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Tetramethylpyrazine analogue T-006 promotes clearance of alpha-synuclein by enhancing proteasome activity in Parkinson disease models

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中国药理学与毒理学杂志 2019年第9期33卷 658-659页

作者： ZHOU He-feng SHAO Min GUO Bao-jian LI Chu-wen LU Yu-cong YANG Xuan-jun LI Sheng-nan LI Hai-tao ZHU Qi ZHONG Han-bing WANG Yu-qiang ZHANG Zai-jun LU Jia-hong lee ming-yuen simon State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences University of MacaoMacao 999078China Department of Bioengineering Zhuhai Campus of Zunyi Medical CollegeZhuhai 519041China Institute of New Drug Research College of PharmacyJinan UniversityGuangzhou 510000China Department of Biology South University of Science and TechnologyShenzhen 518000China

OBJECTIVE To investigate the effects of T-006(tetramethylpyrazine derivative)in promotingα-Synuclein(α-Syn)degradation and evaluated the neuroprotective effects in cellular and animalα-Syn model of Parkinson disease(PD).METHODS The inducible PC12 cells overexpressingα-syn and the homozygous transgenic(Tg)mice expressing A53T humanα-syn were used to evaluate the neuroprotective effects of *** cellular study,MTT,Western blotting,proteasomal activity assay and qRT-PCR were applied to analyze the pharmacological effects and underlying mecha⁃*** gene knock-down and overexpression approaches were used to dissect the molecular signaling *** animal study,ten-month-old homozygousα-Syn Tg mice were treated with T-006(3 mg·kg-1)daily by gavage for four *** Western blotting,immunohistochemistry and behavioral tests were applied to determine the neuropatho⁃logical *** T-006 promoted the degradation of WT and mutantα-Syn in PC12α-Syn inducible cells via an ubiquitin-proteasome system(UPS)dependent and autophagy-lysosome pathway independent *** mecha⁃nism of action involved the upregulation of 20S proteasome subunit LMP7 expression,which leads to activation of the chymotrypsin-like proteasomal activity for protein ***,we demonstrated that T-006 activated PKA/Akt/mTOR pathway upstream for LMP 7 up-regulation and UPS ***,we illustrated that T-006 promoted both Triton-soluble and-insoluble forms ofα-syn and protected againstα-Syn-induced neurotoxicity in A53Tα-Syn Tg *** T-006 is a potent UPS activator which promotes the degradation of pathogenic proteinα-Syn in cellular and animal PD *** study thus high-lights the therapeutic potential of small molecular UPS activator like T-006 in the treatment of PD and related conditions.

关键词： α-synuclein degradation LMP7 proteasome activity Parkinson disease

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Structural and functional characterization of a novel ShK peptide and its analogue from zoanthids (corals)

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中国药理学与毒理学杂志 2018年第9期32卷 708-709页

作者： GONG Gui-yi LIAO Qi-wen Yu-chung TSE simon ming-yuen lee University of Macao Macao China South University of Science and Technology of China Shenzhen 518055 China

OBJECTIVE To identify and characterize a novel neuroprotective ShK peptide and its analogue originated from coral *** *** was collected and subjected to transcriptome sequencing at which further bioinformatics analysis had identified a unigene encoding a putative ShK protein candidate,named as ***1 and its rhodamine derivative(PcShK1-RhoB) were synthesized and tested for the neuroprotective effect in 6-OHDA induced Parkinson disease models in vitro and in ***,zebrafish larvae were co-exposed to 6-OHDA and various doses of the peptides;then,dopaminergic(DA) neurons immunoreactivity and locomotion behavior of the zebrafish larvae were ***,PC12 cells were cultured with 6-OHDA in the absence or presence of different concentrations of *** viability was determined by MTT assay while calcium flow in the PC12 cells was monitored by Fluo-4 fluorescent *** Compared with control group,6-OHDA treatment could lead to DA neurons loss and locomotion deficits in PD model of zebrafish larvae(P<0.01).Both PcS hK 1(2.5,5.0 and 7.5 μmol·L^(-1)) and PcS hK 1-RhoB(0.50 and 0.75 μmol·L^(-1)) were found to protect and restore dopaminergic neurons from6-OHDA mediated injury and locomotion deficiency in the PD zebrafish respectively(P<0.01).In addition,PcShK1(2.5 to 20.0 μmol·L^(-1)) and PcShK1-RhoB(0.6 to 2.5 μmol·L^(-1)) effectively prevented against 6-OHDA toxicity in PC12 cells(P<0.01).Further study revealed that they might exert their neuroprotective effects through regulating the calcium *** PcS hK 1 and PcS hK 1-RhoB show neuroprotective effects on 6-OHDA induced PD models,and the underlying protective mechanisms of these peptides probably involve calcium homeostasis regulation.

关键词： transcriptome coral P. caribaeoru neuroprotective zebrafish calcium homeostasis

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Paeoniflorin Promotes Angiogenesis in A Vascular Insufficiency Model of Zebrafish in vivo and in Human Umbilical Vein Endothelial Cells in vitro

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Chinese Journal of Integrative Medicine 2018年第7期24卷 494-501页

作者： XIN Qi-qi YANG Bin-rui ZHOU He-feng WANG Yan YI Bo-wen CONG Wei-hong lee simon ming-yuen CHEN Ke-ji Clinical Medical College Beijing University of Chinese Medicine State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao Laboratory of Cardiovascular Diseases Xiyuan Hospital China Academy of Chinese Medical Sciences Department of Pharmaceutical Preparation Xiyuan Hospital China Academy of Chinese Medical Sciences

Objective： To investigate the pro-angiogenic effects of paeoniflorin（PF） in a vascular insufficiency model of zebrafish and in human umbilical vein endothelial cells（HUVECs）. Methods： In vivo, the pro-angiogenic effects of PF were tested in a vascular insufficiency model in the Tg（fli-1：EGFP）y1 transgenic zebrafish. The 24 h post fertilization（hpf） embryos were pretreated with vascular endothelial growth factor（VEGF） receptor tyrosine kinase inhibitor Ⅱ（VRI） for 3 h to establish the vascular insufficiency model and then post-treated with PF for 24 h. The formation of intersegmental vessels（ISVs） was observed with a fluorescence microscope. The m RNA expression of fms-like tyrosine kinase-1（flt-1）, kinase insert domain receptor（kdr）, kinase insert domain receptor like（kdrl） and von Willebrand factor（v WF） were analyzed by real-time polymerase chain reaction（PCR）. In vitro, the pro-angiogenic effects of PF were observed in HUVECs in which cell proliferation, migration and tube formation were assessed. Results： PF（6.25–100 μmol/L） could rescue VRI-induced blood vessel loss in zebrafish and PF（25–100 μmol/L）, thereby restoring the m RNA expressions of flt-1, kdr, kdrl and v WF, which were down-regulated by VRI treatment. In addition, PF（0.001–0.03 μmol/L） could promote the proliferation of HUVECs while PF stimulated HUVECs migration at 1.0–10 μmol/L and tube formation at 0.3 μmol/L. Conclusion： PF could promote angiogenesis in a vascular insufficiency model of zebrafish in vivo and in HUVECs in vitro.

关键词： angiogenesis paeoniflorin zebrafish human umbilical vein endothelial cell

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In Vivo Screen Strategies for Discovering Bioactive Compounds Against Cerebrovascular and Neurodegenerative Diseases

In Vivo Screen Strategies for Discovering Bioactive Compound...

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第十四届全国中药和天然药物学术研讨会

作者： simon ming yuen lee University of Macau

＜正＞Cerebrovascular and neurodegenerative diseases are tightly associated with each others and are increasing harmful to our health and *** global disease projection indicates that the healthcare burden derived from these disease problems will continue to *** traditional Chinese medicines（CMs）have also been used to prevent and treat the multi-faceted diseases in China and other Asian *** herbs are potential rich

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Synergistic Effects of Chuanxiong-Chishao Herb-Pair on Promoting Angiogenesis at Network Pharmacological and Pharmacodynamic Levels

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Chinese Journal of Integrative Medicine 2017年第9期23卷 654-662页

作者： WANG Yan GUO Gang YANG Bin-rui XIN Qi-qi LIAO Qi-wen lee simon ming-yuen HU Yuan-jia CHEN Ke-ji CONG Wei-hong Clinical Medical College Beijing University of Chinese Medicine Laboratory of Cardiovascular Diseases Xiyuan Hospital China Academy of Chinese Medical Sciences State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao Department of Acupuncture and Moxibustion Qilu Hospital Affiliated to Shandong University

Objective： To investigate the synergistic effects of Chuanxiong-Chishao herb-pair （CCHP） on promoting angiogenesis in silico and in vivo. Methods： The mechanisms of action of an herb-pair, Chuanxiong- Chishao, were investigated using the network pharmacological and pharmacodynamic strategies involving computational drug target prediction and network analysis, and experimental validation. A set of network pharmacology methods were created to study the herbs in the context of targets and diseases networks, including prediction of target profiles and pharmacological actions of main active compounds in Chuanxiong and Chishao. Furthermore, the therapeutic effects and putative molecular mechanisms of Chuanxiong-Chishao actions were experimentally validated in a chemical-induced vascular insufficiency model of transgenic zebrafish in vivo. The mRNA expression of the predicted targets were further analyzed by real-time polymerase chain reaction （RT-PCR）. Results： The computational prediction results found that the compounds in Chuanxiong have antithrombotic, antihypertensive, antiarrhythmic, and antiatherosclerotic activities, which were closely related to protecting against hypoxic-ischemic encephalopathy, ischemic stroke, myocardial infarction and heart failure. In addition, compounds in Chishao were found to participate in anti-inflammatory effect and analgesics. Particularly, estrogen receptor α （ESR α） and hypoxia-inducible factor 1-α （HIF-1 α） were the most important potential protein targets in the predicted results. In vivo experimental validation showed that post-treatment of tetramethylpyrazine hydrochloride （TMpoHCI） and paeoniflorin （PF） promoted the regeneration of new blood vessels in zebrafish involving up-regulating ESR α mRNA expression. Co-treatment of TMP·HCI and PF could enhance the vessel sprouting in chemical-induced vascular insufficiency zebrafish at the optimal compatibility proportion of PF 10 μ mol/L with TMP·HCI 1 μ mol/L. Conclusions： The networ

关键词： tetramethylpyrazine paeoniflorin,angiogenesis network pharmacology

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Essential oil of Curcuma wenyujin induces apoptosis in human hepatoma cells

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World Journal of Gastroenterology 2008年第27期14卷 4309-4318页

作者： YU Xiao Feng-Qing Yang Shao-Ping Li Guang Hu simon ming-yuen lee Yi-Tao Wang State Drug Clinical Trial Agency Science & Technology Department Sichuan Provincial People's Hospital Sichuan Academy of Medical Science Chengdu 610072 Sichuan Province China Institute of Chinese Medical Sciences University of Macao Av. Padre Tomas Pereira S.J. Taipa Macao China Institute of Chinese Medicine the Chinese University of Hong Kong Hong Kong China

AIM: To investigate the effects of the essential oil of Curcuma wenyujin (CWO) on growth inhibition and on the induction of apoptosis in human HepG2 cancer cells. METHODS: The cytotoxic effect of drugs on HepG2 cells was measured by 3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyltetra-zolium bromide (MTT) assay. DNA fragmentation was visualized by agarose gel electrophoresis. Cell cycle and mitochondrial transmembrane potential (△Ψm) were determined by flow cytometry (FCM). Cytochrome C immunostaining was evaluated by fluorescence microscopy. Caspase-3 enzymatic activity was assayed by the cleavage of Ac-DEVD-R110. Cleaved PARP and active caspase-3 protein levels were measured by FCM using BD? CBA Human Apoptosis Kit. RESULTS: Treatment with CWO inhibited the growth of HepG2 cells in a dose-dependent manner, and the IC50 of CWO was approximately 70 μg/mL. CWO was found to inhibit the growth of HepG2 cells by inducing a cell cycle arrest at S/G2. DNA fragmentation was evidentlyobserved at 70 μg/mL after 72 h of treatment. During the process, cytosolic HepG2 cytochrome C staining showed a markedly stronger green fluorescence than in control cells in a dose-dependent fashion, and CWO also caused mitochondrial transmembrane depolarization. Furthermore, the results clearly demonstrated that both, activity of caspase-3 enzyme and protein levels of cleaved PARP, significantly increased in a dose- dependent manner after treatment with CWO. CONCLUSION: CWO exhibits an antiproliferative effect in HepG2 cells by inducing apoptosis. This growth inhibition is associated with cell cycle arrest, cytochrome C translocation, caspase 3 activation, Poly- ADP-ribose polymerase (PARP) degradation, and loss of mitochondrial membrane potential. This process involves a mitochondria-caspase dependent apoptosis pathway. As apoptosis is an important anti-cancer therapeutic target, these results suggest a potential of CWO as a chemotherapeutic agent.

关键词： Essential oil Curcuma wenyujin, Apoptosis HepG2 Caspase-3 Mitochondrial Cytochrome C Cleaved Poly-ADP-ribose polymerase

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3D-QSAR analysis of a new type of acetylcholinesterase inhibitors

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Science China(Life Sciences) 2007年第6期50卷 726-730页

作者： lee simon M. Y Institute of Chinese Medical Sciences University of Macao Av. Padre Tomas Pereira S. J. Taipa Macao China

Acetylcholinesterase (AChE) inhibitors are an important class of medicinal agents used for the treatment of Alzheimer’s disease. A screening model of AChE inhibitor was used to evaluate the inhibition of a series of phenyl pentenone derivatives. The assay result showed that some compounds displayed higher inhibitory effects. In order to study the relationship between the bioactivities; the structures, 26 compounds with phenyl pentenone scaffold were analyzed. A 3D-QSAR model was constructed using the method of comparative molecular field analysis (CoMFA). The results of cross-validated R[2]cv=0.629, non-cross-validated R[2]=0.972, SE=0.331,; F=72.41 indicate that the 3D-model possesses an ability to predict the activities of new inhibitors,; the CoMFA model would be useful for the future design of new AChE inhibitors.

关键词： acetylcholinesterase (AChE), comparative molecular field analysis (CoMFA), phenyl pentenone derivatives

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Non-occlusive mesenteric ischemia: Diagnostic challenges and perspectives in the era of artificial intelligence

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World Journal of Gastroenterology 2021年第26期27卷 4088-4103页

作者： simon Bourcier Julian Klug lee S Nguyen Department of Intensive Care Medicine University Hospital of GenevaGeneva 1201Switzerland Department of Internal Medicine Groupement Hospitalier de l’Ouest LémaniqueNyon 1260Switzerland Department of Intensive Care Medicine CMC Ambroise ParéNeuilly-sur-Seine 92200France

Acute mesenteric ischemia(AMI)is a severe condition associated with poor prognosis,ultimately leading to death due to multiorgan *** mechanisms may lead to AMI,and non-occlusive mesenteric ischemia(NOMI)represents a particular form of *** is prevalent in intensive care units in critically ill *** NOMI management,promptness and accuracy of diagnosis are paramount to achieve decisive treatment,but the last decades have been marked by failure to improve NOMI prognosis,due to lack of tools to detect this *** real-life diagnostic management relies on a combination of physical examination,several biomarkers,imaging,and endoscopy to detect the possibility of several grades of NOMI,research studies only focus on a few elements at a *** the era of artificial intelligence(AI),which can aggregate thousands of variables in complex longitudinal models,the prospect of achieving accurate diagnosis through machine-learning-based algorithms may be *** the following work,we bring you a state-of-the-art literature review regarding NOMI,its presentation,its mechanics,and the pitfalls of routine work-up diagnostic exams including biomarkers,imaging,and endoscopy,we raise the perspectives of new biomarker exams,and finally we discuss what AI may add to the field,after summarizing what this technique encompasses.

关键词： Mesenteric ischemia Biomarkers Critically ill Machine learning Artificial intelligence

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Command and Control Cities in Global Space-economy Before and after 2008 Geo-economic Transition

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Chinese Geographical Science 2012年第3期22卷 334-342页

作者： Ernest Ka Shing lee simon Xiaobin ZHAO Yang XIE International Center for China Development Studies & Department of Geography Faculty of Social Sciences the University of Hong Kong Hong Kong China Department for Rural Economic Development Research Center of the State Council Beijing 100010 China

The global economic downturn caused primarily by the US sub-prime mortgage crisis in 2007 engendered revenue loss of the multinational corporations. Existing studies have yet to depict the detrimental impacts on city＇s command and control functions induced by the sub-prime mortgage crisis together with its residual wave of global economic recession on the global spatial economy. Recent and previous studies have produced an ＇instant history＇ of the global spatial economy before the global economic downturn undermines the global economy in late 2008. How- ever, the waxes and wanes of major cities＇ command and control functions on the global economic arena before and after the outbreak of financial crisis and its associated geo-economic transitions are still poorly understood. This paper attempts to contribute a new set of customized data to update and fill in the gap in the literature with the investigation of the command and control functions of cities arotmd the world from 2005 to 2009. Particular attentions are paid to the time-space relationship of the geo-economic transition that can capture the recent historical images of the com- mand and control situation of different cities in the world.

关键词： global space-economy command and control cities geo-economic transition China

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One-pot combinatorial modification of the total tanshinones

One-pot combinatorial modification of the total tanshinones

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中国化学会第9届天然有机化学学术会议

作者：田海妍李金行 simon ming yuen lee 叶文才江仁望 Institute of Traditional Chinese Medicine and Natural Products College of PharmacyJinan University The State Key Laboratory for Quality Research in Chinese Medicine University of Macau

＜正＞Tanshinones are natural occurring abietane-type diterpenoid naphthoquinone,widely existing in Salvia species,possessing broad biological activities,such as antitumor and protection of cardiovascular and nerve *** of this kind of natural products were carried out worldwide in order to improve the water solubility and ***,most of these modification studies were focused on the abundant compounds,such as TanshinoneⅡA. In order to get the derivatives of both the major and minor tanshiones,we initiate a

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