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Targeting BCL9/BCL9L enhances antigen presentation by promoting conventional type 1 dendritic cell(cDC1)activation and tumor infiltration

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2804-2818页

作者： Fenglian He Zhongen Wu Chenglong Liu Yuanyuan Zhu Yan Zhou Enming Tian Rina Rosin-Arbesfeld Dehua Yang Ming-Wei Wang Di Zhu department of pharmacology Minhang Hospitaland Key Laboratory of Smart Drug DeliveryShanghai Engineering Research Center of Immune TherapySchool of PharmacyFudan UniversityShanghai 201203China The national Center for Drug Screening and the CAS Key Laboratory of Receptor Research Shanghai Institute of Materia MedicaChinese Academy of Sciences(CAS)Shanghai 201203China department of Microbiology and Immunology Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael department of pharmacology School of Basic Medical SciencesFudan UniversityShanghai 200032China Research Center for Deepsea Bioresources SanyaChina department of Chemistry School of ScienceThe University of TokyoTokyoJapan Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education School of PharmacyHainan Medical UniversityHaikouChina Shandong Academy of pharmaceutical Science JinanChina

Conventional type 1 dendritic cells(cDC1)are the essential antigen-presenting DC subset in antitumor *** B-cell lymphoma 9 and B-cell lymphoma 9-like(BCL9/BCL9L)inhibits tumor growth and boosts immune responses against ***,whether oncogenic BCL9/BCL9L impairs antigen presentation in tumors is still not completely ***,we show that targeting BCL9/BCL9L enhanced antigen presentation by stimulating cDC1 activation and infiltration into *** inhibition of BCL9/BCL9L with a novel inhibitor hsBCL9z96 or Bcl9/Bcl9l knockout mice markedly delayed tumor growth and promoted antitumor CD8^(+)T cell ***,targeting BCL9/BCL9L promoted antigen presentation in *** is due to the increase of cDC1 activation and tumor infiltration by the XCL1-XCR1 ***,using single-cell transcriptomics analysis,we found that Bcl9/Bcl9l deficient cDC1 were superior to wild-type(WT)cDC1 at activation and antigen presentation via NF-κB/IRF1 ***,we demonstrate that targeting BCL9/BCL9L plays a crucial role in cDC1-modulated antigen presentation of tumor-derived antigens,as well as CD8^(+)T cell activation and tumor *** BCL9/BCL9L to regulate cDC1 function and directly orchestrate a positive feedback loop necessary for optimal antitumor immunity could serve as a potential strategy to counter immune suppression and enhance cancer immunotherapy.

关键词： immunity Targeting markedly

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Low-frequency Stimulation at the Subiculum Prevents Extensive Secondary Epileptogenesis in Temporal Lobe Epilepsy

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Neuroscience Bulletin 2024年第5期40卷 564-576页

作者： Yujia Shen Yiwei Gong Xiaoli Da Shajing Gao Shuo Zhang Minjuan Sun Yuanzhi Yang Xiaoyun Qiu Menghan Li Yang Zheng Fan Fei Yi Wang Zhong Chen Cenglin Xu Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province School of Pharmaceutical ScienceZhejiang Chinese Medical UniversityHangzhou310053China Institute of pharmacology and Toxicology NHC and CAMS Key Laboratory of Medical NeurobiologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China department of Neurology First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou310003China department of Pharmacy The First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou310003China

Secondary epileptogenesis is characterized by increased epileptic susceptibility and a tendency to generate epileptiform activities outside the primary *** is one of the major resultants of pharmacoresistance and failure of surgical outcomes in epilepsy,but still lacks effective ***,we aimed to test the effects of low-frequency stimulation(LFS)at the subiculum for secondary epileptogenesis in a mouse ***,secondary epileptogenesis was simulated at regions both contralateral and ipsilateral to the primary focus by applying successive kindling *** kindled at the right CA3 showed higher seizure susceptibilities at both the contralateral CA3 and the ipsilateral entorhinal cortex and had accelerated kindling processes compared with naive *** at the ipsilateral subiculum during the primary kindling progress at the right CA3 effectively prevented secondary epileptogenesis at both the contralateral CA3 and the ipsilateral entorhinal cortex,characterized by decreased seizure susceptibilities and a retarded kindling process at those secondary *** application along with the primary epileptogenesis was ***,the effects of LFS on secondary epileptogenesis were associated with its inhibitory effect at the secondary focus through interfering with the enhancement of synaptic connections between the primary and secondary *** results imply that LFS at the subiculum is an effective preventive strategy for extensive secondary epileptogenesis in temporal lobe epilepsy and present the subiculum as a target with potential translational importance.

关键词： Secondary epileptogenesis Low-frequency stimulation Subiculum Temporal lobe epilepsy

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Insights into optimizing exosome therapies for acute skin wound healing and other tissue repair

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Frontiers of Medicine 2024年第2期18卷 258-284页

作者： Tianjing Sun Mo Li Qi Liu Anyong Yu Kun Cheng Jianxing Ma Sean Murphy Patrick Michael McNutt Yuanyuan Zhang department of Emergency Affiliated Hospital of Zunyi Medical UniversityZunyi563003China department of Nephrology Affiliated Hospital of Zunyi Medical UniversityZunyi563003China Division of pharmacology and pharmaceutical sciences School of PharmacyUniversity of Missouri-Kansas CityKansas CityMO64108USA department of Biochemistry Wake Forest University School of MedicineWinston-SalemNC27157USA Wake Forest Institute of Regenerative Medicine Wake Forest School of MedicineWinston-SalemNC27109USA

Exosome therapy holds great promise as a novel approach to improve acute skin wound *** review provides a comprehensive overview of the current understanding of exosome biology and its potential applications in acute skin wound healing and ***,small extracellular vesicles secreted by various stem cells,have emerged as potent mediators of intercellular communication and tissue *** advantage of exosome therapy is its ability to avoid potential risks associated with stem cell therapy,such as immune rejection or stem cells differentiating into unwanted cell ***,further research is necessary to optimize exosome therapy,not only in the areas of exosome isolation,characterization,and engineering,but also in determining the optimal dose,timing,administration,and frequency of exosome ***,optimization of exosome therapy is critical for the development of more effective and safer exosome-based therapies for acute skin wound healing and other diseases induced by cancer,ischemia,or *** review provides valuable insights into the potential of exosome therapy and highlights the need for further research to optimize exosome therapy for clinical use.

关键词： exosomes stem cells therapeutic impact skin wound healing

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Allosterically activating SHP2 by oleanolic acid inhibits STAT3-Th17 axis for ameliorating colitis

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2598-2612页

作者： Jinbo Hu Wen Liu Yi Zou Chenyang Jiao Jiazhen Zhu Qiang Xu Jianjun Zou Yang Sun Wenjie Guo State Key Laboratory of pharmaceutical Biotechnology Nanjing Drum Tower HospitalSchool of Life SciencesNanjing UniversityNanjing 210093China department of Clinical pharmacology Nanjing First HospitalNanjing Medical UniversityNanjing 210006China Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical UniversityXuzhou 221004China

Src homology 2 domain-containing tyrosine phosphatase 2(SHP2)is an essential tyrosine phosphatase that is pivotal in regulating various cellular signaling pathways such as cell growth,differentiation,and *** activation of SHP2 has been shown to have a therapeutic effect in colitis and Parkinson's ***,the identification of SHP2 activators and a complete understanding of their mechanism is *** used a two-step screening assay to determine a novel allosteric activator of SHP2 that stabilizes it in an open *** acid was identified as a suitable *** binding to R362,K364,and K366 in the active center of the PTP domain,oleanolic acid maintained the active open state of SHP2,which facilitated the binding between SHP2 and its *** oleanolic acid-activated SHP2 hindered Th17 differentiation by disturbing the interaction between STAT3 and IL-6Rαand inhibiting the activation of ***,via the activation of SHP2 and subsequent attenuation of the STAT3-Th17 axis,oleanolic acid effectively mitigated colitis in *** protective effect was abrogated by SHP2 knockout or administration of the SHP2 inhibitor *** findings underscore the potential of oleanolic acid as a promising therapeutic agent for treating inflammatory bowel diseases.

关键词： Oleanolic acid SHP2 STAT3 Th17 Colitis Allosteric activator

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Early proactive monitoring of DNA-thioguanine in patients with Crohn’s disease predicts thiopurine-induced late leucopenia in NUDT15/TPMT normal metabolizers

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World Journal of Gastroenterology 2024年第12期30卷 1751-1763页

作者： Ting Yang Kang Chao Xia Zhu Xue-Ding Wang Sumyuet Chan Yan-Ping Guan Jing Mao Pan Li Shao-Xing Guan Wen Xie Xiang Gao Min Huang school of pharmaceutical sciences Sun Yat-sen UniversityGuangzhou 510006Guangdong ProvinceChina Institute of Clinical pharmacology Sun Yat-sen UniversityGuangzhou 510006Guangdong ProvinceChina department of Gastroenterology The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510655Guangdong ProvinceChina department of Pharmacy The First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080Guangdong ProvinceChina Center for Pharmacogenetics and department of pharmaceutical sciences University of PittsburghPittsburghPA 15261United States

BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of *** optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there are no definitive biomarkers for late risk leucopenia *** To determine the predictive value of early monitoring of DNA-thioguanine(DNATG)or 6-thioguanine nucleotides(6TGN)for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn’s disease(CD).METHODS Blood samples were collected within two months after thiopurine initiation for detection of metabolite *** leucopenia was defined as a leukocyte count<3.5×10^(9)/L over two *** Of 148 patients studied,late leucopenia was observed in 15.6%(17/109)of NUDT15/thiopurine methyltransferase(TPMT)normal and 64.1%(25/39)of intermediate *** patients suffering late leucopenia,early DNATG levels were significantly higher than in those who did not develop late leucopenia(P=4.9×10^(-13)).The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve(AUC)of 0.855(sensitivity 83%,specificity 81%),and in NUDT15/TPMT normal metabolizers,the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902(sensitivity 88%,specificity 85%).6TGN had a relatively poor correlation with late leucopenia whether in the entire sample(P=0.021)or NUDT15/TPMT normal or intermediate metabolizers(P=0.018,P=0.55,respectively).CONCLUSION Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD,especially the former.

关键词： Thiopurine-induced late leucopenia DNA-thioguanine 6-thioguanine nucleotide Proactive therapeutic drug monitoring Crohn’s disease

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RNF6 promotes chronic myelogenous leukemia cell proliferation and migration by stabilizing vimentin via multiple atypical ubiquitinations

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Genes & Diseases 2024年第1期11卷 87-90页

作者： Hongxia Zhang Yueya Zhong Yuanming He Yujia Xu Ying Ren Haixia Zhuang Tong Sun Zhigang Zhu Xinliang Mao Institute of Clinical pharmacology Science and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouGuangdong 510403China Guangdong Provincial Key Laboratory of Protein Modification and Degradation School of Basic Medical SciencesGuangzhou Medical UniversityGuangzhouGuangdong 511436China department of pharmacology College of Pharmaceutical SciencesSoochow UniversitySuzhouJiangsu 215123China Division of Hematology&Oncology Department of GeriatricsGuangzhou First People's HospitalCollege of MedicineSouth China University of TechnologyGuangzhouGuangdong 510180China

Chronic myelogenous leukemia(CML)is a malignancy from bone marrow myeloid stem cells mainly driven by the fusion gene *** addition to BCR-ABL,other genes including RNF6 are also dysregulated in CML cells.1 RNF6,a ubiquitin ligase of the RING family,promotes various cancer cell proliferation,chemoresistance,and tumor growth in vivo by targeting various proteins for ubiquitination and degradation,including SHP1,TLE3,FOXA1,and MAD1.^(2) However,its specific mechanism in CML is not known.

关键词： ubiquitin myelogenous leukemia

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Two types of coumarins-specific enzymes complete the last missing steps in pyran- and furanocoumarins biosynthesis

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Acta Pharmaceutica Sinica B 2024年第2期14卷 869-880页

作者： Yucheng Zhao Yuedong He Liangliang Han Libo Zhang Yuanzheng Xia Fucheng Yin Xiaobing Wang Deqing Zhao Sheng Xu Fei Qiao Yibei Xiao Lingyi Kong department of Resources Science of Traditional Chinese Medicines School of Traditional Chinese Pharmacyand State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China College of Bioscience and Biotechnology Hunan Agricultural UniversityChangsha 410128China Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines Department of Natural Medicinal ChemistryChina Pharmaceutical UniversityNanjing 210009China Key Laboratory of Crop Gene Resources and Germplasm Enhancement in Southern China Ministry of AgricultureTropical Crops Genetic Resources InstituteChinese Academy of Tropical Agricultural SciencesHaikou 517317China Institute of Botany Jiangsu Province and Chinese Academy of SciencesNanjing 210014China department of pharmacology School of Pharmacyand State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China

Pyran-and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans,respectively,exhibiting diverse physiological and medical ***,the biosynthetic mechanisms for their core structures remain poorly *** we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in *** included three distinct *** prenyltransferases(PpPT1e3)responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors,and two novel CYP450 cyclases(PpDC and PpOC)crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran *** analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring *** possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific *** identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic *** study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.

关键词： Tetrahydropyrans Tetrahydrofurans Baldwin rules Coumarins CYP450cyclase

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Microgels for Cell Delivery in Tissue Engineering and Regenerative Medicine

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Nano-Micro Letters 2024年第10期16卷 576-617页

作者： Leyan Xuan Yingying Hou Lu Liang Jialin Wu Kai Fan Liming Lian Jianhua Qiu Yingling Miao Hossein Ravanbakhsh Mingen Xu Guosheng Tang Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical pharmacology the NMPA and State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical Sciences and the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436People's Republic of China school of Automation Hangzhou Dianzi UniversityHangzhou 310018People's Republic of China department of Biomedical Engineering The University of AkronAkronOH 44325USA Wallace H.Coulter department of Biomedical Engineering Georgia Institute of TechnologyAtlantaGA 30332USA

Microgels prepared from natural or synthetic hydrogel materials have aroused extensive attention as multifunctional cells or drug carriers,that are promising for tissue engineering and regenerative *** can also be aggregated into microporous scaffolds,promoting cell infiltration and proliferation for tissue *** review gives an overview of recent developments in the fabrication techniques and applications of microgels.A series of conventional and novel strategies including emulsification,microfluidic,lithography,electrospray,centrifugation,gas-shearing,three-dimensional bioprinting,*** discussed in *** characteristics and applications of microgels and microgel-based scaffolds for cell culture and delivery are elaborated with an emphasis on the advantages of these carriers in cell ***,we expound on the ongoing and foreseeable applications and current limitations of microgels and their aggregate in the field of biomedical *** stimulating innovative ideas,the present review paves new avenues for expanding the application of microgels in cell delivery techniques.

关键词： Microgels Cell delivery Scaffolds 3D bioprinting Single-cell microgels

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Network pharmacology of Xian-Lian-Jie-Du Decoction in Ameliorating Colorectal Cancer

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World Journal of Traditional Chinese Medicine 2024年第1期10卷 83-92页

作者： Ming-Xia Zhao Cheng-Lin Song Qin-Chang Zhang Hao-Jie Du Shu-Qiong Zhang Yu-Xian Shen Yang Sun Hai-Bo Cheng Wen Lv department of Pharmacy School of Basic Medical SciencesAnhui Medical UniversityHefeiAnhuiChina department of Biopharmaceutical Research Institute Anhui Medical UniversityHefeiAnhuiChina department of pharmaceutical Analysis State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijingChina Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor First Clinical CollegeNanjing University of Chinese MedicineNanjingJiangsuChina Deparment of Biotechnology and pharmaceutical sciences State Key Laboratory of Pharmaceutical BiotechnologySchool of Life SciencesNanjing UniversityNanjingJiangsuChina Deparment of Gynecology Institute of Traditional Chinese Medicine of Zhejiang ProvinceTongde Hospital of Zhejiang ProvinceHangzhouZhejiangChina

Objective:In this study,we screened for therapeutic targets of the Xian-Lian-Jie-Du decoction(XLJDD)for colorectal cancer(CRC)and explored the underlying mechanisms using network pharmacology ***:Genes associated with CRC were collected from the Gene Cards *** names of the active compounds of XLJDD were used as keywords in the“chemical name”in the Traditional Chinese Medicine Systems pharmacology(TCMSP)database to search the *** protein-protein interaction(PPI)network was constructed using Cytoscape *** Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed to identify key target ***:A total of 234 XLJDD-related targets and 250 cross-targets between XLJDD and CRC were collected based on the TCMSP and HIT 2.0 databases.A PPI network constructed based on the STRING database revealed interactions for all 250 *** network results revealed TP53,MYC,CCND1,AKT1,CASP3,and STAT3 as core potential *** pathway analysis of the 250 potential XLJDD targets for CRC in the Metascape database was performed using RStudio *** top 12 gene ratio aggregated analysis results were visualized in bubble *** interleukin(IL)-17 signaling pathway had the highest correlation with the tumor necrosis factor(TNF)signaling ***:XLJDD may be effective in ameliorating CRC by controlling inflammatory factors related to the IL-17 and TNF pathways and targeting proto-oncogenes and tumor suppressor genes,including MYC,CCND1,CTNNB1,and TP53.

关键词： Colorectal cancer network pharmacology Xian-Lian-Jie-Du decoction

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High-throughput screening of novel TFEB agonists in protecting against acetaminopheninduced liver injury in mice

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Acta Pharmaceutica Sinica B 2024年第1期14卷 190-206页

作者： Xiaojuan Chao Mengwei Niu Shaogui Wang Xiaowen Ma Xiao Yang Hua Sun Xujia Hu Hua Wang Li Zhang Ruili Huang Menghang Xia Andrea Ballabio Hartmut Jaeschke Hong-Min Ni Wen-Xing Ding department of pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKS 66160USA NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China department of Oncology the First Affiliated Hospital of Anhui Medical UniversityAnhui Medical UniversityHefei 230032China national Center for Advancing Translational sciences National Institutes of HealthBethesdaMD 20892USA Telethon Institute of Genetics and Medicine TIGEMPozzuoliNaples 80131Italy Medical Genetics Department of Translational MedicineFederico II UniversityNaples 80131Italy department of Molecular and Human Genetics Baylor College of MedicineHoustonTX 77030USA department of Internal Medicine Division of GastroenterologyHepatology&MotilityUniversity of Kansas Medical CenterKansas CityKS 66160USA

Macroautophagy(referred to as autophagy hereafter)is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and *** studies showed that autophagy protects against acetaminophen(APAP)-induced injury(AILI)via selective removal of damaged mitochondria and APAP protein *** lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with *** the present study,we showed that transcription factor EB(TFEB),a master transcription factor for lysosomal biogenesis,was impaired by APAP resulting in decreased lysosomal biogenesis in mouse *** loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI,***,overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2(NRF2)activation to protect against *** also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB *** these agonists,salinomycin,an anticoccidial and antibacterial agent,activated TFEB and protected against AILI in *** conclusion,genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.

关键词： Autophagy DILI Drug screening Hepatotoxicity Lysosome Mitochondria Mitophagy NRF2

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