南方医科大学学报 ›› 2024, Vol. 44 ›› Issue (5): 930-940.doi: 10.12122/j.issn.1673-4254.2024.05.15
收稿日期:
2024-01-17
出版日期:
2024-05-20
发布日期:
2024-06-04
通讯作者:
谢曦,罗海彬
E-mail:21211007000005@hainanu.edu.cn;xiexi@hainanu.edu.cn;hbluo@hainanu.edu.cn
作者简介:
李睿镈,硕士,E-mail: 21211007000005@hainanu.edu.cn
基金资助:
Ruibo LI(), Ge GAO, Xi XIE(
), Haibin LUO(
)
Received:
2024-01-17
Online:
2024-05-20
Published:
2024-06-04
Contact:
Xi XIE, Haibin LUO
E-mail:21211007000005@hainanu.edu.cn;xiexi@hainanu.edu.cn;hbluo@hainanu.edu.cn
Supported by:
摘要:
目的 探究槟榔的成分及其促进口腔黏膜下纤维化的机制。 方法 采用Thermo QE plus液相色谱串联高分辨质谱仪和Compound discover 3.2数据处理软件进行槟榔中药化学成分分析,将检测到的化合物以质谱响应值排序,分析排名前20化合物的活性。化合物活性来源根据《中国药典(2015版)》汇总,数据查询基于PubChem、Chemical book 以及Scifinder数据库。借助网络药理学方法分析槟榔影响口腔黏膜下纤维化(OSF)的潜在活性成分、核心靶点及主要影响的生物功能、信号通路。通过整合人类基因数据库(Genecards)、基因组百科全书数据库(KEGG)等数据库获取OSF的作用靶点。以OB≥30%为条件,在中药系统药理学技术平台(TCMSP)中筛选出槟榔可作用于靶点的化合物,并构建靶点-化合物、化合物-中药、靶点-化合物-中药网络。运用MOE软件的分子对接技术,分析成分-靶点结合的可能性,再利用Pymol软件进行分子对接可视化。最后通过免疫组化在临床样本中验证槟榔是否影响PI3K-Akt、MAPK两条通路涉及的主要蛋白,初步验证槟榔诱导OSF的潜在作用机制。 结果 基于网络药理学和槟榔粗提物中筛选出前10的化合物与OSF核心靶点中核心交集基因,确定了槟榔可能通过调控PI3K-Akt与MAPK通路。通过免疫组化在临床样本中验证,细胞膜上的PI3K蛋白表达量在OSF患者组中表达下降(P=0.0002),p-PI3K(P=0.0002)表达量上升,进一步激活下游的AKT1蛋白表达增加(P=0.0006),加剧磷酸化蛋白p-AKT蛋白的表达及堆积(P=0.0013);而在MAPK通路中,OSF患者组对比正常组,通过上调JNK蛋白(P=0.0130),诱导下游AP-1复合蛋白c-jun及c-fos转录因子的活性增加,促使其向细胞核聚集;且OSF患者组较正常组血浆的IL-6(P<0.0001)与IL-8(P=0.0095)含量均上升。 结论 槟榔碱、槟榔次碱、异去甲槟榔碱等槟榔中的主要活性成分可能通过刺激PI3K-Akt与MAPK信号通路,促进炎症介质IL-6及IL-8的表达,诱导胶原增生,导致口腔黏膜下纤维化病变。
李睿镈, 高歌, 谢曦, 罗海彬. 槟榔活性成分诱导口腔黏膜下纤维化的机制:基于网络药理学结合临床样本验证[J]. 南方医科大学学报, 2024, 44(5): 930-940.
Ruibo LI, Ge GAO, Xi XIE, Haibin LUO. Oral submucosal fibrosis induced by active components in areca nut: a network pharmacology-based analysis and validation of the mechanism[J]. Journal of Southern Medical University, 2024, 44(5): 930-940.
NO. | Molecule | Molecular formula | QD (ppm) | Mw | RT (min) | Matching score | Peak area | Relative content (%) |
---|---|---|---|---|---|---|---|---|
1 | Arecoline | C8H13NO2 | -5.75 | 155.09374 | 3.758 | 90.9 | 68518632210 | 45.473 |
2 | Quinic acid | C7H12O6 | -2.88 | 192.06283 | 1.539 | 92.6 | 22692914797 | 15.060 |
3 | Epicatechin | C15H14O6 | -3.42 | 290.07805 | 18.93 | 94.7 | 14748028849 | 9.788 |
4 | Trigonelline HCl | C7H7NO2 | -5.85 | 137.04688 | 1.547 | 87.3 | 12273994597 | 8.146 |
5 | Citric acid | C6H8O7 | -2.05 | 192.02661 | 1.672 | 85.3 | 11231967076 | 7.454 |
6 | Procyanidin B1 | C30H26O12 | -4.2 | 578.14 | 18.324 | 92.4 | 7264204843 | 4.821 |
7 | p-Coumaric acid | C9H8O3 | -5.71 | 164.04641 | 4.772 | 85 | 3213100960 | 2.132 |
8 | (+)-Catechin hydrate | C15H14O6 | -3.73 | 290.07796 | 19.914 | 95.2 | 857006365.1 | 0.569 |
9 | Uridine | C9H12N2O6 | -2.72 | 244.06887 | 4.959 | 93.6 | 835052793.2 | 0.566 |
10 | Isorhamnetin-3-O-nehesperidine | C28H32O16 | -3.49 | 624.16686 | 22.33 | 92.2 | 760984003.5 | 0.505 |
11 | Sucrose | C12H22O11 | -3.26 | 342.1151 | 1.575 | 93.4 | 721956624 | 0.479 |
12 | 4'-O-Glucosylvitexin | C27H30O15 | -4.08 | 594.15604 | 20.961 | 87 | 608955062.8 | 0.404 |
13 | Procyanidin B2 | C30H28O10 | -5.78 | 578.13909 | 19.473 | 90.1 | 563763212.9 | 0.374 |
14 | Rosarin | C20H28O10 | -2.75 | 428.16707 | 22.833 | 79.7 | 480609598 | 0319 |
15 | Isoguanosine | C10H13N5O5 | -2.41 | 283.09099 | 10.894 | 83.8 | 44491969.7 | 0.295 |
16 | Nicotinic acid | C6H5NO2 | -4.82 | 123.03143 | 2.533 | 78 | 432658200.9 | 0.287 |
17 | 5-Hydroxymethylfurfural | C6H6O3 | -5.63 | 126.03098 | 1.912 | 73.9 | 431787858.3 | 0.287 |
18 | 2-Pyrrolidinecarboxylic acid | C5H9NO2 | -5.99 | 115.06264 | 1.547 | 74.7 | 397002912.3 | 0.263 |
19 | L-Tyrosine | C9H11NO3 | -2.26 | 181.07348 | 4.815 | 88.5 | 373792777.1 | 0.248 |
20 | Benzoic acid | C7H6O2 | -6.16 | 122.03603 | 18.932 | 88.4 | 277514777.6 | 0.184 |
表1 海南槟榔提取物前20成分鉴定
Tab.1 Identification of the top 20 components of areca extract from Hainan areca nut
NO. | Molecule | Molecular formula | QD (ppm) | Mw | RT (min) | Matching score | Peak area | Relative content (%) |
---|---|---|---|---|---|---|---|---|
1 | Arecoline | C8H13NO2 | -5.75 | 155.09374 | 3.758 | 90.9 | 68518632210 | 45.473 |
2 | Quinic acid | C7H12O6 | -2.88 | 192.06283 | 1.539 | 92.6 | 22692914797 | 15.060 |
3 | Epicatechin | C15H14O6 | -3.42 | 290.07805 | 18.93 | 94.7 | 14748028849 | 9.788 |
4 | Trigonelline HCl | C7H7NO2 | -5.85 | 137.04688 | 1.547 | 87.3 | 12273994597 | 8.146 |
5 | Citric acid | C6H8O7 | -2.05 | 192.02661 | 1.672 | 85.3 | 11231967076 | 7.454 |
6 | Procyanidin B1 | C30H26O12 | -4.2 | 578.14 | 18.324 | 92.4 | 7264204843 | 4.821 |
7 | p-Coumaric acid | C9H8O3 | -5.71 | 164.04641 | 4.772 | 85 | 3213100960 | 2.132 |
8 | (+)-Catechin hydrate | C15H14O6 | -3.73 | 290.07796 | 19.914 | 95.2 | 857006365.1 | 0.569 |
9 | Uridine | C9H12N2O6 | -2.72 | 244.06887 | 4.959 | 93.6 | 835052793.2 | 0.566 |
10 | Isorhamnetin-3-O-nehesperidine | C28H32O16 | -3.49 | 624.16686 | 22.33 | 92.2 | 760984003.5 | 0.505 |
11 | Sucrose | C12H22O11 | -3.26 | 342.1151 | 1.575 | 93.4 | 721956624 | 0.479 |
12 | 4'-O-Glucosylvitexin | C27H30O15 | -4.08 | 594.15604 | 20.961 | 87 | 608955062.8 | 0.404 |
13 | Procyanidin B2 | C30H28O10 | -5.78 | 578.13909 | 19.473 | 90.1 | 563763212.9 | 0.374 |
14 | Rosarin | C20H28O10 | -2.75 | 428.16707 | 22.833 | 79.7 | 480609598 | 0319 |
15 | Isoguanosine | C10H13N5O5 | -2.41 | 283.09099 | 10.894 | 83.8 | 44491969.7 | 0.295 |
16 | Nicotinic acid | C6H5NO2 | -4.82 | 123.03143 | 2.533 | 78 | 432658200.9 | 0.287 |
17 | 5-Hydroxymethylfurfural | C6H6O3 | -5.63 | 126.03098 | 1.912 | 73.9 | 431787858.3 | 0.287 |
18 | 2-Pyrrolidinecarboxylic acid | C5H9NO2 | -5.99 | 115.06264 | 1.547 | 74.7 | 397002912.3 | 0.263 |
19 | L-Tyrosine | C9H11NO3 | -2.26 | 181.07348 | 4.815 | 88.5 | 373792777.1 | 0.248 |
20 | Benzoic acid | C7H6O2 | -6.16 | 122.03603 | 18.932 | 88.4 | 277514777.6 | 0.184 |
图2 槟榔成分网络药理学分析
Fig.2 Network pharmacological analysis of the components of areca nut. A: Network pharmacology technology flow chart. B: Areca nut active ingredient-disease target for oral submucous fibrosis (OSF). C: Protein-protein interaction. D: Core target acquisition map. E: Intersection of the core target genes of the active ingredients of areca nut and OSF. F: Areca nut-component-target-OSF target interaction map. G: Effect of areca nut active ingredients on GO enrichment of OSF targets. H: KEGG pathway enrichment analysis of the effects of areca nut active ingredients on OSF targets. I: KEGG pathway secondary classification analysis. J: Molecular docking binding energy heat map.
NO. | Molecule ID | Molecule name | OB/% | PubChem ID |
---|---|---|---|---|
A1 | MOL005835 | Guvacine | 98.35 | 40468028 |
A2 | MOL005833 | Arecaine | 84.34 | 6971195 |
A3 | MOL005838 | isoguvacine | 72.17 | 7059534 |
A4 | MOL010481 | WLN: GR DSWR DG | 70.57 | 6625 |
A5 | MOL000004 | Procyanidin B1 | 67.87 | 11250133 |
A6 | MOL000676 | DBP | 64.54 | 3026 |
A7 | MOL004544 | Quinic acid | 63.53 | 37439 |
A8 | MOL001456 | citric acid | 56.22 | 19782904 |
A9 | MOL004365 | Isomenthol | 55.30 | 19244 |
A10 | MOL000492 | Catechin | 54.83 | 9064 |
A11 | MOL002095 | DEP | 52.19 | 6781 |
A12 | MOL000555 | Homoarecoline | 52.03 | 34167 |
A13 | MOL010483 | dehydeoacetic acid | 52.02 | 1712264 |
A14 | MOL000635 | vanilline | 52.00 | 1183 |
A15 | MOL000073 | ent-Epicatechin | 48.96 | 1822932 |
A16 | MOL010485 | EPA | 45.66 | 446284 |
A17 | MOL010482 | WLN: 6OVR BVO6 | 43.74 | 6786 |
A18 | MOL001749 | ZINC03860434 | 43.59 | 7057921 |
A19 | MOL000131 | EIC | 41.90 | 5280450 |
A20 | MOL004454 | ODD | 41.70 | 5282800 |
A21 | MOL000041 | PHA | 41.62 | 6925665 |
A22 | MOL010492 | Arecoline | 40.70 | 2230 |
A23 | MOL002032 | DNOP | 40.59 | 8346 |
A24 | MOL002850 | butylated hydroxytoluene | 40.02 | 31404 |
A25 | MOL000198 | (R)-linalool | 39.80 | 443158 |
A26 | MOL000234 | L-Limonen | 38.09 | 439250 |
A27 | MOL001739 | zoomaric acid | 35.78 | 445638 |
A28 | MOL010488 | 10Z-heptadecenoic acid | 34.42 | 5312435 |
A29 | MOL002372 | (6Z,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene | 33.55 | 11975273 |
A30 | MOL000675 | oleic acid | 33.13 | 445639 |
A31 | MOL010487 | Guvacoline | 32.67 | 160492 |
A32 | MOL000301 | 2-lauroleic acid | 31.42 | 5282729 |
A33 | MOL010489 | Resivit | 30.84 | 71629 |
A34 | MOL003505 | Panosorb | 30.82 | 643460 |
表2 槟榔活性成分筛选
Tab.2 Screening of active ingredients in areca nut
NO. | Molecule ID | Molecule name | OB/% | PubChem ID |
---|---|---|---|---|
A1 | MOL005835 | Guvacine | 98.35 | 40468028 |
A2 | MOL005833 | Arecaine | 84.34 | 6971195 |
A3 | MOL005838 | isoguvacine | 72.17 | 7059534 |
A4 | MOL010481 | WLN: GR DSWR DG | 70.57 | 6625 |
A5 | MOL000004 | Procyanidin B1 | 67.87 | 11250133 |
A6 | MOL000676 | DBP | 64.54 | 3026 |
A7 | MOL004544 | Quinic acid | 63.53 | 37439 |
A8 | MOL001456 | citric acid | 56.22 | 19782904 |
A9 | MOL004365 | Isomenthol | 55.30 | 19244 |
A10 | MOL000492 | Catechin | 54.83 | 9064 |
A11 | MOL002095 | DEP | 52.19 | 6781 |
A12 | MOL000555 | Homoarecoline | 52.03 | 34167 |
A13 | MOL010483 | dehydeoacetic acid | 52.02 | 1712264 |
A14 | MOL000635 | vanilline | 52.00 | 1183 |
A15 | MOL000073 | ent-Epicatechin | 48.96 | 1822932 |
A16 | MOL010485 | EPA | 45.66 | 446284 |
A17 | MOL010482 | WLN: 6OVR BVO6 | 43.74 | 6786 |
A18 | MOL001749 | ZINC03860434 | 43.59 | 7057921 |
A19 | MOL000131 | EIC | 41.90 | 5280450 |
A20 | MOL004454 | ODD | 41.70 | 5282800 |
A21 | MOL000041 | PHA | 41.62 | 6925665 |
A22 | MOL010492 | Arecoline | 40.70 | 2230 |
A23 | MOL002032 | DNOP | 40.59 | 8346 |
A24 | MOL002850 | butylated hydroxytoluene | 40.02 | 31404 |
A25 | MOL000198 | (R)-linalool | 39.80 | 443158 |
A26 | MOL000234 | L-Limonen | 38.09 | 439250 |
A27 | MOL001739 | zoomaric acid | 35.78 | 445638 |
A28 | MOL010488 | 10Z-heptadecenoic acid | 34.42 | 5312435 |
A29 | MOL002372 | (6Z,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene | 33.55 | 11975273 |
A30 | MOL000675 | oleic acid | 33.13 | 445639 |
A31 | MOL010487 | Guvacoline | 32.67 | 160492 |
A32 | MOL000301 | 2-lauroleic acid | 31.42 | 5282729 |
A33 | MOL010489 | Resivit | 30.84 | 71629 |
A34 | MOL003505 | Panosorb | 30.82 | 643460 |
图3 槟榔成分分子对接
Fig.3 Molecular docking of areca nut components. A: Chemical structures of 10 areca nut active ingredients. B: Visualization of molecular docking of some active ingredients of areca nut with the core targets.
Main active ingredients | Binding energy with target (kcal/mol) | ||||||||
---|---|---|---|---|---|---|---|---|---|
Molecule name | PubChem ID | AKT1 (4GV1) | INS (1TYL) | EGF (1NQL) | EGFR (3W2S) | VEGFA (4KZN) | TP53 (3Q01) | MAPK3 (4QTB) | MYC (5I4Z) |
Guvacine | 40468028 | -4.35 | -4.16 | 0.00 | -4.41 | -3.82 | 0.00 | 0.00 | -4.17 |
Arecaine | 6971195 | -4.25 | -4.43 | 0.00 | -4.27 | -3.74 | 0.00 | 0.00 | -4.46 |
isoguvacine | 7059534 | -4.38 | -4.06 | 0.00 | -4.01 | -3.78 | 0.00 | 0.00 | -3.85 |
WLN: GR DSWR DG | 6625 | -5.66 | -4.89 | -5.32 | -4.73 | -4.38 | -4.76 | -5.71 | -4.54 |
Procyanidin B1 | 11250133 | -6.86 | -6.42 | -6.70 | -6.68 | -5.45 | -6.02 | -6.60 | -5.94 |
Quinic acid | 37439 | -4.78 | -4.45 | 0.00 | -5.28 | -4.11 | 0.00 | 0.00 | -4.14 |
ent-Epicatechin | 1822932 | -6.54 | -5.61 | -5.72 | -6.15 | -4.91 | -5.51 | -6.54 | -5.16 |
Arecoline | 2230 | -5.28 | -4.69 | 0.00 | 0.00 | -4.47 | -4.03 | 0.00 | -4.48 |
表3 分子对接打分一览表
Tab.3 Molecular docking scoring list
Main active ingredients | Binding energy with target (kcal/mol) | ||||||||
---|---|---|---|---|---|---|---|---|---|
Molecule name | PubChem ID | AKT1 (4GV1) | INS (1TYL) | EGF (1NQL) | EGFR (3W2S) | VEGFA (4KZN) | TP53 (3Q01) | MAPK3 (4QTB) | MYC (5I4Z) |
Guvacine | 40468028 | -4.35 | -4.16 | 0.00 | -4.41 | -3.82 | 0.00 | 0.00 | -4.17 |
Arecaine | 6971195 | -4.25 | -4.43 | 0.00 | -4.27 | -3.74 | 0.00 | 0.00 | -4.46 |
isoguvacine | 7059534 | -4.38 | -4.06 | 0.00 | -4.01 | -3.78 | 0.00 | 0.00 | -3.85 |
WLN: GR DSWR DG | 6625 | -5.66 | -4.89 | -5.32 | -4.73 | -4.38 | -4.76 | -5.71 | -4.54 |
Procyanidin B1 | 11250133 | -6.86 | -6.42 | -6.70 | -6.68 | -5.45 | -6.02 | -6.60 | -5.94 |
Quinic acid | 37439 | -4.78 | -4.45 | 0.00 | -5.28 | -4.11 | 0.00 | 0.00 | -4.14 |
ent-Epicatechin | 1822932 | -6.54 | -5.61 | -5.72 | -6.15 | -4.91 | -5.51 | -6.54 | -5.16 |
Arecoline | 2230 | -5.28 | -4.69 | 0.00 | 0.00 | -4.47 | -4.03 | 0.00 | -4.48 |
图4 临床验证
Fig.4 Clinical validation. A: HE staining, Masson, SR staining (Original magnification: ×100 or ×200). B: Fibronectin immunohistochemistry and H-score semi-quantitative analysis (×100 or ×200; n≥5). C: SR staining and differentiation of COL I and COL III under polarized light (×100). Orange and red fluorescence indicate Col I. Green fluorescence indicates COL III. D: Immunohistochemical staining of PI3K-Akt pathway proteins (×100 or ×200; n≥5). E: Immunohistochemistry and H-score semi-quantitative analysis of PI3K-Akt pathway proteins (n≥5). F: Immunohistochemical staining of MAPK pathway protein (×100, ×200 or ×400; n≥5). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.
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