通过生物信息学分析女贞子治疗糖尿病肾病的作用机制

doi:10.5246/jcps.2024.11.074

中国药学(英文版) ›› 2024, Vol. 33 ›› Issue (11): 1025-1039.DOI: 10.5246/jcps.2024.11.074

通过生物信息学分析女贞子治疗糖尿病肾病的作用机制

李钦青¹^,², 辛彦利¹, 刘朴霖², 李凯文¹, 景彩芳¹, 张学兰²^,^*(), 贺文彬¹^,^*()

^1. 山西中医药大学国家国际分子中医药联合研究中心山西中医药脑病重点实验室医学, 山西太原 030024
^2. 山东中医药大学, 山东济南 250355

收稿日期:2024-06-15 修回日期:2024-08-11 接受日期:2024-09-20 出版日期:2024-12-10 发布日期:2024-12-10
通讯作者: 张学兰, 贺文彬

Deciphering the therapeutic mechanisms of Fructus Ligustri Lucidi on diabetic nephropathy via bioinformatics analysis

Qinqing Li¹^,², Yanli Xin¹, Pulin Liu², Kaiwen Li¹, Caifang Jing¹, Xuelan Zhang²^,^*(), Wenbin He¹^,^*()

¹ Shanxi Key Laboratory of Traditional Chinese Medicine Encephalopathy, National International Joint Research Center of Molecular Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Taiyuan 030024, Shanxi, China
² Shandong University of Traditional Chinese Medicine, Jinan 250355, Shangdong, China

Received:2024-06-15 Revised:2024-08-11 Accepted:2024-09-20 Online:2024-12-10 Published:2024-12-10
Contact: Xuelan Zhang, Wenbin He
Supported by:
The National Natural Science Foundation of China (Grant No. 81973486, 82173974), the State Administration of Traditional Chinese Medicine Processing Technology Inheritance Project (Grant No. 202259), the National Key Research and Development Plan (Grant No. 2018YFC1707002), the Shanxi Provincial Basic Research Program General Project (Grant No. 202203021211220), and the Study on Processing Synergistic Mechanism of Ligustrum against Diabetic Nephropathy Based on TGFB1/Smads Pathway (Grant No. 2024ZYYA021).

摘要/Abstract

摘要：

本研究旨在通过生物信息学分析, 探讨女贞子治疗糖尿病肾病(DN)的可能机制。本研究通过对DN相关数据集和女贞子基因靶点进行初步的数据库检索, 做了全面的调查。随后, 采用ssGSEA方法对药物靶基因集进行评分, 并根据这些评分对受试者进行分类。此外, 差异分析和富集分析技术随后被用于阐明两组之间差异表达的基因和相关途径。根据ssGSEA评分结果, 将数据分为"高NZZ组"和"低NZZ组"。通过对两组的差异分析, 共鉴定出18个差异表达基因, 其中上调基因14个, 分别为EGR1、CCL2、CDH6、VCAN-AS1、VCAN、C3、MMP7、RNASE6、C1QC、MOXD1、APOC1、SFRP2、CCL21、LUM; 下调基因4个, 分别为OTTHUMG00000152025、RERG、B3GALT2、NELL1。此外, 值得注意的是, 基因VCAN-AS1、CCL21、VCAN、MOXD1、CCL2、SFRP2、MMP7、C3、RNASE6、LUM、C1QC、APOC1和CDH6在DN和High NZZ组中均表现出同步表达模式。富集分析的结果表明, 在与"凋亡细胞清除调节"和"粒细胞趋化性"等相关的途径中显著富集。本研究强调了利用女贞子治疗DN的潜在价值和前景, 揭示了DN患者预后和治疗的新潜在靶点, 为改善这种疾病患者的预后和治疗结果提供了可能的途径。

/attached/file/20241214/20241214114423_929.pdf

关键词: 糖尿病肾病, 女贞子, 生物信息学, 数据分析

Abstract:

This study aimed to investigate the potential mechanisms underlying the therapeutic effects of Fructus Ligustri Lucidi in the treatment of diabetic nephropathy (DN) through bioinformatics analysis. The research commenced with a comprehensive database search for DN-associated datasets and gene targets of Fructus Ligustri Lucidi. Subsequently, the ssGSEA method was employed to score the drug target gene sets, and based on these scores, subjects were categorized. Further analysis involved differential analysis and enrichment analysis techniques to elucidate differentially expressed genes (DEGs) and associated pathways between the two groups. Based on the ssGSEA scoring results, the data were stratified into two groups: the "High NZZ group" and the "Low NZZ group". Through differential analysis, a total of 18 DEGs were identified, comprising 14 upregulated genes (EGR1, CCL2, CDH6, VCAN-AS1, VCAN, C3, MMP7, RNASE6, C1QC, MOXD1, APOC1, SFRP2, CCL21, and LUM) and four downregulated genes (OTTHUMG00000152025, RERG, B3GALT2, and NELL1). Notably, several genes exhibited concurrent expression patterns in both the DN and High NZZ groups, including VCAN-AS1, CCL21, VCAN, MOXD1, CCL2, SFRP2, MMP7, C3, RNASE6, LUM, C1QC, APOC1, and CDH6. Enrichment analysis revealed significant enrichment in pathways related to "regulation of apoptotic cell clearance" and "granulocyte chemotaxis", among others. These findings highlighted the potential value of Fructus Ligustri Lucidi in the treatment of DN and unveiled novel potential targets for prognosis and therapy in DN patients. This study offered promising avenues for enhancing both the prognosis and treatment outcomes for individuals affected by this condition.

Key words: Diabetic kidney disease, Fructus Ligustri Lucidi, Bioinformatics, Data analysis

Supporting:

李钦青, 辛彦利, 刘朴霖, 李凯文, 景彩芳, 张学兰, 贺文彬. 通过生物信息学分析女贞子治疗糖尿病肾病的作用机制[J]. 中国药学(英文版), 2024, 33(11): 1025-1039.

Qinqing Li, Yanli Xin, Pulin Liu, Kaiwen Li, Caifang Jing, Xuelan Zhang, Wenbin He. Deciphering the therapeutic mechanisms of Fructus Ligustri Lucidi on diabetic nephropathy via bioinformatics analysis[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(11): 1025-1039.

图/表 6

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参考文献 35

[1]	Zhong, Y.F.; Lee, K.; He, J.C. SIRT1 is a potential drug target for treatment of diabetic kidney disease. Front. Endocrinol. 2018, 9, 624.
[2]	Xue, R.; Gui, D.K.; Zheng, L.Y.; Zhai, R.N.; Wang, F.; Wang, N.S. Mechanistic insight and management of diabetic nephropathy: recent progress and future perspective. J. Diabetes Res. 2017, 2017, 1839809.
[3]	Sun, G.D.; Li, C.Y.; Cui, W.P.; Guo, Q.Y.; Dong, C.Q.; Zou, H.B.; Liu, S.J.; Dong, W.P.; Miao, L.N. Review of herbal traditional Chinese medicine for the treatment of diabetic nephropathy. J. Diabetes Res. 2016, 2016, 5749857.
[4]	de Boer, I.H.; Rue, T.C.; Hall, Y.N.; Heagerty, P.J.; Weiss, N.S.; Himmelfarb, J. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. 2011, 305, 2532–2539.
[5]	Jiang, G.Z.; Luk, A.O.Y.; Tam, C.H.T.; Xie, F.Y.; Carstensen, B.; Lau, E.S.H.; Lim, C.K.P.; Lee, H.M.; Ng, A.C.W.; Ng, M.C.Y.; Ozaki, R.; Kong, A.P.S.; Chow, C.C.; Yang, X.L.; Lan, H.Y.; Tsui, S.K.W.; Fan, X.D.; Szeto, C.C.; So, W.Y.; Chan, J.C.N.; Ma, R.C.W. Progression of diabetic kidney disease and trajectory of kidney function decline in Chinese patients with Type 2 diabetes. Kidney Int. 2019, 95, 178–187.
[6]	de Zeeuw, D.; Renfurm, R.W.; Bakris, G.; Rossing, P.; Perkovic, V.; Hou, F.F.; Nangaku, M.; Sharma, K.; Heerspink, H.J.L.; Garcia-Hernandez, A.; Larsson, T.E. Efficacy of a novel inhibitor of vascular adhesion protein-1 in reducing albuminuria in patients with diabetic kidney disease (ALBUM): a randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2018, 6, 925–933.
[7]	Doshi, S.M.; Friedman, A.N. Diagnosis and management of type 2 diabetic kidney disease. Clin. J. Am. Soc. Nephrol. 2017, 12, 1366–1373.
[8]	Mauer, M.; Zinman, B.; Gardiner, R.; Suissa, S.; Sinaiko, A.; Strand, T.; Drummond, K.; Donnelly, S.; Goodyer, P.; Gubler, M.C.; Klein, R. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N. Engl. J. Med. 2009, 361, 40–51.
[9]	Tang, G.Y.; Li, S.; Zhang, C.; Chen, H.Y.; Wang, N.; Feng, Y.B. Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management. Acta Pharm. Sin. B. 2021, 11, 2749–2767.
[10]	Luan, R.Q.; Zhao, P.; Zhang, X.L.; Li, Q.Q.; Chen, X.F.; Wang, L. Pharmacodynamics, pharmacokinetics, and kidney distribution of raw and wine-steamed ligustri lucidi fructus extracts in diabetic nephropathy rats. Molecules. 2023, 28, 791.
[11]	Wang, H.; Huang, X.M.; Xu, P.F.; Liu, X.J.; Zhou, Z.H.; Wang, F.H.; Li, J.Y.; Wang, Y.H.; Xian, X.D.; Liu, G.; Huang, W. Apolipoprotein C3 aggravates diabetic nephropathy in type 1 diabetes by activating the renal TLR2/NF-κB pathway. Metabolism. 2021, 119, 154740.
[12]	Jiao, Y.Y.; Jiang, S.M.; Wang, Y.; Yu, T.Y.; Zou, G.M.; Zhuo, L.; Li, W.G. Activation of complement C1q and C3 in glomeruli might accelerate the progression of diabetic nephropathy: evidence from transcriptomic data and renal histopathology. J. Diabetes Investig. 2022, 13, 839–849.
[13]	Tang, S.M.; Wang, X.F.; Deng, T.C.; Ge, H.P.; Xiao, X.C. Identification of C3 as a therapeutic target for diabetic nephropathy by bioinformatics analysis. Sci. Rep. 2020, 10, 13468.
[14]	Jiao, Y.Y.; Jiang, S.M.; Wang, Y.; Yu, T.Y.; Zou, G.M.; Zhuo, L.; Li, W.G. Activation of complement C1q and C3 in glomeruli might accelerate the progression of diabetic nephropathy: evidence from transcriptomic data and renal histopathology. J. Diabetes Investig. 2022, 13, 839–849.
[15]	Wilkening, A.; Krappe, J.; Mühe, A.M.; Lindenmeyer, M.T.; Eltrich, N.; Luckow, B.; Vielhauer, V. C-C chemokine receptor type 2 mediates glomerular injury and interstitial fibrosis in focal segmental glomerulosclerosis. Nephrol. Dial. Transplant. 2020, 35, 227–239.
[16]	Feng, Y.; Zhong, X.; Ni, H.F.; Wang, C.; Tang, T.T.; Wang, L.T.; Song, K.Y.; Tang, R.N.; Liu, H.; Liu, B.C.; Lv, L.L. Urinary small extracellular vesicles derived CCL21 mRNA as biomarker linked with pathogenesis for diabetic nephropathy. J. Transl. Med. 2021, 19, 355.
[17]	Chang, T.T.; Chen, J.W. The role of chemokines and chemokine receptors in diabetic nephropathy. Int. J. Mol. Sci. 2020, 21, 3172.
[18]	Rayego-Mateos, S.; Morgado-Pascual, J.L.; Opazo-Ríos, L.; Guerrero-Hue, M.; García-Caballero, C.; Vázquez-Carballo, C.; Mas, S.; Sanz, A.B.; Herencia, C.; Mezzano, S.; Gómez-Guerrero, C.; Moreno, J.A.; Egido, J. Pathogenic pathways and therapeutic approaches targeting inflammation in diabetic nephropathy. Int. J. Mol. Sci. 2020, 21, 3798.
[19]	Moreno, J.A.; Gomez-Guerrero, C.; Mas, S.; Sanz, A.B.; Lorenzo, O.; Ruiz-Ortega, M.; Opazo, L.; Mezzano, S.; Egido, J. Targeting inflammation in diabetic nephropathy: a tale of hope. Expert Opin. Investig. Drugs. 2018, 27, 917–930.
[20]	Lu, J.; Chen, P.P.; Zhang, J.X.; Li, X.Q.; Wang, G.H.; Yuan, B.Y.; Huang, S.J.; Liu, X.Q.; Jiang, T.T.; Wang, M.Y.; Liu, W.T.; Ruan, X.Z.; Liu, B.C.; Ma, K.L. GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway. Int. J. Biol. Sci. 2022, 18, 96–111.
[21]	Dai, X.; Liao, R.Y.; Liu, C.Q.; Liu, S.; Huang, H.Y.; Liu, J.J.; Jin, T.R.; Guo, H.H.; Zheng, Z.H.; Xia, M.; Ling, W.H.; Xiao, Y.J. Epigenetic regulation of TXNIP-mediated oxidative stress and NLRP3 inflammasome activation contributes to SAHH inhibition-aggravated diabetic nephropathy. Redox Biol. 2021, 45, 102033.
[22]	Hirohama, D.; Abedini, A.; Moon, S.; Surapaneni, A.; Dillon, S.T.; Vassalotti, A.; Liu, H.B.; Doke, T.; Martinez, V.; Dom, Z.M.; Karihaloo, A.; Palmer, M.B.; Coresh, J.; Grams, M.E.; Niewczas, M.A.; Susztak, K. Unbiased human kidney tissue proteomics identifies matrix metalloproteinase 7 as a kidney disease biomarker. J. Am. Soc. Nephrol. 2023, 34, 1279–1291.
[23]	Ke, B.; Fan, C.; Yang, L.; Fang, X. Matrix metalloproteinases-7 and kidney fibrosis. Physiol. 2017, 8, 21.
[24]	Fu, H.Y.; Zhou, D.; Zhu, H.L.; Liao, J.L.; Lin, L.; Hong, X.; Hou, F.F.; Liu, Y.H. Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration. Kidney Int. 2019, 95, 1167–1180.
[25]	Xu, Q.N.; Li, B.J.; Wang, Y.C.; Wang, C.L.; Feng, S.; Xue, L.; Chen, J.H.; Jiang, H. Identification of VCAN as hub gene for diabetic kidney disease immune injury using integrated bioinformatics analysis. Front. Physiol. 2021, 12, 651690.
[26]	Zhang, Y.; Ma, K.L.; Gong, Y.X.; Wang, G.H.; Hu, Z.B.; Liu, L.; Lu, J.; Chen, P.P.; Lu, C.C.; Ruan, X.Z.; Liu, B.C. Platelet microparticles mediate glomerular endothelial injury in early diabetic nephropathy. J. Am. Soc. Nephrol. 2018, 29, 2671–2695.
[27]	Yu, M.X.; Xie, R.J.; Zhang, Y.; Liang, H.; Hou, L.; Yu, C.Y.; Zhang, J.M.; Dong, Z.X.; Tian, Y.; Bi, Y.Y.; Kou, J.J.; Novakovic, V.A.; Shi, J.L. Phosphatidylserine on microparticles and associated cells contributes to the hypercoagulable state in diabetic kidney disease. Nephrol. Dial. Transplant. 2018, 33, 2115–2127.
[28]	van den Berg, B.M.; Wang, G.; Boels, M.G.S.; Avramut, M.C.; Jansen, E.; Sol, W.M.P.J.; Lebrin, F.; van Zonneveld, A.J.; de Koning, E.J.P.; Vink, H.; Gröne, H.J.; Carmeliet, P.; van der Vlag, J.; Rabelink, T.J. Glomerular function and structural integrity depend on hyaluronan synthesis by glomerular endothelium. J. Am. Soc. Nephrol. 2019, 30, 1886–1897.
[29]	Li, Y.J.; Chen, X.C.; Kwan, T.K.; Loh, Y.W.; Singer, J.; Liu, Y.Z.; Ma, J.; Tan, J.; Macia, L.; MacKay, C.R.; Chadban, S.J.; Wu, H.L. Dietary fiber protects against diabetic nephropathy through short-chain fatty acid-mediated activation of G protein-coupled receptors GPR43 and GPR109A. J. Am. Soc. Nephrol. 2020, 31, 1267–1281.
[30]	Lee, J.H.; Kim, D.; Oh, Y.S.; Jun, H.S. Lysophosphatidic acid signaling in diabetic nephropathy. Int. J. Mol. Sci. 2019, 20, 2850.
[31]	Xiao, H.M.; Sun, X.H.; Liu, R.B.; Chen, Z.Q.; Lin, Z.Y.; Yang, Y.; Zhang, M.; Liu, P.Q.; Quan, S.J.; Huang, H.Q. Gentiopicroside activates the bile acid receptor Gpbar1 (TGR5) to repress NF-kappaB pathway and ameliorate diabetic nephropathy. Pharmacol. Res. 2020, 151, 104559.
[32]	Madhusudhan, T.; Ghosh, S.; Wang, H.J.; Dong, W.; Gupta, D.; Elwakiel, A.; Stoyanov, S.; Al-Dabet, M.M.; Krishnan, S.; Biemann, R.; Nazir, S.; Zimmermann, S.; Mathew, A.; Gadi, I.; Rana, R.; Zeng-Brouwers, J.; Moeller, M.J.; Schaefer, L.; Esmon, C.T.; Kohli, S.; Reiser, J.; Rezaie, A.R.; Ruf, W.; Isermann, B. Podocyte integrin- β₃ and activated protein C coordinately restrict RhoA signaling and ameliorate diabetic nephropathy. J. Am. Soc. Nephrol. 2020, 31, 1762–1780.
[33]	Chen, X.W.; Tan, H.S.; Xu, J.; Tian, Y.; Yuan, Q.; Zuo, Y.Y.; Chen, Q.Y.; Hong, X.; Fu, H.Y.; Hou, F.F.; Zhou, L.L.; Liu, Y.H. Klotho-derived peptide 6 ameliorates diabetic kidney disease by targeting Wnt/β-catenin signaling. Kidney Int. 2022, 102, 506–520.
[34]	Sun, H.; Li, H.; Yan, J.; Wang, X.D.; Xu, M.Y.; Wang, M.X.; Fan, B.Z.; Liu, J.Y.; Lin, N.H.; Wang, X.; Li, L.; Zhao, S.T.; Gong, Y.F. Loss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease. Nat. Commun. 2022, 13, 1600.
[35]	Tang, S.C.W.; Yiu, W.H. Innate immunity in diabetic kidney disease. Nat. Rev. Nephrol. 2020, 16, 206–222.

通过生物信息学分析女贞子治疗糖尿病肾病的作用机制

Deciphering the therapeutic mechanisms of Fructus Ligustri Lucidi on diabetic nephropathy via bioinformatics analysis

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