共查询到20条相似文献,搜索用时 15 毫秒
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Wei Liu Chao Xu Hongyan Zhao Pengpeng Xia Ruilong Song Jianhong Gu Xuezhong Liu Jianchun Bian Yan Yuan Zongping Liu 《PloS one》2015,10(11)
Osteoprotegerin (OPG) is known to inhibit differentiation and activation of osteoclasts (OCs) by functioning as a decoy receptor blocking interactions between RANK and RANKL. However, the exact role of OPG in the survival/apoptosis of OCs remains unclear. OPG caused increased rates of apoptosis of both OCs and osteoclast precursor cells (OPCs). The expression of Fas and activated caspase-8 was increased by both 20 ng/mL and 40 ng/mL of OPG, but was markedly decreased at 80 ng/mL. Interestingly, we noted that while levels of Fas ligand (FasL) increased with increasing doses of OPG, the soluble form of FasL in the supernatant decreased. The results of a co-immunoprecipitation assay suggested that the decrease of sFasL might be caused by the binding of OPG. This would block the inhibition of the apoptosis of OCs and OPCs. Furthermore, changes in expression levels of Bax/Bcl-2, cleaved-caspase-9, cleaved-caspased-3 and the translocation of cytochrome c, illustrated that OPG induced apoptosis of OCs and OPCs via the classic Fas/FasL apoptosis pathway, and was mediated by mitochondria. Altogether, our results demonstrate that OPG induces OCs and OPCs apoptosis partly by the Fas/FasL signaling pathway. 相似文献
3.
Acute brain ischemia is accompanied by the intense apoptotic and/or necrotic death of cortical neurons. This review deals with the molecular mechanisms underlying apoptosis, in particular those activated in progressive cerebral ischemic insult. We analyze the data of experimental studies and clinical findings that confirm the principal role of caspase-dependent cell death resulting from acute disorder of the brain circulation. The prospects for the use of apoptosis inhibitors in neurological practice for prevention or minimization of cerebral ischemic injury and reduction of neuronal degeneration within a penumbral zone are discussed. 相似文献
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Curcumin Induces Apoptosis in Human Melanoma Cells through a Fas Receptor/Caspase-8 Pathway Independent of p53 总被引:22,自引:0,他引:22
In this study, we investigated the molecular pathways targeted by curcumin during apoptosis of human melanoma cell lines. We found that curcumin caused cell death in eight melanoma cell lines, four with wild-type and four with mutant p53. We demonstrate that curcumin-induced apoptosis is both dose- and time-dependent. We found that curcumin did not induce p53, suggesting that curcumin activates other apoptosis pathways. Our data show that curcumin activates caspases-3 and -8 but not caspase-9, supporting the rationale that apoptosis occurs via a membrane-mediated mechanism. Both a caspase-8 and broad-based caspase inhibitor, but not a caspase-9 specific inhibitor, suppressed curcumin-induced cell death. To further support our hypothesis that curcumin induces activation of a death receptor pathway, we show that curcumin induces Fas receptor aggregation in a FasL-independent manner and that low-temperature incubation, previously shown to inhibit receptor aggregation, prevented curcumin-induced cell death. Moreover, we demonstrate that expression of dominant negative FADD significantly inhibited curcumin-induced cell death. In addition, our results indicate that curcumin also blocks the NF-kappaB cell survival pathway and suppresses the apoptotic inhibitor, XIAP. Since melanoma cells with mutant p53 are strongly resistant to conventional chemotherapy, curcumin may overcome the chemoresistance of these cells and provide potential new avenues for treatment. 相似文献
6.
Cocaine Induces Apoptosis in Cortical Neurons of Fetal Mice 总被引:6,自引:1,他引:5
Marie-Cécile Nassogne Jamila Louahed †Philippe Evrard Pierre J. Courtoy 《Journal of neurochemistry》1997,68(6):2442-2450
Abstract: Exposure of fetal mouse brain cocultures to cocaine results selectively in the loss of neurites followed by neuronal death. By using enriched neuronal cultures, we here demonstrate that disappearance of neurons, when cultured with cocaine, is caused by apoptosis, based on (1) characteristic morphology of apoptotic nuclei at the level of neurons but not of glial cells by optic microscopy, and on total cell pellets by electron microscopy; (2) fragmentation of total DNA with a typical "ladder" pattern on agarose gels; (3) extensive in situ DNA fragmentation labeling (TUNEL method); and (4) prevention of cell loss by cycloheximide. The major metabolites of cocaine have no detectable effects on neurons, indicating that apoptosis is due to cocaine itself. Inappropriate neuronal apoptosis in cocaine-exposed fetal brain could perturb the neurodevelopmental program and contribute to the quantitative neuronal defects that are too frequently reported in the offspring of cocaine-abusing pregnant women. 相似文献
7.
Withdrawal of Survival Factors Results in Activation of the JNK Pathway in Neuronal Cells Leading to Fas Ligand Induction and Cell Death 总被引:28,自引:3,他引:28 下载免费PDF全文
Helen Le-Niculescu Emanuela Bonfoco Yoshitoshi Kasuya Francois-Xavier Claret Douglas R. Green Michael Karin 《Molecular and cellular biology》1999,19(1):751-763
The JNK pathway modulates AP-1 activity. While in some cells it may have proliferative and protective roles, in neuronal cells it is involved in apoptosis in response to stress or withdrawal of survival signals. To understand how JNK activation leads to apoptosis, we used PC12 cells and primary neuronal cultures. In PC12 cells, deliberate JNK activation is followed by induction of Fas ligand (FasL) expression and apoptosis. JNK activation detected by c-Jun phosphorylation and FasL induction are also observed after removal of either nerve growth factor from differentiated PC12 cells or KCl from primary cerebellar granule neurons (CGCs). Sequestation of FasL by incubation with a Fas-Fc decoy inhibits apoptosis in all three cases. CGCs derived from gld mice (defective in FasL) are less sensitive to apoptosis caused by KCl removal than wild-type neurons. In PC12 cells, protection is also conferred by a c-Jun mutant lacking JNK phosphoacceptor sites and a small molecule inhibitor of p38 mitogen-activated protein kinase and JNK, which inhibits FasL induction. Hence, the JNK-to-c-Jun-to-FasL pathway is an important mediator of stress-induced neuronal apoptosis. 相似文献
8.
Rebecca M. Dixon Jack R. Mellor Jonathan G. Hanley 《The Journal of biological chemistry》2009,284(21):14230-14235
Oxygen and glucose deprivation (OGD) induces delayed cell death in
hippocampal CA1 neurons via Ca2+/Zn2+-permeable,
GluR2-lacking AMPA receptors (AMPARs). Following OGD, synaptic AMPAR currents
in hippocampal neurons show marked inward rectification and increased
sensitivity to channel blockers selective for GluR2-lacking AMPARs. This
occurs via two mechanisms: a delayed down-regulation of GluR2 mRNA expression
and a rapid internalization of GluR2-containing AMPARs during the OGD insult,
which are replaced by GluR2-lacking receptors. The mechanisms that underlie
this rapid change in subunit composition are unknown. Here, we demonstrate
that this trafficking event shares features in common with events that mediate
long term depression and long term potentiation and is initiated by the
activation of N-methyl-d-aspartic acid receptors. Using
biochemical and electrophysiological approaches, we show that peptides that
interfere with PICK1 PDZ domain interactions block the OGD-induced switch in
subunit composition, implicating PICK1 in restricting GluR2 from synapses
during OGD. Furthermore, we show that GluR2-lacking AMPARs that arise at
synapses during OGD as a result of PICK1 PDZ interactions are involved in
OGD-induced delayed cell death. This work demonstrates that PICK1 plays a
crucial role in the response to OGD that results in altered synaptic
transmission and neuronal death and has implications for our understanding of
the molecular mechanisms that underlie cell death during stroke.Oxygen and glucose deprivation
(OGD)3 associated with
transient global ischemia induces delayed cell death, particularly in
hippocampal CA1 pyramidal cells
(1–3),
a phenomenon that involves Ca2+/Zn2+-permeable,
GluR2-lacking AMPARs (4).
AMPARs are heteromeric complexes of subunits GluR1–4
(5), and most AMPARs in the
hippocampus contain GluR2, which renders them calcium-impermeable and results
in a marked inward rectification in their current-voltage relationship
(6–8).
Ischemia induces a delayed down-regulation of GluR2 mRNA and protein
expression (4,
9–11),
resulting in enhanced AMPAR-mediated Ca2+ and Zn2+
influx into CA1 neurons (10,
12). In these neurons,
AMPAR-mediated postsynaptic currents (EPSCs) show marked inward rectification
1–2 days following ischemia and increased sensitivity to 1-naphthyl
acetyl spermine (NASPM), a channel blocker selective for GluR2-lacking AMPARs
(13–16).
Blockade of these channels at 9–40 h following ischemia is
neuroprotective, indicating a crucial role for Ca2+-permeable
AMPARs in ischemic cell death
(16).In addition to delayed changes in AMPAR subunit composition as a result of
altered mRNA expression, it was recently reported that
Ca2+-permable, GluR2-lacking AMPARs are targeted to synaptic sites
via membrane trafficking at much earlier times during OGD
(17). This subunit
rearrangement involves endocytosis of AMPARs containing GluR2 complexed with
GluR1/3, followed by exocytosis of GluR2-lacking receptors containing GluR1/3
(17). However, the molecular
mechanisms behind this trafficking event are unknown, and furthermore, it is
not known whether these trafficking-mediated changes in AMPAR subunit
composition contribute to delayed cell death.AMPAR trafficking is a well studied phenomenon because of its crucial
involvement in long term depression (LTD) and long term potentiation (LTP),
activity-dependent forms of synaptic plasticity thought to underlie learning
and memory. AMPAR endocytosis, exocytosis, and more recently subunit-switching
events (brought about by trafficking that involves endo/exocytosis) are
central to the necessary changes in synaptic receptor complement
(7,
18–20).
It is possible that similar mechanisms regulate AMPAR trafficking during
OGD.PICK1 is a PDZ and BAR (Bin-amphiphysin-Rus) domain-containing protein that
binds, via the PDZ domain, to a number of membrane proteins including AMPAR
subunits GluR2/3. This interaction is required for AMPAR internalization from
the synaptic plasma membrane in response to Ca2+ influx via NMDAR
activation in hippocampal neurons
(21–23).
This process is the major mechanism that underlies the reduction in synaptic
strength in LTD. Furthermore, PICK1-mediated trafficking has recently emerged
as a mechanism that regulates the GluR2 content of synaptic receptors, which
in turn determines their Ca2+ permeability
(7,
20). This is likely to be of
profound importance in both plasticity and pathological mechanisms.
Importantly, PICK1 overexpression has been shown to induce a shift in synaptic
AMPAR subunit composition in hippocampal CA1 neurons, resulting in inwardly
rectifying AMPAR EPSCs via reduced surface GluR2 and no change in GluR1
(24). This suggests that PICK1
may mediate the rapid switch in subunit composition occurring during OGD
(17). Here, we demonstrate
that the OGD-induced switch in AMPAR subunit composition is dependent on PICK1
PDZ interactions, and importantly, that this early trafficking event that
occurs during OGD contributes to the signaling that results in delayed
neuronal death. 相似文献
9.
神经酰胺诱导小鼠皮层神经元凋亡 总被引:2,自引:2,他引:2
本实验以原代培养的小鼠大脑皮层神经元为模型,观察了天然神经酰胺在神经元凋亡中的作用。从测定LDH漏出率、MTT代谢率、DNA凝胶电泳,Giemsa染色以及电镜观察等各个方面,探讨了神经酰胺对神经元的作用模式。研究发现,神经酰胺在500~1000nM浓度范围内,作用12h以上,即可诱导原代培养的皮层神经元凋亡,而且此作用具有时间依赖性和剂量依赖性。表明神经酰胺不仅对HL-60细胞有促凋亡的作用,对大脑皮层神经元同样具有促凋亡的作用。 相似文献
10.
Raju V. S. Rajala 《Molecular neurobiology》2010,42(1):39-47
The retina is an integral part of the central nervous system and retinal cells are known to express insulin receptors (IR),
although their function is not known. This article describes recent studies that link the photoactivation of rhodopsin to
tyrosine phosphorylation of the IR and subsequent activation of phosphoinositide 3-kinase, a neuron survival factor. Our studies
suggest that the physiological role of this process is to provide neuroprotection of the retina against light damage by activating
proteins that protect against stress-induced apoptosis. We focus mainly on our recently identified regulation of the IR pathway
through the G-protein-coupled receptor rhodopsin. Various mutant and knockout proteins of phototransduction cascade have been
used to study the light-induced activation of the retinal IR. Our studies suggest that rhodopsin may have additional previously
uncharacterized signaling functions in photoreceptors. 相似文献
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Apoptosis Induced via AMPA-Selective Glutamate Receptors in Cultured Murine Cortical Neurons 总被引:3,自引:1,他引:3
Abstract: We have investigated the mechanisms of cell death induced by long-term exposure to the glutamate receptor agonist ( S )-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate [( S )-AMPA]. Using primary cultures of pure neurons (95%) grown in serum-free conditions, we found that 24-h exposure to ( S )-AMPA (0.01–1,000 µ M ) induced concentration-dependent neuronal cell death (EC50 = 3 ± 0.5 µ M ) with cellular changes including neurite blebbing, chromatin condensation, and DNA fragmentation, indicative of apoptosis. ( S )-AMPA induced a delayed cell death with DNA fragmentation occurring in ∼50% of cells at concentrations between 100 and 300 µ M detected using terminal transferase-mediated dUTP nick end-labeling (TUNEL) and agarose gel electrophoresis. Apoptotic chromatin condensation was detected using 4,6-diamidino-2-phenylindole, a fluorescent DNA binding dye. Cell death induced by ( S )-AMPA was attenuated by the AMPA receptor-selective antagonist LY293558 (10 µ M ) and the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 50 µ M ), yielding EC50 values of 73 ± 5 and 265 ± 8 µ M , respectively, and was unaffected by the NMDA receptor antagonist MK-801 (10 µ M ). The number of apoptotic nuclei induced by 300 µ M ( S )-AMPA (57%) was also reduced substantially by the antagonists LY293558 and CNQX, with only 20% and 18% of neurons, respectively, staining TUNEL-positive at 24 h. In addition, cycloheximide (0.5 µg/ml) also inhibited ( S )-AMPA-induced DNA fragmentation and cell death. Our results show that long-term exposure to AMPA can induce substantial neuronal death involving apoptosis in cultured cortical neurons, suggesting a wide involvement of AMPA-sensitive glutamate receptors in excitotoxic injury and neurodegenerative pathologies. 相似文献
14.
Abstract: Glutamate-induced glutathione depletion in immature embryonic cortical neurons has been shown to lead to oxidative stress and cell death. We have used this in vitro model to investigate the mechanism(s) by which free radicals induce neuronal degeneration. We find that glutathione depletion leads to hypercondensation and fragmentation of chromatin into spherical or irregular shapes, a morphologic signature of apoptosis. These morphologic changes are accompanied by laddering of DNA into multiple oligonucleosomal fragments and can be prevented by the antioxidants idebenone and butylated hydroxyanisole. Cell death induced by glutathione depletion can also be prevented by inhibitors of macromolecular synthesis. Taken together, these observations suggest that oxidative stress can induce apoptosis in neurons. 相似文献
15.
Longzai Lin Hongbin Chen Yixian Zhang Wei Lin Yong Liu Tin Li Yongping Zeng Jianhao Chen Houwei Du Ronghua Chen Yi Tan Nan Liu 《PloS one》2015,10(9)
IL-10, as a cytokine, has an anti-inflammatory cascade following various injuries, but it remains blurred whether IL-10 protects neurites of cortical neurons after oxygen-glucose deprivation injury. Here, we reported that IL-10, in a concentration-dependent manner, reduced neuronal apoptosis and increased neuronal survival in oxygen-glucose-deprived primary cortical neurons, producing an optimal protective effect at 20ng/ml. After staining NF-H and GAP-43, we found that IL-10 significantly protected neurites in terms of axon length and dendrite number by confocal microscopy. Furthermore, it induced the phosphorylation of AKT, suppressed the activation of caspase-3, and up-regulated the protein expression of GAP-43. In contrast, LY294002, a specific inhibitor of PI3K/AKT, reduced the level of AKT phosphorylation and GAP-43 expression, increased active caspase-3 expression and thus significantly weakened IL-10-mediated protective effect in the OGD-induced injury model. IL-10NA, the IL-10 neutralizing antibody, reduced the level of p-PI3K phosphorylation and increased the expression of active caspase-3. These findings suggest that IL-10 provides neuroprotective effects by protecting neurites through PI3K/AKT signaling pathway in oxygen-glucose-deprived primary cortical neurons. 相似文献
16.
Gum Hwa Lee Zinal Chhangawala Sventja von Daake Jeffrey N. Savas John R. Yates rd Davide Comoletti Gabriella D'Arcangelo 《The Journal of biological chemistry》2014,289(29):20307-20317
Reelin is an extracellular protein that controls many aspects of pre- and postnatal
brain development and function. The molecular mechanisms that mediate postnatal
activities of Reelin are not well understood. Here, we first set out to express and
purify the full length Reelin protein and a biologically active central fragment.
Second, we investigated in detail the signal transduction mechanisms elicited by
these purified Reelin proteins in cortical neurons. Unexpectedly, we discovered that
the full-length Reelin moiety, but not the central fragment, is capable of activating
Erk1/2 signaling, leading to increased p90RSK phosphorylation and the induction of
immediate-early gene expression. Remarkably, Erk1/2 activation is not mediated by the
canonical signal transduction pathway, involving ApoER2/VLDLR and Dab1, that mediates
other functions of Reelin in early brain development. The activation of Erk1/2
signaling likely contributes to the modulation of neuronal maturation and synaptic
plasticity by Reelin in the postnatal and adult brain. 相似文献
17.
Interaction with the gamma-aminobutyric-acid-type-A (GABAA) receptors is recognized as an important component of the mechanism of propofol, a sedative-hypnotic drug commonly used as anesthetic. However the contribution of GABAA receptors to the central nervous system suppression is still not well understood, especially in the thalamocortical network. In the present study, we investigated if intracerebral injection of bicuculline (a GABAA receptor antagonist) into the thalamus ventral posteromedial nucleus (VPM, a thalamus specific relay nuclei that innervated S1 mostly) could reverse propofol-induced cortical suppression, through recording the changes of both spontaneous and somatosensory neural activities in rat’s somatosensory cortex (S1). We found that after injection of bicuculline into VPM, significant increase of neural activities were observed in all bands of local field potentials (total band, 182±6%), while the amplitude of all components in somatosensory evoked potentials were also increased (negative, 121±9% and positive, 124±6%).These data support that the potentiation of GABAA receptor-mediated synaptic inhibition in a thalamic specific relay system seems to play a crucial role in propofol-induced cortical suppression in the somatosensory cortex of rats. 相似文献
18.
Yukio Sasaki Nobuyuki Fukushima Akira Yoshida Hiroshi Ueda 《Cellular and molecular neurobiology》1998,18(5):487-496
1. We investigated the survival of neurons under serum-free conditions without any exogenous signal molecules, using primary cultures of rat cerebral cortex.2. Survival activity, measured with Alamar Blue, showed a cell density dependency under serum-free conditions.3. The addition of fetal bovine serum suppressed the apoptotic cell death accompanied by DNA-laddering and fragmentation specific in low-density cultures, resulting in the disappearance of the cell density dependency of survival.4. These findings suggest that serum factors may substitute for endogenous survival factors from cortical neurons in high-density cultures. 相似文献
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Selective Regulation of Apoptosis: the Cytotoxic Lymphocyte Serpin Proteinase Inhibitor 9 Protects against Granzyme B-Mediated Apoptosis without Perturbing the Fas Cell Death Pathway 总被引:21,自引:3,他引:18 下载免费PDF全文
Catherina H. Bird Vivien R. Sutton Jiuru Sun Claire E. Hirst Andrea Novak Sharad Kumar Joseph A. Trapani Phillip I. Bird 《Molecular and cellular biology》1998,18(11):6387-6398
Cytotoxic lymphocytes (CLs) induce caspase activation and apoptosis of target cells either through Fas activation or through release of granule cytotoxins, particularly granzyme B. CLs themselves resist granule-mediated apoptosis but are eventually cleared via Fas-mediated apoptosis. Here we show that the CL cytoplasmic serpin proteinase inhibitor 9 (PI-9) can protect transfected cells against apoptosis induced by either purified granzyme B and perforin or intact CLs. A PI-9 P1 mutant (Glu to Asp) is a 100-fold-less-efficient granzyme B inhibitor that no longer protects against granzyme B-mediated apoptosis. PI-9 is highly specific for granzyme B because it does not inhibit eight of the nine caspases tested or protect transfected cells against Fas-mediated apoptosis. In contrast, the P1(Asp) mutant is an effective caspase inhibitor that protects against Fas-mediated apoptosis. We propose that PI-9 shields CLs specifically against misdirected granzyme B to prevent autolysis or fratricide, but it does not interfere with homeostatic deletion via Fas-mediated apoptosis. 相似文献