Abstract
Pneumonia is a serious infectious disease with increased morbidity and mortality worldwide. The M. pneumoniae is a major airway pathogen that mainly affects respiratory tract and ultimately leads to the development of pneumonia. The current exploration was aimed to uncover the beneficial properties of pinocembrin against the M. pneumoniae-triggered pneumonia in mice via its anti-inflammatory property. The pneumonia was stimulated to the BALB/c mice via infecting them with M. pneumoniae (100 µl) for 2 days through nasal drops and concomitantly treated with pinocembrin (10 mg/kg) for 3 days. The azithromycin (100 mg/kg) was used as a standard drug. Then the lung weight, nitric oxide, and myeloperoxidase (MPO) activity was assessed. The content of MDA, GSH, and SOD activity was scrutinized using kits. The total cells and DNA amount present in the bronchoalveolar lavage fluid (BALF) was assessed by standard methods. The IL-1, IL-6, IL-8, TNF-α, and TGF contents in the BALF samples and NF-κB level in the lung tissues were assessed using kits. The lung histopathology was assessed microscopically to detect the histological alterations. The 10 mg/kg of pinocembrin treatment substantially decreased the lung weight, nitric oxide (NO) level, and MPO activity. The MDA level was decreased, and GSH content and SOD activity were improved by the pinocembrin treatment. The pinocembrin administered pneumonia animals also demonstrated the decreased total cells, DNA amount, IL-1, IL-6, IL-8, TNF-α, and TGF in the BALF and NF-κB level. The findings of histological studies also witnessed the beneficial role of pinocembrin against M. pneumoniae-infected pneumonia. In conclusion, our findings confirmed that the pinocembrin effectively ameliorated the M. pneumoniae-provoked inflammation and oxidative stress in the pneumonia mice model. Hence, it could be a hopeful therapeutic agent to treat the pneumonia in the future.
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References
Miyashita, N., Kawai, Y., Inamura, N., Tanaka, T., Akaike, H., Teranishi, H., Wakabayashi, T., Nakano, T., Ouchi, K., & Okimoto, N. (2014). Setting a standard for the initiation of steroid therapy in refractory or severe Mycoplasma pneumoniae pneumonia in adolescents and adults. Journal of Infection and Chemotherapy, 21, 153–160.
Bajantri, B., Venkatram, S., & Diaz-Fuentes, G. (2018). Mycoplasma pneumoniae: A potentially severe infection. Journal of Clinical Medicine Research, 10, 535–544.
Sondergaard, M. J., Friis, M. B., Hansen, D. S., Jørgensen, I., & M. (2018). Clinical manifestations in infants and children with Mycoplasma pneumoniae infection. PLoS ONE, 13, e0195288.
Gao, J., Lin, S., Gao, Y., Zou, X., Zhu, J., Chen, M., Wan, H., & Zhu, H. (2019). Pinocembrin inhibits the proliferation and migration and promotes the apoptosis of ovarian cancer cells through down-regulating the mRNA levels of N-cadherin and GABAB receptor. Biomedicine & Pharmacotherapy, 120, 109505.
Kurata, S., Osaki, T., Yonezawa, H., Arae, K., Taguchi, H., & Kamiya, S. (2014). Role of IL-17A and IL- 10 in the antigen induced inflammation model by Mycoplasma pneumoniae. BMC Microbiology, 14, 156.
Wang, J., Cheng, W., Wang, Z., Xin, L., & Zhang, W. (2017). ATF3 inhibits the inflammation induced by Mycoplasma pneumonia in vitro and in vivo. Pediatric Pulmonology, 52, 1163–1170.
Shikha, T., Sudhil, K., & Surinder, K. B. (2012). Mucins and toll-like receptors: Kith and kin in infection and cancer. Cancer Letters, 321, 110–119.
Hwang, M. H., Damte, D., Lee, J. S., Gebru, E., Chang, Z. Q., Cheng, H., Jung, B. Y., Rhee, M. H., & Park, S. C. (2011). Mycoplasma hyopnuemoniae induces pro-inflammatory cytokine and nitric oxide production through NF-κB and MAPK pathways in RAW264.7 cells. Veterinary Research Communications, 35, 21–34.
Lai, J. F., Zindl, C. L., Duffy, L. B., Atkinson, T. P., Jung, Y. W., Rooijen, N., Waites, K. B., Krause, D. C., & Chaplin, D. D. (2010). Critical role of macrophages and their activation via MyD88-NFκB signaling in lung innate immunity to Mycoplasma pneumoniae. PLoS ONE, 5, e14417.
Guo, L., Liu, F., Lu, M. P., Zheng, Q., & Chen, Z. M. (2015). Increased T cell activation in BALF from children with Mycoplasma pneumoniae pneumonia. Pediatric Pulmonology, 50, 814–819.
Zhang, Y., Zhou, Y., Li, S., Yang, D., Wu, X., & Chen, Z. (2016). The clinical characteristics and predictors of refractory Mycoplasma pneumoniae pneumonia in children. PLoS ONE, 11, e156465.
Meffert, M. K., Chang, J. M., Wiltgen, B. J., Fanselow, M. S., & Baltimore, D. (2003). NFkappa B functions in synaptic signaling and behavior. Nature Neuroscience, 6, 1072–1078.
Oishi, T., Narita, M., Matsui, K., Shirai, T., Matsuo, M., & Negishi, J. (2011). Clinical implications of interleukin-18 levels in pediatric patients with Mycoplasma pneumoniae pneumonia. Journal of Infection and Chemotherapy, 17, 803–806.
Chmura, K., Bai, X., Nakamura, M., Kandasamy, P., McGibney, M., & Kuronuma, K. (2008). Induction of IL-8 by Mycoplasma pneumoniae membrane in BEAS-2B cells. American Journal of Physiology. Lung Cellular and Molecular Physiology, 295, 220–230.
Kratzer, E., Tian, Y., Sarich, N., Wu, T., Meliton, A., Leff, A., & Birukova, A. A. (2012). Oxidative stress contributes to lung injury and barrier dysfunction via microtubule destabilization. American Journal of Respiratory Cell and Molecular Biology, 47, 688–697.
Mahmoud Abd El Hafiz, A., Mohammed El Wakeel, L., & Mohammed El Hady, H. (2013). High dose N-acetyl cysteine improves inflammatory response and outcome in patients with COPD exacerbations. Egypt Journal of Chest Disseminated Tuberculosis, 62, 51–57.
Rahman, I., & MacNee, W. (2000). Oxidative stress and regulation of glutathione in lung inflammation. European Respiratory Journal, 16, 534–554.
Esposito, S., Blasi, F., Arosio, C., Fioravanti, L., Fagetti, L., Droghetti, R., Tarsia, P., Allegra, L., & Principi, N. (2000). Importance of acute Mycoplasma pneumoniae and chlamydia pneumoniae infections in children with wheezing. European Respiratory Journal, 16, 1142–1146.
Liu, W. K., Liu, Q., Chen, D. H., Liang, H. X., Chen, X. K., Chen, M. X., Qiu, S. Y., Yang, Z. Y., & Zhou, R. (2014). Epidemiology of acute respiratory infections in children in Guangzhou: A three-year study. PLoS ONE, 9, e96674.
Gullsby, K., & Bondeson, K. (2016). No detection of macrolide-resistant Mycoplasma pneumoniae from Swedish patients, 1996–2013. Infect Ecol Epidemiol, 6, 31374.
Rasul, A., Millimouno, F. M., Ali Eltayb, W., Ali, M., Li, J., & Li, X. M. (2013). Pinocembrin: A novel natural compound with versatile pharmacological and biological activities. BioMed Research International, 2013, 379850.
Hanieh, H., Islam, V. I. H., Saravanan, S., Chellappandian, M., Ragul, K., Durga, A., Venugopal, K., Senthilkumar, V., & Senthilkumar, P. (2017). Pinocembrin, a novel histidine decarboxylase inhibitor with anti-allergic potential in in vitro. European Journal of Pharmacology, 814, 178–186.
Saad, M. A., Salam, R. M. A., Kenawy, S. A., & Attia, A. S. (2015). Pinocembrin attenuates hippocampal inflammation, oxidative perturbations and apoptosis in a rat model of global cerebral ischemia reperfusion. Pharmacological Reports, 67, 115–122.
Said, M. M., Azab, S. S., Saeed, N. M., & El-Demerdash, E. (2018). Antifibrotic mechanism of pinocembrin: Impact on oxidative stress, inflammation and TGF-beta/Smad inhibition in rats. Annals of Hepatology, 17, 307–317.
Lungkaphin, A., Pongchaidecha, A., Palee, S., Arjinajarn, P., Pompimon, W., & Chattipakorn, N. (2015). Pinocembrin reduces cardiac arrhythmia and infarct size in rats subjected to acute myocardial ischemia/reperfusion. Applied Physiology, Nutrition and Metabolism, 40, 1031–1037.
Wang, W., Zheng, L., Xu, L., Tu, J., & Gu, X. (2020). Pinocembrin mitigates depressive-like behaviors induced by chronic unpredictable mild stress through ameliorating neuroinflammation and apoptosis. Molecular Medicine, 26, 53.
Wang, Y., Miao, Y., Mir, A. Z., Cheng, L., Wang, L., Zhao, L., Cui, Q., Zhao, W., & Wang, H. (2016). Inhibition of beta-amyloid-induced neurotoxicity by pinocembrin through Nrf2/HO-1 pathway in SH-SY5Y cells. Journal of the Neurological Sciences, 368, 223–230.
Liu, R., Li, J. Z., Song, J. K., Zhou, D., Huang, C., Bai, X. Y., & Du, G. (2014). Pinocembrin improves cognition and protects the neurovascular unit in Alzheimer related deficits. Neurobiology of Aging, 35, 1275–1285.
Arslan, S., Ozbilge, H., Kaya, E. G., & Er, O. (2011). In vitro antimicrobial activity of propolis, BioPure MTAD, sodium hypochlorite, and chlorhexidine on Enterococcus faecalis and Candida albicans. Saudi Medical Journal, 32, 479–483.
Soromou, L. W., Chu, X., Jiang, L. X., Wei, M. M., Huo, M., Chen, N., & Deng, X. (2012). In vitro and in vivo protection provided by pinocembrin against lipopolysaccharide-induced inflammatory responses. International Immunopharmacology, 14, 66–74.
Shi, L. L., Chen, B. N., Gao, M., Zhang, H. A., Li, Y. J., Wang, L., & Du, G. (2011). The characteristics of therapeutic effect of pinocembrin in transient global brain ischemia/reperfusion rats. Life Sciences, 88, 521–528.
Sang, H., Yuan, N., Yao, S. T., Li, F. R., Wang, J. F., & Fang, Y. Q. (2012). Inhibitory effect of the combination therapy of simvastatin and pinocembrin on atherosclerosis in ApoE-deficient mice. Lipids in Health and Disease, 11, 166.
Punvittayagul, C., Pompimon, W., Wanibuchi, H., Fukushima, S., & Wongpoomchai, R. (2012). Effects of pinocembrin on the initiation and promotion stages of rat hepatocarcinogenesis. Asian Pacific Journal of Cancer Prevention, 13, 2257–2261.
Gao, L. W., Yin, J., Hu, Y. H., Liu, X. Y., Feng, X. L., He, J. X., & Shen, K. L. (2019). The epidemiology of paediatric Mycoplasma pneumoniae pneumonia in North China: 2006 to 2016. Epidemiology and Infection, 147, e192.
Kumar, N., Biswas, S., Hosur Shrungeswara, A., Basu Mallik, S., Hipolith Viji, M., & Elizabeth Mathew, J. (2017). Pinocembrin enriched fraction of Elytranthe parasitica (L.) Danser induces apoptosis in HCT 116 colorectal cancer cells. Journal of Infection and Chemotherapy, 23, 354–359.
Williamson, J., Marmion, B. P., Worswick, D. A., Kok, T.W., Tannock, G., Herd, R., & Harris, R.J., (1992). Laboratory diagnosis of Mycoplasma pneumoniae infection. 4. Antigen capture and PCR-gene amplification for detection of the mycoplasma: Problems of clinical correlation. Epidemiology and Infection, 109(3), 519–537.
Ngeow, Y. F., Suwanjutha, S., Chantarojanasriri, T., Wang, F., Saniel, M., Alejandria, M., & Cheong, Y. M. (2005). An Asian study on the prevalence of atypical respiratory pathogens in community-acquired pneumonia. International Journal of Infectious Diseases, 9, 144–153.
Meyer Sauteur, P. M., Jacobs, B. C., Spuesens, E. B., Jacobs, E., Nadal, D., & Vink, C. (2014). Antibody responses to Mycoplasma pneumoniae: Role in pathogenesis and diagnosis of encephalitis? PLoS Pathogens, 10, e1003983.
Shimizu, T. (2016). Inflammation-inducing factors of Mycoplasma pneumoniae. Frontiers in Microbiology, 7, 414.
Wood, P. R., Kampschmidt, J. C., Dube, P. H., Cagle, M. P., Chaparro, P., Ketchum, N. S., & Brooks, E. G. (2017). Mycoplasma pneumoniae and health outcomes in children with asthma. Annals of Allergy, Asthma & Immunology, 119, 146–152.
Somarajan, S. R., Kannan, T. R., & Baseman, J. B. (2010). Mycoplasma pneumoniae Mpn133 is a cytotoxic nuclease with a glutamic acid-, lysine and serine-rich region essential for binding and internalization but not enzymatic activity. Cellular Microbiology, 12, 1821–1831.
Anjum, M. U., Riaz, H., & Tayyab, H. M. (2017). Acute respiratory tract infections (ARIS); clinico-epidemiolocal profile in children of less than five years of age. Professional Med J, 24, 322–325.
Akkaya, A., & Ozturk, O. (2008). Total antioxidant capacity and C-reactive protein levels in patients with community-acquired pneumonia. Turk JMedicalences, 38, 537–544.
Trefler, S., Rodriguez, A., Martin-Loeches, I., Sanches, V., Marin, J., Llaurado, M., Romeu, M., Diaz, E., Nogues, R., & Giralt, M. (2014). Oxidative stress in immunocompetent patients with severe community-acquired pneumonia. A pilot study. Medicina Intensiva, 38, 73–82.
Biswas, S. K., & Rahman, I. (2009). Environmental toxicity, redox signaling and lung inflammation: The role of glutathione. Molecular Aspects of Medicine, 30, 60–76.
Cemek, M., Caksen, H., Bayiroglu, F., Cemek, F., & Dede, S. (2006). Oxidative stress and enzymic-non-enzymic antioxidant responses in children with acute pneumonia. Cell Biochemistry and Function, 24, 269–273.
Pang, H. X., Qiao, H. M., Cheng, H. J., Zhang, Y. F., Liu, X. J., & Li, J. Z. (2011). Levels of TNF-alpha, IL-6 and IL-10 in bronchoalveolar lavage fluid in children with Mycoplasma pneumoniae pneumonia. Zhongguo Dang Dai ErKe Za Zhi, 13, 808–810.
Yang, J., Hooper, W. C., Phillips, D. J., & Talkington, D. F. (2002). Regulation of proinflammatory cytokines in human lung epithelial cells infected with Mycoplasma pneumoniae. Infection and Immunity, 70, 3649–3655.
Lee, K. E., Kim, K. W., Hong, J. Y., Kim, K. E., & Sohn, M. H. (2013). Modulation of IL-8 boosted by Mycoplasma pneumoniae lysate in human airway epithelial cells. Journal of Clinical Immunology, 33, 1117–1125.
He, J. E., Gao, C. Y., & Li, H. R. (2013). Effect of low-dose methylprednisolone on serum TNF-α level in children with Mycoplasma pneumoniae pneumonia. Zhongguo Dang Dai Er Ke Za Zhi, 15(850–853), 2013.
Hardy, R. D., Jafri, H. S., Olsen, K., Wordemann, M., Hatfield, J., Rogers, B. B., & Ramilo, O. (2001). Elevated cytokine and chemokine levels and prolonged pulmonary airflow resistance in a murine Mycoplasma pneumoniae pneumonia model: A microbiologic, histologic, immunologic, and respiratory plethysmographic profile. Infection and Immunity, 69, 3869–3876.
Kurai, D., Nakagaki, K., Wada, H., Saraya, T., Kamiya, S., Fujioka, Y., & Goto, H. (2013). Mycoplasma pneumoniae extract induces an IL-17-associated inflammatory reaction in murine lung: Implication for mycoplasmal pneumonia. Inflammation, 36, 285–293.
Xu, X. F., Li, X. J., Liu, J. L., Wu, L., & Chen, Z. M. (2016). Serum cytokine profile contributes to discriminating M. pneumoniae pneumonia in children. Cytokine, 86, 73–78.
Tian, F., Han, B., & Duan, M. (2014). Serum tumor necrosis factor-alpha, interleukin-6 and galctin-3 concentrations in children with Mycoplasma pneumoniae pneumonia. Zhongguo Dang Dai Er Ke Za Zhi, 16, 1001–1004.
Andrijevic, I., Matijasevic, J., Andrijevic, L., Kovacevic, T., & Zaric, B. (2014). Interleukin-6 and procalcitonin as biomarkers in mortality prediction of hospitalized patients with community acquired pneumonia. Ann Thorac Med, 9, 162–167.
Yang Jun Hooper, W. C., Phillips, D. J., & Talkington, D. F. (2003). Interleukin-1beta responses to Mycoplasma pneumoniae infection are cell-type specific. Microbial Pathogenesis, 34, 17–25.
Gui, M., Wang, J., Zeng, N., Yang, Q., & Li, Z. (2020). Changes and clinical significance of interleukin in serum and bronchoalveolar lavage fluid of children with different pneumonia. Journal of Pediatric Pharmacy, 26, 1–4.
Zhang, Q., Lenardo, M. J., & Baltimore, D. (2017). 30 years of NF-κB: A blossoming of relevance to human pathobiology. Cell, 168(1–2), 37–57.
Shimizu, T., Kida, Y., & Kuwano, K. (2008). Mycoplasma pneumoniae-derived lipopeptides induce acute inflammatory responses in the lungs of mice. Infection and Immunity, 76(1), 270–277.
Salvatore, C. M., Fonseca-Aten, M., Katz-Gaynor, K., Gomez, A. M., Mejias, A., Somers, C., & Hardy, R. D. (2007). Respiratory tract infection with Mycoplasma pneumoniae in interleukin-12 knockout mice results in improved bacterial clearance and reduced pulmonary inflammation. Infection and immunity, 75(1), 236–242.
Camp, J. V., & Jonsson, C. B. (2017). A role for neutrophils in viral respiratory disease. Frontiers in Immunology, 8, 550.
Yan, Y., Wei, Y., Jiang, W., & Hao, C. (2016). The clinical characteristics of corticosteroid-resistant refractory Mycoplasma pneumoniae pneumonia in children. Science and Reports, 6, 39929.
Chen, Z., Shao, X., Dou, X., Zhang, X., Wang, Y., Zhu, C., Hao, C., Fan, M., Ji, W., & Yan, Y. (2016). Role of the Mycoplasma pneumoniae/interleukin-8/neutrophil axis in the pathogenesis of pneumonia. PLoS ONE, 11, e146377.
Santos, S. S., Brunialti, M. K. C., Rigato, O., Machado, F. R., Silva, E., & Salomao, R. (2012). Generation of nitric oxide and reactive oxygen species by neutrophils and monocytes from septic patients and association with outcomes. Shock, 38(1), 18–23.
Senoner, T., & Dichtl, W. (2019). Oxidative stress in cardiovascular diseases: Still a therapeutic target? Nutrients, 11(9), 2090.
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Qian, J., Xue, M. Pinocembrin Relieves Mycoplasma pneumoniae Infection‑Induced Pneumonia in Mice Through the Inhibition of Oxidative Stress and Inflammatory Response. Appl Biochem Biotechnol 194, 6335–6348 (2022). https://doi.org/10.1007/s12010-022-04081-6
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DOI: https://doi.org/10.1007/s12010-022-04081-6