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Fully synthetic Tn-based three-component cancer vaccine using covalently linked TLR4 ligand MPLA and iNKT cell agonist KRN-7000 as built-in adjuvant effectively protects mice from tumor development

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Acta Pharmaceutica Sinica B 2022年第12期12卷 4432-4445页

作者： Deying Yang Xiang Luo Qinghai Lian Lingqiang Gao Chengxin Wang Xiaoxiao Qi Rong Zhang Zhongqiu Liu Guochao Liao joint laboratory for Translational Cancer research of chinese medicine of the Ministry of Education of the People's Republic of China International Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou 510006China guangdong-hong kong-macao joint lab on chinese medicine and immune disease research Guangzhou 510120China

We present a new strategy for self-adjuvanting vaccine development that has different types of covalently-linked immunostimulants as the carrier *** Tn antigen as the model,a three-component vaccine(MPLA-Tn-KRN7000)containing the TLR4 ligand MPLA and the iNKT cell agonist KRN7000 was designed and *** expands fully synthetic self-adjuvanting vaccine studies that use a single carrier to one with two different types of *** corresponding two-component conjugate vaccines Tn-MPLA,Tn-KRN7000 and Tn-CRM197 were also synthesized,as *** immunological evaluation found that MPLA-Tn-KRN7000 elicits robust Tn-specific and T cell-dependent *** antibodies specifically recognized,bound to and exhibited complement-dependent cytotoxicity against Tn-positive cancer *** addition,MPLA-Tn-KRN7000 increased the survival rate and survival time of tumor-challenged mice,and surviving mice reject further tumor attacks without any additional *** to the glycoprotein vaccine Tn-CRM197,the two-component conjugate vaccines,Tn-MPLA and Tn-KRN7000,and the physical mixture of Tn-MPLA and Tn-KRN7000,MPLA-Tn-KRN7000 showed the most effect at combating tumor cells both in vitro and in *** comparison of immunological studies in wild-type and TLR4 knockout mice,along with the test of binding affinity to CD1d protein suggests that the covalently linked MPLA-KRN7000 immunostimulant induces a synergistic activation of TLR4 and iNKT cell that improves the immunogenicity of *** work demonstrates that MPLA-Tn-KRN7000 has the potential to be a vaccine candidate and provides a new direction for fully synthetic vaccine design.

关键词： Cancer vaccine Tn antigen MPLA KRN7000 Immunotherapy

Size-dependent macrophage-targeting of mannose-modified rosiglitazone liposomes to alleviate inflammatory bowel disease

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chinese Chemical Letters 2024年第1期35卷 385-391页

作者： Erjin Wang Run Han Mingyue Wu Yuan He Yaxin Cheng Jiahong Lu Ying Zheng State Key laboratory of Quality research in chinese medicine Institute of Chinese Medical Sciences(ICMS)University of MacaoMacao 999078China Department of Pharmacy Xuzhou Medical UniversityXuzhou 221004China Faculty of Health Sciences University of MacaoMacao 999078China guangdong-hong kong-macao joint lab on chinese medicine and immune disease research University of MacaoMacao 999078China

Inflammatory bowel disease (IBD) is a refractory chronic intestinal inflammatory disease caused by a malfunction of immune system. As the key immune cells in the intestine, macrophages play an important role in maintaining intestinal homeostasis and tissue repair of the IBD. Pharmacological modulation of macrophage function exhibits the promising therapeutic effect for IBD. In this study, mannose-modified liposomes (MAN-LPs) are prepared for macrophage targeting to improve therapeutic efficiency. Rosiglitazone (ROSI) as an agonist of peroxisome proliferators-activated receptor γ (PPAR-γ) is used as the model drug to fabricate different sized liposomes. The impacts of mannose modification and particle size for macrophage targeting are investigated in cells, zebrafish, and mouse models and the therapeutic effects of the MAN-LPs are evaluated on dextran sulfate sodium (DSS)-induced IBD mouse. Compared to unmodified liposome, MAN-LPs display higher uptake by RAW 264.7 cells and better co-localization with macrophage in zebrafish model. Furthermore, MAN-LPs could effectively accumulate in the inflammatory intestinal sites in IBD mouse model. Most importantly, the targeting ability of MAN-LPs is obviously enhanced with the increasing of particle size, whereas the largest MAN-LPs particles achieve the best anti-inflammatory effect in cells, and a higher therapeutic efficiency in IBD mouse model. Therefore, mannose-modified liposome is a promising strategy for macrophage-targeting in IBD treatment. Particle size of MAN-LPs will affect macrophage targeting ability, as well as the therapeutic effect in-vivo.

关键词： Macrophage targeting Liposome Mannose Particle size Inflammatory bowel disease

Myocardial injury:where inflammation and autophagy meet

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Burns & Trauma 2023年第1期11卷 188-202页

作者： Chunping Liu Yanjiao Liu Huiqi Chen Xiaofei Yang Chuanjian Lu Lei Wang Jiahong Lu State Key laboratory of Quality research in chinese medicine Institute of Chinese Medical SciencesUniversity of MacaoMacaoChina State Key laboratory of Dampness Syndrome of chinese medicine The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou51080China guangdong-hong kong-macao joint lab on chinese medicine and immune disease research Guangzhou510080China

Autophagy is a highly conserved bulk degradation mechanism that degrades damaged organelles,aged proteins and intracellular contents to maintain the homeostasis of the intracellular *** of autophagy can be observed during myocardial injury,during which inflammatory responses are strongly *** can inhibit the inflammatory response and regulate the inflammatory microenvironment by removing invading pathogens and damaged *** addition,autophagy may enhance the clearance of apoptotic and necrotic cells to promote the repair of damaged *** this paper,we briefly review the role of autophagy in different cell types in the inflammatory microenvironment of myocardial injury and discuss the molecular mechanism of autophagy in regulating the inflammatory response in a series of myocardial injury conditions,including myocardial ischemia,ischemia/reperfusion injury and sepsis cardiomyopathy.

关键词： Autophagy Inflammation Myocardial injury

Building on the backbone of CD47-based therapy in cancer:Combination strategies,mechanisms,and future perspectives

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1467-1487页

作者： Zi-Han Ye Wei-Bang Yu Mu-Yang Huang Jun Chen Jin-Jian Lu State Key laboratory of Quality research in chinese medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China Zhongshan School of medicine Sun Yat-sen UniversityGuangzhou 510080China Department of Pharmaceutical Sciences Faculty of Health SciencesUniversity of MacaoMacao 999078China MoE Frontiers Science Center for Precision Oncology University of MacaoMacao 999078China guangdong-hong kong-macao joint lab on chinese medicine and immune disease research University of MacaoMacao 999078China

Described as a“don't eat me”signal,CD47 becomes a vital immune checkpoint in *** interaction with signal regulatory protein alpha(SIRPa)prevents macrophage *** recent years,a growing body of evidences have unveiled that CD47-based combination therapy exhibits a superior anti-cancer *** clinical trials about CD47 have adopted the regimen of collaborating with other therapies or developing CD47-directed bispecific antibodies,indicating the combination strategy as a general trend of the *** this review,clinical and preclinical cases about the current combination strategies targeting CD47 are collected,their underlying mechanisms of action are discussed,and ideas from future perspectives are shared.

关键词： CD47 Combination strategies Bispecific antibodies Clinical data Preclinical data Cancer Mechanisms Future perspectives

2D NMR-based MatchNat Dereplication Strategy Enables Explosive Discovery of Novel Diterpenoid Alkaloids

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chinese Journal of Chemistry 2022年第18期40卷 2169-2178页

作者： Tian-Peng Yin Yi Yu Qing-Hua Liu Ming-Yue Zhou Guo-Yuan Zhu Li-Ping Bai Wei Zhang Zhi-hong Jiang State Key laboratory of Quality research in chinese medicines Macao Institute for Applied Research in Medicine and HealthGuangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious DiseaseMacao University of Science and TechnologyTaipaMacaoChina Faculty of Bioengineering Zhuhai Campus of Zunyi Medical UniversityZhuhaiGuangdong519041 China

The tribe Delphineae,comprising two genera,Aconitum *** Delphinium L.,is the richest source of bioactive diterpenoid alkaloids(DAs),while their highly similar chemical structures create a major challenge for dereplication from complex *** solve the inefficient discovery process of natural DAs,a novel dereplication strategy based on pattern recognition of specific heteronuclear multiple bond correlation(HMBC)signals has been established in this *** strategy utilized the diagnostic signals in the HMBC spectra of C_(19)-DAs,which could indicate the structural *** newly designed software MatchNat allowed in silico recognition of C_(19)-DA *** developed dereplication system was demonstrated to be a practical strategy to dereplicate a variety of natural products from two Delphineae plants,including Aconitum vilmorinianum *** Delphinium pachycentrum *** compounds could be rapidly recognized from the mixture,and novel DAs were found with the aid of ***,targeted isolation led to the explosive discovery of a series of novel *** dereplication system has the potential to be adopted for dereplication of any other class of natural products and has shown promising application as a complementary tool in the nuclear magnetic resonance analysis of traditional chinese medicines.

关键词： NMR spectroscopy Natural products Alkaloids Dereplication Aconitum

IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα

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Acta Pharmaceutica Sinica B 2022年第2期12卷 651-664,F0004页

作者： Juan Liu Yuxin Zhuang Jianlin Wu Qiang Wu Meixian Liu Yue Zhao Zhongqiu Liu Caiyan Wang Linlin Lu Yingjiao Meng Kawai Lei Xiaojuan Li Qibiao Wu Elaine Lai-Han Leung Zhengyang Guo Liang Liu Ting Li State Key laboratory of Quality research in chinese medicine/macao Institute for Applied research in medicine and Health Macao University of Science and TechnologyMacao SAR 999078China International Institute for Translational chinese medicine Guangzhou University of Chinese MedicineGuangzhou 510006China guangdong Provincial Key laboratory of New Drug Screening/laboratory of Anti-inflammatory and Immunomodulatory Pharmacology School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China guangdong-hong kong-macao joint laboratory of Respiratory Infectious disease Macao University of Science and TechnologyMacao SAR 999078China joint laboratory for Translational Cancer research of chinese medicine of the Ministry of Education of the People’s Republic of China Macao University of Science and TechnologyMacao SAR 999078China

Inhibitor of nuclear factor kappa-B kinase subunit beta(IKKβ)is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B(IκBα)and then activate nuclear factor kappa-B(NF-κB).Inhibition of IKKβhas been a therapeutic strategy for inflammatory and autoimmune *** we report that IKKβis constitutively activated in healthy donors and healthy Ikkβ^(C46A)(cysteine 46 mutated to alanine)knock-in mice although they possess intensive IKKβ-IκBα-NF-κB signaling *** indicate that IKKβactivation probably plays homeostatic role instead of causing *** to IkkβWTlittermates,lipopolysaccharides(LPS)could induce high mortality rate in Ikkβ^(C46A) mice which is correlated to breaking the homeostasis by intensively activating p-IκBα-NF-κB signaling and inhibiting phosphorylation of 5’adenosine monophosphate-activated protein kinase(p-AMPK)*** then demonstrated that IKKβkinase domain(KD)phosphorylates AMPKa1 via interacting with residues Thr183,Ser184,and Thr388,while IKKβhelix-loop-helix motifs is essential to phosphorylate IκBαaccording to the previous *** assay further demonstrated that IKKβsimultaneously catalyzes phosphorylation of AMPK and IκBαto mediate ***,activation of AMPK rather than inhibition of IKKβcould substantially rescue LPS-induced mortality in Ikkβ^(C46A) mice by rebuilding the *** conclude that IKKβactivates AMPK to restrict inflammation and IKKβmediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.

关键词： IKKβ Homeostasis Kinase domain AMPK Inflammation IκBα Anti-inflammatory drug Phosphorylation

Targeted protein degradation in cancers:Orthodox PROTACs and beyond

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The Innovation 2023年第3期4卷 5-19页

作者： Jin Li Xinxin Chen Aiping Lu Chao Liang Department of Biology School of Life SciencesSouthern University of Science and TechnologyShenzhen 518055China Institute of Integrated Bioinfomedicine and Translational Science(IBTS) School of Chinese MedicineHong Kong Baptist UniversityHong Kong SAR 999077China State Key laboratory of Proteomics National Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 100850China guangdong–hong kong–macao joint lab on chinese medicine and immune disease research Guangzhou 510006China

Targeted protein degradation(TPD)is emerging as a strategy to overcome the limitations of traditional small-molecule ***-targeting chimera(PROTAC)technology can be used to target proteins by hijacking the ubiquitin-proteasome ***,PROTAC aims to target the“undruggable”majority of proteins in the human *** constant exploration and optimization of PROTACs and the exploitation of other TPD strategies over two decades,TPD has expanded from theoretical studies to clinical strategies,with practical applications in oncological,immunological,and other *** this review,we introduce the mechanisms,features,and molecular targets of orthodox PROTACs and summarize the PROTAC drugs under study as cancer therapeutics in clinical *** also discuss PROTAC derivatives and other TPD strategies,such as lysosome-targeting chimeras,autophagy-targeting chimeras,and molecular glue ***,the studies summarized herein support the full potential of TPD in the biomedical industry.

关键词： overcome summarized herein

research Advances of Traditional chinese medicine in Cancer Immunotherapy

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chinese medicine and Culture 2020年第4期3卷 245-253页

作者： Jing Li Shengqi Wang Neng Wang Zhiyu Wang The research Centre of Integrative Cancer medicine Discipline of Integrated Chinese and Western MedicineThe Second Affiliated Hospital of Guangzhou University of Chinese Medicine guangdong Provincial Key laboratory of Clinical research on Traditional chinese medicine Syndrome Guangdong Provincial Academy of Chinese Medical SciencesGuangdong Provincial Hospital of Chinese Medicine guangdong-hong kong-macao joint lab on chinese medicine and immune disease research Guangzhou University of Chinese Medicine research Center of Integrative medicine School of Basic Medical SciencesGuangzhou University of Chinese MedicineGuangzhouGuangdongChina

Tumorigenesis are closely associated with the immune function of the human *** has emerged as a novel and promising treatment strategy in multiple malignancies in the 21st *** chinese medicine(TCM)has been extensively used for cancer treatment in China and surrounding countries for it exerts efficient therapeutic effects with few side *** recent years,studies have demonstrated that TCM plays a unique and reliable role in regulating tumor *** can enhance the antitumor immune response function by regulating the secretion of cytokines,reshaping the balance of immune cells,and regulating immune checkpoints to relieve the *** addition,TCM can reduce the side effects(e.g.,cytokine storm)of cancer *** on the current research of active immunotherapy and passive immunotherapy,this review summarizes the potential applications and existing problems of TCM in tumor *** review may be helpful in illuminating the scientific basis of TCM in tumor immunotherapy,promoting its internationalization,as well as shedding innovating new strategies for the development of tumor immunotherapy.

关键词： Cytokine immune balance immune checkpoint traditional chinese medicine tumor immunotherapy

Fu-Zheng-Yi-Liu Formula inhibits the stem cells and metastasis of prostate cancer via tumor-associated macrophages/C-C motif chemokine ligand 5 pathway in tumor microenvironment

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chinese Journal of Natural medicines 2024年第6期22卷 501-514页

作者： CHEN Chiwei HUANG Renlun WANG Neng ZHENG Yifeng ZHOU Jianfu YANG Bowen WANG Xuan ZHANG Juping PAN Bo CHEN Zhiqiang WANG Shengqi WANG Zhiyu XIANG Songtao The research Center of Integrative Cancer medicine Discipline of Integrated Chinese and Western Medicinethe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhou 510000China The First Clinical College of Guangzhou University of chinese medicine Guangzhou 510000China guangdong Provincial Key laboratory of Clinical research on Traditional chinese medicine Syndrome Guangdong Provincial Academy of Chinese Medical SciencesGuangdong Provincial Hospital of Chinese MedicineGuangzhou 510000China guangdong-hong kong-macao joint lab on chinese medicine and immune disease research Guangzhou University of Chinese MedicineGuangzhou 510000China The research Center for Integrative medicine School of Basic Medical SciencesGuangzhou University of Chinese MedicineGuangzhou 510000China State Key laboratory of Dampness Syndrome of chinese medicine The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou 510000China

Prostate cancer(PCa)is the second most common malignancy among men *** Fu-Zheng-Yi-Liu(FZYL)Formula has been widely utilized in the treatment of *** study investigates whether the FZYL Formula can inhibit PCa by tar-geting the TAMs/CCL5 *** conducted in vitro co-cultures and in vivo co-injections of PCa cells and TAMs to mimic their *** showed that the FZYL Formula significantly reduced the proliferation,colony formation,subpopulations of PCSCs,and sphere-formation efficacy of PCa cells,even in the presence of TAM ***,the Formula markedly decreased the migration,invasion,and epithelial-mesenchymal transition(EMT)of PCa cells induced by *** FZYL Formula also reversed M2 phenotype polarization in TAMs and dose-dependently reduced their CCL5 expression and secretion,with minimal cytotoxicity *** studies confirmed that the TAMs/CCL5 axis is a critical target of the FZYL Formula,as the addition of exogen-ous CCL5 partially reversed the formula’s inhibitory effects on PCSCs self-renewal in the co-culture ***,the Formula also significantly inhibited the growth of PCa xenografts,bone metastasis,and PCSCs activity in vivo by targeting the TAMs/CCL5 ***,this study not only elucidates the immunomodulatory mechanism of the FZYL Formula in PCa therapy but also highlights the TAMs/CCL5 axis as a promising therapeutic target.

关键词： Traditional chinese medicine Tumor-associated macrophages Prostate cancer stem cells CCL5 Tumor microenvironment