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Inhibition of xanthine oxidase alleviated pancreatic necrosis via HIF-1α-regulated LDHA and NLRP3 signaling pathway in acute pancreatitis

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3591-3604页

作者： Juan Rong Chenxia Han Yan Huang Yiqin Wang Qi Qiu Manjiangcuo Wang Shisheng Wang Rui Wang Juqin Yang Xia Li Chenggong Hu Zhiyao Chen Lihui Deng Wei Huang Qing Xi Dan Du West China Center of Excellence for Pancreatitis Institute of Integrated Traditional Chinese and Western MedicineWest China Hospital/West China Medical SchoolSichuan UniversityChengdu 610041China State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Advanced Mass Spectrometry Center Research Core FacilityFrontiers Science Center for Disease-related Molecular NetworkWest China HospitalSichuan UniversityChengdu 610213China proteomics-Metabolomics Platform Research Core FacilityInstitutes for Systems GeneticsWest China HospitalSichuan UniversityChengdu 610093China Biobank West China HospitalSichuan UniversityChengdu 610093China West China School of Nursing Sichuan UniversityChengdu 610041China Department of Critical Care Medicine West China HospitalSichuan UniversityChengdu 610041China

Acute pancreatitis(AP)is a potentially fatal condition with no targeted treatment *** inhibiting xanthine oxidase(XO)in the treatment of AP has been studied in several experimental models and clinical trials,whether XO is a target of AP and what its the main mechanism of action is remains ***,we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger *** first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP *** also found that allopurinol and febuxostat,as purine-like and non-purine XO inhibitors,respectively,exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time ***,we observed that conditional Xdh overexpression aggravated pancreatic necrosis and *** mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha(HIF-1α)-regulated lactate dehydrogenase A(LDHA)and NOD-like receptor family pyrin domain containing 3(NLRP3)signaling pathways and reduced the enrichment of^(13)C_(6)-glucose to^(13)C_(3)-***,we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels,while pancreatic XO and urate were also increased in severe AP *** results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of severe AP by downregulating HIF-1α-mediated LDHA and NLRP3 signaling pathways.

关键词： Xanthine oxidase inhibitor Multi-omics HIF-1a Necrotizing acute pancreatitis Lactate Therapeutic target NLRP3 Metabolic flux

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Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

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Journal of Pharmaceutical Analysis 2024年第1期14卷 100-114页

作者： Sze Wan Hung Massimiliano Gaetani Yiran Li Zhouyurong Tan Xu Zheng Ruizhe Zhang Yang Ding Gene Chi Wai Man Tao Zhang Yi Song Yao Wang Jacqueline Pui Wah Chung Tak Hang Chan Roman A.Zubarev Chi Chiu Wang Department of Obstetrics&Gynaecology The Chinese University of Hong KongHong KongChina Division of Physiological Chemistry I Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSE 17177Sweden Chemical proteomics Core facility Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSE 17177Sweden Unit of Chemical proteomics Science for Life Laboratory(SciLifeLab)StockholmSE 17177Sweden Center for Reproductive Medicine Henan Key Laboratory of Reproduction and GeneticsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450003China Department of Chemistry McGill UniversityMontrealH3A2K6Canada Department of Pharmacological&Technological Chemistry I.M.Sechenov First Moscow State Medical UniversityMoscow119146Russia Reproduction and Development Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong KongChina School of Biomedical Sciences The Chinese University of Hong KongHong KongChina Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine The Chinese University of Hong KongHong KongChina

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the *** is a major pathophysiology in *** previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain *** this study,we demonstrated that oral ProEGCG can be effective in preventing and treating ***,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,*** simulation and BioLayer interferometry were used to confirm their binding *** results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)*** vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling ***,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

关键词： Molecular targets ProEGCG EGCG Angiogenesis Treatment Endometriosis

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Data-driven drug repositioning using olfactory omics profiles:challenges and perspectives in neurodegeneration

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Neural Regeneration Research 2025年第7期20卷 1997-1998页

作者： Paz Cartas-Cejudo Adriana Cortés Mercedes Lachén-Montes Elena Anaya-Cubero Joaquín Fernández-Irigoyen Enrique Santamaría Clinical Neuroproteomics Unit Proteomics PlatformNavarrabiomedHospitalario Universitario de Navarra(HUN)Universidad Pública de Navarra(UPNA)IdiSNANavarra Institute for Health ResearchPamplonaSpain

Data-driven drug repositioning using olfactory omics profiles-challenges and perspectives in neurodegeneration:Neurodegenerative diseases are characterized by progressive degeneration and loss of neuronal function in the central nervous *** diseases are often characterized as proteinopathies,which are disorders primarily driven by the aggregation or misfolding of specific amyloid proteins within cells,leading to their dysfunction and eventual *** the gain-of-function hypothesis related to the aggregation of these proteins,recently,an alternative hypothesis regarding the loss-of-function of the soluble monomeric proteins during the process of aggregation into amyloids is gaining *** last event is called proteinopenia and refers to conditions characterized by a deficiency or decrease in the levels of specific soluble proteins in the body(Ezzat et al.,2023).It has been demonstrated that levels of soluble proteins involved in neurodegenerative diseases are decreased.

关键词： diseases drug amyloid

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In Vivo Phosphorylation Site Mapping and Functional Characterization of Arabidopsis Phototropin 1

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Molecular Plant 2008年第1期1卷 178-194页

作者： Stuart Sullivan Catriona E. Thomson Douglas J. Lamont Matthew A. Jones John M. Christie Plant Science Group Division of Biochemistry and Molecular Biology. Institute of Biomedical and Life Sciences University of Glasgow. University Avenue. Glasgow Scotland UK fingerprints proteomics facility Post-Genomics and Molecular Interactions Centre. School of Life Sciences MSI/WTB/CIR Complex University of Dundee. Dundee Scotland UK

Phototropins （phot1 and phot2） are blue-light receptor kinases controlling a range of responses that optimize the photosynthetic efficiency of plants. Light sensing is mediated by two flavin-binding motifs, known as LOVl and LOV2, located within the N-terminal region of the protein. Photoexcitation via LOV2 leads to activation of the C-terminal kinase domain and consequently receptor autophosphorylation. However, knowledge of the in-vivo phosphorylation sites for Arabidopsis phototropins is lacking and has impeded progress in elucidating the functional significance of receptor phos- phorylation. We have purified photl from Arabidopsis and identified the in-vivo sites of receptor phosphorylation by liquid chromatography tandem mass spectrometry. Arabidopsis-derived photl binds flavin mononucleotide as chromophore and is phosphorylated at four major sites located upstream of LOV2 （Ser^58, Ser^85, Ser^350, and Ser^410）, three of which are induced by blue light. Nevertheless, structure-function analysis indicates that the biological activity of photl can be attributed to a modular unit comprising the LOV2-kinase region of the protein. Thus, peptide regions upstream of LOV2, including the sites of receptor phosphorylation identified here, do not appear to be important for receptor signaling. By contrast, these regions may be necessary for maximizing stomatal performance and possibly light-induced relocalization of photl.

关键词： Phototropins (phot1 and phot2) lavin-binding motifs

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proteomics analysis of coronary atherosclerotic heart disease with different Traditional Chinese Medicine syndrome types before and after percutaneous coronary intervention

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Journal of Traditional Chinese Medicine 2024年第3期44卷 554-563页

作者： WANG Zhibo LI Ying WANG Daoping MA Bo MIAO Lan REN Junguo LIU Jinghua LIU Jianxun Beijing Key Laboratory of Pharmacology of Chinese Materia Region Institute of Basic Medical SciencesXiyuan HospitalChina Academy of Chinese Medical SciencesNational Clinical Research Center of Cardiovascular Disease of Traditional Chinese MedicineBeijing 100000China the National Key facility for Crop Gene Resources and Genetic Improvement Institute of Crop ScienceChinese Academy of Agricultural ScienceBeijing 100098China Department of Cardiology Beijing Anzhen HospitalCapital Medical UniversityBeijing 100029China

OBJECTIVE: To investigate the underlying protein molecular mechanisms of "Qi stagnation and blood stasis syndrome"(QS) and "Qi deficiency and blood stasis syndrome"(QD), as two subtypes of coronary artery disease(CAD) in Traditional Chinese Medicine(TCM),following percutaneous coronary intervention(PCI).METHODS: In this study, a total of 227 CAD patients with QS and 211 CAD patients with QD were enrolled;all participants underwent PCI. Label-free quantification proteomics were employed to analyze the changes in serum in two subtypes of CAD patients before and 6 months after PCI, aiming to elucidate the intervention mechanism of PCI in treating CAD characterized by two different TCM ***: Biochemical analysis revealed significant changes in tumor necrosis factor-α, high density lipoprotein cholesterol, blood stasis clinical symptoms observation, and Gensini levels in both patient groups post-PCI;Proteomic analysis identified 79 and 95 differentially expressed proteins in the QS and QD patient groups, respectively, compared to their control *** C8 alpha chain, complement factor H,apolipoprotein H, apolipoprotein B, plasminogen,carbonic anhydrase 2, and complement factor Ⅰ were altered in both comparison groups. Furthermore,enrichment analysis demonstrated that cell adhesion and connectivity-related processes underwent changes in QS patients post-PCI, whereas lipid metabolism-related pathways, including the peroxisome proliferator-activated receptor signaling pathway and extracellular matrix receptor interaction, underwent changes in the QD *** protein-protein interaction network analysis further enriched 52 node proteins, including apolipoprotein B,lipoprotein(a), complement C5, apolipoprotein A4,complement C8 alpha chain, complement C8 beta chain,complement C8 gamma chain, apolipoprotein H,apolipoprotein A-Ⅱ, albumin, complement C4-B,apolipoprotein C3, among others. The functional network of these proteins is posited to contribute to

关键词： percutaneous coronary intervention proteomics peptide mapping coronary atherosclerotic heart disease Traditional Chinese Medicine syndrome

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Spatial analysis of the osteoarthritis microenvironment: techniques, insights, and applications

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Bone Research 2024年第1期12卷 1-19页

作者： Xiwei Fan Antonia Rujia Sun Reuben S.E.Young Isaac O.Afara Brett R.Hamilton Louis Jun Ye Ong Ross Crawford Indira Prasadam Centre for Biomedical Technologies Queensland University of TechnologyBrisbaneQLDAustralia School of Mechanical Medical&Process EngineeringQueensland University of TechnologyBrisbaneQLDAustralia Central Analytical Research facility Queensland University of TechnologyBrisbaneQLDAustralia Molecular Horizons University of WollongongWollongongNSWAustralia Department of Technical Physics University of Eastern FinlandKuopioFinland School of Electrical Engineering and Computer Science Faculty of EngineeringArchitecture and Information TechnologyUniversity of QueenslandBrisbaneQLDAustralia Centre for Microscopy and Microanalysis University of QueenslandBrisbaneQLDAustralia The Prince Charles Hospital BrisbaneQLDAustralia

Osteoarthritis(OA)is a debilitating degenerative disease affecting multiple joint tissues,including cartilage,bone,synovium,and adipose *** presents diverse clinical phenotypes and distinct molecular endotypes,including inflammatory,metabolic,mechanical,genetic,and synovial ***,innovative technologies are needed to support the development of effective diagnostic and precision therapeutic *** analysis of bulk OA tissue extracts has limitations due to technical constraints,causing challenges in the differentiation between various physiological and pathological phenotypes in joint *** issue has led to standardization difficulties and hindered the success of clinical *** insights into the spatial variations of the cellular and molecular structures in OA tissues,encompassing DNA,RNA,metabolites,and proteins,as well as their chemical properties,elemental composition,and mechanical attributes,can contribute to a more comprehensive understanding of the disease *** resolved biology enables biologists to investigate cells within the context of their tissue microenvironment,providing a more holistic view of cellular *** advances in innovative spatial biology techniques now allow intact tissue sections to be examined using various-omics lenses,such as genomics,transcriptomics,proteomics,and metabolomics,with spatial *** fusion of approaches provides researchers with critical insights into the molecular composition and functions of the cells and tissues at precise spatial ***,advanced imaging techniques,including high-resolution microscopy,hyperspectral imaging,and mass spectrometry imaging,enable the visualization and analysis of the spatial distribution of biomolecules,cells,and *** these molecular imaging outputs to conventional tissue histology can facilitate a more comprehensive characterization of disease *** review summarizes the rec

关键词： insight Spatial enable

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Implementation of Automated Sample Quality Control in Whole Exome Sequencing

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Journal of Life Sciences 2017年第6期11卷 261-268页

作者： Elisa Viering Jana Molitor Leslie Friedmann Jana Petersen Marie Beckhaus Stephan Wolf Agilent Technologies Inc. Waldbronn 76337 Germany DKFZ Genomics and proteomics Core facility High Throughput Sequencing Unit Heidelberg 69120 Germany

Aims： High-quality DNA as input material for a NGS （next-generation sequencing） workflow is essential for the successful preparation of a DNA library. Additionally, DNA quality has a strong impact on sequencing results. Therefore, it is important to include QC （quality control） steps to assess size, concentration, molarity, and integrity of the DNA during the workflow. Material and Methods： The WES （Whole Exome Sequencing） workflow at the Genomics and proteomics Core facility of DKFZ （the German Cancer Research Center） was performed with several QC steps： QC of the input material, QC of intermediate products during library preparation, and QC of final libraries. The Agilent 4200 TapeStation system, which offers automated sample processing, was used to evaluate quantity, size, molarity, and integrity of the samples. Key Findings： The Agilent Genomic DNA ScreenTape assay offers an unbiased genomic DNA integrity assessment, which enables protocol adaption for optimized library preparation, for example, selection of a suitable shearing protocol. Additionally, QC steps during library preparation such as evaluation of library size, concentration, and molarity ensure maximal sequencing output. Significance： The automated and fast high-throughput analysis of genomic DNA with the 4200 TapeStation system helps to save labor time and costs. Additionally, the easy-to-use system can be integrated as a QC tool into the NGS workflow to ensure successful library preparation. QC steps enable the confirmation of suitable library size and concentration for the workflow.

关键词： NGS FFPE (Formalin-fixed Paraffin-embedded) WES DIN (DNA Integrity Number) QC 4200 TapeStation system.

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Web Resources for Model Organism Studies

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Genomics, proteomics & Bioinformatics 2015年第1期13卷 64-68页

作者： Bixia Tang Yanqing Wang Junwei Zhu Wenming Zhao Core Genomic facility Beijing Institute of Genomics Chinese Academy of Sciences University of Chinese Academy of Sciences

An ever-growing number of resources on model organisms have emerged with the continued development of sequencing technologies. In this paper, we review 13 databases of model organisms, most of which are reported by the National Institutes of Health of the United States（NIH; http：//***/science/models/）. We provide a brief description for each database, as well as detail its data source and types, functions, tools, and availability of access. In addition,we also provide a quality assessment about these databases. Significantly, the organism databases instituted in the early 1990s––such as the Mouse Genome Database（MGD）, Saccharomyces Genome Database（SGD）, and Fly Base––have developed into what are now comprehensive, core authority resources. Furthermore, all of the databases mentioned here update continually according to user feedback and with advancing technologies.

关键词： Model organism Database Genome Bioinformatics Biology

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Analysis of the Arabidopsis Floral Proteome:Detection of over 2000 Proteins and Evidence for Posttranslational Modifications

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Journal of Integrative Plant Biology 2009年第2期51卷 207-223页

作者： Baomin Feng Lianchao Li Xiaofan Zhou Bruce Stanley Hong Ma Department of Biology the Pennsylvania State University University Park PA 16802 USA proteomics and Mass Spectrometry Core facility 003 Althouse Laboratory the Pennsylvania State University University Park PA 16802 USA The Intercollege Graduate Program in Cell and Developmental Biology the Huck Institutes of the Life Sciences the Pennsylvania State University University Park PA 16802 USA Section of Research Resources H093 the College of Medicine the Pennsylvania State University Hershey PA 17033 USA

The proteome of the Arabidopsis flower has not been extensively studied previously. Here, we report a proteomic analysis of the wild type Arabidopsis flower. Using both two-dimensional electrophoresis/mass spectrometry （2-DGEIMS） and multi-dimensional protein identification technology （MudPIT） approaches, we identified 2 446 proteins. Although a single experiment or analysis uncovered only a subset of the proteins we identified, a combination of multiple experiments and analyses facilitated the detection of a greater number of proteins. When proteins are grouped according to RNA expression levels revealed by microarray experiments, we found that proteins encoded by genes with relatively high levels of expression were detected with greater frequencies. On the other hand, at the level of the individual gene/protein, there was not a good correlation between protein spot intensity and microarray values. We also obtained strong evidence for post-translational modification from 2-DGE and MudPIT data. We detected proteins that are annotated to function in protein synthesis, folding, modification, and degradation, as well as the presence of regulatory proteins such as transcription factors and protein kinases. Finally, sequence and evolutionary analysis of genes for active methyl group metabolisms suggests that these genes are highly conserved. Our results allow the formulation of hypotheses regarding post-translational regulation of proteins in the flower, providing new understanding about Arabidopsis flower development and physiology.

关键词： Arabidopsis floral methylation multi-dimensional protein identification technology protein modification proteome.

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A novel expressed prostatic secretion(EPS)-urine metabolomic signature for the diagnosis of clinically significant prostate cancer

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Cancer Biology & Medicine 2021年第2期18卷 604-615页

作者： Denise Drago Annapaola Andolfo Ettore Mosca Alessandro Orro Luigi Nocera Vito Cucchiara MatteoBellone Francesco Montorsi Alberto Briganti ProMeFa Proteomics and Metabolomics FacilityCenter for Omics Sciences(COSR)IRCCS San Raffaele Scientific InstituteMilan 20132Italy Institute of Biomedical Technologies National Research Council(CNR)Milan 20090Italy Department of Urology and Division of Experimental Oncology Urological Research Institute(URI)IRCCS San Raffaele Scientific InstituteMilan 20132Italy Division of Immunology Transplantation and Infectious DiseasesIRCCS San Raffaele Scientific InstituteMilan 20132Italy

Objective:Significant efforts are currently being made to identify novel biomarkers for the diagnosis and risk stratification of prostate cancer(PCa).Metabolomics can be a very useful approach in biomarker discovery because metabolites are an important read-out of the disease when characterized in biological *** aimed to determine a metabolomic signature which can accurately distinguish men with clinically significant PCa from those affected by benign prostatic hyperplasia(BPH).Methods:We first performed untargeted metabolomics using ultrahigh-performance liquid chromatography tandem mass spectrometry on expressed prostatic secretion urine(EPS-urine)from 25 patients affected by BPH and 25 men with clinically significant PCa(defined as Gleason score≥3+4).Diagnosis was histologically confirmed after surgical *** EPS-urine metabolomic approach was then applied to a larger,prospective cohort of 92 consecutive patients undergoing multiparametric magnetic resonance imaging for clinical suspicion of PCa prior to ***:We established a novel metabolomic signature capable of accurately distinguishing PCa from benign tissue.A metabolomic signature was associated with clinically significant PCa in all subgroups of the Prostate Imaging Reporting and Data System(PI-RADS)classification(100%and 89.13%of accuracy when the PI-RADS was in range of 1–2 and 4–5,respectively,and 87.50%in the more critical cases when the PI-RADS was 3).Conclusions:A combination of metabolites and clinical variables can effectively help in identifying PCa patients that might be overlooked by current imaging *** from EPS-urine should help in defining the diagnostic pathway of PCa,thus improving PCa detection and decreasing the number of unnecessary prostate biopsies.

关键词： Prostate cancer EPS-urine metabolomics prediction diagnosis

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