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BML-281 promotes neuronal differentiation by modulating Wnt/Ca2+ and Wnt/PCP signaling pathway

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Abstract

Histone deacetylase (HDAC) inhibitors promote differentiation through post-translational modifications of histones. BML-281, an HDAC6 inhibitor, has been known to prevent tumors, acute dextran sodium sulfate-associated colitis, and lung injury. However, the neurogenic differentiation effect of BML-281 is poorly understood. In this study, we investigated the effect of BML-281 on neuroblastoma SH-SY5Y cell differentiation into mature neurons by immunocytochemistry (ICC), reverse transcriptase PCR (RT-PCR), quantitative PCR (qPCR), and western blotting analysis. We found that the cells treated with BML-281 showed neurite outgrowth and morphological changes into mature neurons under a microscope. It was confirmed that the gene expression of neuronal markers (NEFL, MAP2, Tuj1, NEFH, and NEFM) was increased with certain concentrations of BML-281. Similarly, the protein expression of neuronal markers (NeuN, Synaptophysin, Tuj1, and NFH) was upregulated with BML-281 compared to untreated cells. Following treatment with BML-281, the expression of Wnt5α increased, and downstream pathways were activated. Interestingly, both Wnt/Ca2+ and Wnt/PCP pathways activated and regulated PKC, Cdc42, RhoA, Rac1/2/3, and p-JNK. Therefore, BML-281 induces the differentiation of SH-SY5Y cells into mature neurons by activating the non-canonical Wnt signaling pathway. From these results, we concluded that BML-281 might be a novel drug to differentiation into neuronal cells through the regulation of Wnt signaling pathway to reduce the neuronal cell death.

Headings

BML-281 promotes neuronal differentiation.

BML-281 modulates Wnt/Ca2+ and Wnt/PCP pathway.

Non-canonical Wnt pathway regulates the cell differentiation.

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Data Availability

The original contributions presented in the study are included in the article/Supplementary materials, further inquiries can be directed to the corresponding author.

Abbreviations

AD:

Alzheimer’s disease

APC:

Adenomatosis polyposis coli

CaMKII:

Calmodulin-dependent protein kinase II

CDC42:

Cell division cycle 42

CK1:

Casein kinase 1

CNP:

2’,3’-Cyclic-nucleotide 3’-phosphodiesterase

DAG:

1,2 diacylglycerol

DAPI:

4′,6-Diamidino-2-phenylindole

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

DNA:

Deoxyribonucleic acid

DSS:

Dextran sodium sulfate

Dvl:

Dishevelled

ERK:

Extracellular signal-regulated kinase

FBS:

Fetal bovine serum

Fzd:

Frizzled

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GFAP:

Glial fibrillary acidic protein

GSK-3:

Glycogen synthase kinase-3

HAT:

Histone acetyltransferases

HDAC:

Histone deacetylase

HRP:

Horseradish peroxidase

ICC:

Immunocytochemistry

IP3:

Inositol-1,4,5-triphosphate

JNK:

c-Jun N-terminal kinase

LRP:

Low-density lipoprotein receptor-related protein

MAP2:

Microtubule-associated protein 2

NB:

Neuroblastoma

NEFH:

Neurofilament heavy chain

NEFL:

Neurofilament light chain

NEFM:

Neurofilament medium chain

NeuN:

Neuronal nuclear protein

NFAT:

Nuclear factor associated with T cells

NGS:

Normal goat serum

PD:

Parkinson’s disease

p-GSK3β:

Phosphorylated glycogen synthase kinase 3β

PFA:

Paraformaldehyde

PKC:

Protein kinase C

PLC:

Phospholipase C

qPCR:

Quantitative PCR

RA:

Retinoic acid

Rho:

Ras homologous

RT-PCR:

Reverse transcriptase PCR

S1PC:

S-1-propenylcysteine

SYP:

Synaptophysin

Tuj1:

β-tubulin

References

  1. Chen IC, Sethy B, Liou JP (2020) Recent update of HDAC inhibitors in Lymphoma. Front Cell Dev Biol 8:576391

    Article  PubMed  PubMed Central  Google Scholar 

  2. Bondarev AD et al (2021) Recent developments of HDAC inhibitors: emerging indications and novel molecules. Br J Clin Pharmacol 87(12):4577–4597

    Article  PubMed  Google Scholar 

  3. Lanzi C, Cassinelli G (2022) Combinatorial strategies to potentiate the efficacy of HDAC inhibitors in fusion-positive sarcomas. Biochem Pharmacol 198:114944

    Article  CAS  PubMed  Google Scholar 

  4. Phimmachanh M et al (2020) Histone deacetylases and histone deacetylase inhibitors in Neuroblastoma. Front Cell Dev Biol 8:578770

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bass AKA et al (2021) Comprehensive review for anticancer hybridized multitargeting HDAC inhibitors. Eur J Med Chem 209:112904

    Article  CAS  PubMed  Google Scholar 

  6. Ramaiah MJ, Tangutur AD, Manyam RR (2021) Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy. Life Sci 277:119504

    Article  CAS  PubMed  Google Scholar 

  7. San Jose-Eneriz E et al (2019) HDAC inhibitors in Acute myeloid leukemia. Cancers (Basel), 11(11)

  8. Jenke R et al (2021) Anticancer therapy with HDAC inhibitors: mechanism-based combination strategies and future perspectives. Cancers (Basel), 13(4)

  9. Iaconelli J, Xuan L, Karmacharya R (2019) HDAC6 modulates signaling pathways relevant to synaptic Biology and neuronal differentiation in human stem-cell-derived neurons. Int J Mol Sci, 20(7)

  10. Garcia-Dominguez DJ et al (2021) Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in ewing sarcoma. Oncogene 40(39):5843–5853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sanchez-Molina S et al (2022) Ewing Sarcoma meets epigenetics, Immunology and Nanomedicine: moving Forward into Novel therapeutic strategies. Cancers (Basel), 14(21).

  12. Do A et al (2017) An HDAC6 inhibitor confers Protection and selectively inhibits B-Cell infiltration in DSS-Induced Colitis in mice. J Pharmacol Exp Ther 360(1):140–151

    Article  CAS  PubMed  Google Scholar 

  13. Ghiboub M et al (2021) Selective targeting of epigenetic readers and histone deacetylases in Autoimmune and Inflammatory Diseases: recent advances and future perspectives. J Pers Med, 11(5)

  14. Suzuki JI et al (2018) Anti-inflammatory action of cysteine derivative S-1-propenylcysteine by inducing MyD88 degradation. Sci Rep 8(1):14148

    Article  PubMed  PubMed Central  Google Scholar 

  15. Cheng X et al (2019) Therapeutic potential of targeting the Wnt/beta-catenin signaling pathway in colorectal cancer. Biomed Pharmacother 110:473–481

    Article  CAS  PubMed  Google Scholar 

  16. Frenquelli M, Tonon G (2020) WNT signaling in hematological malignancies. Front Oncol 10:615190

    Article  PubMed  PubMed Central  Google Scholar 

  17. Jang S, Jeong HS (2018) Histone deacetylase inhibition-mediated neuronal differentiation via the wnt signaling pathway in human adipose tissue-derived mesenchymal stem cells. Neurosci Lett 668:24–30

    Article  CAS  PubMed  Google Scholar 

  18. Liu J et al (2022) Wnt/beta-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther 7(1):3

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang M et al (2019) Update on the role of the non-canonical Wnt/Planar Cell polarity pathway in neural tube defects. Cells, 8(10)

  20. Wang H et al (2021) The wnt signaling pathway in Diabetic Nephropathy. Front Cell Dev Biol 9:701547

    Article  PubMed  Google Scholar 

  21. Arredondo SB et al (2020) Role of wnt signaling in adult hippocampal neurogenesis in Health and Disease. Front Cell Dev Biol 8:860

    Article  PubMed  PubMed Central  Google Scholar 

  22. Vallee A, Lecarpentier Y, Vallee JN (2019) Targeting the canonical WNT/beta-Catenin pathway in Cancer Treatment using non-steroidal anti-inflammatory drugs. Cells, 8(7)

  23. Gajos-Michniewicz A, Czyz M (2020) WNT signaling in Melanoma. Int J Mol Sci, 21(14)

  24. He S, Tang S (2020) WNT/beta-catenin signaling in the development of liver cancers. Biomed Pharmacother 132:110851

    Article  CAS  PubMed  Google Scholar 

  25. Lojk J, Marc J (2021) Roles of non-canonical wnt signalling Pathways in Bone Biology. Int J Mol Sci, 22(19)

  26. Flores-Hernandez E et al (2020) Canonical and non-canonical wnt signaling are simultaneously activated by wnts in colon cancer cells. Cell Signal 72:109636

    Article  CAS  PubMed  Google Scholar 

  27. Harb J, Lin PJ, Hao J (2019) Recent development of wnt signaling pathway inhibitors for Cancer therapeutics. Curr Oncol Rep 21(2):12

    Article  PubMed  Google Scholar 

  28. Choi J et al (2023) Effects of HDAC inhibitors on neuroblastoma SH-SY5Y cell differentiation into mature neurons via the wnt signaling pathway. BMC Neurosci 24(1):28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li X et al (2019) MiR-210-3p inhibits osteogenic differentiation and promotes adipogenic differentiation correlated with wnt signaling in ERalpha-deficient rBMSCs. J Cell Physiol 234(12):23475–23484

    Article  CAS  PubMed  Google Scholar 

  30. Simoes RF et al (2021) Refinement of a differentiation protocol using neuroblastoma SH-SY5Y cells for use in neurotoxicology research. Food Chem Toxicol 149:111967

    Article  CAS  PubMed  Google Scholar 

  31. Jang S et al (2010) Functional neural differentiation of human adipose tissue-derived stem cells using bFGF and forskolin. BMC Cell Biol 11:25

    Article  PubMed  PubMed Central  Google Scholar 

  32. Jeong JA et al (2004) Rapid neural differentiation of human cord blood-derived mesenchymal stem cells. NeuroReport 15(11):1731–1734

    Article  CAS  PubMed  Google Scholar 

  33. Trudinger BJ, Giles WB (1989) Clinical and pathologic correlations of umbilical and uterine artery waveforms. Clin Obstet Gynecol 32(4):669–678

    Article  CAS  PubMed  Google Scholar 

  34. Pipis M et al (2022) Charcot-Marie-Tooth disease type 2CC due to NEFH variants causes a progressive, non-length-dependent, motor-predominant phenotype. J Neurol Neurosurg Psychiatry 93(1):48–56

    Article  PubMed  Google Scholar 

  35. Li D et al (2021) NEFM DNA methylation correlates with immune infiltration and survival in breast cancer. Clin Epigenetics 13(1):112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Haenig C et al (2020) Interactome Mapping provides a network of neurodegenerative disease proteins and uncovers widespread protein aggregation in affected brains. Cell Rep 32(7):108050

    Article  CAS  PubMed  Google Scholar 

  37. Jang YK et al (2004) Retinoic acid-mediated induction of neurons and glial cells from human umbilical cord-derived hematopoietic stem cells. J Neurosci Res 75(4):573–584

    Article  CAS  PubMed  Google Scholar 

  38. Mages B et al (2021) The cytoskeletal elements MAP2 and NF-L show substantial alterations in different stroke models while elevated serum levels highlight especially MAP2 as a sensitive biomarker in Stroke Patients. Mol Neurobiol 58(8):4051–4069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Loonstra FC et al (2023) Neuroaxonal and glial markers in patients of the same age with multiple sclerosis. Neurol Neuroimmunol Neuroinflamm, 10(2)

  40. Luck K et al (2020) A reference map of the human binary protein interactome. Nature 580(7803):402–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Crabtree DV et al (2001) Tubulins in the primate retina: evidence that xanthophylls may be endogenous ligands for the paclitaxel-binding site. Bioorg Med Chem 9(8):1967–1976

    Article  CAS  PubMed  Google Scholar 

  42. Baptista I et al (2022) TKTL1 Knockdown impairs Hypoxia-Induced glucose-6-phosphate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase overexpression. Int J Mol Sci, 23(7)

  43. Park M et al (2021) Inhibition of class I HDACs preserves hair follicle inductivity in postnatal dermal cells. Sci Rep 11(1):24056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ho TCS, Chan AHY, Ganesan A (2020) Thirty years of HDAC inhibitors: 2020 insight and Hindsight. J Med Chem 63(21):12460–12484

    Article  CAS  PubMed  Google Scholar 

  45. El-Naggar AM et al (2019) Class I HDAC inhibitors enhance YB-1 acetylation and oxidative stress to block sarcoma metastasis. EMBO Rep 20(12):e48375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Franci G et al (2013) The class I-specific HDAC inhibitor MS-275 modulates the differentiation potential of mouse embryonic stem cells. Biol Open 2(10):1070–1077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Frumm SM et al (2013) Selective HDAC1/HDAC2 inhibitors induce neuroblastoma differentiation. Chem Biol 20(5):713–725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Goder A et al (2018) HDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130. Nat Commun 9(1):764

    Article  PubMed  PubMed Central  Google Scholar 

  49. Kiweler N et al (2018) The histone deacetylases HDAC1 and HDAC2 are required for the growth and survival of renal carcinoma cells. Arch Toxicol 92(7):2227–2243

    Article  CAS  PubMed  Google Scholar 

  50. Lee EC et al (2020) The histone deacetylase inhibitor (MS-275) promotes differentiation of Human Dental Pulp Stem cells into Odontoblast-Like cells Independent of the MAPK signaling system. Int J Mol Sci, 21(16)

  51. Liu J et al (2020) Selective class I HDAC inhibitors based on Aryl Ketone zinc binding induce HIV-1 protein for Clearance. ACS Med Chem Lett 11(7):1476–1483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ma K et al (2018) Histone deacetylase inhibitor MS-275 restores social and synaptic function in a Shank3-deficient mouse model of autism. Neuropsychopharmacology 43(8):1779–1788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shukla S, Tekwani BL (2020) Histone deacetylases inhibitors in neurodegenerative Diseases, neuroprotection and neuronal differentiation. Front Pharmacol 11:537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tomioka T et al (2014) The histone deacetylase inhibitor trichostatin A induces neurite outgrowth in PC12 cells via the epigenetically regulated expression of the nur77 gene. Neurosci Res 88:39–48

    Article  CAS  PubMed  Google Scholar 

  55. Jung GA et al (2008) Valproic acid induces differentiation and inhibition of proliferation in neural progenitor cells via the beta-catenin-Ras-ERK-p21Cip/WAF1 pathway. BMC Cell Biol 9:66

    Article  PubMed  PubMed Central  Google Scholar 

  56. Calmon MF et al (2015) Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer. Epigenetics 10(7):622–632

    Article  PubMed  PubMed Central  Google Scholar 

  57. Campos-Melo D, Hawley ZCE, Strong MJ (2018) Dysregulation of human NEFM and NEFH mRNA stability by ALS-linked miRNAs. Mol Brain 11(1):43

    Article  PubMed  PubMed Central  Google Scholar 

  58. Sanchez C, Diaz-Nido J, Avila J (2000) Phosphorylation of microtubule-associated protein 2 (MAP2) and its relevance for the regulation of the neuronal cytoskeleton function. Prog Neurobiol 61(2):133–168

    Article  CAS  PubMed  Google Scholar 

  59. Memberg SP, Hall AK (1995) Dividing neuron precursors express neuron-specific tubulin. J Neurobiol 27(1):26–43

    Article  CAS  PubMed  Google Scholar 

  60. Verrier JD et al (2013) Role of CNPase in the oligodendrocytic extracellular 2’,3’-cAMP-adenosine pathway. Glia 61(10):1595–1606

    Article  PubMed  PubMed Central  Google Scholar 

  61. Jurga AM et al (2021) Beyond the GFAP-Astrocyte protein markers in the brain. Biomolecules, 11(9)

  62. Anderson MB, Das S, Miller KE (2021) Subcellular localization of neuronal nuclei (NeuN) antigen in size and calcitonin gene-related peptide (CGRP) populations of dorsal root ganglion (DRG) neurons during acute peripheral inflammation. Neurosci Lett 760:135974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ramalingam M, Jang S, Jeong HS (2021) Therapeutic Effects of Conditioned Medium of Neural Differentiated Human Bone Marrow-Derived Stem Cells on Rotenone-Induced Alpha-Synuclein Aggregation and Apoptosis Stem Cells Int, 2021: p. 6658271

  64. Chang CW, Hsiao YT, Jackson MB (2021) Synaptophysin regulates Fusion Pores and Exocytosis Mode in Chromaffin cells. J Neurosci 41(16):3563–3578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Schwarz TJ, Ebert B, Lie DC (2012) Stem cell maintenance in the adult mammalian hippocampus: a matter of signal integration? Dev Neurobiol 72(7):1006–1015

    Article  CAS  PubMed  Google Scholar 

  66. Serafino A et al (2020) Targeting the Wnt/beta-catenin pathway in neurodegenerative diseases: recent approaches and current challenges. Expert Opin Drug Discov 15(7):803–822

    Article  CAS  PubMed  Google Scholar 

  67. Suh H, Deng W, Gage FH (2009) Signaling in adult neurogenesis. Annu Rev Cell Dev Biol 25:253–275

    Article  CAS  PubMed  Google Scholar 

  68. Toda T, Gage FH (2018) Review: adult neurogenesis contributes to hippocampal plasticity. Cell Tissue Res 373(3):693–709

    Article  PubMed  Google Scholar 

  69. Bengoa-Vergniory N, Kypta RM (2015) Canonical and noncanonical wnt signaling in neural stem/progenitor cells. Cell Mol Life Sci 72(21):4157–4172

    Article  CAS  PubMed  Google Scholar 

  70. Inestrosa NC, Varela-Nallar L (2015) Wnt signalling in neuronal differentiation and development. Cell Tissue Res 359(1):215–223

    Article  CAS  PubMed  Google Scholar 

  71. Oliva CA, Montecinos-Oliva C, Inestrosa NC (2018) Wnt signaling in the Central Nervous System: New Insights in Health and Disease. Prog Mol Biol Transl Sci 153:81–130

    Article  CAS  PubMed  Google Scholar 

  72. Arredondo SB et al (2020) Wnt5a promotes differentiation and development of adult-born neurons in the hippocampus by noncanonical wnt signaling. Stem Cells 38(3):422–436

    Article  CAS  PubMed  Google Scholar 

  73. Ortiz-Matamoros A, Arias C (2019) Differential Changes in the number and morphology of the new neurons after chronic infusion of Wnt7a, Wnt5a, and Dkk-1 in the adult Hippocampus in vivo. Anat Rec (Hoboken) 302(9):1647–1657

    Article  CAS  PubMed  Google Scholar 

  74. Schafer ST et al (2015) The wnt adaptor protein ATP6AP2 regulates multiple stages of adult hippocampal neurogenesis. J Neurosci 35(12):4983–4998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Galan L et al (2017) Amyotrophic lateral sclerosis modifies progenitor neural proliferation in adult classic neurogenic brain niches. BMC Neurol 17(1):173

    Article  PubMed  PubMed Central  Google Scholar 

  76. Kase Y et al (2019) Involvement of p38 in Age-Related decline in adult neurogenesis via modulation of wnt signaling. Stem Cell Reports 12(6):1313–1328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Seib DR et al (2013) Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline. Cell Stem Cell 12(2):204–214

    Article  CAS  PubMed  Google Scholar 

  78. Toda T et al (2019) The role of adult hippocampal neurogenesis in brain health and disease. Mol Psychiatry 24(1):67–87

    Article  CAS  PubMed  Google Scholar 

  79. Winner B, Winkler J (2015) Adult neurogenesis in neurodegenerative diseases. Cold Spring Harb Perspect Biol 7(4):a021287

    Article  PubMed  PubMed Central  Google Scholar 

  80. Ekonomou A et al (2015) Stage-specific changes in neurogenic and glial markers in Alzheimer’s disease. Biol Psychiatry 77(8):711–719

    Article  CAS  PubMed  Google Scholar 

  81. Moreno-Jimenez EP et al (2019) Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med 25(4):554–560

    Article  CAS  PubMed  Google Scholar 

  82. Tobin MK et al (2019) Human hippocampal neurogenesis persists in aged adults and Alzheimer’s Disease Patients. Cell Stem Cell 24(6):974–982e3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Fiorentini A et al (2010) Lithium improves hippocampal neurogenesis, neuropathology and cognitive functions in APP mutant mice. PLoS ONE 5(12):e14382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Humphries CE et al (2015) Integrated whole transcriptome and DNA methylation analysis identifies gene networks specific to late-onset Alzheimer’s disease. J Alzheimers Dis 44(3):977–987

    Article  CAS  PubMed  Google Scholar 

  85. Rosi MC et al (2010) Increased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease. J Neurochem 112(6):1539–1551

    Article  CAS  PubMed  Google Scholar 

  86. Alarcon MA et al (2013) A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer’s disease Neurobiol Aging, 34(6): p. 1709 e9-18

  87. Choi SH et al (2018) Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science, 361(6406)

  88. Shruster A, Offen D (2014) Targeting neurogenesis ameliorates danger assessment in a mouse model of Alzheimer’s disease. Behav Brain Res 261:193–201

    Article  PubMed  Google Scholar 

  89. Zhao M et al (2019) Deciphering role of wnt signalling in cardiac mesoderm and cardiomyocyte differentiation from human iPSCs: four-dimensional control of wnt pathway for hiPSC-CMs differentiation. Sci Rep 9(1):19389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cao F et al (2017) miR-214 promotes periodontal ligament stem cell osteoblastic differentiation by modulating Wnt/beta–catenin signaling. Mol Med Rep 16(6):9301–9308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chen LJ et al (2017) Baicalein enhances the osteogenic differentiation of human periodontal ligament cells by activating the Wnt/beta-catenin signaling pathway. Arch Oral Biol 78:100–108

    Article  CAS  PubMed  Google Scholar 

  92. Nie F et al (2020) Kaempferol promotes proliferation and osteogenic differentiation of periodontal ligament stem cells via Wnt/beta-catenin signaling pathway. Life Sci 258:118143

    Article  CAS  PubMed  Google Scholar 

  93. Chen XJ et al (2019) Polydatin promotes the osteogenic differentiation of human bone mesenchymal stem cells by activating the BMP2-Wnt/beta-catenin signaling pathway. Biomed Pharmacother 112:108746

    Article  CAS  PubMed  Google Scholar 

  94. Mazziotta C et al (2021) MicroRNAs Modulate Signaling Pathways in osteogenic differentiation of mesenchymal stem cells. Int J Mol Sci, 22(5)

  95. Sharma AR, Nam JS (2019) Kaempferol stimulates WNT/beta-catenin signaling pathway to induce differentiation of osteoblasts. J Nutr Biochem 74:108228

    Article  CAS  PubMed  Google Scholar 

  96. Ma S et al (2019) microRNA-96 promotes osteoblast differentiation and bone formation in ankylosing spondylitis mice through activating the wnt signaling pathway by binding to SOST. J Cell Biochem 120(9):15429–15442

    Article  CAS  PubMed  Google Scholar 

  97. Strano A et al (2020) Variable outcomes in neural differentiation of human PSCs arise from intrinsic differences in Developmental Signaling Pathways. Cell Rep 31(10):107732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sun X et al (2020) ADNP promotes neural differentiation by modulating Wnt/beta-catenin signaling. Nat Commun 11(1):2984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Jang S, Park JS, Jeong HS (2015) Neural Differentiation of Human Adipose Tissue-Derived Stem Cells Involves Activation of the Wnt5a/JNK Signalling Stem Cells Int, 2015: p. 178618

  100. Pickell Z et al (2020) Histone deacetylase inhibitors: a Novel Strategy for Neuroprotection and Cardioprotection following Ischemia/Reperfusion Injury. J Am Heart Assoc 9(11):e016349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kim HJ et al (2007) Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther 321(3):892–901

    Article  CAS  PubMed  Google Scholar 

  102. Li S et al (2019) Early histone deacetylase inhibition mitigates Ischemia/Reperfusion Brain Injury by reducing Microglia activation and modulating their phenotype. Front Neurol 10:893

    Article  PubMed  PubMed Central  Google Scholar 

  103. Silva MR et al (2018) Neuroprotective effects of valproic acid on brain ischemia are related to its HDAC and GSK3 inhibitions. Pharmacol Biochem Behav 167:17–28

    Article  CAS  PubMed  Google Scholar 

  104. Zhu S et al (2019) Valproic acid attenuates global cerebral ischemia/reperfusion injury in gerbils via anti-pyroptosis pathways. Neurochem Int 124:141–151

    Article  CAS  PubMed  Google Scholar 

  105. Mazzocchi M et al (2022) Peripheral administration of the Class-IIa HDAC inhibitor MC1568 partially protects against nigrostriatal neurodegeneration in the striatal 6-OHDA rat model of Parkinson’s disease. Brain Behav Immun 102:151–160

    Article  CAS  PubMed  Google Scholar 

  106. Su L et al (2020) Neuroprotective mechanism of TMP269, a selective class IIA histone deacetylase inhibitor, after cerebral ischemia/reperfusion injury. Neural Regen Res 15(2):277–284

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported by grants from the National Research Foundation of Korea (Grant Numbers NRF-2021R1I1A3060435 and NRF-2020R1F1A1076616); a Grant from the Chonnam National University Hospital Biomedical Research Institute (BCRI23041);  a Grant from the Research Institute of Medical Sciences (Biomedical Sciences Graduate Program, BMSGP), Chonnma National University; and a Grant from the Korea Institute for Advancement of Technology (KIAT, grant number P0020818) funded by the Korean Government (MOTIE).

We thank to EssayReview for editing and correction of the manuscript.

Funding

This research was supported by grants from the National Research Foundation of Korea (Grant Numbers NRF-2021R1I1A3060435 and NRF-2020R1F1A1076616); a Grant from the Chonnam National University Hospital Biomedical Research Institute (BCRI23041); a Grant from the Research Institute of Medical Sciences (Biomedical Sciences Graduate Program, BMSGP), Chonnam National University; and a Grant from the Korea Institute for Advancement of Technology (KIAT, grant number P0020818) funded by the Korean Government (MOTIE).

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Author notes

  1. Jiyun Choi and Seoyeong Gang contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Chonnam National University Medical School, Jellanamdo, 58128, Republic of Korea

    Jiyun Choi, Seoyeon Gang, Mahesh Ramalingam, Jinsu Hwang, Haewon Jeong, Han-Seong Jeong & Sujeong Jang

  2. Department of Pre-Medical Science, Chonnam National University Medical School, Jellanamdo, 58128, Republic of Korea

    Seoyeon Gang

  3. Department of Physiological Education, Chonnam National University, Gwangju, 61186, Republic of Korea

    Jin Yoo

  4. Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea

    Hyong-Ho Cho

  5. Department of Neurology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea

    Byeong C. Kim

  6. School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186, Republic of Korea

    Geupil Jang

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  1. Jiyun Choi
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Jiyun Choi, Seoyeon Gang, Mahesh Ramalingam, Jinsu Hwang, Haewon Jeong, and Jin Yoo. The first draft of the manuscript was written by Jiyun Choi, Seoyeon Gang, and Sujeong Jang. Financial supports were provided by Hyong-Ho Cho, Byeong C. Kim, Han-Seong Jeong, and Sujeong Jang. The final draft of the manuscript was written by Jiyun Choi, Han-Seong Jeong, and Sujeong Jang. The revised draft of the manuscript was written by Jiyun Choi, Geupil Jang, and Sujeong Jang. All authors read and approved the final manuscript.

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Correspondence to Han-Seong Jeong or Sujeong Jang.

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Choi, J., Gang, S., Ramalingam, M. et al. BML-281 promotes neuronal differentiation by modulating Wnt/Ca2+ and Wnt/PCP signaling pathway. Mol Cell Biochem (2023). https://doi.org/10.1007/s11010-023-04857-2

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