scholarly journals Antiinflammatory Effects of CD95 Ligand (FasL)-induced Apoptosis

1998 ◽  
Vol 188 (5) ◽  
pp. 887-896 ◽  
Author(s):  
Yakun Gao ◽  
John M. Herndon ◽  
Hui Zhang ◽  
Thomas S. Griffith ◽  
Thomas A. Ferguson
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Lymphoid Cells ◽  
Apoptotic Cells ◽  
Immune Deviation ◽  
Inflammatory Reactions ◽  
Cd95 Ligand ◽  
Induced Apoptosis

Apoptosis is critical to homeostasis of multicellular organisms. In immune privileged sites such as the eye, CD95 ligand (FasL)-induced apoptosis controls dangerous inflammatory reactions that can cause blindness. Recently, we demonstrated that apoptotic cell death of inflammatory cells was a prerequisite for the induction of immune deviation after antigen presentation in the eye. In this report, we examine the mechanism by which this takes place. Our results show that Fas- mediated apoptosis of lymphoid cells leads to rapid production of interleukin (IL)-10 in these cells. The apoptotic cells containing IL-10 are responsible for the activation of immune deviation through interaction with antigen-presenting cells (APC). In support of this, we found that apoptotic cells from IL-10+/+ animals fed to APC in vitro promote Th2 cell differentiation, whereas apoptotic IL-10−/− cells, as well as nonapoptotic cells, favor Th1 induction. Thus, apoptotic cell death and tolerance are linked through the production of an antiinflammatory cytokine to prevent dangerous and unwanted immune responses that might compromise organ integrity.

scholarly journals Acidification induces Bax translocation to the mitochondria and promotes ultraviolet light-induced apoptosis

2008 ◽  
Vol 13 (1) ◽  
Author(s):  
Lin Yang ◽  
Yongyu Mei ◽  
Qifeng Xie ◽  
Xiaoyan Han ◽  
Fucheng Zhang ◽  
...  
Keyword(s):  
Cell Death ◽  
Uv Light ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Chemotherapeutic Drugs ◽  
Normal Medium ◽  
Sds Page ◽  
Translocation Assay ◽  
Induced Apoptosis

AbstractIt has been suggested that Bax translocation to the mitochondria is related to apoptosis, and that cytosol acidification contributes to apoptosis events. However, the mechanisms remain obscure. We investigated the effect of acidification on Bax translocation and on ultraviolet (UV) light-induced apoptosis. The Bax translocation assay in vitro showed that Bax translocated to the mitochondria at pH 6.5, whereas no Bax translocation was observed at pH 7.4. VHDBB cells expressing the GFP-Bax fusion protein were treated for 12 h with a pH 6.5 DMEM medium, nigericin (5 μg/ml) and UV light (50 J/cm2), separately or in combination, and Bax translocation to the mitochondria was determined by SDS-PAGE and Western blot, and apoptotic cell death was detected by flow cytometry. The results showed that some of the Bax translocated to the mitochondria in the cells treated with the normal medium, nigericin and UV in combination, whereas all of the Bax translocated to the mitochondria in the cells treated with the pH 6.5 medium, nigericin and UV in combination. In VHDBB cells treated for 12 h with nigericin, UV alone, and UV and nigericin in combination, the respective rates of apoptotic cell death were 25.08%, 33.25% and 52.88%. In cells treated with pH 6.5 medium and nigericin, pH 6.5 medium and UV, and pH 6.5 medium, nigericin and UV in combination, the respective rates of apoptotic cell death increased to 37.19%, 41.42% and 89.44%. Our results indicated that acidification induces Bax translocation from the cytosol to the mitochondria, and promotes UV lightmediated apoptosis. This suggests that there is a possibility of improving cancer treatment by combining acidification with irradiation or chemotherapeutic drugs.

scholarly journals Inhibition of cathepsin K sensitizes oxaliplatin-induced apoptotic cell death by Bax upregulation through OTUB1-mediated p53 stabilization in vitro and in vivo

Oncogene ◽  
2021 ◽  
Author(s):  
Seung Un Seo ◽  
Seon Min Woo ◽  
Shin Kim ◽  
Jong-Wook Park ◽  
Hyun-Shik Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Cathepsin K ◽  
Apoptotic Cell Death ◽  
Mouse Xenograft Model ◽  
Induced Apoptosis ◽  
Cathepsin K Inhibition

AbstractCathepsin K is highly expressed in various types of cancers. However, the effect of cathepsin K inhibition in cancer cells is not well characterized. Here, cathepsin K inhibitor (odanacatib; ODN) and knockdown of cathepsin K (siRNA) enhanced oxaliplatin-induced apoptosis in multiple cancer cells through Bax upregulation. Bax knockdown significantly inhibited the combined ODN and oxaliplatin treatment-induced apoptotic cell death. Stabilization of p53 by ODN played a critical role in upregulating Bax expression at the transcriptional level. Casein kinase 2 (CK2)-dependent phosphorylation of OTUB1 at Ser16 played a critical role in ODN- and cathepsin K siRNA-mediated p53 stabilization. Interestingly, ODN-induced p53 and Bax upregulation were modulated by the production of mitochondrial reactive oxygen species (ROS). Mitochondrial ROS scavengers prevented OTUB1-mediated p53 stabilization and Bax upregulation by ODN. These in vitro results were confirmed by in mouse xenograft model, combined treatment with ODN and oxaliplatin significantly reduced tumor size and induced Bax upregulation. Furthermore, human renal clear carcinoma (RCC) tissues revealed a strong correlation between phosphorylation of OTUB1(Ser16) and p53/Bax expression. Our results demonstrate that cathepsin K inhibition enhances oxaliplatin-induced apoptosis by increasing OTUB1 phosphorylation via CK2 activation, thereby promoting p53 stabilization, and hence upregulating Bax.

scholarly journals Novel Synthesized N-Ethyl-Piperazinyl-Amides of C2-Substituted Oleanonic and Ursonic Acids Exhibit Cytotoxic Effects through Apoptotic Cell Death Regulation

2021 ◽  
Vol 22 (20) ◽  
pp. 10967
Author(s):  
Oxana Kazakova ◽  
Alexandra Mioc ◽  
Irina Smirnova ◽  
Irina Baikova ◽  
Adrian Voicu ◽  
...  
Keyword(s):  
Cell Death ◽  
Ex Vivo ◽  
Apoptotic Cell ◽  
Morphological Changes ◽  
Cancer Cell Line ◽  
Apoptotic Cell Death ◽  
Dapi Staining ◽  
Amide Derivatives ◽  
Induced Apoptosis

A series of novel hybrid chalcone N-ethyl-piperazinyl amide derivatives of oleanonic and ursonic acids were synthesized, and their cytotoxic potential was evaluated in vitro against the NCI-60 cancer cell line panel. Compounds 4 and 6 exhibited the highest overall anticancer activity, with GI50 values in some cases reaching nanomolar values. Thus, the two compounds were further assessed in detail in order to identify a possible apoptosis- and antiangiogenic-based mechanism of action induced by the assessed compounds. DAPI staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that up-regulation of pro-apoptotic Bak gene combined with the down-regulation of the pro-survival Bcl-XL and Bcl-2 genes caused altered ratios between the pro-apoptotic and anti-apoptotic proteins’ levels, leading to overall induced apoptosis. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, suggesting that compounds may induce apoptotic cell death through targeted anti-apoptotic protein inhibition, as well. Ex vivo determinations showed that both compounds did not significantly alter the angiogenesis process on the tested cell lines.

scholarly journals Apoptotic cell death of cultured salamander photoreceptors induced by cccp: CsA-insensitive mitochondrial permeability transition

2001 ◽  
Vol 114 (9) ◽  
pp. 1655-1664
Author(s):  
J.H. Yang ◽  
R.L. Gross ◽  
S.F. Basinger ◽  
S.M. Wu
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Cell Model ◽  
Apoptotic Cell ◽  
Permeability Transition ◽  
Apoptotic Cell Death ◽  
Mitochondrial Inner Membrane ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Photoreceptor degeneration is mediated by apoptosis in several animal models, although the underlying mechanisms are yet to be elucidated. We present here an apoptotic model based on a primary cell culture of tiger salamander photoreceptors, in which treatment with carbonyl cyanide m-chlorophenylhydrazone (cccp), a protonophore, induced apoptosis. Cells exposed to cccp showed condensed nuclei and displayed positive TdT-dUTP terminal nick-end labeling (TUNEL). In addition, 10–100 microM cccp rapidly induced a reduction of Delta psi(m) and > or = 30 microM cccp induced a significant leakage of calcein from mitochondria to cytosol and nucleus, indicating a change in mitochondrial inner membrane permeability. Cyclosporin A (CsA), a transition pore blocker, did not prevent the cccp-induced MPT or the cccp-evoked apoptotic cell death, suggesting that cccp-induced apoptotic process was mediated by a CsA-insensitive pathway. This cell model provides an in vitro tool for studying mechanisms of photoreceptor apoptosis in isolated photoreceptors and may provide clues to the etiology of retinal degeneration.

scholarly journals Cytotoxicity, Antiproliferative Effects, and Apoptosis Induction of Methanolic Extract ofCynometra caulifloraLinn. Whole Fruit on Human Promyelocytic Leukemia HL-60 Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
T-Johari S. A. Tajudin ◽  
Nashriyah Mat ◽  
Abu Bakar Siti-Aishah ◽  
A. Aziz M. Yusran ◽  
Afnani Alwi ◽  
...  
Keyword(s):  
Cell Death ◽  
Methanolic Extract ◽  
Apoptotic Cell ◽  
Mouse Fibroblast ◽  
Promyelocytic Leukemia ◽  
Apoptotic Cell Death ◽  
Apoptotic Cells ◽  
3T3 Cells ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

Methanolic extract ofCynometra cauliflorawhole fruit was assayed for cytotoxicity against the human promyelocytic leukemia HL-60 and the normal mouse fibroblast NIH/3T3 cell lines by using the MTT assay. The CD50of the extract for 72 hours was 0.9 μg/mL whereas the value for the cytotoxic drug vincristine was 0.2 μg/mL. The viability of the NIH/3T3 cells was at 80.0% when treated at 15.0 μg/mL. The extract inhibited HL-60 cell proliferation with dose dependence. AO/PI staining of HL-60 cells treated with the extract revealed that majority of cells were in the apoptotic cell death mode. Flow cytometry analysis of HL-60 cells treated at CD50of the extract showed that the early apoptotic cells were 31.0, 26.3 and 19.9% at 24, 48, and 72 hours treatment, respectively. The percentage of late apoptotic cells was increased from 62.0 at 24 hours to 64.1 and 70.2 at 48 and 72 hours, respectively. Meanwhile, percent of necrotic cells were 4.9, 6.6, and 8.5 at 24, 48, and 72 hours, respectively. This study has shown that the methanolic extract ofC. cauliflorawhole fruit was cytotoxic towards HL-60 cells and induced the cells into apoptotic cell death mode, but less cytotoxic towards NIH/3T3 cells.

scholarly journals Hydrocortisone decreases apoptosis in jejunum of horses subjected to experimental ischemia and reperfusion

2011 ◽  
Vol 31 (6) ◽  
pp. 471-476 ◽  
Author(s):  
Geraldo Eleno S. Alves ◽  
Heloisa M.F. Mendes ◽  
Tiago G.S. Alves ◽  
Rafael R. Faleiros ◽  
Anilton C. Vasconcelos ◽  
...  
Keyword(s):  
Cell Death ◽  
Time Course ◽  
Apoptotic Cell ◽  
Treated Group ◽  
Apoptotic Cell Death ◽  
Apoptotic Cells ◽  
Ischemia And Reperfusion ◽  
Beneficial Effects ◽  
Time Zero ◽  
Venous Ischemia

In order to evaluate the effect of hydrocortisone on apoptosis in the jejunum of horses subjected to ischemia and reperfusion, ten horses were paired and grouped into two groups - treated (n=5) and non treated (n=5). Segments of the jejunum were used as controls (C), or as venous ischemia (VIsc), which were subjected to 2h of ischemia followed by 2 or 12h of reperfusion. C samples were collected at time zero (prior to ischemia) and VIsc samples were collected at 2h of ischemia and at 2 and 12h of reperfusion. TUNEL positive apoptotic cells were counted in 10 microscopical fields in deep mucosa from each horse throughout the time course. After 12h of reperfusion, the number of apoptotic cells in treated group were significantly lower than in untreated animals, indicating that hydrocortisone inhibits apoptosis. These results indicate that hydrocortisone has a beneficial effects favoring the maintenance of jejunal integrity in horses with ischemia and reperfusion injuries by preventing apoptotic cell death.

scholarly journals Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase.

1994 ◽  
Vol 180 (4) ◽  
pp. 1547-1552 ◽  
Author(s):  
M G Cifone ◽  
R De Maria ◽  
P Roncaioli ◽  
M R Rippo ◽  
M Azuma ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Apoptotic Cell ◽  
Human Tumor ◽  
Apoptotic Cell Death ◽  
Cell Surface Receptor ◽  
Cross Linking ◽  
Cell Extracts

Intracellular pathways leading from membrane receptor engagement to apoptotic cell death are still poorly characterized. We investigated the intracellular signaling generated after cross-linking of CD95 (Fas/Apo-1 antigen), a broadly expressed cell surface receptor whose engagement results in triggering of cellular apoptotic programs. DX2, a new functional anti-CD95 monoclonal antibody was produced by immunizing mice with human CD95-transfected L cells. Crosslinking of CD95 with DX2 resulted in the activation of a sphingomyelinase (SMase) in promyelocytic U937 cells, as well as in other human tumor cell lines and in CD95-transfected murine cells, as demonstrated by induction of in vivo sphingomyelin (SM) hydrolysis and generation of ceramide. Direct in vitro measurement of enzymatic activity within CD95-stimulated U937 cell extracts, using labeled SM vesicles as substrates, showed strong SMase activity, which required pH 5.0 for optimal substrate hydrolysis. Finally, all CD95-sensitive cell lines tested could be induced to undergo apoptosis after exposure to cell-permeant C2-ceramide. These data indicate that CD95 cross-linking induces SM breakdown and ceramide production through an acidic SMase, thus providing the first information regarding early signal generation from CD95, and may be relevant in defining the biochemical nature of intracellular messengers leading to apoptotic cell death.

scholarly journals Dapagliflozin Alleviates Renal Fibrosis by Inhibiting RIP1-RIP3-MLKL-Mediated Necroinflammation in Unilateral Ureteral Obstruction

2022 ◽  
Vol 12 ◽  
Author(s):  
Mei Ying Xuan ◽  
Shang Guo Piao ◽  
Jun Ding ◽  
Qi Yan Nan ◽  
Mei Hua Piao ◽  
...  
Keyword(s):  
Cell Death ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Apoptotic Cell ◽  
Subsequent Development ◽  
Unilateral Ureteral Obstruction ◽  
Apoptotic Cell Death ◽  
Inflammasome Activation ◽  
Renal Tubular

Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, offers renoprotection in diabetes. However, potential for use in nondiabetic kidney disease remains unknown. Herein, we assessed whether dapagliflozin alleviates renal fibrosis by interfering with necroinflammation in a rat model of unilateral ureteral obstruction (UUO) and in vitro. After induction of UUO, rats were administered dapagliflozin daily for seven consecutive days. UUO induced significant renal tubular necrosis and overexpression of RIP1-RIP3-MLKL axis proteins; these coincided with NLRP3 inflammasome activation, and subsequent development of renal fibrosis. Oxidative stress caused by UUO is tightly associated with endoplasmic reticulum stress and mitochondrial dysfunction, leading to apoptotic cell death through Wnt3α/β-catenin/GSK-3β signaling; all of which were abolished by both dapagliflozin and specific RIP inhibitors (necrostatin-1 and GSK872). In H2O2-treated HK-2 cells, dapagliflozin and RIP inhibitors suppressed overexpression of RIP1-RIP3-MLKL proteins and pyroptosis-related cytokines, decreased intracellular reactive oxygen species production and apoptotic cell death, whereas cell viability was improved. Moreover, activated Wnt3α/β-catenin/GSK-3β signaling was inhibited by dapagliflozin and Wnt/β-catenin inhibitor ICG-001. Our findings suggest that dapagliflozin ameliorates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3α/β-catenin/GSK-3β signaling in UUO.

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