Identification of the Myogenetic Oligodeoxynucleotides (myoDNs) That Promote Differentiation of Skeletal Muscle Myoblasts by Targeting Nucleolin

differentiation-associated apoptosis of myoblasts. Cell Death Differ. 7, 506–508.

doi: 10.1038/sj.cdd.4400676

Chang, J. H., Chang, E. J., Kim, H. H., and Kim, S. K. (2009). Enhanced

inhibitory effects of a novel CpG motif on osteoclast differentiation via

TREM-2 down-regulation. Biochem. Biophys. Res. Commun. 389, 28–33.

doi: 10.1016/j.bbrc.2009.08.080

Chen, J., Guo, K., and Kastan, M. B. (2012). Interactions of nucleolin and ribosomal

protein L26 (RPL26) in translational control of human p53 mRNA. J. Biol.

Chem. 287, 16467–16476. doi: 10.1074/jbc.M112.349274

Chen, Q., Luo, S., Zhang, Y., and Chen, Z. (2011). Development of a

liquid chromatography-mass spectrometry method for the determination of

ursolic acid in rat plasma and tissue: application to the pharmacokinetic

and tissue distribution study. Anal. Bioanal. Chem. 399, 2877–2884.

doi: 10.1007/s00216-011-4651-x

Cheng, Y., Zhao, G., Zhang, S., Nigim, F., Zhou, G., Yu, Z., et al. (2016).

AS1411-induced growth inhibition of glioma cells by up-regulation of p53

and down-regulation of Bcl-2 and Akt1 via nucleolin. PLoS ONE 11:e0167094.

doi: 10.1371/journal.pone.0167094

Cui, W., Liu, C. X., Zhang, Y. C., Shen, Q., Feng, Z. H., Wang, J., et al.

(2019). A novel oleanolic acid derivative HA-19 ameliorates muscle atrophy

via promoting protein synthesis and preventing protein degradation. Toxicol.

Appl. Pharmacol. 378:114625. doi: 10.1016/j.taap.2019.114625

Dailey, M. M., Miller, M. C., Bates, P. J., Lane, A. N., and Trent, J. O.

(2010). Resolution and characterization of the structural polymorphism of

a single quadruplex-forming sequence. Nucleic Acids Res. 38, 4877–4888.

doi: 10.1093/nar/gkq166

Dumont, N. A., Bentzinger, C. F., Sincennes, M. C., and Rudnicki, M. A. (2015).

Satellite cells and skeletal muscle regeneration. Compr. Physiol. 5, 1027–1059.

doi: 10.1002/cphy.c140068

Fahling, M., Mrowka, R., Steege, A., Nebrich, G., Perlewitz, A., Persson, P.

B., et al. (2006). Translational control of collagen prolyl 4-hydroxylaseα(I) gene expression under hypoxia. J. Biol. Chem. 281, 26089–26101.

doi: 10.1074/jbc.M604939200

Feng, Z., Shen, Y., Wang, L., Cheng, L., Wang, J., Li, Q., et al. (2011).

An oligodeoxynucleotide with promising modulation activity for the

proliferation and activation of osteoblast. Int. J. Mol. Sci. 12, 2543–2555.

doi: 10.3390/ijms12042543

Fukada, S. I. (2018). The roles of muscle stem cells in muscle injury, atrophy and

hypertrophy. J. Biochem. 163, 353–358. doi: 10.1093/jb/mvy019

Girvan, A. C., Teng, Y., Casson, L. K., Thomas, S. D., Juliger, S.,

Ball, M. W., et al. (2006). AGRO100 inhibits activation of nuclear

Amcheslavsky, A., Hemmi, H., Akira, S., and Bar-Shavit, Z. (2005).

Differential contribution of osteoclast- and osteoblast-lineage cells to

CpG-oligodeoxynucleotide (CpG-ODN) modulation of osteoclastogenesis. J.

Bone Miner. Res. 20, 1692–1699. doi: 10.1359/JBMR.050515

Anders, S., Pyl, P. T., and Huber, W. (2015). HTSeq - a python framework

to work with high-throughput sequencing data. Bioinformatics 31, 166–169.

doi: 10.1093/bioinformatics/btu638

Anker, S. D., Ponikowski, P., Varney, S., Chua, T. P., Clark, A. L., Webb-Peploe,

K. M., et al. (1997). Wasting as independent risk factor for mortality in chronic

heart failure. Lancet 349, 1050–1053. doi: 10.1016/S0140-6736(96)07015-8

Babicki, S., Arndt, D., Marcu, A., Liang, Y., Grant, J. R., Maciejewski, A., et al.

(2016). Heatmapper: web-enabled heat mapping for all. Nucleic Acids Res. 44,

W147–W153. doi: 10.1093/nar/gkw419

Barel, M., Le Romancer, M., and Frade, R. (2001). Activation of the

EBV/C3d receptor (CR2, CD21) on human B lymphocyte surface

triggers tyrosine phosphorylation of the 95-kDa nucleolin and its

interaction with phosphatidylinositol 3 kinase. J. Immunol. 166, 3167–3173.

doi: 10.4049/jimmunol.166.5.3167

Bates, P. J., Laber, D. A., Miller, D. M., Thomas, S. D., and Trent, J.

O. (2009). Discovery and development of the G-rich oligonucleotide

AS1411 as a novel treatment for cancer. Exp. Mol. Pathol. 86, 151–164.

doi: 10.1016/j.yexmp.2009.01.004

Bauer, S., Kirschning, C. J., Hacker, H., Redecke, V., Hausmann, S., Akira, S., et al.

(2001). Human TLR9 confers responsiveness to bacterial DNA via speciesspecific CpG motif recognition. Proc. Natl. Acad. Sci. U.S.A. 98, 9237–9242.

doi: 10.1073/pnas.161293498

Bazzicalupi, C., Ferraroni, M., Bilia, A. R., Scheggi, F., and Gratteri, P. (2012).

The crystal structure of human telomeric DNA complexed with berberine: an

interesting case of stacked ligand to G-tetrad ratio higher than 1:1. Nucleic Acids

Res. 41, 632–638. doi: 10.1093/nar/gks1001

Brack, A. S., Conboy, M. J., Roy, S., Lee, M., Kuo, C. J., Keller, C., et al. (2007).

Increased Wnt signaling during aging alters muscle stem cell fate and increases

fibrosis. Science 317, 807–810. doi: 10.1126/science.1144090

Carrero, J. J., Chmielewski, M., Axelsson, J., Snaedal, S., Heimburger, O.,

Barany, P., et al. (2008). Muscle atrophy, inflammation and clinical

outcome in incident and prevalent dialysis patients. Clin. Nutr. 27, 557–564.

doi: 10.1016/j.clnu.2008.04.007

Cerone, M. A., Marchetti, A., Bossi, G., Blandino, G., Sacchi, A., and

Soddu, S. (2000). p53 is involved in the differentiation but not in the

Frontiers in Cell and Developmental Biology | www.frontiersin.org

14

January 2021 | Volume 8 | Article 616706

Shinji et al.

Myogenetic Oligodeoxynucleotides Promote Myoblast Differentiation

Losfeld, M. E., Khoury, D. E., Mariot, P., Carpentier, M., Krust, B., Briand, J.

P., et al. (2009). The cell surface expressed nucleolin is a glycoprotein that

triggers calcium entry into mammalian cells. Exp. Cell Res. 315, 357–369.

doi: 10.1016/j.yexcr.2008.10.039

Macke, T. J., and Case, D. A. (1998). “Modeling unusual nucleic acid

structures,” in Molecular Modeling of Nucleic Acids, eds N. B. Leontis

and J. SantaLucia (Washington, DC: American Chemical Society), 379–393.

doi: 10.1021/bk-1998-0682.ch024

Maier, J. A., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K. E.,

and Simmerling, C. (2015). ff14SB: Improving the accuracy of protein side

chain and backbone parameters from ff99SB. J. Chem. Theory Comput. 11,

3696–3713. doi: 10.1021/acs.jctc.5b00255

Marchildon, F., Lamarche, E., Lala-Tabbert, N., St-Louis, C., and Wiper-Bergeron,

N. (2015). Expression of CCAAT/enhancer binding protein beta in muscle

satellite cells inhibits myogenesis in cancer cachexia. PLoS ONE 10:e0145583.

doi: 10.1371/journal.pone.0145583

McCormick, R., and Vasilaki, A. (2018). Age-related changes in skeletal

muscle: changes to life-style as a therapy. Biogerontology 19, 519–536.

doi: 10.1007/s10522-018-9775-3

Nigar, S., Yamamoto, Y., Okajima, T., Shigemori, S., Sato, T., Ogita, T., et al. (2017).

Synergistic oligodeoxynucleotide strongly promotes CpG-induced interleukin6 production. BMC Immunol. 18:44. doi: 10.1186/s12865-017-0227-7

Nihashi, Y., Ono, T., Kagami, H., and Takaya, T. (2019a). Toll-like receptor liganddependent inflammatory responses in chick skeletal muscle myoblasts. Dev.

Comp. Immunol. 91, 115–122. doi: 10.1016/j.dci.2018.10.013

Nihashi, Y., Umezawa, K., Shinji, S., Hamaguchi, Y., Kobayashi, H., Kono, T.,

et al. (2019b). Distinct cell proliferation, myogenic differentiation, and gene

expression in skeletal muscle myoblasts of layer and broiler chickens. Sci. Rep.

9:16527. doi: 10.1038/s41598-019-52946-4

Norgaard, N. N., Holien, T., Jonsson, S., Hella, H., Espevik, T., Sundan,

A., et al. (2010). CpG-oligodeoxynucleotide inhibits Smad-dependent

bone morphogenetic protein signaling: effects on myeloma cell

apoptosis and in vitro osteoblastogenesis. J. Immunol. 185, 3131–3139.

doi: 10.4049/jimmunol.0903605

Novitch, B. G., Mulligan, G. J., Jacks, T., and Lassar, A. B. (1996). Skeletal

muscle cells lacking the retinoblastoma protein display defects in muscle gene

expression and accumulate in S and G2 phases of the cell cycle. J. Cell Biol. 135,

441–456. doi: 10.1083/jcb.135.2.441

Ou, T. M., Lu, Y. J., Tan, J. H., Huang, Z. S., Wong, K. Y., and Gu, L. Q. (2008). Gquadruplexex: targets in anticancer drug design. ChemMedChem 3, 690–713.

doi: 10.1002/cmdc.200700300

Pohar, J., Lainscek, D., Fukui, R., Yamamoto, C., Miyake, K., Jerala,

R., et al. (2015). Species-specific minimal sequence motif for

oligodeoxyribonucleotides activating mouse TLR9. J. Immunol. 195,

4396–4405. doi: 10.4049/jimmunol.1500600

Porrello, A., Cerone, M. A., Coen, S., Gurtner, A., Fontemaggi, G., Cimino, L., et al.

(2000). p53 regulates myogenesis by triggering the differentiation activity of

pRb. J. Cell Biol. 151, 1295–1304. doi: 10.1083/jcb.151.6.1295

Quemener, A. M., Bachelot, L., Forestier, A., Donnou-Fournet, E., Gilot, D., and

Galibert, M. D. (2020). The powerful world of antisense oligonucleotides: from

bench to bedside. Wiley Interdiscip. Rev. RNA 11:e1594. doi: 10.1002/wrna.1594

Ramos, K. S., Moore, S., Runge, I., Tavera-Garcia, M. A., Cascone, I., Courty, J.,

et al. (2020). The nucleolin antagonist N6L inhibits LINE1 retrotransposon

activity in non-small cell lung carcinoma cells. J. Cancer 11, 733–740.

doi: 10.7150/jca.37776

Reyes-Reyes, E. M., Salipur, F. R., Shams, M., Forsthoefel, M. K., and Bates, P.

J. (2015). Mechanistic studies of anticancer aptamer AS1411 reveal a novel

role for nucleolin in regulating Rac1 activation. Mol. Oncol. 9, 1392–1405.

doi: 10.1016/j.molonc.2015.03.012

Rubin, H. (2003). Cancer cachexia: its correlations and causes. Proc. Natl. Acad.

Sci. U.S.A. 100, 5384–5389. doi: 10.1073/pnas.0931260100

Ruijtenberg, S., and van den Heuvel, S. (2016). Coordinating cell proliferation and

differentiation: antagonism between cell cycle regulators and cell type-specific

gene expression. Cell Cycle 15, 196–212. doi: 10.1080/15384101.2015.1120925

Sackesen, C., van de Veen, W., Akdis, M., Soyer, O., Zumkehr, J., Ruckert, B.,

et al. (2013). Suppression of B-cell activation and IgE, IgA, IgG1 and IgG4

production by mammalian telomeric oligonucleotides. Allergy 68, 593–603.

doi: 10.1111/all.12133

factor-kappaB (NF-kappaB) by forming a complex with NF-kappaB

essential modulator (NEMO) and nucleolin. Mol. Cancer Ther. 5, 1790–1799.

doi: 10.1158/1535-7163.MCT-05-0361

Gu, W., Schneider, J. W., Condorelli, G., Kaushal, S., Mahdavi, V., and NadalGinard, B. (1993). Interaction of myogenic factors and the retinoblastoma

protein mediates muscle cell commitment and differentiation. Cell 72, 309–324.

doi: 10.1016/0092-8674(93)90110-C

Guo, Y., Chen, Y., Wei, Y., Li, H., and Dong, C. (2015). Label-free fluorescent

aptasensor for potassium ion using structure-switching aptamers and

berberine. Spectrochim. Acta A Mol. Biomol. Spectrosc. 136 Pt C, 1635–1641.

doi: 10.1016/j.saa.2014.10.058

Harford, T. J., Kliment, G., Shukla, G. C., and Weyman, C. M. (2017). The muscle

regulatory transcription factor MyoD participates with p53 to directly increase

the expression of the pro-apoptotic Bcl2 family member PUMA. Apoptosis 22,

1532–1542. doi: 10.1007/s10495-017-1423-x

Harford, T. J., Shaltouki, A., and Weyman, C. M. (2010). Increased expression of

the pro-apoptotic Bcl2 family member PUMA and apoptosis by the muscle

regulatory transcription factor MyoD in response to a variety of stimuli.

Apoptosis 15, 71–82. doi: 10.1007/s10495-009-0428-5

Hartmann, G., Weeratna, R. D., Ballas, Z. K., Payette, P., Blackwell, S., Suparto,

I., et al. (2000). Delineation of a CpG phosphorothioate oligodeoxynucleotide

for activating primate immune responses in vitro and in vivo. J. Immunol. 164,

1617–1624. doi: 10.4049/jimmunol.164.3.1617

Hou, X., Shen, Y., Zhang, C., Zhang, L., Qin, Y., Yu, Y., et al. (2012). A specific

oligodeoxynucleotide promotes the differentiation of osteoblasts via ERK and

p38 MAPK pathways. Int. J. Mol. Sci. 13, 7902–7914. doi: 10.3390/ijms13077902

Huang, D. W., Sherman, B. T., and Lempicki, R. A. (2009). Systematic and

integrative analysis of large gene lists using DAVID bioinformatics resources.

Nat. Protoc. 4, 44–57. doi: 10.1038/nprot.2008.211

Iezzi, S., Di Padova, M., Serra, C., Caretti, G., Simone, C., Maklan, E., et al.

(2004). Deacetylase inhibitors increase muscle cell size by promoting myoblast

recruitment and fusion through induction of follistatin. Dev. Cell 6, 673–684.

doi: 10.1016/S1534-5807(04)00107-8

Ikebe, J., Umezawa, K., Kamiya, N., Sugihara, T., Yonezawa, Y., Takano, Y., et al.

(2011). Theory for trivial trajectory parallelization of multicanonical molecular

dynamics and application to a polypeptide in water. J. Comput. Chem. 32,

1286–1297. doi: 10.1002/jcc.21710

Imenshahidi, M., and Hosseinzadeh, H. (2019). Berberine and barberry (Berberis

vulgaris): a clinical review. Phytother. Res. 33, 504–523. doi: 10.1002/ptr.6252

Jia, W., Yao, Z., Zhao, J., Guan, Q., and Gao, L. (2017). New perspectives of

physiological and pathological functions of nucleolin (NCL). Life Sci. 186, 1–10.

doi: 10.1016/j.lfs.2017.07.025

Juliano, R. L. (2018). Intracellular trafficking and endosomal release of

oligonucleotides: What we know and what we don’t. Nucleic Acid Ther. 28,

166–177. doi: 10.1089/nat.2018.0727

Kim, D., Pertea, G., Trapnell, C., Pimentel, H., Kelley, R., and Salzberg,

S. L. (2013). TopHat2: accurate alignment of transcriptomes in the

presence of insertions, deletions and gene fusions. Genome Biol. 14:R36.

doi: 10.1186/gb-2013-14-4-r36

Kim, M., Sung, B., Kang, Y. J., Kim, D. H., Lee, Y., Hwang, S. Y., et al. (2015). The

combination of ursolic acid and leucine potentiates the differentiation of C2C12

murine myoblasts through the mTOR signaling pathway. Int. J. Mol. Med. 35,

755–762. doi: 10.3892/ijmm.2014.2046

Klinman, D., Shirota, H., Tross, D., Sato, T., and Klaschik, S. (2008). Synthetic

oligodeoxynucleotides as modulators of inflammation. J. Leukoc. Biol. 84,

958–964. doi: 10.1189/jlb.1107775

Krieg, A. M., Yi, A. K., Matson, S., Waldschmidt, T. J., Bishop, G. A., Teasdale,

R., et al. (1995). CpG motifs in bacterial DNA trigger direct B-cell activation.

Nature 374, 546–549. doi: 10.1038/374546a0

Li, N., Liu, C., Mi, S., Wang, N., Zheng, X., Li, Y., et al. (2012). Simultaneous

determination of oleanolic acid, p-coumaric acid, ferulic acid, kaemperol and

quercetin in rat plasma by LC-MS-MS and application to a pharmacokinetic

study of Oldenlandia diffusa extract in rats. J. Chromatogr. Sci. 50, 885–892.

doi: 10.1093/chromsci/bms086

Litchfield, L. M., Riggs, K. A., Hockenberry, A. M., Oliver, L. D., Barnhart, K. G.,

Cai, J., et al. (2012). Identification and characterization of nucleolin as a COUPTFII coactivator of retinoic acid receptor beta transcription in breast cancer

cells. PLoS ONE 7:e38278. doi: 10.1371/journal.pone.0038278

Frontiers in Cell and Developmental Biology | www.frontiersin.org

15

January 2021 | Volume 8 | Article 616706

Shinji et al.

Myogenetic Oligodeoxynucleotides Promote Myoblast Differentiation

Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A., and Case, D. A. (2004).

Development and testing of a general amber force field. J. Comput. Chem. 25,

1157–1174. doi: 10.1002/jcc.20035

Wang, T., Chen, C., Larcher, L. M., Barrero, R., and Veedu, R. N. (2019).

Three decades of nucleic acid aptamer technologies: lessons learned, progress

and opportunities on aptamer development. Biotechnol. Adv. 37, 28–50.

doi: 10.1016/j.biotechadv.2018.11.001

Wang, Y., Yamamoto, Y., Shigemori, S., Watanabe, T., Oshiro, K., Wang, X., et al.

(2015). Inhibitory/suppressive oligodeoxynucleotide nanocapsules as simple

oral delivery devices for preventing atopic dermatitis in mice. Mol. Ther. 23,

297–309. doi: 10.1038/mt.2014.239

Yamamoto, Y., Sugimura, R., Watanabe, T., Shigemori, S., Okajima, T., Nigar, S.,

et al. (2017). Class A CpG oligodeoxynucleotide priming rescues mice from

septic shock via activation of platelet-activating factor acetylhydrolase. Front.

Immunol. 8:1049. doi: 10.3389/fimmu.2017.01049

Yang, G., Wan, M., Zhang, Y., Sun, L., Sun, R., Hu, D., et al. (2010). Inhibition

of a C-rich oligodeoxynucleotide on activation of immune cells in vitro

and enhancement of antibody response in mice. Immunology 131, 501–512.

doi: 10.1111/j.1365-2567.2010.03322.x

Yazdian-Robati, R., Bayat, P., Oroojalian, F., Zargari, M., Ramezani, M.,

Taghdisi, S. M., et al. (2019). Therapeutic applications of AS1411

aptamer, an update review. Int. J. Biol. Macromol. 155, 1420–1431.

doi: 10.1016/j.ijbiomac.2019.11.118

Yu, G., and He, Q. Y. (2016). ReactomePA: an R/Bioconductor package for

reactome pathway analysis and visualization. Mol. BioSyst. 12, 477–479.

doi: 10.1039/C5MB00663E

Zhang, L., Wang, X. H., Wang, H., Du, J., and Mitch, W. E. (2010). Satellite cell

dysfunction and impeired IGF-1 signaling cause CKD-induced muscle atrophy.

J. Am. Soc. Nephrol. 21, 419–427. doi: 10.1681/ASN.2009060571

Zou, W., Amcheslavsky, A., and Bar-Shavit, Z. (2003). CpG oligodeoxynucleotides

modulate the osteoclastogenic activity of osteoblasts via toll-like

receptor 9. J. Biol. Chem. 278, 16732–16740. doi: 10.1074/jbc.

M212473200

Shaltouki, A., Freer, M., Mei, Y., and Weyman, C. M. (2007). Increased expression

of the pro-apoptotic Bcl2 family member PUMA is required for mitochondrial

release of cytochrome C and the apoptosis associated with skeletal myoblast

differentiation. Apoptosis 12, 2143–2154. doi: 10.1007/s10495-007-0135-z

Shen, Y., Feng, Z., Lin, C., Hou, X., Wang, X., Wang, J., et al. (2012).

An oligodeoxynucleotide that induces differentiation of bone marrow

mesenchymal stem cells to osteoblasts in vitro and reduces alveolar

bone loss in rats with periodontitis. Int. J. Mol. Sci. 13, 2877–2892.

doi: 10.3390/ijms13032877

Shinji, S., Nakamura, S., Nihashi, Y., Umezawa, K., and Takaya, T. (2020a).

Berberine and palmatine inhibit growth of human rhabdomyosarcoma cells.

Biosci. Biotechnol. Biochem. 84, 63–75. doi: 10.1080/09168451.2019.1659714

Shinji, S., Umezawa, K., Nihashi, Y., Nakamura, S., Shimosato, T., and Takaya,

T. (2020b). Identification of the myogenetic oligodeoxynucleotides (myoDNs)

that promote differentiation of skeletal muscle myoblasts by targeting

nucleolin. bioRxiv doi: 10.1101/2020.10.07.330472

Siddiqui-Jain, A., Grand, C. L., Bearss, D. J., and Hurley, L. H. (2002). Direct

evidence for a G-quadruplex in a promoter region and its targeting with a

small molecule to repress c-MYC transcription. Proc. Natl. Acad. Sci. U.S.A. 99,

11593–11598. doi: 10.1073/pnas.182256799

Soddu, S., Blandino, G., Scardigli, R., Coen, S., Marchetti, A., Rizzo, M. G.,

et al. (1996). Interference with p53 protein inhibits hematopoietic and muscle

differentiation. J. Cell Biol. 134, 193–204. doi: 10.1083/jcb.134.1.193

Szklarczyk, D., Gable, A. L., Lyon, D., Junge, A., Wyder, S., Huerta-Cepas, J.,

et al. (2019). STRING v11: protein-protein association networks with increased

coverage, supporting functional discovery in genome-wide experimental

datasets. Nucleic Acids Res. 47, D607–D613. doi: 10.1093/nar/gky1131

Takagi, M., Absalon, M. J., McLure, K. G., and Kastan, M. B. (2005). Regulation of

p53 translation and induction after DNA damage by ribosomal protein L26 and

nucleolin. Cell 123, 49–63. doi: 10.1016/j.cell.2005.07.034

Takaya, T., Nihashi, Y., Kojima, S., Ono, T., and Kagami, H. (2017). Autonomous

xenogenic cell fusion of murine and chick skeletal muscle myoblasts. Anim. Sci.

J. 88, 1880–1885. doi: 10.1111/asj.12884

Tang, Z., Qiu, H., Luo, L., Liu, N., Zhong, J., Kang, K., et al. (2017). miR-34b

modulates skeletal muscle cell proliferation and differentiation. J. Cell. Biochem.

118, 4285–4295. doi: 10.1002/jcb.26079

Teng, Y., Girvan, A. C., Casson, L. K., Pierce, W. M. Jr, Qian, M., Thomas, S. D.,

et al. (2007). AS1411 alters the localization of a complex containing protein

arginine methyltransferase 5 and nucleolin. Cancer Res. 67, 10491–10500.

doi: 10.1158/0008-5472.CAN-06-4206

Tsui, V., and Case, D. A. (2000). Theory and applications of the generalized

born solvation model in macromolecular simulations. Biopolymers 56, 275–291.

doi: 10.1002/1097-0282(2000)56:4<275::AID-BIP10024>3.0.CO;2-E

Vollmer, J., and Krieg, A. M. (2009). Immunotherapeutic applications of CpG

oligodeoxynucleotide TLR9 agonists. Adv. Drug Deliv. Rev. 61, 195–204.

doi: 10.1016/j.addr.2008.12.008

Wang, H., Chen, Y., Lu, X. A., Liu, G., Fu, Y., and Luo, Y. (2015). Endostatin

prevents dietary-induced obesity by inhibiting adipogenesis and angiogenesis.

Diabetes 64, 2442–2456. doi: 10.2337/db14-0528

Frontiers in Cell and Developmental Biology | www.frontiersin.org

Conflict of Interest: Shinshu University has been assigned the invention of

myoDNs by TT, KU, and TS, and Japan Patent Application 2018-568609 has been

filed on February 15, 2018.

The remaining authors declare that the research was conducted in the absence of

any commercial or financial relationships that could be construed as a potential

conflict of interest.

Copyright © 2021 Shinji, Umezawa, Nihashi, Nakamura, Shimosato and Takaya.

This is an open-access article distributed under the terms of the Creative Commons

Attribution License (CC BY). The use, distribution or reproduction in other forums

is permitted, provided the original author(s) and the copyright owner(s) are credited

and that the original publication in this journal is cited, in accordance with accepted

academic practice. No use, distribution or reproduction is permitted which does not

comply with these terms.

16

January 2021 | Volume 8 | Article 616706

...