Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fixed rabies viruses (CVS-11 strain) were inoculated intramuscularly to C57BL/6J mice, and the pathomorphological changes of the spinal cord including dorsal root spinal ganglion cells were investigated. At 4 days postinoculation (PI), viral antigens were first detected in the spinal neurons and dorsal root spinal ganglion cells without producing morphological changes. At 5 days PI, mild infiltration of lymphocytes was observed around the central canal, small blood vessels and leptomeninges. Cells positive to anti-Iba1 and anti-GFAP antibodies increased significantly from 3 to 5 days PI, respectively. Microglia changed their morphological forms to be ramified or amoeboid, and astroglia extended their cytoplasm from the leptomeninges to the parenchyma. At 7 days PI, apoptotic cells were found in the spinal cord and dorsal root spinal ganglion using TUNEL. We confirmed that most of T lymphocytes and a minority of microglial cells underwent apoptosis, using a combination of TUNEL and immunostaining with antibodies to viral phosphoprotein, CD3, Iba1 and GFAP. On the other hand, astroglial cells and virus-infected nerve cells were negative against TUNEL and cleaved caspase-3 antibody. These findings indicate that T lymphocytes and microglial cells died by apoptosis, whereas virus-infected nerve cells died by necrosis. This was accompanied by increased numbers and morphological changes of glial cells associated with the pathogenesis of CVS-11 in the C57BL/6J mouse.
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PMID:Pathology of the spinal cord of C57BL/6J mice infected with rabies virus (CVS-11 strain). 1934

Tumorigenesis in human glioblastoma multiforme (GBM) is driven by several genetic abnormalities with disruption of important molecular pathways, such as p53/MDM2/p14ARF and EGFR/PTEN/Akt/mTOR. The malignant progression of human GBM is also primarily associated with a peculiar multistep pathophysiological process characterized by intratumoral ischemic necrosis (i.e. pseudopalisading necrosis) and activation of the hypoxia-inducible factor (HIF)-1alpha pathway with consequent peritumoral microvascular proliferation and infiltrative behaviour. Predictable preclinical animal models of GBM should recapitulate the main pathobiological hallmarks of the human disease. In this study we describe two murine orthotopic xenograft models using U87MG and U251 human cell lines. Ten Balb/c nude male mice were orthotopically implanted with either U87MG (5 mice) or U251 (5 mice) cell lines. Intracranial tumor growth was monitored through Magnetic Resonance Imaging (MRI). Immunohistopathological examination of the whole cranium was performed 30 days after implantation. U251 orthotopic xenografts recapitulated the salient pathobiological features described for human GBM, including invasive behaviour, wide areas of pseudopalisading necrosis, florid peripheral angiogenesis, GFAP and vimentin expression, nonfunctional p53 expression, striking active-caspase-3 and HIF-1alpha expression along pseudopalisades. U87MG orthotopic xenografts proved to be very dissimilar from human GBM, showing expansile growth, occasional necrotic foci without pseudopalisades, intratumoral lacunar pattern of angiogenesis, lack of GFAP expression, functional p53 expression and inconsistent HIF-1alpha expression. Expression of pAkt was upregulated in both models. The results obtained suggest that the U251 orthotopic model may be proposed as a predictive and reliable tool in preclinical studies since it recapitulates the most salient pathobiological features reported for human GBM.
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PMID:Immunohistopathological and neuroimaging characterization of murine orthotopic xenograft models of glioblastoma multiforme recapitulating the most salient features of human disease. 1947 34

The objective of the EU funded integrated project "ACuteTox" is to develop a strategy in which general cytotoxicity, together with organ-specific endpoints and biokinetic features, are taken into consideration in the in vitro prediction of oral acute systemic toxicity. With regard to the nervous system, the effects of 23 reference chemicals were tested with approximately 50 endpoints, using a neuronal cell line, primary neuronal cell cultures, brain slices and aggregated brain cell cultures. Comparison of the in vitro neurotoxicity data with general cytotoxicity data generated in a non-neuronal cell line and with in vivo data such as acute human lethal blood concentration, revealed that GABA(A) receptor function, acetylcholine esterase activity, cell membrane potential, glucose uptake, total RNA expression and altered gene expression of NF-H, GFAP, MBP, HSP32 and caspase-3 were the best endpoints to use for further testing with 36 additional chemicals. The results of the second analysis showed that no single neuronal endpoint could give a perfect improvement in the in vitro-in vivo correlation, indicating that several specific endpoints need to be analysed and combined with biokinetic data to obtain the best correlation with in vivo acute toxicity.
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PMID:Neuronal in vitro models for the estimation of acute systemic toxicity. 1961 35

Thymosin-beta4 (Tbeta4) is a major actin monomer-binding peptide in mammalian tissues and plays a crucial role in the nervous system in synaptogenesis, neuronal survival and migration, axonal growth, and plastic changes of dendritic spines. However, it is unknown whether Tbeta4 is also involved in challenges with external stress such as ethanol-induced neurotoxicity. In the present study, we investigated the effects of Tbeta4 on ethanol-induced neurotoxicity in cultured cerebral cortical astrocytes and the underlying mechanisms. Primarily cultured astrocytes were treated with 1 microg/ml Tbeta4 2 h prior to administration of 100 mM ethanol for 0.5, 1, 3 and 6 days, respectively. The results showed that ethanol caused neurotoxicity in cultured astrocytes, as shown by declined cell viability, distinct astroglial apoptosis and increased intracellular peroxidation. Tbeta4 markedly promoted cell viability, ameliorated the injury of intracellular glial fibrillary acidic protein-immunopositive cytoskeletal structures, reduced the percentage of apoptotic astrocyte and cellular DNA fragmentation, suppressed caspase-3 activity and upregulated Bcl-2 expression, inhibited the accumulation of reactive oxygen species and production of malondialdehyde in ethanol-treated astrocytes in a time-dependent manner. These data indicated that Tbeta4 attenuates ethanol-induced neurotoxicity in cultured cortical astrocytes through inhibition of apoptosis signaling, and one of the mechanisms underlying the capacity of Tbeta4 to suppress apoptosis may in part be due to its effect of anti-peroxidation.
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PMID:Thymosin-beta4 attenuates ethanol-induced neurotoxicity in cultured cerebral cortical astrocytes by inhibiting apoptosis. 1968 60

Pancreatic triglyceride lipase (PTL), an enzyme of digestive system, plays very important roles in the digestion and absorption of lipids. However, its distribution and function in the central nervous system (CNS) remains unclear. In the present study, we mainly investigated the expression and cellular localization of PTL during traumatic brain injury (TBI). Western blot and RT-PCR analysis revealed that PTL was present in normal rat brain cortex. It gradually increased, reached a peak at the 3rd day after TBI, and then decreased. Double immunofluorescence staining showed that PTL was co-expressed with neuron, but had a few colocalizations in astrocytes. When TBI occurred in the rat cortex, the expression of PTL gradually increased, reached the peak at the 3rd day after TBI, and then decreased. Importantly, more PTL was colocalized with astrocytes, which is positive for proliferating cell nuclear antigen (PCNA). In addition, Western blot detection showed that the 3rd day post injury was not only the proliferation peak indicated by the elevated expression of PCNA, glial fibrillary acidic protein (GFAP) and cyclin D1, but also the apoptotic peak implied by the alteration of caspase-3 and bcl-2. These data suggested that PTL may be involved in the pathophysiology of TBI and PTL may be complicated after injury, more PTL was colocalized with astrocytes. Importantly, injury-induced expression of PTL was colabelled by proliferating cell nuclear antigen (proliferating cells marker), and the western blot for GFAP, PCNA and cyclin D1, showed that 3 days post injury was the proliferation peak, in coincidence to it, the protein level change of caspase-3 and bcl-2 revealed that the stage was peak of apoptotic too. These data suggested that PTL may be involved in the pathophysiology of TBI and that PTL may be implicated in the proliferation of astrocytes and the recovery of neurological outcomes. But the inherent mechanisms remained unknown. Further studies are needed to confirm the exact role of PTL after brain injury.
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PMID:Regulated expression of pancreatic triglyceride lipase after rat traumatic brain injury. 1976 Apr 87

In contrast to mammals, adult teleost fish exhibit a vast potential for central nervous system regeneration after injury. Among other mechanisms, this capacity is mediated by replacement of cells lost to injury by new neurons and glia. Here, we examined the spatio-temporal dynamics of apoptosis, and its relationship to the generation and the differentiation of new cells, during this cell replacement phase. As an experimental paradigm, caudal transection of the spinal cord in the teleost fish Apteronotus leptorhynchus was used. During the cell replacement phase, there was a rather constant percentage of new cells (identified by incorporation of 5-bromo-2'-deoxyuridine into newly synthesized DNA) that underwent apoptosis (identified by anti-active caspase-3 immunolabeling). Many of these cells were also immunopositive for the marker proteins Hu C/D or glial fibrillary acidic protein, indicating that a large portion of cells undergo apoptosis after differentiation into neurons or glia, respectively. The spatial distribution of apoptotic cells was uneven, displaying a radial peak in the mid parenchymal regions and a longitudinal peak at the site of the initial spinal transection. The latter persisted for over 100 days post-injury, indicating possible problems in the integration of new cells at the interface between the old, intact tissue and the regenerated portion of the spinal cord. Taken together, the results of the present study are consistent with the hypothesis that apoptosis plays a role in the development of the new tissue during the cell replacement phase of the regenerating teleostean spinal cord.
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PMID:Dynamics of caspase-3-mediated apoptosis during spinal cord regeneration in the teleost fish, Apteronotus leptorhynchus. 1978 69

Mildronate, a representative of the aza-butyrobetaine class of drugs with proven cardioprotective efficacy, was recently found to prevent dysfunction of complex I in rat liver mitochondria. The present study demonstrates that mildronate also acts as a neuroprotective agent. In a mouse model of azidothymidine (anti-HIV drug) neurotoxicity, mildronate reduced the azidothymidine-induced alterations in mouse brain tissue: it normalized the increase in caspase-3, cellular apoptosis susceptibility protein (CAS) and iNOS expression assessed by quantitative and semi-quantitative analysis. Mildronate also normalized the changes in cytochrome c oxidase (COX) expression, reduced the expression of glial fibrillary acidic protein (GFAP) and cellular infiltration. The present results show that the neuroprotective action of mildronate results at least partially from anti-neurodegenerative (anti-apoptotic) and anti-inflammatory mechanisms. It might be suggested that the molecular conformation of mildronate can facilitate its easy binding to mitochondria, and regulate the expression of different signal molecules, hence maintaining cellular signaling and survival.
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PMID:Neuroprotective properties of mildronate, a mitochondria-targeted small molecule. 2003 18

Glioblastoma is a highly lethal brain tumor of the human primary nervous system tumors. Previous studies demonstrated that glioblastoma stem cells were able to initiate and reform the original cancer. In this study, we found that there were expression and activation of STAT3, a key signal transduction factor and oncoprotein, in human glioblastoma stem cells (GSCs). STAT3 plays a key role in proliferation, apoptosis and differentiation in embryonic stem cells and several cancer types. To investigate the effects of STAT3 on human GSCs, the expression and activation of STAT3 were suppressed by RNAi mediated with lentivirus. We demonstrated that siRNA of STAT3 significantly suppressed STAT3 expression and activation and resulted in inhibition of cell growth in GSCs. Knockdown of STAT3 induces apoptosis and reduces significantly expression of Bcl-2 and cyclin-D in human primary GSCs, whereas no significance was achieved in BAX and caspase-3 expression. Inhibition of STAT3 expression is associated not only with decreasing of CD133+ cell proportion and increasing of GFAP and MBP expression, but also with decrease of the capacity to initiate a tumor in human primary GSCs. Together, these studies suggest that STAT3 is an important target for human GSCs in regulation of GSCs growth, apoptosis, differentiation and tumorigenic potential.
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PMID:Knockdown of STAT3 expression by RNAi suppresses growth and induces apoptosis and differentiation in glioblastoma stem cells. 2051 2

Toll-like receptors play an important role in the innate immune response, although emerging evidence indicates their role in brain injury and neurodegeneration. Alcohol abuse induces brain damage and can sometimes lead to neurodegeneration. We recently found that ethanol can promote TLR4 signaling in glial cells by triggering the induction of inflammatory mediators and causing cell death, suggesting that the TLR4 response could be an important mechanism of ethanol-induced neuroinflammation. This study aims to establish the potential role of TLR4 in both ethanol-induced glial activation and brain damage. Here we report that TLR4 is critical for ethanol-induced inflammatory signaling in glial cells since the knockdown of TLR4, by using both small interfering RNA or cells from TLR4-deficient mice, abolished the activation of microtubule-associated protein kinase and nuclear factor-kappaB pathways and the production of inflammatory mediators by astrocytes. Our results demonstrate, for the first time, that whereas chronic ethanol intake upregulates the immunoreactive levels of CD11b (microglial marker) and glial fibrillary acidic protein (astrocyte marker), and also increases caspase-3 activity and inducible nitric oxide synthase, COX-2, and cytokine levels [interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6] in the cerebral cortex of female wild-type mice, TLR4 deficiency protects against ethanol-induced glial activation, induction of inflammatory mediators, and apoptosis. Our findings support the critical role of the TLR4 response in the neuroinflammation, brain injury, and possibly in the neurodegeneration induced by chronic ethanol intake.
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PMID:Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. 2055 80

It has been reported that lysosomal proteases play important roles in ischemic and excitotoxic neuronal cell death. We have previously reported that cathepsin B expression increased remarkably after traumatic brain injury (TBI). The present study sought to investigate the effects of a selective cathepsin B inhibitor (CBI) [N-L-3-trans-prolcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline] on cell death and behavioral deficits in our model. We examined the levels of cathepsin B enzymatic activity and its expression by double labelling damaged cells in the brain slice with propidium iodide (PI) and anticathepsin B. The results showed an elevated enzymatic activity associated with TBI-induced increase in a mature form of cathepsin B, suggesting that cathepsin B may play a role in TBI-induced cell injury. PI was found to label cells positive for the neuronal-specific nuclear marker NeuN, whereas fewer GFAP-positive cells were labelled by PI, suggesting that neurons are more sensitive to cell death induced by TBI. Additionally, we found that pretreatment with CBI remarkably attenuated TBI-induced cell death, lesion volume, and motor and cognitive dysfunction. To analyze the mechanism of action of cathepsin B in the cell death signaling pathway, we assessed DNA fragmentation by electrophoresis, Bcl-2/Bax protein expression levels, Bid cleavage, cytochrome c release, and caspase-3 activation. The results imply that cathepsin B contributes to TBI-induced cell death through the present programmed cell necrosis and mitochondria-mediated apoptotic pathways.
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PMID:Cathepsin B contributes to traumatic brain injury-induced cell death through a mitochondria-mediated apoptotic pathway. 2065 46


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