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Tanshinone IIA Suppresses Non-Small Cell Lung Cancer Through Beclin-1-Mediated Autophagic Apoptosis

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Engineering 2022年第12期19卷 128-138页

作者： Shasha Bai Sainan Cui Wenhao Wen elaine lai-han leung Jing Bai Huiyuan Lin Yongfei Cui Lei Yang Zhongqiu Liu Yuan Zheng Rong Zhang School of Pharmaceutical Sciences Guangzhou University of Chinese MedicineGuangzhou 510006China State Key Laboratory of Quality Research in Chinese Medicine/Macao Institute for Applied Research in Medicine and Health Macao University of Science and TechnologyMacao 999078China Cardiothoracic Surgery Department The Second Clinical College of Guangzhou University of Chinese MedicineGuangdong Provincial Hospital of Chinese MedicineGuangzhou 510006China

It is necessary to develop a new strategy for treatment of lung cancer since it is the main cause of cancer *** IIA(Tan IIA),an active ingredient of a commonly used traditional Chinese herb Salvia miltiorrhiza,provides a new direction to develop a new strategy for the *** has been found that Tan IIA could inhibit lung cancer in vitro and in vivo by inducing autophagic *** IIA increased apoptotic cells and the expression of cleaved caspase 3 and cleaved caspase 9,decreased B-cell lymphoma-2(Bcl-2)/Bcl-2 associated X protein(Bax)ratio in human non-small cell lung cancer(NSCLC)cell lines,which was promoted by an autophagy activator Rapamycin,and weaken by autophagy inhibitor 3-methyladenine(3-MA).In addition,Tan IIA induced more autophagosomes,up-regulated light chain 3b(LC-3B)I and LC-3B II conversion and less sequestosome 1(SQSTM1/p62)expression,which cannot be weakened by the caspase 3 ***,overexpression of LC-3B gene(LC3B)and downregulation of autophagic gene 5(ATG5)further confirmed that Tan IIA induced autophagic apoptosis in NSCLC cell ***-1 gene(BECN1)overexpression and silence attenuated the effects of Tan IIA,suggesting autophagic apoptosis that Tan IIA induced was dependent on ***,our study demonstrated a new treatment mechanism of Tan IIA and suggested that Tan IIA is a potential new anti-cancer therapeutic option.

关键词： Tan IIA Autophagy Apoptosis Beclin-1

Herbal formula BaWeiBaiDuSan alleviates polymicrobial sepsis-induced liver injury via increasing the gut microbiota Lactobacillus johnsonii and regulating macrophage anti-inflammatory activity in mice

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Acta Pharmaceutica Sinica B 2023年第8期13卷 1164-1179页

作者： Xiaoqing Fan Chutian Mai Ling Zuo Jumin Huang Chun Xie Zebo Jiang Runze Li Xiaojun Yao Xingxing Fan Qibiao Wu Peiyu Yan Liang Liu Jianxin Chen Ying Xie elaine lai-han leung Dr.Neher’s Biophysics Laboratory for Innovative Drug Discovery State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyTaipaMacao 999078China Beijing University of Chinese Medicine Beijing 100029China Cancer Center Faculty of Health Science、MOE Frontiers Science Center for Precision OncologyUniversity of MacaoMacao 999078China Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging the Fifth Affiliated HospitalSun Yat-sen UniversityZhuhai 519000China State Key Laboratory of Dampness Syndrome of Chinese Medicine the Second Affiliated Hospital of Guangzhou University of Chinese Medicine(Guangdong Provincial Hospital of Chinese Medicine)Guangzhou 510120China

Sepsis-induced liver injury(SILI)is an important cause of septicemia ***(BWBDS)was extracted from a formula of Panax ginseng ***,Lilium brownie *** ex Miellez *** Baker,Polygonatum sibiricum *** Redoute,Lonicera japonica Thunb.,Hippophae rhamnoides Linn.,Amygdalus Communis Vas,Platycodon grandiflorus(Jacq.)***.,and Cortex ***,we investigated whether the BWBDS treatment could reverse SILI by the mechanism of modulating gut *** protected mice against SILI,which was associated with promoting macrophage anti-inflammatory activity and enhancing intestinal *** selectively promoted the growth of Lactobacillus johnsonii(***)in cecal ligation and puncture treated *** microbiota transplantation treatment indicated that gut bacteria correlated with sepsis and was required for BWBDS anti-sepsis ***,*** significantly reduced SILI by promoting macrophage anti-inflammatory activity,increasing interleukin-10+M2 macrophage production and enhancing intestinal ***,heat inactivation ***(***)treatment promoted macrophage anti-inflammatory activity and alleviated *** findings revealed BWBDS and gut microbiota *** as novel prebiotic and probiotic that may be used to treat *** potential underlying mechanism was at least in part,via ***-dependent immune regulation and interleukin-10+M2 macrophage production.

关键词： BaWeiBaiDuSan Sepsis-induced liver injury Network pharmacology 16S PacBio SMRT sequencing Lactobacillus johnsonii Macrophages Interleukin-10

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

ROS-Responsive Berberine Polymeric Micelles Effectively Suppressed the Inflammation of Rheumatoid Arthritis by Targeting Mitochondria

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Nano-Micro Letters 2020年第6期12卷 138-151页

作者： Xing-xing Fan Meng-ze Xu elaine lai-han leung Cai Jun Zhen Yuan Liang Liu State Key Laboratory of Quality Research in Chinese Medicine Macao Institute For Applied Research in Medicine and HealthMacao University of Science and TechnologyAvenida Wai LongTaipaMacao SARChina Faculty of Health Sciences University of MacaoTaipaMacao SARChina

Rheumatoid arthritis(RA)is an autoimmune disease,which attacks human joint system and causes lifelong inflammatory *** date,no cure is available for RA and even the ratio of achieving remission is very ***,to enhance the efficacy of RA treatment,it is essential to develop novel approaches specifically targeting pathological *** this study,we discovered that RA synovial fibroblasts exhibited higher reactive oxygen species(ROS)and mitochondrial superoxide level,which were adopted to develop ROS-responsive nano-medicines in inflammatory microenvironment for enhanced RA treatment.A selenocystamine-based polymer was synthesized as a ROS-responsive carrier nanoplatform,and berberine serves as a tool *** assembling,ROS-responsive berberine polymeric micelles were fabricated,which remarkably increased the uptake of berberine in RA fibroblast and improved in vitro and in vivo efficacy ten times ***,the anti-RA effect of micelles was blocked by the co-treatment of AMPK inhibitor or palmitic acid,indicating that the mechanism of micelles was carried out through targeting mitochondrial,suppressing lipogenesis and finally inhibiting cellular *** together,our ROS-responsive nano-medicines represent an effective way of preferentially releasing prodrug at the inflammatory microenvironment and improving RA therapeutic efficacy.

关键词： Rheumatoid arthritis Reactive oxygen species Nanoparticles Berberine Oxygen consumption rate

Microbiome technology empowers the development of traditional Chinese medicine

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Science China(Life Sciences) 2020年第11期63卷 1759-1761页

作者： Hongtao Liu Junping Zheng Hsin-Chih lai Baifei Hu Lin Zhu elaine lai-han leung Hong Wei College of Basic Medicine Hubei University of Chinese MedicineWuhan 430065China Department of Medical Biotechnology and Laboratory Science Chang Gung UniversityTao-Yuan 33302China State Key Laboratory of Quality Research in Chinese Medicine Macao Institute for Applied Research in Medicine and HealthMacao University of Science and TechnologyMacao SARChina Central Laboratory Clinical Medicine Scientific and Technical Innovation ParkShanghai Tenth People’s HospitalTongji UniversityShanghai 200435China State Key Laboratory of Agricultural Microbiology College of Animal Sciences and TechnologyHuazhong Agricultural UniversityWuhan 430070China

Application of microbiome technology to traditional Chinese medicine (TCM). Microbiome refers to the integration of composition, genetic information and bio-function of all microbial species under a specific environment.

关键词： environment. powers technology

miR-7/TGF-β2 axis sustains acidic tumor microenvironment-induced lung cancer metastasis

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Acta Pharmaceutica Sinica B 2022年第2期12卷 821-837页

作者： Tao Su Suchao Huang Yanmin Zhang Yajuan Guo Shuwei Zhang Jiaji Guan Mingjing Meng Linxin Liu Caiyan Wang Dihua Yu Hiu-Yee Kwan Zhiying Huang Qiuju Huang elaine lai-han leung Ming Hu Ying Wang Zhongqiu Liu Linlin Lu Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China Guangzhou University of Chinese MedicineGuangzhou 510006China Department of Molecular and Cellular Oncology the University of Texas MD Anderson Cancer CenterHoustonTX 77030USA School of Chinese Medicine Hong Kong Baptist UniversityHong Kong 999077China 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 Department of Pharmacological and Pharmaceutical Sciences University of HoustonHoustonTX 77204USA

Acidosis,regardless of hypoxia involvement,is recognized as a chronic and harsh tumor microenvironment(TME)that educates malignant cells to thrive and *** overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression,the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical ***,chemical-induced and transgenic mouse models for colon,liver and lung cancer were established,***-7 and TGF-β2 expressions were examined in clinical tissues(n=184).RNA-seq,miRNA-seq,proteomics,biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer *** data show that lung cancer is sensitive to the increased acidification of TME,and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5 ***-β2 is a direct target of miR-7-5 *** reduced expression of miR-7-5 p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung ***,overexpression of miR-7-5 p reduces the acidic p H-enhanced lung cancer ***,the human lung tumor samples also show a reduced miR-7-5 p expression but an elevated level of activated TGF-β2;the expressions of both miR-7-5 p and TGF-β2 are correlated with patients’*** are the first to identify the role of the miR-7/TGF-β2 axis in acidic p H-enhanced lung cancer *** study not only delineates how acidification directly affects tumorigenesis,but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer(NSCLC)*** study opens an avenue to explore the p H-sensitive subcellular components as novel therapeutic targets for cancer treatment.

关键词： Acidic tumor microenvironment miR-7-5p TGF-β2 Metastasis Lung cancer pH Invasion

Traditional Chinese Medicine as a Treatment for Rheumatoid Arthritis:From Empirical Practice to Evidence-Based Therapy

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Engineering 2019年第5期5卷 895-906页

作者： Hu-Dan Pan Yao Xiao Wan-Ying Wang Ru-Tong Ren elaine lai-han leung Liang Liu State Key Laboratory of Quality Research in Chinese Medicine Macao Institute for Applied Research in Medicine and HealthMacao University of Science and TechnologyMacaoChina State Key Laboratory of Respiratory Disease Guangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China Department of Respiratory and Critical Care Medicine Affiliated Taihe Hospital of Hubei University of MedicineHubei 442000China

Rheumatoid arthritis(RA)is a common autoimmune condition with an elusive *** and biological disease-modifying drugs sometimes fail or produce only partial *** Chinese medicine(TCM)has long been used in China as a treatment for RA and is achieving everincreasing acceptance *** treatments are traditionally guided by the theory of treatment based on TCM syndrome differentiation;however,they remain a matter of empirical practice relying on TCM theories and doctors’own experience,which places severe restrictions on worldwide TCM ***,TCM is a treasure trove for drug discovery,particularly as a treatment for complicated human *** discoveries of artemisinin as a treatment for malaria and of TCM–arsenic trioxide(As2O3)combination therapy as a treatment for acute promyelocytic leukemia(APL)are excellent examples of the great value of *** RA treatments,many Chinese medicinal herbs and their formulas,extracts,ingredients,and even single compounds have been used in clinical *** Chinese proprietary medicines(CPMs)derived from TCM formulas or herbal bioactive components,such as the controlled-release ZhengQingFengTongNing(ZQFTN)Tablets,Tripterygium Glycoside Tablets,and Total Glucosides of Peony(TGP)Capsules,have been included in the National Health Insurance Directory of China,and show comparable therapeutic efficacies to those of western chemical drugs with fewer side *** TCM research has advanced,particularly in the use of multidisciplinary technologies,the scientific foundations and characteristics of the use of TCM to treat RA have been revealed,and the quality of TCM treatments have been increasingly ***,TCM generally lacks sufficient clinical and laboratory data to be consistent with international standards for quality,safety,and efficacy in order to support its application ***,intensive basic and clinical studies on TCM are required.I

关键词： Traditional Chinese medicine Rheumatoid arthritis Evidence-based therapy Perspective

Compound C620-0696,a new potent inhibitor targeting BPTF,the chromatin-remodeling factor in non-small-cell lung cancer

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Frontiers of Medicine 2020年第1期14卷 60-67,F0004页

作者： Jiahui Xu Qianqian Wang elaine lai han leung Ying Li Xingxing Fan Qibiao Wu Xiaojun Yao Liang Liu State Key Laboratory of Quality Research in Chinese Medicine Macao Institute for Applied Research in Medicine and HealthMacao University of Science and TechnologyMacao(SAR)519020China Respiratory Medicine Department Taihe HospitalHubei University of MedicineShiyan 236600China Department of Thoracic Surgery Guangzhou Institute of Respiratory Health and State Key Laboratory of Respiratory DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510182China

Bromodomain PHD-finger transcription factor(BPTF)is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or *** is also involved in oncogene transcription in diverse progressions of *** clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers,no potent and selective inhibitor targeting the BPTF bromodomain has been *** this study,we identified a potential inhibitor,namely,C620-0696,by computational docking modeling to target *** of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF ***,C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer(NSCLC)*** suppressed the expression of the BPTF target gene c-MYC,which is known as an oncogenic transcriptional regulator in various cancers.C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle ***,our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules,supporting further exploration of the use of these inhibitors in oncology.

关键词： BPTF small molecule epigenetics non-small-cell lung cancer

Curcumenol triggered ferroptosis in lung cancer cells via lncRNA H19/miR-19b-3p/FTH1 axis

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Bioactive Materials 2022年第7期7卷 23-36页

作者： Ruonan Zhang Ting Pan Yu Xiang Mingming Zhang han Xie Zimao Liang Bi Chen Cong Xu Jing Wang Xingxing Huang Qianru Zhu Ziming Zhao Quan Gao Chengyong Wen Wencheng Liu Weirui Ma Jiao Feng Xueni Sun Ting Duan elaine lai-han leung Tian Xie Qibiao Wu Xinbing Sui State Key Laboratory of Quality Research in Chinese Medicines Faculty of Chinese MedicineMacao University of Science and TechnologyMacao School of Pharmacy and Department of Medical Oncology The Affiliated Hospital of Hangzhou Normal UniversitySchool of MedicineHangzhou Normal UniversityHangzhou311121ZhejiangChina Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines China Engineering Laboratory of Development and Application of Traditional Chinese Medicines China Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province Hangzhou Normal UniversityHangzhou311121ZhejiangChina Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health Guangzhou510006China

Curcumenol,an effective ingredient of Wenyujin,has been reported that exerted its antitumor potential in a few cancer ***,the effect and molecular mechanism of curcumenol in lung cancer are largely ***,we found that curcumenol induced cell death and suppressed cell proliferation in lung cancer ***,we demonstrated that ferroptosis was the predominant method that contributed to curcumenol-induced cell death of lung cancer in vitro and vivo for the first ***,using RNA sequencing,we found that the long non-coding RNA H19(lncRNA H19)was significantly downregulated in lung cancer cells treated with curcumenol,when compared to untreated *** of lncRNA H19 eliminated the anticancer effect of curcumenol,while lncRNA H19 knockdown promoted ferroptosis induced by curcumenol ***,we showed that lncRNA H19 functioned as a competing endogenous RNA to bind to miR-19b-3p,thereby enhanced the transcription activity of its endogenous target,ferritin heavy chain 1(FTH1),a marker of *** conclusion,our data show that the natural product curcumenol exerted its antitumor effects on lung cancer by triggering ferroptosis,and the lncRNA H19/miR-19b-3p/FTH1 axis plays an essential role in curcumenol-induced ferroptotic cell ***,our findings will hopefully provide a valuable drug for treating lung cancer patients.

关键词： Curcumenol Ferroptosis Lung cancer lncRNA H19 miRNA-19b-3p FTH1