Beijing Hospital and Beijing Institute of Geriatrics

Beijing, China

Beijing Hospital and Beijing Institute of Geriatrics

Beijing, China
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Dai D.-P.,Beijing Hospital and Beijing Institute of Geriatrics | Wang S.-H.,Wenzhou University | Wang S.-H.,Peoples Hospital of Lishui | Geng P.-W.,Wenzhou University | And 2 more authors.
Basic and Clinical Pharmacology and Toxicology | Year: 2014

Of the 57 reported CYP2C9 alleles, to date, 36 of them have been identified in the Chinese population. The aim of this study was to assess the catalytic characteristics of these allelic isoforms and their effects on the metabolism of glimepiride in vitro. Baculovirus-mediated expressing system was used to highly express wild-type and the 35 CYP2C9 allelic variants in insect cell microsomes. Then, the enzymatic characteristics of each variant were evaluated using glimepiride as the substrate. Reactions were performed at 37°C with the insect microsomes and 0.125-10 μM glimepiride for 40 min. After termination, the products were extracted and used for signal collection by LC-MS/MS. Of the 36 tested CYP2C9 allelic isoforms, only four variants (CYP2C9.40, CYP2C9.47, CYP2C9.51 and CYP2C9.54) exhibited similar relative clearance values to that of wild-type CYP2C9.1. In addition, one variant (CYP2C9.36) showed a higher intrinsic clearance value than the wild-type protein, while the remaining 30 CYP2C9 allelic isoforms exhibited significantly decreased clearance values (from 0.1% to 87.2%) compared to CYP2C9.1. This study provided the most comprehensive data on the enzymatic activities of all reported CYP2C9 variants in the Chinese population with regard to the commonly used antidiabetic drug, glimepiride. Our results indicate that most of the tested rare alleles significantly decrease the catalytic activity of CYP2C9 variants towards glimepiride hydroxylation in vitro. © 2013 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Xu R.-A.,Wenzhou University | Gu E.-M.,Wenzhou University | Zhou Q.,Wenzhou University | Yuan L.,Wenzhou University | And 3 more authors.
Drug Design, Development and Therapy | Year: 2016

Background: CYP2D6 is one of the most important members of the cytochrome P450 superfamily. Its genetic polymorphism significantly influences the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. Methods and results: The aim of this research was mainly to explore the catalytic activities of 22 newly reported CYP2D6 isoforms (2D6*87, *88, *89, *90, *91, *92, *93, *94, *95, *96,*97, *98, *R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C, R497C) on dapoxetine in vitro. The research was designed with an appropriate incubation system in test tubes and carried out in the constant temperature water. Through detecting its two metabolites desmethyldapoxetine and dapoxetine-N-oxide, the available data were obtained to explain the influence of CYP2D6 polymorphism on the substrate drug dapoxetine. As a result, the intrinsic clearance (Vmax/Km) values of most variants were significantly altered when compared with the counterpart of CYP2D6*1, with most of these variants exhibiting either reduced Vmaxand/or increased Kmvalues. For dapoxetine demethylation pathway (which produces desmethyldapoxetine), 2D6*89 and E215K exhibited no markedly decreased relative clearance of 92.81% and 97.70%, respectively. The relative clearance of rest 20 variants exhibited decrease in different levels, ranging from 20.44% to 90.90%. For the dapoxetine oxidation pathway (which produces dapoxetine-N-oxide), the relative clearance values of three variants, 2D6*90, *94, and V342M, exhibited no markedly increased relative clearance of 106.17%, 107.78%, and 109.98%, respectively; the rest 19 variants exhibited significantly decreased levels ranging from 27.56% to 84.64%. In addition, the kinetic parameters of two CYP2D6 variants (2D6*92 and 2D6*96) could not be detected, due to the defect of the CYP2D6 gene. Conclusion: As the first report of all aforementioned alleles for dapoxetine metabolism, these data may help in the clinical assessment of the metabolic elimination of dapoxetine and may provide fundamental information for further clinical studies. © 2016 Xu et al.

Xu M.,Peking University | Zhao M.,Peking University | Yang R.,Peking University | Yang R.,Beijing Hospital and Beijing Institute of Geriatrics | And 3 more authors.
International Immunopharmacology | Year: 2013

This study investigated the effect of dietary nucleotides (NTs) on immune function in female Balb/C mice, which randomly distributed into six groups: one control group, one NF-free (NF) control group and four NT groups. NTs ranged from 0.0025% to 0.64%. Compared with the control group, the NF could significantly weaken the activity of T lymphocytes and macrophages, as well as decreased the activity of B lymphocytes and NK cell. NF significantly decreased the ratio of CD4+/CD8+, whereas, it increased Tr percentage. In comparison with the NF group, the concentration of serum IL-2 and IL-4 showed an increase trend. Meanwhile, the granular cell macrophages colony stimulating factor (GM-CSF) increased significantly in the 0.04% NT group. The ratio of Th1/Th2 also showed an increasing trend after the supplements of NTs. There were no significant differences between the control and 0.04% NT group. Nevertheless, no significant differences in weight gain and lymphoid organ indices were observed in our study. These results indicate that NT supplements can prevent hypoimmunity which result from NF diet. 0.04% NTs is the healthy optimal supply proportion in mice diet. © 2013 Elsevier B.V. All rights reserved.

Pang J.,Beijing Hospital and Beijing Institute of Geriatrics | Cui J.,Beijing Hospital and Beijing Institute of Geriatrics | Gong H.,Beijing Hospital and Beijing Institute of Geriatrics | Xi C.,Beijing Normal University | Zhang T.-M.,Beijing Hospital and Beijing Institute of Geriatrics
Journal of Cellular Physiology | Year: 2015

High serum free fatty acids levels are associated with the development of insulin resistance in type 2 diabetes; however, the precise mechanisms underlying this lipid toxicity are unclear. To investigate whether PARP1 activation and NAD depletion are involved in the impairment of insulin sensitivity associated with lipotoxicity, HepG2 cells were cultured with 500μM oleic acid for 48h. Oleic acid-treated cells exhibited increased ROS generation, lipid accumulation and PARP1 activation. Treatment with the PARP1 inhibitor PJ34 and transfection with PARP1 small interfering RNA both prevented the oleic acid-induced impairment of the insulin signaling pathway. Furthermore, treatment with PJ34 reversed the oleic acid-induced decrease in intracellular NAD concentration, while exogenous NAD protected cells against oleic acid-induced insulin insensitivity. Combined NAD and PJ34 administration did not enhance the effects obtained by treatment with either NAD or PJ34 alone. Interestingly, when cells were treated with the SIRT1 inhibitor EX527, the protective effects of PJ34 and NAD treatment were diminished. Taken together, these data suggest that NAD depletion by PARP1 activation is essential for the modulation of insulin sensitivity in oleic acid-induced lipotoxicity. © 2014 Wiley Periodicals, Inc.

Pang J.,Beijing Hospital and Beijing Institute of Geriatrics | Xi C.,Beijing Normal University | Dai Y.,Peking Union Medical College | Gong H.,Beijing Hospital and Beijing Institute of Geriatrics | Zhang T.,Beijing Hospital and Beijing Institute of Geriatrics
Medical Science Monitor | Year: 2012

It is widely accepted that chronic hyperglycemia induces DNA oxidative damage in type 2 diabetes, but little is known about the effect of hyperglycemia on the DNA repair system which plays a critical role in the maintenance of genomic DNA stability in diabetes. To investigate the alteration of base excision repair (BER) genes under hyperglycemia, the relative expression of the mRNAs of the BER genes ogg1, polb, lig3, xrcc1, and parp1 - were quantified using real-time PCR in HepG2 hepatocytes incubated with 5.5 mM or 30 mM glucose. High levels of glucose induced ROS accumulation and DNA damage, paralleling the dynamic alterations of BER mRNA expression. Compared to 5.5 mM glucose-treated cells, ogg1 and pol b mRNA expression transiently increased at day 1 and decreased after day 4 in cells exposed to 30 mM glucose. Exposure to 30 mM glucose increased the activity of PARP1, which led to reduced cellular NAD content and insulin receptor phosphorylation. Exposure to high concentrations of glucose initially led to the increased expression of BER mRNAs to counteract hyperglycemia-induced DNA damage; however, long-term exposure to high glucose concentrations reduced the expression of mRNA from BER genes, leading to accumulated DNA damage. © Med Sci Monit.

Dai D.-P.,Beijing Hospital and Beijing Institute of Geriatrics | Wang Y.-H.,Shandong University | Wang S.-H.,Wenzhou University | Geng P.-W.,Wenzhou University | And 3 more authors.
Acta Pharmacologica Sinica | Year: 2013

Aim: Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme that is responsible for the metabolism of approximately 15% of clinically important drugs. The aim of this study was to assess the catalytic characteristics of 37 CYP2C9 allelic isoforms found in Chinese Han population on the metabolism of tolbutamide in vitro. Methods: The wild-type and 36 CYP2C9 variants were expressed in sf21 insect cells using a baculovirus-mediated expression system. Then the insect microsomes were prepared for assessing the metabolic characteristics of each variant toward the CYP2C9-specific drug substrate tolbutamide. Results: Of 36 allelic variants tested, the intrinsic clearance values of 2 allelic isoforms (CYP2C9.36 and CYP2C9.51) were much higher than the wild-type CYP2C9.1 protein, 3 allelic isoforms (CYP2C9.11, CYP2C9.56 and N418T) exhibited similar intrinsic clearance values as the wild-type enzyme, whereas the other 31 variants showed significantly reduced intrinsic clearance values, ranging from 0.08% to 66.88%, for tolbutamide. Conclusion: Our study provides the most comprehensive data concerning the enzymatic activity of the CYP2C9 variants that are present in the Chinese Han population, and our data suggest that most of the carriers of these alleles might be paid more attention when using CYP2C9 mediated drugs clinically. © 2013 CPS and SIMM.

Wang Y.-H.,Wenzhou Medical College | Pan P.-P.,Beijing Institute of Geriatrics | Dai D.-P.,Beijing Hospital and Beijing Institute of Geriatrics | Wang S.-H.,Beijing Institute of Geriatrics | And 3 more authors.
Xenobiotica | Year: 2014

1. CYP2C9 is an important member of the cytochrome P450 enzyme superfamily, with 57 CYP2C9 allelic variants being previously reported. Among these variants, we recently identified 21 novel alleles in the Han Chinese population. The aim of this study was to assess the catalytic activities of 36 CYP2C9 variants found in the Chinese population toward losartan in vitro. 2. Insect microsomes expressing the 36 CYP2C9 variants were incubated with 0.5-25μM losartan for 30min at 37°C. Next, the products were extracted, and signal detection was performed using high-performance liquid chromatography. 3. Compared with wild-type CYP2C9.1, the intrinsic clearance (Vmax/Km) values of all variants except for CYP2C9.56 were significantly altered. One variant exhibited markedly increased values (>250%), whereas 33 variants exhibited significantly decreased values (from 20 to 96%) due to increased Km and/or decreased Vmax values. 4. These findings suggest that more attention should be paid to subjects carrying these infrequent CYP2C9 alleles when administering losartan in the clinic. © 2014 Informa UK Ltd.

Ma L.,Beijing Hospital and Beijing Institute of Geriatrics | Ma L.,Beijing University of Chinese Medicine | Liu X.,Beijing Hospital and Beijing Institute of Geriatrics | Zhao Y.,Beijing Hospital and Beijing Institute of Geriatrics | And 3 more authors.
PLoS ONE | Year: 2013

Oxidized low-density lipoprotein (ox-LDL) is an important risk factor in the development of atherosclerosis. LOX-1, a lectin-like receptor for ox-LDL, is present primarily on endothelial cells and upregulated by ox-LDL, tumor necrosis factor a, shear stress, and cytokines in atherosclerosis. Recent studies demonstrated that ginkgolide B, a platelet-activating factor receptor antagonist, has antiinflammatory and antioxidant effects on endothelial and nerve cells. The present study investigated the effects of ginkgolide B on LOX-1 expression and the possible mechanism of action. Our results showed that ginkgolide B inhibited LOX-1 and intercellular cell adhesion molecule-1 (ICAM-1) expression in ox-LDL-stimulated endothelial cells through a mechanism associated with the attenuation of Akt activation. Similar data were obtained by silencing Akt and LY294002. We also evaluated Sirt1 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. These molecules play a protective role in endothelial cell injury. The results showed that ginkgolide B increased Sirt1 expression in ox-LDL-treated cells. The inhibitory effects of ginkgolide B on LOX-1 and ICAM-1 expression were reduced in Sirt1 siRNA-transfected cells. Nrf2 expression was increased in ox-LDL-treated cells, and ginkgolide B downregulated Nrf2 expression. These results suggest that ginkgolide B reduces Nrf2 expression by inhibiting LOX-1 expression, consequently reducing oxidative stress injury in ox-LDL-stimulated cells. Altogether, these results indicate that the protective effect of ginkgolide B on endothelial cells may be attributable to a decrease in LOX-1 expression and an increase in Sirt1 expression in ox-LDL-stimulated endothelial cells, the mechanism of which is linked to the inhibition of Akt activation. Ginkgolide B may be a multiple-target drug that exerts protective effects in ox-LDL-treated human umbilical vein endothelial cells. © 2013 Ma et al.

Dai D.P.,Beijing Hospital and Beijing Institute of Geriatrics | Zhou X.Y.,Beijing Hospital and Beijing Institute of Geriatrics | Cai J.P.,Beijing Hospital and Beijing Institute of Geriatrics
Tissue Antigens | Year: 2014

Novel allele HLA-A*24:02:87 has one nucleotide change with A*24:02:01:01 in exon 3 at position 594 C>T © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Jin J.,Beijing Hospital and Beijing Institute of Geriatrics | Zhang T.,Beijing Hospital and Beijing Institute of Geriatrics
Cellular Physiology and Biochemistry | Year: 2013

Background/Aims:. The aim of this study was to elucidate the effects of glucose restriction (GR) on cell replicative senescence in vitro by human diploid fibroblasts IMR-90. Methods: IMR-90 cells were cultured under 40, 60% GR or high glucose medium and biomarkers of cell senescence were compared with cells cultured in normal glucose medium (5.5 mM glucose). The impact of different concentrations of glucose and initial passages on cell replicative senescence were assessed by cell survival days, cumulative population doublings (PD), cell proliferation rate (CPR) and SA-β-gal site-stain. Results: When compared with control cells, mean survival days and lifespan of IMR-90 were increased 16.7% and 11.4% by 40% GR (3.3 mM glucose). However, mean survival days and lifespan of IMR-90 were decreased 31.0% and 26.9% by HG treatment (25.0 mM glucose). The effects on survival days of IMR-90 were associated not only with different glucose concentrations but also with initial passages. The CPR of IMR-90 could be retarded by GR culture and this effect was especially associated with GR degree. It was 87% positive cells of SA-β-gal in aging stages and more slim and fibrous cells were observed in 40% GR group than NG group onset from 26 PD. Conclusion: Mean survival days and lifespan of human diploid fibroblasts IMR-90 were extended by glucose restriction. The higher GR levels, the earlier onset of GR, the larger benefits on extending survival days of IMR-90 could be observed. Slowing down cell proliferation by GR increased the number of cell survival days, an effect associated with GR levels. High glucose induced premature senescence of IMR-90 when started from any passages. © 2013 S. Karger AG, Basel.

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