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Research article

Molecular and Cellular Microbiology (MCM)  |  Biochemistry and Physiology

Clostridium difficile Toxin A Induces Reactive Oxygen Species Production and p38 MAPK Activation to Exert Cellular Toxicity in Neuronal Cells

Peng Zhang 1, Ji Hong 1, I Na Yoon 1, Jin Ku Kang 2, Jae Sam Hwang 3 and Ho Kim 1*

1Department of Life Science, College of Natural Science, Daejin University, Pocheon 11159, Republic of Korea, 2Lee Gil Ya Cancer and Diabetes Institute, Gachon University Graduate School of Medicine, Incheon 21936, Republic of Korea, 3Department of Agricultural Biology, National Academy of Agricultural Science, RDA, Wanju 55365, Republic of Korea

Received: February 15, 2017; Accepted: March 17, 2017

J. Microbiol. Biotechnol. 2017; 27(6): 1163-1170

Published June 28, 2017 https://doi.org/10.4014/jmb.1702.02041

Copyright © The Korean Society for Microbiology and Biotechnology.

Abstract

Clostridium difficile releases two exotoxins, toxin A and toxin B, which disrupt the epithelial cell barrier in the gut to increase mucosal permeability and trigger inflammation with severe diarrhea. Many studies have suggested that enteric nerves are also directly involved in the progression of this toxin-mediated inflammation and diarrhea. C. difficile toxin A is known to enhance neurotransmitter secretion, increase gut motility, and suppress sympathetic neurotransmission in the guinea pig colitis model. Although previous studies have examined the pathophysiological role of enteric nerves in gut inflammation, the direct effect of toxins on neuronal cells and the molecular mechanisms underlying toxin-induced neuronal stress remained to be unveiled. Here, we examined the toxicity of C. difficile toxin A against neuronal cells (SH-SY5Y). We found that toxin A treatment time- and dose-dependently decreased cell viability and triggered apoptosis accompanied by caspase-3 activation in this cell line. These effects were found to depend on the up-regulation of reactive oxygen species (ROS) and the subsequent activation of p38 MAPK and induction of p21Cip1/Waf1. Moreover, the N-acetyl-Lcysteine (NAC)-induced down-regulation of ROS could recover the viability loss and apoptosis of toxin A-treated neuronal cells. These results collectively suggest that C. difficile toxin A is toxic for neuronal cells, and that this is associated with rapid ROS generation and subsequent p38 MAPK activation and p21Cip1/Waf1 up-regulation. Moreover, our data suggest that NAC could inhibit the toxicity of C. difficile toxin A toward enteric neurons.

Keywords

Clostridium difficile, toxin A, gut inflammation, neuronal cells (SH-SY5Y), enteric nerve dysfunction, apoptosis

References

  1. Abdrakhmanova GR, AlSharari S, Kang M, Damaj MI, Akbarali HI. 2010. α7-nAChR-mediated suppression of hyperexcitability of colonic dorsal root ganglia neurons in experimental colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 299: G761-G768.
    Pubmed PMC CrossRef
  2. Beyak MJ, Vanner S. 2005. Inflammation-induced hyperexcitability of nociceptive gastrointestinal DRG neurones: the role of voltage-gated ion channels. Neurogastroenterol. Motil. 17: 175186.
    CrossRef
  3. Moore BA, Stewart TM, Hill C, Vanner SJ. 2002. TNBS ileitis evokes hyperexcitability and changes in ionic membrane properties of nociceptive DRG neurons. Am. J. Physiol. Gastrointest. Liver Physiol. 282: G1045-G1051.
    Pubmed CrossRef
  4. Malykhina AP, Qin C, Greenwood-van Meerveld B, Foreman RD, Lupu F, Akbarali HI. 2006. Hyperexcitability of convergent colon and bladder dorsal root ganglion neurons after colonic inflammation: mechanism for pelvic organ cross-talk. Neurogastroenterol. Motil. 18: 936-948.
    Pubmed CrossRef
  5. Li N, Lu R, Yu Y, Lu Y, Huang L, Jin J, et al. 2016. Protective effect of Periplaneta americana extract in ulcerative colitis rats induced by dinitrochlorobenzene and acetic acid. Pharm. Biol. 54: 2560-2567.
    Pubmed CrossRef
  6. Yu SJ, Grider JR, Gulick MA, Xia CM, Shen S, Qiao LY. 2012. Up-regulation of brain-derived neurotrophic factor is regulated by extracellular signal-regulated protein kinase 5 and by nerve growth factor retrograde signaling in colonic afferent neurons in colitis. Exp. Neurol. 238: 209-217.
    Pubmed PMC CrossRef
  7. Poli E, Lazzaretti M, Grandi D, Pozzoli C, Coruzzi G. 2001. Morphological and functional alterations of the myenteric plexus in rats with TNBS-induced colitis. Neurochem. Res. 26:1085-1093.
    Pubmed CrossRef
  8. Liu M, Kay JC, Shen S, Qiao LY. 2015. Endogenous BDNF augments NMDA receptor phosphorylation in the spinal cord v ia PLCgamma, PKC, and PI3K/Akt pathways during colitis. J. Neuroinflammation 12: 151.
    Pubmed PMC CrossRef
  9. Pelletier AM, Venkataramana S, Miller KG, Bennett BM, Nair DG, Lourenssen S, et al. 2010. Neuronal nitric oxide inhibits intestinal smooth muscle growth. Am. J. Physiol. Gastrointest. Liver Physiol. 298: G896-G907.
    Pubmed CrossRef
  10. Shen J, Song Y, Lin Y, Wu X, Yan Y, Niu M, et al. 2015. Nrdp1 is associated with neuronal apoptosis in lipopolysaccharide-induced neuroinflammation. Neurochem. Res. 40: 971-979.
    Pubmed CrossRef
  11. Just I, Selzer J, Wilm M, von Eichel-Streiber C, Mann M, Aktories K. 1995. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375: 500-503.
    Pubmed CrossRef
  12. Just I, Wilm M, Selzer J, Rex G, von Eichel-Streiber C, Mann M, et al. 1995. The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. J. Biol. Chem. 270: 1393213936.
    CrossRef
  13. Just I, Selzer J, von Eichel-Streiber C, Aktories K. 1995. The low molecular mass GTP-binding protein Rho is affected by toxin A from Clostridium difficile. J. Clin. Invest. 95: 1026-1031.
    Pubmed PMC CrossRef
  14. Kang JK, Hwang JS, Nam HJ, Ahn KJ, Seok H, Kim SK, et al. 2011. The insect peptide coprisin prevents Clostridium difficile-mediated acute inflammation and mucosal damage through selective antimicrobial activity. Antimicrob. Agents Chemother. 55: 4850-4857.
    Pubmed PMC CrossRef
  15. Kim H, Rhee SH, Pothoulakis C, Lamont JT. 2007. Inflammation and apoptosis in Clostridium difficile enteritis is mediated by PGE2 up-regulation of Fas ligand. Gastroenterology 133: 875-886.
    Pubmed CrossRef
  16. Kim H, Rhee SH, Kokkotou E, Na X, Savidge T, Moyer MP, et al. 2005. Clostridium difficile toxin A regulates inducible cyclooxygenase-2 and prostaglandin E2 synthesis in colonocytes via reactive oxygen species and activation of p38 MAPK. J. Biol. Chem. 280: 21237-21245.
    Pubmed CrossRef
  17. Kim H, Kokkotou E, Na X, Rhee SH, Moyer MP, Pothoulakis C, et al. 2005. Clostridium difficile toxin Ainduced colonocyte apoptosis involves p53-dependent p21(WAF1/CIP1) induction via p38 mitogen-activated protein kinase. Gastroenterology 129: 1875-1888.
    Pubmed CrossRef
  18. Kim DH, Hwang JS, Lee IH, Nam ST, Hong J, Zhang P, et al. 2016. The insect peptide CopA3 increases colonic epithelial cell proliferation and mucosal barrier function to prevent inflammatory responses in the gut. J. Biol. Chem. 291: 3209-3223.
    Pubmed PMC CrossRef
  19. Na X, Zhao D, Koon HW, Kim H, Husmark J, Moyer MP, et al. 2005. Clostridium difficile toxin B activates the EGF receptor and the ERK/MAP kinase pathway in human colonocytes. Gastroenterology 128: 1002-1011.
    Pubmed CrossRef
  20. Riegler M, Sedivy R, Sogukoglu T, Castagliuolo I, Pothoulakis C, Cosentini E, et al. 1997. Epidermal growth factor attenuates Clostridium difficile toxin A- and B-induced damage of human colonic mucosa. Am. J. Physiol. 273:G1014-G1022.
    Pubmed
  21. Castagliuolo I, LaMont JT, Letourneau R, Kelly C, O’Keane JC, Jaffer A, et al. 1994. Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology 107: 657-665.
    CrossRef
  22. Pothoulakis C, Karmeli F, Kelly CP, Eliakim R, Joshi MA, O’Keane CJ, et al. 1993. Ketotifen inhibits Clostridium difficile toxin A-induced enteritis in rat ileum. Gastroenterology 105:701-707.
    CrossRef
  23. Pothoulakis C, Castagliuolo I, LaMont JT, Jaffer A, O’Keane JC, Snider RM, et al. 1994. CP-96,345, a substance P antagonist, inhibits rat intestinal responses to Clostridium difficile toxin A but not cholera toxin. Proc. Natl. Acad. Sci. USA. 91: 947-951.
    Pubmed PMC CrossRef
  24. Xia Y, Hu HZ, Liu S, Pothoulakis C, Wood JD. 2000. Clostridium difficile toxin A excites enteric neurones and suppresses sympathetic neurotransmission in the guinea pig. Gut 46: 481-486.
    Pubmed PMC CrossRef
  25. Jodal M, Holmgren S, Lundgren O, Sjoqvist A. 1993. Involvement of the myenteric plexus in the cholera toxinind uced net f luid secretion in t he r at s mall i ntestine. Gastroenterology 105: 1286-1293.
    CrossRef
  26. Camilleri M, Nullens S, Nelsen T. 2012. Enteroendocrine and neuronal mechanisms in pathophysiology of acute infectious diarrhea. Dig. Dis. Sci. 57: 19-27.
    Pubmed PMC CrossRef
  27. Abdrakhmanova GR, Kang M, Imad Damaj M, Akbarali HI. 2012. Nicotine suppresses hyperexcitability of colonic sensory neurons and visceral hypersensivity in mouse model of colonic inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 302: G740-G747.
    Pubmed PMC CrossRef
  28. Leffler DA, Lamont JT. 2015. Clostridium difficile infection. N. Engl. J. Med. 372: 1539-1548.
    Pubmed CrossRef
  29. Kim DH, Lee IH, Nam ST, Hong J, Zhang P, Hwang JS, et al. 2014. Neurotropic and neuroprotective activities of the earthworm peptide Lumbricusin. Biochem. Biophys. Res. Commun. 448: 292-297.
    Pubmed CrossRef
  30. Kang BR, Kim H, Nam SH, Yun EY, Kim SR, Ahn MY, et al. 2012. CopA3 peptide from Copris tripartitus induces apoptosis in human leukemia cells via a caspase-independent pathway. BMB Rep. 45: 85-90.
    Pubmed CrossRef
  31. Matte I, Lane D, Cote E, Asselin AE, Fortier LC, Asselin C, et al. 2009. Antiapoptotic proteins Bcl-2 and Bcl-XL inhibit Clostridium difficile toxin A-induced cell death in human epithelial cells. Infect. Immun. 77: 5400-5410.
    Pubmed PMC CrossRef
  32. He D, Sougioultzis S, Hagen S, Liu J, Keates S, Keates AC, et al. 2002. Clostridium difficile toxin A triggers human colonocyte IL-8 release via mitochondrial oxygen radical generation. Gastroenterology 122: 1048-1057.
    Pubmed CrossRef
  33. Warny M, Keates AC, Keates S, Castagliuolo I, Zacks JK, Aboudola S, et al. 2000. p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J. Clin. Invest. 105: 1147-1156.
    Pubmed PMC CrossRef
  34. Braun F, Bertin-Ciftci J, Gallouet AS, Millour J, Juin P. 2011. Serum-nutrient starvation induces cell death mediated by Bax and Puma that is counteracted by p21 and unmasked by Bcl-x(L) inhibition. PLoS One 6: e23577.
    Pubmed PMC CrossRef
  35. Zhong M, Ma W, Zhang X, Wang Y, Gao X. 2016. Tetramethyl pyrazine protects hippocampal neurons against anoxia/reoxygenation injury through inhibiting apoptosis mediated by JNK/MARK signal pathway. Med. Sci. Monit. 22: 5082-5090.
    Pubmed PMC CrossRef
  36. Qi Y, Zhang M, Li H, Frank JA, Dai L, Liu H, et al. 2014. MicroRNA-29b regulates ethanol-induced neuronal apoptosis in the developing cerebellum through SP1/RAX/PKR cascade. J. Biol. Chem. 289: 10201-10210.
    Pubmed PMC CrossRef
  37. Aerbajinai W, Zhu J, Gao Z, Chin K, Rodgers GP. 2007. Thalidomide induces gamma-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis. Blood 110: 2864-2871.
    Pubmed PMC CrossRef

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Article

Research article

J. Microbiol. Biotechnol. 2017; 27(6): 1163-1170

Published online June 28, 2017 https://doi.org/10.4014/jmb.1702.02041

Copyright © The Korean Society for Microbiology and Biotechnology.

Clostridium difficile Toxin A Induces Reactive Oxygen Species Production and p38 MAPK Activation to Exert Cellular Toxicity in Neuronal Cells

Peng Zhang 1, Ji Hong 1, I Na Yoon 1, Jin Ku Kang 2, Jae Sam Hwang 3 and Ho Kim 1*

1Department of Life Science, College of Natural Science, Daejin University, Pocheon 11159, Republic of Korea, 2Lee Gil Ya Cancer and Diabetes Institute, Gachon University Graduate School of Medicine, Incheon 21936, Republic of Korea, 3Department of Agricultural Biology, National Academy of Agricultural Science, RDA, Wanju 55365, Republic of Korea

Received: February 15, 2017; Accepted: March 17, 2017

Abstract

Clostridium difficile releases two exotoxins, toxin A and toxin B, which disrupt the epithelial
cell barrier in the gut to increase mucosal permeability and trigger inflammation with severe
diarrhea. Many studies have suggested that enteric nerves are also directly involved in the
progression of this toxin-mediated inflammation and diarrhea. C. difficile toxin A is known to
enhance neurotransmitter secretion, increase gut motility, and suppress sympathetic
neurotransmission in the guinea pig colitis model. Although previous studies have examined
the pathophysiological role of enteric nerves in gut inflammation, the direct effect of toxins on
neuronal cells and the molecular mechanisms underlying toxin-induced neuronal stress
remained to be unveiled. Here, we examined the toxicity of C. difficile toxin A against neuronal
cells (SH-SY5Y). We found that toxin A treatment time- and dose-dependently decreased cell
viability and triggered apoptosis accompanied by caspase-3 activation in this cell line. These
effects were found to depend on the up-regulation of reactive oxygen species (ROS) and the
subsequent activation of p38 MAPK and induction of p21Cip1/Waf1. Moreover, the N-acetyl-Lcysteine
(NAC)-induced down-regulation of ROS could recover the viability loss and
apoptosis of toxin A-treated neuronal cells. These results collectively suggest that C. difficile
toxin A is toxic for neuronal cells, and that this is associated with rapid ROS generation and
subsequent p38 MAPK activation and p21Cip1/Waf1 up-regulation. Moreover, our data suggest
that NAC could inhibit the toxicity of C. difficile toxin A toward enteric neurons.

Keywords: Clostridium difficile, toxin A, gut inflammation, neuronal cells (SH-SY5Y), enteric nerve dysfunction, apoptosis

References

  1. Abdrakhmanova GR, AlSharari S, Kang M, Damaj MI, Akbarali HI. 2010. α7-nAChR-mediated suppression of hyperexcitability of colonic dorsal root ganglia neurons in experimental colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 299: G761-G768.
    Pubmed KoreaMed CrossRef
  2. Beyak MJ, Vanner S. 2005. Inflammation-induced hyperexcitability of nociceptive gastrointestinal DRG neurones: the role of voltage-gated ion channels. Neurogastroenterol. Motil. 17: 175186.
    CrossRef
  3. Moore BA, Stewart TM, Hill C, Vanner SJ. 2002. TNBS ileitis evokes hyperexcitability and changes in ionic membrane properties of nociceptive DRG neurons. Am. J. Physiol. Gastrointest. Liver Physiol. 282: G1045-G1051.
    Pubmed CrossRef
  4. Malykhina AP, Qin C, Greenwood-van Meerveld B, Foreman RD, Lupu F, Akbarali HI. 2006. Hyperexcitability of convergent colon and bladder dorsal root ganglion neurons after colonic inflammation: mechanism for pelvic organ cross-talk. Neurogastroenterol. Motil. 18: 936-948.
    Pubmed CrossRef
  5. Li N, Lu R, Yu Y, Lu Y, Huang L, Jin J, et al. 2016. Protective effect of Periplaneta americana extract in ulcerative colitis rats induced by dinitrochlorobenzene and acetic acid. Pharm. Biol. 54: 2560-2567.
    Pubmed CrossRef
  6. Yu SJ, Grider JR, Gulick MA, Xia CM, Shen S, Qiao LY. 2012. Up-regulation of brain-derived neurotrophic factor is regulated by extracellular signal-regulated protein kinase 5 and by nerve growth factor retrograde signaling in colonic afferent neurons in colitis. Exp. Neurol. 238: 209-217.
    Pubmed KoreaMed CrossRef
  7. Poli E, Lazzaretti M, Grandi D, Pozzoli C, Coruzzi G. 2001. Morphological and functional alterations of the myenteric plexus in rats with TNBS-induced colitis. Neurochem. Res. 26:1085-1093.
    Pubmed CrossRef
  8. Liu M, Kay JC, Shen S, Qiao LY. 2015. Endogenous BDNF augments NMDA receptor phosphorylation in the spinal cord v ia PLCgamma, PKC, and PI3K/Akt pathways during colitis. J. Neuroinflammation 12: 151.
    Pubmed KoreaMed CrossRef
  9. Pelletier AM, Venkataramana S, Miller KG, Bennett BM, Nair DG, Lourenssen S, et al. 2010. Neuronal nitric oxide inhibits intestinal smooth muscle growth. Am. J. Physiol. Gastrointest. Liver Physiol. 298: G896-G907.
    Pubmed CrossRef
  10. Shen J, Song Y, Lin Y, Wu X, Yan Y, Niu M, et al. 2015. Nrdp1 is associated with neuronal apoptosis in lipopolysaccharide-induced neuroinflammation. Neurochem. Res. 40: 971-979.
    Pubmed CrossRef
  11. Just I, Selzer J, Wilm M, von Eichel-Streiber C, Mann M, Aktories K. 1995. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375: 500-503.
    Pubmed CrossRef
  12. Just I, Wilm M, Selzer J, Rex G, von Eichel-Streiber C, Mann M, et al. 1995. The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. J. Biol. Chem. 270: 1393213936.
    CrossRef
  13. Just I, Selzer J, von Eichel-Streiber C, Aktories K. 1995. The low molecular mass GTP-binding protein Rho is affected by toxin A from Clostridium difficile. J. Clin. Invest. 95: 1026-1031.
    Pubmed KoreaMed CrossRef
  14. Kang JK, Hwang JS, Nam HJ, Ahn KJ, Seok H, Kim SK, et al. 2011. The insect peptide coprisin prevents Clostridium difficile-mediated acute inflammation and mucosal damage through selective antimicrobial activity. Antimicrob. Agents Chemother. 55: 4850-4857.
    Pubmed KoreaMed CrossRef
  15. Kim H, Rhee SH, Pothoulakis C, Lamont JT. 2007. Inflammation and apoptosis in Clostridium difficile enteritis is mediated by PGE2 up-regulation of Fas ligand. Gastroenterology 133: 875-886.
    Pubmed CrossRef
  16. Kim H, Rhee SH, Kokkotou E, Na X, Savidge T, Moyer MP, et al. 2005. Clostridium difficile toxin A regulates inducible cyclooxygenase-2 and prostaglandin E2 synthesis in colonocytes via reactive oxygen species and activation of p38 MAPK. J. Biol. Chem. 280: 21237-21245.
    Pubmed CrossRef
  17. Kim H, Kokkotou E, Na X, Rhee SH, Moyer MP, Pothoulakis C, et al. 2005. Clostridium difficile toxin Ainduced colonocyte apoptosis involves p53-dependent p21(WAF1/CIP1) induction via p38 mitogen-activated protein kinase. Gastroenterology 129: 1875-1888.
    Pubmed CrossRef
  18. Kim DH, Hwang JS, Lee IH, Nam ST, Hong J, Zhang P, et al. 2016. The insect peptide CopA3 increases colonic epithelial cell proliferation and mucosal barrier function to prevent inflammatory responses in the gut. J. Biol. Chem. 291: 3209-3223.
    Pubmed KoreaMed CrossRef
  19. Na X, Zhao D, Koon HW, Kim H, Husmark J, Moyer MP, et al. 2005. Clostridium difficile toxin B activates the EGF receptor and the ERK/MAP kinase pathway in human colonocytes. Gastroenterology 128: 1002-1011.
    Pubmed CrossRef
  20. Riegler M, Sedivy R, Sogukoglu T, Castagliuolo I, Pothoulakis C, Cosentini E, et al. 1997. Epidermal growth factor attenuates Clostridium difficile toxin A- and B-induced damage of human colonic mucosa. Am. J. Physiol. 273:G1014-G1022.
    Pubmed
  21. Castagliuolo I, LaMont JT, Letourneau R, Kelly C, O’Keane JC, Jaffer A, et al. 1994. Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology 107: 657-665.
    CrossRef
  22. Pothoulakis C, Karmeli F, Kelly CP, Eliakim R, Joshi MA, O’Keane CJ, et al. 1993. Ketotifen inhibits Clostridium difficile toxin A-induced enteritis in rat ileum. Gastroenterology 105:701-707.
    CrossRef
  23. Pothoulakis C, Castagliuolo I, LaMont JT, Jaffer A, O’Keane JC, Snider RM, et al. 1994. CP-96,345, a substance P antagonist, inhibits rat intestinal responses to Clostridium difficile toxin A but not cholera toxin. Proc. Natl. Acad. Sci. USA. 91: 947-951.
    Pubmed KoreaMed CrossRef
  24. Xia Y, Hu HZ, Liu S, Pothoulakis C, Wood JD. 2000. Clostridium difficile toxin A excites enteric neurones and suppresses sympathetic neurotransmission in the guinea pig. Gut 46: 481-486.
    Pubmed KoreaMed CrossRef
  25. Jodal M, Holmgren S, Lundgren O, Sjoqvist A. 1993. Involvement of the myenteric plexus in the cholera toxinind uced net f luid secretion in t he r at s mall i ntestine. Gastroenterology 105: 1286-1293.
    CrossRef
  26. Camilleri M, Nullens S, Nelsen T. 2012. Enteroendocrine and neuronal mechanisms in pathophysiology of acute infectious diarrhea. Dig. Dis. Sci. 57: 19-27.
    Pubmed KoreaMed CrossRef
  27. Abdrakhmanova GR, Kang M, Imad Damaj M, Akbarali HI. 2012. Nicotine suppresses hyperexcitability of colonic sensory neurons and visceral hypersensivity in mouse model of colonic inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 302: G740-G747.
    Pubmed KoreaMed CrossRef
  28. Leffler DA, Lamont JT. 2015. Clostridium difficile infection. N. Engl. J. Med. 372: 1539-1548.
    Pubmed CrossRef
  29. Kim DH, Lee IH, Nam ST, Hong J, Zhang P, Hwang JS, et al. 2014. Neurotropic and neuroprotective activities of the earthworm peptide Lumbricusin. Biochem. Biophys. Res. Commun. 448: 292-297.
    Pubmed CrossRef
  30. Kang BR, Kim H, Nam SH, Yun EY, Kim SR, Ahn MY, et al. 2012. CopA3 peptide from Copris tripartitus induces apoptosis in human leukemia cells via a caspase-independent pathway. BMB Rep. 45: 85-90.
    Pubmed CrossRef
  31. Matte I, Lane D, Cote E, Asselin AE, Fortier LC, Asselin C, et al. 2009. Antiapoptotic proteins Bcl-2 and Bcl-XL inhibit Clostridium difficile toxin A-induced cell death in human epithelial cells. Infect. Immun. 77: 5400-5410.
    Pubmed KoreaMed CrossRef
  32. He D, Sougioultzis S, Hagen S, Liu J, Keates S, Keates AC, et al. 2002. Clostridium difficile toxin A triggers human colonocyte IL-8 release via mitochondrial oxygen radical generation. Gastroenterology 122: 1048-1057.
    Pubmed CrossRef
  33. Warny M, Keates AC, Keates S, Castagliuolo I, Zacks JK, Aboudola S, et al. 2000. p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J. Clin. Invest. 105: 1147-1156.
    Pubmed KoreaMed CrossRef
  34. Braun F, Bertin-Ciftci J, Gallouet AS, Millour J, Juin P. 2011. Serum-nutrient starvation induces cell death mediated by Bax and Puma that is counteracted by p21 and unmasked by Bcl-x(L) inhibition. PLoS One 6: e23577.
    Pubmed KoreaMed CrossRef
  35. Zhong M, Ma W, Zhang X, Wang Y, Gao X. 2016. Tetramethyl pyrazine protects hippocampal neurons against anoxia/reoxygenation injury through inhibiting apoptosis mediated by JNK/MARK signal pathway. Med. Sci. Monit. 22: 5082-5090.
    Pubmed KoreaMed CrossRef
  36. Qi Y, Zhang M, Li H, Frank JA, Dai L, Liu H, et al. 2014. MicroRNA-29b regulates ethanol-induced neuronal apoptosis in the developing cerebellum through SP1/RAX/PKR cascade. J. Biol. Chem. 289: 10201-10210.
    Pubmed KoreaMed CrossRef
  37. Aerbajinai W, Zhu J, Gao Z, Chin K, Rodgers GP. 2007. Thalidomide induces gamma-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis. Blood 110: 2864-2871.
    Pubmed KoreaMed CrossRef