Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

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

Research Article

Exploring miRNA-related Molecular Targets of Erchen Decoction against Lipid Metabolism Disorder using a Network Pharmacologic Approach

Author(s): Shanshan Ding, Qiliang Chen, Yiqing Huang, Xiaomei Li, Yujuan Chai, Candong Li and Tetsuya Asakawa*

Volume 25, Issue 6, 2022

Published on: 02 March, 2021

Page: [986 - 997] Pages: 12

DOI: 10.2174/1386207324666210302093300

Open Access Journals Promotions 2
Abstract

Background: Erchen Decoction (ECD) is a complex herbal formulation widely used for treating lipid metabolism disorder (LMD) in China. This study aims to explore the microRNA (miRNA)-related molecular targets of ECD against LMD using a network pharmacology approach (NPA)

Methods: We randomly divided 20 male Sprague Dawley rats into two groups; 10 rats were normal controls, and the other 10 rats were fed a high-fat diet (HFD) for 12 weeks to establish an LMD model. Differentially expressed miRNAs (DE-miRs, HFD vs. Control) in the rats’ liver tissues were identified by miRNA sequencing and validated with qRT-PCR. Finally, the miRNArelated molecular targets for ECD activity against LMD were identified using a standard NPA by finding the intersection between identified DE-miRs-related targets and ECD-related targets.

Result: We identified 8 DE-miRs and 968 targets and compared them to 262 ECD-related targets. A final list of 22 candidate targets was identified. Using a confidence score of >0.4, the network of (protein-protein interaction) PPI relationships exhibited 22 nodes and 67 edges. The GO and KEGG enrichment analyses revealed 171 molecular targets and 59 pathways, which were associated with ECD against LMD.

Conclusion: The identified molecular targets and pathways suggest that complex mechanisms are involved in ECD’s mechanism of action, and immune-inflammation-related mechanisms are closely associated with the effects of ECD. The targets obtained in this study will guide future studies on the pharmacologic effects of ECD.

Keywords: Lipid metabolism disorder, microRNA, network pharmacology approach, erchen decoction, molecular targets, high-fat diet.

« Previous
Graphical Abstract
[1]
Abulizi, A.; Camporez, J.P.; Jurczak, M.J.; Høyer, K.F.; Zhang, D.; Cline, G.W.; Samuel, V.T.; Shulman, G.I.; Vatner, D.F. Adipose glucocorticoid action influences whole-body metabolism via modulation of hepatic insulin action. FASEB J., 2019, 33(7), 8174-8185.
[http://dx.doi.org/10.1096/fj.201802706R] [PMID: 30922125]
[2]
Alisi, A.; Da Sacco, L.; Bruscalupi, G.; Piemonte, F.; Panera, N.; De Vito, R.; Leoni, S.; Bottazzo, G.F.; Masotti, A.; Nobili, V. Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease. Lab. Invest., 2011, 91(2), 283-293.
[http://dx.doi.org/10.1038/labinvest.2010.166] [PMID: 20956972]
[3]
Ash, G.I.; Kostek, M.A.; Lee, H.; Angelopoulos, T.J.; Clarkson, P.M.; Gordon, P.M.; Moyna, N.M.; Visich, P.S.; Zoeller, R.F.; Price, T.B.; Devaney, J.M.; Gordish-Dressman, H.; Thompson, P.D.; Hoffman, E.P.; Pescatello, L.S. Glucocorticoid Receptor (NR3C1) Variants Associate with the Muscle Strength and Size Response to Resistance Training. PLoS One, 2016, 11(1), e0148112.
[http://dx.doi.org/10.1371/journal.pone.0148112] [PMID: 26821164]
[4]
Chen, L.P.; Cai, Y.M.; Li, J.S. Medication rules of famous veteran traditional Chinese medicine doctor in treatment of chronic bronchitis based on implicit structure model. Zhongguo Zhongyao Zazhi, 2017, 42(8), 1609-1616.
[PMID: 29071870]
[5]
Cheng, J.C.; Chang, H.M.; Fang, L.; Sun, Y.P.; Leung, P.C. TGF-β1 up-regulates connexin43 expression: a potential mechanism for human trophoblast cell differentiation. J. Cell. Physiol., 2015, 230(7), 1558-1566.
[http://dx.doi.org/10.1002/jcp.24902] [PMID: 25560303]
[6]
Das, S.; Mohamed, I.N.; Teoh, S.L.; Thevaraj, T.; Ku Ahmad Nasir, K.N.; Zawawi, A.; Salim, H.H.; Zhou, D.K. Micro-RNA and the Features of Metabolic Syndrome: A Narrative Review. Mini Rev. Med. Chem., 2020, 20(7), 626-635.
[http://dx.doi.org/10.2174/1389557520666200122124445] [PMID: 31969099]
[7]
Ding, S.; Kang, J.; Tong, L.; Lin, Y.; Liao, L.; Gao, B. Erchen Decoction Ameliorates Lipid Metabolism by the Regulation of the Protein CAV-1 and the Receptors VLDLR, LDLR, ABCA1, and SRB1 in a High-Fat Diet Rat Model. Evid. Based Complement. Alternat. Med., 2018, 2018, 5309490.
[http://dx.doi.org/10.1155/2018/5309490] [PMID: 30402126]
[8]
Donohoe, F.; Wilkinson, M.; Baxter, E.; Brennan, D.J. Mitogen-Activated Protein Kinase (MAPK) and Obesity-Related Cancer. Int. J. Mol. Sci., 2020, 21(4), E1241.
[http://dx.doi.org/10.3390/ijms21041241] [PMID: 32069845]
[9]
Elias, I.; Franckhauser, S.; Ferré, T.; Vilà, L.; Tafuro, S.; Muñoz, S.; Roca, C.; Ramos, D.; Pujol, A.; Riu, E.; Ruberte, J.; Bosch, F. Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance. Diabetes, 2012, 61(7), 1801-1813.
[http://dx.doi.org/10.2337/db11-0832] [PMID: 22522611]
[10]
Gao, B.Z.; Chen, J.C.; Liao, L.H.; Xu, J.Q.; Lin, X.F.; Ding, S.S. Erchen Decoction Prevents High-Fat Diet Induced Metabolic Disorders in C57BL/6 Mice. Evid. Based Complement. Alternat. Med., 2015, 2015, 501272.
[http://dx.doi.org/10.1155/2015/501272] [PMID: 26504476]
[11]
Guo, J.; Fang, W.; Sun, L.; Lu, Y.; Dou, L.; Huang, X.; Sun, M.; Pang, C.; Qu, J.; Liu, G.; Li, J. Reduced miR-200b and miR-200c expression contributes to abnormal hepatic lipid accumulation by stimulating JUN expression and activating the transcription of srebp1. Oncotarget, 2016, 7(24), 36207-36219.
[http://dx.doi.org/10.18632/oncotarget.9183] [PMID: 27166182]
[12]
Hirosumi, J.; Tuncman, G.; Chang, L.; Görgün, C.Z.; Uysal, K.T.; Maeda, K.; Karin, M.; Hotamisligil, G.S. A central role for JNK in obesity and insulin resistance. Nature, 2002, 420(6913), 333-336.
[http://dx.doi.org/10.1038/nature01137] [PMID: 12447443]
[13]
Hubler, M.J.; Kennedy, A.J. Role of lipids in the metabolism and activation of immune cells. J. Nutr. Biochem., 2016, 34, 1-7.
[http://dx.doi.org/10.1016/j.jnutbio.2015.11.002] [PMID: 27424223]
[14]
Jiang, M.; Li, J.; Peng, Q.; Liu, Y.; Liu, W.; Luo, C.; Peng, J.; Li, J.; Yung, K.K.; Mo, Z. Neuroprotective effects of bilobalide on cerebral ischemia and reperfusion injury are associated with inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation. J. Neuroinflammation, 2014, 11, 167.
[http://dx.doi.org/10.1186/s12974-014-0167-6] [PMID: 25256700]
[15]
KEGG.. AGE-RAGE signaling pathway in diabetic complications, 2020.
[16]
KEGG. GnRH signaling pathway, 2020.
[17]
Kyriakis, J.M.; App, H.; Zhang, X.F.; Banerjee, P.; Brautigan, D.L.; Rapp, U.R.; Avruch, J. Raf-1 activates MAP kinase-kinase. Nature, 1992, 358(6385), 417-421.
[http://dx.doi.org/10.1038/358417a0] [PMID: 1322500]
[18]
Lee, S.M.; Lee, J.; Kang, E.; Kim, H.L.; Hwang, G.S.; Jung, J. Lipidomic analysis reveals therapeutic effects of Yijin-Tang on high-fat/high-cholesterol diet-induced obese mice. Phytomedicine, 2020, 74, 152936.
[http://dx.doi.org/10.1016/j.phymed.2019.152936] [PMID: 31088684]
[19]
Liu, H.; Zeng, L.; Yang, K.; Zhang, G. A Network Pharmacology Approach to Explore the Pharmacological Mechanism of Xiaoyao Powder on Anovulatory Infertility. Evid. Based Complement. Alternat. Med., 2016, 2016, 2960372.
[http://dx.doi.org/10.1155/2016/2960372] [PMID: 28074099]
[20]
Meng, Q.; Wang, P.; Wang, L.; Cao, Z.; Sun, R. A 50-case clinical observation on using erchen decoction for treating hyperlipidemia. Pharmacology and Clinics of Chinese Materia Medica, 2007, 23(6), 75-76.
[21]
Nasias, D.; Evangelakos, I.; Nidris, V.; Vassou, D.; Tarasco, E.; Lutz, T.A.; Kardassis, D. Significant changes in hepatic transcriptome and circulating miRNAs are associated with diet-induced metabolic syndrome in apoE3L.CETP mice. J. Cell. Physiol., 2019, 234(11), 20485-20500.
[http://dx.doi.org/10.1002/jcp.28649] [PMID: 31016757]
[22]
Ortega, F.J.; Mercader, J.M.; Catalán, V.; Moreno-Navarrete, J.M.; Pueyo, N.; Sabater, M.; Gómez-Ambrosi, J.; Anglada, R.; Fernández-Formoso, J.A.; Ricart, W.; Frühbeck, G.; Fernández-Real, J.M. Targeting the circulating microRNA signature of obesity. Clin. Chem., 2013, 59(5), 781-792.
[http://dx.doi.org/10.1373/clinchem.2012.195776] [PMID: 23396142]
[23]
Ortega, F.J.; Mercader, J.M.; Moreno-Navarrete, J.M.; Rovira, O.; Guerra, E.; Esteve, E.; Xifra, G.; Martínez, C.; Ricart, W.; Rieusset, J.; Rome, S.; Karczewska-Kupczewska, M.; Straczkowski, M.; Fernández-Real, J.M. Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization. Diabetes Care, 2014, 37(5), 1375-1383.
[http://dx.doi.org/10.2337/dc13-1847] [PMID: 24478399]
[24]
Parhofer, K.G. The Treatment of Disorders of Lipid Metabolism. Dtsch. Arztebl. Int., 2016, 113(15), 261-268.
[http://dx.doi.org/10.3238/arztebl.2016.0261] [PMID: 27151464]
[25]
Pearson, G.; Robinson, F.; Beers Gibson, T.; Xu, B.E.; Karandikar, M.; Berman, K.; Cobb, M.H. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr. Rev., 2001, 22(2), 153-183.
[PMID: 11294822]
[26]
Pirola, C.J.; Fernández Gianotti, T.; Castaño, G.O.; Mallardi, P.; San Martino, J.; Mora Gonzalez Lopez Ledesma, M.; Flichman, D.; Mirshahi, F.; Sanyal, A.J.; Sookoian, S. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut, 2015, 64(5), 800-812.
[http://dx.doi.org/10.1136/gutjnl-2014-306996] [PMID: 24973316]
[27]
Rayner, K.J.; Suárez, Y.; Dávalos, A.; Parathath, S.; Fitzgerald, M.L.; Tamehiro, N.; Fisher, E.A.; Moore, K.J.; Fernández-Hernando, C. MiR-33 contributes to the regulation of cholesterol homeostasis. Science, 2010, 328(5985), 1570-1573.
[http://dx.doi.org/10.1126/science.1189862] [PMID: 20466885]
[28]
Rodríguez-Acebes, S.; Palacios, N.; Botella-Carretero, J.I.; Olea, N.; Crespo, L.; Peromingo, R.; Gómez-Coronado, D.; Lasunción, M.A.; Vázquez, C.; Martínez-Botas, J. Gene expression profiling of subcutaneous adipose tissue in morbid obesity using a focused microarray: distinct expression of cell-cycle- and differentiation-related genes. BMC Med. Genomics, 2010, 3, 61.
[http://dx.doi.org/10.1186/1755-8794-3-61] [PMID: 21182758]
[29]
Romao, J.M.; Jin, W.; He, M.; McAllister, T.; Guan, L.L. Altered microRNA expression in bovine subcutaneous and visceral adipose tissues from cattle under different diet. PLoS One, 2012, 7(7), e40605.
[http://dx.doi.org/10.1371/journal.pone.0040605] [PMID: 22815773]
[30]
Ru, P.; Guo, D. microRNA-29 mediates a novel negative feedback loop to regulate SCAP/SREBP-1 and lipid metabolism. RNA Dis., 2017, 4(1), e1525.
[PMID: 28664184]
[31]
Rydén, M.; Arvidsson, E.; Blomqvist, L.; Perbeck, L.; Dicker, A.; Arner, P. Targets for TNF-alpha-induced lipolysis in human adipocytes. Biochem. Biophys. Res. Commun., 2004, 318(1), 168-175.
[http://dx.doi.org/10.1016/j.bbrc.2004.04.010] [PMID: 15110769]
[32]
Sedgeman, L.R.; Michell, D.L.; Vickers, K.C. Integrative roles of microRNAs in lipid metabolism and dyslipidemia. Curr. Opin. Lipidol., 2019, 30(3), 165-171.
[http://dx.doi.org/10.1097/MOL.0000000000000603] [PMID: 30985366]
[33]
Sud, N.; Zhang, H.; Pan, K.; Cheng, X.; Cui, J.; Su, Q. Aberrant expression of microRNA induced by high-fructose diet: implications in the pathogenesis of hyperlipidemia and hepatic insulin resistance. J. Nutr. Biochem., 2017, 43, 125-131.
[http://dx.doi.org/10.1016/j.jnutbio.2017.02.003] [PMID: 28284064]
[34]
Suksangrat, T.; Phannasil, P.; Jitrapakdee, S. miRNA Regulation of Glucose and Lipid Metabolism in Relation to Diabetes and Non-alcoholic Fatty Liver Disease. Adv. Exp. Med. Biol., 2019, 1134, 129-148.
[http://dx.doi.org/10.1007/978-3-030-12668-1_7] [PMID: 30919335]
[35]
Sung, H.K.; Doh, K.O.; Son, J.E.; Park, J.G.; Bae, Y.; Choi, S.; Nelson, S.M.; Cowling, R.; Nagy, K.; Michael, I.P.; Koh, G.Y.; Adamson, S.L.; Pawson, T.; Nagy, A. Adipose vascular endothelial growth factor regulates metabolic homeostasis through angiogenesis. Cell Metab., 2013, 17(1), 61-72.
[http://dx.doi.org/10.1016/j.cmet.2012.12.010] [PMID: 23312284]
[36]
Tam, J.; Duda, D.G.; Perentes, J.Y.; Quadri, R.S.; Fukumura, D.; Jain, R.K. Blockade of VEGFR2 and not VEGFR1 can limit diet-induced fat tissue expansion: role of local versus bone marrow-derived endothelial cells. PLoS One, 2009, 4(3), e4974.
[http://dx.doi.org/10.1371/journal.pone.0004974] [PMID: 19333381]
[37]
Wang, J.; Chen, W.; Jia, L.; Zhang, L.; Xu, Y.; Sun, H.; Yang, G. Effects of Erchen Decoction and Taohong Siwu Decoction on Nox4/NF-κB/HIF-1αsignaling pathway in aorta of ApoE~(-/-) atherosclerosis mice. Zhonghua Zhongyiyao Zazhi, 2019, 6, 2417-2420.
[38]
Wisdom, R.; Johnson, R.S.; Moore, C. c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms. EMBO J., 1999, 18(1), 188-197.
[http://dx.doi.org/10.1093/emboj/18.1.188] [PMID: 9878062]
[39]
Xie, T.H.; Chen, R.H.; Mao, T.Y.; Guo, Y.; Chen, C.; Li, N.; Shi, L.; Jia, B.; Han, Y.F.; Tan, C.; Li, X. Yinchen and Erchen detection ameliorates non-alcoholic steatohepatitis by regulating JNK1 and AP-1 protein expression. Chinese Journal of Integrated Traditional and Western Medicine on Digestion, 2017, 25, 943-947.
[40]
Yang, G.; Lu, J.; Luo, X. Effect of Modified Lymphocyte Subsets Erchen Decoction in Patients with Diabetes on Phlegm-Dampness Mellitus Peripheral Blood T Syndrome of Type 2. Guiding J. TCM, 2017, 18, 66-69.
[41]
Yang, H.J.; Yim, N.H.; Lee, K.J.; Gu, M.J.; Lee, B.; Hwang, Y.H.; Ma, J.Y. Simultaneous determination of nine bioactive compounds in Yijin-tang via high-performance liquid chromatography and liquid chromatography-electrospray ionization-mass spectrometry. Integr. Med. Res., 2016, 5(2), 140-150.
[http://dx.doi.org/10.1016/j.imr.2016.04.005] [PMID: 28462109]
[42]
Yang, T.; Yang, Y.; Wang, D.; Li, C.; Qu, Y.; Guo, J.; Shi, T.; Bo, W.; Sun, Z.; Asakawa, T. The clinical value of cytokines in chronic fatigue syndrome. J. Transl. Med., 2019, 17(1), 213.
[http://dx.doi.org/10.1186/s12967-019-1948-6] [PMID: 31253154]
[43]
Zaiou, M.; El Amri, H.; Bakillah, A. The clinical potential of adipogenesis and obesity-related microRNAs. Nutr. Metab. Cardiovasc. Dis., 2018, 28(2), 91-111.
[http://dx.doi.org/10.1016/j.numecd.2017.10.015] [PMID: 29170059]
[44]
Zaiou, M.; Rihn, B.H.; Bakillah, A. Epigenetic regulation of genes involved in the reverse cholesterol transport through interaction with miRNAs. Front. Biosci., 2018, 23, 2090-2105.
[http://dx.doi.org/10.2741/4692] [PMID: 29772548]
[45]
Zhang, H.; Ta, N.; Chen, P.; Wang, H. Erchen Decoction and Linguizhugan Decoction Ameliorate Hepatic Insulin Resistance by Inhibiting IRS-1Ser307 Phosphorylation In Vivo and In Vitro. Evid. Based Complement. Alternat. Med., 2017, 2017, 1589871.
[http://dx.doi.org/10.1155/2017/1589871] [PMID: 28630632]
[46]
Zhang, Y.; Kishi, H.; Kobayashi, S. Add-on therapy with traditional Chinese medicine: An efficacious approach for lipid metabolism disorders. Pharmacol. Res., 2018, 134, 200-211.
[http://dx.doi.org/10.1016/j.phrs.2018.06.004] [PMID: 29935947]
[47]
Zhu, Y.; Gao, Y.; Tao, C.; Shao, M.; Zhao, S.; Huang, W.; Yao, T.; Johnson, J.A.; Liu, T.; Cypess, A.M.; Gupta, O.; Holland, W.L.; Gupta, R.K.; Spray, D.C.; Tanowitz, H.B.; Cao, L.; Lynes, M.D.; Tseng, Y.H.; Elmquist, J.K.; Williams, K.W.; Lin, H.V.; Scherer, P.E. Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals. Cell Metab., 2016, 24(3), 420-433.
[http://dx.doi.org/10.1016/j.cmet.2016.08.005] [PMID: 27626200]

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