Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Solid tumors, which routinely experience necrosis and ischemia, release and degrade adenine nucleotides. This process may lead, depending on the expression of enzymes that regulate adenosine, to the generation of extracellular adenosine. Since genes encoding ecto-5'-nucleotidase (eN) and adenosine deaminase (ADA) contain TCF/LEF consensus binding sites, we asked whether Wnt/beta-catenin signaling, a pathway that is deregulated in several human tumors, targets the expression of these genes and thus influence extracellular adenosine generation. Our results show that beta-catenin strongly increased the activity of the 969-bp promoter of eN and this increase depended on the presence of TCF-1 transcription factor. Reciprocally, the eN promoter activity was decreased by co-transfection of APC, a beta-catenin antagonist. The expression of endogenous eN mRNA was increased either in Cos-7 cells transfected with a mutated beta-catenin and TCF-1 or in Rat-1 cells transformed by the Wnt-1 oncogene. In Rat-1 cells, expression of Wnt-1 correlated with increased eN protein levels and enzymatic activity and a concomitant decrease of adenosine deaminase mRNA and enzymatic activity. This expression profile is accompanied by a threefold increase in the generation of extracellular adenosine. Our study demonstrates a link between the Wnt signaling and the regulation of two enzymes that control the metabolism of adenosine.
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PMID:Wnt and beta-catenin signaling target the expression of ecto-5'-nucleotidase and increase extracellular adenosine generation. 1514 41

It is well established that a condition of hypercoagulation due to deficiencies of antithrombin III, protein C and protein S may result in thrombo-embolism. To evaluate the possibility of hypercoagulation in acute mesenteric ischemia (AMI); clinical features, ECG changes, drug history, the length of intestine remaining after the resection and mortality of 15 consecutive patients were recorded and plasma levels of antithrombin III, Protein C and protein S were measured. Antihypertensive, antidiabetic and digitalis were the main drugs used by the patients. Atrial fibrillation was the main ECG finding (60%). AMI was attributed to thrombo-embolic phenomena because of atrial fibrillation in these patients. Levels of antithrombin III and protein S were lower in patients without atrial fibrillation compared to those with the condition (mean values 16.18 vs. 18.04 and 87.33 vs. 94.22 respectively) but the difference was not statistically significant. Levels of Protein C were lower and the length of intestine remaining after resection was shorter in patients without, compared to those with, atrial fibrillation (mean values 77.00 vs. 88.66, and 52.5 cm vs. 86.11 cm respectively). The difference was statistically significant (p < 0.05). Postoperative mortality rate was 33.3% (5 patients) and the length of intestine remaining after resection was the main determining factor in the prognosis of the patients. We conclude that a condition of hypercoagulation due to a deficiency of protein C has a significant role in the pathogenesis of AMI especially in patients without atrial fibrillation.
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PMID:Significance of antithrombin III, protein C and protein S in acute mesenteric ischemia patients. 1515 76

The last few years have clarified the tight link between inflammation and coagulation. In addition to the identification of new regulatory mechanisms of the coagulation system and of an explosive number of mediators of inflammation, it is now clear that the existence of a positive feed-back between inflammation and coagulation leads to reciprocal activation of both pathways. Plasma levels of acute phase proteins involved in coagulation and fibrinolysis are elevated during inflammation, while natural anticoagulant mechanisms are depressed. Pro-inflammatory cytokines "activate" cell membranes exposed to flowing blood (endothelium, platelets, monocytes, neutrophils) which from physiologically inert or anticoagulant become procoagulant. Increased tissue factor expression results in increased thrombin formation within the microcirculation. Thrombin is central to fibrin deposition but it also plays a key role in cell-mediated mechanisms involving inflammation, cell proliferation and activation of the natural anticoagulant protein C. Depression of natural anticoagulant mechanisms, occurring in severe sepsis, results in uncontrolled thrombin formation, with pro-inflammatory activity prevailing, and the feed-back loop of inflammation and coagulation ultimately leading to multi-organ failure. However, both in the clinical setting and in animal experiments, heparin or direct anticoagulants have shown no effect on survival even if blocking fibrin deposition. Organ failure is only partially due to the thrombotic occlusion of the microcirculation, while other mechanisms of endothelial damage are probably more relevant in the development of ischemia. The endothelium is central to the maintenance of the natural anticoagulant mechanisms (TFPI, antithrombin, protein C). The protein C system, in addition to dumping thrombin formation, specifically modulates inflammation by cell signaling. This system is markedly depressed in severe sepsis. The infusion of activated protein C, or restoring normal levels of protein C within the circulation - depending on the individual bleeding risk are powerful tools to treat the endothelitis responsible for the clinical sequelae of severe sepsis.
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PMID:[Protein C and coagulation in sepsis]. 1518 14

In France, the incidence of meningococcal infections is increasing and the most severe presentation, called purpura fulminans, has still a death rate of 20-25%. Diagnosis of invasive meningococcal infection must be evoked in any child presenting with febrile purpura (vasculitic rash not disappearing with "tumbler test"); a fulminating form must be suspected in the presence of only one ecchymosis and signs of infection, remembering that recognition of shock is difficult in children. The Health Authority recommend to administer a third generation cephalosporin promptly for any child with signs of infection and an ecchymotic purpura (>3 mm of diameter), and then to refer the patient to the hospital. Children with purpura fulminans should be referred to a paediatric intensive care unit. Management includes antibiotics, steroids, fluid resuscitation and catecholamines (be aware of hypoglycaemia, particularly in infants, and hypocalcaemia). Treatment of cutaneous necrosis and distal ischemia is difficult and still controversial: antithrombin, protein C, tissue plasminogen activator and vasodilator infusion have no proved efficacy. Cases must be rapidly notified to the Public Health Service who will institute chemoprophylaxis for close contacts. Given the predominance of serogroup B in France, we hope that an efficient vaccine will soon become available.
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PMID:[Meningococcal purpura fulminans in children]. 1529 72

Activated protein C (APC), a natural anticoagulant, is formed from protein C by the action of thrombin bound to thrombomodulin on the endothelial cell surface. APC regulates the coagulation system by inactivating the activated form of factors V and VIII in the presence of protein S. Tumor necrosis factor-alpha (TNF-alpha) plays critical roles in the development of disseminated intravascular coagulation, acute respiratory distress syndrome and shock in sepsis by inducing endothelial cell damage through activation of neutrophils. APC reduces the pulmonary endothelial cell injury and hypotension in rats administered endotoxin (ET) by inhibiting TNF-alpha production through inhibition of its transcription. Furthermore, APC reduces the ischemia/reperfusion-induced renal injury and the stress-induced gastric mucosal injury in rats. Inhibition by APC of the endothelial cell damage inhibited the decrease in the endothelial production of prostacyclin in vivo. These therapeutic effects could not be attributed to its anticoagulant effects, but to inhibition of TNF-alpha production. APC inhibits ET-induced TNF-alpha production in vitro in human monocytes by inhibiting activation of NFkappaB and AP-1 by inhibiting degradation of IkappaB and mitogen-activated protein kinase pathways, respectively. Recombinant APC was reported to reduce the mortality of patients with severe sepsis. These observations strongly suggest that APC might be involved not only in regulation of the coagulation system, but in regulation of inflammatory responses by preventing endothelial cell injury. Furthermore, APC reduced the spinal cord injury induced by compression-trauma or ischemia/reperfusion by inhibiting TNF-alpha production in rats, suggesting that APC may be a potential therapeutic agent for spinal cord injury in which only limited therapeutic measures are currently available.
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PMID:Prevention of endothelial cell injury by activated protein C: the molecular mechanism(s) and therapeutic implications. 1532 May 13

Activation of the coagulation cascade during invasive infection can result in purpura fulminans, with rapid progression of tissue ischemia, or may manifest as abnormal clotting indices alone. Although severe derangements in coagulation are associated with organ dysfunction and increased mortality, the contribution of coagulopathy to the pathophysiology of sepsis remains incompletely understood. Over the past decade, investigators have evaluated several therapeutic anticoagulant strategies in sepsis, and manipulation of the coagulation system has emerged as a key concept in the current management of this disease. Clinical observations during treatment of septic patients with the endogenous anticoagulant activated protein C have stimulated additional study of interactions between endothelial injury, coagulation, and inflammation. This review describes clotting abnormalities during sepsis and discusses the clinical experience with therapeutic strategies intended to oppose excessive coagulation.
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PMID:Coagulation in sepsis. 1548 34

Although thrombolytic effects of tissue plasminogen activator (tPA) are beneficial, its neurotoxicity is problematic. Here, we report that tPA potentiates apoptosis in ischemic human brain endothelium and in mouse cortical neurons treated with N-methyl-D-aspartate (NMDA) by shifting the apoptotic pathways from caspase-9 to caspase-8, which directly activates caspase-3 without amplification through the Bid-mediated mitochondrial pathway. In vivo, tPA-induced cerebral ischemic injury in mice was reduced by intracerebroventricular administration of caspase-8 inhibitor, but not by caspase-9 inhibitor, in contrast to controls in which caspase-9 inhibitor, but not caspase-8 inhibitor, was protective. Activated protein C (APC), a serine protease with anticoagulant, anti-inflammatory and antiapoptotic activities, which is neuroprotective during transient ischemia and promotes activation of antiapoptotic mechanisms in brain cells by acting directly on endothelium and neurons, blocked tPA vascular and neuronal toxicities in vitro and in vivo. APC inhibited tPA-induced caspase-8 activation of caspase-3 in endothelium and caspase-3-dependent nuclear translocation of apoptosis-inducing factor in NMDA-treated neurons and reduced tPA-mediated cerebral ischemic injury in mice. Data suggest that tPA shifts the apoptotic signal in stressed brain cells from the intrinsic to the extrinsic pathway which requires caspase-8. APC blocks tPA's neurovascular toxicity and may add substantially to the effectiveness of tPA therapy for stroke.
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PMID:Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. 1558 Feb 49

Catastrophic antiphospholipid syndrome (CAPS) is a severe and rare variant of antiphospholipid syndrome (APS) characterized by acute multiorgan failure due to small vessel thrombi in patients with positive antiphospholipid antibodies. We report a fatal case of catastrophic antiphospholipid syndrome in a young woman with a history of polymyositis and Hodgkin lymphoma. The patient was admitted to hospital because of severe foot pain following several weeks of skin ulcerations. Doppler ultrasonography showed evidence of arterial ischemia of the both lower extremities. Despite anticoagulation, immunosuppression, plasmapheresis and antibiotic therapy, she developed cutaneous gangrene, retroperitoneal hematoma, ileus, and acute respiratory and renal failure that resulted in death. Autopsy showed multifocal vascular injury and microthrombi with associated hemorrhages and infarcts in multiple organs. The patient had normal levels of functional protein C and protein S and a normal level of plasma homocysteine. Tests for common thromophilic gene mutations including prothrombin 20210, factor V Leiden 1691, and methylene tetrahydrofolate reductase 677 were negative. To our knowledge, this is the first CAPS patient with molecular studies for genetic prothrombotic mutations. Our report showed that there was no association between the development of CAPS and inherited thromophilia.
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PMID:Catastrophic antiphospholipid syndrome: a rare cause of disseminated microvascular thrombotic injury - a case report with pathological and molecular correlative studies. 1574 23

We studied the role of endogenous activated protein C (APC), the major physiological anti-coagulant with concomitant anti-inflammatory properties, on ischemia/reperfusion (I/R) in 45 patients participating in a larger trial comparing three immunosuppressive protocols in cadaveric renal transplantation: perioperative anti-thymocyte globulin (ATG, Fresenius AG, Bad Homburg, Germany), perioperative basiliximab and conventional triple therapy. Blood samples for assessing plasma APC, protein C, and lactoferrin concentrations, neutrophil CD11b and L-selectin expressions and blood leukocyte differential counts were obtained preoperatively and before reperfusion from central venous cannula, complemented with simultaneous samples from iliac artery and graft vein for calculation of transrenal differences (Delta) of study parameters at 1 and 5 min after reperfusion. Unlike basiliximab or conventional therapy groups, ATG infusion induced a substantial increase in plasma APC concentration (119 [88-144]% before infusion vs. 232 [85-1246]% after infusion, p<0.001), resulting in renal graft sequestration of APC at 1 min after reperfusion (Delta=-72 [-567 to 12]%, p<0.001). Graft APC consumption was associated with transrenal reduction of neutrophil activation markers (L-selectin r=0.7, p=0.01; lactoferrin r=-0.6, p=0.02; CD11b r=-0.8, p=0.001), and with both warm (r=0.6, p=0.01) and cold ischemia time (r=0.6, p=0.02) and donor age (r=0.6, p=0.01). These findings suggest that APC has an anti-inflammatory role in I/R injury in clinical renal transplantation.
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PMID:Activated protein C reduces graft neutrophil activation in clinical renal transplantation. 1609 99

Calciphylaxis is a rare condition of induced systemic hypersensitivity in which tissues respond to appropriate challenging agents with a sudden local calcification. It is characterized by acute calcium deposition in the medial layer of small and intermediate dermal vasculature that can lead to epidermal ischemia, ulceration, and necrosis. Calciphylaxis typically occurs in patients with end-stage renal disease who are undergoing dialysis and who have secondary hyperparathyroidism. Even in this population the incidence is less than 1%. The cause of calciphylaxis is unknown. However, it has been suggested that deficiencies of protein C and protein S may play a role in the pathophysiology of this disorder. Our patient is the fourth with cirrhosis to be reported to have developed calciphylaxis and adds further evidence that low levels of these anticoagulant factors may be an important etiologic factor for development of calciphylaxis. This report should alert the clinician that calciphylaxis occurs in patients with cirrhosis and should stimulate further research concerning the possible role of protein C and protein S deficiency in calciphylaxis.
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PMID:Calciphylaxis: a rare association with alcoholic cirrhosis. Are deficiencies in protein C and S the cause? 1610 46


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