Comparison of Clinical Efficacy and Safety of Metformin Sustained-Release Tablet (II) (Dulening) and Metformin Tablet (Glucophage) in Treatment of Type 2 Diabetes Mellitus.

Objectives: This study investigated the clinical efficacy and safety of metformin hydrochloride sustained-release (SR) tablet (II) produced by Dulening and the original metformin hydrochloride tablet produced by Glucophage in the treatment of type 2 diabetes mellitus (T2DM). Methods: This randomized, open and parallel controlled clinical trial consecutively recruited a total of 886 patients with T2DM in 40 clinical centers between May 2016 and December 2018. These patients were randomly assigned to the Dulening group (n=446), in which patients were treated with Dulening metformin SR tablets, and the Glucophage group (n=440), in which patients were treated with Glucophage metformin tablets, for 16 weeks. The changes in the levels of glycated hemoglobin (HbAc1) and fasting blood glucose (FBG) as well as weight loss were compared between these two groups. Also, the overall incidence of adverse drug reactions (ADRs) and the incidence of ADR of the gastrointestinal system observed in patients of these two groups were also compared. Results: There were no significant differences in demographic and basal clinical characteristics between these two groups. The Dulening and Glucophage groups showed comparable levels of decrease in HbA1c levels, FBG and weight loss after 12-week treatment (all p>0.05). The Dulening group had a significantly lower overall incidence of ADRs as well as gastrointestinal ADR than the Glucophage group. Conclusions: Metformin SR tablets (II) and the original metformin tablets exhibit similar therapeutic efficacy in the treatment of T2DM, but metformin SR tablets (II) has the significantly lower incidence of ADRs than the original metformin tablets.

HDAC5 Inhibits Hepatic Lipogenic Genes Expression by Attenuating the Transcriptional Activity of Liver X Receptor.

BACKGROUND/AIMS: Liver X receptor (LXR), a member of the nuclear receptor superfamily, is known to induce the expression of SREBP-1c and ChREBP, two master regulators of hepatic lipogenesis. Histone deacyetylases (HDACs) have been shown to play critical roles in glucose and lipids metabolism. However, the exact role of HDAC5 in lipogenesis remains elusive. METHODS: mRNA and protein levels of HDAC5 were analyzed by quantitative real-time PCR and Western blots in high-fat-diet-induced and leptin receptor deficiency-induced obese mice. HDAC5 was overexpressed or depleted in HepG2 cells, followed by analysis of cellular triglycerides contents. Quantitative real-time PCR was used to detect the expression levels of lipogenic genes. Luciferase reporter assay was used to determine the regulation of HDAC on the transcriptional activity of LXR. Co-immunoprecipitation experiment was used to determine the interaction between HDAC5 and LXR. RESULTS: We found that mRNA and protein expression levels of hepatic HDAC5 were reduced in high-fat-diet-induced and leptin receptor deficiency-induced obese mice. In vitro studies further demonstrated that knockdown of HDAC5 promoted cellular triglycerides accumulation, accompanied with up-regulation of lipogenic genes. At the molecular level, HDAC5 was shown to interact with LXR, thereby attenuating its transcriptional activity. CONCLUSION: Overall, our data suggest that hepatic HDAC5 is an important regulator of lipogenesis.

Activation of activator protein 2 alpha by aspirin alleviates atherosclerotic plaque growth and instability in vivo.

AIMS: Aspirin has been used for the secondary prevention and treatment of cardiovascular disease for several decades. We investigated the roles of transcriptional factor activator protein 2α (AP-2α) in the beneficial effects of aspirin in the growth and vulnerability of atherosclerotic plaque. METHODS AND RESULTS: In mice deficient of apolipoprotein E (Apoe-/-), aspirin (20, 50 mg/kg/day) suppressed the progression of atherosclerosis in aortic roots and increased the plaque stability in carotid atherosclerotic plaques induced by collar-placement. In vivo lentivirus-mediated RNA interference of AP-2α reversed the inhibitory effects of aspirin on atherosclerosis in Apoe-/- mice. Mechanically, aspirin increased AP-2α phosphorylation and its activity, upregulated IkBα mRNA and protein levels, and reduced oxidative stress in cultured vascular smooth muscle cells. Furthermore, deficiency of AP-2α completely abolished aspirin-induced upregulation of IkBα levels and inhibition of oxidative stress in Apoe-/- mice. Clinically, conventional doses of aspirin increased AP-2α phosphorylation and IkBα protein expression in humans subjects. CONCLUSION: Aspirin activates AP-2α to upregulate IkBα gene expression, resulting in attenuations of plaque development and instability in atherosclerosis.

Association of gene polymorphisms in ABO blood group chromosomal regions and menstrual disorders.

This study aimed to investigate whether single nucleotide polymorphisms (SNPs) located near the gene of the ABO blood group play an important role in the genetic aetiology of menstrual disorders (MDs). Polymerase chain reaction-ligase detection reaction technology was used to detect eight SNPs near the ABO gene location on the chromosomes in 250 cases of MD and 250 cases of normal menstruation. The differences in the distribution of each genotype, as well as the allele frequency in the normal and control groups, were analysed using Pearson's χ2 test to search for disease-associated loci. SHEsis software was used to analyse the linkage disequilibrium and haplotype frequencies and to inspect the correlation between haplotypes and the disease. Compared with the control group, the experimental group exhibited statistically significant differences in the genotype distribution frequencies of the rs657152 locus of the ABO blood group gene and the rs17250673 locus of the tumour necrosis factor cofactor 2 (TRAF2) gene, which is located downstream of the ABO gene. The allele distribution frequencies of rs657152 and rs495828 loci in the ABO blood group gene exhibited significant differences between the groups. Dominant and recessive genetic model analysis of each locus revealed that the experimental group exhibited statistically significant differences from the control group in the genotype distribution frequencies of rs657152 and rs495828 loci, respectively. These results indicate that the ABO blood group gene and TRAF2 gene may be a cause of MDs.

Randomized controlled clinical trial of a combination therapy of vildagliptin plus an α-glucosidase inhibitor for patients with type II diabetes mellitus.

The aim of this study was to assess the efficacy of a combination therapy of vildagliptin plus an α-glucosidase inhibitor for patients with type II diabetes mellitus. Type II diabetic patients exhibiting poor glycemic control following α-glucosidase inhibitor treatment for at least two months were selected and randomly distributed into vildagliptin and placebo groups. The body weight, fasting blood glucose (FBG), postprandial glucose (PPG), glycated hemoglobin (HBA1c) and blood lipid levels and hepatorenal functions of the patients were determined before and 12 weeks after the trial. Following the trial, the FBG, PPG, HbA1c, cholesterol (CHOL) and triglyceride (TG) levels in the vildagliptin group were significantly decreased compared with the pretreatment levels (P<0.05), whereas only the PPG level in the placebo group decreased (P<0.05). The FBG, PPG and HbA1c levels in the vildagliptin group were markedly lower than those in the placebo group 12 weeks after the trial. A comparison of the body weights and hepatorenal functions before and after the trial or between groups did not show statistically significant differences. The combination therapy of vildagliptin plus an α-glucosidase inhibitor effectively reduced the FBG, PPG and HbA1c levels in patients without inducing weight gain or hepatorenal dysfunction. However, the therapy may have caused a reduction in the blood lipid levels.

A randomized controlled clinical trial of vildagliptin plus metformin combination therapy in patients with type II diabetes mellitus.

The aim of the present study was to assess the efficacy and safety of vildagliptin plus metformin combination therapy in patients with type II diabetes mellitus. Type II diabetic patients with poor glycemic control following at least three months of metformin treatment were selected and randomized into two groups. Vildagliptin or placebo was administered with metformin. Body weight, fasting blood glucose (FBG), postprandial glucose (PPG), glycated hemoglobin (HbA1c), blood lipid and hepatorenal function levels were analyzed in the patients prior to and 24-weeks after the trial. FBG, PPG and HbA1c levels of the patients in the vildagliptin group significantly decreased following the trial, whereas no statistically significant differences were observed in the various indicators of the placebo group prior to and following the trial. The FBG, PPG and HbA1c levels in the vildagliptin group were significantly lower compared with the placebo group 24-weeks after the trial. Comparisons of body weight, blood lipid and hepatorenal function between the groups prior to and following the trial exhibited no statistically significant differences. Therefore, vildagliptin plus metformin combination therapy effectively reduced FBG, PPG and HbA1c levels in patients with no risk of weight gain or hepatorenal dysfunction.

[Anti-inflammation of simvastatin by polarization of murine macrophages from M1 phenotype to M2 phenotype].

OBJECTIVE: To explore the effects of statin on pro-inflammatory macrophage phenotype in a murine M1 macrophage model. METHODS: Macrophages isolated from murine bone barrow were stimulated with interferon-gamma (IFN-γ) and lipopolysaccharide (LPS) to establish a M1 macrophage model. And 1.0, 2.5, 5.0 µmol/L of simvastatin were added to M1 macrophages for a 9-hour culture. Cell surface markers CD16/23 and CD206 were detected by fluorescence activated cell sorter (FACS) and interleukin-10 (IL-10) and IL-12 by ELISA. RESULTS: The CD16/32 expression was 86.39% ± 2.24% and IL-12 secretion (1562 ± 217) pg/ml in IFN-γ and LPS-stimulated macrophages. After a 9-hour incubation with 1.0, 2.5, 5.0 µmol/L simvastatin, the CD206 expression levels were 68.10% ± 2.48%, 75.28% ± 1.66%, 86.32% ± 2.19% and the secretion of IL-10 (500 ± 5), (675 ± 28) and (916 ± 15) pg/ml respectively. By analysis of variance and q test of mean, the difference was statistically significant (all P < 0.01) between the groups of M1 model (9.67% ± 5.48%, (298 ± 11) pg/ml) . And the phenotypic features were similar to those of the groups of M2 model. CONCLUSION: Simvastatin may inhibit inflammation by enhancing the switching of M1 macrophage to M2 macrophage phenotype.

[Reduced circulating endothelial progenitor cells is a risk factor of coronary slow flow].

OBJECTIVE: To explore if reduced number of circulating endothelial progenitor cells (EPCs) is a risk factor for patients with coronary slow flow (CSF). METHODS: Thirty patients with CSF and 30 age and gender matched control subjects with normal coronary angiography were included in the study. Mononuclear cells were isolated from peripheral blood by Ficoll density gradient centrifugation and plated on fibronectin-coated culture dishes. EPCs were characterized as adherent cells double positive for DiI-AcLDL-uptake and lectin-binding by converted fluorescence microscope (×200). RESULTS: Smoking, diabetes mellitus, hypertension and the levels of plasma lipoprotein profile were similar between the two groups (all P > 0.05). The number of EPCs was significantly lower in patients with CSF compared with control subjects (35.7 ± 5.9 vs.53.2 ± 5.9, P < 0.01). TIMI frame counts was correlated with circulating EPCs number (OR = 0.424, 95%CI 0.358 - 0.621, P < 0.01) and not associated with gender, age, smoking, diabetes mellitus, hypertension and the levels of plasma lipoprotein profile. CONCLUSION: Decreased circulating EPCs is an independent risk factor for CSF.

Effect of fluvastatin and valsartan, alone and in combination, on postprandial vascular inflammation and fibrinolytic activity in patients with essential hypertension.

Postprandial hypertriglyceridemia is associated with a series of atherogenic abnormalities, including a prothrombotic state and inflammation. Hypertensive patients have exaggerated postprandial triglyceride response. The benefit of combined treatment of statin and angiotensin II type 1 receptor blocker (ARB) has been demonstrated in diabetic patients. The aim of this investigation was to explore the effect of a statin, fluvastatin, and the ARB valsartan, alone and in combination, on fibrinolytic activity and inflammation after a high-fat meal in patients with essential hypertension (EHP). A total of 53 EHP patients were studied. The concentrations of plasma lipid profiles, soluble P-selectin, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type I (PAI-1) antigens were measured in fasting state and at 4 hours after a single high-fat meal (800 calories; 50 g fat). Patients randomly accepted placebo, fluvastatin 40 mg/day, valsartan 80 mg/day, or both for 1 week. Then a high-fat meal and assay of plasma samples were repeated. The postprandial plasma triglyceride, soluble P-selectin, PAI-1, and t-PA antigen concentrations significantly increased after a high-fat meal. Postprandial plasma concentration of triglyceride was significantly correlated with that of soluble P-selectin and PAI-1 antigen, respectively (P<0.001). The postprandial increase in plasma P-selectin, PAI-1, and t-PA antigen levels was attenuated by 1-week fluvastatin-alone and valsartan-alone treatments; their combination is more effective on both fasting and postprandial P-selectin, plasma PAI-1, and t-PA antigen levels. The improvement of these plasma variables was not significantly related to the changes of plasma lipids and blood pressure. In conclusion, postprandial hypertriglyceridemia induces postprandial fibrinolytic dysfunction and vascular inflammation in patients with essential hypertension after a high-fat meal. Short-term combined treatment with fluvastatin and valsartan more effectively inhibits this postprandial atherogenic change in plasma than monotherapy.

Atorvastatin reduces tissue factor expression in adipose tissue of atherosclerotic rabbits.

BACKGROUND: We have recently demonstrated that tissue factor (TF) expression increases in adipose tissues/adipocytes of cholesterol-fed rabbit, which is associated with a hypercoagulable state that contributes to thrombosis. In this study, we evaluated the ability of atorvastatin to modulate TF expression in cholesterol-fed rabbit and the regulatory mechanism. METHODS: Male rabbits were randomly fed with normal diet and high-cholesterol diet for 8 weeks, following 4 weeks, those fed high-cholesterol diet were randomly assigned to atorvastatin or starch. At the end of 12 weeks, subcutaneous adipose was collected, and culture adipocyte. TF mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). TF concentrations were determined with ELISA. The in vitro effect of atorvastatin and mevalonate (MVA) on TF production in adipocytes was observed. RESULTS: Atorvastatin reduced serum TC and LDL-C levels (P<0.05), and decreased plasma TF concentration and expression in adipose tissues/adipocytes from cholesterol-fed rabbits. In vitro, atorvastatin dose-dependently suppressed TF expression and protein secretion in adipocytes. MVA reversed the inhibitory effect of atorvastatin on TF expression in concentration-dependent manner. CONCLUSIONS: Results provide further support for the antithrombotic effect of atorvastatin. It also indicated that mevalonate pathway may play an important role in TF expression in adipocyte.

Atorvastatin reduces plasminogen activator inhibitor-1 expression in adipose tissue of atherosclerotic rabbits.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) expression are increased in adipose tissues/adipocytes of obese mice, which is associated with a hypofibrinolytic state that contributes to thrombosis. We recently demonstrated that PAI-1 expression increases in adipose tissues/adipocytes of cholesterol-fed rabbits. In this study, we evaluated the ability of atorvastatin to modulate PAI-1 expression in cholesterol-fed rabbits and the regulatory mechanism. METHODS: Male rabbits were randomly fed with normal diet and high-cholesterol diet for 8 weeks, following 4 weeks, those fed high-cholesterol diet were randomly assigned to 2.5 mg/kg/day atorvastatin or starch. At the end of 12 weeks, subcutaneous adipose was collected, and culture adipocyte. PAI-1 mRNA was detected by RT-PCR. PAI-1 concentrations were determined with ELISA. The effect of atorvastatin and mevalonate (MVA) on PAI-1 production in adipocytes in vitro was observed. RESULTS: Atorvastatin significantly reduced serum TC and LDL-C concentrations (p<0.05), and decreased plasma PAI-1 concentration and PAI-1 expression in adipose tissues/adipocytes from cholesterol-fed rabbits. In vitro, atorvastatin dose-dependently suppressed PAI-1 expression and protein secretion in adipocytes. MVA reversed the inhibitory effect of atorvastatin on PAI-1 expression in concentration-dependent manner. CONCLUSIONS: Atorvastatin reduces plasma PAI-1 concentration and PAI-1 expression in adipose tissue and adipocyte of atherosclerotic rabbit, and inhibits PAI-1 expression and protein secretion in adipocytes in vitro, suggesting that it may have an antithrombtic effect. We also suggest that the mevalonate pathway may play an important role in PAI-1 expression in adipocyte.

Valsartan reduces interleukin-1beta secretion by peripheral blood mononuclear cells in patients with essential hypertension.

BACKGROUND: Chronic low-grade inflammation response may contribute to the pathology of essential hypertension. Angiotensin II (Ang II) may be partly responsible for this process. Our early studies showed that individuals with essential hypertension had increased interleukin-1beta (IL-1beta) secretion by peripheral blood mononuclear cells (PBMCs). In this study, we investigated whether treatment with valsartan, an angiotensin receptor blocker, lowered IL-1beta secretion by PBMCs in patients with essential hypertension. METHODS: Twenty-four patients with essential hypertension were randomized to treatment with valsartan (80 mg/day, group B) or matching routine therapy group (group A) for 2 weeks. PBMCs were isolated by gradient centrifugation. IL-1beta concentrations in supernatant from PBMCs were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with routine therapy group, patients treated with valsartan had decreased secretion of IL-1beta in PBMCs after stimulated by lipopolysaccharide (2857+/-643 vs. 2146+/-508 pg/ml, P<0.05). CONCLUSIONS: We suggest a direct anti-inflammatory effect of valsartan and a pro-inflammatory effect of Ang II in patients with essential hypertension.

[Relationship between ATP-binding cassette transporter 1 R219K genetic variation and blood lipids].

OBJECTIVE: To investigate whether ATP-binding cassette transporter 1 (ABCA1) R219K genetic variation is correlated with blood lipids. METHOD: Specimens of peripheral blood were collected from 692 patients with cerebral apoplexy, aged 62 +/- aged 12, and 352 sex- and age-matched persons without cardio-cerebro-vascular disease. Polymerase chain reaction-restricted fragments length polymorphism (PCR-RFLP) was used to determine the ABCA1 genotype: RR type (177 bp), RK type (177 bp, 107 bp, and 70 bp); and KK type (107 bp and 70 bp). The RR and KK type products were sequenced. RESULTS: The level of HDL-C showed an upward trend in the sequence of RR, RK, and KK genotypes with a significant difference between RR genotype (1.3 mmol/L +/- 0.4 mmol/L) and KK genotype (1.4 mmol/L +/- 0.4 mmol/L), especially in the males. The levels of TG tended downward in the sequence of RR, RK, and KK genotypes, however, without a significant difference between any 2 genotypes. Linear regression analysis showed that the HDL-C level was positively correlated with age in the noncarriers of ABCA1R219K genetic variation (RR genotype), and the TC level was negatively correlated with age in the carriers (RK + KK genotype). In the cohort aged

Atorvastatin reduces plasma MCP-1 in patients with acute coronary syndrome.

BACKGROUND: The monocyte chemoattractant protein-1 (MCP-1) is a chemokine responsible for the recruitment of monocytes to sites of inflammation. MCP-1 may play critical roles in plaque instability. Anti-inflammation may be one benefit of statin drugs in acute coronary syndrome (ACS). We investigated the effects of atorvastatin therapy on plasma MCP-1 concentrations and production of MCP-1 released by peripheral blood monocytes from ACS patients. METHODS: Forty patients with ACS were randomly separated into two groups, those receiving conventional therapy (Group A, n=20), and conventional therapy+atorvastatin (10 mg/day, Group B, n=20). The study the effects of atorvastatin on secretion and expression of MCP-1, human peripheral blood monocytes from healthy donors were incubated with atorvastatin (0.1-10 micromol/l) for up to 24 h in vitro. MCP-1 concentrations in plasma and monocytes culture supernatants were measured by enzyme-linked immunosorbent assays (ELISA). MCP-1 expression was measured by RT-PCR. RESULTS: Plasma concentrations of MCP-1 were significantly lower after 4 weeks therapy in both groups of patients [Group A from 97.4 (50.1-164) to 72.6 (36.3-156) pg/ml, Group B from 101 (60-178) to 45 (29-91) pg/ml, (P<0.05, respectively)]. Compared with conventional therapy alone, atorvastatin significantly further reduced plasma MCP-1 concentrations. There was no significant correlation between the degree of changes in plasma MCP-1 and LDL-C. In vitro, atorvastatin inhibits production of MCP-1 up to 73%, in a concentration-dependent manner, and suppressed MCP-1 expression in peripheral blood monocytes. CONCLUSIONS: Atorvastatin reduced plasma MCP-1 concentrations in patients with ACS. These effects may explain some clinical benefits of statins in the treatment of these patients.

Gemfibrozil reduces release of tumor necrosis factor-alpha in peripheral blood mononuclear cells from healthy subjects and patients with coronary heart disease.

BACKGROUND: Inflammatory process plays an important role in the pathogenesis of coronary heart disease (CHD). With the growing use of gemfibrozil and other fibrates, their anti-inflammatory effects have been noted. But little is known about the effect of gemfibrozil on tumor necrosis factor (TNF)-alpha secretion in peripheral blood mononuclear cells (PBMC) from patients with coronary heart disease. METHODS: PBMC were obtained from CHD patients (n=16) and healthy controls (n=13). PBMC (2x10(6) cells/ml) were cultured in 24-well plates with or without Ang II (10(-8), 10(-7), 10(-6) mol/l), or Ang II (10(-6) mol/l) plus gemfibrozil (10(-6), 10(-5), 10(-4) mol/l). After 24-h incubation, the supernatants were separated, and TNF-alpha was measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: Spontaneous release of TNF-alpha was 299.2+/-110.7 pg/ml in PBMC from CHD patients and 179.3+/-78.2 pg/ml in PBMC from control subjects (P<0.05). Incubated with Ang II (10(-8), 10(-7), 10(-6) mol/l), TNF-alpha secretion was 307.7+/-141.8, 318.9+/-135.6, 328.6+/-123.9 pg/ml in PBMC from CHD patients, and 225.3+/-135.4, 224.1+/-141.0,218.7+/-134.8 pg/ml in PBMC from control subjects, respectively. Ang II did not significantly trigger TNF-alpha secretion in both groups. Compared with that incubated with Ang II (10(-6) mol/l) alone, release of TNF-alpha intervened by gemfibrozil (10(-6),10(-5),10(-4) mol/l) decreased to 279.4+/-132.2, 268.0+/-132.7, 226.6+/-102.7 pg/ml in PBMC from CHD patients, and 177.6+/-94.4, 156.1+/-69.4, 105.3+/-52.7 pg/ml in the control group, respectively. Gemfibrozil (10(-5),10(-4) mol/l) significantly inhibited TNF-alpha secretion in both groups (P<0.05). CONCLUSIONS: Our data demonstrated that gemfibrozil reduced release of TNF-alpha in PBMC both from CHD patients and controls. This effect may partially be relevant to the clinical benefits of gemfibrozil in the treatment of dyslipidemia and atherosclerosis.