Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain lysosomes were isolated from rat cerebra by Percoll density gradient centrifugation. The lysosomes had little and no contamination by marker enzymes from mitochondria and other organellae, respectively, and the yield was approximately 14% of the postnuclear supernatant. The activities of cathespins B, L, and/or J were similar to those of liver or kidney lysosomes, but the levels of cathepsin H activity were much lower than those of liver or kidney lysosomes. The degradation of native L-lactate dehydrogenase (LDH) and rat serum albumin by the isolated brain lysosomes in vitro was markedly suppressed by a low level of the cysteine proteinase inhibitor cystatin alpha, with slight inhibition of the activities of cathepsins B, L, and/or J. The degradation of rat serum albumin was also considerably inhibited by N-(L-3-trans-propylcarbamoyloxirane-2-carbonyl)- L-isoleucyl-L-proline (CA-074), a selective inhibitor of cathepsin B. In contrast, the degradation of brain proteins from the postmitochondrial supernatant by the same brain lysosomes was not or little suppressed by the same concentration of either inhibitor. However, it was considerably suppressed by leupeptin with marked inhibition of the activities of cathepsins B, L, and/or J, and with only slight inhibition of cathepsin H, indicating that cysteine proteinases that are highly sensitive to leupeptin are involved in the lysosomal degradation of the brain proteins. It was also moderately suppressed by pepstatin, an inhibitor of cathepsin D and was almost completely suppressed by a combination of leupeptin and pepstatin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Simple preparation of rat brain lysosomes and their proteolytic properties. 858 28

The levels of marker enzymes for liver function, namely transaminases (SGPT, SGOT), creatine phosphokinase (CPK), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were estimated in the sera of burn patients by administering trypsin: chymotrypsin preparation and comparing with an untreated group. Neutrophil proteolytic activity was also measured by assaying the lysosomal enzymes, namely neutrophil elastase and cathepsin D. Our earlier studies have already proved the efficacy of the above enzyme preparation to burn patients on the enhancement of vascular responses during the acute phase of the burn injury. These beneficial responses were brought about by the modulation of acute phase proteins expressed in the liver. Hence, it is of interest to study the changes in the above mentioned liver enzymes and certain lysosomal enzymes in the serum during the first 10 days of burn injury. The levels of liver and lysosomal enzymes markedly decreased in the treated group when compared with the untreated group. The enzyme studies clearly indicated that the initial rise in the liver enzymes was minimized in the treated group when compared with the untreated group and this helped in reducing the stress to the liver in the treated cases. The increase in the activity of alpha 1-antitrypsin and alpha 2-macroglobulin and decreased levels of C-reactive protein are attributed to the reduction of proteolytic enzyme levels in the treated group and minimizing the degradative changes during wound repair.
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PMID:Serum enzymatic changes modulated using trypsin: chymotrypsin preparation during burn wounds in humans. 956 24

Retinal pigment epithelial cells carry out phagocytosis and digestion of material shed from the photoreceptor outer segments. In this process, the integrity of lysosomal enzymes is of major importance. In the present study the effects of tamoxifen, toremifene and chloroquine on the activity of two lysosomal enzymes (cathepsin D and N-acetyl-beta-D-glucosaminidase) in the retinal pigment epithelial cells were studied. Retinal pigment epithelial cells from pig eyes were cultured for two weeks in Dulbecco's Modified Eagle Medium, after which the cells were exposed to 1-40 microM concentrations of tamoxifen citrate, toremifene citrate and chloroquine diphosphate. To eliminate possible medium-borne oestrogenic mechanisms, the test was repeated using phenol red-free medium with charcoal-stripped fetal calf serum. The exposure time was one week, after which the lysosomal enzymes cathepsin D and N-acetyl-beta-glucosaminidase were determined. Cellular injuries were assessed by quantifying the leakage of lactate dehydrogenase into the culture medium. Cathepsin D and N-acetyl-beta-D-glucosaminidase showed different sensitivities to tamoxifen, toremifene and chloroquine. The main lysosomal protease cathepsin D was more sensitive than N-acetyl-beta-D-glucosaminidase to the effects of tamoxifen and toremifene, possibly due to their antioestrogenic properties. The phenol red-free medium with charcoal-stripped serum seemed to make the drugs more effective than the reference medium. Chloroquine had only a minor effect on the lysosomal protease cathepsin D, but a clearer effect could be seen on N-acetyl-beta-glucosaminidase.
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PMID:Effects of tamoxifen, toremifene and chloroquine on the lysosomal enzymes in cultured retinal pigment epithelial cells. 986 42

Talc ore may contain several other minerals including calcite, dolomite, magnesite, tremolite, anthophyllite, antigorite, quartz, pyrophyllite, micas, or chlorites. Talc products are sold in a multitude of grades which have physical or functional characteristics especially suited for particular applications, so occupational and consumer exposures to talc are complex. Epidemiology studies have suggested an association between non-fibrous talc and lung cancer risk. Talc was nominated by the National Institute of Occupational Safety and Health (NIOSH) for study by the NTP because of widespread human exposure and because of the lack of adequate information on its chronic toxicity and potential carcinogenicity. Toxicology and carcinogenicity studies of talc (non-asbestiform, cosmetic grade), a finely powdered hydrous magnesium silicate, were conducted by exposing groups of F344/N rats to aerosols for 6 hours per day, 5 days per week for up to 113 weeks (males) or 122 weeks (females). Groups of B6C3F1 mice were exposed similarly for up to 104 weeks. LIFETIME STUDY IN RATS: Groups of 49 or 50 male and 50 female rats were exposed to aerosols of 0, 6, or 18 mg/m(3) talc until mortality in any exposure group reached 80% (113 weeks for males and 122 weeks for females). These exposures were selected based on 4-week inhalation studies of the terminal lung talc burden in F344/N rats; concentrations greater than 18 mg/m(3) were expected to overwhelm lung clearance mechanisms and impair lung function. These exposure concentrations provided a dose equivalent of 0, 2.8, or 8.4 mg/kg per day for male rats and 0, 3.2, or 9.6 mg/kg per day for female rats. In a special study, additional groups of 22 male and 22 female rats were similarly exposed and examined for interim pathology evaluations or pulmonary function tests after 6, 11, 18, and 24 months and lung biochemistry and cytology studies after 24 months. The talc aerosols had a median mass aerodynamic diameter of 2.7 mm in the 6 mg/m(3) chamber and a median diameter of 3.2 mm in the 18 mg/m(3) chamber, with geometric standard deviations of 1.9 mm. However, there was a 7-week period beginning at study week 11 during which the chamber concentration for the 18 mg/m(3) rats varied from approximately 30 to 40 mg/m(3) because of difficulties with the aerosol concentration monitoring system. Further, there was a 12-week period beginning at approximately week 70 during which there were difficulties in generating the talc aerosol, and the chamber concentrations for rats and mice were substantially lower than the target concentrations. Survival, Body Weights, and Clinical Findings: The survival of male and female rats exposed to talc was similar to that of the controls. Mean body weights of rats exposed to 18 mg/m(3) were slightly lower than those of controls after week 65. No clinical findings were attributed to talc exposure. Pathology Findings: Absolute and relative lung weights of male rats exposed to 18 mg/m(3) were significantly greater than those of controls at the 6-, 11-, and 18-month interim evaluations and at the end of the lifetime study, while those of female rats exposed to 18 mg/m(3) were significantly greater at the 11-, 18-, and 24-month interim evaluations and at the end of the lifetime study. Inhalation exposure of rats to talc produced a spectrum of inflammatory, reparative, and proliferative processes in the lungs. Granulomatous inflammation occurred in nearly all exposed rats and the severity increased with exposure duration and concentration. Hyperplasia of the alveolar epithelium and interstitial fibrosis occurred in or near foci of inflammation in many exposed rats, while squamous metaplasia of the alveolar epithelium and squamous cysts were also occasionally seen. Accumulations of macrophages (histiocytes), most containing talc particles, were found in the peribronchial lymphoid tissue of the lung and in the bronchial and mediastinal Iymph nodes. In female rats, the incidences of alveolar/bronchiolar adenoma, carcinoma, and adenoma or carcinoma (combined) in the 18 mg/m(8 mg/m(3) group were significantly greater than those of controls. The incidences of pulmonary neoplasms in exposed male rats were similar to those in controls. Minor alterations attributed to talc exposure were also observed in the upper respiratory tract. Hyperplasia of the respiratory epithelium of the nasal mucosa in males and accumulation of cytoplasmic, eosinophilic droplets in the nasal mucosal epithelium in male and female rats occurred with a concentration-related increased incidence in the exposed groups. Adrenal medulla pheochromocytomas [benign, malignant, or complex (combined)] occurred with a significant positive trend in male and female rats, and the incidences in the 18 mg/m(3) groups were significantly greater than those of controls. Although adrenal medulla hyperplasia occurred with similar frequency among exposed and control females, the incidences of hyperplasia in exposed males were significantly lower than in controls. Lung Talc Burden: Lung talc burdens of male and female rats exposed to 6 mg/m(3) were similar and increased progressively from 6 to 24 months. Lung talc burdens of females exposed to 18 mg/m(3) also increased progressively from 6 to 24 months, while those of males exposed to 18 mg/m(3) remained about the same after 18 months. Lung burdens were generally proportional to exposure concentration at each interim evaluation. Pulmonary Function, Bronchoalveolar Lavage, and Lung Biochemistry: In exposed male and female rats there was a concentration-related impairment of respiratory function which increased in severity with increasing exposure duration. The impairment was characterized by reductions in lung volume (total lung capacity, vital capacity, and forced vital capacity), lung compliance, gas exchange efficiency (carbon monoxide diffusing capacity), and nonuniform intrapulmonary gas distribution. After 24 months, males exposed to 6 mg/m(3) talc had a significant increase in beta-glucuronidase and polymorphonuclear leukocytes; males exposed 18 mg/m(3) had significant increases in b -glucuronidase, lactate dehydrogenase, alkaline phosphatase, and total protein in bronchoalveolar lavage fluid. All exposed females had significantly increased a-glucuronidase, lactate dehydrogenase, alkaline phosphatase, total protein, and polymorphonuclear leukocytes; 18 mg/m(3) females also had significantly increased glutathione reductase. Viability and phagocytic activity of macrophages recovered from lavage fluid were not affected by talc exposure. Total lung collagen was significantly increased in rats at both exposure concentrations after 24 months, while collagenous peptides in lavage fluid and the percentages of newly synthesized protein from females, but not males, were also significantly increased at the 6 or 18 mg/m(3) levels. In addition, lung proteinase activity, primarily cathepsin D-like activity, was significantly greater in exposed males and females. Rats exposed to talc also had significant increases in collagenous peptides and acid proteinase in lung homogenates. 2-YEAR STUDY IN MICE: Groups of 47 to 49 male and 48 to 50 female mice were exposed to aerosols containing 0, 6, or 18 mg/m(3) talc for up to 104 weeks. These exposures were selected based on 4-week inhalation studies of the terminal lung talc burden in B6C3F1 mice; concentrations greater than 18 mg/m(3) were expected to overwhelm lung clearance mechanisms and impair lung function. These exposure concentrations provide a dose equivalent of 0, 2, or 6 mg/kg per day for male mice and 0, 1.3, or 3.9 mg/kg per day for female mice. In a special study, additional groups of 39 or 40 male and 39 or 40 female mice similarly exposed were examined for interim pathology evaluations, lung biochemistry, and cytology studies after 6, 12, and 18 months of exposure. The talc aerosols had a median mass aerodynamic diameter of 3.3 mm with a geometric standard deviation of 1.9 mm in the 6 mg/m(3) chamber, and a median diameter of 3.6 mm with a geometric standard deviation of 2.0 mm in the 18 mg/m(3) chamber. Further, there was a 12-week period beginning at approximately week 70 during which there were difficulties in generating the talc aerosol, and the chamber concentrations for rats and mice were substantially lower than the target concentrations. Survival, Body Weights, and Clinical Findings: Survival and final mean body weights of male and female mice exposed to talc were similar to those of the controls. There were no clinical findings attributed to talc exposure. Pathology Findings: Inhalation exposure of mice to talc was associated with chronic active inflammation and the accumulation of macrophages in the lung. In contrast to rats, hyperplasia of the alveolar epithelium, squamous metaplasia, or interstitial fibrosis were not associated with the inflammatory response in mice, and the incidences of pulmonary neoplasms in exposed and control groups of mice were similar. Accumulations of macrophages (histiocytes) containing talc particles were also present in the bronchial Iymph node. In the upper respiratory tract, cytoplasmic alteration, consisting of the accumulation of cytoplasmic eosinophilic droplets in the nasal mucosal epithelium, occurred with a concentration-related increased incidence in exposed male and female mice. Lung Talc Burden: Lung talc burdens of mice exposed to 6 mg/m(3) were similar between males and females and increased progressively from 6 to 24 months, except for males at 18 months. The lung talc burdens of mice exposed to 18 mg/m(3) were also similar between the sexes at each interim evaluation. Although the talc burdens of males and females increased substantially from 6 to 24 months, the values at 12 and 18 months were similar. Generally, lung burdens of mice exposed to 18 mg/m(3) were disproportionately greater than those of mice exposed to 6 mg/m(3), suggesting that clearance of talc from the lung was impaired, or impaired to a greater extent, in mice exposed to 18 mg/m(3) than in mice exposed to 6 mg/m(3). Bronchoalveolar Lavage and Lung Biochemistry: Increases in total protein, beta-glucuronidase, lactate dehydrogenase, glutathione reductase, total nucleated cells, and polymorphonuclear leukocytes in bronchoalveolar lavage fluid were observed primarily in mice exposed to 18 mg/m(3), although some parameters were also increased in mice exposed to 6 mg/m(3). The amount of collagenous peptides in lavage fluid and total lung collagen were increased in male and female mice exposed to 18 mg/m(3). Acid proteinase activity, principally cathepsin D-like activity, of lung homogenate supernatant fluid was also significantly increased in mice at the 18 mg/m(3) exposure concentration. CONCLUSIONS: Under the conditions of these inhalation studies, there was some evidence of carcinogenic activity of talc in male F344/N rats based on an increased incidence of benign or malignant pheochromocytomas of the adrenal gland. There was clear evidence of carcinogenic activity of talc in female F344/N rats based on increased incidences of alveolar/bronchiolar adenomas and carcinomas of the lung and benign or malignant pheochromocytomas of the adrenal gland. There was no evidence of carcinogenic activity of talc in male or female B6C3F1 mice exposed to 6 or 18 mg/m(3). The principal toxic lesions associated with inhalation exposure to the same concentrations of talc in rats included chronic granulomatous inflammation, alveolar epithelial hyperplasia, squamous metaplasia and squamous cysts, and interstitial fibrosis of the lung. These lesions were accompanied by impaired pulmonary function characterized primarily by reduced lung volumes, reduced dynamic and/or quasistatic lung compliance, reduced gas exchange efficiency, and nonuniform intrapulmonary gas distribution. In mice, inhalation exposure to talc produced chronic inflammation of the lung with the accumulation of alveolar macrophages. Synonyms: talcum; agalite; emtal 596; non-asbestiform talc; non-fibrous talc; steatite; hydrous magnesium silicate
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PMID:NTP Toxicology and Carcinogenesis Studies of Talc (CAS No. 14807-96-6)(Non-Asbestiform) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1261 90

The aim of this work was to compare the influence of amosite-asbestos and wollastonite fibrous dusts combined with cigarette smoke on chosen cytotoxic parameters of bronchoalveolar lavage fluid (BALF) in rats. Fisher 344 rats inhaled wollastonite or amosite fibrous dusts (60 or 30 mg x m(-3) air) one hour every two days combined with daily breathing of diluted mainstream tobacco smoke (30 mg of TPM x m(-3) air). The experiment lasted 6 months. After sacrifying the animals bronchoalveolar lavage (BAL) was performed and the viability and phagocytic activity of alveolar macrophages (AM), lactate dehydrogenase (LDH) and alkaline phosphatase activity (in the cell-free BALF), acid phosphatase (ACP) and cathepsin D activity (in cell-free BALF and BAL cell suspension) were examined. Exposure to amosite without tobacco smoke significantly decreased the viability of AM and increased the cathepsin D activity in BAL cells. Exposure to wollastonite significantly increased only the cathepsin D activity in BAL cells. Smoking significantly depressed the phagocytic activity of AM and amplified the amosite-induced increase of lysosomal enzyme activities--especially the activity of cathepsin D in BAL cells.
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PMID:Evaluation of bronchoalveolar lavage fluid cytotoxic parameters after inhalation exposure to amosite and wollastonite fibrous dusts combined with cigarette smoke. 1514 67

In this study, we have examined the potential of second-generation antisense chimeric 2'-O-(2-methoxy)ethyl/DNA phosphorothioate oligonucleotides (ONs) to affect cell growth through non-antisense mechanisms. Evaluation of a series of ONs demonstrated that only a small number were cytotoxic at concentrations close to those required for antisense activity. Toxicity of the ONs appeared to be sequence dependent and could be affected by base and backbone modifications. Caspase-3 activation occurs with some ONs and it is most likely secondary to necrosis rather than apoptosis, since cells treated with toxic ONs did not show chromatin condensation, but did exhibit high-extracellular lactate dehydrogenase activity. Caspase-3 activation does not correlate with and appears not to be required for the inhibition of cell proliferation. Toxicity was only observed when ONs were delivered intracellularly. The mechanism by which one of the most cytotoxic ON produces cytotoxicity was investigated in more detail. Treatment with the cytotoxic ON caused disruption of lysosomes and Pepstatin A, a specific inhibitor of aspartic proteases, reduced the cytotoxicity of the ON. Reduction of lysosomal aspartic protease cathepsin D by prior treatment with cathepsin D-specific antisense ON did not attenuate the cytotoxicity, suggesting that other aspartic proteases play a crucial role in the cellular proliferation inhibition by ONs.
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PMID:Sequence-dependent cytotoxicity of second-generation oligonucleotides. 1560 56

The proteins that are neosynthesized and secreted in the different regions of the human epididymis were determined by in vitro biosynthesis of epididymal tubules, and the luminal proteins were collected by microperfusion of each tubule. The preparations were analyzed by two-dimensional gel electrophoresis and the proteins were identified by mass spectrometry. Some of the major proteins identified corresponded to serum compounds such as albumin, transferrin and alpha-1-antitrypsin. The other proteins identified included lactotransferrin, clusterin, PEBP, NCP2/CTP/HE1, HE3, Crisp, actin, calmodulin, E12, PGDS, l-lactate dehydrogenase, malate dehydrogenase, carbonic anhydrase, triose phosphate isomerase, glutamyltransferase, glutathione S-transferase P, thioredoxin peroxidase, superoxide dismutase, cathepsin D and cystatin. Epididymal activity is highly regionalized in most species. However, in this study in humans, there were only minor changes in the major proteins secreted. It is suggested that this specificity might be related to the difference between species in the location of the epididymis where sperm become fertile.
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PMID:Human epididymal secretome and proteome. 1643 Oct 15

Changes in some lung cytotoxic parameters after exposure to refractory ceramic fibres (RCF) or to cigarette smoke (S) and after combined exposure to RCF+S were studied in male Wistar rats in order to evaluate their potential adverse health effects. Four groups of rats were treated as follows : 1) intratracheally instilled by saline solution (0.4 ml); 2) intratracheally instilled by 4 mg of RCF; 3) exposed only to S (85 mg of total particulate matter/m(3) air ) for two hours daily; 4) exposed to RCF+S. After 6 months the animals were exsanguinated and the bronchoalveolar lavage (BAL) was perfomed. Viability and phagocytic activity of alveolar macrophages (AM), activity of lactate dehydrogenase (LDH) in cell-free BAL fluid (cf-BALF), acid phosphatase (ACP) and cathepsin D (CATD) in cfBALF, in BALF cells and in the lung tissue were estimated. Viability of AM was depressed by every type of exposure with RCF+S effect being at least additive. Phagocytic activity of AM increased in the presence of RCF. No significant changes in LDH activity were found. Activities of lysosomal enzymes measured in the lung tissue homogenates were not significantly changed, but those in the cfBALF increased especially after exposure to S with most expressive increase in BALF cells after exposure to S and RCF+S. In the case of CATD the effect of RCF+S was more than additive. The results point out to the persistence of the RCF exposure cytotoxic effects and their amplification by cigarette smoke.
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PMID:Lung cytotoxicity of combined exposure to refractory ceramic fibres and cigarette smoke. 1660 93

Damp dwellings represent suitable conditions for extended indoor moulds. A cellulolytic micromycete Stachybotrys chartarum (Ehrenb.) Hughes is considered to be a tertiary colonizer of surfaces in affected buildings. Known adverse health effects of S. chartarum result from its toxins--trichothecenes or atranones, as well as spirolactams. Mechanism of their potential pathological effects on the respiratory tract has not yet been sufficiently clarified. The cytotoxic effects of complex chloroform-extractable endo- (in biomass) and exometabolites (in cultivation medium) of an indoor S. chartarum isolate of an atranone chemotype, grown on a liquid medium with yeast extract and sucrose at 25 degrees C for 14 d, on lung tissue were evaluated in the 3-day experiment. For the purpose, 4 mg of toxicants were intratracheally instilled in 200 g Wistar male rats. A trichothecene mycotoxin diacetoxyscirpenol was used as the positive control. Bronchoalveolar lavage (BAL) parameters--viability and phagocytic activity of alveolar macrophages (AM), activity of lactate dehydrogenase, acid phosphatase and cathepsin D in cell-free BAL fluid (BALF), as well as in BAL cells, were measured. Acute exposure to the metabolites caused statistically significant changes, indicating lung tissue injury in the experimental animals. Decreased AM viability and increased activity of lysosomal enzyme cathepsin D in BAL cells after fungal exometabolite exposure were the most impressive. As toxic principles were found predominantly in the growth medium, toxins were more likely responsible for lung cell damage than e.g. fungal cell wall components. S. chartarum toxic metabolites can contribute to the ill health of occupants of mouldy building after inhalation of contaminated aerosol.
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PMID:Pulmonary cytotoxicity of secondary metabolites of Stachybotrys chartarum (Ehrenb.) Hughes. 1719 98

We previously reported that N-(4-hydroxyphenyl)retinamide (4HPR) inhibits retinoblastoma tumor growth in a murine model in vivo and kills Y79 retinoblastoma cells in vitro. In this work, we assayed different cell death-related parameters, including mitochondrial damage and caspase activation, in Y79 cells exposed to 4HPR. 4HPR induced cytochrome c release from mitochondria, caspase-3 activation, and oligonucleosomal DNA fragmentation. However, pharmacologic inactivation of caspases by the pan-caspase inhibitor BOC-D-fmk, or specific caspase-3 inhibition by Z-DEVD-fmk, was not sufficient to prevent cell death, as assessed by loss of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction, lactate dehydrogenase release, disruption of mitochondrial transmembrane potential (Deltapsi(m)), and ATP depletion. We found that 4HPR causes lysosomal membrane permeabilization and cytosolic relocation of cathepsin D. Pepstatin A partially rescued cell viability and reduced DNA fragmentation and cytosolic cytochrome c. The antioxidant N-acetylcysteine attenuated cathepsin D relocation into the cytosol, suggesting that lysosomal destabilization is dependent on elevation of reactive oxygen species and precedes mitochondrial dysfunction. Activation of AKT, which regulates energy level in the cell, by the retinal survival facto]r insulin-like growth factor I was impaired and insulin-like growth factor I was ineffective against ATP and Deltapsi(m) loss in the presence of 4HPR. Lysosomal destabilization, associated with mitochondrial dysfunction, was induced by 4HPR also in other cancer cell lines, including PC3 prostate adenocarcinoma and the vascular tumor Kaposi sarcoma KS-Imm cells. The novel finding of a lysosome-mediated cell death pathway activated by 4HPR could have implications at clinical level for the development of combination chemoprevention and therapy of cancer.
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PMID:Novel cell death pathways induced by N-(4-hydroxyphenyl)retinamide: therapeutic implications. 1723 88


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