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1.
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
2.
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
3.
China Journal of Chinese Materia Medica ; (24): 2618-2621, 2012.
Article Dans Chinois | WPRIM | ID: wpr-263875

Résumé

<p><b>OBJECTIVE</b>To study and compare the anti-inflammatory effect and molecular mechanism of artemisinin and dihydroartemisinin.</p><p><b>METHOD</b>Mouse mononuclear macrophage RAW264.7 cells were stimulated to release inflammatory mediators such as TNF-alpha, IL-6 and NO, in order to assess the drugs' inhibitory effect on macrophage's release of above inflammatory mediators. The levels of TNF-alpha and IL-6 were determined by ELISA and the cytotoxicity was determined by MTT method. The protein expression of iNOS, COX-2 and beta-actin were tested by Western blot. The enzymatic activity of COX-2 was determined by colorimetric method.</p><p><b>RESULT</b>Dihydroartemisinin significantly inhibited LPS-induced release of TNF-alpha, IL-6 and NO from RAW264.7 in mice with the concentration range of 12.5 - 100 micromol x L(-1), and showed good dose dependence. Artemisinin only inhibited the IL-6 release to a certain extent.</p><p><b>CONCLUSION</b>Dihydroartemisinin inhibits macrophages from releasing inflammatory factors TNF-alpha and IL-6 and inflammatory mediators NO by down-regulating iNOS protein. Artemisinin may help dihydroartemisinin to show its anti-inflammatory effect through metabolism.</p>


Sujets)
Animaux , Souris , Anti-inflammatoires , Pharmacologie , Artémisinines , Pharmacologie , Lignée cellulaire , Expression des gènes , Médiateurs de l'inflammation , Allergie et immunologie , Interleukine-6 , Génétique , Allergie et immunologie , Macrophages , Allergie et immunologie , Monoxyde d'azote , Allergie et immunologie , Facteur de nécrose tumorale alpha , Génétique , Allergie et immunologie
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