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Acta Pharmaceutica Sinica B 2023年第1期13卷 425-439页

作者： Dezhi Sui Changzhi Li Xueying Tang Xianmin Meng Junqiang Ding Qiongfen Yang Zhaowei Qi Xinrong Liu Yihui Deng Yanzhi Song College of Pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China

Immunoscenescence plays a key role in the initiation and development of tumors.Furthermore,immunoscenescence also impacts drug delivery and cancer therapeutic efficacy.To reduce the impact of immunosenescence on anti-tumor therapy,this experimental plan aimed to use neutrophils with tumor tropism properties to deliver sialic acid(SA)-modified liposomes into the tumor,kill tumor cells via SA-mediated photochemotherapy,enhance infiltration of neutrophils into the tumor,induce immunogenic death of tumor cells with chemotherapy,enhance infiltration of CD8^(+)T cells into the tumordraining lymph nodes and tumors of immunosenescent mice,and achieve SA-mediated photochemotherapy.We found that CD8^(+)T cell and neutrophil levels in 16-month-old mice were significantly lower than those in 2-and 8-month-old mice;16-month-old mice exhibited immunosenescence.The anti-tumor efficacy of SA-mediated non-photochemotherapy declined in 16-month-old mice,and tumors recurred after scabbing.SA-mediated photochemotherapy enhanced tumor infiltration by CD8^(+)T cells and neutrophils,induced crusting and regression of tumors in 8-month-old mice,inhibited metastasis and recurrence of tumors and eliminated the immunosenescence-induced decline in antitumor therapeutic efficacy in 16-month-old mice via the light-heat-chemical-immunity conversion.

关键词： Immunosenescence sialic acid Photochemotherapy CD8^(+)T cells Doxorubicin Neutrophils Indocyanine green Liposomes

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells

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Cellular & Molecular Immunology 2022年第5期19卷 577-587页

作者： Weiqi Hong Jingyun Yang Jun Zou Zhenfei Bi Cai He Hong Lei Xuemei He Xue Li Aqu Alu Wenyan Ren Zeng Wang Xiaohua Jiang Kunhong Zhong Guowen Jia Yun Yang Wenhai Yu Qing Huang Mengli Yang Yanan Zhou Yuan Zhao Dexuan Kuang Junbin Wang Haixuan Wang Siyuan Chen Min Luo Ziqi Zhang Tiangi Lu Li Chen Haiying Que Zhiyao He Qiu Sun Wei Wang Guobo Shen Guangwen Lu Zhiwei Zhao Li Yang Jinliang Yang Zhenling Wang Jiong Li Xiangrong Song Lunzhi Dai Chong Chen Jia Geng Maling Gou Lu Chen Haohao Dong Yong Peng Canhua Huang Zhiyong Qian Wei Cheng Changfa Fan Yuquan Wei Zhaoming Su Aiping Tong Shuaiyao Lu Xiaozhong Peng Xiawei Wei Laboratory of Aging Research and Cancer Drug Targeting State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityNo.17Block 3Southern Renmin RoadChengduSichuan610041China National Kunming High-level Biosafety Primate Research Center Institute of Medical BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeYunnanChina Westvac Biopharm Co. Ltd.No.618Fenghuang RoadShuangliu DistrictChengduSichuanChina Division of Animal Model Research Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug Control102629BeijingChina State Key Laboratory of Medical Molecular Biology Department of Molecular Biology and BiochemistryInstitute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijingChina

Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

关键词： COVID-19 SARS-CoV-2 neutrophil extracellular traps histones sialic acid

Blockade of neutrophil recruitment to tumor sites based on sialic acid-modified nanoplatforms enhances the efficacy of checkpoint blockade immunotherapy

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Asian Journal of Pharmaceutical Sciences 2023年第2期18卷 94-105页

作者： Meng Chen Zhaowei Qi Xianmin Meng Shuo Wang Xueying Zheng Miao Hu Xinrong Liu Yanzhi Song Yihui Deng School of Pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China

Checkpoint inhibitors are designed to rejuvenate depleted or suppressed T cells in the tumor microenvironment,relying on the immune system to control and kill tumors.However,accumulating evidence indicates that tumor-infiltrating neutrophils impede the proliferation and activation of T cells and determine the resistance to checkpoint blockade and chemotherapy.In this study,sialic acid ligand-modified colchicine derivative phospholipid complexes specifically targeted tumor-associated neutrophils in the peripheral blood,blocked neutrophil accumulation in tumors,and attenuated the inhibitory effect of infiltrating neutrophils on T cells.Neutrophil blocking therapy enhanced the immunotherapy effect of the PD-L1 antibody in S180 advanced tumors and 4T1 breast cancer.Our study found that PD-L1 antibody monotherapy increased the tumor infiltration of immunosuppressive neutrophils.Combination therapy with neutrophil blocking can greatly reduce tumor-infiltrating neutrophils and increase the proliferation of cytotoxic CD8^(+) T lymphocytes in the tumor.The combination therapy significantly improved the survival rate of mice with advanced S180 tumors and increased the sensitivity of immune checkpoint inhibitors to 4T1 cold tumors.

关键词： Neutrophil blockade Combination immunotherapy sialic acid

Thermo-responsive imprinted hydrogel with switchable sialic acid recognition for selective cancer cell isolation from blood

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Bioactive Materials 2021年第5期6卷 1308-1317页

作者： Yue Ma Yimei Yin Li Ni Haohan Miao Yingjia Wang Cheng Pan Xiaohua Tian Jianming Pan Tianyan You Bin Li Guoqing Pan Institute for Advanced Materials School of Materials Science and EngineeringJiangsu UniversityZhenjiangJiangsu 212013PR China School of Chemistry and Chemical Engineering Jiangsu UniversityZhenjiangJiangsu 212013PR China Jiangsu Agrochem Laboratory ChangzhouJiangsu 213022PR China Key Laboratory of Modern Agricultural Equipment and Technology Ministry of EducationSchool of Agricultural Equipment EngineeringJiangsu UniversityZhenjiangJiangsu 212013PR China Department of Orthopaedic Surgery The First Affiliated HospitalOrthopaedic InstituteMedical CollegeSoochow UniversitySuzhouJiangsu 215006PR China

In this work,a sialic acid(SA)-imprinted thermo-responsive hydrogel layer was prepared for selective capture and release of cancer cells.The SA-imprinting process was performed at 37℃ using thermo-responsive functional monomer,thus generating switchable SA-recognition sites with potent SA binding at 37℃and weak binding at a lower temperature(e.g.,25℃).Since SA is often overexpressed at the glycan terminals of cell membrane proteins or lipids,the SA-imprinted hydrogel layer could be used for selective cancer cell recognition.Our results confirmed that the hydrogel layer could efficiently capture cancer cells from not only the culture medium but also the real blood samples.In addition,the captured cells could be non-invasively released by lowing the temperature.Considering the non-invasive processing mode,considerable capture efficiency,good cell selectivity,as well as the more stable and durable SA-imprinted sites compared to natural antibodies or receptors,this thermo-responsive hydrogel layer could be used as a promising and general platform for cell-based cancer diagnosis.

关键词： Molecular imprinting Cell capture and release Thermo-responsive hydrogels Molecular recognition sialic acid

Colorimetric-assisted photoelectrochemical sensing for dual-model detection of sialic acid via oxidation-power mediator integration

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Chinese Chemical Letters 2023年第3期34卷 269-273页

作者： Yuanyuan Cheng Rong-Mei Kong Wenao Hu Xiaoxia Tian Lingdong Zhang Lian Xia Fengli Qu School of Chemistry and Chemical Engineering Qufu Normal UniversityQufu 273165China

Development of sensitive and accurate methods for sialic acid(SA) determination is of great significance in early cancer diagnosis.Here,a colorimetric-assisted Photoelectrochemical(PEC) sensor was constructed for SA detection based on the two pairs of cis-diol groups in SA molecule.With the specific recognition of SA via the two pairs of cis-diol groups,the prepared gold-modified Bi_(2)S_(3)(AuNPs@Bi_(2)S_(3)) and metal organic framework(Au@PCN-224) were introduced to the electrode and formed a sandwich structure.Based on the properties of inert electroconductivity and nanozyme of the PCN-224,dual-readout of photocurrent and visualization was achieved with the presence of 3',3',5',5'-tetramethylbenzidine(TMB).Moreover,to intensify the visualization signal,Ce^(3+) was employed as the mediator to boost the catalysis capability by transferring energy from PCN-224 surface to the whole system.With the unique SA recognition and the mediation of Ce^(3+),both the photocurrent and the visualization signals sensitively responded with the SA concentration linearly.The present method showed greatly high sensitivity,selectivity and accuracy for SA detection with a limit of detection of 1.44μmol/L and a wide linear range of 5-1000μmol/L.This method provided a new promising platform for SA detection and a potential strategy for design of novel biosensors with dual-model readout.

关键词： sialic acid Photoelectrochemical sensor Visualization Metal organic frameworks Dual-mode readout

Metabolic fate of dietary sialic acid and its infuence on gut and oral bacteria

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Systems Microbiology and Biomanufacturing 2022年第1期2卷 41-49页

作者： Jianrong Wu Zhang Leilei Mengdan Qiang Hongtao Zhang Xiaobei Zhan Key Laboratory of Carbohydrate Chemistry and Biotechnology Ministry of EducationSchool of BiotechnologyJiangnan UniversityNo.1800 Lihu AveWuxi 214122JiangsuChina

In recent years,the biological functions of human milk oligosaccharides and the potential toxic efects of red meat on human health have attracted considerable attention.sialic acid is an important carbohydrate in milk and red meat,corresponding to sialylated oligosaccharides and N-glycolylneuraminic acid(NeuGc,one type of sialic acid).Herein,we reviewed the metabolic fate of dietary sialic acid in the body and their efects on gut and oral microbes.In summary,dietary NeuAc monomer is directly excreted through urine after being assimilated through the intestines and is not utilized by the human body;in contrast,dietary NeuGc from red meat is easily utilized by the human body and can be incorporated into the brain and other organs.Sialoglycans can be partially utilized by the human body,but they do not afect the cognitive development and growth of children.Dietary sialic acid may mainly regulate the growth and metabolism of gastrointestinal microbiota and human health and development through the gut–brain axis.

关键词： sialic acid Metabolic fate Oral bacteria Gut microbiota Red meat

ROLE OF sialic acid RESIDUES IN IRON BINDING BY HUMAN LACTOFERRIN

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Chinese Journal of Cancer Research 1995年第2期7卷 79-85页

作者：李振甫 Beijing Institute for Cancer Research The School of Oncology Beijing Medical University Beijing Department of Biology New York University USA

Lactoferrin(Lf-α)is a major constithent of the secondary granules of neutrophils, and is thought to be involved in bacteriostasis through high affinity binding of plasma Fe required for microbial growth.Lf-αis also the major Fe binding protein in milk. Fe bound to Lf-αis available for metabolic use.but the mechanism of Fe release from Lf-αis unknown.Treatment of human Lf-α with neuraminidase to remove sialic acid residues reduced its ability to bind Fe and caused release of Fe already bound to the protein. Reduction in Fe binding capacity was dependent on time of exposure to and concentration of neuraminidase,and was due to Lf-αloss or degradation. Readdition of sialic arid to desialylated Lf -a using a-2, 6-sialyltransferase restored Fe binding.The results suggest that sialylationdesialylation reactions could play a role in physiologic binding and release of Fe from the very high affinity binding sites of Lf -α.

关键词： Lactoferrin-α sialic acid Fe binding.

Application of sialic acid/polysialic acid in the drug delivery systems

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Asian Journal of Pharmaceutical Sciences 2014年第2期9卷 75-81页

作者： Ting Zhang Zhennan She Zhenjun Huang Jing Li Xiang Luo Yihui Deng School of Pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China

The properties of modified biomaterial are gaining more and more importance in drug delivery systems.sialic acid(SA)and polysialic acid(PSA)serve as endogenous substances,which are non-immunogenic and biodegradable.At the same time,SA modification of the drugs/carriers can enhance the uptake of tumor cell and retention in brain;PSA modifi-cation can reduce the immunogenicity of the proteins or polypeptides and increase circulation time of the modified drugs/carriers in the blood,thus achieving active targeting effect.These properties offer a variety of opportunities for applications in drug delivery systems.This article summarizes the biological functions of SA and PSA and presents the technologies of SA/PSA modified small molecule drugs,proteins and carriers in drug delivery systems.

关键词： sialic acid Polysialic acid Drug delivery system Active targeting Circulation time

Effects of sialic acid from Edible Bird Nest on Cell Viability Associated with Brain Cognitive Performance in Mice

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World Journal of Traditional Chinese Medicine 2019年第4期5卷 214-219页

作者： Siti Khadijah Abdul Khalid Aswir Abd Rashed Saleha Abdul Aziz Hafandi Ahmad Departments of Veterinary Preclinical Sciences Faculty of Veterinary MedicineUniversiti Putra MalaysiaSerdangSelangor Departments of Veterinary Pathology and Microbiology Faculty of Veterinary MedicineUniversiti Putra MalaysiaSerdangSelangor Department of Nutrition Metabolic and Cardiovascular ResearchInstitute for Medical ResearchJalan PahangKuala LumpurMalaysia

Background:Edible bird nest(EBN)is a natural food product rich in glycoprotein such as sialic acid,which has been reported to improve brain functions.The EBN is widely consumed due to its higher nutritional contents and antioxidant status;however,an interaction of EBN on brain cell metabolic activity and viability are still unclear.Objective:The objectives of this study were to identify the effect of sialic acid from EBN on the cell viability and to determine the appropriate concentration of sialic acid on cognitive performance in mice.Materials and Methods:The viability of pheochromocytoma and neuroblastoma cell lines were tested using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay.For in vivo study,7-week-old female BALB/c mice were randomly assigned into four treatment groups and were treated with sialic acid for 21 days.At day 22,all mice were tested on cognitive performance by Y-maze test.Results:Treatment concentration of sialic acid extract and sialic acid standard at 60μg/mL(0.6 ppm)increased cell viability and showed no cytotoxicity effects in pheochromocytoma and neuroblastoma cell lines.In addition,an administration of higher dose of sialic acid at 0.6 ppm in animals improved Y-maze test performance,which they showed significantly higher number of entries and time spent in the novel arm.Conclusion:Thus,the current study shows that the sialic acid extract at 0.6 ppm improved brain cognitive performance in mice associated with an increased viability of pheochromocytoma and neuroblastoma cell lines.

关键词： Cell viability cognitive function edible bird nest mice sialic acid

Determination of cytokine regulated glycan expression by using molecularly imprinted polymers targeting sialic acid

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Journal of Cancer Metastasis and Treatment 2019年第7期4卷 41-49页

作者： Yuecheng Zhang Kushtrim Llapashtica Sudhirkumar Shinde Borje Sellergren Zahra El-Schich Anette Gjorloff Wingren Department of Biomedical Sciences Faculty of Health and SocietyMalmo UniversityMalmo 20506Sweden

Cancer cells often have an increased amount of glycans, such as sialic acid (SA), on the cell surface, which normally play an important role in cell growth, proliferation and differentiation. In this study, SA expression is determined by fluorescent nanoprobes, molecularly imprinted polymers, SA-MIPs. The nanoprobes are synthesized with an imprinting approach to produce tailor-made fluorescent core-shell particles with high affinity for cell surface SA. Inflammation and cytokine production are well known tumor promoters, modulating the cellular microenvironment, including an aberrant cell surface glycan pattern. The recombinant cytokines IL-4, IL-6, IL-8 and a cocktail of cytokines collected from stimulated T leukemia Jurkat cells were used to induce in vitro inflammation in two cell lines, and thereafter analyzed with the use of SA-MIPs and flow cytometry. One of the cell lines showed a different binding pattern of SA-MIPs after treatment with recombinant cytokines and the cytokine cocktail. This study shows that SA-MIPs can be an important tool in the investigation of overexpressed glycans in the tumor microenvironment.

关键词： Cancer cytokine glycans molecularly imprinted polymers sialic acid