Dextromethorphan attenuates NADPH oxidase-regulated glycogen synthase kinase 3 and NF-B activation and reduces nitric oxide production in group a streptococcal infection

Chia Ling Chen, Miao Huei Cheng, Chih Feng Kuo, Yi Lin Cheng, Ming Han Li, Chih Peng Chang, Jiunn Jong Wu, Robert Anderson, Shuying Wang, Pei-Jane Tsai, Ching Chuan Liu, Yee Shin Linc

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Group A Streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), an antitussive drug, has been demonstrated to efficiently reduce inflammatory responses, thereby contributing to an increased survival rate of GAS-infected mice. However, the anti-inflammatory mechanisms underlying DM treatment in GAS infection remain unclear. DM is known to exert neuroprotective effects through an NADPH oxidase-dependent regulated process. In the present study, membrane translocation of NADPH oxidase subunit p47phox and subsequent reactive oxygen species (ROS) generation induced by GAS infection were significantly inhibited via DM treatment in RAW264.7 murine macrophage cells. Further determination of proinflammatory mediators revealed that DM effectively suppressed inducible nitric oxide synthase (iNOS) expression and NO, tumor necrosis factor alpha, and interleukin-6 generation in GAS-infected RAW264.7 cells as well as in air-pouch-infiltrating cells from GAS/DM-treated mice. GAS infection caused AKT dephosphorylation, glycogen synthase kinase-3 (GSK-3) activation, and subsequent NF-B nuclear translocation, which were also markedly inhibited by treatment with DM and an NADPH oxidase inhibitor, diphenylene iodonium. These results suggest that DM attenuates GAS infection-induced overactive inflammation by inhibiting NADPH oxidase-mediated ROS production that leads to downregulation of the GSK-3/NF-B/NO signaling pathway.

Original languageEnglish
Article numbere02045-17
JournalAntimicrobial agents and chemotherapy
Volume62
Issue number6
DOIs
Publication statusPublished - 2018 Jun

Fingerprint

Dextromethorphan
Glycogen Synthase Kinase 3
Streptococcal Infections
NADPH Oxidase
Streptococcus
Nitric Oxide
Infection
Reactive Oxygen Species
Antitussive Agents
Necrotizing Fasciitis
Neuroprotective Agents
Nitric Oxide Synthase Type II
Septic Shock
Interleukin-6
Anti-Inflammatory Agents
Down-Regulation
Tumor Necrosis Factor-alpha
Macrophages
Air
Inflammation

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Chen, Chia Ling ; Cheng, Miao Huei ; Kuo, Chih Feng ; Cheng, Yi Lin ; Li, Ming Han ; Chang, Chih Peng ; Wu, Jiunn Jong ; Anderson, Robert ; Wang, Shuying ; Tsai, Pei-Jane ; Liu, Ching Chuan ; Linc, Yee Shin. / Dextromethorphan attenuates NADPH oxidase-regulated glycogen synthase kinase 3 and NF-B activation and reduces nitric oxide production in group a streptococcal infection. In: Antimicrobial agents and chemotherapy. 2018 ; Vol. 62, No. 6.
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abstract = "Group A Streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), an antitussive drug, has been demonstrated to efficiently reduce inflammatory responses, thereby contributing to an increased survival rate of GAS-infected mice. However, the anti-inflammatory mechanisms underlying DM treatment in GAS infection remain unclear. DM is known to exert neuroprotective effects through an NADPH oxidase-dependent regulated process. In the present study, membrane translocation of NADPH oxidase subunit p47phox and subsequent reactive oxygen species (ROS) generation induced by GAS infection were significantly inhibited via DM treatment in RAW264.7 murine macrophage cells. Further determination of proinflammatory mediators revealed that DM effectively suppressed inducible nitric oxide synthase (iNOS) expression and NO, tumor necrosis factor alpha, and interleukin-6 generation in GAS-infected RAW264.7 cells as well as in air-pouch-infiltrating cells from GAS/DM-treated mice. GAS infection caused AKT dephosphorylation, glycogen synthase kinase-3 (GSK-3) activation, and subsequent NF-B nuclear translocation, which were also markedly inhibited by treatment with DM and an NADPH oxidase inhibitor, diphenylene iodonium. These results suggest that DM attenuates GAS infection-induced overactive inflammation by inhibiting NADPH oxidase-mediated ROS production that leads to downregulation of the GSK-3/NF-B/NO signaling pathway.",
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Dextromethorphan attenuates NADPH oxidase-regulated glycogen synthase kinase 3 and NF-B activation and reduces nitric oxide production in group a streptococcal infection. / Chen, Chia Ling; Cheng, Miao Huei; Kuo, Chih Feng; Cheng, Yi Lin; Li, Ming Han; Chang, Chih Peng; Wu, Jiunn Jong; Anderson, Robert; Wang, Shuying; Tsai, Pei-Jane; Liu, Ching Chuan; Linc, Yee Shin.

In: Antimicrobial agents and chemotherapy, Vol. 62, No. 6, e02045-17, 06.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dextromethorphan attenuates NADPH oxidase-regulated glycogen synthase kinase 3 and NF-B activation and reduces nitric oxide production in group a streptococcal infection

AU - Chen, Chia Ling

AU - Cheng, Miao Huei

AU - Kuo, Chih Feng

AU - Cheng, Yi Lin

AU - Li, Ming Han

AU - Chang, Chih Peng

AU - Wu, Jiunn Jong

AU - Anderson, Robert

AU - Wang, Shuying

AU - Tsai, Pei-Jane

AU - Liu, Ching Chuan

AU - Linc, Yee Shin

PY - 2018/6

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AB - Group A Streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), an antitussive drug, has been demonstrated to efficiently reduce inflammatory responses, thereby contributing to an increased survival rate of GAS-infected mice. However, the anti-inflammatory mechanisms underlying DM treatment in GAS infection remain unclear. DM is known to exert neuroprotective effects through an NADPH oxidase-dependent regulated process. In the present study, membrane translocation of NADPH oxidase subunit p47phox and subsequent reactive oxygen species (ROS) generation induced by GAS infection were significantly inhibited via DM treatment in RAW264.7 murine macrophage cells. Further determination of proinflammatory mediators revealed that DM effectively suppressed inducible nitric oxide synthase (iNOS) expression and NO, tumor necrosis factor alpha, and interleukin-6 generation in GAS-infected RAW264.7 cells as well as in air-pouch-infiltrating cells from GAS/DM-treated mice. GAS infection caused AKT dephosphorylation, glycogen synthase kinase-3 (GSK-3) activation, and subsequent NF-B nuclear translocation, which were also markedly inhibited by treatment with DM and an NADPH oxidase inhibitor, diphenylene iodonium. These results suggest that DM attenuates GAS infection-induced overactive inflammation by inhibiting NADPH oxidase-mediated ROS production that leads to downregulation of the GSK-3/NF-B/NO signaling pathway.

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