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24-11-2023 | Wilson's Disease | Original Article

Network pharmacology-based approach to understand the effect and mechanism of chrysophanol against cognitive impairment in Wilson disease

Authors: Xiao-yan Zhang, Xie Wang, Ting Ye, Nan Shao, Jie Wang, Biao Cai, Dao-jun Xie

Published in: Metabolic Brain Disease | Issue 1/2024

Abstract

Wilson disease (WD) is a rare hereditary copper metabolism disorder, wherein cognitive impairment is a common clinical symptom. Chrysophanol (CHR) is an active compound with neuroprotective effects. The study aims to investigate the neuroprotective effect of CHR in WD and attempted to understand the potential mechanisms. Network pharmacology analysis was applied to predict the core target genes of CHR against cognitive impairment in WD. The rats fed with copper-laden diet for 12 weeks, and the effect of CHR on the copper content in liver and 24-h urine, the learning and memory ability, the morphological changes and the apoptosis level of neurons in hippocampal CA1 region, the expression level of Bax, Bcl-2, Cleaved Caspase-3, p-PI3K, PI3K, p-AKT, and AKT proteins were detected. Network pharmacology analysis showed that cell apoptosis and PI3K-AKT signaling pathway might be the main participants in CHR against cognitive impairment in WD. The experiments showed that CHR could reduce the copper content in liver, increase the copper content in 24-h urine, improve the ability of the learning and memory, alleviate the damage and apoptosis level of hippocampal neurons, down-regulate the expression of Bax, Cleaved Caspase-3, and up-regulate the expressions of Bcl-2, p-PI3K/PI3K, p-AKT/AKT. These results suggested that CHR could alleviate cognitive impairment in WD by inhibiting cell apoptosis and triggering the PI3K-AKT signaling pathway.

Graphical abstract

Chitranshi N, Dheer Y, Gupta V, Abbasi M, Mirzaei M, You Y, Chung R, Graham SL, Gupta V (2017) PTPN11 induces endoplasmic stress and apoptosis in SH-SY5Y cells. Neuroscience 364:175–189. https://doi.org/10.1016/j.neuroscience.2017.09.028CrossRefPubMed

Chu X, Zhou S, Sun R, Wang L, Xing C, Liang R, Kong Q (2018) Chrysophanol relieves cognition deficits and neuronal loss through inhibition of inflammation in diabetic mice. Neurochem Res 43:972–983. https://doi.org/10.1007/s11064-018-2503-1CrossRefPubMed

Cui WH, Zhang HH, Qu ZM, Wang Z, Zhang DJ, Wang S (2022) Effects of chrysophanol on hippocampal damage and mitochondrial autophagy in mice with cerebral ischemia reperfusion. Int J Neurosci 132:613–620. https://doi.org/10.1080/00207454.2020.1830085CrossRefPubMed

Członkowska A, Litwin T, Dusek P, Ferenci P, Lutsenko S, Medici V, Rybakowski JK, Weiss KH, Schilsky ML (2018) Wilson disease. Nat Rev Dis Primers 4:21. https://doi.org/10.1038/s41572-018-0018-3CrossRefPubMedPubMedCentral

Gao J, Yang S, Xie G, Pan J, Zhu F (2022) Integrating network pharmacology and experimental verification to explore the pharmacological mechanisms of aloin against gastric cancer. Drug Des Devel Ther 16:1947–1961. https://doi.org/10.2147/dddt.S360790CrossRefPubMedPubMedCentral

Han X, Yang Y, Qi J, Zhang M, Xue Y, Chu X, Jia Q, Sun S, Guan S (2022) Protective effects and possible mechanism of 6-gingerol against arsenic trioxide-induced nephrotoxicity based on network pharmacological analysis and experimental validation. Int Immunopharmacol 110:108926. https://doi.org/10.1016/j.intimp.2022.108926CrossRefPubMed

Hsu PC, Chen YH, Cheng CF, Kuo CY, Sytwu HK (2021) Interleukin-6 and Interleukin-8 Regulate STAT3 Activation Migration/Invasion and EMT in Chrysophanol-Treated Oral Cancer Cell Lines. Life (Basel) 11. https://doi.org/10.3390/life11050423

Jackson NM, Ceresa BP (2017) EGFR-mediated apoptosis via STAT3. Exp Cell Res 356:93–103. https://doi.org/10.1016/j.yexcr.2017.04.016CrossRefPubMedPubMedCentral

Jiao W, Mi S, Sang Y, Jin Q, Chitrakar B, Wang X, Wang S (2022) Integrated network pharmacology and cellular assay for the investigation of an anti-obesity effect of 6-shogaol. Food Chem 374:131755. https://doi.org/10.1016/j.foodchem.2021.131755CrossRefPubMed

Kirk FT, Munk DE, Laursen TL, Vilstrup H, Ott P, Grønbæk H, Lauridsen MM, Sandahl TD (2021) Cognitive impairment in stable Wilson disease across phenotype. Metab Brain Dis 36:2173–2177. https://doi.org/10.1007/s11011-021-00804-6CrossRefPubMed

Nogales C, Mamdouh ZM, List M, Kiel C, Casas AI, Schmidt H (2022) Network pharmacology: curing causal mechanisms instead of treating symptoms. Trends Pharmacol Sci 43:136–150. https://doi.org/10.1016/j.tips.2021.11.004CrossRefPubMed

Rangarajan SK, Sugadev SJX, Philip S (2022) Bedside cognitive assessments in Wilson's disease: Comparing cases and matched controls. J Neurosci Rural Pract 13:795–799. https://doi.org/10.25259/jnrp-2021-11-25-r2-(2189)

Sandahl TD, Laursen TL, Munk DE, Vilstrup H, Weiss KH, Ott P (2020) The prevalence of Wilson’s disease: An update. Hepatology 71:722–732. https://doi.org/10.1002/hep.30911CrossRefPubMed

Schilsky ML (2017) Wilson disease: Diagnosis, treatment, and follow-up. Clin Liver Dis 21:755–767. https://doi.org/10.1016/j.cld.2017.06.011CrossRefPubMed

Song G, Zhang Y, Yu S, Lv W, Guan Z, Sun M, Wang J (2019) Chrysophanol attenuates airway inflammation and remodeling through nuclear factor-kappa B signaling pathway in asthma. Phytother Res 33:2702–2713. https://doi.org/10.1002/ptr.6444CrossRefPubMed

Tang L, Gao J, Li X, Cao X, Zhou B (2022) Molecular mechanisms of luteolin against atopic dermatitis based on network pharmacology and in vivo experimental validation. Drug Des Devel Ther 16:4205–4221. https://doi.org/10.2147/dddt.S387893CrossRefPubMedPubMedCentral

Walker JA, Quirke P (2001) Viewing apoptosis through a “TUNEL.” J Pathol 195:275–276. https://doi.org/10.1002/path.979CrossRefPubMed

Wang M, Suo L, Yang S, Zhang W (2021) CircRNA 001372 reduces inflammation in propofol-induced neuroinflammation and neural apoptosis through PIK3CA/Akt/NF-κB by miRNA-148b-3p. J Invest Surg 34:1167–1177. https://doi.org/10.1080/08941939.2020.1771639CrossRefPubMed

Wang X, Wang Y, Zhu Y, Yan L, Zhao L (2019) Neuroprotective effect of S-trans, trans-farnesylthiosalicylic acid via inhibition of RAS/ERK pathway for the treatment of alzheimer’s disease. Drug Des Devel Ther 13:4053–4063. https://doi.org/10.2147/dddt.S233283CrossRefPubMedPubMedCentral

Xia P, Marjan M, Liu Z, Zhou W, Zhang Q, Cheng C, Zhao M, Tao Y, Wang Z, Ye Z (2022) Chrysophanol postconditioning attenuated cerebral ischemia-reperfusion injury induced NLRP3-related pyroptosis in a TRAF6-dependent manner. Exp Neurol 357:114197. https://doi.org/10.1016/j.expneurol.2022.114197CrossRefPubMed

Xu J, Jiang H, Li J, Cheng KK, Dong J, Chen Z (2015) 1H NMR-based metabolomics investigation of copper-laden rat: a model of Wilson’s disease. PLoS One 10:e0119654. https://doi.org/10.1371/journal.pone.0119654CrossRefPubMedPubMedCentral

Xu Y, Chen W, Chen Z, Huang M, Yang F, Zhang Y (2021) Mechanism of action of xiaoyao san in treatment of ischemic stroke is related to anti-apoptosis and activation of PI3K/Akt pathway. Drug Des Devel Ther 15:753–767. https://doi.org/10.2147/dddt.S280217CrossRefPubMedPubMedCentral

Yang J, Pan Y, Li X, Wang X (2015) Atorvastatin attenuates cognitive deficits through Akt1/caspase-3 signaling pathway in ischemic stroke. Brain Res 1629:231–239. https://doi.org/10.1016/j.brainres.2015.10.032CrossRefPubMed

Ye T, Li X, Zhou P, Ye S, Gao H, Hua R, Ma J, Wang Y, Cai B (2020) Chrysophanol improves memory ability of d-galactose and Aβ(25–35) treated rat correlating with inhibiting tau hyperphosphorylation and the CaM-CaMKIV signal pathway in hippocampus. 3 Biotech 10:111. https://doi.org/10.1007/s13205-020-2103-z

Ye T, Gao HW, Xuan WT, Ye S, Zhou P, Li XQ, Wang Y, Song H, Liu YY, Cai B (2020b) The regulating mechanism of chrysophanol on protein level of CaM-CaMKIV to protect PC12 cells against Aβ(25–35)-induced damage. Drug Des Devel Ther 14:2715–2723. https://doi.org/10.2147/dddt.S245128CrossRefPubMedPubMedCentral

Yu T, Zheng E, Li Y, Li Y, Xia J, Ding Q, Hou Z, Ruan XZ, Zhao L, Chen Y (2021) Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated hepatocytes. Exp Cell Res 399:112438. https://doi.org/10.1016/j.yexcr.2020.112438CrossRefPubMed

Yuan XZ, Yang RM, Wang XP (2021) Management perspective of Wilson’s disease: Early diagnosis and individualized therapy. Curr Neuropharmacol 19:465–485. https://doi.org/10.2174/1570159x18666200429233517CrossRefPubMedPubMedCentral

Yusuf MA, Singh BN, Sudheer S, Kharwar RN, Siddiqui S, Abdel-Azeem AM, Fernandes Fraceto L, Dashora K, Gupta VK (2019) Chrysophanol: A Natural Anthraquinone with Multifaceted Biotherapeutic Potential. Biomolecules 9. https://doi.org/10.3390/biom9020068

Zhang PN, Tang JY, Yang KZ, Zheng QY, Dong ZC, Geng YL, Liu YN, Liu WJ (2022) Integrated network pharmacology analysis and experimental validation to investigate the molecular mechanism of triptolide in the treatment of membranous nephropathy. Drug Des Dev Ther 16:4061–4076. https://doi.org/10.2147/dddt.S386031CrossRef

Zhao X, Qiao D, Guan D, Wang K, Cui Y (2022a) Chrysophanol ameliorates hemin-induced oxidative stress and endoplasmic reticulum stress by regulating MicroRNA-320-5p/Wnt3a pathway in HT22 cells. Oxid Med Cell Longev 2022:9399658. https://doi.org/10.1155/2022/9399658CrossRefPubMedPubMedCentral

Zhao Y, Zhang J, Zhang Y, Zhang Y, Zhang X, Zheng Y, Wang H, Wang X, Fu J (2022b) Network pharmacology-based strategy to investigate pharmacological mechanisms of andrographolide for treatment of vascular cognitive impairment. Int Immunopharmacol 108:108756. https://doi.org/10.1016/j.intimp.2022.108756CrossRefPubMed

Zhao Y, Fang Y, Li J, Duan Y, Zhao H, Gao L, Luo Y (2016) Neuroprotective effects of chrysophanol against inflammation in middle cerebral artery occlusion mice. Neurosci Lett 630:16–22. https://doi.org/10.1016/j.neulet.2016.07.036CrossRefPubMed

Zhou Z, Chen B, Chen S, Lin M, Chen Y, Jin S, Chen W, Zhang Y (2020) Applications of network pharmacology in traditional chinese medicine research. Evid Based Complement Alternat Med 2020:1646905. https://doi.org/10.1155/2020/1646905CrossRefPubMedPubMedCentral

Title: Network pharmacology-based approach to understand the effect and mechanism of chrysophanol against cognitive impairment in Wilson disease
Authors: Xiao-yan Zhang
Xie Wang
Ting Ye
Nan Shao
Jie Wang
Biao Cai
Dao-jun Xie
Publication date: 24-11-2023
Publisher: Springer US
Keywords: Wilson's Disease
Wilson's Disease
Published in: Metabolic Brain Disease / Issue 1/2024
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-023-01321-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Network pharmacology-based approach to understand the effect and mechanism of chrysophanol against cognitive impairment in Wilson disease

Abstract

Graphical abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Graphical abstract

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