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Apoptosis can be induced in primary cultures of mouse thymocytes using the glucocorticoid dexamethasone. Addition of the polyamine spermine simultaneously with dexamethasone reduces the induction of apoptosis compared to treatment with dexamethasone alone. We investigated the signal transduction pathway at the mitochondrial level in order to elucidate spermine's protective effect. Mitochondrial involvement is evident due to the loss of mitochondrial transmembrane potential, release of cytochrome c into the cytosol and activation of caspase-9 in dexamethasone-treated thymocytes. The addition of spermine inhibited the release of cytochrome c from the mitochondria into the cytosol, and also the activation of caspase-9. When the mitogen concanavalin A (Con A) was added to dexamethasone- plus spermine-treated thymocytes, the number of apoptotic cells in the pre-G(1)peak was reduced compared to thymocytes treated with only dexamethasone plus spermine. Comparing concanavalin A added to dexamethasone-treated or to dexamethasone plus spermine-treated thymocytes, showed a markedly reduced pre-G(1)peak in the latter. Thus, the spermine-induced inhibition of cytochrome c release confers a survival advantage on thymocytes. 相似文献
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Fra-1 substitutes for c-Fos in AP-1-mediated signal transduction in retinal apoptosis 总被引:5,自引:0,他引:5
Wenzel A Iseli HP Fleischmann A Hafezi F Grimm C Wagner EF Remé CE 《Journal of neurochemistry》2002,80(6):1089-1094
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Hashimoto T Ashida H Sano T Furuyashiki T Shiotani B Kanazawa K Danno G 《Mutation research》2000,457(1-2):57-67
3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is a potent carcinogen present in cooked meat. Although the target of this carcinogen is mainly in the liver, Trp-P-1 is distributed in the thymus and spleen as well as in the liver after administration. However, the cytotoxic effect of Trp-P-1 on lymphocytes has not been examined in detail. In the present study, we investigated the cytotoxicity of Trp-P-1 against rat splenocytes and thymocytes. Trp-P-1 reduced viability of both types of cells in the same manner, the LD50 at 6 h in culture was 15 μM, and the time for the 50% decrease in cell viability (t1/2) at 20 μM was 3 h. In both types of cells, Trp-P-1 caused the activation of caspase-3-like proteases and the cleavage of poly(ADP-ribose) polymerase, both of which are biochemical markers of apoptosis. On the other hand, DNA fragmentation occured in splenocytes, but not in thymocytes although Trp-P-1 activated 32–34 kDa nucleases that may not be able to degrade DNA into nucleosomal units. These results indicated that Trp-P-1 induces apoptosis in both splenocytes and thymocytes by different mechanisms in which distinct apoptotic pathways may exist downstream of the caspase cascade. 相似文献
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Hsieh HL Sun CC Wu CB Wu CY Tung WH Wang HH Yang CM 《Journal of cellular biochemistry》2008,103(6):1732-1746
Sphingosine 1-phosphate (S1P) has been shown to regulate expression of several genes in vascular smooth muscle cells (VSMCs) and contributes to arteriosclerosis. However, the mechanisms regulating epidermal growth factor receptor (EGFR) expression by S1P in aortic VSMCs remain unclear. Western blotting and RT-PCR analyses showed that S1P induced EGFR mRNA and protein expression in a time- and concentration-dependent manner, which was attenuated by inhibitors of MEK1/2 (U0126) and phosphatidylinositide 3-kinase (PI3K; wortmannin), and transfection with dominant negative mutants of ERK and Akt, respectively. These results suggested that S1P-induced EGFR expression was mediated through p42/p44 MAPK and PI3K/Akt pathways in VSMCs. In accordance with these findings, S1P stimulated phosphorylation of p42/p44 MAPK and Akt which was attenuated by U0126 and wortmannin, respectively. Furthermore, S1P-induced EGFR upregulation was blocked by a selective NF-kappaB inhibitor helenalin. Immunofluorescent staining and reporter gene assay revealed that S1P-induced activation of NF-kappaB was blocked by wortmannin, but not by U0126, suggesting that activation of NF-kappaB was mediated through PI3K/Akt. Moreover, S1P-induced EGFR expression was inhibited by an AP-1 inhibitor curcumin and tanshinone IIA. S1P-stimulated AP-1 subunits (c-Jun and c-Fos mRNA) expression was attenuated by U0126 and wortmannin, suggesting that MEK and PI3K/ERK cascade linking to AP-1 was involved in EGFR expression. Upregulation of EGFR by S1P may exert a phenotype modulation of VSMCs. This hypothesis was supported by pretreatment with AG1478 or transfection with shRNA of EGFR that attenuated EGF-stimulated proliferation of VSMCs pretreated with S1P, determined by XTT assay. These results demonstrated that in VSMCs, activation of Akt/NF-kappaB and ERK/AP-1 pathways independently regulated S1P-induced EGFR expression in VSMCs. Understanding the mechanisms involved in S1P-induced EGFR expression on VSMCs may provide potential therapeutic targets in the treatment of arteriosclerosis. 相似文献
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Takashi Hashimoto Hitoshi Ashida Takashi Sano Takashi Furuyashiki Bunsyo Shiotani Kazuki Kanazawa Gen-ichi Danno 《Mutation research》2000,457(1-2)
3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is a potent carcinogen present in cooked meat. Although the target of this carcinogen is mainly in the liver, Trp-P-1 is distributed in the thymus and spleen as well as in the liver after administration. However, the cytotoxic effect of Trp-P-1 on lymphocytes has not been examined in detail. In the present study, we investigated the cytotoxicity of Trp-P-1 against rat splenocytes and thymocytes. Trp-P-1 reduced viability of both types of cells in the same manner, the LD50 at 6 h in culture was 15 μM, and the time for the 50% decrease in cell viability (t1/2) at 20 μM was 3 h. In both types of cells, Trp-P-1 caused the activation of caspase-3-like proteases and the cleavage of poly(ADP-ribose) polymerase, both of which are biochemical markers of apoptosis. On the other hand, DNA fragmentation occured in splenocytes, but not in thymocytes although Trp-P-1 activated 32–34 kDa nucleases that may not be able to degrade DNA into nucleosomal units. These results indicated that Trp-P-1 induces apoptosis in both splenocytes and thymocytes by different mechanisms in which distinct apoptotic pathways may exist downstream of the caspase cascade. 相似文献
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JNK and AP-1 mediate apoptosis induced by bortezomib in HepG2 cells via FasL/caspase-8 and mitochondria-dependent pathways 总被引:3,自引:0,他引:3
Lauricella M Emanuele S D'Anneo A Calvaruso G Vassallo B Carlisi D Portanova P Vento R Tesoriere G 《Apoptosis : an international journal on programmed cell death》2006,11(4):607-625
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Kanmogne GD Primeaux C Grammas P 《Biochemical and biophysical research communications》2005,333(4):1107-1115
Pulmonary hypertension associated with human immunodeficiency virus (HIV) infection also involves injury to the lung endothelium. However, the pathogenesis of HIV-induced pulmonary hypertension is not known; we hypothesized that HIV or secreted viral proteins could play a role in vascular injury and the increased frequency of pulmonary hypertension observed in HIV-infected patients. Here, we report that exposure of HIV-1 gp120 proteins to primary human lung microvascular endothelial cells causes apoptosis, as assessed by TUNEL assay, Annexin-V staining, and DNA laddering. Using ribonuclease protection assay and Western blotting we find that gp120-induced apoptosis of lung endothelial cells involves a down-regulation in Bcl-xl mRNA and proteins. In addition, gp120 significantly increases secretion of the potent vasoconstrictor endothelin-1 by human lung endothelial cells. These data suggest that secreted HIV gp120 proteins induce lung endothelial cell injury and could contribute to the development of HIV-associated pulmonary hypertension. 相似文献
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Li RJ Qiu SD Wang HX Tian H Wang LR Huo YW 《Apoptosis : an international journal on programmed cell death》2008,13(8):959-971
Androgen receptor (AR) mediates a wide range of cellular processes, such as proliferation, differentiation and apoptosis.
Here we sought to identify whether AR was located in pancreatic beta-cells and investigate its functions in type 1 diabetes
induced by multiple low doses of streptozotocin. Double/triple immunofluorescence, Western blot and semi-quantitative RT-PCR
were carried out to determine variances of AR expression in beta-cells and correlation between AR and apoptosis/proliferation
of beta-cells with progress of diabetes. In addition, in vitro primary beta-cells from control mice were cultured for 3 days
or 6 days with compound stimulation in order to further identify effect of AR on beta-cell apoptosis and proliferation. AR
expression in beta-cells peaked in control and 1-day diabetic mice, gradually and significantly decreased, even disappeared
in diabetic mice with progress of diabetes. TUNEL-positive beta-cells were concomitant with overexpression of AR, and Ki67-positive
beta-cells showed extremely weak, even negative AR staining. In vitro, AR could mediate beta-cell apoptosis, and AR antagonist
flutamide contributed to beta-cell proliferation. In conclusion, AR is abundantly expressed in pancreatic beta-cell cytoplasm
of control mice. With progress of type 1 diabetes, decrement of AR expression in diabetic mice contributes to prohibit beta-cells
from apoptosis, and is strongly associated with beta-cell proliferation. 相似文献
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Zheng R Zhang Z Lv X Fan J Chen Y Wang Y Tan R Liu Y Zhou Q 《Cell biology international》2008,32(4):427-435
Studies have shown that polycystin-1, encoded by PKD1, the major ADPKD, may have a central role in regulating both apoptosis and proliferation, which could prevent the malignant transformation of affected cells. However, as a putative tumor suppressor, direct studies on the possibility that polycystin-1 may play a role in cancer cells' biological properties have not yet been reported. We have demonstrated that the apoptosis of cancer cells was induced by overexpression of polycystin-1. After transfection with polycystin-1, three cancer cell lines, HepG2, A549, and SW480, showed significantly increased apoptosis compared with the respective control groups. This was accompanied by cell cycle arrest at G(0)/G(1) phase, whereas cell proliferation was not significantly affected. Overexpression of polycystin-1 induces apoptosis in cancer cells, at least partially, through Wnt and a caspase-dependent pathway. 相似文献
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Recent experiments suggest that Xenopus Neurotrophin Receptor Homolog 1 (NRH1) proteins act through the planar cell polarity pathway to regulate convergent extension movements during gastrulation and neurulation. We show in this paper that NRH1 proteins are also required for the proper expression of mesodermally expressed genes such as Xbra and Chordin, and to a lesser extent, of Xwnt11. Loss of NRH1 function is followed, during gastrula and neurula stages, by a dramatic increase in apoptosis. Apoptosis is delayed by injection of Xbra RNA, suggesting that cell death is a consequence, at least in part, of the down-regulation of this gene, and it is also delayed by expression of activated forms of Rho, Rac and Cdc42. These small GTPases have previously been implicated in the planar cell polarity pathway in Xenopus and, in other systems, in the regulation of apoptosis. We conclude that the effects of NRH1 proteins include the regulation of mesodermal gene expression and that the disruption of gastrulation that is caused by their loss of function is a consequence of the down-regulation of Xbra and other genes, in addition to direct interference with the planar cell polarity pathway. The apoptosis observed in embryos lacking NRH1 function is not an indirect consequence of the disruption of gastrulation, and indeed it may contribute to the observed morphological defects. 相似文献
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Regulation of inward rectifier potassium current ionic channel remodeling by AT1‐Calcineurin‐NFAT signaling pathway in stretch‐induced hypertrophic atrial myocytes 下载免费PDF全文
Jionghong He Yanan Xu Long Yang Guiling Xia Na Deng Yongyao Yang Ye Tian Zenan Fu Yongqi Huang 《Cell biology international》2018,42(9):1149-1159