Interactions Between p38 Mitogen-Activated Protein Kinase and Caspase-3 in Cerebral Endothelial Cell Death After Hypoxia-Reoxygenation

Background To explore whether cytotoxicity of local anesthetics is related to apoptosis, the authors examined how local anesthetics affect mitogen-activated protein kinase (MAPK) family members, extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs)-stress-activated protein kinases, and p38 kinase, which are known to play important roles in apoptosis. Methods Cell death was evaluated using PC12 cells. Morphologic changes of cells, cellular membrane, and nuclei were observed. DNA fragmentation was electrophoretically assayed. Western blot analysis was performed to analyze phosphorylation of the MAPK family, cleavage of caspase-3 and poly(adenosine diphosphate-ribose) polymerase. Intracellular Ca2+ concentration was measured using a calcium indicator dye. Results Tetracaine-induced cell death was shown in a time- and concentration-dependent manner and characterized by nuclear condensation or fragmentation, membrane blebbing, and internucleosomal DNA fragmentation. Caspase-3 activation and phosphorylation of ERK, JNK, and p38 occurred in the cell death. PD98059, an inhibitor of ERK, enhanced tetracaine-induced cell death and JNK phosphorylation, whereas ERK phosphorylation was inhibited. Curcumin, an inhibitor of JNK pathway, attenuated the cell death. Increase of intracellular Ca2+ concentration was detected. In addition to the increase of ERK phosphorylation and the decrease of JNK phosphorylation, two Ca2+ chelators protected cells from death. Neither cell death nor phosphorylation of the MAPK family was caused by tetrodotoxin. Nifedipine did not affect tetracaine-induced apoptosis. Conclusions Tetracaine induces apoptosis of PC12 cells via the MAPK family. ERK activation protects cells from death, but JNK plays the opposite role. Toxic Ca2+ influx caused by tetracaine seems to be responsible for the cell death, but blocking of Na+ channels or L-type Ca2+ channels is unlikely involved in the tetracaine's action for apoptosis.

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Induction of Caspase-Mediated Cell Death by Matrix Metalloproteinases in Cerebral Endothelial Cells after Hypoxia—Reoxygenation

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000122747.72175.47 ◽

2004 ◽

Vol 24 (7) ◽

pp. 720-727 ◽

Cited By ~ 91

Author(s):

Sun-Ryung Lee ◽

Eng H. Lo

Keyword(s):

Endothelial Cells ◽

Cell Death ◽

Endothelial Cell ◽

Matrix Metalloproteinases ◽

Caspase 3 ◽

Cell Matrix ◽

Matrix Interactions ◽

Endothelial Cell Death ◽

Cell Matrix Interactions ◽

Hypoxia Reoxygenation

Matrix metalloproteinases (MMPs) may contribute to the pathophysiology of cerebral ischemia by degrading matrix components in the neurovascular unit. In this study, the authors document a pathway by which MMPs interfere with cell—matrix interactions and trigger caspase-mediated cytotoxicity in brain endothelial cells. Hypoxia—reoxygenation induced endothelial cytotoxicity. Cytoprotection with zDEVD-fmk confirmed that cell death was partly caspase mediated. The temporal profile of caspase-3 activation was matched by elevations in MMP-2 and MMP-9. MMP inhibitors significantly decreased caspase-3 activation and reduced endothelial cell death. Degradation of matrix fibronectin confirmed the presence of extracellular proteolysis. Increasing integrin-linked kinase signaling with the β1 integrin-activating antibody (8A2) ameliorated endothelial cytotoxicity. The results suggest that MMP-9 and MMP-2 contribute to caspase-mediated brain endothelial cell death after hypoxia—reoxygenation by disrupting cell—matrix interactions and homeostatic integrin signaling.

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Phosphorylation of p38 Mitogen-Activated Protein Kinase Downstream of Bax-Caspase-3 Pathway Leads to Cell Death Induced by High d-Glucose in Human Endothelial Cells

Diabetes ◽

10.2337/diabetes.50.6.1472 ◽

2001 ◽

Vol 50 (6) ◽

pp. 1472-1481 ◽

Cited By ~ 116

Author(s):

Hironori Nakagami ◽

Ryuichi Morishita ◽

Kei Yamamoto ◽

Shin-ichi Yoshimura ◽

Yoshiaki Taniyama ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Death ◽

Protein Kinase ◽

Caspase 3 ◽

Mitogen Activated Protein Kinase ◽

Human Endothelial Cells ◽

Mitogen Activated Protein

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Amyloid β Peptide–Induced Cerebral Endothelial Cell Death Involves Mitochondrial Dysfunction and Caspase Activation

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200106000-00008 ◽

2001 ◽

Vol 21 (6) ◽

pp. 702-710 ◽

Cited By ~ 83

Author(s):

Jan Xu ◽

Shawei Chen ◽

Grace Ku ◽

S. Hinan Ahmed ◽

Jinming Xu ◽

...

Keyword(s):

Cell Death ◽

Endothelial Cell ◽

Mitochondrial Dysfunction ◽

Caspase 3 ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Caspase Activation ◽

Cerebral Endothelial Cell ◽

Mitochondrial Dna Damage ◽

Endothelial Cell Death

Amyloid β peptide (Aβ), a 39 to 43 amino acid fragment of the β-amyloid precursor protein (βAPP), forms insoluble fibrillar accumulation in neurofibrillary tangles and vascular plaques. Aβ has been implicated in neuronal and vascular degeneration in brain regions susceptible to plaque formation because of its cytotoxic effect on neurons and endothelial cells (ECs). The authors used a murine cerebral endothelial cell (CEC) line and primary cultures of bovine CECs to explore the cytotoxic mechanism of Aβ. Aβ 1–40 and Aβ 25–35 peptides caused cell death in a dose-dependent and time-dependent manner. Exposure to either Aβ 25–35 or Aβ 1–40 at 10 μmol/L for 48 hours caused at least 40% cell death. Cerebral endothelial cell death was characterized by nuclear condensation, mitochondrial dysfunction, and nuclear and mitochondrial DNA damage. Aβ 25–35 activated both caspase-8 and caspase-3 in murine CECs. zVAD-fmk, a broad-spectrum caspase inhibitor, prevented Aβ 25–35-induced increase in caspase-3 activity and CEC death. N-acetyl-cysteine, an antioxidant, also prevented Aβ-induced cell death. Together, these findings indicate that Aβ-mediated CEC death is an apoptotic process that is characterized by increased oxidative stress, caspase activation, mitochondrial dysfunction, and nuclear and mitochondrial DNA damage.

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3,3′-Diindolylmethane Induction of p75NTR-Dependent Cell Death via the p38 Mitogen-Activated Protein Kinase Pathway in Prostate Cancer Cells

Cancer Prevention Research ◽

10.1158/1940-6207.capr-08-0202 ◽

2009 ◽

Vol 2 (6) ◽

pp. 566-571 ◽

Cited By ~ 16

Author(s):

Fatima S. Khwaja ◽

Shehla Wynne ◽

Isadora Posey ◽

Daniel Djakiew

Keyword(s):

Prostate Cancer ◽

Cell Death ◽

Protein Kinase ◽

Cancer Cells ◽

Mitogen Activated Protein Kinase ◽

Prostate Cancer Cells ◽

Mitogen Activated Protein ◽

Dependent Cell ◽

Kinase Pathway

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Homocysteine induces cerebral endothelial cell death by activating the acid sphingomyelinase ceramide pathway

Progress in Neuro-Psychopharmacology and Biological Psychiatry ◽

10.1016/j.pnpbp.2013.05.003 ◽

2013 ◽

Vol 45 ◽

pp. 21-27 ◽

Cited By ~ 7

Author(s):

Jiunn-Tay Lee ◽

Giia-Sheun Peng ◽

Shao-Yuan Chen ◽

Chang-Hung Hsu ◽

Chun-Chieh Lin ◽

...

Keyword(s):

Cell Death ◽

Endothelial Cell ◽

Acid Sphingomyelinase ◽

Cerebral Endothelial Cell ◽

Endothelial Cell Death

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Propyl gallate induces cell death and inhibits invasion of human trophoblasts by blocking the AKT and mitogen-activated protein kinase pathways

Food and Chemical Toxicology ◽

10.1016/j.fct.2017.09.049 ◽

2017 ◽

Vol 109 ◽

pp. 497-504 ◽

Cited By ~ 4

Author(s):

Changwon Yang ◽

Whasun Lim ◽

Fuller W. Bazer ◽

Gwonhwa Song

Keyword(s):

Cell Death ◽

Protein Kinase ◽

Propyl Gallate ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein

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Platyphyllenone Induces Autophagy and Apoptosis by Modulating the AKT and JNK Mitogen-Activated Protein Kinase Pathways in Oral Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22084211 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4211

Author(s):

Yen-Tze Liu ◽

Hsin-Yu Ho ◽

Chia-Chieh Lin ◽

Yi-Ching Chuang ◽

Yu-Sheng Lo ◽

...

Keyword(s):

Protein Kinase ◽

Oral Cancer ◽

Protein Expression ◽

Caspase 3 ◽

Therapeutic Option ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Dependent Manner ◽

Cancer Proliferation ◽

Mitogen Activated Protein

Platyphyllenone is a type of diarylheptanoid that exhibits anti-inflammatory and chemoprotective effects. However, its effect on oral cancer remains unclear. In this study, we investigated whether platyphyllenone can promote apoptosis and autophagy in SCC-9 and SCC-47 cells. We found that it dose-dependently promoted the cleavage of PARP; caspase-3, -8, and -9 protein expression; and also led to cell cycle arrest at the G2/M phase. Platyphyllenone up-regulated LC3-II and p62 protein expression in both SCC-9 and SCC-47 cell lines, implying that it can induce autophagy. Furthermore, the results demonstrated that platyphyllenone significantly decreased p-AKT and increased p-JNK1/2 mitogen-activated protein kinase (MAPK) signaling pathway in a dose-dependent manner. The specific inhibitors of p-JNK1/2 also reduced platyphyllenone-induced cleavage of PARP, caspase-3, and caspase -8, LC3-II and p62 protein expression. These findings are the first to demonstrate that platyphyllenone can induce both autophagy and apoptosis in oral cancers, and it is expected to provide a therapeutic option as a chemopreventive agent against oral cancer proliferation.

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