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)

Therapeutic effects of four types of recombinant superoxide dismutase (SOD) derivatives, conjugates with polysaccharides, carboxymethyl (SOD-CMD) and diethylaminoethyl (SOD-DEAED) dextrans and galactosylated (Gal-SOD) and mannosylated (Man-SOD) derivatives, on hepatic ischemia/reperfusion injury were studied in rats. Hepatic injury induced by transient occlusion and subsequent reflow of hepatic blood was evaluated by the analysis of biliary excretion of bromosulfophthalein (BSP) injected intravenously. At a dose of 10000 units/kg, native SOD and SOD-DEAE did not show any significant effect and SOD-CMD showed slight effect. On the other hand, Gal-SOD and Man-SOD, targeted to the liver parenchymal and nonparenchymal cells, respectively, by a receptor-mediated endocytosis, exhibited superior inhibitory effects. These results demonstrated that these glycosylated SOD derivatives were useful for the prevention of hepatic ischemia/reperfusion injury.
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PMID:Therapeutic effects of superoxide dismutase derivatives modified with mono- or polysaccharides on hepatic injury induced by ischemia/reperfusion. 144 73

Arterial gene transfer offers a promising new approach for the treatment of vascular disorders. However, no data are available about the gene transfer efficiency in human arteries in vivo. The aim of this study was to evaluate the safety and feasibility of catheter-mediated adenoviral gene transfer in human peripheral arteries. Ten patients (8 females, 2 males, mean age 80 +/- 8 years) suffering from chronic critical leg ischemia with a prior decision for amputation were recruited in the study. Gene transfer was performed in eight patients in conjunction with a conventional percutaneous transluminal angioplasty, using a perfusion coil balloon catheter. Two patients served as controls. Increasing concentrations of replication-deficient adenoviruses (titers from 1 x 10(8) to 4 x 10(10) PFU) containing a nuclear-targeted beta-galactosidase marker gene were administered into the arteries over 10 min via the catheter. Amputations were performed 20 to 51 hr after the procedures and gene transfer efficiency was evaluated in the transduced arteries using X-Gal staining for beta-galactosidase activity. Beta-galactosidase gene transfer was well tolerated and no adverse tissue responses or systemic complications were observed in any of the patients. Gene transfer was successful in six of the eight patients. Gene transfer efficiency varied between 0.04 and 5.0% of all arterial cells. Transgene expression was detected in smooth muscle cells, endothelial cells, and macrophages and in tunica adventitia. However, transgene activity was not evenly distributed in the arterial wall and no transgene activity was found beneath advanced atherosclerotic lesions. The safety and feasibility of in vivo gene transfer by adenoviral vectors to human peripheral arteries were established. Although improvements are still required in gene transfer efficiency, these findings suggest that adenoviruses can be used to deliver therapeutically active genes into human arteries.
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PMID:Adenovirus-mediated gene transfer to lower limb artery of patients with chronic critical leg ischemia. 968 19

Four types of bovine liver catalase (CAT) derivatives, succinylated (Suc-CAT), galactosylated (Gal-CAT), mannosylated (Man-CAT), and polyethylene glycol conjugate (PEG-CAT), were synthesized and their pharmacokinetics and therapeutic potential in a hepatic ischemia/reperfusion injury model were studied in mice. About 90% of the CAT enzymatic activity was retained after chemical modification. Biodistribution studies showed that 111indium (111In)-Gal-CAT accumulated selectively in the liver parenchymal cells as 111In-CAT, whereas an increased amount of 111In-Suc-CAT and 111In-Man-CAT was delivered to liver nonparenchymal cells. 111In-PEG-CAT exhibited prolonged retention in plasma. Pharmacokinetic analysis revealed that the hepatic uptake clearances of 111In-Suc-CAT, 111In-Gal-CAT, and 111In-Man-CAT were much greater than that of 111In-CAT, whereas that of 111In-PEG-CAT was very small. In the ischemia/reperfusion injury model, in which hepatic injury was induced by occlusion of the portal vein for 30 min followed by 1 h reperfusion, the elevation of plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase levels was slightly inhibited by treatment with native CAT or Gal-CAT. PEG-CAT was less potent. In contrast, Suc-CAT and Man-CAT effectively suppressed the increase in plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase. Coinjection of mannosylated superoxide dismutase marginally improved the inhibitory effects of CAT derivatives. These results demonstrate that targeted CAT delivery to liver nonparenchymal cells via chemical modification is a promising approach to prevent hepatic injuries caused by reactive oxygen species. The potential usefulness of combining of CAT and superoxide dismutase derivatives is also demonstrated.
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PMID:Targeted delivery and improved therapeutic potential of catalase by chemical modification: combination with superoxide dismutase derivatives. 1021 2

Leucocyte migration into lymphatic tissues or inflammatory sites depends upon the expression of adhesion molecules. Among these molecules, the selectins expressed on endothelial cells (E- and P-selectins) and leucocytes (L-selectin) recognize carbohydrate ligands such as sialyl Lewis A or sialyl Lewis X oligosaccharides due to the same positioning of NeuAc, Gal and Fuc residues in both isomeric structures. We have shown that the sialic acid residue could be replaced by a sulfate group such as in the sulfated Lewis A pentasaccharide, one of the most potent monovalent ligand for human E-selectin, which was shown to be very active in the prevention of ischemia reperfusion lung injury. In the same way, we have prepared through chemoenzymatic syntheses, two disulfated Lewis X pentasaccharides, the sulfated analogs of carbohydrate ligands found on GLYCAM 1, the natural receptor of L-selectin. Finally, based on the double recognition of L-selectin with Lewis type and glycosaminoglycan structures, we tentatively introduced a possible link between the selectin- and the integrin-mediated lymphocyte adhesion systems.
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PMID:[Oligosaccharide sulfate inhibitors of selectin-sugar interactions in inflammatory processes]. 1042 56

Neutrophils can cause parenchymal cell injury in the liver during ischemia-reperfusion and endotoxemia. Neutrophils relevant for the injury accumulate in sinusoids, transmigrate, and adhere to hepatocytes. To investigate the role of E- and L-selectin in this process, C3Heb/FeJ mice were treated with 700 mg/kg galactosamine and 100 microgram/kg endotoxin (Gal/ET). Immunogold labeling verified the expression of E-selectin on sinusoidal endothelial cells 4 hours after Gal/ET injection. In addition, Gal/ET caused up-regulation of Mac-1 (CD11b/CD18) and shedding of L-selectin from circulating neutrophils. Gal/ET induced hepatic neutrophil accumulation (422 +/- 32 polymorphonuclear leukocytes [PMN]/50 high power fields [HPF]) and severe liver injury (plasma alanine transaminase [ALT] activities: 4,120 +/- 960 U/L; necrosis: 44 +/- 3%) at 7 hours. Treatment with an anti-E-selectin antibody (3 mg/kg, intravenously) at the time of Gal/ET administration did not significantly affect hepatic neutrophil accumulation and localization. However, the anti-E-selectin antibody significantly attenuated liver injury as indicated by reduced ALT levels (-84%) and 43% less necrotic hepatocytes. In contrast, animals treated with an anti-L-selectin antibody or L-selectin gene knock out mice were not protected against Gal/ET-induced liver injury. However, E-, L-, and P-selectin triple knock out mice showed significantly reduced liver injury after Gal/ET treatment as indicated by lower ALT levels (-65%) and reduced necrosis (-68%). Previous studies showed that circulating neutrophils of E-selectin-overexpressing mice are primed and activated similar to neutrophils adhering to E-selectin in vitro. Therefore, we conclude that blocking E-selectin or eliminating this gene may have protected against Gal/ET-induced liver injury in vivo by inhibiting the full activation of neutrophils during the transmigration process.
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PMID:Pathophysiologic importance of E- and L-selectin for neutrophil-induced liver injury during endotoxemia in mice. 1105 49

Higher primates, including humans, have high levels of pre-existing naturally circulating antibodies that predominantly recognize the epitope Gal (1,3-Gal), which is highly expressed on the surface of xenogenic cells. Deposition of these antibodies on the endothelial cell surface of vascularized xenografts leads to an activation of the classical pathway of the complement system, resulting in tissue ischemia and necrosis with rapid demise of the xenograft. This hyperacute rejection (HAR) is always a major barrier in xenograft transplantation and should be minimized by accurately monitoring the naturally occurring antibodies. In the present study, we utilized a simple and rapid flow cytometric (FCM) assay to monitor the presence of these naturally occurring antibodies. We found that the FCM assay is very effective in measuring human antibodies bound to the xenogenic cells, which cause cytotoxicity. This assay could be useful in the pre- and post-xenotransplantation monitoring of xenoantibodies, thus, helping in the development of strategies to block the binding of preformed human antibodies to the xenograft in order to overcome the problem of HAR.
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PMID:Detection of xenoantibodies using a simple flow cytometric assay. 1147 24

In the past two decades, transplantation has become a preferred modality of treatment of end-stage failure of vital organs. Currently, with the significant improvement in short-term graft survival rates, the main effort is concentrated on prolonging the functional life span of transplanted organs. One of the theories which were put forward to explain the progressive deterioration of transplant function was that of replicative senescence. Senescence of an organ or tissue results from age and/or environmental stress-dependant modification of cellular function. With time, the accumulation of cellular alterations may lead to deleterious effects in various organs and tissues and adversely affect transplants. In this article we are reviewing the candidate mechanisms of senescence such as telomere shortening, genetic regulation and environmental-'toxic' factors and are examining the implications of the theory of replicative senescence for organ allograft. We are also presenting our experiments with renal ischemia/reperfusion in rat serving as a model of kidney transplantation, where baseline kidney telomere length and novel marker of cellular senescence--senescence associated beta-Galactosidase (SA-Gal) expression in tissue served as markers. For the first time in vivo, we were able to show that with aging of the animals the amount of senescent cells in kidney tissue was increasing, while the average renal tissue telomere length was decreasing. The degree of tissue senescence, as determined by amount of SA-Gal positively stained cells, was inversely correlated with the recovery of the kidney function after ischemia/reperfusion injury. These results confirm the theory of replicative senescence in organ ischemia for the first time in vivo, and quantitatively validate the direct correlation between the amount of senescent cells in the organ and its susceptibility to ischemic injury. We conclude that recent advances in study of the cellular basis of senescence, in vitro and especially in vivo, may hold clues to the understanding of events which could be implicated in the damage or protection of organ allografts.
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PMID:Replicative senescence in organ transplantation-mechanisms and significance. 1218 Aug 26

Ischemia-reperfusion injury (I/R injury) is a common cause of acute renal failure. Recovery from I/R injury requires renal tubular regeneration. Hematopoietic stem cells (HSC) have been shown to be capable of differentiating into hepatocytes, cardiac myocytes, gastrointestinal epithelial cells, and vascular endothelial cells during tissue repair. The current study tested the hypothesis that murine HSC can contribute to the regeneration of renal tubular epithelial cells after I/R injury. HSC isolated from male Rosa26 mice that express beta-galactosidase constitutively were transplanted into female nontransgenic mice after unilateral renal I/R injury. Four weeks after HSC transplantation, beta-galactosidase-positive cells were detected in renal tubules of the recipients by X-Gal staining. PCR analysis of the male-specific Sry gene and Y chromosome fluorescence in situ hybridization confirmed the presence of male-derived cells in the kidneys of female recipients. Antibody co-staining showed that beta-galactosidase was primarily expressed in renal proximal tubules. This is the first report to show that HSC can differentiate into renal tubular cells after I/R injury. Because of their availability, HSC may be useful for cell replacement therapy of acute renal failure.
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PMID:Hematopoietic stem cells contribute to the regeneration of renal tubules after renal ischemia-reperfusion injury in mice. 1270 89

The crucial role of complement and naturally occurring anti-Gal antibodies in hyperacute rejection of pig transplants to Old World monkeys, apes and humans is well established. This rejection can be prevented by manipulating either system. Although cells, tissues or organs from pigs made transgenic for human complement regulatory proteins escape hyperacute rejection, there is an increasing evidence of a role for complement also in the subsequent acute vascular or delayed xenograft rejection. Furthermore, complement contributes in a general manner to ischemia-reperfusion injury (IRI), irrespective of the organ source. Early complement-mediated endothelial cell activation, although not sufficient to induce hyperacute rejection, may contribute to reduced long-time graft performance. Control of fluid-phase complement activation by soluble complement inhibitors might be an important adjuvant to transgenic organs from the time of organ harvesting through the first post-transplant period. Pharmacologic manipulation of complement is a field in expansion, though still in its infancy. Although an optimal transgenic and cloned pig may be close to reality, the role of complement in xenotransplantation needs to be fully elucidated and a treatment regimen for fluid-phase inhibition is warranted. The story of complement in xenotransplantation is not completed but under continuous revision.
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PMID:Perspectives on complement in xenotransplantation. 1291 19

Strong evidence suggests that replicative senescence is involved in vivo because senescent cells have been detected in human tissues associated with physiological and pathological aging processes. Chronic allograft nephropathy (CAN) appears to be a major determinant of long-term survival in kidney transplantation. Several mechanisms are potentially involved; the aim of this study was to assess the impact of replicative senescence in CAN. Replicative senescent cells were detected on renal tissue cryosection using expression of a specific marker, senescence-associated beta-galactosidase (SA-beta-Gal) at pH 6. A total of 80 frozen renal samples (67 cases of CAN and 13 controls) were studied. To validate this marker, we measured in situ telomere length in cells expressing or not expressing SA-beta-Gal using a validated quantitative fluorescence in situ hybridization technique. The presence of senescent cells was correlated with clinicopathologic data. Telomere length was significantly lower in cells expressing SA-beta-Gal than in cells that did not. Replicative senescence was present in 45 out of 67 (67%) biopsy specimens and was significantly associated with the severity of CAN. No correlation with the notion of a previous episode of acute tubular necrosis, acute rejection, extrarenal epuration, duration of cold ischemia, and the delay between transplantation and biopsy was observed. However, the age of the donor, but not that of the recipient, was correlated with the occurrence of senescent cells. These results suggest that replicative senescence is a mechanism that might be involved in the development of CAN. The age of the donor appears to be the major determinant factor in replicative senescence.
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PMID:The role of replicative senescence in chronic allograft nephropathy. 1456 89


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