Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calpain has been implicated in excitotoxic neurode-generation, but its mechanism of action particularly in adult brains remains unclear. We generated mutant mice lacking or overexpressing calpastatin, the only solely calpain-specific inhibitor ever identified or synthesized. Modulation of calpastatin expression caused no defect in the mice under normal conditions, indicating that calpastatin functions as a negative regulator of calpain only under pathological conditions. Kainate-evoked excitotoxicity in hippocampus resulted in proteolytic activation of a proapoptotic Bcl-2 subfamily member (Bid), nuclear translocation of mitochondria-derived DNA fragmentation factors (apoptosis-inducing factor and endonuclease G), DNA fragmentation, and nuclear condensation in pyramidal neurons. These apoptotic responses were significantly augmented by calpastatin deficiency. Consistently calpastatin overexpression suppressed them. No evidence of caspase-3 activation was detected. Our results demonstrated that calpain mediates excitotoxic signals through mobilization of proapoptotic factors in a caspase-independent manner. These mutant mice will serve as useful tools for investigating calpain involvement in various diseases.
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PMID:Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways in adult brains: evidence from calpastatin mutant mice. 1569 48

Aberrant calpain activation is a key mediator of neuron death. We examined the cell-permeable calpain inhibitor MDL28170 in the pathophysiological processes after spinal cord injury (SCI) including p35-p25- cyclin-dependent kinase-5 (Cdk5) activation, tau hyperphosphorylation, neuron cell death, calpain I activation, astrogliosis, and microglia activation. Our study showed that intrathecal administration of MDL28170 improved neurologic dysfunction, prevented neuron loss, decreased the number of apoptotic cells, and abated astrogliosis and microglia activation 7 days after spinal cord hemisection in rats. Reverse transcription polymerase chain reaction demonstrated calpain inhibition significantly attenuated the ratio of proapoptotic Bax/anti-apoptotic Bcl-2 mRNA in the lesion and penumbra after SCI. Calpain, the calcium-activated proteolytic enzyme, was found to digest p35 to its truncated product, p25. Moreover, abnormal Cdk5 activation by p25 and subsequent tau hyperphosphorylation triggers pathologic events leading to neurodegeneration and neurofibrillary tangles. We found p35-p25-Cdk5 activation and tau hyperphosphorylation in SCI, and then we showed that intrathecal MDL28170 treatment could diminish p35 truncation, and abrogate aberrant tau phosphorylation. Double labeling of calpain I and phosphorylated tau (AT8) in the same cells of spinal cord lesion further implicated pathogenesis of SCI. In conclusion, MDL28170 abated calpain I activation, inhibited apoptosis and neuron loss, quenched microglia and astrocyte activation, and significantly improved neurologic deficit one week after spinal cord hemisection. The neuroprotective mechanisms of calpain inhibitor in SCI could be attenuating upregulation of Bax/Bcl-2 ratio, preventing p35 truncation in the lesion and penumbra, and abrogating tau hyperphosphorylation.
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PMID:Calpain inhibitor inhibits p35-p25-Cdk5 activation, decreases tau hyperphosphorylation, and improves neurological function after spinal cord hemisection in rats. 1571 81

Recent studies have highlighted that female sex hormones represent potential neuroprotective agents against damage produced by acute and chronic injuries in the adult brain. Clinical reports have documented the effectiveness of estrogens to attenuate symptoms associated with Parkinson's disease, and to reduce the risk of Alzheimer's disease and cerebrovascular stroke. This evidence is corroborated by numerous experimental studies documenting the protective role of female sex hormones both in vitro and in vivo. Accordingly, estrogens have been shown to promote survival and differentiation of several neuronal populations maintained in culture, and to reduce cell death associated with excitotoxicity, oxidative stress, serum deprivation or exposure to beta-amyloid. The neuroprotective effects of estrogens have been widely documented in animal models of neurological disorders, such as Alzheimer's and Parkinson's diseases, as well as cerebral ischemia. Although estrogens are known to exert several direct effects on neurones, the cellular and molecular mechanisms implicated in their protective actions on the brain are not completely understood. Thus, on the basis of clinical and experimental evidence, in this review, we discuss recent findings concerning the neuronal effects of estrogens that may contribute to their neuroprotective actions. Both estrogen receptor-dependent and -independent mechanisms will be described. These include modulation of cell death regulators, such as Bcl-2, Akt and calpain, as well as interaction with growth factors, such as BDNF, NGF, IGF-I and their receptors. The anti-inflammatory effects of estrogens will also be described, namely their ability to reduce brain levels of inflammatory mediators, cytokines and chemokines. Finally, a brief overview about receptor-independent mechanisms of neuroprotection will aim at describing the antioxidant effects of estrogens, as well as their ability to modulate neurotransmission.
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PMID:From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens. 1596 77

Glutamate toxicity has been implicated in cell death in neurodegenerative diseases and injuries. Glutamate-induced Ca2+ influx may mediate activation of calpain, a Ca2+-dependent cysteine protease, which in turn may degrade key cytoskeletal proteins. We investigated glutamate-mediated apoptosis of VSC4.1 motoneurons and functional neuroprotection by calpain inhibition. Exposure of VSC4.1 cells to 10 microM glutamate for 24 hr caused significant increases in intracellular free [Ca2+], as determined by fura-2 assay. Pretreatment of cells with 10 or 25 microM calpeptin (a cell-permeable calpain-specific inhibitor) for 1 hr prevented glutamate-induced Ca2+ influx. Western blot analyses showed an increase in Bax:Bcl-2 ratio, release of cytochrome c from mitochondria, and calpain and caspase-3 activities during apoptosis. Cell morphology, as evaluated by Wright staining, indicated predominantly apoptotic features following glutamate exposure. ApopTag assay further substantiated apoptotic features morphologically as well as biochemically. Our data showed that calpeptin mainly prevented calpain-mediated proteolysis and apoptosis and maintained whole-cell membrane potential, indicating functional neuroprotection. The results imply that calpeptin may serve as a therapeutic agent for preventing motoneuron degeneration, which occurs in amyotrophic lateral sclerosis and spinal cord injury. In this investigation, we also examined glutamate receptor subtypes involved in the initiation of apoptosis in VSC4.1 cells following exposure to glutamate. Our results indicated that the N-methyl-D-aspartate (NMDA) receptors contributed more than alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors to glutamate-mediated Ca2+ influx and cell death mechanism. Inhibition of the activities of both NMDA and AMPA receptors protected VSC4.1 cells from glutamate toxicity and preserved whole-cell membrane potential.
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PMID:Calpain activation in apoptosis of ventral spinal cord 4.1 (VSC4.1) motoneurons exposed to glutamate: calpain inhibition provides functional neuroprotection. 1596 45

In this study, we have evaluated the cytotoxic effect of combining two HDAC inhibitors, SAHA and TSA, with TRAIL in human multiple myeloma cell lines. Low doses of SAHA or TSA enhanced the cytotoxic and apoptotic effects of TRAIL and upregulated the surface expression of TRAIL death receptors (DR4 and/or DR5). SAHA and TSA induced G1 phase cell cycle growth arrest by upregulating p21(WAF1) and p27(Kip1) expression and by inhibiting E2F transcriptional activity. The enhanced TRAIL effect after pretreatment with HDAC inhibitors was consistent with the upregulation of the proapoptotic Bcl-2 family members (Bim, Bak, Bax, Noxa, and PUMA), the downregulation of the anti-apoptotic members of the Bcl-2 family (Bcl-2 and Bcl-X(L)), and IAPs. SAHA and TSA dissipated the mitochondrial membrane potential and enhanced the release of Omi/HtrA2 and AIF from the mitochondria to the cytosol. The cytotoxic effect of both SAHA and TSA was caspase- and calpain-independent. Inhibition of NF(kappa)B activation by the proteasome inhibitor, MG132, enhanced the apoptotic effect of TSA. Our study demonstrated the enhancing effects of HDAC inhibitors on apoptosis when combined with TRAIL and, for the first time, emphasized the role of AIF in mediating the cytotoxic effects of HDAC inhibitors.
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PMID:Interactive effects of HDAC inhibitors and TRAIL on apoptosis are associated with changes in mitochondrial functions and expressions of cell cycle regulatory genes in multiple myeloma. 1602 44

Bfl-1/A1 is generally recognized as a Bcl-2-related inhibitor of apoptosis. We show that Bfl-1 undergoes constitutive ubiquitin/proteasome-mediated turnover. Moreover, while Bfl-1 suppresses apoptosis induced by staurosporine or cytokine withdrawal, it is proapoptotic in response to tumor necrosis factor (TNF) receptor activation in FL5.12 pro-B cells. Its anti- versus proapoptotic effect is regulated by two proteolytic events: (1) its constitutive proteasome-mediated turnover and (2) its TNF/cycloheximide (CHX)-induced cleavage by mu-calpain, or a calpain-like activity, coincident with acquisition of a proapoptotic phenotype. In vitro studies suggest that calpain-mediated cleavage of Bfl-1 occurs between its Bcl-2 homology (BH)4 and BH3 domains. This would be consistent with the generation of a proapoptotic Bax-like BH1-3 molecule. Overall, our studies uncovered two new regulatory mechanisms that play a decisive role in determining Bfl-1's prosurvival versus prodeath activities. These findings might provide important clues to counteract chemoresistance in tumor cells that highly express Bfl-1.
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PMID:Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor. 1609 3

Ischemia triggers an inflammatory response that precipitates cell death during reperfusion. Several studies have shown that tissues are protected by ischemic preconditioning (IP) consisting of 10 min of ischemia followed by 10 min of reperfusion just before ischemia. The molecular basis of this protective effect is poorly understood. We used cDNA arrays (20K) to compare global gene expression in liver biopsies from living human liver donors who underwent IP (n=7) or not (n=7) just before liver devascularization. Microarray data were analyzed using pairedt test with a type I error rate fixed at alpha = 2.5 10(6) (Bonferroni correction). We found that 60 genes were differentially expressed (36 over- and 24 underexpressed in preconditioning group). After IP, the most significantly overexpressed gene was IL-1Ra. This was confirmed by immunoblotting. Differentially expressed were genes involved in apoptosis (NOD2, ephrin-A1, and calpain) and in the carbohydrate metabolism. A significant increase in the amount of the anti-apoptotic protein Bcl-2 in preconditioned livers but no change in the cleavage of procaspase-3, -8, and -9 was observed. We also observed an increase in the amount in the inducible nitric oxide synthase. Therefore, the benefits of IP may be associated with the overproduction of IL-1Ra, Bcl-2, and NO countering the proinflammatory and proapoptotic effects generated during ischemia-reperfusion.
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PMID:Ischemic preconditioning modulates the expression of several genes, leading to the overproduction of IL-1Ra, iNOS, and Bcl-2 in a human model of liver ischemia-reperfusion. 1619 70

Increases in Ca2+ influx through the L-type Ca2+ channel (LTCC, Cav1.2) augment sarcoplasmic reticulum (SR) Ca2+ loading and the amplitude of the cytosolic Ca2+ transient to enhance cardiac myocyte contractility. Our hypothesis is that persistent increases in Ca2+ influx through the LTCC cause apoptosis if the excessive influx results in SR Ca2+ overload. Feline ventricular myocytes (VMs) in primary culture were infected with either an adenovirus (Ad) containing a rat Cav1.2 beta2a subunit-green fluorescent protein (GFP) fusion gene (Adbeta2a) to increase Ca2+ influx or with AdGFP as a control. Significantly fewer beta2a-VMs (21.4+/-5.6%) than GFP-VMs (99.6+/-1.7%) were viable at 96 hours. A fraction of beta2a-VMs (20.8+/-1.8%) contracted spontaneously (SC-beta2a-VMs), and viability was significantly correlated with the percentage of SC-beta2a-VMs. Higher percentages of apoptotic nuclei, DNA laddering, and cytochrome C release were detected in beta2a-VMs. This apoptosis was prevented with pancaspase or caspase-3 or caspase-9 inhibitors. L-type calcium current (I(Ca-L)) density was greater in beta2a-VMs (23.4+/-2.8 pA/pF) than in GFP-VMs (7.6+/-1.6 pA/pF). SC-beta2a-VMs had higher diastolic intracellular Ca2+ (Indo-1 ratio: 1.1+/-0.1 versus 0.7+/-0.03, P<0.05) and systolic Ca2+ transients (1.89+/-0.27 versus 0.80+/-0.08) than GFP-VMs. Inhibitors of Ca2+ influx, SR Ca2+ uptake and release, mitochondrial Ca2+ uptake, mitochondrial permeation transition pore, calpain, and Bcl-2-associated X protein protected beta2a-VMs from apoptosis. These results show that persistent increases in Ca2+ influx through the I(Ca-L) enhance contractility but lead to apoptosis through a mitochondrial death pathway if SR Ca2+ overload is induced.
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PMID:Ca2+ influx-induced sarcoplasmic reticulum Ca2+ overload causes mitochondrial-dependent apoptosis in ventricular myocytes. 1621 May 47

Apoptosis, or programmed cell death, is an essential physiological process that plays a critical role in development and tissue homeostasis. The progress of apoptosis is regulated in an orderly way by a series of signal cascades under certain circumstances. The caspase-cascade system plays vital roles in the induction, transduction and amplification of intracellular apoptotic signals. Caspases, closely associated with apoptosis, are aspartate-specific cysteine proteases and members of the interleukin-1beta-converting enzyme family. The activation and function of caspases, involved in the delicate caspase-cascade system, are regulated by various kinds of molecules, such as the inhibitor of apoptosis protein, Bcl-2 family proteins, calpain, and Ca2+. Based on the latest research, the members of the caspase family, caspase-cascade system and caspase-regulating molecules involved in apoptosis are reviewed.
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PMID:Caspase family proteases and apoptosis. 1627 Jan 50

Status epilepticus (SE)-induced neuronal death is morphologically necrotic and is initiated by excessive glutamate release, which activates postsynaptic N-methyl-D-aspartate (NMDA) receptors and triggers receptor-mediated calcium influx (excitotoxicity). This results in activation of intracellular proteases and neuronal nitric oxide synthase, with generation of free radicals, and damage to cellular membranes, structural proteins, and essential enzymes. Programmed cell death mechanisms, such as p53 activation, activation of cell death-promoting Bcl-2 family members, and endonuclease-induced DNA laddering, occur in SE-induced neuronal death. Caspase-independent excitotoxic mechanisms, such as NMDA-induced calpain I activation, with activation and translocation of the cell death-promoting Bcl-2 family member Bid from cytoplasm to mitochondria, and subsequent translocation of apoptosis-inducing factor and endonuclease G to nuclei (which cause large-scale and internucleosomal DNA cleavage, respectively), may be triggered by SE. Poly(ADP-ribose) polymerase-1 (PARP-1) activation and cysteinyl cathepsin and DNase II release from lysosomes may occur following SE as well, but these events await future investigation. In the future, rational combinations of central nervous system-penetrable neuroprotective agents, based on our knowledge of excitotoxic mechanisms, may be useful in refractory human SE.
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PMID:Prolonged seizures and cellular injury: understanding the connection. 1627 99


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