumulation of hepatocytes induced by PA, suggesting that the lipid accumulation model in vitro was properly induced. ZXD could effectively improve the lipid accumulation of hepatocytes induced by PA. Oil red O staining also demonstrated that ZXD improved the lipid accumulation in the liver of HFD mice. JC-1 staining for mitochondrial membrane potential indicated that ZXD effectively reversed the decrease in mitochondrial membrane potential caused by hepatocyte injury induced by PA, activated PGC-1α, and up-regulated the expression of its target genes, such as ACADS, CPT-1α, CPT-1ß, UCP-1, ACSL-1, and NRF-1. In addition, as revealed by the Western blot and immunohistochemistry, ZXD up-regulated the protein expression levels of LKB1, p-AMPK, p-ACC, and PGC-1α in vivo and in vitro. In conclusion, ZXD can improve NAFLD and its mechanism may be related to the regulation of the LKB1/AMPK/PGC-1α pathway.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Alanina Transaminase/metabolismo , Animais , Dieta Hiperlipídica , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo
4.
Nat Prod Res ; 36(5): 1230-1235, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33401972

RESUMO

Two new sesquiterpenes, named selina-4(14),7,11-trien-9-ol (1) and selina-4(14),11-dien-7-ol (2), along with two known compounds were isolated from rhizomes of Atractylodes macrocephala Koidz. All structures were assigned on the basis of detailed spectroscopic analyses. The absolute configuration of 1 was established by TDDFT-ECD calculations. Compound 1 was found to moderately inhibit LSD1 activity with IC50 value of 34.0 µM. Compounds 1 and 4 exhibited a regulate effect on Keap1-Nrf2-ARE pathway.[Formula: see text].


Assuntos
Atractylodes , Sesquiterpenos , Atractylodes/química , Proteína 1 Associada a ECH Semelhante a Kelch/análise , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Rizoma/química , Sesquiterpenos/química
5.
Acta Pharm Sin B ; 11(11): 3542-3552, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34900535

RESUMO

The mammalian target of rapamycin (mTOR)-sterol regulatory element-binding proteins (SREBPs) signaling promotes lipogenesis. However, mTOR inhibitors also displayed a significant side effect of hyperlipidemia. Thus, it is essential to develop mTOR-specific inhibitors to inhibit lipogenesis. Here, we screened the endogenous inhibitors of mTOR, and identified that FKBP38 as a vital regulator of lipid metabolism. FKBP38 decreased the lipid content in vitro and in vivo via suppression of the mTOR/P70S6K/SREBPs pathway. 3,5,6,7,8,3',4'-Heptamethoxyflavone (HMF), a citrus flavonoid, was found to target FKBP38 to suppress the mTOR/P70S6K/SREBPs pathway, reduce lipid level, and potently ameliorate hyperlipidemia and insulin resistance in high fat diet (HFD)-fed mice. Our findings suggest that pharmacological intervention by targeting FKBP38 to suppress mTOR/P70S6K/SREBPs pathway is a potential therapeutic strategy for hyperlipidemia, and HMF could be a leading compound for development of anti-hyperlipidemia drugs.

6.
J Ethnopharmacol ; 264: 113380, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32918994

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn is popularly used as a herbal medicine and food additive in the world. Sea buckthorn flavonoids (SF) is reported to have an ameliorative effect on obesity and hyperlipidemia (HLP). AIM: To identify the major bioactive compounds and the lipid-lowering mechanism of SF. METHODS: We used network pharmacology analysis and in vitro experiments to identify the major bioactive compounds and the lipid-lowering mechanism of SF. RESULTS: A total of 12 bioactive compounds, 60 targets related to SF and HLP were identified, and a component-target-disease network was constructed. The KEGG analysis revealed that SF regulated cholesterol metabolism, fat digestion and absorption, and PPAR signaling pathways in HLP. The experimental validation indicated that sea buckthorn flavonoids extract (SFE) and 4 bioactive compounds reduced lipid droplet accumulation, up-regulated the mRNA expression of PPAR-γ, PPAR-α, ABCA1 and CPT1A, etc, down-regulated SREBP-2 and its target gene LDLR, which are closely related to cholesterol conversion into bile acids, de novo synthesis and fatty acids oxidation. The major bioactive flavonoid isorhamnetin (ISOR) also increased the protein expression of PPAR-γ, LXRα and CYP7A1. CONCLUSION: SF might promote cholesterol transformation into bile acids and cholesterol efflux, inhibit cholesterol de novo synthesis and accelerate fatty acids oxidation for ameliorating HLP.


Assuntos
Flavonoides/farmacologia , Hippophae , Extratos Vegetais/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Flavonoides/isolamento & purificação , Flavonoides/uso terapêutico , Humanos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Mapas de Interação de Proteínas/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Reprodutibilidade dos Testes
7.
Fitoterapia ; 147: 104730, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32971205

RESUMO

One new bisesquiterpenoid, biepiasreorlid II (1), three new sesquiterpene lactones 8α-methoxy-epiasterolid (4), 3ß-acetoxyl-8-epiasterolid (5), and 3ß-acetoxyl-atractylenolide I (6), along with five known analogues (2-3 and 7-9), were obtained from rhizome of Atractylodes macrocephala Koidz. All structures were assigned on the basis of detailed spectroscopic analyses. The absolute configuration of 1 was established by the analysis of single-crystal X-ray diffraction with Ga Kα radiation, and 4-6 were elucidated by TDDFT-ECD calculations. The CREB agonistic activity was investigated in HEK293T cells using dual luciferase reporter assay. Compounds 1, 2, 5, and 7-9 exhibited strong to agonistic activities on CREB.


Assuntos
Atractylodes/química , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Lactonas/farmacologia , Sesquiterpenos/farmacologia , China , Células HEK293 , Humanos , Lactonas/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Rizoma/química , Sesquiterpenos/isolamento & purificação
8.
Chin J Nat Med ; 14(11): 823-834, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27914526

RESUMO

Menopausal metabolic syndrome (MMS) is a series of syndrome caused by ovarian function decline and hormone insufficiency, and is a high risk factor for cardiovascular diseases (CVD) and type II diabetes mellitus (T2DM). Erzhiwan (EZW), composed of Herba Ecliptae and Fructus Ligustri Lucidi, is a traditional Chinese herbal formula that has been used to treat menopausal syndrome for many years. We added Herba Epimedii, Radix Rehmanniae, and Fructus Corni into EZW, to prepare a new formula, termed Jiawei Erzhiwan (JE). The present study was designed to determine the anti-MMS effects of JE using ovariectomized (OVX) adult female rats that were treated with JE for 4 weeks, and ß-tc-6 cells and INS cells were used to detected the protect effectiveness of JE. Our results showed JE could increase insulin sensitivity and ameliorated hyperlipidemia. Metabolomics analysis showed that the serum levels of branched and aromatic amino acids were down-regulated in serum by JE administration. Moreover, JE enhanced the function of islet ß cells INS-1 and ß-tc-6, through increasing the glucose stimulated insulin secretion (GSIS), which was abolished by estrogen receptor (ER) antagonist, indicating that JE functions were mediated by ER signaling. Additionally, JE did not induce tumorigenesis in rat mammary tissue or promoted proliferation of MCF-7 and Hela cells. In conclusion, our work demonstrated that JE ameliorated OVX-induced glucose and lipid metabolism disorder through activating estrogen receptor pathway and promoting GSIS in islet ß cells, thus indicating that JE could be a safe and effective medication for MMS therapy.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Menopausa/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Animais , Feminino , Glucose/metabolismo , Humanos , Secreção de Insulina , Menopausa/metabolismo , Síndrome Metabólica/metabolismo , Camundongos , Ratos , Ratos Sprague-Dawley
9.
Biochem Pharmacol ; 122: 42-61, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27816546

RESUMO

SREBPs play important roles in the regulation of lipid metabolism, and are closely related to the occurrence and development of many metabolic diseases. Small molecular inhibitors of SERBPs are important tools in developing efficient treatment of metabolic diseases. However, there are no listing drug targeting SREBPs. Therefore, there is an urgent need to develop highly specific small molecules that inhibit SREBPs. In this study, using a hepatocyte-based high-throughput screening, we identified anhydroicaritin (AHI) as a novel inhibitor of SREBPs. HepG2, HL-7702, and human primary hepatocytes were used to verify the effects of AHI. We explored the mechanism by which AHI blocks the binding of SCAP/SREBPs complex with Sec23α/24D via regulating LKB1/AMPK/mTOR pathway. AHI reduced liver cell lipid level by preventing de novo lipogenesis. In diet induced obese mice, AHI ameliorated obesity, insulin resistance, fatty accumulation in liver and hyperlipemia. In conclusion, AHI improves diet-induced obesity and alleviates insulin resistance by suppressing SREBPs maturation which is dependent on LKB1/AMPK/mTOR pathway. Thus, AHI can serve as a leading compound for pharmacological control of metabolic diseases.


Assuntos
Benzopiranos/farmacologia , Resistência à Insulina , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , Adenilato Quinase/genética , Adenilato Quinase/metabolismo , Animais , Benzopiranos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Estrutura Molecular , Proteínas de Ligação a Elemento Regulador de Esterol/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
10.
Chin J Nat Med ; 14(10): 746-756, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28236404

RESUMO

As a culinary and medicinal herb, rosemary is widely used. The present work aimed to investigate the effects of rosemary extracts on metabolic diseases and the underlying mechanisms of action. Liver cells stably expressing SREBP reporter were used to evaluate the inhibitory effects of different fractions of rosemary extracts on SREBP activity. The obese mice induced by Western-type diet were orally administered with rosemary extracts or vehicle for 7 weeks, the plasma and tissue lipids were analyzed. SREBPs and their target genes were measured by quantitative RT-PCR. We demonstrated that the petroleum ether sub-fraction of rosemary extracts (PER) exhibited the best activity in regulating lipid metabolism by inhibiting SREBPs, while water and n-BuOH sub-fraction showed the SREBPs agonist-effect. After PER treatment, there was a significant reduction of total SREBPs in liver cells. PER not only decreased SREBPs nuclear abundance, but also inhibited their activity, resulting in decreased expression of SREBP-1c and SREBP-2 target genes in vitro and in vivo. Inhibiting SREBPs by PER decreased the total triglycerides and cholesterol contents of the liver cells. In the mice fed with Western-type diet, PER treatment decreased TG, TC, ALT, glucose, and insulin in blood, and improved glucose tolerance and insulin sensitivity. Furthermore, PER treatment also decreased lipid contents in liver, brown adipose tissue, and white adipose tissue. Our results from the present study suggested that petroleum ether fraction of rosemary extracts exhibited the best potential of improving lipid metabolism by inhibiting SREBPs activity.


Assuntos
Hiperlipidemias/tratamento farmacológico , Resistência à Insulina , Petróleo/análise , Extratos Vegetais/administração & dosagem , Rosmarinus/química , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Alcanos/química , Animais , Colesterol/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética
11.
Biomaterials ; 73: 149-59, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26409000

RESUMO

Combination therapy is usually considered as a promising strategy owing to its advantages such as reduced doses, minimized side effects and improved therapeutic efficiency in a variety of diseases including diabetes. Here we synthesized a new highly intracellular stimuli-sensitive chitosan-graft-metformin (CS-MET) prodrug by imine reaction between oxidative chitosan and metformin for type 2 diabetes (T2D) therapy. Hypothetically, CS-MET functions dually as an anti-diabetes prodrug as well as a gene delivery vector without superfluous materials. CS-MET formed nanocomplexes with therapeutic gene through electrostatic interactions and entered cells by Organic Cation Transporter (OCT)-independent endocytosis. The incorporation of metformin into chitosan has been found to increase endosomal escape via the proton sponge effect. When vector carrying a short-hairpin RNA (shRNA) silencing sterol regulatory element-binding protein (SREBP), a major transcription factor involved in de novo lipogenisis, it reduced the SREBP mRNA and proteins efficiently. Furthermore, by intraperitoneal injection, CS-MET/shSREBP nanocomplexes effectively knocked down SREBP in livers of western-type diet (WD)-induced obese C57BL/6J mice, markedly reversed insulin resistance and alleviated the fatty liver phenotype without obvious toxic effects. Thus we were able to show that the intracellular stimuli-sensitive CS-MET prodrug renders a potential platform to increase the anti-diabetes activity with synergistic enhancement of gene therapy.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Nanoestruturas/química , Polímeros/química , Pró-Fármacos/química , Animais , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Quitosana/administração & dosagem , Endocitose , Fígado Gorduroso/metabolismo , Terapia Genética/métodos , Vetores Genéticos , Teste de Tolerância a Glucose , Células Hep G2 , Homeostase , Humanos , Iminas/química , Lipídeos/química , Metformina/administração & dosagem , Metformina/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Microscopia Confocal , Oxigênio/química , Fenótipo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Eletricidade Estática , Proteína de Ligação a Elemento Regulador de Esterol 1/química
12.
Chin J Nat Med ; 12(3): 229-40, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24702812

RESUMO

AIM: To profile the chemical constituents in Jinqi Jiangtang tablets. METHOD: Based on the chromatographic retention behavior, fragmentation patterns of chemical components, and published literatures, a high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (HPLC-ESI-Q-TOF/MS) method was established to characterize and identify components in Jinqi Jiangtang tablets. RESULTS: A total of 52 chemical compounds, including eight iridoid glycosides, seven phenolic acids, twelve alkaloids, six flavonoids, and nineteen saponins, were identified in Jinqi Jiangtang tablets. CONCLUSION: The established method could serve as a powerful tool for structural characterization and quality control of this Chinese herbal preparation.


Assuntos
Astrágalo (Planta) , Coptis , Medicamentos de Ervas Chinesas/química , Lonicera , Alcaloides/análise , Cromatografia Líquida de Alta Pressão , Flavonoides/análise , Glicosídeos Iridoides/análise , Fenóis/análise , Saponinas/análise , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
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