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Oxidative stress-initiated one-carbon metabolism drives the generation of interleukin-10-producing B cells to resolve pneumonia

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Cellular & Molecular Immunology 2024年第1期21卷 19-32页

作者： Ying Fu Baichao Yu Qi Wang Zhou Lu Hushan Zhang Dan Zhang Feifei Luo Ronghua Liu Luman Wang Yiwei Chu Department of Immunology School of Basic Medical SciencesShanghai Key Laboratory of Medical Epigenetics and MetabolismInstitutes of Biomedical SciencesFudan UniversityShanghaiChina Zhongshan Hospital Institute of Clinical Science Zhongshan HospitalShanghaiChina Zhaotong Health Vocational College ZhaotongYunnanChina Department of Digestive Diseases Huashan HospitalFudan UniversityShanghaiChina Shanghai Fifth People’s Hospital Fudan UniversityShanghaiChina

The metabolic reprogramming underlying the generation of regulatory B cells during infectious diseases remains unknown.Using a Pseudomonas aeruginosa-induced pneumonia model,we reported that IL-10-producing B cells(IL-10+B cells)play a key role in spontaneously resolving infection-mediated inflammation.Accumulated cytosolic reactive oxygen species(ROS)during inflammation were shown to drive IL-10+B-cell generation by remodeling one-carbon metabolism.Depletion of the enzyme serine hydroxymethyltransferase 1(Shmt1)led to inadequate one-carbon metabolism and decreased IL-10+B-cell production.Furthermore,increased one-carbon flux elevated the levels of the methyl donor S-adenosylmethionine(SAM),altering histone H3 lysine 4 methylation(H3K4me)at the Il10 gene to promote chromatin accessibility and upregulate Il10 expression in B cells.Therefore,the one-carbon metabolism-associated compound ethacrynic acid(EA)was screened and found to potentially treat infectious pneumonia by boosting IL-10+B-cell generation.Overall,these findings reveal that ROS serve as modulators to resolve inflammation by reprogramming one-carbon metabolism pathways in B cells.

关键词： IL-10-producing B cell Reactive oxygen species one-carbon metabolism H3K4me Pneumonia

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Impact of increasing one-carbon metabolites on traumatic brain injury outcome using pre-clinical models

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Neural Regeneration Research 2024年第8期19卷 1728-1733页

作者： Sanika M.Joshi Theresa Currier Thomas Nafisa M.Jadavji College of Osteopathic Medicine Midwestern UniversityGlendaleCAUSA Department of Biomedical Sciences Midwestern UniversityGlendaleCAUSA Department of Child Health College of Medicine–PhoenixUniversity of ArizonaPhoenixAZUSA College of Veterinary Medicine Midwestern UniversityGlendaleCAUSA Department of Neuroscience Carleton UniversityOttawaCanada

Traumatic brain injury is a major cause of death and disability worldwide,affecting over 69 million individuals yearly.one-carbon metabolism has been shown to have beneficial effects after brain damage,such as ischemic stroke.However,whether increasing one-carbon metabolite vitamins impacts traumatic brain injury outcomes in patients requires more investigation.The aim of this review is to evaluate how one-carbon metabolites impact outcomes after the onset of traumatic brain injury.PubMed,Web of Science,and Google Scholar databases were searched for studies that examined the impact of B-vitamin supplementation on traumatic brain injury outcomes.The search terms included combinations of the following words:traumatic brain injury,dietary supplementation,one-carbon metabolism,and B-vitamins.The focus of each literature search was basic science data.The year of publication in the literature searches was not limited.Our analysis of the literature has shown that dietary supplementation of B-vitamins has significantly improved the functional and behavioral recove ry of animals with traumatic brain injury compared to controls.Howeve r,this improvement is dosage-dependent and is contingent upon the onset of supplementation and whether there is a sustained or continuous delive ry of vitamin supplementation post-traumatic brain injury.The details of supplementation post-traumatic brain injury need to be further investigated.Overall,we conclude that B-vitamin supplementation improves behavioral outcomes and reduces cognitive impairment post-traumatic brain injury in animal model systems.Further investigation in a clinical setting should be stro ngly considered in co njunction with current medical treatments for traumatic brain injury-affected individuals.

关键词： folic acid nicotinamide one-carbon metabolism riboflavin traumatic brain injury vitamin B12 vitamin B2 vitamin B3

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Gene expression profiles of the one-carbon metabolism pathway

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Journal of Genetics and Genomics 2009年第5期36卷 277-282页

作者： Yin Leng Lee Xinran Xu Sylvan Wallenstein Jia Chen Department of Community and Preventive Medicine Mount Sinai School of Medicine New York 10029 USA Department of Microbiology Mount Sinai School of Medicine New York 10029 USA Department of Pediatrics Mount Sinai School of Medicine New York 10029 USA Department of Oncological Science Mount Sinai School of Medicine New York 10029 USA

one-carbon metabolism plays a critical role in both DNA methylation and DNA synthesis. Accumulating evidence has shown that interruptions of this pathway are associated with many disease outcomes including cardiovascular diseases and cancers. Mechanistic studies have been performed on genetic polymorphisms involved in one-carbon metabolism. However, expression profiles of these inter-related genes are not well-known. In this study, we examined the gene expression profiles of 11 one-carbon metabolizing genes by quantifying the mRNA level of the lymphocyte among 54 healthy individuals and explored the correlations of these genes. We found these genes were expressed in lymphocytes at moderate levels and showed significant inter-person variations, We also applied principle component analysis to explore potential patterns of expression. The components identified by the program agreed with existing knowledge about one-carbon metabolism. This study helps us better understand the biological functions of one-carbon metabolism.

关键词： one-carbon metabolism expression principle component analysis （PCA）

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Maternal dietary deficiencies in folic acid or choline worsen stroke outcomes in adult male and female mouse offspring

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Neural Regeneration Research 2023年第11期18卷 2443-2448页

作者： McCoy Clementson Lauren Hurley Sarah Coonrod Calli Bennett Purvaja Marella Agnes S.Pascual Kasey Pull Brandi Wasek Teodoro Bottiglieri Olga Malysheva Marie A.Caudill Nafisa M.Jadavji Department of Biomedical Sciences Midwestern UniversityGlendaleAZUSA College of Osteopathic Medicine Midwestern UniversityGlendaleAZUSA College of Veterinary Medicine Midwestern UniversityGlendaleAZUSA Center of Metabolomics Institute of Metabolic DiseaseBaylor Scott&White Research InstituteDallasTXUSA Division of Nutritional Sciences Cornell UniversityIthacaNYUSA Department of Neuroscience Carleton UniversityOttawaONCanada Department of Child Health College of Medicine–PhoenixUniversity of ArizonaPhoenixAZUSA

Maternal one-carbon metabolism plays an important role in early life programming.There is a well-established connection between the fetal environment and the health status of the offspring.Howeve r,there is a knowledge gap on how maternal nutrition impacts stro ke outcomes in offspring.The aim of our study was to investigate the role of maternal dietary deficiencies in folic acid or choline on stroke outcomes in 3-month-old offspring.Adult female mice were fed a folic acid-deficient diet,choline-deficient diet,or control diet 4 weeks before pregnancy.They we re continued on diets during pregnancy and la ctation.Male and female offspring were weaned onto a control diet and at 2 months of age were subjected to ischemic stroke within the sensorimotor cortex via photothrombotic damage.Mothers maintained on either a folic acid-deficient diet or choline-deficient diet had reduced levels of S-adenosylm ethionine in the liver and S-adenosylhomocysteine in the plasma.After ischemic stro ke,motor function was impaired in 3-month-old offspring from mothers receiving either a folic acid-deficient diet or choline-deficient diet compared to the animals receiving a control diet.In brain tissue,there was no difference in ischemic damage volume.When protein levels were assessed in ischemic brain tissue,there were lower levels of active caspase-3 and hypoxia-inducible factor 1α in males compared to females and betaine levels were reduced in offspring from the mothers receiving a choline-deficient diet.Our results demonstrate that a deficient maternal diet at critical time points in neurodevelopment results in worse stro ke outcomes.This study emphasizes the importance of maternal diet and the impact it can have on offspring health.

关键词： apoptosis choline metabolism folic acid ischemic stroke maternal diet motor function one-carbon metabolism stroke outcome

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Whole-genome RNAi screen identifies methylation-related genes influencing lipid metabolism in Caenorhabditis elegans

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Journal of Genetics and Genomics 2018年第5期45卷 259-272页

作者： Xiaotong Zhu Yangli Liu Hong Zhang Pingsheng Liu National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China

Lipid droplets （LDs） are highly conserved multifunctional cellular organelles and aberrant lipid storage in LDs can lead to many metabolic diseases. However, the molecular mechanisms governing lipid dynamic changes remain elusive, and the high-throughput screen of genes influencing LD morphology was limited by lacking specific LD marker proteins in the powerful genetic tool Caenorhabditis elegons. In this study, we established a new method to conduct whole-genome RNAi screen using LD resident protein DHS-3 as a LD marker, and identified 78 genes involved in significant LD morphologic changes. Among them, mrhf-1, as well as a series of methylation-related genes, was found dramatically influencing lipid metabolism. SREBP-1 and SCD1 homologs in C. elegans were involved in the lipid metabolic change of rnthf-1（RNAi） worms, and the regulation of ATGL-1 also contributed to it by decreasing triacylglycerol （TAG） hydrolysis. Overall, this study not only identified important genes involved in LD dynamics, but also provided a new tool for LD study using C. elegans, with implications for the study of lipid metabolic diseases.

关键词： Lipid droplet C.elegans RNAi screen Lipid metabolism one-carbon metabolism

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PHGDH as a mechanism for resistance in metabolically-driven cancers

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Cancer Drug Resistance 2020年第4期3卷 762-774页

作者： Richa Rathore Charles R.Schutt Brian A.Van Tine Division of Medical Oncology Washington University in St.LouisSt.LouisMO 63110USA Siteman Cancer Center St.LouisMO 63110USA

At the forefront of cancer research is the rapidly evolving understanding of metabolic reprogramming within cancer cells.The expeditious adaptation to metabolic inhibition allows cells to evolve and acquire resistance to targeted treatments,which makes therapeutic exploitation complex but achievable.3-phosphoglycerate dehydrogenase(PHGDH)is the rate-limiting enzyme of de novo serine biosynthesis and is highly expressed in a variety of cancers,including breast cancer,melanoma,and Ewing’s sarcoma.This review will investigate the role of PHGDH in normal biological processes,leading to the role of PHGDH in the progression of cancer.With an understanding of the molecular mechanisms by which PHGDH expression advances cancer growth,we will highlight the known mechanisms of resistance to cancer therapeutics facilitated by PHGDH biology and identify avenues for combatting PHGDH-driven resistance with inhibitors of PHGDH to allow for the development of effective metabolic therapies.

关键词： PHGDH cancer metabolism serine one-carbon metabolism folate cycle drug resistance

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