Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic implication of Sonic Hedgehog as a potential modulator in ischemic injury

  • Review
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Sonic Hedgehog (SHh) is a homology protein that is involved in the modeling and development of embryonic tissues. As SHh plays both protective and harmful roles in ischemia, any disruption in the transduction and regulation of the SHh signaling pathway causes ischemia to worsen. The SHh signal activation occurs when SHh binds to the receptor complex of Ptc-mediated Smoothened (Smo) (Ptc-smo), which initiates the downstream signaling cascade. This article will shed light on how pharmacological modifications to the SHh signaling pathway transduction mechanism alter ischemic conditions via canonical and non-canonical pathways by activating certain downstream signaling cascades with respect to protein kinase pathways, angiogenic cytokines, inflammatory mediators, oxidative parameters, and apoptotic pathways. The canonical pathway includes direct activation of interleukins (ILs), angiogenic cytokines like hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and hypoxia-inducible factor alpha (HIF-), which modulate ischemia. The non-canonical pathway includes indirect activation of certain pathways like mTOR, PI3K/Akt, MAPK, RhoA/ROCK, Wnt/-catenin, NOTCH, Forkhead box protein (FOXF), Toll-like receptors (TLR), oxidative parameters such as GSH, SOD, and CAT, and some apoptotic parameters such as Bcl2. This review provides comprehensive insights that contribute to our knowledge of how SHh impacts the progression and outcomes of ischemic injuries.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Availability of data and materials

Not applicable.

Abbreviations

ADP:

Adenosine di-phosphate

AIDS:

Auto Immune Diseases

AMI:

Acute myocardial infarction

AML:

Acute Myeloid Leukemia

ANG:

Angiotensin

ATP:

Adenosine tri-phosphate

BAX:

Bcl2-associated X protein

BBB:

Blood Brain Barrier

BCL2:

B-cell leukemias and lymphoma

BUN:

Blood Urea Nitrogen

CAT:

Catalase

Ci:

Cubitus interruptus

CNS:

Central Nervous System

COX:

Cyclooxygenase

CREB:

Camp-response element binding protein

CXCR:

C-X-C chemokine receptor

DHh:

Desert Hedgehog

EGF:

Epidermal Growth Factor

ERK:

Extracellular signal-regulated kinase

ETC:

Electron Transport Chain

FGF:

Fibroblast Growth Factor

FOXO:

Forkhead Box Protein

Fz:

Frizzled

GDP:

Guanosine di-Phosphate

GLI:

Glioblastoma

GPCR:

G-Protein Coupled Receptor

GSH:

Glutathione

GTP:

Guanosine tri-phosphate

HGF:

Hepatocyte Growth Factor

HGFR:

Hepatocyte Growth Factor Receptor

HIF-α:

Hypoxia-inducible factor-α

HPASMC:

Human Pulmonary Artery Smooth Muscle Cells

HUVECs:

Human umbilical vein endothelial cells

iCAM:

Intracellular adhesion molecule

IFN-γ:

Interferon-γ

IGF:

Insulin-like Growth Factor

Ihh:

Indian Hedgehog

ILs:

Interleukins

IRI:

Ischemia Reperfusion Injury

JAK:

Janus Kinase

JNK:

C-Jun-N-terminal kinase

L-Arg:

L-Arginine

LEVs:

Large extracellular vesicles

LOX:

Lipoxygenase

MACS:

Magnetic-activated cell sorting

MAPK:

Mitogen-activated Protein Kinase

MCAO:

Middle cerebral artery occlusion model

MCP-1α:

Monocyte Chemoattractant Protein-1α

MDA:

Malondialdehyde

MEK:

Mitogen-activated protein kinase

MI:

Myocardial Infraction

MIP:

Macrophage Inflammatory Protein

MMP:

Membrane metalloproteinase

MPTPs:

Mitochondrial Permeability Transition Pores

mTOR:

Mammalian Target of Rapamycin

NB:

Neurobasal

ND:

Neurodegenerative Diseases

Nf-κB:

Nuclear factor kappa B

NO:

Nitric Oxide

NOS:

Nitric oxide synthase

NOTCH:

Neurogenic locus notch homolog protein

Nox2:

NADPH Oxide

OGD:

Oxygen glucose deprivation

PAMsHGF:

PAM associated Hepatocyte growth factor

PDGF:

Platelet-derived Growth Factor

PI3K:

Phosphoinositide-3-kinase–protein Kinase

PTCH1:

Patch1

RhoA/ROCK:

Rho-associated protein kinase

ROS:

Reactive Oxygen Species

SAG:

Smoothened agonist

SDF:

Stromal cell-derived factor

SGLT:

Sodium-glucose transport protein

SHh:

Sonic Hedgehog

SMCs:

Smooth muscle cells

Smo:

Smoothened

SOD:

Superoxide dismutase

SP CELLS:

Side population cells

SSD:

Sterol Sensing Domain

STAT:

Signal Transducer and Activator of Transcription

SUFU:

Suppressor of fused homolog

TGF-β:

Transforming Growth Factor-β

TLR:

Toll-like Receptors

TNF-α:

Tumor Necrosis Factor-α

VEGF:

Vascular Endothelial Growth Factor

References

  1. Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Ischemia/reperfusion. Compr Physiol. 2016. https://doi.org/10.1002/cphy.c160006.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kim JJ, Yoon J, Lee YJ, Park B, Jung DH. Predictive value of the atherogenic index of plasma (AIP) for the risk of incident ischemic heart disease among non-diabetic Koreans. Nutrients. 2021;13(9):3231. https://doi.org/10.3390/nu13093231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Khan MA, Hashim MJ, Mustafa H, Baniyas MY, Al Suwaidi SK, AlKatheeri R, et al. Global epidemiology of ischemic heart disease: results from the global burden of disease study. Cureus. 2020. https://doi.org/10.7759/cureus.9349.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ospel J, Singh N, Ganesh A, Goyal M. Sex and gender differences in stroke and their practical implications in acute care. J Stroke. 2023;25(1):16. https://doi.org/10.5853/jos.2022.04077.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Smiley DA, Khalil RA. Estrogenic compounds, estrogen receptors and vascular cell signaling in the aging blood vessels. Curr Med Chem. 2009;16(15):1863–87. https://doi.org/10.2174/092986709788186093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chan DZL, Kerr A, Grey C, Selak V, Lee MAW, Lund M, et al. Contrasting trends in heart failure incidence in younger and older New Zealanders. Heart. 2022;108(4):300–6. https://doi.org/10.1136/heartjnl-2021-319853.

    Article  PubMed  Google Scholar 

  7. Sharma V, Singh TG, Mannan A. Therapeutic implications of glucose transporters (GLUT) in cerebral ischemia. Neurochem Res. 2022;47(8):2173–86. https://doi.org/10.1007/s11064-022-03620-1.

    Article  CAS  PubMed  Google Scholar 

  8. Ford TJ, Ong P, Sechtem U, Beltrame J, Camici PG, Crea F, et al. Assessment of vascular dysfunction in patients without obstructive coronary artery disease: why, how, and when. JACC Cardiovasc Interv. 2020;13(16):1847–64. https://doi.org/10.1016/j.jcin.2020.05.052.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cheng H, Huang H, Guo Z, Chang Y, Li Z. Role of prostaglandin E2 in tissue repair and regeneration. Theranostics. 2021;11(18):8836–54. https://doi.org/10.7150/thno.63396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang H, Yan Q, Wang X, Chen X, Chen Y, Du J, Chen L. The role of mitochondria in liver ischemia-reperfusion injury: from aspects of mitochondrial oxidative stress, mitochondrial fission, mitochondrial membrane permeable transport pore formation, mitophagy, and mitochondria-related protective measures. Oxid Med Cell Longev. 2021. https://doi.org/10.1155/2021/6670579.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Paggio A, Checchetto V, Campo A, Menabò R, Di Marco G, Di Lisa F, et al. Identification of an ATP-sensitive potassium channel in mitochondria. Nature. 2019;572(7771):609–13. https://doi.org/10.1038/s41586-019-1498-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang J, Ding W, Liu J, Wan J, Wang M. Scavenger receptors in myocardial infarction and ischemia/reperfusion injury: the potential for disease evaluation and therapy. J Am Heart Assoc. 2023;12:e027862. https://doi.org/10.1161/JAHA.122.027862.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Yousufuddin M, Young N. Aging and ischemic stroke. Aging (Albany NY). 2019;11(9):2542. https://doi.org/10.18632/aging.101931.

    Article  PubMed  Google Scholar 

  14. Thapa K, Khan H, Singh TG, Kaur A. Traumatic brain injury: mechanistic insight on pathophysiology and potential therapeutic targets. J Mol Neurosci. 2021;71(9):1725–42. https://doi.org/10.1007/s12031-021-01841-7.

    Article  CAS  PubMed  Google Scholar 

  15. Miceli V, Bulati M, Gallo A, Iannolo G, Busà R, Conaldi PG, et al. Role of mesenchymal stem/stromal cells in modulating ischemia/reperfusion injury: current state of the art and future perspectives. Biomedicines. 2023;11(3):689. https://doi.org/10.3390/biomedicines11030689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lucchinetti E, Bestmann L, Feng J, Freidank H, Clanachan AS, Finegan BA, et al. Remote ischemic preconditioning applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass graft surgery: lack of synergy or evidence of antagonism in cardioprotection? Anesthesiologists. 2012;116(2):296–310. https://doi.org/10.1097/ALN.0b013e318242349a.

    Article  CAS  Google Scholar 

  17. Heiss WD. The ischemic penumbra: how does tissue injury evolve? Ann N Y Acad Sci. 2012;1268(1):26–34. https://doi.org/10.1111/j.1749-6632.2012.06668.x.

    Article  PubMed  Google Scholar 

  18. Catanese L, Tarsia J, Fisher M. Acute ischemic stroke therapy overview. Circ Res. 2017;120(3):541–58. https://doi.org/10.1161/CIRCRESAHA.116.309278.

    Article  CAS  PubMed  Google Scholar 

  19. Garg C, Khan H, Kaur A, Singh TG, Sharma VK, Singh SK. Therapeutic implications of sonic hedgehog pathway in metabolic disorders: novel target for effective treatment. Pharmacol Res. 2022;179:106194. https://doi.org/10.1016/j.phrs.2022.106194.

    Article  CAS  PubMed  Google Scholar 

  20. Ok CY, Singh RR, Vega F. Aberrant activation of the hedgehog signaling pathway in malignant hematological neoplasms. Am J Pathol. 2012;180(1):2–11. https://doi.org/10.1016/j.ajpath.2011.09.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Skoda AM, Simovic D, Karin V, Kardum V, Vranic S, Serman L. The role of the Hedgehog signaling pathway in cancer: a comprehensive review. Bosn J Basic Med Sci. 2018;18(1):8. https://doi.org/10.17305/bjbms.2018.2756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jeng KS, Chang CF, Lin SS. Sonic hedgehog signaling in organogenesis, tumors, and tumor microenvironments. Int J Mol Sci. 2020;21(3):758. https://doi.org/10.3390/ijms21030758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Effendi WI, Nagano T. The Hedgehog signaling pathway in idiopathic pulmonary fibrosis: resurrection time. Int J Mol Sci. 2022;23(1):171. https://doi.org/10.3390/ijms23010171.

    Article  CAS  Google Scholar 

  24. Rana T, Behl T, Sehgal A, Sachdeva M, Mehta V, Sharma N, Singh S, Bungau S. Exploring Sonic Hedgehog cell signaling in neurogenesis: its potential role in depressive behavior. Neurochem Res. 2021;46(7):1589–602. https://doi.org/10.1007/s11064-021-03307-z.

    Article  CAS  PubMed  Google Scholar 

  25. Bosanac I, Maun HR, Scales SJ, Wen X, Lingel A, Bazan JF, et al. The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling. Nat Struct Mol Biol. 2009;16(7):691–7. https://doi.org/10.1038/nsmb.1632.

    Article  CAS  PubMed  Google Scholar 

  26. Maity T, Fuse N, Beachy PA. Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly. Proc Natl Acad Sci U S A. 2005;102(47):17026–31. https://doi.org/10.1073/pnas.0507848102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jeong J, McMahon AP. Cholesterol modification of Hedgehog family proteins. J Clin Invest. 2002;110(5):591–6. https://doi.org/10.1172/JCI16506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bürglin TR. The Hedgehog protein family. Genome Biol. 2008;9:1–9. https://doi.org/10.1186/gb-2008-9-11-241.

    Article  CAS  Google Scholar 

  29. Qian H, Cao P, Hu M, Gao S, Yan N, Gong X. Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm. Nat Commun. 2019;10(1):2320. https://doi.org/10.1038/s41467-019-10234-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Athar M, Tang X, Lee JL, Kopelovich L, Kim AL. Hedgehog signalling in skin development and cancer. Exp Dermatol. 2006;15(9):667–77. https://doi.org/10.1111/j.1600-0625.2006.00473.x.

    Article  CAS  PubMed  Google Scholar 

  31. Belgacem YH, Hamilton AM, Shim S, Spencer KA, Borodinsky LN. The many hats of sonic hedgehog signaling in nervous system development and disease. J Dev Biol. 2016;4(4):35. https://doi.org/10.3390/jdb4040035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Charytoniuk D, Porcel B, Gomez JR, Faure H, Ruat M, Traiffort E. Sonic Hedgehog signalling in the developing and adult brain. J Physiol Paris. 2002;96(1–2):9–16. https://doi.org/10.1016/s0928-4257(01)00075-4.

    Article  CAS  PubMed  Google Scholar 

  33. Zhong C, Wang B. Regulation of cholesterol binding to the receptor patched1 by its interactions with the ligand Sonic Hedgehog (Shh). Front Mol Biosci. 2022. https://doi.org/10.3389/fmolb.2022.831891.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Cohen MM Jr. The hedgehog signaling network. Am J Med Genet A. 2003;123(1):5–28. https://doi.org/10.1002/ajmg.a.20495.

    Article  Google Scholar 

  35. Teperino R, Aberger F, Esterbauer H, Riobo N, Pospisilik JA. Canonical and non-canonical Hedgehog signalling and the control of metabolism. Semin Cell Dev Biol. 2014;33:81–92. https://doi.org/10.1016/j.semcdb.2014.05.007.

    Article  CAS  PubMed  Google Scholar 

  36. Hooper JE, Scott MP. Communicating with hedgehogs. Nat Rev Mol Cell Biol. 2005;6(4):306–17. https://doi.org/10.1038/nrm1622.

    Article  CAS  PubMed  Google Scholar 

  37. Chen Y, Nagib MM, Yasmen N, Sluter MN, Littlejohn TL, Yu Y, et al. Neuroinflammatory mediators in acquired epilepsy: an update. Inflamm Res. 2023;72(4):683–701. https://doi.org/10.1007/s00011-023-01700-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mannan A, Garg N, Singh TG, Kang HK. Peroxisome proliferator-activated receptor-gamma (PPAR-ɣ): molecular effects and its importance as a novel therapeutic target for cerebral ischemic injury. Neurochem Res. 2021;46(11):2800–31. https://doi.org/10.1007/s11064-021-03402-1.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang JM, An J. Cytokines, inflammation and pain. Int Anesthesiol Clin. 2007;45(2):27. https://doi.org/10.1097/AIA.0b013e318034194e.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mourouzis K, Oikonomou E, Siasos G, Tsalamadris S, Vogiatzi G, Antonopoulos A, et al. Pro-inflammatory cytokines in acute coronary syndromes. Curr Pharm Des. 2020;26(36):4624–47. https://doi.org/10.2174/1381612826666200413082353.

    Article  CAS  PubMed  Google Scholar 

  41. Schroeter M, Jander S, Witte OW, Stoll G. Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion. J Neuroimmunol. 1994;55(2):195–203. https://doi.org/10.1016/0165-5728(94)90010-8.

    Article  CAS  PubMed  Google Scholar 

  42. Shichita T, Ito M, Yoshimura A. Post-ischemic inflammation regulates neural damage and protection. Front Cell Neurosci. 2014;8:319. https://doi.org/10.3389/fncel.2014.00319.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Jung M, Ma Y, Iyer RP, DeLeon-Pennell KY, Yabluchanskiy A, Garrett MR, Lindsey ML. IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol. 2017;112(3):33. https://doi.org/10.1007/s00395-017-0622-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Garcia JM, Stillings SA, Leclerc JL, Phillips H, Edwards NJ, Robicsek SA, Hoh BL, Blackburn S, Doré S. Role of interleukin-10 in acute brain injuries. Front Neurol. 2017;8:244. https://doi.org/10.3389/fneur.2017.00244.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Lobo-Silva D, Carriche GM, Castro AG, Roque S, Saraiva M. Balancing the immune response in the brain: IL-10 and its regulation. J Neuroinflammation. 2016;13(1):297. https://doi.org/10.1186/s12974-016-0763-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Borsini A, Zunszain PA, Thuret S, Pariante CM. The role of inflammatory cytokines as key modulators of neurogenesis. Trends Neurosci. 2015;38(3):145–57. https://doi.org/10.1016/j.tins.2014.12.006.

    Article  CAS  PubMed  Google Scholar 

  47. Jin J, Xu F, Zhang Y, Guan J, Fu J. Myocardial ischemia-reperfusion injury is probably due to the excessive production of mitochondrial ROS caused by the activation of 5-HT degradation system mediated by PAF receptor. Mol Immunol. 2023;155:27–43. https://doi.org/10.1016/j.molimm.2023.01.004.

    Article  CAS  PubMed  Google Scholar 

  48. Martins-Marques T, Rodriguez-Sinovas A, Girao H. Cellular crosstalk in cardioprotection: where and when do reactive oxygen species play a role? Free Radic Biol Med. 2021;169:397–409. https://doi.org/10.1016/j.freeradbiomed.2021.03.044.

    Article  CAS  PubMed  Google Scholar 

  49. Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003;552(2):335–44. https://doi.org/10.1113/jphysiol.2003.049478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mishra P, Chan DC. Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol. 2014;15(10):634–46. https://doi.org/10.1038/nrm3877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fındık O, Yılmaz MY, Yazır Y, Rençber SF, Sarıhan KK, Kunt AT. Investigation of the protective effect of enoxaparin and ticagrelor pretreatment against ischemia-reperfusion injury in rat lung tissue. Rev Assoc Med Bras. 2019;65:1193–200. https://doi.org/10.1590/1806-9282.65.9.1193.

    Article  PubMed  Google Scholar 

  52. MaikeKrenz C, TheodoreKalogeris R. Cell survival programs and ischemia/reperfusion: hormesis, preconditioning, and cardioprotection. In: Colloquium series on integrated systems physiology, vol 5, no 3. Morgan & Claypool Publishers; 2013. https://doi.org/10.4199/C00090ED1V01Y201309ISP044

  53. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6(4):389–95. https://doi.org/10.1038/74651.

    Article  CAS  PubMed  Google Scholar 

  54. Liu L, Zhao B, Xiong X, Xia Z. The neuroprotective roles of sonic hedgehog signaling pathway in ischemic stroke. Neurochem Res. 2018;43:2199–211. https://doi.org/10.1007/s11064-018-2645-1.

    Article  CAS  PubMed  Google Scholar 

  55. Carballo GB, Honorato JR, de Lopes GP, Spohr TC. A highlight on Sonic hedgehog pathway. Cell Commun Signal. 2018;16:1–5. https://doi.org/10.1186/s12964-018-0220-7.

    Article  CAS  Google Scholar 

  56. Fernandes-Silva H, Correia-Pinto J, Moura RS. Canonical sonic hedgehog signaling in early lung development. J Dev Biol. 2017;5(1):3. https://doi.org/10.3390/jdb5010003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Salaritabar A, Berindan-Neagoe I, Darvish B, Hadjiakhoondi F, Manayi A, Devi KP, et al. Targeting Hedgehog signaling pathway: paving the road for cancer therapy. Pharmacol Res. 2019;141:466–80. https://doi.org/10.1016/j.phrs.2019.01.014.

    Article  CAS  PubMed  Google Scholar 

  58. Jiang K, Jia J. Smoothened regulation in response to Hedgehog stimulation. Front Biol (Beijing). 2015;10(6):475–86. https://doi.org/10.1007/s11515-015-1385-8.

    Article  PubMed  Google Scholar 

  59. Kowatsch C, Woolley RE, Kinnebrew M, Rohatgi R, Siebold C. Structures of vertebrate patched and smoothened reveal intimate links between cholesterol and Hedgehog signalling. Curr Opin Struct Biol. 2019;57:204–14. https://doi.org/10.1016/j.sbi.2019.05.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Niewiadomski P, Niedziółka SM, Markiewicz Ł, Uśpieński T, Baran B, Chojnowska K. Gli proteins: regulation in development and cancer. Cells. 2019;8(2):147. https://doi.org/10.3390/cells8020147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo HW. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers. 2016;8(2):22. https://doi.org/10.3390/cancers8020022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Striz I, Brabcova E, Kolesar L, Sekerkova A. Cytokine networking of innate immunity cells: a potential target of therapy. Clin Sci. 2014;126(9):593–612. https://doi.org/10.1042/CS20130497.

    Article  CAS  Google Scholar 

  63. Du B, Lin C, Bian Z, Xu B. An insight into anti-inflammatory effects of fungal beta-glucans. Trends Food Sci Technol. 2015;41(1):49–59. https://doi.org/10.1016/j.tifs.2014.09.002.

    Article  CAS  Google Scholar 

  64. Zhu H, Hu S, Li Y, Sun Y, Xiong X, Hu X, et al. Interleukins and ischemic stroke. Front Immunol. 2022. https://doi.org/10.3389/fimmu.2022.828447.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Tobin MK, Bonds JA, Minshall RD, Pelligrino DA, Testai FD, Lazarov O. Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab. 2014;34(10):1573–84. https://doi.org/10.1038/jcbfm.2014.130.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Torres FI. Hemorrhagic shock and the microvasculature. Compr Physiol. 2017;8(1):61–101. https://doi.org/10.1002/cphy.c170006.

    Article  Google Scholar 

  67. Homma T, Kinugawa S, Takahashi M, Sobirin MA, Saito A, Fukushima A, et al. Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice. J Mol Cell Cardiol. 2013;62:179–88. https://doi.org/10.1016/j.yjmcc.2013.06.004.

    Article  CAS  PubMed  Google Scholar 

  68. Lively S, Hutchings S, Schlichter LC. Molecular and cellular responses to interleukin-4 treatment in a rat model of transient ischemia. J Neuropathol Exp Neurol. 2016;75(11):1058–71. https://doi.org/10.1093/jnen/nlw081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Su YC, Li SC, Wu YC, Wang LM, Chao KS, Liao HF. Resveratrol downregulates interleukin-6-stimulated sonic hedgehog signaling in human acute myeloid leukemia. Evid Based Complementary Altern Med. 2013. https://doi.org/10.1155/2013/547430.

    Article  Google Scholar 

  70. Yang J, Ran M, Li H, Lin Y, Ma K, Yang Y, et al. New insight into neurological degeneration: inflammatory cytokines and blood–brain barrier. Front Mol Neurosci. 2022. https://doi.org/10.3389/fnmol.2022.1013933.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Spaccapelo L, Galantucci M, Neri L, Contri M, Pizzala R, D’Amico R, et al. Up-regulation of the canonical Wnt-3A and Sonic hedgehog signaling underlies melanocortin-induced neurogenesis after cerebral ischemia. Eur J Pharmacol. 2013;707(1–3):78–86. https://doi.org/10.1016/j.ejphar.2013.03.030.

    Article  CAS  PubMed  Google Scholar 

  72. Fallah A, Sadeghinia A, Kahroba H, Samadi A, Heidari HR, Bradaran B, et al. Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-dependent diseases. Biomed Pharmacother. 2019;110:775–85. https://doi.org/10.1016/j.biopha.2018.12.022.

    Article  CAS  PubMed  Google Scholar 

  73. Bhatia S, Babbar R, Zehravi M, Singh B, Chandel P, Hasan MM, et al. Angiogenic footprints in diabetic retinopathy: opportunities for drug development. Biotechnol Genet Eng Rev. 2022;11:1–25. https://doi.org/10.1080/02648725.2022.2102880.

    Article  CAS  Google Scholar 

  74. Stryker ZI, Rajabi M, Davis PJ, Mousa SA. Evaluation of angiogenesis assays. Biomedicines. 2019;7(2):37. https://doi.org/10.3390/biomedicines7020037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, et al. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest. 2003;111(12):1843–51. https://doi.org/10.1172/JCI17977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Cosky EE, Ding Y. The role of vascular endothelial growth factor in angiogenesis and brain circulation after stroke. Brain Circ. 2018;4(2):73. https://doi.org/10.4103/bc.bc_8_18.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Banai S, Shweiki D, Pinson A, Chandra M, Lazarovici G, Keshet E. Upregulation of vascular endothelial growth factor expression induced by myocardial ischaemia: implications for coronary angiogenesis. Cardiovasc Res. 1994;28(8):1176–9. https://doi.org/10.1093/cvr/28.8.1176.

    Article  CAS  PubMed  Google Scholar 

  78. Lawson ND, Vogel AM, Weinstein BM. Sonic Hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell. 2002;3(1):127–36. https://doi.org/10.1016/s1534-5807(02)00198-3.

    Article  CAS  PubMed  Google Scholar 

  79. Wang X, Li C, Gong H. Morphological and functional changes in bone marrow mesenchymal stem cells in rats with heart failure. Exp Ther Med. 2017;13(6):2888–92. https://doi.org/10.3892/etm.2017.4341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Fu JR, Liu WL, Zhou JF, et al. Sonic hedgehog protein promotes bone marrow-derived endothelial progenitor cell proliferation, migration and VEGF production via PI 3-kinase/Akt signaling pathways. Acta Pharmacol Sin. 2006;27(6):685–93. https://doi.org/10.1111/j.1745-7254.2006.00335.x.

    Article  CAS  PubMed  Google Scholar 

  81. Chen SC, Huang M, He QW, Zhang Y, Opoku EN, Yang H, Jin HJ, Xia YP, Hu B. Administration of sonic hedgehog protein induces angiogenesis and has therapeutic effects after stroke in rats. Neuroscience. 2017;352:285–95. https://doi.org/10.1016/j.neuroscience.2017.03.054.

    Article  CAS  PubMed  Google Scholar 

  82. Ahmed AE, Sindi RA, Yousef NA, Hussein HA, Badr MR, Syaad KMA, Al-Saeed FA, et al. Impact of epidermal growth factor and/or β-mercaptoethanol supplementations on the in vitro produced buffaloes’ embryos. Front Vet Sci. 2023;10:1138220. https://doi.org/10.3389/fvets.2023.1138220.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Lim SO, Li CW, Xia W, Hsu JL, Raftery D, Djukovic D, et al. EGFR signaling enhances aerobic glycolysis in triple-negative breast cancer cells to promote tumor growth and immune escape. Cancer Res. 2016;76(5):1284–96. https://doi.org/10.1158/0008-5472.CAN-15-2478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Voisin L, Foisy S, Giasson E, Lambert C, Moreau P, Meloche S. EGF receptor transactivation is obligatory for protein synthesis stimulation by G protein-coupled receptors. Am J Physiol Cell Physiol. 2002;283(2):C446–55. https://doi.org/10.1152/ajpcell.00261.2001.

    Article  CAS  PubMed  Google Scholar 

  85. Geng Y, Li J, Wang F, Li Q, Wang X, Sun L, Li W. Epidermal growth factor promotes proliferation and improves restoration after intestinal ischemia-reperfusion injury in rats. Inflammation. 2013;36(3):670–9. https://doi.org/10.1007/s10753-012-9591-x.

    Article  CAS  PubMed  Google Scholar 

  86. Arda-Pirincci P, Bolkent S. The role of epidermal growth factor in prevention of oxidative injury and apoptosis induced by intestinal ischemia/reperfusion in rats. Acta Histochem. 2014;116(1):167–75. https://doi.org/10.1016/j.acthis.2013.07.005.

    Article  CAS  PubMed  Google Scholar 

  87. Lei K, Thi-Kim VuH, Mohan RD, McKinney SA, Seidel CW, Alexander R, et al. Egf signaling directs neoblast repopulation by regulating asymmetric cell division in planarians. Dev Cell. 2016;38(4):413–29. https://doi.org/10.1016/j.devcel.2016.07.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ma J, Jin G. Epidermal growth factor protects against myocardial ischaemia reperfusion injury through activating Nrf2 signalling pathway. Free Radic Res. 2019;53(3):313–23. https://doi.org/10.1080/10715762.2019.1584399.

    Article  CAS  PubMed  Google Scholar 

  89. Bijlsma MF, Groot AP, Oduro JP, Franken RJ, Schoenmakers SHHF, Peppelenbosch MP, et al. Hypoxia induces a hedgehog response mediated by HIF-1alpha. J Cell Mol Med. 2009;13(8B):2053–60. https://doi.org/10.1111/j.1582-4934.2008.00491.x.

    Article  PubMed  Google Scholar 

  90. Budimir I, Tomasović-Lončarić Č, Kralik K, Kralik K, Čonkaš J, Eljuga D, et al. Higher expressions of SHH and AR are associated with a positive receptor status and have impact on survival in a cohort of Croatian breast cancer patients. Life (Basel). 2022;12(10):1559. https://doi.org/10.3390/life12101559.

    Article  CAS  PubMed  Google Scholar 

  91. Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991;5(12):1806–14. https://doi.org/10.1210/mend-5-12-1806.

    Article  CAS  PubMed  Google Scholar 

  92. Cannito S, Novo E, Parola M. Therapeutic pro-fibrogenic signaling pathways in fibroblasts. Adv Drug Deliv Rev. 2017;121:57–84. https://doi.org/10.1016/j.addr.2017.05.017.

    Article  CAS  PubMed  Google Scholar 

  93. Tuuminen R, Dashkevich A, Keränen MA, Raissadati A, Krebs R, Jokinen JJ, et al. Platelet-derived growth factor-B protects rat cardiac allografts from ischemia-reperfusion injury. Transplantation. 2016;100(2):303–13. https://doi.org/10.1097/TP.0000000000000909.

    Article  CAS  PubMed  Google Scholar 

  94. Song G, Fang Y, Wang X, Wu S, Song H. The effects of platelet-derived growth factor in rat cardiac allograft vasculopathy and fibrosis. Transplant Proc. 2008;40(8):2716–9. https://doi.org/10.1016/j.transproceed.2008.07.119.

    Article  CAS  PubMed  Google Scholar 

  95. Raisky O, Nykänen AI, Krebs R, Hollmén M, Keränen MA, Tikkanen JM, et al. VEGFR-1 and-2 regulate inflammation, myocardial angiogenesis, and arteriosclerosis in chronically rejecting cardiac allografts. Arterioscler Thromb Vasc Biol. 2007;27(4):819–25. https://doi.org/10.1161/01.ATV.0000260001.55955.6c.

    Article  CAS  PubMed  Google Scholar 

  96. Sil S, Periyasamy P, Thangaraj A, Chivero ET, Buch S. PDGF/PDGFR axis in the neural systems. Mol Aspects Med. 2018;62:63–74. https://doi.org/10.1016/j.mam.2018.01.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Krupinski J, Issa R, Bujny T, Slevin M, Kumar P, Kumar S, et al. A putative role for platelet-derived growth factor in angiogenesis and neuroprotection after ischemic stroke in humans. Stroke. 1997;28(3):564–73. https://doi.org/10.1161/01.str.28.3.564.

    Article  CAS  PubMed  Google Scholar 

  98. Arimura K, Ago T, Kamouchi M, Nakamura K, Ishitsuka K, Kuroda J, et al. PDGF receptor β signaling in pericytes following ischemic brain injury. Curr Neurovasc Res. 2012;9(1):1–9. https://doi.org/10.2174/156720212799297100.

    Article  CAS  PubMed  Google Scholar 

  99. Yao Q, Renault MA, Chapouly C, Vandierdonck S, Belloc I, Jaspard-Vinassa B, et al. Sonic hedgehog mediates a novel pathway of PDGF-BB–dependent vessel maturation. Blood. 2014;123(15):2429–37. https://doi.org/10.1182/blood-2013-06-508689.

    Article  CAS  PubMed  Google Scholar 

  100. Karlsson L, Bondjers C, Betsholtz C. Roles for PDGF-A and Sonic Hedgehog in development of mesenchymal components of the hair follicle. Development. 1999;126(12):2611–21. https://doi.org/10.1242/dev.126.12.2611.

    Article  CAS  PubMed  Google Scholar 

  101. Cecchi F, Rabe DC, Bottaro DP. The hepatocyte growth factor receptor: structure, function and pharmacological targeting in cancer. Curr Signal Transduct Ther. 2011;6(2):146–51. https://doi.org/10.2174/157436211795659955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Xu X, Zheng L, Yuan Q, Zhen G, Crane JL, Zhou X, et al. Transforming growth factor-β in stem cells and tissue homeostasis. Bone Res. 2018;6(1):2. https://doi.org/10.1038/s41413-017-0005-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang LS, Wang H, Zhang QL, Yang ZJ, Kong FX, Wu CT. Hepatocyte growth factor gene therapy for ischemic diseases. Hum Gene Ther. 2018;29(4):413–23. https://doi.org/10.1089/hum.2017.217.

    Article  CAS  PubMed  Google Scholar 

  104. Miller SB, Martin DR, Kissane JO, Hammerman MR. Hepatocyte growth factor accelerates recovery from acute ischemic renal injury in rats. Am J Physiol. 1994;266(1):F129–34. https://doi.org/10.1152/ajprenal.1994.266.1.F129.

    Article  PubMed  Google Scholar 

  105. Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S. Enhanced expression of hepatocyte growth factor/c-Met by myocardial ischemia and reperfusion in a rat model. Circulation. 1997;95(11):2552–8. https://doi.org/10.1161/01.cir.95.11.2552.

    Article  CAS  PubMed  Google Scholar 

  106. Coon V, Laukert T, Pedone CA, Laterra J, Kim KJ, Fults DW. Molecular therapy targeting Sonic Hedgehog and hepatocyte growth factor signaling in a mouse model of MedulloblastomaShh-and HGF-targeted therapy in medulloblastoma. Mol Cancer Ther. 2010;9(9):2627–36. https://doi.org/10.1158/1535-7163.MCT-10-0486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Riaud M, Hilairet G, Sindji L, Perdomo L, Montero-Menei CN, Martinez MC. Pharmacology active microcarriers delivering HGF associated with extracellular vesicles for myocardial repair. Eur J Pharm Biopharm. 2021;169:268–79. https://doi.org/10.1016/j.ejpb.2021.10.018.

    Article  CAS  PubMed  Google Scholar 

  108. Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 2006;70(5):1469–80. https://doi.org/10.1124/mol.106.027029.

    Article  CAS  PubMed  Google Scholar 

  109. Conde E, Alegre L, Blanco-Sánchez I, Sáenz-Morales D, Aguado-Fraile E, Ponte B, et al. Hypoxia inducible factor 1-alpha (HIF-1 alpha) is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival. PLoS One. 2012;7(3):e33258. https://doi.org/10.1371/journal.pone.0033258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Sarkar K, Cai Z, Gupta R, Parajuli N, Fox-Talbot K, Darshan MS, et al. Hypoxia-inducible factor 1 transcriptional activity in endothelial cells is required for acute phase cardioprotection induced by ischemic preconditioning. Proc Natl Acad Sci U S A. 2012;109(26):10504–9. https://doi.org/10.1073/pnas.1208314109.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Wang G, Zhang Z, Xu Z, Yin H, Bai L, Ma Z, et al. Activation of the sonic hedgehog signaling controls human pulmonary arterial smooth muscle cell proliferation in response to hypoxia. Biochim Biophys Acta. 2010;1803(12):1359–67. https://doi.org/10.1016/j.bbamcr.2010.09.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ozturk H, Tuncer MC, Ozturk H, Buyukbayram H. Nitric oxide regulates expression of Sonic Hedgehog and hypoxia-inducible factor-1α in an experimental model of kidney ischemia-reperfusion. Ren Fail. 2007;29(3):249–56. https://doi.org/10.1080/08860220601166289.

    Article  CAS  PubMed  Google Scholar 

  113. Yin S, Bai X, Xin D, Li T, Chu X, Ke H, et al. Corrigendum to “neuroprotective effects of the sonic hedgehog signaling pathway in ischemic injury through promotion of synaptic and neuronal health.” Neural Plast. 2021. https://doi.org/10.1155/2021/9762592.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2018;9(6):7204. https://doi.org/10.18632/oncotarget.23208.

    Article  PubMed  Google Scholar 

  115. Cheng HC, Qi RZ, Paudel H, Zhu HJ. Regulation and function of protein kinases and phosphatases. Enzyme Res. 2011. https://doi.org/10.4061/2011/794089.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Hommes DW, Peppelenbosch MP, Van Deventer SJ. Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti-inflammatory targets. Gut. 2003;52(1):144–51. https://doi.org/10.1136/gut.52.1.144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhong J, Shi G. Editorial: regulation of inflammation in chronic disease. Front Immunol. 2019;10:737. https://doi.org/10.3389/fimmu.2019.00737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36(6):320–8. https://doi.org/10.1016/j.tibs.2011.03.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93. https://doi.org/10.1016/j.cell.2012.03.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Aoyagi T, Kusakari Y, Xiao CY, Inouye BT, Takahashi M, Scherrer-Crosbie M, et al. Cardiac mTOR protects the heart against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2012;303(1):H75-85. https://doi.org/10.1152/ajpheart.00241.2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhang T, Guo J, Gu J, Chen K, Li H, Wang J. Protective role of mTOR in liver ischemia/reperfusion injury: involvement of inflammation and autophagy. Oxid Med Cell Longev. 2019. https://doi.org/10.1155/2019/7861290.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Huang Z, Han Z, Ye B, Dai Z, Shan P, Lu Z, et al. Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes. Eur J Pharmacol. 2015. https://doi.org/10.1016/j.ejphar.2015.05.028.

    Article  PubMed  Google Scholar 

  123. Zeng Q, Fu Q, Wang X, Zhao Y, Liu H, Li Z, et al. Protective effects of sonic hedgehog against ischemia/reperfusion injury in mouse skeletal muscle via AKT/mTOR/p70S6K signaling. Cell Physiol Biochem. 2017;43(5):1813–28. https://doi.org/10.1159/000484068.

    Article  CAS  PubMed  Google Scholar 

  124. Zhu T, Wang L, Wang LP, Wan Q. Therapeutic targets of neuroprotection and neurorestoration in ischemic stroke: applications for natural compounds from medicinal herbs. Biomed Pharmacother. 2022;148:112719. https://doi.org/10.1016/j.biopha.2022.112719.

    Article  CAS  PubMed  Google Scholar 

  125. Klein SD, Nguyen DC, Bhakta V, Wong D, Chang VY, Davidson TB, Martinez-Agosto JA. Mutations in the sonic hedgehog pathway cause macrocephaly-associated conditions due to crosstalk to the PI3K/AKT/mTOR pathway. Am J Med Genet A. 2019;179(12):2517–31. https://doi.org/10.1002/ajmg.a.61368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Gu C, Zhang Q, Li Y, Li R, Feng J, Chen W, et al. The PI3K/AKT pathway-the potential key mechanisms of traditional Chinese medicine for stroke. Front Med (Lausanne). 2022;9:900809. https://doi.org/10.3389/fmed.2022.900809.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Kumar M, Bansal N. Implications of phosphoinositide 3-kinase-akt (PI3K-Akt) pathway in the pathogenesis of Alzheimer’s disease. Mol Neurobiol. 2022;59(1):354–85. https://doi.org/10.1007/s12035-021-02611-7.

    Article  CAS  PubMed  Google Scholar 

  128. Vara JÁ, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30(2):193–204. https://doi.org/10.1016/j.ctrv.2003.07.007.

    Article  CAS  Google Scholar 

  129. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96(6):857–68. https://doi.org/10.1016/s0092-8674(00)80595-4.

    Article  CAS  PubMed  Google Scholar 

  130. Mullonkal CJ, Toledo-Pereyra LH. Akt in ischemia and reperfusion. J Invest Surg. 2007;20(3):195–203. https://doi.org/10.1080/08941930701366471.

    Article  PubMed  Google Scholar 

  131. Arcaro A, Guerreiro AS. The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications. Curr Genomics. 2007;8(5):271–306. https://doi.org/10.2174/138920207782446160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Lan R, Xiang J, Zhang Y, Wang GH, Bao J, Li WW, Zhang W, et al. PI3K/Akt pathway contributes to neurovascular unit protection of Xiao-Xu-Ming decoction against focal cerebral ischemia and reperfusion injury in rats. Evid Based Complement Alternat Med. 2013. https://doi.org/10.1155/2013/459467.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Zhang W, Zhang JQ, Meng FM, Xue FS. Dexmedetomidine protects against lung ischemia–reperfusion injury by the PI3K/Akt/HIF-1α signaling pathway. J Anesth. 2016;30:826–33. https://doi.org/10.1007/s00540-016-2214-1.

    Article  PubMed  Google Scholar 

  134. Zhang Z, Yao L, Yang J, Wang Z, Du G. PI3K/Akt and HIF-1 signaling pathway in hypoxia-ischemia. Mol Med Rep. 2018;18(4):3547–54. https://doi.org/10.3892/mmr.2018.9375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Madhala-Levy D, Williams VC, Hughes SM, Reshef R, Halevy O. Cooperation between Shh and IGF-I in promoting myogenic proliferation and differentiation via the MAPK/ERK and PI3K/Akt pathways requires smo activity. J Cell Physiol. 2012;227(4):1455–64. https://doi.org/10.1002/jcp.22861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Dai R, Xia Y, Mao L, Mei Y, Xue Y, Hu B. Involvement of PI3K/Akt pathway in the neuroprotective effect of Sonic hedgehog on cortical neurons under oxidative stress. J Huazhong Univ Sci Technol Med Sci. 2012;32:856–60. https://doi.org/10.1007/s11596-012-1047-x.

    Article  CAS  Google Scholar 

  137. Yin S, Bai X, Xin D, Li T, Chu X, Ke H, et al. Neuroprotective effects of the sonic hedgehog signaling pathway in ischemic injury through promotion of synaptic and neuronal health. Neural Plast. 2020. https://doi.org/10.1155/2020/8815195.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Paulis L, Fauconnier J, Cazorla O, Thireau J, Soleti R, Vidal B, et al. Activation of Sonic hedgehog signaling in ventricular cardiomyocytes exerts cardioprotection against ischemia reperfusion injuries. Sci Rep. 2015;5(1):7983. https://doi.org/10.1038/srep07983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Saklani P, Khan H, Gupta S, Kaur A, Singh TG. Neuropeptides: potential neuroprotective agents in ischemic injury. Life Sci. 2022;288:120186. https://doi.org/10.1016/j.lfs.2021.120186.

    Article  CAS  PubMed  Google Scholar 

  140. Olea-Flores M, Zuñiga-Eulogio MD, Mendoza-Catalán MA, Rodríguez-Ruiz HA, Castañeda-Saucedo E, Ortuño-Pineda C, et al. Extracellular-signal regulated kinase: a central molecule driving epithelial–mesenchymal transition in cancer. Int J Mol Sci. 2019;20(12):2885. https://doi.org/10.3390/ijms20122885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Wang MC, Wang D, Lu YH, Li ZH, Jing HY. Protective effect of MAPK signaling pathway mediated by ITGB3 gene silencing on myocardial ischemia-reperfusion injury in mice and its mechanism. Eur Rev Med Pharmacol Sci. 2021;25(2):820–36. https://doi.org/10.26355/eurrev_202101_24647.

    Article  PubMed  Google Scholar 

  142. Chen J, Wang W, Zhang Q, Li F, Lei T, Luo D, et al. Low molecular weight fucoidan against renal ischemia–reperfusion injury via inhibition of the MAPK signaling pathway. PLoS One. 2013;8(2):e56224. https://doi.org/10.1371/journal.pone.0056224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kessaris N, Jamen F, Rubin LL, Richardson WD. Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signalling pathways in neocortical precursors. Development. 2004;131(6):1289–98. https://doi.org/10.1242/dev.01027.

    Article  CAS  PubMed  Google Scholar 

  144. Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y, et al. Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2007;104(12):5103–8. https://doi.org/10.1073/pnas.0701158104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Elia D, Madhala D, Ardon E, Reshef R, Halevy O. Sonic hedgehog promotes proliferation and differentiation of adult muscle cells: Involvement of MAPK/ERK and PI3K/Akt pathways. Biochim Biophys Acta. 2007;1773(9):1438–46. https://doi.org/10.1016/j.bbamcr.2007.06.006.

    Article  CAS  PubMed  Google Scholar 

  146. Liu J, Gao HY, Wang XF. The role of the Rho/ROCK signaling pathway in inhibiting axonal regeneration in the central nervous system. Neural Regen Res. 2015;10(11):1892. https://doi.org/10.4103/1673-5374.170325.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Ridley AJ. Rho GTPases and cell migration. J Cell Sci. 2001;114(15):2713–22. https://doi.org/10.1242/jcs.114.15.2713.

    Article  CAS  PubMed  Google Scholar 

  148. Gao HC, Zhao H, Zhang WQ, Li YQ, Ren LQ. The role of the Rho/Rock signaling pathway in the pathogenesis of acute ischemic myocardial fibrosis in rat models. Exp Ther Med. 2013;5(4):1123–8. https://doi.org/10.3892/etm.2013.935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Renault MA, Roncalli J, Tongers J, Thorne T, Klyachko E, Misener S, et al. Sonic hedgehog induces angiogenesis via Rho kinase-dependent signaling in endothelial cells. J Mol Cell Cardiol. 2010;49(3):490–8. https://doi.org/10.1016/j.yjmcc.2010.05.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. He QW, Xia YP, Chen SC, Wang Y, Huang M, Huang Y, et al. Astrocyte-derived sonic hedgehog contributes to angiogenesis in brain microvascular endothelial cells via RhoA/ROCK pathway after oxygen–glucose deprivation. Mol Neurobiol. 2013;47:976–87. https://doi.org/10.1007/s12035-013-8396-8.

    Article  CAS  PubMed  Google Scholar 

  151. Huaitong X, Yuanyong F, Yueqin T, Peng Z, Wei S, Kai S. Microvesicles releasing by oral cancer cells enhance endothelial cell angiogenesis via Shh/RhoA signaling pathway. Cancer Biol Ther. 2017;18(10):783–91. https://doi.org/10.1080/15384047.2017.1373213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Hu Z, Chen Y, Zhu S, Feng X, Zhang B, Huang J. Sonic hedgehog promotes proliferation and migration of fibroblast-like synoviocytes in rheumatoid arthritis via Rho/ROCK signaling. J Immunol Res. 2022. https://doi.org/10.1155/2022/3423692.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Lu W, Chen Z, Wen J. RhoA/ROCK signaling pathway and astrocytes in ischemic stroke. Metab Brain Dis. 2021;36:1101–8. https://doi.org/10.1007/s11011-021-00709-4.

    Article  CAS  PubMed  Google Scholar 

  154. Wettschureck N, Offermanns S. Rho/Rho-kinase mediated signaling in physiology and pathophysiology. J Mol Med. 2002;80(10):629. https://doi.org/10.1007/s00109-002-0370-2.

    Article  CAS  PubMed  Google Scholar 

  155. Qian C, Cao X. Regulation of Toll-like receptor signaling pathways in innate immune responses. Ann N Y Acad Sci. 2013;1283(1):67–74. https://doi.org/10.1111/j.1749-6632.2012.06786.x.

    Article  CAS  PubMed  Google Scholar 

  156. Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:461. https://doi.org/10.3389/fimmu.2014.00461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Stevens SL, Ciesielski TM, Marsh BJ, Yang T, Homen DS, Boule JL, et al. Toll-like receptor 9: a new target of ischemic preconditioning in the brain. J Cereb Blood Flow Metab. 2008;28(5):1040–7. https://doi.org/10.1038/sj.jcbfm.9600606.

    Article  CAS  PubMed  Google Scholar 

  158. Pulskens WP, Teske GJ, Butter LM, Roelofs JJ, Van Der Poll T, Florquin S, et al. Toll-like receptor-4 coordinates the innate immune response of the kidney to renal ischemia/reperfusion injury. PLoS One. 2008;3(10):e3596. https://doi.org/10.1371/journal.pone.0003596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ye L, Feng Z, Doycheva D, Malaguit J, Dixon B, Xu N, Zhang JH, et al. CpG-ODN exerts a neuroprotective effect via the TLR9/pAMPK signaling pathway by activation of autophagy in a neonatal HIE rat model. Exp Neurol. 2018;301:70–80. https://doi.org/10.1016/j.expneurol.2017.12.008.

    Article  CAS  PubMed  Google Scholar 

  160. Ghorpade DS, Holla S, Kaveri SV, Bayry J, Patil SA, Balaji KN. Sonic hedgehog-dependent induction of microRNA 31 and microRNA 150 regulates Mycobacterium bovis BCG-driven toll-like receptor 2 signaling. Mol Cell Biol. 2013;33(3):543–56. https://doi.org/10.1128/MCB.01108-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Yaddanapudi K, De Miranda J, Hornig M, Lipkin WI. Toll-like receptor 3 regulates neural stem cell proliferation by modulating the Sonic Hedgehog pathway. PLoS One. 2011;6(10):e26766. https://doi.org/10.1371/journal.pone.0026766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Nijhawan P, Behl T, Bungau S, Uddin MS, Zengin G, Arora S. Molecular insights into therapeutic promise of targeting of Wnt/β-catenin signaling pathway in obesity. Mol Biol Rep. 2020;47(10):8091–100. https://doi.org/10.1007/s11033-020-05784-x.

    Article  CAS  PubMed  Google Scholar 

  163. Mo Z, Zeng Z, Liu Y, Zeng L, Fang J, Ma Y. Activation of Wnt/Beta-catenin signaling pathway as a promising therapeutic candidate for cerebral ischemia/reperfusion injury. Front Pharmacol. 2022. https://doi.org/10.3389/fphar.2022.914537.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Kriska J, Hermanova Z, Knotek T, Tureckova J, Anderova M. On the common journey of neural cells through ischemic brain injury and Alzheimer’s disease. Int J Mol Sci. 2021;22(18):9689. https://doi.org/10.3390/ijms22189689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Schneider FT, Schänzer A, Czupalla CJ, Thom S, Engels K, Schmidt MH, et al. Sonic hedgehog acts as a negative regulator of β-catenin signaling in the adult tongue epithelium. Am J Pathol. 2010;177(1):404–14. https://doi.org/10.2353/ajpath.2010.091079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Moreau N, Mauborgne A, Couraud PO, Romero IA, Weksler BB, Villanueva L, et al. Could an endoneurial endothelial crosstalk between Wnt/β-catenin and Sonic Hedgehog pathways underlie the early disruption of the infraorbital blood–nerve barrier following chronic constriction injury? Mol Pain. 2017;13:1744806917727625. https://doi.org/10.1177/1744806917727625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Kopan R. Notch signaling. Cold Spring Harb Perspect Biol. 2012;4(10):a011213. https://doi.org/10.1101/cshperspect.a011213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Zen AA, Madeddu P. Notch signalling in ischaemia-induced angiogenesis. Biochem Soc Trans. 2009;37(6):1221–7. https://doi.org/10.1042/BST0371221.

    Article  CAS  Google Scholar 

  169. Liu S, Cao Y, Qu M, Zhang Z, Feng L, Ye Z, et al. Curcumin protects against stroke and increases levels of Notch intracellular domain. Neurol Res. 2016;38(6):553–9. https://doi.org/10.1080/01616412.2016.1187804.

    Article  CAS  PubMed  Google Scholar 

  170. Hirashima M. Regulation of endothelial cell differentiation and arterial specification by VEGF and Notch signaling. Anat Sci Int. 2009;84:95–101. https://doi.org/10.1007/s12565-009-0026-1.

    Article  CAS  PubMed  Google Scholar 

  171. Lou YL, Guo F, Liu F, Gao FL, Zhang PQ, Niu X, et al. miR-210 activates notch signaling pathway in angiogenesis induced by cerebral ischemia. Mol Cell Biochem. 2012;370:45–51. https://doi.org/10.1007/s11010-012-1396-6.

    Article  CAS  PubMed  Google Scholar 

  172. Morrow D, Cullen JP, Liu W, Guha S, Sweeney C, Birney YA, et al. Sonic Hedgehog induces Notch target gene expression in vascular smooth muscle cells via VEGF-A. Arterioscler Thromb Vasc Biol. 2009;29(7):1112–8. https://doi.org/10.1161/ATVBAHA.109.186890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9(6):685–93. https://doi.org/10.1038/nm0603-685.

    Article  CAS  PubMed  Google Scholar 

  174. Wang S, Xiao Z, Hong Z, Jiao H, Zhu S, Zhao Y, et al. FOXF1 promotes angiogenesis and accelerates bevacizumab resistance in colorectal cancer by transcriptionally activating VEGFA. Cancer Lett. 2018;439:78–90. https://doi.org/10.1016/j.canlet.2018.09.026.

    Article  CAS  PubMed  Google Scholar 

  175. Sharma VK, Singh TG, Singh S, Garg N, Dhiman S. Apoptotic pathways and Alzheimer’s disease: probing therapeutic potential. Neurochem Res. 2021;46(12):3103–22. https://doi.org/10.1007/s11064-021-03418-7.

    Article  CAS  PubMed  Google Scholar 

  176. Fan D, Liu C, Guo Z, Huang K, Peng M, Li N, et al. Resveratrol promotes angiogenesis in a FoxO1-dependent manner in hind limb ischemia in mice. Molecules. 2021;26(24):7528. https://doi.org/10.3390/molecules26247528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Guo S, Mangal R, Dandu C, Geng X, Ding Y. Role of forkhead box protein O1 (FoxO1) in stroke: a literature review. Aging Dis. 2022;13(2):521. https://doi.org/10.14336/AD.2021.0826.

    Article  PubMed  PubMed Central  Google Scholar 

  178. Ren X, Ustiyan V, Pradhan A, Cai Y, Havrilak JA, Bolte CS, et al. FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells. Circ Res. 2014;115(8):709–20. https://doi.org/10.1161/CIRCRESAHA.115.304382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Kappel BA, Stöhr R, De Angelis L, Mavilio M, Menghini R, Federici M. Posttranslational modulation of FoxO1 contributes to cardiac remodeling in post-ischemic heart failure. Atherosclerosis. 2016;249:148–56. https://doi.org/10.1016/j.atherosclerosis.2016.04.001.

    Article  CAS  PubMed  Google Scholar 

  180. Kumamoto H, Ohki K, Ooya K. Expression of Sonic hedgehog (SHH) signaling molecules in ameloblastomas. J Oral Pathol Med. 2004;33(3):185–90. https://doi.org/10.1111/j.0904-2512.2004.00070.x.

    Article  CAS  PubMed  Google Scholar 

  181. Kanda S, Mitsuyasu T, Nakao Y, Kawano S, Goto Y, Matsubara R, et al. Anti-apoptotic role of the sonic hedgehog signaling pathway in the proliferation of ameloblastoma. Int J Oncol. 2013;43(3):695–702. https://doi.org/10.3892/ijo.2013.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Delloye-Bourgeois C, Gibert B, Rama N, Delcros JG, Gadot N, Scoazec JY, et al. Sonic Hedgehog promotes tumor cell survival by inhibiting CDON pro-apoptotic activity. PLoS Biol. 2013;11(8):e1001623. https://doi.org/10.1371/journal.pbio.1001623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Hardwick JM, Soane L. Multiple functions of BCL-2 family proteins. Cold Spring Harb Perspect Biol. 2013;5(2):a008722. https://doi.org/10.1101/cshperspect.a008722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Brocheriou V, Hagège AA, Oubenaïssa A, Lambert M, Mallet VO, Duriez M, et al. Cardiac functional improvement by a human Bcl-2 transgene in a mouse model of ischemia/reperfusion injury. J Gene Med. 2000;2(5):326–33. https://doi.org/10.1002/1521-2254(200009/10)2:5%3c326::AID-JGM133%3e3.0.CO;2-1.

    Article  CAS  PubMed  Google Scholar 

  185. Wu C, Fujihara H, Yao J, Qi S, Li H, Shimoji K, et al. Different expression patterns of Bcl-2, Bcl-xl, and Bax proteins after sublethal forebrain ischemia in C57Black/Crj6 mouse striatum. Stroke. 2003;34(7):1803–8. https://doi.org/10.1161/01.STR.0000077255.15597.69.

    Article  CAS  PubMed  Google Scholar 

  186. Bigelow RL, Chari NS, Undén AB, Spurgers KB, Lee S, Roop DR, et al. Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1. J Biol Chem. 2004;279(2):1197–205. https://doi.org/10.1074/jbc.M310589200.

    Article  CAS  PubMed  Google Scholar 

  187. Li SJ, Mei QH, Zeng SY, Lai LL, Quan J, Zhang X. Protective effect of sonic hedgehog signaling pathway activation on acute myocardial infarction. J Biol Regul Homeost Agents. 2020;34(2):367–78. https://doi.org/10.23812/19-451-A-64.

    Article  CAS  PubMed  Google Scholar 

  188. Lv T, Shen L, Yang L, Diao W, Yang Z, Zhang Y, et al. Polydatin ameliorates dextran sulfate sodium-induced colitis by decreasing oxidative stress and apoptosis partially via Sonic hedgehog signaling pathway. Int Immunopharmacol. 2018;64:256–63. https://doi.org/10.1016/j.intimp.2018.09.009.

    Article  CAS  PubMed  Google Scholar 

  189. Zhang RY, Qiao ZY, Liu HJ, Ma JW. Sonic hedgehog signaling regulates hypoxia/reoxygenation-induced H9C2 myocardial cell apoptosis. Exp Ther Med. 2018;16(5):4193–200. https://doi.org/10.3892/etm.2018.6678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Chen KY, Chiu CH, Wang LC. Anti-apoptotic effects of Sonic hedgehog signalling through oxidative stress reduction in astrocytes co-cultured with excretory-secretory products of larval Angiostrongylus cantonensis. Sci Rep. 2017. https://doi.org/10.1038/srep41574.

    Article  PubMed  PubMed Central  Google Scholar 

  191. Ghasemi H, Pegah A, Tayebinia H, Khazaei S, Feizi F, Mazaheri S, et al. The overexpression of Sonic Hedgehog associates with collateral development and amelioration of oxidative stress in stroke patients. J Stroke Cerebrovasc Dis. 2022;31(5):106408. https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106408.

    Article  PubMed  Google Scholar 

  192. Dai R, Xia Y, Mao L, Mei Y, Xue Y, Hu B. Involvement of PI3K/Akt pathway in the neuroprotective effect of Sonic hedgehog on cortical neurons under oxidative stress. J Huazhong Univ Sci Technol Med Sci J. 2012;32:856–60. https://doi.org/10.1007/s11596-012-1047-x.

    Article  CAS  Google Scholar 

  193. Yamazaki Y, Arita K, Harada S, Tokuyama S. Activation of c-Jun N-terminal kinase and p38 after cerebral ischemia upregulates cerebral sodium-glucose transporter type 1. J Pharmacol Sci. 2018;138(4):240–6. https://doi.org/10.1016/j.jphs.2017.02.016.

    Article  CAS  PubMed  Google Scholar 

  194. Jeong CW, Yoo KY, Lee SH, Jeong HJ, Lee CS, Kim SJ. Curcumin protects against regional myocardial ischemia/reperfusion injury through activation of RISK/GSK-3β and inhibition of p38 MAPK and JNK. J Cardiovasc Pharmacol Ther. 2012;17(4):387–94. https://doi.org/10.1177/1074248412438102.

    Article  CAS  PubMed  Google Scholar 

  195. Bijlsma MF, Groot AP, Oduro JP, Franken RJ, Schoenmakers SH, Peppelenbosch MP, et al. Hypoxia induces a hedgehog response mediated by HIF-1α. J Cell Mol Med. 2009;13(8b):2053–60. https://doi.org/10.1111/j.1582-4934.2008.00491.x.

    Article  PubMed  Google Scholar 

  196. Giarretta I, Gaetani E, Bigossi M, Tondi P, Asahara T, Pola R. The Hedgehog signaling pathway in ischemic tissues. Int J Mol Sci. 2019;20(21):5270. https://doi.org/10.3390/ijms20215270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Mackie AR, Klyachko E, Thorne T, Schultz KM, Millay M, Ito A, et al. Sonic hedgehog–modified human CD34+ cells preserve cardiac function after acute myocardial infarction. Circ Res. 2012;111(3):312–21. https://doi.org/10.1161/CIRCRESAHA.112.266015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Zhang Q, Wang L, Wang S, Cheng H, Xu L, Pei G, et al. Signaling pathways and targeted therapy for myocardial infarction. Signal Transduct Target Ther. 2022;7(1):78. https://doi.org/10.1038/s41392-022-00925-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Ge G, Zhang H, Li R, Liu H. The function of SDF-1-CXCR4 axis in SP cells-mediated protective role for renal ischemia/reperfusion injury by SHH/GLI1-ABCG2 pathway. Shock. 2017;47(2):251–9. https://doi.org/10.1097/SHK.0000000000000694.

    Article  CAS  PubMed  Google Scholar 

  200. Gupta R, Mackie AR, Misener S, Liu L, Losordo DW, Kishore R. Endothelial smoothened-dependent hedgehog signaling is not required for sonic hedgehog induced angiogenesis or ischemic tissue repair. Lab Invest. 2018;98(5):682–91. https://doi.org/10.1038/s41374-018-0028-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Benameur T, Soleti R, Porro C, Andriantsitohaina R, Martínez MC. Microparticles carrying Sonic hedgehog favor neovascularization through the activation of nitric oxide pathway in mice. PLoS One. 2010;5(9):e12688. https://doi.org/10.1371/journal.pone.0012688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Cao W, Zhang C, Chen R, Wu Q, Xu R, Zhang L, et al. A novel cerebroprotein hydrolysate, CH1, ameliorates chronic focal cerebral ischemia injury by promoting white matter integrity via the Shh/Ptch-1/Gli-1 signaling pathway. Neuropsychiatr Dis Treat. 2020;16:3209–24. https://doi.org/10.2147/NDT.S289990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Pratap A, Panakanti R, Yang N, Lakshmi R, Modanlou KA, Eason JD, et al. Cyclopamine attenuates acute warm ischemia reperfusion injury in cholestatic rat liver: hope for marginal livers. Mol Pharm. 2011;8(3):958–68. https://doi.org/10.1021/mp200115v.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are grateful to the Chitkara College of Pharmacy, Chitkara University, Punjab, India for providing the necessary facilities to carry out the research work.

Funding

The authors received no financial support for this study.

Author information

Author notes

  1. Maneesh Mohan and Ashi Mannan contributed equally as the first authors of this work.

Authors and Affiliations

  1. Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India

    Maneesh Mohan, Ashi Mannan & Thakur Gurjeet Singh

Authors
  1. Maneesh Mohan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ashi Mannan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thakur Gurjeet Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: TGS. Wrote the manuscript: MM and AM. Editing of the Manuscript: AM and TGS. Critically reviewed the article: TGS. Supervision: TGS. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Thakur Gurjeet Singh.

Ethics declarations

Conflict of interest

There are no conflicts of interest.

Ethical approval and consent to participate

Not applicable.

Consent to participate

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mohan, M., Mannan, A. & Singh, T.G. Therapeutic implication of Sonic Hedgehog as a potential modulator in ischemic injury. Pharmacol. Rep 75, 838–860 (2023). https://doi.org/10.1007/s43440-023-00505-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43440-023-00505-0

Keywords

Search

Navigation