전체메뉴
검색
Article Search

JMB Journal of Microbiolog and Biotechnology

QR Code QR Code

Research article

References

  1. Borges A, Saavedra MJ, Simoes M. 2015. Insights on antimicrobial resistance, biofilms and the use of phytochemicals as new antimicrobial agents. Curr. Med. Chem. 22: 2590-2614.
    Pubmed CrossRef
  2. Shah PM. 2005. The need for new therapeutic agents: what is the pipeline? Clin. Microbiol. Infect. 11 Suppl 3: 36-42.
    Pubmed CrossRef
  3. Subramani R, Narayanasamy M, Feussner KD. 2017. Plantderived antimicrobials to fight against multi-drug-resistant human pathogens. 3 Biotech 7: 172.
  4. Molyneux RJ, Lee ST, Gardner DR, Panter KE, James LF. 2007. Phytochemicals: the good, the bad and the ugly? Phytochemistry 68: 2973-2985.
    Pubmed CrossRef
  5. Simoes M, Bennett RN, Rosa EA. 2009. Understanding antimicrobial activities of phytochemicals against multidrug resistant bacteria and biofilms. Nat. Prod. Rep. 26: 746-757.
    Pubmed CrossRef
  6. Nagarajan S, Namasivayam N. 2014. Silibinin alleviates hyperlipidaemia, restores mucin content, modulates TGF-β and fosters apoptosis in experimental rat colon carcinogenesis. J. Funct. Foods 11: 472-481.
    CrossRef
  7. Hu S, Zhang X, Chen F, Wang M. 2017. Dietary polyphenols as photoprotective agents against UV radiation. J. Funct. Foods 30: 108-118.
    CrossRef
  8. Cheung CW, Gibbons N, Johnson DW, Nicol DL. 2010. Silibinin - a promising new treatment for cancer. Anticancer Agents Med. Chem. 10: 186-195.
    Pubmed CrossRef
  9. Abed I, Al-Moula R, Abdulhasan G. 2015. Antibacterial effect of flavonoids extracted from seeds of Silybum marianum against common pathogenic bacteria. World J. Exp. Biosci. 3: 36-39.
  10. de Oliveira DR, Tintino SR, Braga MF, Boligon AA, Athayde ML, Coutinho HD, et al. 2015. In vitro antimicrobial and modulatory activity of the natural products silymarin and silibinin. Biomed. Res. Int. 2015: 292797.
    Pubmed
  11. Jung HJ, Lee DG. 2008. Synergistic antibacterial effect between silybin and N,N’-dicyclohexylcarbodiimide in clinical Pseudomonas aeruginosa isolates. J. Microbiol. 46: 462-467.
    Pubmed CrossRef
  12. Lee YS, Jang KA, Cha JD. 2012. Synergistic antibacterial effect between silibinin and antibiotics in oral bacteria. J. Biomed. Biotechnol. 2012: 618081.
    Pubmed PMC CrossRef
  13. Yun DG, Lee DG. 2016. Silibinin triggers yeast apoptosis related to mitochondrial Ca2+ influx in Candida albicans. Int. J. Biochem. Cell Biol. 80: 1-9.
    Pubmed CrossRef
  14. Hakansson AP, Roche-Hakansson H, Mossberg AK, Svanborg C. 2011. Apoptosis-like death in bacteria induced by HAMLET, a human milk lipid-protein complex. PLoS One 6: e17717.
    Pubmed PMC CrossRef
  15. Elmore S. 2007. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35: 495-516.
    Pubmed PMC CrossRef
  16. Dwyer DJ, Camacho DM, Kohanski MA, Callura JM, Collins JJ. 2012. Antibiotic-induced bacterial cell death exhibits physiological and biochemical hallmarks of apoptosis. Mol. Cell 46: 561-572.
    Pubmed PMC CrossRef
  17. Janion C. 2008. Inducible SOS response system of DNA repair and mutagenesis in Escherichia coli. Int. J. Biol. Sci. 4: 338-344.
    Pubmed PMC CrossRef
  18. Little JW. 1991. Mechanism of specific LexA cleavage:autodigestion and the role of RecA coprotease. Biochimie 73: 411-421.
    CrossRef
  19. Raghuraman H, Chattopadhyay A. 2007. Melittin: a membrane-active peptide with diverse functions. Biosci. Rep. 27: 189-223.
    Pubmed CrossRef
  20. Lee W, Kim KJ, Lee DG. 2014. A novel mechanism for the antibacterial effect of silver nanoparticles on Escherichia coli. Biometals 27: 1191-1201.
    Pubmed CrossRef
  21. Dominguez DC. 2004. Calcium signalling in bacteria. Mol. Microbiol. 54: 291-297.
    Pubmed CrossRef
  22. Martinez MM, Reif RD, Pappas D. 2010. Detection of apoptosis: a review of conventional and novel techniques. Anal. Methods 2: 996-1004.
    CrossRef
  23. Bradford MM. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72: 248-254.
    CrossRef
  24. Yun DG, Lee DG. 2016. Antibacterial activity of curcumin via apoptosis-like response in Escherichia coli. Appl. Microbiol. Biotechnol. 100: 5505-5514.
    Pubmed CrossRef
  25. Palomino OM, Gouveia NM, Ramos S, Martin MA, Goya L. 2017. Protective effect of Silybum marianum and silibinin on endothelial cells submitted to high glucose concentration. Planta Med. 83: 97-103.
    Pubmed
  26. Li L, S un J , Xia S, T ian X, Cheserek MJ, Le G . 2016. Mechanism of antifungal activity of antimicrobial peptide APP, a cell-penetrating peptide derivative, against Candida albicans: intracellular DNA binding and cell cycle arrest. Appl. Microbiol. Biotechnol. 100: 3245-3253.
    Pubmed CrossRef
  27. Cerella C, Diederich M, Ghibelli L. 2010. The dual role of calcium as messenger and stressor in cell damage, death, and survival. Int. J. Cell Biol. 2010: 546163.
    Pubmed PMC CrossRef
  28. Domínguez DC, Guragain M, Patrauchan M. 2015. Calcium binding proteins and calcium signaling in prokaryotes. Cell Calcium 57: 151-165.
    Pubmed CrossRef
  29. Dwyer DJ, Winkler JA. 2013. Identification and characterization of programmed cell death markers in bacterial models. Methods Mol. Biol. 1004: 145-159.
    Pubmed CrossRef
  30. Erental A, Kalderon Z, Saada A, Smith Y, Engelberg-Kulka H. 2014. Apoptosis-like death, an extreme SOS response in Escherichia coli. mBio 5: e01426-e01414.
    Pubmed PMC CrossRef
  31. Sung WS, Lee DG. 2007. The candidacidal activity of indole3-carbinol that binds with DNA. IUBMB Life 59: 408-412.
    Pubmed CrossRef
  32. Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ. 2007. A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130: 797-810.
    Pubmed CrossRef
  33. Muthuswamy S, Rupasinghe HV. 2007. Fruit phenolics as natural antimicrobial agents: selective antimicrobial activity of catechin, chlorogenic acid and phloridzin. J. Food Agric. Environ. 5: 81.
  34. Lee DG, Kim HK, Park Y, Park SC, Woo ER, Jeong HG, et al. 2003. Gram-positive bacteria specific properties of silybin derived from Silybum marianum. Arch. Pharm. Res. 26: 597-600.
    Pubmed CrossRef
  35. Cushnie TPT, Lamb AJ. 2005. Antimicrobial activity of flavonoids. Int. J. Antimicrob. Agents 26: 343-356.
    Pubmed CrossRef
  36. Specht KG, Rodgers MA. 1991. Plasma membrane depolarization and calcium influx during cell injury by photodynamic action. Biochim. Biophys. Acta 1070: 60-68.
    CrossRef
  37. Guo J, Lao Y, Chang D. 2009. Calcium and apoptosis, pp. 597-622. Handbook of Neurochemistry and Molecular Neurobiology. Springer, New York.
  38. Segawa K, Nagata S. 2015. An apoptotic ‘eat me’ signal:phosphatidylserine exposure. Trends Cell Biol. 25: 639-650.
    Pubmed CrossRef
  39. Crowley LC, Marfell BJ, Scott AP, Waterhouse NJ. 2016. Quantitation of apoptosis and necrosis by annexin V binding, propidium iodide uptake, and flow cytometry. Cold Spring Harb Protoc. 2016: pdb.prot087288.
  40. Grasl-Kraupp B, Ruttkay-Nedecky B, Koudelka H, Bukowska K, Bursch W, Schulte-Hermann R. 1995. In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology 21: 1465-1468.
    Pubmed
  41. McIlwain DR, Berger T, Mak TW. 2013. Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol. 5: a008656.
    Pubmed PMC CrossRef
  42. Madeo F, Herker E, Wissing S, Jungwirth H, Eisenberg T, Frohlich KU. 2004. Apoptosis in yeast. Curr. Opin. Microbiol. 7: 655-660.
    Pubmed CrossRef
  43. Cox MM. 2007. Regulation of bacterial RecA protein function. Crit. Rev. Biochem. Mol. Biol. 42: 41-63.
    Pubmed CrossRef
  44. Silva MT. 2010. Secondary necrosis: the natural outcome of the complete apoptotic program. FEBS Lett. 584: 4491-4499.
    Pubmed CrossRef
  45. Jayaraman P, Sakharkar MK, Lim CS, Tang TH, Sakharkar KR. 2010. Activity and interactions of antibiotic and phytochemical combinations against Pseudomonas aeruginosa in vitro. Int. J. Biol. Sci. 6: 556-568.
    Pubmed PMC CrossRef
  46. Surai P. 2015. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives. Antioxidants 4:204-247.
    Pubmed PMC CrossRef
  47. Mittler R, Vanderauwera S, Suzuki N, Miller G, Tognetti VB, Vandepoele K, et al. 2011. ROS signaling: the new wave? Trends Plant Sci. 16: 300-309.
    Pubmed CrossRef
  48. Ray PD, Huang B-W, Tsuji Y. 2012. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal. 24: 981-990.
    Pubmed PMC CrossRef
  49. Zhang J, Wang X, Vikash V, Ye Q, Wu D, Liu Y, et al. 2016. ROS and ROS-mediated cellular signaling. Oxid. Med. Cell Longev. 2016: 4350965.
    Pubmed PMC CrossRef
  50. Lin MH, Cheng CH, Chen KC, Lee WT, Wang YF, Xiao CQ, et al. 2014. Induction of ROS-independent JNK-activationmediated apoptosis by a novel coumarin-derivative, DMAC, in human colon cancer cells. Chem. Biol. Interact. 218: 42-49.
    Pubmed CrossRef
  51. Ko CH, Shen SC, Hsu CS, Chen YC. 2005. Mitochondrialdependent, reactive oxygen species-independent apoptosis by myricetin: roles of protein kinase C, cytochrome c, and caspase cascade. Biochem. Pharmacol. 69: 913-927.
    Pubmed CrossRef
  52. Park SE, Song JD, Kim KM, Park YM, Kim ND, Yoo YH, et al. 2007. Diphenyleneiodonium induces ROS-independent p53 expression and apoptosis in human RPE cells. FEBS Lett. 581: 180-186.
    Pubmed CrossRef

Article

Research article

J. Microbiol. Biotechnol. 2017; 27(12): 2129-2140

Published online December 28, 2017 https://doi.org/10.4014/jmb.1710.10029

Copyright © The Korean Society for Microbiology and Biotechnology.

Reactive Oxygen Species Depletion by Silibinin Stimulates Apoptosis-Like Death in Escherichia coli

Bin Lee 1 and Dong Gun Lee 1*

School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Program), College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea

Received: October 23, 2017; Accepted: November 6, 2017

Abstract

Silibinin is the major active component of silymarin, extracted from the medicinal plant
Silybum marianum. Silibinin has potent antibacterial activity; however, the exact mechanism
underlying its activity has not been elucidated. Here, we investigated the novel mechanism of
silibinin against Escherichia coli. Time-kill kinetic assay showed that silibinin possess a
bactericidal effect at minimal inhibitory concentration (MIC) and higher concentrations (2-
and 4-fold MIC). At the membrane, depolarization and increased intracellular Ca2+ levels were
observed, considered as characteristics of bacterial apoptosis. Additionally, cells treated with
MIC and higher concentrations showed apoptotic features like DNA fragmentation,
phosphatidylserine exposure, and caspase-like protein expression. Generally, apoptotic death
is closely related with ROS generation; however, silibinin did not induce ROS generation but
acted as a scavenger of intracellular ROS. These results indicate that silibinin dosedependently
induces bacterial apoptosis-like death, which was affected by ROS depletion,
suggesting that silibinin is a potential candidate for controlling bacteria.

Keywords: Bacterial apoptosis-like death, Escherichia coli, silibinin, reactive oxygen species depletion

References

  1. Borges A, Saavedra MJ, Simoes M. 2015. Insights on antimicrobial resistance, biofilms and the use of phytochemicals as new antimicrobial agents. Curr. Med. Chem. 22: 2590-2614.
    Pubmed CrossRef
  2. Shah PM. 2005. The need for new therapeutic agents: what is the pipeline? Clin. Microbiol. Infect. 11 Suppl 3: 36-42.
    Pubmed CrossRef
  3. Subramani R, Narayanasamy M, Feussner KD. 2017. Plantderived antimicrobials to fight against multi-drug-resistant human pathogens. 3 Biotech 7: 172.
  4. Molyneux RJ, Lee ST, Gardner DR, Panter KE, James LF. 2007. Phytochemicals: the good, the bad and the ugly? Phytochemistry 68: 2973-2985.
    Pubmed CrossRef
  5. Simoes M, Bennett RN, Rosa EA. 2009. Understanding antimicrobial activities of phytochemicals against multidrug resistant bacteria and biofilms. Nat. Prod. Rep. 26: 746-757.
    Pubmed CrossRef
  6. Nagarajan S, Namasivayam N. 2014. Silibinin alleviates hyperlipidaemia, restores mucin content, modulates TGF-β and fosters apoptosis in experimental rat colon carcinogenesis. J. Funct. Foods 11: 472-481.
    CrossRef
  7. Hu S, Zhang X, Chen F, Wang M. 2017. Dietary polyphenols as photoprotective agents against UV radiation. J. Funct. Foods 30: 108-118.
    CrossRef
  8. Cheung CW, Gibbons N, Johnson DW, Nicol DL. 2010. Silibinin - a promising new treatment for cancer. Anticancer Agents Med. Chem. 10: 186-195.
    Pubmed CrossRef
  9. Abed I, Al-Moula R, Abdulhasan G. 2015. Antibacterial effect of flavonoids extracted from seeds of Silybum marianum against common pathogenic bacteria. World J. Exp. Biosci. 3: 36-39.
  10. de Oliveira DR, Tintino SR, Braga MF, Boligon AA, Athayde ML, Coutinho HD, et al. 2015. In vitro antimicrobial and modulatory activity of the natural products silymarin and silibinin. Biomed. Res. Int. 2015: 292797.
    Pubmed
  11. Jung HJ, Lee DG. 2008. Synergistic antibacterial effect between silybin and N,N’-dicyclohexylcarbodiimide in clinical Pseudomonas aeruginosa isolates. J. Microbiol. 46: 462-467.
    Pubmed CrossRef
  12. Lee YS, Jang KA, Cha JD. 2012. Synergistic antibacterial effect between silibinin and antibiotics in oral bacteria. J. Biomed. Biotechnol. 2012: 618081.
    Pubmed KoreaMed CrossRef
  13. Yun DG, Lee DG. 2016. Silibinin triggers yeast apoptosis related to mitochondrial Ca2+ influx in Candida albicans. Int. J. Biochem. Cell Biol. 80: 1-9.
    Pubmed CrossRef
  14. Hakansson AP, Roche-Hakansson H, Mossberg AK, Svanborg C. 2011. Apoptosis-like death in bacteria induced by HAMLET, a human milk lipid-protein complex. PLoS One 6: e17717.
    Pubmed KoreaMed CrossRef
  15. Elmore S. 2007. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35: 495-516.
    Pubmed KoreaMed CrossRef
  16. Dwyer DJ, Camacho DM, Kohanski MA, Callura JM, Collins JJ. 2012. Antibiotic-induced bacterial cell death exhibits physiological and biochemical hallmarks of apoptosis. Mol. Cell 46: 561-572.
    Pubmed KoreaMed CrossRef
  17. Janion C. 2008. Inducible SOS response system of DNA repair and mutagenesis in Escherichia coli. Int. J. Biol. Sci. 4: 338-344.
    Pubmed KoreaMed CrossRef
  18. Little JW. 1991. Mechanism of specific LexA cleavage:autodigestion and the role of RecA coprotease. Biochimie 73: 411-421.
    CrossRef
  19. Raghuraman H, Chattopadhyay A. 2007. Melittin: a membrane-active peptide with diverse functions. Biosci. Rep. 27: 189-223.
    Pubmed CrossRef
  20. Lee W, Kim KJ, Lee DG. 2014. A novel mechanism for the antibacterial effect of silver nanoparticles on Escherichia coli. Biometals 27: 1191-1201.
    Pubmed CrossRef
  21. Dominguez DC. 2004. Calcium signalling in bacteria. Mol. Microbiol. 54: 291-297.
    Pubmed CrossRef
  22. Martinez MM, Reif RD, Pappas D. 2010. Detection of apoptosis: a review of conventional and novel techniques. Anal. Methods 2: 996-1004.
    CrossRef
  23. Bradford MM. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72: 248-254.
    CrossRef
  24. Yun DG, Lee DG. 2016. Antibacterial activity of curcumin via apoptosis-like response in Escherichia coli. Appl. Microbiol. Biotechnol. 100: 5505-5514.
    Pubmed CrossRef
  25. Palomino OM, Gouveia NM, Ramos S, Martin MA, Goya L. 2017. Protective effect of Silybum marianum and silibinin on endothelial cells submitted to high glucose concentration. Planta Med. 83: 97-103.
    Pubmed
  26. Li L, S un J , Xia S, T ian X, Cheserek MJ, Le G . 2016. Mechanism of antifungal activity of antimicrobial peptide APP, a cell-penetrating peptide derivative, against Candida albicans: intracellular DNA binding and cell cycle arrest. Appl. Microbiol. Biotechnol. 100: 3245-3253.
    Pubmed CrossRef
  27. Cerella C, Diederich M, Ghibelli L. 2010. The dual role of calcium as messenger and stressor in cell damage, death, and survival. Int. J. Cell Biol. 2010: 546163.
    Pubmed KoreaMed CrossRef
  28. Domínguez DC, Guragain M, Patrauchan M. 2015. Calcium binding proteins and calcium signaling in prokaryotes. Cell Calcium 57: 151-165.
    Pubmed CrossRef
  29. Dwyer DJ, Winkler JA. 2013. Identification and characterization of programmed cell death markers in bacterial models. Methods Mol. Biol. 1004: 145-159.
    Pubmed CrossRef
  30. Erental A, Kalderon Z, Saada A, Smith Y, Engelberg-Kulka H. 2014. Apoptosis-like death, an extreme SOS response in Escherichia coli. mBio 5: e01426-e01414.
    Pubmed KoreaMed CrossRef
  31. Sung WS, Lee DG. 2007. The candidacidal activity of indole3-carbinol that binds with DNA. IUBMB Life 59: 408-412.
    Pubmed CrossRef
  32. Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ. 2007. A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130: 797-810.
    Pubmed CrossRef
  33. Muthuswamy S, Rupasinghe HV. 2007. Fruit phenolics as natural antimicrobial agents: selective antimicrobial activity of catechin, chlorogenic acid and phloridzin. J. Food Agric. Environ. 5: 81.
  34. Lee DG, Kim HK, Park Y, Park SC, Woo ER, Jeong HG, et al. 2003. Gram-positive bacteria specific properties of silybin derived from Silybum marianum. Arch. Pharm. Res. 26: 597-600.
    Pubmed CrossRef
  35. Cushnie TPT, Lamb AJ. 2005. Antimicrobial activity of flavonoids. Int. J. Antimicrob. Agents 26: 343-356.
    Pubmed CrossRef
  36. Specht KG, Rodgers MA. 1991. Plasma membrane depolarization and calcium influx during cell injury by photodynamic action. Biochim. Biophys. Acta 1070: 60-68.
    CrossRef
  37. Guo J, Lao Y, Chang D. 2009. Calcium and apoptosis, pp. 597-622. Handbook of Neurochemistry and Molecular Neurobiology. Springer, New York.
  38. Segawa K, Nagata S. 2015. An apoptotic ‘eat me’ signal:phosphatidylserine exposure. Trends Cell Biol. 25: 639-650.
    Pubmed CrossRef
  39. Crowley LC, Marfell BJ, Scott AP, Waterhouse NJ. 2016. Quantitation of apoptosis and necrosis by annexin V binding, propidium iodide uptake, and flow cytometry. Cold Spring Harb Protoc. 2016: pdb.prot087288.
  40. Grasl-Kraupp B, Ruttkay-Nedecky B, Koudelka H, Bukowska K, Bursch W, Schulte-Hermann R. 1995. In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology 21: 1465-1468.
    Pubmed
  41. McIlwain DR, Berger T, Mak TW. 2013. Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol. 5: a008656.
    Pubmed KoreaMed CrossRef
  42. Madeo F, Herker E, Wissing S, Jungwirth H, Eisenberg T, Frohlich KU. 2004. Apoptosis in yeast. Curr. Opin. Microbiol. 7: 655-660.
    Pubmed CrossRef
  43. Cox MM. 2007. Regulation of bacterial RecA protein function. Crit. Rev. Biochem. Mol. Biol. 42: 41-63.
    Pubmed CrossRef
  44. Silva MT. 2010. Secondary necrosis: the natural outcome of the complete apoptotic program. FEBS Lett. 584: 4491-4499.
    Pubmed CrossRef
  45. Jayaraman P, Sakharkar MK, Lim CS, Tang TH, Sakharkar KR. 2010. Activity and interactions of antibiotic and phytochemical combinations against Pseudomonas aeruginosa in vitro. Int. J. Biol. Sci. 6: 556-568.
    Pubmed KoreaMed CrossRef
  46. Surai P. 2015. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives. Antioxidants 4:204-247.
    Pubmed KoreaMed CrossRef
  47. Mittler R, Vanderauwera S, Suzuki N, Miller G, Tognetti VB, Vandepoele K, et al. 2011. ROS signaling: the new wave? Trends Plant Sci. 16: 300-309.
    Pubmed CrossRef
  48. Ray PD, Huang B-W, Tsuji Y. 2012. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal. 24: 981-990.
    Pubmed KoreaMed CrossRef
  49. Zhang J, Wang X, Vikash V, Ye Q, Wu D, Liu Y, et al. 2016. ROS and ROS-mediated cellular signaling. Oxid. Med. Cell Longev. 2016: 4350965.
    Pubmed KoreaMed CrossRef
  50. Lin MH, Cheng CH, Chen KC, Lee WT, Wang YF, Xiao CQ, et al. 2014. Induction of ROS-independent JNK-activationmediated apoptosis by a novel coumarin-derivative, DMAC, in human colon cancer cells. Chem. Biol. Interact. 218: 42-49.
    Pubmed CrossRef
  51. Ko CH, Shen SC, Hsu CS, Chen YC. 2005. Mitochondrialdependent, reactive oxygen species-independent apoptosis by myricetin: roles of protein kinase C, cytochrome c, and caspase cascade. Biochem. Pharmacol. 69: 913-927.
    Pubmed CrossRef
  52. Park SE, Song JD, Kim KM, Park YM, Kim ND, Yoo YH, et al. 2007. Diphenyleneiodonium induces ROS-independent p53 expression and apoptosis in human RPE cells. FEBS Lett. 581: 180-186.
    Pubmed CrossRef