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)

TNF-alpha is a pro-inflammatory cytokine that plays a key role in disorders due to HIV-1 infection and replication such as Kaposi sarcoma, wasting, aphthous ulcerations and progression to AIDS. The controversial drug thalidomide is anti-inflammatory, anti-angiogenic and a selective inhibitor of TNF-alpha that is being studied as a treatment for HIV-1-related disorders, immune disorders and cancer. The cellular and molecular mechanism of thalidomide is unclear despite renewed clinical interest in the drug. Previous data from this laboratory indicate that thalidomide decreases cell growth and cell-cell interactions of human T leukemic cells. The specific aim of the present study is to determine whether thalidomide administration induces cell death via apoptosis. Low dose thalidomide treatment of human T leukemic cells exhibited rapid increases in caspase-3 activity, annexin V-FITC binding and DNA disintegration that is characteristic of apoptosis. These data indicate that low doses of thalidomide signal human T leukemic cells to die by apoptosis, which is a possible method of altering inflammatory cells and inflammatory activities.
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PMID:Exposure to the anti-TNF-alpha drug thalidomide induces apoptotic cell death in human T leukemic cells. 1468 94

Our previous studies indicate that hearts from septic rats have decreased work with oxygen wasting. The present studies test if there is energy deficit, changes in cardiac mitochondrial content and caspase activation during sepsis. Anesthetized, male Sprague-Dawley rats received no surgical treatment (control), laparotomy (sham), or laparotomy with cecal ligation and puncture (CLP) to induce polymicrobial septic shock. Hearts were isolated 12-14 h later. Cardiac work, oxygen consumption, substrate oxidation and energy stores were measured in perfused hearts. Normalized density of mitochondria was determined in ventricles without perfusion by morphometric analysis with electron microscopy. Citrate synthase activity was assessed in homogenates and isolated mitochondria. Cardiac work decreased significantly in CLP (47%), while oxygen consumption and glucose oxidation were unchanged compared with control or sham hearts (oxygen and substrate wasting). Tissue adenosine triphosphate, creatine phosphate and glycogen were lower in CLP hearts (energy deficit). Mitochondrial grid intersects decreased significantly from 151 +/- 8 sham to 130 +/- 4 CLP out of 361 possible intersects and autophagy was observed in CLP hearts. Total activity of citrate synthase decreased in homogenates (99 +/- 8 micromol/min/g wet weight sham vs. 62 +/- 7 CLP, P < 0.05) and in the mitochondrial fraction (27 +/- 1 micromol/min/g wet weight sham to 22 +/- 1 CLP, P < 0.05). Calculated mitochondrial content decreased from 63 +/- 4 mg protein/g wet weight sham to 46 +/- 5 CLP, P < 0.05 (mitochondrial depletion). Caspase-3 activity doubled and tumor necrosis factor alpha content tripled in CLP hearts. CONCLUSIONS. - Oxygen and substrate wasting in CLP occurs with fewer mitochondria and energy deficit, processes that are coincident with caspase-3 activation.
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PMID:Metabolic dysfunction and depletion of mitochondria in hearts of septic rats. 1473 56

In cancer cachexia both cardiac and skeletal muscle suffer an important protein mobilization as a result of increased proteolysis. Administration of the beta2-agonist formoterol to both rats and mice bearing highly cachectic tumors resulted in an important reversal of the muscle-wasting process. The anti-wasting effects of the drug were based on both an activation of the rate of protein synthesis and an inhibition of the rate of muscle proteolysis. Northern blot analysis revealed that formoterol treatment resulted in a decrease in the mRNA content of ubiquitin and proteasome subunits in gastrocnemius muscles; this, together with the decreased proteasome activity observed, suggest that the main anti-proteolytic action of the drug may be based on an inhibition of the ATP-ubiquitin-dependent proteolytic system. Interestingly, the beta2-agonist was also able to diminish the increased rate of muscle apoptosis (measured as DNA laddering as well as caspase-3 activity) present in tumor-bearing animals. The present results indicate that formoterol exerted a selective, powerful protective action on heart and skeletal muscle by antagonizing the enhanced protein degradation that characterizes cancer cachexia, and it could be revealed as a potential therapeutic tool in pathologic states wherein muscle protein hypercatabolism is a critical feature such as cancer cachexia or other wasting diseases.
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PMID:Anticachectic effects of formoterol: a drug for potential treatment of muscle wasting. 1537 90

Advanced congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. We previously showed that angiotensin II infusion in rats produces cachexia secondarily to increased muscle proteolysis and also decreases levels of circulating and skeletal muscle IGF-1. Here we show that angiotensin II markedly downregulates phospho-Akt and activates caspase-3 in skeletal muscle, leading to actin cleavage, an important component of muscle proteolysis, and to increased apoptosis. These changes are blocked by muscle-specific expression of IGF-1, likely via the Akt/mTOR/p70S6K signaling pathway. We also demonstrate that mRNA levels of the ubiquitin ligases atrogin-1 and muscle ring finger-1 are upregulated in angiotensin II-infused WT, but not in IGF-1-transgenic, mice. These findings strongly suggest that angiotensin II downregulation of IGF-1 in skeletal muscle is causally related to angiotensin II-induced wasting. Because the renin-angiotensin system is activated in many catabolic conditions, our findings have broad implications for understanding mechanisms of skeletal muscle wasting and provide a rationale for new therapeutic approaches.
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PMID:Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting. 1565 Jul 72

Wasting of skeletal muscle (cachexia) is associated with a variety of chronic or inflammatory disorders and has long been recognized as a poor prognostic sign. It is currently accepted that the cytokine tumor necrosis factor alpha (TNF-alpha; cachectin) plays a key role in the development of this condition. TNF-alpha-induced apoptotic cell death represents a potential mechanism by which muscle wasting can occur. Evidence has accumulated that the cytokine interferon gamma (IFN-gamma) may act as a modulator of TNF-alpha signalling. Thus, the present study was designed to elucidate if TNF-alpha can directly induce apoptosis in differentiated myotubes, to assess the potential anti-apoptotic properties of IFN-gamma and to get insight into the signalling pathways implicated in the modulatory effects of IFN-gamma. Myoblasts of the murine cell line C2C12 were allowed to differentiate in a low serum containing media and myogenesis assessed by muscle specific protein expression. Non-proliferating, polynucleated, fully differentiated myotubes were obtained after seven days in differentiation media. Exposure of C2C12 myotubes to TNF-alpha for 48 h induced apoptosis characterized by enhanced caspase-3 activity, which resulted in poly(ADP-ribose) polymerase (PARP) cleavage and increased histone-associated-DNA fragmentation. These effects were fully reverted in the presence of IFN-gamma. This cytokine induced down-regulation of the subtype 2 of TNF-alpha receptors (TNF-R2), enhanced TNF-alpha-induced NF-kappaB translocation to the nucleus and binding to DNA and increased the immunoreactivity of the protein c-IAP1, a member of the inhibitor of apoptosis (IAP) gene family whose synthesis is stimulated by NF-kappaB at the transcriptional level. Together, these results demonstrate that TNF-alpha directly induces apoptosis in differentiated myotubes and suggest that the cytokine IFN-gamma, might represent a new immunoadjuvant therapeutic tool for managing cachexia.
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PMID:IFN-gamma prevents TNF-alpha-induced apoptosis in C2C12 myotubes through down-regulation of TNF-R2 and increased NF-kappaB activity. 1612 53

Numerous experimental and clinical studies have shown that skeletal muscle apoptotis may increase in wasting conditions and suggest that apoptosis might contribute to the loss of lean body mass. Data in cancer patients are still lacking. The present study aimed at verifying whether apoptosis was enhanced in the skeletal muscle of 16 patients with gastric cancer with respect to controls. A biopsy specimen was obtained from the rectus abdominis muscle. The occurrence of apoptosis in muscle biopsies was determined morphologically by the fluorescent transferase-mediated dUTP nick end labeling assay and by immunohistochemistry for caspase-3 and caspase-1. Mean weight loss was 6+/-2% in cancer patients and 0.5+/-0.1% in controls (p<0.0001). Serum albumin levels (g/dL) were 3.7+/-0.3 in cancer patients and 4.1+/-0.2 in controls (p<0.05). The percentage of apoptotic myonuclei was similar in cancer patients and in controls (1.5+/-0.3 versus 1.4+/-0.2, respectively; p=ns), in gastric cancer patients with mild (1.6+/-0.4) or moderate-severe weight loss (1.4+/-0.5) (p=ns), and in the different stages of disease (stages I-II: 1.5+/-0.7; stage III: 1.3+/-0.4; stage IV: 1.6+/-0.3; p=ns). By immunohistochemistry, caspase-1 and caspase-3 positive fibers were absent in controls and in neoplastic patients. Poly-ADP-ribosyl polymerase, a typical caspase-3 substrate whose processing is indicative of caspase-3 activation, was not cleaved in muscle biopsies of cancer patients. These data suggest that skeletal muscle apoptosis is not increased in neoplastic patients with mild-moderate weight loss and argue against the hypotheses that caspase-3 activation might be an essential step of myofibrillar proteolysis in cancer-related muscle wasting.
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PMID:Skeletal muscle apoptosis is not increased in gastric cancer patients with mild-moderate weight loss. 1669 91

Calpains have been proposed to be involved in the cytoskeletal remodeling and wasting of skeletal muscle. However, limited data are available about the specific involvement of each calpain in the early stages of muscle atrophy. The aims of this study were to determine whether calpains 1 and 2 are autolyzed after a short period of muscle disuse, and, if so, where in the myofibers the autolyzed products are localized. In the rat soleus muscle, 5 days of immobilization increased autolyzed calpain 1 in the particulate and not the soluble fraction. Conversely, autolyzed calpain 2 was not found in the particulate fraction, whereas it was increased in the soluble fraction after immobilization. In the less atrophied plantaris muscle, no difference was noted between the control and immobilized groups whatever the fraction or calpain. Other proteolytic pathways were also investigated. The ubiquitin-proteasome pathway was activated in both skeletal muscles, and caspase 3 was activated only in the soleus muscle. Taken together, our data suggest that calpains 1 and 2 are involved in atrophy development in slow type muscle exclusively and that they have different regulation and protein targets. Moreover, the activation of proteolytic pathways appears to differ in slow and fast muscles, and the proteolytic mechanisms involved in fast-type muscle atrophy remain unclear.
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PMID:Differential localization of autolyzed calpains 1 and 2 in slow and fast skeletal muscles in the early phase of atrophy. 1718 28

Porcine circovirus type 2 (PCV2) is associated with several syndromes in growing pigs, including postweaning multisystemic wasting syndrome and porcine dermatitis and nephropathy syndrome. In the present study, a previously undescribed neurovascular disorder associated with a PCV2 infection is described. Sixteen pigs showed clinical signs of wasting and neurologic deficits. Acute hemorrhages and edema of cerebellar meninges and parenchyma due to a necrotizing vasculitis resulted in degeneration and necrosis of the gray and white matter. Few to numerous PCV2 DNA and antigen-bearing endothelial cells were detected in affected areas of the brain using in situ hybridization and immunohistochemistry. Conventional histochemical stains, as well as the detection of caspase 3 activity and DNA strand breaks by the terminal transferase dUTP nick end labeling assay, showed numerous apoptotic endothelial cells in the vascular lesions observed. Sequencing of various brain-derived PCV2-specific amplicons revealed a strong identity between different isolates and an 89 to 100% identity to previous isolates. The phylogenetic tree showed that there was no clustering of isolates correlating to clinical signs or geographic distribution. This previously undescribed PCV2-associated neurologic disease has features of both postweaning multisystemic wasting syndrome and, to a lesser extent, porcine dermatitis and nephropathy syndrome. The available evidence suggests that direct virus-induced apoptosis of endothelial cells plays a role in the pathogenesis of this unusual PCV2-associated cerebellar vasculitis.
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PMID:Porcine circovirus type 2-associated cerebellar vasculitis in postweaning multisystemic wasting syndrome (PMWS)-affected pigs. 1784 34

Progressive spinal muscular atrophy (SMA), the most prevalent hereditary lower motor neuron disease, is caused by mutations in the telomeric copy of the survival of motor neuron (SMN1) gene. Unlike other cells, lower motor neurons cannot tolerate low levels of smn protein. However, it is unclear as to the nature of the cell death involved. There is evidence that lower motor neurons undergo apoptosis in SMA, leading to muscle weakness and wasting. This study investigated whether SMN1 regulation in a motor neuron model affected indices of apoptotic cell death. Decreased smn expression in neuroblastoma hybrid (NSC-34) cell lines by small interfering RNA (siRNA) was demonstrated at the mRNA and protein level. Smn-depleted cells showed elevated caspase-3 activity, decreased cell viability and increased percentage of TUNEL positive cells. Conversely, NSC-34 cell smn overexpression by adenoviral gene transfer decreased staurosporine-induced caspase-3 elevation and mitigated induced cell toxicity as assessed by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. However, increased smn expression by itself did not increase cell viability. These data suggest not only that decreased smn levels increase apoptosis in an in vitro model of SMA, but also that increased smn can protect against neural injury.
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PMID:Survival motor neuron protein regulates apoptosis in an in vitro model of spinal muscular atrophy. 1836 39

KI0477959 (Herbkines) has been used for the purpose of development of physical strength in wasting diseases, like cancer. In the present study, apoptosis-inducing activities of butanol fraction of KI0477959 were studied in human leukemia cell line, HL-60 cells. KI0477959 increased cytotoxicity but had less effect on human peripheral blood mononuclear cells. KI0477959-induced apoptosis was accompanied by activation of caspase-3 and specific proteolytic cleavage of poly-ADP-ribose polymerase. Increased apoptosis was reduced by treatment with p38 and extracellular signal-regulated protein kinase (ERK) inhibitors. These results suggest that KI0477959 induces apoptosis through activation of caspase-3, p38, and ERK in HL-60 cells.
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PMID:Induction of apoptosis by KI0477959 through activation of caspase-3 in human leukemia cell line, HL-60 cells. 1878 24


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