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Profiling the mid-adult cecal microbiota associated with host healthy by using herbal formula Kang Shuai Lao Pian treated mid-adult mice

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Chinese Journal of Natural Medicines 2020年第2期18卷 90-102页

作者： GONG Shu-Qing YE Ting-Ting WANG Mei-Xia HONG Zhu-Ping LIU Li CHEN Huan QIAN Jing pharmaceutical Informatics Institute College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China key laboratory of Microbial technology and Bioinformatics of Zhejiang Province NMPA Key laboratory for Testing and Risk Warning of Pharmaceutical MicrobiologyZhejiang Institute of MicrobiologyHangzhou 310012China Technical Center Chiatai Qingchunbao Pharmaceutical Co.Ltd.Hangzhou 310023China

With the occurrence of aging process,decreased neuron dopamine,disrupted brown adipose tissue(BAT)remodeling and decreased butyrate level all reflect a weak host healthy in certain degree.Nevertheless,the signs of mid-adult gut microbiota,and its association with host healthy are not well understood.In current study,we deemed to illustrate the associations of age,neuron dopamine,BAT remodeling,butyrate and gut microbiota with the aid of traditional herbal formula Kang Shuai Lao Pian(KSLP),which is known for its anti-aging effect.Here,ELISA was performed to detect the production of brain dopamine,the mass of inguinal white adipose tissue versus interscapular brown adipose tissue(iWAT/iBAT)was calculated and considered as a sign of BAT remodeling,16 S rRNA gene sequencing was used to the detection of gut microbiota profiling and gas chromatography was used to measure the butyrate level in mice feces.Our results indicated mid-adult mice already present distinctive gut microbiota profiling compared with young mice,concomitant with which are the lower brain dopamine level and disrupted brown adipose remodeling.KSLP treatment improved the host healthy and regulated gut microbiota with enriched Firmicutes at the expense of Bacteroidetes,particularly increased the relative abundance of bacteria functionally related to dopamine and butyrate productions,which suggest KSLP treatment constructs a healthier gut environment.In conclusion,modulation of gut microbiota and butyrate may connectively regulate dopamine production and BAT remodeling through gut-brain axis and gut-metabolism axis.

关键词： Mid-adult Gut microbiota Host health Gut-brain axis Gut-metabolism axis

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一个新的感应铜离子的双组分信号转导系统

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Science Bulletin 2022年第2期67卷 198-212,M0004页

作者：余梁曹荞陈未中杨娜娜杨财广季泉江吴敏 Taeok Bae 蓝乐夫 University of Chinese Academy of Sciences Beijing 100049China State key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Physical Science and technology ShanghaiTech UniversityShanghai 201210China Department of Biomedical Sciences University of North DakotaGrand Forks ND 58203-9037USA Department of microbiology and Immunology Indiana University School of Medicine-NorthwestGary IN 46408USA School of pharmaceutical Science and technology Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China NMPA Key Laboratory for Testing Technology of Pharmaceutical Microbiology Shanghai Institute for Food and Drug ControlShanghai 201203China

铜是生物体所必需的一种微量元素,但过量的铜会产生毒性.在感染宿主的过程中,病原菌需感知外界铜离子(浓度)的变化来调节体内相关基因表达以维持自身生存.本文利用铜绿假单胞菌为研究模型,揭示了一个新的感应铜离子的双组分信号转导系... 详细信息

铜是生物体所必需的一种微量元素,但过量的铜会产生毒性.在感染宿主的过程中,病原菌需感知外界铜离子(浓度)的变化来调节体内相关基因表达以维持自身生存.本文利用铜绿假单胞菌为研究模型,揭示了一个新的感应铜离子的双组分信号转导系统并命名其为DsbRS.在缺乏铜胁迫的生长条件下,双组分信号转导系统DsbRS中的组氨酸蛋白激酶DsbS具磷酸酯酶活性,抑制了应答调控蛋白DsbR的磷酸化激活.在铜胁迫的生长环境下,铜离子与DsbS的周质空间区域结合,导致DsbR的转录调节活性升高,极可能是由于DsbS的磷酸酯酶活性受到抑制所致.磷酸化的DsbR直接结合到dsbDEG操纵子(编码催化蛋白质二硫键形成的Dsb家族蛋白)的启动子区域并激活dsbDEG的表达来抵抗铜的毒性. DsbRS基因和dsbDEG的同源基因簇,以及相应的DsbR结合位点TTA-N8-TTAA,在细菌界中广泛分布.这些研究结果表明DsbRS对Dsb基因的转录调控是细菌应答铜胁迫的一种新的机制,为有效利用铜制剂抗细菌感染提供了新的切入点.

关键词：抗细菌感染感染宿主铜绿假单胞菌磷酸酯酶铜离子铜制剂双组分信号转导系统二硫键形成

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Dendrobium officinale Kimura et Migo and American ginseng mixture: A Chinese herbal formulation for gut microbiota modulation

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Chinese Journal of Natural Medicines 2020年第6期18卷 446-459页

作者： LIU Cheng-Zhi CHEN Wei WANG Mei-Xia WANG Ying CHEN Li-Qing ZHAO Feng SHI Ya LIU Hui-Jun DOU Xiao-Bing LIU Chao CHEN Huan key laboratory of Microbial technology and Bioinformatics of Zhejiang Province Zhejiang Institute of MicrobiologyHangzhou 310012China nmpa key laboratory for testing and Risk Warning of pharmaceutical microbiology Zhejiang Institute of MicrobiologyHangzhou 310012China Hangzhou Huqing yu tang Traditional Chinese Medicine Mordernize Institute Hangzhou 311100China College of Life Science Zhejiang Chinese Medical UniversityHangzhou 310053China Department of Orthopaedics Sir Sun Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhou 310009China

Dendrobium officinale Kimura et Migo(D. officinale) is a famous traditional Chinese medicine(TCM). A mixture of D. officinale and American ginseng has been shown to enhance cell-mediated immunity, humoral immunity, and monocyte/macrophage functions in mice. Here, the effects of a D. officinale and American ginseng mixture on the structure of gut microbial community in dogs were examined using high-throughput 16S rRNA gene amplicon sequencing. The data revealed that while the mixture did not change the diversity of gut microbial community significantly, differences among individuals were significantly reduced. Furthermore, the mixture-responsive operational taxonomic units(OTUs) exhibited a phase-dependent expression pattern. Fifty-five OTUs were found to exhibit a mixture-induced expression pattern, among which one third were short-chain fatty acid(SCFA)-producing genera and the others were probiotic genera included Lactobacillus spp., Sutterella, Alistipes, Anaerovorax, Bilophila, Coprococcus, Gordonibacter, Oscillibacter, among others. By contrast, 36% of the OTUs exhibiting a mixture-repressed expression pattern were disease-associated microorganisms, and six genera, namely Actinomyces, Escherichia/Shigella, Fusobacterium, Slackia, Streptococcus and Solobacterium, were associated with cancer. In addition, five genera were closely associated with diabetes, namely Collinsella,Rothia, Howardella, Slackia and Intestinibacter. Our results indicate that this D. officinale and American ginseng mixture may be used as a prebiotic agent to enhance SCFA-producing genera and prevent gut dysbiosis.

关键词： Dendrobium officinale American Ginseng Gut Microbiota 16S rRNA

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Bimetallic nanoparticles as cascade sensitizing amplifiers for low-dose and robust cancer radio-immunotherapy

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1787-1800页

作者： Yupeng Wang Lina Wang Tao Li Min Ouyang Hejian Xiong Dongfang Zhou Department of Ultrasonic Diagnosis Zhujiang HospitalKey Laboratory of Mental Health of the Ministry of EducationNMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China testing and Analysis Center Hebei Normal UniversityShijiazhuang 050024China Department of Mechanical Engineering The University of Texas at DallasRichardsonTX 75080USA

Radiotherapy(RT)is one of the most feasible and routinely used therapeutic modalities for treating malignant tumors.In particular,immune responses triggered by RT,known as radio-immunotherapy,can partially inhibit the growth of distantly spreading tumors and recurrent tumors.How-ever,the safety and efficacy of radio-immunotherapy is impeded by the radio-resistance and poor immu-nogenicity of tumor.Herein,we report oxaliplatin(IV)-iron bimetallic nanoparticles(OXA/Fe NPs)as cascade sensitizing amplifiers for low-dose and robust radio-immunotherapy.The OXA/Fe NPs exhibit tumor-specific accumulation and activation of OXA(I)and Fe^(2+)in response to the reductive and acidic microenvironment within tumor cells.The cascade reactions of the released metallic drugs can sensitize RT by inducing DNA damage,increasing ROS and O_(2) levels,and amplifying the immunogenic cell death(ICD)effect after RT to facilitate potent immune activation.As a result,OXA/Fe NPs-based low-dose RT triggered a robust immune response and inhibited the distant and metastatic tumors effectively by a strong abscopal effect.Moreover,a long-term immunological memory effect to protect mice from tumor rechal-lenging is observed.Overall,the bimetallic NPs-based cascade sensitizing amplifier system offers an effi-cient radio-immunotherapy regimen that addresses the key challenges.

关键词： Bimetallic nanoparticles Radio-immunotherapy Cascade sensitizing amplifier,Oxaliplatin Fenton-typeHaber-Weiss reaction Radiosensitization Immunogenic cell death Radio-resistance

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Bautype: Capsule and Lipopolysaccharide Serotype Prediction for Acinetobacter baumannii Genome

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Infectious Microbes & Diseases 2020年第1期2卷 18-25页

作者： Xiaoting Hua Qian Liang Li Fang Jintao He Meixia Wang Wenjie Hong Sebastian Leptihn Hengliang Wang Yunsong Yu Huan Chen Department of Infectious Diseases Sir Run Run Shaw HospitalCollege of MedicineZhejiang UniversityHangzhouChina key laboratory of Microbial technology and Bioinformatics of Zhejiang Province Zhejiang Institute of MicrobiologyHangzhou 310012China nmpa key laboratory for testing and Risk Warning of pharmaceutical microbiology Zhejiang Institute of MicrobiologyHangzhou 310012China Zhejiang University-University of Edinburgh Institute School of MedicineZhejiang UniversityHangzhouChina State key laboratory of Pathogens and Biosecurity Beijing Institute of BiotechnologyBeijingChina.

Acinetobacter baumannii has three clusters of genes for polysaccharide synthesis.Capsular polysaccharides and lipopolysaccharides are major virulence determinants in many Gram-negative bacteria,and play key roles in the overall fitness and virulence in A.baumannii,meanwhile poly-beta-1-6-N-acetylglucosamine was critical for biofilm formation.A variety of studies have been conducted which focused on the surveillance of antimicrobial resistance genes and clones in A.baumannii.However,a tool to perform serotype prediction in A.baumannii is still lacking.Here we present Bautype,a tool for whole genome sequencingbased K and O locus typing in A.baumannii.Using Bautype,users can upload and analyze the genome assembled in a web browser,with the results being displayed in a tabular or graphical format.We demonstrated the high accuracy of predicting K and O locus diversity using Bautype when analyzing more than 3000 A.baumannii genomes.Using our software,we were able to analyze K and O locus diversity among 593 genomes belonging to ST208(3 K and 8 O).These diverse loci can serve as epidemiological markers for Multi-drug Resistance(MDR)strain subtyping.We also identified 45 novel O locus types.Our findings highlight the importance in monitoring the capsule type and LOS of A.baumannii strains for which Bautype is a tailored clinical software.Bautype is available at http://***.

关键词： serotype LOS CPS Acinetobacter WGS

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铜绿假单胞菌利用HinK感知组胺并控制细菌的致病力

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Science Bulletin 2021年第11期66卷 1101-1118,M0004页

作者：王娅娅曹荞曹芹甘建华孙宁杨财广 Taeok Bae 吴敏蓝乐夫 State key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China College of Life Science Northwest UniversityXi'an 710069China University of Chinese Academy of Sciences Beijing 100049China State key laboratory of Genetic Engineering Shanghai Public Health Clinical CenterCollaborative Innovation Center of Genetics and DevelopmentSchool of Life SciencesFudan UniversityShanghai 201438China The State key laboratory of Chemical Biology and Drug Discovery Department of Applied Biology and Chemical TechnologyThe Hong Kong Polytechnic UniversityHong Kong 999077China School of pharmaceutical Science and technology Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China Department of microbiology and Immunology Indiana University School of Medicine-NorthwestGary IN 46408USA Department of Biomedical Sciences University of North DakotaGrand Forks ND 58203-9037USA NMPA Key Laboratory for Testing Technology of Pharmaceutical Microbiology Shanghai Institute for Food and Drug ControlShanghai 201203China

在感染过程中,细菌刺激宿主的免疫细胞产生和释放组胺.然而,细菌如何对组胺进行应答及其在细菌感染中的作用尚不清楚.本研究发现铜绿假单胞菌的转录调节因子HinK在细菌对组胺进行应答的过程中起着决定性的作用.HinK直接激活组胺摄取和... 详细信息

在感染过程中,细菌刺激宿主的免疫细胞产生和释放组胺.然而,细菌如何对组胺进行应答及其在细菌感染中的作用尚不清楚.本研究发现铜绿假单胞菌的转录调节因子HinK在细菌对组胺进行应答的过程中起着决定性的作用.HinK直接激活组胺摄取和代谢、铁获取及假单胞菌喹诺酮类信号生物合成等相关基因的表达.在含组胺的培养基中,HinK的转录激活活性受到强烈的诱导;进一步的研究发现组胺代谢物咪唑-4-乙酸与HinK结合从而激活HinK的转录调控活性.基于细菌感染动物模型,发现组胺可增强铜绿假单胞菌的致病能力,同时,HinK基因的缺失导致铜绿假单胞菌的致病能力显著下降.这些结果揭示了细菌利用宿主调节信号分子促进致病力的一种新机制.

关键词：铜绿假单胞菌调节信号细菌感染免疫细胞感染过程致病力转录调节因子致病能力

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On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1740-1754页

作者： Xiaoqing Liu Shuang Liang Xiao Sang Lili Chang Shunli Fu Han Yang Huizhen Yang Yongjun Liu Na Zhang Department of Pharmaceutics Key Laboratory of Chemical Biology(Ministry of Education)NMPA Key Laboratory for Technology Research and Evaluation of Drug ProductsSchool of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Cancer immunotherapy has become a promising strategy.However,the effectiveness of immunotherapy is restricted in"cold tumors"characterized with insufficient T cells intratumoral infiltration and failed T cells priming.Herein,an on-demand integrated nano-engager(JOT-Lip)was developed to convert cold tumors to hot via"increased DNA damage and dual immune checkpoint inhibition"strategy.JOT-Lip was engineered by co-loading oxaliplatin(Oxa)and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies(Tim-3 mAb)coupled on the liposomal surface by metalloproteinase-2(MMP-2)-sensitive linker.JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death(ICD)of Oxa,thus promoting T cells intratumoral infiltration.In addition,JQ1 inhibited PD-1/PD-L1 pathway,achieving dual immune checkpoint inhibition combining with Tim-3 mAb,thus effectively promoting T cells priming.It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns(DAMPs),but also enhanced T cells intratumoral infiltration and promoted T cell priming,which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects.Collectively,our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot,which holds great potential in clinical cancer chemoimmunotherapy.

关键词： Nano-engager Cold tumors Increased DNA damage Augmented immunogenic cell death Dual immune checkpoint inhibition BRD4 inhibition Differ-targeting delivery MMP-2 sensitive

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Application of Nano-Delivery Systems in Lymph Nodes for Tumor Immunotherapy

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Nano-Micro Letters 2023年第9期15卷 275-309页

作者： Yiming Xia Shunli Fu Qingping Ma Yongjun Liu Na Zhang Department of Pharmaceutics Key Laboratory of Chemical Biology(Ministry of Education)NMPA Key Laboratory for Technology Research and Evaluation of Drug ProductsSchool of Pharmaceutical SciencesCheeloo College of MedicineShandong University44 Wenhua Xi RoadJinan 250012ShandongPeople’s Republic of China

Immunotherapy has become a promising research“hotspot”in cancer treatment.“Soldier”immune cells are not uniform throughout the body;they accumulate mostly in the immune organs such as the spleen and lymph nodes(LNs),etc.The unique structure of LNs provides the microenvironment suitable for the survival,activation,and proliferation of multiple types of immune cells.LNs play an important role in both the initiation of adaptive immunity and the generation of durable anti-tumor responses.Antigens taken up by antigen-presenting cells in peripheral tissues need to migrate with lymphatic fluid to LNs to activate the lymphocytes therein.Meanwhile,the accumulation and retaining of many immune functional compounds in LNs enhance their efficacy significantly.Therefore,LNs have become a key target for tumor immunotherapy.Unfortunately,the nonspecific distribution of the immune drugs in vivo greatly limits the activation and proliferation of immune cells,which leads to unsatisfactory anti-tumor effects.The efficient nano-delivery system to LNs is an effective strategy to maximize the efficacy of immune drugs.Nano-delivery systems have shown beneficial in improving biodistribution and enhancing accumulation in lymphoid tissues,exhibiting powerful and promising prospects for achieving effective delivery to LNs.Herein,the physiological structure and the delivery barriers of LNs were summarized and the factors affecting LNs accumulation were discussed thoroughly.Moreover,developments in nano-delivery systems were reviewed and the transformation prospects of LNs targeting nanocarriers were summarized and discussed.

关键词： Cancer therapy Immunotherapy Lymph nodes Nano-delivery systems

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Natural polysaccharide-based smart CXCR4-targeted nano-system for magnified liver fibrosis therapy

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Chinese Chemical Letters 2024年第2期35卷 341-346页

作者： Liqiong Sun Xinping Luo Chenxi Zhou Zhanwei Zhou Minjie Sun College of Horticulture Nanjing Agricultural UniversityNanjing 210095China nmpa key laboratory for Research and Evaluation of pharmaceutical Preparations and Excipients State Key Laboratory of Natural MedicinesDepartment of PharmaceuticsChina Pharmaceutical UniversityNanjing 210009China

Activated hepatic stellate cells(aHSCs),the main source of extracellular matrix deposition,are key targets in liver fibrosis.However,no effective drug specific to aHSCs has been clinically applied due to poor drug delivery efficiency.Herein,we designed a CXC chemokine receptor 4(CXCR4)-targeted reactive oxygen species(ROS)-responsive platform AMD-Dex-ROS-responsive-sorafenib(ARS)based on natural polysaccharide and thioctic acid frame,which can deliver anti-fibrosis drug represented by sorafenib specifically to aHSCs on account of CXCR4 over-expression on aHSCs,and smartly disassemble via ROS-responsive thioketal rupture relying on high intracellular ROS in HSCs,realized on-demand drug release and effective liver fibrosis reversion.Notably,in this platform,the CXCR4 antagonist AMD3100 not only enhanced aHSCs targeting efficiency of sorafenib but also effectively magnified the aHSCs elimination of sorafenib by blocking stroma cell derived factor-1(SDF-1)/CXCR4-induced aHSCs protection,resulting in synergistic anti-fibrosis effect.The platform provided a new approach for drug delivery system design and liver fibrosis treatment.

关键词： Nanoparticle CXCR4 antagonism ROS-responsive Hepatic stellate cells Liver fibrosis

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Recent advances in droplet microfluidics for microbiology

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Chinese Chemical Letters 2022年第4期33卷 1729-1742页

作者： Ziyi He Hao Wu Xianghua Yan Wu Liu State key laboratory of Agricultural microbiology College of Veterinary MedicineHuazhong Agricultural UniversityWuhan430070China Interdisciplinary Sciences Institute Huazhong Agricultural UniversityWuhan 430070China State key laboratory of Agricultural microbiology College of Animal Sciences and TechnologyHuazhong Agricultural UniversityWuhan 430070China Hubei Hongshan laboratory Wuhan 430070China The Cooperative Innovation Center of Sustainable Pig Production Wuhan 430070China Hubei Provincial Engineering laboratory for Pig Precision Feeding and Feed Safety technology Wuhan 430070China Institute of pharmaceutical Analysis School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Advances in microbiology rely on innovations in technology. Droplet microfluidics, as a versatile and powerful technique that allows high-throughput generation and manipulation of subnanoliter volume droplets, has become an indispensable tool shifting experimental paradigms in microbiology. Droplet microfluidics has opened new avenues to various microbiological research, from resolving single-cell heterogeneity to investigating spatiotemporal dynamics of microbial communities, from precise quantitation of microbiota to systematic decipherment of microbial interactions, and from isolating rare and uncultured microbes to improving genetic engineered strains. In this review, we present recent advances of droplet microfluidics in various fields of microbiology: i) microbial cultivation, ii) microorganism detection and characterization, iii) antibiotic susceptibility testing, iv) microbial interactions, v) microbial biotechnology.We also provide our perspectives on the challenges and future directions for droplet microfluidic-based microbiology research.

关键词： Droplet microfluidics Microorganisms Antibiotic susceptibility testing Microbial interactions Microbial biotechnology

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