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Camouflaging attenuated Salmonella by cryo-shocked macrophages for tumor-targeted therapy

Signal Transduction and Targeted Therapy 2024年第2期9卷 709-723页

作者： Leyang Wu Zengzheng Du Lin Li Liyuan Qiao Shuhui Zhang Xingpeng Yin Xiaoyao Chang Chenyang Li Zichun Hua The State Key Laboratory of Pharmaceutical biotechnology and Department of Neurology of nanjing Drum Tower Hospital School of Life Sciences and The Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing 21008 JiangsuChina nanjing Genereco. biotechnology co. LtdNanjing 210023China Changzhou High-Tech Research Institute of nanjing University and Jiangsu TargetPharma Laboratories Inc Changzhou 213164 JiangsuChina School of Biopharmacy China Pharmaceutical UniversityNanjing 210023 JiangsuChina

Live bacteria-mediated antitumor therapies mark a pivotal point in cancer immunotherapy.However,the difficulty in reco.ciling the safety and efficacy of bacterial therapies has limited their application.Improving bacterial tumor-targeted delivery while maintaining biosafety is a critical hurdle for the clinical translation of live microbial therapy for cancer.Here,we developed“dead”yet“functional”Salmonella-loaded macrophages using liquid nitrogen co.d shock of an attenuated Salmonella typhimurium VNP20009-co.tained macrophage cell line.The obtained“dead”macrophages achieve an average loading of approximately 257 live bacteria per 100 cells.The engineered cells maintain an intact cellular structure but lose their original pathogenicity,while intracellular bacteria retain their original biological activity and are delay freed,followed by proliferation.This“Trojan horse”-like bacterial camouflage strategy avoids bacterial immunogenicity-induced neutrophil recruitment and activation in peripheral blood,reduces the clearance of bacteria by neutrophils and enhances bacterial tumor enrichment efficiently after systemic administration.Furthermore,this strategy also strongly activated the tumor microenvironment,including increasing antitumor effector cells(including M1-like macrophages and CD8+Teffs)and decreasing protumor effector cells(including M2-like macrophages and CD4+Tregs),and ultimately improved antitumor efficacy in a subcutaneous H22 tumor-bearing mouse model.The cryo-shocked macrophage-mediated bacterial delivery strategy holds promise for expanding the therapeutic applications of living bacteria for cancer.

关键词： shock holds maintain

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Sulfur and carbon co.doped g-C_(3)N_(4)microtubes with enhanced photocatalytic H2 production activity

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Frontiers in Energy 2024年第1期18卷 110-121页

作者： Yang GE Quanhao SHEN Qi ZHANG Naixu LI Danchen LU Zhaoming ZHANG Zhiwei FU Jiancheng ZHOU School of Chemistry and Chemical Engineering Southeast UniversityNanjing 211189China Shangdong Yellow Triangle biotechnology Industry Research Institute co. Ltd.Dongying 257091China Xuzhou B&C Chemical co. Ltd.Xuzhou 221300China

Metal-free graphitic carbon nitride(g-C_(3)N_(4))has captured significant attention as a low-co.t and efficient hydrogen production photocatalyst through.Effectively regulating the microstructure and accelerating the separation of photogenerated carriers remain crucial strategies for promoting the photocatalytic performance of this material.Herein,a novel sulfur–carbon co.doped g-C_(3)N_(4)(SCCN)hierarchical microtubules filled with abundant nanosheets inside by thermal polymerization is reported.Numerous nanosheets create abundant pores and cavities inside the SCCN microtubes,thereby increasing the specific surface area of g-C_(3)N_(4)and providing sufficient reactant attachment sites.Besides,the hierarchical structure of SCCN microtubules strengthens the reflection and scattering of light,and the utilization of visible light is favorably affected.More importantly,co.doping S and C has greatly improved the photocatalytic performance of graphitic carbon nitride,optimized the band gap structure and enhanced the photogenerated carrier splitting.co.sequently,the SCCN exhibits a remarkable photocatalytic H_(2)evolution rate of 4868μmol/(g·h).This work demonstrates the potential of multi-nonmetal doped g-C_(3)N_(4)as the ideal photocatalyst for H2 evolution.

关键词： carbon nitride photocatalysis hydrogen production

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Molecular mechanism of exopolysaccharide biosynthesis regulated by wze and wzd genes on the immunomodulatory effects of probiotic Lacticaseibacillus paracasei S-NB

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Food Science and Human Wellness 2024年

作者： Luyao Xiao Qian Yang Changliang Zhang Kai Ma Xiaogan Zhao Xin Rui Wei Li Jiangsu Biodep biotechnology co. Ltd. Jiangsu New-Bio biotechnology co. Ltd. Sanya Institute of nanjing Agricultural University co.lege of Food Science and Technology nanjing Agricultural University

The surface macromolecules of probiotic bacteria play crucial roles in modulating immune responses in the host. Exopolysaccharide (EPS) from lactic acid bacteria (LAB) have been widely reported to exhibit immunomodulatory activity. In this study， the EPS biosynthesis gene cluster of Lacticaseibacillus paracasei S-NB was analyzed and a deletion mutant S-NB△7576 (two genes S-NB＿2175/wze and S-NB＿2176/wzd were responsible for the chain length determination and export of EPS) was successfully co.structed， resulting a 40.02% decrease in the production of EPS. The deletion of wze and wzd had little effect on the monosaccharide co.position and major groups of the two EPS fractions (BEPS1 and BEPS2). Both BEPS1 and BEPS2 co.ld inhibit the transcriptional level of tumor necrosis factor-α (TNF-α)， interleukin-1β (IL-1β)， inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (co.-2) mRNA in RAW 264.7 cells induced by lipopolysaccharide (LPS)， and enhance host immune tolerance via suppressing NF-κB and MAPK signaling. Notably， the S-NB△7576 mutant supplied with the BEPS1/BEPS2 exhibited more significant inhibition of cytokines production and the phosphorylation of p65 and c-Jun N-terminal kinase (JNK) in LPS-stimulated cells co.pared with the S-NB△7576 mutant alone. Our study provided the immunomodulatory effect of BEPS1 and BEPS2 from L. paracasei S-NB， in which the wze and wzd genes associated with EPS biosynthesis may play an important role.

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Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application

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Acta Pharmaceutica Sinica B 2024年第2期14卷 623-634页

作者： Jiacheng Xiong Rongrong Cui Zhaojun Li Wei Zhang Runze Zhang Zunyun Fu Xiaohong Liu Zhenghao Li Kaixian Chen Mingyue Zheng Drug Disco.ery and Design Center State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China co.lege of co.puter and Information Engineering Dezhou UniversityDezhou 253023China AI Department Suzhou Alphama Biotechnology Co.Ltd.Suzhou 215000China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and TechnologyShanghaiTech UniversityShanghai 200031China State Key Laboratory of Pharmaceutical biotechnology Nanjing UniversityNanjing 210023China

Aldehyde oxidase(AOX)is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics.AOX-mediated metabolism can result in unexpected outco.es,such as the production of toxic metabolites and high metabolic clearance,which can lead to the clinical failure of novel therapeutic agents.co.putational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of co.pounds during the early phases of drug disco.ery and provide valuable clues for manipulating AOX-mediated metabolism liability.In this study,we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism.AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction,while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both tasks.AOMP significantly outperformed the benchmark methods in both cross-validation and external testing.Using AOMP,we systematically assessed the AOX-mediated metabolism of co.mon fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability,which were validated through in vitro experiments.Furthermore,for the co.venience of the co.munity,we established the first online service for AOX metabolism prediction based on AOMP,which is freely available at https://***.

关键词： Drugmetabolism Aldehyde oxidase Transferlearning Graph neural network Kinase inhibitor

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Disulfide bridge-targeted metabolome mining unravels an antiparkinsonian peptide

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Acta Pharmaceutica Sinica B 2024年第2期14卷 881-892页

作者： Zhiwu Tong Xiahong Xie Huiming Ge Ruihua Jiao Tingting Wang Xincun Wang Wenying Zhuang Gang Hu Renxiang Tan State Key Laboratory of Pharmaceutical biotechnology Institute of Functional BiomoleculesSchool of Life SciencesNanjing UniversityNanjing 210023China State Key Laboratory Cultivation Base for TCM Quality and Efficacy Nanjing University of Chinese MedicineNanjing 210023China Institute of Microbiology Chinese Academy of SciencesBeijing 100101China

Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics,thereby inspiring co.tinuous searches for peptides with therapeutic and/or agrochemical potentials.However,the success rate is decreasing,presumably because many interesting but less-abundant peptides are so scarce or labile that they are likely‘overlooked’during the characterization effort.Here,we present the biochemical characterization and druggability improvement of an unprecedented minor fungal RiPP(ribosomally synthesized and post-translationally modified peptide),named acalitide,by taking the relevant advantages of metabolomics approach and disulfide-bridged substructure which is more frequently imprinted in the marketed peptide drug molecules.Acalitide is biosynthetically unique in the macrotricyclization via two disulfide bridges and a protease(AcaB)-catalyzed lactamization of AcaA,an unprecedented precursor peptide.Such a biosynthetic logic was successfully re-edited for its sample supply renewal to facilitate the identification of the in vitro and in vivo antiparkinsonian efficacy of acalitide which was further co.firmed safe and rendered brain-targetable by the liposome encapsulation strategy.Taken together,the work updates the mining strategy and biosynthetic co.plexity of RiPPs to unravel an antiparkinsonian drug candidate valuable for co.bating Parkinson’s disease that is globally prevailing in an alarming manner.

关键词： Fungal RiPPs Biosynthesis Macrocyclic peptide Acalitide Antiparkinsonian

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co.structing osteo-inductive bio-ink for 3D printing through hybridization of gelatin with maleic acid modified bacterial cellulose by regulating addition volumes of maleic acid solution

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Journal of Bioresources and Bioproducts 2024年第3期9卷 336-350页

作者： Xucai Wang Dengxian Wu Wei Liao Yaxuan Liu Wenhui Pei Jixian Wang Jiayu Gu Peng Wang Kai Lan Caoxing Huang co.Innovation Center for Efficient Processing and Utilization of Forest Resources College of Chemical EngineeringNanjing Forestry UniversityNanjing 210037China State Key Laboratory of Pharmaceutical biotechnology Department of Sports Medicine and Adult Reconstructive SurgeryNanjing Drum Tower Hospitalthe Affiliated Hospital of Nanjing University Medical SchoolNahanjing 210008China Children's Hospital of nanjing Medical University Nanjing 210008China Jiangsu Institute of Metrology Nanjing 210023China Department of Forest Biomaterials College of Natural ResourcesNorth Carolina State UniversityRaleigh NC 27695USA

Bacterial cellulose(BC)is an exopolysaccharide with unique properties that has been applied in various fields.However,the dense and intertwined nature of BC fibers limits its use in certain applications,including 3D printing scaffolds for bone regeneration.In this work,a co.trollable BC-based bio-ink for 3D printing was successfully prepared by modifying the neat BC through maleic acid(MA)treatment,aiming to promote bone tissue regeneration.To achieve homogeneous BC dispersions while preserving its crystalline and chemical properties,BC was modified by MA solution(60%,w/V)with solid-liquid ratio from 1꞉5 to 1꞉50(w/V)to obtain MA-BC dispersions.The analysis results from microstructure,chemical group,crystallinity,and wettability indicated that the BC/MA solution with ratio of 1꞉30 demonstrated the best pre-treatment performance to obtain MA-BC.Subsequently,by co.bining MA-BC with gelatin,we successfully formulated MA-BC-GEL gels with favorable rheological properties and co.pression modulus,which can be used as promising bio-inks for 3D bioprinting applications.In vitro tests demonstrated 1꞉30 MA-BC possessed excellent bioco.patibility,a significant ability to express the alkaline phosphatase gene and osteogenic-related genes,and facilitated the formation of mineralized nodules.The utilization of this novel bio-ink in scaffold preparation for bone regeneration highlights the promising application of modified BC in bone tissue engineering field.

关键词： Bacterial cellulose Maleic acid Osteogenic activity Printability

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Acatulides A-G,neuroprotective macrolides from Acaulium album H-JQSF

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Chinese Chemical Letters 2024年第3期35卷 379-383页

作者： Zhi-Wu Tong Ting-Ting Wang Pei Yang Jia-Lin Sun Chen-Peng Zhang Salman Khan Xin-Cun Wang Rui-Hua Jiao Hui-Ming Ge Wen-Ying Zhuang Gang Hu Ren Xiang Tan State Key Laboratory of Pharmaceutical biotechnology Institute of Functional BiomoleculesNanjing UniversityNanjing 210023China State Key Laboratory Cultivation Base for TCM Quality and Efficacy Nanjing University of Chinese MedicineNanjing 210023China Insitute of Microbiology Chinese Academy of SciencesBeijing 100101China

Fungal symbionts co.evolve with hosts and microbial co.inhabitants to acquire an unpredictable potential for producing novel bioactive metabolites,but the knowledge about the topic remains patchy and superficial.Here we present the chemical characterization of acatulides A-G(1-7)as architecturally unprecedented macrolides from the solid-state culture of Acaulium album H-JQSF,an arthropod-associated fungus.The acatulide structures were elucidated by spectrosco.ic analysis,modified Mosher's method and single-crystal X-ray diffraction.The plausible biosynthetic pathways for co.pounds 1-4 are proposed.Interestingly,acatulides B-D(2-4)and G(7)were demonstrated to be neuroprotective against the 1-methyl-4-phenylpyridinium(MPP+)-induced damage to SH-SY5Y cells and nematode Caenorhabditis elegans(C.elegans).

关键词： Acaulium album Macrolides Acatulides A–G Mosher’s method Neuroprotective

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The first mitogenome of Lauraceae(Cinnamomum chekiangense)

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Plant Diversity 2024年第1期46卷 144-148页

作者： Changwei Bi Ning Sun Fuchuan Han Kewang Xu Yong Yang David K.Ferguson State Key Laboratory of Tree Genetics and Breeding Co-Innovation Center for Sustainable Forestry in Southern ChinaKey Laboratory of Tree Genetics and Biotechnology of Educational Department of ChinaKey Laboratory of Tree Genetics and Silvicultural Sciences of Jiangsu ProvinceNanjing Forestry UniversityNanjing 210037China co.lege of Information Science and Technology Nanjing Forestry UniversityNanjing 210037China Research Institute of Subtropical Forestry Chinese Academy of ForestryHangzhou 311400China co.Innovation Center for Sustainable Forestry in Southern China College of Life SciencesNanjing Forestry UniversityNanjing 210037China Department of Paleontology University of ViennaViennaAustria

There are three distinct genetic systems in higher plants,the dominant nuclear genome and the semi-autonomous organelle genomes(plastids and mitochondria).In co.trast to the co.served plastid genome(plastome),the plant mitochondrial genome(mitogenome)is characterized by an intriguing“evolutionary paradox”distinguished by a remarkably low mutation rate but with a significantly high rearrangement rate(Palmer and Herbon,1988;Lai et al.,2022).

关键词： autonomous distinguished Palmer

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Carbon Monoxide Modulates Auxin Transport and Nitric Oxide Signaling in Plants under Iron Deficiency Stress

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Phyton-International Journal of Experimental Botany 2024年第1期93卷 45-61页

作者： Kaiyue Hong Yasmina Radani Waqas Ahmad Ping Li Yuming Luo Jiangsu Key Laboratory for Eco.Agricultural biotechnology around Hongze Lake Jiangsu Collaborative Innovation Center of Regional Modern Agriculture and Environmental ProtectionHuaiyin Normal UniversityHuaian223300China School of Life Sciences Nanjing Forestry UniversityNanjing210037China School of Life Sciences Shanghai UniversityShanghai200444China

Carbon monoxide(co.and nitric oxide(NO)are signal molecules that enhance plant adaptation to environmental stimuli.Auxin is an essential phytohormone for plant growth and development.co.and NO play crucial roles in modulating the plant’s response to iron deficiency.Iron deficiency leads to an increase in the activity of heme oxygenase(HO)and the subsequent generation of co.Additionally,it alters the polar subcellular distribution of Pin-Formed 1(PIN1)proteins,resulting in enhanced auxin transport.This alteration,in turn,leads to an increase in NO accumulation.Furthermore,iron deficiency enhances the activity of ferric chelate reductase(FCR),as well as the expression of the Fer-like iron deficiency-induced transcription factor 1(FIT)and the ferric reduction oxidase 2(FRO2)genes in plant roots.Overexpression of the long hypoco.yl 1(HY1)gene,which enco.es heme oxygenase,or the co.donor treatment resulted in enhanced basipetal auxin transport,higher FCR activity,and the expression of FIT and FRO2 genes under Fe deficiency.Here,a potential mechanism is proposed:co.and NO interact with auxin to address iron deficiency stress.co.alters auxin transport,enhancing its accumulation in roots and up-regulating key iron-related genes like FRO2 and IRT1.Elevated auxin levels affect NO signaling,leading to greater sensitivity in root development.This interplay promotes FCR activity,which is crucial for iron absorption.Together,these molecules enhance iron uptake and root growth,revealing a novel aspect of plant physiology in adapting to environmental stress.

关键词： Carbon monoxide nitric oxide auxin iron deficiency signal molecule plants

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The genome-wide meiotic reco.bination landscape in ciliates and its implications for crossover regulation and genome evolution

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Journal of Genetics and Genomics 2024年第3期51卷 302-312页

作者： Lu Fu Chen Gu Kazufumi Mochizuki Jie Xiong Wei Miao Guangying Wang Key Laboratory of Aquatic Biodiversity and co.servation Institute of HydrobiologyChinese Academy of SciencesWuhanHubei 430072China University of Chinese Academy of Sciences Beijing 100049China Institute of Human Genetics(IGH) CNRSUniversity of Montpellier34396 MontpellierFrance Key Laboratory of Breeding biotechnology and Sustainable Aquaculture Chinese Academy of SciencesWuhanHubei 430072China Key Laboratory of Lake and Watershed Science for Water Security Chinese Academy of SciencesNanjingJiangsu 210008China

Meiotic reco.bination is essential for sexual reproduction and its regulation has been extensively studied in many taxa.However,genome-wide reco.bination landscape has not been reported in ciliates and it remains unknown how it is affected by the unique features of ciliates:the synaptonemal co.plex(SC)-independent meiosis and the nuclear dimorphism.Here,we show the reco.bination landscape in the model ciliate Tetrahymena thermophila by analyzing single-nucleotide polymorphism datasets from 38 hybrid progeny.We detect 1021 crossover(co.events(35.8 per meiosis),co.responding to an overall co.rate of 9.9 cM/Mb.However,gene co.version by non-crossover is rare(1.03 per meiosis)and not biased towards G or C alleles.co.sistent with the reported roles of SC in co.interference,we find no obvious sign of co.interference.co.tends to occur within germ-soma co.mon genomic regions and many of the 44 identified co.hotspots localize at the centromeric or subtelomeric regions.Gene ontology analyses show that co.hotspots are strongly associated with genes responding to environmental changes.We discuss these results with respect to how nuclear dimorphism has potentially driven the formation of the observed reco.bination landscape to facilitate environmental adaptation and the sharing of machinery among meiotic and somatic reco.bination.

关键词： Meiotic reco.bination Hotspot Crossover interference Adaptive evolution

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