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1.
Chinese Journal of Natural Medicines (English Ed.) ; (6): 572-579, 2018.
Article Dans Anglais | WPRIM | ID: wpr-812373

Résumé

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis. Therefore, FXR is a potential drug target for several metabolic syndromes, especially those related to lipidemia disorders. In the present study, we identified small molecule SIPI-7623, a derivative of an extract from Oriental wormwood (Artemisia capillaris), and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase (CYP7A1), downregulated the expression of sterol-regulatory element-binding protein 1c (SREBP-1c) in the liver, and inhibited the expression of ileal bile acid binding-protein (IBABP) in the ileum of rats. We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride. SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro HepG2 cell models, ameliorated diet-induced atherosclerosis, and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo. Furthermore, SIPI-7623 decreased the extent of atherosclerotic lesions. Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis. In conclusion, SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.


Sujets)
Animaux , Humains , Mâle , Lapins , Rats , Artemisia , Chimie , Athérosclérose , Traitement médicamenteux , Génétique , Métabolisme , Cholestérol , Métabolisme , Cholesterol 7-alpha-hydroxylase , Génétique , Métabolisme , Médicaments issus de plantes chinoises , Hyperlipidémies , Traitement médicamenteux , Génétique , Métabolisme , Hypolipémiants , Foie , Métabolisme , Rat Sprague-Dawley , Récepteurs cytoplasmiques et nucléaires , Génétique , Métabolisme , Protéine-1 de liaison à l'élément de régulation des stérols , Génétique , Métabolisme , Triglycéride , Métabolisme
2.
Chinese Journal of Natural Medicines (English Ed.) ; (6): 572-579, 2018.
Article Dans Anglais | WPRIM | ID: wpr-773584

Résumé

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis. Therefore, FXR is a potential drug target for several metabolic syndromes, especially those related to lipidemia disorders. In the present study, we identified small molecule SIPI-7623, a derivative of an extract from Oriental wormwood (Artemisia capillaris), and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase (CYP7A1), downregulated the expression of sterol-regulatory element-binding protein 1c (SREBP-1c) in the liver, and inhibited the expression of ileal bile acid binding-protein (IBABP) in the ileum of rats. We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride. SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro HepG2 cell models, ameliorated diet-induced atherosclerosis, and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo. Furthermore, SIPI-7623 decreased the extent of atherosclerotic lesions. Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis. In conclusion, SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.


Sujets)
Animaux , Humains , Mâle , Lapins , Rats , Artemisia , Chimie , Athérosclérose , Traitement médicamenteux , Génétique , Métabolisme , Cholestérol , Métabolisme , Cholesterol 7-alpha-hydroxylase , Génétique , Métabolisme , Médicaments issus de plantes chinoises , Hyperlipidémies , Traitement médicamenteux , Génétique , Métabolisme , Hypolipémiants , Foie , Métabolisme , Rat Sprague-Dawley , Récepteurs cytoplasmiques et nucléaires , Génétique , Métabolisme , Protéine-1 de liaison à l'élément de régulation des stérols , Génétique , Métabolisme , Triglycéride , Métabolisme
3.
Chinese Journal of Natural Medicines (English Ed.) ; (6): 768-776, 2014.
Article Dans Anglais | WPRIM | ID: wpr-812202

Résumé

AIM@#JS-38 (mitothiolore), a synthetic version of a metabolite isolated from Xenorhabdus sp., was evaluated for its anti-tumor and white blood cell (WBC) elevating activities.@*METHOD@#These anti-proliferative activities were assessed in vitro using a panel of ten cell lines. The anti-tumor activities were tested in vivo using B16 allograft mouse models and xenograft models of A549 human lung carcinoma and QGY human hepatoma in nude mice. The anti-tumor interactions of JS-38 and cyclophosphamide (CTX) or 5-fluorouracil (5-Fu) were studied in a S180 sarcoma model in ICR mice. Specific stimulatory effects were determined on peripheral neutrophils in normal and CTX- and 5-Fu-induced neutropenic mice.@*RESULTS@#The IC50 values ranged from 0.1 to 2.0 μmol·L(-1). JS-38 (1 μmol·L(-1)) caused an increase in A549 tumor cell apoptosis. Multi-daily gavage of JS-38 (15, 30, and 60 mg·kg(-1)·d(-1)) inhibited in vivo tumor progression without a significant effect on body weight. JS-38 additively enhanced the in vivo anti-tumor effects of CTX or 5-Fu. JS-38 increased peripheral neutrophil counts and neutrophil rates in normal BALB/c mice almost as effectively as granulocyte colony-stimulating factor (G-CSF). In mice with neutropenia induced by CTX or 5-Fu, JS-38 rapidly restored neutrophil counts.@*CONCLUSION@#These results suggest that JS-38 has anti-tumor activity, and also has the ability to increase peripheral blood neutrophils.


Sujets)
Animaux , Femelle , Humains , Souris , Antinéoplasiques , Métabolisme , Numération cellulaire , Hydrocarbures fluorés , Métabolisme , Tumeurs du poumon , Traitement médicamenteux , Souris de lignée BALB C , Souris de lignée ICR , Granulocytes neutrophiles , Biologie cellulaire , Xenorhabdus , Chimie , Métabolisme
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