Network Pharmacology Study of Huangqi-Huangjing in the Treatment of Diabetic Nephropathy and Diabetic Cardiomyopathy

Bohan Lu; Lei-Huang; Xudong Chen; Jun Hong; Nake-Jin; Xuechen Zhao; Zhongmin Su; Jiacheng Rong*

Bohan Lu, Lei-Huang, Xudong Chen, Jun Hong, Nake-Jin, Xuechen Zhao, Zhongmin Su and Jiacheng Rong*

Volume4-Issue11
Dates: Received: 2023-11-04 | Accepted: 2023-11-15 | Published: 2023-11-17
Pages: 1557-1569

Abstract

Objective: To systematically investigate the mechanism of Huangqi-Huangjing in the treatment of Diabetic Nephropathy (DN) and Diabetic Cardiomyopathy (DC) using network pharmacology and molecular docking analysis. To provide a theoretical basis for the development of new drugs for the treatment of DN and DC.

Methods: The active ingredients and therapeutic targets of Huangqi-Huangjing, DN and DC were predicted and screened using TCMSP, GeneCards, DisGeNet and OMIM databases. Networks of active ingredients and targets were mapped using Cytoscape 3.8.2, Protein-Protein Interactions (PPI) were analyzed using the STRING database, and enrichment analysis of key targets was performed using “clusterProfiler” in R. Molecular docking of active ingredients and key targets was performed by Autodock vina.

Results: A total of twenty-six active drug compounds, including diosgenin, formononetin, 7-O-methyl isomucronulatol, and 207 potential targets of Huangqi-Huangjing were obtained. PPI network analysis showed that targets such as AKT1, JUN, TP53, HSP90AA1 and RELA were associated with both huangqi-huangjing and DN-DC. GO and KEGG pathway analysis showed that most of these targets were involved in pathways such as Th17 cell differentiation, IL-17 signaling pathway, and AGE-
RAGE signaling pathway in diabetic complications. Docking studies showed that diosgenin has ideal binding activity to TP53, RELA and AKT1.

Conclusion: The active ingredients of Huangqi-Huangjing such as diosgenin may act on DN and DC through different targets such as TP53, RELA and AKT1, which can help to develop innovative drugs for effective treatment of DN and DC.

FullText HTML FullText PDF DOI: 10.37871/jbres1830

Certificate of Publication

Copyright

How to cite this article

Lu B, Huang L, Chen X, Hong J, Jin N, Zhao X, Su Z, Rong J. Network Pharmacology Study of Huangqi-Huangjing in the Treatment of Diabetic Nephropathy and Diabetic Cardiomyopathy. J Biomed Res Environ Sci. 2023 Oct 17; 4(11): 1557-1569. doi: 10.37871/jbres1830, Article ID: JBRES1830, Available at: https://www.jelsciences.com/articles/jbres1830.pdf

Subject area(s)

Pharmacology

Diabetes

Nephrology

Cardiovascular Diseases

References

Thomas MC, Brownlee M, Susztak K, Sharma K, Jandeleit-Dahm KA, Zoungas S, Rossing P, Groop PH, Cooper ME. Diabetic kidney disease. Nat Rev Dis Primers. 2015 Jul 30;1:15018. doi: 10.1038/nrdp.2015.18. PMID: 27188921; PMCID: PMC7724636.
Blair M. Diabetes Mellitus Review. Urol Nurs. 2016 Jan-Feb;36(1):27-36. PMID: 27093761.
Alicic RZ, Rooney MT, Tuttle KR. Diabetic Kidney Disease: Challenges, Progress, and Possibilities. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2032-2045. doi: 10.2215/CJN.11491116. Epub 2017 May 18. PMID: 28522654; PMCID: PMC5718284.
Hölscher ME, Bode C, Bugger H. Diabetic Cardiomyopathy: Does the Type of Diabetes Matter? Int J Mol Sci. 2016 Dec 18;17(12):2136. doi: 10.3390/ijms17122136. PMID: 27999359; PMCID: PMC5187936.
Afkarian M, Zelnick LR, Hall YN, Heagerty PJ, Tuttle K, Weiss NS, de Boer IH. Clinical Manifestations of Kidney Disease Among US Adults With Diabetes, 1988-2014. JAMA. 2016 Aug 9;316(6):602-10. doi: 10.1001/jama.2016.10924. PMID: 27532915; PMCID: PMC5444809.
Boucek P. Diabetická nefropatie/diabetické onemocnení ledvin [Diabetic nephropathy/diabetic kidney disease]. Vnitr Lek. 2013 Mar;59(3):201-3. Czech. PMID: 23713188.
Wang Y, Liu T, Ma F, Lu X, Mao H, Zhou W, Yang L, Li P, Zhan Y. A Network Pharmacology-Based Strategy for Unveiling the Mechanisms of Tripterygium Wilfordii Hook F against Diabetic Kidney Disease. J Diabetes Res. 2020 Nov 20;2020:2421631. doi: 10.1155/2020/2421631. PMID: 33274236; PMCID: PMC7695487.
Li S, Zhang B. Traditional Chinese medicine network pharmacology: theory, methodology and application. Chin J Nat Med. 2013 Mar;11(2):110-20. doi: 10.1016/S1875-5364(13)60037-0. PMID: 23787177.
Sang Z, Zhou L, Fan X, McCrimmon RJ. Radix astragali (huangqi) as a treatment for defective hypoglycemia counterregulation in diabetes. Am J Chin Med. 2010;38(6):1027-1038.
Kim J, Moon E, Kwon S. Effect of Astragalus membranaceus extract on diabetic nephropathy. Endocrinol Diabetes Metab Case Rep. 2014;2014:140063. doi: 10.1530/EDM-14-0063. Epub 2014 Sep 1. PMID: 25298884; PMCID: PMC4176648.
Liu S, Jia QJ, Peng YQ, Feng TH, Hu ST, Dong JE, Liang ZS. Advances in Mechanism Research on Polygonatum in Prevention and Treatment of Diabetes. Front Pharmacol. 2022 Feb 8;13:758501. doi: 10.3389/fphar.2022.758501. PMID: 35211009; PMCID: PMC8861320.
Shi Y, Si D, Chen D, Zhang X, Han Z, Yu Q, Liu J, Si J. Bioactive compounds from Polygonatum genus as anti-diabetic agents with future perspectives. Food Chem. 2023 May 15;408:135183. doi: 10.1016/j.foodchem.2022.135183. Epub 2022 Dec 12. PMID: 36566543.
Wang ZY, Wang X, Zhang DY, Hu YJ, Li S. [Traditional Chinese medicine network pharmacology: development in new era under guidance of network pharmacology evaluation method guidance]. Zhongguo Zhong Yao Za Zhi. 2022 Jan;47(1):7-17. Chinese. doi: 10.19540/j.cnki.cjcmm.20210914.702. PMID: 35178906.
Lai X, Xin W, Hu Y, Su SB, Li W, Lu A. Network Pharmacology and Traditional Medicine. Front Pharmacol. 2020;11:1194.
Ru J, Li P, Wang J, Zhou W, Li B, Huang C, Li P, Guo Z, Tao W, Yang Y, Xu X, Li Y, Wang Y, Yang L. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform. 2014 Apr 16;6:13. doi: 10.1186/1758-2946-6-13. PMID: 24735618; PMCID: PMC4001360.
Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, Feng T, Zhou L, Tang W, Zhan L, Fu X, Liu S, Bo X, Yu G. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021 Jul 1;2(3):100141. doi: 10.1016/j.xinn.2021.100141. PMID: 34557778; PMCID: PMC8454663.
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. doi: 10.1093/nar/28.1.235. PMID: 10592235; PMCID: PMC102472.
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009 Dec;30(16):2785-91. doi: 10.1002/jcc.21256. PMID: 19399780; PMCID: PMC2760638.
Lee MMY, McMurray JJV, Lorenzo-Almorós A, Kristensen SL, Sattar N, Jhund PS, Petrie MC. Diabetic cardiomyopathy. Heart. 2019 Feb;105(4):337-345. doi: 10.1136/heartjnl-2016-310342. Epub 2018 Oct 18. PMID: 30337334.
Mou X, Zhou DY, Zhou D, Liu K, Chen LJ, Liu WH. A bioinformatics and network pharmacology approach to the mechanisms of action of Shenxiao decoction for the treatment of diabetic nephropathy. Phytomedicine. 2020 Apr;69:153192. doi: 10.1016/j.phymed.2020.153192. Epub 2020 Feb 22. PMID: 32200292.
Schmidt AM. Diabetes Mellitus and Cardiovascular Disease. Arterioscler Thromb Vasc Biol. 2019 Apr;39(4):558-568. doi: 10.1161/ATVBAHA.119.310961. PMID: 30786741; PMCID: PMC6532416.
Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972 Nov 8;30(6):595-602. doi: 10.1016/0002-9149(72)90595-4. PMID: 4263660.
Liu ZH. Nephrology in china. Nat Rev Nephrol. 2013 Sep;9(9):523-8. doi: 10.1038/nrneph.2013.146. Epub 2013 Jul 23. PMID: 23877587.
Zhou XF, Zhou WE, Liu WJ, Luo MJ, Wu XQ, Wang Y, Liu P, Wen YM, Li JL, Zhao TT, Zhang HJ, Zhao HL, Li P. A Network Pharmacology Approach to Explore the Mechanism of HuangZhi YiShen Capsule for Treatment of Diabetic Kidney Disease. J Transl Int Med. 2021 Jun 18;9(2):98-113. doi: 10.2478/jtim-2021-0020. PMID: 34497749; PMCID: PMC8386324.
Qi C, Mao X, Zhang Z, Wu H. Classification and Differential Diagnosis of Diabetic Nephropathy. J Diabetes Res. 2017;2017:8637138. doi: 10.1155/2017/8637138. Epub 2017 Feb 20. PMID: 28316995; PMCID: PMC5337846.
Chen Y, Song X, Luo Y, Li G, Luo Y, Wang Z, He R, Lu J, Xiong G, Cheng H, Li H, Yang S. Network Pharmacology Approach to Investigate the Mechanism of Danggui-Shaoyao-San against Diabetic Kidney Disease. Evid Based Complement Alternat Med. 2023 Jan 3;2023:9208017. doi: 10.1155/2023/9208017. PMID: 36636607; PMCID: PMC9831705.
Gan Q, Wang J, Hu J, Lou G, Xiong H, Peng C, Zheng S, Huang Q. The role of diosgenin in diabetes and diabetic complications. J Steroid Biochem Mol Biol. 2020 Apr;198:105575. doi: 10.1016/j.jsbmb.2019.105575. Epub 2019 Dec 30. PMID: 31899316.
Arya P, Kumar P. Diosgenin: An ingress towards solving puzzle for diabetes treatment. J Food Biochem. 2022 Dec;46(12):e14390. doi: 10.1111/jfbc.14390. Epub 2022 Sep 15. PMID: 36106684.
Kanchan DM, Somani GS, Peshattiwar VV, Kaikini AA, Sathaye S. Renoprotective effect of diosgenin in streptozotocin induced diabetic rats. Pharmacol Rep. 2016 Apr;68(2):370-7. doi: 10.1016/j.pharep.2015.10.011. Epub 2015 Nov 14. PMID: 26922541.
Wu Y, Ye F, Lu Y, Yong H, Yin R, Chen B, Yong Y. Diosgenin glucoside protects against myocardial injury in diabetic mice by inhibiting RIP140 signaling. Am J Transl Res. 2018 Nov 15;10(11):3742-3749. PMID: 30662624; PMCID: PMC6291728.
Oza MJ, Kulkarni YA. Formononetin Treatment in Type 2 Diabetic Rats Reduces Insulin Resistance and Hyperglycemia. Front Pharmacol. 2018 Jul 18;9:739. doi: 10.3389/fphar.2018.00739. PMID: 30072892; PMCID: PMC6058024.
Huang Q, Chen H, Yin K, Shen Y, Lin K, Guo X, Zhang X, Wang N, Xin W, Xu Y, Gui D. Formononetin Attenuates Renal Tubular Injury and Mitochondrial Damage in Diabetic Nephropathy Partly via Regulating Sirt1/PGC-1α Pathway. Front Pharmacol. 2022 May 12;13:901234. doi: 10.3389/fphar.2022.901234. PMID: 35645821; PMCID: PMC9133725.
Zhuang K, Jiang X, Liu R, Ye C, Wang Y, Wang Y, Quan S, Huang H. Formononetin Activates the Nrf2/ARE Signaling Pathway Via Sirt1 to Improve Diabetic Renal Fibrosis. Front Pharmacol. 2021 Jan 13;11:616378. doi: 10.3389/fphar.2020.616378. PMID: 33519483; PMCID: PMC7845558.
Wang YY, Liu RX, Guo B, Xiao Y, Shi MJ, Pi MJ, Wen QY, Zhang GZ. [Down-regulation of PTEN expression in kidney and its role in development of diabetic nephropathy in rats]. Sheng Li Xue Bao. 2011 Aug 25;63(4):325-32. Chinese. PMID: 21861051.
Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell. 2017 Mar 23;169(1):132-147.e16. doi: 10.1016/j.cell.2017.02.031. PMID: 28340339; PMCID: PMC5556182.
Zhang SZ, Qiu XJ, Dong SS, Zhou LN, Zhu Y, Wang MD, Jin LW. MicroRNA-770-5p is involved in the development of diabetic nephropathy through regulating podocyte apoptosis by targeting TP53 regulated inhibitor of apoptosis 1. Eur Rev Med Pharmacol Sci. 2019 Feb;23(3):1248-1256. doi: 10.26355/eurrev_201902_17018. PMID: 30779094.
Riley T, Sontag E, Chen P, Levine A. Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol. 2008 May;9(5):402-12. doi: 10.1038/nrm2395. PMID: 18431400.
Ohiro Y, Garkavtsev I, Kobayashi S, Sreekumar KR, Nantz R, Higashikubo BT, Duffy SL, Higashikubo R, Usheva A, Gius D, Kley N, Horikoshi N. A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF). FEBS Lett. 2002 Jul 31;524(1-3):163-71. doi: 10.1016/s0014-5793(02)03049-1. PMID: 12135761.
Yamagishi S. Advanced glycation end products and receptor-oxidative stress system in diabetic vascular complications. Ther Apher Dial. 2009 Dec;13(6):534-9. doi: 10.1111/j.1744-9987.2009.00775.x. PMID: 19954478.
Vlassara H, Striker GE. AGE restriction in diabetes mellitus: a paradigm shift. Nat Rev Endocrinol. 2011 May 24;7(9):526-39. doi: 10.1038/nrendo.2011.74. PMID: 21610689; PMCID: PMC3708644.
Wang B, Yao K, Wise AF, Lau R, Shen HH, Tesch GH, Ricardo SD. miR-378 reduces mesangial hypertrophy and kidney tubular fibrosis via MAPK signalling. Clin Sci (Lond). 2017 Mar 1;131(5):411-423. doi: 10.1042/CS20160571. Epub 2017 Jan 4. PMID: 28053239.
Ururahy MA, de Souza KS, Oliveira YM, Loureiro MB, da Silva HP, Freire-Neto FP, Bezerra JF, Luchessi AD, Doi SQ, Hirata RD, Almeida Md, Arrais RF, Hirata MH, de Rezende AA. Association of polymorphisms in IL6 gene promoter region with type 1 diabetes and increased albumin-to-creatinine ratio. Diabetes Metab Res Rev. 2015 Jul;31(5):500-6. doi: 10.1002/dmrr.2621. Epub 2014 Dec 8. PMID: 25384728.