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Tian M, Huang W, Chen J, Liu X, Wang H, Pan X, Wang L, Li Q, Gao L, Ye Y. The extract from Quzhou Aurantii Fructus attenuates cough variant asthma through inhibiting the TRPV1/Ca 2+/NFAT/TSLP pathway and ferroptosis via TRPV1 mediation in ovalbumin-induced mice. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119038. [PMID: 39510426 DOI: 10.1016/j.jep.2024.119038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/20/2024] [Accepted: 11/04/2024] [Indexed: 11/15/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cough variant asthma (CVA), a prevalent chronic inflammatory disease, is the most common cause of chronic cough. Over the years, the aqueous extract of Quzhou Aurantii Fructus (QAFA) has been widely used to treat respiratory diseases, particularly cough. AIM OF THE STUDY This study aimed to elucidate the therapeutic effect of QAFA on allergen-induced CVA, providing deep insights into the underlying mechanisms. MATERIALS AND METHODS Ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was employed to characterize the compositions, while UPLC was used to quantify the contents of its major components in QAFA. CVA model was established via sensitization and atomization with ovalbumin (OVA), and received 600 and 1200 mg/kg of QAFA via intragastric gavage. Cough response was assessed by stimulation with capsaicin (CAP). Then, airway hyperresponsiveness (AHR), ELISA, western blotting, RT-qPCR, and histological analyses, were applied to assess pulmonary function, pathological changes, and investigate mechanisms in CVA mice following QAFA treatment through the TRPV1/Ca2+-dependent NFAT-induced expression of TSLP and ferroptosis. Additionally, the effects and mechanisms of QAFA were validated using IL-4, CAP for stimulation, capsazepine (CPZ) for inhibition, and TRPV1 siRNA transfection in cells. RESULTS Chemical analysis revealed that QAFA primarily contained sixteen compounds, with four main components including narirutin, naringin, hesperidin, and neohesperidin. In vivo, QAFA treatment alleviated cough and AHR, while concurrently reducing airway inflammation and mucus secretion in CVA mice. These effects were achieved by suppressing the TRPV1/NFAT/TSLP pathway and modulating the expression of ferroptosis-related proteins. In vitro, siTRPV1-transfected BEAS-2B cells demonstrated the involvement of the TRPV1 channel in IL-4-mediated Ca2+ influxes, ferroptosis, and regulation of TSLP production. QAFA and CPZ suppressed IL-4-induced TSLP production via the TRPV1/NFAT pathway and regulated the levels of ferroptosis-related proteins, while CAP counteracted the effect of QAFA on TSLP production in BEAS-2B cells. Furthermore, QAFA reduced IL-4 or CAP induced Ca2+ influx and IL-4 induced ferroptosis through TRPV1 mediation. CONCLUSIONS This study demonstrated that QAFA improved pulmonary function and alleviated asthmatic inflammatory response in treating CVA probably through suppressing the TRPV1/Ca2+/NFAT/TSLP pathway and ferroptosis via TRPV1 mediation.
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Affiliation(s)
- Meizi Tian
- School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, 311300, China
| | - Wenkang Huang
- School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, 311300, China
| | - Jiahui Chen
- School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, 311300, China
| | - Xiaotong Liu
- School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, 311300, China
| | - Haiou Wang
- School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, 311300, China
| | - Xiaoya Pan
- School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, 311300, China
| | - Lixia Wang
- Changshan Characteristic Industry Development Center, Quzhou, Zhejiang, 324000, China
| | - Qin Li
- School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, 311300, China
| | - Lijuan Gao
- School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, 311300, China.
| | - Yiping Ye
- School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, 311300, China.
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Wang Y, Peng M, Yang X, Tu L, Liu J, Yang Y, Li R, Tang X, Hu Y, Zhang G, Zhao Q, Lu Q. Total alkaloids in Fritillaria cirrhosa D. Don alleviate OVA-induced allergic asthma by inhibiting M2 macrophage polarization. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118935. [PMID: 39396718 DOI: 10.1016/j.jep.2024.118935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/29/2024] [Accepted: 10/11/2024] [Indexed: 10/15/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Fritillaria cirrhosa D. Don (FCD) is a traditional Chinese medicine used to treat respiratory disorders, known for its effects in clearing heat, moistening the lungs, resolving phlegm, and relieving cough. Additionally, the total alkaloids extracted from FCD can alleviate asthma symptoms and reduce airway inflammation. However, no studies have investigated the effects of total alkaloids on lung macrophages. AIM OF THE STUDY This study explored whether the total alkaloids of FCD (TAs-FCD) reduce M2 macrophage polarization and, consequently, attenuate airway remodeling in asthmatic mice. This study further elucidated its mechanism of action in treating allergic asthma. MATERIALS AND METHODS The extracted TAs-FCD was analyzed for its composition using UPLC-Q-TOF/MS. Network pharmacology was employed to identify the active ingredients and potential mechanisms of TAs-FCD in the treatment of allergic asthma. A mouse model of ovalbumin-induced allergic asthma was established, adopted, and validated through in vivo experiments. Hematoxylin-eosin staining (H&E), immunohistochemistry (IHC), immunofluorescence staining (IF), enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), and real-time fluorescence quantitative polymerase chain reaction (q-PCR) were used to investigate the role of TAs-FCD in inhibiting M2 macrophage polarization in the context of allergic asthma. RESULTS A total of 66 active ingredients were screened from 116 compounds using SWISSADME. The targets of these 66 compounds were predicted by SwissTargetPrediction, resulting in 808 unique drug targets after excluding duplicates. Additionally, 1756 targets related to allergic asthma were identified from the DisGeNET, Genecard, and OMIM databases. This led to 267 cross-targets between the active ingredient targets and allergic asthma targets, including interleukin (IL)-1β, tumor necrosis factor (TNF), and STAT3. Animal experiments demonstrated that TAs-FCD improved histopathological injury in mouse lungs, reduced peri-airway collagen fiber accumulation, airway mucus secretion, and airway smooth muscle proliferation. TAs-FCD also lowered IL-1β, TNF-α and IL-4 levels in lung tissues and alleviated airway inflammation. Furthermore, TAs-FCD significantly reduced levels of Arg1 and CD206, which are closely associated with M2 macrophages, and downregulated the expression of p-STAT3 and p-JAK2. CONCLUSION TAs-FCD may inhibit M2 macrophage polarization by regulating the JAK2/STAT3 pathway, thereby alleviating airway remodeling and inflammation in allergic asthmatic mice.
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Affiliation(s)
- Yu Wang
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Pharmacy, Chengdu University, Chengdu, 610106, China
| | - Meihao Peng
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Pharmacy, Chengdu University, Chengdu, 610106, China
| | - Xin Yang
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China
| | - Liming Tu
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China
| | - Jiamin Liu
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Pharmacy, Chengdu University, Chengdu, 610106, China
| | - Yixi Yang
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China
| | - Rui Li
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China
| | - Xue Tang
- Chengdu Analytical Applications Center, Shimadzu (China) Co Ltd., Chengdu, 610023, China
| | - Yuqing Hu
- Shangri-La Tianquan Chuanbei Technology Co., Ltd., Yunnan, 674401, China
| | - Guowu Zhang
- Shangri-La Tianquan Chuanbei Technology Co., Ltd., Yunnan, 674401, China
| | - Qi Zhao
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China.
| | - Qiuxia Lu
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China.
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Hu Y, Wang M, Luo Y, Xie J, Jiao L, Tang W, Deng Y, Yao B. Therapeutic potency and possible mechanism of Wuhu decoction underlying asthmatic progression via Th1/Th2 imbalance. J Thorac Dis 2025; 17:265-277. [PMID: 39975754 PMCID: PMC11833591 DOI: 10.21037/jtd-24-804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 11/22/2024] [Indexed: 02/21/2025]
Abstract
Background Cough variant asthma (CVA) is a disease with no definitive diagnosis or pathogenic causes, and still lacks effective and safe treatment. Wuhu decoction is a traditional Chinese medicine with potential effects against CVA, of which underlying mechanism remains elusive. The aim of this study is to explore the therapeutic potential of Wuhu decoction against CVA. Methods The CVA mice model was established by ovalbumin (OVA) treatment. The airway hyperresponsiveness and remodeling were assessed. The pulmonary inflammatory injury was determined by counting of inflammatory cells and serum OVA-specific immunoglobulin E (IgE) in bronchoalveolar lavage fluid, as well as the amount of CD4+, CD8+ or CD25+ T cells. The Th1/Th2 balance was evaluated by type specific cytokines. The level of antisense long non-coding RNA TRPM2 (lncTRPM2-AS) and its downstream targets were determined by mRNA and protein detection, respectively. Results Wuhu decoction could improve airway hyperresponsiveness and remodeling in OVA-induced asthmatic mice model by regulating Th1/Th2 balance and affecting pulmonary inflammatory injury. On the molecular level, Wuhu decoction significantly inhibited the expression of lncTRPM2-AS, which was found to be a critical modulator of Th1/Th2 balance. Meanwhile, overexpression of lncTRPM2-AS could abolish Wuhu decoction-mediated protection effects on OVA-induced asthmatic mice model. Conclusions This study discovered the protective function of Wuhu decoction against CVA and illustrated its molecular mechanism, highlighting the therapeutic application of Wuhu decoction for asthma treatment.
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Affiliation(s)
- Yan Hu
- Department of Pediatrics, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Mengqing Wang
- Department of Pediatrics, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Yinhe Luo
- Teaching and Research Office of Chinese and Western Combination, Hunan University of Chinese Medicine, Changsha, China
| | - Jing Xie
- Department of Pediatrics, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Luojia Jiao
- Department of Organizational Personnel Department, Hunan University of Chinese Medicine, Changsha, China
| | - Wei Tang
- Department of Acupuncture and Massage, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Yijue Deng
- Department of Pediatrics, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Bing Yao
- Department of Pediatrics, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
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Zheng J, Yang H, Liu C, Zhang R, Yibulayimu N, Jin X. Ethanol Extract of Anacyclus pyrethrum Root Ameliorates Cough-Variant Asthma Through the TLR4/NF-κB Pathway and Wnt/β-Catenin Pathway. Mol Biotechnol 2024; 66:3274-3284. [PMID: 37910337 DOI: 10.1007/s12033-023-00935-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 10/09/2023] [Indexed: 11/03/2023]
Abstract
Cough-variant asthma (CVA) has been recognized as the initial stage or pre-asthmatic state of classic asthma, which characterized by cough as the primary clinical presentation. Inhaled glucocorticoids, oral leukotriene receptor antagonists and antihistamines are the clinical treatments, but their efficacy is not satisfactory. Some traditional Chinese medicine (TCM) has been reported to have certain advantages in the treatment of CVA, but the underlying molecular mechanisms are still unclear. Recent research has indicated that Anacyclus pyerhrurm (L) DC. is commonly used in the treatment of human diseases. The aim of our study was to evaluate the anti-inflammatory and anti-oxidative mechanism of the ethanol extract of Anacyclus pyrethrum (L) DC. root (EEAP) in a model of CVA. In our study, we indicated that EEAP ameliorated CVA by reducing cough frequency and inflammatory effect and oxidative stress in an in vivo rat model of CVA. In addition, EEAP ameliorated LPS-induced cell apoptosis and regulated inflammatory effect and oxidative stress in vitro. Mechanistically, EEAP exerted anti-inflammatory effects through regulating the TLR4/NF-κB pathway and Wnt/β-catenin pathway, and overexpressing TLR4 or activating the Wnt/β-catenin pathway by SKL2001 reversed EEAP-exerted effects in LPS-exposed BEAS-2B and 16-HBE cells. In conclusion, EEAP attenuated cell apoptosis, inflammation and oxidative stress through restraining the TLR4/NF-κB pathway and Wnt/β-catenin pathway in CVA, which shown that EEAP might be a promising therapeutic agent for CVA and may provide a theoretical basis for clinical treatment with CVA patients.
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Affiliation(s)
- Jun Zheng
- Department of Critical Care Medicine, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hao Yang
- Department of Pharmacy, The Sixth Affiliated Hospital of Xinjiang Medical University, No. 39, Wuxing South Road, TianShan District, Urumqi, 830000, China
| | - Changjiang Liu
- Department of Pharmacy, The Sixth Affiliated Hospital of Xinjiang Medical University, No. 39, Wuxing South Road, TianShan District, Urumqi, 830000, China
| | - Rui Zhang
- Department of Pharmacy, The Sixth Affiliated Hospital of Xinjiang Medical University, No. 39, Wuxing South Road, TianShan District, Urumqi, 830000, China
| | - Nadire Yibulayimu
- Market Supervision and Administration Bureau of Huocheng County, HuoCheng, Ili, China
| | - Xiaoyue Jin
- Department of Pharmacy, The Sixth Affiliated Hospital of Xinjiang Medical University, No. 39, Wuxing South Road, TianShan District, Urumqi, 830000, China.
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Cao JY, Wang YC, Deng XX. Efficacy of β2-adrenergic receptor agonist combined with corticosteroid in the treatment of children with cough variant asthma. World J Clin Cases 2023; 11:7610-7618. [DOI: 10.12998/wjcc.v11.i31.7610] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/07/2023] [Accepted: 10/26/2023] [Indexed: 11/06/2023] Open
Abstract
BACKGROUND Cough variant asthma (CVA) is one of the most common respiratory diseases in children, which has a serious impact on the quality of life and daily activities of children. For severe CVA, immunomodulatory drugs are needed.
AIM To evaluate the efficacy of salmeterol combined with budesonide in the treatment of pediatric CVA.
METHODS 130 children with CVA from January 2020 to December 2022 were prospectively selected and randomly divided into an observation group (salmeterol combined with budesonide) and a control group (budesonide combined with a placebo). Compare the clinical efficacy of two groups before and after intervention. The evaluation parameters include cough frequency score, nocturnal cough arousal, and lung function indicators. Serum inflammatory markers, immune function markers and airway anatomical indicators were also measured.
RESULTS After the intervention, the total effective rate of the observation group was significantly higher than that of the control group, and the cough frequency score and the night cough wake rate of the observation group were lower than that of the control group, with a statistically significant difference. In addition, the changes of lung function indicators, serum markers and immune function markers in the observation group were better than those in the control group.
CONCLUSION The clinical efficacy of salmeterol combined with Budesonide in the treatment of CVA is better than that of Budesonide alone.
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Affiliation(s)
- Jun-Yi Cao
- Department of Pediatrics, The First People's Hospital of Jiangxia District, Wuhan 430200, Hubei Province, China
| | - Ying-Chun Wang
- Department of Pediatrics, The First People's Hospital of Jiangxia District, Wuhan 430200, Hubei Province, China
| | - Xiao-Xia Deng
- Department of Pediatric Respiratory, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430070, Hubei Province, China
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Lee SW, Lyu YR, Yang WK, Kim SH, Kim SY, Kang W, Jung IC, Lee BJ, Choi JY, Lee MY, Park YC. Efficacy and Safety of Yukmijihwang-Tang in the Treatment of Cough-Variant Asthma: Study Protocol for a Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Complement Med Res 2023; 30:424-430. [PMID: 37604125 DOI: 10.1159/000533252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/20/2023] [Indexed: 08/23/2023]
Abstract
BACKGROUND Cough-variant asthma (CVA), a precursor of typical asthma, is the main cause of chronic cough. We hypothesize that yukmijihwang-tang (YJT), which has been used for chronic cough in traditional medicine and has been reported to have an anti-inflammatory effect, could be an adjuvant to asthma treatment. METHODS We plan a randomized, double-blind, placebo-controlled, multicenter, phase 2 trial to investigate the efficacy and safety of YJT in CVA patients. A total of 60 patients with CVA will be recruited and randomly assigned to either a high-dose YJT group, standard-dose YJT group, or control group (placebo) in a 1:1:1 allocation ratio after a 2-week run-in period. For the run-in period, only inhaled corticosteroids (ICSs) will be used, and the investigational drug will be administered once a day with concomitant ICS for 6 weeks. Data will be collected at baseline, week 3, and week 6, and the primary outcome measure will be the mean cough symptom score (CSS) change before and after medication. The secondary outcome measures will include the Leicester cough questionnaire-Korean version (LCQ-K) score, eosinophil count and eosinophil cationic protein level, pulmonary function test, and the number of uses of rescue medication, and so on. CONCLUSION This study aimed to evaluate the efficacy and safety of YJT in concomitant treatment with ICS in patients with CVA and to determine the optimal dosage of YJT. The results are expected to provide evidence for the use of YJT as an adjuvant treatment for CVA. Hintergrund Cough-Variant-Asthma (CVA), eine Frühform von typischem Asthma, ist die Hauptursache von chronischem Husten. Unserer Vermutung nach könnte Yukmijihwang-Tang (YJT), das in der traditionellen Medizin zur Behandlung von chronischem Husten eingesetzt wird und das Berichten zufolge einen entzündungshemmenden Effekt hat, unterstützend in der Asthma-Therapie wirken. Method en: Wir planen eine randomisierte, doppelblinde, placebokontrollierte, multizentrische Phase-2-Studie, um die Wirksamkeit und Sicherheit von YJT bei Patienten mit CVA zu untersuchen. Insgesamt werden 60 CVA-Patienten für die Studie rekrutiert und nach einer zweiwöchigen Run-in-Phase randomisiert im Verhältnis 1:1:1 einer Gruppe mit hochdosiertem YJT, einer Gruppe, die YJT in der Standarddosierung erhält oder einer Kontrollgruppe (Placebo) zugewiesen. Während der Run-in-Phase werden nur inhalative Corticosteroide (ICS) verwendet, und das Prüfpräparat wird über 6 Wochen einmal täglich gleichzeitig mit den ICS angewendet. Die Datenerhebung erfolgt bei Studienbeginn, in Woche 3 sowie in Woche 6, und das primäre Zielkriterium ist die Änderung des mittleren Hustenscores (cough symptom score, CSS) vor und nach der Anwendung der Medikamente. Zu den sekundären Zielkriterien gehören der Score des Leicester Hustenfragebogens - koreanische Version (LCQ-K), die Eosinophilenzahl und der Spiegel an eosinophilem kationischen Protein, Lungenfunktionstests sowie die Anzahl der Anwendungen von Bedarfsmedikation usw. Schlussfolgerung Ziel dieser Studie ist es, die Wirksamkeit und Sicherheit von YJT bei gleichzeitiger Behandlung mit ICS bei Patienten mit CVA zu bewerten und die optimale YJT-Dosis zu ermitteln. Es wird erwartet, dass die Ergebnisse Belege für die Anwendung von YJT als adjuvante Therapie bei CVA liefern werden. Registrierung der Studie WHO International Clinical Trials Registry Platform, Clinical Research Information Service (CRIS), KCT0006994, registriert am 10. Februar 2022, https://cris.nih.go.kr/cris/search/detailSearch.do/21743.
Affiliation(s)
- Su Won Lee
- Division of Respiratory Medicine, Department of Internal Medicine, College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea,
| | - Yee Ran Lyu
- Division of Respiratory Medicine, Department of Internal Medicine, College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
- Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Won Kyung Yang
- Division of Respiratory Medicine, Department of Internal Medicine, College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
- Institute of Traditional Medicine and Bioscience, Daejeon University, Daejeon, Republic of Korea
| | - Seung Hyung Kim
- Institute of Traditional Medicine and Bioscience, Daejeon University, Daejeon, Republic of Korea
| | - Si Yeon Kim
- Department of Statistics, Graduate School, Daejeon University, Daejeon, Republic of Korea
| | - Weechang Kang
- Department of Statistics, Graduate School, Daejeon University, Daejeon, Republic of Korea
| | - In Chul Jung
- Department of Neuropsychology, College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
| | - Beom Joon Lee
- Division of Allergy, Immune and Respiratory System, Department of Internal Medicine, College of Oriental Medicine, Kyung-Hee University, Seoul, Republic of Korea
| | - Jun Yong Choi
- Department of Internal Medicine, School of Korean Medicine, Pusan National University, Busan, Republic of Korea
| | - Mee Young Lee
- Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Yang Chun Park
- Division of Respiratory Medicine, Department of Internal Medicine, College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
- Institute of Traditional Medicine and Bioscience, Daejeon University, Daejeon, Republic of Korea
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Nguyen V, Zhang Q, Pan F, Jin Q, Sun M, Tangthianchaichana J, Du S, Lu Y. Zi-Su-Zi decoction improves airway hyperresponsiveness in cough-variant asthma rat model through PI3K/AKT1/mTOR, JAK2/STAT3 and HIF-1α/NF-κB signaling pathways. JOURNAL OF ETHNOPHARMACOLOGY 2023; 314:116637. [PMID: 37187363 DOI: 10.1016/j.jep.2023.116637] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/05/2023] [Accepted: 05/12/2023] [Indexed: 05/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cough-variant asthma (CVA) is one of the most common causes of chronic cough. Its pathogenesis is closely related to chronic airway inflammation and airway hyperresponsiveness. CVA belongs to the category of "wind cough" in Traditional Chinese medicine (TCM). Zi-Su-Zi decoction (ZSD) is a Chinese herbal formula that is clinically used for the treatment of cough and asthma, especially CVA. However, the mechanism of action remains unclear. AIM OF THE STUDY In this study, we aimed to explore the potential mechanism by which ZSD improves CVA airway hyperresponsiveness. MATERIALS AND METHODS The targets of ZSD in CVA were studied using a Network pharmacology. The main chemical components of ZSD were detected and analyzed using ultra-high-pressure liquid chromatography (UHPLC-MS/MS). In animal experiments, the rat model of CVA was established using Ovalbumin (OVA)/Aluminum hydroxide (AL(OH)3) sensitization. Moreover, the experiment also evaluated cough symptoms, percentage of eosinophils (EOS%), pulmonary function tests, histopathological sections, blood cytokine levels, mRNA and protein levels. RESULTS The results showed that Network pharmacology suggested 276 targets of ZSD and CVA and found that ZSD treatment with CVA was closely related to the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. UHPLC-MS/MS revealed that ZSD contained 52 main chemical components. Compared with the model group, the cough symptoms of the rats in the different ZSD concentration groups were relieved, the EOS% index was lowered, and body weight was increased. HE staining showed that ZSD reduced airway inflammation, edema and hyperplasia, thereby improving the pathological structure of lung tissue, and the effect of high-dose ZSD was especially significant. Our most important finding was that ZSD blocked the entry of hypoxia-inducible factor-1α (HIF-1α), signal transducer and activator of transcription-3 (STAT3) and nuclear factor kappa-B (NF-κB) into the nucleus by interfering with PI3K/AKT1/mechanistic target of rapamycin (mTOR), and janus kinase 2 (JAK2) signaling factors. Consequently, inhibiting the release of cytokines and immunoglobulin-E, thereby reducing airway hyperresponsiveness (AHR) and partially reverses airway remodeling. CONCLUSIONS This study showed that ZSD can improve airway hyperresponsiveness and partially reverse airway remodeling by inhibiting the PI3K/AKT1/mTOR, JAK2/STAT3 and HIF-1α/NF-κB signaling pathways. Therefore, ZSD is an effective prescription for the treatment of CVA.
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Affiliation(s)
- Vietdung Nguyen
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 100029, Beijing, China
| | - Qing Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 100029, Beijing, China
| | - Fei Pan
- School of Clinical Medicine, Beijing University of Chinese Medicine, 100029, Beijing, China
| | - Qi Jin
- School of Clinical Medicine, Beijing University of Chinese Medicine, 100029, Beijing, China
| | - Meng Sun
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 100029, Beijing, China
| | - Jakkree Tangthianchaichana
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 100029, Beijing, China; Chulabhorn International College of Medicine, Thammasat University, 12121, Pathum Thani, Thailand
| | - Shouying Du
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 100029, Beijing, China.
| | - Yang Lu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 100029, Beijing, China.
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Qiao YN, Lin SZ, Duan XZ, Yang MH, Zhang XF, Li JJ, Kang SN, Wang YT, Zhang Y, Feng XC. A randomized, double-blind, placebo-controlled multicenter clinical trial of Xiehuang Jiejing granule in the treatment of cough variant asthma in children. Medicine (Baltimore) 2022; 101:e31636. [PMID: 36401471 PMCID: PMC9678501 DOI: 10.1097/md.0000000000031636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Cough variant asthma (CVA), also called concealed asthma or allergic asthma, is the most common cause of chronic cough in children. The disorder is mainly characterized by a nonproductive dry cough associated with a high recurrence rate that is conventionally treated with antibiotics, anti-inflammatory medications, cough suppressants, or expectorants. For millennia, Chinese herbal medicine (CHM) has been used widely in China to treat pediatric CVA cases, although high-quality evidence of CHM efficacy is lacking. In this study, the effectiveness and safety of Xiehuangjiejing (XHJJ) granule will be evaluated when used alone to treat children with CVA. METHODS AND ANALYSIS A randomized, double-blind, parallel, placebo-controlled multicenter trial will be conducted over the course of 2 weeks. A total of 180 CVA patients of ages between 4 and 7 years old will be randomly assigned to the experimental group (XHJJ granules, 4.5 g administered 3 times daily) or control group (matched placebo, 4.5 g administered 3 times daily) in a 2:1 ratio based on subject number per group, respectively. The trial will consist of a 7-day medical interventional stage and a 7-day follow-up stage. On day 7 of the follow-up stage, an evaluation of all subjects will be carried out to assess cough symptom score as the primary outcome and several secondary outcomes, including TCM (traditional Chinese medicine) syndrome score, lung function, and dosage of salbutamol aerosol inhaler therapy. Safety assessments will also be evaluated during the trial. DISCUSSION The aim of this study was to examine the effectiveness and safety of Xiehuangjiejing (XHJJ) granule using a trial protocol designed to yield high-quality, statistically robust results for use in evaluating CHM as a treatment for CVA in children.
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Affiliation(s)
- Yi-Na Qiao
- Changchun University of Chinese Medicine, Changchun, China
| | - Shuang-Zhu Lin
- Department of Respiratory Medicine, Children’s Diagnosis and Treatment Center, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, China
| | - Xiao-Zheng Duan
- Department of Respiratory Medicine, Children’s Diagnosis and Treatment Center, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, China
| | - Ming-Hang Yang
- Changchun University of Chinese Medicine, Changchun, China
| | | | - Jing-Jing Li
- Changchun University of Chinese Medicine, Changchun, China
| | - Sai-Nan Kang
- Changchun University of Chinese Medicine, Changchun, China
| | - Yu-Ting Wang
- Changchun University of Chinese Medicine, Changchun, China
| | - Ying Zhang
- Center for Evidence-based Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xiao-Chun Feng
- Department of Respiratory Medicine, Children’s Diagnosis and Treatment Center, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, China
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Exploration in the Mechanism of Zhisou San for the Treatment of Cough Variant Asthma Based on Network Pharmacology. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1698571. [PMID: 35815290 PMCID: PMC9259218 DOI: 10.1155/2022/1698571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/05/2022] [Accepted: 06/06/2022] [Indexed: 11/18/2022]
Abstract
Background Cough variant asthma (CVA) has no definitive diagnosis or pathogenic causes, and there is currently no effective and safe treatment. Methods The network pharmacology was employed to investigate possible targets of Zhisou San (ZSS) in CVA treatment. The main chemical constituents of seven herbs in ZSS were collected based on the TCMSP. To explain the main mechanism, we sequentially screened the targets of each active ingredient and constructed the network of “herb-ingredient-target-disease.” The core targets of ZSS were further confirmed by the molecular docking analysis. Furthermore, pulmonary function, histopathology, and biochemical assays in mice were used to investigate the effect of ZSS on the treatment of CVA. Results A total of 137 active ingredients and 86 potential targets for the ZSS in the treatment of CVA were screened, which were connected with the regulation of inflammatory response and immune balance, such as IL-17 signaling pathway, Th17 cell differentiation, TNF signaling pathway, Toll-like receptor signaling pathway, MAPK signaling pathway, T-cell receptor signaling pathway, Th1 and Th2 cell differentiation, and other signaling pathways closely related to the pathogenesis of CVA. Thereinto, 29 core targets contained 8 of the highest scores and could evidently bind to components such as stigmasterol, quercetin, stemoninine B, luteolin, and β-sitosterol predicted by molecular docking. Furthermore, experiments in vivo were conducted for further validation that ZSS had essential effects on lung function and histopathology as well as the inflammatory state in CVA mice, which was significantly related to regulating the Th17/Treg immune balance to reduce inflammation as the important pharmacological mechanism. Conclusion This study revealed that ZSS has multicomponent and multipathway characteristics of ZSS in the treatment of CVA, which was primarily associated with inflammation and Th17/Treg immune balance. This study provides a scientific foundation for systematically elaborating the pharmacological activities and mechanism of ZSS, as well as explaining the reliability of the TCM compatibility theory.
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Du Y, Luan J, Jiang RP, Liu J, Ma Y. Myrcene exerts anti-asthmatic activity in neonatal rats via modulating the matrix remodeling. Int J Immunopathol Pharmacol 2021; 34:2058738420954948. [PMID: 32962470 PMCID: PMC7517990 DOI: 10.1177/2058738420954948] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Myrcene (MC), an organic hydrocarbon, was found to exert anti-inflammatory, analgesic, antimutagenic and antioxidant properties. However, the protective role of MC has not been reported against neonatal asthma. Wistar rats induced with asthma were administered with MC; while asthma control and vehicle control were maintained without MC administration. At the end of the experimental period, lung histology, inflammatory cell counts, cytokine analysis, matrix protein expressions were elucidated. Rats administered with MC exerted significant (P < 0.05) defense in protecting the lung tissue with the evidenced restoration of alveolar thickening of the lung tissues. Also, the present study elicited the anti-asthmatic activity of MC, especially via modulating the extracellular matrix protein expression in the asthma-induced animals, while a significant reduction (P < 0.05) in the fibrotic markers were found in MC treated animals. Moreover, the protective effect of MC was evidenced with reduced leukocyte infiltration in BALF, hypersensitive specific IgE levels with a profound decrease in the inflammatory cytokines such as IL-2, IL-4, IL-18, and IL-21 in MC administered animals compared to the asthma-induced group. To an extent, the markers of asthmatic inflammation such as CD14, MCP-1, and TARC were also found to be attenuated in MC exposed animals. The possible application of MC is a promising drug for the treatment of asthma-mediated complications.
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Affiliation(s)
- Yanhui Du
- Department of Pediatrics, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jie Luan
- Department of Pediatrics, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Ren Peng Jiang
- Department of Pediatrics, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Juan Liu
- Department of Pediatrics, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yan Ma
- Department of Pediatrics, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
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Network Pharmacology Strategy to Investigate the Pharmacological Mechanism of HuangQiXiXin Decoction on Cough Variant Asthma and Evidence-Based Medicine Approach Validation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:3829092. [PMID: 33178315 PMCID: PMC7647767 DOI: 10.1155/2020/3829092] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 09/11/2020] [Accepted: 09/24/2020] [Indexed: 12/04/2022]
Abstract
Objective To investigate the pharmacological mechanism of HuangQiXiXin decoction (HQXXD) on cough variant asthma (CVA) and validate the clinical curative effect. Methods The active compounds and target genes of HQXXD were searched using TCMSP. CVA-related target genes were obtained using the GeneCards database. The active target genes of HQXXD were compared with the CVA-related target genes to identify candidate target genes of HQXXD acting on CVA. A medicine-compound-target network was constructed using Cytoscape 3.6.0 software, and a protein-protein interaction (PPI) network was constructed using the STRING database. Gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using RGUI3.6.1 and Cytoscape 3.6.0. We searched the main database for randomized controlled trials of HQXXD for CVA. We assessed the quality of the included studies using the Cochrane Reviewers' Handbook. A meta-analysis of the clinical curative effect of HQXXD for CVA was conducted using the Cochrane Collaboration's RevMan 5.3 software. Results We screened out 48 active compounds and 217 active target genes of HQXXD from TCMSP. The 217 active target genes of HQXXD were compared with the 1481 CVA-related target genes, and 132 candidate target genes for HQXXD acting on CVA were identified. The medicine-compound-target network and PPI network were constructed, and the key compounds and key targets were selected. GO function enrichment and KEGG pathway enrichment analysis were performed. Meta-analysis showed that the total effective rate of the clinical curative effect was significantly higher in the experimental group than the control group. Conclusion The pharmacological mechanism of HQXXD acting on CVA has been further determined, and the clinical curative effect of HQXXD on CVA is remarkable.
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Wang Y, Xu C, Xu B, Li L, Li W, Wang W, Wu M. Xiaoai Jiedu Recipe Inhibits Proliferation and Metastasis of Non-Small Cell Lung Cancer Cells by Blocking the P38 Mitogen-Activated Protein Kinase (MAPK) Pathway. Med Sci Monit 2019; 25:7538-7546. [PMID: 31590176 PMCID: PMC6792514 DOI: 10.12659/msm.917115] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Lung cancer is the leading cause of cancer deaths in the world. Its major histopathological subtype is non-small cell lung cancer (NSCLC). Xiaoai Jiedu recipe (XJR) is a traditional Chinese medicine formula that can suppress growth and invasion of tumor cells. Here, we assessed the antitumor effect of XJR on NSCLC explored the underlying mechanisms. MATERIAL AND METHODS Three concentrations of XJR (low, middle, and high) were used to treat A549 cells. Cell Counting Kit-8 and colony formation assay were used to measure proliferation of A549 cells. Apoptosis was evaluated by Hoechst 33342 staining and flow cytometry. The expression of apoptosis-associated proteins was measured by Western blot analysis. Transwell and scratch wound healing assay were used to assess invasion and migration, respectively, of A549 cells. The expression of p38 MAPK pathway-associated proteins were measured using Western blot analysis. RESULTS XJR suppressed proliferation and promoted apoptosis of A549 cells, especially in the high-dose group. The expression of Bcl-2 was reduced with increasing expression of Bax, cleaved caspase-3, and cleaved caspase-9. Invasion and migration abilities of A549 cells were inhibited after XJR treatment. XJR treatment decreased the expression levels of phosphorylated p38 (p-p38), p-ERK, and p-JNK in a dose-dependent manner. CONCLUSIONS The results demonstrated that XJR can inhibit proliferation, invasion, and migration, and induce apoptosis of NSCLC by blocking the p38 MAPK pathway, which shows the potential of XJR as a new treatment of NSCLC.
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Affiliation(s)
- Yuchao Wang
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland).,Endoscopic Center of Nanjing Chest Hospital, Nanjing, Jiangsu, China (mainland)
| | - Chunhua Xu
- Endoscopic Center of Nanjing Chest Hospital, Nanjing, Jiangsu, China (mainland)
| | - Bin Xu
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland).,Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu, China (mainland)
| | - Li Li
- Institute of Oncology, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Wenting Li
- Institute of Oncology, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Wei Wang
- Endoscopic Center of Nanjing Chest Hospital, Nanjing, Jiangsu, China (mainland)
| | - Mianhua Wu
- Institute of Oncology, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
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