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Probiotics modulate the microbiota-gut-brain axis and improve memory deficits in aged SAMP8 mice

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Acta Pharmaceutica Sinica B 2020年第3期10卷 475-487页

作者： Xueqin Yang Dongke Yu Li Xue Hui Li Junrong Du Department of Pharmacology Key Laboratory of Drug-Targeting and Drug Delivery System of the Education MinistrySichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu610041China Department of pharmacy Personalized Drug Therapy Key Laboratory of Sichuan Province Sichuan Academy of Medical Sciences&Sichuan Provincial People's HospitalChengdu610072China

ProBiotic-4 is a probiotic preparation composed of Bifidobacterium lactis,Lactobacillus casei,Bifidobacterium bifidum,and Lactobacillus *** study aims to investigate the effects of ProBiotic-4 on the microbiota-gut-brain axis and cognitive deficits,and to explore the underlying molecular mechanism using senescence-accelerated mouse prone 8(SAMP8)***-4 was orally administered to 9-month-old SAMP8 mice for 12 *** observed that ProBiotic-4 significantly improved the memory deficits,cerebral neuronal and synaptic injuries,glial activation,and microbiota composition in the feces and brains of aged SAMP8 ***-4 substantially attenuated aging-related disruption of the intestinal barrier and blood-brain barrier,decreased interleukin-6 and tumor necrosis factor-αat both mRNA and protein levels,reduced plasma and cerebral lipopolysaccharide(LPS)concentration,toll-like receptor 4(TLR4)expression,and nuclear factor-κB(NF-κB)nuclear translocation in the *** addition,not only did ProBiotic-4 significantly decreased the levels ofγ-H2 AX,8-hydroxydesoxyguanosine,and retinoic-acid-inducible gene-I(RIG-I),it also abrogated RIG-I multimerization in the *** findings suggest that targeting gut microbiota with probiotics may have a therapeutic potential for the deficits of the microbiota-gut-brain axis and cognitive function in aging,and that its mechanism is associated with inhibition of both TLR4-and RIG-I-mediated NF-κB signaling pathway and inflammatory responses.

关键词： Microbiota-gut-brain axis Cognitive decline TLR4 RIG-I NF-κB Probiotics SAMP8 mice

Synergistic Brønsted Base/Photoredox-Catalyzed Three-Component Coupling with Malonates to Synthesize δ-Hydroxy Esters and δ-Keto Esters

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Chinese Journal of Chemistry 2024年第9期42卷 957-962页

作者： Ting Li Wei Wang Ming Dong Zhije Zhang Sha Yu Zhengchu Chen Siping Wei Dong Yi Green Pharmaceutical Technology key laboratory of Luzhou City Central Nervous System Drug Key Laboratory of Sichuan ProvinceSchoolof PharmacySouthwestMedicalUniversityLuzhouSichuan 646000China Nuclear Medicine and molecular Imaging key laboratory of Sichuan Province LuzhouSichuan 646000China

Multicomponent alkene 1,2-dicarbofunctionalizations(DCFs)have emerged as a powerful strategy to rapidly incorporate both two carbon subunits across one C-C double bond in one step for enhancing molecular complexity and *** the best of our knowledge,there is only one report on photoredox-catalyzed three-component DCFs with malonates through the radical−radical cross-coupling,while photoredox-catalyzed radical-polar crossover(RPC)-type DCFs with malonates were still ***,we describe a redox-neutral RPC-type 1,2-dialkylation of styrenes with malonates and aldehydes through the synergistic Brønsted base/photoredox catalysis *** transition-metal-free strategy provides an efficient and clean approach to a broad variety ofδ-hydroxy esters and also features exceptionally mild conditions,wide compatibility of substrate scope and functional groups,and high atomic ***,three-component 1,2-alkylacylation from the same starting materials was achieved in one-pot manner through such RPC-type coupling and subsequent two-electron oxidation process,providing a set ofδ-keto esters of interest in pharmaceutical research.

关键词： Alkene difunctionalization Photoredox catalysis Malonates Radical reactions C-C coupling Synthetic methods Aldehydes Alkylation Multicomponentreactions

Developing macromolecular therapeutics:the future drug-of-choice

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Frontiers of Chemical Science and Engineering 2010年第1期4卷 10-17页

作者： Huining HE Weibing DONG Junbo GONG Jingkang WANG Victor C.YANG tianjin key laboratory for Modern drug Delivery and High Efficiency Tianjin UniversityTianjin 300072China State key laboratory of Chemical Engineering Tianjin UniversityTianjin 300072China School of Chemical Engineering Tianjin UniversityTianjin 300072China Department of Pharmaceutical Sciences College of PharmacyUniversity of Michigan428 Church StreetAnn ArborMI 48109-1065USA

Macromolecular drugs including peptides,proteins,antibodies,polysaccharides and nucleic acids have been widely used for therapy of major diseases such as carcinoma and AIDS as well as cardiovascular and neurodegenerative disorders among other medical *** to their unmatched properties of high selectivity and efficiency,macromolecular drugs have been recognized as the drug-of-choice of the *** worldwide progress on macromolecular therapeutics still remains in the infant stage and is therefore wide open for equalground competition,R&D related to macromolecular drugs should be considered as the main point of focus in China in setting up its strategic plans in pharmaceutical *** this article,research strategies and drug delivery approaches that should be adopted to enhance the therapeutic effects of macromolecular drugs are *** addition,comments concerning how to implement such strategies to excel from competition in this challenging research field,such as the design of innovative and highly effective delivery systems of macromolecular drugs with self-owned intellectual property rights,are provided.

关键词： macromolecular drugs drug delivery systems therapeutic efficacy

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 ***,the molecular mechanisms underlying its development are still *** 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 *** of MELK expression inhibits the migration and invasion of LUAD cells,which may be mediated by Twist1,Slug,MMP7,and *** of MELK promoted the growth of LUAD cells in medium,3D Matrigel,and nude *** of MELK by OTSSP167 arrested cycle of LUAD cells at G2/M phase via PLK1-CDC25C-CDK1 pathway,and triggered apoptosis-mediated ***,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

Nanomedicine integrating the lipidic derivative of 5-fluorouracil,miriplatin and PD-L1 si RNA for enhancing tumor therapy

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Chinese Chemical Letters 2024年第6期35卷 385-391页

作者： An Lu Yuhao Guo Yi Yan Lin Zhai Xiangyu Wang Weiran Cao Zijie Li Zhixia Zhao Yujie Shi Yuanjun Zhu Xiaoyan Liu Huining He Zhiyu Wang Jian-Cheng Wang Beijing key laboratory of molecular Pharmaceutics and New drug Delivery Systems State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China tianjin key laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics School of PharmacyTianjin Medical UniversityTianjin 300070China Department of Immuno-oncology The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011China Department of pharmacy Clinical Trial Research CenterChina-Japan Friendship HospitalBeijing 100029China laboratory of innovative formulations and pharmaceutical excipients Ningbo Institute of Marine MedicinePeking UniversityNingbo 315832China

Immunosuppressive microenvironments present critical problems in clinical *** regulate the tumor immune microenvironment for enhancing antitumor effect,a combination of immune checkpoint inhibitors(ICIs)with chemotherapeutics has been applied *** this study,miriplatin(MiPt),the lipidic derivative of 5-fluorouracil(Fu-OA),as well as the programmed death ligand 1(PD-L1)target si RNA(siPD-L1)were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles(NPs)for *** vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by ***,in vivo results revealed that LipPt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of Mi Pt,5-fluorouracil,and Lip@siPD-L1 NPs(delivery of siPD-L1 by liposomes).The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of Mi Pt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells,which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint *** Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.

关键词： Chemo-immunotherapy Immune checkpoint inhibition Gene silencing Miriplatin Macrophage phagocytosis Nanotechnology

Curcumin based combination therapy for anti-breast cancer： from in vitro drug screening to in vivo efficacy evaluation

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Frontiers of Chemical Science and Engineering 2016年第3期10卷 383-388页

作者： Sunhui Chen Qiuling Liang Shuping Xie Ergang Liu Zhili Yu Lu Sun Meong Cheol Shin Seung Jin Lee Huining He Victor C. Yang tianjin key laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics) School of Pharmacy Tianjin Medical University Tianjin 300070 China Collaborative Irmovation Center of Chemical Science and Chemical Engineering School of Chemical Engineering and Technology Tianjin University Tianjin 300072 China college of pharmacy and research Institute of Pharmaceutical Sciences Gyeongsang National University Jinjudaero Jinju Gyeongnam 660-751 Republic of Korea Department of pharmacy Ewha Womans University 11-1 Daehyun-dong Seodaemun-gu Seoul 120-750 Republic of Korea Department of Pharmaceutical Sciences College of Pharmacy University of Michigan Ann Arbor 48109-1065 MI USA Department of molecular Medicine and Biopharmaceutical Sciences Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy Seoul National University Seoul Republic of Korea

While drug resistance appears to be an inevitable problem of an increasing number of anticancer drugs in monotherapy, combination drug therapy has become a prosperous method to reduce the administered total drug dosages as well as overcome the drug resistance of carcinoma cells. Curcumin, considered to possess multi- faceted roles in cancer treatment according to its multiple anti-neoplastic mechanisms as a depressor of chemo- resistance, can significantly facilitate its anti-cancer functions and improve therapeutic effects via combination usage with a variety of other drugs with different reaction mechanisms. To explore this possibility, four anti-cancer chemotherapeutic agents that all possess a certain degree of drug resistance problems, including three tyrosine kinase inhibitors （erlotinib, sunitinib and sorafenib） that are acting on different cell pathways and a typical anticancer drug doxorubicin, were combined with curcumin individually to examine the synergistic anti-tumor effect both in vitro and in vivo. Results revealed that sunitinib combined with curcumin at the molar ratio of 0.46 yielded the most potent synergistic effect in vitro, and was therefore chosen for further animal evaluation. To further enhance the anti- cancer effect, bovine serum albumin （BSA） nanoparticles were utilized as a carrier to deliver the selected drug combination in situ. Preliminary in vivo findings confirmed our hypothesis of being able to maintain a similar injected drug ratio for prolonged time periods in tested animals by our approach, thereby maximizing the therapeutic potency yet minimizing the toxicity of these drugs. This work could open up a new avenue on combination drug therapy and realization the clinical utility of such drugs.

关键词： curcumin sunitinib synergistic effect bovine serum albumin (BSA) nano-carriers

Preparation of Magnetic Microsphere-Gold Nanoparticle- Immobilized Enzyme Batch Reactor and Its Application to Enzyme Inhibitor Screening in Natural Extracts by Capillary Electrophoresis

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Chinese Journal of Chemistry 2017年第6期35卷 943-948页

作者： Hengshan Wang Pingtan Lin Shulin Zhao Shuting Li Xin Lu Hong Liang State key laboratory for the Chemistry and molecular Engineering of Medicinal Resources College of Chemistry and Pharmacy Guangxi Normal University Guilin Guangxi 541004 China

A novel strategy for screening the enzyme inhibitors from the natural products by capillary electrophoresis （CE） with a pre column enzyme batch reactor prepared by magnetic microsphere （MB）-gold nanoparticles （AuNPs） is reported. The enzyme batch reactor was prepared by immobilizing the enzymes on the MB conjugated AuNPs （MB-AuNPs）. To demonstrate this strategy, xanthine oxidase （XOD） was employed as a model for the activity of the enzyme, inhibition study, and inhibitor screening. With the developed CE method, the enzyme activity was de- termined by the quantification of the peak area of the product. Enzyme inhibition can be read out directly from the reduced peak area of product in comparison to a reference electropherogram obtained in the absence of any inhibitor A statistical parameter Z＇ factor was recommended for evaluation of the accuracy of a drug screening system. In the present study, it was calculated to be 0.7, implying a good accuracy. The screening of two natural extracts from Cortex Phellodendri and Rhizoma Galangae showed that they were positive for XOD inhibition by the present method. Using this immobilized enzyme technology combined with CE separation not only provides the advantages such as convenience, rapidity and low cost, but also provides a new platform for discovering enzyme-inhibitor drug lead compounds.

关键词： capillary electrophoresis inhibitor screening enzyme reactor xanthine oxidase

Solvent-Regulated Diastereodivergent [3+2] Annulations of CF_(3)-Containing Morita-Baylis-Hillman Carbonates with Cyclic Sulfonimines

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Chinese Journal of Chemistry 2022年第10期40卷 1185-1189页

作者： Bao-xin Liu Ru-Jie Yan Wei Du Ying-Chun Chen key laboratory of drug-Targeting and drug Delivery System of the Education Ministry and Sichuan Province and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengduSichuan 610041China college of pharmacy Third Military Medical UniversityShapingbaChongqing 400038China

A solvent-regulated diastereodivergent[3+2]annulation reaction between Morita-Baylis-Hillman carbonates from aryl trifluoromethyl ketones and cyclic sulfonimines is developed under the catalysis of a modified cinchona alkaloid,furnishing diverse polycyclic products bearing vicinal quaternary stereogenic centers with outstanding enantioselectivity and moderate to high diastereoselectivity.

关键词： Diastereodivergent synthesis [3+2]annulation Trifluoromethyl group Lewis bases Solvent effects

The newly emerged SARS-Like coronavirus HCoV-EMC also has an “Achilles’ heel”: current effective inhibitor targeting a 3C-like protease

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Protein & Cell 2013年第4期4卷 248-250页

作者： Zhilin Ren Liming Yan Ning Zhang Yu Guo Cheng Yang Zhiyong Lou Zihe Rao college of pharmacy and State key laboratory of Medicinal Chemical Biology Nankai UniversityTianjin 300071China Structural Biology laboratory and MOE laboratory of Protein Science School of Medicine and Life ScienceTsinghua UniversityBeijing 100084China National laboratory of Macromolecules Institute of BiophysicsChinese Academy of ScienceBeijing 100101China Emerging Infection Disease Program High-throughput Molecular Drug Discovery CenterTianjin Joint Academy of Biomedicine and TechnologyTianjin 300457China

From the global outbreak of SARS-CoV caused infection disease in 2003,coronaviruses(CoVs)are known to be a great threat to the human ***,a new SARS-like coronavirus,human betacoronavirus 2c EMC/2012(HCoV-EMC),has been identified and the appearance of this new CoV raises concerns that a new spread of CoV may occurs in the *** solving the crystal structure of HCoV-EMC main protease with a wide-spectrum anti-CoV inhibitor N3,we confi rmed that that N3 blocks the function of HCoV-EMC main protease through a similar mechanism to other *** with the good pharmaceutical features,N3 is conceivable to be effective to HCoV-EMC and other CoVs appearing in the *** fi ndings make it convincing that CoVs will not be a threat to human health.

关键词： EMC SARS Together