Generic placeholder image

Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294


Small Molecule Regulation of Stem Cells that Generate Bone, Chondrocyte, and Cardiac Cells

Author(s): John R. Cashman*

Volume 20 , Issue 26 , 2020

Page: [2344 - 2361] Pages: 18

DOI: 10.2174/1568026620666200820143912

Price: $65


Embryonic stem cells (ESCs) are stem cells (SCs) that can self-renew and differentiate into a myriad of cell types. The process of developing stemness is determined by signaling molecules that drive stem cells to a specific lineage. For example, ESCs can differentiate into mature cells (e.g., cardiomyocytes) and mature cardiomyocytes can be characterized for cell beating, action potential, and ion channel function. A goal of this Perspective is to show how small molecules can be used to differentiate ESCs into cardiomyocytes and how this can reveal novel aspects of SC biology. This approach can also lead to the discovery of new molecules of use in cardiovascular disease.

Human induced pluripotent stem cells (hiPSCs) afford the ability to produce unlimited numbers of normal human cells. The creation of patient-specific hiPSCs provides an opportunity to study cell models of human disease. The second goal is to show that small molecules can stimulate hiPSC commitment to cardiomyocytes. How iPSCs can be used in an approach to discover new molecules of use in cardiovascular disease will also be shown in this study.

Adult SCs, including mesenchymal stem cells (MSCs), can likewise participate in self-renewal and multilineage differentiation. MSCs are capable of differentiating into osteoblasts, adipocytes or chondrocytes. A third goal of this Perspective is to describe differentiation of MSCs into chondrogenic and osteogenic lineages. Small molecules can stimulate MSCs to specific cell fate both in vitro and in vivo. In this Perspective, some recent examples of applying small molecules for osteogenic and chondrogenic cell fate determination are summarized. Underlying molecular mechanisms and signaling pathways involved are described. Small molecule-based modulation of stem cells shows insight into cell regulation and potential approaches to therapeutic strategies for MSC-related diseases.

Keywords: Stem cells, Embryonic stem cells, Chondrocyte, Cardiomyocytes, Cardiovascular disease, Ion channel function.

Graphical Abstract
Mason, C.; Dunnill, P. A brief definition of regenerative medicine. Regen. Med., 2008, 3(1), 1-5.
[ ] [PMID: 18154457]
Li, W.; Li, K.; Wei, W.; Ding, S. Chemical approaches to stem cell biology and therapeutics. Cell Stem Cell, 2013, 13(3), 270-283.
[ ] [PMID: 24012368]
Ao, A.; Hao, J.; Hong, C.C. Regenerative chemical biology: current challenges and future potential. Chem. Biol., 2011, 18(4), 413-424.
[ ] [PMID: 21513877]
Green, E.M.; Lee, R.T. Proteins and small molecules for cellular regenerative medicine. Physiol. Rev., 2013, 93(1), 311-325.
[ ] [PMID: 23303911]
Xu, Y.; Shi, Y.; Ding, S. A chemical approach to stem-cell biology and regenerative medicine. Nature, 2008, 453(7193), 338-344.
[ ] [PMID: 18480815]
Lyssiotis, C.A.; Lairson, L.L.; Boitano, A.E.; Wurdak, H.; Zhu, S.; Schultz, P.G. Chemical control of stem cell fate and developmental potential. Angew. Chem. Int. Ed. Engl., 2011, 50(1), 200-242.
[ ] [PMID: 21184400]
Tiscornia, G.; Vivas, E.L.; Izpisúa Belmonte, J.C. Diseases in a dish: modeling human genetic disorders using induced pluripotent cells. Nat. Med., 2011, 17(12), 1570-1576.
[ ] [PMID: 22146428]
Ying, Q.L.; Wray, J.; Nichols, J.; Batlle-Morera, L.; Doble, B.; Woodgett, J.; Cohen, P.; Smith, A. The ground state of embryonic stem cell self-renewal. Nature, 2008, 453(7194), 519-523.
[ ] [PMID: 18497825]
Chambers, I.; Colby, D.; Robertson, M.; Nichols, J.; Lee, S.; Tweedie, S.; Smith, A. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell, 2003, 113(5), 643-655.
[ ] [PMID: 12787505]
Takahashi, K.; Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 2006, 126(4), 663-676.
[ ] [PMID: 16904174]
Hnatiuk, A.; Mercola, M. Stars in the night sky: ipsc-cardiomyocytes return the patient context to drug screening. Cell Stem Cell, 2019, 24(4), 506-507.
[ ] [PMID: 30951657]
Matsa, E.; Ahrens, J.H.; Wu, J.C. Human induced pluripotent stem cells as a platform for personalized and precision cardiovascular medicine. Physiol. Rev., 2016, 96(3), 1093-1126.
[ ] [PMID: 27335446]
Turdiev, A.; Filiutovich, O.; Mirkin, F.; Byk, G. A peptide from Testudo horsfieldii tortoise spleen as a potential helper for reducing acute radiation syndrome. J. Pept. Sci., 2019, 25(9), e3202
[ ] [PMID: 31313444]
Naveiras, O.; Nardi, V.; Wenzel, P.L.; Hauschka, P.V.; Fahey, F.; Daley, G.Q. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature, 2009, 460(7252), 259-263.
[ ] [PMID: 19516257]
Moreno-Indias, I.; Tinahones, F.J. Impaired adipose tissue expandability and lipogenic capacities as ones of the main causes of metabolic disorders. J. Diabetes Res., 2015, 2015, 970375
[ ] [PMID: 25922847]
Willems, E.; Lanier, M.; Forte, E.; Lo, F.; Cashman, J.; Mercola, M. A chemical biology approach to myocardial regeneration. J. Cardiovasc. Transl. Res., 2011, 4(3), 340-350.
[ ] [PMID: 21424858]
Bergmann, O.; Bhardwaj, R.D.; Bernard, S.; Zdunek, S.; Barnabé-Heider, F.; Walsh, S.; Zupicich, J.; Alkass, K.; Buchholz, B.A.; Druid, H.; Jovinge, S.; Frisén, J. Evidence for cardiomyocyte renewal in humans. Science, 2009, 324(5923), 98-102.
[ ] [PMID: 19342590]
Senyo, S.E.; Steinhauser, M.L.; Pizzimenti, C.L.; Yang, V.K.; Cai, L.; Wang, M.; Wu, T.D.; Guerquin-Kern, J.L.; Lechene, C.P.; Lee, R.T. Mammalian heart renewal by pre-existing cardiomyocytes. Nature, 2013, 493(7432), 433-436.
[ ] [PMID: 23222518]
Takahashi, T.; Lord, B.; Schulze, P.C.; Fryer, R.M.; Sarang, S.S.; Gullans, S.R.; Lee, R.T. Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation, 2003, 107(14), 1912-1916.
[ ] [PMID: 12668514]
Sadek, H.; Hannack, B.; Choe, E.; Wang, J.; Latif, S.; Garry, M.G.; Garry, D.J.; Longgood, J.; Frantz, D.E.; Olson, E.N.; Hsieh, J.; Schneider, J.W. Cardiogenic small molecules that enhance myocardial repair by stem cells. Proc. Natl. Acad. Sci. USA, 2008, 105(16), 6063-6068.
[ ] [PMID: 18420817]
Wu, X.; Ding, S.; Ding, Q.; Gray, N.S.; Schultz, P.G. Small molecules that induce cardiomyogenesis in embryonic stem cells. J. Am. Chem. Soc., 2004, 126(6), 1590-1591.
[ ] [PMID: 14871063]
Wei, Z.L.; Petukhov, P.A.; Bizik, F.; Teixeira, J.C.; Mercola, M.; Volpe, E.A.; Glazer, R.I.; Willson, T.M.; Kozikowski, A.P. Isoxazolyl-serine-based agonists of peroxisome proliferator-activated receptor: design, synthesis, and effects on cardiomyocyte differentiation. J. Am. Chem. Soc., 2004, 126(51), 16714-16715.
[ ] [PMID: 15612696]
Gnecchi, M.; Zhang, Z.; Ni, A.; Dzau, V.J. Paracrine mechanisms in adult stem cell signaling and therapy. Circ. Res., 2008, 103(11), 1204-1219.
[ ] [PMID: 19028920]
Russell, J.L.; Goetsch, S.C.; Aguilar, H.R.; Frantz, D.E.; Schneider, J.W. Targeting native adult heart progenitors with cardiogenic small molecules. ACS Chem. Biol., 2012, 7(6), 1067-1076.
[ ] [PMID: 22413910]
Russell, J.L.; Goetsch, S.C.; Aguilar, H.R.; Coe, H.; Luo, X.; Liu, N.; van Rooij, E.; Frantz, D.E.; Schneider, J.W. Regulated expression of pH sensing G Protein-coupled receptor-68 identified through chemical biology defines a new drug target for ischemic heart disease. ACS Chem. Biol., 2012, 7(6), 1077-1083.
[ ] [PMID: 22462679]
Bushway, P.J.; Mercola, M. High-throughput screening for modulators of stem cell differentiation. Methods Enzymol., 2006, 414, 300-316.
[ ] [PMID: 17110199]
Thorne, C.A.; Hanson, A.J.; Schneider, J.; Tahinci, E.; Orton, D.; Cselenyi, C.S.; Jernigan, K.K.; Meyers, K.C.; Hang, B.I.; Waterson, A.G.; Kim, K.; Melancon, B.; Ghidu, V.P.; Sulikowski, G.A.; LaFleur, B.; Salic, A.; Lee, L.A.; Miller, D.M., III; Lee, E. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat. Chem. Biol., 2010, 6(11), 829-836.
[ ] [PMID: 20890287]
Emami, K.H.; Nguyen, C.; Ma, H.; Kim, D.H.; Jeong, K.W.; Eguchi, M.; Moon, R.T.; Teo, J.L.; Kim, H.Y.; Moon, S.H.; Ha, J.R.; Kahn, M. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription. [corrected]. Proc. Natl. Acad. Sci. USA, 2004, 101(34), 12682-12687.
[ ] [PMID: 15314234]
Beyer, C.; Reichert, H.; Akan, H.; Mallano, T.; Schramm, A.; Dees, C.; Palumbo-Zerr, K.; Lin, N.Y.; Distler, A.; Gelse, K.; Varga, J.; Distler, O.; Schett, G.; Distler, J.H. Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis. Ann. Rheum. Dis., 2013, 72(7), 1255-1258.
[ ] [PMID: 23595143]
Saraswati, S.; Alfaro, M.P.; Thorne, C.A.; Atkinson, J.; Lee, E.; Young, P.P. Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling. PLoS One, 2010, 5(11), e15521
[ ] [PMID: 21170416]
Lu, J.; Ma, Z.; Hsieh, J.C.; Fan, C.W.; Chen, B.; Longgood, J.C.; Williams, N.S.; Amatruda, J.F.; Lum, L.; Chen, C. Structure-activity relationship studies of small-molecule inhibitors of Wnt response. Bioorg. Med. Chem. Lett., 2009, 19(14), 3825-3827.
[ ] [PMID: 19410457]
Martins-Neves, S.R.; Paiva-Oliveira, D.I.; Fontes-Ribeiro, C.; Bovée, J.V.M.G.; Cleton-Jansen, A.M.; Gomes, C.M.F. IWR-1, a tankyrase inhibitor, attenuates Wnt/β-catenin signaling in cancer stem-like cells and inhibits in vivo the growth of a subcutaneous human osteosarcoma xenograft. Cancer Lett., 2018, 414, 1-15.
[ ] [PMID: 29126913]
Zhang, X.; Chen, L.; Wang, Y.; Ding, Y.; Peng, Z.; Duan, L.; Ju, G.; Ren, Y.; Wang, X. Macrophage migration inhibitory factor promotes proliferation and neuronal differentiation of neural stem/precursor cells through Wnt/β-catenin signal pathway. Int. J. Biol. Sci., 2013, 9(10), 1108-1120.
[ ] [PMID: 24339732]
Willems, E.; Spiering, S.; Davidovics, H.; Lanier, M.; Xia, Z.; Dawson, M.; Cashman, J.; Mercola, M. Small-molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cell-derived mesoderm. Circ. Res., 2011, 109(4), 360-364.
[ ] [PMID: 21737789]
Willems, E.; Cabral-Teixeira, J.; Schade, D.; Cai, W.; Reeves, P.; Bushway, P.J.; Lanier, M.; Walsh, C.; Kirchhausen, T.; Izpisua Belmonte, J.C.; Cashman, J.; Mercola, M. Small molecule-mediated TGF-β type II receptor degradation promotes cardiomyogenesis in embryonic stem cells. Cell Stem Cell, 2012, 11(2), 242-252.
[ ] [PMID: 22862949]
Cashman, J.R.; MacDougall, J.M. Dynamic medicinal chemistry in the elaboration of morphine-6-glucuronide analogs. Curr. Top. Med. Chem., 2005, 5(6), 585-594.
[ ] [PMID: 16022681]
Okolotowicz, K.J.; Bushway, P.; Lanier, M.; Gilley, C.; Mercola, M.; Cashman, J.R. 1,5-Disubstituted benzimidazoles that direct cardiomyocyte differentiation from mouse embryonic stem cells. Bioorg. Med. Chem., 2015, 23(17), 5282-5292.
[ ] [PMID: 26278027]
Vidler, L.R.; Watson, I.A.; Margolis, B.J.; Cummins, D.J.; Brunavs, M. Investigating the behavior of published pains alerts using a pharmaceutical company data set. ACS Med. Chem. Lett., 2018, 9(8), 792-796.
[ ] [PMID: 30128069]
Lanier, M.; Schade, D.; Willems, E.; Tsuda, M.; Spiering, S.; Kalisiak, J.; Mercola, M.; Cashman, J.R. Wnt inhibition correlates with human embryonic stem cell cardiomyogenesis: a structure-activity relationship study based on inhibitors for the Wnt response. J. Med. Chem., 2012, 55(2), 697-708.
[ ] [PMID: 22191557]
Hurtado, C.; Safarova, A.; Smith, M.; Chung, R.; Bruyneel, A.A.N.; Gomez-Galeno, J.; Oswald, F.; Larson, C.J.; Cashman, J.R.; Ruiz-Lozano, P.; Janiak, P.; Suzuki, T.; Mercola, M. Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ. Sci. Rep., 2019, 9(1), 10811.
[ ] [PMID: 31346210]
Längle, D.; Marquardt, V.; Heider, E.; Vigante, B.; Duburs, G.; Luntena, I.; Flötgen, D.; Golz, C.; Strohmann, C.; Koch, O.; Schade, D. Design, synthesis and 3D-QSAR studies of novel 1,4-dihydropyridines as TGFβ/Smad inhibitors. Eur. J. Med. Chem., 2015, 95, 249-266.
[ ] [PMID: 25817775]
Lee, H.A.; Hyun, S.A.; Park, S.G.; Kim, K.S.; Kim, S.J. Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization. Korean J. Physiol. Pharmacol., 2016, 20(1), 119-127.
[ ] [PMID: 26807031]
Längle, D.; Halver, J.; Rathmer, B.; Willems, E.; Schade, D. Small molecules targeting in vivo tissue regeneration. ACS Chem. Biol., 2014, 9(1), 57-71.
[ ] [PMID: 24372447]
AHA; AHA Update, 2010.Available from: .
Porrello, E.R.; Mahmoud, A.I.; Simpson, E.; Hill, J.A.; Richardson, J.A.; Olson, E.N.; Sadek, H.A. Transient regenerative potential of the neonatal mouse heart. Science, 2011, 331(6020), 1078-1080.
[ ] [PMID: 21350179]
Choi, W.Y.; Gemberling, M.; Wang, J.; Holdway, J.E.; Shen, M.C.; Karlstrom, R.O.; Poss, K.D. In vivo monitoring of cardiomyocyte proliferation to identify chemical modifiers of heart regeneration. Development, 2013, 140(3), 660-666.
[ ] [PMID: 23293297]
Olson, E.N.; Schneider, M.D. Sizing up the heart: development redux in disease. Genes Dev., 2003, 17(16), 1937-1956.
[ ] [PMID: 12893779]
Kehat, I.; Gepstein, A.; Spira, A.; Itskovitz-Eldor, J.; Gepstein, L. High-resolution electrophysiological assessment of human embryonic stem cell-derived cardiomyocytes: a novel in vitro model for the study of conduction. Circ. Res., 2002, 91(8), 659-661.
[ ] [PMID: 12386141]
Germanguz, I.; Sedan, O.; Zeevi-Levin, N.; Shtrichman, R.; Barak, E.; Ziskind, A.; Eliyahu, S.; Meiry, G.; Amit, M.; Itskovitz-Eldor, J.; Binah, O. Molecular characterization and functional properties of cardiomyocytes derived from human inducible pluripotent stem cells. J. Cell. Mol. Med., 2011, 15(1), 38-51.
[ ] [PMID: 20041972]
Laflamme, M.A.; Chen, K.Y.; Naumova, A.V.; Muskheli, V.; Fugate, J.A.; Dupras, S.K.; Reinecke, H.; Xu, C.; Hassanipour, M.; Police, S.; O’Sullivan, C.; Collins, L.; Chen, Y.; Minami, E.; Gill, E.A.; Ueno, S.; Yuan, C.; Gold, J.; Murry, C.E. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat. Biotechnol., 2007, 25(9), 1015-1024.
[ ] [PMID: 17721512]
van Laake, L.W.; Passier, R.; Doevendans, P.A.; Mummery, C.L. Human embryonic stem cell-derived cardiomyocytes and cardiac repair in rodents. Circ. Res., 2008, 102(9), 1008-1010.
[ ] [PMID: 18436793]
Fiedler, L.R.; Chapman, K.; Xie, M.; Maifoshie, E.; Jenkins, M.; Golforoush, P.A.; Bellahcene, M.; Noseda, M.; Faust, D.; Jarvis, A.; Newton, G.; Paiva, M.A.; Harada, M.; Stuckey, D.J.; Song, W.; Habib, J.; Narasimham, P.; Aqil, R.; Sanmugalingam, D.; Yan, R.; Pavanello, L.; Sano, M.; Wang, S.C.; Sampson, R.D.; Kanayaganam, S.; Taffet, G.E.; Michael, L.H.; Entman, M.L.; Tan, T.H.; Harding, S.E.; Low, C.M.R.; Tralau-Stewart, C.; Perrior, T.; Schneider, M.D. MAP4K4 inhibition promotes survival of human stem cell-derived cardiomyocytes and reduces infarct size in vivo. Cell Stem Cell, 2019, 24(2), 579-591.
Blinova, K.; Dang, Q.; Millard, D.; Smith, G.; Pierson, J.; Guo, L.; Brock, M.; Lu, H.R.; Kraushaar, U.; Zeng, H.; Shi, H.; Zhang, X.; Sawada, K.; Osada, T.; Kanda, Y.; Sekino, Y.; Pang, L.; Feaster, T.K.; Kettenhofen, R.; Stockbridge, N.; Strauss, D.G.; Gintant, G. International multisite study of human-induced pluripotent stem cell-derived cardiomyocytes for drug proarrhythmic potential assessment. international multisite study of human-induced pluripotent stem cell-derived cardiomyocytes for drug proarrhythmic potential assessment. Cell Rep., 2018, 24(13), 3582-3592.
[ ] [PMID: 30257217]
Warren, C.R.; Jaquish, C.E.; Cowan, C.A. The nextgen genetic association studies consortium: a foray into in vitro population genetics. Cell Stem Cell, 2017, 20(4), 431-433.
[ ] [PMID: 28388427]
Koplan, B.A.; Stevenson, W.G. Ventricular tachycardia and sudden cardiac death. Mayo Clin. Proc., 2009, 84(3), 289-297.
[ ] [PMID: 19252119]
McKeithan, W.L.; Savchenko, A.; Yu, M.S.; Cerignoli, F.; Bruyneel, A.A.N.; Price, J.H.; Colas, A.R.; Miller, E.W.; Cashman, J.R.; Mercola, M. An automated platform for assessment of congenital and drug-induced arrhythmia with hipsc-derived cardiomyocytes. Front. Physiol., 2017, 8, 766.
[ ] [PMID: 29075196]
Waring, M.J.; Arrowsmith, J.; Leach, A.R.; Leeson, P.D.; Mandrell, S.; Owen, R.M.; Pairaudeau, G.; Pennie, W.D.; Pickett, S.D.; Wang, J.; Wallace, O.; Weir, A. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat. Rev. Drug Discov., 2015, 14(7), 475-486.
[ ] [PMID: 26091267]
Sager, P.T.; Gintant, G.; Turner, J.R.; Pettit, S.; Stockbridge, N. Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium. Am. Heart J., 2014, 167(3), 292-300.
[ ] [PMID: 24576511]
Romero, K.; Woosley, R.L. Clinical pharmacology of antiarrhythmic drugs.In: . Cardiovascular Therapeutics: A Companion to Braunwald’s Heart Disease, 4th ed; Elsevier: Amsterdam, 2013, pp. 343-364.
Mitcheson, J.S.; Chen, J.; Lin, M.; Culberson, C.; Sanguinetti, M.C. A structural basis for drug-induced long QT syndrome. Proc. Natl. Acad. Sci. USA, 2000, 97(22), 12329-12333.
[ ] [PMID: 11005845]
Terrenoire, C.; Wang, K.; Tung, K.W.; Chung, W.K.; Pass, R.H.; Lu, J.T.; Jean, J.C.; Omari, A.; Sampson, K.J.; Kotton, D.N.; Keller, G.; Kass, R.S. Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. J. Gen. Physiol., 2013, 141(1), 61-72.
[ ] [PMID: 23277474]
Cerignoli, F.; Charlot, D.; Whittaker, R.; Ingermanson, R.; Gehalot, P.; Savchenko, A.; Gallacher, D.J.; Towart, R.; Price, J.H.; McDonough, P.M.; Mercola, M. High throughput measurement of Ca2+ dynamics for drug risk assessment in human stem cell-derived cardiomyocytes by kinetic image cytometry. J. Pharmacol. Toxicol. Methods, 2012, 66(3), 246-256.
[ ] [PMID: 22926323]
Miller, E.W.; Lin, J.Y.; Frady, E.P.; Steinbach, P.A.; Kristan, W.B., Jr; Tsien, R.Y. Optically monitoring voltage in neurons by photo-induced electron transfer through molecular wires. Proc. Natl. Acad. Sci. USA, 2012, 109(6), 2114-2119.
[ ] [PMID: 22308458]
De Bellis, M.; De Luca, A.; Desaphy, J.F.; Carbonara, R.; Heiny, J.A.; Kennedy, A.; Carocci, A.; Cavalluzzi, M.M.; Lentini, G.; Franchini, C.; Camerino, D.C. Combined modifications of mexiletine pharmacophores for new lead blockers of Na(v)1.4 channels. Biophys. J., 2013, 104(2), 344-354.
[ ] [PMID: 23442856]
De Luca, A.; Natuzzi, F.; Desaphy, J.F.; Loni, G.; Lentini, G.; Franchini, C.; Tortorella, V.; Camerino, D.C. Molecular determinants of mexiletine structure for potent and use-dependent block of skeletal muscle sodium channels. Mol. Pharmacol., 2000, 57(2), 268-277.
[PMID: 10648636]
De Luca, A.; Talon, S.; De Bellis, M.; Desaphy, J.F.; Franchini, C.; Lentini, G.; Catalano, A.; Corbo, F.; Tortorella, V.; Conte-Camerino, D. Inhibition of skeletal muscle sodium currents by mexiletine analogues: specific hydrophobic interactions rather than lipophilia per se account for drug therapeutic profile. Naunyn Schmiedebergs Arch. Pharmacol., 2003, 367(3), 318-327.
[ ] [PMID: 12644906]
Franchini, C.; Carocci, A.; Catalano, A.; Cavalluzzi, M.M.; Corbo, F.; Lentini, G.; Scilimati, A.; Tortorella, P.; Camerino, D.C.; De Luca, A. Optically active mexiletine analogues as stereoselective blockers of voltage-gated Na(+) channels. J. Med. Chem., 2003, 46(24), 5238-5248.
[ ] [PMID: 14613326]
Roselli, M.; Carocci, A.; Budriesi, R.; Micucci, M.; Toma, M.; Di Cesare Mannelli, L.; Lovece, A.; Catalano, A.; Cavalluzzi, M.M.; Bruno, C.; De Palma, A.; Contino, M.; Perrone, M.G.; Colabufo, N.A.; Chiarini, A.; Franchini, C.; Ghelardini, C.; Habtemariam, S.; Lentini, G. Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues. Eur. J. Med. Chem., 2016, 121, 300-307.
[ ] [PMID: 27267000]
Hu, R.M.; Tester, D.J.; Li, R.; Sun, T.; Peterson, B.Z.; Ackerman, M.J.; Makielski, J.C.; Tan, B.H. Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients. Channels (Austin), 2018, 12(1), 176-186.
[ ] [PMID: 29983085]
Mao, A.S.; Mooney, D.J. Regenerative medicine: Current therapies and future directions. Proc. Natl. Acad. Sci. USA, 2015, 112(47), 14452-14459.
[ ] [PMID: 26598661]
Squillaro, T.; Peluso, G.; Galderisi, U. Clinical trials with mesenchymal stem cells: an update. Cell Transplant., 2016, 25(5), 829-848.
[ ] [PMID: 26423725]
Dimarino, A.M.; Caplan, A.I.; Bonfield, T.L. Mesenchymal stem cells in tissue repair. Front. Immunol., 2013, 4, 201.
[ ] [PMID: 24027567]
Kimelman, N.; Pelled, G.; Helm, G.A.; Huard, J.; Schwarz, E.M.; Gazit, D. Review: gene- and stem cell-based therapeutics for bone regeneration and repair. Tissue Eng., 2007, 13(6), 1135-1150.
[ ] [PMID: 17516852]
Shi, N.; Foley, K.; Lenhart, G.; Badamgarav, E. Direct healthcare costs of hip, vertebral, and non-hip, non-vertebral fractures. Bone, 2009, 45(6), 1084-1090.
[ ] [PMID: 19664735]
Betz, R.R. Limitations of autograft and allograft: new synthetic solutions. Orthopedics, 2002, 25(5)(Suppl.), s561-s570.
[ ] [PMID: 12038843]
Petite, H.; Viateau, V.; Bensaïd, W.; Meunier, A.; de Pollak, C.; Bourguignon, M.; Oudina, K.; Sedel, L.; Guillemin, G. Tissue-engineered bone regeneration. Nat. Biotechnol., 2000, 18(9), 959-963.
[ ] [PMID: 10973216]
Yuan, H.; Fernandes, H.; Habibovic, P.; de Boer, J.; Barradas, A.M.; de Ruiter, A.; Walsh, W.R.; van Blitterswijk, C.A.; de Bruijn, J.D. Osteoinductive ceramics as a synthetic alternative to autologous bone grafting. Proc. Natl. Acad. Sci. USA, 2010, 107(31), 13614-13619.
[ ] [PMID: 20643969]
Kitsugi, T.; Yamamuro, T.; Nakamura, T.; Kotani, S.; Kokubo, T.; Takeuchi, H. Four calcium phosphate ceramics as bone substitutes for non-weight-bearing. Biomaterials, 1993, 14(3), 216-224.
[ ] [PMID: 8386554]
Robey, P.G. Cell sources for bone regeneration: the good, the bad, and the ugly (but promising). Tissue Eng. Part B Rev., 2011, 17(6), 423-430.
[ ] [PMID: 21797663]
Wu, X.; Ding, S.; Ding, Q.; Gray, N.S.; Schultz, P.G. A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells. J. Am. Chem. Soc., 2002, 124(49), 14520-14521.
[ ] [PMID: 12465946]
Leucht, P.; Minear, S.; Ten Berge, D.; Nusse, R.; Helms, J.A. Translating insights from development into regenerative medicine: the function of Wnts in bone biology. Semin. Cell Dev. Biol., 2008, 19(5), 434-443.
[ ] [PMID: 18824114]
Rodríguez-Carballo, E.; Ulsamer, A.; Susperregui, A.R.; Manzanares-Céspedes, C.; Sánchez-García, E.; Bartrons, R.; Rosa, J.L.; Ventura, F. Conserved regulatory motifs in osteogenic gene promoters integrate cooperative effects of canonical Wnt and BMP pathways. J. Bone Miner. Res., 2011, 26(4), 718-729.
[ ] [PMID: 20878775]
Manchikanti, L.; Centeno, C.J.; Atluri, S.; Albers, S.L.; Shapiro, S.; Malanga, G.A.; Abd-Elsayed, A.; Jerome, M.; Hirsch, J.A.; Kaye, A.D.; Aydin, S.M.; Beall, D.; Buford, D.; Borg-Stein, J.; Buenaventura, R.M.; Cabaret, J.A.; Calodney, A.K.; Candido, K.D.; Cartier, C.; Latchaw, R.; Diwan, S.; Dodson, E.; Fausel, Z.; Fredericson, M.; Gharibo, C.G.; Gupta, M.; Kaye, A.M.; Knezevic, N.N.; Kosanovic, R.; Lucas, M.; Manchikanti, M.V.; Mason, R.A.; Mautner, K.; Murala, S.; Navani, A.; Pampati, V.; Pastoriza, S.; Pasupuleti, R.; Philip, C.; Sanapati, M.R.; Sand, T.; Shah, R.V.; Soin, A.; Stemper, I.; Wargo, B.W.; Hernigou, P. Bone marrow concentrate (bmc) therapy in musculoskeletal disorders: evidence-based policy position statement of American society of interventional pain physicians (ASIPP). Pain Physician, 2020, 23(2), E85-E131.
[PMID: 32214287]
Carragee, E.J.; Hurwitz, E.L.; Weiner, B.K. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J., 2011, 11(6), 471-491.
[ ] [PMID: 21729796]
Morrell, N.T.; Leucht, P.; Zhao, L.; Kim, J.B.; ten Berge, D.; Ponnusamy, K.; Carre, A.L.; Dudek, H.; Zachlederova, M.; McElhaney, M.; Brunton, S.; Gunzner, J.; Callow, M.; Polakis, P.; Costa, M.; Zhang, X.M.; Helms, J.A.; Nusse, R. Liposomal packaging generates Wnt protein with in vivo biological activity. PLoS One, 2008, 3(8), e2930
[ ] [PMID: 18698373]
Dai, J.; Li, Y.; Zhou, H.; Chen, J.; Chen, M.; Xiao, Z. Genistein promotion of osteogenic differentiation through BMP2/SMAD5/RUNX2 signaling. Int. J. Biol. Sci., 2013, 9(10), 1089-1098.
[ ] [PMID: 24339730]
Arjmandi, B.H.; Alekel, L.; Hollis, B.W.; Amin, D.; Stacewicz-Sapuntzakis, M.; Guo, P.; Kukreja, S.C. Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis. J. Nutr., 1996, 126(1), 161-167.
[ ] [PMID: 8558297]
Marini, H.; Minutoli, L.; Polito, F.; Bitto, A.; Altavilla, D.; Atteritano, M.; Gaudio, A.; Mazzaferro, S.; Frisina, A.; Frisina, N.; Lubrano, C.; Bonaiuto, M.; D’Anna, R.; Cannata, M.L.; Corrado, F.; Adamo, E.B.; Wilson, S.; Squadrito, F. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann. Intern. Med., 2007, 146(12), 839-847.
[ ] [PMID: 17577003]
Chen, Y.X.; Zhu, D.Y.; Xu, Z.L.; Yin, J.H.; Yu, X.W.; Mei, J.; Gao, Y.S.; Zhang, C.Q. The protective effect of cordycepin on alcohol-induced osteonecrosis of the femoral head. Cell. Physiol. Biochem., 2017, 42(6), 2391-2403.
[ ] [PMID: 28848161]
Dixit, M.; Raghuvanshi, A.; Gupta, C.P.; Kureel, J.; Mansoori, M.N.; Shukla, P.; John, A.A.; Singh, K.; Purohit, D.; Awasthi, P.; Singh, D.; Goel, A. Medicarpin, a Natural Pterocarpan, Heals cortical bone defect by activation of notch and wnt canonical signaling pathways. PLoS One, 2015, 10(12), e0144541
[ ] [PMID: 26657206]
Jie, Z.; Shen, S.; Zhao, X.; Xu, W.; Zhang, X.; Huang, B.; Tang, P.; Qin, A.; Fan, S.; Xie, Z. Activating β-catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK. FASEB J., 2019, 33(3), 4236-4247.
[ ] [PMID: 30526042]
Yang, Z.; Huang, J.H.; Liu, S.F.; Zhao, Y.J.; Shen, Z.Y.; Wang, Y.J.; Bian, Q. The osteoprotective effect of psoralen in ovariectomy-induced osteoporotic rats via stimulating the osteoblastic differentiation from bone mesenchymal stem cells. Menopause, 2012, 19(10), 1156-1164.
[PMID: 22781784]
Wang, C.; Al-Ani, M.K.; Sha, Y.; Chi, Q.; Dong, N.; Yang, L.; Xu, K. Psoralen protects chondrocytes, exhibits anti-inflammatory effects on synoviocytes, and attenuates monosodium iodoacetate-induced osteoarthritis. Int. J. Biol. Sci., 2019, 15(1), 229-238.
[ ] [PMID: 30662362]
Bian, Q.; Liu, S.F.; Huang, J.H.; Yang, Z.; Tang, D.Z.; Zhou, Q.; Ning, Y.; Zhao, Y.J.; Lu, S.; Shen, Z.Y.; Wang, Y.J. Oleanolic acid exerts an osteoprotective effect in ovariectomy-induced osteoporotic rats and stimulates the osteoblastic differentiation of bone mesenchymal stem cells in vitro. Menopause, 2012, 19(2), 225-233.
[ ] [PMID: 22011754]
Shu, B.; Zhao, Y.; Wang, Y.; Wang, G.; Shang, X.; Britt, M.; Olmedo, M.; Chelly, M.; Morandi, M.M.; Barton, S.; Dong, Y. Oleanolic acid enhances mesenchymal stromal cell osteogenic potential by inhibition of notch signaling. Sci. Rep., 2017, 7(1), 7002.
[ ] [PMID: 28765584]
Cashman, J.R.; Ryan, D.R.; Chen, S. Human biomolecular research institute, assignee. compounds and matrices for use in bone growth and repair. U.S. Patent 14/776,995. 2016.
Johnson, K.; Zhu, S.; Tremblay, M.S.; Payette, J.N.; Wang, J.; Bouchez, L.C.; Meeusen, S.; Althage, A.; Cho, C.Y.; Wu, X.; Schultz, P.G. A stem cell-based approach to cartilage repair. Science, 2012, 336(6082), 717-721.
[ ] [PMID: 22491093]
Decker, R.S.; Koyama, E.; Enomoto-Iwamoto, M.; Maye, P.; Rowe, D.; Zhu, S.; Schultz, P.G.; Pacifici, M. Mouse limb skeletal growth and synovial joint development are coordinately enhanced by Kartogenin. Dev. Biol., 2014, 395(2), 255-267.
[ ] [PMID: 25238962]
Wang, S.J.; Qin, J.Z.; Zhang, T.E.; Xia, C. Intra-articular injection of kartogenin-incorporated thermogel enhancing osteoarthritis treatment. Front Chem., 2019, 7, 677.
[ ] [PMID: 31681730]
Sinha, S.; Chen, J.K. Purmorphamine activates the hedgehog pathway by targeting smoothened. Nat. Chem. Biol., 2006, 2(1), 29-30.
[ ] [PMID: 16408088]
Sharma, S.; Kaur, A.; Sharma, S. Preconditioning potential of purmorphamine: a hedgehog activator against ischaemic reperfusion injury in ovariectomised rat heart. Perfusion, 2018, 33(3), 209-218.
[ ] [PMID: 29065787]
Dewan, A.K.; Gibson, M.A.; Elisseeff, J.H.; Trice, M.E. Evolution of autologous chondrocyte repair and comparison to other cartilage repair techniques. BioMed Res. Int., 2014, 2014, 272481
[ ] [PMID: 25210707]
Delgado, R.N.; Mansky, B.; Ahanger, S.H.; Lu, C.; Andersen, R.E.; Dou, Y.; Alvarez-Buylla, A.; Lim, D.A. Maintenance of neural stem cell positional identity by mixed-lineage leukemia 1. Science, 2020, 368(6486), 48-53.
[ ] [PMID: 32241942]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy