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Emerging role of ubiquitination/deubiquitination modification of PD-1/PD-L1 in cancer immunotherapy

Genes & Diseases 2023年第3期10卷 848-863页

作者： Peng Ding Zhiqiang Ma Yizeng Fan yingtong feng Changjian Shao Minghong Pan Yimeng Zhang Di Huang Jing Han Yi Hu Xiaolong Yan Department of Thoracic Surgery Tangdu HospitalThe Air Force Military Medical UniversityXi'anShaanxi 710038China Department of Medical Oncology Senior Department of OncologyThe Fifth Medical Center of PLA General HospitalBeijing 100853China Department of Urology The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi 710061China Department of Ophthalmology Tangdu HospitalThe Air Force Medical UniversityXi'anShaanxi 710038China

As members of the immune checkpoint family, PD-1 and its ligand PD-L1 play critical roles in maintaining the balance between autoimmunity and tolerance. The interaction of PD-1/PD-L1 is also involved in tumor evasion inside the tumor microenvironment, caused by reduced T cell activation, proliferation, cytotoxic secretion, and survival. Previous research has shown that the expression level of PD-1/PD-L1 may be regulated by ubiquitin-mediated proteasome degradation, which is an important mode of post-translational modification (PTM). PD-1/PD-L1 ubiquitin modification research in tumor immunotherapy is the subject of the present review, which aims to assess the most recent developments in this area. We offer a short explanation of PD-1/PD-L1 as well as some basic background information on the UPS system and discuss many routes that target E3s and DUBs, respectively, in the regulation of PD-1/PD-L1 in tumor immunotherapy. In addition, we offer numerous innovative prospective research areas for the future, as well as novel immunotherapy concepts and ideas. Taken together, the information compiled herein should serve as a comprehensive repository of information about tumor immunotherapy that is currently available, and it should be useful in the design of future studies, as well as the development of potential targets and strategies for future tumor immunotherapy.

关键词： Cancer Deubiquitination Immunotherapy PD-1 PD-L1 Ubiquitination

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Neuroprotective effects of Shaoyao Gancao decoction against excitatory damage in PC12 cells based on the Src-NR2-nNOS pathway

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Journal of Traditional Chinese Medical Sciences 2024年第3期11卷 293-302页

作者： Xiaoxu Fan Hongyan Ma Tiantian Zhou Min Fu Zhiyuan Qiao yingtong feng Zhen Wang Yiwei Shen Jingxia Wang School of Traditional Chinese Medicine Beijing University of Chinese MedicineBeijing 102488China School of Traditional Chinese Medicine Xinjiang Medical UniversityUrumqi 830017China The Centre for Translational Biology Research Institute of McGill University Health CentreMontréal H4A 3J1Canada

Objective:To explore the neuroprotective effects of the Shaoyao Gancao decoction(SGD)against excitatory damage in PC12 cells and the role of the Src-NR2-nNOS pathway mediation by SGD in regulatingγ-aminobutyric acid(GABA)-glutamate(Glu)***: N-Methyl-d-aspartic acid(NMDA)was used to establish a PC12 cell excitability injury *** investigate the neuroprotective effect of SGD,a cell counting kit-8(CCK-8)assay was used to determine PC12 cell viability,Annexin V/Propidium Iodide(Annexin V/PI)double staining was used to determine PC12 cell apoptosis,and Ca^(2+)concentration was observed using laser confocal *** receptor agonists and antagonists were used to analyze the neuroprotective interactions betweenγ-aminobutyric acid(GABA)and NMDA ***,molecular biology techniques were used to determine mRNA and protein expression in the Src-NR2-nNOS *** analyzed the correlations between the regulatory sites of GABA and NMDA interactions,excitatory neurotoxicity,and brain damage at the molecular ***: NMDA excitotoxic injury manifested as a significant decrease in cell activity,increased apoptosis and caspase-3 protein expression,and a significant increase in intracellular Ca^(2+)*** of SGD,a GABAA receptor agonist(muscimol),or a GABAB receptor agonist(baclofen)decreased intracellular Ca^(2+)concentrations,attenuated apoptosis,and reversed NMDA-induced upregulation of caspase-3,Src,NMDAR2A,NMDAR2B,and ***,a GABA_(A)receptor antagonist(bicuculline)and a GABA_(B)receptor antagonist(saclofen)failed to significantly increase excitatory ***: Taken together,these results not only provide an experimental basis for SGD administration in the clinical treatment of central nervous system injury diseases,but also suggest that the Src-NR2A-nNOS pathway may be a valuable target in excitotoxicity treatment.

关键词： Shaoyao Gancao decoction PC12 N-Methyl-D-aspartic acid(NMDA) γ-aminobutyric acid(GABA) Src nNOs

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Virologica Sinica 2023年第5期38卷 813-826页

作者： Yang Li Lele Xu Dian Jiao Zifang Zheng Zhihao Chen Yang Jing Zhiwei Li Zhiqian Maa yingtong feng Xuyang Guo Yumiao Wang Yuan He Haixue Zheng Shuqi Xiao State Key Laboratory for Animal Disease Control and Prevention College of Veterinary MedicineLanzhou UniversityLanzhou Veterinary Research InstituteChinese Academy of Agricultural SciencesLanzhou730046China College of Veterinary Medicine Northwest A&F UniversityYangling712100China

Porcine reproductive and respiratory syndrome(PRRS)is one of the most significant diseases affecting the pig industry *** PRRSV mutation rate is the highest among the RNA *** date,NADC30-like PRRSV and highly pathogenic PRRSV(HP-PRRSV)are the dominant epidemic strains in China;however,commercial vaccines do not always provide sufficient cross-protection,and the reasons for insufficient protection are *** study isolated a wild-type NADC30-like PRRSV,SX-YL1806,from Shaanxi *** challenge experiments in piglets showed that commercial modified live virus(MLV)vaccines provided good protection against ***,it could not provide sufficient protection against the novel strain *** explore the reasons for this phenomenon,we compared the genomic homology between the MLV strain and HP-PRRSV or NADC30-like PRRSV and found that the MLV strain had a lower genome similarity with NADC30-like *** neutralization assay showed that MLV-immune serum slightly promoted the homologous HP-PRRSV replication and significantly promoted the heterologous NADC30-like PRRSV strain replication in vitro,suggesting that antibody-dependent enhancement(ADE)might also play a role in decreasing MLV protective *** findings expand our understanding of the potential factors affecting the protective effect of PRRSV MLV vaccines against the NADC30-like strains.

关键词： NADC30-like PRRSV Modified live virus(MLV)vaccines Genomic similarity Antibody dependent enhancement(ADE) Cross protection

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Protective mechanism of Paeoniae Radix Alba against chemical liver injury based on network pharmacology,molecular docking,and in vitro experiments

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Journal of Traditional Chinese Medical Sciences 2024年第1期11卷 55-66页

作者： Shuangqiao Liu Xin Liu Sijia Jiang Min Fu Jinxi Hu Jiaqi Liu Xiaoxu Fan yingtong feng Shujing Zhang Jingxia Wang School of Traditional Chinese Medicine Beijing University of Chinese MedicineBeijing 102488China School of Traditional Chinese Medicine Xinjiang Medical UniversityUrumqi 830017China The Centre for Translational Biology Research Institute of McGill University Health CentreMontr eal H4A 3J1Canada

Objective:To explore and validate the potential targets of Paeoniae Radix Alba(***,Bai Shao)in protecting against chemical liver injury through network pharmacology,molecular docking technology,and in vitro cell ***:Network pharmacology was used to identify the common potential targets of *** and chemical liver *** docking was used to fit the components,which were subsequently verified in vitro.A cell model of hepatic fibrosis was established by activating hepatic stellate cell(HSC)-LX2 cells with 10 ng/mL transforming growth factor-β*** cells were exposed to different concentrations of total glucosides of paeony(TGP),the active substance of ***,and then evaluated using the cell counting kit-8 assay,enzyme-linked immunosorbent assay,and western ***:Analysis through network pharmacology revealed 13 key compounds of ***,and the potential targets for preventing chemical liver injury were IL-6,AKT serine/threonine kinase 1,jun protooncogene,heat shock protein 90 alpha family class A member 1(HSP90AA1),peroxisome proliferator activated receptor gamma(PPARG),PTGS2,and *** Ontology(GO)enrichment analysis indicated the involvement of response to drugs,membrane rafts,and peptide *** Encyclopedia of Genes and Genomes(KEGG)enrichment analysis revealed that the main pathways involved lipid and atherosclerosis and chemical carcinogenesis-receptor *** and albiflorin exhibited strong affinity for HSP90AA1,PTGS2,PPARG,and *** concentrations of TGP can inhibit the expression of COL-I,COL-III,IL-6,TNF-a,IL-1β,HSP-90a,and PTGS2 while increasing the expression of PPAR-γand CASP3 in activated HSC-LX2 ***:*** primarily can regulate targets such as HSP90AA1,PTGS2,PPARG,***,the main active compound of ***,protects against chemical liver injury by reducing the inflammatory response,activating apoptotic proteins,and promoting the apoptosis of activated HSCs.

关键词： Paeoniae Radix Alba Total glycosides of paeony Chemical liver injury Liver fibrosis Network pharmacology Hepatic stellate cells

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Genomic Characteristics and Pathogenicity of a New Recombinant PRRSV

Genomic Characteristics and Pathogenicity of a New Recombina...

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中国微生物学会兽医微生物学专业委员会暨中国畜牧兽医学会生物制品学分会2021年学术论坛

作者： Yang Li Xingqian Du Lele Xu Zhiqian Ma Zhiwei Li yingtong feng Dian Jiao Shuqi Xiao College of Veterinary Medicine Northwest A&F University

Recombination is considered an important property that accelerate the rapid evolution and enriches the genetic diversity of porcine reproductive and respiratory syndrome virus(PRRSV).Recombinant PRRSV isolates sometimes have different genetic *** report a recombinant PRRSV(SD-YL1712)isolated from a pig *** genome of SD-YL1712 was 15014 nucleotides in length and its nucleotide and amino acid sequence conservation was higher than that of JXA1 PRRSV except for within its NSP2 *** NSP2 region of SDYL1712 shared the highest nucleotide(85.9%) and amino acid(84.1%) identities with NADC30 *** addition,SD-YL1712 possessed a characteristic 131-amino acid deletion in the Nsp2 *** recombination breakpoints were detected at nt2134 and nt3958 within the NSP2 region,which revealed that SD-YL1712 originated from a recombination event between NADC30-like and HP-PRRSV-derived MLV-like ***,SD-YL1712 had an additional deletion at position 586,similar to that of ***,SD-YL1712 exhibited similarly high pathogenicity as HP-PRRSV JXA1,which was higher than that of the CHla *** analysis indicated that SD-YL1712 might be a transitional isolate in the evolution of TJbd1401 to TJnh1501.

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不同喹啉不溶物的特性及对中间相转化过程的影响

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燃料化学学报 1995年第1期23卷 62-68页

作者：水恒福冯映桐袁晓敏华东冶金学院

采用￣１３Ｃ－ＮＭＲ、ｘ－ｒａｙ衍射、扫描和透射电镜研究了二种ＱＩ──原生ＱＩ、次生ＱＩ（喹啉不溶物）结构，并通过热转化试验考察了它们对中间相热转化过程的影响。结果表明，原生ＱＩ是由炭黑状固体小圆球组成，并包含有煤粉... 详细信息

采用￣１３Ｃ－ＮＭＲ、ｘ－ｒａｙ衍射、扫描和透射电镜研究了二种ＱＩ──原生ＱＩ、次生ＱＩ（喹啉不溶物）结构，并通过热转化试验考察了它们对中间相热转化过程的影响。结果表明，原生ＱＩ是由炭黑状固体小圆球组成，并包含有煤粉、焦粉等夹杂物，属非晶态混和物。它在中间相转化过程中，促使中间相小球体较早生成，并阻碍中间相球体融并，导致中间相热转化最终固体产物的镶嵌结构生成。次生ＱＩ微晶排列有序性较好，属中间相组织或中间相前躯体，对中间相的成长过程有利。

关键词：煤焦油沥青喹啉不溶物中间相转化

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围产期使用抗菌药物对PRRSV阳性猪场母猪和仔猪生产性能的影响

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畜牧兽医学报 2024年第6期55卷 2751-2760页

作者：肖书奇刘俊冯英桐李洋徐乐乐中国农业科学院兰州兽医研究所兰州大学动物医学与生物安全学院动物疫病防控全国重点实验室兰州730046 西北农林科技大学动物医学院杨凌712100

旨在评估围产期使用抗菌药物对猪繁殖与呼吸综合征病毒(PRRSV)阳性猪场母猪和仔猪生产性能的影响。从广西某规模化PRRSV阳性猪场挑选280头临产母猪随机分为5组,在其围产期分别用替米考星、泰妙菌素、多西环素和泰万菌素等兽医常用抗生素... 详细信息

旨在评估围产期使用抗菌药物对猪繁殖与呼吸综合征病毒(PRRSV)阳性猪场母猪和仔猪生产性能的影响。从广西某规模化PRRSV阳性猪场挑选280头临产母猪随机分为5组,在其围产期分别用替米考星、泰妙菌素、多西环素和泰万菌素等兽医常用抗生素,对照组不使用抗菌药物。采集各组断奶仔猪前腔静脉血进行PRRSV核酸和抗体检测,以评估各药物对防控仔猪PRRSV感染的效果;统计各组断奶仔猪腹泻窝数及比率,以探究常用抗生素对仔猪腹泻的防控效果;统计各组断奶母猪的断配间隔及断奶7、10 d内发情配种率,统计各组仔猪的窝均断奶数、断奶存活率和断奶重等生产指标,以评估围产期常用抗生素使用对母猪和仔猪生产性能的影响并计算使用药物所带来的经济效益。结果表明:泰万菌素、替米考星组断奶仔猪PRRSV核酸阳性检出率为0%,且PRRSV抗体水平显著高于对照组;泰万菌素组仔猪的腹泻率低于其它用药组及对照组;相关生产指标统计显示,与其他组相比,泰万菌素组仔猪断奶存活率及断奶均重最高,母猪的断配间隔最短,窝均损失资产更低。综上,本研究评估了围产期使用兽医临床常用抗生素对PRRSV阳性猪场母猪和仔猪生产性能的影响,发现使用泰万菌素可以有效阻断PRRSV垂直传播,提升仔猪抗体水平,显著改善断奶仔猪腹泻率;使用泰万菌素显著提升了仔猪断奶存活率及断奶均重,缩短了母猪的断配间隔,降低了窝均损失资产。本研究的开展为规模化PRRSV阳性猪场的有效药物使用提供了重要试验数据和理论支持,为在PRRSV大流行背景下实现规模化猪场降本增效提供了必要的补充措施。

关键词：猪繁殖与呼吸综合征规模化猪场围产期抗生素泰万菌素

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中间相沥青高温炭的氧化动力学研究

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燃料与化工 2000年第6期31卷 296-299页

作者：水恒福冯映桐周华华东冶金学院马鞍山市职教中心

研究了２种镁碳砖粘结剂高温炭的氧化动力学，结果表明，中间相沥青粘结剂比酚醛树脂粘结剂高温炭具有更好的抗氧化性能，脱除了原生喹啉不溶物后，可提高中间相沥青粘结剂的抗氧化性能。

关键词：中间相沥青高温炭氧化动力学镁碳砖粘结剂

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探讨藿骨牡蛎方调节绝经后骨质疏松症大鼠破骨-成骨平衡的作用及其机制

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北京中医药大学学报 2024年第4期47卷 506-515页

作者：姜斯佳冯颖童刘佳琪扈觐玺华姞安李伟王景霞北京中医药大学中医学院北京100029

目的基于破骨-成骨平衡探讨藿骨牡蛎方(淫羊藿、骨碎补、生牡蛎)对绝经后骨质疏松症(PMOP)大鼠的防治作用及其机制。方法将48只雌性SD大鼠按体质量分为假手术组、模型组、强骨胶囊组(0.054 g/kg)、碳酸钙组(1.670 g/kg)、藿骨牡蛎方低... 详细信息

目的基于破骨-成骨平衡探讨藿骨牡蛎方(淫羊藿、骨碎补、生牡蛎)对绝经后骨质疏松症(PMOP)大鼠的防治作用及其机制。方法将48只雌性SD大鼠按体质量分为假手术组、模型组、强骨胶囊组(0.054 g/kg)、碳酸钙组(1.670 g/kg)、藿骨牡蛎方低剂量组(0.188 g/kg)、藿骨牡蛎方高剂量组(0.375 g/kg),每组8只。适应性喂养后,除假手术组仅切除卵巢附近等体积脂肪,其余大鼠以双侧卵巢去势手术建立PMOP模型。造模成功后灌胃相应药物,连续90 d。酶联免疫吸附测定(ELISA)法检测血清雌二醇(E2)、雌激素受体α(ERα)、Ⅰ型前胶原氨基端原肽(PINP)、抗酒石酸酸性磷酸酶5b(TRACP-5b);比色法检测血清总抗氧化能力(T-AOC)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、丙二醛(MDA);显微计算机断层成像检测大鼠股骨骨密度(BMD)、骨小梁数量(Tb.N)、骨小梁厚度(***)、骨小梁分离度(***)和结构模型指数(SMI),并观察松质骨显微结构;蛋白质印迹法检测大鼠股骨组织骨保护素(OPG)、核因子κB受体活化因子配体(RANKL)、核因子κB受体激活因子(RANK)、叉头框蛋白O3α(FoxO3α)、Wnt2、β-连环蛋白(β-catenin)、过氧化物酶体增殖物激活受体γ(PPARγ)蛋白表达。结果(1)强骨胶囊组与藿骨牡蛎方低、高剂量组大鼠血清E2、ERα含量较模型组增加(P<0.05)。(2)与模型组比较,强骨胶囊组与藿骨牡蛎方高剂量组大鼠血清PINP、TRACP-5b含量下降(P<0.05),PINP/TRACP-5b升高(P<0.05)。(3)与模型组比较,强骨胶囊组、碳酸钙组及藿骨牡蛎方低、高剂量组T-AOC、SOD、CAT活性升高,MDA含量下降(P<0.05)。(4)与模型组比较,强骨胶囊组及藿骨牡蛎方低、高剂量组大鼠BMD、***、Tb.N增加,***、SMI降低(P<0.05);碳酸钙组大鼠BMD增加,***降低(P<0.05)。(5)与模型组比较,强骨胶囊组及藿骨牡蛎方低、高剂量组大鼠RANKL、RANK、FoxO3α、PPARγ蛋白表达下降,OPG、Wnt2、β-catenin蛋白表达增加(P<0.05)。结论藿骨牡蛎方可明显提高PMOP大鼠雌激素水平,抑制破骨细胞分化,降低骨吸收水平;缓解氧化应激,促进成骨分化、抑制成脂分化,提高骨形成水平,恢复破骨细胞与成骨细胞稳态平衡,从而达到防治PMOP的作用。此作用可能是通过OPG/RANKL/RANK及FoxO3α/Wnt2/β-catenin/PPARγ通路调节的。

关键词：绝经后骨质疏松症藿骨牡蛎方雌激素骨形成骨吸收大鼠

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基于PI3K/AKT/mTOR通路探讨白芍总苷对化学性肝损伤肝阴虚证大鼠的保护作用及机制

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北京中医药大学学报 2024年第3期47卷 341-351页

作者：李丽范晓旭华姞安扈觐玺冯颖童沈奕玮王祯王景霞北京中医药大学中医学院北京102488

目的基于磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(AKT)/哺乳动物雷帕霉素靶蛋白(mTOR)通路关键因子探讨白芍总苷对化学性肝损伤肝阴虚证大鼠的保护作用及机制。方法将40只雄性SD大鼠按照体质量随机区组分为空白组、模型组、一贯煎组、白芍... 详细信息

目的基于磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(AKT)/哺乳动物雷帕霉素靶蛋白(mTOR)通路关键因子探讨白芍总苷对化学性肝损伤肝阴虚证大鼠的保护作用及机制。方法将40只雄性SD大鼠按照体质量随机区组分为空白组、模型组、一贯煎组、白芍总苷组,每组10只。除空白组外,其余各组大鼠连续6周腹腔注射20%四氯化碳橄榄油溶液,并灌胃甲状腺片(30 mg/kg)以制备化学性肝损伤肝阴虚证病证结合大鼠模型。造模期间,空白组、模型组大鼠每天灌胃蒸馏水,一贯煎组及白芍总苷组大鼠分别灌胃一贯煎水煎液(635 mg/kg)及白芍总苷混悬液(50 mg/kg),连续6周。给药期间每2周检测大鼠体质量、肛温;给药结束后观察大鼠24 h摄食量和摄水量、舌面湿度;采用酶联免疫吸附测定法检测血清环磷酸腺苷(cAMP)、环磷酸鸟苷(cGMP)、白细胞介素-1(IL-1)、白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、白细胞介素-10(IL-10)、白细胞介素-1受体拮抗剂(IL-1Ra)含量,并计算cAMP/cGMP;采用比色法检测血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、γ-谷氨酰转肽酶(γ-GT)、碱性磷酸酶(ALP)、总胆红素(TBIL)、总胆汁酸(TBA)含量;采用Masson染色法观察肝脏纤维化程度,并计算胶原面积百分比;采用实时荧光PCR法和蛋白质印迹法检测大鼠肝脏PI3K、AKT和mTOR mRNA及蛋白表达水平。结果与空白组比较,模型组大鼠第2、4、6周体质量降低,第2、4、6周肛温升高,24 h摄食量增加;cAMP升高、cGMP下降、cAMP/cGMP升高,IL-1、IL-6、TNF-α含量均升高,IL-10、IL-1Ra含量均降低,ALT、AST、γ-GT、ALP、TBIL、TBA水平均升高,肝脏胶原面积百分比增加,PI3K、AKT和mTOR mRNA及蛋白磷酸化表达升高(均P<0.05)。与模型组比较,白芍总苷组大鼠第2、4、6周肛温下降,24 h摄食量和饮水量减少,舌面湿度升高;一贯煎组和白芍总苷组大鼠cAMP降低、cGMP升高、cAMP/cGMP下降,IL-1、IL-6、TNF-α均下降,IL-10升高,肝脏胶原面积百分比降低;白芍总苷组大鼠ALT、AST、γ-GT、ALP、TBIL均下降,PI3K、AKT和mTOR mRNA及蛋白磷酸化表达降低(均P<0.05)。结论白芍总苷对化学性肝损伤肝阴虚证大鼠具有较好的保护作用,可能是通过抑制PI3K/AKT/mTOR通路的激活,减少促炎细胞因子分泌,增加抗炎细胞因子释放,从而发挥白芍调节阴阳平衡的作用。

关键词：白芍总苷化学性肝损伤肝阴虚证炎症因子磷脂酰肌醇3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白通路大鼠

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