The Efficacy and Underlying Pathway Mechanisms of ShiDuGao Treatment for Anus Eczema Based on GEO Datasets and Network Pharmacology

Published: January 12, 2024

doi:

Song Wang*^1,2,3, Wanyi Xiao*^1,2, Anqi He², Jinyan Jia², Gang Liu²

¹Department of General Surgery,Tianjin Medical University General Hospital, ²Tianjin General Surgery Institute, ³Department of General Surgery,Zibo Municipal Hospital

Summary

This investigative effort sought to elucidate the mechanism of topical drug administration using a synergistic integration of network pharmacology and gene expression omnibus (GEO) datasets. This article evaluated the feasibility, target, and mechanism of ShiDuGao (SDG) in treating anus eczema.

Abstract

Anus eczema is a chronic and recurrent inflammatory skin disease affecting the area around the anus. While the lesions primarily occur in the anal and perianal skin, they can also extend to the perineum or genitalia. ShiDuGao (SDG) has been found to possess significant reparative properties against anal pruritus, exudation control, moisture reduction, and skin repair. However, the genetic targets and pharmacological mechanisms of SDG on anal eczema have yet to be comprehensively elucidated and discussed. Consequently, this study employed a network pharmacological approach and utilized gene expression omnibus (GEO) datasets to investigate gene targets. Additionally, a protein-protein interaction network (PPI) was established, resulting in the identification of 149 targets, of which 59 were deemed hub genes, within the “drug-target-disease” interaction network.

The gene function of SDG in the treatment of perianal eczema was assessed through the utilization of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. Subsequently, the anti-perianal eczema function and potential pathway of SDG, as identified in network pharmacological analysis, were validated using molecular docking methodology. The biological processes associated with SDG-targeted genes and proteins in the treatment of anus eczema primarily encompass cytokine-mediated responses, inflammatory responses, and responses to lipopolysaccharide, among others. The results of the pathway enrichment and functional annotation analyses suggest that SDG plays a crucial role in preventing and managing anal eczema by regulating the Shigellosis and herpes simplex virus 1 infection pathways. Network pharmacology and GEO database analysis confirms the multi-target nature of SDG in treating anal eczema, specifically by modulating TNF, MAPK14, and CASP3, which are crucial hub targets in the TNF and MAPK signaling pathways. These findings provide a clear direction for further investigation into SDG’s therapeutic mechanism for anal eczema while highlighting its potential as an effective treatment approach for this debilitating condition.

Introduction

Anal eczema is an allergic skin condition that affects the perianal region and mucosa, exhibiting various clinical manifestations¹. The characteristic symptoms include anal erythema, papules, blisters, erosion, exudates, and crusting. These symptoms mostly arise due to scratching, thickening, and roughness of the affected area².

Anal eczema, characterized by a prolonged duration of the disease, recurrent attacks, and challenging treatment, can have adverse effects on patients' physical and mental health³. The pathogenesis of anal eczema is not yet clear, and modern medicine suggests that it may be related to local anal lesions, diet, environment, genetics, and other factors⁴. In addition to avoiding contact with irritants and potential allergens, the treatment of anal eczema mainly focuses on methods such as inhibiting inflammation, anti-allergy, and relieving itching⁵.

SDG has been extensively utilized for the treatment of anal eczema and other anal conditions. SDG regulates anal skin exudation, reduces moisture, repairs anal skin, and effectively addresses pruritus⁶^,⁷^,⁸. Furthermore, SDG has the potential to regulate perianus microbiota, thereby improving anus eczema⁹^,¹⁰.

Network pharmacology, a novel and interdisciplinary, cutting-edge bioinformatic approach in the realm of artificial intelligence and big data, provides an in-depth exploration of traditional Chinese medicine. This discipline emphasizes the systemic expounding of molecular correlation rules between drugs and diseases from an ecological network perspective. It has been extensively adopted for various aspects, including identifying key active ingredients in herb extracts, deciphering their global mechanisms of action, formulating drug combinations, and studying prescription compatibility. Traditional Chinese prescriptions exhibit the attributes of multi-component and multi-target, signifying their substantial adaptability to the realm of network pharmacology. Driven by this methodology, fresh perspectives have emerged in the examination of complex traditional Chinese medicine systems, furnishing robust technical support for clinical application rationalization and drug innovation¹¹^,¹²^,¹³^,¹⁴.

This study aims to explore the mechanism of effectiveness of SDG in the treatment of anal eczema. This investigative effort sought to elucidate the mechanism of topical drug administration using a synergistic integration of network pharmacology and GEO datasets. The findings provide valuable insights into the efficacy and underlying mechanisms of SDG in the management of anus eczema, indicating its potential as an effective therapeutic approach for this condition.The detailed workflow diagram of the study is presented in Figure 1.

Protocol

This study does not refer to ethical approval and consent to participate. The data used in this study was obtained from gene databases. 1. Prediction of disease targets Access the GeneCards database (https://www.genecards.org) and online Mendelian inheritance in man database (OMIM, https://www.omim.org), utilizing "anus eczema" as the search term for disease targets. Download the spreadsheets of the disease targets. Delete the repeated targets to …

Representative Results

Anus eczema-related genes, SDG target genes, and common targets A total of 958 potential gene candidates were screened in Genecards and 634 in OMIM databases, while duplicates were excluded. To gain a comprehensive understanding of anal eczema-related genes, the findings from multiple databases were amalgamated, yielding a total of 958 distinct genes. Consequently, a protein-protein interaction network (PPI) specific to anal eczema was meticulously formulated. SDG is composed of five traditional Ch…

Discussion

Atopic dermatitis is a specific form of eczema that shares underlying mechanisms with eczema. Hub genes believed to be related to this condition are TNF, MAPK14, and CASP3. The therapeutic effects of SDG on anal eczema are mainly attributed to its action on the TNF and MAPK signaling pathways via these three hub genes¹⁷.

SDG includes five distinct drugs: indigo naturalis, golden cypress, calcined gypsum, calamine, and Chinese Gall. In traditional Chinese medicine, calci…

Declarações

The authors have nothing to disclose.

Acknowledgements

None.

Materials

AutoDockTools	AutoDock	https://autodocksuite.scripps.edu/adt/
Cytoscape 3.9.1	Cytoscape	https://cytoscape.org/
GeneCards database	GeneCards	https://www.genecards.org
GEO database	National Center for Biotechnology Information	https://www.ncbi.nlm.nih.gov/geo/
GEO2R tool	National Center for Biotechnology Information	https://ncbi.nlm.nih.gov/geo/geo2r/
Metascape	Metascape	https://metascape.org/
Online Mendelian inheritance in man database	OMIM	https://www.omim.org
RCSB protein database	RCSB Protein Data Bank (RCSB PDB)	http://www.pdb.org/
STRING database	STRING	https://string-db.org/
Swiss ADME database	Swiss Institute of Bioinformatics	http://www.swissadme.ch/index.php
Traditional Chinese Medicine system's pharmacology database (TCMSP)	Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform	http://tcmspw.com/tcmsp.php
Venny2.1	BioinfoGP	https://bioinfogp.cnb.csic.es/tools/venny/index.html

Referências

Ma, M., Lu, H., Yang, Z., Chen, L., Li, Y., Zhang, X. Differences in microbiota between acute and chronic perianal eczema. Medicina. 100 (16), e25623 (2021).
Dietrich, C. F., Hoch, F. Anal eczema. Revue Therapeutique. 78 (9), 509-512 (2021).
Dietrich, A., Ruzicka, T., Hermans, C. Differential diagnosis of anal eczema. Hautarzt. 66 (6), 400-407 (2015).
Rohde, H. Anal eczema, condylomata acuminata. Deutsche Medizinische Wochenschrift. 133 (6), 245-246 (2008).
Havlickova, B., Weyandt, G. H. Therapeutic management of anal eczema: an evidence-based review. International Journal of Clinical Practice. 68 (11), 1388-1399 (2014).
Rainer, B. M., et al. Characterization and analysis of the skin microbiota in Rosacea: A case-control study. American Journal of Clinical Dermatology. 21 (1), 139-147 (2020).
Park, S. Y., Kim, H. S., Lee, S. H., Kim, S. Characterization and analysis of the skin microbiota in acne: Impact of systemic antibiotics. Journal of Clinical Medicine. 9 (1), 168 (2020).
Woo, Y. R., Lee, S. H., Cho, S. H., Lee, J. D., Kim, H. S. Characterization and analysis of the skin microbiota in Rosacea: Impact of systemic antibiotics. Journal of Clinical Medicine. 9 (1), 185 (2020).
Zheng, Y., et al. Alterations in the skin microbiome are associated with disease severity and treatment in the perioral zone of the skin of infants with atopic dermatitis. European Journal of Clinical Microbiology & Infectious Diseases. 38 (9), 1677-1685 (2019).
Totté, J. E. E., et al. Nasal and skin microbiomes are associated with disease severity in paediatric atopic dermatitis. The British Journal of Dermatology. 181 (4), 796-804 (2019).
Zhao, X. Y., Yang, Y. Y., Jl Feng, ., Feng, C. I. Network pharmacology prediction and experimental validation of Trichosanthes-Fritillaria thunbergii action mechanism against lung adenocarcinoma. Journal of Visualized Experiments. (193), e64847 (2023).
Zeng, B., et al. Network pharmacology prediction and metabolomics validation of the mechanism of Fructus Phyllanthi against hyperlipidemia. Journal of Visualized Experiments. (194), e65071 (2023).
Wang, T., Jiang, X., Ruan, Y., Li, L., Chu, L. The mechanism of action of the combination of Astragalus membranaceus and Ligusticum chuanxiong in the treatment of ischemic stroke based on network pharmacology and molecular docking. Medicina. 101 (28), e29593 (2022).
Wang, T., et al. Exploring the mechanism of luteolin by regulating microglia polarization based on network pharmacology and in vitro experiments. Scientific Reports. 13 (1), 13767 (2023).
Qi-Yue, Y., et al. From natural dye to herbal medicine: a systematic review of chemical constituents, pharmacological effects and clinical applications of indigo naturalis. Chinese Medicine. 15 (1), 127 (2020).
André, C., Dumur, J. P., Hrabina, M., Lefebvre, E., Sicard, H. Juniperus ashei: the gold standard of the Cuppressaceae. Allergie et Immunologie. 32 (3), 104-106 (2000).
Weidinger, S., Novak, N. Atopic dermatitis. Lancet. 387 (10023), 1109-1122 (2016).
Cai, L. L., Wu, Y., He, J. Network pharmacology of Shidu ointment in the treatment of EGFR-TKIs induced acneiform eruptions. China Pharmaceuticals. 29 (16), 5 (2020).
Gu, S., et al. Mechanisms of indigo naturalis on treating ulcerative colitis explored by GEO gene chips combined with network pharmacology and molecular docking. Scientific Reports. 10 (1), 15204 (2020).
Lou, Y., Ma, Y., Jin, J., Zhu, H. Oral realgar-indigo naturalis formula plus retinoic acid for acute promyelocytic leukemia. Frontiers in Oncology. 10, 597601 (2021).
Zhang, Q., et al. Psoriasis treatment using Indigo Naturalis: Progress and strategy. Journal of Ethnopharmacology. 297, 115522 (2022).
Naganuma, M., et al. Efficacy of Indigo Naturalis in a multicenter randomized controlled trial of patients with ulcerative colitis. Gastroenterology. 154 (4), 935-947 (2018).
Yang, Q. Y., et al. Exploring the mechanism of Indigo Naturalis in the treatment of ulcerative colitis based on TLR4/MyD88/NF-κB signaling pathway and gut microbiota. Frontiers in Pharmacology. 12, 674416 (2021).
Sun, Z., et al. Indigo Naturalis alleviates dextran sulfate sodium-induced colitis in rats via altering gut microbiota. Frontiers in Microbiology. 11, 731 (2020).
Cao, H., et al. Immune and metabolic regulation mechanism of Dangguiliuhuang decoction against insulin resistance and hepatic steatosis. Frontiers in Pharmacology. 8, 445 (2017).
Min, S. Y., Park, C. H., Yu, H. W., Park, Y. J. Anti-inflammatory and anti-allergic effects of saponarin and its impact on signaling pathways of RAW 264.7, RBL-2H3, and HaCaT cells. International Journal of Molecular Sciences. 22 (16), 8431 (2021).
Seo, K. H., et al. Saponarin from barley sprouts inhibits NF-κB and MAPK on LPS-induced RAW 264.7 cells. Food & Function. 5 (11), 3005-3013 (2014).
Moreno-Anzúrez, N. E., et al. A cytotoxic and anti-inflammatory campesterol derivative from genetically transformed hairy roots of Lopezia racemosa Cav. (Onagraceae). Molecules. 22 (1), 118 (2017).
Numao, N., et al. Tryptanthrin attenuates TLR3-mediated STAT1 activation in THP-1 cells. Immunologic Research. 70 (5), 688-697 (2022).
Veni, A., Lokeswari, T. S., Pavithra, D., Sugapriya, T. Melianone inhibits secreted aspartic proteases (SAP), a virulence factor during hyphal formation in Candida albicans. Current Computer-Aided Drug Design. 18 (5), 327-336 (2022).
Veni, A., Lokeswari, T. S., Krishna Kumari, G. N., Gayathri, D., Sudandiradoss, C. Bioactivity of melianone against Salmonella and in silico prediction of a membrane protein target. 3 Biotech. 10 (10), 460 (2020).
Ma, M., Lu, H., Yang, Z., Chen, L., Li, Y., Zhang, X. Differences in microbiota between acute and chronic perianal eczema. Medicina. 100 (16), e25623 (2021).
Williams, H. C., Chalmers, J. Prevention of atopic dermatitis. Acta Dermato-Venereologica. 100 (12), (2020).
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 in Pharmacological Sciences. 43 (2), 136-150 (2022).
Wang, T., Zhou, Y., Wang, K., Jiang, X., Wang, J., Chen, J. Prediction and validation of potential molecular targets for the combination of Astragalus membranaceus and Angelica sinensis in the treatment of atherosclerosis based on network pharmacology. Medicine (Baltimore). 101 (26), e29762 (2022).
Jiang, X., et al. Exploration of Fuzheng Yugan mixture on COVID-19 based on network pharmacology and molecular docking. Medicine (Baltimore). 102 (3), e32693 (2023).
Dong, Y., Zhao, Q., Wang, Y. Network pharmacology-based investigation of potential targets of astragalus membranaceous-angelica sinensis compound acting on diabetic nephropathy. Scientific Reports. 11 (1), 19496 (2021).
Wang, T., Jiang, X., Lu, Y., Ruan, Y., Wang, J. Identification and integration analysis of a novel prognostic signature associated with cuproptosis-related ferroptosis genes and relevant lncRNA regulatory axis in lung adenocarcinoma. Aging (Albany NY). 15 (5), 1543-1563 (2023).
Wang, T., Jiang, X., Ruan, Y., Zhuang, J., Yin, Y. Based on network pharmacology and in vitro experiments to prove the effective inhibition of myocardial fibrosis by Buyang Huanwu decoction). Bioengineered. 13 (5), 13767-13783 (2022).

Play Video

PDF

DOI

DOWNLOAD MATERIALS LIST

Citar este artigo

Wang, S., Xiao, W., He, A., Jia, J., Liu, G. The Efficacy and Underlying Pathway Mechanisms of ShiDuGao Treatment for Anus Eczema Based on GEO Datasets and Network Pharmacology. J. Vis. Exp. (203), e66453, doi:10.3791/66453 (2024).