{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:49:58Z","timestamp":1790786998934,"version":"4.1.0"},"reference-count":58,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82274404"],"award-info":[{"award-number":["82274404"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82104348"],"award-info":[{"award-number":["82104348"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Scientific Research Project of \u201cLeading Program\u201d by First-class Discipline of NJUCM","award":["ZYXYL2024-015"],"award-info":[{"award-number":["ZYXYL2024-015"]}]},{"name":"Regional Innovation and Development Joint Fund of National Natural Science Foundation of China","award":["U23A20502"],"award-info":[{"award-number":["U23A20502"]}]},{"name":"High Level Key Discipline Construction Project of the National Administration of Traditional Chinese Medicine - Resource Chemistry of Chinese Medicinal Materials","award":["zyyzdxk-2023083"],"award-info":[{"award-number":["zyyzdxk-2023083"]}]},{"name":"Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine","award":["ZYYCXTD-D-202005"],"award-info":[{"award-number":["ZYYCXTD-D-202005"]}]},{"name":"the Six Talents Peaks Project","award":["JNHB-066"],"award-info":[{"award-number":["JNHB-066"]}]},{"name":"the Major Projects of Natural Science Foundation of Universities in Jiangsu Province","award":["23KJA360005"],"award-info":[{"award-number":["23KJA360005"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81573555"],"award-info":[{"award-number":["81573555"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>The herbal pair of Trichosanthis Pericarpium \u2013 Trichosanthis Radix (TP-TR) is derived from the classic prescription Bei-Mu-Gua-Lou-San in Yixue Xinwu, which is commonly used to treat lung heat and cough. Both originate from <jats:italic>Trichosanthes kirilowii<\/jats:italic> Maxim, a medicinal plant known for its effects to clear heat, dissolve phlegm, promote salivation, and relieve dryness. However, the compatibility, pharmacological synergy and gut-lung axis regulation mechanisms of TP-TR remain unclear. This study innovatively explores the therapeutic effects and underlying mechanisms of TP-TR in COPD through microbiome and amino acid metabolism. A COPD rat model was established to evaluate the efficacy of TP-TR. The gut microbiota was analyzed with 16S rRNA sequencing, while the metabolites in serum and lung were analyzed by UPLC-MS\/MS. Functional prediction of the microbiome and differential metabolite analysis were performed using KEGG\/SMP. The LPS, CSE \u2013 induced cell model was used to validate the impact of TP-TR and its active components on amino acid metabolism. The results demonstrated that TP-TR significantly improved pulmonary function, alleviated inflammation, modulated gut microbiota composition (e.g., <jats:italic>Lactobacillus<\/jats:italic>, <jats:italic>g_ Novosphingobium<\/jats:italic>), and regulated metabolic disturbances in COPD rats. Notably, amino acid metabolic pathways were consistently enriched across microbiota function prediction and untargeted metabolomic analyses of serum and lung. Targeted metabolomics further confirmed alterations in amino acid levels. Moreover, TP-TR, along with cucurbitacin B, cynaroside, glutamine, guanine, and apigenin induced alterations in the amino acid content of model cells. These findings reveal a novel mechanism by which TP-TR ameliorates COPD through gut microbiota regulation and amino acid metabolism modulation along the gut-lung axis.<\/jats:p>","DOI":"10.1371\/journal.pone.0330621","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T17:27:53Z","timestamp":1755883673000},"page":"e0330621","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Investigating the Trichosanthis Pericarpium - Trichosanthis Radix herbal pair\u2019s role in alleviating COPD through gut microbiota function, metabolomics analysis and cell validation experiment"],"prefix":"10.1371","volume":"20","author":[{"given":"Yushan","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelei","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erxin","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingling","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shulan","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huangqin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-ao","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2664-0551","authenticated-orcid":true,"given":"Pei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"issue":"1","key":"pone.0330621.ref001","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S2213-2600(23)00461-7","article-title":"GOLD COPD report: 2024 update","volume":"12","author":"P Venkatesan","year":"2024","journal-title":"Lancet Respir Med"},{"issue":"5","key":"pone.0330621.ref002","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/S2213-2600(21)00555-5","article-title":"Pathogenesis of chronic obstructive pulmonary disease: understanding the contributions of gene-environment interactions across the lifespan","volume":"10","author":"A Agust\u00ed","year":"2022","journal-title":"Lancet Respir Med"},{"key":"pone.0330621.ref003","article-title":"Burden of chronic obstructive pulmonary disease and its attributable risk factors in 204 countries and territories, 1990-2019: results from the Global Burden of Disease Study 2019","volume":"378","author":"S Safiri","year":"2022","journal-title":"BMJ"},{"key":"pone.0330621.ref004","doi-asserted-by":"crossref","first-page":"1404615","DOI":"10.3389\/fimmu.2024.1404615","article-title":"Inflammation mechanism and research progress of COPD","volume":"15","author":"J Xu","year":"2024","journal-title":"Front Immunol"},{"issue":"5","key":"pone.0330621.ref005","doi-asserted-by":"crossref","first-page":"965","DOI":"10.3390\/antiox11050965","article-title":"Oxidative Stress in Chronic Obstructive Pulmonary Disease","volume":"11","author":"PJ Barnes","year":"2022","journal-title":"Antioxidants (Basel)"},{"issue":"12","key":"pone.0330621.ref006","doi-asserted-by":"crossref","first-page":"6351","DOI":"10.3390\/ijms22126351","article-title":"The Serpin Superfamily and Their Role in the Regulation and Dysfunction of Serine Protease Activity in COPD and Other Chronic Lung Diseases","volume":"22","author":"GA Kelly-Robinson","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"3","key":"pone.0330621.ref007","doi-asserted-by":"crossref","first-page":"471","DOI":"10.23736\/S0026-4806.22.08024-7","article-title":"New drugs under development for COPD","volume":"113","author":"I Uwagboe","year":"2022","journal-title":"Minerva Med"},{"issue":"10","key":"pone.0330621.ref008","first-page":"2869","article-title":"Based on data mining and network pharmacology, the law and mechanism of traditional Chinese medicine medication for chronic obstructive pulmonary disease were studied","volume":"43","author":"F Wu","year":"2021","journal-title":"Chin Tradit Patent Med"},{"issue":"7","key":"pone.0330621.ref009","doi-asserted-by":"crossref","first-page":"861","DOI":"10.3390\/antiox13070861","article-title":"Antioxidant and Neuroprotective Effects of Seed Oils from Trichosanthes kirilowii and T. laceribractea in Caenorhabditis elegans: A Comparative Analysis and Mechanism Study","volume":"13","author":"W Wang","year":"2024","journal-title":"Antioxidants (Basel)"},{"issue":"6","key":"pone.0330621.ref010","first-page":"1617","article-title":"Analysis of quality markers based on efficacy and material base of different medicinal parts of Trichosanthes kirilowii","volume":"51","author":"YT Tang","year":"2020","journal-title":"Chinese Traditional and Herbal Drugs"},{"key":"pone.0330621.ref011","doi-asserted-by":"crossref","first-page":"117096","DOI":"10.1016\/j.jep.2023.117096","article-title":"Optimal compatibility proportional screening of Trichosanthis Pericarpium - Trichosanthis Radix and its anti - Inflammatory components effect on experimental zebrafish and coughing mice","volume":"319","author":"P Liu","year":"2024","journal-title":"J Ethnopharmacol"},{"issue":"1","key":"pone.0330621.ref012","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1186\/s12967-022-03481-w","article-title":"The treatment of Qibai Pingfei Capsule on chronic obstructive pulmonary disease may be mediated by Th17\/Treg balance and gut-lung axis microbiota","volume":"20","author":"Y Jia","year":"2022","journal-title":"J Transl Med"},{"issue":"1","key":"pone.0330621.ref013","doi-asserted-by":"crossref","first-page":"2414805","DOI":"10.1080\/19490976.2024.2414805","article-title":"The role and mechanism of gut-lung axis mediated bidirectional communication in the occurrence and development of chronic obstructive pulmonary disease","volume":"16","author":"X Song","year":"2024","journal-title":"Gut Microbes"},{"key":"pone.0330621.ref014","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.2147\/COPD.S376714","article-title":"Metabolomics Reveals Dysregulated Sphingolipid and Amino Acid Metabolism Associated with Chronic Obstructive Pulmonary Disease","volume":"17","author":"J Kim","year":"2022","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"issue":"15","key":"pone.0330621.ref015","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.3390\/cells11152283","article-title":"Reprogramming of Amino Acid Metabolism Differs between Community-Acquired Pneumonia and Infection-Associated Exacerbation of Chronic Obstructive Pulmonary Disease","volume":"11","author":"H Arshad","year":"2022","journal-title":"Cells"},{"issue":"9","key":"pone.0330621.ref016","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1164\/rccm.202206-1066TR","article-title":"The Bidirectional Gut-Lung Axis in Chronic Obstructive Pulmonary Disease","volume":"207","author":"L Wang","year":"2023","journal-title":"Am J Respir Crit Care Med"},{"key":"pone.0330621.ref017","doi-asserted-by":"crossref","first-page":"796288","DOI":"10.3389\/fimmu.2022.796288","article-title":"Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging","volume":"13","author":"Y Mou","year":"2022","journal-title":"Front Immunol"},{"issue":"5","key":"pone.0330621.ref018","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.chom.2024.04.004","article-title":"Microbiota metabolism of intestinal amino acids impacts host nutrient homeostasis and physiology","volume":"32","author":"T-T Li","year":"2024","journal-title":"Cell Host Microbe"},{"key":"pone.0330621.ref019","doi-asserted-by":"crossref","first-page":"868086","DOI":"10.3389\/fmicb.2022.868086","article-title":"COPD and Gut-Lung Axis: How Microbiota and Host Inflammasome Influence COPD and Related Therapeutics","volume":"13","author":"L Qu","year":"2022","journal-title":"Front Microbiol"},{"key":"pone.0330621.ref020","doi-asserted-by":"crossref","first-page":"1270661","DOI":"10.3389\/fphar.2024.1270661","article-title":"Bufei Huoxue capsule attenuates COPD-related inflammation and regulates intestinal microflora, metabolites","volume":"15","author":"Y Li","year":"2024","journal-title":"Front Pharmacol"},{"key":"pone.0330621.ref021","first-page":"6615615","article-title":"Mechanism of Yifei Decoction Combined with MitoQ on Inhibition of TGF\u03b21\/NOX4 and PDGF\/ROCK Signal Pathway in Idiopathic Pulmonary Fibrosis","volume":"2021","author":"L Chen","year":"2021","journal-title":"Evid Based Complement Alternat Med"},{"issue":"7","key":"pone.0330621.ref022","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.3390\/molecules24071440","article-title":"Comparative Analysis of Carbohydrates, Nucleosides and Amino Acids in Different Parts of Trichosanthes kirilowii Maxim. by (Ultra) High-Performance Liquid Chromatography Coupled with Tandem Mass Spectrometry and Evaporative Light Scattering Detector Methods","volume":"24","author":"H-Q Zhang","year":"2019","journal-title":"Molecules"},{"issue":"14","key":"pone.0330621.ref023","first-page":"3494","article-title":"Regional differences of nucleosides and amino acids in Elaphuri Davidiani Cornu","volume":"46","author":"Q Wang","year":"2021","journal-title":"Zhongguo Zhong Yao Za Zhi"},{"issue":"1","key":"pone.0330621.ref024","doi-asserted-by":"crossref","first-page":"60","DOI":"10.3892\/etm.2020.9492","article-title":"Long non-coding RNA maternally expressed gene regulates cigarette smoke extract induced lung inflammation and human bronchial epithelial apoptosis via miR-149-3p","volume":"21","author":"Z Lei","year":"2021","journal-title":"Exp Ther Med"},{"issue":"5","key":"pone.0330621.ref025","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s10565-020-09522-8","article-title":"Regulation of DNA methylation signatures on NF-\u03baB and STAT3 pathway genes and TET activity in cigarette smoke extract-challenged cells\/COPD exacerbation model in vitro","volume":"36","author":"G Kaur","year":"2020","journal-title":"Cell Biol Toxicol"},{"issue":"04","key":"pone.0330621.ref026","first-page":"1766","article-title":"The effect of streptococcus uberis infection on amino acid metabolism in mammary epithelial cells","volume":"55","author":"JY Lu","year":"2024","journal-title":"Acta Vet Zootech Sin"},{"issue":"10342","key":"pone.0330621.ref027","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1016\/S0140-6736(22)00470-6","article-title":"Chronic obstructive pulmonary disease","volume":"399","author":"SA Christenson","year":"2022","journal-title":"Lancet"},{"issue":"6","key":"pone.0330621.ref028","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1111\/resp.14041","article-title":"Chronic obstructive pulmonary disease exacerbation fundamentals: Diagnosis, treatment, prevention and disease impact","volume":"26","author":"M MacLeod","year":"2021","journal-title":"Respirology"},{"key":"pone.0330621.ref029","doi-asserted-by":"crossref","first-page":"964112","DOI":"10.3389\/fmicb.2022.964112","article-title":"A microsatellite DNA-derived oligodeoxynucleotide attenuates lipopolysaccharide-induced acute lung injury in mice by inhibiting the HMGB1-TLR4-NF-\u03baB signaling pathway","volume":"13","author":"C Zhang","year":"2022","journal-title":"Front Microbiol"},{"key":"pone.0330621.ref030","doi-asserted-by":"crossref","first-page":"821941","DOI":"10.3389\/fphar.2022.821941","article-title":"Potential Natural Small Molecular Compounds for the Treatment of Chronic Obstructive Pulmonary Disease: An Overview","volume":"13","author":"L-Y Li","year":"2022","journal-title":"Front Pharmacol"},{"issue":"4","key":"pone.0330621.ref031","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0225560","article-title":"Oral feeding with probiotic Lactobacillus rhamnosus attenuates cigarette smoke-induced COPD in C57Bl\/6 mice: Relevance to inflammatory markers in human bronchial epithelial cells","volume":"15","author":"JL Carvalho","year":"2020","journal-title":"PLoS One"},{"key":"pone.0330621.ref032","author":"JM Liu","year":"2023"},{"key":"pone.0330621.ref033","doi-asserted-by":"crossref","first-page":"154831","DOI":"10.1016\/j.phymed.2023.154831","article-title":"The activities and mechanisms of intestinal microbiota metabolites of TCM herbal ingredients could be illustrated by a strategy integrating spectrum-effects, network pharmacology, metabolomics and molecular docking analysis: Platycodin D as an example","volume":"115","author":"Y-H Zhong","year":"2023","journal-title":"Phytomedicine"},{"key":"pone.0330621.ref034","doi-asserted-by":"crossref","first-page":"1042189","DOI":"10.3389\/fphar.2022.1042189","article-title":"Gut microbiome and human health: Exploring how the probiotic genus Lactobacillus modulate immune responses","volume":"13","author":"S Rastogi","year":"2022","journal-title":"Front Pharmacol"},{"key":"pone.0330621.ref035","doi-asserted-by":"crossref","first-page":"798350","DOI":"10.3389\/fmicb.2021.798350","article-title":"Feeding Bacillus subtilis ATCC19659 to Broiler Chickens Enhances Growth Performance and Immune Function by Modulating Intestinal Morphology and Cecum Microbiota","volume":"12","author":"TM Mohamed","year":"2022","journal-title":"Front Microbiol"},{"issue":"5","key":"pone.0330621.ref036","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1111\/all.13709","article-title":"Bacterial secretion of histamine within the gut influences immune responses within the lung","volume":"74","author":"W Barcik","year":"2019","journal-title":"Allergy"},{"issue":"3","key":"pone.0330621.ref037","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/s41590-020-00856-3","article-title":"Microbial metabolism of L-tyrosine protects against allergic airway inflammation","volume":"22","author":"TP Wypych","year":"2021","journal-title":"Nat Immunol"},{"issue":"1","key":"pone.0330621.ref038","doi-asserted-by":"crossref","DOI":"10.1111\/bcpt.70065","article-title":"p-Cresol and p-Cresyl Sulphate Boost Oxidative Stress: A Systematic Review of Recent Evidence","volume":"137","author":"R Renaldi","year":"2025","journal-title":"Basic Clin Pharmacol Toxicol"},{"issue":"1","key":"pone.0330621.ref039","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.aninu.2020.11.003","article-title":"Mutual interaction between gut microbiota and protein\/amino acid metabolism for host mucosal immunity and health","volume":"7","author":"L Wu","year":"2021","journal-title":"Anim Nutr"},{"issue":"1","key":"pone.0330621.ref040","doi-asserted-by":"crossref","first-page":"5886","DOI":"10.1038\/s41467-020-19701-0","article-title":"Disease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease","volume":"11","author":"KL Bowerman","year":"2020","journal-title":"Nat Commun"},{"issue":"11","key":"pone.0330621.ref041","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1016\/j.tem.2020.02.012","article-title":"Gut Microbial Metabolites of Aromatic Amino Acids as Signals in Host-Microbe Interplay","volume":"31","author":"Y Liu","year":"2020","journal-title":"Trends Endocrinol Metab"},{"key":"pone.0330621.ref042","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.2147\/COPD.S359428","article-title":"The Bufei Jianpi Formula Improves Mucosal Immune Function by Remodeling Gut Microbiota Through the SCFAs\/GPR43\/NLRP3 Pathway in Chronic Obstructive Pulmonary Disease Rats","volume":"17","author":"J Mao","year":"2022","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"key":"pone.0330621.ref043","doi-asserted-by":"crossref","first-page":"1441015","DOI":"10.3389\/fmicb.2024.1441015","article-title":"Protective effect of Shenqi Wenfei Formula against lipopolysaccharide\/cigarette smoke-induced COPD in Rat based on gut microbiota and network pharmacology analysis","volume":"15","author":"M Shi","year":"2024","journal-title":"Front Microbiol"},{"key":"pone.0330621.ref044","doi-asserted-by":"crossref","first-page":"114060","DOI":"10.1016\/j.ecoenv.2022.114060","article-title":"Probiotics ameliorates pulmonary inflammation via modulating gut microbiota and rectifying Th17\/Treg imbalance in a rat model of PM2.5 induced lung injury","volume":"244","author":"Y Wu","year":"2022","journal-title":"Ecotoxicol Environ Saf"},{"issue":"7","key":"pone.0330621.ref045","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1038\/s12276-020-0469-y","article-title":"Fecal microbial transplantation and a high fiber diet attenuates emphysema development by suppressing inflammation and apoptosis","volume":"52","author":"YO Jang","year":"2020","journal-title":"Exp Mol Med"},{"issue":"13","key":"pone.0330621.ref046","doi-asserted-by":"crossref","first-page":"7130","DOI":"10.3390\/ijms23137130","article-title":"Cucurbitacin B Down-Regulates TNF Receptor 1 Expression and Inhibits the TNF-\u03b1-Dependent Nuclear Factor \u03baB Signaling Pathway in Human Lung Adenocarcinoma A549 Cells","volume":"23","author":"E Kusagawa","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"3","key":"pone.0330621.ref047","first-page":"384","article-title":"Screening of effective antioxidant components from Trichosanthes extract and assessment of their antioxidant activity","volume":"42","author":"M Sun","year":"2022","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao"},{"issue":"12","key":"pone.0330621.ref048","first-page":"1331","article-title":"Research progress on glutamine metabolism in pulmonary fibrosis","volume":"34","author":"EG Yin","year":"2021","journal-title":"J Med Res Combat Trauma Care"},{"issue":"16","key":"pone.0330621.ref049","doi-asserted-by":"crossref","first-page":"5230","DOI":"10.3390\/jcm12165230","article-title":"Biomarkers of the L-Arginine\/Dimethylarginine\/Nitric Oxide Pathway in People with Chronic Airflow Obstruction and Obstructive Sleep Apnoea","volume":"12","author":"J Hannemann","year":"2023","journal-title":"J Clin Med"},{"issue":"1","key":"pone.0330621.ref050","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1186\/s12931-019-1133-8","article-title":"Dysregulation of the endothelial nitric oxide pathway is associated with airway inflammation in COPD","volume":"20","author":"B Csoma","year":"2019","journal-title":"Respir Res"},{"key":"pone.0330621.ref051","doi-asserted-by":"crossref","first-page":"627503","DOI":"10.3389\/fphar.2021.627503","article-title":"Arginine Therapy for Lung Diseases","volume":"12","author":"JA Scott","year":"2021","journal-title":"Front Pharmacol"},{"issue":"1","key":"pone.0330621.ref052","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3390\/ijms22010056","article-title":"Human Nitric Oxide Synthase-Its Functions, Polymorphisms, and Inhibitors in the Context of Inflammation, Diabetes and Cardiovascular Diseases","volume":"22","author":"M Kr\u00f3l","year":"2020","journal-title":"Int J Mol Sci"},{"key":"pone.0330621.ref053","doi-asserted-by":"crossref","first-page":"11786469241232871","DOI":"10.1177\/11786469241232871","article-title":"Kynurenine Pathway in Respiratory Diseases","volume":"17","author":"G Pamart","year":"2024","journal-title":"Int J Tryptophan Res"},{"issue":"9","key":"pone.0330621.ref054","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.3390\/antiox12091713","article-title":"Advances in the Use of N-Acetylcysteine in Chronic Respiratory Diseases","volume":"12","author":"D Mokra","year":"2023","journal-title":"Antioxidants (Basel)"},{"issue":"7","key":"pone.0330621.ref055","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1021\/acschemneuro.0c00544","article-title":"Paeoniflorin and Plycyrrhetinic Acid Synergistically Alleviate MPP+\/MPTP-Induced Oxidative Stress through Nrf2-Dependent Glutathione Biosynthesis Mechanisms","volume":"12","author":"H Dong","year":"2021","journal-title":"ACS Chem Neurosci"},{"key":"pone.0330621.ref056","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.ijbiomac.2021.03.075","article-title":"Role of receptor tyrosine kinases mediated signal transduction pathways in tumor growth and angiogenesis-New insight and futuristic vision","volume":"180","author":"XL Huang","year":"2021","journal-title":"Int J Biol Macromol"},{"issue":"1","key":"pone.0330621.ref057","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s12964-021-00770-7","article-title":"The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK\/STAT signalling","volume":"19","author":"J Fiebelkow","year":"2021","journal-title":"Cell Commun Signal"},{"issue":"29","key":"pone.0330621.ref058","doi-asserted-by":"crossref","first-page":"7043","DOI":"10.1007\/s00216-024-05608-y","article-title":"Metabolic fate of the natural anticancer agent cucurbitacin B: an LC-MS\/MS-enabled profiling of its major phase I and II conjugates in vivo","volume":"416","author":"W-Y Liu","year":"2024","journal-title":"Anal Bioanal Chem"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0330621","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T17:28:01Z","timestamp":1755883681000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0330621"}},"subtitle":[],"editor":[{"given":"Zhiling","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,8,22]]},"references-count":58,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8,22]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0330621","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,22]]}}}