[Show abstract][Hide abstract] ABSTRACT: Transplantation of bone marrow mesenchymal stem cells (BMSCs) has been developed as a new method of treating diseases of the peripheral nervous system. While netrin-1 is a critical molecule for axonal path finding and nerve growth, it may also affect vascular network formation. Here, we investigated the effect of transplanting BMSCs that produce netrin-1 in a rat model of sciatic nerve crush injury. We introduced a sciatic nerve crush injury, and then injected 1×10(6) BMSCs infected by a recombinant adenovirus expressing netrin-1 Ad5-Netrin-1-EGFP or culture medium into the injured part in the next day. At day 7, 14 and 28 after injection, we measured motor nerve conduction and detected mRNA expressions of netrin-1 receptors UNC5B and Deleted in Colorectal Cancer (DCC), and neurotrophic factors brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) by real-time PCR. We also detected protein expressions of BDNF and NGF by Western blotting assays and examined BMSCs that incorporated into myelin and vascellum. The results showed that BMSCs infected by Ad5-Netrin-1-EGFP significantly improved the function of the sciatic nerve, and led to increased expression of BDNF and NGF (P<0.05). Moreover, 28 days after injury, more Schwann cells were found in BMSCs infected by Ad5-Netrin-1-EGFP compared to control BMSCs. In conclusion, transplantation of BMSCs that produce netrin-1 improved the function of the sciatic nerve after injury. This method may be a new treatment of nerve injury.
[Show abstract][Hide abstract] ABSTRACT: This study was aimed to explore the associations between the combined effects of several polymorphisms in the PPAR-γ and RXR-α gene and environmental factors with the risk of metabolic syndrome by back-error propagation artificial neural network (BPANN). We established the model based on data gathered from metabolic syndrome patients (n = 1012) and normal controls (n = 1069) by BPANN. Mean impact value (MIV) for each input variable was calculated and the sequence of factors was sorted according to their absolute MIVs. Generalized multifactor dimensionality reduction (GMDR) confirmed a joint effect of PPAR-γ and RXR-α based on the results from BPANN. By BPANN analysis, the sequences according to the importance of metabolic syndrome risk factors were in the order of body mass index (BMI), serum adiponectin, rs4240711, gender, rs4842194, family history of type 2 diabetes, rs2920502, physical activity, alcohol drinking, rs3856806, family history of hypertension, rs1045570, rs6537944, age, rs17817276, family history of hyperlipidemia, smoking, rs1801282 and rs3132291. However, no polymorphism was statistically significant in multiple logistic regression analysis. After controlling for environmental factors, A1, A2, B1 and B2 (rs4240711, rs4842194, rs2920502 and rs3856806) models were the best models (cross-validation consistency 10/10, P = 0.0107) with the GMDR method. In conclusion, the interaction of the PPAR-γ and RXR-α gene could play a role in susceptibility to metabolic syndrome. A more realistic model is obtained by using BPANN to screen out determinants of diseases of multiple etiologies like metabolic syndrome.
[Show abstract][Hide abstract] ABSTRACT: Nateglinide, N-(trans-4-isopropylcyclohexyl-carbonyl)-d-phenylalanine, is a potent insulin secretagogue designed to restore early-phase insulin secretion. It increases pancreatic insulin secretion by competitively binding to sulfonylurea receptors inhibiting adenosine triphosphate-sensitive potassium channels and thus reducing blood glucose levels. The drug has a rapid onset (causing immediate insulin release) and a short duration (allowing insulin to return to baseline levels between meals) of insulinotropic action.
To meet the requirements for marketing a new generic product, this study was designed to compare the pharmacokinetic parameters and relative fasting bioavailability of new generic (test) formulation of nateglinide with the reference formulation of nateglinide in healthy Chinese male volunteers.
This open-label, single-dose, randomized-sequence, 2-way crossover study was performed at Nanjing First Hospital of Nanjing Medical University. Eligible subjects were healthy male volunteers who were randomly assigned in a 1:1 ratio to receive a single 60-mg (0.88 mg/kg) dose of the 2 formulations, followed by a 1-week washout period and then administration of the alternate formulation. Study drugs were administered after a 10-hour overnight fast. Concentrations of nateglinide were determined by using a validated LC-MS method. For analysis of pharmacokinetic properties, including C(max), AUC(0-10), and AUC(0-∞), blood samples were obtained at intervals over the 10-hour period after study drug administration. As established by the State Food and Drug Administration, the formulations were assumed bioequivalent if 90% CIs for the test/reference ratios of ln-transformed values of C(max) and AUC (obtained by using ANOVA) were within the predetermined equivalence range (80%-125%). Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) and by questioning subjects about adverse events.
The 90% CIs for nateglinide were as follows: C(max), 98.4% to 118.6%; AUC(0-10), 99.5% to 110.3%. Both C(max) and AUC(0-10) met the predetermined criteria for assuming bioequivalence. The relative bioavailability of the test formulation was estimated to be 102.1% (13.5%). One volunteer (5%) experienced a headache after administration of the test formulation. This resolved spontaneously within 1 hour and was considered by the investigators to be mild. No serious adverse events were reported. No period or sequence effects were observed.
In this study of healthy Chinese male volunteers, a single 60-mg dose of nateglinide (test formulation) met the regulatory criteria for assuming bioequivalence to the established reference formulation. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TRC-11001754.
[Show abstract][Hide abstract] ABSTRACT: Polymorphisms in peroxisome proliferator activated receptor-γ (PPAR-γ) and retinoid X receptor-α (RXR-α) gene may alter metabolic syndrome (MetS) risks by increasing or decreasing the human adiponectin promoter activity in cells. To test this statement, three potentially functional SNPs of PPAR-γ and four SNPs of RXR-α with minor allele frequency (MAF) ≥0.05 in the Chinese Han population were identified from NCBI dbSNPs database to evaluate their associations with MetS.
TaqMan assay was performed to test the genotypes in MetS patients (n = 901) and normal controls (n = 1009). Serum adiponectin concentration was measured by ELISA kit.
The variant genotypes rs2920502CG and CG/CC, rs4240711GG and AG/GG, rs4842194CC and CT/CC, rs3132291CT, CC and CT/CC were associated with MetS. Furthermore, in the haplotype of PPAR-γ gene, compared with the most common haplotype GC, haplotype CC was associated with an increased risk of MetS (crude p = 0.017). In the haplotype of RXR-α gene, haplotype GCGC was associated with a significant protective effect for MetS [adjusted p = 0.002, OR (95% CI) = 0.718 (0.585-0.882)] compared with the most common haplotype GTAT. After taking smoking, alcohol consumption and physical activity as environmental adjustment factors into the analysis, the result showed A1 A2 A4 A5 A6 A7 B1 (rs3856806, rs2920502, rs180128, rs1045570, rs3132291, rs4240711, rs4842194) was the best model (cross-validation consistency 10/10, p = 0.0107).
The present study suggested that the variant genotypes in PPAR-γ gene could increase the risk of MetS; however, genotypes in RXR-α gene could decrease the risk of MetS in a Chinese Han population.
Archives of medical research 04/2012; 43(3):233-42. DOI:10.1016/j.arcmed.2012.03.006 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our aim was to investigate whether the ADIPOQ gene polymorphisms are associated with the metabolic syndrome (MetS). Genotypes of MetS patients (n=1049) and normal controls (n= 1092) were analysed by TaqMan® assay, and serum adiponectin concentration was measured by ELISA. The variant genotypes rs266729CG; rs1063539GC, GC/CC; rs16861205AA and rs7649121AT, AT/TT (Adjusted P=0.037, 0.044, 0.025, 0.011, 0.019, 0.020, respectively) of the ADIPOQ gene were associated with MetS. Patients with rs266729CG, CG/GG genotypes (P=0.034, 0.035) and rs7649121AT, AT/TT genotypes (P=0.013, 0.022) had higher levels of serum adiponectin than those with the CC and AA genotypes respectively. Furthermore, the prevalence of haplotypes GGAAAATC and GGGTAACC was lower in cases (10.7% and 4.5%) than in controls (12.1% and 5.9%) [Adjusted ORs (95% CIs)=0.70 (0.54–0.91), 0.65 (0.46–0.92)]. The ADIPOQ gene variants associated with the risk of MetS in this study must be validated by further functional studies to reveal any potential effects on metabolism.
Annals of Human Genetics 03/2012; 76(2):101-9. DOI:10.1111/j.1469-1809.2012.00699.x · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our study was designed to explore the applied characteristics of the back propagation artificial neural network (BPANN) on studying the genetic variants in adipnectin ADIPOQ, peroxisome proliferator-activated receptor (PPAR)-γ, and retinoid X receptor-α (RXR-α) genes and type 2 diabetes mellitus (T2DM) risks in a Chinese Han population.
We used BPANN as the fitting model based on data gathered from T2DM patients (n=913) and normal controls (n=1,001). The mean impact value (MIV) for each input variables were calculated, and the sequence of the factors according to their absolute MIVs was sorted.
The results from BPANN were compared with multiple logistic regression analysis, and the generalized multifactor dimensionality reduction (GMDR) method was used to calculate the joint effects of ADIPOQ, PPAR-γ, and RXR-α genes. By BPANN analysis, the sequence according to the importance of the T2DM risk factors was in the order of serum adiponectin level, rs3856806, rs7649121, hypertension, rs3821799, rs17827276, rs12495941, rs4240711, age, rs16861194, waist circumference, rs2241767, rs2920502, rs1063539, alcohol drinking, smoking, hyperlipoproteinemia, gender, rs3132291, T2DM family history, rs4842194, rs822394, rs1801282, rs1045570, rs16861205, rs6537944, body mass index, rs266729, and rs1801282. However, compared with multiple logistic regression analysis, only 11 factors were statistically significant. After overweight and obesity were taken as environment adjustment factors into the analysis, model A2 B4 C5 C6 C8 (rs3856806, rs4240711, rs7649121, rs3821799, rs12495941) was the best model (coefficient of variation consistency=10/10, P=0.0107) in the GMDR method.
These results suggested the interactions of ADIPOQ, PPAR-γ, and RXR-α genes might play a role in susceptibility to T2DM. BPANN could be used to analyze the risk factors of diseases and provide more complicated relationships between inputs and outputs.
[Show abstract][Hide abstract] ABSTRACT: This study was to evaluate the association between ADIPOQ gene variants and type 2 diabetes mellitus (T2DM). TaqMan(®) assay was performed to test the genotypes in T2DM patients (n = 1,105) and normal control subjects (n = 1,107). Serum adiponectin concentration was measured by ELISA kit. The variant genotypes rs7649121AT and rs7649121AT/TT, compared with the AA genotype, were associated with a significantly decreased risk of T2DM [Adjusted OR (95% CI) = 0.79(0.66-0.95), 0.80(0.67-0.96), respectively]. In stratified analysis, rs2241767AG genotype increased the risk of T2DM in obesity group [Adjusted OR (95% CI) = 1.32(1.03-1.69)]. Patients with genotype AG/GG of rs2241767 had lower levels of serum adiponectin than those with the genotype AA (P = 0.044). Haplotype analyses were not significant. Crossover analysis of rs7649121 and environmental risk factor (obesity) indicated that the protect effect of rs7649121AT/TT maybe offset by the environmental risk. Those who exposed to environmental risk factor (obesity) had a chance to attack T2DM compared with those who did not expose to the two factors [Adjusted OR (95% CI) = 1.64(1.30-2.06)]. This study suggested that the ADIPOQ gene polymorphisms were associated with the risk of T2DM in a Chinese Han population.
[Show abstract][Hide abstract] ABSTRACT: The serum levels of adiponectin are paradoxically decreased in obesity and may play important roles in the development of type 2 diabetes mellitus (T2DM). Potentially functional polymorphisms in the peroxisome proliferator-activated receptor-γ (PPAR-γ) and retinoid X receptor-α (RXR-α) genes may alter T2DM risks by increasing the human adiponectin promoter activity in cells. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in PPAR-γ and RXR-α were associated with risk of T2DM. To test this hypothesis, three potentially functional SNPs of PPAR-γ and four of RXR-α with a minor allele frequency of ≥ 0.05 in the Chinese Han population were identified from the National Center for Biotechnology Information dbSNPs database to evaluate their association with T2DM.
Polymerase chain reaction-restriction fragment length polymorphism was performed to test the genotypes in T2DM patients (n = 540) and normal controls (n = 604).
The variant genotypes rs2920502CC, rs3856806CT, rs3856806CT/TT, and rs4240711AG/GG were associated with T2DM. Furthermore, the prevalences of haplotype GTC and CTG in PPAR-γ and GTAC in RXR-α were less frequent in cases (17.1%, 2.6%, and 2.4%, respectively) than in controls (22.3%, 3.8%, and 6.6%, respectively), whereas GTGT in RXR-α was more frequent in cases (6.9%) than in controls (4.4%) (P < 0.05 for both two-sided χ(2) test and thousand times permutation tests). Patients with genotype CT/TT of rs3856806 and genotype AG/GG of rs4240711 had higher levels of serum adiponectin than those with the genotype CC and genotype AA (P = 0.026 and 0.021, respectively). Model X2 X5 X6 X7 (rs3856806, rs3132291, rs4240711, and rs4842194) was the best model with the highest test balanced accuracy (0.5764) (cross-validation consistency = 10/10) in the multifactor dimensionality reduction method.
The PPAR-γ and RXR-α gene variants associated with the development of T2DM in this study must be investigated in a larger population to reveal any potential effects on metabolism.
[Show abstract][Hide abstract] ABSTRACT: Peroxisome proliferator-activated receptor (PPAR-γ),which is mainly involved in adipocyte differentiation, has been suggested to play an important role in the pathogenesis of insulin resistance and atherosclerosis. We investigated the frequencies of two common tagging polymorphisms of the PPAR-γ gene and two of PPAR-α with minor allele frequency (MAF) ≥0.05 in the Chinese Han population and analyzed the correlation between the different genotypes and the risk of type 2 diabetes mellitus (T2DM). TaqMan® assay was performed to test the genotypes in T2DM patients (n = 1,105) and normal controls (n = 1,107). Serum adiponectin concentration was measured by ELISA kit. The variant genotypes rs17817276GG, rs3856806CT and rs3856806CT/TT of PPAR-γ were associated with T2DM, P = 0.023,0.037 and 0.018, respectively. Furthermore, the prevalence of haplotype GT in PPAR-γ was less frequent in the case subjects (0.3%) than in the controls (1.9%) [P < 0.001,OR(95%CI)=0.13 (0.06-0.31)]. Patients with genotype TT of rs3856806 had a higher serum level of adiponectin than those with the genotype CC and CT (P = 0.031 and 0.038, respectively). There was no statistically significant difference between patients and controls in genotype distribution of rs6537944 and rs1045570 of the RXR-α gene. The present study suggests that the variant genotypes in the PPAR-γ gene could decrease the risk for the development of T2DM in the Chinese Han population.