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ABSTRACT: Chidamide (CS055/HBI-8000) is a new histone deacetylase (HDAC) inhibitor of the benzamide class currently under clinical development in cancer indications. This study reports the in vitro and in vivo antitumor characteristics of the compound.
Selectivity and potency of chidamide in inhibition of HDAC isotypes were analyzed by using a panel of human recombinant HDAC proteins. Tumor cell lines either in culture or inoculated in nude mice were used for the evaluation of the compound's antitumor activity. To investigate the immune cell-mediated antitumor effect, isolated peripheral blood mononuclear cells from healthy donors were treated with chidamide, and cytotoxicity and expression of relevant surface proteins were analyzed. Microarray gene expression studies were performed on peripheral white blood cells from two T-cell lymphoma patients treated with chidamide.
Chidamide was found to be a low nanomolar inhibitor of HDAC1, 2, 3, and 10, the HDAC isotypes well documented to be associated with the malignant phenotype. Significant and broad spectrum in vitro and in vivo antitumor activity, including a wide therapeutic index, was observed. Chidamide was also shown to enhance the cytotoxic effect of human peripheral mononuclear cells ex vivo on K562 target cells, accompanied by the upregulation of proteins involved in NK cell functions. Furthermore, the expression of a number of genes involved in immune cell-mediated antitumor activity was observed to be upregulated in peripheral white blood cells from two T-cell lymphoma patients who responded to chidamide administration.
The results presented in this study provide evidence that chidamide has potential applicability for the treatment of a variety of tumor types, either as a single agent or in combination therapies.
Cancer Chemotherapy and Pharmacology 11/2011; 69(4):901-9. · 2.83 Impact Factor
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ABSTRACT: 1The aim of this study was to investigate the capacity of chiglitazar to improve insulin resistance and dyslipidemia in monosodium L-glutamate (MSG) obese rats and to determine whether its lipid-lowering effect is mediated through its activation of PPARα.2Chiglitazar is a PPARα/γ dual agonist.3The compound improved impaired insulin and glucose tolerance; decreased plasma insulin level and increased the insulin sensitivity index and decreased HOMA index. Euglycemic hyperinsulinemic clamp studies showed chiglitazar increased the glucose infusion rate in MSG obese rats.4Chiglitazar inhibited alanine gluconeogenesis, lowered the hepatic glycogen level in MSG obese rats. Like rosiglitazone, chiglitazar promoted the differentiation of adipocytes and decreased the maximal diameter of adipocytes. In addition, chiglitazar decreased the fibrosis and lipid accumulation in the islets and increased the size of islets.5Chiglitazar reduced plasma triglyceride, total cholesterol (TCHO), nonesterified fatty acids (NEFA) and low density lipoprotein-cholesterol levels; lowered hepatic triglyceride and TCHO contents; decreased muscular NEFA level. Unlike rosiglitazone, chiglitazar showed significant increase of mRNA expression of PPARα, CPT1, BIFEZ, ACO and CYP4A10 in the liver of MSG obese rats.6These data suggest that PPARα/γ coagonist, such as chiglitazar, affect lipid homeostasis with different mechanisms from rosiglitazone, chiglitazar may have better effects on lipid homeostasis in diabetic patients than selective PPARγ agonists.British Journal of Pharmacology (2006) 148, 610–618. doi:10.1038/sj.bjp.0706745
British Journal of Pharmacology 01/2009; 148(5):610 - 618. · 4.41 Impact Factor
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ABSTRACT: The dried, immature fruit of Citrus aurantium L., 'Zhiqiao' in Chinese, has been used to treat cardiovascular diseases in traditional Chinese medicine for centuries. Naringenin and hesperetin and their glycosides present in considerable amounts (about 10 approximately 15%) in the herb. The aim of this study is to test whether naringenin and hesperetin influence adiponectin expression, which plays an important role in glucose and lipid metabolism with antiatherogenic and anti-inflammatory properties. Treatment with naringenin and hesperetin enhanced adiponectin transcription in differentiated 3T3-L1 cells. Both naringenin and hesperetin induced peroxisome proliferator-activated receptor (PPAR)gamma-controlled luciferase expression in a dose-dependent manner (20-160 microM), whereas only naringenin possessed significant activity to activate PPARalpha. These results suggested the two flavonoids might exert antiatherogenic effects partly through activating PPAR and up-regulating adiponectin expression in adipocytes. Our findings give new insight for the molecular explanations for the therapeutic effects of Zhiqiao.
Phytotherapy Research 08/2008; 22(10):1400-3. · 2.09 Impact Factor
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ABSTRACT: 1. The aim of this study was to investigate the capacity of chiglitazar to improve insulin resistance and dyslipidemia in monosodium L-glutamate (MSG) obese rats and to determine whether its lipid-lowering effect is mediated through its activation of PPARalpha. 2. Chiglitazar is a PPARalpha/gamma dual agonist. 3. The compound improved impaired insulin and glucose tolerance; decreased plasma insulin level and increased the insulin sensitivity index and decreased HOMA index. Euglycemic hyperinsulinemic clamp studies showed chiglitazar increased the glucose infusion rate in MSG obese rats. 4. Chiglitazar inhibited alanine gluconeogenesis, lowered the hepatic glycogen level in MSG obese rats. Like rosiglitazone, chiglitazar promoted the differentiation of adipocytes and decreased the maximal diameter of adipocytes. In addition, chiglitazar decreased the fibrosis and lipid accumulation in the islets and increased the size of islets. 5. Chiglitazar reduced plasma triglyceride, total cholesterol (TCHO), nonesterified fatty acids (NEFA) and low density lipoprotein-cholesterol levels; lowered hepatic triglyceride and TCHO contents; decreased muscular NEFA level. Unlike rosiglitazone, chiglitazar showed significant increase of mRNA expression of PPARalpha, CPT1, BIFEZ, ACO and CYP4A10 in the liver of MSG obese rats. 6. These data suggest that PPARalpha/gamma coagonist, such as chiglitazar, affect lipid homeostasis with different mechanisms from rosiglitazone, chiglitazar may have better effects on lipid homeostasis in diabetic patients than selective PPARgamma agonists.
British Journal of Pharmacology 08/2006; 148(5):610-8. · 4.41 Impact Factor
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ABSTRACT: Both peroxisome proliferator-activated receptor (PPAR)-gamma and hormone-sensitive lipase (HSL) play important roles in lipid metabolism and insulin sensitivity. We demonstrate that expression of the HSL gene is up-regulated by PPARgamma and PPARgamma agonists (rosiglitazone and pioglitazone) in the cultured hepatic cells and differentiating preadipocytes. Rosiglitazone treatment also results in up-regulation of the HSL gene in liver and skeleton muscle from an experimental obese rat model, accompanied by the decreased triglyceride content in these tissues. The proximal promoter (-87 bp of the human HSL gene) was found to be essential for PPARgamma-mediated transactivating activity. This important promoter region contains two GC-boxes and binds the transcription factor specificity protein-1 (Sp1) but not PPARgamma. The Sp1-promoter binding activity can be endogenously enhanced by PPARgamma and rosiglitazone, as demonstrated by analysis of EMSA and chromatin immunoprecipitation assay. Mutations in the GC-box sequences reduce the promoter binding activity of Sp1 and the transactivating activity of PPARgamma. In addition, mithramycin A, the specific inhibitor for Sp1-DNA binding activity, abolishes the PPARgamma-mediated up-regulation of HSL. These results indicate that PPARgamma positively regulates the HSL gene expression, and up-regulation of HSL by PPARgamma requires the involvement of Sp1. Taken together, this study suggests that HSL may be a newly identified PPARgamma target gene, and up-regulation of HSL may be an important mechanism involved in action of PPARgamma agonists in type 2 diabetes.
Endocrinology 03/2006; 147(2):875-84. · 4.46 Impact Factor
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ABSTRACT: The dried rhizome of Ligusticum chuanxiong Hort. (Umbelliferae) is a traditional Chinese medicine (TCM) herb for the prevention and treatment of inflammatory and cardiovascular diseases. However, the role of phthalide lactones from Ligusticum chuanxiong in the therapeutic actions is not yet fully understood. In the present study, two phthalide lactones from the herb, Z-ligustilide and senkyunolide A, were identified and characterized as inhibitors of lipopolysaccharide (LPS)-induced TNF-alpha production in monocytes. The results of gene expression studies showed that the observed TNF-alpha suppression was related to their inhibitory activity on TNF-alpha mRNA transcription. Furthermore, the two phthalides exhibited significant suppressive effects on TNF-alpha-mediated nuclear factor-kappaB (NF-kappaB) activation in reporter gene assays. Taken together, the results suggest that Z-ligustilide and senkyunolide A may have potential applications in the treatment of inflammation and related diseases based on their inhibitory activity on TNF-alpha production and TNF-alpha bioactivity. New insights into the therapeutic basis of the TCM herb, Ligusticum chuanxiong, are presented.
Planta Medica 10/2005; 71(9):808-13. · 2.15 Impact Factor
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ABSTRACT: Based on the structural characters of PPAR modulators, a virtual combinatorial library containing 1226,625 compounds was constructed using SMILES strings. Selected ADME filters were employed to compel compounds having poor drug-like properties from this library. This library was converted to sdf and mol2 files by CONCORD 4.0, and was then docked to PPARgamma by DOCK 4.0 to identify new chemical entities that may be potential drug leads against type 2 diabetes and other metabolic diseases. The method to construct virtual combinatorial library using SMILES strings was further visualized by Visual Basic.net that can facilitate the needs of generating other type virtual combinatorial libraries.
European Journal of Medicinal Chemistry 08/2005; 40(7):632-40. · 3.35 Impact Factor
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ABSTRACT: Retinoid X receptor (RXR) forms heterodimers with peroxisome proliferator-activated receptors (PPARs, with subtypes of alpha, delta and gamma), and the heterodimers can be activated by either an RXR or a PPAR subtype-specific ligand. Based on the chemical structure of the RXR natural ligand, 9-cis-retinoic acid (9-cis-RA), we designed and synthesized a retinoid-like compound, CS018. In vitro characterizations by cell-based reporter gene assays indicated that CS018 activated RXR homodimers and the heterodimers of RXR with PPARs, but not with farnesoid X-activated receptor (FXR) and liver X-activated receptor (LXR). Furthermore, RT-PCR results showed that CS018 induced the expression of the PPARgamma target genes, CD36 and lipoprotein lipase (LPL). In vivo studies on the diabetic db/db mice demonstrated that CS018 dramatically lowered the animal blood glucose levels. CS018 thus may represent a new retinoid-like compound that activates RXR/PPARs and has potential therapeutic applications in type 2 diabetes and other metabolic diseases.
Biological & Pharmaceutical Bulletin 08/2005; 28(7):1192-6. · 1.66 Impact Factor
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Zhibin Li,
Chenzhong Liao,
Ben C B Ko,
Song Shan,
Edith H Y Tong,
Zihui Yin,
Desi Pan,
Vincent K W Wong,
Leming Shi,
Zhi-Qiang Ning,
Weiming Hu,
Jiaju Zhou,
Stephen S M Chung, Xian-Ping Lu
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ABSTRACT: Lipid accumulation in nonadipose tissues is increasingly linked to the development of type 2 diabetes in obese individuals. We report here the design, synthesis, and evaluation of a series of novel PPARalpha selective activators containing 1,3-dicarbonyl moieties. Structure-activity relationship studies led to the identification of PPARalpha selective activators (compounds 10, 14, 17, 18, and 21) with stronger potency and efficacy to activate PPARalpha over PPARgamma and PPARdelta. Experiments in vivo showed that compounds 10, 14, and 17 had blood glucose lowering effect in diabetic db/db mouse model after two weeks oral dosing. The data strongly support further testing of these lead compounds in other relevant disease animal models to evaluate their potential therapeutic benefits.
Bioorganic & Medicinal Chemistry Letters 08/2004; 14(13):3507-11. · 2.55 Impact Factor
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ABSTRACT: The peroxisome proliferator-activated receptors (PPARs) have increasingly become attractive targets for developing novel anti-type 2 diabetic drugs. We employed comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to study three-dimensional quantitative structure-activity relationship (3D QSAR) based on existing agonists of PPARgamma (including five thiazolidinediones and 74 tyrosine-based compounds). Predictive 3D QSAR models with conventional r2 and cross-validated coefficient (q2) values up to 0.974 and 0.642 for CoMFA and 0.979 and 0.686 for COMSIA were established using the SYBYL package. These models were validated by a test set containing 18 compounds. The CoMFA and CoMSIA field distributions are in general agreement with the structural characteristics of the binding pockets of PPARgamma, which demonstrates that the 3D QSAR models built here are very useful in predicting activities of novel compounds for activating PPARgamma.
Journal of Molecular Modeling 07/2004; 10(3):165-77. · 1.80 Impact Factor
