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Discovery of a potent and highly selective inhibitor of SIRT6.against pancreatic cancer metastasis in vivo

Acta Pharmaceutica Sinica B 2024年第3期14卷 1302-1316页

作者： Xinyuan Xu Qian Zhang Xufeng Wang Jing Jin Chengwei Wu Li Feng Xiuyan Yang Mingzhu Zhao Yingyi Chen Shaoyong Lu Zhen Zheng Xiaobing Lan Yi Wang Yan Zheng Xuefeng Lu Qiufen Zhang Jian Zhang State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Medicinal Chemistry and Bioinformaticscenter Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of General Surgery Huashan HospitalCancer Metastasis InstituteFudan UniversityShanghai 200040China Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic disease School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefei 230026China Department of Assisted Reproduction Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China College of Pharmacy Ningxia Medical UniversityYinchuan 750004China Department of pancreatic Surgery Shanghai General HospitalShanghai Key Laboratory of Pancreatic DiseaseInstitute of Pancreatic DiseaseShanghai Jiao Tong University School of MedicineShanghai 200080China

pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour ***6.can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic ***,highly selective and potency SIRT6.inhibitor that can be used in vivo is yet to be ***,we developed a noveSIRT6.allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(5.) value of 0.98±0.13.mol/***,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3.at concentrations up to 100μmol/*** allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural ***,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver *** our knowledge,this is the first study to reveal the in vivo effects of SIRT6.inhibitors on liver metastatic pancreatic *** not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6.but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.

关键词： SIRT6 Inhibitor Allosteric Selectivity Cocrystal pancreatic cancer metastasis

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EGFR-targeted and gemcitabine-incorporated chemogene for combinatorial pancreatic cancer treatment

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Nano Research 2024年第2期17卷 848-857页

作者： Miao Xie Qiushuang Zhang Yuanyuan Guo Lijuan Zhu Xinyuan Zhu Chuan Zhang school of Chemistry and Chemical Engineering Frontiers Science Center for Transformative MoleculesInstitute of Molecular MedicineSixth people’s HospitalSchool of MedicineShanghai Key Laboratory for Molecular Engineering of Chiral DrugsShanghai Jiao Tong UniversityShanghai 200240China Department of Radiology Shanghai Jiao Tong University Affiliated Sixth People’s HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200233China Institute of Molecular medicine Shanghai Jiao Tong University Affiliated Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China

pancreatic cancer stands out as a recognized intractable tumor due to its high malignancy and mortality rates,which are largely attributed to the insensitivity of current clinical chemotherapies or *** chemo and gene therapy that integrates different therapeutic targets,may increase the chemosensitivity of pancreatic cancer and synergistically enhance the antitumor ***,conventional co-delivery of gene and chemo drugs is intensively dependent on complex nanoparticle delivery systems,thus would be limited by unstable drug packaging,nonspecific biodistribution,and biosafety ***,we rationally designed an epidermal growth factor-receptor(EGFR)-targeted and gemcitabine-incorporated oligonucleotide(termed as chemogene)with anti-Bcl-2 sequence,which achieves simple and precise integration of gemcitabine into a gene regulative agent,as well as the EGFR-targeted delivery for pancreatic cancer *** solid-phase synthesis,gemcitabine,as the first-line chemodrug for pancreatic cancer,is introduced to the antisense oligonucleotide to replace all cytosine nucleosides to obtain the gemcitabine-integrated chemogene(Ge-ASO^(Bcl-2)).Thereafter,Ge-ASO^(Bcl-2)is covalently coupled with EGFR nanobody to construct the final targeted chemogene without any exogenous ***,this nanobody-conjugated chemogene exhibits remarkable tumor targeting capability and antitumor effects both in vitro and in vivo,which initiates a first step toward the application of combinatorial chemo and gene therapy for future pancreatic cancer treatment.

关键词： antisense oligonucleotide chemogene nanobody drug delivery system pancreatic cancer

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Current Immunotherapy Strategies for Rheumatoid Arthritis:The Immunoengineering and Delivery Systems

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Research 2024年第3期2023卷 169-189页

作者： Chenyu Zhang Peixiang Ma An Qin Liao Wang Kerong Dai Yuanyuan Liu Jie Zhao Zuyan Lu school of medicine Shanghai UniversityShanghaiChina Clinical and Translational Research center for 3. Printing Technology Shanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina shanghai Key Laboratory of Orthopedic Implants Department of Orthopedic SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina shanghai Frontiers Science center of Degeneration and Regeneration in Skeletal System ShanghaiChina.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease accompanied by persistent multiarticular synovitis and cartilage degradation. The present clinical treatments are limited to disease-modifying anti-rheumatic drugs (DMARDs) and aims to relieve pain and control the inflammation of RA. Despite considerable advances in the research of RA, the employment of current clinical procedure is enormous, hindered by systemic side effect, frequent administration, tolerance from long-lasting administration, and high costs. Emerging immunoengineering-based strategies, such as multiple immune-active nanotechnologies via mechanism-based immunology approaches, have been developed to improve specific targeting and to reduce adverse reactions for RA treatments. Here, we review recent studies in immunoengineering for the treatment of RA. The prospect of future immunoengineering treatment for RA has also been discussed.

关键词： drugs Rheumatoid treatment

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FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression

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International Journal of Oral Science 2024年第2期16卷 333-348页

作者： Zhonglong Liu Xiaoyan Meng Yuxin Zhang Jingjing Sun Xiao Tang Zhiyuan Zhang Liu Liu Yue He Department of Oral Maxillofacial&Head and Neck Oncology Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineNational Clinical Research Center for Oral DiseaseShanghaiChina Department of Oral Surgery Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineCollege of StomatologyShanghai Jiao Tong UniversityNational Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghaiChina Department of Oral Pathology Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineNational Clinical Research Center for Oral Disease ShanghaiShanghaiChina

SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor *** glycosylation has been intricately linked with immune escape and tumor ***7A is a highly glycosylated protein with five glycosylated *** underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are ***,we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma,and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides(Asn 105.15.,25.,3.0,and 6.2)via a direct protein‒protein interaction.A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the *** EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8,whereas TGF-β1 promotes abnormal glycosylation of SEMA7A via induction of epithelial–mesenchymal *** N-glycosylation of SEMA7A leads to the differentiation of CD8^(+)T cells along a trajectory toward an exhausted state,thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell *** of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based ***,we also define RBM4.a splice regulator,as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative *** findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.

关键词： aberrant squamous SEMA

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Topological reorganization and functional alteration of distinct genomic components in gallbladder cancer

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Frontiers of medicine 2024年第1期18卷 109-127页

作者： Guoqiang Li Peng Pu Mengqiao Pan Xiaoling Weng Shimei Qiu Yiming Li Sk Jahir Abbas Lu Zou Ke Liu Zheng Wang Ziyu Shao Lin Jiang Wenguang Wu Yun Liu Rong Shao Fatao Liu Yingbin Liu Department of Biliary-pancreatic Surgery Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200127China State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer InstituteShanghai200127China shanghai Key Laboratory of Biliary Tract disease Shanghai200082China Department of Health Science and Engineering University of Shanghai for Science and TechnologyShanghai200082China shanghai Tenth People’s hospital of tongji {3. Shanghai200072China Department of General Surgery Xinhua HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200082China Department of Pharmacology Shanghai Jiao Tong University School of MedicineShanghai200025China

Altered three-dimensional architecture of chromatin influences various genomic regulators and subsequent gene expression in human ***,knowledge of the topological rearrangement of genomic hierarchical layers in cancer is largely ***,by taking advantage of in situ Hi-C,RNA-sequencing,and chromatin immunoprecipitation sequencing(ChIP-seq),we investigated structural reorganization and functional changes in chromosomal compartments,topologically associated domains(TADs),and CCCTC binding factor(CTCF)-mediated loops in gallbladder cancer(GBC)tissues and cell *** observed that the chromosomal compartment A/B switch was correlated with CTCF binding levels and gene expression *** inter-TAD interactions with weaker TAD boundaries were identified in cancer cell lines relative to normal ***,the chromatin short loops and cancer unique loops associated with chromatin remodeling and epithelial–mesenchymal transition activation were enriched in cancer compared with their control ***-specific enhancer–promoter loops,which contain multiple transcription factor binding motifs,acted as a central element to regulate aberrant gene *** of individual enhancers in each loop anchor that connects with promoters led to the inhibition of their corresponding gene ***,our data offer the landscape of hierarchical layers of cancer genome and functional alterations that contribute to the development of GBC.

关键词： 3. genome cancer TADs loop gene regulation

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Trajectory of COVID-19 response and management strategy in china:scientific rationale driven strategy adjustments

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Frontiers of medicine 2024年第1期18卷 19-30页

作者： Zeyu Zhang Yue Yan Lina Zhao Yizhou Bian Ning Zhao You Wu Dahai Zhao Zongjiu Zhang Institute for hospital Management Tsinghua UniversityBeijing100084China school of medicine Tsinghua UniversityBeijing100084China school of International and Public Affairs Shanghai Jiao Tong UniversityShanghai200030China Yale university-shanghai jiao {3. university Joint {5. for Health Policy Shanghai Jiao Tong UniversityShanghai200030China

The pneumonia caused by novel coronavirus SARS-CoV-2 infection in early December 2019,which was later named coronavirus disease 2019(COVID-19)by the World Health Organization(WHO),rapidly spread across the *** has made extraordinary efforts to this unprecedented pandemic,put its response and control at a very high level of infectious disease management(Category B but with measures for Category A),given top priority to the people and their lives,and balanced the pandemic control and socio-economic *** more than three years’fighting against this disease,{3. downgraded the management of COVID-19 to Category B infectious disease on January 8,2023.and the WHO declared the end of public health emergency on May {6.***,the ending of pandemic does not mean that the disease is no longer a health *** against COVID-19 from {3. and the whole world should be learned to prepare well for the future public health *** article gives a systematic review of the trajectory of COVID-19 development in {3.,summarizes the critical policy arrangements and provides evidence for the adjustment during policy making process,so as to share experiences with international community and contribute to the global health for all humanity.

关键词： COVID-19 public health response and control strategy science-based policy making

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Exosome-encapsulated lncRNA HOTAIRM1 contributes to PM_(2.5.-aggravated COPD airway remodeling by enhancing myofibroblast differentiation

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Science china(Life Sciences) 2024年第5期67卷 970-985页

作者： Huaqi Guo Luo Fei Hengyi Yu Yan Li Yan Feng Shaowei Wu Yan Wang The Ninth People’s hospital of shanghai jiao {3. {4. {5. of {6. Shanghai 200011China school of Public Health Shanghai Jiao Tong University School of MedicineShanghai 200020China Department of Occupational and Environmental Health Sciences School of Public HealthXi’an Jiao Tong University Health Science CenterXi’an 710049China

Emphysema,myofibroblast accumulation and airway remodeling can occur in the lungs due to exposure to atmospheric pollution,especially fine particulate matter(PM_(2.5.),leading to chronic obstructive pulmonary disease(COPD).Specifically,bronchial epithelium-fibroblast communication participates in airway remodeling,which results in *** increasing number of studies are now being conducted on the role of exosome-mediated cell-cell communication in disease ***,we investigated whether exosomes generated from bronchial epithelial cells could deliver information to normal stromal fibroblasts and provoke cellular responses,resulting in airway obstruction in *** studied the mechanism of exosome-mediated intercellular communication between human bronchial epithelial(HBE) cells and primary lung fibroblasts(pLFs).We found that PM_(2.5.-induced HBE-derived exosomes promoted myofibroblast differentiation in ***,the exosomal lncRNA expression profiles derived from PM_(2.5.-treated HBE cells and nontreated HBE cells were investigated using an Agilent Human LncRNA *** coculture assays and direct exosome treatment,we found that HBE cell-derived exosomal HOTAIRM1 facilitated the myofibroblast differentiation of ***,we discovered that exosomal HOTAIRM1 enhanced p LF proliferation to secrete excessive collagen secretion,leading to airway obstruction by stimulating the TGF-β/SMAD3.signaling ***,PM_(2.5.reduced FEV1/FVC and FEV1 and increased the level of serum exosomal HOTAIRM1 in healthy people;moreover,serum exosomal HOTAIRM1 was associated with PM_(2.5.-related reductions in FEV1/FVC and *** findings show that PM_(2.5.triggers alterations in exosome components and clarify that one of the paracrine mediators of myofibroblast differentiation is bronchial epithelial cell-derived HOTAIRM1,which has the potential to be an effective prevention and therapeutic target for PM_(2.5.-induced COPD.

关键词： PM2.5 exosomal lncRNAs HOTAIRM1 chronic obstructive pulmonary disease

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Aβ-Aggregation-Generated Blue Autofluorescence Illuminates Senile Plaques as well as Complex Blood and Vascular Pathologies in Alzheimer’s disease

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Neuroscience Bulletin 2024年第8期40卷 1115-1126页

作者： Hualin Fu Jilong Li Chunlei Zhang Peng Du Guo Gao Qiqi Ge Xinping Guan Daxiang Cui Institute of Nano Biomedicine and Engineering School of Sensing Science and EngineeringSchool of Electronic Information and Electrical EngineeringShanghai Jiao Tong UniversityShanghai 200240China Institute of Marine Equipment Shanghai Jiao Tong UniversityShanghai 200240China National center for Translational medicine Shanghai Jiao Tong UniversityShanghai 200240China Department of Colorectal Surgery School of MedicineXinhua HospitalShanghai Jiao Tong UniversityShanghai 200092China Department of Automation Shanghai Jiao Tong UniversityShanghai 200240China The Key Laboratory of System Control and Information Processing Ministry of EducationShanghai 200240China

Senile plaque blue autofluorescence was discovered around 4. years ago,however,its impact on Alzheimer’s disease(AD)pathology has not been fully *** analyzed senile plaques with immunohistochemistry and fluorescence imaging on AD brain sections and also Aβ aggregation in *** DAPI or Hoechst staining,the nuclear blue fluorescence could only be correctly assigned after subtracting the blue plaque *** flower-like structures wrapping dense-core blue fluorescence formed by cathepsin D staining could not be considered central-nucleated neurons with defective lysosomes since there was no nuclear staining in the plaque core when the blue autofluorescence was *** Aβ self-oligomers and Aβ/hemoglobin heterocomplexes generated blue *** Aβ amyloid blue autofluorescence not only labels senile plaques but also illustrates red cell aggregation,hemolysis,cerebral amyloid angiopathy,vascular plaques,vascular adhesions,and *** summary,we conclude that Aβ-aggregation-generated blue autofluorescence is an excellent multi-amyloidosis marker in Alzheimer’s disease.

关键词： Senile plaque Blue autofluorescence Aβ Amyloid aggregation Hemoglobin Cathepsin D.Microaneurysm Alzheimer's disease

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Cross-sectional network analysis of plasma proteins/metabolites correlated with pathogenesis and therapeutic response in acute promyelocytic leukemia

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Frontiers of medicine 2024年第2期18卷 327-343页

作者： Niu Qiao Yizhu Lyu Feng Liu Yuliang Zhang Xiaolin Ma Xiaojing Lin Junyu Wang Yinyin Xie Ruihong Zhang Jing Qiao Hongming Zhu Li Chen Hai Fang tong Yin Zhu Chen Qiang Tian Saijuan Chen shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China Department of Hematology Second Hospital of Dalian Medical UniversityDalian116021China

The treatment of PML/RARA+acute promyelocytic leukemia(APL)with all-trans-retinoic acid and arsenic trioxide(ATRA/ATO)has been recognized as a model for translational medicine *** an altered microenvironment is a general cancer hallmark,how APL blasts shape their plasma composition is poorly ***,we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters,proteomes,and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction *** study revealed the two prominent features of the APL plasma,suggesting a possible involvement of APL blasts in modulating plasma *** was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts,and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/***,results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage,which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular ***,our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.

关键词： acute promyelocytic leukemia plasma proteomics plasma metabolomics cross-sectional correlation network pathogenesis treatment

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Pipeline of New Drug Treatment for Non-alcoholic Fatty Liver disease/Metabolic Dysfunction-associated Steatotic Liver disease

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Journal of Clinical and Translational Hepatology 2024年第9期12卷 802-814页

作者： Ye Hu Chao Sun Ying Chen Yu-Dong Liu Jian-Gao Fan Department of Gastroenterology Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Geriatrics Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Gastroenterology Changxing branch of Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina

Given the global prevalence and rising incidence of metabolic dysfunction-associated steatotic liver disease(MASLD),the absence of licensed medications is striking.A deeper understanding of the heterogeneous nature of MASLD has recently contributed to the discovery of novel groups of agents and the potential repurposing of currently available *** therapies center on four major *** the close relationship between MASLD and type 2 diabetes,the first approach involves antidiabetic medications,including incretins,thiazolidinedione insulin sensitizers,and sodium-glucose cotransporter 2 *** second approach targets hepatic lipid accumulation and the resultant metabolic *** in this group include peroxisome proliferatoractivated receptor agonists(e.g.,pioglitazone,elafibranor,saroglitazar),bile acid-farnesoid X receptor axis regulators(obeticholic acid),de novo lipogenesis inhibitors(aramchol,NDI-010976.,and fibroblast growth factor 21/19 *** third approach focuses on targeting oxidative stress,inflammation,and *** in this group include antioxi-dants(vitamin E),tumor necrosis factor a pathway regulators(emricasan,pentoxifylline,ZSP16.1),and immune modulators(cenicriviroc,belapectin).The final group targets the gut(IMM-124.,solithromycin).Combination therapies targeting different pathogenetic pathways may provide an alternative to MASLD treatment with higher efficacy and fewer side *** review aimed to provide an update on these medications.

关键词： NAFLD MASLD Clinical trial Medication Hypoglycemic agents Intermediary metabolism

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