Key Laboratory for Organ Failure Research

Guangzhou, China

Key Laboratory for Organ Failure Research

Guangzhou, China
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Hou F.,Southern Medical University | Hou F.,Key Laboratory for Organ Failure Research | Jiang J.,Southern Medical University | Jiang J.,Key Laboratory for Organ Failure Research | And 27 more authors.
BMC Nephrology | Year: 2012

Background: Cardiovascular disease (CVD) is the main cause of death in patients on chronic dialysis. The question whether dialysis modality impacts cardiovascular risk remains to be addressed. China Collaborative Study on Dialysis, a multi-centers cohort study, was performed to evaluate cardiovascular morbidity during maintenance hemodialysis (HD) and peritoneal dialysis (PD). Method. The cohort consisted of chronic dialysis patients from the database of 9 of the largest dialysis facilities around China. The inclusion period was between January 1, 2005, and December 1, 2010. Cardiovascular morbidity was defined as the presence of clinically diagnosed ischemic heart disease, heart failure, peripheral vascular disease, and/or stroke. The patients who had cardiovascular morbidity before initiation of dialysis were excluded. Data collection was based on review of medical record. Result: A total of 2,388 adult patients (1,775 on HD and 613 on PD) were enrolled. Cardiovascular morbidity affected 57% patients and was comparable between HD and PD patients. However, clinically diagnosed ischemic heart disease and stroke was more prevalent in PD than HD patients. When the patients were stratified by age or dialysis vintage, the cardiovascular morbidity was significantly higher in PD than HD among those aged 50years or older, or those receiving dialysis over 36months. Multivariate analysis revealed that the risk factors for cardiovascular morbidity had different pattern in PD and HD patients. Hyperglycemia was the strongest risk factor for cardiovascular morbidity in PD, but not in HD patients. Hypertriglyceridemia and hypoalbuminemia were independently associated with CVD only in PD patients. Conclusions: Cardiovascular morbidity during chronic dialysis was more prevalent in PD than HD patients among those with old age and long-term dialysis. Metabolic disturbance-related risk factors were independently associated with CVD only in PD patients. Better understanding the impact of dialysis modality on CVD would be an important step for prevention and treatment. © 2012 Hou et al.; licensee BioMed Central Ltd.

Wu W.,Southern Medical University | Wu W.,Panyu Central Hospital | Wang Y.,Southern Medical University | Wang Y.,Key Laboratory for Organ Failure Research | And 15 more authors.
Investigative Radiology | Year: 2013

OBJECTIVE: Ultrasound molecular imaging has the potential to detect activated platelets, thus identifying atherosclerotic plaque instability before onset of serious clinical events. However, it has not been well defined in inflammatory arterial thrombosis. We hypothesized that microbubbles (MBs) target glycoprotein IIb/IIIa (GP IIb/IIIa) could achieve a noninvasive in vivo detection of inflammatory thrombosis in large arteries through contrast-enhanced ultrasound (CEU) imaging. MATERIALS AND METHODS: Lipid shell-based gas-filled MBs were modified covalently with a cyclic Arg-Gly-Asp (RGD) peptide (MB-cRGD) targeted to activated GP IIb/IIIa or a negative control peptide (MB-CON) via thiol-maleimide coupling. Adherence of MB-cRGD and MB-CON to GP IIb/IIIa was determined in vitro by using a parallel plate flow chamber at variable shear stress (0.5-8 dynes/cm). Inflammatory platelet thrombosis was induced by periadvential application of arachidonic acid (AA) to one of the bilateral carotids of C57BL/6 mice (n = 20) and confirmed through intravital fluorescence microscopy. Attachment of MBs was determined in vivo with CEU imaging of bilateral carotids in the AA application mice with (n = 10) or without (n = 10) pretreatment of GP IIb/IIIa antagonist. The expression of integrin GP IIb/IIIa was assessed through immunohistochemistry. RESULTS: Microbubble-cRGD but not MB-CON had excellent affinity to GP IIb/IIIa under all shear stress conditions. Successful inflammatory platelet activation and thrombosis in AA application carotids were noted through intravital fluorescence microscopy. Contrast video intensity from adhered MB-cRGD in the thrombi was significantly higher than that from MB-CON (P < 0.05). Video intensity of MB-cRGD in the thrombi was suppressed significantly by preblocking with GP IIb/IIIa antagonist (P < 0.05) but not for MB-CON. Immunohistochemical finding demonstrates that expression of integrin GP IIb/IIIa in the thrombi was abundant; it was inhibited significantly through pretreatment with GP IIb/IIIa antagonist (P < 0.05). CONCLUSIONS: Cyclic RGD-modified MBs targeted to GP IIb/IIIa with CEU are capable of detecting inflammation-activated platelets and thrombosis in large arteries, thus providing a potential tool for identification of vulnerable atherosclerotic plaques. Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Chen P.-A.,Southern Medical University | Chen P.-A.,Key Laboratory For Organ Failure Research | Xu Z.-H.,Southern Medical University | Huang Y.-L.,Southern Medical University | And 12 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2014

Myocardial energy expenditure (MEE) and 2-oxoglutarate are elevated in chronic heart failure (CHF) patients compared with healthy controls. To explore whether 2-oxoglutarate could reflect the levels of MEE and predict the prognosis of CHF, 219 CHF patients and 66 healthy controls were enrolled. 2-Oxoglutarate was assayed with Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC/MS/MS). CHF patients were divided into 4 groups according to interquartile range of MEE and followed for death or recurrent hospital admission due to CHF for the mean follow-up time 6.64±0.16months. 2-Oxoglutarate was increased in CHF patients compared with controls (P<0.01) and correlated with estimated glomerular filtration rate (r=0.142, P=0.036), age (r=-0.269, P<0.01) and MEE levels (r=0.307, P<0.01) in a multiple linear correlation analysis in CHF patients. Furthermore, 2-oxoglutarate (OR=3.470, 95% CI=1.557 to 7.730, P=0.002), N-terminal pro-B-type natriuretic peptide (OR=4.013, 95% CI=1.553 to 10.365, P=0.004), age (OR=1.611, 95% CI=1.136 to 2.283, P=0.007) and left ventricular ejection fraction (OR=7.272, 95% CI=3.110 to 17.000, P<0.001) were independently associated with MEE on multiple logistic regression analysis. Kaplan-Meier event curves showed that high 2-oxoglutarate levels were associated with adverse outcomes (Log Rank, Chi2=4.026, P=0.045). This study showed that serum 2-oxoglutarate is associated with MEE levels, which can be used as potential biomarkers for MEE, and it can reflect the clinical severity and short-term outcome of CHF. © 2014 Elsevier B.V.

Zhou Q.,Southern Medical University | Zhou Q.,Guangdong Provincial Institute of Nephrology | Zhou Q.,Key Laboratory for Organ Failure Research | Zhao C.,Southern Medical University | And 17 more authors.
BMC Nephrology | Year: 2012

Background: Acute worsening of renal function, an independent risk factor for adverse outcomes in acute decompensated heart failure (ADHF), occurs as a consequence of new onset kidney injury (AKI) or acute deterioration of pre-existed chronic kidney disease (CKD) (acute-on-chronic kidney injury, ACKI). However, the possible difference in prognostic implication between AKI and ACKI has not been well established. Methods: We studied all consecutive patients hospitalized with ADHF from 2003 through 2010 in Nanfang Hospital. We classified patients as with or without pre-existed CKD based on the mean estimated glomerular filtration rate (eGFR) over a six-month period before hospitalization. AKI and ACKI were defined by RIFLE criteria according to the increase of the index serum creatinine. Results: A total of 1,005 patients were enrolled. The incidence of ACKI was higher than that of AKI. The proportion of patients with diuretic resistance was higher among patients with pre-existed CKD than among those without CKD (16.9% vs. 9.9%, P = 0.002). Compared with AKI, ACKI was associated with higher risk for in-hospital mortality, long hospital stay, and failure in renal function recovery. Pre-existed CKD and development of acute worsening of renal function during hospitalization were the independent risk factors for in-hospital death after adjustment by the other risk factors. The RIFLE classification predicted all-cause and cardiac mortality in both AKI and ACKI. Conclusions: Patients with ACKI were at greatest risk of adverse short-term outcomes in ADHF. Monitoring eGFR and identifying CKD should not be ignored in patients with cardiovascular disease. © 2012 Zhou et al.; licensee BioMed Central Ltd.

Du Z.,Southern Medical University | Du Z.,Key Laboratory for Organ Failure Research | Zeng Q.,Southern Medical University | Zeng Q.,Key Laboratory for Organ Failure Research | And 8 more authors.
Experimental and Clinical Cardiology | Year: 2014

Background/Objective: Metabolomics studies have demonstrated that the serum and urine metabolic profiles of patients with chronic heart failure are different from those of patients with normal heart function. However, it is difficult to eliminate irrelevant factors, such as metabolic diseases, diet, activity status and other factors that can affect patient metabolic profiles. Therefore, we used a rat model with coronary artery ligation to mimic the pathogenesis of ischemic heart failure and subsequent chromatography/mass spectroscopy (GC/MS) analysis to determine whether the observed differences in serum metabolic profiles were caused by heart failure. Methods: Fifty-one male SD rats (SPF) were randomized into the sham group and the surgery group. The rat model of chronic ischemic heart failure was prepared by coronary artery ligation. Venous blood from the inferior vena cava was collected after ligation for 4 weeks and the plasma was extracted for serum metabolomics analysis. Results: PCA score plot data revealed significant metabolic differences between the severe heart failure group and the control group, but no significant differences were observed between the slight heart failure group and the control group. A stable and reliable OPLS-DA model was created and used to filter out 44 types of metabolite differences. The levels of free fatty acids, glucose, and lactate were significantly elevated in rats with severe heart failure. Conclusions: The serum metabolic profiles of rats with severe heart failure were markedly different from those of sham rats. A total of 44 metabolites exhibited differences between the severe heart failure and control groups.

Wu Z.-L.,Southern Medical University | Ren H.,Key Laboratory for Organ Failure Research | Ren H.,Southern Medical University | Lai W.-Y.,Southern Medical University | And 9 more authors.
Journal of Ethnopharmacology | Year: 2014

Ethnopharmacological relevance Sclederma of Poria cocos (Hoelen) has been used as a diuretic in traditional Asian medicine. However, the underlying mechanism by which Sclederma of Poria cocos (hoelen) exerts its diuretic effect has not been well identified. The aim of the present study was to evaluate the effects of Sclederma of Poria cocos (hoelen) in rats with chronic heart failure (CHF) induced by acute myocardial infarction and to investigate the underlying mechanisms. Materials and methods An aqueous extract of Sclederma of Poria cocos (hoelen) (2.4 g/kg/d, 1.2 g/kg/d or 0.6 g/kg/d) or furosemide (20 mg/kg/d) was administered orally to male Sprague-Dawley rats starting on the day of coronary ligation. The urine output of all rats was quantified and collected every day for 1 or 4 weeks. The expression of aquaporin-2 (AQP2) was examined after treatment for 1 or 4 weeks. Results Urinary output increased significantly and urinary osmolality decreased after oral administration of Sclederma of Poria cocos (hoelen) for both 1 and 4 weeks. Sclederma of Poria cocos (hoelen) caused less electrolyte disorder than furosemide. Furthermore, Sclederma of Poria cocos (hoelen) reduced the levels of plasma BNP in CHF rats, whereas furosemide had no effect. Importantly, both mRNA and protein expression of AQP2 were down-regulated and urinary excretion of AQP2 was decreased after administration of Sclederma of Poria cocos (hoelen) to CHF rats. Similarly, Sclederma of Poria cocos (hoelen) reduced plasma arginine vasopressin (AVP) level and down-regulated vasopressin type 2 receptor (V2R) mRNA expression. Conclusions Sclederma of Poria cocos (hoelen) exerts its diuretic effect and improves cardiac function in CHF rats via the AVP-V2R-AQP2 axis. © 2014 Elsevier Ireland Ltd. All rights reserved.

Zhou Q.G.,Southern Medical University | Zhou Q.G.,Key Laboratory for Organ Failure Research | Peng X.,Southern Medical University | Peng X.,Key Laboratory for Organ Failure Research | And 8 more authors.
Journal of Cellular Physiology | Year: 2010

Accumulation of advanced oxidation protein products (AOPPs) is prevalent in metabolic syndromes, a condition with impaired preadipocytes differentiation. In the present study, we tested the hypothesis that AOPPs disturb preadipocyte differentiation. Exposure of 3T3-L1 preadipocytes to increased levels of AOPPs inhibited accumulation of intracellular triglyceride and decreased the expression of the essential markers of matured adipocytes, such as adipocyte fatty-acid-binding protein (aP2), CAAT/enhancer-binding protein (C/EBP)-α, and peroxisome proliferator-activated receptor (PPAR)-γ, in response to standard adipogenic induction. Inhibitory effects of AOPPs on preadipocytes differentiation was time sensitive, which occurred at the early stage of differentiation. In the presence of AOPPs, induction of preadipocytes differentiation resulted in upregulated expression of C/EBP homologous protein (CHOP) and CUG-Triplet repeat-binding protein (CUGBP), two important inhibitors of preadipocytes differentiation. In addition, treatment with AOPPs increased abundance of C/EBP-β-liver enriched inhibitory protein (C/EBP-β-LIP), a truncated C/EBP-β isoform without adipogenic activity. Moreover, AOPPs-treated preadipocytes expressed a macrophage marker F4/80 and overexpressed tumor necrosis factor-α and interleukin-6 via nuclear factor-κB (NF-κB)-dependent pathway. However, blocking inflammation with NF-κB inhibitor failed to improve AOPPs-induced inhibition of preadipocytes differentiation. These data suggest that accumulation of AOPPs may inhibit differentiation of preadipocytes and activate inflammation in these cells. This information might have implication for understanding the impairment of preadipocytes differentiation and fat inflammation seen in metabolic syndrome. © 2010 Wiley-Liss, Inc.

Cao W.,Southern Medical University | Cao W.,Guangdong Provincial Institute of Nephrology | Cao W.,Key Laboratory for Organ Failure Research | Zhou Q.G.,Southern Medical University | And 17 more authors.
Journal of Hypertension | Year: 2011

Objective: Inappropriate activation of the intrarenal renin-angiotensin system (RAS) plays an important role in the pathogenesis of hypertension and renal injury. However, the underlying mechanisms remain elusive. Proteinuria has been shown to elicit the renal activation of RAS. The present study was performed to test the intracellular signal pathway involved in albumin-triggered activation of RAS. DESIGN AND Methods: NRK52E cells, a rat renal proximal tubular cell line, were incubated with increased levels of albumin. The rat model of protein overload was established in female Wistar-Kyoto rats that were subjected to unilateral nephrectomy followed by daily intraperitoneal injection of BSA at various doses (0.5, 1.0, and 5.0 g/kg) or combination with intragastric administration of apocynin (100 mg/kg per day), an inhibitor of NADPH oxidase. Results: Exposure of the cells to high levels of albumin activated the RAS through the endocytic receptors megalin and cubilin. High levels of albumin triggered the production of intracellular reactive oxygen species by a protein kinase C (PKC)-NADPH oxidase-dependent pathway and this, in turn, led to activation of nuclear factor-κB (NF-κB) and activation protein-1 (AP-1). Inhibition of PKC or NADPH oxidase abolished albumin-induced activation of RAS. In a protein overload rat model, activation of RAS in renal proximal tubular cells was significantly increased, coincident with activation of PKC, NADPH oxidase, NF-κB, and AP-1. Chronic inhibition of NADPH oxidase by apocynin largely ameliorated intrarenal activation of RAS. Conclusion: Exposure of renal tubular epithelial cells with high levels of albumin triggers activation of RAS via a PKC-NADPH oxidase-dependent pathway. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Du Z.,Southern Medical University | Du Z.,Key Laboratory for Organ Failure Research | Shen A.,Southern Medical University | Huang Y.,Southern Medical University | And 15 more authors.
PLoS ONE | Year: 2014

Objective: Elevated myocardial energy expenditure (MEE) is related with reduced left ventricular ejection fraction, and has also been documented as an independent predictor of cardiovascular mortality. However, the serum small-molecule metabolite profiles and pathophysiological mechanisms of elevated MEE in heart failure (HF) are still lacking. Herein, we used 1H-NMR-based metabolomics analysis to screen for potential biomarkers of MEE in HF. Methods: A total of 61 subjects were enrolled, including 46 patients with heart failure and 15 age-matched controls. Venous serum samples were collected from subjects after an 8-hour fast. An INOVA 600 MHz nuclear magnetic resonance spectrometer with Carr-Purcell-Melboom-Gill (CPMG) pulse sequence was employed for the metabolomics analysis and MEE was calculated using colored Doppler echocardiography. Metabolomics data were processed using orthogonal signal correction and regression analysis was performed using the partial least squares method. Results: The mean MEE levels of HF patients and controls were 139.61±58.18 cal/min and 61.09±23.54 cal/min, respectively. Serum metabolomics varied with MEE changed, and 3-hydroxybutyrate, acetone and succinate were significantly elevated with the increasing MEE. Importantly, these three metabolites were independent of administration of angiotensin converting enzyme inhibitor, β-receptor blockers, diuretics and statins (P>0.05). Conclusions: These results suggested that in patients with heart failure, MEE elevation was associated with significant changes in serum metabolomics profiles, especially the concentration of 3-hydroxybutyrate, acetone and succinate. These compounds could be used as potential serum biomarkers to study myocardial energy mechanism in HF patients. © 2014 Du et al.

Gao J.,Southern Medical University | Gao J.,Key Laboratory for Organ Failure Research | Shao Y.,Southern Medical University | Shao Y.,General Hospital of Jinan Military Region | And 6 more authors.
Journal of Human Genetics | Year: 2010

The role of an advanced glycation end product/receptor for advanced glycation end product (AGE/RAGE) system in the pathogenesis of coronary artery disease (CAD) is not fully understood. To clarify whether polymorphisms of the RAGE gene were related to CAD, we performed a case-control study in Chinese Han patients. The allele frequencies and genotype distribution combinations of the -429T/C, 1704G/T and G82S polymorphisms of the RAGE gene were compared in 200 cases of hypertension (HT), 155 cases of CAD combined with HT (CAD&HT), 175 cases of CAD and 170 control subjects. Polymerase chain reaction-restriction fragment length polymorphism was used for detection of genotypic variants. The S allele frequency of the G82S polymorphism was higher in the CAD (odds ratio (OR), 2.303, 95% confidence interval (CI) 1.553-3.416; P<0.001, P corr<0.003) and CAD&HT (OR, 1.842; 95% CI 1.219-2.785; P<0.003, P corr 0.009) groups when compared with the control group. However, the S allele frequency was not significantly different between the CAD and the CAD&HT patient groups (P=0.223), and no statistically significant difference of genotype or allele frequency distributions was observed in the HT group (P>0.05). Meanwhile, serum CRP was significantly associated with the G82S variant. Haplotype-based logistic regression analysis revealed that haplotype G-Ser-T (OR, 1.670; 95% CI, 1.017-2.740; P=0.043), compared with the reference haplotype T-Gly-T, was associated with an increased risk of CAD after adjusting for other risk factors. Further analysis limited to non-diabetic participants exhibited similar significant findings. The haplotype carrying the G82S variant of the RAGE gene was significantly associated with an increased risk of CAD, but not with HT patients. Moreover, a remarkable association of the G82S variant with serum CRP levels implied that the prevalence of RAGE 82S allelic variation might influence susceptibility to CAD by affecting vascular inflammation. © 2010 The Japan Society of Human Genetics All rights reserved.

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