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References

  1. 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
  2. Just I, Wilm M, Selzer J, Rex G, von Eichel-Streiber C, Mann M, Aktories K. 1995. The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. J. Biol. Chem. 270: 13932-13936.
    Pubmed CrossRef
  3. 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
  4. Kim H, Kokkotou E, Na X, Rhee SH, Moyer MP, Pothoulakis C, Lamont JT. 2005. Clostridium difficile toxin A-induced colonocyte apoptosis involves p53-dependent p21(WAF1/CIP1) induction via p38 mitogen-activated protein kinase. Gastroenterology 129: 1875-1888.
    Pubmed CrossRef
  5. Kim H, Rhee SH, Kokkotou E, Na X, Savidge T, Moyer MP, et al. 2005. Clostridium difficile t oxin A r egulates induc ible 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
  6. 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
  7. Kokkotou E, Espinoza DO, Torres D, Karagiannides I, Kosteletos S, Savidge T, et al. 2009. Melanin-concentrating hormone (MCH) modulates C difficile toxin A-mediated enteritis in mice. Gut 58: 34-40.
    Pubmed PMC CrossRef
  8. Kokkotou E, Moss AC, Michos A, Espinoza D, Cloud JW, Mustafa N, et al. 2008. Comparative efficacies of rifaximin and vancomycin for treatment of Clostridium difficileassociated diarrhea and prevention of disease recurrence in hamsters. Antimicrob. Agents Chemother. 52: 1121-1126.
    Pubmed PMC CrossRef
  9. Pothoulakis C, Lamont JT. 2001. Microbes and microbial toxins: paradigms for microbial-mucosal interactions II. The integrated response of the intestine to Clostridium difficile toxins. Am. J. Physiol. Gastrointest. Liver Physiol. 280: G178-G183.
    Pubmed
  10. Pothoulakis C. 2000. Effects of Clostridium difficile toxins on epithelial cell barrier. Ann. NY Acad. Sci. 915: 347-356.
    Pubmed CrossRef
  11. 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
  12. Pothoulakis C, Castagliuolo I, Leeman SE, Wang CC, Li H, Hoffman BJ, Mezey E. 1998. Substance P receptor expression in intestinal epithelium in Clostridium difficile toxin A enteritis in rats. Am. J. Physiol. 275: G68-G75.
    Pubmed
  13. 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
  14. Playford RJ. 1995. Peptides and gastrointestinal mucosal integrity. Gut 37: 595-597.
    Pubmed PMC CrossRef
  15. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. 1993. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75: 805-816.
    CrossRef
  16. Izawa H, Yamamoto H, Damdinsuren B, Ikeda K, Tsujie M, Suzuki R, et al. 2005. Effects of p21cip1/waf1 overexpression on growth, apoptosis and differentiation in human colon carcinoma cells. Int. J. Oncol. 27: 69-76.
    CrossRef
  17. Hing TC, Ho S, Shih DQ, Ichikawa R, Cheng M, Chen J, et al. 2013. The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated
  18. 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
  19. Wang XY, He ZC, Song LY, Spencer S, Yang LX, Peng F, et al. 2011. Chemotherapeutic effects of bioassay-guided extracts of the American cockroach, Periplaneta americana. Integr. Cancer Ther. 10: NP12-NP23.
    Pubmed CrossRef
  20. Jiang Y, Wang X, Jin C, Chen X, Li J, Wu Z, et al. 2006. Inhibitory effect of Periplaneta americana extrac t on 3LL lung cancer in mice. Zhongguo Fei Ai Za Zhi 9: 488-491.
    Pubmed
  21. Zhang HW, Wei LY, Zhao G, Yang YJ, Liu SZ, Zhang ZY, et al. 2016. Periplaneta americana extract used in patients with systemic inflammatory response syndrome. World J. Emerg. Med. 7: 50-54.
    Pubmed PMC CrossRef
  22. Zhang H, Wei L, Zhang Z, Liu S, Zhao G, Zhang J, Hu Y. 2013. Protective effect of Periplaneta americana extract on intestinal mucosal barrier function in patients with sepsis. J. Tradit. Chin. Med. 33: 70-73.
    CrossRef
  23. Tonk M, Vilcinskas A, Rahnamaeian M. 2016. Insect antimicrobial peptides: potential tools for the prevention of skin cancer. Appl. Microbiol. Biotechnol. 100: 7397-7405.
    Pubmed PMC CrossRef
  24. 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: 32093223.
    CrossRef
  25. 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
  26. 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
  27. 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
  28. Kim DH, Lee IH, Nam ST, Hong J, Zhang P, Lu LF, et al. 2015. Antimicrobial peptide, lumbricusin, ameliorates motor dysfunction and dopaminergic neurodegeneration in a mouse model of Parkinson’s disease. J. Microbiol. Biotechnol. 25: 16401647.
    Pubmed CrossRef
  29. Vayalil PK, Iles KE, Choi J, Yi AK, Postlethwait EM, Liu RM. 2007. Glutathione suppresses TGF-beta-induced PAI-1 expression by inhibiting p38 and JNK MAPK and the binding of AP-1, SP-1, and Smad to the PAI-1 promoter. Am. J. Physiol. Lung Cell Mol. Physiol. 293: L1281-L1292.
    Pubmed PMC CrossRef
  30. Ruch RJ, Crist KA, Klaunig JE. 1989. Effects of culture duration on hydrogen peroxide-induced hepatocyte toxicity. Toxicol. Appl. Pharmacol. 100: 451-464.
    CrossRef
  31. Nam ST, Seok H, Kim DH, Nam HJ, Kang JK, Eom JH, et al. 2012. Clostridium difficile toxin A inhibits erythropoietin receptor-mediated colonocyte focal adhesion through inactivation of Janus kinase-2. J. Microbiol. Biotechnol. 22:1629-1635.
    Pubmed CrossRef
  32. Nam HJ, Oh AR, Nam ST, Kang JK, Chang JS, Kim DH, et al. 2012. The insect peptide CopA3 inhibits lipopolysaccharideinduced macrophage activation. J. Pept. Sci. 18: 650-656.
    Pubmed CrossRef

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Article

Research article

J. Microbiol. Biotechnol. 2017; 27(4): 694-700

Published online April 28, 2017 https://doi.org/10.4014/jmb.1612.12012

Copyright © The Korean Society for Microbiology and Biotechnology.

The American Cockroach Peptide Periplanetasin-2 Blocks Clostridium Difficile Toxin A-Induced Cell Damage and Inflammation in the Gut

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

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

Received: December 15, 2016; Accepted: February 2, 2017

Abstract

Clostridium difficile, which causes pseudomembranous colitis, releases toxin A and toxin B.
These toxins are considered to be the main causative agents for the disease pathogenesis, and
their expression is associated with a marked increase of apoptosis in mucosal epithelial cells.
Colonic epithelial cells are believed to form a physical barrier between the lumen and the
submucosa, and abnormally increased mucosal epithelial cell apoptosis is considered to be an
initial step in gut inflammation responses. Therefore, one approach to treating
pseudomembranous colitis would be to develop agents that block the mucosal epithelial cell
apoptosis caused by toxin A, thus restoring barrier function and curing inflammatory
responses in the gut. We recently isolated an antimicrobial peptide, Periplanetasin-2 (Peri-2,
YPCKLNLKLGKVPFH) from the American cockroach, whose extracts have shown great
potential for clinical use. Here, we assessed whether Peri-2 could inhibit the cell toxicity and
inflammation caused by C. difficile toxin A. Indeed, in human colonocyte HT29 cells, Peri-2
inhibited the toxin A-induced decrease in cell proliferation and ameliorated the cell apoptosis
induced by this toxin. Moreover, in the toxin A-induced mouse enteritis model, Peri-2 blocked
the mucosal disruption and inflammatory response caused by toxin A. These results suggest
that the American cockroach peptide Peri-2 could be a possible drug candidate for addressing
the pseudomembranous colitis caused by C. difficile toxin A.

Keywords: American cockroach peptide, Clostridium difficile, toxin A, inflammation, colonic epithelial cells, apoptosis

References

  1. 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
  2. Just I, Wilm M, Selzer J, Rex G, von Eichel-Streiber C, Mann M, Aktories K. 1995. The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. J. Biol. Chem. 270: 13932-13936.
    Pubmed CrossRef
  3. 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
  4. Kim H, Kokkotou E, Na X, Rhee SH, Moyer MP, Pothoulakis C, Lamont JT. 2005. Clostridium difficile toxin A-induced colonocyte apoptosis involves p53-dependent p21(WAF1/CIP1) induction via p38 mitogen-activated protein kinase. Gastroenterology 129: 1875-1888.
    Pubmed CrossRef
  5. Kim H, Rhee SH, Kokkotou E, Na X, Savidge T, Moyer MP, et al. 2005. Clostridium difficile t oxin A r egulates induc ible 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
  6. 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
  7. Kokkotou E, Espinoza DO, Torres D, Karagiannides I, Kosteletos S, Savidge T, et al. 2009. Melanin-concentrating hormone (MCH) modulates C difficile toxin A-mediated enteritis in mice. Gut 58: 34-40.
    Pubmed KoreaMed CrossRef
  8. Kokkotou E, Moss AC, Michos A, Espinoza D, Cloud JW, Mustafa N, et al. 2008. Comparative efficacies of rifaximin and vancomycin for treatment of Clostridium difficileassociated diarrhea and prevention of disease recurrence in hamsters. Antimicrob. Agents Chemother. 52: 1121-1126.
    Pubmed KoreaMed CrossRef
  9. Pothoulakis C, Lamont JT. 2001. Microbes and microbial toxins: paradigms for microbial-mucosal interactions II. The integrated response of the intestine to Clostridium difficile toxins. Am. J. Physiol. Gastrointest. Liver Physiol. 280: G178-G183.
    Pubmed
  10. Pothoulakis C. 2000. Effects of Clostridium difficile toxins on epithelial cell barrier. Ann. NY Acad. Sci. 915: 347-356.
    Pubmed CrossRef
  11. 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
  12. Pothoulakis C, Castagliuolo I, Leeman SE, Wang CC, Li H, Hoffman BJ, Mezey E. 1998. Substance P receptor expression in intestinal epithelium in Clostridium difficile toxin A enteritis in rats. Am. J. Physiol. 275: G68-G75.
    Pubmed
  13. 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
  14. Playford RJ. 1995. Peptides and gastrointestinal mucosal integrity. Gut 37: 595-597.
    Pubmed KoreaMed CrossRef
  15. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. 1993. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75: 805-816.
    CrossRef
  16. Izawa H, Yamamoto H, Damdinsuren B, Ikeda K, Tsujie M, Suzuki R, et al. 2005. Effects of p21cip1/waf1 overexpression on growth, apoptosis and differentiation in human colon carcinoma cells. Int. J. Oncol. 27: 69-76.
    CrossRef
  17. Hing TC, Ho S, Shih DQ, Ichikawa R, Cheng M, Chen J, et al. 2013. The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated
  18. 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
  19. Wang XY, He ZC, Song LY, Spencer S, Yang LX, Peng F, et al. 2011. Chemotherapeutic effects of bioassay-guided extracts of the American cockroach, Periplaneta americana. Integr. Cancer Ther. 10: NP12-NP23.
    Pubmed CrossRef
  20. Jiang Y, Wang X, Jin C, Chen X, Li J, Wu Z, et al. 2006. Inhibitory effect of Periplaneta americana extrac t on 3LL lung cancer in mice. Zhongguo Fei Ai Za Zhi 9: 488-491.
    Pubmed
  21. Zhang HW, Wei LY, Zhao G, Yang YJ, Liu SZ, Zhang ZY, et al. 2016. Periplaneta americana extract used in patients with systemic inflammatory response syndrome. World J. Emerg. Med. 7: 50-54.
    Pubmed KoreaMed CrossRef
  22. Zhang H, Wei L, Zhang Z, Liu S, Zhao G, Zhang J, Hu Y. 2013. Protective effect of Periplaneta americana extract on intestinal mucosal barrier function in patients with sepsis. J. Tradit. Chin. Med. 33: 70-73.
    CrossRef
  23. Tonk M, Vilcinskas A, Rahnamaeian M. 2016. Insect antimicrobial peptides: potential tools for the prevention of skin cancer. Appl. Microbiol. Biotechnol. 100: 7397-7405.
    Pubmed KoreaMed CrossRef
  24. 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: 32093223.
    CrossRef
  25. 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
  26. 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
  27. 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
  28. Kim DH, Lee IH, Nam ST, Hong J, Zhang P, Lu LF, et al. 2015. Antimicrobial peptide, lumbricusin, ameliorates motor dysfunction and dopaminergic neurodegeneration in a mouse model of Parkinson’s disease. J. Microbiol. Biotechnol. 25: 16401647.
    Pubmed CrossRef
  29. Vayalil PK, Iles KE, Choi J, Yi AK, Postlethwait EM, Liu RM. 2007. Glutathione suppresses TGF-beta-induced PAI-1 expression by inhibiting p38 and JNK MAPK and the binding of AP-1, SP-1, and Smad to the PAI-1 promoter. Am. J. Physiol. Lung Cell Mol. Physiol. 293: L1281-L1292.
    Pubmed KoreaMed CrossRef
  30. Ruch RJ, Crist KA, Klaunig JE. 1989. Effects of culture duration on hydrogen peroxide-induced hepatocyte toxicity. Toxicol. Appl. Pharmacol. 100: 451-464.
    CrossRef
  31. Nam ST, Seok H, Kim DH, Nam HJ, Kang JK, Eom JH, et al. 2012. Clostridium difficile toxin A inhibits erythropoietin receptor-mediated colonocyte focal adhesion through inactivation of Janus kinase-2. J. Microbiol. Biotechnol. 22:1629-1635.
    Pubmed CrossRef
  32. Nam HJ, Oh AR, Nam ST, Kang JK, Chang JS, Kim DH, et al. 2012. The insect peptide CopA3 inhibits lipopolysaccharideinduced macrophage activation. J. Pept. Sci. 18: 650-656.
    Pubmed CrossRef