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Acta Pharmaceutica Sinica B 2024年第1期14卷 241-255页

作者： Xuezhi Yang Yingjie Zhao Qi wei Xuemin Zhu Luping Wang Wankang Zhang Xiaoyi Liu Jiajie Kuai Fengling Wang wei wei institute of clinical pharmacology Anhui Medical UniversityKey Laboratory of Anti-Inflammatory and Immune MedicineAnhui Collaborative Innovation Center of Anti-Inflammatory and Immune MedicineMinistry of EducationHefei 230032China Department of clinical pharmacology the Second Affiliated Hospital of Anhui Medical UniversityHefei 230601China

Rheumatoid arthritis(RA)is an autoimmune disease with a complex ***-derived macrophages(MDMs)infiltration are associated with RA *** have reported the deletion of G-protein-coupled receptor kinase 2(GRK2)reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor ***,as more GRK2-interacting proteins were discovered,the GRK2 interactome mechanisms in RA have been ***,in the collagen-induced arthritis mouse model,we performed genetic GRK2 deletion using GRK2^(f/f)Lyz2-Cre^(+/−)*** inflammation and M1 polarization were improved in GRK2^(f/f)Lyz2-Cre^(+/−)*** experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptorγ(PPARγ)as a new GRK2-interacting *** further confirmed that fms-related tyrosine kinase 1(Flt-1),which promoted macrophage migration to induce angiogenesis,was inhibited by GRK2-PPARγ***,excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPARγligand-binding domain and enhanced Flt-1 ***,the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology,Flt-1^(+)macrophages induced-synovial inflammation,and ***,we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular *** GRK2 activity is a viable strategy to inhibit MDMs infiltration,affording a distinct way to control joint inflammation and angiogenesis of RA.

关键词： GRK2 Monocyte-derived macrophages Rheumatoid arthritis PPARg Flt-1

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Viral-mediated gene therapy in pediatric neurological disorders

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World Journal of Pediatrics 2024年第6期20卷 533-555页

作者： Jing Peng wei-wei Zou Xiao-Lei Wang Zhi-Guo Zhang Ran Huo Li Yang Department of Pediatrics Clinical Research Center for Chidren Neurodevelopmental disablities of Hunan ProvinceXiangya HospitalCentral South UniversityChangsha 410008China Reproductive Medicine Center Department of Obstetrics and Gynecologythe First Affiliated Hospital of Anhui Medical UniversityHefeiChina State Key Laboratory of Reproductive Medicine Nanjing Medical UniversityNanjingChina

Background Due to the broad application of next-generation sequencing,the molecular diagnosis of genetic disorders in pediatric neurology is no longer an unachievable ***,treatments for neurological genetic disorders in children remain primarily *** the other hand,with the continuous evolution of therapeutic viral vectors,gene therapy is becoming a clinical *** this perspective,we wrote this review to illustrate the current state regarding viral-mediated gene therapy in childhood neurological *** sources We searched databases,including PubMed and Google Scholar,using the keywords"adenovirus vector,""lentivirus vector,"and"AAv"for gene therapy,and"immunoreaction induced by gene therapy vectors,""administration routes of gene therapy vectors,"and"gene therapy"with"NCL,""SMA,""DMD,""congenital myopathy,""MPS""leukodystrophy,"or"pediatric metabolic disorders".We also screened the database of *** using the keywords"gene therapy for children"and then filtered the results with the ones aimed at neurological *** time range of the search procedure was from the inception of the databases to the *** We presented the characteristics of commonly used viral vectors for gene therapy for pediatric neurological disorders and summarized their merits and drawbacks,the administration routes of each vector,the research progress,and the clinical application status of viral-mediated gene therapy on pediatric neurological *** Viral-mediated gene therapy is on the brink of broad clinical ***-mediated gene therapy will dramatically change the treatment pattern of childhood neurological disorders,and many children with incurable diseases will meet the dawn of a ***,the vectors must be optimized for better safety and efficacy.

关键词： Gene therapy Neurological disorders Pediatrics Viral vectors

Evolution of chemistry and selection technology for DNA-encoded library

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Acta Pharmaceutica Sinica B 2024年第2期14卷 492-516页

作者： Peixiang Ma Shuning Zhang Qianping Huang Yuang Gu Zhi Zhou wei Hou wei Yi Hongtao Xu Shanghai Key Laboratory of Orthopedic Implants Department of OrthopedicsShanghai Ninth People’s HospitalShanghai Jiao Tong UniversitySchool of MedicineShanghai 200025China Shanghai institute for Advanced Immunochemical Studies ShanghaiTech UniversityShanghai 201210China Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target&clinical pharmacology The NMPA and State Key Laboratory of Respiratory DiseaseGuangzhou Medical UniversityGuangzhou 511436China College of Pharmaceutical Science and institute of Drug Development&Chemical Biology Zhejiang University of TechnologyHangzhou 310014China

DNA-encoded chemical library(DEL)links the power of amplifiable genetics and the nonself-replicating chemical phenotypes,generating a diverse chemical *** analogy with the biological world,the DEL world can evolve by using a chemical central dogma,wherein DNA replicates using the PCR reactions to amplify the genetic codes,DNA sequencing transcripts the genetic information,and DNA-compatible synthesis translates into chemical ***,DNA-compatible synthesis is the key to expanding the DEL chemical ***,the evolution-driven selection system pushes the chemicals to evolve under the selective pressure,i.e.,desired selection *** this perspective,we summarized recent advances in expanding DEL synthetic toolbox and panning strategies,which will shed light on the drug discovery harnessing in vitro evolution of chemicals via DEL.

关键词： DNA-encoded library Drug discovery High-throughput selection DNA-compatible synthesis In vitro evolution Chemical central dogma

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Strengthening pharmacotherapy research for COVID-19-induced pulmonary fibrosis

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World Journal of clinical Cases 2024年第5期12卷 875-879页

作者： Yan-Miao Liu Jing Zhang Jing-Jing Wu wei-wei Guo Fu-Shan Tang The First clinical institute Zunyi Medical UniversityZunyi 563006Guizhou ProvinceChina Key Laboratory of clinical Pharmacy in Zunyi City Zunyi Medical UniversityZunyi 563006Guizhou ProvinceChina Department of Respiratory Medicine Central Hospital in Jinchang CityJinchang 737102Gansu ProvinceChina Department of clinical Pharmacy Key Laboratory of Basic Pharmacology of Guizhou Province and School of PharmacyZunyi Medical UniversityZunyi 563006Guizhou ProvinceChina Key Laboratory of Basic pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education Zunyi Medical UniversityZunyi 563006Guizhou ProvinceChina

The global spread of severe acute respiratory syndrome coronavirus 2 has resulted in a significant number of individuals developing pulmonary fibrosis(PF),an irreversible lung *** condition can manifest within a short inter-val following the onset of pneumonia symptoms,sometimes even within a few *** lung transplantation is a potentially lifesaving procedure,its limited availability,high costs,intricate surgeries,and risk of immunological rejection present significant *** optimal timing of medication administration for coronavirus disease 2019(COVID-19)-induced PF remains *** this,it is crucial to explore pharmacotherapy interventions,involving early and preventative treatment as well as pharmacotherapy options for advanced-stage ***,studies have demonstrated disparities in anti-fibrotic treatment based on race and gender *** mutations may also impact therapeutic *** research efforts on pharmacotherapy interventions,while considering relevant pharmacological factors and optimizing the timing and dosage of medication administration,will lead to enhanced,personalized,and fair treatment for individuals impacted by COVID-19-related *** measures are crucial in lessening the burden of the disease on healthcare systems and improving patients'quality of life.

关键词： COVID-19 Pulmonary fibrosis Pharmacotherapy intervention Medication administration Timing Dosage

Computed tomography-based radiomics to predict early recurrence of hepatocellular carcinoma post-hepatectomy in patients background on cirrhosis

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World Journal of Gastroenterology 2024年第15期30卷 2128-2142页

作者： Gui-Xiang Qian Zi-Ling Xu Yong-Hai Li Jian-Lin Lu Xiang-Yi Bu Ming-Tong wei wei-Dong Jia Department of Hepatic Surgery Anhui Provincial HospitalThe First Affiliated Hospital of USTCDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei 230001Anhui ProvinceChina Department of Hepatic Surgery Anhui Provincial Hospital Affiliated to Anhui Medical UniversityAnhui Medical UniversityHefei 230001Anhui ProvinceChina Department of Anorectal Surgery the First People’s Hospital of HefeiHefei 230001Anhui ProvinceChina

BACKGROUND The prognosis for hepatocellular carcinoma(HCC)in the presence of cirrhosis is unfavourable,primarily attributable to the high incidence of *** To develop a machine learning model for predicting early recurrence(ER)of posthepatectomy HCC in patients with cirrhosis and to stratify patients’overall survival(OS)based on the predicted risk of *** In this retrospective study,214 HCC patients with cirrhosis who underwent curative hepatectomy were *** feature selection was conducted using the least absolute shrinkage and selection operator and recursive feature elimination ***-radiologic features were selected through univariate and multivariate logistic regression *** machine learning methods were used for model comparison,aiming to identify the optimal *** model’s performance was evaluated using the receiver operating characteristic curve[area under the curve(AUC)],calibration,and decision curve ***,the Kaplan-Meier(K-M)curve was used to evaluate the stratification effect of the model on patient *** Within this study,the most effective predictive performance for ER of post-hepatectomy HCC in the background of cirrhosis was demonstrated by a model that integrated radiomics features and clinical-radiologic *** the training cohort,this model attained an AUC of 0.844,while in the validation cohort,it achieved a value of *** K-M curves illustrated that the combined model not only facilitated risk stratification but also exhibited significant discriminatory ability concerning patients’*** The combined model,integrating both radiomics and clinical-radiologic characteristics,exhibited excellent performance in HCC with *** K-M curves assessing OS revealed statistically significant differences.

关键词： Machine learning Radiomics Hepatocellular carcinoma Cirrhosis Early recurrence Overall survival Computed tomography Prognosis Risk factor Delta-radiomics

Current status and trends in small nucleic acid drug development:Leading the future

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Acta Pharmaceutica Sinica B 2024年第9期14卷 3802-3817页

作者： Yuxi Miao Chen Fu Zhaojin Yu Lifeng Yu Yu Tang Minjie wei Department of pharmacology School of PharmacyChina Medical UniversityShenyang 110122China Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation China Medical UniversityShenyang 110122China Liaoning medical Diagnosis and Treatment Center Shenyang 110000China Department of Oncology Cancer Hospital of China Medical UniversityLiaoning Cancer Hospital and InstituteShenyang 110042China

Small nucleic acid drugs,composed of nucleotides,represent a novel class of pharmaceuticals that differ significantly from conventional small molecule and antibody-based *** agents function by selectively targeting specific genes or their corresponding messenger RNAs(mRNAs),further modulating gene expression and regulating translation-related *** examples within this category include antisense oligonucleotides(ASO),small interfering RNAs(siRNAs),micro-RNAs(miRNAs),and *** emergence of small nucleic acid drugs as a focal point in contemporary biopharmaceutical research is attributed to their remarkable specificity,facile design,abbreviated development cycles,expansive target spectrum,and prolonged *** challenges such as poor stability,immunogenicity,and permeability issues have been addressed through the integration of chemical modifications and the development of drug delivery *** review provides an overview of the current status and prospective trends in small nucleic acid drug *** with a historical context,we introduce the primary classifications and mechanisms of small nucleic acid ***,we delve into the advantages of the *** and Drug Administration(FDA)approved drugs and mainly discuss the challenges encountered during their *** from researching chemical modification and delivery system that efficiently deliver and enrich small nucleic acid drugs to target tissues,promoting endosomal escape is a critical scientific question and important research direction in siRNA drug *** directions in this field will prioritize addressing these challenges to facilitate the clinical transformation of small nucleic acid drugs.

关键词： Small nucleic acid drugs Oligonucleotide drugs siRNA ASO miRNA Aptamer RNAi Drug development

Therapeutic effects of glucosides of Cheanomeles speciosa on collagen-induced arthritis in mice

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Acta Pharmacologica Sinica 2004年第11期 111-117页

作者： Ling-ling ZHANG, wei wei, Shang-xue YAN, Xiang-yang HU, Wu-yi SUNinstitute of clinical pharmacology, anhui medical university, Hefei 230032, China

AIM: To investigate the therapeutic effect of the glucosides of Cheanomeles speciosa (GCS) on the collagen-induced arthritis (CIA) in mice. METHODS: Mice were divided randomly into six groups, including normal, CIA, CIA+GCS (60, 120, and 240 mg/kg) and CIA+glucosides of Tripterygium wilfordii (GTW) groups. CIA model was based on mice. The effect of GCS in CIA mice was measured by paw-swelling, arthritis scores, and histo-pathological assessment of synovium. Indices of thymus and spleens were measured. Thymocytes and splenocytes proliferation, activity of interleukin-1 (IL-1), and interleukin-2 (IL-2) were assayed by MTT and [3H]TdR method. The level of anti-collagen type Ⅱ (CII) antibody in serum and prostaglandin E (PGE) in ankle were assayed by ELISA and ultraviolet spectrophotometer method, respectively. RESULTS: The onset of paw-swelling was on d 24 after injection of emulsion. The peak of secondary inflammation appeared on d 36 and then declined after d 40. GCS and GTW significantly reduced paw-swe

关键词： glucosides Cheanomeles speciosa experimental arthritis inflammation immunity

GRK2 mediated degradation of SAV1 initiates hyperplasia of fibroblast-like synoviocytes in rheumatoid arthritis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1222-1240页

作者： Paipai Guo Ji Jiang Rui Chu Feng He Mingli Ge Ruhong Fang Qiuyun Guan Huijuan Cheng Chunru Jiang Tiantian Su Zhenduo Zhu Hao Liu wei wei Shihao Zhang Qingtong Wang institute of clinical pharmacology Anhui Medical UniversityKey Laboratory of Anti-inflammatory and Immune MedicineMinistry of EducationCollaborative Innovation Center of Anti-inflammatory and Immune MedicinesHefei 230032China School of Pharmacy Bengbu Medical CollegeBengbu 233030China The Third Affiliated Hospital of anhui medical university(the First People’s Hospital of Hefei) Hefei 230061China

Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint *** Yes-associated protein(YAP),which is a powerful transcription co-activator for proliferative genes,was observed in the nucleus of inflammatory FLSs with unknown upstream *** Gene Expression Omnibus database analysis,it was found that Salvador homolog-1(SAV1),the pivotal negative regulator of the Hippo-YAP pathway,was slightly downregulated in RA ***,SAV1 protein expression is extremely ***,it was revealed that SAV1 is phosphorylated,ubiquitinated,and degraded by interacting with an important serine-threonine kinase,G protein-coupled receptor(GPCR)kinase 2(GRK2),which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E2(PGE2)in *** process further contributes to the decreased phosphorylation,nuclear translocation,and transcriptional potency of YAP,and leads to aberrant FLSs *** depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and ***,paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical ***,these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA.

关键词： Rheumatoid arthritis Fibroblast-like synoviocytes G protein-coupled receptor kinase 2 Salvador homolog-1 Yes-associated protein

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Traditional Chinese Medicine Erhuang Suppository for Treatment of Persistent High-risk Human Papillomavirus Infection and Its Impact on Transcriptome of Uterine Cervix

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Current medical Science 2024年第4期44卷 841-853页

作者： Zi-zhuo WANG Hui-li WANG wei XIONG Juan DU Rong LIU Department of Obstetrics and Gynecology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Department of pharmacology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China

Objective High-risk human papillomavirus(HR-HPV)infection is the chief cause of cervical intraepithelial neoplasia(CIN)and cervical *** Erhuang suppository(EHS)is a traditional Chinese medicine(TCM)prepared from realgar(As2S2),Coptidis rhizoma,alumen,and borneolum syntheticum and has been used for antiviral and antitumor ***,whether EHS can efficiently alleviate HR-HPV infection remains *** study was conducted to evaluate the efficacy of EHS for the treatment of persistent HR-HPV infection in the uterine *** In this study,we evaluated the therapeutic efficacy of EHS in a randomized controlled clinical trial with a 3-month ***,70 patients with persistent HR-HPV infection were randomly assigned to receive intravaginal administration of EHS or *** DNA,ThinPrep cytologic test(TCT),colposcopy,and safety evaluation were carried out after *** analysis was performed to compare transcriptome profiles before and after EHS treatment.A K14-HPV16 mouse model was generated to confirm the efficiency of *** After 3 months,74.3%(26/35)of the patients in the treatment group were HPV negative,compared to 6.9%(2/29)in the placebo ***-throughput microarrays revealed distinct transcriptome profiles after *** differentially expressed genes were significantly enriched in complement activation,immune response,and apoptotic *** K14-HPV16 mouse model also validated the remarkable efficacy of *** This study demonstrated that EHS is effective against HR-HPV infection and cervical ***,no obvious systemic toxicity was observed in patients during the *** superior efficacy and safety of EHS demonstrated its considerable value as a potential cost-effective drug for the treatment of HPV infection and HPV-related cervical diseases.

关键词： Traditional Chinese Medicine Erhuang suppository human papillomavirus cervical diseases transcriptomics