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Distinct but correct: generating diversified and entity-revised medical response

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Science China(Information sciences) 2024年第3期67卷 94-113页

作者： Bin LI Bin SUN Shutao LI Encheng CHEN Hongru LIU Yixuan WENG Yongping BAI Meiling HU College of Electrical and Information Engineering Hunan University school of Mathematics Sun Yat-sen University JD Technology National Laboratory of Pattern Recognition Institute of AutomationChinese Academy of Sciences xiangya Hospital of Central South University Teaching and Research Section of Clinical Nursing Xiangya Hospital of Central South University

Medical dialogue generation(MDG) is applied for building medical dialogue systems for intelligent consultation. Such systems can communicate with patients in real time, thereby improving the efficiency of clinical diagnosis. However, predicting correct entities and correctly generating distinct responses remain a great challenge. Inspired by actual doctors’ responses to patients, we consider MDG a two-stage task: entity prediction and dialogue generation. For entity prediction, we design an ent-mac post pre-training strategy by leveraging external medical entity knowledge to enhance the pre-trained model. For dialogue generation, we propose an entity-aware fusion MDG method in which predicted entities are integrated into the dialogue generation model through different encoding fusion mechanisms, using information from different sources. Because the diverse beam search algorithm can produce responses with entities that deviate from the predicted entities, an entity-revised diverse beam search is proposed to correct the entities entailed in the generated responses and make the generated responses more distinct. The experimental results on the China Conference on Knowledge Graph and Semantic Computing 2021(A/B tests) and the International Conference on Learning Representations 2021(online test) datasets show that the proposed method outperforms several state-of-the-art methods, which demonstrates its practicability and effectiveness.

关键词： medical entity prediction ent-mac post pre-training strategy entity-aware fusion medical dialogue generation encoding fusion mechanism entity-revised diverse beam search

Discovery of GluN2A subtype-selective N-methyl-d-aspartate(NMDA)receptor ligands

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1987-2005页

作者： Liyang Jiang Na Liu Fabao Zhao Boshi Huang Dongwei Kang Peng Zhan Xinyong Liu Department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

The N-methyl-d-aspartate(NMDA)receptors,which belong to the ionotropic Glutamate receptors,constitute a family of ligand-gated ion channels.Within the various subtypes of NMDA receptors,the GluN1/2A subtype plays a significant role in central nervous system(CNS)disorders.The present article aims to provide a comprehensive review of ligands targeting GluN2A-containing NMDA receptors,encompassing negative allosteric modulators(NAMs),positive allosteric modulators(PAMs)and competitive antagonists.Moreover,the ligands’structure–activity relationships(SARs)and the binding models of representative ligands are also discussed,providing valuable insights for the clinical rational design of effective drugs targeting CNS diseases.

关键词： NMDA receptors GluN2A subtype Subtype-selective ligands SARs Protein ligand interactions

Advantages of nanocarriers for basic research in the field of traumatic brain injury

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Neural Regeneration Research 2024年第2期19卷 237-245页

作者： Xingshuang Song Yizhi Zhang Ziyan Tang Lina Du school of pharmaceutical sciences Shandong University of Traditional Chinese MedicineJinanShandong ProvinceChina Department of Pharmaceutics Beijing Institute of Radiation MedicineBeijingChina

A major challenge for the efficient treatment of traumatic brain injury is the need for therapeutic molecules to cross the blood-brain barrier to enter and accumulate in brain tissue.To overcome this problem,researchers have begun to focus on nanocarriers and other brain-targeting drug delivery systems.In this review,we summarize the epidemiology,basic pathophysiology,current clinical treatment,the establishment of models,and the evaluation indicators that are commonly used for traumatic brain injury.We also report the current status of traumatic brain injury when treated with nanocarriers such as liposomes and vesicles.Nanocarriers can overcome a variety of key biological barriers,improve drug bioavailability,increase intracellular penetration and retention time,achieve drug enrichment,control drug release,and achieve brain-targeting drug delivery.However,the application of nanocarriers remains in the basic research stage and has yet to be fully translated to the clinic.

关键词： blood-brain barriers brain targeting central nervous system extracellular vesicles inflammatory factor microglial cell nanocarriers nanoparticles neural restoration traumatic brain injury

Research Progress on the Association between Schizophrenia and Toxoplasma gondii Infection

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Biomedical and Environmental sciences 2024年第6期37卷 647-660页

作者： Yiting Zhu Xiaohui Yang Miaoru Chen Yu Hu Yunfeng Chang Xiang Wu Department of Forensic Medicine Science Xiangya School of Basic MedicineCentral South UniversityChangsha 410013HunanChina Nursing Department The Third Xiangya Hospital of Central South UniversityChangsha 410013HunanChina Department of Basic Medicine Science Xiangya School of Basic MedicineCentral South UniversityChangsha 410013HunanChina Department of Parasitology Xiangya School of Basic MedicineCentral South UniversityChangsha 410013HunanChina

Toxoplasma gondii(T.gondii or Tg),is an obligatory intracellular parasite with humans as its intermediate hosts.In recent years,significant correlations between T.gondii infection and schizophrenia have been reported,including the possible mediating mechanisms.Currently,mechanisms and hypotheses focus on central neurotransmitters,immunity,neuroinflammation,and epigenetics;however,the exact underlying mechanisms remain unclear.In this article,we review the studies related to T.gondii infection and schizophrenia,particularly the latest research progress.Research on dopamine(DA)and other neurotransmitters,the blood-brain barrier,inflammatory factors,disease heterogeneity,and other confounders is also discussed.In addition,we also summarized the results of some new epidemiological investigations.

关键词： Toxoplasma gondii Schizophrenia Neurotransmitters Neuroinflammation Immunity Epigenetics

Anti-Inflammatory Glycosaminoglycan Oligosaccharides from Colwellia psychrerythraea 34H Capsule:Synthesis and Biological Evaluation

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CCS Chemistry 2024年第7期6卷 1698-1711页

作者： Zhongtang Li Xiaoyu Sun Yuchao Wang Ao Sun Linbo Fu Tongtong Geng Zihui Zhang Ximin Lv Qian Wang Jing Wang Baodi Gou Xiangbao Meng Zhongjun Li State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191

Capsular polysaccharides(CPS)of Colwellia psychrerythraea 34H consist of linear tetrasaccharides repeating units in a glycosaminoglycan-like fashion.Their biological function is likely involved in the cold adaptation of microbial organisms.The low availability of these glycosaminoglycan structures greatly limits the study of their functions and biological activities.Here,an efficient semisynthetic strategy for CPS tetrasaccharide derivatives is achieved by using disaccharide units degraded from hyaluronic acids.This new synthetic process is suitable for largescale preparation,and several rare tetrasaccharide derivatives containing GalA-GalNAc were readily obtained in high yields.Biological evaluation of their anti-inflammatory effects demonstrated that these CPS tetrasaccharides effectively attenuated the lipopolysaccharide-induced sepsis and acute lung injury by decreasing macrophage infiltration and secretion of microphage-related cytokines in mice.All these results suggest that this new type of CPS tetrasaccharide can be developed as an anti-inflammation agent.

关键词： glycosaminoglycan oligosaccharide glycosylation anti-inflammatory agent acute lung injury

PINK1 is involved in determining the cellular autophagic hierarchy

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Science China(Life sciences) 2024年第5期67卷 1087-1088页

作者： Zhuchen Zhou Zhong Chen Yanrong Zheng Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province School of Pharmaceutical SciencesZhejiang Chinese Medical UniversityHangzhou 311402China

The protein PINK1 plays a crucial role in the regulation of the cellular autophagic hierarchy.Autophagy,a highly conserved biological process,serves as a mechanism for the degradation of intracellular components by lysosomes.Autophagosomes play a pivotal role in this process by selectively sequestering specific targets,including damaged organelles,protein aggregates,and pathogens.

关键词： PINK1 determining hierarchy

A sequential continuous flow synthesis and purification process of calcium dibutyryladenosine cyclophosphate

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Chinese Chemical Letters 2024年第2期35卷 402-406页

作者： Liming Cao Maolin Sun Chaoming Liang Lei Yang Yueyue Ma Ruihua Cheng Yanxiong Ke Wei Yu Jinxing Ye Engineering Research Center of pharmaceutical Process Chemistry Ministry of EducationSchool of PharmacyEast China University of Science and TechnologyShanghai 200237China school of Biomedical and pharmaceutical sciences Guangdong University of TechnologyGuangzhou 510006China Shanghai No.1 Biochemical& pharmaceutical Co. Ltd.Shanghai 200080China

Calcium dibutyryladenosine cyclophosphate is a widely used cardiovascular drug.The traditional batch synthesis process suffers from long reaction times,tedious operations,and unstable yields.Herein,a sequential continuous flow synthesis combined with a multistage in-line purification process of calcium dibutyryladenosine cyclophosphate was developed.The acylation reaction was completed in a continuous coil reactor at 160℃ in 20 min.And the high toxic solvent pyridine was replaced by acetonitrile.Furthermore,the multistage in-line purification process was integrated into the homemade 3D circular cyclone-type micromixer chip.Combining with the membrane phase separators,the residence time of the purification step was 30 s.The isolated yield of this sequential continuous process was 92%with 99%purity.

关键词： Flow chemistry Calcium dibutyryladenosine cyclophosphate Continuous flow synthesis In-line purification 3D circular cyclone-type micromixer chip

Development of LAG-3/FGL1 blocking peptide and combination with radiotherapy for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1150-1165页

作者： Yuzhen Qian Yixuan Sun Peishang Shi Xiuman Zhou Qiongqiong Zhang Qingyu Dong Shengzhe Jin Lu Qiu Xiaoshuang Niu Xiaowen Zhou Wenshan Zhao Yahong Wu Wenjie Zhai Yanfeng Gao school of Life sciences Zhengzhou UniversityZhengzhou 450001China school of pharmaceutical sciences(Shenzhen) Shenzhen Campus of Sun Yat-sen UniversityShenzhen 518107China International Joint Laboratory for Protein and Peptide Drugs of Henan Province Zhengzhou UniversityZhengzhou 450001China

Aside from antibodies,peptides show great potential as immune checkpoint inhibitors(ICIs)due to several advantages,such as better tumor penetration and lower cost.Lymphocyte-activation gene 3(LAG-3)is an immune checkpoint which can induce T cell dysfunction through interaction with its soluble ligand fibrinogen like protein-1(FGL1).Here,we found that LAG-3 expression was higher than programmed cell death protein 1(PD-1)in multiple human cancers by TCGA databases,and successfully identified a LAG-3 binding peptide LFP-6 by phage display bio-panning,which specifically blocks the interaction of LAG-3/FGL1 but not LAG-3/MHC-II.Subsequently,D-amino acids were introduced to substitute the N-and C-terminus of LFP-6 to obtain the proteolysis-resistant peptide LFP-D1,which restores T cell function in vitro and inhibits tumor growth in vivo.Further,a bispecific peptide LFOP targeting both PD-1/PD-L1 and LAG-3/FGL1 was designed by conjugating LFP-D1 with PD-1/PD-L1blocking peptide OPBP-1(8-12),which activates T cell with enhanced proliferation and IFN-γ production.More importantly,LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune response.In conclusion,we developed a novel peptide blocking LAG-3/FGL1 which can restore T cell function,and the bispecific peptide synergizes with radiotherapy to further enhance the antitumor immune response.

关键词： LAG-3 FGL1 PD-1 PD-L1 Peptide Immune checkpoint Radiotherapy Cancer immunotherapy

Targeted anti-tumor synergistic effects of Myc decoy oligodeoxynucleotides-loaded selenium nanostructure combined with chemoradiotherapy on LNCaP prostate cancer cells

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Oncology Research 2024年第1期32卷 101-125页

作者： ROGHAYEH GHORBANI MAHMOUD GHARBAVI ALI SHARAFI ELHAM RISMANI HAMED REZAEEJAM YOUSEF MORTAZAVI BEHROOZ JOHARI Department of Medical Biotechnology School of MedicineZanjan University of Medical SciencesZanjanIran Nanotechnology Research Center Ahvaz Jundishapur University of Medical SciencesAhvazIran Zanjan pharmaceutical Biotechnology Research Center Zanjan University of Medical SciencesZanjanIran Department of pharmaceutical Biotechnology School of PharmacyZanjan University of Medical SciencesZanjanIran Molecular Medicine Department Biotechnology Research CenterPasteur Institute of IranPasteur AvenueTehranIran Department of Radiology Technology School of Allied Medical SciencesZanjan University of Medical SciencesZanjanIran

In the present study,we investigated the synergistic effects of targeted methotrexate-selenium nanostructure containing Myc decoy oligodeoxynucleotides along with X-irradiation exposure as a combination therapy on LNCaP prostate cancer cells.Myc decoy ODNs were designed based on the promoter of Bcl-2 gene and analyzed by molecular docking and molecular dynamics assays.ODNs were loaded on the synthesized Se@BSA@Chi-MTX nanostructure.The physicochemical characteristics of nanostructures were determined by FTIR,DLS,UV-vis,TEM,EDX,in vitro release,and hemolysis tests.Subsequently,the cytotoxicity properties of them with and without X-irradiation were investigated by uptake,MTT,cell cycle,apoptosis,and scratch assays on the LNCaP cell line.The results of DLS and TEM showed negative charge(−9 mV)and nanometer size(40 nm)for Se@BSA@Chi-DEC-MTX NPs,respectively.The results of FTIR,UV-vis,and EDX showed the proper interaction of different parts and the correct synthesis of nanoparticles.The results of hemolysis showed the hemocompatibility of this nanoparticle in concentrations less than 6 mg/mL.The ODNs release from the nanostructures showed a pH-dependent manner,and the release rate was 15%higher in acidic pH.The targeted Se@BSA@Chi-labeled ODN-MTX NPs were efficiently taken up by LNCaP cells by targeting the prostate-specific membrane antigen(PSMA).The significant synergistic effects of nanostructure(containing MTX drug)treatment along with X-irradiation showed cell growth inhibition,apoptosis induction(~57%),cell cycle arrest(G2/M phase),and migration inhibition(up to 90%)compared to the control.The results suggested that the Se@BSA@Chi-DEC-MTX NPs can potentially suppress the cell growth of LNCaP cells.This nanostructure system can be a promising approach for targeted drug delivery and chemoradiotherapy in prostate cancer treatment.

关键词： Chemoradiotherapy Combination therapy Decoy oligodeoxynucleotides Myc transcription factor Selenium nanoparticle Prostate cancer