Biotechnology Bulletin ›› 2024, Vol. 40 ›› Issue (1): 145-159.doi: 10.13560/j.cnki.biotech.bull.1985.2023-0351
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HE Shi-yu1(), ZENG Zhong-da2, LI Bo-yan1()
Received:
2023-04-15
Online:
2024-01-26
Published:
2024-02-06
Contact:
LI Bo-yan
E-mail:heshiyu0123@yeah.net;boyan.li@gmc.edu.cn
HE Shi-yu, ZENG Zhong-da, LI Bo-yan. Application Progress of Spatially Resolved Metabolomics in Disease Diagnosis Research[J]. Biotechnology Bulletin, 2024, 40(1): 145-159.
检测方法 Detection method | NMR | GC-MS | LC-MS | MSI |
---|---|---|---|---|
灵敏度 | 一般 | 较高 | 高 | 高 |
分辨率 | 较高 | 较高 | 高 | 高,可达μm级 |
重现性 | 好 | 较好 | 较好 | 好 |
样品前处理方式 | 较简单,无需衍生化 | 繁琐,样品需做衍生化处理 | 简单 | 简单,样品无需衍生化且无需标记 |
适用范围 | 分子物质,可检测糖类、氨基酸类等含氢水溶性小分子 | 分子物质,可检测极性小的易挥发、可衍生化且不易降解的含活性氢基团物质 | 分子物质,可检测极性大的化合物,或不稳定、难挥发、难衍生化的物质 | 组织、单细胞均可 |
Table 1 Typical metabonomic detection methods
检测方法 Detection method | NMR | GC-MS | LC-MS | MSI |
---|---|---|---|---|
灵敏度 | 一般 | 较高 | 高 | 高 |
分辨率 | 较高 | 较高 | 高 | 高,可达μm级 |
重现性 | 好 | 较好 | 较好 | 好 |
样品前处理方式 | 较简单,无需衍生化 | 繁琐,样品需做衍生化处理 | 简单 | 简单,样品无需衍生化且无需标记 |
适用范围 | 分子物质,可检测糖类、氨基酸类等含氢水溶性小分子 | 分子物质,可检测极性小的易挥发、可衍生化且不易降解的含活性氢基团物质 | 分子物质,可检测极性大的化合物,或不稳定、难挥发、难衍生化的物质 | 组织、单细胞均可 |
类别 Item | MALDI-MSI | SIMS imaging | LAESI-MSI | DESI-MSI |
---|---|---|---|---|
离子源 | MALDI | SIMS | LAESI | DESI |
电离类型 | 软 | 静态:软 动态:硬 | 软 | 软 |
空间分辨率 | 最低可至1.4,多数 5-100 | 静态:0.1-10 动态:0.01-1 | 2.4-200 | 最低可至10-20,多数50-200 |
样品制备 | 需要 | 需要 | 无需 | 几乎无需 |
质量范围/Da | 300-100 000 | 静态:1-3 000 动态:1-250 | 1-5 000 | 100-10 000 |
扫描深度/μm | 0.1-20 | 0.5-10 | 0.1-50 | 1-500 |
检测限 | amol-fmol | fmol-pmol | fmol-pmol | fmol-pmol |
适用范围 | 代谢物、脂类、多聚糖、多肽、蛋白质、核酸 | 元素、代谢物、脂类 | 代谢物、脂类、多肽、含水量大的样本 | 代谢物、脂类、多肽 |
定量能力 | 可行 | 静态:困难 动态:可行 | 可行 | 可行 |
工作环境 | 常压/真空 | 真空 | 常压 | 常压 |
Table 2 Typical mass spectrometry imaging techniques
类别 Item | MALDI-MSI | SIMS imaging | LAESI-MSI | DESI-MSI |
---|---|---|---|---|
离子源 | MALDI | SIMS | LAESI | DESI |
电离类型 | 软 | 静态:软 动态:硬 | 软 | 软 |
空间分辨率 | 最低可至1.4,多数 5-100 | 静态:0.1-10 动态:0.01-1 | 2.4-200 | 最低可至10-20,多数50-200 |
样品制备 | 需要 | 需要 | 无需 | 几乎无需 |
质量范围/Da | 300-100 000 | 静态:1-3 000 动态:1-250 | 1-5 000 | 100-10 000 |
扫描深度/μm | 0.1-20 | 0.5-10 | 0.1-50 | 1-500 |
检测限 | amol-fmol | fmol-pmol | fmol-pmol | fmol-pmol |
适用范围 | 代谢物、脂类、多聚糖、多肽、蛋白质、核酸 | 元素、代谢物、脂类 | 代谢物、脂类、多肽、含水量大的样本 | 代谢物、脂类、多肽 |
定量能力 | 可行 | 静态:困难 动态:可行 | 可行 | 可行 |
工作环境 | 常压/真空 | 真空 | 常压 | 常压 |
疾病类型 Disease type | 研究对象 Research object | 研究技术与方法 Research techniques and methods | 关键代谢物 Key metabolite | 参与途径 Ways of participation | 文献 Reference |
---|---|---|---|---|---|
肿瘤 | 前列腺癌 | MALDI-MSI、DESI-MSI | 丝裂原活化蛋白激酶/细胞外信号调节激酶、硫酸胆固醇、磷脂酰肌醇和胆绿素还原酶B,多种磷脂类丰度增加,柠檬酸盐水平显著下降 | Mitogen-activated protein kinase(MAPK), Phosphatidylinositol 3-kinase(PI3K)代谢通路 | [ |
乳腺癌 | MALDI-MSI、DESI-MSI | L-肉碱和短链酰基肉碱,肉碱棕榈酰转移酶1A、肉碱/酰基肉碱转移酶和肉碱棕榈酰转移酶2,脂肪酸和磷脂组成明显变化 | 脂肪酸β-氧化途径 | [ | |
膀胱癌 | 红外基质辅助激光解吸电喷雾电离质谱成像IR-MALDESI MSI | 游离脂肪酸显著增加,肌醇磷脂、磷脂酸聚集 | 脂质代谢 | [ | |
结直肠癌 | AFADESI-MSI、MALDI-MSI、DESI-MSI | N,O-双-(三甲基甲硅烷基)苯丙氨酸丰度上调,长链脂肪酸、极长链脂肪酸和多种氧化磷脂增加 | 脂质代谢 | [ | |
胃癌 | 液体提取-电声喷雾电离-傅里叶变换离子回旋共振质谱成像LE-ESSI MSI FTICR-MSI、MALDI-MSI、DESI-MSI | 血清磷脂酰胆碱(32:0)、磷脂酰胆碱(34:3) | 胆碱代谢 | [ | |
肝细胞癌 | AFADESI-MSI | 有机酸及其衍生物丰度上调,不同微区存在差异代谢物 | 氨基酸代谢(β-丙氨酸代谢、精氨酸和脯氨酸代谢),胆碱代谢,甘油磷脂代谢 | [ | |
非小细胞肺癌 | 2D-imaging MSI | 鞘磷脂和多种磷脂酰丝氨酸减少,以及磷脂酰乙醇胺和磷脂酰胆碱种类增加 | 磷脂谱代谢差异 | [ | |
甲状腺癌 | 2D DESI-MSI | 神经酰胺和甘油磷酸肌醇相对丰度上调 | 脂质代谢 | [ | |
口腔鳞状细胞癌 | DESI-MSI | 14种特征脂质代谢物 | 脂质代谢 | [ | |
神经精神疾病 | 阿尔茨海默病 | TOF-SIMS imaging、MALDI-MSI | 硫苷脂丰度下调,腺嘌呤和腺嘌呤核糖核酸浓度显著下降,溶血磷脂酰肌醇以及花生四烯酸缀合的磷脂酰肌醇显示出在Aβ斑块特异性定位 | 嘌呤代谢途径,脂质与β淀粉样蛋白(Aβ)肽异常沉积驱动阿尔茨海默病发生 发展的机制 | [ |
癫痫 | DESI-MSI | 磷脂酰胆碱和磷脂酰乙醇胺表达减少 | Kennedy代谢途径 | [ | |
中风 | MALDI-MSI | 谷氨酸、N-乙酰天冬氨酸呈差异性变化 | 氨基酸代谢 | [ | |
精神分裂症 | DESI-MSI | 磷脂酰胆碱水平降低 | 胆碱代谢 | [ | |
创伤性脑损伤 | MALDI-MSI | 酰基肉碱代谢差异 | 脂肪酸代谢 | [ | |
糖尿病及其并发症 | 糖尿病 | MALDI-MSI、 Nano-DESI-MSI | 肾小球三磷酸腺苷与单磷酸腺苷(ATP/AMP)的比例增加,且鞘磷脂(d18:1/16:0)在糖尿病大鼠中累积、酰基肉碱在肾组织中明显增加 | 鞘脂代谢 | [ |
糖尿病肾病 | 液体萃取表面分析质谱成像LESA-MSI、AFADESI-MSI、MALDI-MSI | 多种脂肪酸、磷脂类代谢物有明显差异性改变且改变具有区域特异性,肉碱类和胆碱类代谢物也发生表达差异 | 亚油酸代谢、花生四烯酸代谢、α-亚麻酸代谢、甘油磷脂代谢和三羧酸循环(TCA) | [ | |
糖尿病脑病 | AFADESI-MSI | 脂肪醛(Fals)在DE大鼠脑中区域性特异性分布并且在大脑皮层、海马体和杏仁核中富集,脑区域特异性发生脂代谢紊乱,线粒体代谢功能障碍 | 糖酵解和戊糖磷酸途径(PPP) | [ | |
其他 | 乙肝 | MALDI-MSI | 磷脂酰胆碱显著减少 | 胆碱代谢 | [ |
传染病 | MALDI-MSI | 脂质A、肉毒素(SAP1)、前列腺素E2(PGE2)代谢异常 | 脂肪酸代谢 | [ | |
动脉粥样硬化 | DESI-MSI、MALDI-MSI | 鞘磷脂和氧化胆固醇酯丰度上调 | 坏死性凋亡、鞘脂信号通路和甘油磷脂代谢 | [ | |
视网膜病变 | MALDI-MSI | 磷脂酰乙醇胺在病变部位丰度下调,鞘氨醇髓鞘则更丰富 | 氨基酸代谢 | [ | |
心力衰竭 | TOF-SIMS imaging | 存在差异代谢谱,细胞中代谢差异体现在溶血磷脂酸、PI、PE | 脂质代谢 | [ |
Table 3 Applications of spatially resolved metabolomics in disease diagnosis
疾病类型 Disease type | 研究对象 Research object | 研究技术与方法 Research techniques and methods | 关键代谢物 Key metabolite | 参与途径 Ways of participation | 文献 Reference |
---|---|---|---|---|---|
肿瘤 | 前列腺癌 | MALDI-MSI、DESI-MSI | 丝裂原活化蛋白激酶/细胞外信号调节激酶、硫酸胆固醇、磷脂酰肌醇和胆绿素还原酶B,多种磷脂类丰度增加,柠檬酸盐水平显著下降 | Mitogen-activated protein kinase(MAPK), Phosphatidylinositol 3-kinase(PI3K)代谢通路 | [ |
乳腺癌 | MALDI-MSI、DESI-MSI | L-肉碱和短链酰基肉碱,肉碱棕榈酰转移酶1A、肉碱/酰基肉碱转移酶和肉碱棕榈酰转移酶2,脂肪酸和磷脂组成明显变化 | 脂肪酸β-氧化途径 | [ | |
膀胱癌 | 红外基质辅助激光解吸电喷雾电离质谱成像IR-MALDESI MSI | 游离脂肪酸显著增加,肌醇磷脂、磷脂酸聚集 | 脂质代谢 | [ | |
结直肠癌 | AFADESI-MSI、MALDI-MSI、DESI-MSI | N,O-双-(三甲基甲硅烷基)苯丙氨酸丰度上调,长链脂肪酸、极长链脂肪酸和多种氧化磷脂增加 | 脂质代谢 | [ | |
胃癌 | 液体提取-电声喷雾电离-傅里叶变换离子回旋共振质谱成像LE-ESSI MSI FTICR-MSI、MALDI-MSI、DESI-MSI | 血清磷脂酰胆碱(32:0)、磷脂酰胆碱(34:3) | 胆碱代谢 | [ | |
肝细胞癌 | AFADESI-MSI | 有机酸及其衍生物丰度上调,不同微区存在差异代谢物 | 氨基酸代谢(β-丙氨酸代谢、精氨酸和脯氨酸代谢),胆碱代谢,甘油磷脂代谢 | [ | |
非小细胞肺癌 | 2D-imaging MSI | 鞘磷脂和多种磷脂酰丝氨酸减少,以及磷脂酰乙醇胺和磷脂酰胆碱种类增加 | 磷脂谱代谢差异 | [ | |
甲状腺癌 | 2D DESI-MSI | 神经酰胺和甘油磷酸肌醇相对丰度上调 | 脂质代谢 | [ | |
口腔鳞状细胞癌 | DESI-MSI | 14种特征脂质代谢物 | 脂质代谢 | [ | |
神经精神疾病 | 阿尔茨海默病 | TOF-SIMS imaging、MALDI-MSI | 硫苷脂丰度下调,腺嘌呤和腺嘌呤核糖核酸浓度显著下降,溶血磷脂酰肌醇以及花生四烯酸缀合的磷脂酰肌醇显示出在Aβ斑块特异性定位 | 嘌呤代谢途径,脂质与β淀粉样蛋白(Aβ)肽异常沉积驱动阿尔茨海默病发生 发展的机制 | [ |
癫痫 | DESI-MSI | 磷脂酰胆碱和磷脂酰乙醇胺表达减少 | Kennedy代谢途径 | [ | |
中风 | MALDI-MSI | 谷氨酸、N-乙酰天冬氨酸呈差异性变化 | 氨基酸代谢 | [ | |
精神分裂症 | DESI-MSI | 磷脂酰胆碱水平降低 | 胆碱代谢 | [ | |
创伤性脑损伤 | MALDI-MSI | 酰基肉碱代谢差异 | 脂肪酸代谢 | [ | |
糖尿病及其并发症 | 糖尿病 | MALDI-MSI、 Nano-DESI-MSI | 肾小球三磷酸腺苷与单磷酸腺苷(ATP/AMP)的比例增加,且鞘磷脂(d18:1/16:0)在糖尿病大鼠中累积、酰基肉碱在肾组织中明显增加 | 鞘脂代谢 | [ |
糖尿病肾病 | 液体萃取表面分析质谱成像LESA-MSI、AFADESI-MSI、MALDI-MSI | 多种脂肪酸、磷脂类代谢物有明显差异性改变且改变具有区域特异性,肉碱类和胆碱类代谢物也发生表达差异 | 亚油酸代谢、花生四烯酸代谢、α-亚麻酸代谢、甘油磷脂代谢和三羧酸循环(TCA) | [ | |
糖尿病脑病 | AFADESI-MSI | 脂肪醛(Fals)在DE大鼠脑中区域性特异性分布并且在大脑皮层、海马体和杏仁核中富集,脑区域特异性发生脂代谢紊乱,线粒体代谢功能障碍 | 糖酵解和戊糖磷酸途径(PPP) | [ | |
其他 | 乙肝 | MALDI-MSI | 磷脂酰胆碱显著减少 | 胆碱代谢 | [ |
传染病 | MALDI-MSI | 脂质A、肉毒素(SAP1)、前列腺素E2(PGE2)代谢异常 | 脂肪酸代谢 | [ | |
动脉粥样硬化 | DESI-MSI、MALDI-MSI | 鞘磷脂和氧化胆固醇酯丰度上调 | 坏死性凋亡、鞘脂信号通路和甘油磷脂代谢 | [ | |
视网膜病变 | MALDI-MSI | 磷脂酰乙醇胺在病变部位丰度下调,鞘氨醇髓鞘则更丰富 | 氨基酸代谢 | [ | |
心力衰竭 | TOF-SIMS imaging | 存在差异代谢谱,细胞中代谢差异体现在溶血磷脂酸、PI、PE | 脂质代谢 | [ |
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