Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have utilized specific, irreversible inhibitors of cysteine proteinases to examine the role of renal cathepsin B and cathepsin L in the proteinuria which occurs in an experimental model of human glomerular disease. Administration of trans-epoxysuccinyl-L-leucylamido-(3-methyl)butane (Ep475) a specific, irreversible inhibitor of cysteine proteinases, including cathepsins B and L, significantly reduced proteinuria in rats with experimentally induced, neutrophil-independent, anti-GBM antibody disease (controls: 10 +/- 1 mg/24 h, N = 8; anti-GBM antibody disease: 203 +/- 30 mg/24 h, N = 8; anti-GBM antibody disease + Ep475: 112 +/- 13 mg/24 h, mean +/- SEM, N = 6, P less than 0.05). There was a marked reduction in the activity of both cathepsin B and cathepsin L in renal cortices obtained from Ep475-treated rats compared to either saline-treated controls or rats treated with anti-GBM IgG only. Administration of Z-Phe-Tyr(O-t-butyl)CHN2, a specific, irreversible cysteine proteinase inhibitor with a high degree of selectivity toward cathepsin L, also caused a reduction in anti-GBM antibody-induced proteinuria (90 +/- 18 mg/24 h, N = 6, P less than 0.05). This reduction in proteinuria was accompanied by a marked decrease (-84%) in the specific activity of renal cortical cathepsin L in Z-Phe-Tyr(O-t-butyl)CHN2-treated rats. However, cathepsin B activity was unchanged. There was no significant change in the renal anti-GBM antibody uptake, plasma urea nitrogen, or plasma creatinine values in the Z-Phe-Tyr(O-t-butyl)CHN2-treated rats compared to rats treated with anti-GBM IgG only or saline-treated controls. These data document the ability of cysteine proteinase inhibitors to decrease the proteinuria which occurs in a neutrophil-independent model of human anti-GBM antibody disease and suggest an important role for cathepsin L in the pathophysiology of the proteinuria which occurs in this model.
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PMID:Evidence suggesting a role for cathepsin L in an experimental model of glomerulonephritis. 189 42

The acute phase of glomerular injury in a model of antiglomerular basement membrane, antibody-induced glomerulonephritis (antiGBM-GN) in rabbits was shown to be neutrophil-dependent using nitrogen mustard depletion studies. Administration of desferrioxamine (DFX) prevented the development of proteinuria in this model of renal injury [24 hr protein excretion (mean +/- SEM): antiGBM-GN/DFX = 16.2 +/- 2.9 mg compared with antiGBM-GN control = 271.5 +/- 92.2 mg, P less than 0.01]. Antibody binding levels, glomerular filtration rates, circulating complement and neutrophil counts, glomerular C3 deposition, and neutrophil infiltration did not differ between DFX treated and antiGBM-GN groups. In vitro assay systems to assess oxygen radical production [superoxide anion (O2-) and hydroxyl radical (OH.)] by neutrophils activated via the interaction of antiGBM antibody, GBM and complement were established. In these assays, DFX inhibited OH. production by immunologically-stimulated neutrophils (ISN) [nM diphenol/hr/10(6) cells, mean +/- SEM, ISN/DFX = 8 +/- 2 compared with ISN = 191 +/- 22, P less than 0.01] while production of O2- was not affected [nM O2-/hr/10(6) cells, mean +/- SEM, ISN/DFX = 29.1 +/- 4.3 compared with ISN = 32.6 +/- 2.5, P greater than 0.05]. These studies demonstrate that the iron chelator desferrioxamine can prevent neutrophil-dependent immune renal injury by interfering with neutrophil function. Treatment with the hydroxyl radical scavenger dimethylthiourea also significantly attenuated renal injury in antiGBM-GN. Together, the in vivo and in vitro data strongly suggest that neutrophil-dependent immunological renal injury is mediated via hydroxyl radical production by activated neutrophils within glomeruli.
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PMID:Hydroxyl radical mediation of immune renal injury by desferrioxamine. 302 99

Proteinuria is a major manifestation of glomerular disease (glomerulonephritis, GN). We examined the effect of trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane (E-64), a specific and irreversible cysteine proteinase inhibitor, on urinary protein excretion in a complement- and neutrophil-independent model of antiglomerular basement membrane (GBM) antibody disease. A single injection of rabbit antirat-GBM IgG produced a marked increase in urinary protein excretion 24hr after injection. In two separate studies using different pools of antiGBM IgG, administration of E-64 (5mg every 6h starting 2hr prior to induction of GN) reduced proteinuria (-45 +/- 7%, and -41 +/- 14%, Mean +/- SEM, n = 6; P less than 0.001) in the 24 hour period following induction of the disease. This reduction in urinary protein excretion was accompanied by a marked decrease in the specific activity of the cysteine proteinases cathepsins B and L in glomeruli (B: -97%; L: -84%) and renal cortex (B: -87%; L: -75%) isolated from the same E-64-treated rats compared to same saline-treated controls. These data, combined with the specificity of E-64 for cysteine proteinases, suggest a potential role for cysteine proteinases in the increased GBM permeability and proteinuria in this experimental model of glomerular disease.
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PMID:The cysteine proteinase inhibitor, E-64, reduces proteinuria in an experimental model of glomerulonephritis. 317 11

In order to reveal structural damage to the glomerular basement membranes occurring in crescentic glomerulonephritis and the subsequent connective tissue organization of the crescent, 14 kidney biopsies were treated with detergents to remove cellular components and the tissue remaining examined by transmission (TEM) and scanning (SEM) electron microscopy. The fourteen biopsies were divided into two groups for analysis. Group I (7 cases) contained necrotizing lesions and cellular crescents. Acellular TEM (ATEM) revealed widespread lysis of mesangial matrix, while acellular SEM (ASEM) of five cases revealed three general patterns of GBM necrosis. Group II (7 cases) contained fibrocellular and fibrosis crescents. ATEM and ASEM revealed that collagen fibers initially form along fibrin fibrils and eventually result in formation of lacunar spaces occupied by cells of the crescent. Fibrous crescents were associated with prominent glomerular tuft distortion and entrapment of normal capillary loops. Continuity between interstitial space, matrix of crescent and mesangium were often observed. These observations suggest that lysis of mesangial matrix is extensive and precedes GBM lysis while the pattern of GBM damage fits best with local release of lytic factors. Furthermore, the architectural distortion and continuity which develops between normally segregated compartments (mesangial-interstitial) indicate that both the initial necrosis and the reparative response to injury, contribute substantially to overall nephron dysfunction.
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PMID:Glomerular basement membrane necrosis and crescent organization. 339 85

An isolated perfused kidney system (IPK) was used to study the direct intrarenal hemodynamic effects of binding of anti-glomerular-basement membrane (anti-GBM) antibody in the absence of all other circulating humoral and cellular inflammatory mediators. Control IPK's (perfused with Krebs-Henseleit buffered 5% albumin solution containing non-immune globulin) had a renal vascular resistance (RVR) mean +/- SEM 3.10 +/- 0.47 mm Hg/ml/min and a GFR mean +/- SEM 0.63 +/- 0.8 ml/min/g. Anti-GBM antibody administration raised RVR (4.83 +/- 0.52 mm Hg/ml/min, P less than 0.01) and lowered GFR (0.34 +/- 0.04 ml/min/g, P less than 0.01). Perfusate renin activity was higher after antibody administration (684 +/- 87 ng AI/ml/hr compared with control 308 +/- 42 ngAI/ml/hr, P less than 0.01). Treatment with Sar1Ala8All (3 X 10(-6) M) or captopril (10 mg/ml) attenuated antibody-induced vasoconstriction (RVR mm Hg/ml/min, Sara1Ala8All = 3.78 +/- 0.13 captopril = 3.26 +/- 0.12, both P less than 0.05 compared with anti-GBM alone). Both inhibitors of the renin-angiotensin system (RAS) also aggrevated the decline in GFR seen after antibody administration (GFR ml/min/g, Sara1Ala8All = 0.24 +/- 0.05, Captopril = 0.18 +/- 0.03, both P less than 0.05 compared with anti-GBM alone). These IPK studies demonstrate that anti-GBM antibody itself may directly induce intrarenal hemodynamic alterations in the absence of complement activation, neutrophil infiltration, neural influences or circulating vasoactive substances. The results from perfusate renin sampling and blockade of the RAS provide evidence that anti-GBM antibody deposition activates the intrarenal RAS and thereby induces significant hemodynamic alterations.
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PMID:Intrarenal hemodynamic alterations induced by anti-GBM antibody. 355 Feb 17

We have studied the effect of peripheral blood mononuclear cells (PBMC) from nephrotic patients on the incorporation of 35Sulfate in rat glomerular basement membrane. 35Sulfate uptake increased when glomeruli were incubated with PBMC from 10 patients with idiopathic minimal lesion nephrotic syndrome (IMLNS) in relapse compared to simultaneous assays on 5 controls (2295 +/- 643 cpm/mg dry glomerular weight, mean +/- SEM, and 962 +/- 248 cpm/mg, respectively) (P less than 0.02). 35Sulfate incorporation did not increase when glomeruli were incubated with PBMC from seven nephrotic patients with other glomerulopathies (1283 +/- 642 cpm/mg) as compared to controls (1016 +/- 503 cpm/mg). No significant differences in 35Sulfate uptake were seen between glomerular cultures with and without control PBMC. These data show that PBMC from patients with IMLNS in relapse alter, at least in the rat GBM, the metabolism of sulfated compounds. Since these compounds have a role in glomerular permeability, this finding may have pathogenic significance.
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PMID:Effect of peripheral blood mononuclear cells from patients with nephrotic syndrome on uptake of 35sulfate by glomerular basement membrane. 405 37

We have characterized the endothelin (ET) receptor subtypes present within normal human cerebral cortex (CC), glioblastoma multiforme (GBM), and meningiomas (MGs), using two subtype-selective radioligands, [125I]-PD151242 (ETA) and [125I]-BQ3020 (ETB). For saturation experiments, sections of tissue were incubated with increasing concentrations (8 pM-4 nM) of either [125I]-PD151242 or [125I]-BQ3020 in incubation buffer (22 degrees C, 2 h). In saturation binding assays, [125I]-PD151242 bound with high affinity to a single population of ET receptors (n = individuals; +/- SEM) in normal CC (n = 3; Kd 1.23 +/- 0.20 nM; Bmax 28.10 +/- 9.04 fmol/mg protein), GBM (n = 5; Kd 1.62 +/- 0.20 nM; Bmax 147.04 +/- 62.8 fmol/mg protein), and MGs (n = 3; Kd 3.10 +/- 0.44 nM; Bmax 290.3 +/- 105.8 fmol/mg protein). [125I]-BQ3020 also bound with high affinity to a single population of ET receptors in normal CC (n = 3; Kd 4.54 +/- 1.58 nM; Bmax 190.5 +/- 88.8 fmol/mg protein), GBM (n = 4; Kd 1.38 +/- 0.28 nM; Bmax 234.0 +/- 153.6 fmol/mg protein), and MGs (n = 3; Kd 0.25 +/- 0.09 nM; Bmax 22.8 +/- 18.0 fmol/mg protein). To determine receptor subtype localization, autoradiography was performed after incubation of sections with 0.1 nM [125I]-ET-1 (ETA and ETB), [125I]-PD151242 (ETA), and [125I]-BQ3020 (ETB). Autoradiography demonstrated a high concentration of ETA receptors within the pial and intraparenchymal vessels and meninges overlying the CC. Gray and white matter were diffusely ETB-positive. GBM had a strongly vascular pattern of ETA distribution. ETA receptors were dense and homogeneous in MGs. [125I]-PD151242 binds with high affinity to human pial and intraparenchymal vessels and is able to clearly delineate the microvasculature in GBM. Selective ETA receptor manipulation may have potential benefits in cerebrovascular disease and neoplasia without producing detrimental effects on the predominantly ETB-positive brain parenchyma.
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PMID:Characterization of endothelin receptors in human brain cortex, gliomas, and meningiomas. 858 29

We report the use of photodynamic therapy (PDT) in the treatment of 20 patients with newly diagnosed malignant supratentorial gliomas. There were 10 males and 10 females; their mean age was 56 years and the mean Karnofsky score was 75. Eleven patients had glioblastoma multiforme (GBM) and 9 had malignant astrocytoma (MA). Intravenous porphyrin photosensitizer was administered 12-36 h prior to surgery and photoillumination. At operation all patients had the tumor subtotally resected followed by intraoperative cavitary photoillumination. Interstitial photoillumination using fibers with 2-cm diffusing tips supplemented the cavitary illumination in 3 patients. The total light energy delivered ranged from 570 to 4050 J (median = 1260 J). The energy density ranged from 15 to 110 J/cm2 (median = 32 J/cm2). All but two had postoperative radiation therapy (5000 cGy in 5 weeks). No untoward effects of radiation in conjunction with PDT were identified. There was 1 postoperative death and 1 patient had a persistent increase in postoperative neurological deficit. The median survival of these 20 patients with newly diagnosed malignant gliomas was 44 weeks with a 1- and 2-year survival of 40 and 15%, respectively. The median survival of these patients with newly diagnosed GBM was 37 weeks with a 1- and 2-year survival of 35 and 0%, respectively, and the median survival for MA was 48 weeks with a 1- and 2-year survival of 44 and 33%, respectively. Six patients with a Karnofsky score of > 70 who received a light dose of > 1260 J (mean energy density = 62 +/- 20 SEM J/cm2) had a median survival of 92 weeks with a 1- and 2-year survival of 83 and 33% respectively. Patients with malignant astrocytic tumors (GBM and MA) have a very poor prognosis. Nevertheless PDT is safe in newly diagnosed patients with supratentorial malignant gliomas who undergo postoperative radiation and appears to prolong survival in selected patients when an adequate light dose is used. Further improvement in survival may be expected with higher light doses.
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PMID:Photodynamic therapy for malignant newly diagnosed supratentorial gliomas. 961 92

With the aim of improving the treatment of glioblastoma multiforme, we investigated the potential of thalidomide to enhance the effectiveness of cisplatin chemotherapy in a rat glioma model. Female F344 rats were implanted with 9L gliosarcoma tumors either intracranially or subcutaneously and treated with 1 mg/kg cisplatin injected i.p. or with 1% thalidomide in the food or with these treatments combined. Cisplatin in combination with thalidomide significantly reduced both the subcutaneous tumor volume at 30 days to 22 +/- 5% (mean +/- SEM, P < 0.001) and the intracranial tumor volume at 18 days to 44 +/- 15% (P < 0.05) of that with cisplatin alone. Thalidomide selectively increased the cisplatin concentration 10-fold in intracranial tumors (P < 0.05) and 2-fold in the subcutaneous tumors (P < 0.05) without increasing its concentration in major organs including brain and kidney. Cisplatin combined with thalidomide caused a significant decrease in vascular endothelial growth factor (VEGF) levels by 73% in intracranial tumors (P < 0.05) and by 50% in subcutaneous tumors (P < 0.05) and caused the level of active hepatic growth factor (a-HGF) to double in both the subcutaneous and intracranial tumors (P < 0.05), suggesting this treatment altered the vasculature in these tumors. We conclude the increased efficacy of cisplatin in the presence of thalidomide was due to the selective increase in cisplatin concentration within the tumors and speculate that this is the result of thalidomide or the cisplatin/thalidomide combination, selectively altering the tumor vasculature. Based on the selective effects of thalidomide on tumor cisplatin concentrations and the resulting increase in efficacy, thalidomide may also increase the efficacy of other drugs that are presently considered ineffective against glioma.
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PMID:Enhancement of cisplatin efficacy by thalidomide in a 9L rat gliosarcoma model. 1753 79

In vivo suppression of glioblastoma multiforme (GBM) in Wistar rats using silica-shelled biocatalytic Pt(NH(3))(4)Cl(2) nanoparticles is reported. These nanoparticles were synthesized by a sol-gel technique and characterized by SEM and HRTEM imaging. We confirmed morphological uniformity (30 nm) and surface acidity of the nanoparticles, respectively, by TEM imaging and FTIR spectral analysis. Interestingly, treatment of Wistar rats intraperitoneally inoculated with C(6) cells using the biocatalysts resulted in considerable tumor shrinkage. Efficiency of the biocatalyst to shrink a tumor is superior to that by the commercial cytotoxic agent cisplatin. The tumor suppression property of Pt(NH(3))(4)Cl(2) nanoparticles is attributed to catalytic damage of DNA in C(6) cells.
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PMID:Nanostructured Pt(NH(3))(4)Cl(2)/SiO(2) for nanomedicine: catalytic degradation of DNA in cancer cells. 2211 Aug 76


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