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CCL9/CCR1 axis-driven chemotactic nanovesicles for attenuating metastasis of SMAD4-deficient colorectal cancer by trapping TGF-β

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3711-3729页

作者： Boning Niu Tianyi Tian Lu Wang Yinmei Tian Tian Tian Yuanyuan Guo Hu Zhou Zhiping Zhang Tongji School of Pharmacy Huazhong University of Science and TechnologyWuhan 430030China Department of Oncology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Pharmacy Liyuan HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China School of Pharmaceutical Sciences Fujian Provincial Key Laboratory of Innovative Drug Target ResearchHigh Throughput Drug Screening PlatformXiamen UniversityXiamen 361102China National Engineering Research Center for Nanomedicine Huazhong University of Science and TechnologyWuhan 430030China Hubei Engineering Research centre for Novel drug Delivery System Huazhong University of Science and TechnologyWuhan 430030China

SMAD4 deficiency in colorectal cancer(CRC)is highly correlated with liver metastasis and high mortality,yet there are few effective precision therapies ***,we show that CCR1^(+)-granulocytic myeloid-derived suppressor cells(G-MDSCs)are highly infiltrated in SMAD4-deficient CRC via CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models,*** excessive TGF-β,secreted by tumor-infiltrated CCR1^(+)-G-MDSCs,suppresses the immune response of cytotoxic T lymphocytes(CTLs),thus facilitating ***,we develop engineered nanovesicles displaying CCR1 and TGFBR2 molecules(C/T-NVs)to chemotactically target the tumor driven by CCL9/CCR1 axis and trap TGF-βthrough TGF-β-TGFBR2 specific *** C/T-NVs counteract CCR1^(+)-G-MDSC infiltration through competitive responding CCL9/CCR1 axis.C/T-NVs-induced intratumoral TGF-βexhaustion alleviates the TGF-β-suppressed immune response of ***,C/T-NVs attenuate liver metastasis of SMAD4-deficient *** further exploration,high expression of programmed cell death ligand-1(PD-L1)is observed in clinical specimens of SMAD4-deficient *** C/T-NVs with anti-PD-L1 antibody(aPD-L1)induces tertiary lymphoid structure formation with sustained activation of CTLs,CXCL13^(+)-CD4^(+)T,CXCR5^(+)-CD20^(+)B cells,and enhanced secretion of cytotoxic cytokine interleukin-21 and IFN-γaround tumors,thus eradicating metastatic *** strategy elicits pleiotropic antimetastatic immunity,paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC.

关键词： SMAD4-deficient CRC Metastasis G-MDSCs TGF-β CCR1 TGFBR2

Exploring the effects of taurolidine on tumor weight and microvessel density in a murine model of osteosarcoma

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Oncology Research 2024年第7期32卷 1163-1172页

作者： LISANNE K.A.NEIJENHUIS LEUTA L.NAUMANN SONIA A.M.FERKEL SAMUEL J.S.RUBIN STEPHAN ROGALLA Division of Gastroenterology and Hepatology Department of MedicineSchool of MedicineStanford UniversityStanford94305USA Department of Surgery Leiden University Medical CenterLeiden2333 ZAThe Netherlands centre for Human drug Research Leiden2333 CLThe Netherlands Department of General VisceralVascular and Thoracic SurgeryCharite University Medicine BerlinBerlin10117Germany

Background:Osteosarcoma is the most common malignant primary bone *** prognosis for patients with disseminated disease remains very poor despite recent advancements in ***,current treatment regimens bear a signiﬁcant risk of serious side ***,there is an unmet clinical need for effective therapies with improved safety proﬁ*** is an antibacterial agent that has been shown to induce cell death in different types of cancer cell ***:In this study,we examined both the antineoplastic and antiangiogenic effects of taurolidine in animal models of osteosarcoma.K7M2 murine osteosarcoma cells were injected,both intramuscular and intraperitoneal,into 60 BALB/c mice on day *** were then randomized to receive treatment with taurolidine 2%(800 mg/kg),taurolidine 1%(400 mg/kg),or NaCl 0.9%control for seven days by intravenous or intraperitoneal ***:After 35 days,mice were euthanized,and the tumors were harvested for *** mice were excluded from the analysis due to *** weight was signiﬁcantly lower in the 2%taurolidine intraperitoneal treatment group from day 9 to 21,consistent with elevated mortality in this *** tumor weight was signiﬁcantly lower in the 1%(p=0.003)and 2%(p=0.006)intraperitoneal taurolidine treatment groups compared to the *** antineoplastic effects were observed on intramuscular tumors or for intravenous administration of *** were no signiﬁcant differences in microvessel density or mitotic rate between treatment *** body weight and elevated mortality in the 2%taurolidine intraperitoneal group suggest that the lower 1%dose is ***:In conclusion,there is no evidence of antiangiogenic activity,and the antitumor effects of taurolidine on osteosarcoma observed in this study are ***,its toxic proﬁle grants further *** these observations,further research is necessary to

关键词： Osteosarcoma Taurolidine Cancer treatment Chemotherapy Murine models

Matching traditional Chinese medicine and western medicine-based research:Advanced nutraceutical development for proactive gastric cancer prevention

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World Journal of Gastrointestinal Oncology 2024年第9期16卷 3798-3819页

作者： Matteo Micucci Bian-Zhao Xiang Chen-Min Ting Hiu-Yee Kwan Michele Mari Michele Retini Sabrina Burattini Riham Osman Udodinma Jude Okeke Fuad Othman Abdullah Federico Gianfanti Michela Battistelli Department of Biomolecular Sciences University of Urbino Carlo BoUrbino 61029Italy Hong Kong Chinese Medicine Clinical Study centre Chinese EQUATOR CentreSchool of Chinese MedicineChinese Clinical Trial Registry(Hong Kong)Hong Kong Baptist UniversityHong Kong 999077China centre for Chinese Herbal Medicine drug Development Hong Kong Baptist UniversityHong Kong 999077China centre for Cancer and Inflammation Research School of Chinese MedicineHong Kong Baptist UniversityHong Kong 999077China Department of Chemistry College of ScienceSalahaddin University-ErbilErbil 44001Iraq Department of Pharmacognosy Faculty PharmacyTishk International UniversityErbil 44001Iraq Institute of Oncology Research Bellinzona CH6500Switzerland Universitàdella Svizzera Italiana Lugano CH6900Switzerland

Gastric cancer(GC),the third leading cause of cancer-related death globally,is complex and *** review explores multidisciplinary investigations of traditional Chinese medicine(TCM)combined with Western medical practices,emphasizing the development of nutraceuticals for cancer *** advanced analytical chemistry and food chemistry techniques,this study investigated how TCM components may be optimized for nutraceutical *** on molecular interactions with GC pathways,particularly the NF-κB,PI3K/Akt,and Wnt/β-catenin pathways,we examined the effects of TCM polyherbal formulas,extracts,and isolated *** agents modulate apoptosis and cellular proliferation,underscoring their potential in preventive *** convergence of nutraceutical and medicine food homology studies highlights a significant shift towards integrating TCM-derived compounds in a preventive health *** approach aims not only to enhance efficacy and reduce side effects but also to champion a preventive paradigm using personalized medicine to advance proactive health maintenance and disease *** combination of TCM and western medical practices offers promising avenues for future research and practical applications in GC prevention.

关键词： Traditional Chinese medicine Precision medicine Molecular network Phytochemistry Food chemistry Nutraceuticals Gastric cancer

Risk factors of adverse drug reaction from non-steroidal anti-inflammatory drugs in Shanghai patients with arthropathy

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Acta Pharmacologica Sinica 2004年第3期25卷 103-111页

作者： Wen SHI2,Yong-ming WANG,Shao-li LI3,Min YAN3,Duan Li,Bin-yan CHEN,Neng-neng CHENG Department of Pharmacology,School of Pharmacy,Fudan University,Shanghai 200032 The Center for drug reevaluation and 3 The Center for Adverse drug Reaction Monitoring,State Food and drug Administration,Beijing 100061,China Department of Pharmacology School of Pharmacy Fudan University The Center for drug reevaluation and The Center for Adverse drug Reaction Monitoring State Food and Drug Administration Beijing 100061 China

AIM: The study was to screen the possible risk factors of adverse drug reaction (ADR) induced by non-steroidal anti-inflammatory drugs (NSAIDs) in Shanghai patients with arthropathy. METHODS: The subjects were ran- domly selected from a database of outpatients with arthropathy from 9 main hospitals in Shanghai. A door to door retrospective epidemiological survey was used to collect demographic information about the patients, both indi- vidual and familial. This included data on their medical histories, lifestyle and dietary habits, history of smoking and alcohol consumption, history of drug therapy, quality of life (QOL) prior to NSAIDs intake, history of NSAIDs therapy and its ADR events, etc. Descriptive statistical methods and univariate analysis were also used to identify possible risk factors for ADRs induced by NSAIDs. RESULTS: Of the 1002 patients surveyed, the average length of NSAIDs intake was 2 years. ADR incidence from different NSAIDs was high, in a range from 46.7 %-66.2 %. In general, the candidate risk factors for ADRs were different for each NSAID. Each of the candidate risk factors were defined and studied in order to evaluate its role in the determination of ADRs from NSAIDs. “Family history of ADRs caused by NSAIDs” was found to be a significant risk factor for the four commonly used NSAIDs: meloxicam, diclofenac, nimesulide, and nabumetone. CONCLUSION: A retrospective epidemiological survey was useful in detecting the risk factors for ADRs caused by NSAIDs. The study found that different NSAIDs might have different risk factors and that there is no single risk factor universally applicable to all NSAIDs.

关键词： non-steroidal anti-inflammatory drugs adverse drug reaction risk factors retrospective studies quality of life

Multitarget Thiol-Activated Tetrapyridyl Gold(Ⅲ)Complexes for Hypoxic Cancer Therapy

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CCS Chemistry 2024年第3期6卷 783-797页

作者： Xue-Quan Zhou Selda Abyar Imma Carbo-Bague Lan Wang Sebastian Türck Maxime ASiegler Uttara Basu Ingo Ott Rongfang Liu Adriaan PIJzerman Sylvestre Bonnet Institute of Biopharmaceutical and Health Engineering Tsinghua Shenzhen International Graduate School(SIGS)Tsinghua UniversityShenzhen 518055 Leiden Institute of Chemistry Leiden University2333 CC Leiden Department of Chemistry Simon Fraser UniversityBurnabyBritish Columbia V5A 1S6 Institute of Medicinal and Pharmaceutical Chemistry Technische Universität Braunschweig38106 Braunschweig Department of Chemistry Johns Hopkins UniversityBaltimoreMaryland 21218 Division of drug Discovery&Safety Leiden Academic Centre for Drug ResearchLeiden University2333 CC Leiden

Gold complexes have emerged as promising anticancer metallodrugs due to their efficient thioredoxin reductase(TrxR)inhibition,which disturbs the redox balance of cancer ***,in this model,the role of the ligand(s)coordinated to gold is often *** this work,we present a series of tetrapyridyl Au(Ⅲ)complexes that exhibit thiol-induced release of a Au(Ⅰ)ion and a tetrapyridyl *** formation of a free Au(Ⅰ)center is responsible for the expected TrxR ***,the released ligand,which was visible in cells due to its intense blue fluorescence,showed excellent binding properties to the hERG potassium ***,these ligands ended up in the lysosomes,resulting in significant lysosome ***,the Au(Ⅲ)complexes presented in this work showed broad-spectrum anticancer properties,both in hypoxic 2D monolayers and 3D tumor *** suggest that the interaction of the released Au(Ⅰ)center and the tetrapyridyl ligand with two different protein targets may combine into prodrugs that overcome hypoxia-induced drug deactivation.

关键词： anticancer Au(Ⅲ)complexes enzyme inhibtion potassium channel affinity lysosome damage cell imaging prodrug

Anion cascade reactions Ⅲ:Synthesis of 3-isoquinuclidone bridged polycyclic lactams

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Chinese Chemical Letters 2024年第2期35卷 426-430页

作者： Zhiguo Zhang Bingbing Shi Xiyang Cao Nana Ma Hao Wu Xingjie Zhang Guisheng Zhang Key Laboratory of Green Chemical Media and Reactions Ministry of EducationCollaborative Innovation Centre of Henan Province for Green Manufacturing of Fine ChemicalsNMPA Key Laboratory for Research and Evaluation of Innovative DrugSchool of Chemistry and Chemical EngineeringHenan Normal UniversityXinxiang 453007China

Bridged polycyclic lactams are important structural units in organic functional materials,natural products,and pharmaceuticals.A flexible and efficient anion cascade reaction was developed for the preparation of bridged polycyclic lactams from readily available malonamides and 1,4‑*** highly substituted bridged polycyclic lactams were synthesized in good to excellent yields by tandem nucleophilic sequences in the presence of t BuOK in commercially available EtOH solvent at 60℃.Notably,the simple reactions can be run on a gram ***,bis-Michael addition reaction and hemiaminalization reactions are involved in the tandem transformation.

关键词： Anion cascade reactions 3-Isoquinuclidone Bridged polycyclic lactams Bis-Michael addition reaction Hemiaminalization

Encoding and display technologies for combinatorial libraries in drug discovery:The coming of age from biology to therapy

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3362-3384页

作者： Yu Fan Ruibing Feng Xinya Zhang Zhen-Liang Wang Feng Xiong Shuihua Zhang Zhang-Feng Zhong Hua Yu Qing-Wen Zhang Zhang Zhang Yitao Wang Guodong Li Macao centre for Research and Development in Chinese Medicine State Key Laboratory of Quality Research in Chinese MedicineInstitute of Chinese Medical SciencesUniversity of MacaoMacao SAR 999078China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao SAR 999078China International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative drug Development Ministry of Education(MoE)of People’s Republic of ChinaCollege of PharmacyJinan UniversityGuangzhou 510632China Zhuhai UM Science and Technology Research Institute Zhuhai 519031China Department of Pharmacy Guangzhou Red Cross HospitalFaculty of Medical ScienceJinan UniversityGuangzhou 510632China Geriatric Medicine First People’s Hospital of XinXiang and the Fifth Affiliated Hospital of Xinxiang Medical CollegeXinxiang 453100China Shenzhen Innovation Center for Small Molecule drug Discovery Co. Ltd.Shenzhen 518000China

drug discovery is a sophisticated process that incorporates scientific innovations and cuttingedge *** to traditional bioactivity-based screening methods,encoding and display technologies for combinatorial libraries have recently advanced from proof-of-principle experiments to promising tools for pharmaceutical hit discovery due to their high screening efficiency,throughput,and resource *** review systematically summarizes the development history,typology,and prospective applications of encoding and displayed technologies,including phage display,ribosomal display,mRNA display,yeast cell display,one-bead one-compound,DNA-encoded,peptide nucleic acidencoded,and new peptide-encoded technologies,and examples of preclinical and clinical *** discuss the progress of novel targeted therapeutic agents,covering a spectrum from small-molecule inhibitors and nonpeptidic macrocycles to linear,monocyclic,and bicyclic peptides,in addition to *** also address the pending challenges and future prospects of drug discovery,including the size of screening libraries,advantages and disadvantages of the technology,clinical translational potential,and market *** review is intended to establish a comprehensive high-throughput drug discovery strategy for scientific researchers and clinical drug developers.

关键词： drug screening Phage display DNA-encoded chemical libraries Peptide-encoded chemical libraries Clinical drugs

Transparency and reporting characteristics of randomized controlled trials with Chinese herbal medicine formulas interventions

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Frontiers of Medicine 2024年第4期18卷 757-761页

作者： Juan Wang Dongni Shi Yaochen Wang Xuanqi Zhang Han Li Xihong Wang Shufeng Luo Lihan Hu Jiashuai Deng Lin Zhang Chung Tai Lau Chung Wah Cheng Fei Han Ji Li Ping Wang Aiping Lyu Zhaoxiang Bian Xuan Zhang Institute for Research and Continuing Education Hong Kong Baptist UniversityShenzhen518057China Chinese EQUATOR centre Hong Kong Baptist UniversityHKSAR999077China School of Traditional Chinese Medicine Tianjin University of Chinese MedicineTianjin301617China School of Chinese Medicine Beijing University of Chinese MedicineBeijing100105China School of Chinese Medicine Hong Kong Baptist UniversityHKSAR999077China Department of Pediatrics Guang’anmen HospitalChina Academy of Chinese Medical SciencesBeijing100053China Xiyuan Hospital China Academy of Chinese Medical SciencesBeijing100091China centre for Chinese Herbal Medicine drug Development Hong Kong Baptist UniversityHKSAR999077China

To enhance the clarity and transparency of reporting in trials involving Chineseherbal medicine(CHM)formulas,the CONSORT extension specifically tailored for CHM formulas(CONSORT-CHM Formulas 2017)was introduced in 2017[1].This statement,along with its corresponding checklist,outlines key elements essential for reporting in randomized controlled trials(RCTs)related tothe rationale,design,analysis,and interpretation of interventions using CHM *** CONSORT-CHM Formulas 2017 elaborated on 7 of 25 CONSORT checklist items,namely title,abstract and keywords,backgrounds and objectives,participants,interventions,outcomes,generalizability,and interpretation.

关键词： formulas statement rational

Treatment with β-sitosterol ameliorates the effects of cerebral ischemia/reperfusion injury by suppressing cholesterol overload, endoplasmic reticulum stress, and apoptosis

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Neural Regeneration Research 2024年第3期19卷 642-649页

作者： Xiuling Tang Tao Yan Saiying Wang Qingqing Liu Qi Yang Yongqiang Zhang Yujiao Li Yumei Wu Shuibing Liu Yulong Ma Le Yang Precision Pharmacy&drug Development Center Department of PharmacyTangdu HospitalAir Force Medical UniversityXi’anShaanxi ProvinceChina Department of Clinical Pharmacy Jinling HospitalMedical School of Nanjing UniversityNanjingJiangsu ProvinceChina Department of Pharmacology School of PharmacyAir Force Medical UniversityXi’anShaanxi ProvinceChina Department of Anesthesiology The First Medical Center of Chinese PLA General HospitalBeijingChina Department of Anatomy Histology and Embryology and K.K.Leung Brain Research CentreAir Force Medical UniversityXi’anShaanxi ProvinceChina

β-Sitosterol is a type of phytosterol that occurs naturally in *** studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic *** we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced *** investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic *** addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its *** conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.

关键词： apoptosis blood-brain barrier β-sitosterol cerebral ischemia/reperfusion injury cholesterol overload cholesterol transport endoplasmic reticulum stress ischemic stroke molecular docking NPC1L1