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1.
Intermittent hypoxia attenuates ischemia/reperfusion induced apoptosis in cardiac myocytes via regulating Bcl-2/Bax expression 总被引:18,自引:0,他引:18
Intermittent hypoxia has been shown to provide myocardial protection against ishemiaJreperfusion-induced injury.Cardiac myocyte loss through apoptosis has been reported in ischemia/reperfusion injury. Our aim was to investigate whether intermittent hypoxia could attenuate ischemia/reperfusion-induced apoptosis in cardiac myocytes and its potential mechanisms. Adult male Sprague-Dawley rats were exposed to hypoxia simulated 5000 m in a hypobaric chamber for 6 h/day, lasting 42 days. Normoxia group rats were kept under normoxic conditions. Isolated perfused hearts from both groups were subjected to 30 min of global ischemia followed by 60 min reperfusion.Incidence of apoptosis in cardiac myocytes was determined by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) and DNA agarose gel electrophoresis. Expressions of apoptosis related proteins,Bax and Bcl-2, in cytosolic and membrane fraction were detected by Western Blotting. After ischemia/reperfusion,enhanced recovery of cardiac function was observed in intermittent hypoxia hearts compared with normoxia group.Ischemia/reperfusion-induced apoptosis, as evidenced by TUNEL-positive nuclei and DNA fragmentation, was significantly reduced in intermittent hypoxia group compared with normoxia group. After ischemia/reperfusion,expression of Bax in both cytosolic and membrane fractions was decreased in intermittent hypoxia hearts comparedwith normoxia group. Although ischemia/reperfusion did not induce changes in the level of Bcl-2 expression in cytosolic fraction between intermittent hypoxia and normoxia groups, the expression of Bcl-2 in membrane fraction was upregulated in intermittent hypoxia group compared with normoxia group. These results indicated that the cardioprotection of intermittent hypoxia against ischemia/reperfusion injury appears to be in part due to reducemyocardial apoptosis. Intermittent hypoxia attenuated ischemia/reperfusion-induced apoptosis via increasing the ratio of Bcl-2/Bax, especially in membrane fraction. 相似文献
2.
Nagaraj NS Vigneswaran N Zacharias W 《Apoptosis : an international journal on programmed cell death》2007,12(1):125-139
Tumor hypoxia interferes with the efficacy of chemotherapy, radiotherapy, and tumor necrosis factor-α. TRAIL (tumor necrosis
factor-related apoptosis inducing ligand) is a potent apoptosis inducer that limits tumor growth without damaging normal cells
and tissues in vivo. We present evidence for a central role of lysosomal cathepsins in hypoxia and/or TRAIL-induced cell death in oral squamous
cell carcinoma (OSCC) cells. Hypoxia or TRAIL-induced activation of cathepsins (B, D and L), caspases (-3 and -9), Bid cleavage,
release of Bax and cytochrome c, and DNA fragmentation were blocked independently by zVAD-fmk, CA074Me or pepstatin A, consistent
with the involvement of lysosomal cathepsin B and D in cell death. Lysosome stability and mitochondrial membrane potential
were reduced in hypoxia and TRAIL-induced apoptosis. However, TRAIL treatment under hypoxic condition resulted in diminished
apoptosis rates compared to treatment under normoxia. This inhibitory effect of hypoxia on TRAIL-induced apoptosis may be
based on preventing Bax activation and thus protecting mitochondria stability. Our data show that TRAIL or hypoxia independently
triggered activation of cathepsin B and D leading to apoptosis through Bid and Bax, and suggest that hypoxic tissue regions
provide a selective environment for highly apoptosis-resistant clonal cells. Molecular therapy approaches based on cathepsin
inhibitors need to address this novel tumor-preventing function of cathepsins in OSCC. 相似文献
3.
Zecchin KG Seidinger AL Chiaratti MR Degasperi GR Meirelles FV Castilho RF Vercesi AE 《Journal of bioenergetics and biomembranes》2007,39(2):186-194
It has been previously shown that Walker 256 tumor cells express a high content of the anti-apoptotic protein Bcl-2 which
protects mitochondria against the damaging effects of Ca2+. In the present study, we analyze H2O2-induced apoptotic death in two different types of tumor cells: Walker 256 and SCC-25. Treatment with H2O2 (4mM) increased reactive oxygen species generation and the concentration of cytosolic free Ca2+. These alterations preceded apoptosis in both cell lines. In Walker cells, which show a high Bcl-2/Bax ratio, apoptosis was
dependent on calcineurin activation and independent of changes in mitochondrial membrane potential (Δ < eqid1 > m), as well as cytochrome c release. In contrast, in SCC-25 cells, which show a lower Bcl-2/Bax ratio, apoptosis was preceded by a decrease in Δ < eqid2 > m, mitochondrial permeability transition, and cytochrome c release. Caspase-3 activation occurred in both cell lines. The data suggest that although the high Bcl-2/Bax ratio protected
the mitochondria of Walker cells from oxidative stress, it was not sufficient to prevent apoptosis through calcineurin pathways. 相似文献
4.
We have shown previously that depletion of polyamines delays apoptosis induced by camptothecin in rat intestinal epithelial cells (IEC-6). Mitochondria play an important role in the regulation of apoptosis in mammalian cells because apoptotic signals induce mitochondria to release cytochrome c. The latter interacts with Apaf-1 to activate caspase-9, which in turn activates downstream caspase-3. Bcl-2 family proteins are involved in the regulation of cytochrome c release from mitochondria. In this study, we examined the effects of polyamine depletion on the activation of the caspase cascade, release of cytochrome c from mitochondria, and expression and translocation of Bcl-2 family proteins. We inhibited ornithine decarboxylase, the first rate-limiting enzyme in polyamine synthesis, with alpha-difluoromethylornithine (DFMO) to deplete cells of polyamines. Depletion of polyamines prevented camptothecin-induced release of cytochrome c from mitochondria and decreased the activity of caspase-9 and caspase-3. The mitochondrial membrane potential was not disrupted when cytochrome c was released. Depletion of polyamines decreased translocation of Bax to mitochondria during apoptosis. The expression of antiapoptotic proteins Bcl-x(L) and Bcl-2 was increased in DFMO-treated cells. Caspase-8 activity and cleavage of Bid were decreased in cells depleted of polyamines. These results suggest that polyamine depletion prevents IEC-6 cells from apoptosis by preventing the translocation of Bax to mitochondria, thus preventing the release of cytochrome c. 相似文献
5.
目的:探讨红景天苷(Sal)能否通过改善心肌缺血,调控心肌细胞死亡受体和线粒体介导的凋亡途径相关蛋白,减少心肌细胞凋亡,发挥对力竭心脏的保护作用。方法:雄性SD大鼠,随机分为4组(n=6):对照组(Con)、力竭组(EE)、低剂量和高剂量Sal预处理力竭组(SLE、SHE)。分别给予Sal 15、30 mg/(kg·d)或生理盐水(3 ml/(kg·d))腹腔注射15 d。Con组不进行游泳训练,EE组、SLE组、SHE组于腹腔给药结束后次日参照Thomas力竭标准,一次性游泳运动至力竭。力竭运动结束后即刻麻醉取血和心脏,观测心肌缺血缺氧面积和心肌细胞凋亡指数(AI),测定血清中缺血修饰清蛋白(IMA)、心肌肌钙蛋白I(cTnI)、脑钠肽(BNP)和心肌细胞Bcl-2相关的X蛋白(Bax)、B淋巴细胞瘤-2(Bcl-2)的含量及心肌TNF受体超家族成员6 (Fas)、细胞色素C(Cyto-C)、天冬氨酸蛋白水解酶-3(Caspase-3)、天冬氨酸蛋白水解酶-8(Caspase-8)、天冬氨酸蛋白水解酶-9(Caspase-9)的表达情况。结果:与Con组比较,EE组大鼠心肌缺血缺氧面积、血清IMA、cTnI、BNP含量、AI和Bax水平、心脏Fas、Cyto-C、Caspase-3、Caspase-8、Caspase-9蛋白表达均显著增加(P<0.01),心肌Bcl-2表达水平明显降低(P<0.01);与EE组比较,Sal显著改善力竭大鼠心肌缺血缺氧面积、明显降低力竭大鼠血清IMA、cTnI、BNP含量和AI、Bax水平及心肌Fas、Cyto-C、Caspase-3、Caspase-8、Caspase-9的蛋白表达(P<0.01),明显提高心肌Bcl-2表达水平(P<0.01)。结论:红景天苷可通过改善心肌缺血,以及抑制死亡受体和线粒体凋亡通路相关蛋白Fas、Cyto-C、Caspase-3、Caspase-8、Caspase-9的表达,减少心肌细胞凋亡,从而发挥对力竭心脏的保护作用。 相似文献
6.
Apoptosis modulatory activities of transiently expressed Bcl-2: Roles in cytochrome c release and Bax regulation 总被引:12,自引:0,他引:12
Hou Q Cymbalyuk E Hsu SC Xu M Hsu YT 《Apoptosis : an international journal on programmed cell death》2003,8(6):617-629
Bcl-2 and Bcl-XL are pro-survival members of the Bcl-2 family. These proteins have been shown to antagonize the pro-apoptotic activity of Bax and promote cell survival through blocking Bax translocation from the cytosol to mitochondria and by preventing the release of cytochrome c. However, it has been recently reported that transiently expressed Bcl-2 unexpectedly leads to significant cell toxicity. To study this intriguing phenomenon, we have carried out further analyses into the properties of transiently expressed Bcl-2. We found that various isoforms of human and different species of Bcl-2 were equally capable of inducing apoptosis. In addition, we discovered that transient expression of Bcl-2, unlike its pro-survival homolog Bcl-XL, can lead to the release of cytochrome c from mitochondria and that the resulting cell death can be inhibited by caspase and calpain inhibitors. Moreover, we have shown that unlike the pro-apoptotic protein Bid, the toxicity associated with the transient expression of Bcl-2 occurs independent of the activity of the endogenous Bax. Finally, we found that in spite of its intrinsic toxicity, transiently expressed Bcl-2 is fully capable of blocking the ectopically expressed Bax from localizing to mitochondria. Taken together, these studies demonstrate that transiently expressed Bcl-2 displays opposing functional properties. 相似文献
7.
Mitochondrial apoptosis pathway is an important target of cardioprotective signalling. Tanshinones, a group of major bioactive compounds isolated from Salvia miltiorrhiza, have been reported with actions against inflammation, oxidative stress, and myocardial ischemia reperfusion injury. However, the actions of these compounds on the chronic hypoxia-related mitochondrial apoptosis pathway have not been investigated. In this study, we examined the effects and molecular mechanisms of two major tanshonones, tanshinone IIA (TIIA) and cryptotanshinone (CT) on hypoxia induced apoptosis in H9c2 cells. Cultured H9c2 cells were treated with TIIA and CT (0.3 and 3 μΜ) 2 hr before and during an 8 hr hypoxic period. Chronic hypoxia caused a significant increase in hypoxia inducible factor 1α expression and the cell late apoptosis rate, which was accompanied with an increase in caspase 3 activity, cytochrome c release, mitochondria membrane potential and expression of pro-apoptosis proteins (Bax and Bak). TIIA and CT (0.3 and 3 μΜ), in concentrations without affecting the cell viability, significantly inhibited the late apoptosis and the changes of caspase 3 activity, cytochrome c release, and mitochondria membrane potential induced by chronic hypoxia. These compounds also suppressed the overexpression of Bax and reduced the ratio of Bax/Bcl-2. The results indicate that TIIA and CT protect against chronic hypoxia induced cell apoptosis by regulating the mitochondrial apoptosis signaling pathway, involving inhibitions of mitochondria hyperpolarization, cytochrome c release and caspase 3 activity, and balancing anti- and pro-apoptotic proteins in Bcl-2 family proteins. 相似文献
8.
Ye Yuan Yong-yi Wang Xin Liu Bin Luo Lei Zhang Fei Zheng Xing-Yuan Li Ling-Yun Guo Lu Wang Miao Jiang Ya-mu Pan Yu-wen Yan Jian-ye Yang Shi-You Chen Jia-Ning Wang Jun-Ming Tang 《Journal of cellular physiology》2019,234(12):22921-22934
Bax triggers cell apoptosis by permeabilizing the outer mitochondrial membrane, leading to membrane potential loss and cytochrome c release. However, it is unclear if proteasomal degradation of Bax is involved in the apoptotic process, especially in heart ischemia-reperfusion (I/R)-induced injury. In the present study, KPC1 expression was heightened in left ventricular cardiomyocytes of patients with coronary heart disease (CHD), in I/R-myocardium in vivo and in hypoxia and reoxygenation (H/R)-induced cardiomyocytes in vitro. Overexpression of KPC1 reduced infarction size and cell apoptosis in I/R rat hearts. Similarly, the forced expression of KPC1 restored mitochondrial membrane potential (MMP) and cytochrome c release driven by H/R in H9c2 cells, whereas reducing cell apoptosis, and knockdown of KPC1 by short-hairpin RNA (shRNA) deteriorated cell apoptosis induced by H/R. Mechanistically, forced expression of KPC1 promoted Bax protein degradation, which was abolished by proteasome inhibitor MG132, suggesting that KPC1 promoted proteasomal degradation of Bax. Furthermore, KPC1 prevented basal and apoptotic stress-induced Bax translocation to mitochondria. Bax can be a novel target for the antiapoptotic effects of KPC1 on I/R-induced cardiomyocyte apoptosis and render mechanistic penetration into at least a subset of the mitochondrial effects of KPC1. 相似文献
9.
Wang Z Liang R Huang GS Piao Y Zhang YQ Wang AQ Dong BX Feng JL Yang GR Guo Y 《Apoptosis : an international journal on programmed cell death》2006,11(10):1851-1860
Cathepsin D (cat D) reportedly plays an important role in certain apoptotic processes, the downstream pathways of which involve
release of cytochrome c (cyt c) from mitochondria and activation of the caspase cascade. Previous studies revealed that the B-cell lymphoma 2 (Bcl-2) family
members Bax or Bid play important roles in apoptotic signal transduction between cat D and mitochondria. Here, we show that
glucosamine sulfate (GS) inhibits the proliferation and induces apoptosis of human chronic myelogenous leukemia K562 cells
in vitro. GS interfered with the maturation of cat D. Activation of caspase-3, cleavage of poly-(ADP-ribose)-polymerase, release of
cyt c, and downregulation of Bcl-xL accompanied GS-induced apoptosis, and these processes were inhibited by the cat D inhibitor
pepstatin A. However, we did not detect any altered gene expression of Bcl-2, Bax, or Bid during apoptosis. Translocation
of cat D from the lysosome to the cytosol was observed in GS-treated K562 cells. These findings suggest that GS-induced K562
cell apoptosis involves the translocation of cat D from the lysosome to the cytosol. Furthermore, our findings suggest that
downregulation of Bcl-xL (but not Bcl-2, Bax, or Bid) connects cat D and the mitochondrial pathway, which causes the release
of cyt c and activation of the caspase cascade during GS-induced apoptosis of K562 cells. 相似文献
10.
Oxidative stress plays an important role in mediating ventricular remodeling and dysfunction in heart failure (HF), but its mechanism of action has not been fully elucidated. In this study we determined whether a combination of antioxidant vitamins reduced myocyte apoptosis, beta-adrenergic receptor desensitization, and sarcoplasmic reticular (SR) Ca2+ ATPase downregulation in HF after myocardial infarction (MI) and whether these effects were associated with amelioration of left ventricular (LV) remodeling and dysfunction. Vitamins (vitamin C 300 mg and vitamin E 300 mg) were administered to rabbits 1 week after MI or sham operation for 11 weeks. The results showed that MI rabbits exhibited cardiac dilation and LV dysfunction measured by fractional shortening and the maximal rate of pressure rise (dP/dt), an index of contractility. These changes were associated with elevation of oxidative stress, decreases of mitochondrial Bcl-2 and cytochrome c proteins, increases of cytosolic Bax and cytochrome c proteins, caspase 9 and caspase 3 activities and myocyte apoptosis, and downregulation of beta-adrenergic receptor sensitivity and SR Ca2+ ATPase. Combined treatment with vitamins C and E diminished oxidative stress, increased mitochondrial Bcl-2 protein, decreased cytosolic Bax, prevented cytochrome c release from mitochondria to cytosol, reduced caspase 9 and caspase 3 activities and myocyte apoptosis, blocked beta-adrenergic receptor desensitization and SR Ca2+ ATPase downregulation, and attenuated LV dilation and dysfunction in HF after MI. The results suggest that antioxidant therapy may be beneficial in HF. 相似文献
11.
Aubert M Pomeranz LE Blaho JA 《Apoptosis : an international journal on programmed cell death》2007,12(1):19-35
Expression of HSV-1 genes leads to the induction of apoptosis in human epithelial HEp-2 cells but the subsequent synthesis
of infected cell protein prevents the process from killing the cells. Thus, viruses unable to produce appropriate prevention
factors are apoptotic. We now report that the addition of either a pancaspase inhibitor or caspase-9-specific inhibitor prevented
cells infected with an apoptotic HSV-1 virus from undergoing cell death. This result indicated that HSV-1-dependent apoptosis
proceeds through the mitochondrial apoptotic pathway. However, the pancaspase inhibitor did not prevent the release of cytochrome
c from mitochondria, implying that caspase activation is not required for this induction of cytochrome c release by HSV-1. The release of cytochrome c was first detected at 9 hpi while caspase-9, caspase-3 and PARP processing were detected at 12 hpi. Finally, Bax accumulated
at mitochondria during apoptotic, but not wild type HSV-1 infection. Together, these findings indicate that HSV-1 blocks apoptosis
by precluding mitochondrial cytochrome c release in a caspase-independent manner and suggest Bax as a target in infected human epithelial cells. 相似文献
12.
Caspases play important roles in the initiation and progression of apoptosis. In experimental models of ATP depletion, we
have demonstrated the activation of caspase-9, -8, and -3, which is followed by the development of apoptotic morphology. To
determine the specific contribution of caspase-9 to ATP depletion-induced apoptosis, we transfected renal epithelial cells
with its endogenous dominant-negative inhibitor caspase-9S. Two cell clones with stable transfection were obtained. These
clones expressed caspase-9S, and the cytosol isolated from these cells was resistant to cytochrome c-induced caspase activation in vitro. The clones were then examined for ATP depletion-induced apoptosis. Compared with the wild-type cells, the caspase-9S clones
were markedly resistant to apoptosis in this model. Caspase activation was also inhibited. Surprisingly, these clones also
showed significantly less cytochrome c release during ATP-depletion. Moreover, Bax translocation to mitochondria was inhibited, suggesting that these clones were
resistant to apoptosis not only at the cytosolic caspase activation level but also at the upstream mitochondrial level. To
gain insights into the mitochondrial resistance, we analyzed the expression of Bcl-2 family proteins. While the expression
of Bax, Bak, and Bcl-2 was comparable to the wild-type cells, the selected clones showed specific up-regulation of Bcl-XL,
an anti-apoptotic protein. We conclude that the selected clones were resistant to apoptosis at two levels. In the cytosol,
they expressed dominant negative caspase-9, and at the mitochondria they up-regulated Bcl-XL. 相似文献
13.
Chai WS Zhu XM Li SH Fan JX Chen BY 《Apoptosis : an international journal on programmed cell death》2008,13(6):833-843
Pseudomonas aeruginosa is a gram-negative opportunistic pathogen that is cytotoxic towards a variety of eukaryotic cells. To investigate the effect
of this bacterium on monocyte, we infected human U937 cells with the P. aeruginosa strain in vitro. To explore the expression of Bcl-2 and Bax as well as caspase-3/9 activation in the apoptosis of human U937
cells induced by P. aeruginosa, Hoechst 33258 staining and Giemsa staining as well as Flow cytometry analysis were used to determine the rate of apoptosis,
and the expressions of Bcl-2 and Bax were assayed by RT-PCR and Western blotting respectively. Bax protein conformation change
was assayed by immunoprecipitation. Cytochrome c release was measured by Western blotting. Moreover, exposure of U937 cells to P. aeruginosa measured caspase-3/9 activity. It was found that the apoptosis of human U937 cells could be induced by Pseudomonas aeruginosa in a dose- and time-dependent manner. Also, there were a tendency of alterations with an increased expression level of Bax
and a reduced expression level of Bcl-2, increased levels of cytochrome c release, and also with an increased activation of caspase-3/9 and Bax protein conformation change. For the evaluation of
the role of caspases, caspase-3/9 inhibitors Z-DEVD-FMK and Z-LEHD-FMK respectively were used. The results were further confirmed
by the observation that the caspase inhibitors Z-DEVD-FMK and Z-LEHD-FMK blocked P. aeruginosa-induced U937 apoptosis. It is concluded that P. aeruginosa can induce apoptosis with an up-regulated expression of Bax and a down-regulated expression of Bcl-2, which resulted in increased
levels of cytochrome c release and increased caspase-3 and -9 in human U937 cells. 相似文献
14.
Gokulakrishnan Adikesavan Magendira Mani Vinayagam Liyakath Ali Abdulrahman Thirunavukkarasu Chinnasamy 《Molecular biology reports》2013,40(12):6533-6545
The present study brings out the preventive role of (?)-epigallocatechin-gallate (EGCG) on cardiac mitochondrial metabolism and apoptosis in cigarette smoke (CS)-exposed rats. The CS-exposed rats showed significantly decreased activities of TCA cycle enzymes and mitochondrial enzymatic antioxidants, on the other hand, mitochondrial lipid peroxidation was increased and GSH level was decreased. Further, CS exposure was found to induce cardiac apoptosis through release of cytochrome c into the cytosol, cleavage of pro-caspase-3 to active caspase-3, up-regulation of pro-apoptotic (Bax) and down-regulation of antiapoptotic (Bcl-2) molecules. The CS-induced apoptosis was further confirmed by mitochondrial and nuclear ultra structural apoptotic features as evaluated by electron microscopic studies. EGCG supplementation shelters the activities of TCA cycle enzymes and antioxidant enzymes, with concomitant decrease in lipid peroxidation and increase in GSH level. EGCG administration inhibited apoptosis through the inhibition of cytochrome c release into cytosol, activation of pro-caspase-3, down regulation of Bax and significant up regulation of Bcl-2. EGCG reversed the ultra structural apoptotic alterations of mitochondria and nucleus. The present study has provided experimental evidences that the EGCG treatment enduring to cardio protection at mitochondrial level. 相似文献
15.
Franziska B. Mullauer Jan H. Kessler Jan Paul Medema 《Apoptosis : an international journal on programmed cell death》2009,14(2):191-202
Betulinic acid (BetA) is a plant-derived pentacyclic triterpenoid that exerts potent anti-cancer effects in vitro and in vivo,
but is non toxic to untransformed cells. In our previous study we observed that BetA consistently induced cell death in a
broad panel of tumor cell lines. Apoptosis induced by BetA involves activation of caspases, PARP cleavage and DNA fragmentation
and was suggested to depend on the mitochondrial pathway. However, conflicting results have been reported with respect to
the role of the pro- and anti-apoptotic members of the Bcl-2 family, which are often aberrantly regulated in tumors and thereby
confer growth and survival advantages. Here we show that BetA-induced apoptosis critically depends on the release of cytochrome
c from the mitochondria and formation of the apoptosome. Nevertheless, over-expression of Bcl-2 or Bcl-XL only provides limited
protection against BetA-induced apoptosis. More importantly, Bax/Bak deficient cells are as sensitive to BetA as their wild-type
counterparts, suggesting that cytochrome c is released in a non-classical fashion. In agreement, pre-incubation with cyclosporin A indicated a crucial role for the
mitochondrial permeability transition pore (PT) in the induction of apoptosis. Our observations therefore indicate that BetA
affects mitochondria and induces cytochrome c release directly via PT Pore. This is only temporarily prevented by anti-apoptotic members of the Bcl-2 family, but independent
of Bax and Bak. These findings help to explain the remarkable broad efficacy of BetA against tumor cells of different origin
and its effect in tumor cells that are resistant to other chemotherapeutic agents. 相似文献
16.
Fatemeh Shaerzadeh Shabnam Zeighamy Alamdary Mohammad Ali Esmaeili Nazanin Namazi Sarvestani Fariba Khodagholi 《Neurochemical research》2011,36(12):2216-2226
Herein, we investigated the protective effect of Salvia sahendica against H2O2-induced cell death in rat pheochromocytoma (PC12) cells. Our data show that S. sahendica blocks apoptosis pathway by inhibition of cytochrome c release from mitochondria and leakage of calcium from endoplasmic reticulum. It also activates/inactivates two members of
Bcl-2 family, Bax and Bcl-2. Bax inhibition and Bcl-2 activation suppress release of cytochrome c from mitochondria that prevents cleavage of caspase-3. Besides S. sahendica suppresses ER stress via attenuation of intracellular levels of calcium. Suppression of ER stress decreased calpain activation
and subsequently cleavage of caspase-12. Altogether, these results indicate that S. sahendica protects PC12 cells treated with H2O2 via suppression of upstream factors of apoptosis pathway. While oxidative stress is an early event in Alzheimer disease,
it seems that S. sahendica prevents deleterious effects of reactive oxygen species by stabilizing mitochondrial membranes and inhibiting ER stress. 相似文献
17.
Bit Na Seo Jung Min Ryu Seung Pil Yun Ji Hoon Jeon Su Shin Park Keon Bong Oh Jin-Ki Park Ho Jae Han 《Apoptosis : an international journal on programmed cell death》2013,18(7):811-824
Delphinidin, gallic acid, betulinic acid, and ursolic acid, which are bio-active ingredients in a variety of fruits, vegetables, and herbs, have potent antioxidant activity and various biological activities. However, it is not clear whether these bio-active ingredients can significantly contribute to the protection of embryonic stem (ES) cells from hypoxia-induced apoptosis. In the present study, hypoxia-induced ES cells apoptosis with time, which were abrogated by pretreatment with all ingredients. Hypoxia-induced ROS generation was blocked by pretreatment with all ingredients in a dose-dependent manner, with the maximum ROS scavenging effect observed for delphinidin. Hypoxia increased phosphorylation of JNK and NF-κB were blocked by pretreatment of delphinidin as well as NAC. Hypoxia decreased phosphorylation of Aktthr308 and ser473; these decreases were reversed by pretreatment with delphinidin or NAC. However, Akt inhibition did not affect NF-κB phosphorylation. Delphinidin attenuated the hypoxia-induced increase in Bax, cleaved caspase-9, cleaved caspase-3, and decrease in Bcl-2, which were diminished by pretreatment of Akt inhibitor. Hypoxia induced Bax translocation from the cytosol to mitochondria. Furthermore, hypoxia induced mitochondria membrane potential loss and cytochrome c release in cytosol, which were blocked by delphinidin pretreatment. Hypoxia induced cleavage of procaspase-9 and procaspase-3 which were blocked by delphinidin or SP600125, but Akt inhibitor abolished the protection effect of delphinidin. Moreover, inhibition of JNK and NF-κB abolished hypoxia-induced ES cell apoptosis and inhibition of Akt attenuated delphinidin-induced blockage of apoptosis. The results indicate that delphinidin can prevent hypoxia-induced apoptosis of ES cells through the inhibition of JNK and NF-κB phosphorylation, and restoration of Akt phosphorylation. 相似文献
18.
Victor Umansky Frank Ratter Stefan Lampel Mariana Bucur Volker Schirrmacher Alexey Ushmorov 《Experimental cell research》2001,265(2):274
We have recently shown that nitric-oxide (NO)-induced apoptosis in Jurkat human leukemia cells requires degradation of mitochondria phospholipid cardiolipin, cytochrome c release, and activation of caspase-9 and caspase-3. Moreover, an inhibitor of lipid peroxidation, Trolox, suppressed apoptosis in Jurkat cells induced by NO donor glycerol trinitrate. Here we demonstrate that this antiapoptotic effect of Trolox occurred despite massive release of the mitochondrial protein cytochrome c into the cytosol and mitochondrial damage. Incubation with Trolox caused a profound reduction of intracellular ATP concentration in Jurkat cells treated by NO. Trolox prevented cardiolipin degradation and caused its accumulation in Jurkat cells. Furthermore, Trolox markedly downregulated the NO-mediated activation of caspase-9 and caspase-3. Caspase-9 is known to be activated by released cytochrome c and together with caspase-3 is considered the most proximal to mitochondria. Our results suggest that the targets of the antiapoptotic effect of Trolox are located downstream of the mitochondria and that caspase activation and subsequent apoptosis could be blocked even in the presence of cytochrome c released from the mitochondria. 相似文献
19.
“The large scale remodeling of mitochondria during apoptosis is a necessary step for the complete release of cytochrome c” has been a tenet since 2002. However, more recent findings strongly indicate that the large-scale remodeling previously described actually takes place after the release of cytochrome c and in a caspase-dependent manner, bringing into question whether mitochondria remodeling is necessary. In a more recent article, however, it was shown that a much more subtle form of remodeling is taking place which is only observable by electron tomography. In the Bcl-2 inhibitable Bax/Bak-dependent intrinsic pathway of apoptosis, the release of cytochrome c from mitochondria is a consequence of two carefully coordinated events: formation of outer membrane pores and opening of crista junctions triggered by Opa1 oligomer disassembly, and both steps are necessary for the complete release of cytochrome c. We review the recent literature pertaining to the coordinated release of cytochrome c during cell death. 相似文献
20.
缺氧环境下大鼠骨髓间充质干细胞凋亡相关蛋白和mRNA的表达 总被引:2,自引:0,他引:2
目的探讨大鼠骨髓间充质干细胞(MSCs)在缺氧环境下凋亡相关蛋白和mRNA的表达。方法将接种的P3细胞置于94%N2、1%O2和5%CO2缺氧箱中37℃孵育,分别于0.5h、1h、2h、4h、6h、8h和12h取出分别应用Annexin V/PI双染法进行流式细胞仪(FCM)分析MSCs凋亡率(Apoptotic Rate,AR),并同步用免疫细胞化学、western blotting和Rt-PCR等方法检测Bax/Bcl-2,Fas/FasL和Caspase-3蛋白和mRNA的表达。结果1.缺氧前,免疫细胞化学法未检测到Bcl-2、Bax、Fas、FasL和Caspase-3蛋白表达,缺氧0.5h后均可较强表达;2.各缺氧时间点Bcl-2、Bax、Fas、FasL、Caspase-3蛋白和mRNA表达较缺氧前均显著性增高(P均〈0.05);随缺氧时间延伸,Bcl-2蛋白和mRNA表达不显著增加(P〉0.05),而Bax、Fas、FasL、Caspase-3蛋白和mRNA表达均显著增加(P均〈0.05),但缺氧6-12h时间点之间表达均没有统计学意义(P均〉0.05);3.AR和Bcl-2/Bax蛋白(r1=0.417,P=0.043)及mRNA(r2=-0.435,P=0.040)呈显著负相关,而和Fas(r1=0.639,P=0.025;r2=0.711,P=0.018)、Fas-L(r1=0.581,P=0.022;r2=0.605,P=0.037)、Caspase-3(r1=0.704,P=O.014;r2=0.657,P=0.026)蛋白及mRNA均呈显著正相关。结论在缺氧促进MSCs凋亡的过程中,Bcl-2蛋白和mRNA可能起着保护作用,而Bax、Fas-L、Fas、Caspase-3蛋白和mRNA可能在MsCs凋亡的进程中起着促进作用。 相似文献