Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08758 (annexin V)
 9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously showed that neuregulin-1 (NRG-1) protected neurons from death in vivo following focal ischemia. The goal of this study was to develop an in vitro rat ischemia model to examine the cellular and molecular mechanisms involved in the neuroprotective effects of NRG-1 on ischemia-induced neuronal death. Rat B-35 neuroblastoma cells differentiated by serum withdrawal, developed enhanced neuronal characteristics including, neurite extension and upregulation of neuronal markers of differentiation. When B35 neurons were subjected to oxygen glucose deprivation (OGD)/reoxygenation or glutamate, widespread neuronal death was seen after both treatments. Treatment with NRG-1 immediately after OGD significantly increased neuronal survival. NRG-1 administration also resulted in a significant decrease in annexin V, an early marker of apoptosis. However, the neurotoxic actions of glutamate were unaffected by NRG-1. The neuroprotective effects of NRG-1 were prevented by an inhibitor of the phosphatidylinositol-3-kinase/Akt pathway. These results provide a new model to gain insight into the mechanisms employed by NRG-1 to protect neurons from ischemic brain injury.
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PMID:Neuroprotective effects of neuregulin-1 on B35 neuronal cells following ischemia. 1841 Sep 12

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) that works with a liver/kidney/intestine-restricted glucose-6-phosphatase-alpha (G6Pase-alpha) to maintain glucose homeostasis between meals. Clinically, GSD-Ib patients manifest disturbed glucose homeostasis and neutrophil dysfunctions but the cause of the latter is unclear. Neutrophils express the ubiquitously expressed G6PT and G6Pase-beta that together transport G6P into the endoplasmic reticulum (ER) lumen and hydrolyze it to glucose. Because we expected G6PT-deficient neutrophils to be unable to produce endogenous glucose, we hypothesized this would lead to ER stress and increased apoptosis. Using GSD-Ib mice, we showed that GSD-Ib neutrophils exhibited increased production of ER chaperones and oxidative stress, consistent with ER stress, increased annexin V binding and caspase-3 activation, consistent with an increased rate of apoptosis. Bax activation, mitochondrial release of proapoptotic effectors, and caspase-9 activation demonstrated the involvement of the intrinsic mitochondrial pathway in these processes. The results demonstrate that G6P translocation and hydrolysis are required for normal neutrophil functions and support the hypothesis that neutrophil dysfunction in GSD-Ib is due, at least in part, to ER stress and increased apoptosis.
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PMID:Neutrophil stress and apoptosis underlie myeloid dysfunction in glycogen storage disease type Ib. 1842 Aug 28

Angiopathy is a major complication of diabetes. Abnormally high blood glucose is a crucial risk factor for endothelial cell damage. Nuclear factor-kappaB (NF-kappaB) has been demonstrated as a mediated signaling in hyperglycemia or oxidative stress-triggered apoptosis of endothelial cells. Here we explored the efficacy of honokiol, a small molecular weight natural product, on NADPH oxidase-related oxidative stress-mediated NF-kappaB-regulated signaling and apoptosis in human umbilical vein endothelial cells (HUVECs) under hyperglycemic conditions. The methods of morphological Hoechst staining and annexin V/propidium iodide staining were used to detect apoptosis. Submicromolar concentrations of honokiol suppressed the increases of NADPH oxidase activity, Rac-1 phosphorylation, p22(phox) protein expression, and reactive oxygen species production in high glucose (HG)-stimulated HUVECs. The degradation of IkappaBalpha and increase of NF-kappaB activity were inhibited by honokiol in HG-treated HUVECs. Moreover, honokiol (0.125-1 microM) also suppressed HG-induced cyclooxygenase (COX)-2 upregulation and prostaglandin E(2) production in HUVECs. Honokiol could reduce increased caspase-3 activity and the subsequent apoptosis and cell death triggered by HG. These results imply that inhibition of NADPH oxidase-related oxidative stress by honokiol suppresses the HG-induced NF-kappaB-regulated COX-2 upregulation, apoptosis, and cell death in HUVECs, which has the potential to be developed as a therapeutic agent to prevent hyperglycemia-induced endothelial damage.
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PMID:Inhibition of NADPH oxidase-related oxidative stress-triggered signaling by honokiol suppresses high glucose-induced human endothelial cell apoptosis. 1842 12

Eryptosis, the suicidal death of erythrocytes, is characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. Eryptosis is triggered by several stress conditions including isotonic cell shrinkage (Cl(-) removal) and energy depletion (glucose removal). Both are effective through an increase in the cytosolic Ca(2+) concentration. Phosphatidylserine-exposing erythrocytes are cleared from circulating blood. Enhanced eryptosis thus leads to anemia. Accordingly, drugs interfering with eryptosis may prove useful in the treatment of anemia. The present study explored, whether caffeine interferes with eryptosis. Erythrocyte phosphatidylserine exposure was estimated from annexin V-binding, cell volume from forward scatter and cytosolic Ca(2+) activity from Fluo3 fluorescence. Under control conditions, eryptosis affected less than 5% of the erythrocytes and was not significantly modified by the presence of caffeine (50-500 microM). Glucose depletion (for 48 hours) significantly increased Fluo3 fluorescence and annexin V-binding and decreased forward scatter, effects partially reversed by caffeine (500 microM). Low Cl(-) solution (Cl(-) exchanged by gluconate for 48 hours) similarly increased annexin V-binding and decreased forward scatter, effects again reversed by caffeine (50-500 microM). In conclusion, caffeine inhibits Ca(2+) entry following glucose depletion and thus counteracts eryptosis during isotonic cell shrinkage and energy depletion.
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PMID:Caffeine inhibits suicidal erythrocyte death. 1876 52

Zidovudine, a drug widely used in the treatment of AIDS, has been shown to influence cytosolic calcium activity in HIV-infected lymphocytes. Thus, zidovudine may modify the activity of Ca(2+)-permeable ion channels. In erythrocytes, activation of Ca(2+)-permeable cation channels stimulates eryptosis, the suicidal erythrocyte death. Eryptosis is characterized by cell shrinkage (apparent from a decrease of forward scatter) and phosphatidylserine (PS) exposure (apparent from annexin V-binding) at the erythrocyte surface. Triggers of eryptosis include isotonic cell shrinkage (Cl(-) replacement by gluconate), energy depletion (removal of glucose) or exposure to a variety of drugs including azathioprine. The present study explored, whether zidovudine influences the activity of erythrocytic Ca(2+)-permeable cation channels and eryptosis. Whole-cell patch-clamp recordings indeed revealed that zidovudine blocked the Ca(2+)-permeable cation channels activated by Cl(-) removal. In the presence of Cl(-) and glucose, the percentage of annexin V-binding cells was low and not significantly modified by the presence of zidovudine. Both, Cl(-) removal and glucose depletion increased annexin V-binding and decreased forward scatter, effects significantly blunted by zidovudine (2 microg/ml). According to Fluo3 fluorescence, zidovudine (2 microg/ml) did not significantly modify cytosolic Ca(2+) concentration under control conditions, but significantly blunted the increase in cytosolic Ca(2+) activity following glucose depletion. Furthermore, zidovudine significantly inhibited azathioprine-induced eryptosis. The present observations disclose a completely novel effect of zidovudine, i.e. its inhibitory influence on Ca(2+) entry and subsequent suicidal erythrocyte death during isotonic cell shrinkage or energy depletion.
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PMID:Inhibition of cation channels and suicidal death of human erythrocytes by zidovudine. 1882 39

Diabetes can cause a wide variety of vascular complications and endothelial dysfunction. In this study, human vascular endothelial cells were exposed to 5.5 mM and 33 mM glucose for 5 d in the absence and presence of 1 to 20 mug/mL roasted licorice (Glycyrrhiza inflata Bat.) ethanol extracts (rLE). Caspase-3 activation and Annexin V staining revealed that high glucose induced endothelial apoptotic toxicity with a generation of reactive oxygen species (ROS) and these effects were reversed by rLE at >/=1 mug/mL in a dose-dependent manner. Cytoprotective rLE substantially reduced high glucose-induced expression of endothelial nitric oxide synthase (eNOS), and hence attenuated the formation of peroxynitrite radicals derived from NO. In addition, rLE suppressed expression of PKCbeta2 and activation of NADPH oxidase subunit of p22phox promoted by high glucose. However, rLE </=1 mug/mL did not modulate the high glucose-triggered activation of ASK-JNK signaling pathway. Our results suggest that PKCbeta2 expression and NADPH oxidase-dependent superoxide production and eNOS-mediated peroxynitrite generation may be essential mechanisms responsible for increased oxidative stress and endothelial apoptosis in chronic hyperglycemic conditions. Thus, rLE may be a beneficial agent most likely contributing to prevention of vascular NADPH oxidase induction and preservation of endothelial nitric oxide availability, resulting in blunting diabetes-associated endothelial dysfunction and vascular complications.
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PMID:Blockade of nitroxidative stress by roasted licorice extracts in high glucose-exposed endothelial cells. 1884 Oct 76

AMP-activated protein kinase (AMPK), an energy-sensing enzyme, counteracts energy depletion by stimulation of energy production and limitation of energy utilization. On energy depletion, erythrocytes undergo suicidal death or eryptosis, triggered by an increase in cytosolic Ca(2+) activity ([Ca(2+)](i)) and characterized by cell shrinkage and phosphatidylserine (PS) exposure at the erythrocyte surface. The present study explored whether AMPK participates in the regulation of eryptosis. Western blotting and confocal microscopy disclosed AMPK expression in erythrocytes. [Ca(2+)](i) (Fluo3 fluorescence), cell volume (forward scatter), and PS exposure (annexin V binding) were determined by fluorescence-activated cell sorting (FACS) analysis. Glucose removal increased [Ca(2+)](i), decreased cell volume, and increased PS exposure. The AMPK-inhibitor compound C (20 microM) did not significantly modify eryptosis under glucose-replete conditions but significantly augmented the eryptotic effect of glucose withdrawal. An increase in [Ca(2+)](i) by Ca(2+) ionophore ionomycin triggered eryptosis, an effect blunted by the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR; 1 mM). As compared with erythrocytes from wild-type littermates (ampk(+/+)), erythrocytes from AMPKalpha1-deficient mice (ampk(-/-)) were significantly more susceptible to the eryptotic effect of energy depletion. The ampk(-/-) mice were anemic despite excessive reticulocytosis, and they suffered from severe splenomegaly, again pointing to enhanced erythrocyte turnover. The observations disclose a critical role of AMPK in the survival of circulating erythrocytes.
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PMID:Regulation of erythrocyte survival by AMP-activated protein kinase. 1905 47

We herein report cytotoxicity of advanced glycation end-products (AGEs) on pancreatic beta cells. AGEs stimulated reactive oxygen species (ROS) generation but did not arrest proliferation of the INS-1 cell line. Pancreatic beta cell lines or primary cultured islets possess a receptor for AGE (RAGE), and its expression increased after AGE treatment. TUNEL staining and FACS analysis using annexin V/PI antibodies showed that apoptosis increased in INS-1 cells or primary cultured islets when incubated with BSA conjugated with glyceraldehyde (AGE2) or glucoaldehyde (AGE3), compared with those conjugated with glucose (AGE1). Reaction of INS-1 cells to Ki67, which is a cellular marker for proliferation, was also increased after AGE treatment. The ability of primary cultured islets to secrete insulin was retained even after AGE treatment under either low or high glucose conditions. The antiserum against RAGE partially prevented AGE-induced cellular events. Treatment of beta cells with the antioxidant metallothionein results in a significant reduction in pathologic changes. AGEs might be able to induce apoptosis as well as proliferation of pancreatic beta cell lines or primary cultured islets. Moreover, antibody array showed that RAD51 and RAD52 were significantly decreased in AGE2-treated INS-1 cells. AGEs might inhibit homologous DNA recombination for repairing DNA of INS-1 cells damaged by ROS generation. It might be suggested that treatment of AGEs resulted in ROS production and apoptosis through their receptor on pancreatic beta cells. AGEs might deteriorate function of pancreatic beta cells in patients with long-term hyperglycemia.
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PMID:Induction of apoptosis of Beta cells of the pancreas by advanced glycation end-products, important mediators of chronic complications of diabetes mellitus. 1912 Mar 18

Diabetic retinopathy (DR) is a leading cause of vision loss among working-age adults. Retinal endothelial cell apoptosis is an early event in DR, and oxidative stress is known to play an important role in this pathology. Recently, we found that high glucose induces apoptosis in retinal neural cells by a caspase-independent mechanism. Here, we investigated the mechanisms underlying retinal endothelial cell apoptosis induced by high glucose and oxidative/nitrosative stress conditions. Endothelial cells (TR-iBRB2 rat retinal endothelial cell line) were exposed to high glucose (long-term exposure, 7 days), or to NOC-18 (nitric oxide donor; 250microM) or H(2)O(2) (100microM) for 24h. Cell viability was assessed by the MTT assay and cell proliferation by [methyl-(3)H]-thymidine incorporation into DNA. Apoptotic cells were detected with Hoechst or Annexin V staining. Active caspases were detected by an apoptosis detection kit. Active caspase-3 and apoptosis-inducing factor (AIF) protein levels were assessed by Western blot or immunohistochemistry. High glucose, NOC-18 and H(2)O(2) increased apoptosis in retinal endothelial cells. High glucose and mannitol decreased cell proliferation, but mannitol did not induce apoptosis. Caspase activation did not increase in high glucose- or NOC-18-treated cells, but it increased in cells exposed to H(2)O(2). However, the protein levels of AIF decreased in mitochondrial fractions and increased in nuclear fractions, in all conditions. These results are the first demonstrating that retinal endothelial cell apoptosis induced by high glucose is independent of caspase activation, and is correlated with AIF translocation to the nucleus. NOC-18 and H(2)O(2) also activate a caspase-independent apoptotic pathway, although H(2)O(2) can also induce caspase-mediated apoptosis.
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PMID:High glucose and oxidative/nitrosative stress conditions induce apoptosis in retinal endothelial cells by a caspase-independent pathway. 1914 53

Klotho, a membrane protein mainly expressed in parathyroid glands, kidney, and choroid plexus, counteracts aging and increases the life span. Accordingly, life span is significantly shorter in Klotho-deficient mice (klotho(-/-)) than in their wild-type littermates (klotho(+/+)). The pleotropic effects of Klotho include inhibition of 1,25-dihydroxyvitamin D(3)(1,25(OH)(2)D(3)) formation. Vitamin D-deficient diet reverses the shortening of life span in klotho(-/-) mice. In a variety of cells, 1,25(OH)(2)D(3) stimulates Ca(2+) entry. In erythrocytes, increased Ca(2+) entry stimulates suicidal erythrocyte death, which is characterized by cell shrinkage and phosphatidylserine exposure at the erythrocyte surface. The present study explored the putative impact of Klotho on eryptosis. According to Fluo3 fluorescence, cytosolic Ca(2+) concentration was significantly larger in klotho(-/-) erythrocytes as compared to klotho(+/+) erythrocytes. According to annexin V-binding, phosphatidylserine exposure was significantly enhanced, and according to forward scatter, cell volume significantly decreased in klotho(-/-) erythrocytes as compared to klotho(+/+) erythrocytes. Energy depletion (13 h glucose depletion) and oxidative stress (35 min 1 mM tert-butyl-hydroxyl-peroxide [tert-BOOH]) increased phosphatidylserine exposure to values again significantly larger in klotho(-/-) erythrocytes as compared to klotho(+/+) erythrocytes. Reticulocyte number was significantly increased in klotho (-/-) mice, pointing to enhanced erythrocyte turnover. Vitamin D-deficient diet reversed the enhanced Ca(2+) entry and annexin V-binding of klotho(-/-) erythrocytes. The present observations reveal a novel function of Klotho, i.e., the at least partially vitamin D-dependent regulation of cytosolic Ca(2+) activity in and suicidal death of erythrocytes.
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PMID:Accelerated suicidal erythrocyte death in Klotho-deficient mice. 1918 92


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