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Tumorigenic bacteria in colorectal cancer:mechanisms and treatments

Cancer Biology & Medicine 2022年第2期19卷 147-162页

作者： Sha Li Jinyi Liu Xiangjin Zheng Liwen Ren Yihui Yang Wan Li Weiqi Fu Jinhua Wang Guanhua Du The State key laboratory of Bioactive Substance and Function of Natural Medicines Beijing 100050China Key Laboratory of Drug Target Research and Drug Screen Institute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical CollegeBeijing 100050China

Colorectal cancer(CRC)is the third most common and the second most fatal cancer.In recent years,more attention has been directed toward the role of gut microbiota in the initiation and development of CRC.Some bacterial species,such as Fusobacterium nucleatum,Escherichia coli,Bacteroides fragilis,Enterococcus faecalis,and Salmonella sp.have been associated with CRC,based upon sequencing studies in CRC patients and functional studies in cell culture and animal models.These bacteria can cause host DNA damage by genotoxic substances,including colibactin secreted by pks+Escherichia coli,B.fragilis toxin(BFT)produced by Bacteroides fragilis,and typhoid toxin(TT)from Salmonella.These bacteria can also indirectly promote CRC by influencing host-signaling pathways,such as E-cadherin/β-catenin,TLR4/MYD88/NF-κB,and SMO/RAS/p38 MAPK.Moreover,some of these bacteria can contribute to CRC progression by helping tumor cells to evade the immune response by suppressing immune cell function,creating a proinflammatory environment,or influencing the autophagy process.Treatments with the classical antibacterial drugs,metronidazole or erythromycin,the antibacterial active ingredients,M13@Ag(electrostatically assembled from inorganic silver nanoparticles and the protein capsid of bacteriophage M13),berberine,and zerumbone,were found to inhibit tumorigenic bacteria to different degrees.In this review,we described progress in elucidating the tumorigenic mechanisms of several CRC-associated bacteria,as well as progress in developing effective antibacterial therapies.Specific bacteria have been shown to be active in the oncogenesis and progression of CRC,and some antibacterial compounds have shown therapeutic potential in bacteria-induced CRC.These bacteria may be useful as biomarkers or therapeutic targets for CRC.

关键词： Colorectal cancer microbiota tumorigenic mechanism genotoxicity cancer pathways tumor immunity

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MELK is an oncogenic kinase essential for metastasis,mitotic progression,and programmed death in lung carcinoma

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Signal Transduction and targeted Therapy 2021年第1期6卷 83-94页

作者： Qin Tang Wan Li Xiangjin Zheng Liwen Ren Jinyi Liu Sha Li Jinhua Wang Guanhua Du The State key laboratory of Bioactive Substance and Function of Natural Medicines BeijingChina Key Laboratory of Drug Target Research and Drug Screen Institute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical College100050 BeijingChina

Lung cancer is the fastest growth rate of morbidity and mortality in nearly a decade,and remains difficult to treat.Furthermore,the molecular mechanisms underlying its development are still unclear.In this study,bioinformatics analysis showed that MELK was highly expressed in lung cancer and negatively correlated to the survival of lung adenocarcinoma(LUAD).Immunohistochemistry analysis of LUAD patient tissues revealed there were a high level of MELK expression in LUAD.Knockdown of MELK expression inhibits the migration and invasion of LUAD cells,which may be mediated by Twist1,Slug,MMP7,and N-catenin.Overexpression of MELK promoted the growth of LUAD cells in medium,3D Matrigel,and nude mice.Inhibition of MELK by OTSSP167 arrested cycle of LUAD cells at G2/M phase via PLK1-CDC25C-CDK1 pathway,and triggered apoptosis-mediated pyroptosis.Together,these data indicate that MELK is critical for metastasis,mitotic progression,and programmed death of LUAD and may be a promising therapeutic target for LUAD.

关键词： metastasis PLK1 lung

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Multifunctional regulatory protein connective tissue growth factor (CTGF):A potential therapeutic target for diverse diseases

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1740-1760页

作者： Minyang Fu Dandan Peng Tianxia Lan Yuquan Wei Xiawei Wei laboratory of Aging research and Cancer drug target State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China

Connective tissue growth factor(CTGF),a multifunctional protein of the CCN family,regulates cell proliferation,differentiation,adhesion,and a variety of other biological processes.It is involved in the disease-related pathways such as the Hippo pathway,p53 and nuclear factor kappa-B(NF-κB)pathways and thus contributes to the developments of inflammation,fibrosis,cancer and other diseases as a downstream effector.Therefore,CTGF might be a potential therapeutic target for treating various diseases.In recent years,the research on the potential of CTGF in the treatment of diseases has also been paid more attention.Several drugs targeting CTGF(monoclonal antibodies FG3149 and FG3019)are being assessed by clinical or preclinical trials and have shown promising outcomes.In this review,the cellular events regulated by CTGF,and the relationships between CTGF and pathogenesis of diseases are systematically summarized.In addition,we highlight the current researches,focusing on the preclinical and clinical trials concerned with CTGF as the therapeutic target.

关键词： CTGF CCN2 CCN family Fibrosis Cancer targeted therapy Immunotherapy Therapeutic strategies

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Nanoparticles targeting tumor-associated macrophages:A novel anti-tumor therapy

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Nano research 2022年第3期15卷 2177-2195页

作者： Siyuan Chen Furong Qin Manni Wang Yuquan Wei Zhiyong Qian Xiawei Wei laboratory of Aging research and Cancer drug target State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China

The immunosuppressive tumor microenvironment(TME)is crucial in the occurrence of tumorigenesis,metastasis,and drug resistance.Among all stromal cells,tumor-associated macrophages(TAMs)are recognized as vital components causing the TME to be favorable for cancer cells and are also main targets in cancer immunotherapy.To date,nanoparticle(NP)-based drug delivery systems,as new technology platforms,have exhibited considerable advantages,such as targeted drug delivery at tumor sites,enhanced drug transport efficiency,and controllable drug release profiles,which provide new approaches for cancer therapy.Regarding TAM-targeting nanoparticles,various therapeutic strategies have been developed by varying their design,namely,by blocking TAM recruitment,promoting TAM transformation,and directly diminishing existing TAMs.In the current review,we provide a brief overview of the role of TAMs in the tumor microenvironment and their functions and highlight strategies for TAM targeting.Moreover,the applications of nanoparticles in targeting TAMs to improve cancer therapeutic efficiency are summarized.

关键词： tumors immunotherapy tumor-associated macrophages nanoparticles

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The biology,function,and applications of exosomes in cancer

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Acta Pharmaceutica Sinica B 2021年第9期11卷 2783-2797页

作者： Jinyi Liu Liwen Ren Sha Li Wan Li Xiangjin Zheng Yihui Yang Weiqi Fu Jie Yi Jinhua Wang Guanhua Du The State key laboratory of Bioactive Substance and Function of Natural Medicines Beijing 100050China Key Laboratory of Drug Target Research and Drug Screen Institute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical CollegeBeijing 100050China Department of Clinical laboratory Peking Union Medical College HospitalBeijing 100730China

Exosomes are cell-derived nano vesicles with diameters from 30 to 150 nm,released upon fusion of multi vesicular bodies with the cell surface.They can transport nucleic acids,proteins,and lipids for intercellular communication and activate signaling pathways in target cells.In cancers,exosomes may participate in growth and metastasis of tumors by regulating the immune response,blocking the epithelial-mesenchymal transition,and promoting angiogenesis.They are also involved in the development of resistance to chemotherapeutic drugs.Exosomes in liquid biopsies can be used as non-invasive biomarkers for early detection and diagnosis of cancers.Because of their amphipathic structure,exosomes are natural drug delivery vehicles for cancer therapy.

关键词： Exosomes Tumor immunity Tumor metastasis drug resistance Biomarkers drug delivery

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targeting RAS-RAF-MEK-ERK signaling pathway in human cancer:Current status in clinical trials

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Genes & Diseases 2023年第1期10卷 76-88页

作者： Yanlin Song Zhenfei Bi Yu Liu Furong Qin Yuquan Wei Xiawei Wei laboratory of Aging research and Cancer drug target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuan610041China

Molecular target inhibitors have been regularly approved by Food and drug Administration(FDA)for tumor treatment,and most of them intervene in tumor cell proliferation and metabolism.The RAS-RAF-MEK-ERK pathway is a conserved signaling pathway that plays vital roles in cell proliferation,survival,and differentiation.The aberrant activation of the RAS-RAF-MEK-ERK signaling pathway induces tumors.About 33%of tumors harbor RAS mutations,while 8%of tumors are driven by RAF mutations.Great efforts have been dedicated to targeting the signaling pathway for cancer treatment in the past decades.In this review,we summarized the development of inhibitors targeting the RAS-RAF-MEK-ERK pathway with an emphasis on those used in clinical treatment.Moreover,we discussed the potential combinations of inhibitors that target the RAS-RAF-MEK-ERK signaling pathway and other signaling pathways.The inhibitors targeting the RAS-RAF-MEK-ERK pathway have essentially modified the therapeutic strategy against various cancers and deserve more attention in the current cancerresearchandtreatment.

关键词： Clinical trials Molecular target therapy RAS-RAF-MEK-ERK signaling pathway

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Secondary metabolites of petri-dish cultured Antrodia camphorata and their hepatoprotective activities against alcohol-induced liver injury in mice

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Chinese Journal of Natural Medicines 2019年第1期17卷 33-42页

作者： WU Yu TIAN Wen-Jing GAO Shuo LIAO Zu-Jian WANG Guang-Hui LO Jir-Mehng LIN Pei-Hsin ZENG De-Quan QIU Da-Ren LIU Xiang-Zhong ZHOU Mi LIN Ting CHEN Hai-Feng Fujian Provincial key laboratory of Innovative drug target School of Pharmaceutical SciencesXiamen University Industrial Technology research Institute

Antrodia camphorata, a well-known and highly valued edible medicinal mushroom with intriguing activities like liver protection, has been traditionally used for the treatment of alcoholic liver disease. A. camphorata shows highly medicinal and commercial values with the demand far exceeds the available supply. Thus, the petri-dish cultured A. camphorata(PDCA) is expected to develope as a substitute. In this paper, nineteen triterpenes were isolated from PDCA, and thirteen of them were the unique anthroic acids in A. camphorata, including the main content antcin K, which suggested that PDCA produced a large array of the same anthroic acids as the wild one. Furthermore, no obvious acute toxicity was found suggesting the edible safety of PDCA. In mice alcohol-induced liver injury model, triglyceride(TG), aspartate aminotransferase(AST), alanine aminotransferase(ALT), and malondialdehyde(MDA) had been reduced by the PDCA powder as well as the main content antcin K, which indicated that the PDCA could protect alcoholic liver injury in mice model and antcin K could be the effective component responsible for the hepatoprotective activities of PDCA against alcoholic liver diseases.

关键词： Petri-dish Antrodia camphorata Hepatoprotective

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SARS-CoV-2 variants,immune escape,COVID-19 vaccine,and therapeutic strategies

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Science China(Life Sciences) 2023年第2期66卷 406-410页

作者： Haiying Que Li Chen Xiawei Wei laboratory of Aging research and Cancer drug target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China

The global pandemic of coronavirus disease 2019(COVID-19) caused by severe acute respiratory syndrome coronavirus2(SARS-CoV-2) has brought considerable challenges to worldwide public health and the economy. Over 535 million confirmed cases and 6.3 million deaths of COVID-19 were reported as of June 17, 2022(https://covid19.***.int/).

关键词： acute respiratory vaccine

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Increasing stiffness promotes pulmonary retention of ligand-directed dexamethasone-loaded nanoparticle for enhanced acute lung inflammation therapy

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Bioactive Materials 2023年第2期20卷 539-547页

作者： Yinglan Yu Shujie Li Yuan Yao Xinran Shen Lian Li Yuan Huang key laboratory of drug-targeting and drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu610041China

Inhaled nanoparticles(NPs)need to penetrate the bronchial mucosa to deliver drug payloads deeply in the lung for amplified local therapy.However,the bronchial mucociliary barrier eliminates NPs rapidly,which considerably limits their mucosal penetration.In this study,we find that surface ligand modification and stiffness adjustment of NPs contribute to the significantly enhanced bronchial mucosal absorption and pulmonary retention of inhaled drugs.We utilize neonatal Fc receptor ligand(FcBP)to modify the rationally designed low stiffness NPs(Soft-NP)and high stiffness NPs(Stiff-NP)to target bronchial mucosa.In an acute lung inflammation rat model,after intranasal administration with dexamethasone-loaded NPs,Stiff-NP endowed with FcBP displays superior therapeutic effects.The in vitro data demonstrate that the promotion effect of FcBP to bronchial mucosal absorption of Stiff-NP dominates over Soft-NP.This could be attributed to the higher affinity between ligand-receptor when incorporating FcBP on the Stiff-NP surface.Meanwhile,high stiffness modulates more actin filaments aggregation to mediate endocytosis,along with strengthened Ca2+signal to enhance exocytosis.Conclusively,we highlight that FcBP-modified NPs with higher stiffness would be a potential pulmonary drug delivery system.

关键词： Pulmonary drug delivery Mucus barrier Epithelial barrier Stiffness Ligand modification Acute lung inflammation

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A new and promising application of gene editing: CRISPR-controlled smart materials for tissue engineering,bioelectronics, and diagnostics

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Science China(Life Sciences) 2019年第11期62卷 1547-1549页

作者： Weiqi Hong Mengyuan Huang Yuquan Wei Xiawei Wei laboratory of Aging research and Cancer drug target State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan University

A recent study published in the journal Science by Collins et al.proposed a programmable clustered regularly interspaced short palindromic repeats(CRISPR)-responsive smart material containing the CRISPR-associated nuclease,Casl2a,and hydrogels containing DNA to deliver biological information via changes in material properties(English et al.,2019).

关键词： CRISPR smart journal

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