Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isotretinoin (13-cis retinoic acid (13-cis RA)) is the most potent inhibitor of sebum production, a key component in the pathophysiology of acne, yet its mechanism of action remains largely unknown. The effects of 13-cis RA, 9-cis retinoic acid (9-cis RA), and all-trans retinoic acid (ATRA) on cell proliferation, apoptosis, and cell cycle proteins were examined in SEB-1 sebocytes and keratinocytes. 13-cis RA causes significant dose-dependent and time-dependent decreases in viable SEB-1 sebocytes. A portion of this decrease can be attributed to cell cycle arrest as evidenced by decreased DNA synthesis, increased p21 protein expression, and decreased cyclin D1. Although not previously demonstrated in sebocytes, we report that 13-cis RA induces apoptosis in SEB-1 sebocytes as shown by increased Annexin V-FITC staining, increased TUNEL staining, and increased cleaved caspase 3 protein. Furthermore, the ability of 13-cis RA to induce apoptosis cannot be recapitulated by 9-cis RA or ATRA, and it is not inhibited by the presence of a retinoid acid receptor (RAR) pan-antagonist AGN 193109. Taken together these data indicate that 13-cis RA causes cell cycle arrest and induces apoptosis in SEB-1 sebocytes by a RAR-independent mechanism, which contributes to its sebosuppressive effect and the resolution of acne.
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PMID:13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes. 1898 67

Troglitazone (TRO)-induced cytotoxicity was investigated in HepG2 cells. The cells were exposed to TRO as well as rosiglitazone (RSG) at concentrations of 0, 25, 50 and 75 microM for 48 h. Total proteins were separated by two-dimensional electrophoresis and visualized by silver staining. We focused on a protein spot at an approximate molecular weight of 35 kDa and isoelectric point (pI) of 5.7, which appeared only with the cytotoxic concentrations (50 and 75 microM) of TRO, but not with the low concentration (25 microM) of TRO or any concentrations of RSG. This protein spot was subjected to amino acid sequence analysis and identified as ribosomal protein P0 (P0). Interestingly, without any significant induction of its protein and mRNA, P0 was dephosphorylated depending on the concentration- and time-dependent manner of TRO-induced cytotoxicity. Pretreatment with a general caspase inhibitor, Z-VAD.fmk, prevented cleavage of caspase-3 but demonstrated a slight improvement of cytotoxicity induced by TRO. Thus, these effects could not prevent the dephosphorylation of P0. Our results strongly suggest that a post-translational modification, dephosphorylation, of P0 is associated with TRO-induced cytotoxicity.
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PMID:Dephosphorylation of ribosomal protein P0 in response to troglitazone-induced cytotoxicity. 1689 17

Apoptosis has been shown to contribute to the development of acute and chronic renal failure. The antiapoptotic action of the heme oxygenase (HO) system may represent an important protective mechanism in kidney pathology. We examined whether the lack of HO-1 would influence apoptosis in clipped kidneys of two-kidney, one-clip (2K1C) rats. Five-day-old Sprague-Dawley rats were injected in the left ventricle with approximately 5 x 10(9) colony-forming units/ml of retrovirus containing rat HO-1 antisense (LSN-RHO-1-AS) or control retrovirus (LXSN). After 3 mo, a 0.25-mm U-shaped silver clip was placed around the left renal artery. Animals were killed 3 wk later. Clipping the renal artery in LSN-RHO-1-AS rats did not result in increased HO-1 expression. In contrast to LXSN animals, 2K1C LSN-RHO-1-AS rats showed increased expression of cyclooxygenase 2 (COX-2) and higher 3-nitrotyrosine (3-NT) content as well as increased expression of the proapoptotic protein Apaf-1 and caspase-3 activity. Clipping the renal artery in LXSN rats resulted in increased expression of the antiapoptotic proteins Bcl-2 and Bcl-xl, while clipping the renal artery in LSN-RHO-1-AS rats did not change Bcl-2 levels and decreased the levels of Bcl-xl. Treatment of LSN-RHO-1-AS rats with cobalt protoporphyrin resulted in induction of renal HO-1, which was accompanied by decreases in blood pressure, COX-2, 3-NT, and caspase-3 activity, and increased expression of anti-apoptotic molecules (Bcl-2, Bcl-xl, Akt and p-Akt) in the clipped kidneys. These findings underscore the prominent role of HO-1 in counteracting apoptosis in this 2K1C renovascular hypertension model.
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PMID:Genetic suppression of HO-1 exacerbates renal damage: reversed by an increase in the antiapoptotic signaling pathway. 1694 May 61

This study determined the role of caspase-3 in phencyclidine (PCP)-induced neurodegeneration in postnatal rats. PCP administration to postnatal day 7 rats induced a dose-dependent increase in caspase-3 enzymatic activity in frontal cortex, striatum, and hippocampus. Enzymatic activation was present at 4 h, peaked between 6 and 12 h, and disappeared by 24 h. Further, cleaved caspase-3-immunoreactive neurons were detected as early as 2 h in the cortex, and were found throughout the brain, including, in addition, the thalamus and striatum. Within the cingulate, frontal, parietal, and retrosplenial cortices, immunoreactivity was specific for layers II-IV (especially layer II). Neurons positive for both silver staining and terminal deoxynucleotidyl transferase biotin-d-UTP nick-end labeling (TUNEL) were found in the same brain regions and subregions. Double labeling experiments confirmed that cleaved caspase-3 and TUNEL were coexpressed in many neurons in all brain regions and subregions studied. Temporal studies revealed that procaspase-3 cleavage preceded TUNEL staining by about 3 h, with many neurons being positive for both caspase-3 and TUNEL 9 h after PCP treatment. In organotypic corticostriatal slices, PCP caused a concentration- and time-dependent cleavage of procaspase-3 that was also colocalized with TUNEL staining in layers II-IV of the parietal cortex. Caspase-3 activation again preceded PCP-induced DNA damage assessed by TUNEL. PCP-induced neuronal death in vitro as measured by TUNEL staining was blocked 85% by Ac-AAVALLPAVLLALLAPDEVD-CHO, a cell-permeable selective caspase-3 inhibitor. These data demonstrate that caspase-3 activation plays a necessary role in the regionally selective neuronal death induced by PCP in the developing rat brain.
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PMID:The role of caspase-3 activation in phencyclidine-induced neuronal death in postnatal rats. 1698 4

In order to investigate the in vivo effect of metals used in dentistry, we investigated the effect of direct contact with metal plates (20 x 20 x 0.5 mm3) made of gold (Au), silver (Ag), copper (Cu) or palladium (Pd) on human promyelocytic leukemic HL-60 cells grown in RPMI1640 medium supplemented with 10% fetal bovine serum. When 0.5 mL of cell suspension was applied to the metal plates, cells were precipitated on the surface of the metal plate within 10 min. Contact with Cu induced a rapid decline of cell viability, the smear pattern of DNA fragmentation, and only minor activation of caspase-3. These effects were accompanied by a progressive decrease in the extracellular concentration of methionine, cysteine and histidine, with a corresponding increase in the concentration of methionine sulfoxide. Electron microscopy showed that contact with Cu induced vacuolization and cytoplasmic damage, prior to nuclear damage, without affecting the cell surface microvilli or mitochondrial integrity. Contact with the other metals did not induce such changes during the 3 h incubation, nor was any hormetic response (beneficial action at lower concentration) observed in the cells with any metals. Addition of N-acetyl-L-cysteine (4-5 mM) almost completely abrogated the Cu-induced cytotoxicity, whereas sodium ascorbate (0.1-0.5 mM) and catalase (6,000(1)-30,000 units/mL) were ineffective. Numerous serum proteins were adsorbed to the Ag plate, while bovine serum albumin was the major protein adsorbed to other metal plates. The present study suggests that direct contact with Cu induced non-apoptotic cell death by an oxidation-involved mechanism. The present model system may be applicable to the study of the interaction between cells and dental restorative materials.
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PMID:Biological impact of contact with metals on cells. 1709 67

Neuronal ceroid lipofuscinosces/Batten disease (NCL) is a devastating group of neurodegenerative diseases caused by genetic disruptions in lysosomal function. Cathepsin D (CD) is a major lysosomal protease, and mutations in CD that render it enzymatically defective have been reported recently in subsets of NCL patients. The targeted deletion of CD in mice results in extensive neuropathology, including biochemical and morphological evidence of apoptosis and autophagic stress (aberrant autophagosome accumulation), effects that are similar to those observed in NCL. To determine the contribution of Bax-dependent apoptosis in this mouse model of NCL, combined Bax- and CD-deficient mice were generated. Morphological analysis of CD-deficient mouse brains indicated large numbers of pyknotic neurons and neurons with marked cytoplasmic swellings containing undigested lipofuscin. Cell death and apoptosis were evidenced by increases in terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactivity and activation of caspase-3, respectively. DeOlmos silver-positive neurons were abundant in CD-deficient brain and correlated with neuron loss, as indicated by significant decreases in NeuN (neuronal nuclear antigen)-positive neurons. Lysosome dysfunction and autophagic stress were apparent in CD-deficient brain as indicated by the accumulation of autofluorescent storage material and by increased levels of LC3-II (light chain 3-II, a selective autophagosome marker), respectively. Bax deletion significantly inhibited caspase-3 activation and hippocampal TUNEL reactivity but did not prevent the majority of CD deficiency-induced neuropathology, including the persistence of pyknotic neurons, elevated cortical TUNEL reactivity, lysosome dysfunction and autophagic stress, neurodegeneration, and neuron loss. Together, these results suggest that CD deficiency-induced neuropathology does not require Bax-dependent apoptosis and highlights the importance of caspase-independent neuron death and neurodegeneration resulting from the genetic disruption of lysosome function.
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PMID:Cathepsin D deficiency induces persistent neurodegeneration in the absence of Bax-dependent apoptosis. 1731 3

Ketamine is widely used as a pediatric anesthetic. Studies in developing rodents have indicated that ketamine-induced anesthesia results in brain cell death. Additional studies are needed to determine if ketamine anesthesia results in brain cell death in the nonhuman primate and if so, to begin to define the stage of development and the duration of ketamine anesthesia necessary to produce brain cell death. Rhesus monkeys (N = 3 for each treatment and control group) at three stages of development (122 days of gestation and 5 and 35 postnatal days [PNDs]) were administered ketamine intravenously for 24 h to maintain a surgical anesthetic plane, followed by a 6-h withdrawal period. Similar studies were performed in PND 5 animals with 3 h of ketamine anesthesia. Animals were subsequently perfused and brain tissue processed for analyses. Ketamine (24-h infusion) produced a significant increase in the number of caspase 3-, Fluoro-Jade C- and silver stain-positive cells in the cortex of gestational and PND 5 animals but not in PND 35 animals. Electron microscopy indicated typical nuclear condensation and fragmentation in some neuronal cells, and cell body swelling was observed in others indicating that ketamine-induced neuronal cell death is most likely both apoptotic and necrotic in nature. Ketamine increased N-methyl-D-aspartate (NMDA) receptor NR1 subunit messenger RNA in the frontal cortex where enhanced cell death was apparent. Earlier developmental stages (122 days of gestation and 5 PNDs) appear more sensitive to ketamine-induced neuronal cell death than later in development (35 PNDs). However, a shorter duration of ketamine anesthesia (3 h) did not result in neuronal cell death in the 5-day-old monkey.
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PMID:Ketamine-induced neuronal cell death in the perinatal rhesus monkey. 1742 5

The goal of this study was to characterize the impact of induction or inhibition of the heme-HO system on renal apoptosis in clipped and non-clipped kidneys from 2K1C hypertensive rats. Male Sprague-Dawley rats had a 0.25 mm silver clip placed around the left renal artery. Four groups of rats were studied: sham operated animals, 2K1C control rats, 2K1C rats received weekly injections of CoPP (5 mg/100 g body wt, administered subcutaneously), and 2K1C rats pretreated with SnMP (5 mg/ 100g body wt, administered intraperitoneally three times a week). The animals were sacrificed three weeks after surgery. We measured systolic blood pressure, plasma renin activity, non-clipped and clipped kidney HO-1 and HO-2 protein expression, HO activity, heme content, nitrotyrosine levels, and activation of selected pro- and anti-apoptotic proteins. Systolic blood pressure and plasma renin activity were significantly higher in 2K1C rats compared to sham rats. Compared to kidneys from sham animals, clipped kidneys from 2K1C rats showed a significant increase in HO-1 expression with increases in HO activity (26%), heme content (47%) and nitrotyrosine levels (49%), accompanied by an increase in caspase-3 and caspase-9 activity. In contrast, non-clipped kidneys from 2K1C rats showed no differences in HO-1 expression, HO activity, heme content, nitrotyrosine levels and caspase activity compared to sham rats. In clipped kidneys from 2K1C rats, inhibition of HO activity by SnMP augmented caspase-3 and caspase-9 activity and decreased expression of the anti-apoptotic Bcl-2 protein, while induction of HO-1 with CoPP strongly inhibited the activity of both caspases and increased the induction of Bcl-2 and Bcl-xl proteins. These findings demonstrate that the clipped kidneys responded to decreased renal perfusion pressure and increased oxidative stress by activation of the heme-HO system, which exerts antiapoptotic action via mechanisms involving decreased caspase-3 and caspase-9 activity, and increased expression of antiapoptotic molecules.
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PMID:Induction of heme oxygenase-1 in renovascular hypertension is associated with inhibition of apoptosis. 1753 Nov 61

Methylmercury is an environmental contaminant with special selectivity for cerebellar granule cells. The aim of this study was to determine the effect of long-term methylmercury exposure on cell viability and cellular proteome in cultured cerebellar granule cells. Primary cultures of mice cerebellar granule cells were treated with 0-300 nM methylmercury at 2 days in vitro (div) and afterwards the cells were harvested at 12 div. 100 nM methylmercury produced loss of cell viability, reduced intracellular glutamate content and increased lipid peroxidation. Glutamate transport was not modified by methylmercury treatment. Cell death induced by 300 nM methylmercury at 8 div was apoptotic without producing activation of caspase 3. Extracts of total protein were separated by 2D electrophoresis. Around 800 protein spots were visualized by silver staining in SDS-polyacrylamide gels. Gel images were digitized and protein patterns were analysed by image analysis. Several spots were identified through a combination of peptide mass fingerprinting and matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS). The mitochondrial protein 3-ketoacid-coenzyme A transferase I was decreased up to 39% of controls at concentrations of methylmercury that did not produce cytotoxic effects, whereas the cytoplasmic proteins lactate dehydrogenase chain B and actin did not change.
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PMID:Cell viability and proteomic analysis in cultured neurons exposed to methylmercury. 1761 7

Under natural conditions and in some experimental models, rabies virus infection of the central nervous system causes relatively mild histopathological changes, without prominent evidence of neuronal death despite its lethality. In this study, the effects of rabies virus infection on the structure of neurons were investigated with experimentally infected transgenic mice expressing yellow fluorescent protein (YFP) in neuronal subpopulations. Six-week-old mice were inoculated in the hind-limb footpad with the CVS strain of fixed virus or were mock infected with vehicle (phosphate-buffered saline). Brain regions were subsequently examined by light, epifluorescent, and electron microscopy. In moribund CVS-infected mice, histopathological changes were minimal in paraffin-embedded tissue sections, although mild inflammatory changes were present. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and caspase-3 immunostaining showed only a few apoptotic cells in the cerebral cortex and hippocampus. Silver staining demonstrated the preservation of cytoskeletal integrity in the cerebral cortex. However, fluorescence microscopy revealed marked beading and fragmentation of the dendrites and axons of layer V pyramidal neurons in the cerebral cortex, cerebellar mossy fibers, and axons in brainstem tracts. At an earlier time point, when mice displayed hind-limb paralysis, beading was observed in a few axons in the cerebellar commissure. Toluidine blue-stained resin-embedded sections from moribund YFP-expressing animals revealed vacuoles within the perikarya and proximal dendrites of pyramidal neurons in the cerebral cortex and hippocampus. These vacuoles corresponded with swollen mitochondria under electron microscopy. Vacuolation was also observed ultrastructurally in axons and in presynaptic nerve endings. We conclude that the observed structural changes are sufficient to explain the severe clinical disease with a fatal outcome in this experimental model of rabies.
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PMID:Structural abnormalities in neurons are sufficient to explain the clinical disease and fatal outcome of experimental rabies in yellow fluorescent protein-expressing transgenic mice. 1794 40


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