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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 diet.Consequently,therapy adherence is often experienced as an additional burden.In this study,transcriptional profiling was conducted parallel to high-resolution metabolomics on,respectively,liver tissue and serum samples of Fah-deficient mice.The experimental workflow of our study is shown in Figure 1A.Canonical pathway analyses showed manifest activation of the NRF2-stress response,associated with hepatocellular damage and mainly driven by a markedly increased oxidative burden.Other altered canonical pathways were primarily a downstream consequence of the latter.Furthermore,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 development.Finally,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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Therapeutic potential of traditional Chinese medicine for the treatment of NAFLD:A promising drug Potentilla discolor Bunge

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3529-3547页

作者： Longshan Ji Qian Li Yong He Xin Zhang Zhenhua Zhou Yating Gao Miao Fang Zhuo Yu Robim M.Rodrigues Yueqiu Gao Man Li Laboratory of Cellular Immunity Institute of Clinical ImmunologyShanghai Key Laboratory of Traditional Chinese MedicineShuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineKey Laboratory of Liver and Kidney Diseases(Shanghai University of Traditional Chinese Medicine)Ministry of EducationShanghai 201203China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China department of Hepatopathy Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai 201203China department of in vitro toxicology and dermato-cosmetology Faculty of Medicine and PharmacyVrije Universiteit BrusselBrussels 1000Belgium

Nonalcoholic fatty liver disease(NAFLD)is characterized by excessive accumulation of hepatic lipids and metabolic stress-induced liver injury.There are currently no approved effective pharmacological treatments for NAFLD.Traditional Chinese medicine(TCM)has been used for centuries to treat patients with chronic liver diseases without clear disease types and mechanisms.More recently,TCM has been shown to have unique advantages in the treatment of NAFLD.We performed a systematic review of the medical literature published over the last two decades and found that many TCM formulas have been reported to be beneficial for the treatment of metabolic dysfunctions,including Potentilla discolor Bunge(PDB).PDB has a variety of active compounds,including flavonoids,terpenoids,organic acids,steroids and tannins.Many compounds have been shown to exhibit a series of beneficial effects for the treatment of NAFLD,including anti-oxidative and anti-inflammatory functions,improvement of lipid metabolism and reversal of insulin resistance.In this review,we summarize potential therapeutic effects of TCM formulas for the treatment of NAFLD,focusing on the medicinal properties of natural active compounds from PDB and their underlying mechanisms.We point out that PDB can be classified as a novel candidate for the treatment and prevention of NAFLD.

关键词： Nonalcoholic fatty liver disease(NAFLD) Traditional Chinese medicine Acupuncture Potentilla discolor Bunge(PDB) Natural active compounds Anti-oxidative Anti-inflammatory Lipid metabolism Insulin resistance Endoplasmic reticulum stress Intestinal microflora

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Development and application of a novel method to assess exposure levels of sensitizing and irritating substances leaching from menstrual hygiene products

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Emerging Contaminants 2021年第1期7卷 116-123页

作者： Q.Marcelis A.Gatzios E.Deconinck V.Rogiers T.Vanhaecke B.Desmedt department of in vitro toxicology and dermato-cosmetology Vrije Universiteit BrusselLaarbeeklaan 1031090JetteBelgium Medicines and Health Products SciensanoJuliette Wytsmanstraat 141050BrusselsBelgium

Menstrual hygiene products(MHPs)like tampons,sanitary towels and panty liners are widely used by women and come in close contact with the intimate parts of the human body,which consist of mucosae that lack the important barrier function of normal skin.Hence,substances leaching from MHP can easily penetrate and become systemically available.This study aims to develop a new in chemico methodology that allows to identify and measure realistic consumer exposure levels of several skin sensitizers and irritants leaching from MHPs under simulated use conditions.To assess the leaching of chemicals from MHPs,a menstrual fluid simulant(MFS)simulating pH,osmolarity and protein binding was first established.Subsequently,an analytical methodology was developed for nine well-known skin sensitizers and skin irritants.In short,the MFS samples underwent salting-out assisted liquid-liquid extraction before ultra-high performance liquid chromatography coupled with a triple-quadrupole mass spectrometry analysis.Validation was performed according to the total error approach with acceptability limits of±15%regarding the total analytical error(including systematic and random bias).Fifteen commercially available MHPs were assessed.Six products were found to leach at least one of the following five sensitizing and irritating compounds:a-isomethyl ionone,benzyl salicylate,hexyl cinnamaldehyde,linalool and piperonal.Piperonal was the most abundant compound leaching from the MHPs,with leaching concentration levels measured to 28.22 mg/g.In addition,the leaching level of benzyl salicylate was found to be 11.03 mg/g.The latter fragrance concentration is above 10 mg/g and would trigger mandatory labelling if the Cosmetic Regulation would apply for MHPs.However,none of the identified and quantified skin sensitizers were mentioned on the packaging.In conclusion,this novel methodology makes it possible to estimate realistic human exposure levels to skin sensitizers and irritants through the use of MHPs.Availability of these exposure estimates is

关键词： Consumer product safety Menstrual hygiene products Fragrance Skin sensitization Skin irritation

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TAT-Gap19通过抑制啮齿动物星形胶质细胞的连接蛋白43半通道发挥抗惊厥作用

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神经损伤与功能重建 2018年第6期13卷 325-325页

作者： Walrave L Pierre A Albertini G Aourz N De Bundel D Van Eeckhaut A Vinken M Giaume C Leybaert L Smolders I 聂昊 department of Pharmaceutical Chemistry Drug Analysis and Drug Information Research group Experimental Pharmacology (EFAR) Center for Neurosciences (C4N) Vrije Universiteit Brussel department of in vitro toxicology and dermato-cosmetology Vrije Universiteit Brussel Center for Interdisciplinary Research in Biology (CIRB) Collège de France Physiology group Department of Basic Medical Sciences Ghent University

越来越多的证据表明,星形胶质细胞连接蛋白43(Cx43)信号在癫痫中发挥至关重要的作用。但是,由于通过实验方法鉴别Cx43间隙连接通道(GJCs)和半通道(HCs)的技术尚不成熟,导致目前尚无法确定哪个通道在癫痫的发生中发挥更重要的作用。因此... 详细信息

越来越多的证据表明,星形胶质细胞连接蛋白43(Cx43)信号在癫痫中发挥至关重要的作用。但是,由于通过实验方法鉴别Cx43间隙连接通道(GJCs)和半通道(HCs)的技术尚不成熟,导致目前尚无法确定哪个通道在癫痫的发生中发挥更重要的作用。因此,本研究观察TAT-Gap19(Cx模拟肽)是否通过抑制Cx43半通道而非Cx43间隙连接通道影响实验诱导的啮齿动物癫痫发作。急性海马切片小鼠染料摄取实验表明,星形胶质Cx43半通道响应化学惊厥毛果芸香碱的作用而开放,并且可被TAT-Gap19抑制。体内实验中,毛果芸香碱诱导的癫痫发作及相伴随的D-丝氨酸微透析液的增长水平被Cx43半通道的抑制所抑制。此外,TAT-Gap19的抗惊厥作用被外源性D-丝氨酸给药逆转,这表明,抑制Cx43半通道可以通过降低细胞外D-丝氨酸水平来防止癫痫发作。抑制Cx43半通道的抗惊厥特性在电癫痫小鼠模型(如急性6 Hz难治性癫痫发作模型和慢性6 Hz角膜点燃模型)中得到了进一步的证实。总而言之,这些结果表明,Cx43半通道在癫痫发作中可以起到一定作用,并且有成为癫痫治疗中新型用药靶点的潜力。

关键词： TAT-Gap19 星形胶质细胞星形细胞连接蛋白43半通道毛果芸香碱癫痫

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