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Network Pharmacology-Based Approach to Unveil the Therapeutic Mechanism of Viburnum opulus L. on Glomerulonephritis

Year 2025, Volume: 46 Issue: 2, 348 - 359, 30.06.2025

Şeyda Kaya , Sevgi Durna Daştan

https://doi.org/10.17776/csj.1669595

Abstract

This study aimed to investigate the potential targets and pathways of the bioactive compounds of Viburnum opulus L. – a plant recognized in ethnopharmacology for its therapeutic applications in renal disorders - on glomerulonephritis (GN) disease. The phytochemical profile of V. opulus was obtained from review articles in the literature on plant contents. GN-associated target genes were retrieved from the GeneCards database, and interaction mapping was conducted using Cytoscape 3.10.0. The intersection of compound - target - disease was imported into the STRING database to create a PPI network. GO and KEGG enrichment analyses were applied to define the biological functions of the targets. A molecular docking study simulated the binding capabilities of key targets and active ingredients. A total of 9 bioactive constituents were identified from V. opulus, with rutin and quercetin demonstrating the highest binding affinities. The resulting compound–target interaction network consisted of 125 nodes and 358 edges. Central hub proteins within the PPI network included TP53, SRC, and EGFR indicating their potential role in the mechanism of action. GO and KEGG analyses suggested that the treatment of GN by V. opulus mainly involves the generation of cellular response to chemical and oxidative stress, protein tyrosine kinase activity, transcription regulatory complex, and other biological processes. The results of KEGG enrichment analysis indicate that V. opulus mainly involves some pathways, such as chemical carcinogenesis-receptor activation, EGFR tyrosine kinase inhibitor resistance in the treatment of GN. Molecular docking data presented that rutin and quercetin have the highest affinity score with TP53, SRC, and EGFR proteins. Overall, this study reveals the active compounds and potential molecular pathways of V. opulus in the treatment of GN and presents a source for further basic studies.

Keywords

Viburnum opulus Glomerulonephritis Network pharmacology Molecular docking

Thanks

I am grateful to thank Sivas Cumhuriyet University for their support and permission to access the Maestro Schrödinger program.

References

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  • [15] Tang D., Chen M., Huang X., Zhang G., Zeng L., Zhang G., et al., SRplot: A free online platform for data visualization and graphing, PLoS One, 18 (2023) e0294236.
  • [16] Burley S.K., Bhikadiya C., Bi C., Bittrich S., Chen L., Crichlow G.V., et al., RCSB Protein Data Bank: powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences, Nucleic Acids Res., 49 (2021) D437–D451.
  • [17] Kim S., Chen J., Cheng T., Gindulyte A., He J., He S., et al., PubChem 2019 update: improved access to chemical data, Nucleic Acids Res., 47 (2019) D1102–D1109.
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  • [24] Ferraz C.R., Carvalho T.T., Manchope M.F., Artero N.A., Rasquel-Oliveira F.S., Fattori V., et al., Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development, Molecules, 25 (2020) 762.
  • [25] Ullah A., Munir S., Badshah S.L., Khan N., Ghani L., Poulson B.G., et al., Important Flavonoids and Their Role as a Therapeutic Agent, Molecules, 25 (2020) 5243.
  • [26] Crozier A., Jaganath I.B., Clifford M.N., Dietary phenolics: chemistry, bioavailability and effects on health, Nat. Prod. Rep., 26 (2009) 1001.
  • [27] Cui W., Hu G., Peng J., Mu L., Liu J., Qiao L., Quercetin Exerted Protective Effects in a Rat Model of Sepsis via Inhibition of Reactive Oxygen Species (ROS) and Downregulation of High Mobility Group Box 1 (HMGB1) Protein Expression, Med. Sci. Monit., 25 (2019) 5795–5800.
  • [28] Karimi A., Naeini F., Asghari Azar V., Hasanzadeh M., Ostadrahimi A., Niazkar H.R., et al., A comprehensive systematic review of the therapeutic effects and mechanisms of action of quercetin in sepsis, Phytomedicine, 86 (2021) 153567.
  • [29] de Pádua Lúcio K., Rabelo A.C.S., Araújo C.M., Brandão G.C., de Souza G.H.B., da Silva R.G., et al., Anti‐Inflammatory and Antioxidant Properties of Black Mulberry (Morus nigra L.) in a Model of LPS‐Induced Sepsis, Oxid. Med. Cell. Longev., 2018 (2018) 5048031.
  • [30] Li X., Wei S., Niu S., Ma X., Li H., Jing M., et al., Network pharmacology prediction and molecular docking-based strategy to explore the potential mechanism of Huanglian Jiedu Decoction against sepsis, Comput. Biol. Med., 144 (2022) 105389.
  • [31] Liu Q., Yu S., Zhao W., Qin S., Chu Q., Wu K., EGFR-TKIs resistance via EGFR-independent signaling pathways, Mol. Cancer, 17(1) (2018) 53.
  • [32] Bollée G., Flamant M., Schordan S., Fligny C., Rumpel E., Milon M., et al., Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis, Nat. Med., 17(10) (2011) 1242–1250.
  • [33] Tang J., Liu N., Zhuang S., Role of epidermal growth factor receptor in acute and chronic kidney injury, Kidney Int., 83(5) (2013) 804–810.
  • [34] Chen J., Chen J.-K., Nagai K., Plieth D., Tan M., Lee T.-C., et al., EGFR Signaling Promotes TGFβ-Dependent Renal Fibrosis, J. Am. Soc. Nephrol., 23 (2) (2012) 215–224.
  • [35] Striker L.J., Doi T., Elliot S., Striker G.E., The contribution of glomerular mesangial cells to progressive glomerulosclerosis, Semin. Nephrol., 9 (4) (1989) 318–328.
  • [36] alal D.I., Kone B.C., Src activation of NF-kappaB augments IL-1beta-induced nitric oxide production in mesangial cells, J. Am. Soc. Nephrol., 17(1) (2006) 99–106.
  • [37] Gruden G., Araf S., Zonca S., Burt D., Thomas S., Gnudi L., et al., IGF-I induces vascular endothelial growth factor in human mesangial cells via a Src-dependent mechanism, Kidney Int., 63(4) (2003) 1249–1255.
  • [38] Wu H., Shi Y., Deng X., Su Y., Du C., Wei J., et al., Inhibition of c-Src/p38 MAPK pathway ameliorates renal tubular epithelial cells apoptosis in db/db mice, Mol. Cell. Endocrinol., 417 (2015) 27–35.
  • [39] Wang J., Zhuang S., Src family kinases in chronic kidney disease, Am. J. Physiol. Renal Physiol., 313 (3) (2017) F721–F728.
  • [40] Vousden K.H., Prives C., Blinded by the Light: The Growing Complexity of p53, Cell, 137(3) (2009) 413–431.
  • [41] Overstreet J.M., Gifford C.C., Tang J., Higgins P.J., Samarakoon R., Emerging role of tumor suppressor p53 in acute and chronic kidney diseases, Cell. Mol. Life Sci., 79(9) (2022) 474.
  • [42] Molitoris B.A., Dagher P.C., Sandoval R.M., Campos S.B., Ashush H., Fridman E., et al., siRNA Targeted to p53 Attenuates Ischemic and Cisplatin-Induced Acute Kidney Injury, J. Am. Soc. Nephrol., 20(8) (2009) 1754–1764.

Year 2025, Volume: 46 Issue: 2, 348 - 359, 30.06.2025

Şeyda Kaya , Sevgi Durna Daştan

https://doi.org/10.17776/csj.1669595

Abstract

References

  • [1] Madsen K.M., Nielsen C.S., Tisher C., Anatomy of the Kidney, Brenner and Rector's The Kidney, (2008).
  • [2] Chadban S., Atkins R., Glomerulonephritis, The Lancet, 365 (2005) 1797–1806.
  • [3] Houghton P.J., Traditional plant medicines as a source of new drugs, Trease and Evans’ Pharmacognosy, Elsevier, (2009) 62–74.
  • [4] Kajszczak D., Zakłos-Szyda M., Podsędek A., Viburnum opulus L.- A Review of Phytochemistry and Biological Effects, Nutrients, 12 (2020) 3398.
  • [5] Li L., Yang L., Yang L., He C., He Y., Chen L., et al., Network pharmacology: a bright guiding light on the way to explore the personalized precise medication of traditional Chinese medicine, Chin. Med., 18(1) (2023) 146.
  • [6] Hopkins A.L., Network pharmacology: the next paradigm in drug discovery, Nat. Chem. Biol., 4(11) (2008) 682–690.
  • [7] Torres P.H.M., Sodero A.C.R., Jofily P., Silva-Jr F.P., Key Topics in Molecular Docking for Drug Design, Int. J. Mol. Sci., 20(18) (2019) 4574.
  • [8] Polka D., Podsędek A., Koziołkiewicz M., Comparison of Chemical Composition and Antioxidant Capacity of Fruit, Flower and Bark of Viburnum opulus, Plant Foods Hum. Nutr., 74 (2019) 436–442.
  • [9] Stelzer G., Rosen N., Plaschkes I., Zimmerman S., Twik M., Fishilevich S., et al., The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses, Curr. Protoc. Bioinform., 54 (2016).
  • [10] Daina A., Michielin O., Zoete V., SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules, Nucleic Acids Res., 47 (2019) W357–W364.
  • [11] Shannon P., Markiel A., Ozier O., Baliga N.S., Wang J.T., Ramage D., et al., Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks, Genome Res., 13 (2003) 2498–2504.
  • [12] Bardou P., Mariette J., Escudié F., Djemiel C., Klopp C., jvenn: an interactive Venn diagram viewer, BMC Bioinform., 15 (2014) 293.
  • [13] Szklarczyk D., Kirsch R., Koutrouli M., Nastou K., Mehryary F., Hachilif R., et al., The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest, Nucleic Acids Res., 51 (2023) D638–D646.
  • [14] Zhou Y., Zhou B., Pache L., Chang M., Khodabakhshi A.H., Tanaseichuk O., et al., Metascape provides a biologist-oriented resource for the analysis of systems-level datasets, Nat. Commun., 10 (2019) 1523.
  • [15] Tang D., Chen M., Huang X., Zhang G., Zeng L., Zhang G., et al., SRplot: A free online platform for data visualization and graphing, PLoS One, 18 (2023) e0294236.
  • [16] Burley S.K., Bhikadiya C., Bi C., Bittrich S., Chen L., Crichlow G.V., et al., RCSB Protein Data Bank: powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences, Nucleic Acids Res., 49 (2021) D437–D451.
  • [17] Kim S., Chen J., Cheng T., Gindulyte A., He J., He S., et al., PubChem 2019 update: improved access to chemical data, Nucleic Acids Res., 47 (2019) D1102–D1109.
  • [18] Schrödinger Release 2021-3: Maestro, LLC, New York, Schrödinger, (2021).
  • [19] Liu T., Gao Y.C., Qin X.J., Gao J.R., Exploring the mechanism of Jianpi Qushi Huayu Formula in the treatment of chronic glomerulonephritis based on network pharmacology, Naunyn Schmiedebergs Arch. Pharmacol., 394 (12) (2021) 2451–2470.
  • [20] Venuthurupalli S.K., Hoy W.E., Healy H.G., Cameron A., Fassett R.G., CKD.QLD: establishment of a chronic kidney disease [CKD] registry in Queensland, Australia, BMC Nephrol., 18 (2017) 189.
  • [21] Kizilay F., Ulker V., Celik O., Ozdemir T., Cakmak O., Can E., et al., The evaluation of the effectiveness of Gilaburu (Viburnum opulus L.) extract in the medical expulsive treatment of distal ureteral stones, Turk. J. Urol., 45 (Suppl. 1) (2019) 63–69.
  • [22] Rock K.L., Kono H., The Inflammatory Response to Cell Death, Annu. Rev. Pathol., 3 (2008) 99–126.
  • [23] Ambriz-Perez D.L., Leyva-Lopez N., Gutierrez-Grijalva E.P., Heredia J.B., Phenolic compounds: Natural alternative in inflammation treatment. A Review, Cogent Food Agric., 2 (2016) 1131412.
  • [24] Ferraz C.R., Carvalho T.T., Manchope M.F., Artero N.A., Rasquel-Oliveira F.S., Fattori V., et al., Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development, Molecules, 25 (2020) 762.
  • [25] Ullah A., Munir S., Badshah S.L., Khan N., Ghani L., Poulson B.G., et al., Important Flavonoids and Their Role as a Therapeutic Agent, Molecules, 25 (2020) 5243.
  • [26] Crozier A., Jaganath I.B., Clifford M.N., Dietary phenolics: chemistry, bioavailability and effects on health, Nat. Prod. Rep., 26 (2009) 1001.
  • [27] Cui W., Hu G., Peng J., Mu L., Liu J., Qiao L., Quercetin Exerted Protective Effects in a Rat Model of Sepsis via Inhibition of Reactive Oxygen Species (ROS) and Downregulation of High Mobility Group Box 1 (HMGB1) Protein Expression, Med. Sci. Monit., 25 (2019) 5795–5800.
  • [28] Karimi A., Naeini F., Asghari Azar V., Hasanzadeh M., Ostadrahimi A., Niazkar H.R., et al., A comprehensive systematic review of the therapeutic effects and mechanisms of action of quercetin in sepsis, Phytomedicine, 86 (2021) 153567.
  • [29] de Pádua Lúcio K., Rabelo A.C.S., Araújo C.M., Brandão G.C., de Souza G.H.B., da Silva R.G., et al., Anti‐Inflammatory and Antioxidant Properties of Black Mulberry (Morus nigra L.) in a Model of LPS‐Induced Sepsis, Oxid. Med. Cell. Longev., 2018 (2018) 5048031.
  • [30] Li X., Wei S., Niu S., Ma X., Li H., Jing M., et al., Network pharmacology prediction and molecular docking-based strategy to explore the potential mechanism of Huanglian Jiedu Decoction against sepsis, Comput. Biol. Med., 144 (2022) 105389.
  • [31] Liu Q., Yu S., Zhao W., Qin S., Chu Q., Wu K., EGFR-TKIs resistance via EGFR-independent signaling pathways, Mol. Cancer, 17(1) (2018) 53.
  • [32] Bollée G., Flamant M., Schordan S., Fligny C., Rumpel E., Milon M., et al., Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis, Nat. Med., 17(10) (2011) 1242–1250.
  • [33] Tang J., Liu N., Zhuang S., Role of epidermal growth factor receptor in acute and chronic kidney injury, Kidney Int., 83(5) (2013) 804–810.
  • [34] Chen J., Chen J.-K., Nagai K., Plieth D., Tan M., Lee T.-C., et al., EGFR Signaling Promotes TGFβ-Dependent Renal Fibrosis, J. Am. Soc. Nephrol., 23 (2) (2012) 215–224.
  • [35] Striker L.J., Doi T., Elliot S., Striker G.E., The contribution of glomerular mesangial cells to progressive glomerulosclerosis, Semin. Nephrol., 9 (4) (1989) 318–328.
  • [36] alal D.I., Kone B.C., Src activation of NF-kappaB augments IL-1beta-induced nitric oxide production in mesangial cells, J. Am. Soc. Nephrol., 17(1) (2006) 99–106.
  • [37] Gruden G., Araf S., Zonca S., Burt D., Thomas S., Gnudi L., et al., IGF-I induces vascular endothelial growth factor in human mesangial cells via a Src-dependent mechanism, Kidney Int., 63(4) (2003) 1249–1255.
  • [38] Wu H., Shi Y., Deng X., Su Y., Du C., Wei J., et al., Inhibition of c-Src/p38 MAPK pathway ameliorates renal tubular epithelial cells apoptosis in db/db mice, Mol. Cell. Endocrinol., 417 (2015) 27–35.
  • [39] Wang J., Zhuang S., Src family kinases in chronic kidney disease, Am. J. Physiol. Renal Physiol., 313 (3) (2017) F721–F728.
  • [40] Vousden K.H., Prives C., Blinded by the Light: The Growing Complexity of p53, Cell, 137(3) (2009) 413–431.
  • [41] Overstreet J.M., Gifford C.C., Tang J., Higgins P.J., Samarakoon R., Emerging role of tumor suppressor p53 in acute and chronic kidney diseases, Cell. Mol. Life Sci., 79(9) (2022) 474.
  • [42] Molitoris B.A., Dagher P.C., Sandoval R.M., Campos S.B., Ashush H., Fridman E., et al., siRNA Targeted to p53 Attenuates Ischemic and Cisplatin-Induced Acute Kidney Injury, J. Am. Soc. Nephrol., 20(8) (2009) 1754–1764.
There are 42 citations in total.

Details

Primary Language English
Subjects Biological Network Analysis, Molecular Docking
Journal Section Natural Sciences
Authors

Şeyda Kaya 0000-0001-8489-8687

Sevgi Durna Daştan 0009-0003-8565-6841

Publication Date June 30, 2025
Submission Date April 4, 2025
Acceptance Date May 28, 2025
Published in Issue Year 2025Volume: 46 Issue: 2

Cite

APA Kaya, Ş., & Durna Daştan, S. (2025). Network Pharmacology-Based Approach to Unveil the Therapeutic Mechanism of Viburnum opulus L. on Glomerulonephritis. Cumhuriyet Science Journal, 46(2), 348-359. https://doi.org/10.17776/csj.1669595