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)

Lysosomal proteases, although tightly regulated under physiological conditions, are known to contribute to cell injury after various forms of tissue ischemia have occurred. Because cathepsin B is a prominent lysosomal protease found in brain parenchyma, the authors hypothesized that it may contribute to neuronal cell death after focal cerebral ischemia. The authors measured the expression and spatial distribution of cathepsin B within the ischemic brain in 43 animals by means of immunohistochemical analysis in a rat model of transient middle cerebral artery (MCA) occlusion. Cathepsin B activity was also measured within specific ischemic brain regions by using an in vitro assay (22 animals). In addition, the authors tested the therapeutic effect of preischemic intraventricular administration of stefin A, a cysteine protease inhibitor, on the volume of cerebral infarction after transient MCA occlusion (15 animals). Increased cathepsin B immunoreactivity was detected exclusively within the ischemic neurons after 2 hours of reperfusion following a 2-hour MCA occlusion. Cathepsin B immunolocalization in the ischemic region decreased by 24 hours of reperfusion, but then increased by 48 hours of reperfusion because the infarct was infiltrated by inflammatory cells. Increased immunolocalization of cathepsin B in the inflammatory cells located in the necrotic infarct core continued through 7 days of reperfusion. Cathepsin B enzymatic activity was significantly increased in the ischemic tissue at 2, 8, and 48 hours, but not at 24 hours of reperfusion after 2 hours of MCA occlusion. Continuous intraventricular infusion of stefin A, before 2 hours of MCA occlusion (15 animals), significantly reduced infarct volume compared with control animals (12 animals): the percentage of hemispheric infarct volume was 20+/-3.9 compared with 33+/-3.5 (standard error of the mean; p = 0.025). These data indicate that neuronal cathepsin B undergoes increased expression and activation within 2 hours of reperfusion after a 2-hour MCA occlusion and may be a mechanism contributing to neuronal cell death. Intraventricular infusion of stefin A, an inhibitor of cathepsin B, significantly reduces cerebral infarct volume in rats.
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PMID:Cathepsin B and middle cerebral artery occlusion in the rat. 934 80

In healthy subjects, the 3 known pancreatic trypsinogens, which are endopeptidases belonging to the chymotrypsin superfamily, are activated by enterokinase and partial autoactivation in the duodenum. The premature activation of trypsinogen in the pancreatic interstitium, with the subsequent activation of other pancreatic zymogens, is believed to lead to the autodigestion of the gland, this being the first event in acute pancreatitis. The mechanisms that lead to trypsinogen, activation in acute pancreatitis are largely unknown. However, ischemia, hypercalcemia and the activation of cathepsin B (by cholecystokinin) are thought to be of importance. The easiest and most reliable way to assess trypsinogen activation is the measurement of the activation peptide, TAP, in urine, plasma, pancreatic tissue or ascitic fluid. In the animal model of acute pancreatitis, TAP in ascites and pancreatic tissue has been shown to correlate with the presence and extent of necroses. It has proven to be a good marker for the severity of pancreatitis and is a useful marker in examining the pathophysiology and possible treatment modalities in the animal model of acute pancreatitis. Studies on TAP in human acute pancreatitis were most commonly focused on urinary TAP. Within a 48-hour time frame after the onset of the disease, TAP was a good predictor of the severity of acute pancreatitis. The main advantage over other markers, such as CRP, is that TAP is the earliest marker of necrosis to be increased. Also, increased levels of TAP in ascitic fluid were shown to correlate well with pancreatic necroses. In our experience, plasma TAP was found to have a "diagnostic window" within the first 3 days predicting pancreatic necroses. Positive TAP gave a very good positive prediction and a high specificity towards the development of pancreatic necroses, but did not differ between necrotizing pancreatitis with systemic complications or uncomplicated necrotizing pancreatitis. We therefore think that plasma TAP is a very good marker for local complication in acute pancreatitis and its routine measurements may help to identify patients at a high risk within the first days of the disease.
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PMID:Mechanism and role of trypsinogen activation in acute pancreatitis. 1057 41

This study was designed to evaluate the possible role of cytokines (IL-1 and TNF-alpha) in the pathogenesis of pancreatic injuries induced by pancreatic ischemia-reperfusion and to evaluate the protective effect of the cytokine suppressive agent, FR167653, against pancreatic injuries. Pancreatic ischemia-reperfusion was induced in rats by ligating the celiac and caudate mesenteric arteries by small metallic clips for 45 min, after this ischemia, the metal clips were removed. Four hours after removing the metal clips, the animals were used for the experiments. In this model, mild hyperamylsemia and significant increases in pancreatic water and trypsin content were observed. Significant increases in serum IL-1 and TNF-alpha were also observed, as compared with the control rats. Pancreatic subcellular redistribution of lysosomal enzyme cathepsin B from the lysosomal fraction to the zymogen fraction was also observed. However, treatment with FR167653 at a dose of 0.5 mg/kg.hr significantly prevented all these pancreatic injuries. These results indicate that cytokines such as IL-1 and TNF-alpha might be involved in the pathogenesis of pancreatic injuries induced by ischemia-reperfusion, and that a cytokine suppressive agent might be of therapeutic value for the treatment of pancreatic ischemia.
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PMID:Cytokine Suppressive Agent Prevents Pancreatic Injuries Induced by Ischemia-Reperfusion in Rats. 1106 14

In the last decade, the molecular mechanisms of apoptosis, a major type of active cell death (type I cell death) have largely been clarified in mammalian cells. Particularly, the caspase family of proteinases has been shown to play crucial roles in the execution of apoptosis. Differing from apoptosis, type II cell death is known to be associated with autophagosomes/autolysosomes and appear in the developing nervous system (CLARKE, 1990). We have previously shown that delayed neuronal death occurring in the CA1 pyramidal layer of the gerbil hippocampus after brief forebrain ischemia is apoptotic in nature and autophagosomes/autolysosomes abundantly appear in the neurons before DNA fragmentation. To further understand the roles of autophagosomes/autolysosomes in active cell death, we examined the apoptosis of PC12 cells using morphological and biochemical techniques. PC12 cells are known to undergo apoptosis when cultured in the absence of serum. In such an environment, the mitochondrial pathway of apoptosis is activated; cytochrome c is released from mitochondria, and caspase-9/caspase-3 are activated. We have first examined morphological features of PC12 cells during the apoptotic process following serum deprivation, and found that autophagy is induced from the early stage of the process in the cells before typical nuclear changes. When autophagy is inhibited in the cells by 3-methyladenine, an autophagy inhibitor, they are largely protected from apoptosis. In relation to the induction of autophagy in PC12 cells following serum deprivation, immunoreactivity, protein amounts, and the proteolytic activity of lysosomal proteinases, particularly cathepsins B and D, are all greatly altered; those of cathepsin B drastically decrease in the cells from the early stage of serum-deprived cultures, whereas those of cathepsin D increase. Moreover, PC12 cells overexpressing cathepsin D undergo apoptosis more rapidly in serum-deprived cultures than wild-type cells, whereas those overexpressing cathepsin B increase the viability. These lines of evidence suggest that autophagy is involved in PC12 cell death following serum deprivation, this type of cell death being regulated by lysosomal proteinases, cathepsins B and D, downstream autophagy.
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PMID:Autophagic cell death and its execution by lysosomal cathepsins. 1157 20

To clarify the mechanism of muscle fiber destruction in sarcoid myopathy, muscle biopsy specimens were examined from patients with sarcoid myopathy, polymyositis, or dermatomyositis. In sarcoid myopathy, noncaseating granulomatous lesions were located in the perimysium or endomysium or both. Little fiber atrophy, caused by mechanical compression of the granuloma, was seen, and there was no evidence of ischemia-induced changes (i.e., perifascicular atrophy) due to microangiopathy in muscles. Immunoreactivity for membrane-associated cytoskeletal proteins such as dystrophin and merosin was detected homogeneously along the surface of many small granulomas in intrafascicular lesions. These granulomas showed a characteristic phenotypic cellular distribution: CD68(+) and CD4(+) cells were present in the center, and some CD8(+) cells were found at the periphery, indicating typical sarcoid granuloma formation in each muscle fiber. Strong expression of proteases such as cathepsin B, calpain II and ubiquitin-proteasome was observed in macrophages and epithelioid cells but not in lymphocytes in granulomas within muscle fibers or those in the endomysium or perimysium. The expression intensity was stronger in premature-stage granulomas than in late-stage granulomas. Weak expression of these proteases was detected mainly in some muscle fibers invaded by epithelioid cells and macrophages and in a few atrophic or necrotic fibers adjacent to inflammatory foci but not in fibers of fascicles without granuloma formation or in fibers in perifascicular areas. Our results suggest that muscle fiber destruction in sarcoid myopathy is caused mainly by direct invasion of granulomatous inflammatory cells into muscle fibers during the process of granuloma formation rather than by mechanical compression or ischemia. Furthermore, the proteases derived from epithelioid cells and macrophages may play an important role in muscle fiber destruction.
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PMID:Cellular distribution of proteolytic enzymes in the skeletal muscle of sarcoid myopathy. 1207 Jun 62

1. Caspases play a critical role in apoptosis, and are considered to be key targets for the design of cytoprotective drugs. As part of our antiapoptotic drug-discovery effort, we have synthesized and characterized Z-VD-fmk, MX1013, as a potent, irreversible dipeptide caspase inhibitor. 2. MX1013 inhibits caspases 1, 3, 6, 7, 8, and 9, with IC50 values ranging from 5 to 20 nm. MX1013 is selective for caspases, and is a poor inhibitor of noncaspase proteases, such as cathepsin B, calpain I, or Factor Xa (IC50 values >10 microm). 3. In several cell culture models of apoptosis, including caspase 3 processing, PARP cleavage, and DNA fragmentation, MX1013 is more active than tetrapeptide- and tripeptide-based caspase inhibitors, and blocked apoptosis at concentrations as low as 0.5 microm. 4. MX1013 is more aqueous soluble than tripeptide-based caspase inhibitors such as Z-VAD-fmk. 5. At a dose of 1 mg kg-1 i.v., MX1013 prevented liver damage and the lethality caused by Fas death receptor activation in the anti-Fas mouse-liver apoptosis model, a widely used model of liver failure. 6. At a dose of 20 mg kg-1 (i.v. bolus) followed by i.v. infusion for 6 or 12 h, MX1013 reduced cortical damage by approximately 50% in a model of brain ischemia/reperfusion injury. 7. At a dose of 20 mg kg-1 (i.v. bolus) followed by i.v. infusion for 12 h, MX1013 reduced heart damage by approximately 50% in a model of acute myocardial infarction. 8. Based on these studies, we conclude that MX1013, a dipeptide pan-caspase inhibitor, has a good combination of in vitro and in vivo properties. It has the ability to protect cells from a variety of apoptotic insults, and is systemically active in three animal models of apoptosis, including brain ischemia.
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PMID:MX1013, a dipeptide caspase inhibitor with potent in vivo antiapoptotic activity. 1297 77

Cystatin C is distributed in all human tissues and fluids with a particular abundance in the cerebrospinal fluid. Cystatin C is a strong endogenous inhibitor of lysosomal cysteine proteases, such as cathepsin B, L, H and S, that are involved in various biological processes such as degradation of cellular proteins and regulation of enzymes, as well as in pathological processes. Pharmacological inhibition of cathepsins has been shown to reduce neuronal damage after brain ischemia, suggesting that cystatin C is an endogenous neuroprotectant. Cystatin C has also amyloidogenic properties and is co-localized with beta-amyloid in degenerated neurons in Alzheimer's disease, suggesting a role in neuronal degeneration. To test the hypothesis that endogenous cystatin C is neuroprotective during brain ischemia, global and focal brain ischemia was induced in mice with the cystatin C gene knocked out. Following focal ischemia, larger brain infarcts were found in cystatin C knockout mice, probably due to a reduced inhibition of the cathepsins during ischemia. In contrast, brain damage after global ischemia was diminished in cystatin C knockout mice, suggesting that cystatin C has an aggravating effect on selective neuronal damage after global ischemia.
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PMID:Gene deletion of cystatin C aggravates brain damage following focal ischemia but mitigates the neuronal injury after global ischemia in the mouse. 1545 Mar 54

Hepatic steatosis predisposes the liver to cold ischemia-warm reperfusion (CI/WR) injury by unclear mechanisms. Because hepatic steatosis has recently been associated with a lysosomal pathway of apoptosis, our aim was to determine whether this cell-death pathway contributes to CI/WR injury of steatotic livers. Wild-type and cathepsin B-knockout (Ctsb(-/-)) mice were fed the methionine/choline-deficient (MCD) diet for 2 wk to induce hepatic steatosis. Mouse livers were stored in the University of Wisconsin solution for 24 h at 4 degrees C and reperfused for 1 h at 37 degrees C in vitro. Immunofluorescence analysis of the lysosomal enzymes cathepsin B and D showed a punctated intracellular pattern consistent with lysosomal localization in wild-type mice fed a standard diet after CI/WR injury. In contrast, cathepsin B and D fluorescence became diffuse in livers from wild-type mice fed MCD diet after CI/WR, indicating that lysosomal permeabilization had occurred. Hepatocyte apoptosis was rare in both normal and steatotic livers in the absence of CI/WR injury but increased in wild-type mice fed an MCD diet and subjected to CI/WR injury. In contrast, hepatocyte apoptosis and liver damage were reduced in Ctsb(-/-) and cathepsin B inhibitor-treated mice fed the MCD diet following CI/WR injury. In conclusion, these findings support a prominent role for the lysosomal pathway of apoptosis in steatotic livers following CI/WR injury.
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PMID:Cathepsin B inactivation attenuates hepatocyte apoptosis and liver damage in steatotic livers after cold ischemia-warm reperfusion injury. 1547 11

Tumor necrosis factor (TNF)-alpha-induced hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure. TNF-alpha exerts a variety of effects that are mediated mainly by TNF-receptor 1 (TNF-R1) in cell death. The activation of TNF-R1 leads to the activation of multiple apoptotic pathways involving the activation of the pro-death Bcl-2 family proteins, reactive oxygen species, C-Jun NH2-terminal kinase, cathepsin B, acidic sphingomyelinase and neutral sphingomyelinase. These pathways are closely interlinked and mainly act on mitochondria, which release the apoptogenic factors and other events, resulting in apoptosis. This article reviews the recent progress in the molecular mechanisms of TNF-alpha-induced apoptosis in hepatocytes, and discusses how these molecular findings are shaping our understanding of the pathogenesis of liver diseases and our strategy to develop novel therapeutics.
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PMID:Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. 1560 73

We tested the hypothesis that chronically ischemic (IS) myocardium induces autophagy, a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, which could protect against the consequences of further ischemia. Chronically instrumented pigs were studied with repetitive myocardial ischemia produced by one, three, or six episodes of 90 min of coronary stenosis (30% reduction in baseline coronary flow followed by reperfusion every 12 h) with the non-IS region as control. In this model, wall thickening in the IS region was chronically depressed by approximately 37%. Using a nonbiased proteomic approach combining 2D gel electrophoresis with in-gel proteolysis, peptide mapping by MS, and sequence database searches for protein identification, we demonstrated increased expression of cathepsin D, a protein known to mediate autophagy. Additional autophagic proteins, cathepsin B, heat shock cognate protein Hsc73 (a key protein marker for chaperone-mediated autophagy), beclin 1 (a mammalian autophagy gene), and the processed form of microtubule-associated protein 1 light chain 3 (a marker for autophagosomes), were also increased. These changes, not evident after one episode, began to appear after two or three episodes and were most marked after six episodes of ischemia, when EM demonstrated autophagic vacuoles in chronically IS myocytes. Conversely, apoptosis, which was most marked after three episodes, decreased strikingly after six episodes, when autophagy had increased. Immunohistochemistry staining for cathepsin B was more intense in areas where apoptosis was absent. Thus, autophagy, triggered by ischemia, could be a homeostatic mechanism, by which apoptosis is inhibited and the deleterious effects of chronic ischemia are limited.
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PMID:Autophagy in chronically ischemic myocardium. 1617 25


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