Biomedical subjects

Hui Chen

Publications and source records attributed to Hui Chen.

At least 145 records · Page 8Linked to original sources

PubMed2004

[Effects of urotensin II on cultured cardiac fibroblast proliferation and collagen type I mRNA expression].

OBJECTIVE: To observe the effect of urotensin II on cultured cardiac fibroblast collagen type I mRNA expression and proliferation, thereby to explore the role of urotensin II in myocardial remodeling in the event of cardiac failure. METHODS: Cardiac fibroblasts of neonatal Sprague-Dawley rats isolated by trypsin digestion method were stimulated by urotensin II at varied concentrations when the cells reached growth arrest. MTT assay was employed to measure the proliferation and determine the number of the cells, and reverse transcriptional (RT)-PCR used to detect the collagen mRNA expression. RESULTS: With the increase of urotensin II concentration, the optical density at 570 nm of the fibroblasts as shown by MTT assay first increased but then decreased, and remained at a significantly higher level in the cells treated with 1x10(-8) or 1x10(-9) mol/L urotensin II as compared with the control (P<0.05). The collagen type I mRNA levels of the cells treated with 1x10(-7), 1x10(-8) or 1x10(-9) mol/L urotensin II were significantly higher than that of the control cells (P<0.01). CONCLUSION: Urotensin II can directly induce cardiac fibroblast proliferation and significantly increase collagen type I mRNA expression, suggesting the crucial role of urotensin II in myocardial remodeling.

Animals↗

PubMed2004

[Experimental and clinical study on the treatment of ischemic skin flap with topical application of PGE1].

OBJECTIVE: To evaluate the efficiency of PGE(1) in relieving the circulatory disorder of ischemic skin flap. METHODS: New Zealand rabbits were employed in the study with skip flaps each with the size of 2.5 x 6.0 cm(2) being raised from the back. PGE(1) cream in different concentrations, i.e. 0.2%, 0.4%, 0.8% was respectively topically applied to the skin flaps forming 3 groups (n = 10 in each group), while pure cream without PGE(1) was applied to those in control group (n = 30). The PGE(1) was applied 1 hour after the flap was opened, raised and sutured back. Blood perfusion in the flap was measured with Laser Doppler flowmetry before and 5, 10, 15, 20, 30, 45 and 60 mins after PGE(1) application. The tissue samples from the skin flap were harvested at 2 hours after PGE(1) application for immunohistological staining, and the cross sectional area of capillary lumens was measured under microscope. The survival area of the flap was assessed on the 3(rd) day after operation for the calculation of relative survival length of the flap. Clinically, PGE(1) ointment was applied onto the skin flap vulnerable to necrosis, and the outcome of the flap was observed thereafter. RESULTS: The blood perfusion in animal skin flaps was increased evidently after PGE(1) application, especially at 30 mins after PGE(1) usage when compared with that in control group (P < 0.05). The capillaries in the skin flap in PGE(1) application groups were dilated obviously after drug usage as observed under microscope (P < 0.05). The survival area and relative survival length in groups 1 and 2 on the 3(rd) post-operational day were much more increased when compared with those in other groups (P < 0.01). Clinically, the skin flaps treated with PGE(1) survived well even in the distal end of the flaps. CONCLUSION: The blood perfusion and the survival rate of the skin flaps could be improved by local application of PGE(1) in concentrations of 0.2% or 0.4%.

Adult↗

PubMed2004

[Experimental studies and clinical application of quickly prefabricated random skin flap].

OBJECTIVE: To enlarge the ratio of length to width of a prefabricated random skin flap in a short period, in order to meet a special clinical need. METHODS: A white rat and a white mini-pig was chosen for an animal model for the experiment. They were divided into the experimental group and the control. The prefabricated flap was formed as the planned design. In the experimental group, the flaps were treated with a desired pressure in certain intervals at the planned part of the flap. We estimated and inspected the digitized perfusion of flap microcirculation, and made overcong and wide random skin flap survive within 24 hours, and this technique was finally used for the clinical wound treatment. RESULTS: As expected, the survival area of the flap in the experimental group was significantly larger than the control. This technique was successfully used to repair the defects of the special sites in plastic and reconstructive surgery. CONCLUSION: The method of quickly prefabricated random flap could enlarge the ratio of length to width of the flap and put the flap in shape in short time. With the digitized estimating and inspecting, this method could obviously improve the survival area of the random flap and could also be very useful for the clinical treatment.

Adult↗

PubMed2004

[Effects of different doses of hydrocortisone on acute lung injury in rats with early septic shock induced by Escherichia coli].

OBJECTIVE: To observe the effects of different doses of hydrocortisone (HC) on acute lung injury (ALI) and inflammatory response in rats at early stage of septic shock induced by Escherichia coli and to investigate the possible mechanisms for such differences. METHODS: ALI model of early septic shock was induced in rats by two injections of Escherichia coli at 5 hours interval, with the first intraperitoneal injection of 6.50 x 10(10) cfu/kg and followed by an external jugular vein injection of 2.00 x 10(11) cfu/kg. Forty Wistar rats were randomly divided into the following five groups: normal control, ALI without HC treatment, high-dose HC (150 mg/kg), medium-dose HC (20 mg/kg) and low-dose HC (6 mg/kg). Two hours after the treatment, the specimens were collected for histopathological examination and the biological indexes of lung injury were measured. The expressions of intercellular adhesion molecule-1 (ICAM-1) and glucocorticoid receptor (GR) in lung tissues were also investigated by immunohistochemical assays. RESULTS: The biological indexes of lung injury [wet/dry weight ratio (g/g), total protein concentration in bronchoalveolar lavage fluid (mg/L) and lung permeability index (10(-3))] in ALI group (4.76 +/- 0.10, 278.96 +/- 60.45, 4.73 +/- 0.60) were significantly increased as compared to those in normal control group (4.10 +/- 0.07, 67.46 +/- 13.27, 1.12 +/- 0.15) (P < 0.05). The grades of ALI pathologic changes in ALI group (11.13 +/- 1.13) was significantly higher than that in the normal control group (0.50 +/- 0.53, P < 0.05). The ratio of expression area of ICAM-1 in ALI group (0.149 +/- 0.037) was significantly increased as compared to that in the normal control group (0.051 +/- 0.018) (P < 0.05). The ratio of expression area of GR all group (0.043 +/- 0.037) was significantly decreased as compared to that in the normal Control group (0.124 +/- 9.040) (P < 0.05) After administration of HC, all the lung injury indexes, pathological grades and the ratios of expression area of ICAM-1 and GR were significantly improved, with the most remarkable effects observed in the low-dose HC group. The expressions of ICAM-1 and GR showed a significantly negative linear correlation (r = 0.55, P < 0.0001). CONCLUSION: These results indicated that the low-dose HC treatment had the most remarkable effects of improving the biological indexes of lung injury, inflammatory mediators and pathological changes. These HC dose dependent therapeutic effects might be associated with the level of GR expression.

Acute Lung Injury↗

PubMed2004

[Association between tumor necrosis factor-beta polymorphisms and coronary heart disease in a Chinese population].

OBJECTIVE: To investigate the association between tumor necrosis factor-beta (TNF-beta) gene polymorphisms and coronary heart disease (CHD). METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequence specific primer-PCR (PCR-SSP) were used for the detection of TNF-beta genotype in 210 patients with CHD and 186 healthy controls. The serum TNF-beta levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The frequencies of CC, CA and AA genotypes of C804A in patients and controls were 25.7% and 37.1%, 49.5% and 45.7%, 24.8% and 17.2%, respectively; there were statistically significant differences in the distributions of the genotypes (P<0.05) and the allele frequencies (P<0.05) between the two groups; the risk of suffering from CHD in those of AA and CA genotypes was 1.704 times that in those of CC genotype (OR=1.704, 95%CI: 1.109-2.617). However, there was no significant difference in the distribution of the genotype of G252A between the patients and controls, though significant difference was seen between the subgroups of the CHD group. The serum TNF-beta and high sensitive C-reactive protein (hsCRP) levels of the patients were significantly higher than those of the controls (P<0.05); however, there were no significant differences in regard to different TNF-beta genotypes among the patients and controls respectively. CONCLUSION: The single nucleotide polymorphism (SNP) at position 804 in the exon 3 of TNF-beta gene is associated with CHD and the allele A may be a risk factor for CHD in Chinese. The polymorphism of G252A may not play an important role in the pathogenesis of CHD.

Aged↗

PubMed2004

[Genetic polymorphisms of six short tandem repeat loci in the Han population of Henan province in China].

OBJECTIVE: To investigate the allele frequencies of six short tandem repeats (STR) loci D12S391, D5S818, D18S51, PAHI3, D8S1179, D3S1358 in the Han population of Henan province and to obtain preliminary data. METHODS: DNA was extracted with phenol-chloroform from 140 EDTA-blood specimens of healthy unrelated individuals in Henan population; multiplex PCR technique and PAGE vertical electrophoresis were used to screen the genotype frequencies of six STR systems in Henan population. RESULTS: The test for Hardy-Weinberg equilibrium revealed that the genotype distribution was correspondent with the expected. The observed heterozygosities of six loci were 0.871, 0.769, 0.871, 0.773, 0.901, 0.722. The calculated discrimination power is 0.9999998, the calculated power of exclusion is 0.99845, the calculated matching probability is 2.39 x 10(-7). CONCLUSION: All of the six loci in this study have high power of discrimination and exclusion; they may be very useful genetic markers for individual identification, paternity test and genetics purposes.

Alleles↗

PubMed2004

[Surgical treatment of transcranial middle cranial fossa-lateral skull base malignant tumor].

OBJECTIVE: To evaluate the surgical method of transcranial middle cranial fossa-lateral skull base malignant tumor. METHODS: Sixteen patients with transcranial middle cranial fossa-lateral skull base malignant tumors were treated by three surgical methods. (1) Postauricular "C" form incision, combined with subtotal resection of temporal bone and high lateral neck approach to resect tumors located in middle cranial fossa, lateral skull base, and parotid region. (2) Temporal side "tungue" form incision, middle cranial fossa approach to resect tumors inside and outside the skull. (3) Temporal-auricular-mandible swing approach to resect tumors in parapharyngeal-infratemporal fossa-middle cranial fossa. Thirteen of the 16 cases received radiotherapy postoperatively. RESULTS: After operation, 11 of the 16 cases survived more than three years, five cases died within three years. Three-year-survival rate was 69%. CONCLUSIONS: Our results showed that the three surgical methods adopted could fully expose the internal and external skull lesion to remove the extensive malignant tumors. For late stage malignant tumors of the skull base, it should be treated aggressively by combination of surgical therapy and postoperative radiotherapy.

Adult↗

PubMed2004

[Determination of aceclofenac in human plasma by reversed-phase high performance liquid chromatography].

A simple and rapid reversed-phase high performance liquid chromatographic (RP-HPLC) method for the determination of aceclofenac in human plasma has been established. Plasma samples from 18 male volunteers were collected. The samples were extracted with ether, and the extractant was redissolved in the mobile phase after dried by N2 at 37 degrees C. Chromatography was performed on an ODS column with methanol-0.1 mol/L ammonium acetate (pH 6.0) (7:3, v/v) as the mobile phase. The flow rate was 1.0 mL/min. The UV-Vis detector was set at 275 nm. The linear range was from 0.05 mg/L to 40.0 mg/L with a correlation coefficient of 0.9999. The intra-day and inter-day relative standard deviations (RSDs) for assaying the plasma samples containing three levels of aceclofenac were 1.84%-7.13% and 3.40%-9.33% (n = 5), respectively. The mean absolute recovery was 82.5% and the mean relative recovery was 100.3%. This sensitive and selective method can be used for clinical pharmacokinetic study of aceclofenac.

Adult↗

PubMed2004

[Adsorption studies of gamma-aminopropyltrimethoxysilane on iron surfaces by surface-enhanced Raman spectroscopy].

The films of gamma-aminopropyltrimethoxysilane (gamma-APS) on iron electrode surfaces were studied. The silane films were characterized by in-situ Surface-Enhanced Raman Spectroscopy (SERS). It has been found that the potential-dependent Surface-enhanced Raman Spectroscopy are useful for diagnosing the formation and structure of gamma-APS moieties bound onto the surface of metal substrates. Results of SERS indicated that the silanol and amino groups were adsorbed competitively on the metal surfaces. At the same time, the electrode potential, and illumination of laser all have great influence on the nature of these head groups. It was also found that the different states of amine transformed with the change in the potential.

English Abstract↗

PubMed2003

Quantitative analysis of synthetic polymers using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Quantitative analyses of synthetic polymers were accomplished using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS). Many factors have hindered the development of quantitative measurement of polymers via MALDI TOF MS, e.g., laser power, matrix, cation salt, and cocrystallization. By probing the optimal conditions, two sets of polymers were studied. Fair repeatability of the samples ensures acceptable results. In set 1, two poly(ethylene glycols) with different end groups showed equal desorption/ionization efficiencies. Two synthetic polymers in set 2 with different chemical properties resulted in different MALDI responses. Good linearity was achieved by plotting the relationship between the sample concentration ratio and the total signal intensity ratio in both sets.

Journal Article↗

PubMed2003

Sustainability science and engineering: the emergence of a new metadiscipline.

A case is made for growth of a new metadiscipline of sustainability science and engineering. This new field integrates industrial, social, and environmental processes in a global context. The skills required for this higher level discipline represent a metadisciplinary endeavor, combining information and insights across multiple disciplines and perspectives with the common goal of achieving a desired balance among economic, environmental, and societal objectives. Skills and capabilities that are required to support the new metadiscipline are summarized. Examples of integrative projects are discussed in the areas of sustainability metrics and integration of industrial, societal, and environmental impacts. It is clear that a focus on green engineering that employs pollution prevention and industrial ecology alone are not sufficient to achieve sustainability, because even systems with efficient material and energy use can overwhelm the carrying capacity of a region or lead to other socially unacceptable outcomes. To meet the educational and human resource needs required for this new discipline, the technological and environmental awareness of society must be elevated and a sufficient and diverse pool of human talent must be attracted to this discipline.

Conservation of Natural Resources↗

PubMed2003

TACE is required for fetal murine cardiac development and modeling.

Tumor necrosis factor-alpha converting enzyme (TACE) is a membrane-anchored, Zn-dependent metalloprotease, which belongs to the ADAM (a disintegrin and metalloprotease) family. TACE functions as a membrane sheddase to release the ectodomain portions of many transmembrane proteins, including the precursors of TNFalpha, TGFalpha, several other cytokines, as well as the receptors for TNFalpha, and neuregulin (ErbB4). Mice with TACE(DeltaZn/DeltaZn) null mutation die at birth with phenotypic changes, including failure of eyelid fusion, hair and skin defects, and abnormalities of lung development. Abnormal fetal heart development was not previously described. Herein, we report that TACE(DeltaZn/DeltaZn) null mutant mice by late gestation exhibit markedly enlarged fetal hearts with increased myocardial trabeculation and reduced cell compaction, mimicking the pathological changes of noncompaction of ventricular myocardium. In addition, larger cardiomyocyte cell size and increased cell proliferation were observed in ventricles of TACE(DeltaZn/DeltaZn) knockout mouse hearts. At the molecular level, reduced expression of epidermal growth factor receptor, attenuated protein cleavage of ErbB4, and changes in MAPK activation were also detected in TACE(DeltaZn/DeltaZn) knockout heart tissues. The data suggest that TACE-mediated cell surface protein ectodomain shedding plays an essential and a novel regulatory role during cardiac development and modeling.

ADAM Proteins↗

PubMed2003

Adiponectin stimulates production of nitric oxide in vascular endothelial cells.

Adiponectin is secreted by adipose cells and mimics many metabolic actions of insulin. However, mechanisms by which adiponectin acts are poorly understood. The vascular action of insulin to stimulate endothelial production of nitric oxide (NO), leading to vasodilation and increased blood flow is an important component of insulin-stimulated whole body glucose utilization. Therefore, we hypothesized that adiponectin may also stimulate production of NO in endothelium. Bovine aortic endothelial cells in primary culture loaded with the NO-specific fluorescent dye 4,5-diaminofluorescein diacetate (DAF-2 DA) were treated with lysophosphatidic acid (LPA) (a calcium-releasing agonist) or adiponectin (10 microg/ml bacterially produced full-length adiponectin). LPA treatment increased production of NO by approximately 4-fold. Interestingly, adiponectin treatment significantly increased production of NO by approximately 3-fold. Preincubation of cells with wortmannin (phosphatidylinositol 3-kinase inhibitor) blocked only adiponectin- but not LPA-mediated production of NO. Using phospho-specific antibodies, we observed that either adiponectin or insulin treatment (but not LPA treatment) caused phosphorylation of both Akt at Ser473 and endothelial nitric-oxide synthase (eNOS) at Ser1179 that was inhibitable by wortmannin. We next transfected bovine aortic endothelial cells with dominant-inhibitory mutants of Akt (Akt-AAA) or AMP-activated protein kinase (AMPK) (AMPKK45R). Neither mutant affected production of NO in response to LPA treatment. Importantly, only AMPKK45R, but not Akt-AAA, caused a significant partial inhibition of NO production in response to adiponectin. Moreover, AMPK-K45R inhibited phosphorylation of eNOS at Ser1179 in response to adiponectin but not in response to insulin. We conclude that adiponectin has novel vascular actions to directly stimulate production of NO in endothelial cells using phosphatidylinositol 3-kinase-dependent pathways involving phosphorylation of eNOS at Ser1179 by AMPK. Thus, the effects of adiponectin to augment metabolic actions of insulin in vivo may be due, in part, to vasodilator actions of adiponectin.

AMP-Activated Protein Kinases↗

PubMed2003

Mouse 3-phosphoinositide-dependent protein kinase-1 undergoes dimerization and trans-phosphorylation in the activation loop.

Activation of mouse 3-phosphoinositide-dependent protein kinase-1 (mPDK1) requires phosphorylation at a conserved serine residue, Ser244, in the activation loop. However, the mechanism by which mPDK1 is phosphorylated at this site remains unclear. We have found that kinase-defective mPDK1 (mPDK1KD), but not a kinase-defective mPDK1 in which Ser244 was replaced with alanine (mPDK1KD/S244A), is significantly phosphorylated in intact cells and is a direct substrate of wild-type mPDK1 fused to the yellow fluorescence protein. Phosphoamino acid analysis and phosphopeptide mapping studies revealed that mPDK1 trans-autophosphorylation occurred mainly on Ser244. On the other hand, Ser399 and Thr516, two recently identified autophosphorylation sites of mPDK1, are phosphorylated primarily through a cis mechanism. In vivo labeling studies revealed that insulin stimulated both mPDK1KD and mPDK1KD/S244A phosphorylation in Chinese hamster ovary cells overexpressing the insulin receptor. However, Western blot analysis using a phosphospecific antibody revealed no increase in insulin-stimulated phosphorylation of Ser244 in these cells overexpressing mPDK1. mPDK1 undergoes dimerization in cells and this self-association is enhanced by kinase inactivation. Deletion of the extreme C terminus disrupts mPDK1 dimerization and Ser244 trans-phosphorylation, suggesting that dimerization is important for mPDK1 trans-phosphorylation. Taken together, our results show that mPDK1 autophosphorylation occurs at multiple sites through both cis and trans mechanisms and suggest that dimerization and trans-phosphorylation may serve as mechanisms to regulate PDK1 activity in cells.

3-Phosphoinositide-Dependent Protein Kinases↗

PubMed2003

Sorption behaviors of aromatic anions on loess soil modified with cationic surfactant.

Modification of soils with hydrophobic cationic surfactants is an effective approach for enhancing the sorptive capabilities of soil in the vadose zone for the purpose of retaining organic contaminants prior to cleanup. The objective of this study was to examine the sorptive behavior of the cationic surfactant-modified loess soil for aromatic anions in the aqueous phase in an attempt to define the sorptive mechanisms. Some dominant factors governing the sorption, such as ionic strength and divalent heavy metal cation, were investigated. The sorption isotherms of 2,4-dinitrophenol (DNP) and benzoic acid (BA) in the modified soil samples were obtained using the batch equilibration method. Under the laboratory conditions, the modified loess soil utilized in this study was prepared by replacing the cations of loess soil with a cationic surfactant-hexadecyltrimethylammonium (HDTMA) bromide. The acidic aromatic compounds, DNP and BA existing as aromatic anions in the natural mixture of loess soil and aqueous phase, were selected as indicator compounds to measured the sorption behaviors of aromatic anions on the HDTMA-modified loess soil. The results confirmed that the sorptive capabilities of aromatic anions in loess soil were greatly enhanced by modification with HDTMA. The increase of ionic strength and the addition of divalent heavy metal cation Zn(2+) significantly increased the sorption of aromatic anions on the HDTMA-modified loess soil. In binary solute systems, the sorbed amounts either of DNP or BA on the HDTMA-modified loess soil were reduced if two compounds existed simultaneously in the soil. This results indicated that competitive adsorption between the two aromatic anions occurred in soil matrix.

2,4-Dinitrophenol↗

PubMed2003

Cholesterol-lowering effect of a theaflavin-enriched green tea extract: a randomized controlled trial.

BACKGROUND: Tea consumption has been associated with decreased cardiovascular risk, but potential mechanisms of benefit are ill-defined. While epidemiologic studies suggest that drinking multiple cups of tea per day lowers low-density lipoprotein cholesterol (LDL-C), previous trials of tea drinking and administration of green tea extract have failed to show any impact on lipids and lipoproteins in humans. Our objective was to study the impact of a theaflavin-enriched green tea extract on the lipids and lipoproteins of subjects with mild to moderate hypercholesterolemia. METHODS: Double-blind, randomized, placebo-controlled, parallel-group trial set in outpatient clinics in 6 urban hospitals in China. A total of 240 men and women 18 years or older on a low-fat diet with mild to moderate hypercholesterolemia were randomly assigned to receive a daily capsule containing theaflavin-enriched green tea extract (375 mg) or placebo for 12 weeks. Main outcome measures were mean percentage changes in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglyceride levels compared with baseline. RESULTS: After 12 weeks, the mean +/- SEM changes from baseline in total cholesterol, LDL-C, HDL-C, and triglyceride levels were -11.3% +/- 0.9% (P =.01), -16.4% +/- 1.1% (P =.01), 2.3% +/- 2.1% (P =.27), and 2.6% +/- 3.5% (P =.47), respectively, in the tea extract group. The mean levels of total cholesterol, LDL-C, HDL-C, and triglycerides did not change significantly in the placebo group. No significant adverse events were observed. CONCLUSION: The theaflavin-enriched green tea extract we studied is an effective adjunct to a low-saturated-fat diet to reduce LDL-C in hypercholesterolemic adults and is well tolerated.

Adult↗

PubMed2003

Peroxisome proliferator-activated receptor-gamma represses GLUT4 promoter activity in primary adipocytes, and rosiglitazone alleviates this effect.

The synthetic thiazolidinedione ligands of peroxisome proliferator-activated receptor-gamma (PPARgamma) improve insulin sensitivity in type II diabetes and induce GLUT4 mRNA expression in fat and muscle. However, the molecular mechanisms involved are still unclear. We studied the regulatory effects of PPARgamma and its ligands on GLUT4 gene expression in primary rat adipocytes and CHO-K1 cells cotransfected with PPARgamma and the GLUT4 promoter reporter. PPARgamma1 and PPARgamma2 repressed the activity of the GLUT4 promoter in a dose-dependent manner. Whereas this repression was augmented by the natural ligand 15Delta-prostaglandin J2, it was completely alleviated by rosiglitazone (Rg). Ligand binding-defective mutants PPARgamma1-L468A/E471A and PPARgamma2-L496A/E499A retained the repression effect, which was unaffected by Rg, whereas the PPARgamma2-S112A mutant exhibited a 50% reduced capacity to repress GLUT4 promoter activity. The -66/+163 bp GLUT4 promoter region was sufficient to mediate PPARgamma inhibitory effects. The PPARgamma/retinoid X receptor-alpha heterodimer directly bound to this region, whereas binding was abolished in the presence of Rg. Thus, we show that PPARgamma represses transcriptional activity of the GLUT4 promoter via direct and specific binding of PPARgamma/retinoid X receptor-alpha to the GLUT4 promoter. This effect requires an intact Ser112 phosphorylation site on PPARgamma and is completely alleviated by Rg, acting via its ligand-binding domain. These data suggest a novel mechanism by which Rg exerts its antidiabetic effects via detaching PPARgamma from the GLUT4 gene promoter, thus leading to increased GLUT4 expression and enhanced insulin sensitivity.

Adipocytes↗

PubMed2003

A selective and oral small molecule inhibitor of vascular epithelial growth factor receptor (VEGFR)-2 and VEGFR-1 inhibits neovascularization and vascular permeability.

Vascular endothelial growth factor (VEGF) is a key driver of the neovascularization and vascular permeability that leads to the loss of visual acuity in diabetic retinopathy and neovascular age-related macular degeneration. Our aim was to identify an orally active, selective small molecule kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-2 with activity against both VEGF-induced angiogenesis and vascular permeability. We used a biochemical assay to identify 3-[5-methyl-2- (2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-proprionic acid (SU10944), a pyrrole indolinone, which is a potent ATP-competitive inhibitor of VEGFR-2 (Ki of 21 +/- 5 nM). In cellular assays, SU10944 inhibited VEGF-induced receptor autophosphorylation (IC50 of 227 +/- 80 nM) as well as downstream signaling (IC50 of 102 +/- 27 nM). In biochemical assays, SU10944 exhibits potent inhibitory activity against VEGFR-1; weak activity against other related subgroup members, including stem cell factor receptor (SCFR), platelet-derived growth factor receptor beta (PDGFRbeta), and fibroblast growth factor receptor-1 (FGFR-1); and no detectable activity against other protein tyrosine kinases such as epidermal growth factor receptor (EGFR), Src, and hepatocyte growth factor receptor. In cellular assays, the selectivity for SU10944 to inhibit VEGFR is maintained compared with other tyrosine kinases (IC50 for SCFR of 1.6 +/- 0.3 microM, for PDGFRbeta of 30.6 +/- 13.3 microM, for FGFR-1 of >50 microM, and for EGFR of >50 microM). Upon oral administration, SU10944 gave a clear dose response in the corneal micropocket model with an ED50 value for inhibition of neovascularization of approximately 30 mg/kg and a maximum inhibition of 95% at 300 mg/kg. Similarly, upon oral administration in the Miles assay, SU10944 potently inhibited VEGF-induced vascular permeability. Our data indicate that small molecule inhibitors of VEGFR signaling have the potential to ameliorate VEGF-induced neovascularization as well as vascular permeability.

3T3 Cells↗