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Hydroxysafflor Yellow A Confers Neuroprotection from Focal Cerebral Ischemia by Modulating the Crosstalk Between JAK2/STAT3 and SOCS3 Signaling Pathways

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Natural bioactive compounds have increasingly proved to be promising in evidence- or target-directed treatment or modification of a spectrum of diseases including cerebral ischemic stroke. Hydroxysafflor yellow A (HSYA), a major active component of the safflower plant, has drawn more interests in recent year for its multiple pharmacological actions in the treatment of cerebrovascular and cardiovascular diseases. Although the Janus kinase signaling, such as JAK2/STAT3 pathway, has been implicated in the modulation of the disease, the inhibition or activation of the pathway that contributed to the neuronal prevention from ischemic damages remains controversial. In this study, a series of experiments were performed to examine the dose- and therapeutic time window-related pharmacological efficacies of HSYA with emphasis on the HSYA-modulated interaction of JAK2/STAT3 and SOCS3 signaling in the MCAO rats. We found that HSYA treatment significantly rescued the neurological and functional deficits in a dose-dependent manner in the MCAO rats within 3 h after ischemia. HSYA treatment with a dosage of 8 mg/kg or higher markedly downregulated the expression of the JAK2-mediated signaling that was activated in response to ischemic insult, while it also promoted the expression of SOCS3 coordinately. In the subsequent experiments with the use of the JAK2 inhibitor WP1066, we found that the treatment of WP1066 alone or combination of WP1066/HSYA all exhibited inhibitory effects on JAK2-mediated signaling, while there was no influence on the SOCS3 activity of corresponding efficacious data in the MCAO rats, suggesting that excessive activation of JAK2/STAT3 might be necessary for HSYA to provoke SOCS3-negative feedback signaling. Taking together, our study demonstrates that HSYA might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways that eventually contributed to its therapeutic roles against cerebral ischemic stroke.

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  1. Bacigaluppi M, Comi G, Hermann DM (2010) Animal models of ischemic stroke part two: modeling cerebral ischemia. Open Neurol J 4:34–38

  2. Baggiolini M (1995) Guidebook to cytokines and their receptors. FEBS Lett 369:347–348

  3. Chao J, Dai Y, Verpoorte R, Lam W, Cheng YC, Pao LH, Zhang W, Chen S (2017) Major achievements of evidence-based traditional Chinese medicine in treating major diseases. Biochem Pharmacol 139:94–104

  4. Chen YC, Wu JS, Yang ST, Huang CY, Chang C, Sun GY, Lin TN (2012) Stroke, angiogenesis and phytochemicals. Front Biosci 4:599–610

  5. Chen L, Xiang Y, Kong L, Zhang X, Sun B, Wei X, Liu H (2013) Hydroxysafflor yellow A protects against cerebral ischemia–reperfusion injury by anti-apoptotic effect through pi3k/akt/gsk3β pathway in rat. Neurochem Res 38:2268–2275

  6. Chen HS, Qi SH, Shen JG (2015) One-compound-multi-target: combination prospect of natural compounds with thrombolytic therapy in acute ischemic stroke. Curr Neuropharmacol 15:134–156

  7. Christophe BR, Mehta SH, Garton ALA, Sisti J (2017) Current and future perspectives on the treatment of cerebral ischemia. Expert Opin Pharmacother 18:573–580

  8. Darnell JE, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to ifns and other extracellular signaling proteins. Science 264:1415–1421

  9. Demers G, Meurer WJ, Shih R, Rosenbaum S, Vilke GM (2012) Tissue plasminogen activator and stroke: review of the literature for the clinician. J Emerg Med 43:1149–1154

  10. D'Ippolito S, Marana R, Nicuolo FD, Castellani R, Veglia M, Stinson J, Scambia G, Simone ND (2012) Effect of low molecular weight heparins (LMWHs) on antiphospholipid antibodies (aPL)-mediated inhibition of endometrial angiogenesis. PLoS ONE 7(1):29660

  11. Dong W, Xian Y, Yuan W, Huifeng Z, Tao W, Zhiqiang L, Shan F, Ya F, Hongli W, Jinghuan W (2016) Catalpol stimulates VEGF production via the JAK2/STAT3 pathway to improve angiogenesis in rats stroke model. J Ethnopharmacol 191:169–179

  12. Feng ZM, He J, Jiang JS, Chen Z, Yang YN, Zhang PC (2013) NMR solution structure study of the representative component hydroxysafflor yellow A and other quinochalcone c-glycosides from carthamus tinctorius. J Nat Prod 76:270–274

  13. Garcia JH, Wagner S, Liu KF, Hu XJ (1995) Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Stat Valid Stroke 26:627–634

  14. Gertz K, Kronenberg G, Kälin RE, Baldinger T, Werner C, Balkaya M, Eom GD, Hellmannregen J, Kröber J, Miller KR (2012) Essential role of interleukin-6 in post-stroke angiogenesis. Brain 135:1964–1980

  15. Guo S, Li ZZ, Gong J, Xiang M, Zhang P, Zhao GN, Li M, Zheng A, Zhu X, Lei H (2015) Oncostatin m confers neuroprotection against ischemic stroke. J Neurosci 35:12047–12062

  16. Hatashita S, Hoff JT, Salamat SM (1988) Ischemic brain edema and the osmotic gradient between blood and brain. J Cereb Blood Flow Metab 8:552–559

  17. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müllernewen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1–20

  18. Jia L, Wang F, Gu X, Weng Y, Sheng M, Wang G, Li S, Du H, Yu W (2017) Propofol postconditioning attenuates hippocampus ischemia-reperfusion injury via modulating JAK2/STAT3 pathway in rats after autogenous orthotropic liver transplantation. Brain Res 1657:202–207

  19. Jiang JS, He J, Feng ZM, Zhang PC (2010) Two new quinochalcones from the florets of carthamus tinctorius. Org Lett 12:1196–1199

  20. Jin Y, Zhang XL, Shi H, Xiao YS, Ke YX, Xue XY, Zhang FF, Liang XM (2008) Characterization of C-glycosyl quinochalcones in carthamus tinctorius L. by ultraperformance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. Rapid Commun Mass Spectrom Rcm 22:1275–1287

  21. Kershaw NJ, Murphy JM, Lucet IS, Nicola NA, Babon JJ (2013) Regulation of janus kinases by SOCS proteins. Biochem Soc T 41:1042–1047

  22. Krebs DL, Hilton DJ (2000) SOCS: physiological suppressors of cytokine signaling. J Cell Sci 113(Pt 16):2813–2819

  23. Kubo M, Hanada T, Yoshimura A (2003) Suppressors of cytokine signaling and immunity. Nat Immunol 4:1169–1176

  24. Kwon O, Kim KW, Kim MS (2016) Leptin signalling pathways in hypothalamic neurons. Cell Mol Life Sci 73:1457–1477

  25. Li S, Li Y, Ying F, Jing H, Xu Y, Hao L, Yan C (2013) Capacity of HSYA to inhibit nitrotyrosine formation induced by focal ischemic brain injury. Nitric Oxide Biol Chem 35:144–151

  26. Li H, Wu J, Shen H, Yao X, Liu C, Pianta S, Han J, Borlongan CV, Chen G (2017a) Autophagy in hemorrhagic stroke: mechanisms and clinical implications. Prog Neurobiol 163–164:79–97

  27. Li Y, Zhang X, Cui L, Rong C, Ye Z, Cong Z, Zhu X, He T, Shen Z, Dong L (2017b) Salvianolic acids enhance cerebral angiogenesis and neurological recovery by activating JAK2/STAT3 signaling pathway after ischemic stroke in mice. J Neurochem 143:87–99

  28. Liu Z, Li C, Li M, Li D, Liu K (2004) The subchronic toxicity of hydroxysafflor yellow A of 90 days repeatedly intraperitoneal injections in rats. Toxicology 203:139–143

  29. Liu X, Zhang X, Zhang J, Kang N, Zhang N, Wang H, Xue J, Yu J, Yang Y, Cui H (2014) Diosmin protects against cerebral ischemia/reperfusion injury through activating JAK2/STAT3 signal pathway in mice. Neuroscience 268:318–327

  30. Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91

  31. Lv Y, Qian Y, Fu L, Chen X, Zhong H, Wei X (2015) Hydroxysafflor yellow A exerts neuroprotective effects in cerebral ischemia reperfusion-injured mice by suppressing the innate immune tlr4-inducing pathway. Eur J Pharmacol 769:324–332

  32. Mengya X, Qingna S, Yiyi W, Yan C, Nan Z (2016) Hydroxysafflor yellow A increases BDNF and NMDARs in the hippocampus in a vascular dementia rat model. Brain Res 1642:419–425

  33. O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A (2015) The JAK-STAT pathway: impact on human disease and therapeutic intervention. Ann Rev Med 66:311–328

  34. Raible DJ, Frey LC, Brooks-Kayal AR (2014) Effects of JAK2-STAT3 signaling after cerebral insults. JAK-STAT 3:e29510

  35. Redondoblanco S, Fernández J, Gutiérrezdelrío I, Villar CJ, Lombó F (2017) New insights toward colorectal cancer chemotherapy using natural bioactive compounds. Front Pharmacol 8:109

  36. Satriotomo I, Bowen KK, Vemuganti R (2006) JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia. J Neurochem 98:1353–1368

  37. Shan LQ, Ma S, Qiu XC, Zhou Y, Zhang Y, Zheng LH, Ren PC, Wang YC, Fan QY, Ma BA (2010) Hydroxysafflor yellow A protects spinal cords from ischemia/reperfusion injury in rabbits. BMC Neuroscience 11:1–8

  38. Shyu WC, Lin SZ, Chiang MF, Chen DC, Su CY, Wang HJ, Liu RS, Tsai CH, Li H (2008) Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke. J Clin Investig 118:133–148

  39. Suganami E, Takagi H, Ohashi H, Suzuma K, Suzuma I, Oh H, Watanabe D, Ojima T, Suganami T, Fujio Y (2004) Leptin stimulates ischemia-induced retinal neovascularization: possible role of vascular endothelial growth factor expressed in retinal endothelial cells. Diabetes 53:2443–2448

  40. Tamiya T, Kashiwagi I, Takahashi R, Yasukawa H, Yoshimura A (2011) Suppressors of cytokine signaling (SOCS) proteins and JAK/STAT pathways: regulation of T-cell inflammation by SOCS1 and SOCS3. Arterioscler Thromb Vasc Biol 31:980–985

  41. Tian J, Li G, Liu Z, Fu F (2008) Hydroxysafflor yellow A inhibits rat brain mitochondrial permeability transition pores by a free radical scavenging action. Pharmacology 82:121–126

  42. Villarino AV, Kanno Y, O'Shea JJ (2017) Mechanisms and consequences of JAK-STAT signaling in the immune system. Nat Immunol 18:374–384

  43. Wang G, Zhou D, Wang C, Gao Y, Zhou Q, Qian G, Decoster MA (2010) Hypoxic preconditioning suppresses group III secreted phospholipase A2-induced apoptosis via JAK2-STAT3 activation in cortical neurons. J Neurochem 114:1039–1048

  44. Wang XL, Qiao CM, Liu JO, Li CY (2017) Inhibition of the SOCS1-JAK2-STAT3 signaling pathway confers neuroprotection in rats with ischemic stroke. Cell Physiol Biochem 44:85–98

  45. Wardlaw JM, Murray V, Berge E, Del ZG, Sandercock P, Lindley RL, Cohen G (2012) Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 379:2364–2372

  46. Wei X, Liu H, Sun X, Fu F, Zhang X, Wang J, An J, Ding H (2005) Hydroxysafflor yellow A protects rat brains against ischemia-reperfusion injury by antioxidant action. Neurosci Lett 386:58–62

  47. Wunderlich CM, Hövelmeyer N, Wunderlich FT (2013) Mechanisms of chronic JAK-STAT3-SOCS3 signaling in obesity. JAK-STAT 2:e23878

  48. Zhang Z, Wu Z, Zhu X, Hui X, Pan J, Xu Y (2014) Hydroxy-safflor yellow a inhibits neuroinflammation mediated by Aβ1-42 in BV-2 cells. Neurosci Lett 562:39–44

  49. Zhu H, Zou L, Tian J, Du G, Gao Y (2013) SMND-309, a novel derivative of salvianolic acid B, protects rat brains ischemia and reperfusion injury by targeting the JAK2/STAT3 pathway. Eur J Pharmacol 714:23–31

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This work was supported in part by grants from the National Natural Science Foundation of China (81503370 to LY, 31171019 to ZZ and 81470829 to JZ), Shanghai Natural Science Foundation (19ZR1447900 to LY), and MOST China–Israel Cooperation (2016YFE0130500 to XHC), and an opening grant from Key Laboratory of Brain Functional Genomics (ECNU), Ministry of Education, ECNU (JZ).

Author information

LY, ZLL, WDH, XHC, QJZ, ZZ, and JZ conceived the project, planned the experiments, and analyzed and interpreted the data with support from HFC, ZLL, YHD, JT, and CX. LY, ZLL, WDH, HFC, ZLL, JT, and CX performed all experiments. LY, ZLL, WDH, QJZ, ZZ, and JZ prepared and reviewed the manuscript. All authors contributed to and approved the final manuscript.

Correspondence to Qiujuan Zhang or Zheng Zhao or Jun Zhang.

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All the authors declare that they have no conflict of interest.

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All procedures performed in studies involving animals were in accordance with NIH Animal Welfare Act guidance and were approved by the Institutional Animal Care and Use Committee (IACUC approval ID #M07016) of the East China Normal University.

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Yu, L., Liu, Z., He, W. et al. Hydroxysafflor Yellow A Confers Neuroprotection from Focal Cerebral Ischemia by Modulating the Crosstalk Between JAK2/STAT3 and SOCS3 Signaling Pathways. Cell Mol Neurobiol (2020). https://doi.org/10.1007/s10571-020-00812-7

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  • Hydroxysafflor yellow A
  • Cerebral ischemia
  • Negative feedback signaling
  • JAK2/STAT3 pathway
  • SOCS3