The nuclear hormone receptor PPARgamma is activated by several agonists, including members of the thiazolidinedione group of insulin sensitizers. Pleiotropic beneficial effects of these agonists, independent of their blood glucose-lowering effects, have recently been demonstrated in the vasculature. PPARgamma agonists have been shown to lower blood pressure in animals and humans, perhaps by suppressing the renin-angiotensin (Ang)-aldosterone system (RAAS), including the inhibition of Ang II type 1 receptor expression, Ang-II-mediated signaling pathways, and Ang-II-induced adrenal aldosterone synthesis/secretion. PPARgamma agonists also inhibit the progression of atherosclerosis in animals and humans, possibly through a pathway involving the suppression of RAAS and the thromboxane A2 system, as well as the protection of endothelial function. Moreover, PPARgamma-agonist-mediated renal protection, especially the reduction of albuminuria, has been observed in diabetic nephropathy, including animal models of the disease, and in non-diabetic renal dysfunction. The renal protective activities may reflect, at least in part, the ability of PPARgamma agonists to lower blood pressure, protect endothelial function, and cause vasodilation of the glomerular efferent arterioles. Additionally, anti-neoplastic effects of PPARgamma agonists have recently been described. Based on the multiple therapeutic actions of PPARgamma agonists, they will no doubt lead to novel approaches in the treatment of lifestyle-related and other diseases.
Animals ; Atherosclerosis/prevention & control ; Humans ; Hypertension/drug therapy ; Hypoglycemic Agents/*pharmacology ; Kidney Diseases/etiology ; PPAR gamma/*agonists ; PPAR-beta/agonists

A series of tetrahydroisoquinoline derivatives were prepared and their peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonistic activities were evaluated to obtain more potent PPAR agonist. All of them were new compounds, and their structures were confirmed by 1H NMR and HR-MS. Three compounds exhibited higher agonistic activities of PPARgamma than that of the comparison, six compounds exhibited higher agonistic activities of PPARalpha than that of the comparison, and compound 8a was discovered as a highly potent PPARalpha/gamma agonist that is much more active than that of WY14643 and rosiglitazone. The development of potent PPAR agonists may offer a new choice for the treatment of diabetes.
Drug Design ; HEK293 Cells ; Humans ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; pharmacology ; PPAR alpha ; agonists ; metabolism ; PPAR gamma ; agonists ; metabolism ; Structure-Activity Relationship ; Tetrahydroisoquinolines ; chemical synthesis ; chemistry ; pharmacology ; Transfection

A series of novel tetrahydrocarboline derivatives was designed and synthesized in order to discover more potent peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual regulators. The structures of these compounds were confirmed by 1H NMR and HR-MS; their PPAR-regulating activities were evaluated in vitro. Compounds 6h, 6n, 6p and 6q exhibited more potent PPARalpha agonistic activities than the control drug WY14643, while compounds 60, 6g, 6i and 6q exhibited more potent PPARgamma agonistic activities than the control drug rosiglitazone. Compound 6q was discovered as a potent PPARalpha/gamma dual agonist and deserves further investigation.
Animals ; Carbolines ; chemical synthesis ; chemistry ; pharmacology ; Cells, Cultured ; Drug Design ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; pharmacology ; Molecular Structure ; PPAR alpha ; agonists ; PPAR gamma ; agonists ; Peroxisome Proliferator-Activated Receptors ; agonists ; Pyrimidines ; metabolism ; Structure-Activity Relationship ; Thiazolidinediones ; metabolism ; Transfection

Atherosclerosis ; blood ; drug therapy ; etiology ; C-Reactive Protein ; analysis ; Humans ; Lipoproteins, LDL ; blood ; PPAR gamma ; agonists ; Vasculitis ; complications

In-vitro assay methods were established to evaluate transactivation and binding activity of compounds on peroxisome proliferator-activated receptor y (PPARγ). Firstly, plasmids were constructed for transactivation assay of PPARγ response element (PPRE) triggered reporter gene expression, and for cell-based binding activity assay of the chimeric receptor, which was fused with PPARγ ligand binding domain (LBD) and yeast transcriptional activator Gal4. Secondly, by using PPARy competitive binding assay based on time resolved-fluorescence resonance energy transfer (TR-FRET), affinities of compounds and drugs to PPARγ were evaluated. In application of these above methods, the PPARγ activating potency and characteristics of different compounds were evaluated, and a novel benzeneselfonamide derivative, ZLJ01, was found to have comparable binding activity and affinity with the well-known PPARy agonist, but lack of PPRE mediated transactivation activity. In preliminary study on in-vitro hypoglycemic activity, ZLJ1 was found to promote insulin-stimulated glucose uptake by liver cells. Therefore, we believe that combining transactivation and binding activity as well as affinity evaluation, the system could be used to screen non-agonist PPARγ ligand as anovel PPARγ modulator
Genes, Reporter ; Hepatocytes ; Hypoglycemic Agents ; chemistry ; Ligands ; PPAR gamma ; agonists ; chemistry ; Plasmids ; Response Elements ; Sulfonamides ; chemistry ; Transcriptional Activation

AIMTo find new peroxisome proliferator-activated y agonists with high activity and low toxicity.

METHODSBased on JTT-501 and JTT-20993, new isoxazolidine-3,5-dione and noncyclic 1,3-dicarbonyl compounds were designed and synthesized. Their insulin-sensitizing activities were evaluated.

RESULTSEight new compounds were obtained. The structures of synthesized compounds were characterized by NMR, MS and IR. Four compounds (1A-4A) showed insulin-sensitizing activities.

CONCLUSIONCompounds (1A and 3A) showed excellent insulin-sensitizing activities and should be worth further investigation.

3T3-L1 Cells ; Animals ; Glucose ; metabolism ; Hypoglycemic Agents ; agonists ; chemical synthesis ; pharmacology ; Insulin ; pharmacology ; Isoxazoles ; chemical synthesis ; pharmacology ; Mice ; PPAR gamma ; agonists ; chemical synthesis ; pharmacology

The effects of DK2, a peroxisome proliferator-activated receptor &gamma; agonist, on cultured human pterygium fibroblasts (HPFs) in virto were studied. The HPFs were incubated with 0-200 μmol/L DK2 for 12-72 h. The MTT method was used to assay the bio-activity of DK2 at different doses and time. The cytotoxic effect of DK2 was measured by LDH release assay. The cell cycle distribution and apoptosis were flow cytometrically detected. The expression of proliferating cell nuclear antigen (PCNA) in each group was detected by real-time PCR (RT-PCR) and Western blotting. The results showed that administration of 1-75 μmol/L DK2 for 12-72 h could significantly inhibit HPF proliferation in a dose- and time-dependent manner. DK2-treated cells did not release significant amount of LDH as compared with rosiglitazone-treated cells. After treatment with DK2 at concentrations of 15, 25 μmol/L for 24 h, the number of HPFs in G(0)/G(1) phase was significantly increased while that in S phase was significantly decreased (P<0.05), leading to arrest at G(0)/G(1) phase. The apoptosis rates of HPF cells in drug-treated groups were significantly higher than the rate of control group (P<0.05). At the dosage range between 15-25 μmol/L, DK2 could inhibit the expression of PCNA mRNA and protein in HPFs in a dose-dependent fashion (P<0.05). It was concluded that PPAR&gamma; agonist can significantly inhibit HPF proliferation, resulting in the arrest at G(0)/G(1) phase, induce the apoptosis of HPFs, and suppress the synthesis of PCNA, in dose- and time-dependent manners.
Adult ; Apoptosis ; drug effects ; Cell Proliferation ; drug effects ; Cells, Cultured ; Female ; Fibroblasts ; pathology ; Humans ; Middle Aged ; PPAR gamma ; agonists ; Proliferating Cell Nuclear Antigen ; metabolism ; Pterygium ; pathology

OBJECTIVETo explore if PPARgamma agonist rosiglitazone could enhance the anti-atherosclerotic effects of mouse peroxisome proliferator-activated receptor gamma1 (PPARgamma1) gene transfer in apolipoprotein-knock out mice.

METHODSAdult ApoE-knock out mice were fed a Western-diet for 20-weeks and then injected with PBS, Ad. PPARgamma1 (5 x 10(8)pfu) or Ad. GFP (5 x 10(8)pfu) via jugular vein. Another group of mice were intervened with rosiglitazone (dissolved in 0.5% cellulose acetate, 4 mg.kg(-1).d(-1), per gavage) 1 week before Ad. PPARgamma1 injection (n = 10, each group). Two weeks later, the lipid core and plaque composition were characterized with oil red O staining and Movat method respectively. The expression of PPARgamma, SM-actin, MOMA-2, MMP-9/TIMP-1, CD40/CD40L and TF antigens in aortic roots and plaques among four groups were compared semi-quantitatively using immunohistochemical technology.

RESULTSAll parameters were similar between AdGFP and PBS groups (P > 0.05). The area of plaque were significantly decreased and oil red O staining area significantly increased in AdPPARgamma1 [(0.86 +/- 0.12) mm(2), (150 +/- 35) x 10(3) microm(2)] and AdPPARgamma1 + RO [(0.79 +/- 0.15) mm(2), (270 +/- 49) x 10(3) microm(2)] treated mice compared with AdGFP group [(0.98 +/- 0.17) mm(2), (80 +/- 21) x 10(3) microm(2)] all P < 0.05. Elastic fiber, collagen and proteoglycan in plaques were also significantly increased in AdPPARgamma1 and AdPPARgamma1 + RO groups. Upregulation of PPARgamma, SM-actin, TIMP-1 antigen activity and downregulation of MOMA-2, MMP-9, CD40/CD40L and TF antigen activity in AdPPARgamma1 and most significantly in AdPPARgamma1 + RO group were observed (P < 0.05).

CONCLUSIONAnti-atherosclerotic effects of PPARgamma1 gene transfer in ApoE-knock out mice could be enhanced by PPARgamma agonist rosiglitazone.

Animals ; Apolipoproteins E ; deficiency ; genetics ; Atherosclerosis ; genetics ; Gene Transfer Techniques ; Male ; Mice ; Mice, Knockout ; PPAR gamma ; agonists ; genetics ; metabolism ; Peroxisome Proliferator-Activated Receptors ; metabolism ; Thiazolidinediones ; pharmacology ; Transfection

OBJECTIVETo investigate the effects of GW4064, a farnesoid X receptor (FXR) agonist, on adiponectin and its receptors during the differentiation of 3T3-L1 preadipocytes and on adiponectin receptors in HepG2 cells.

METHODSThe mRNA expressions of FXR, PPAR&gamma;2, adiponectin, AdipoR1, and AdipoR2 and the protein levels of adiponectin on days 0, 2, 4, 6, and 8 during the differentiation of 3T3-L1 preadipocytes treated with GW4064 were detected by fluorescent real-time PCR and ELISA, respectively. The mRNA expressions of AdipoR1 and AdipoR2 in HepG2 cells were also examined at 0, 12, 24, and 48 h after GW4064 treatment.

RESULTSThe mRNA expressions of FXR, PPAR&gamma;2, adiponectin, and AdipoR2 in 3T3-L1 preadipocytes and AdipoR2 in HepG2 cells treated with GW4064 was significantly increased compared with the control group (all P<0.05). The protein level of adiponectin was also significantly increased after GW4064 treatment. The expression of AdipoR1 in either 3T3-L1 preadipocytes or HepG2 cells showed no significant changes after GW4064 treatment.

CONCLUSIONGW4064 can up-regulate the expressions of FXR, PPAR&gamma;2, adiponectin, AdipoR2 in 3T3-L1 preadipocytes and AdipoR2 in HepG2 cells. As adiponectin and its receptors are two important factors in the treatment of non-alcoholic fatty liver disease, FXR agonist may potentially produce therapeutic effect on non-alcoholic fatty liver disease and can regulate adipocytes via up-regulating PPAR&gamma; during adipocyte differentiation.

3T3-L1 Cells ; Adiponectin ; metabolism ; Animals ; Cell Differentiation ; drug effects ; Hep G2 Cells ; Humans ; Isoxazoles ; pharmacology ; Mice ; PPAR gamma ; metabolism ; Receptors, Adiponectin ; metabolism ; Receptors, Cytoplasmic and Nuclear ; agonists

Animals ; Aorta ; metabolism ; pathology ; Atherosclerosis ; etiology ; metabolism ; pathology ; Cholesterol, Dietary ; Male ; Matrix Metalloproteinase 2 ; metabolism ; PPAR gamma ; agonists ; Rabbits ; Random Allocation