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Mimotope peptide modified pompon mum-like magnetic microparticles for precise recognition,capture and biotransformation analysis of rituximab in biological fluids

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1317-1328页

作者： Jiawen Yang Aixuan Zhou Minyi Li Qiaoxian He Jingwei Zhou Jacques Crommen Wentao Wang Zhengjin Jiang Qiqin Wang institute of Pharmaceutical Analysis College of Pharmacy/State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education(MOE)of ChinaJinan UniversityGuangzhou 510632China laboratory for the Analysis of Medicines Department of Pharmaceutical SciencesCIRMUniversity of LiegeLiege B-4000Belgium SCIEX Shanghai 200050China

Due to low immobilized ligand density,limited binding capacity,and severe interference from serum proteins,developing ideal peptide-based biomaterials for precise recognition and in vivo analysis of biopharmaceuticals remains a huge challenge.In this study,mimotope peptide modified pompon mum-like biomimetic magnetic microparticles(MMPs,3.8μm)that mimic the specific functionalities of CD20 on malignant B cells were developed for the first time.Benefit from the numerous ligand binding sites(Ni^(2+))on the pompon mum-like MMPs,these novel materials achieved≥10 times higher peptide ligand densities(>2300 mg/g)and antibody binding capacities(1380 mg/g)compared to previous reported biomaterials.Leveraging the high specificity of the mimotope peptide,rituximab can be precisely recognized and enriched from cell culture media or serum samples.We also established an LC-MS/MS method using the MMPs for tracking rituximab biotransformation in patient serum.Intriguingly,deamidation of Asn55 and Asn33,as well as oxidation of Met81 and Met34 were observed at the key complementarity determining regions of rituximab,which could potentially influence antibody function and require careful monitoring.Overall,these versatile biomimetic MMPs demonstrate superior recognition and enrichment capabilities for target antibodies,offering interesting possibilities for biotransformation analysis of biopharmaceuticals in patient serum.

关键词： Therapeutic monoclonal antibody Mimotope peptide Precise recognition Peptide-based biomaterials Biotransformation Patient serum

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Cinobufotalin prevents bone loss induced by ovariectomy in mice through the BMPs/SMAD and Wnt/β-catenin signaling pathways

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Animal Models and Experimental Medicine 2024年第3期7卷 208-221页

作者： Da-zhuang Lu Li-jun Zeng Yang Li Ran-li Gu Meng-long Hu Ping Zhang Peng Yu Xiao Zhang Zheng-wei Xie Hao Liu Yong-sheng Zhou Department of Prosthodontics Peking University School and Hospital of StomatologyBeijingChina national Center of Stomatology BeijingChina national Clinical Research Center for Oral Diseases BeijingChina beijing key laboratory of Digital Stomatology BeijingChina Department of Cariology and Endodontology Peking University School and Hospital of StomatologyBeijingChina Peking University International Cancer institute Peking University Health Science CenterPeking UniversityBeijingChina Central laboratory Peking University School and Hospital of StomatologyBeijingChina national Engineering Research Center of Oral Biomaterials and Digital Medical Devices BeijingChina

Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy prediction system(DLEPS)is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin(CB),a traditional Chinese medicine(TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphological analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells(hBMMSCs)were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot(WB),immunofluorescence(IF),etc.Results:A safe concentration(0.25mg/kg in vivo,0.05μM in vitro)of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.

关键词： BMPs/SMAD bone loss cinobufotalin hBMMSCs osteogenesis osteoporosis Wnt/β-catenin signaling pathways

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Genome engineering of the human gut microbiome

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Journal of Genetics and Genomics 2024年第5期51卷 479-491页

作者： Linggang Zheng Juntao Shen Ruiyue Chen Yucan Hu Wei Zhao Elaine Lai-Han Leung Lei Dai Dr Neher's Biophysics laboratory for Innovative drug Discovery/State key laboratory of Quality Research in Chinese Medicine Macao University of Science and TechnologyTaipaMacao 999078China CAS key laboratory of Quantitative Engineering Biology Shenzhen Institute of Synthetic BiologyShenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China University of Chinese Academy of Sciences Beijing 100049China Cancer Center Faculty of Health ScienceUniversity of MacaoMacao 999078China MOE Frontiers Science Center for Precision Oncology University of MacaoMacao 999078China

The human gut microbiome,a complex ecosystem,significantly influences host health,impacting crucial aspects such as metabolism and immunity.To enhance our comprehension and control of the molecular mechanisms orchestrating the intricate interplay between gut commensal bacteria and human health,the exploration of genome engineering for gut microbes is a promising frontier.Nevertheless,the complexities and diversities inherent in the gut microbiome pose substantial challenges to the development of effective genome engineering tools for human gut microbes.In this comprehensive review,we provide an overview of the current progress and challenges in genome engineering of human gut commensal bacteria,whether executed in vitro or in situ.A specific focus is directed towards the advancements and prospects in cargo DNA delivery and high-throughput techniques.Additionally,we elucidate the immense potential of genome engineering methods to enhance our understanding of the human gut microbiome and engineer the microorganisms to enhance human health.

关键词： Non-model gut commensals Genomeediting reagents Cargo delivery High-throughput genome engineering

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Genomic characterization of peritoneal lavage cytology-positive gastric cancer

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Chinese Journal of Cancer Research 2024年第1期36卷 66-77页

作者： Zhouqiao Wu Tingfei Gu Changxian Xiong Jinyao Shi Jingpu Wang Ting Guo Xiaofang Xing Fei Pang Ning He Rulin Miao Fei Shan Yuan Zhou Ziyu Li Jiafu Ji key laboratory of Carcinogenesis and Translational Research(Ministry of Education/beijing) Gastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China Department of Biomedical Informatics Department of Physiology and PathophysiologyCenter for Noncoding RNA MedicineMOE Key Lab of Cardiovascular SciencesSchool of Basic Medical SciencesPeking UniversityBeijing 100191China State key laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchGastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China

Objective: Positive peritoneal lavege cytology(CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric cancer.Methods: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. Whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric cancer.Results: Least absolute shrinkage and selection operator(LASSO) algorithm identified 43 cytology-positive marker genes, while Mut Sig CV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology(CY0).Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.

关键词： Cytology gastric carcinoma peritoneal metastasis whole exome sequencing

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A regression approach for seismic first-break picking

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Petroleum Science 2024年第3期21卷 1584-1596页

作者： Huan Yuan San-Yi Yuan Jie Wu Wen-Jing Sang Yu-He Zhao CNPC key laboratory of Geophysical Exploration China University of Petroleum (Beijing) Research institute of Petroleum Exploration & Development—Northwest (NWGI) Key Laboratory of reservoir characterization of CNPCPetroChina

The picking efficiency of seismic first breaks(FBs) has been greatly accelerated by deep learning(DL)technology. However, the picking accuracy and efficiency of DL methods still face huge challenges in low signal-to-noise ratio(SNR) situations. To address this issue, we propose a regression approach to pick FBs based on bidirectional long short-term memory(Bi LSTM) neural network by learning the implicit Eikonal equation of 3D inhomogeneous media with rugged topography in the target region. We employ a regressive model that represents the relationships among the elevation of shots, offset and the elevation of receivers with their seismic traveltime to predict the unknown FBs, from common-shot gathers with sparsely distributed traces. Different from image segmentation methods which automatically extract image features and classify FBs from seismic data, the proposed method can learn the inner relationship between field geometry and FBs. In addition, the predicted results by the regressive model are continuous values of FBs rather than the discrete ones of the binary distribution. The picking results of synthetic data shows that the proposed method has low dependence on label data, and can obtain reliable and similar predicted results using two types of label data with large differences. The picking results of9380 shots for 3D seismic data generated by vibroseis indicate that the proposed method can still accurately predict FBs in low SNR data. The subsequent stacked profiles further illustrate the reliability and effectiveness of the proposed method. The results of model data and field seismic data demonstrate that the proposed regression method is a robust first-break picker with high potential for field application.

关键词： First-break picking Low signal-to-noise ratio Regression BiLSTM Traveltime Geometry Noisy seismic data

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The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1951-1964页

作者： Longsheng Wang Jie Zhang Wenxin Zhang Mingming Zheng Hongjie Guo Xiaohui Pan Wen Li Bo Yang Ling Ding Zhejiang Province key laboratory of Anti-Cancer drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China The Innovation institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Nanhu Brain-Computer Interface institute Hangzhou 311100China

Adenosine(Ado)is significantly elevated in the tumor microenvironment(TME)compared to normal tissues.It binds to adenosine receptors(AdoRs),suppressing tumor antigen presentation and immune cell activation,thereby inhibiting tumor adaptive immunity.Ado downregulates major histocompatibility complex II(MHC II)and co-stimulatory factors on dendritic cells(DCs)and macrophages,inhibiting antigen presentation.It suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor(TCR)binding and signal transduction.Ado also inhibits chemokine secretion and KCa3.1 channel activity,impeding effector T cell trafficking and infiltration into the tumor site.Furthermore,Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion,upregulating immune checkpoint proteins,and enhancing immune-suppressive cell activity.Reducing Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other immunotherapies.Preclinical and clinical development of inhibitors targeting Ado generation or AdoRs is underway.Therefore,this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity,as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.

关键词： Adenosine Adenosine receptors Adenosine-generating enzymes Tumor microenvironment Immune suppression Immune escape Clinical treatment Targeting drugs

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Evolution of chemistry and selection technology for DNA-encoded library

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Acta Pharmaceutica Sinica B 2024年第2期14卷 492-516页

作者： Peixiang Ma Shuning Zhang Qianping Huang Yuang Gu Zhi Zhou Wei Hou Wei Yi Hongtao Xu Shanghai key laboratory of Orthopedic Implants Department of OrthopedicsShanghai Ninth People’s HospitalShanghai Jiao Tong UniversitySchool of MedicineShanghai 200025China Shanghai institute for Advanced Immunochemical Studies ShanghaiTech UniversityShanghai 201210China Guangzhou Municipal and Guangdong Provincial key laboratory of Molecular Target&Clinical Pharmacology The NMPA and State Key Laboratory of Respiratory DiseaseGuangzhou Medical UniversityGuangzhou 511436China College of Pharmaceutical Science and institute of drug Development&Chemical Biology Zhejiang University of TechnologyHangzhou 310014China

DNA-encoded chemical library(DEL)links the power of amplifiable genetics and the nonself-replicating chemical phenotypes,generating a diverse chemical world.In analogy with the biological world,the DEL world can evolve by using a chemical central dogma,wherein DNA replicates using the PCR reactions to amplify the genetic codes,DNA sequencing transcripts the genetic information,and DNA-compatible synthesis translates into chemical phenotypes.Importantly,DNA-compatible synthesis is the key to expanding the DEL chemical space.Besides,the evolution-driven selection system pushes the chemicals to evolve under the selective pressure,i.e.,desired selection strategies.In this perspective,we summarized recent advances in expanding DEL synthetic toolbox and panning strategies,which will shed light on the drug discovery harnessing in vitro evolution of chemicals via DEL.

关键词： DNA-encoded library drug discovery High-throughput selection DNA-compatible synthesis In vitro evolution Chemical central dogma

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Targeted therapeutic effects of oral magnetically driven pectin nanoparticles containing chlorogenic acid on colon cancer

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Particuology 2024年第1期84卷 53-59页

作者： Huatai Zhu Limei Zhang Fujia Kou Jingyang Zhao Jiandu Lei Jing He beijing key laboratory of Lignocellulosic Chemistry Beijing Forestry UniversityBeijing100083China institute of Biopharmaceutical and Health Engineering Tsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhen518055China

Oral colonic nano-drug delivery system has attracted growing attention in treating colon cancer for their excellent characteristics.However,the unique and complex structure of the gastrointestinal tract is still an obstacle to the safe delivery of drugs targeting sites in colon tumors.Here,we designed magnetically driven dual-targeted oral colonic nanoparticles loaded with chlorogenic acid using pectin and oleic acid-modified iron oxide(Fe3O4@OA).Specific degradation of pectin by pectinase produced by colonic flora and magnetic fields applied to the colon confers specific targeting of nanoparticles to the colon.In order to overcome the challenge of preparing magnetically driven nanoparticles with small and homogeneous particle sizes by a single conventional method,we developed the combined ultrasound-emulsification technique.The average particle size of the prepared nanoparticles was 81.04±1.02 nm,which showed good drug release in the simulated colonic environment.In vitro anticancer studies,the drug-loaded nanoparticles possess an obvious toxicity and apoptosis-inducing ability against cancer cells.Meanwhile,the hemolysis results demonstrated the safety of the nanoplatform(PET/CGA/Fe_(3)O_(4)@OA).This work holds broad prospects as a new treatment modality for colon cancer.

关键词： Pectin Chlorogenic acid Ultrasound-emulsion Magnetically driven Colon cancer Colon targeted

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Asymmetric Synthesis of Dihydrospirotryprostatin B via a Silica Gel-Mediated Cyclization of Tryptamine-Ynamide

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Chinese Journal of Chemistry 2024年第12期42卷 1355-1359页

作者： Changhong Han Lu Yang Kaizong Yao Sen Zhang Jiayue Fu Hanyang Sun Hongsheng Xu Bin Lin Maosheng Cheng Yongxiang Liu key laboratory of Structure:Based drug Design and Discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyangLiaoning 110016China Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyangLiaoning 110016China institute of drug Research in Medicine Capital of China BenxiLiaoning 117000China Zhejiang Shapuaisi Pharmaceutical Co. LtdPinghuZhejiang 314299China

Comprehensive Summary An asymmetric synthesis of dihydrospirotryprostatin B was achieved in 15 steps(8 purifications)from L-tryptophan.The main feature of our synthetic strategy is the efficient construction of spirocyclic oxindole intermediate containing a chiral quaternary carbon center,involving the silica gel-mediated cyclization of tryptamine-ynamide and oxidation under neat conditions.

关键词： Asymmetric synthesis Alkaloids Dihydrospirotryprostatin B Tryptamine-ynamide Cross-coupling Silica gel-mediated cyclization Oxidation

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Immunostimulatory gene therapy combined with checkpoint blockade reshapes tumor microenvironment and enhances ovarian cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 854-868页

作者： Yunzhu Lin Xiang Wang Shi He Zhongxin Duan Yunchu Zhang Xiaodong Sun Yuzhu Hu Yuanyuan Zhang Zhiyong Qian Xiang Gao Zhirong Zhang key laboratory of drug Targeting and drug Delivery Systems Ministry of EducationWest China School of PharmacySichuan UniversityChengdu 610041China Department of Pharmacy Evidence-based Pharmacy CenterWest China Second University HospitalKey Laboratory of Birth Defects and Related Diseases of Women and ChildrenSichuan UniversityChengdu 610041China Department of Neurosurgery and institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Department of Radiation Oncology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China West China School of Basic Medical Sciences&Forensic Medicine Sichuan UniversityChengdu 610041China

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor(i PDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of p IL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation,macrophage polarization and DC maturation. The F-DPC/p IL-12/i PDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/p IL-12/i PDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

关键词： IL-12encodinggene Checkpointblocker Nanoparticles Targeted delivery Tumormicroenvironment Immune escape Ovarian cancer Immunotherapy

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