Generic placeholder image

Combinatorial Chemistry & High Throughput Screening


ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Effect and Mechanisms of Huangqi-Shanzhuyu in the Treatment of Diabetic Nephropathy based on Network Pharmacology and In Vitro Experiments

Author(s): Yu Han*, Shufei Wei, Chao Liu, Ying Nie, Shizhao Yuan, Yinghua Ma, Yile Zhao and Guying Zhang

Volume 27, Issue 14, 2024

Published on: 10 October, 2023

Page: [2078 - 2089] Pages: 12

DOI: 10.2174/0113862073241153231003094411

Price: $65


Background: Huangqi-Shanzhuyu (HS), a classic combination of Chinese herbal formulae, has been widely used for the treatment of diabetic nephropathy (DN). However, its pharmacological mechanism of action is still unclear.

Methods: The active ingredients of HS and their potential targets were identified through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the DN-related targets were determined from GeneCards, Online Mendelian Inheritance in Man (OMIM), PharmGkb, and Therapeutic Target Database (TTD). The Cytoscape software was used to construct a herb-disease-target network and screen core genes. STRING was employed to generate a protein-protein interaction (PPI) network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict the mechanism of action of HS in DN. Animal experiments and molecular docking were used to verify the potential mechanism.

Results: In total, 40 active ingredients and 180 effective targets of HS in DN were identified and 1115 DN-related targets were retrieved. From the PPI network, VEGFA, AKT1, IL6, IL1B, TP53, MMP9, PTGS2, CASP3, EGF and EGFR were identified as core genes. The anti-DN mechanism mainly involved multiple signaling pathways such as AGEs-RAGE. Animal experiments and molecular docking analysis confirmed that HS downregulated the expression of IL-1 and IL-6 via kaempferol-mediated inhibition of JNK1 phosphorylation.

Conclusion: HS exhibits a therapeutic effect in DN through its multiple ingredients that act on several targets and multiple signaling pathways, including AGEs-RAGE.

Keywords: Huangqi shanzhuyu, diabetic nephropathy, molecular docking, JNK, OMIM, TTD.

Graphical Abstract
Valencia, W.M.; Florez, H. How to prevent the microvascular complications of type 2 diabetes beyond glucose control. BMJ, 2017, 356, i6505.
[] [PMID: 28096078]
Arora, M.K.; Singh, U.K. Molecular mechanisms in the pathogenesis of diabetic nephropathy: An update. Vascul. Pharmacol., 2013, 58(4), 259-271.
[] [PMID: 23313806]
Kopel, J.; Pena-Hernandez, C.; Nugent, K. Evolving spectrum of diabetic nephropathy. World J. Diabetes, 2019, 10(5), 269-279.
Samsu, N. Diabetic nephropathy: Challenges in pathogenesis, diagnosis, and treatment. BioMed Res. Int., 2021, 2021, 1-17.
[] [PMID: 34307650]
Tang, G.; Li, S.; Zhang, C.; Chen, H.; Wang, N.; Feng, Y. Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management. Acta Pharm. Sin. B, 2021, 11(9), 2749-2767.
[] [PMID: 34589395]
Peng, Y.; Ren, D.; Song, Y.; Hu, Y.; Wu, L.; Wang, Q.; He, Y.; Zhou, H.; Liu, S.; Cong, H. Effects of a combined fucoidan and traditional Chinese medicine formula on hyperglycaemia and diabetic nephropathy in a type II diabetes mellitus rat model. Int. J. Biol. Macromol., 2020, 147, 408-419.
[] [PMID: 31881302]
Shang, X.N. Systematic Review of Astragalus Injection Combined with ACEI or ARB in the Treatment of Stage III and IV Diabetic Nephropathy; Beijing University of Chinese Medicine, 2017.
Gao, X.; Liu, Y.; An, Z.; Ni, J. Active components and pharmacological effects of cornus officinalis: Literature review. Front. Pharmacol., 2021, 12, 633447.
[] [PMID: 33912050]
Zhou, Y.C.; Zhang, L.J.; Zhang, Y.L. New progress on chemical constituents and pharmacological effects of cornus officinalis. Inf. Tradit. Chin. Med., 2020, 37(01), 114-120.
Liu, J.; Chen, B.G.; Zhang, X.C. Characteristics of medication use in traditional Chinese medicine. J. Tradit. Chin. Med., 2016, 15(05), 39-41.
Yang, C.M.; Cheng, W.; Li, Y.Y.; Gao, J.D. Based on real-world data, we discussed the treatment of diabetic nephropathy by traditional Chinese medicine Study of medication rules. Mod. Traditional Chin. Med. Materia Medica-World Sci. Technol., 2022, 24(10), 3949-3957.
Ha, J. SMAP: Similarity-based matrix factorization framework for inferring miRNA-disease association. Knowl. Base. Syst., 2023, 263, 110295.
Jiashuo, W.U.; Fangqing, Z.; Zhuangzhuang, L.I.; Weiyi, J.; Yue, S. Integration strategy of network pharmacology in Traditional Chinese Medicine: A narrative review. J. Tradit. Chin. Med., 2022, 42(3), 479-486.
[PMID: 35610020]
Nogales, C.; Mamdouh, Z.M.; List, M.; Kiel, C.; Casas, A.I.; Schmidt, H.H.H.W. Network pharmacology: Curing causal mechanisms instead of treating symptoms. Trends Pharmacol. Sci., 2022, 43(2), 136-150.
[] [PMID: 34895945]
Liao, H.; Hu, L.; Cheng, X.; Wang, X.; Li, J.; Banbury, L.; Li, R. Are the therapeutic effects of huangqi (Astragalus membranaceus) on diabetic nephropathy correlated with its regulation of macrophage inos activity? J. Immunol. Res., 2017, 2017, 1-9.
[] [PMID: 29250558]
Wu, C.; Wang, J.; Zhang, R.; Zhao, H.; Li, X.; Wang, L.; Liu, P.; Li, P. Research progress on Cornus officinalis and its active compounds in the treatment of diabetic nephropathy. Front. Pharmacol., 2023, 14, 1207777.
[] [PMID: 37475719]
Hosseini, A.; Razavi, B.M.; Banach, M.; Hosseinzadeh, H. Quercetin and metabolic syndrome: A review. Phytother. Res., 2021, 35(10), 5352-5364.
[] [PMID: 34101925]
Yang, Y.; Chen, Z.; Zhao, X.; Xie, H.; Du, L.; Gao, H.; Xie, C. Mechanisms of Kaempferol in the treatment of diabetes: A comprehensive and latest review. Front. Endocrinol., 2022, 13, 990299.
[] [PMID: 36157449]
Babu, S.; Jayaraman, S. An update on β-sitosterol: A potential herbal nutraceutical for diabetic management. Biomed. Pharmacother., 2020, 131, 110702.
[] [PMID: 32882583]
Kanehisa, M.; Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res., 2000, 28(1), 27-30.
[] [PMID: 10592173]
Chen, Y.; Chen, J.; Jiang, M.; Fu, Y.; Zhu, Y.; Jiao, N.; Liu, L.; Du, Q.; Wu, H.; Xu, H.; Sun, J. Loganin and catalpol exert cooperative ameliorating effects on podocyte apoptosis upon diabetic nephropathy by targeting AGEs-RAGE signaling. Life Sci., 2020, 252, 117653.
[] [PMID: 32277978]
Wu, X.Q.; Zhang, D.D.; Wang, Y.N.; Tan, Y.Q.; Yu, X.Y.; Zhao, Y.Y. AGE/RAGE in diabetic kidney disease and ageing kidney. Free Radic. Biol. Med., 2021, 171, 260-271.
[] [PMID: 34019934]
Khalid, M.; Petroianu, G.; Adem, A. Advanced glycation end products and diabetes mellitus: Mechanisms and perspectives. Biomolecules, 2022, 12(4), 542.
[] [PMID: 35454131]
Li, J.; Ji, T.; Su, S.; Zhu, Y.; Chen, X.; Shang, E.; Guo, S.; Qian, D.; Duan, J. Mulberry leaves ameliorate diabetes via regulating metabolic profiling and AGEs/RAGE and p38 MAPK/NF-κB pathway. J. Ethnopharmacol., 2022, 283, 114713.
[] [PMID: 34626776]
Jeong, S.R.; Park, H.Y.; Kim, Y.; Lee, K.W. Methylglyoxal-derived advanced glycation end products induce matrix metalloproteinases through activation of ERK/JNK/NF-κB pathway in kidney proximal epithelial cells. Food Sci. Biotechnol., 2020, 29(5), 675-682.
[] [PMID: 32419966]
Abdelkader, N.F.; Ibrahim, S.M.; Moustafa, P.E.; Elbaset, M.A. Inosine mitigated diabetic peripheral neuropathy via modulating GLO1/AGEs/RAGE/NF-κB/Nrf2 and TGF-β/PKC/TRPV1 signaling pathways. Biomed. Pharmacother., 2022, 145, 112395.
[] [PMID: 34775239]
Stenvinkel, P.; Ketteler, M.; Johnson, R.J.; Lindholm, B.; Pecoits-Filho, R.; Riella, M.; Heimbürger, O.; Cederholm, T.; Girndt, M. IL-10, IL-6, and TNF-α: Central factors in the altered cytokine network of uremia—The good, the bad, and the ugly. Kidney Int., 2005, 67(4), 1216-1233.
[] [PMID: 15780075]
Amdur, R.L.; Feldman, H.I.; Gupta, J.; Yang, W.; Kanetsky, P.; Shlipak, M.; Rahman, M.; Lash, J.P.; Townsend, R.R.; Ojo, A.; Roy-Chaudhury, A.; Go, A.S.; Joffe, M.; He, J.; Balakrishnan, V.S.; Kimmel, P.L.; Kusek, J.W.; Raj, D.S. Inflammation and progression of CKD: The CRIC study. Clin. J. Am. Soc. Nephrol., 2016, 11(9), 1546-1556.
[] [PMID: 27340285]
Taslıpınar, A.; Yaman, H.; Yılmaz, M.I.; Demırbas, S.; Saglam, M.; Taslıpınar, M.Y.; Agıllı, M.; Kurt, Y.G.; Sonmez, A.; Azal, O.; Bolu, E.; Yenıcesu, M.; Kutlu, M. The relationship between inflammation, endothelial dysfunction and proteinuria in patients with diabetic nephropathy. Scand. J. Clin. Lab. Invest., 2011, 71(7), 606-612.
[] [PMID: 21864054]
Papaoikonomou, S.; Tentolouris, N.; Tousoulis, D.; Papadodiannis, D.; Miliou, A.; Papageorgiou, N.; Hatzis, G.; Stefanadis, C. The association of the 174G>C polymorphism of interleukin 6 gene with diabetic nephropathy in patients with type 2 diabetes mellitus. J. Diabetes Complications, 2013, 27(6), 576-579.
[] [PMID: 23871133]
Chang, W.T.; Huang, M.C.; Chung, H.F.; Chiu, Y.F.; Chen, P.S.; Chen, F.P.; Lee, C.Y.; Shin, S.J.; Hwang, S.J.; Huang, Y.F.; Hsu, C.C. Interleukin-6 gene polymorphisms correlate with the progression of nephropathy in Chinese patients with type 2 diabetes: A prospective cohort study. Diabetes Res. Clin. Pract., 2016, 120, 15-23.
[] [PMID: 27500547]
Ung, T.T.; Nguyen, T.T.; Lian, S.; Li, S.; Xia, Y.; Kim, N.H.; Jung, Y.D. Nicotine stimulates IL-6 expression by activating the AP-1 and STAT-3 pathways in human endothelial EA.hy926 cells. J. Cell. Biochem., 2019, 120(4), 5531-5541.
[] [PMID: 30317657]
Xiao, W.; Hodge, D.R.; Wang, L.; Yang, X.; Zhang, X.; Farrar, W.L. NF-kappaB activates IL-6 expression through cooperation with c-Jun and IL6-AP1 site, But is independent of its IL6-NFkappaB regulatory site in autocrine human multiple myeloma cells. Cancer Biol. Ther., 2004, 3(10), 1007-1017.
[] [PMID: 15467434]
Jang, S.; Kelley, K.W.; Johnson, R.W. Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc. Natl. Acad. Sci. , 2008, 105(21), 7534-7539.
[] [PMID: 18490655]
Saklatvala, J.; Dean, J.; Finch, A. Protein kinase cascades in intracellular signalling by interleukin-I and tumour necrosis factor. Biochem. Soc. Symp., 1999, 64, 63-77.
[PMID: 10207621]
Li, W.; Zheng, S.; Tang, C.; Zhu, Y.; Wang, X. JNK-AP-1 pathway involved in interleukin-1β-induced calcitonin gene-related peptide secretion in human type II alveolar epithelial cells. Peptides, 2007, 28(6), 1252-1259.
[] [PMID: 17481780]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy