Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Identifying NFKB1, STAT3, and CDKN1A as Baicalein’s Potential Hub Targets in Parkinson’s Disease-related α-synuclein-mediated Pathways by Integrated Bioinformatics Strategies

Author(s): Xingjian Li, Qiyin Deng, Yaoyun Kuang, Hengxu Mao, Meiling Yao, Changsong Lin, Xiaodong Luo and Pingyi Xu*

Volume 29, Issue 30, 2023

Published on: 18 October, 2023

Page: [2426 - 2437] Pages: 12

DOI: 10.2174/0113816128259065231011114116

Price: $65

Abstract

Background: The overexpression, accumulation, and cell-to-cell transmission of α-synuclein leads to the deterioration of Parkinson’s disease (PD). Previous studies suggest that Baicalein (BAI) can bind to α-synuclein and inhibit α-synuclein aggregation and secretion. However, it is still unclear whether BAI can intervene with the pathogenic molecules in α-synuclein-mediated PD pathways beyond directly targeting α-synuclein per se.

Methods: This study aimed to systematically investigate BAI’s potential targets in PD-related A53T mutant α-synuclein-mediated pathways by integrating data mining, network pharmacological analysis, and molecular docking simulation techniques.

Results: The results suggest that BAI may target genes that are dysregulated in synaptic transmission, vesicle trafficking, gene transcription, protein binding, extracellular matrix formation, and kinase activity in α-synucleinmediated pathways. NFKB1, STAT3, and CDKN1A are BAI’s potential hub targets in these pathways.

Conclusion: Our findings highlight BAI's potentiality to modulate α-synuclein-mediated pathways beyond directly targeting α-synuclein per se.

« Previous
[1]
Tansey MG, Wallings RL, Houser MC, Herrick MK, Keating CE, Joers V. Inflammation and immune dysfunction in Parkinson disease. Nat Rev Immunol 2022; 22(11): 657-73.
[http://dx.doi.org/10.1038/s41577-022-00684-6] [PMID: 35246670]
[2]
Grosso Jasutkar H, Oh SE, Mouradian MM. Therapeutics in the pipeline targeting α-synuclein for Parkinson’s disease. Pharmacol Rev 2022; 74(1): 207-37.
[http://dx.doi.org/10.1124/pharmrev.120.000133] [PMID: 35017177]
[3]
Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson disease. JAMA 2020; 323(6): 548-60.
[http://dx.doi.org/10.1001/jama.2019.22360] [PMID: 32044947]
[4]
Turcano P, Mielke MM, Bower JH, et al. Levodopa-induced dyskinesia in Parkinson disease. Neurology 2018; 91(24): e2238-43.
[http://dx.doi.org/10.1212/WNL.0000000000006643] [PMID: 30404780]
[5]
Garcia-Ruiz PJ, Martinez CJC, Alonso-Canovas A, et al. Impulse control disorder in patients with Parkinson’s disease under dopamine agonist therapy: A multicentre study. J Neurol Neurosurg Psychiatry 2014; 85(8): 840-4.
[http://dx.doi.org/10.1136/jnnp-2013-306787] [PMID: 24434037]
[6]
Yi S, Wang L, Wang H, Ho MS, Zhang S. Pathogenesis of α-synuclein in Parkinson’s disease: From a neuron-glia crosstalk perspective. Int J Mol Sci 2022; 23(23): 14753.
[http://dx.doi.org/10.3390/ijms232314753] [PMID: 36499080]
[7]
Lyra P, Machado V, Rota S, Chaudhuri KR, Botelho J, Mendes JJ. Revisiting alpha-synuclein pathways to inflammation. Int J Mol Sci 2023; 24(8): 7137.
[http://dx.doi.org/10.3390/ijms24087137] [PMID: 37108299]
[8]
Chou TW, Chang NP, Krishnagiri M, et al. Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB. Cell Death Dis 2021; 12(8): 756.
[http://dx.doi.org/10.1038/s41419-021-04049-0] [PMID: 34333522]
[9]
Dutta D, Jana M, Majumder M, Mondal S, Roy A, Pahan K. Selective targeting of the TLR2/MyD88/NF-κB pathway reduces α-synuclein spreading in vitro and in vivo. Nat Commun 2021; 12(1): 5382.
[http://dx.doi.org/10.1038/s41467-021-25767-1] [PMID: 34508096]
[10]
Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: A leading role for STAT3. Nat Rev Cancer 2009; 9(11): 798-809.
[http://dx.doi.org/10.1038/nrc2734] [PMID: 19851315]
[11]
Lin D, Zhang H, Zhang J, et al. α-synuclein induces neuroinflammation injury through the IL6ST-AS/STAT3/HIF-1α axis. Int J Mol Sci 2023; 24(2): 1436.
[http://dx.doi.org/10.3390/ijms24021436]
[12]
Fan Y, Mao R, Yang J. NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 2013; 4(3): 176-85.
[http://dx.doi.org/10.1007/s13238-013-2084-3] [PMID: 23483479]
[13]
Qin H, Buckley JA, Li X, et al. Inhibition of the JAK/STAT pathway protects against α-synuclein-induced neuroinflammation and dopaminergic neurodegeneration. J Neurosci 2016; 36(18): 5144-59.
[http://dx.doi.org/10.1523/JNEUROSCI.4658-15.2016] [PMID: 27147665]
[14]
Verma DK, Seo BA, Ghosh A, et al. Alpha-synuclein preformed fibrils induce cellular senescence in Parkinson’s disease models. Cells 2021; 10(7): 1694.
[http://dx.doi.org/10.3390/cells10071694] [PMID: 34359864]
[15]
Ho DH, Seol W, Son I. Upregulation of the p53-p21 pathway by G2019S LRRK2 contributes to the cellular senescence and accumulation of α-synuclein. Cell Cycle 2019; 18(4): 467-75.
[http://dx.doi.org/10.1080/15384101.2019.1577666] [PMID: 30712480]
[16]
Pei T, Yan M, Huang Y, Wei Y, Martin C, Zhao Q. Specific flavonoids and their biosynthetic pathway in Scutellaria baicalensis. Front Plant Sci 2022; 13: 866282.
[http://dx.doi.org/10.3389/fpls.2022.866282] [PMID: 35310641]
[17]
Liang W, Huang X, Chen W. The effects of baicalin and baicalein on cerebral ischemia: A review. Aging Dis 2017; 8(6): 850-67.
[http://dx.doi.org/10.14336/AD.2017.0829] [PMID: 29344420]
[18]
Chmiel M, Stompor-Gorący M. Promising role of the Scutellaria baicalensis root hydroxyflavone–baicalein in the prevention and treat-ment of human diseases. Int J Mol Sci 2023; 24(5): 4732.
[http://dx.doi.org/10.3390/ijms24054732] [PMID: 36902160]
[19]
Sowndhararajan K, Deepa P, Kim M, Park SJ, Kim S. Baicalein as a potent neuroprotective agent: A review. Biomed Pharmacother 2017; 95: 1021-32.
[http://dx.doi.org/10.1016/j.biopha.2017.08.135] [PMID: 28922719]
[20]
Li X, Zhang G, Nie Q, et al. Baicalein blocks α-synuclein secretion from SN4741 cells and facilitates α-synuclein polymerization to big complex. Neurosci Lett 2017; 655: 109-14.
[http://dx.doi.org/10.1016/j.neulet.2017.06.031] [PMID: 28676257]
[21]
Li Y, Zhao J, Hölscher C. Therapeutic potential of baicalein in Alzheimer’s disease and Parkinson’s disease. CNS Drugs 2017; 31(8): 639-52.
[http://dx.doi.org/10.1007/s40263-017-0451-y] [PMID: 28634902]
[22]
Zhu M, Rajamani S, Kaylor J, Han S, Zhou F, Fink AL. The flavonoid baicalein inhibits fibrillation of alpha-synuclein and disaggregates existing fibrils. J Biol Chem 2004; 279(26): 26846-57.
[http://dx.doi.org/10.1074/jbc.M403129200] [PMID: 15096521]
[23]
Yao Y, Tang Y, Zhou Y, Yang Z, Wei G. Baicalein exhibits differential effects and mechanisms towards disruption of α-synuclein fibrils with different polymorphs. Int J Biol Macromol 2022; 220: 316-25.
[http://dx.doi.org/10.1016/j.ijbiomac.2022.08.088] [PMID: 35981677]
[24]
Hu Q, Uversky VN, Huang M, et al. Baicalein inhibits α-synuclein oligomer formation and prevents progression of α-synuclein accumulation in a rotenone mouse model of Parkinson’s disease. Biochim Biophys Acta Mol Basis Dis 2016; 1862(10): 1883-90.
[http://dx.doi.org/10.1016/j.bbadis.2016.07.008] [PMID: 27425033]
[25]
Yuan Y, Men W, Shan X, et al. Baicalein exerts neuroprotective effect against ischaemic/reperfusion injury via alteration of NF-kB and LOX and AMPK/Nrf2 pathway. Inflammopharmacology 2020; 28(5): 1327-41.
[http://dx.doi.org/10.1007/s10787-020-00714-6] [PMID: 32418004]
[26]
Li J, Ma J, Wang KS, et al. Baicalein inhibits TNF-α-induced NF-κB activation and expression of NF-κB-regulated target gene products. Oncol Rep 2016; 36(5): 2771-6.
[http://dx.doi.org/10.3892/or.2016.5108] [PMID: 27667548]
[27]
Han P, Shang J, Chen DL, et al. Baicalein mediates anticancer effect on cholangiocarcinoma through co-targeting the AKT/NF-κB and STAT3 signaling pathway. Process Biochem 2021; 102: 304-14.
[http://dx.doi.org/10.1016/j.procbio.2021.01.017]
[28]
Xu J, Liu J, Yue G, et al. Therapeutic effect of the natural compounds baicalein and baicalin on autoimmune diseases. Mol Med Rep 2018; 18(1): 1149-54.
[http://dx.doi.org/10.3892/mmr.2018.9054] [PMID: 29845272]
[29]
Yao J, Liu T, Chen RJ, Liang J, Li J, Wang CG. Sphingosine-1-phosphate signal transducer and activator of transcription 3 signaling pathway contributes to baicalein-mediated inhibition of dextran sulfate sodium-induced experimental colitis in mice. Chin Med J 2020; 133(3): 292-300.
[http://dx.doi.org/10.1097/CM9.0000000000000627] [PMID: 31904729]
[30]
Zhong X, Surh YJ, Do SG, et al. Baicalein inhibits dextran sulfate sodium-induced mouse colitis. J Cancer Prev 2019; 24(2): 129-38.
[http://dx.doi.org/10.15430/JCP.2019.24.2.129] [PMID: 31360692]
[31]
Ma D, Chen S, Wang H, et al. Baicalein induces apoptosis of pancreatic cancer cells by regulating the expression of miR-139-3p and miR-196b-5p. Front Oncol 2021; 11: 653061.
[http://dx.doi.org/10.3389/fonc.2021.653061] [PMID: 33996574]
[32]
Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13(11): 2498-504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[33]
Chin CH, Chen SH, Wu HH, Ho CW, Ko MT, Lin CY. cytoHubba: Identifying hub objects and sub-networks from complex interactome. BMC Syst Biol 2014; 8(S4): S11.
[http://dx.doi.org/10.1186/1752-0509-8-S4-S11] [PMID: 25521941]
[34]
Kim S, Chen J, Cheng T, et al. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res 2021; 49(D1): D1388-95.
[http://dx.doi.org/10.1093/nar/gkaa971] [PMID: 33151290]
[35]
Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: Archive for functional genomics data sets-update. Nucleic Acids Res 2013; 41(Database issue): D991-5.
[PMID: 23193258]
[36]
Edgar R, Domrachev M, Lash AE. Gene expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 2002; 30(1): 207-10.
[http://dx.doi.org/10.1093/nar/30.1.207] [PMID: 11752295]
[37]
Ryan SD, Dolatabadi N, Chan SF, et al. Isogenic human iPSC Parkinson’s model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription. Cell 2013; 155(6): 1351-64.
[http://dx.doi.org/10.1016/j.cell.2013.11.009] [PMID: 24290359]
[38]
Zhang Y, James M, Middleton FA, Davis RL. Transcriptional analysis of multiple brain regions in Parkinson’s disease supports the involvement of specific protein processing, energy metabolism, and signaling pathways, and suggests novel disease mechanisms. Am J Med Genet B Neuropsychiatr Genet 2005; 137B(1): 5-16.
[http://dx.doi.org/10.1002/ajmg.b.30195] [PMID: 15965975]
[39]
Zheng B, Liao Z, Locascio JJ, et al. PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med 2010; 2(52): 52ra73.
[http://dx.doi.org/10.1126/scitranslmed.3001059] [PMID: 20926834]
[40]
R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2022. Available from: https://www.R-project.org/
[41]
Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015; 43(7): e47.
[http://dx.doi.org/10.1093/nar/gkv007] [PMID: 25605792]
[42]
Kolde R. pheatmap: Pretty Heatmaps, version 1.0.12. 2019. Available from: https://CRAN.R-project.org/package=pheatmap
[43]
Yu G. ggplotify: Convert Plot to 'grob' or 'ggplot' Object, version 0.1.0. 2021. Available from: https://CRAN.R-project.org/package=ggplotify
[44]
Wickham H. ggplot2: Elegant Graphics for Data Analysis. Springer 2016.
[45]
Oliveros JC. An Interactive Tool for Comparing Lists with Venn’s Diagrams. Available from: https://bioinfogp.cnb.csic.es/tools/venny/index.html
[46]
Szklarczyk D, Gable AL, Lyon D, et al. STRING v11: Protein–protein association networks with increased coverage, supporting func-tional discovery in genome-wide experimental datasets. Nucleic Acids Res 2019; 47(D1): D607-13.
[http://dx.doi.org/10.1093/nar/gky1131] [PMID: 30476243]
[47]
Carlson M. org.Hs.eg.db: Genome wide annotation for Human, version 3.15.0. 2022. Available from: https://bioconductor.org/packages/release/data/annotation/html/org.Hs.eg.db.html
[48]
Wu T, Hu E, Xu S, et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation 2021; 2(3): 100141.
[http://dx.doi.org/10.1016/j.xinn.2021.100141] [PMID: 34557778]
[49]
Yu G, Wang LG, Han Y, He QY. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS 2012; 16(5): 284-7.
[http://dx.doi.org/10.1089/omi.2011.0118] [PMID: 22455463]
[50]
Yu G, Wang LG, Yan GR, He QY. DOSE: An R/Bioconductor package for disease ontology semantic and enrichment analysis. Bioinformatics 2015; 31(4): 608-9.
[http://dx.doi.org/10.1093/bioinformatics/btu684] [PMID: 25677125]
[51]
Doncheva NT, Morris JH, Holze H, et al. Cytoscape stringApp 2.0: Analysis and visualization of heterogeneous biological networks. J Proteome Res 2022; 22(2): 637-46.
[PMID: 36512705]
[52]
Sing T, Sander O, Beerenwinkel N, Lengauer T. ROCR: Visualizing classifier performance in R. Bioinformatics 2005; 21(20): 3940-1.
[http://dx.doi.org/10.1093/bioinformatics/bti623] [PMID: 16096348]
[53]
Kassambara A. ggpubr: 'ggplot2' Based Publication Ready Plots, version 0.5.0. 2022. Available from: https://CRAN.R-project.org/package=ggpubr
[54]
Müller CW, Rey FA, Sodeoka M, Verdine GL, Harrison SC. Structure of the NF-κB p50 homodimer bound to DNA. Nature 1995; 373(6512): 311-7.
[http://dx.doi.org/10.1038/373311a0] [PMID: 7830764]
[55]
Bai L, Zhou H, Xu R, et al. A potent and selective small-molecule degrader of stat3 achieves complete tumor regression in vivo. Cancer Cell 2019; 36(5): 498-511.e17.
[http://dx.doi.org/10.1016/j.ccell.2019.10.002] [PMID: 31715132]
[56]
Choi WS, Liu B, Shen Z, Yang W. Structure of human BCCIP and implications for binding and modification of partner proteins. Protein Sci 2021; 30(3): 693-9.
[http://dx.doi.org/10.1002/pro.4026] [PMID: 33452718]
[57]
Burley SK, Bhikadiya C, Bi C, 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 2021; 49(D1): D437-51.
[http://dx.doi.org/10.1093/nar/gkaa1038] [PMID: 33211854]
[58]
RCSB Protein Data Bank (RCSB PDB). Available from: https://www.rcsb.org/
[59]
Fährrolfes R, Bietz S, Flachsenberg F, et al. ProteinsPlus: A web portal for structure analysis of macromolecules. Nucleic Acids Res 2017; 45(W1): W337-43.
[http://dx.doi.org/10.1093/nar/gkx333] [PMID: 28472372]
[60]
Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30(16): 2785-91.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[61]
O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform 2011; 3(1): 33.
[http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]
[62]
The Open Babel Package, version 2.3.1. Available from: https://openbabel.org/wiki/Main_Page
[63]
Eberhardt J, Santos-Martins D, Tillack AF, Forli S. AutoDock Vina 1.2.0: New docking methods, expanded force field, and python bindings. J Chem Inf Model 2021; 61(8): 3891-8.
[http://dx.doi.org/10.1021/acs.jcim.1c00203] [PMID: 34278794]
[64]
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31(2): 455-61.
[PMID: 19499576]
[65]
The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC. Available from: https://pymol.org/2/
[66]
Adasme MF, Linnemann KL, Bolz SN, et al. PLIP 2021: Expanding the scope of the protein–ligand interaction profiler to DNA and RNA. Nucleic Acids Res 2021; 49(W1): W530-4.
[http://dx.doi.org/10.1093/nar/gkab294] [PMID: 33950214]
[67]
Salentin S, Schreiber S, Haupt VJ, Adasme MF, Schroeder M. PLIP: Fully automated protein–ligand interaction profiler. Nucleic Acids Res 2015; 43(W1): W443-7.
[http://dx.doi.org/10.1093/nar/gkv315] [PMID: 25873628]
[68]
Hung KC, Huang HJ, Wang YT, Lin AMY. Baicalein attenuates α-synuclein aggregation, inflammasome activation and autophagy in the MPP+-treated nigrostriatal dopaminergic system in vivo. J Ethnopharmacol 2016; 194: 522-9.
[http://dx.doi.org/10.1016/j.jep.2016.10.040] [PMID: 27742410]
[69]
Shen W, Zhai S, Surmeier DJ. Striatal synaptic adaptations in Parkinson’s disease. Neurobiol Dis 2022; 167: 105686.
[http://dx.doi.org/10.1016/j.nbd.2022.105686] [PMID: 35272023]
[70]
Akrioti E, Karamitros T, Gkaravelas P, Kouroupi G, Matsas R, Taoufik E. Early signs of molecular defects in ipsc-derived neural stems cells from patients with familial Parkinson’s disease. Biomolecules 2022; 12(7): 876.
[http://dx.doi.org/10.3390/biom12070876] [PMID: 35883433]
[71]
Hirsch EC, Standaert DG. Ten unsolved questions about neuroinflammation in Parkinson’s disease. Mov Disord 2021; 36(1): 16-24.
[http://dx.doi.org/10.1002/mds.28075] [PMID: 32357266]
[72]
Nagatsu T, Mogi M, Ichinose H, Togari A. Changes in cytokines and neurotrophins in Parkinson’s disease. J Neural Transm Suppl 2000; 277-90.
[http://dx.doi.org/10.1007/978-3-7091-6301-6_19] [PMID: 11205147]
[73]
Martin-Bastida A, Tilley BS, Bansal S, Gentleman SM, Dexter DT, Ward RJ. Iron and inflammation: In vivo and post-mortem studies in Parkinson’s disease. J Neural Transm 2021; 128(1): 15-25.
[http://dx.doi.org/10.1007/s00702-020-02271-2] [PMID: 33079260]
[74]
P19838 · NFKB1_HUMAN. Available from: https://www.uniprot.org/uniprotkb/P19838/entry#family_and_domains
[75]
NF-κB. Available from: https://en.wikipedia.org/wiki/NF-%CE%BAB
[76]
Sgrignani J, Garofalo M, Matkovic M, Merulla J, Catapano CV, Cavalli A. Structural biology of STAT3 and its implications for anticancer therapies development. Int J Mol Sci 2018; 19(6): 1591.
[http://dx.doi.org/10.3390/ijms19061591] [PMID: 29843450]
[77]
Zhang T, Kee WH, Seow KT, Fung W, Cao X. The coiled-coil domain of Stat3 is essential for its SH2 domain-mediated receptor binding and subsequent activation induced by epidermal growth factor and interleukin-6. Mol Cell Biol 2000; 20(19): 7132-9.
[http://dx.doi.org/10.1128/MCB.20.19.7132-7139.2000] [PMID: 10982829]
[78]
Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 2009; 1(4): a000034.
[http://dx.doi.org/10.1101/cshperspect.a000034] [PMID: 20066092]
[79]
Klæstrup IH, Just MK, Holm KL, et al. Impact of aging on animal models of Parkinson’s disease. Front Aging Neurosci 2022; 14: 909273.
[http://dx.doi.org/10.3389/fnagi.2022.909273] [PMID: 35966779]
[80]
Miller SJ, Campbell CE, Jimenez-Corea HA, Wu GH, Logan R. Neuroglial senescence, α-synucleinopathy, and the therapeutic potential of senolytics in Parkinson’s disease. Front Neurosci 2022; 16: 824191.
[http://dx.doi.org/10.3389/fnins.2022.824191] [PMID: 35516803]
[81]
CDKN1A (cyclin-dependent kinase inhibitor 1A). Available from: https://atlasgeneticsoncology.org/gene/139/cdkn1a-%28cyclin-dependent-kinase-inhibitor-1a%29
[82]
de los Reyes Corrales T, Losada-Pérez M, Casas-Tintó S. JNK pathway in CNS pathologies. Int J Mol Sci 2021; 22(8): 3883.
[http://dx.doi.org/10.3390/ijms22083883] [PMID: 33918666]
[83]
Xin Z, Himmelbauer MK, Jones JH, et al. Discovery of CNS-penetrant apoptosis signal-regulating kinase 1 (ASK1) inhibitors. ACS Med Chem Lett 2020; 11(4): 485-90.
[http://dx.doi.org/10.1021/acsmedchemlett.9b00611] [PMID: 32292554]

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