Biomedical subjects

Xian-Ping Lu

Publications and source records attributed to Xian-Ping Lu.

7 recordsLinked to original sources

PubMed2006

The PPARalpha/gamma dual agonist chiglitazar improves insulin resistance and dyslipidemia in MSG obese rats.

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.

Adipose Tissue↗

PubMed2005

Peroxisome proliferator-activated receptor-gamma transcriptionally up-regulates hormone-sensitive lipase via the involvement of specificity protein-1.

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.

Adipocytes↗

PubMed2005

Construction of a virtual combinatorial library using SMILES strings to discover potential structure-diverse PPAR modulators.

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.

Combinatorial Chemistry Techniques↗

PubMed2005

Phthalide Lactones from Ligusticum chuanxiong inhibit lipopolysaccharide-induced TNF-alpha production and TNF-alpha-mediated NF-kappaB Activation.

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.

Benzofurans↗

PubMed2005

A new retinoid-like compound that activates peroxisome proliferator-activated receptors and lowers blood glucose in diabetic mice.

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.

Alkenes↗

PubMed2004

Design, synthesis, and evaluation of a new class of noncyclic 1,3-dicarbonyl compounds as PPARalpha selective activators.

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.

Adipose Tissue↗

PubMed2004

3D QSAR studies on peroxisome proliferator-activated receptor gamma agonists using CoMFA and CoMSIA.

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.

Computer Simulation↗