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Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism

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Genes & Diseases 2022年第4期9卷 1129-1142页

作者： brendan p.norman Andrew S.Davison Juliette H.Hughes Hazel Sutherland peter J.M.Wilson Neil G.Berry Andrew T.Hughes Anna M.Milan Jonathan C.Jarvis norman B.Roberts Lakshminarayan R.Ranganath George Bou-Gharios James A.Gallagher Institute of Life Course and Medical Sciences University of LiverpoolWilliam Henry Duncan Building6 West Derby StreetLiverpoolL78TXUK Department of Clinical Biochemistry&Metabolic Medicine Liverpool Clinical LaboratoriesRoyal Liverpool University HospitalPrescot StreetLiverpoolL78XPUK School of Sport&Exercise Sciences Liverpool John Moores UniversityTom Reilly BuildingByrom StreetLiverpoolL33AFUK Department of Chemistry University of LiverpoolCrown StreetLiverpoolL697ZDUK

Alkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of active enzyme homogentisate 1,2-dioxygenase (HGD). The primary consequence of HGD deficiency is increased circulating homogentisic acid (HGA), the main agent in the pathology of AKU disease. Here we report the first metabolomic analysis of AKU homozygous Hgd knockout (Hgd−/−) mice to model the wider metabolic effects of Hgd deletion and the implication for AKU in humans. Untargeted metabolic profiling was performed on urine from Hgd−/− AKU (n = 15) and Hgd+/− non-AKU control (n = 14) mice by liquid chromatography high-resolution time-of-flight mass spectrometry (Experiment 1). The metabolites showing alteration in Hgd−/− were further investigated in AKU mice (n = 18) and patients from the UK National AKU Centre (n = 25) at baseline and after treatment with the HGA-lowering agent nitisinone (Experiment 2). A metabolic flux experiment was carried out after administration of 13C-labelled HGA to Hgd−/−(n = 4) and Hgd+/−(n = 4) mice (Experiment 3) to confirm direct association with HGA. Hgd−/− mice showed the expected increase in HGA, together with unexpected alterations in tyrosine, purine and TCA-cycle pathways. Metabolites with the greatest abundance increases in Hgd−/− were HGA and previously unreported sulfate and glucuronide HGA conjugates, these were decreased in mice and patients on nitisinone and shown to be products from HGA by the 13C-labelled HGA tracer. Our findings reveal that increased HGA in AKU undergoes further metabolism by mainly phase II biotransformations. The data advance our understanding of overall tyrosine metabolism, demonstrating how specific metabolic conditions can elucidate hitherto undiscovered pathways in biochemistry and metabolism.

关键词： Alkaptonuria Biotransformation Metabolism Metabolomics Mice

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Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal metastases

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World Journal of Gastroenterology 2014年第38期20卷 14018-14032页

作者： Reza Mirnezami brendan J Moran Kate Harvey Tom Cecil Kandiah Chandrakumaran norman Carr Faheez Mohamed Alexander H Mirnezami Section of Biosurgery and Surgical Technology Department of Surgery and CancerImperial College London10th Floor QEQM BuildingSt Mary’s Hospital National pseudomyxoma peritonei Centre Hampshire Hospitals Foundation Trust Somers Cancer Research Building University of Southampton Cancer Sciences DivisionSouthampton University Hospital NHS Trust

AIM: To systematically review the available evidence regarding cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IpC) for colorectal peritoneal metastases (CpM).

关键词： Colorectal cancer peritoneal metastasis Cytoreductive surgery Intraperitoneal chemotherapy Hyperthermic intraperitoneal chemotherapy

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Short-term nitisinone discontinuation of hereditary tyrosinemia type 1 mice causes metabolic alterations in glutathione metabolism/biosynthesis and multiple amino acid degradation pathways

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Genes & Diseases 2023年第5期10卷 1759-1762页

作者： Colemonts-Vroninks Haaike norman p.brendan Van Laere Sven Davison S.Andrew Marcélis Lionel Casimir Georges Goyens philippe Claes paul De Bundel Dimitri Martens Geert Ranganath Lakshminarayan Rao Vanhaecke Tamara Gallagher James A De Kock Joery Vrije Universiteit Brussel Liver Therapy&Evolution TeamIn Vitro Toxicology and Dermato-Cosmetology(IVTD)Research GroupFaculty of Medicine and PharmacyLaarbeeklaan 103Brussels B-1090Belgium Vrije Universiteit Brussel Experimental Pharmacology(EFAR)Research GroupFaculty of Medicine and PharmacyLaarbeeklaan 103Brussels B-1090Belgium University of Liverpool Dept.of Musculoskeletal&Ageing ScienceInstitute of Life Course&Medical SciencesLiverpool L78TXUnited Kingdom Vrije Universiteit Brussel Interfaculty Center Data Processing and StatisticsFaculty of Medicine and PharmacyLaarbeeklaan 103Brussels B-1090Belgium Liverpool University Hospitals NHS Foundation Trust Clinical Biochemistry and Metabolic MedicineLiverpool L35PSUnited Kingdom UniversitéLibre de Bruxelles Laboratoire de PédiatrieBrussels B-1050Belgium Vrije Universiteit Brussel In Vitro Liver Disease Modelling TeamIn Vitro Toxicology and Dermato-Cosmetology(IVTD)Research GroupFaculty of Medicine and PharmacyLaarbeeklaan 103Brussels B-1090Belgium AZ Delta General Hospital Department of Laboratory MedicineRoeselare 8800Belgium Ghent University Department of Biomolecular MedicineGhent 9052Belgium

Hereditary tyrosinemia type 1(HT1)is a life-threatening disease caused by the patient's inability to break down tyrosine due to loss-of-function mutations in the fumarylacetoacetate hydrolase(FAH)enzyme(Fig.S1).Currently,the only available life-saving treatment is nitisinone(NTBC).However,nitisinone therapy comes with debilitating side effects and requires a strict drug regime combined with a tyrosine-and phenylalanine-restricted ***,therapy adherence is often experienced as an additional *** this study,transcriptional profiling was conducted parallel to high-resolution metabolomics on,respectively,liver tissue and serum samples of Fah-deficient *** experimental workflow of our study is shown in Figure *** pathway analyses showed manifest activation of the NRF2-stress response,associated with hepatocellular damage and mainly driven by a markedly increased oxidative *** altered canonical pathways were primarily a downstream consequence of the ***,we observed an overall aminoacidemia and changes related to aminoacyl-tRNA biosynthesis,which postulates that short-term nitisinone discontinuation can already put the patient at risk for hepatocellular carcinoma ***,we did not only identify changes in numerous pathways,directly and indirectly,related to the metabolism of tyrosine and glutathione but also the presence of“side-chain”metabolites,such as y-glutamyl-and N-acetyl-coupled amino acids,indicating that non-directly related pathways like phase II biotransformation reactions are also affected.

关键词： continuation Figure hereditary

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Rapid,high-resolution detection of environmental change over continental scales from satellite data–the Earth Observation Data Cube

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International Journal of Digital Earth 2016年第1期9卷 106-111页

作者： Adam Lewis Leo Lymburner Matthew B.J.purss brendan Brooke Ben Evans Alex Ip Arnold G.Dekker James R.Irons Stuart Minchin norman Mueller Simon Oliver Dale Roberts Barbara Ryan Medhavy Thankappan Rob Woodcock Lesley Wyborn Geoscience Australia CanberraAustralia National Computational Infrastructure Australian National UniversityCanberraAustralia Commonwealth Scientific and Industrial Research Organisation CanberraAustralia NASA Goddard Space Flight Center GreenbeltMDUSA Research School of Finance Actuarial Studies and Applied StatisticsANUCanberraAustralia The Group on Earth Observations Secretariate GenevaSwitzerland

The effort and cost required to convert satellite Earth Observation(EO)data into meaningful geophysical variables has prevented the systematic analysis of all available *** overcome these problems,we utilise an integrated High performance Computing and Data environment to rapidly process,restructure and analyse the Australian Landsat data *** this approach,the EO data are assigned to a common grid framework that spans the full geospatial and temporal extent of the observations–the EO Data *** approach is pixel-based and incorporates geometric and spectral calibration and quality assurance of each Earth surface reflectance *** demonstrate the utility of the approach with rapid time-series mapping of surface water across the entire Australian continent using 27 years of continuous,25 m resolution *** preliminary analysis of the Landsat archive shows how the EO Data Cube can effectively liberate high-resolution EO data from their complex sensor-specific data structures and revolutionise our ability to measure environmental change.

关键词： Earth Observation Data Cube HpD HpC surface water Landsat Australia

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抓大鱼放大鱼无利渔业保护

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环球科学 2013年第4期 58-59页

作者：布伦丹·伯雷尔(brendan Borrell) 刘荣(翻译) 纽约艾丽西亚帕特森基金会不详

1913年4月的一天，在挪威渔村莫斯肯斯，白雪皑皑的群山看起来似乎从海面直插云霄，渔民约翰·诺曼（Johan norman）钓起一条雌性鳕鱼。他量了量这条鱼，从吻部到尾尖正好82厘米，然后他拿出小刀，刮下一些鳞片放入一个小信封，寄往挪... 详细信息

1913年4月的一天，在挪威渔村莫斯肯斯，白雪皑皑的群山看起来似乎从海面直插云霄，渔民约翰·诺曼（Johan norman）钓起一条雌性鳕鱼。他量了量这条鱼，从吻部到尾尖正好82厘米，然后他拿出小刀，刮下一些鳞片放入一个小信封，寄往挪威俾尔根的海洋研究所。

关键词：鳕鱼保护渔业海洋研究所挪威信封

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