基于生物信息学分析铁死亡调控基因与牙周炎的关系

doi:10.7518/gjkq.2023082

摘要/Abstract

摘要：

目的通过生物信息学方法探究牙周炎与铁死亡之间的关系。方法从基因表达数据库（GEO）中下载数据集GS16134，在铁死亡数据库（FerrDb）中下载铁死亡的驱动和抑制基因。利用R软件对数据进行标准化处理，“limma”包筛选牙周炎中差异表达的基因（P<0.05）。利用基因本体（GO）以及京都基因和基因组百科全书（KEGG）对差异基因进行分析，确定其主要的功能及通路。构建蛋白互作网络，筛选关键mRNA。结果一共筛选出50个在牙周炎牙龈组织样本和健康牙龈组织样本中存在差异性表达的铁死亡调控基因。GO功能和KEGG通路结果表明，差异基因主要参与氧化应激反应，并集中在Xc-系统通路及铁代谢通路。结论铁死亡调控基因在牙周炎组织样本中存在差异表达，这些基因主要在氧化应激和铁代谢通路上发挥作用，表明二者之间存在相关性。推测铁死亡可能通过脂质过氧化以及铁代谢异常对炎症，甚至对牙槽骨骨改建造成影响，本研究为牙周炎的发生发展机制提供了新的见解和思路。

关键词: 牙周炎, 铁死亡, 生物信息分析

Abstract:

Objective Bioinformatics methods were used to investigate the correlation between periodontitis and ferroptosis. Methods Dataset GS16134 was downloaded from the GEO database, and the driver and suppressor genes of ferroptosis were downloaded from the ferroptosis database (FerrDb). R soft was used to standardize the data, and the “limma” package was used to screen for differentially expressed genes in periodontitis (P<0.05). GO and KEGG analyses were conducted to analyze the differentially expressed genes and identify their main functions and pathways. Protein interaction network was used to screen for key mRNAs. Results Fifty differentially expressed ferroptosis regulatory genes were screened in periodontitis gingival tissue samples and healthy gingival tissue samples. Results of GO function and KEGG pathway analyses showed that the differentially expressed genes mainly participated in the oxidative stress reaction, and they were mainly concentrated in the ferroptosis pathway. Conclusion Ferroptosis regulatory genes were differentially expressed in periodontitis tissue samples, and these genes primarily functioned in the oxidative stress and iron metabolism pathways, indicating a correlation between the two. Ferroptosis may affect inflammation and even bone remodeling of alveolar bone through lipid peroxidation, as well as abnormal iron metabolism. This study provides new insights into the mechanism of periodontitis development.

Key words: periodontitis, ferroptosis, bioinformation

中图分类号:

R 781.4+2

罗晓洁,王德续,陈晓涛. 基于生物信息学分析铁死亡调控基因与牙周炎的关系[J]. 国际口腔医学杂志, 2023, 50(6): 661-668.

Luo Xiaojie,Wang Dexu,Chen Xiaotao. Relationship between periodontitis and ferroptosis based on bioinformatics analysis[J]. Int J Stomatol, 2023, 50(6): 661-668.

图/表 9

图 1

图 2

表 1

图 3

表 2

图 4

图 5

图 6

参考文献 30

1	Kassebaum NJ, Bernabé E, Dahiya M, et al. Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression[J]. J Dent Res, 2014, 93(11): 1045-1053.
2	Pihlstrom BL, Michalowicz BS, Johnson NW. Pe-riodontal diseases[J]. Lancet, 2005, 366(9499): 1809-1820.
3	Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072.
4	Sun YT, Chen P, Zhai BT, et al. The emerging role of ferroptosis in inflammation[J]. Biomed Pharmacother, 2020, 127: 110108.
5	Papapanou PN, Behle JH, Kebschull M, et al. Subgingival bacterial colonization profiles correlate with gingival tissue gene expression[J]. BMC Microbiol, 2009, 9: 221.
6	Ritchie ME, Phipson B, Wu D, et al. Limma powers differential expression analyses for RNA-sequen-cing and microarray studies[J]. Nucleic Acids Res, 2015, 43(7): e47.
7	Cai W, Li H, Zhang Y, et al. Identification of key biomarkers and immune infiltration in the synovial tissue of osteoarthritis by bioinformatics analysis[J]. PeerJ, 2020, 8: e8390.
8	Sczepanik FSC, Grossi ML, Casati M, et al. Perio-dontitis is an inflammatory disease of oxidative stress: we should treat it that way[J]. Periodontol 2000, 2020, 84(1): 45-68.
9	Chen MM, Cai WJ, Zhao SF, et al. Oxidative stress-related biomarkers in saliva and gingival crevicular fluid associated with chronic periodontitis: a syste-matic review and meta-analysis[J]. J Clin Periodontol, 2019, 46(6): 608-622.
10	Wang Y, Andrukhov O, Rausch-Fan X. Oxidative stress and antioxidant system in periodontitis[J]. Front Physiol, 2017, 8: 910.
11	Cao JY, Dixon SJ. Mechanisms of ferroptosis[J]. Cell Mol Life Sci, 2016, 73(11/12): 2195-2209.
12	Koppula P, Zhuang L, Gan BY. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy[J]. Protein Cell, 2021, 12(8): 599-620.
13	Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation[J]. Trends Cell Biol, 2016, 26(3): 165-176.
14	李春燕, 孙传政, 宋鑫. 肿瘤细胞死亡的一种新形式: 铁死亡[J]. 中国生物化学与分子生物学报, 2019, 35(11): 1208-1214.
	Li CY, Sun CZ, Song X. A new form of tumor cell death: ferroptosis[J]. Chin J Biochem Mol Biol, 2019, 35(11): 1208-1214.
15	Gluschko A, Farid A, Herb M, et al. Macrophages target Listeria monocytogenes by two discrete non-canonical autophagy pathways[J]. Autophagy, 2022, 18(5): 1090-1107.
16	Chen HY, Sun Q, Zhang CG, et al. Identification and validation of CYBB, CD86, and C3AR1 as the key genes related to macrophage infiltration of gastric cancer[J]. Front Mol Biosci, 2021, 8: 756085.
17	Galaris D, Barbouti A, Pantopoulos K. Iron homeostasis and oxidative stress: an intimate relationship[J]. Biochim Biophys Acta Mol Cell Res, 2019, 1866(12): 118535.
18	Brown CW, Amante JJ, Chhoy P, et al. Prominin2 drives ferroptosis resistance by stimulating iron export[J]. Dev Cell, 2019, 51(5): 575-586.e4.
19	Kuang YB, Wang Q. Iron and lung cancer[J]. Cancer Lett, 2019, 464: 56-61.
20	Hou W, Xie YC, Song XX, et al. Autophagy promotes ferroptosis by degradation of ferritin[J]. Autophagy, 2016, 12(8): 1425-1428.
21	Guo W, Zhao YH, Li HX, et al. NCOA4-mediated ferritinophagy promoted inflammatory responses in periodontitis[J]. J Periodontal Res, 2021, 56(3): 523-534.
22	Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer[J]. Nat Rev Cancer, 2017, 17(9): 528-542.
23	Ni S, Yuan Y, Qian Z, et al. Hypoxia inhibits RANKL-induced ferritinophagy and protects osteoclasts from ferroptosis[J]. Free Radic Biol Med, 2021, 169: 271-282.
24	Jin CY, Zhang P, Zhang M, et al. Inhibition of SLC7A11 by sulfasalazine enhances osteogenic differentiation of mesenchymal stem cells by modula-ting BMP2/4 expression and suppresses bone loss in ovariectomized mice[J]. J Bone Miner Res, 2017, 32(3): 508-521.
25	Han B, Geng H, Liu L, et al. GSH attenuates RANKL-induced osteoclast formation in vitro and LPS-induced bone loss in vivo [J]. Biomed Pharmacother, 2020, 128: 110305.
26	Huynh H, Wan YH. mTORC1 impedes osteoclast differentiation via calcineurin and NFATc₁ [J]. Commun Biol, 2018, 1: 29.
27	Fujita H, Ochi M, Ono M, et al. Glutathione accele-rates osteoclast differentiation and inflammatory bone destruction[J]. Free Radic Res, 2019, 53(2): 226-236.
28	Lee DE, Kim JH, Choi SH, et al. Periodontitis mainly increases osteoclast formation via enhancing the differentiation of quiescent osteoclast precursors into osteoclasts[J]. J Periodontal Res, 2015, 50(2): 256-264.
29	Agidigbi TS, Kang IS, Kim C. Inhibition of MEK/ERK upregulates GSH production and increases RANKL-induced osteoclast differentiation in RAW 264.7 cells[J]. Free Radic Res, 2020, 54(11/12): 894-905.
30	Ledesma-Colunga MG, Weidner H, Vujic Spasic M, et al. Shaping the bone through iron and iron-related proteins[J]. Semin Hematol, 2021, 58(3): 188-200.

Metrics

Viewed

Full text

Abstract

Cited

Shared

Discussed

GO ID	GO Term	Gene ID	数目
GO:006979	氧化应激反应	ALOX5/SLC7A11/TLR4/NFE2L2/PRDX6/EPAS1/DUOX1/MYB/CYBB/DUOX2/NQO1/GCLC/HMOX1/GCH1/MAP1LC3A	15
GO:0062197	细胞化学应激反应	ALOX5/SLC7A11/TLR4/NFE2L2/PRDX6/EPAS1/MYB/CYBB/ATM/NQO1/HMOX1/GCH1/MAP1LC3A	13
GO:0034599	细胞氧化应激反应	ALOX5/SLC7A11/TLR4/NFE2L2/PRDX6/EPAS1/MYB/CYBB/NQO1/HMOX1/GCH1/MAP1LC3A	12

Pathway ID	描述	Gene ID	数目
hsa04216	铁死亡通路	FTH1/SLC7A11/SAT1/CYBB/VDAC2/NCOA4/ACSL4/SLC40A1/SLC3A2/GCLC/HMOX1/ACSL3/MAP1LC3A	13
hsa04621	NOD样受体信号通路	TLR4/CYBB/VDAC2/PANX1/ATG16L1/MAPK14/MAP1LC3A	7
hsa04140	自噬通路	ATG3/ATG16L1/ULK1/WIPI1/HRAS/MAP1LC3A	6

[1]	傅豫, 何薇, 黄兰. 铁死亡在口腔疾病中的研究进展[J]. 国际口腔医学杂志, 2024, 51(1): 36-44.
[2]	黄元鸿,彭显,周学东. 骨碎补在治疗口腔骨相关疾病的研究进展[J]. 国际口腔医学杂志, 2023, 50(6): 679-685.
[3]	龚美灵,程兴群,吴红崑. 牙周炎与帕金森病相关性的研究进展[J]. 国际口腔医学杂志, 2023, 50(5): 587-593.
[4]	孙佳,韩烨,侯建霞. 白细胞介素-6-铁调素信号轴调控牙周炎相关性贫血致病机制的研究进展[J]. 国际口腔医学杂志, 2023, 50(3): 329-334.
[5]	刘体倩,梁星,刘蔚晴,李晓虹,朱睿. 咬合创伤在牙周炎发生发展中的作用及机制的研究进展[J]. 国际口腔医学杂志, 2023, 50(1): 19-24.
[6]	李琼,于维先. 白藜芦醇治疗牙周炎及其生物利用度的研究进展[J]. 国际口腔医学杂志, 2023, 50(1): 25-31.
[7]	黄伟琨,徐秋艳,周婷. 黄芩苷抑制脂多糖促巨噬细胞氧化应激损伤作用的研究[J]. 国际口腔医学杂志, 2022, 49(5): 521-528.
[8]	周剑鹏,谢旭东,赵蕾,王骏. 辅助性T细胞17及白细胞介素17在牙周炎中的作用及机制的研究进展[J]. 国际口腔医学杂志, 2022, 49(5): 586-592.
[9]	陈荟宇,白明茹,叶玲. 信号素3A与口腔常见病关系的研究进展[J]. 国际口腔医学杂志, 2022, 49(5): 593-599.
[10]	周佳佳,赵蕾,徐欣. 牙周炎相关基因多态性的研究进展[J]. 国际口腔医学杂志, 2022, 49(4): 432-440.
[11]	马玉,左玉,张鑫. 光动力疗法辅助治疗牙周炎治疗效果的Meta分析[J]. 国际口腔医学杂志, 2022, 49(3): 305-316.
[12]	钱素婷,丁玲敏,纪雅宁,林军. 微小RNA在牙周炎龈沟液中的表达差异及对牙周炎的调控机制[J]. 国际口腔医学杂志, 2022, 49(3): 349-355.
[13]	蒋端,申道南,赵蕾,吴亚菲. 内皮发育调节基因-1与牙周炎相关性的研究进展[J]. 国际口腔医学杂志, 2022, 49(2): 244-248.
[14]	白慧敏,张雨薇,孟姝,刘程程. 特异性促炎症消退介质在牙周炎中作用的研究进展[J]. 国际口腔医学杂志, 2022, 49(1): 85-93.
[15]	黄晓慧,祁本婷,杨洁,刘玉,孙卫斌. 机械性邻面菌斑控制措施对牙周非手术治疗效果影响的系统评价[J]. 国际口腔医学杂志, 2021, 48(6): 656-663.