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)

Cytokines regulate both aspecific inflammatory responses and specific immune responses. Inflammatory changes occur in the organ transplant as a result of tissue trauma and ischemia/reperfusion in the organ donor and at the time of transplant operation. There is a possibility that cytokines play a role in mediating theses changes. These aspecific inflammatory changes may not only affect graft function but also influence graft immunogenicity (enhanced MHC and adhesion molecule expression) and thus, vulnerability to rejection. Cytokines orchestrate the specific immune response elicited by organ transplantation. Relevance of cytokines to the rejection reaction is multifactorial in nature: 1) promotion of the proliferation an differentiation of specific alloreactive T and B cells clones and differentiation and activation of CTL and NK cells, 2) chemotactic effect and induction of the expression of adhesion molecules, 3) enhancement of MHC class I and II expression, and 4) direct cytotoxic effect on the target grafted cells. Therefore, modulation of cytokine activity either specifically (monoclonal antibody, soluble receptor, etc.) or aspecifically (cyclosporin, FK 506, Rapamycin, steroids, etc.) is essential in controlling graft rejection. Determination of circulating cytokines and cytokines measurement within the biological fluids produced by an organ transplant may help in the diagnosis of rejection episodes and other complications following organ transplantation.
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PMID:Cytokines and organ transplantation. A review. 923 12

The neuroprotective properties of drugs binding to FKBP12, with and without subsequent inhibition of calcineurin, were investigated in rat models of ischemic embolic stroke. Drug effects on brain infarct volumes evoked by transient middle cerebral artery occlusion (MCAO) and by permanent MCAO were determined in vivo by T2-weighted magnetic resonance imaging and post mortem by triphenyltetrazolium chloride staining and histology. Drugs binding to FKBP12 and inhibiting calcineurin, such as FK506 and SDZ ASM 981, dose dependently reduced the infarct volumes, determined 48 h after MCAO by both magnetic resonance imaging and triphenyltetrazolium chloride staining but only in the transient MCAO model. In vivo potencies to reduce brain infarcts paralleled the in vitro potencies to inhibit calcineurin. Histological staining after 6 days of survival showed that the neuroprotective effects were permanent. Rapamycin, known to bind with similar affinity to FKBP12 but not to inhibit calcineurin, was not neuroprotective but abolished the neuroprotective effects of FK506 when coadministered. In the permanent MCAO models, FK506 showed no effect when injected before and little effect when injected after MCAO. Measurements of core temperatures after MCAO in controls and drug-treated rats do not support hypothermia being the mechanism responsible for neuroprotection. We conclude that drugs inhibiting calcineurin activity are neuroprotective in focal cerebral ischemia/reperfusion but not in permanent ischemia models, possibly by preventing reperfusion injury.
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PMID:Calcineurin inhibitors FK506 and SDZ ASM 981 alleviate the outcome of focal cerebral ischemic/reperfusion injury. 991 71

Ischaemia was obtained in vitro by subjecting nerve-growth-factor-differentiated PC12 cells to glucose deprivation plus anoxia. During ischaemia the rate of protein synthesis was significantly inhibited, and eIF4E-binding protein (4E-BP1) and eukaryotic initiation factor 4E (eIF4E) were significantly dephosphorylated in parallel. In addition, ischaemia induced an enhancement of the association of 4E-BP1 to eIF4E, which in turn decreased eIF4F formation, whereas no degradation of initiation factor 4G was observed. The treatment of PC12 cells with the specific p38 mitogen-activated protein kinase inhibitor SB203580 induced eIF4E dephosphorylation but did not cause any effect on protein synthesis rate. Rapamycin, the inhibitor of mammalian target of rapamycin ('mTOR'), but not PD98059, the inhibitor of extracellular signal-regulated protein kinases ('ERK1/2'), induced similar effects on 4E-BP1 phosphorylation to ischaemia; nevertheless, 4E-BP1-eIF4E complex levels were higher in ischaemia than in rapamycin-treated cells. In addition, both protein synthesis rate and eIF4F formation were lower in ischaemic cells than in rapamycin-treated cells.
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PMID:Ischaemia induces changes in the association of the binding protein 4E-BP1 and eukaryotic initiation factor (eIF) 4G to eIF4E in differentiated PC12 cells. 1102 17

The immunosuppressive effect of rapamycin is mediated by inhibition of interleukin-2-stimulated T cell proliferation. We report for the first time that rapamycin also inhibits growth factor-induced proliferation of cultured mouse proximal tubular (MPT; IC(50) ~1 ng/ml) cells and promotes apoptosis of these cells by impairing the survival effects of the same growth factors. On the basis of these in vitro data, we tested the hypothesis that rapamycin would impair recovery of renal function after ischemic acute renal failure induced in vivo by renal artery occlusion (RAO). Rats given daily injections of rapamycin or vehicle were subjected to RAO or sham surgery. Rapamycin had no effect on the glomerular filtration rate (GFR) of sham-operated animals. In rats subjected to RAO, GFR fell to comparable levels 1 day later in vehicle- and rapamycin-treated rats (0.25 +/- 0.08 and 0.12 +/- 0.05 ml. min(-1). 300 g(-1), respectively) (P = not significant). In vehicle-treated rats subjected to RAO, GFR increased to 0.61 +/- 0.08 ml. min(-1). 300 g(-1) on day 3 (P < 0.02 vs. day 1) and then rose further to 0.99 +/- 0.09 ml. min(-1). 300 g(-1) on day 4 (P < 0.02 vs. day 3). By contrast, GFR did not improve in rapamycin-treated rats subjected to RAO over the same time period. Rapamycin also increased apoptosis of tubular cells while markedly reducing their proliferative response after RAO. Furthermore, rapamycin inhibited activation of 70-kDa S6 protein kinase (p70(S6k)) in cultured MPT cells as well as in the renal tissue of rats subjected to RAO. We conclude that rapamycin severely impairs the recovery of renal function after ischemia-reperfusion injury. This effect appears to be due to the combined effects of increased tubular cell loss (via apoptosis) and profound inhibition of the regenerative response of tubular cells. These effects are likely mediated by inhibition of p70(S6k).
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PMID:Rapamycin impairs recovery from acute renal failure: role of cell-cycle arrest and apoptosis of tubular cells. 1155 17

Renal tubular cells die by apoptosis as well as necrosis in experimental models of ischemic and toxic acute renal failure as well as in humans with acute tubular necrosis. It is not yet possible, however, to determine the relative contribution of these two forms of cell death to loss of renal tubular cells in acute tubular necrosis. The beneficial effect of administering growth factors to animals with acute tubular necrosis is probably related to the potent antiapoptotic (survival) effects of growth factors as well as to their proliferative effects. Rapamycin inhibits both of these effects of growth factors and delays the recovery of renal function after acute tubular necrosis by inhibiting renal tubular cell regeneration and by increasing renal tubular cell loss by apoptosis. The administration of caspase inhibitors ameliorates ischemia-reperfusion injury in multiple organs including the kidney. However, the extent to which this protective effect of caspase inhibition is caused by reduced intrarenal inflammation, or by amelioration of renal tubular cell loss due to apoptosis, remains uncertain. In addition to caspase inhibition, the apoptotic pathway offers many potential targets for therapeutic interventions to prevent renal tubular cell apoptosis.
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PMID:Role of apoptosis in the pathogenesis of acute renal failure. 1198 Dec 60

Elevated levels of free fatty acids (FFA) have been implicated in the pathogenesis of neuronal injury and death induced by cerebral ischemia. This study evaluated the effects of immunosuppressants agents, calcineurin inhibitors and blockade of endoplasmic reticulum (ER) calcium channels on free fatty acid formation and efflux in the ischemic/reperfused (I/R) rat brain. Changes in the extracellular levels of arachidonic, docosahexaenoic, linoleic, myristic, oleic and palmitic acids in cerebral cortical superfusates during four-vessel occlusion-elicited global cerebral ischemia were examined using a cortical cup technique. A 20-min period of ischemia elicited large increases in the efflux of all six FFAs, which were sustained during the 40 min of reperfusion. Cyclosporin A (CsA) and trifluoperazine, which reportedly inhibit the I/R elicited opening of a mitochondrial permeability transition (MPT) pore, were very effective in suppressing ischemia/reperfusion evoked release of all six FFAs. FK506, an immunosuppressant which does not directly affect the MPT, but is a calcineurin inhibitor, also suppressed the I/R-evoked efflux of FFAs, but less effectively than CsA. Rapamycin, a derivative of FK506 which does not inhibit calcineurin, did not suppress I/R-evoked FFA efflux. Gossypol, a structurally unrelated inhibitor of calcineurin, was also effective, significantly reducing the efflux of docosahexaenoic, arachidonic and oleic acids. As previous experiments had implicated elevated Ca(2+) levels in the activation of phospholipases with FFA formation, agents affecting endoplasmic reticulum stores were also evaluated. Dantrolene, which blocks the ryanodine receptor (RyR) channel of the ER, significantly inhibited I/R-evoked release of docosahexaenoic, arachidonic, linoleic and oleic acids. Ryanodine, which can either accentuate or block Ca(2+) release, significantly enhanced ischemia/reperfusion-elicited efflux of linoleic acid, with non-significant increases in the efflux of myristic, arachidonic, palmitic and oleic acids. Xestospongin C, an inhibitor of the inositol triphosphate (IP(3)R) channel, failed to affect I/R-evoked FFA efflux. Thapsigargin, an inhibitor of the Ca(2+)-ATPase ER uptake pump, elicited significant elevations in the efflux of myristic, arachidonic and linoleic acids, in the absence of ischemia. Collectively, the data suggest an involvement of both ER and mitochondrial Ca(2+) stores in the chain of events which lead to PLA(2) activation and FFA formation.
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PMID:Effects of immunosuppressants, calcineurin inhibition, and blockade of endoplasmic reticulum calcium channels on free fatty acid efflux from the ischemic/reperfused rat cerebral cortex. 1244 75

Renal transplant is the treatment of choice for the patient with end stage renal disease. Spain is the country with the highest donation rate (33 ppm). However, at present this figure is stabilized. The development of non-beating heart programmes, living-donor nephrectomy (specially laparoscopic nephrectomy) programmes, and may be xenotransplantation in a non-immediate future could increase the transplantation activity. The knowledge of preservation mechanisms, specially with the use of perfusion machines allows to rescue for transplantation kidneys with a long warm-ischemia time. Furthermore, these machines are useful for analyzing viability markers. The new immunosuppressive drugs: Tacrolimus, Mycophenolate-Mophetil, Rapamycin and monoclonal antibodies against alpha chain of the interleukine-2 receptor (Basoliximab and Dazcizumab) have reduced the incidence of acute rejection in the immediate renal transplant period. However, its effect in the long-term follow-up period is still a matter of controversy. The incidence of tumour in the renal transplant recipient is increased, specially those of lymphoma, skin cancer and Kaposi sarcoma. Periodical exams for detecting the development of tumours are mandatory in this population. Finally, xenotransplantation is an attractive alternative, although immunological, infective and ethical barriers should previously be resolved.
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PMID:[Present and future of kidney transplantation]. 1264 71

Sirolimus, a macrocyclic lactone that displays a novel mechanism of immunosuppressive action, is a critical-dose drug requiring therapeutic drug monitoring for optimal outcomes. This immunosuppressive agent was studied in two multicenter, blinded clinical trials to reduce the incidence of acute rejection episodes when used in combination with cyclosporine and steroids versus azathioprine or placebo comparators. Cyclosporine withdrawal studies documented a long-term benefit of chronic sirolimus therapy on renal function, albeit with a modestly enhanced incidence of acute rejection episodes. I believe that minimal initial cyclosporine exposures de novo mitigate the need for eventual withdrawal for chronic nephropathy while preserving the immunosuppressive synergy during the maintenance phase. Recipients treated de novo with a sirolimus-cyclosporine combination tolerate steroid withdrawal at 1 month after living-donor or at 3 to 6 months after cadaveric kidney transplantation with only a 5% risk of acute rejection episodes and 6% incidence of chronic reactions within 3 years. However, sirolimus exacerbates the hypertriglyceridemic and hypercholesterolemic proclivities of transplant recipients and exerts myelosuppressive effects. Due to its apparent lack of nephrotoxicity, sirolimus has been employed for induction therapy in a calcineurin antagonist-free regimen in combination with either basiliximab or rabbit antilymphocyte sera for weak or strong immune responders, respectively, followed by introduction of a calcineurin antagonist upon resolution of the ischemia-reperfusion injury.
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PMID:Sirolimus: a ten-year perspective. 1501 4

A prospective, pilot trial was started to evaluate the effect of a sirolimus-based immunosuppressive regimen on acute and chronic rejection in de novo lung transplant patients. Primary lung transplant (LTx) recipients received a sirolimus- and tacrolimus-based immunosuppressive therapy immediately after transplantation. Both immunosuppressants were administered with trough level adjusted, while steroid administration was minimized. Four patients were enrolled (2 single-lung transplants, 1 double-lung transplant, 1 heart-lung transplant) in the study. Mean ischemia time was 387 +/- 92 minutes. Acute rejection (at least Grade A1 ISHLT) was detected in 1 patient. Incidence of infection was 0.6 infection per 100 patient-days (3 Aspergillus infections). Until hospital discharge mean sirolimus trough level was 6.2 +/- 1.2 ng/ml. Depending upon mean sirolimus trough levels of each patient, severe wound-healing complications were seen in 3 patients, resulting in bronchial airway dehiscence in 2 patients with lethal outcome in 1 patient. As a result of these complications, we revised the study design after inclusion of only 4 patients: Sirolimus administration is now started after completion of bronchial wound-healing. Sirolimus-based immunosuppressive therapy administered immediately after lung transplantation seems to be associated with severe wound-healing complications of the bronchial anastomosis.
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PMID:Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression. 1513 83

Ischemia-reperfusion (I-R) injury in transplanted kidney, a key pathogenic event of delayed graft function (DGF), is characterized by tubular cell apoptosis and interstitial inflammation. Akt-mammalian target of rapamycin-S6k and NF-kappaB-inducing kinase (NIK)-NF-kappaB axis are the two main signaling pathways regulating cell survival and inflammation. Rapamycin, an immunosuppressive drug inhibiting the Akt axis, is associated with a prolonged DGF. The aim of this study was to evaluate Akt and NF-kappaB axis activation in patients who had DGF and received or not rapamycin and in a pig model of I-R and the role of coagulation priming in this setting. In graft biopsies from patients who were not receiving rapamycin, phosphorylated Akt increased in proximal tubular, interstitial, and mesangial cells with a clear nuclear translocation. The same pattern of activation was observed for S6k and NIK. However, in rapamycin-treated patients, a significant reduction of S6k but not Akt and NIK activation was observed. A time-dependent activation of phosphatidylinositol 3-kinase, Akt, S6k, and NIK was observed in the experimental model with the same pattern reported for transplant recipients who did not receive rapamycin. Extensive interstitial and glomerular fibrin deposition was observed both in pig kidneys upon reperfusion and in DGF human biopsies. It is interesting that the activation of both Akt and NIK-NF-kappaB pathways was induced by thrombin in cultured proximal tubular cells. In conclusion, the data suggest that (1) coagulation may play a pathogenic role in I-R injury; (2) the Akt axis is activated after I-R, and its inhibition may explain the prolonged DGF observed in rapamycin-treated patients; and (3) NIK activation in I-R and DGF represents a proinflammatory, rapamycin-insensitive signal, potentially leading to progressive graft injury.
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PMID:Ischemia-reperfusion induces glomerular and tubular activation of proinflammatory and antiapoptotic pathways: differential modulation by rapamycin. 1546 72


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