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Impacts of Nutlin-3a and exercise on murine double minute 2-enriched glioma treatment

Neural Regeneration Research 2025年第4期20卷 1135-1152页

作者： Yisheng Chen Zhongcheng Fan Zhiwen Luo Xueran Kang Renwen Wan Fangqi Li Weiwei Lin Zhihua Han Beijie Qi Jinrong Lin Yaying Sun Jiebin Huang Yuzhen Xu Shiyi Chen Department of Sport Medicine Huashan HospitalFudan UniversityShanghaiChina Department of Orthopedic Surgery Hainan Province Clinical Medical CenterHaikou Affiliated Hospital of Central South University Xiangya School of MedicineHaikouHainan ProvinceChina Department of Basic Medicine Shanghai Jiao Tong University School of MedicineShanghai Jiao Tong UniversityShanghaiChina Department of Neurosurgery Second Affiliated Hospital of Zhejiang University School of MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina Department of Orthopedics Shanghai General HospitalSchool of Medicine Shanghai Jiao Tong UniversityShanghaiChina Department of Infectious Diseases Children’s Hospital of Fudan UniversityNational Children’s Medical CenterShanghaiChina Department of Rehabilitation The Second Affiliated Hospital of Shandong First Medical UniversityTaianShandong ProvinceChina

Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients,with evidence suggesting exercise may reduce mortality risks and aid neural *** role of the small ubiquitin-like modifier(SUMO)protein,especially post-exercise,in cancer progression,is gaining attention,as are the potential anti-cancer effects of *** used machine learning to create the exercise and SUMO-related gene signature(ESLRS).This signature shows how physical activity might help improve the outlook for low-grade glioma and other *** demonstrated the prognostic and immunotherapeutic significance of ESLRS markers,specifically highlighting how murine double minute 2(MDM2),a component of the ESLRS,can be targeted by *** underscores the intricate relationship between natural compounds such as nutlin-3 and immune *** comprehensive CRISPR screening,we validated the effects of specific ESLRS genes on low-grade glioma *** also revealed insights into the effectiveness of Nutlin-3a as a potent MDM2 inhibitor through molecular docking and dynamic ***-3a inhibited glioma cell proliferation and activated the p53 *** efficacy decreased with MDM2 overexpression,and this was reversed by Nutlin-3a or *** using a low-grade glioma mouse model highlighted the effect of physical activity on oxidative stress and molecular pathway ***,both physical exercise and Nutlin-3a administration improved physical function in mice bearing tumors derived from MDM2-overexpressing *** results suggest the potential for Nutlin-3a,an MDM2 inhibitor,with physical exercise as a therapeutic approach for glioma *** research also supports the use of natural products for therapy and sheds light on the interaction of exercise,natural products,and immune regulation in cancer treatment.

关键词： exercise and SUMO-related gene signatures(ESLRS) glioblastoma management low-grade glioma natural bioactives neural regeneration physical exercise

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Hepatocellular carcinoma recurrence after liver transplant:An Australian single-centre study

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World Journal of Transplantation 2025年第1期15卷 105-114页

作者： Matthew G Garas Luis Calzadilla-Bertot Briohny W Smith Luc Delriviere Byron Jaques Lingjun Mou Leon A Adams Gerry C MacQuillan George Garas Gary P Jeffrey Michael C Wallace Medical School University of Western AustraliaNedlands 6009Western AustraliaAustralia Department of Hepatology Sir Charles Gairdner HospitalNedlands 6009Western AustraliaAustralia Department of Surgery Sir Charles Gairdner HospitalNedlands 6009Western AustraliaAustralia

BACKGROUND Hepatocellular carcinoma(HCC)is a leading cause of cancer-related deaths *** transplantation(LT)offers the most effective *** recurrence is the strongest risk factor that decreases post-LT survival in patients transplanted for *** rate of HCC recurrence is generally reported as 8%-20%in the *** predictors of HCC have already been researched,however,to our knowledge there are no published studies on this topic using Australian *** To determine the rate and identify predictors of HCC recurrence in a contemporary western Australian LT *** We performed a retrospective cohort study of all liver transplants in patients with HCC at Sir Charles Gairdner hospital between 2006 and *** was collected from various health record databases and included recipient demographics,serum biochemistry,radiology,operation notes,explant histopathology and details of *** survival of HCC patients post-LT,stratified for recurrence,was calculated by Kaplan Meier *** and multivariate Cox regression was used to determine predictors of HCC recurrence *** Between 1/1/2006 and 12/31/2021,119 patients were transplanted with HCC.8.4%of subjects developed recurrent HCC after LT with median follow-up time of 5.4 *** median time to recurrence was 2.9 years±0.75 *** comparing baseline characteristics,a greater proportion of subjects with recurrence had common characteristics on explant histopathology,including>3 viable nodules(P=0.001),vascular invasion(P=0.003)and poorly differentiated HCC(P=0.03).Unadjusted survival curves showed lower 1-year,3-year,5-year and 10-year survival rates in subjects with HCC recurrence compared to those without HCC recurrence(90%vs 92%,70%vs 88%,42%vs 80%,14%vs 76%,respectively;log rank P<0.001).CONCLUSION HCC recurrence was low at 8.4%in this contemporary Australian cohort,however it significantly impacted post-LT *** studies are requir

关键词： Liver cancer Recurrence Liver transplantation Hepatocellular carcinoma Predictors Post-transplant survival Australian data

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Huanglian-Renshen-Decoction Maintains Isletβ-Cell Identity in T2DM Mice through Regulating GLP-1 and GLP-1R in Both Islet and Intestine

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Chinese Journal of Integrative Medicine 2025年第1期31卷 39-48页

作者： WU Wen-bin GAO Fan TANG Yue-heng WANG Hong-zhan DONG Hui LU Fu-er YUAN Fen Institution of Integrated Traditional Chinese and western Medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Department of Integrated Traditional Chinese and western Medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China

Objective: To elucidate the effect of Huanglian-Renshen-Decoction(HRD) on ameliorating type 2 diabetes mellitus by maintaining islet β-cell identity through regulating paracrine and endocrine glucagon-like peptide-1(GLP-1)/GLP-1 receptor(GLP-1R) in both islet and intestine. Methods: The db/db mice were divided into the model(distilled water), low-dose HRD(LHRD, 3 g/kg), high-dose HRD(HHRD, 6 g/kg), and liraglutide(400 μg/kg) groups using a random number table, 8 mice in each group. The db/m mice were used as the control group(n=8, distilled water). The entire treatment of mice lasted for 6 weeks. Blood insulin, glucose, and GLP-1levels were quantified using enzyme-linked immunosorbent assay kits. The proliferation and apoptosis factors of islet cells were determined by immunohistochemistry(IHC) and immunofluorescence(IF) staining. Then,GLP-1, GLP-1R, prohormone convertase 1/3(PC1/3), PC2, v-maf musculoaponeurotic fibrosarcoma oncogene homologue A(MafA), and pancreatic and duodenal homeobox 1(PDX1) were detected by western blot, IHC,IF, and real-time quantitative polymerase chain reaction, respectively. Results: HRD reduced the weight and blood glucose of the db/db mice, and improved insulin sensitivity at the same time(P<0.05 or P<0.01). HRD also promoted mice to secrete more insulin and less glucagon(P<0.05 or P<0.01). Moreover, it also increased the number of islet β cell and decreased islet α cell mass(P<0.01). After HRD treatment, the levels of GLP-1,GLP-1R, PC1/3, PC2, MafA, and PDX1 in the pancreas and intestine significantly increased(P<0.05 or P<0.01).Conclusion: HRD can maintain the normal function and identity of islet β cell, and the underlying mechanism is related to promoting the paracrine and endocrine activation of GLP-1 in pancreas and intestine.

关键词： type 2 diabetes mellitus Huanglian-Renshen-Decoction isletβcell glucagon-like peptide-1 glucagon-like peptide-1 receptor Chinese medicine

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Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance

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Neural Regeneration Research 2025年第3期20卷 695-714页

作者： Beibei Wu Yuqing Liu Hongli Li Lemei Zhu Lingfeng Zeng Zhen Zhang Weijun Peng Department of Integrated Traditional Chinese&western Medicine The Second Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina Academician Workstation Changsha Medical UniversityChangshaHunan ProvinceChina Yangsheng College of Traditional Chinese Medicine Guizhou University of Traditional Chinese MedicineGuiyangGuizhou ProvinceChina Qinhuangdao Shanhaiguan Pharmaceutical Co. LtdQinhuangdaoHebei ProvinceChina National Clinical Research Center for Mental Disorder The Second Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina

Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary *** amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease *** abnormalities are commonly observed in patients with Alzheimer's *** liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's ***,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's *** this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol ***,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

关键词： ABCA1 Alzheimer's disease amyloid-beta apolipoprotein E cholesterol metabolism liver liver X receptor low-density lipoprotein receptor-related protein 1 peripheral clearance tauroursodeoxycholic acid

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IL-22/IL-22R1 pathway enhances cholangiocarcinoma progression via ERK1/2 activation

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World Journal of Gastrointestinal Oncology 2025年第3期17卷 246-269页

作者： Jin Zhou Jing-Rui Chen Jin-Ming Li Shuang-Qing Han Xi-Yue Deng Zhong-Min Li Wen Tong Chao Wang Yi Bai Ya-Min Zhang The First central Clinical School Tianjin Medical UniversityTianjin 300192China Department of Hepatobiliary and Pancreatic Surgery Tianjin Nankai HospitalTianjin 300070China Department of Hepatobiliary Surgery Tianjin First Central HospitalTianjin 300070China

BACKGROUND IL-22 plays a pivotal role in the processes of inflammation and tissue healing.,but its role in cholangiocarcinoma(CCA)remains *** study explored the IL-22/IL-22R1 pathway and its impact on CCA progression through the ERK1/2 signaling *** To determine the mechanism of the IL-22/IL-22R1 pathway in CCA and provide new directions for its clinical *** IL-22R1 expression was assessed in human and rat CCA tissues utilizing immunohistochemical techniques,western blot analysis,and quantitative reverse transcription *** impact of IL-22 on CCA cells was assessed in vitro via tests for proliferation,migration,invasion,and apoptosis *** rat models of thioacetamide-induced CCA and subcutaneous xenografts in nude mice were used to assess the in vivo ***1/2 inhibitors were applied to elucidate the mechanistic role of the *** IL-22R1 was overexpressed in CCA cell lines and ***-22 treatment increased the phosphorylation of ERK1/2,promoting tumor cell proliferation,migration,invasion,and resistance to ***1/2 inhibition considerably reversed these effects both in vitro and in *** The IL-22/IL-22R1 axis promotes CCA progression by activating ERK1/2 *** this pathway with ERK1/2 inhibitors offers potential therapeutic strategies for CCA.

关键词： Cholangiocarcinoma IL-22 IL-22R1 ERK1/2 Cancer progression

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Emodin promotes the recovery of rheumatoid arthritis by regulating the crosstalk between macrophage subsets and synovial fibroblast subsets

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Animal Models and Experimental Medicine 2025年第1期8卷 44-56页

作者： Lianying Cheng Xiaofeng Rong Department of Integrated Traditional Chinese and western Medicine The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina

Background : To study the relationships among emodin, synovial fibroblasts (FLSs), and macrophages (STMs) to provide guidance for the use of emodin in rheumatoid arthritis (RA) treatment. Methods : RA clinical samples from patients with different pathological processes were collected, and the correlations between the subsets of FLSs and STMs and pathological processes were analyzed via flow cytometry. In vitro experimental methods such as enzyme linked immunosorbent assay (ELISA), western blotting, Transwell assays, CCK- 8 assays and cell coculture were used to assess cell proliferation, migration and secretion of inflammatory factors. A collagen- induced arthritis mouse model was constructed to investigate the therapeutic potential of emodin in RA by flow cytometry, micro- CT and staining. Results : Unique subsets of FLSs and STMs, namely, FAPα ^(+)THY1 − FLSs, FAPα ^(+)THY1 ^(+)FLSs, and MerTK ^(pos) TREM2 ^(high) STMs, were identified in synovial tissues from RA patients. The number of MerTK ^(pos) TREM2 ^(high) STMs was negatively correlated with the degree of damage in RA, while the number of FAPα ^(+)THY1 − FLSs was positively correlated with damage. On the one hand, emodin promoted the aggregation of MerTKposTREM2high STMs. Moreover, MerTK pos TREM2 high STM- mediated secretion of exosomes was promoted, which can inhibit the secretion of pro- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs and promote the secretion of anti- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs, thereby inhibiting FAPα ^(+)THY1 − FLS proliferation and migration, improving the local immune microenvironment, and inhibiting RA damage. Conclusion : Emodin was shown to regulate the aggregation of STM subsets and exosome secretion, affecting the secretion, proliferation and migration of inflammatory factors in FLS subsets, and ultimately achieving good therapeutic efficacy in RA patients, suggesting that it has important clinical value.

关键词： emodin fibroblast synoviocytes macrophages rheumatoid arthritis

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Tranylcypromine upregulates Sestrin 2 expression to ameliorate NLRP3-related noise-induced hearing loss

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Neural Regeneration Research 2025年第5期20卷 1483-1494页

作者： Xihang Chen Zhifeng Chen Menghua Li Weiwei Guo Shuolong Yuan Liangwei Xu Chang Lin Xi Shi Wei Chen Shiming Yang Senior Department of Otolaryngology Head and Neck Surgery Chinese PLA General HospitalChinese PLA Medical SchoolBeijingChina State Key Laboratory of Hearing and Balance Science BeijingChina National Clinical Research Center for Otolaryngologic Diseases BeijingChina Key Laboratory of Hearing Science Ministry of EducationBeijingChina Beijing Key Laboratory of Hearing Impairment Prevention and Treatment BeijingChina Department of Otorhinolaryngology Head and Neck Surgery The First Affiliated Hospital of Fujian Medical UniversityFuzhouFujian ProvinceChina Department of Otolaryngology Head and Neck Surgery The 940th Hospital of Joint Logistics Support Force of Chinese PLALanzhouGansu ProvinceChina Key Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical SciencesHainan UniversityHaikouHainan ProvinceChina Academician Workstation of hainan University School of Pharmaceutical SciencesYazhou BaySanyaHainan ProvinceChina

Noise-induced hearing loss is the primary non-genetic factor contributing to auditory ***,there are currently no effective pharmacological interventions for patients with noise-induced hearing ***,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory *** established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 *** found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with *** noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with *** findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell ***,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy *** treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)*** conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing *** findings suggest that inhibiting lysine-specific demethylase 1 is a

关键词： 4-hydroxynonenal apoptosis autophagy cleaved caspase-3 inflammation NOD-like receptor family pyrin domain-containing 3(NLRP3) noise-induced hearing loss oxidative stress Sestrin2 tranylcypromine

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Photo-controllable multiple and orthogonal regulation of gene expression by chemically modified oligonucleotides

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Science China Chemistry 2025年第2期68卷 694-704页

作者： Yang Wang Qiu-Long Zhang Yan Liu Liang-Liang Wang Chao-Qun Wu Ming Shao Xiwen Xing Juan Du Liang Xu Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute School of Pharmaceutical SciencesHainan UniversityHaikou 570228China central Laboratory Department of The Second Affiliated hospital School of MedicineThe Chinese University of Hong KongShenzhen&Longgang District People’s Hospital of ShenzhenShenzhen 518172China MOE Key Laboratory of Bioinorganic and Synthetic Chemistry School of ChemistrySun Yat-sen UniversityGuangzhou 510275China Department of Biotechnology College of Life Science and TechnologyJinan University InstitutionGuangzhou 510632China School of Pharmacy and Medical Technology Putian UniversityPutian 351100China

Gene expression must be precisely regulated in cells and functional nucleic acids are the most widely utilized tools for gene *** of how these nucleic acid tools work in the cellular environment can precisely manipulate gene expression through a non-invasive *** we report a methodology on multiplex photocontrol of functional nucleic acids to achieve totally temporal and orthogonal regulation of gene expression in living *** select two functional nucleic acid systems as examples,DNAzyme and CRISPR/Cas9,and demonstrate the power of light control for precise gene manipulation by rational design of chemically modified oligonucleotides through introduction of two photocleavable *** the previous modulation of functional nucleic acids by simply activating or deactivating,we successfully achieve versatile controlling patterns using light as the governing *** design represents a generalized pathway towards the photo-controllable functional nucleic acids,which greatly enriches the toolbox for optogenetic studies.

关键词： functional nucleic acids optogenetics modified oligonucleotides gene technology

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Longitudinal assessment of peripheral organ metabolism and the gut microbiota in an APP/PS1 transgenic mouse model of Alzheimer’s disease

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Neural Regeneration Research 2025年第10期20卷 2982-2997页

作者： Hongli Li Jianhua Huang Di Zhao Lemei Zhu Zheyu Zhang Min Yi Weijun Peng Department of Integrated Traditional Chinese&western Medicine The Second Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina National Clinical Research Center for Metabolic Diseases ChangshaHunan ProvinceChina Hunan Academy of Chinese Medicine ChangshaHunan ProvinceChina Academician Workstation Changsha Medical UniversityChangshaHunan ProvinceChina

Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut *** aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease *** do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of ***-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 ***,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 *** findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.

关键词： Alzheimer’s disease APP/PS1 mice brain-kidney axis gut microbiota heart-brain axis liver-brain axis lung-brain axis microbiota-gut-brain axis peripheral organ metabolism spleen-brain axis

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Efficacy and Safety of Zihua Wenfei Zhisou Granule in Treatment of Postinfectious Cough: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase Ⅱ Clinical Trial

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Chinese Journal of Integrative Medicine 2025年第1期31卷 3-10页

作者： LI Ting LIU Xue-mei YANG Mei WU Yan-qing LIU Wei MAO Bing JIANG Hong-li Division of Pulmonary Medicine Department of Internal MedicineInstitute of Integrated Traditional Chinese and Western MedicineWest China HospitalSichuan UniversityChengdu610041China Department of Pulmonary Diseases State Key Laboratory of Biotherapy of ChinaWest China HospitalSichuan UniversityChengdu610041China

Objective: To evaluate the efficacy and safety of Chinese medicine(CM) Zihua Wenfei Zhisou Granule(ZWZG) in postinfectious cough(PIC) patients with CM syndrome of wind-cold invading Fei(Lung,WCIF). Methods: This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled phase Ⅱclinical trial. PIC patients with WCIF syndrome were recruited from the Respiratory Departments in 6 hospitals across China between March 2019 and December 2020. Eligible patients were randomly assigned to group A(ZWZG-matched placebo 15 g), group B(active ZWZG 15 g), and group C(active ZWZG 10 g plus ZWZGmatched placebo 5 g) in a 1:1:1 ratio. All medications were taken orally 3 times daily for 14 consecutive days. The primary outcomes were cough relief rate and cough disappearance rate. The secondary outcomes included time to cough relief, time to cough disappearance, and changes in cough symptom score(CSS), cough Visual Analog Scale(VAS) value, Cough-Specific Quality of Life Questionnaire(CQLQ) score, and CM syndrome score from baseline(day 0) to post-treatment(day 14). Adverse events(AEs) in each group were recorded. Results: A total of 198 patients were included in the full analysis set(FAS) and safety analysis set(SS), while 183 were enrolled in the per-protocol analysis set(PPS). In the FAS population, the cough relief rate was 47.76%, 90.77% and 84.85%in groups A, B, and C, respectively;while the cough disappearance rate was 31.34%, 72.31% and 68.18%,respectively. The cough relief rates and cough disappearance rates in groups B and C were significantly higher than group A(P<0.0001). Both the median time to cough relief and cough disappearance in groups B and C were shorter than group A(P<0.0001). Compared with group A, groups B and C showed significantly greater improvements from baseline to post-treatment in CSS during daytime and nighttime as well as VAS(P<0.05).There were no significant differences in changes from baseline to post-treatment in CQLQ and CM syndrome

关键词： postinfectious cough Zihua Wenfei Zhisou Granule randomized controlled trial Chinese medicine

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