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author:("Hu, jingning")
Non-surgical bleeding (NSB) is a major complication among heart failure (HF) patients supported by CF-LVADs. Understanding the hemostatic defects contributing to NSB after CF-LVAD implantation is crucial for prevention of this adverse event. The aim of this study was to examine the link between platelet GPIbα ectodomain shedding and NSB in CF-LVAD recipients and to identify a potential biomarker of NSB.
Serial blood samples were collected from thirty five HF patients supported with CF-LVADs. Platelet function was evaluated by Platelet Function Analyzer 100® and thromboelastography (TEG). Platelet GPIbα shedding, von Villebrand factor (vWF) antigen and vWF collagen binding capacity were determined using enzyme-linked immunosorbent assays (ELISAs). The structural analysis of vWF was performed by gel electrophoresis. These platelet functional measures with vWF parameters of the patients who experienced NSB between 4 to 32 days after CF-LVAD implantation (bleeder) were analyzed against those without NSB (non-bleeder). Blood samples from seven healthy individuals were collected to obtain the healthy reference values for the laboratory assays.
Elevated GPIbα shedding was found to be a preexisting condition in all HF patients prior to CF-LVAD implantation. Post-operative level of GPIbα shedding increased and remained elevated in the bleeder group while a consistent decrease was found in the non-bleeder group. A receiver operating characteristic (ROC) analysis indicated that the level of GPIbα shedding has a predictive power of NSB in patients supported with CF-LVADs.
Platelet GPIbα ectodomain shedding which attenuates platelet reactivity is associated with NSB. Plasma GPIbα level may potentially be used to refine bleeding risk stratification in CF-LVAD patients.
PMCID: PMC3947169  PMID: 24055626
heart failure; left ventricular assist device; non-surgical bleeding; platelet GPIbα shedding
3.  Mesenchymal Stem Cell Transplantation Improves Regional Cardiac Remodeling Following Ovine Infarction 
This study tested the hypothesis that mesenchymal stem cells (MSCs) could improve pathological remodeling of the adjacent myocardium abutting the infarct after myocardial infarction. Allogeneic ovine MSCs were transplanted into the adjacent zone by intracardiac injection 4 hours after infarction. Results showed that remodeling and contractile strain alteration were improved in the adjacent zone of the MSC-treated group.
Progressive cardiac remodeling, including the myopathic process in the adjacent zone following myocardial infarction (MI), contributes greatly to the development of cardiac failure. Cardiomyoplasty using bone marrow-derived mesenchymal stem cells (MSCs) has been demonstrated to protect cardiomyocytes and/or repair damaged myocardium, leading to improved cardiac performance, but the therapeutic effects on cardiac remodeling are still under investigation. Here, we tested the hypothesis that MSCs could improve the pathological remodeling of the adjacent myocardium abutting the infarct. Allogeneic ovine MSCs were transplanted into the adjacent zone by intracardiac injection 4 hours after infarction. Results showed that remodeling and contractile strain alteration were reduced in the adjacent zone of the MSC-treated group. Cardiomyocyte hypertrophy was significantly attenuated with the normalization of the hypertrophy-related signaling proteins phosphatidylinositol 3-kinase α (PI3Kα), PI3Kγ, extracellular signal-regulated kinase (ERK), and phosphorylated ERK (p-ERK) in the adjacent zone of the MSC-treated group versus the MI-alone group. Moreover, the imbalance of the calcium-handling proteins sarcoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA2a), phospholamban (PLB), and sodium/calcium exchanger type 1 (NCX-1) induced by MI was prevented by MSC transplantation, and more strikingly, the activity of SERCA2a and uptake of calcium were improved. In addition, the upregulation of the proapoptotic protein Bcl-xL/Bcl-2-associated death promoter (BAD) was normalized, as was phospho-Akt expression; there was less fibrosis, as revealed by staining for collagen; and the apoptosis of cardiomyocytes was significantly inhibited in the adjacent zone by MSC transplantation. Collectively, these data demonstrate that MSC implantation improved the remodeling in the region adjacent to the infarct after cardiac infarction in the ovine infarction model.
PMCID: PMC3659738  PMID: 23197875
Adult stem cells; Mesenchymal stem cells; Stem cell transplantation; Myocardial infarction; Heart remodeling
4.  Effects of Long-Term Cranberry Supplementation on Endocrine Pancreas in Aging Rats 
The effects of long-term cranberry consumption on age-related changes in endocrine pancreas are not fully understood. Here we treated male Fischer 344 rats with either 2% whole cranberry powder supplemented or normal rodent chow from 6 to 22 month old. Both groups displayed an age-related decline in basal plasma insulin concentrations, but this age-related decline was delayed by cranberry. Cranberry supplementation led to increased β-cell glucose responsiveness during the oral glucose tolerance test. Portal insulin concentration was 7.6-fold higher in rats fed cranberry, coupled with improved β-cell function. However, insulin resistance values were similar in both groups. Total β-cell mass and expression of pancreatic and duodenal homeobox 1 and insulin within islets were significantly enhanced in rats fed cranberry relative to controls. Furthermore, cranberry increased insulin release of an insulin-producing β-cell line, revealing its insulinotropic effect. These findings suggest that cranberry is of particular benefit to β-cell function in normal aging rats.
PMCID: PMC3193520  PMID: 21768504
Cranberry; Insulin release; Pancreatic β-cell function; Pancreatic β-cell mass; Aging
5.  Adiponectin protects rat hippocampal neurons against excitotoxicity 
Age  2010;33(2):155-165.
Adiponectin exerts multiple regulatory functions in the body and in the hypothalamus primarily through activation of its two receptors, adiponectin receptor1 and adiponectin receptor 2. Recent studies have shown that adiponectin receptors are widely expressed in other areas of the brain including the hippocampus. However, the functions of adiponectin in brain regions other than the hypothalamus are not clear. Here, we report that adiponectin can protect cultured hippocampal neurons against kainic acid-induced (KA) cytotoxicity. Adiponectin reduced the level of reactive oxygen species, attenuated apoptotic cell death, and also suppressed activation of caspase-3 induced by KA. Pretreatment of hippocampal primary neurons with an AMPK inhibitor, compound C, abolished adiponectin-induced neuronal protection. The AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, attenuated KA-induced caspase-3 activity. These findings suggest that the AMPK pathway is critically involved in adiponectin-induced neuroprotection and may mediate the antioxidative and anti-apoptotic properties of adiponectin.
PMCID: PMC3127462  PMID: 20842535
Adiponectin; Neuroprotection; Hippocampus; Kainic acid; AMPK
6.  The Recombination Protein RAD52 Cooperates with the Excision Repair Protein OGG1 for the Repair of Oxidative Lesions in Mammalian Cells▿  
Molecular and Cellular Biology  2009;29(16):4441-4454.
Oxidized bases are common types of DNA modifications. Their accumulation in the genome is linked to aging and degenerative diseases. These modifications are commonly repaired by the base excision repair (BER) pathway. Oxoguanine DNA glycosylase (OGG1) initiates BER of oxidized purine bases. A small number of protein interactions have been identified for OGG1, while very few appear to have functional consequences. We report here that OGG1 interacts with the recombination protein RAD52 in vitro and in vivo. This interaction has reciprocal functional consequences as OGG1 inhibits RAD52 catalytic activities and RAD52 stimulates OGG1 incision activity, likely increasing its turnover rate. RAD52 colocalizes with OGG1 after oxidative stress to cultured cells, but not after the direct induction of double-strand breaks by ionizing radiation. Human cells depleted of RAD52 via small interfering RNA knockdown, and mouse cells lacking the protein via gene knockout showed increased sensitivity to oxidative stress. Moreover, cells depleted of RAD52 show higher accumulation of oxidized bases in their genome than cells with normal levels of RAD52. Our results indicate that RAD52 cooperates with OGG1 to repair oxidative DNA damage and enhances the cellular resistance to oxidative stress. Our observations suggest a coordinated action between these proteins that may be relevant when oxidative lesions positioned close to strand breaks impose a hindrance to RAD52 catalytic activities.
PMCID: PMC2725742  PMID: 19506022
7.  Adipogenic Signaling in Rat White Adipose Tissue: Modulation by Aging and Calorie Restriction 
Experimental gerontology  2007;42(8):733-744.
Alterations in adipogenesis could have significant impact on several aging processes. We previously reported that calorie restriction (CR) in rats significantly increases the level of circulating adiponectin, a distinctive marker of differentiated adipocytes, leading to a concerted modulation in the expression of key transcription target genes and, as a result, to increased fatty acid oxidation and reduced deleterious lipid accumulation in other tissues. These findings led us to investigate further the effects of aging on adipocytes and to determine how CR modulates adipogenic signaling in vivo. CR for 2 and 25 months, significantly increased the expression of PPARγ, C/EBPβ and Cdk-4, and partially attenuated age-related decline in C/EBPα expression relative to rats fed ad libitum (AL). As a result, adiponectin was upregulated at both mRNA and protein levels, resulting in activation of target genes involved in fatty acid oxidation and fatty acid synthesis, and greater responsiveness of adipose tissue to insulin. Moreover, CR significantly decreased the ratio of C/EBPß isoforms LAP/LIP, suggesting the suppression of gene transcription associated with terminal differentiation while facilitating preadipocytes proliferation. Morphometric analysis revealed a greater number of small adipocytes in CR relative to AL feeding. Immunostaining confirmed that small adipocytes were more strongly positive for adiponectin than the large ones. Overall these results suggest that CR increased the expression of adipogenic factors, and maintained the differentiated state of adipocytes, which is critically important for adiponectin biosynthesis and insulin sensitivity.
PMCID: PMC1978194  PMID: 17624709
C/EBPs; PPAR; Lipid Metabolism; Insulin Sensitivity; Insulin/Insulin-Like Signaling
8.  Phosphorylation of human oxoguanine DNA glycosylase (α-OGG1) modulates its function 
Nucleic Acids Research  2005;33(10):3271-3282.
Oxoguanine DNA glycosylase (OGG1) initiates the repair of 8-oxoguanine (8-oxoG), a major oxidative DNA base modification that has been directly implicated in cancer and aging. OGG1 functions in the base excision repair pathway, for which a molecular hand-off mechanism has been proposed. To date, only one functional and a few physical protein interactions have been reported for OGG1. Using the yeast two-hybrid system and a protein array membrane, we identified two novel protein interactions of OGG1, with two different protein kinases: Cdk4, a serine-threonine kinase, and c-Abl, a tyrosine kinase. We confirmed these interactions in vitro using recombinant proteins and in vivo by co-immunoprecipitation from whole cell extracts. OGG1 is phosphorylated in vitro by Cdk4, resulting in a 2.5-fold increase in the 8-oxoG/C incision activity of OGG1. C-Abl tyrosine phosphorylates OGG1 in vitro; however, this phosphorylation event does not affect OGG1 8-oxoG/C incision activity. These results provide the first evidence that a post-translational modification of OGG1 can affect its catalytic activity. The distinct functional outcomes from serine/threonine or tyrosine phosphorylation may indicate that activation of different signal transduction pathways modulate OGG1 activity in different ways.
PMCID: PMC1143695  PMID: 15942030

Results 1-8 (8)