检索结果-南通市图书馆

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

Acta Pharmaceutica Sinica B 2024年第2期14卷 533-578页

作者： Xiaopeng Peng Zhihao Hu Limei Zeng Meizhu Zhang Congcong Xu Benyan Lu Chengpeng Tao Weiming Chen Wen Hou Kui Cheng Huichang Bi Wanyi Pan Jianjun Chen College of Pharmacy Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of EducationGannan Medical UniversityGanzhou 314000China College of Basic medicine Gannan Medical UniversityGanzhou 314000China Guangdong Provincial key laboratory of New Drug Screening NMPA Key Laboratory for Research and Evaluation of Drug MetabolismSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators(e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges,including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result,the design of new epigenetic modulators(e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging(Hy T) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review,we aim to provide an in-depth illustration of new degrading strategies(2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

关键词： Epigenetic Degrader PROTAC Molecularglue Hydrophobic tagging

来源：

维普期刊数据库

同方期刊数据库评论

在线全文

学校读者我要写书评

暂无评论

A positive feedback inhibition of isocitrate dehydrogenase 3βon paired-box gene 6 promotes Alzheimer-like pathology

引用

Signal Transduction and Targeted Therapy 2024年第5期9卷 2324-2340页

作者： Xin Wang Qian Liu Hai-tao Yu Jia-zhao Xie Jun-ning Zhao Zhi-ting Fang Min Qu Yao Zhang Ying Yang Jian-Zhi Wang Department of Pathophysiology School of Basic MedicineKey Laboratory of Education Ministry of China/Hubei Province for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina Department of Fundamental medicine Wuxi School of MedicineJiangnan UniversityWuxiJiangsu 214122China Hubei Provincial key laboratory for Applied Toxicology Hubei Provincial Center for Disease Control and PreventionHubei Provincial Academy of Preventive MedicineWuhan 430000China Endocrine Department of Liyuan Hospital Key Laboratory of Ministry of Education of China for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430077China Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226000China

Impaired brain glucose metabolism is an early indicator of Alzheimer’s disease(AD);however,the fundamental mechanism is unknown.In this study,we found a substantial decline in isocitrate dehydrogenase 3β(IDH3β)levels,a critical tricarboxylic acid cycle enzyme,in AD patients and AD-transgenic mice’s brains.Further investigations demonstrated that the knockdown of IDH3βinduced oxidation-phosphorylation uncoupling,leading to reduced energy metabolism and lactate accumulation.The resulting increased lactate,a source of lactyl,was found to promote histone lactylation,thereby enhancing the expression of paired-box gene 6(PAX6).As an inhibitory transcription factor of IDH3β,the elevated PAX6 in turn inhibited the expression of IDH3β,leading to tau hyperphosphorylation,synapse impairment,and learning and memory deficits resembling those seen in AD.In AD-transgenic mice,upregulating IDH3βand downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies.Collectively,our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3β-lactate-PAX6-IDH3β.Breaking this loop by upregulating IDH3βor downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.

关键词： metabolism Alzheimer impaired

来源：

维普期刊数据库评论

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Nanomedicine Disrupts Stromal Barriers to Augment Drug Penetration for Improved Cancer Therapy

引用

Chinese Journal of Chemistry 2024年第10期42卷 1175-1189页

作者： Guo-Feng Luo Wei-Hai Chen Xian-Zheng Zhang state key laboratory of Oral&Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of EducationHubei KeyLaboratory of StomatologySchool&Hospital of StomatologyWuhan UniversityWuhanHubei 430079China key laboratoryof Biomedical Polymers of ministry of education&Departmentof Chemistry Wuhan UniversityWuhanHubei 430072China

Tumor stroma composing diverse extracellular matrixes(ECM)and stromal cells shapes a condensed physical barrier,which severely hampers the efficient accessibility of nanomedicine to tumor cells,especially these deep-seated in the core of tumor.Such barrier significantly compromises the antitumor effects of drug-loaded nanomedicine,revealing the remarkable importance of disrupting stromal barrier for improved tumor therapy with deep penetration ability.To achieve this goal,various nanoparticle-based strategies have been developed,including direct depleting ECM components via delivering anti-fibrotic agents or targeting stromal cells to suppress ECM expression,dynamic regulation of nanoparticles’physicochemical properties(i.e.,size,surface charge,and morphology),mechanical force-driven deep penetration,natural/biomimetic self-driven nanomedicine,and transcytosis-inducing nanomedicine.All these nanostrategies were systemically summarized in this review,and the design principles for obtaining admirable nanomedicine were included.With the rapid development of nanotechnology,elaborate design of multifunctional nanomedicine provides new opportunities for overcoming the critical stromal barriers to maximize the therapeutic index of various therapies,such as chemotherapy,photodynamic therapy,and immunotherapy.

关键词： Nanomedicine Tumor stroma Deep penetration Enhanced drug perfusion Cancer therapy Drug carriers Biomaterials Nanotechnology

来源：

维普期刊数据库评论

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Prenatal cadmium exposure impairs neural tube closure via inducing excessive apoptosis in neuroepithelium

引用

Journal of Environmental Sciences 2024年第4期138卷 572-584页

作者： Shiyong Zhu Xuenan Li Xueyan Dai Jinlong Li College of Veterinary medicine Northeast Agricultural UniversityHarbin 150030China key laboratory of the Provincial education Department of Heilongjiang for Common Animal Disease Prevention and Treatment Northeast Agricultural UniversityHarbin 150030China Heilongjiang key laboratory for laboratory Animals and Comparative medicine Northeast Agricultural UniversityHarbin 150030China

Birth defects have become a public health concern.The hazardous environmental factors exposure to embryos could increase the risk of birth defects.Cadmium,a toxic environmental factor,can cross the placental barrier during pregnancy.Pregnant woman may be subjected to cadmium before taking precautionary protective actions.However,the link between birth defects and cadmium remains obscure.Cadmium exposure can induce excessive apoptosis in neuroepithelium during embryonic development progresses.Cadmium exposure activated the p53 via enhancing the adenosine 5‘-monophosphate(AMP)-activated protein kinase(AMPK)and reactive oxygen species'(ROS)level.And cadmium decreases the level of Paired box 3(Pax3)and murine double minute 2(Mdm2),disrupting the process of p53 ubiquitylation.And p53 accumulation induced excessive apoptosis in neuroepithelium during embryonic development progresses.Excessive apoptosis led to the failure of neural tube closure.The study emphasizes that environmental materials may increase the health risk for embryos.Cadmium caused the failure of neural tube closure during early embryotic day.Pregnant women may be exposed by cadmium before taking precautionary protective actions,because of cadmium concentration-containing foods and environmental tobacco smoking.This suggests that prenatal cadmium exposure is a threatening risk factor for birth defects.

关键词： Cadmium Neural tube closure Excessive apoptosis p53 Embryogenesis

来源：

维普期刊数据库

同方期刊数据库评论

在线全文

学校读者我要写书评

暂无评论

Establishment of a humanized ST6GAL1 mouse model for influenza research

引用

Animal Models and Experimental medicine 2024年第3期7卷 337-346页

作者： Lyu Chao Han Feng Gao Qian Lv Limin Lu Ziwei Lu Shuangshuang Li Xiaoyan Hu Yuechao Yang Mengjie Zhao Yingze Liu Jun Lu Xuancheng Duo Shuguang National key laboratory of Intelligent Tracking and Forecasting for Infectious Diseases Chinese Center for Disease Control and PreventionBeijingChina Institute of Zoology Chinese Academy of SciencesBeijingChina NHC key laboratory of Biosafety National Key Laboratory of Intelligent Tracking and Forecasting for Infectious DiseasesNational Institute for Viral Disease Control and PreventionChinese Center for Disease Control and PreventionBeijingChina Zhejiang Provincial key laboratory of Medical Genetics Key Laboratory of Laboratory MedicineMinistry of EducationSchool of Laboratory Medicine and Life SciencesWenzhou Medical UniversityWenzhouChina

Background:This study aimed to construct and characterize a humanized influenza mouse model expressing hST6GAL1.Methods:Humanized fragments,consisting of the endothelial cell-specific K18 promoter,human ST6GAL1-encoding gene,and luciferase gene,were microinjected into the fertilized eggs of mice.The manipulated embryos were transferred into the oviducts of pseudopregnant female mice.The offspring were identified using PCR.Mice exhibiting elevated expression of the hST6GAL1 gene were selectively bred for propagation,and in vivo analysis was performed for screening.Expression of the humanized gene was tested by performing immunohistochemical(IHC)analysis.Hematologic and biochemical analyses using the whole blood and serum of humanized hST6GAL1 mice were performed.Results:Successful integration of the human ST6GAL1 gene into the mouse genome led to the overexpression of human SiaT ST6GAL1.Seven mice were identified as carrying copies of the humanized gene,and the in vivo analysis indicated that hST6GAL1gene expression in positive mice mirrored influenza virus infection characteristics.The IHC results revealed that hST6GAL1 was expressed in the lungs of humanized mice.Moreover,the hematologic and biochemical parameters of the positive mice were within the normal range.Conclusion:A humanized influenza mouse model expressing the hST6GAL1 gene was successfully established and characterized.

关键词： hST6GAL1 humanized mice influenza animal model

来源：

维普期刊数据库

同方期刊数据库评论

在线全文

学校读者我要写书评

暂无评论

Effect of mechanical stresses on degradation behavior of high-purity magnesium in bone environments

引用

Journal of Materials Science & Technology 2024年第4期171卷 252-261页

作者： Yan Yao Jie Xia Lizhen Wang Yuanming Gao Xili Ding Chao Wang Yubo Fan key laboratory of Biomechanics and Mechanobiology(Beihang University) Ministry of EducationBeijing Advanced Innovation Center for Biomedical EngineeringSchool of Biological Science and Medical EngineeringSchool of Engineering MedicineBeihang UniversityBeijing 100083China

High-purity(HP)magnesium(Mg)has emerged as a promising biomaterial for supporting functional bone tissue.Our previous study found that mechanical stresses and the surrounding fibrotic tissue(subcuta-neous)both play crucial roles in the degradation of HP Mg.However,due to challenges in the degradation and regeneration process in vivo,it remains unclear how stress affects HP Mg degradation in bone en-vironments,limiting its further application.In this study,novel loading devices were designed and the effects of tensile and compressive stresses on HP Mg degradation in vivo and in vitro bone environments were quantitatively analyzed.In addition,bone osteointegration around HP Mg was explored preliminar-ily.Tensile stress increases the degradation rate of HP Mg in vivo and in vitro.HP Mg degradation in vivo is more sensitive to stress factors than in vitro,but the sensitivity decreases with corrosion time.The volume loss rate of HP Mg is multilinear with the applied stress and degradation time.The volume of bone tissue surrounding HP Mg is larger in the no-stress group compared to the stressed groups,which is more pronounced with increasing implantation time.These results provide valuable insights for optimiz-ing the design of HP Mg-based implants considering load conditions.This will help to achieve a balance between the degradation rate of the implant and the regeneration rate of the surrounding bone.

关键词： High-purity magnesium Quantitative stresses Degradation Bone environments In vivo and in vitro

来源：

维普期刊数据库评论

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Helicobacter pylori and immunotherapy for gastrointestinal cancer

引用

The Innovation 2024年第2期5卷 51-60页

作者： Keren Jia Yang Chen Yi Xie Xicheng Wang Yajie Hu Yu Sun Yanshuo Cao Liyan Zhang Yakun Wang Zhenghang Wang Zhihao Lu Jian Li Xiaotian Zhang Lin Shen key laboratory of Carcinogenesis and Translational Research(ministry of education/Beijing) Department of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China key laboratory of Carcinogenesis and Translational Research(ministry of education/Beijing) Department of PathologyPeking University Cancer Hospital&InstituteBeijing 100142China

Helicobacter pylori infection is associated with the risk of gastrointestinal(GI)cancers;however,its impact on immunotherapy for GI cancers remains uncertain.In this study,we included 10,122 patients who underwent ^(13)C-urea breath tests.Among 636 patients with Epstein-Barr virus–negative microsatellite-stable gastric cancer(GC)who were treated with anti-PD-1/PD-L1 therapy,H.pylori–positive patients exhibited significantly longer immune-related progression-free survival(irPFS)compared with H.pylori–negative patients(6.97 months versus 5.03 months,p<0.001,hazard ratio[HR]0.76,95%confidence interval[CI]0.62–0.95,p=0.015).Moreover,the H.pylori–positive group demonstrated a trend of 4 months longer median immune-related overall survival(irOS)than the H.pylori–negative group.H.pylori–positive GC displayed higher densities of PD-L1+cells and nonexhausted CD8+T cells,indicative of a“hot”tumor microenvironment.Transcriptomic analysis revealed that H.pylori–positive GC shared molecular characteristics similar to those of immunotherapy-sensitive GC.However,H.pylori–positive patients with DNA mismatch repair–deficient(dMMR)/microsatellite instability–high(MSI-H)colorectal adenocarcinoma and esophageal squamous cell carcinoma(ESCC)had shorter irPFS compared with H.pylori–negative patients(16.13 months versus not reached,p=0.042,HR 2.26,95%CI 1.13–4.50,p=0.021 and 5.57 months versus 6.97 months,p=0.029,HR 1.59,95%CI 1.14–2.23,p=0.006,respectively).The difference in irOS between H.pylori–positive and–negative patients had the same trend as that between dMMR/MSI-H colorectal adenocarcinoma and ESCC patients.We also identified a trend of shorter irPFS and irOS in H.pylori–positive liver cancer and pancreatic cancer patients.In summary,our findings supported that H.pylori infection is a beneficial factor for GC immunotherapy by shaping hot tumor microenvironments.However,in dMMR/MSI-H colorectal adenocarcinoma and ESCC patients,H.pylori adversely affects the efficacy of immunotherapy.

关键词： immunotherapy gastrointestinal pylori

来源：

维普期刊数据库评论

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Interconnection of cellular autophagy and endosomal vesicle trafficking and its role in hepatitis B virus replication and release

引用

Virologica Sinica 2024年第1期39卷 24-30页

作者： Jia Li Yong Lin Xueyu Wang Mengji Lu Institute for Virology University Hospital EssenUniversity of Duisburg-EssenEssen45122Germany key laboratory of Molecular Biology of Infectious Diseases(Chinese ministry of education) Chongqing Medical UniversityChongqing400016China The key laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou310000China

Hepatitis B virus(HBV)produces and releases various particle types,including complete virions,subviral particles with envelope proteins,and naked capsids.Recent studies demonstrate that HBV exploits distinct intracellular membrane trafficking pathways,including the endosomal vesicle trafficking and autophagy pathway,to assemble and release viral and subviral particles.Herein,we summarize the findings about the distinct roles of autophagy and endosomal membrane trafficking and the interaction of both pathways in HBV replication,assembly,and release.

关键词： Amphisome Autophagy Endosomal vesicle Hepatitis B virus(HBV)

来源：

维普期刊数据库评论

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Multi-omics analysis of adamantinomatous craniopharyngiomas reveals distinct molecular subgroups with prognostic and treatment response significance

引用

中华医学杂志(英文版) 2024年第7期137卷 859-870页

作者： Wang Xianlong Zhao Chuan Lin Jincheng Liu Hongxing Zeng Qiuhong Chen Huadong Wang Ye Xu Dapeng Chen Wen Xu Moping Zhang En Lin Da Lin Zhixiong Sanbo Brain Hospital Capital Medical University Beijing 100093 Department of Bioinformatics School of Medical Technology and Engineering key laboratory of Medical Bioinformatics key laboratory of ministry of education for Gastrointestinal Cancer Fujian Medical University Fuzhou Fujian 350122 China Department of Neurosurgery

Background: Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies.Methods: Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (84 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively.Results: Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/β-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox,P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group (P <0.01). In the preliminary screening of subtyping markers, CD38 was significantly downregulated in WNT compared with ImA and ImB (P = 0.01).Conclusions: ACP comprises three molecular subtypes with disti

关键词： Craniopharyngioma Central nervous system tumor Precision medicine beta Catenin Proto-Oncogene Proteins B-raf

来源：

同方期刊数据库评论

在线全文

同方期刊数据库

学校读者我要写书评

暂无评论

Characteristics of gut microbiota determine effects of specific probiotics strains in patients with functional constipation

引用

Chinese Medical Journal 2024年第1期137卷 120-122页

作者： Haohao Zhang Lijuan Sun Zhixin Zhao Yao Zhou Yuyao Liu Nannan Zhang Junya Yan Shibo Wang Renlong Li Jing Zhang Xueying Wang Wenjiao Li Yan Pan Meixia Wang Bing Luo Mengbin Li Zhihong Sun Yongxiang Zhao Yongzhan Nie State key laboratory of Targeting Oncology National Center for International Research of Bio-targeting TheranosticsGuangxi Key Laboratory of Bio-targeting TheranosticsCollaborative Innovation Center for Targeting Tumor Diagnosis and TherapyGuangxi Talent Highland of Bio-targeting TheranosticsGuangxi Medical UniversityNanningGuangxi 530021China State key laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi’anShaanxi 710032China key laboratory of Resource Biology and Biotechnology in Western China Ministry of EducationSchool of MedicineNorthwest UniversityXi’anShaanxi 710000China key laboratory of Dairy Biotechnology and Engineering Ministry of EducationKey Laboratory of Dairy Products ProcessingMinistry of Agriculture and Rural AffairsInner Mongolia Key Laboratory of Dairy Biotechnology and EngineeringInner Mongolia Agricultural UniversityHohhotInner Mongolia 010018China

To the Editor:Probiotics are a promising treatment modality for functional constipation(FC);however,the factors affecting individual responses to probiotics remain unclear.Growing evidence has identified that there is a strong relationship among the gut microbiota and constipation and related gut-brain axis.[1]The gut microbiota may modulate the gut functions via gut metabolites or trigger the release of gut hormones,such as peptide YY,gastric inhibitory polypeptide,and 5-hydroxytryptamine.[2]In turn,gut hormones affect gut secretion,motility,and sensation through their receptors located on epithelial,enteric,and smooth muscle cells.[2]Based on these findings,exogenous probiotics have been used in patients with constipation;however,few have produced consistent results.[3]In this study,we investigated the efficacy and safety of several specific probiotics strains for constipation,and also examined the potential reasons for the individualized effects of probiotics,which may facilitate interventional decisionmaking for FC patients.

关键词： constipation patients sensation

来源：

维普期刊数据库

同方期刊数据库评论

在线全文

学校读者我要写书评

暂无评论

欢迎您,

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

在线全文

在线全文

在线全文

在线全文

在线全文

在线全文

在线全文

在线全文

在线全文

在线全文

请选择保存的检索档案：

请选择收藏分类：

通借通还

欢迎您,

建议与咨询 留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

在线全文

在线全文

在线全文

在线全文

在线全文

在线全文

在线全文

在线全文

在线全文

在线全文

请选择保存的检索档案： 新增检索档案 确定 取消

请选择收藏分类： 新增自定义分类 确定 取消

通借通还

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

请选择保存的检索档案：

请选择收藏分类：