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Cilostazol protects diabetic rats from vascular inflammation via nuclear factor-kappa B-dependent down-regulation of vascular cell adhesion molecule-1 expression.
Gao Ling;Wang Furong;Wang Bo;Gong Bendi;Zhang Jie;Zhang Xiumei;Zhao Jiaju
J Pharmacol Exp Ther 2006年 318卷1期 页码:53-8
Animals|Diabetes Mellitus, Experimental/drug therapy/metabolism|Down-Regulation/drug effects/physiology|Endothelium, Vascular/drug effects/metabolism|Gene Expression Regulation/drug effects/physiology|Male|NF-kappa B/antagonists & inhibitors/metabolism|Rats|Rats, Sprague-Dawley|Tetrazoles/pharmacology/therapeutic use|Vascular Cell Adhesion Molecule-1/biosynthesis|Vascular Diseases/metabolism/prevention & contro
Vascular cell adhesion molecule (VCAM)-1 plays a critical role in the initiation and development of vascular inflammation and selective inhibition of adhesion molecules expressed by endothelial cells may present a new therapeutic strategy for the treatment of vascular complications associated with diabetes mellitus. Increasing evidence indicates that cilostazol, a cAMP phosphodiesterase inhibitor, reduces VCAM-1 expression on endothelial cells. In this study, we have tested the effect of cilostazol on the development of vascular inflammation in rats with streptozotocin-induced diabetes and determined the mechanism by which cilostazol prevents diabetes-induced vascular inflammation in the aorta. Diabetic rats were treated with different dose of cilostazol (27 or 9 mg/kg/day) for 8 weeks, and aortae were removed for the evaluation of vascular inflammation. The VCAM-1 protein expression and VCAM-1 mRNA transcripts were analyzed by immunohistochemical staining and in situ hybridization assay, respectively. Our results demonstrated that cilostazol treatment prevents the overexpression of VCAM-1 and protects diabetic rats from vascular inflammation. More importantly, our mechanistic studies suggested that cilostazol controls the VCAM-1 overexpression via inhibiting the activation of nuclear factor-kappaB.
Association of the CTLA4 gene with Graves' disease in the Chinese Han population.
Zhao Shuang-Xia;Pan Chun-Ming;Cao Huang-Ming;Han Bing;Shi Jing-Yi;Liang Jun;Gao Guan-Qi;Peng Yong-De;Su Qing;Chen Jia-Lun;Zhao Jia-Jun;Song Huai-Don
PLoS One 2010年 5卷3期 页码:e9821
Antigens, CD/genetics|CTLA-4 Antigen|Case-Control Studies|China|Cohort Studies|False Positive Reactions|Gene Frequency|Genetic Predisposition to Disease|Genotype|Geography|Graves Disease/ethnology/genetics|Humans|Models, Genetic|Odds Ratio|Polymorphism, Single Nucleotide|Regression Analysi
To determine whether genetic heterogeneity exists in patients with Graves' disease (GD), the cytotoxic T-lymphocyte associated 4 (CTLA-4) gene, which is implicated a susceptibility gene for GD by considerable genetic and immunological evidence, was used for association analysis in a Chinese Han cohort recruited from various geographic regions. Our association study for the SNPs in the CTLA4 gene in 2640 GD patients and 2204 control subjects confirmed that CTLA4 is the susceptibility gene for GD in the Chinese Han population. Moreover, the logistic regression analysis in the combined Chinese Han cohort revealed that SNP rs231779 (allele frequencies p = 2.81x10(-9), OR = 1.35, and genotype distributions p = 2.75x10(-9), OR = 1.42) is likely the susceptibility variant for GD. Interestingly, the logistic regression analysis revealed that SNP rs35219727 may be the susceptibility variant to GD in the Shandong population; however, SNP, rs231779 in the CTLA4 gene probably independently confers GD susceptibility in the Xuzhou and southern China populations. These data suggest that the susceptibility variants of the CTLA4 gene varied between the different geographic populations with GD.
Chronic palmitate exposure inhibits AMPKalpha and decreases glucose-stimulated insulin secretion from beta-cells: modulation by fenofibrate.
Sun Ying;Ren Meng;Gao Guan-qi;Gong Bendi;Xin Wei;Guo Hua;Zhang Xiu-juan;Gao Ling;Zhao Jia-ju
Acta Pharmacol Sin 2008年 29卷4期 页码:443-50
AMP-Activated Protein Kinases/antagonists & inhibitors|Animals|Cell Culture Techniques|Cell Line, Tumor|Cells, Cultured|Dose-Response Relationship, Drug|Fenofibrate/pharmacology|Glucose/pharmacology|Insulin/secretion|Insulin-Secreting Cells/drug effects/metabolism|Insulinoma/metabolism|Islets of Langerhans/cytology/drug effects/physiology|Luminescence|Luminescent Measurements|Male|PPAR alpha/metabolism|Palmitates/pharmacology|Rats|Rats, Wista
Adenosine monophosphate-activated protein kinase (AMPK), a vital regulator of glucose metabolism, may affect insulin secretion in beta-cells. However, the role of AMPK in beta-cell lipotoxicity remains unclear. Fenofibrate has been reported to regulate lipid homeostasis and is involved in insulin secretion in pancreatic beta-cells. In the present study, we aimed to investigate the effect of palmitate on AMPK expression and glucose-stimulated insulin secretion (GSIS) in rat islets and INS-1 beta-cell, as well as the effect of fenofibrate on AMPK and GSIS in INS-1 cells treated with palmitate.
Integrative Analysis of mRNA and miRNA Array Data Reveals the Suppression of Retinoic Acid Pathway in Regulatory T Cells of Graves' Disease
Wang, Z;Fan, XH;Zhang, RR;Lin, ZW;Lu, T;Bai, X;Li, WC;Zhao, JJ;Zhang, QY
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 2014年 99卷12期 页码:E2620-E2627
AUTOIMMUNE THYROID-DISEASES; ACUTE PROMYELOCYTIC LEUKEMIA; FOXP3 EXPRESSION; DIFFERENTIATION; MICRORNAS; RECEPTOR; IMPAIRMENT; TOLERANCE; COLITIS; T(H)17
Context: It is well known that regulatory T cells (Tregs) are abnormal in Graves' disease (GD) and play crucial roles in the breakdown of immune tolerance and GD development. However, there are controversies about whether the quantity and/or function of Tregs is aberrant in GD. The molecular mechanism of Tregs abnormality and its effects on GD development was still unclear, until now.;-;Objective: MiRNAs play important roles in the function and development of the immune system including Tregs. To reveal the Tregs abnormality and its molecular mechanism in GD, we systematically studied the quantity and immunosuppressive function as well as the differential expression profiles of miRNA and mRNA of Tregs in newly diagnosed patients with GD using TaqMan miRNA array and mRNA microarray.;-;Results: Our results showed that the quantity and immunosuppressive function of Tregs in initial patients with GD was significantly decreased. More importantly, the retinoic acid (RA) pathway was markedly suppressed and its agonist, all-trans retinoic acid, could notably improve the quantity and immunosuppressive function of Tregs from patients with GD in vitro. In addition, many other pathways including protein ubiquitination and circadian rhythm were also significantly regulated in Tregs of GD.;-;Conclusions: This integrative study first revealed the expression profiles of mRNA/miRNA in Tregs of initial GD and RA pathway might play important roles in GD development. Our results implied that all-trans RA, which had been used for a long time in the clinical setting, had potential value in the treatment of GD and was worthy of additional study.
Alpha-lipoic acid attenuates insulin resistance and improves glucose metabolism in high fat diet-fed mice
Yang, Y;Li, W;Liu, Y;Li, Y;Gao, L;Zhao, JJ
ACTA PHARMACOLOGICA SINICA 2014年 35卷10期 页码:1285-1292
ACTIVATED PROTEIN-KINASE; GLYCOGEN-SYNTHESIS; HEPATIC STEATOSIS; MOUSE-LIVER; CHREBP; GLUCONEOGENESIS; AMPK; ACCUMULATION; LIPOGENESIS; EXPRESSION
Aim: To investigate whether alpha-lipoic acid (ALA) could attenuate the insulin resistance and metabolic disorders in high fat diet-fed mice.;-;Methods: Male mice were fed a high fat diet (HFD) plus ALA (100 and 200 mg.kg(-1).d(-1)) or HFD plus a positive control drug metformin (300 mg.kg(-1).d(-1)) for 24 weeks. During the treatments, the relevant physiological and metabolic parameters of the mice were measured. After the mice were euthanized, blood samples and livers were collected. The expression of proteins and genes related to glucose metabolism in livers were analyzed by immunoblotting and real time-PCR.;-;Results: HFD induced non-alcoholic fatty liver disease (NAFLD) and abnormal physiological and metabolic parameters in the mice, which were dose-dependently attenuated by ALA. ALA also significantly reduced HFD-induced hyperglycemia and insulin resistance in HFD-fed mice. Furthermore, ALA significantly upregulated the glycolytic enzymes GCK, HK-1 and PK, and the glycogen synthesis enzyme GS, and downregulated the gluconeogenic enzymes PEPCK and G6Pase, thus decreased glucose production, and promoted glycogen synthesis and glucose utilization in livers. Moreover, ALA markedly increased PKB/Akt and GSK3 beta phosphorylation, and nuclear carbohydrate response element binding protein (ChREBP) expression in livers. Metformin produced similar effects as ALA in HFD-fed mice.;-;Conclusion: ALA is able to sustain glucose homeostasis and prevent the development of NAFLD in HFD-fed mice.
The adverse events profile of anti-IGF-1R monoclonal antibodies in cancer therapy
Ma, HH;Zhang, TH;Shen, HC;Cao, HX;Du, JJ
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 2014年 77卷6期 页码:917-928
GROWTH-FACTOR-I; CELL LUNG-CANCER; ADVANCED SOLID TUMORS; INHIBITOR FIGITUMUMAB CP-751,871; FACTOR RECEPTOR INHIBITORS; PHASE-II; EWING SARCOMA; COMBINATION; CIXUTUMUMAB; ONCOLOGY
Aim(s) Insulin-like growth factor-1 receptor (IGF-1R) targeted therapies have become one of the intriguing areas in anticancer drug development during the last decade. As one of these therapies, anti-IGF-1R monoclonal antibodies (mAbs) are also advancing further in development. Our purpose was to conduct a systematic review of the adverse events (AEs) caused by anti-IGF-1R monoclonal antibodies in cancer therapy. Methods We searched the termIGF-1R monoclonal antibody' in the Pubmed database and found 389 related articles. After elaborate selection, 15 clinical studies that satisfied our criteria were then adopted for further analysis. We extracted all the useful information about the AEs of mAbs from the enrolled studies. Every kind of reported AE as well as corresponding incidences were summed up and calculated. We compared AE incidence differences in two age groups, and analyzed toxicities of mAbs used as a single agent or combined with chemotherapies. Finally, the differences of AE profiles between individual mAbs were also valued. Results AEs were more severe in the lower age group and 13 of 19 AE incidences in the single-agent group were significantly lower than in the combination group (P < 0.05). R1507 seemed to show a worse AE profile than cixutumumab and figitumumab. Conclusions When anti-IGF-1R mAbs are used for cancer therapy, it is essential to choose the proper drug and combined chemotherapies to reduce AE occurrences. Also, administration of these mAbs to younger patients should be more carefully supervised. Furthermore, some more frequently observed AEs for specific mAb should be paid adequate attention.
Functional thyrotropin receptor expression in the ventricle and the effects on ventricular BNP secretion
Huang, W;Xu, J;Jing, F;Chen, WB;Gao, L;Yuan, HT;Zhao, JJ
ENDOCRINE 2014年 46卷2期 页码:328-339 影响因子:3.279
THYROID-STIMULATING HORMONE; COENZYME-A REDUCTASE; SUBCLINICAL HYPOTHYROIDISM; HEART-FAILURE; CARDIAC-FUNCTION; IN-VITRO; DILATED CARDIOMYOPATHY; GENE-EXPRESSION; MESSENGER-RNA; RISK-FACTOR
Elevated thyrotropin (TSH) and hypercholesterolemia commonly coexist in patients with subclinical hypothyroidism, which can cause and aggravate heart disease. However, it is unclear whether TSH has a direct effect on cardiac function. To determine the expression of the thyrotropin receptor (TSHR) and the effects of TSH on ventricular function, we analyzed the ventricular tissues and thyroid glands from normal rats and mice and the H9c2 cardiomyocyte cell line. The results revealed that TSHR was expressed at the transcriptional and protein levels by PCR, immunoblotting, immunohistochemistry and immunofluorescence. The mRNA levels of beta-MHC and the expression of pCREB and HMGCR in the ventricle were significantly lower in Tshr (-/-) mice than in wild-type (WT) mice (p < 0.05), but serum NT-proBNP levels were similar between WT and Tshr (-/-) mice. After synchronization, H9c2 cells were stimulated with several concentrations of TSH for various time periods. TSH up-regulated beta-MHC mRNA expression in H9c2 cells. Cyclic adenosine monophosphate (cAMP) production and downstream signaling, such as pCREB and HMGCR expression and NT-proBNP secretion, increased in dose- and time-dependent manners. The TSH-stimulated effects were suppressed by an adenylyl cyclase inhibitor, a protein kinase A (PKA) inhibitor and HMGCR inhibitors (all p < 0.05). The data indicate functional TSHR is expressed in ventricular myocytes and mediates TSH-induced BNP secretion and HMGCR up-regulation through the cAMP/PKA/pCREB signaling pathway. Our findings suggest a potentially novel pathophysiological role of TSH in heart failure-associated hypothyroidism.
Swimming improves high-fat induced insulin resistance by regulating lipid and energy metabolism and the insulin pathway in rats
Song, A;Wang, C;Ren, LP;Zhao, JJ
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 2014年 33卷6期 页码:1671-1679
HUMAN SKELETAL-MUSCLE; BINDING PROTEIN FAMILY; GLUCOSE-UPTAKE; MITOFUSIN 2; IN-VIVO; MITOCHONDRIAL DYNAMICS; TRIGLYCERIDE SYNTHESIS; ACID TRANSLOCASE; EXERCISE; ACTIVATION
In this study, we aimed to determine the preventive and therapeutic effects of swimming on insulin resistance in high-fat-fed rats. Sprague-Dawley rats were divided into 4 groups and fed for 8 weeks as follows: i) the control (Con) group fed a control diet; ii) the high-fat (HF) group fed a high-fat diet; iii) the treatment (ST) group fed a high-fat diet and trained with swimming from the 4th week; and iv) the prevention (SP) group fed a high-fat diet and trained with swimming from the 1st week of the experiment. A hyperinsulinemic-euglycemic clamp was used to evaluate the insulin sensitivity of the rats. The ultrastructure of the liver cells was observed by electron microscopy. Hepatic lipid accumulation was observed by Oil Red 0 staining. Quantitative RT-PCR and western blot analysis were performed to detect the expression of proteins related to lipid metabolism, energy metabolism and insulin signaling transduction. After 8 weeks of feeding, compared with the Con group, the glucose infusion rate (GIR) was significantly decreased; a significant lipid accumulation was observed in the liver, while the ultrastructure of the liver cells was damaged in the HF group. Proteins related to lipid metabolism in the liver and skeletal muscle, including FAT and FABP were upregulated, while CPT1 and PPAR levels were downregulated in the HF group. The levels of the energy-metabolism-related molecules, AMPK alpha 2, PGCl alpha, PGC1 beta and MFN2 were downregulated in skeletal muscle in the HF group. The expression levels of insulin signaling transduction molecules, INSR, IRS1, PI3K/p85, AKT2 and GLUT4, as well as the phosphorylation levels of INSR, IRS1, PI3K/p85 and AKT2 were lower in skeletal muscles in the HF rats. Compared with HF group, the GIR levels were significantly increased in the ST and SP groups. Lipid accumulation and damage to the ultrastructure of the liver cells were improved in both groups. The expression of molecules related to lipid metabolism in the liver and skeletal muscle, energy metabolism in skeletal muscle and insulin signaling transduction were all markedly upregulated. In conclusion, swimming can effectively improve insulin sensitivity and even prevent insulin resistance by affecting the expression of proteins related to lipid metabolism, energy metabolism and insulin signaling transduction in rats fed a high-fat diet.
Chronic leucine exposure results in reduced but reversible glucose-stimulated insulin secretion in INS-1 cells
Zhang, XJ;Han, WX;Jiang, XY;Li, M;Gao, L;Zhao, JJ
MOLECULAR MEDICINE REPORTS 2014年 9卷6期 页码:2554-2558
PANCREATIC BETA-CELLS; FATTY-ACIDS; GENE; LIPOTOXICITY; EXPRESSION; HOMEOBOX-1; PDX-1; DIFFERENTIATION; TRANSCRIPTION; GLUCOKINASE
Previous studies have demonstrated that sustained high leucine exposure decreases glucose-stimulated insulin secretion (GSIS). However, whether this effect is recoverable following the removal of leucine is unclear. Pancreatic/duodenal homeobox-1 (PDX-1) and its downstream target, glucose transporter 2 (GLUT2), are reported to be positively associated with insulin secretion. However, it also remains unclear whether the effect of leucine on GSIS is accompanied by alterations in PDX-1 and GLUT2. In the present study, insulin secretion, insulin content, PDX-1 and GLUT2 protein expression in INS-1 (rat insulinoma cell line) cells were assessed following a 24-h incubation in 40 mmol/1 leucine. Half of the cells were incubated in leucine-free media for a further 24 h to observe the abovementioned effects. In contrast to the control, 40 mmol/1 leucine for 24 or 48 h diminished GSIS at high glucose concentrations by 11% (P=0.026) or 22% (P=0.003), insulin content by 14% (P=0.008) or 20% (P=0.002), as well as decreasing PDX-1 and GLUT2 expression. When leucine was removed from the media for a further 24-h incubation, in comparison with those cells that were maintained in leucine treatment for 24 and 48 h, the high GSIS increased by 13% (P=0.032) and 27% (P=0.002), insulin content was augmented by 10% (P=0.014) and 20% (P=0.003), and the protein expression of PDX-1 and GLUT2 also increased. The present study demonstrates that sustained high concentrations of leucine induce a reversible impairment of GSIS and alter insulin content, which is mediated by PDX-1 and GLUT2, in INS-1 cells.
The relationship between endogenous testosterone and lipid profile in middle-aged and elderly Chinese men
Zhang, N;Zhang, HQ;Zhang, X;Zhang, BC;Wang, FR;Wang, CG;Zhao, M;Yu, C;Gao, L;Zhao, JJ;Guan, QB
EUROPEAN JOURNAL OF ENDOCRINOLOGY 2014年 170卷4期 页码:487-494
HORMONE-BINDING GLOBULIN; CARDIOVASCULAR RISK-FACTORS; LOW SERUM TESTOSTERONE; APOLIPOPROTEIN-A-I; METABOLIC SYNDROME; OLDER MEN; SUBCLINICAL HYPOTHYROIDISM; MYOCARDIAL-INFARCTION; INSULIN-RESISTANCE; REFERENCE RANGE
Objective: To evaluate the relationship between serum total testosterone (TT) level and lipid profile after adjusting for some traditional confounding factors, free thyroid hormones and TSH in Chinese men.;-;Methods: This was a retrospective study based on an epidemiological investigation including 11 000 subjects. Bivariate and partial correlation analysis, multiple linear regression analysis, and a general linear model were used to assess the influence of TT on the lipid profile. Additionally, the odds ratios (ORs) (95% CIs) for hypertriglyceridemia and low HDL-C in relation to TT categories were calculated using logistic regression analysis.;-;Results: A total of 4114 subjects whose mean age was 56.04 +/- 8.75 years were finally analyzed. There was a significant linear trend toward lower total cholesterol (TC), lower triglycerides (TG), and higher HDL-C with increasing serum TT, which remained significant after adjusting for age, BMI, fasting blood glucose, systolic blood pressure, free triiodothyronine, free thyroxine, and TSH. Compared with the bottom quartile of TT, the adjusted OR (95% CI) for hypertriglyceridemia and low HDL-C was 0.082 (0.048- 0.138, P=0.000) and 0.669 (0.503-0.891, P=0.006) respectively in the top quartile of TT.;-;Conclusions: TT was correlated negatively and linearly with TC, TG, and LDL-C and positively and linearly with HDL-C. Low TT might have adverse effects on the lipid profile and thus represent a risk factor for hypercholesterolemia, hypertriglyceridemia, high LDL-C, and low HDL-C, suggesting the importance of maintaining an appropriate TT level in men.
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