Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is still a need for a better method of detecting immature ganglion cells in paraffin sections of colorectal luminal biopsies in cases suspected of Hirschsprung's disease. The lysosomal aspartic proteinase cathepsin D has been immunolocalized to various cell types, including ganglion cells. We investigated its expression in intestinal ganglion cells to determine whether it could be used as an aid in the detection of immature ganglion cells in rectal biopsies from children suspected of having Hirschsprung's disease. Routinely processed tissues of eight adult intestines resected for gunshot wounds and six ganglioneuromas (for mature ganglion cells), of six colons resected for neonatal necrotizing enterocolitis (for immature ganglion cells), and of 11 cases of suspected and three cases of known Hirschsprung's disease were immunostained with a polyclonal antibody to cathepsin D using the avidin-biotin-peroxidase method. In all cases, all ganglion cell bodies present showed intense granular cytoplasmic reactivity for cathepsin D. The granules crowded the cytoplasm and formed a collarette around the nucleus. In the submucosa, the only other immunoreactive cells were histiocytes, but they could be distinguished from ganglion cells by their characteristic nuclear features and their occurrence singly and unassociated with nerves. The three resection specimens with Hirschsprung's disease showed a clear transition between the ganglionic and the aganglionic segments. We conclude that cathepsin D is a promising marker of immature ganglion cells in cases suspected of Hirschsprung's disease.
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PMID:Cathepsin D in intestinal ganglion cells. A potential aid to diagnosis in suspected Hirschsprung's disease. 904 87

The estrogenic activity of dieldrin, toxaphene, and an equimolar mixture of both compounds (dieldrin/toxaphene) was investigated in the 21-day-old B6C3F1 mouse uterus, MCF-7 human breast cancer cells, and in yeast-based reporter gene assays. Treatment of the animals with 17beta-estradiol (E2) (0.0053 kg/day x3) resulted in a 3.1-, 4.8-, and 7.8-fold increase in uterine wet weight, peroxidase activity, and progesterone receptor binding, respectively. In contrast, treatment with 2.5, 15 and 60 micromol/kg (x3) doses of toxaphene, dieldrin, or dieldrin/toxaphene (equimolar) did not significantly induce a dose-dependent increase in any of the E2-induced responses. The organochlorine pesticides alone and the binary mixture did not bind to the mouse uterine estrogen receptor (ER) in a competitive binding assay using [3H]E2 as the radioligand. In parallel studies, estrogenic activities were determined in MCF-7 cells by using a cell proliferation assay and by determining induction of chloramphenicol acetyl transferase (CAT) activity in MCF-7 cells transiently transfected with plasmids containing estrogen-responsive 5'-promoter regions from the rat creatine kinase B and human cathepsin D genes. E2 caused a 24-fold increase in CAT activity in MCF-7 cells transiently transfected with creatine kinase B and a 3.8-fold increase in cells transiently transfected with the human cathepsin D construct. Treatment of MCF-7 cells with dieldrin, toxaphene, or an equimolar mixture of dieldrin plus toxaphene (10(-8)-10(-5) M) did not significantly induce cell proliferation or CAT activity in the transient transfection experiment with both plasmids. The relative competitive binding of the organochlorine pesticides was determined by incubating MCF-7 cells with 10(-9) M [3H]E2 in the presence or absence of 2 x 10(-7) M unlabeled E2 (to determine nonspecific binding), toxaphene (10(-5) M), dieldrin (10(-5) M), and equimolar concentrations of the dieldrin plus toxaphene mixture (10(-5) M). The binding observed for [3H]E2 in the whole cell extracts was displaced by unlabeled E2, whereas the organochlorine pesticides and binary mixture exhibited minimal to nondetectable competitive binding activity. E2 caused a 5000-fold induction of beta-galactosidase (beta-gal) activity in yeast transformed with the human ER and a double estrogen responsive element upstream of the beta-gal reporter gene. Treatment with 10(-6)-10(-4) M chlordane, dieldrin, toxaphene, or an equimolar mixture of dieldrin/toxaphene did not induce activity, whereas 10(-4) M endosulfan caused a 2000-fold increase in beta-gal activity. Diethylstilbestrol caused a 20-fold increase in activity in yeast transformed with the mouse ER and a single estrogen responsive element upstream of the beta-gal reporter gene. Dieldrin, chlordane, toxaphene, and endosulfan induced a 1.5- to 4-fold increase in activity at a concentration of 2.5 x 10(-5) M. Synergistic transactivation was not observed for any equimolar binary mixture of the pesticides at concentrations of either 2.5 x 10(-5) M or 2.5 x 10(-4) M. The results of this study demonstrate that for several estrogen-responsive assays in the mouse uterus, MCF-7 human breast cancer cells, and yeast-based reporter gene assays, the activities of both dieldrin and toxaphene were minimal, and no synergistic interactions were observed with a binary mixture of the two compounds.
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PMID:Estrogenic activity of a dieldrin/toxaphene mixture in the mouse uterus, MCF-7 human breast cancer cells, and yeast-based estrogen receptor assays: no apparent synergism. 907 11

Activation of the endosomal-lysosomal system and altered expression of various lysosomal hydrolases have been implicated in several senescence-dependent neurodegenerative disorders and occurs, to a lesser extent, in the course of normal brain aging. The progressive accumulation of autofluorescent, peroxidase-positive astrocytic granules represents a highly consistent biomarker of aging in the vertebrate CNS. The sulfhydryl agent cysteamine greatly accelerates the accumulation of these glial inclusions in situ and in primary brain cell cultures. We previously determined that these glial inclusions are derived from abnormal mitochondria which undergo fusion with lysosomal elements in a complex autophagic process. In the present study, we demonstrate that cysteamine suppresses cathepsin B mRNA levels and immunoreactive protein in cultured astroglia, whereas cathepsin D mRNA and protein levels are significantly augmented by CSH exposure in these cells. Moreover, cathepsin D (but not cathepsin B) exhibits robust colocalization to the red autofluorescent inclusions. Concordant with our in vitro observations, cathepsin B immunoreactivity is prominent in the hypothalamic ventromedial nucleus which accumulates few autofluorescent glial inclusions during aging and is relatively inapparent in the heavily granulated hypothalamic arcuate nucleus. Conversely, cathepsin D is prominent in the aging arcuate nucleus where it colocalizes to the autofluorescent inclusions and exhibits scant immunoreactivity in the adjacent ventromedial nuclear complex. In senescent astroglia, oxidative stress may down-regulate the cathepsin B gene as part of a concerted cellular stress (heat shock) response. Glial cathepsin D, on the other hand, resists stress-related inhibition and may play an important role in disposing of oxidatively modified mitochondria in the aging and degenerating nervous system.
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PMID:A cellular stress model for the differential expression of glial lysosomal cathepsins in the aging nervous system. 934 47

3,3',4,4'-Tetrachlorobiphenyl (tetraCB) binds to the aryl hydrocarbon receptor (AhR), and several reports have demonstrated that AhR agonists exhibit antiestrogenic and antitumorigenic activities in human breast cancer cells, the rodent uterus and breast. In contrast, a recent study showed that 3,3',4,4'-tetraCB bound the estrogen receptor (ER) and exhibited ER agonist activities, and we therefore have reinvestigated the estrogenic and antiestrogenic activities of 3,3',4,4'-tetraCB. Our results showed that 3,3',4,4'tetraCB and a structurally related analog, 3,3',4,4',5-pentaCB, did not bind the mouse uterine or human ER, did not induce proliferation of MCF-7 or T47D human breast cancer cells or induce reporter gene activity in cells transfected with E2-responsive constructs derived from the creatine kinase B (pCKB) or cathepsin D (pCD) gene promoters. Moreover, 3,3',4,4'-tetraCB and 3,3',4,4',5-pentaCB did not induce an increase in uterine wet weight, peroxidase activity or progesterone receptor binding in the 21-25-day-old female B6C3F1 mouse uterus. In contrast, both compounds inhibited 17beta-estradiol (E2)-induced cell proliferation and transactivation in MCF-7/T47D cells and uterine responses in B6C3F1 mice; surprisingly inhibition of E2-induced reporter gene activity was not observed in T47D cells transfected with pCKB, and this was observed as a cell-specific response with other AhR agonists. Additionally, 3,3',4,4'-tetraCB significantly inhibited mammary tumor growth in female Sprague-Dawley rats initiated with 7,12-dimethylbenzanthracene. Our results indicate that 3,3',4,4'-tetraCB does not exhibit ER agonist activity but exhibits a broad spectrum of antiestrogenic responses consistent with ligand-mediated AhR-ER crosstalk.
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PMID:3,3'4,4'-Tetrachlorobiphenyl exhibits antiestrogenic and antitumorigenic activity in the rodent uterus and mammary cells and in human breast cancer cells. 993 58

Chinese hamster ovary cell mutants defective in the post-uptake degradation of low-density lipoprotein (LDL) in lysosomes were selected from mutagenized cells by novel three-step screening. First, in the presence of LDL, clones sensitive to an inhibitor of the rate-limiting enzyme of the cholesterol biosynthetic pathway, 3-hydroxy-3-methylglutaryl-CoA reductase, were isolated. Second, from the selected clones, those lacking in the degradation of a constituent of a fluorescent LDL were qualitatively screened by microscopy. Third, the clones were further screened by previously established quantitative analytical flow cytometry that detects the early-phase disintegration of LDL by lysosomal acid hydrolases. One of the isolated mutant clones, LEX1 (Lysosome-Endosome X 1), was a recessive mutant, and exhibited a specific disorder in the late endocytic pathway. LEX1 cells showed an unusual perinuclear aggregate of vesicles, heterogeneously positive for lysosomal glycoprotein-B/cathepsin D and rab7, yet negative for the cation-independent mannose 6-phosphate receptor. The aggregate was formed around the microtubule organizing center, and was disrupted by nocodazole treatment. Internalized octadecyl rhodamine B-labeled LDL (R18-LDL) was accumulated in the perinuclear rab7-positive vesicles. In a Percoll density gradient, neither internalized R18-LDL nor internalized horseradish peroxidase was efficiently chased into heavy lysosomal fractions positive for beta-hexosaminidase. LEX1 cells showed differences in the activity and subcellular distribution of lysosomal enzymes. These characteristics of LEX1 cells are consistent with the ideas that the perinuclear vesicle aggregate is an arrested intermediate of direct fusion or divergence between lysosomes and rab7-positive, cation-independent mannose 6-phosphate receptor-negative late endosomes, and that equilibrium between the lysosomes and the late endosomes is shifted towards the late endosomes in LEX1 cells. Such fusion or divergence between the late endosomes and the lysosomes would determine an appropriate equilibrium between them, and might thereby play an important role for proper lysosomal digestive functions. LEX1 mutant cells would be helpful for the dissection of the as yet unrevealed details of the late endocytic membrane dynamics and for the identification of factors involved in the process arrested by the mutation.
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PMID:An arrested late endosome-lysosome intermediate aggregate observed in a Chinese hamster ovary cell mutant isolated by novel three-step screening. 1008 48

The effects of pleuran, beta-glucan isolated from Pleurotus ostreatus, were studied in a model of acute colitis in rats. Pleuran was given either as a 2% food component or as 0.44% pleuran hydrogel drink over 4 weeks. Colitis was induced by intraluminal instillation of 4% acetic acid and after 48 h the extent of colonic damage and several biochemical parameters were examined. Pleuran supplementation both in food and in drinking fluid significantly decreased the disposition to colitis. The macroscopic damage score was reduced by 51% or 67% by pleuran diet and pleuran hydrogel drink, respectively. Pleuran did not influence the final body weights of rats but prevented significantly colonic wet weight increase which was observed in the control diet group. The enhanced activity of myeloperoxidase in the inflamed colonic segment was reduced by pleuran diets, reflecting decreased neutrophil infiltration. The colonic damage was accompanied by decreased activities of lysosomal enzymes--acid phosphatase and cathepsin D--in the control untreated group, whereas in the pleuran groups the decrease was significantly attenuated. Both pleuran regimens reduced the content of conjugated dienes in the colon, liver and erythrocytes. In contrast to this fact, activities of antioxidant enzymes in erythrocytes and the colon were not so greatly influenced. Significant increase was found only in the case of SOD activity in sham operated rat erythrocytes under influence of both pleuran regimes and in the case of GST activity in erythrocytes of pleuran hydrogel group. The mechanism of the described protective effect of pleuran is not yet fully understood. Our results indicate that the pleuran-enhanced antioxidant defence of the colonic wall against the inflammatory attack may have come into play.
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PMID:Effect of pleuran (beta-glucan from Pleurotus ostreatus) in diet or drinking fluid on colitis in rats. 1171 51

Exaggerated neutrophil responses are a critical component in the pathogenesis of periodontal disease. We investigated whether leukocyte activity in aggressive periodontitis (AP) is increased compared with that in chronic periodontitis (CP) by gingival crevicular fluid (GCF) analysis of myeloperoxidase (MPO), beta-N-acetyl-hexosaminidase (beta-NAH), cathepsin D (CD), and elastase-alpha-1-proteinase inhibitor complex (alpha-1-EPI) before and 6 months after therapy. Initial AP neutrophil responses were significantly amplified compared with those in CP (MPO, 3.2-fold; beta-NAH, 37.5-fold; CD, 2.2-fold; alpha-1-EPI, 1.4-fold; p < 0.05). Surgical therapy resulted in a significant reduction of GCF markers compared with non-surgical treatment. However, the changes in clinical parameters were not different between AP and CP (P > 0.05). Analysis of the results suggests that the local inflammatory response in AP is characterized by increased release of inflammatory mediators of neutrophil origin into the GCF. Analysis of the data further suggests that surgical therapy is a more predictable method for removal of the pro-inflammatory etiology.
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PMID:Amplified crevicular leukocyte activity in aggressive periodontal disease. 1235 72

As Alzheimer's disease (AD) is a complex disease, we decided to estimate how previously reported genetic polymorphisms interact to increase the risk for the disease. Five candidate genes were chosen: apolipoprotein E (APOE), alpha 2-macroglobulin, cathepsin D, myeloperoxidase and nitric oxide synthase. Genotyping was performed in 100 cases of late-onset AD and 100 healthy controls. We found a highly significant difference in APOE epsilon 4 distribution between groups (P<0.005). However, no evidence of association for other studied loci was found. Cumulative analysis of five genetic polymorphisms was performed, but it also failed to reveal any synergistic effect of candidate genes greater than that caused by APOE itself. Our results suggest that the APOE epsilon 4 allele is the only known genetic risk factor for late-onset, sporadic AD.
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PMID:Simultaneous analysis of five genetic risk factors in Polish patients with Alzheimer's disease. 1278 37

We show that insulin-dependent signals regulate azurophil granule-selective macroautophagy in human myeloid cells. Depletion of insulin from an insulin-transferrin-supplemented serum-free medium caused growth retardation of myeloblastic HL-60 cells, in which sequestration of electronic-dense cytoplasmic materials by autophagosomes was observed. Positive immunoreactivity with anti-CD68, anti-cathepsin D, and anti-myeloperoxidase antibodies indicated that the sequestrated materials were azurophil granules, the granulocyte/macrophage lineage-specific lysosome-like particles. By contrast, other organelles, including the mitochondria, endoplasmic reticulum, and Golgi apparatus remained intact, indicating that the macroautophagy selectively targeted azurophil granules. The addition of insulin induced rapid activations of p70S6K and Akt, and the cells were rescued from macroautophagy. Rapamycin, an inhibitor of mammalian target of rapamycin, did not block the insulin-mediated rescue from macroautophagy, although it nullified the activation of p70S6K and cell growth. Low doses of LY294002, a phosphatidyl-inositol-3-kinase inhibitor, which abolished cell growth and p70S6K activity but did not influence Akt activity, did not block the insulin-mediated rescue either. By contrast, low doses of Akt-specific inhibitors, which inhibited neither cell growth nor p70S6K activity, completely blocked the insulin-mediated rescue from macroautophagy. Thus, insulin-dependent signals are responsible for the control of azurophil granule-selective macroautophagy via Akt-dependent pathways, while p70S6K-dependent pathways promote cell growth.
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PMID:Insulin-dependent signaling regulates azurophil granule-selective macroautophagy in human myeloblastic cells. 1296 Feb 28

Neutrophils play an important role in the pathogenesis of rheumatoid arthritis (RA) and various inflammatory conditions, by accumulation and liberation of active proteolytic enzymes. The effect of milk extract of Semecarpus anacardium Linn. nuts (SA) at a dosage of 150 mg kg(-1) body weight day(-1) for 14 days on adjuvant arthritis was studied to gain some insight into this intriguing disease in relation to neutrophil functions. The decreased phagocytic function of neutrophils (phagocytic index and avidity index) found in adjuvant arthritis was significantly increased by the administration of the drug SA. Increased levels of reactive oxygen species (superoxide radical, hydroxyl radical, H2O2 and myeloperoxidase), lysosomal enzymes (acid phosphatase and cathepsin D) and increased accumulation of neutrophils in the joints observed in adjuvant arthritic animals were reverted back to near normal levels by treatment with SA. The results of this study indicate that SA can be considered to be a good therapeutic agent for inflammation and arthritis.
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PMID:Effect of Semecarpus anacardium Linn. nut milk extract on rat neutrophil functions in adjuvant arthritis. 1591 68


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