Abstract
Cheong-Pye-Ko (CPK) and Kyung-Ok-Ko (KOK) are traditional herbal medicine prescriptions that have been used in oriental medicine as tonics for pulmonary-related diseases for centuries. However, the effects of a mixture of CPK and KOK (C-KOK) on cytokine-mediated pulmonary damage have not yet been elucidated. This study used lipopolysaccharide (LPS)-activated human pulmonary artery endothelial cells (HPAECs) to examine the effects of C-KOK on the induction of heme oxygenase-1 (HO-1) and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, a mouse model was used to determine if C-KOK affected the expression of tumor necrosis factor (TNF)-α and iNOS in the lung tissues of LPS-treated mice. The results showed that C-KOK induced the translocation of Nrf2 from the cytosol to the nucleus by increasing Nrf2-antioxidant response elements (ARE) activity, increased the expression of HO-1, and decreased IL-1β and iNOS/NO production in the LPS-activated HPAECs. Specifically, the suppression of iNOS/NO expression from the administration of C-KOK was reversed by the RNAi knockdown of HO-1. In conclusion, these findings indicated that C-KOK produced a critical anti-inflammatory effect due to its HO-1 dependent downregulation of p-STAT-1 and NF-κB and the resultant inhibition of iNOS and also suggested that TNF-α was a potential target for HO-1. Therefore, the administration of C-KOK showed efficacy and might be a novel approach for the treatment of inflammatory pulmonary disease.
Similar content being viewed by others
References
Waza, A. A., Z. Hamid, S. Ali, S. A. Bhat, and M. A. Bhat (2018) A review on heme oxygenase-1 induction: is it a necessary evil. Inflamm. Res. 67: 579–588.
Tsoyi, K., T. Y. Lee, Y. S. Lee, H. J. Kim, H. G. Seo, J. H. Lee, and K. C. Chang (2009) Heme-oxygenase-1 induction and carbon monoxide-releasing molecule inhibit lipopolysaccharide (LPS)-induced high-mobility group box 1 release in vitro and improve survival of mice in LPS- and cecal ligation and puncture-induced sepsis model in vivo. Mol. Pharmacol. 76: 173–182.
Raghunath, A., K. Sundarraj, R. Nagarajan, F. Arfuso, J. Bian, A. P. Kumar, G. Sethi, and E. Perumal (2018) Antioxidant response elements: Discovery, classes, regulation and potential applications. Redox Biol. 17: 297–314.
Jang, M., M. J. Lee, J. M. Lee, C. S. Bae, S. H. Kim, J. H. Ryu, and I. H. Cho (2014) Oriental medicine Kyung-Ok-Ko prevents and alleviates dehydroepiandrosterone-induced polycystic ovarian syndrome in rats. PLos One. 9: e87623.
Ye, Y., G X. Chou, D. D. Mu, H. Wang, J. H. Chu, A. K. M. Leung, W. F. Fong, and Z. L. Yu (2010) Screening of Chinese herbal medicines for antityrosinase activity in a cell free system and B16 cells. J. Ethnopharmacol. 129: 387–390.
Kim, T. H., K. M. Lee, N. D. Hong, and Y. S. Jung (2016) Anti-platelet and anti-thrombotic effect of a traditional herbal medicine Kyung-Ok-Ko. J. Ethnopharmacol. 178: 172–179.
Im, L. R., J. Y. Ahn, J. H. Kim, M. Xin, S. U. Kwon, Y. K. Kim, D. K. Kim, and Y. M. Lee (2011) Inhibitory effect of kyungohkgo in the development of 2,4-dinitrochlorobenzene-induced atopic dermatitis in NC/Nga mice. Arch. Pharm. Res. 34: 317–321.
Lee, S., Y. J. Shin, J. H. Park, S. M. Kim, and C. S. Park (2008) An analysis of the gyungokgo’s ingredients and a comparison study on anti-oxidation effects according to the kinds of extract. Kor. J. Herbology. 23: 123–136.
Lee, W. and J. S. Bae (2019) Inhibitory effects of Kyung-Ok-Ko, traditional herbal prescription, on particulate matter-induced vascular barrier disruptive responses. Int. J. Environ. Health Res. 29: 301–311.
Kim, J. E., W. Lee, S. Yang, S. H. Cho, M. C. Baek, G. Y. Song, and J. S. Bae (2019) Suppressive effects of rare ginsenosides, Rk1 and Rg5, on HMGB1-mediated septic responses. Food Chem. Toxicol. 124: 45–53.
Lee, I. C. and J. S. Bae (2019) Pelargonidin protects against renal injury in a mouse model of sepsis. J. Med. Food. 22: 57–61.
Lee, B. S., C. Lee, S. Yang, S. K. Ku, and J. S. Bae (2019) Renal protective effects of zingerone in a mouse model of sepsis. BMB Rep. 52: 271–276.
Lee, Y., M. H. Jeong, K. J. Kim, S. H. Baek, J. S. Hur, and Y. J. Son (2018) The extract of Ramalina litoralis inhibits osteoclast differentiation. Biotechnol. Bioprocess Eng. 23: 634–640.
Jang, M. H., N. H. Kang, S. Mukherjee, and J. W. Yun (2018) Theobromine, a methylxanthine in cocoa bean, stimulates thermogenesis by inducing white fat browning and activating brown adipocytes. Biotechnol. Bioprocess Eng. 23: 617–626.
Lee, W., S. K. Ku, J. E. Kim, G. E. Choi, G Y. Song, and J. S. Bae (2019) Pulmonary protective functions of rare ginsenoside Rg4 on particulate matter-induced inflammatory responses. Biotechnol. Bioprocess Eng. 24: 445–453.
Tsoyi, K., H. J. Kim, J. S. Shin, D. H. Kim, H. J. Cho, S. S. Lee, S. K. Ahn, H. S. Yun-Choi, J. H. Lee, H. G. Seo, and K. C. Chang (2008) HO-1 and JAK-2/STAT-1 signals aie involved in preferential inhibition of iNOS over COX-2 gene expression by newly synthesized tetrahydroisoquinoline alkaloid, CKD712, in cells activated with lipopolysacchride. Cell. Signal. 20: 1839–1847.
Tsoyi, K., I. T. Nizamutdinova, H. J. Jang, L. Mun, H. J. Kim, H. G Seo, J. H. Lee, and K. C. Chang (2010) Carbon monoxide from CORM-2 reduces HMGB1 release through regulation of IFN-beta/JAK2/STAT-1/INOS/NO signaling but not COX-2 in TLR-activated macrophages. Shock. 34: 608–614.
Wullaert, A., M. C. Bonnet, and M. Pasparakis (2011) NF-kappaB in the regulation of epithelial homeostasis and inflammation. Cell Res. 21: 146–158.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest Statement The authors have no conflicts of interest to declare.
Ethical Statement Animal protocol was endorsed by the Kyungpook National University Animal Care Committee (IRB No. KNU 2017-102) and no informed consent was required for this study.
Additional information
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Lee, IC., Ryu, CW. & Bae, JS. Novel Herbal Medicine C-KOK Suppresses the Inflammatory Gene iNOS via the Inhibition of p-STAT-1 and NF-κB. Biotechnol Bioproc E 25, 536–542 (2020). https://doi.org/10.1007/s12257-020-0126-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12257-020-0126-2