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)

Numerous cardiomyocytes were found to show autophagic vacuolar degeneration in the UM-X7.1 hamster model of human dilated cardiomyopathy, and autophagy-related proteins--i.e., ubiquitin, cathepsin D and Rab7--were upregulated in those hearts. Importantly, Evans blue-positive cardiomyocytes with leaky plasma membranes were also positive for cathepsin D, suggesting a link between autophagic degeneration and cell death. Treatment with granulocyte colony-stimulating factor (G-CSF) significantly improved survival, cardiac function and remodeling in these animals, and such beneficial effects were accompanied by a reduction in autophagy, an increase in cardiomyocyte size, and a reduction in myocardial fibrosis. G-CSF-induced changes in molecular signaling included activation of Akt and Stat3 (signal transducer and activator of transcription-3), a reduction in the level of myocardial tumor necrosis factor-alpha, and an increase in those of matrix metalloproteinases. In contrast, neither cardiomyocyte apoptosis nor regeneration of cardiomyocytes from bone marrow-derived cells was significant. It thus appears that autophagic death and autophagy-dependent degeneration are important contributors to loss of cardiomyocyte function in the cardiomyopathic hamster and that G-CSF exerts a beneficial effect, mainly via an anti-autophagic mechanism.
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PMID:Autophagic degeneration and death of cardiomyocytes in heart failure. 1687 10

Arginine is a conditionally essential amino acid and exerts anabolic effects. We studied the effects of enteral arginine on whole-body and duodenal protein metabolism. Eight healthy fasted volunteers received randomly a 5-hr enteral infusion of either arginine (Arg; 20 g) or an isonitrogenous amino acid mixture (AA) and an IV infusion of [13C]leucine. Duodenal biopsies were performed. Whole-body protein turnover and duodenal protein synthesis (FSR) were calculated from GC/MS-assessed enrichment. The mRNA levels for major components of proteolytic pathways, ubiquitin, cathepsin D, and m-calpain, were evaluated by RT-PCR. Results were compared using paired Wilcoxon test. Endogenous, oxidative, and nonoxidative leucine fluxes were not different after Arg and AA infusions, respectively. Duodenal mucosal protein FSR (71% +/- 26% vs 81% +/- 30%/day) and mRNA levels of ubiquitin, cathepsin D, and m-calpain were also similar after Arg and AA infusions. We conclude that in healthy subjects, arginine infusion exerts no effect on whole-body and duodenal protein metabolism. Whether arginine might specifically affect these parameters in catabolic or inflammatory situations remains to be determined.
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PMID:Lack of effect of acute enteral arginine infusion on whole-body and intestinal protein metabolism in humans. 1740 37

Regulated secretory vesicles produce, store, and secrete active peptide hormones and neurotransmitters that function in cell-cell communication. To gain knowledge of the protein systems involved in such secretory vesicle functions, we analyzed proteins in the soluble and membrane fractions of dense core secretory vesicles purified from neuroendocrine chromaffin cells. Soluble and membrane fractions of these vesicles were subjected to SDS-PAGE separation, and proteins from systematically sectioned gel lanes were identified by microcapillary LC-MS/MS (microLC-MS/MS) of tryptic peptides. The identified proteins revealed functional categories of prohormones, proteases, catecholamine neurotransmitter metabolism, protein folding, redox regulation, ATPases, calcium regulation, signaling components, exocytotic mechanisms, and related functions. Several novel secretory vesicle components involved in proteolysis were identified consisting of cathepsin B, cathepsin D, cystatin C, ubiquitin, and TIMP, as well carboxypeptidase E/H and proprotein convertases that are known to participate in prohormone processing. Significantly, the membrane fraction exclusively contained an extensive number of GTP nucleotide-binding proteins related to Rab, Rho, and Ras signaling molecules, together with SNARE-related proteins and annexins that are involved in trafficking and exocytosis of secretory vesicle components. Membranes also preferentially contained ATPases that regulate proton translocation. These results implicate membrane-specific functions for signaling and exocytosis that allow these secretory vesicles to produce, store, and secrete active peptide hormones and neurotransmitters released from adrenal medulla for the control of physiological functions in health and disease. In summary, this proteomic study illustrates secretory vesicle protein systems utilized for the production and secretion of regulatory factors that control neuroendocrine functions.
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PMID:Proteomics of neuroendocrine secretory vesicles reveal distinct functional systems for biosynthesis and exocytosis of peptide hormones and neurotransmitters. 1740 50

Various types of eosinophilic neurons (ENs) are found in the post-ischemic brain. We examined the temporal profile of ENs in the core and peripheral regions of the ischemic cortex, and analyzed the relationship to the expression of various cell death-related factors. Unilateral forebrain ischemia was induced in Mongolian gerbils by transient common carotid artery occlusions, and the brains from 3 h to 2 weeks post-ischemia were prepared for morphometric and immunohistochemical analysis of ENs. ENs with minimally abnormal nuclei and swollen cell bodies appeared at 3 h in the ischemic core and at 12 h in the periphery. In both locations multiple cell death-related factors including calcium, micro-calpain, cathepsin D, 78 kDa glucose-regulated protein (GRP78) and ubiquitin were activated. In the ischemic core, pyknosis and irregularly atrophic cytoplasm peaked at 12 h, which was associated with significant increases in staining for calcium and micro-calpain. ENs with pyknosis and scant cytoplasm peaked at 4 days and were positive for TUNEL and calcium staining. In the ischemic periphery, ENs had slightly atrophic cytoplasm and sequentially developed pyknosis, karyorrhexis and karyolysis over 1 week. These cells were positive for TUNEL and calcium staining. All types of EN were negative for caspase 3. There may be two region-dependent pathways of EN changes in the post-ischemic brain: pyknosis with cytoplasmic shrinkage in the core, and nuclear disintegration with slightly atrophic cytoplasm in the periphery. This difference coordinates different activation patterns of cell death-related factors in ENs.
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PMID:Two region-dependent pathways of eosinophilic neuronal death after transient cerebral ischemia. 1862 83

The lysosomal apoptosis pathway is a potentially interesting therapeutic target. Since apoptosis involving the lysosomal pathway has been described to involve cathepsins, we screened a drug library for agents that induce cathepsin-dependent apoptosis. Using pharmacological inhibitors and siRNA, we identified 2 structurally related agents (NSC687852 and NSC638646) that induced cathepsin D-dependent caspase-cleavage activity in human breast cancer cells. Both agents were found to induce the mitochondrial apoptosis pathway. NSC687852 and NSC638646 were found to inhibit the activity of ubiquitin isopeptidases and to induce the accumulation of high-molecular-mass ubiquitins in cells. We show that 3 other inhibitors of the proteasome degradation pathway induce lysosomal membrane permeabilization (LMP) and that cathepsin-D siRNA inhibits apoptosis induced by these agents. We conclude that a screen for cathepsin-dependent apoptosis-inducing agents resulted in the identification of ubiquitin isopeptidase inhibitors and that proteasome inhibitors with different mechanisms of action induce LMP and cathepsin D-dependent apoptosis.
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PMID:Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin-proteasome system. 1908 26

Neurons of the central nervous system (CNS) tissue are terminally differentiated cells and have large volumes, unlike cells of peripheral tissues. Such neurons possess abundant lysosomes in which damaged and unneeded intracellular constituents are degraded. A cellular process to bring the unneeded constituents to lysosomes is referred to as macroautophagy (autophagy), which is essential for the maintenance of cellular metabolism under physiological conditions. In fact, mice deficient in Atg7 or Atg5 specifically in CNS tissue have ubiquitin aggregates in neurons and massive loss of cerebral and cerebellar cortical neurons, resulting in neurodegeneration and short life span. In addition, acceleration of autophagy induced by the loss of lysosomal proteinases such as cathepsin D or cathepsins B and L, or by hypoxic/ischemic (H/I) brain injury, causes neurodegeneration. Moreover, lysosomes with undigested materials due to loss of proteinases are enwrapped by double membranes to produce autophagosomes, resulting in the further accumulation of autolysosomes. H/I brain injury at birth that is an important cause of cerebral palsy, mental retardation, and epilepsy causes energy failure, oxidative stress, and unbalanced ion fluxes, leading to a high induction of autophagy in brain neurons. Since mice that are unable to execute autophagy (due to brain-specific deletion of Atg7 or Atg5) die as a result of massive loss of cerebral and cerebellar neurons with accumulation of ubiquitin aggregates, induction of neuronal autophagy after H/I injury is generally considered neuroprotective, as it maintains cellular homeostasis. However, our data showing that H/I injury-induced pyramidal neuron death in the neonatal hippocampus is largely prevented by Atg7 deficiency indicate the presence of autophagic neuron death. In this section, we introduce various methods for the detection of autophagic neuron death in addition to other death modes of CNS neurons.
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PMID:Autophagic neuron death. 1921 1

Efferent ductules of the male reproductive tract contain high concentrations of estrogen receptors (ER), which are essential for the regulation of fluid reabsorption and maintenance of normal epithelial morphology. Treatments with the antiestrogen ICI 182,780 and 17beta-estradiol cause a reduction in ERalpha expression; however, the mechanisms governing the down-regulation are undetermined. In other tissues, the ubiquitin-proteasome pathway appears to have a dominant role in regulating ERalpha turnover, although in the efferent ductules, an abundance of epithelial lysosomes could also participate in protein turnover. To study this activity, the expressions of proteasome, ubiquitin, and markers for the endocytotic apparatus (early endosome antigen-1 [EEA1], clusterin, and cathepsin D) were examined in rat efferent ductules and initial segment of epididymis. Distinct cellular, subcellular, and regional distributions of these proteins were observed in the epithelial cells. A gradient of proteasome, ubiquitin, EEA1, and clusterin staining was seen in the efferent ducts, which decreased 30%-41% from the proximal zone to the terminal common duct. Antiestrogen treatment resulted in significant decreases in proteasome, EEA1, and clusterin in the efferent ducts. Localization of ubiquitin-proteasome and endocytotic pathway components suggests that differential regulation is required for protein degradation and turnover in efferent ductules and head of the epididymis.
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PMID:Cellular and regional distributions of ubiquitin-proteasome and endocytotic pathway components in the epithelium of rat efferent ductules and initial segment of the epididymis. 1926 34

To examine the functional significance and morphological characteristics of starvation-induced autophagy in the adult heart, we made green fluorescent protein-microtubule-associated protein 1-light chain 3 (LC3) transgenic mice starve for up to 3 days. Electron microscopy revealed round, homogenous, electron-dense lipid droplet-like vacuoles that initially appeared in cardiomyocytes as early as 12 hours after starvation; these vacuoles were identified as lysosomes based on cathepsin D-immunopositive reactivity and acid phosphatase activity. The increase in the number of lysosomes depended on the starvation interval; typical autophagolysosomes with intracellular organelles also appeared, and their numbers increased at the later phases of starvation. Myocardial expression of autophagy-related proteins, LC3-II, cathepsin D, and ubiquitin, increased, whereas both myocardial ATP content and starvation integral decreased. Treatment with bafilomycin A1, an autophagy inhibitor, did not affect cardiac function in normally fed mice but significantly depressed cardiac function and caused significant left ventricular dilatation in mice starved for 3 days. The cardiomyocytes were occupied with markedly accumulated lysosomes in starved mice treated with bafilomycin A1, and both the myocardial amino acid content, which was increased during starvation, and the myocardial ATP content were severely decreased, potentially contributing to cardiac dysfunction. The present findings suggest a critical role of autophagy in the maintenance of cardiac function during starvation in the adult.
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PMID:Functional significance and morphological characterization of starvation-induced autophagy in the adult heart. 1934 65

To examine the functional significance and detailed morphological characteristics of starvation-induced autophagy in the adult heart, we starved green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) transgenic mice for up to 3 days. Electron microscopy revealed that, after as little as 12 hours of starvation, round and homogenously electron-dense lipid droplet-like vacuoles appeared in cardiomyocytes. These were determined to be lysosomes based on cathepsin D immunopositivity and acid phosphatase activity. The number of these lysosomes increased with starvation time, and typical autolysosomes with intracellular organelles destined for degradation appeared and increased in number at later times during the starvation period. Myocardial expression of the autophagy-related proteins LC3-II, cathepsin D and ubiquitin increased, while myocardial ATP content decreased, as the starvation interval proceeded. Treatment with bafilomycin A(1), an autophagy inhibitor, did not affect cardiac function in normally fed mice, but it significantly depressed cardiac function and caused significant left ventricular dilatation in the mice starved for 3 days. Cardiomyocytes from starved mice treated with bafilomycin A(1) showed marked accumulation of lysosomes, and the myocardial amino acid content, which increased during starvation in normally fed mice, as well as the myocardial ATP content, were severely reduced, which likely contributed to the cardiac dysfunction. The present findings suggest autophagy plays a critical role in the maintenance of cardiac function during starvation in the adult.
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PMID:Autophagy maintains cardiac function in the starved adult. 1958 30

Sporadic motor neuron disease (MND) is characterized by progressive degeneration of motor neurons and intraneuronal cytoplasmic translocation and deposition of the nuclear protein TDP-43. There is a paucity of data on the subcellular mechanisms of the nuclear-cytoplasmic trafficking of TDP-43, particularly about the precise role of the endosomal-lysosomal system (ELS). In the present study, using a neuron-specific morphometric approach, we examined the expression of the early endosomal marker Rab5 and lysosomal cathepsins B, D, F, and L as well as PAS-stained structures in the anterior horn cells in 11 individuals affected by sporadic MND and 5 age-matched controls. This was compared with the expression of ubiquitin, p62 and TDP-43 and its phosphorylated form. The principal finding was the increased expression of the endosomal marker Rab5 and lysosomal cathepsin D, and of PAS-positive structures in motor neurons of MND cases. Furthermore, the area-portion of Rab5 immunoreactivity correlated well with the intracellular accumulation of ubiquitin, p62 and (phosphorylated) TDP-43. However, double immunolabelling and immunogold electron microscopy excluded colocalization of phosphorylated TDP-43 with the ELS. These data contrast with observations on neuronal cytopathology in Alzheimer's or prion diseases where the disease-specific proteins are processed within endosomes, and suggest a distinct role of the ELS in MND.
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PMID:Increased neuronal Rab5 immunoreactive endosomes do not colocalize with TDP-43 in motor neuron disease. 2055 62


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