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Rapid and sensitive detection of Epstein-Barr virus antibodies in nasopharyngeal carcinoma by chemiluminescence strips based on iron-porphyrin single atom nanozyme

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Nano research 2024年第3期17卷 1827-1836页

作者： Daji Wang Jie Wang Dan Liu Jiuyang He Meiying Wang Haibing Huang Guohui Nie Hui Ding Xiyun Yan Nanozyme Synthesis center Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China center for drug evaluation National Medical Products AdministrationBeijing 100022China Shenzhen Key Laboratory of nanozymes and Translational Cancer research Department of Otolaryngologyand Shenzhen Institute of Translational MedicineShenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science CenterShenzhen 518035China CAS engineering Laboratory for Nanozyme Key Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China Department of Rheumatology and Immunology Shenzhen Second People’s HospitalThe First Affiliated Hospital of Shenzhen UniversityShenzhen 518055China

The correlation between Epstein-Barr virus(EBV)infection and nasopharyngeal carcinoma(NPC)risk has been extensively researched.The continual monitoring of EBV-IgAs provides a promising approach of NPC screening in its early stage.In this study,we successfully synthesized a single-atom nanozyme(SANzyme)through the application of iron-porphyrin based metal organic framework(MOF-FeP).The MOF-FeP possesses precisely-defined electronic and geometric structures that accurately mimic highly-evolved catalytic site of natural peroxidase.The peroxidase-like activity of MOF-FeP enables it to catalyze the chemiluminescence of luminol substrate.By integrating MOF-FeP into a traditional strip,we created a rapid and highly-sensitive evaluation tool for detecting EBV-IgAs.Importantly,the MOF-FeP strip enables the simultaneous detection of three EBV-IgAs,greatly improving the accuracy of EBV-associated NPC screening.The sensitivities of the MOF-FeP strip(75.56%–93.30%)surpass those of current enzyme-linked immunosorbent assay(ELISA)methods(64.44%–82.22%).This test takes only 16 min to perform as opposed to the customary 1–2 h required for standard ELISA.Additionally,the MOF-FeP strip is suitable for whole blood samples,thereby significantly simplifying the sample preparation and detection process.In conclusion,the MOF-FeP strip combines the simplicity of traditional strip with the high catalytic activity of SANzyme.Our innovative MOF-FeP strip offers a new point-of-care strategy for EBV-IgAs detection,which is expected to markedly facilitate early screening for EBV-associated diseases.

关键词： iron-porphyrin single-atom nanozyme(SANzyme) chemiluminescence strips Epstein-Barr virus(EBV) nasopharyngeal carcinoma(NPC) antibody detection

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Centranthera grandiflore alleviates alcohol-induced oxidative stress and cell apoptosis

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Chinese Journal of Natural Medicines 2022年第8期20卷 572-579页

作者： GAO Xin-Mei DONG Wen-Han XIA Chun-Lei MA Zhuo-Yi WANG Ying SARRA Setrerrahmane XU Han-Mei QI Wei-Yan the engineering research center of synthetic peptide drug discovery and evaluation Jiangsu ProvinceState Key Laboratory of Natural MedicinesMinistry of EducationDepartment of Marine PharmacyChina Pharmaceutical UniversityNanjing 211198China Science and Technology Administration Department of Yunnan Agricultural University Yunnan 650205China Nanjing Anji Biotechnology Co. Ltd.Nanjing 210033China

Alcohol liver disease(ALD)has become a global threat to human health.It is associated with a wide range of liver diseases including alcohol fatty liver,steatosis,fibrosis and cirrhosis,and finally leads to liver cancer and even death.Centranthera grandiflora is a traditional Chinese medicinal herb commonly used to treat ALD,but no research about its mechanism is available.This study evaluated the hepatoprotective effect and mechanism of C.grandiflora against alcohol-induced liver injury in mice.We found that the ethanol extracts of C.grandiflora(CgW)alleviated the alcohol-induced liver injury,enhanced the levels of antioxidant enzymes,and reduced the amount of lipid peroxides.CgW also affected cell apoptosis by inhibiting the activity of Bax,cleaved-caspase 3 and cleaved-caspase 9,and increasing the activity of Bcl-2.In conclusion,the results showed that CgW can effectively improve ALD through alleviating oxidative stress and inhibiting cell apoptosis for the first time.This study suggested that C.grandiflora is a promising herbal medicine for ALD treatment.

关键词： Centranthera grandiflora Alcohol liver diseases Oxidative stress Apoptosis Hepatoprotective effect

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Trends in insulin resistance:insights into mechanisms and therapeutic strategy

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Signal Transduction and Targeted Therapy 2022年第8期7卷 2762-2786页

作者： Mengwei Li Xiaowei Chi Ying Wang Sarra Setrerrahmane Wenwei Xie Hanmei Xu the engineering research center of synthetic peptide drug discovery and evaluation of Jiangsu Province China Pharmaceutical UniversityNanjing 210009China State Key Laboratory of Natural Medicines Ministry of EducationChina Pharmaceutical UniversityNanjing 210009China Development center for Medical Science&Technology National Health Commission of the People’s Republic of China 100044 BeijingChina NANJING ANJI BIOTECHNOLOGY CO.LTD Nanjing 210033China

The centenary of insulin discovery represents an important opportunity to transform diabetes from a fatal diagnosis into a medically manageable chronic condition.Insulin is a key peptide hormone and mediates the systemic glucose metabolism in different tissues.Insulin resistance(IR)is a disordered biological response for insulin stimulation through the disruption of different molecular pathways in target tissues.Acquired conditions and genetic factors have been implicated in IR.Recent genetic and biochemical studies suggest that the dysregulated metabolic mediators released by adipose tissue including adipokines,cytokines,chemokines,excess lipids and toxic lipid metabolites promote IR in other tissues.IR is associated with several groups of abnormal syndromes that include obesity,diabetes,metabolic dysfunction-associated fatty liver disease(MAFLD),cardiovascular disease,polycystic ovary syndrome(PCOS),and other abnormalities.Although no medication is specifically approved to treat IR,we summarized the lifestyle changes and pharmacological medications that have been used as efficient intervention to improve insulin sensitivity.Ultimately,the systematic discussion of complex mechanism will help to identify potential new targets and treat the closely associated metabolic syndrome of IR.

关键词： metabolism stimulation diagnosis

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Natural killer cell-derived exosomal miR-1249-3p attenuates insulin resistance and inflammation in mouse models of type 2 diabetes

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Signal Transduction and Targeted Therapy 2021年第12期6卷 3783-3795页

作者： Ying Wang Mengwei Li Lin Chen Huan Bian Xiangying Chen Huilin Zheng Peiwei Yang Quan Chen Hanmei Xu the engineering research center of synthetic peptide drug discovery and evaluation of Jiangsu Province China Pharmaceutical University210009 NanjingChina State Key Laboratory of Natural Medicines Ministry of EducationChina Pharmaceutical University210009 NanjingChina

Natural killer(NK)cells have been suggested to be associated with type 2 diabetes by regulating systemic inflammation.However,the mechanism by which NK cells regulate insulin sensitivity remains unknown.This study shows that NK-derived exosomes from lean mice attenuate obesity-induced insulin resistance and inflammation in mice of type 2 diabetes.Moreover,lean NK-derived exosomes enhance insulin sensitivity and relieve inflammation in adipocytes and hepatocytes.MiR-1249-3p,which is significantly upregulated in lean NK-derived exosomes,can be transferred from NK cells to adipocytes and hepatocytes via exosomes.NKderived exosomal miR-1249-3p dramatically induces cellular insulin sensitivity and relieves inflammation.Mechanistically,exosomal miR-1249-3p directly targets SKOR1 to regulate the formation of ternary complex SMAD6/MYD88/SMURF1,which mediates glucose homeostasis by suppressing the TLR4/NF-κB signaling pathway.This study reveals an emerging role for NK-derived exosomal miR1249-3p in remission of insulin resistance,and provides a series of potential therapeutic targets in type 2 diabetes.

关键词： inflammation miR124 killer

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Integrins as attractive targets for cancer therapeutics

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Acta Pharmaceutica Sinica B 2021年第9期11卷 2726-2737页

作者： Meng Li Ying Wang Mengwei Li Xuezhen Wu Sarra Setrerrahmane Hanmei Xu National Institutes for Food and drug Control Beijing 102629China State Key Laboratory of Natural Medicines Ministry of Educationthe Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu ProvinceDepartment of Marine PharmacyChina Pharmaceutical University Nanjing 211198ChinaAffiliated Hospital of Chifeng CollegeInner Mongolia Autonomous Region 024005China

Integrins are transmembrane receptors that have been implicated in the biology of various human physiological and pathological processes.These molecules facilitate cell-extracellular matrix and cell-cell interactions,and they have been implicated in fibrosis,inflammation,thrombosis,and tumor metastasis.The role of integrins in tumor progression makes them promising targets for cancer treatment,and certain integrin antagonists,such as antibodies and synthetic peptides,have been effectively utilized in the clinic for cancer therapy.Here,we discuss the evidence and knowledge on the contribution of integrins to cancer biology.Furthermore,we summarize the clinical attempts targeting this family in anti-cancer therapy development.

关键词： Integrins Extracellular matrix Tumor progression Targeted drug Antagonists Clinical trial

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Optimized functional and structural design of dual-target LMRAP,a bifunctional fusion protein with a 25-amino-acid antitumor peptide and GnRH Fc fragment

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Acta Pharmaceutica Sinica B 2020年第2期10卷 262-275页

作者： Meng Li Hanmei Xu Junzhi Wang Shenyang Pharmaceutical University Shenyang 110016China Key Laboratory of the Ministry of Health for research on Quality and Standardization of Biotech Products National Institutes for Food and Drug ControlBeijing 102629China State Key Laboratory of Natural Medicines Ministry of Educationthe Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu ProvinceDepartment of Marine PharmacyChina Pharmaceutical UniversityNanjing 211198China

To develop fusion protein of a GnRH Fc fragment and the integrin targeting AP25 antitumor peptide for GnRH receptor-expressing cancer therapy.The LMRAP fusion protein was constructed.A transwell invasion assay was performed.The gene mRNA and protein levels of GnRHR-I,α5β1,andαvβ3 in different cancer cell lines were assessed.Cell proliferation was measured using a cell counting kit-8.An antagonist assay was performed on GnRH receptors.Anti-tumor activity was evaluated with a mouse xenograft tumor model.Immunohistochemistry(IHC)was applied to detect CD31 and CD34 expressions.Pharmacokinetic characteristics were determined with an indirect competition ELISA.The developed bifunctional fusion protein LMRAP not only inhibited HUVEC invasion,but also inhibited proliferation of GnRHR-I,α5β1,and high expression cancer cells.The IC50 for LMRAP in the GnRH receptor was 6.235 x 10-4 mol/L.LMRAP significantly inhibited human prostate cancer cell line22 RV1 proliferation in vivo and in vitro.LMRAP significantly inhibited CD31 and CD34 expressions.The elimination half-life of the fusion protein LMRAP was 33 h in rats.The fusion protein made of a GnRH Fc fragment and the integrin targeting AP25 peptide retained the bifunctional biological activity of GnRHR blocking,angiogenesis inhibition,prolonged half-life and good tolerance.

关键词： Fusion protein GnRH Integrin Angiogenesis Prostate cancer

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Signal Transduction and Targeted Therapy 2022年第7期7卷 2533-2544页

作者： Xi Shi Zihao Wang Wei Ren Long Chen Cong Xu Menghua Li Shiyong Fan Yuru Xu Mengbing Chen Fanjun Zheng Wenyuan Zhang Xinbo Zhou Yue Zhang Shiwei Qiu Liyuan Wu Peng Zhou Xinze Lv Tianyu Cui Yuehua Qiao Hui Zhao Weiwei Guo Wei Chen Song Li Wu Zhong Jian Lin Shiming Yang Department of Pharmacy Peking University Third HospitalBeijingChina Artificial Auditory Laboratory of Jiangsu Province Xuzhou Medical UniversityXuzhouChina National engineering research center for the Emergency drug Beijing Institute of Pharmacology and ToxicologyBeijingChina College of Otolaryngology Head and Neck Surgery Chinese PLA General HospitalBeijingChina National Clinical research center for Otolaryngologic Diseases BeijingChina Key Lab of Hearing Science Ministry of EducationBeijingChina Beijing Key Lab of Hearing Impairment for Prevention and Treatment BeijingChina synthetic and Functional Biomolecules center Beijing National Laboratory for Molecular SciencesKey Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of EducationCollege of Chemistry and Molecular EngineeringInnovation Center for GenomicsPeking UniversityBeijingChina

Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide.However,the presence of the blood-labyrinth barrier(BLB)on the surface of the inner ear capillaries greatly hinders the effectiveness of systemic drugs for prevention and intervention due to the low permeability,which restricts the entry of most drug compounds from the bloodstream into the inner ear tissue.Here,we report the finding of a novel receptor,low-density lipoprotein receptor-related protein 1(LRP1),that is expressed on the BLB,as a potential target for shuttling therapeutics across this barrier.As a proof-ofconcept,we developed an LRP1-binding peptide,IETP2,and covalently conjugated a series of model small-molecule compounds to it,including potential drugs and imaging agents.All compounds were successfully delivered into the inner ear and inner ear lymph,indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the BLB.The discovery of the receptor LRP1 will illuminate developing strategies for crossing the BLB and for improving systemic drug delivery for inner ear disorders.

关键词： drugs prevention barrier

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Genetically-engineered“all-in-one”vaccine platform for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3622-3635页

作者： Aihua Wu Yingzhi Chen Hairui Wang Ya Chang Meng Zhang Pengfei Zhao Yisi Tang Qin Xu Zhuangzhi Zhu Yang Cao Yongzhuo Huang State Key Laboratory of drug research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Artemisinin research center the First Affiliated HospitalGuangzhou University of Chinese MedicineGuangzhou 510450China National Pharmaceutical engineering research center China State Institute of Pharmaceutical IndustryShanghai 201203China Zhongshan Institute for drug discovery Institutes of Drug Discovery and DevelopmentChinese Academy of SciencesZhongshan 528437China University of Chinese Academy of Sciences Beijing 100049China NMPA Key Laboratory for Quality research and evaluation of Pharmaceutical Excipients Shanghai 201203China

An essential step for cancer vaccination is to break the immunosuppression and elicit a tumor-specific immunity.A major hurdle against cancer therapeutic vaccination is the insufficient immune stimulation of the cancer vaccines and lack of a safe and efficient adjuvant for human use.We discovered a novel cancer immunostimulant,trichosanthin(TCS),that is a clinically used protein drug in China,and developed a well-adaptable protein-engineering method for making recombinant protein vaccines by fusion of an antigenic peptide,TCS,and a cell-penetrating peptide(CPP),termed an"allin-one"vaccine,for transcutaneous cancer immunization.The TCS adjuvant effect on antigen presentation was investigated and the antitumor immunity of the vaccines was investigated using the different tumor models.The vaccines were prepared via a facile recombinant method.The vaccines induced the maturation of DCs that subsequently primed CD8^(+)T cells.The TCS-based immunostimulation was associated with the STING pathway.The general applicability of this genetic engineering strategy was demonstrated with various tumor antigens(i.e.,legumain and TRP2 antigenic peptides)and tumor models(i.e.,colon tumor and melanoma).These findings represent a useful protocol for developing cancer vaccines at low cost and time-saving,and demonstrates the adjuvant application of TCSdan old drug for a new application.

关键词： Trichosanthin Legumain TRP2 Transcutaneous immunization Adjuvant Cancer vaccine Protein engineering

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Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2443-2461页

作者： Nazi Song Hongjiao Xu Jiahua Liu Qian Zhao Hui Chen Zhibin Yan Runling Yang Zhiteng Luo Qi Liu Jianmei Ouyang Shuohan Wu Suijia Luo Shuyin Ye Runfeng Lin Xi Sun Junqiu Xie Tian Lan Zhongdao Wu Rui Wang Xianxing Jiang School of Pharmaceutical Sciences Guangdong Provincial Key Laboratory of Chiral Molecule and Drug DiscoverySun Yat-sen UniversityGuangzhou 510006China Department of Parasitology of Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhou 510006China Key Laboratory of Tropical Disease Control Ministry of EducationSun Yat-sen UniversityGuangzhou 510006China Provincial engineering Technology research center for Biological Vector Control Sun Yat-sen UniversityGuangzhou 510006China research Unit of peptide Science Chinese Academy of Medical SciencesLanzhou 730000China Key Laboratory of Preclinical Study for New drugs of Gansu Province School of Basic Medical SciencesLanzhou UniversityLanzhou 730000China Shenzhen Turier Biotech.Co. Ltd.Shenzhen 518118China Guangdong Pharmaceutical University Guangzhou 510006China

Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor(GLP-1 R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl_(4), a-naphthyl-isothiocyanate(ANIT), bile duct ligation(BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix(ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl_(4)-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of proinflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha(NFκB/IKBa) pathways as well as cJun N-terminal kinase(JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1 R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl_(4)-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.

关键词： GLP-1R GCGR Liver fibrosis Inflammation Apoptosis Candidate peptides

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Recent advances in the diversification of chromones and flavones by direct C-H bond activation or functionalization

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Chinese Chemical Letters 2020年第12期31卷 3073-3082页

作者： Shanghui Tian Tian Luo Yanping Zhu Jie-Ping Wan College of Chemistry and Chemical engineering Jiangxi Normal UniversityNanchang 330022China School of Pharmacy Key Laboratory of Molecular Pharmacology and Drug EvaluationMinistry of EducationCollaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of ShandongYantai UniversityYantai 264005China

Chromone and flavone are both central backbones of natural products and clinical medicines.Synthesis of diversely functionalized chromones and flavones constitutes significant research contents of the modern synthetic science because abundant molecular libraries of such types are crucial in providing candidate compounds for the discovery of new pharmaceuticals and functional materials.The direct C—H bond activation or functionalization on these heterocyclic backbones provides highly powerful tools for the rapid accesses to densely functionalized chromone and flavone derivatives.Considering the importance of the functionalized chromone and flavone compounds as well as the notable advances in the synthesis of such products by direct C—H activation or functionalization,we review herein the research advances in the C—H bond activation and functionalization reactions of chro mone and flavones,in hope of showing the current states and promise of the research domain.

关键词： Chromones Flavones C—H bond Activation Functionalization

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