{"title":"梅尼埃病患者内淋巴囊腔液的非靶向代谢组学分析","authors":"Li Huang, Qin Wang, Chao Huang, Zhou Zhou, Anquan Peng, Zhiwen Zhang","doi":"10.1007/s10162-023-00887-1","DOIUrl":null,"url":null,"abstract":"<p><p>Dysfunction of the endolymphatic sac (ES) is one of the etiologies of Meniere's disease (MD), the mechanism of which remains unclear. The aim of the present study was to explore the molecular pathological characteristics of ES during the development of MD. Metabolomic profiling of ES luminal fluid from patients with MD and patients with acoustic neuroma (AN) was performed. Diluted ES luminal fluid (ELF) samples were obtained from 10 patients who underwent endolymphatic duct blockage for the treatment of intractable MD and from 6 patients who underwent translabyrinthine surgery for AN. ELF analysis was performed using liquid chromatography-mass spectrometry before the raw data were normalized and subjected to subsequent statistical analysis by MetaboAnalyst. Using thresholds of P ≤ 0.05 and variable important in projection > 1, a total of 111 differential metabolites were screened in the ELF, including 52 metabolites in negative mode and 59 in positive mode. Furthermore, 15 differentially altered metabolites corresponding to 15 compound names were identified using a Student's t-test, including 7 significant increased metabolites and 8 significant decreased metabolites. Moreover, two differentially altered metabolites, hyaluronic acid (HA) and 4-hydroxynonenal (4-HNE), were validated to be upregulated in the epithelial lining of the ES, as well as in the subepithelial connective-tissue in patients with MD comparing with that in patients with AN. Among these differentially altered metabolites, an upregulated expression of HA detected in the ES lumen of the patients with MD was supposed to be associated with the increased endolymph in ES, while an increased level of 4-HNE found in the ELF of the patients with MD provided direct evidence to support that oxidative damage and inflammatory lesions underlie the mechanism of MD. Furthermore, citrate and ethylenediaminetetraacetic acid were detected to be decreased substantially in the ELF of the patients with MD, suggesting the elevated endolymphatic Ca<sup>2+</sup> in the ears with chronic endolymphatic hydrops is likely to be associated with the reduction of these two chelators of Ca<sup>2+</sup> in ES. The results in the present study indicate metabolomic analysis in the ELF of the patients with MD can potentially improve our understanding on the molecular pathophysiological mechanism in the ES during the development of MD.</p>","PeriodicalId":56283,"journal":{"name":"Jaro-Journal of the Association for Research in Otolaryngology","volume":"24 2","pages":"239-251"},"PeriodicalIF":2.4000,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10121990/pdf/","citationCount":"0","resultStr":"{\"title\":\"Untargeted Metabolomic Analysis in Endolymphatic Sac Luminal Fluid from Patients with Meniere's Disease.\",\"authors\":\"Li Huang, Qin Wang, Chao Huang, Zhou Zhou, Anquan Peng, Zhiwen Zhang\",\"doi\":\"10.1007/s10162-023-00887-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Dysfunction of the endolymphatic sac (ES) is one of the etiologies of Meniere's disease (MD), the mechanism of which remains unclear. The aim of the present study was to explore the molecular pathological characteristics of ES during the development of MD. Metabolomic profiling of ES luminal fluid from patients with MD and patients with acoustic neuroma (AN) was performed. Diluted ES luminal fluid (ELF) samples were obtained from 10 patients who underwent endolymphatic duct blockage for the treatment of intractable MD and from 6 patients who underwent translabyrinthine surgery for AN. ELF analysis was performed using liquid chromatography-mass spectrometry before the raw data were normalized and subjected to subsequent statistical analysis by MetaboAnalyst. Using thresholds of P ≤ 0.05 and variable important in projection > 1, a total of 111 differential metabolites were screened in the ELF, including 52 metabolites in negative mode and 59 in positive mode. Furthermore, 15 differentially altered metabolites corresponding to 15 compound names were identified using a Student's t-test, including 7 significant increased metabolites and 8 significant decreased metabolites. Moreover, two differentially altered metabolites, hyaluronic acid (HA) and 4-hydroxynonenal (4-HNE), were validated to be upregulated in the epithelial lining of the ES, as well as in the subepithelial connective-tissue in patients with MD comparing with that in patients with AN. Among these differentially altered metabolites, an upregulated expression of HA detected in the ES lumen of the patients with MD was supposed to be associated with the increased endolymph in ES, while an increased level of 4-HNE found in the ELF of the patients with MD provided direct evidence to support that oxidative damage and inflammatory lesions underlie the mechanism of MD. Furthermore, citrate and ethylenediaminetetraacetic acid were detected to be decreased substantially in the ELF of the patients with MD, suggesting the elevated endolymphatic Ca<sup>2+</sup> in the ears with chronic endolymphatic hydrops is likely to be associated with the reduction of these two chelators of Ca<sup>2+</sup> in ES. The results in the present study indicate metabolomic analysis in the ELF of the patients with MD can potentially improve our understanding on the molecular pathophysiological mechanism in the ES during the development of MD.</p>\",\"PeriodicalId\":56283,\"journal\":{\"name\":\"Jaro-Journal of the Association for Research in Otolaryngology\",\"volume\":\"24 2\",\"pages\":\"239-251\"},\"PeriodicalIF\":2.4000,\"publicationDate\":\"2023-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10121990/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Jaro-Journal of the Association for Research in Otolaryngology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s10162-023-00887-1\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/1/30 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Jaro-Journal of the Association for Research in Otolaryngology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10162-023-00887-1","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/1/30 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
摘要
内淋巴囊(ES)功能障碍是梅尼埃病(MD)的病因之一,其发病机制尚不清楚。本研究旨在探索梅尼埃病发病过程中 ES 的分子病理特征。研究人员对 MD 患者和听神经瘤(AN)患者的 ES 管腔液进行了代谢组学分析。稀释的ES管腔液(ELF)样本来自10名接受内淋巴管阻塞治疗的难治性MD患者和6名接受迷宫手术治疗的听神经瘤患者。在对原始数据进行归一化处理并随后使用 MetaboAnalyst 进行统计分析之前,使用液相色谱-质谱法对 ELF 进行了分析。采用P≤0.05的阈值和投影中重要变量>1的变量,在ELF中共筛选出111种差异代谢物,包括52种阴性代谢物和59种阳性代谢物。此外,通过学生 t 检验,确定了与 15 个化合物名称相对应的 15 个差异变化代谢物,其中包括 7 个显著增加的代谢物和 8 个显著减少的代谢物。此外,经验证,与 AN 患者相比,MD 患者 ES 上皮内膜以及上皮下结缔组织中的两种差异变化代谢物--透明质酸(HA)和 4-羟基壬烯醛(4-HNE)--出现上调。在这些发生不同程度改变的代谢物中,在 MD 患者 ES 管腔中检测到的 HA 表达上调可能与 ES 内淋巴增加有关,而在 MD 患者 ELF 中发现的 4-HNE 水平升高则直接证明了氧化损伤和炎症病变是 MD 的发病机制。此外,在 MD 患者的 ELF 中检测到柠檬酸盐和乙二胺四乙酸大幅减少,这表明慢性内淋巴水肿耳内淋巴 Ca2+ 的升高可能与 ES 中这两种 Ca2+ 螯合剂的减少有关。本研究的结果表明,对 MD 患者耳内淋巴水肿的代谢组学分析有可能加深我们对 MD 发病过程中 ES 分子病理生理机制的了解。
Untargeted Metabolomic Analysis in Endolymphatic Sac Luminal Fluid from Patients with Meniere's Disease.
Dysfunction of the endolymphatic sac (ES) is one of the etiologies of Meniere's disease (MD), the mechanism of which remains unclear. The aim of the present study was to explore the molecular pathological characteristics of ES during the development of MD. Metabolomic profiling of ES luminal fluid from patients with MD and patients with acoustic neuroma (AN) was performed. Diluted ES luminal fluid (ELF) samples were obtained from 10 patients who underwent endolymphatic duct blockage for the treatment of intractable MD and from 6 patients who underwent translabyrinthine surgery for AN. ELF analysis was performed using liquid chromatography-mass spectrometry before the raw data were normalized and subjected to subsequent statistical analysis by MetaboAnalyst. Using thresholds of P ≤ 0.05 and variable important in projection > 1, a total of 111 differential metabolites were screened in the ELF, including 52 metabolites in negative mode and 59 in positive mode. Furthermore, 15 differentially altered metabolites corresponding to 15 compound names were identified using a Student's t-test, including 7 significant increased metabolites and 8 significant decreased metabolites. Moreover, two differentially altered metabolites, hyaluronic acid (HA) and 4-hydroxynonenal (4-HNE), were validated to be upregulated in the epithelial lining of the ES, as well as in the subepithelial connective-tissue in patients with MD comparing with that in patients with AN. Among these differentially altered metabolites, an upregulated expression of HA detected in the ES lumen of the patients with MD was supposed to be associated with the increased endolymph in ES, while an increased level of 4-HNE found in the ELF of the patients with MD provided direct evidence to support that oxidative damage and inflammatory lesions underlie the mechanism of MD. Furthermore, citrate and ethylenediaminetetraacetic acid were detected to be decreased substantially in the ELF of the patients with MD, suggesting the elevated endolymphatic Ca2+ in the ears with chronic endolymphatic hydrops is likely to be associated with the reduction of these two chelators of Ca2+ in ES. The results in the present study indicate metabolomic analysis in the ELF of the patients with MD can potentially improve our understanding on the molecular pathophysiological mechanism in the ES during the development of MD.
期刊介绍:
JARO is a peer-reviewed journal that publishes research findings from disciplines related to otolaryngology and communications sciences, including hearing, balance, speech and voice. JARO welcomes submissions describing experimental research that investigates the mechanisms underlying problems of basic and/or clinical significance.
Authors are encouraged to familiarize themselves with the kinds of papers carried by JARO by looking at past issues. Clinical case studies and pharmaceutical screens are not likely to be considered unless they reveal underlying mechanisms. Methods papers are not encouraged unless they include significant new findings as well. Reviews will be published at the discretion of the editorial board; consult the editor-in-chief before submitting.