Hongying Liu

Peroxisome Proliferator-Activated Receptor δ -Agonist, GW501516, Ameliorates Insulin Resistance, Improves Dyslipidaemia in Monosodium l -Glutamate Metabolic Syndrome Mice

We evaluated the effects of GW501516, a specific peroxisome proliferator-activated receptor beta/delta (PPARdelta) agonist in metabolic syndrome mice, obtained by perinatal injection of monosodium L-glutamate, to investigate the efficacy of GW501516 against metabolic syndrome and the effectiveness of PPARdelta activation as therapeutic target for metabolic syndrome. After 14 days treatment, GW501516 effectively improved the glucose intolerance, normalized the fasted blood glucose, and increased the serum high-density lipoprotein cholesterol (HDL-C) level. Postprandial blood glucose, serum insulin, leptin, free fatty acid (FFA) levels, and total cholesterol/HDL-C ratio were also significantly decreased. Moreover, semiquantitative reverse transcription-polymerase chain reaction results indicated that the above phenotypes might be due to (i) enhancement of fatty acid oxidation in muscle, adipose tissue and the liver; (ii) improvement of insulin-stimulated glucose transportation in skeletal muscle and adipose tissue; and (iii) reduced local glucocorticoid synthesis. Therefore, GW501516 could significantly ameliorate dyslipidaemia and insulin resistance in monosodium L-glutamate mice and activation of PPARdelta could be envisioned as a useful strategy against human metabolic syndrome and related diseases.

Beneficial effects of C36, a novel breaker of advanced glycation endproducts cross-links, on the cardiovascular system of diabetic rats.

Advanced glycation endproducts (AGE) have been implicated in the pathogenesis of diabetic complications, including diabetic cardiovascular dysfunctions. 3‐benzyloxycarbonylmethyl‐4‐methyl‐thiazol‐3‐ium bromide (C36), a novel AGE breaker, was investigated for its beneficial effects on the cardiovascular system of diabetic rats.

Novel fatty acid synthase (FAS) inhibitors: Design, synthesis, biological evaluation, and molecular docking studies

Several novel series of C75 derivatives were synthesized and evaluated for their FAS inhibitory activities. The results showed compound 4-methylene-2-octyl-5-oxo-tetrahydro-thiophene-3-carboxylic acid (1c) had more effective FAS inhibitory (IC(50) was 2.56 microM and T.I. was 9.26) and potent anti-tumor activities on HL60 and Hela cells in vitro (IC(50) were 5.38 microM and 46.10 microM, respectively).

C16, a novel advanced glycation endproduct breaker, restores cardiovascular dysfunction in experimental diabetic rats

AbstractAim:Advanced glycation endproducts (AGE) have been implicated in the pathogenesis of diabetic complications, including diabetic cardiovascular dysfunction. 3-[2-(4-Bromo-phenyl)-1-methyl-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazol-3-ium bromide (C16), a novel AGE breaker, was investigated for its effects on the development of cardiovascular disease in diabetic rats.Methods:Rats that had streptozotocin-induced diabetes for 12 weeks were divided into groups receiving C16 or vehicle by gavage.Results:In hemodynamic studies of the left ventricle, C16 treatment (25 or 50 mg/kg) for 4 weeks resulted in a significant increase in left ventricular systolic pressure, +dp/dtmax, and -dp/dtmax as compared with vehicletreated diabetic rats. Furthermore, in hemodynamic studies of the cardiovascular system, C16 (12.5, 25, or 50 mg/kg) treatment for 4 weeks resulted in a dosedependent and significant increase in cardiac output, a reduction of total peripheral resistance, and an increase in systemic arterial compliance when compared with vehicle-treated diabetic rats. Biochemical studies showed that C16 treatment also resulted in a significant decrease in immunoglobulin G-red blood cell surface crosslink content and an increase in collagen solubility. Morphological and immunohistochemical examinations indicated that C16 was able to prevent increases of the collagen type III/I ratio in the aorta and decrease the accumulation of AGE in the aorta.Conclusion:C16 has the ability to reduce AGE accumulation in tissues in vivo, and can restore diabetes-associated cardiovascular disorders in rats. This provides a potential therapeutic approach for cardiovascular disease associated with diabetes and aging in humans.

P633H, a novel dual agonist at peroxisome proliferator‐activated receptors α and γ, with different anti‐diabetic effects in db/db and KK‐Ay mice

Background and purpose:  Peroxisome proliferator‐activated receptors (PPARs) are attractive targets for the treatment of type 2 diabetes and the metabolic syndrome. P633H (2‐[4‐(2‐Fluoro‐benzenesulphonyl)‐piperazin‐1‐yl]‐3‐{4‐[2‐(5‐methyl‐2‐phenyl‐oxazol‐4‐yl)‐ethoxy]‐phenyl}‐propionic acid), a novel PPARα/γ dual agonist, was investigated for its very different effects on insulin resistance and dyslipidemia in db/db and KK‐Ay mice.

Synthesis and antitumor activity of 5-[1-(3-(dimethylamino)propyl)-5-halogenated-2-oxoindolin-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamides

We report herein the design and synthesis of novel 1-[3-(dimethylamino)propyl]indolin-2-one derivatives based on the structural features of Sunitinib, a known multitargeted receptor tyrosine kinase inhibitor, and TMP-20, a previously discovered compound with good antitumor activity in our lab. These newly synthesized derivatives were evaluated for in vitro activity against five human cancer cell lines and VEGF/bFGF-stimulated HUVECs. Results revealed that all of the target compounds 1a-p show potent antitumor activity, compounds 1e-h (IC(50)s: 0.45-5.08 μM) are more active than Sunitinib (IC(50)s: 1.35-6.61 μM), and the most active compound 1 h (IC(50): 0.47-3.11 μM) is 2.1-4.6-fold more potent than Sunitinib against all five cancer cell lines. In addition, like Sunitinib, 1a-p have higher selectivity on VEGF-stimulated HUVEC other than bFGF-stimulated HUVEC.

Novel selective antagonist of the cannabinoid CB1 receptor, MJ15, with prominent anti-obesity effect in rodent models.

MJ15, a novel cannabinoid CB(1) receptor selective antagonist was discovered. In receptor binding assays, MJ15 displayed a high affinity for rat cannabinoid CB(1) receptor (K(i)=27.2 pM, and IC(50)=118.9 pM), but a much lower affinity for rat cannabinoid CB(2) receptor (only 46% inhibition at 10 microM). At the cellular level, the IC(50) values against activation of cannabinoid CB(1) and CB(2) receptors induced by Win55212-2 in specially designed EGFP-CB(1)_U2OS and EGFP-CB(2)_U2OS cells were 0.11 microM and >10 microM, respectively. In addition, MJ15 dose-dependently blocked Win55212-2 mediated increase of intracellular Ca(2+) levels in hippocampal cells and reversed the inhibitory effects of cannabinoid CB(1) receptor agonist on forskolin-stimulated adenylyl cyclase activity in CHO cells expressing the human cannabinoid CB(1) receptor. In animal experiments, MJ15 demonstrated remarkable effects from 20 to 40 mg/kg, including promoted the small intestine peristalsis in ICR mice and inhibited food intake and body weight increase in diet-induced obesity (DIO) rat and mouse. 40 mg/kg MJ15 significantly reduced food intake at initial 2 weeks of treatment, prevented the increase of body weight and adipose by 46% and 28% respectively in DIO rats, and reduced body weight and adipose gain by 70% and 23% respectively in early onset obesity DIO mice after 4 weeks treatment. Meanwhile, dyslipidemia were ameliorated in both models. Taken together the in vitro and in vivo data, MJ15 is demonstrated to be a potent and selective cannabinoid CB(1) receptor antagonist and holds a prominent potency in obesity and dyslipidemia treatment.

C333H, a novel PPARα/γ dual agonist, has beneficial effects on insulin resistance and lipid metabolism

AbstractAim:To examine the effects of novel peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist C333H on insulin resistance and lipid metabolism.Methods:An established dual-luciferase reporter gene assay system was used in vitro to test the activity of C333H with respect to the transcription of human PPARα and PPARγ. A preadipocyte differentiation assay and reverse transcription-polymerase chain reaction were used to detect the functional activities of C333H. In db/db mice, the effects of C333H were investigated with respect to lowering of blood glucose and lipid levels.Results:C333H was determined to be a novel PPARα/γ dual agonist because it strongly induced luciferase activity on human PPARα and PPARγ, promoting the differentiation of preadipocytes to adipocytes, and functioning in upregulating the expression of some glucose and lipid metabolic target genes of the PPAR. In addition, C333H efficiently reduced blood lipid and glucose concentrations in db/db diabetic mice.Conclusion:C333H has dual action on both PPARα and PPARγ, and might be of interest for the amelioration of lipid metabolic disorders and insulin resistance associated with type 2 diabetes.

The novel compound Z060228 inhibits assembly of the HBV capsid.

AIMS The effective anti-HBV drugs on the market are mainly immunomodulators or nucleoside analogs. The uses of INF-α and lamivudine (3TC) are considerably limited by their low response rate, side effects, drug resistance and HBV recurrence. Thus, new mechanism-based drugs remain in urgent need. This study aimed to investigate the anti-HBV effects of the novel compound Z060228 and to confirm its anti-HBV mechanisms. MAIN METHODS HepG2.2.15 cells and HBV-transgenic mice were used to evaluate the anti-HBV activity of Z060228. Conformational changes of the capsid structure induced by Z060228 were detected with high-resolution electron microscopy (EM), size-exclusion chromatography (SEC), and atomic force microscopy (AFM). KEY FINDINGS The HBV DNA replication in the supernatants of the HepG2.2.15 cells was effectively inhibited by Z060228 and Bay41-4109. In the liver of HBV-transgenic mice, the HBcAg content was significantly decreased and HBV DNA replication was also inhibited after high-dose (30 mg/kg) Z060228 treatment. Z060228 and Bay41-4109 exhibited similar effects on the self-assembly of Cp149. SEC data revealed that Z060228 altered the equilibrium (a state of stability) of Cp149 assembly. EM data further demonstrated that Z060228 could prevent Cp149 from self-assembling to the correct core particles. Additionally, AFM results showed that a low concentration of Z060228 caused Cp149 syncretizing, whereas a high concentration caused Cp149 to polymerize. SIGNIFICANCE Z060228 was demonstrated to be a potential capsid targeting anti-HBV drug candidate. The methods employed here could be used as a general strategy to study mechanisms of self-assembling protein-targeted drugs.

Novel selective cannabinoid CB 1 receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects

Aim:To characterize the biological profiles of MJ08, a novel selective CB1 receptor antagonist.Methods:Radioligand binding assays were performed using rat brain and spleen membrane preparations. CB1 and CB2 receptor redistribution and intracellular Ca2+ ([Ca2+]i) assays were performed with IN CELL Analyzer. Inverse agonism was studied using intracellular cAMP assays, and in guinea-pig ileum and mouse vas deferens smooth muscle preparations. In vivo pharmacologic profile was assessed in diet-induced obesity (DIO) mice.Results:In radioligand binding assay, MJ08 selectively antagonized CB1 receptor (IC50=99.9 nmol/L). In EGFP-CB1_U2OS cells, its IC50 value against CB1 receptor activation was 30.23 nmol/L (SR141716A: 32.16 nmol/L). WIN 55,212-2 (1 μmol/L) increased [Ca2+]i in the primary cultured hippocampal neuronal cells and decreased cAMP accumulation in CHO-hCB1 cells. MJ08 (10 nmol/L–10 μmol/L) blocked both the WIN 55,212-2-induced effects. Furthermore, MJ08 reversed the inhibition of electrically evoked twitches of mouse vas deferens by WIN 55,212-2 (pA2=10.29±1.05). MJ08 and SR141716A both showed an inverse agonism activity by markedly promoting the contraction force and frequency of guinea pig ileum muscle. MJ08 significantly increased the cAMP level in CHO-hCB1 cells with an EC50 value of 78.6 nmol/L, which was lower than the EC50 value for SR141716A (159.2 nmol/L). Besides the more potent pharmacological effects of cannabinoid CB1 receptor antagonism in DIO mice, such as reducing food intake, decreasing body weight, and ameliorating dyslipidemia, MJ08 (10 mg/kg) unexpectedly raised the fasted blood glucose in vivo.Conclusion:MJ08 is a novel, potent and selective CB1 receptor antagonist/inverse agonist with potent bioactive responses in vitro and in vivo that may be useful for disclosure the versatile nature of CB1 receptors.