Gypenoside inhibits ox-LDL uptake and foam cell formation through enhancing Sirt1-FOXO1 mediated autophagy flux restoration.

BACKGROUND: Gypenoside (GP) is the major bioactive constituent of G. pentaphyllum, a traditional Chinese medicine. It has been reported that GP can affect autophagy and lipid metabolism in cultured cells. We hypothesize that GP can inhibit foam cell formation in cultured macrophages through autophagy modulation. METHODS: THP1 cells were cultured and treated with oxidized low-density lipoprotein (ox-LDL), followed by GP treatment at different concentrations. The autophagy flux was evaluated using western blot and confocal microscope analyses. The ox-LDL uptake and foam cell formation abilities were measured. RESULTS: We found that ox-LDL impaired the autophagy flux in the cultured macrophages, indicated by a significant reduction of LC3-II and autophagosome puncta quantification, as well as an accumulation of p62 proteins. GP treatment, however, dose-dependently restored the autophagy flux impaired by ox-LDL and reduced the ox-LDL uptake and foam cell transformation from THP1 cells, which can be alleviated, or exacerbated, by modulation of autophagy status using autophagy enhancer or inhibitor. Coimmunoprecipitation assays showed that GP up-regulated Srit1 and FOXO1 expression and enhanced their direct interaction, and thus contributed to the regulation of autophagy. CONCLUSION: GP inhibits ox-LDL uptake and foam cell formation through enhancing Sirt1-FOXO1 mediated autophagy flux restoration, suggesting this compound has therapeutic potential for atherosclerosis.

SM22α (Smooth Muscle Protein 22-α) Promoter-Driven IGF1R (Insulin-Like Growth Factor 1 Receptor) Deficiency Promotes Atherosclerosis.

Objective- IGF-1 (insulin-like growth factor 1) is a major autocrine/paracrine growth factor, which promotes cell proliferation, migration, and survival. We have shown previously that IGF-1 reduced atherosclerosis and promoted features of stable atherosclerotic plaque in Apoe-/- mice-an animal model of atherosclerosis. The aim of this study was to assess effects of smooth muscle cell (SMC) IGF-1 signaling on the atherosclerotic plaque. Approach and Results- We generated Apoe-/- mice with IGF1R (IGF-1 receptor) deficiency in SMC and fibroblasts (SM22α [smooth muscle protein 22 α]-CreKI/IGF1R-flox mice). IGF1R was decreased in the aorta and adventitia of SM22α-CreKI/IGF1R-flox mice and also in aortic SMC, embryonic, skin, and lung fibroblasts isolated from SM22α-CreKI/IGF1R-flox mice. IGF1R deficiency downregulated collagen mRNA-binding protein LARP6 (La ribonucleoprotein domain family, member 6) and vascular collagen, and mice exhibited growth retardation. The high-fat diet-fed SM22α-CreKI/IGF1R-flox mice had increased atherosclerotic burden and inflammatory responses. α-SMA (α-smooth muscle actin)-positive plaque cells had reduced proliferation and elevated apoptosis. SMC/fibroblast-targeted decline in IGF-1 signaling decreased atherosclerotic plaque SMC, markedly depleted collagen, reduced plaque fibrous cap, and increased plaque necrotic cores. Aortic SMC isolated from SM22α-CreKI/IGF1R-flox mice had decreased cell proliferation, migration, increased sensitivity to apoptosis, and these effects were associated with disruption of IGF-1-induced Akt signaling. Conclusions- IGF-1 signaling in SMC and in fibroblast is a critical determinant of normal vascular wall development and atheroprotection.

Nuclear complex of glyceraldehyde-3-phosphate dehydrogenase and DNA repair enzyme apurinic/apyrimidinic endonuclease I protect smooth muscle cells against oxidant-induced cell death.

Atherosclerotic plaque destabilization is the major determinant of most acute coronary events. Smooth muscle cell (SMC) death contributes to plaque destabilization. Here, we describe a novel antiapoptotic mechanism in vascular SMCs that involves interaction of nuclear glyceraldehyde-3-phosphate dehydrogenase (GAPDH) with apurinic/apyrimidinic endonuclease 1 (Ape1), the major oxidized DNA repair enzyme. GAPDH down-regulation potentiated H2O2-induced DNA damage and SMC apoptosis. Conversely, GAPDH overexpression decreased DNA damage and protected SMCs against apoptosis. Ape1 down-regulation reversed the resistance of GAPDH-overexpressing cells to DNA damage and apoptosis, which indicated that Ape1 is indispensable for GAPDH-dependent protective effects. GAPDH bound Ape1 in the SMC nucleus, and blocking (or oxidation) of GAPDH active site cysteines suppressed GAPDH/Ape1 interaction and potentiated apoptosis. GAPDH up-regulated Ape1 via a transcription factor homeobox protein Hox-A5-dependent mechanism. GAPDH levels were reduced in atherosclerotic plaque SMCs, and this effect correlated with oxidative stress and SMC apoptosis. Thus, we demonstrated that nuclear GAPDH/Ape1 interaction preserved Ape1 activity, reduced DNA damage, and prevented SMC apoptosis. Suppression of SMC apoptosis by maintenance of nuclear GAPDH/Ape1 interactions may be a novel therapy to increase atherosclerotic plaque stability.-Hou, X., Snarski, P., Higashi, Y., Yoshida, T., Jurkevich, A., Delafontaine, P., Sukhanov, S. Nuclear complex of glyceraldehyde-3-phosphate dehydrogenase and DNA repair enzyme apurinic/apyrimidinic endonuclease I protect smooth muscle cells against oxidant-induced cell death.

NOTCH3 gene polymorphism is associated with the prognosis of gliomas in Chinese patients.

Recent studies show that NOTCH3 is involved in the glioma development and it is also a prognostic factor for glioma patients. However, the gene polymorphism of NOTCH3 in gliomas prognosis remains unknown.A total of 266 patients were enrolled into this study. The NOTCH3 gene polymorphism at 3 loci, including C>T polymorphism at nucleotide 381, C>A polymorphism at 474 and G>A polymorphism at 684 were determined. All patients received the surgical treatment and/or chemotherapy and/or radiotherapy.We found that the 684G>A polymorphism affects the tumor NOTCH3 expression level and is closely associated with a higher tumor grade, poorer tumor differentiation, and karnofsky performance score in these glioma patients. More importantly, the 684G>A polymorphism is significantly associated with the prognosis of these patients regardless of their treatment manner.Our study indicates that the NOTCH3 gene 684G>A polymorphism may be used as a prognosis marker for gliomas.

Apelin Gene Therapy Increases Autophagy via Activation of Sirtuin 3 in Diabetic Heart.

Heart failure is the leading cause of death in diabetic patients. Recently we showed that apelin gene therapy attenuates heart failure following myocardial infarction. This study further explored the potential mechanisms by which apelin may reduce cardiac injury in Postmyocardial infarction (MI)) model of diabetes. Wild type and Sirt3 knockout (Sirt3 KO) mice were induced into diabetes by intra-peritoneal (i.p.) Streptozotocin (STZ). STZ mice were then subjected to MI followed by immediate intramyocardial injection with Adenovirus-apelin (Ad-apelin). Ad-apelin treatment resulted in over expression of apelin in the ischemic hearts of STZ mice. Apelin over expression led to a significant increase in Sirt3 expression. Apelin over expression significantly reduced gp91phox expression. This was accompanied by a significant reduction of reactive oxygen species formation. Ad-apelin treatment also dramatically reduced NF-κb-p65 expression in WT-STZ mice. Over expression of apelin further enhanced autophagy markers (LC3-II and beclin-1) expression in post-MI heart. Most intriguingly, knockout of Sirt3 in STZ mice abolished these beneficial effects of apelin treatment. In vitro, knockout of Sirt3 in EPCs significantly enhanced high glucose-induced ROS formation. Conversely, treatment of Sirt3 KO-EPCs with NADPH oxidase inhibitor led to two fold increase in LC3-II levels. Our studies demonstrate that apelin increases autophagy via up regulation of Sirt3 and suppression of ROS-NF-κb pathway in diabetic heart.

Sirt3 is essential for apelin-induced angiogenesis in post-myocardial infarction of diabetes.

Heart failure following myocardial infarction (MI) is the leading cause of death in diabetic patients. Angiogenesis contributes to cardiac repair and functional recovery in post-MI. Our previous study shows that apelin (APLN) increases Sirtuin 3 (Sirt3) expression and ameliorates diabetic cardiomyopathy. In this study, we further investigated the direct role of Sirt3 in APLN-induced angiogenesis in post-MI model of diabetes. Wild-type (WT) and Sirt3 knockout (Sirt3KO) mice were induced into diabetes by i.p. streptozotocin (STZ). STZ mice were then subjected to MI followed by immediate intramyocardial injection with adenovirus-apelin (Ad-APLN). Our studies showed that Sirt3 expression was significantly reduced in the hearts of STZ mice. Ad-APLN treatment resulted in up-regulation of Sirt3, angiopoietins/Tie-2 and VEGF/VEGFR2 expression together with increased myocardial vascular densities in WT-STZ+MI mice, but these alterations were not observed in Sirt3KO-STZ+MI mice. In vitro, overexpression of APLN increased Sirt3 expression and angiogenesis in endothelial progenitor cells (EPC) from WT mice, but not in EPC from Sirt3KO mice. APLN gene therapy increases angiogenesis and improves cardiac functional recovery in diabetic hearts via up-regulation of Sirt3 pathway.

Role of osteoprotegerin and its gene polymorphisms in the occurrence of left ventricular hypertrophy in essential hypertensive patients.

The aim of the study was to investigate the role of osteoprotegerin (OPG) in left ventricular hypertrophy (LVH) development in patients with essential hypertension (EH). A total of 1092 patients diagnosed with EH were recruited. The LVHs were determined and OPG gene polymorphisms were genotyped. Patients with LVH had a significantly higher mean serum OPG level than those without LVH. The 1181CC genotype carriers had significantly lower risk for LVH compared with GC and GG genotype carriers. The serum OPG level and OPG 1181 G>C polymorphism were found to be independent risk factors for the occurrence of LVH in hypertensive patients. In vitro study shows that OPG overexpression upregulates cell surface size, protein synthesis per cell, and hypertrophy- and fibrosis-related proteins in both cardiomyocytes and cardiac fibroblasts, whereas OPG inhibition can abolish the above-mentioned changes. Consistent with the in vitro data, our in vivo study revealed that the OPG administration induced the LVH in hypertensive rats. This study is the first to report the close association between OPG and LVH development in EH patients and the regulatory effect of OPG on cardiomyocytes and cardiac fibroblasts.

Polymorphism -433 C>T of the Osteopontin gene is associated with the susceptibility to develop gliomas and their prognosis in a Chinese cohort.

AIM: To investigate role of the Osteopontin (OPN) genetic polymorphisms in the susceptibility to gliomas and their prognosis. METHODS: A total of 248 Chinese glioma patients and 281 age and sex matched healthy controls were recruited. The genetic polymorphisms at three loci, namely, -156 GG>G, -443 C>T and -66T>G, were determined. The log-rank test and Kaplan- Meier analysis were introduced to assess the effect of OPN gene polymorphisms on patient survival. RESULTS: We found that the genotype frequencies of OPN -443 C>T polymorphism were significantly different between glioma patients and controls. Multivariable analyses showed a higher risk for gliomas in -443 CC genotype carriers compared to -443TT carriers (P<0.001). In addition, we also found the OPN -443 C>T polymorphism was closely related to the gliomas' tumor grade. The -443 C>T polymorphism also affected the tumor OPN expression level, but not the serum OPN level. More importantly, the -443 C>T polymorphism was significantly associated with the prognosis of these patients regardless of their treatment status. The patients with -443CC genotype had a poorer prognosis than those with -443TT and -443CT genotypes. In contrast, the -156 G>GG and -66T>G polymorphisms were not associated with risk, clinical characteristics, or prognosis of gliomas. CONCLUSION: This study suggests that the -443C>T gene polymorphisms may be used as a molecular marker for glioma occurrence and clinical outcome in glioma patients.

HIF-1α genetic variants and protein expression confer the susceptibility and prognosis of gliomas.

To investigate the role of HIF-1α genetic polymorphism of c.1772C>T and c.1790G>A in the incidence and prognosis of gliomas in a Chinese cohort, a total of 387 gliomas patients and 437 age- and sex-matched healthy controls were recruited. The genetic polymorphism of c.1772C>T and c.1790G>A was determined. We found that the genotype distribution at c.1772C>T showed significant difference between patients and controls. Multivariable analyses showed a significantly higher risk for gliomas in 1772TT genotype carriers (odds ratio 2.68, with CC as reference). In addition, we also found a significantly higher risk for grade III + IV gliomas was observed in 1772TT genotype carriers (odds ratio 2.21, with CC as reference). The overall survival rates in patients with 1772TT or 1772CT genotype were markedly lower compared with patients with CC (both P < 0.01). Our in vitro studies revealed that HIF-1α regulates the proliferation, migration and invasion of human glioma U251 cells. This study suggests that the c.1772C>T polymorphisms may be used as a molecular marker for gliomas occurrence, grades and clinical outcome in gliomas patients.

Advanced glycation endproducts trigger autophagy in cadiomyocyte via RAGE/PI3K/AKT/mTOR pathway.

UNLABELLED: Previous studies showed that the accumulation of advanced glycation end products (AGEs) induce cardiomyocyte apoptoisis, leading to heart dysfunction. However, the effect of AGEs on another cell death pathway, autophagy, in cardiomyocytes remains unknown. METHODS: Rat neonate cardiomyocytes were cultured and treated with AGEs at different concentration. Two classic autophagy markers, microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1, were detected by western blot assay. The inhibition of RAGE and phosphatidylinositol 3-phosphate kinase (PI3K)/Akt/mTOR pathway were applied to cells, respectively. RESULTS: AGEs administration enhanced the expression of Beclin-1 and LC3 II in cardiomyocytes, increased the number of autophagic vacuoles and impaired the cell viability in dose-dependant manners. Also, AGEs inhibited the PI3K/Akt/mTOR pathway via RAGE. Inhibition of RAGE with RAGE antibody reduced expression of Beclin-1 and LC3 II/I and inhibited the cellular autophagy, accompanied by the reactivation of PI3K/Akt/mTOR pathway in cultured cells. Notably, the presence of inhibition of PI3K/Akt/mTOR pathway abolished the protective effect of RAGE inhibition on cardiomyocytes. CONCLUSION: This study provides evidence that AGEs induces cardiomyocyte autophagy by, at least in part, inhibiting the PI3K/Akt/mTOR pathway via RAGE.

Apelin gene therapy increases myocardial vascular density and ameliorates diabetic cardiomyopathy via upregulation of sirtuin 3.

Microvascular insufficiency contributes to cardiac hypertrophy and worsens heart dysfunction in diabetic cardiomyopathy. Our recent study shows that apelin may protect ischemic heart failure via upregulation of sirtuin 3 (Sirt3) and angiogenesis. This study investigated whether apelin promotes angiogenesis and ameliorates diabetic cardiomyopathy via activation of Sirt3. Wild-type (WT) and diabetic db/db mice were administrated with adenovirus-apelin to overexpressing apelin. In WT mice, overexpression of apelin increased Sirt3, VEGF/VEGFR2, and angiopoietin-1 (Ang-1)/Tie-2 expression in the heart. In vitro, treatment of endothelial cells (EC) with apelin increased VEGF and Ang-1 expression. In EC isolated from Sirt3KO mice, however, apelin treatment did not upregulate VEGF and Ang-1 expression. Moreover, apelin-induced angiogenesis was diminished in Sirt3KO mice. In db/db mice, the basal levels of apelin and Sirt3 expression were significantly reduced in the heart. This was accompanied by a significant reduction of capillary and arteriole densities in the heart. Overexpression of apelin increased Sirt3, VEGF/VEGFR2, and Ang-1/Tie-2 expression together with improved vascular density in db/db mice. Overexpression of apelin further improved cardiac function in db/db mice. Treatment with apelin significantly attenuated high glucose (HG)-induced reactive oxygen species (ROS) formation and EC apoptosis. The protection of apelin against HG-induced ROS formation and EC apoptosis was diminished in Sirt3KO-EC. We conclude that apelin gene therapy increases vascular density and alleviates diabetic cardiomyopathy by a mechanism involving activation of Sirt3 and upregulation of VEGF/VEGFR2 and Ang-1/Tie-2 expression.

Polymorphism of the RAGE affects the serum inflammatory levels and risk of ischemic stroke in a Chinese population.

BACKGROUND: Increasing evidence shows that inflammation plays an important role in the occurrence and progression of acute ischemic stroke. The receptor for advanced glycation end products (RAGE) has been documented to involve in the pathogenic mechanisms of a variety of neurological diseases, including ischemic stroke (IS). However, the impact of RAGE gene polymorphisms on the susceptibility to IS has not been reported. We thus explored the association between RAGE gene polymorphisms and the susceptibility to IS. METHOD: A total of 384 patients with IS and 425 healthy controls were enrolled in this study. Three genetic polymorphisms of RAGE gene (82G/S, -429T/C and -374T/A) were determined. The serum levels of soluble RAGE (sRAGE), intetleukin-6 (IL-6), high sensitivity-C reaction protein (hs-CRP) and plasminogen activator inhibitor-1 (PAI-1) were detected. RESULTS: Among the studied polymorphisms, only the polymorphism at 82G/S of RAGE gene was associated with the risk for ischemic stroke irrespective of the stroke subtypes. The 82S/S homozygote carriers had a significantly increased risk for ischemic stroke [adjusted odds ratio (OR): 2.297; p<0.001]. The haplotype analyses showed that the C-429S82T-374 and T-429S82A-374 had higher risk to develop IS (OR=1.864 and 1.931, respectively, all p<0.01), while the C-429G82T-374 showed a protective effect against IS susceptibility (OR=0.568, p=0.001). In addition, the 82S/S homozygote carriers had a higher inflammatory level compared with 82G/S and 82G/G genotypes, indicated by lower serum sRAGE level, higher serum IL-6, hs-CRP and PAI-1 levels. The polymorphisms at -374 and -429 loci did not influence the stroke risk and the above mentioned inflammation cytokines. CONCLUSION: Our results showed a close correlation between the 82G/S polymorphism and the susceptibility to IS, suggesting the 82G/S polymorphism may be used as a genetic marker for the prediction of stroke occurrence in high risk subjects.

Myocardial injection of apelin-overexpressing bone marrow cells improves cardiac repair via upregulation of Sirt3 after myocardial infarction.

Our previous study shows that treatment with apelin increases bone marrow cells (BMCs) recruitment and promotes cardiac repair after myocardial infarction (MI). The objective of this study was to investigate whether overexpression of apelin in BMCs improved cell therapy and accelerated cardiac repair and functional recovery in post-MI mice. Mouse myocardial infarction was achieved by coronary artery ligation and BMCs overexpressing apelin (apelin-BMCs) or GFP (GFP-BMCs) were injected into ischemic area immediately after surgery. In vitro, exposure of cultured BMCs to apelin led to a gradual increase in SDF-1á and CXCR4 expression. Intramyocardial delivery of apelin-BMCs in post-MI mice resulted in a significant increase number of APJ⁺/c-kit⁺/Sca1⁺ cells in the injected area compared to GFP-BMCs treated post-MI mice. Treatment with apelin-BMCs increased expression of VEGF, Ang-1 and Tie-2 in post-MI mice. Apelin-BMCs treatment also significantly increased angiogenesis and attenuated cardiac fibrosis formation in post-MI mice. Most importantly, treatment with apelin-BMCs significantly improved left ventricular (LV) systolic function in post-MI mice. Mechanistically, Apelin-BMCs treatment led to a significant increase in Sirtuin3 (Sirt3) expression and reduction of reactive oxygen species (ROS) formation. Treatment of cultured BMCs with apelin also increased Notch3 expression and Akt phosphorylation. Apelin treatment further attenuated stress-induced apoptosis whereas knockout of Sirt3 abolished anti-apoptotic effect of apelin in cultured BMCs. Moreover, knockout of Sirt3 significantly attenuated apelin-BMCs-induced VEGF expression and angiogenesis in post-MI mice. Knockout of Sirt3 further blunted apelin-BMCs-mediated improvement of cardiac repair and systolic functional recovery in post-MI mice. These data suggest that apelin improves BMCs therapy on cardiac repair and systolic function in post-MI mice. Upregulation of Sirt3 may contribute to the protective effect of apelin-BMCs therapy.

Polymorphisms of receptor for advanced glycation end products and risk of epithelial ovarian cancer in Chinese patients.

BACKGROUND: Given the roles of receptor for advanced glycation end products (RAGE) in the pathogenesis of carcinogenesis, we propose that RAGE polymorphisms may be associated with risk of epithelial ovarian carcinoma (EOC). METHOD: This case-control study included 190 women over 40 years of age who were diagnosed with primary EOC and 210 healthy control subjects. RAGE gene polymorphisms, including 82G>S,-374T>A,-429C>T,and 1704G>T were determined. RESULTS: We found that only the frequencies of the 82G>S polymorphisms were significantly different between the EOC cases and controls. The 82SS genotype was significantly higher in EOC patients than in controls (37.89% vs. 23.33%,P<0.001). With the 82 GG genotype as reference, the OR for 82SS homozygous carriers reached to 2.65 (95% CI: 1.54-4.58; P =0.0004) after adjustment for age, smoking status, body mass index, family history, usage of contraceptives, tubal ligation history, use of menopausal hormones and menopausal status. The 82S allele carriage presented a higher risk for EOC (OR=1.71; 95% CI, 1.29-2.26; P=0.0002). The polymorphisms of 1704G>T,-374T>A and -429C>T did not affect the EOC risk. CONCLUSION: This result suggests that the 82G>S polymorphism of RAGE gene may be associated with the susceptibility of EOC.

Protective role of granulocyte colony-stimulating factor against adriamycin induced cardiac, renal and hepatic toxicities.

Adriamycin (ADR) causes dose-dependant toxicities in heart, liver and kidneys via inducing the peroxidative alterations in organ tissues. Recent studies showed that the granulocyte colony-stimulating factor (G-CSF) exerts beneficial effects on heart, liver and kidney injuries induced by different pathological conditions. We hypothesize that G-CSF have a protective effect on ADR induced cardiac, renal and hepatic toxicities by inhibiting the peroxidative alterations in organ tissues. Wistar rats were randomly divided into control, ADR, ADR+phosphate buffered saline (PBS) and ADR+G-CSF group (n=16 in each group). ADR was administered intraperitoneally every other day at the dose of 2.5 microg/kg each time per rat (total six times of injection during 2 weeks). Rats in the ADR+G-CSF group were injected subcutaneously with G-CSF at the dose of 50 microg/(kg day) (for 8 consecutive days). After 8 weeks, the serum and urine biochemistry variables were determined. The malondialdehyde (MDA) level and the glutathione (GSH) content in the heart, the liver and the kidney tissues were measured. ADR caused significant cardiac, renal and hepatic toxicities indicated by the serum and urine biochemistry variables. The tissue MDA level in the heart, kidney and liver in rats treated with ADR were markedly elevated, while the GSH content in these tissues were significantly reduced. G-CSF administration palliated the cardiac, renal and hepatic toxicities. Notably, G-CSF induced significant reduction of MDA level and increase of GSH content in the heart, kidney and liver tissues. This study suggests that G-CSF play an overall protective effect on ADR-induced toxicities in heart, liver and kidneys and the inhibition of tissue peroxidative alterations might contribute to this beneficial effect.

Gender-specific effect of estrogen receptor-1 gene polymorphisms in coronary artery disease and its angiographic severity in Chinese population.

BACKGROUND: The role of common polymorphisms of the estrogen receptor-1 in coronary artery disease (CAD) and it association with angiographic severity reminds conflicting in sexes and different races. METHODS: Two-hundred ten angiographically defined Chinese CAD patients and 174 control subjects were enrolled. DNA was obtained and the polymorphisms were analyzed by the polymerase chain reaction. The region containing the PvuII T/C and the XbaI A/G sites was amplified. PCR product was cleaved with the restriction endonucleases. RESULTS: No significant differences in PvuII and XbaI genotype and allele frequencies were noted between the CAD and controls.However, when stratified by gender, we noticed the PvuII genotype and allele frequencies were significantly different between CAD and controls, but in male group only, not in female group. Diabetes, hypertension, high LDL levels and the PvuII CC genotype were independent risk factors for CAD. PvuII CC was associated with the angiographic severity of CAD measuring by the number of diseased vessels as well. For XbaI, no association was found with the CAD susceptibility before and after gender stratification. CONCLUSION: This study revealed a gender-specific effect of PvuII polymorphism in Chinese CAD subjects. PvuII gene polymorphisms affect CAD susceptibility in man only. The PvuII CC is a risk factor for CAD and it is associated with angiographic CAD severity.

The G501C polymorphism of oxidized LDL receptor gene [OLR-1] is associated with susceptibility and serum C-reactive protein concentration in Chinese essential hypertensives.

BACKGROUND: Oxidized LDL receptor gene 1 (OLR-1) polymorphism is reportedly associated with several cardiovascular conditions. However, its relationship with essential hypertension remains unknown. The aim of this study is to explore the association of OLR-1 polymorphism at position 501 in the open reading frame (G501C), with the susceptibility of essential hypertension. METHODS: 2-hundred eighty Chinese essential hypertensive and 284 control subjects were enrolled and genetic study was performed. The clinical data, i.e., sex, age, blood pressure, body mass index, smoking history, lipid profile and serum C-reactive protein concentration in both hypertensives and controls were obtained. RESULTS: A significant difference in OLR-1 genotype distributions was noted between the hypertensives and the controls (GG: 67.9% vs. 70.8%; GC: 20.0% vs. 23.6%; CC: 12.1% vs. 5.6%, P=0.021). For G and C allele frequencies, the difference between these 2 groups was significant as well (G: 67.5% vs. 23.5%, C: 82.6% vs. 17.4%, P=0.011). Logistic regression analysis revealed that the CC genotype is an independent risk factor for hypertension (OR=3.036, 95% CI: 1.572-6.174, P=0.016). Furthermore, when the serum C-reactive protein concentration in the hypertensive group was studied according to OLR-1 genotypes, the serum CRP concentration in CC homozygous carriers were found significantly higher than that in GC and GG carriers (1.53+/-0.32, 1.31+/-0.32 and 2.94+/-1.29 respectively, P=0.002). CONCLUSIONS: The CC genotype of OLR-1 G501C polymorphism is associated with susceptibility and serum C-reactive protein concentration in Chinese essential hypertensive population.

Cyclin D1 gene polymorphism and susceptibility to childhood acute lymphoblastic leukemia in a Chinese population.

Cyclin D1 is a key protein involved in cell cycle regulation. A common A870G single nucleotide polymorphism in exon 4 of the cyclin D1 gene (CCND1) has an effect on the transcription of 2 different cyclin D1 messenger RNAs. Correlation between genetic polymorphism of A870G of CCND1 and clinical outcome among patients with acute lymphoblastic leukemia (ALL) has been reported. However, the effect on ALL occurrence remains unclear. To examine the genotypic frequency of CCND1 polymorphism, we performed a case-control study in a Chinese population of 183 children with ALL and 190 healthy controls. The genetic frequency of CCND1 had a significant overall correlation in patients and controls. The AA genotype of CCND1 showed a tendency to increase ALL risk 3.2898-fold compared with the AG + GG genotype (P = .0207). Stratification of patients according to cell type, risk level, and chemotherapeutic response showed significance for the AA genotype in T-cell ALL, ALL with high risk, and no complete remission (P = .047, P = .011, and P = .007, respectively). No gene dosage effect was observed in this study. The results of the present study suggested that CCND1 genetic polymorphism may be related to the occurrence of ALL in a population of Chinese children.