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Engineering biomimetic nanosystem targeting multiple tumor radioresistance hallmarks for enhanced radiotherapy

Science China(Life Sciences) 2024年第7期67卷 1398-1412页

作者： Shuxiang Wang Hongmei Cao Cui-Cui Zhao Qian Wang Dianyu Wang Jinjian Liu Lijun Yang Jianfeng Liu State key laboratory of Advanced Medical Materials and Devices Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear MedicineKey Laboratory of Radiopharmacokinetics for Innovative DrugsTianjin Institutes of Health ScienceInstitute of Radiation MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300192China Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for CancerTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Prevention and Therapy(Tianjin)Key Laboratory of Breast Cancer Prevention and TherapyTianjin Medical UniversityMinistry of EducationTianjin 300060China

Tumor cells establish a robust self-defense system characterized by hypoxia,antioxidant overexpression,DNA damage repair,and so forth to resist *** one of these features is insufficient to overcome radioresistance due to the feedback mechanisms initiated by tumor cells under ***,we herein developed an engineering biomimetic nanosystem(M@HHPt)masked with tumor cell membranes and loaded with a hybridized protein-based nanoparticle carrying oxygens(O_(2))and cisplatin prodrugs(Pt(Ⅳ))to target multiple tumor radioresistance hallmarks for enhanced *** administration,M@HHPt actively targeted and smoothly accumulated in tumor cells by virtue of its innate homing abilities to realize efficient co-delivery of O_(2)and Pt(Ⅳ).O_(2)introduction induced hypoxia alleviation cooperated with Pt(Ⅳ)reduction caused glutathione consumption greatly amplified radiotherapy-ignited cellular oxidative ***,the released cisplatin effectively hindered DNA damage repair by crosslinking with radiotherapy-produced DNA ***,M@HHPt-sensitized radiotherapy significantly suppressed the proliferation of lung cancer H1975 cells with an extremely high sensitizer enhancement ratio of 1.91 and the progression of H1975 tumor models with an excellent tumor inhibition rate of 94.7%.Overall,this work provided a feasible strategy for tumor radiosensitization by overcoming multiple radioresistance mechanisms.

关键词： biomimetic nanosystem hypoxia alleviation glutathione consumption oxidative stress amplification DNA damage fixation radiosensitization

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Pyridapeptides F–I,cyclohexapeptides from marine sponge-derived Streptomyces ***-4539

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Chinese Chemical Letters 2024年第7期35卷 341-344页

作者： Shuige Zhao Pengcheng Yan Peipei Liu Haishan Liu Ning Li Peng Fu Weiming Zhu key laboratory of Marine drugs Ministry of Education of ChinaSchool of Medicine and PharmacyOcean University of ChinaQingdao 266003China key laboratory for Marine drugs and Bioproducts Laoshan LaboratoryQingdao 266237China School of Biological Science and Technology University of JinanJi'nan 250022China key laboratory for Biosensors of Shandong Province Biology InstituteQilu University of TechnologyJi'nan 250103China

Four new cyclohexapeptides,pyridapeptides F–I(1–4),were isolated from the fermentation broth of marine sponge-derived Streptomyces *** pyridapeptides F–H(1–3)are composed ofβ-hydroxyleucine,alanine,O-methylthreonine,hexahydropyridazine-3-carboxylic acid,5-hydroxytetrahydropyridazine-3-carboxylic acid,and(2S,3R,4E,6E)-2-amino-3–hydroxy-4,6-dienoic acid *** I(4)contains(2S,3R,4E,6E)-2-amino-3–hydroxy-8-methylnona-4,6-dienoic acid residue and a very rare glycose residue,*** structures were determined based on spectroscopic analysis and chemical *** G–I(2–4)have the 2,3,6-trideoxyhexose units glycosylated at theγ-OH-TPDA residue,displayed significant antiproliferative activity against four(PC9,MKN45,Hep G2,K562)or two(PC9,MKN45)human cancer cell lines.

关键词： Marine microorganism Streptomyces Cyclopeptide glycosides Pyridapeptides Antiproliferative activity

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Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease

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Neural Regeneration Research 2024年第11期19卷 2467-2479页

作者： Yong Tang Jing Wei Xiao-Fang Wang Tao Long Xiaohong Xiang Liqun Qu Xingxia Wang Chonglin Yu Xingli Xiao Xueyuan Hu Jing Zeng Qin Xu Anguo Wu Jianming Wu Dalian Qin Xiaogang Zhou Betty Yuen-Kwan Law Dr.Neher’s Biophysics laboratory for Innovative Drug Discovery State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacao Special Administrative RegionChina Sichuan key Medical laboratory of New Drug Discovery and Druggability Evaluation luzhou key laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica Southwest Medical UniversityLuzhouSichuan ProvinceChina Eye School and key laboratory of Sichuan Province Ophthalmopathy Prevention&Cure and Visual Function Protection of Chengdu University of TCM ChengduSichuan ProvinceChina School of Basic Medical Sciences Southwest Medical UniversityLuzhouSichuan ProvinceChina Department of Ophthalmology The Affiliated Hospital of Southwest Medical UniversityLuzhouSichuan ProvinceChina Department of Neurology The First People’s Hospital of NeijiangNeijiangSichuan ProvinceChina

Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer’s *** Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases,including Parkinson’s and Huntington’s diseases,however,the effect of Citri Reticulatae Semen on Alzheimer’s disease remains *** the current study,the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first *** Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of *** addition,Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro,and suppress amyloid-beta-induced pathology such as paralysis,in a transgenic Caenorhabditis elegans in vivo ***,genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was *** importantly,Citri Reticulatae Semen extract was confirmed to improve cognitive impairment,neuronal injury and amyloid-beta burden in 3×Tg Alzheimer’s disease *** revealed by both in vitro and in vivo models,these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer’s disease via its neuroprotective autophagic effects.

关键词： Alzheimer’s disease amyloid-beta apoptosis autophagy Caenorhabditis elegans Citri Reticulatae Semen

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An effective pharmacological hydrogel induces optic nerve repair and improves visual function

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Science China(Life Sciences) 2024年第3期67卷 529-542页

作者： Lipeng Wang Shan Zhang Yawen Han Shuo Tang Jiarui Li Lina Bu Dongyu Zhao Hongkui Deng Department of cell Biology Schoolof Basic Medical SciencesPeking University Stem Cell Research CenterStateKey Laboratoryof Naturaland Biomimetic DrugsPeking University Health Science Center Beijing 100191China MOE key laboratory of cell Proliferation and Differentiation College of Life SciencesPeking-Tsinghua Center for Life SciencesPeking UniversityBeijing 100871China Academy for Advanced Interdisciplinary Studies Peking UniversityBeijing 100871China Changping laboratory Beijing 102206China Department of Ophthalmology Peking University People's Hospital Eye Diseases and Optometry InstituteBeijing 100871China Department of Biomedical Informatics School of Basic Medical SciencesPeking UniversityBeijing 100191China

Irreversible eye lesions, such as glaucoma and traumatic optic neuropathy, can cause blindness;however, no effective treatments exist. The optic nerve, in particular, lacks the capacity to spontaneously regenerate, requiring the development of an effective approach for optic nerve repair, which has proven challenging. Here, we demonstrate that a combination of the small molecules 3BDO and trichostatin A(TSA)—which regulate mTOR and HDAC, respectively—packaged in thermosensitive hydrogel for 4-week-sustained release after intravitreal injection, effectively induced optic nerve regeneration in a mouse model of optic nerve crush injury. Moreover, this combination of 3BDO and TSA also protected axon projections and improved visual responses in an old mouse model(11 months old) of glaucoma. Taken together, our data provide a new, local small molecule-based treatment for the effective induction of optic nerve repair, which may represent a foundation for the development of pharmacological methods to treat irreversible eye diseases.

关键词： retinal ganglion cell axon regeneration old-age glaucoma small molecules pharmacological hydrogel visual function repair

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Trametinib boosts palbociclib’s efficacy in breast cancer via autophagy inhibition

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Oncology Research 2024年第7期32卷 1197-1207页

作者： ANGUO WU JIAO YAN TING SU CHI FENG XIN LONG YIRU PAN RUPEI YE TIAN XIA HANAN LONG JIANMING WU XIULI XIAO Sichuan key Medical laboratory of New Drug Discovery and Druggability Evaluation Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia MedicaKey Laboratory of Medical Electrophysiology of Ministry of EducationSchool of PharmacySouthwest Medical UniversityLuzhou646000China The Department of Pathology The Affiliated Hospital of Southwest Medical UniversityLuzhou646000China The Department of Pathology Mianyang Central HospitalSchool of MedicineUniversity of Electronic Science and Technology of ChinaMianyang621000China The Department of Pathology Yongchuan Hospital of Chongqing Medical UniversityChongqing402160China School of Basic Medical Sciences Southwest Medical UniversityLuzhou646000China School of Clinical Medical Sciences Southwest Medical UniversityLuzhou646000China

Breast cancer,a predominant global health issue,requires ongoing exploration of new therapeutic ***(PAL),a well-known cyclin-dependent kinase(CDK)inhibitor,plays a critical role in breast cancer *** its efﬁcacy is recognized,the interplay between PAL and cellular autophagy,particularly in the context of the RAF/MEK/ERK signaling pathway,remains insufﬁciently *** study investigates PAL’s inhibitory effects on breast cancer using both in vitro(MCF7 and MDA-MB-468 cells)and in vivo(tumor-bearing nude mice)*** at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib(TRA),an MEK inhibitor,our research seeks to address the challenge of PAL-induced drug ***ﬁndings reveal that PAL signiﬁcantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A ***,PAL also induces protective autophagy,potentially leading to drug resistance via the RAF/MEK/ERK pathway *** TRA effectively neutralized this autophagy,enhancing PAL’s anti-tumor efﬁcacy.A combination of PAL and TRA synergistically reduced cell viability and proliferation,and in vivo studies showed notable tumor size *** conclusion,the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance,offering a new horizon in breast cancer treatment.

关键词： Palbociclib Trametinib Protective autophagy RAF/MEK/ERK MCF7 MDA-MB-468

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A DNA Force Circuit for Exploring Protein-Protein Interactions at the Single-Molecule Level

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Chinese Journal of Chemistry 2024年第13期42卷 1456-1464页

作者： Kangkang Ma Luoan Xiong Zhuofei Wang Xin Hu Lihua Qu Xuetong Zhao Yao Li Zhongbo Yu State key laboratory of Medicinal Chemical Biology Frontiers Science Center for Cell Responsesand College of PharmacyNankai University38 Tongyan RoadTianjin 300350China School of Physics and key laboratory of Functional Polymer Materials of Ministry of Education Nankai Universityand Collaborative Innovation Center of Chemical Science and EngineeringTianjin 300071China

Protein-protein interactions(PPls)play a crucial role in drug discovery and disease ***,the development of effective drugs targeting PPls remains challenging due to limited methodologies for probing their spatiotemporal ***,we propose a single-molecule approach using a unique force circuit to investigate Ppl dynamics and anisotropy under mechanical *** conventional techniques,this approach enables the manipulation and real-time monitoring of individual proteins at specific amino acids with defined geometry,offering insights into molecular mechanisms at the single-molecule *** DNA force circuit was constructed using click chemistry conjugation methods and genetic code expansion techniques,facilitating orthogonal conjugation between proteins and nucleic *** SET domain of the MLL1 protein and the tail of histone H3 were used as a model system to demonstrate the application of the DNA force *** the use of atomic force microscopy and magnetic tweezers,optimized assembly procedures were *** DNA force circuit provides an exceptional platform for studying the anisotropy of PPis and holds promise for advancing drug discovery research targeted at PPIs.

关键词： Single-molecule studies Protein-protein interactions Click chemistry Genetic code expansion Molecular dynamics

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Intermittent fasting boosts antitumor immunity by restricting CD11b^(+)Ly6C^(low)Ly6G^(low) cell viability through glucose metabolism in murine breast tumor model

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Food Science and Human Wellness 2024年第4期13卷 2327-2345页

作者： Chenghao Fu Zhehao Liang Zemiao Niu Ning Chen Yuemin Li Zhenhua Liang Yanwei Huo Hao Xi Rong Wang Yonghuan Yan Xiaoruo Gan Mengtian Wang Yun Huang Yan Zhang Mingming Gao Pin Lü Postdoctoral Station for Basic Medicine Cardiovascular Medical Science CenterDepartment of Cell BiologyKey Laboratory of Neural and Vascular Biology of Ministry of EducationHebei Medical UniversityShijiazhuang 050017China Hebei key laboratory of Forensic Medicine College of Forensic MedicineHebei Medical UniversityShijiazhuang 050017China Hebei Food Safety key laboratory Hebei Food Inspection and Research InstituteShijiazhuang 050091China laboratory of Lipid Metabolism Department of Biochemistry and Molecular BiologyKey Laboratory of Medical Biotechnology of Hebei ProvinceShijiazhuang 050017China

Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or ***,it is still uncertain how to select immunotherapy drugs to combine with intermittent *** we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast *** this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor ***,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic *** investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of *** the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)*** summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.

关键词： Intermittent fasting Ly6G^(low)myeloid-derived suppressor cell apoptosis Extramedullary hematopoiesis Colony stimulating factor Glucose metabolism restriction

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Ononin inhibits triple-negative breast cancer lung metastasis by targeting the EGFR-mediated PI3K/Akt/mTOR pathway

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Science China(Life Sciences) 2024年第9期67卷 1849-1866页

作者： Kumar Ganesan Cong Xu Jianming Wu Bing Du Qingqing Liu Yue Sui Cailu Song Jinhui Zhang Hailin Tang Jianping Chen School of Chinese Medicine LKS Faculty of MedicineThe University of Hong KongHong Kong 999077China School of Pharmacy Southwest Medical UniversityEducation Ministry Key Laboratory of Medical ElectrophysiologySichuan Key Medical Laboratory of New Drug Discovery and Druggability EvaluationLuzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia MedicaSouthwest Medical UniversityLuzhou 646000China College of Food Science South China Agricultural UniversityGuangzhou 510642China State key laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou 510080China

The spreading of cancer cells from the primary tumor site to other parts of the body,known as metastasis,is the leading cause of cancer recurrence and mortality in patients with triple-negative breast cancer(TNBC).Overexpression of epidermal growth factor receptor(EGFR)is observed in approximately 70%of TNBC *** is crucial for promoting tumor metastasis and associated with poor ***,it is vital to identify effective therapeutic strategies targeting EGFR ***,an isoflavonoid found in various plants,such as clover and soybeans,has been shown to have anticancer properties in several *** the present study,we aimed to investigate the effects of ononin on TNBC lung metastasis and the associated molecular *** used various assays,including cell viability,colony formation,Transwell,wound healing,ELISA,Western blotting,and staining techniques,to achieve this *** results demonstrated that ononin effectively suppressed cellular proliferation and induced apoptosis,as evidenced by the cell viability assay,colony formation assay,and expression of apoptosis markers,and reduced the metastatic capabilities of TNBC *** effects were achieved through the direct suppression of cell adhesion,invasiveness and ***,in TNBC xenograft lung metastatic models,ononin treatment significantly reduced tumor growth and lung ***,ononin reversed the epithelial-mesenchymal transition(EMT)by downregulating the expression of EMT markers and matrix metalloproteinases,as confirmed by Western blot ***,ononin treatment reduced EGFR phosphorylation and suppressed the PI3K,Akt,and m TOR signaling pathways,which was further confirmed using EGFR agonists or ***,ononin treatment did not exert any toxic effects on liver or kidney *** conclusion,our findings suggest that ononin is a safe and potentially therapeutic treatment for TNBC metastasis that targets the EGFRm

关键词： ononin TNBC breast cancer lung metastasis EGFR PI3k/Akt EMT therapeutic effect

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Iron-based layered double hydroxide packed with metal-organic frameworks for enhanced overall water-splitting electrocatalysis

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Tungsten 2024年第4期6卷 859-868页

作者： Long Chen Yun Luo Zhi-Peng Yu Yi-Kun Cheng Yang Zheng Li He Jia-Hao Xiong Wen-Wen Kong key laboratory for Green Process of Chemical Engineering of Xinjiang Bingtuan School of Chemistry and Chemical Engineering Shihezi University Institute of Scientific Research Luzhou North Chemistry Industry Co.Ltd International Iberian Nanotechnology laboratory (INL) CAS key laboratory of Functional Materials and Devices for Special Environments Xinjiang Key Laboratory of Electronic Information Materials and Devices Center of Materials Science and Optoelectronics Engineering Xinjiang Technical Institute of Physics and Chemistry of CAS

Designing hybrid materials with numerous catalytic active sites,high specific surface area,and interfacial interactions is an effective strategy to improve electrocatalytic *** this work,iron-based metal organic frameworks（Fe-MOFs）@（Co,Ni）Fe-layered double hydroxide（LDH） is successfully constructed using the similar "MOF growing on LDH" strategy for oxygen evolution reaction and hydrogen evolution reaction in the alkaline *** synthesized hybrid materials in this particular way show excellent electrochemical overall water-splitting performance with the cell voltage of 1.62 V at10 mA·cm-2in the alkaline environment due to the optimized adsorption/desorption properties of metal ions on oxygencontaining species and interfacial effects of hybrid ***-MOFs@（Co,Ni）Fe-LDH also exhibits excellent hydrogen and oxygen production efficiency of 370 and 175 μL·min-1,*** work draws on an effective approach to the fabrication of MOF@LDH structures and provides new insights into overall water-splitting in alkaline conditions.

关键词： Electrocatalysis Interfacial interactions Layered double hydroxide Metal–organic frameworks (MOFs) Water splitting

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Discovery of TK-642 as a highly potent,selective,orally bioavailable pyrazolopyrazine-based allosteric SHP2 inhibitor

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3624-3642页

作者： Kai Tang Shu Wang Siqi Feng Xinyu Yang Yueyang Guo Xiangli Ren Linyue Bai Bin Yu Hong-Min Liu Yihui Song School of Pharmaceutical Sciences&key laboratory of Advanced Drug Preparation Technologies Ministry of EducationZhengzhou UniversityZhengzhou 450001China College of Chemistry Pingyuan LaboratoryState Key Laboratory of Antiviral DrugsZhengzhou UniversityZhengzhou 450001China Tianjian laboratory of Advanced Biomedical Sciences Institute of Advanced Biomedical SciencesZhengzhou UniversityZhengzhou 450000China State key laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

Src homology-2-containing protein tyrosine phosphatase 2(SHP2)is a promising therapeutic target for cancer *** this work,we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors,leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent,selective,orally bioavailable allosteric SHP2 inhibitor(SHP2WT IC_(50)=2.7 nmol/L)with favorable pharmacokinetic profiles(F=42.5%;t_(1/2)=2.47 h).Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the“tunnel”allosteric site of ***-642 could effectively suppress cell proliferation(KYSE-520 cells IC_(50)=5.73μmol/L)and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling ***,oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model,with a T/C value of 83.69%.Collectively,TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer.

关键词： Protein tyrosine phosphatase Pyrazolopyrazine SHP2 inhibitor Esophageal cancer

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