Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2017

Open Access 01-12-2017 | Research article

Xue-fu-Zhu-Yu decoction protects rats against retinal ischemia by downregulation of HIF-1α and VEGF via inhibition of RBP2 and PKM2

Authors: Shu-Qiu Tan, Xue Geng, Jorn-Hon Liu, Wynn Hwai-Tzong Pan, Li-Xiang Wang, Hui-Kang Liu, Lei Hu, Hsiao-Ming Chao

Published in: BMC Complementary Medicine and Therapies | Issue 1/2017

Login to get access

Abstract

Background

Retinal ischemia-related eye diseases result in visual dysfunction. This study investigates the protective effects and mechanisms of Xue-Fu-Zhu-Yu decoction (XFZYD) with respect to retinal ischemia.

Methods

Retinal ischemia (I) was induced in Wistar rats by a high intraocular pressure (HIOP) of 120 mmHg for 1 h, which was followed by reperfusion of the ischemic eye; the fellow untreated eye acted as a control. Electroretinogram (ERG), biochemistry and histopathology investigations were performed.

Results

Significant ischemic changes occurred after ischemia including decreased ERG b-wave ratios, less numerous retinal ganglion cells (RGCs), reduced inner retinal thickness, fewer choline acetyltransferase (ChAT) labeled amacrine cell bodies, increased glial fibrillary acidic protein (GFAP) immunoreactivity and increased vimentin Müller immunolabeling. These were accompanied by significant increases in the mRNA/protein concentrations of vascular endothelium growth factor, hypoxia-inducible factor-1α, pyruvate kinase M2 and retinoblastoma-binding protein 2. The ischemic changes were concentration-dependently and significantly altered when XFZYD was given for seven consecutive days before or after retina ischemia, compared to vehicle. These alterations included enhanced ERG b-wave amplitudes, more numerous RGCs, enhanced inner retinal thickness, a greater number of ChAT immunolabeled amacrine cell bodies and decreased GFAP/vimentin immunoreactivity. Furthermore, decreased mRNA levels of VEGF, HIF-1α, PKM2, and RBP2 were also found. Reduced protein concentrations of VEGF, HIF-1α, PKM2, and RBP2 were also demonstrated. Furthermore, there was an inhibition of the ischemia-associated increased ratios (target protein/β-actin) in the protein levels of VEGF, HIF-1α, PKM2, and RBP2, which were induced by Shikonin, JIB-04 or Avastin.

Conclusion

XFZYD would seem to protect against well-known retinal ischemic changes via a synergistic inhibition of RBP2 and PKM2, as well as down-regulation of HIF-1α and a reduction in VEGF secretion.
Appendix
Available only for authorised users
Literature
2.
go back to reference Peng PH, Chao HM, Juan SH, Chen CF, Liu JH, Ko ML. Pharmacological preconditioning by low dose cobalt protoporphyrin induces heme oxygenase-1 overexpression and alleviates retinal ischemia-reperfusion injury in rats. Curr Eye Res. 2011;36(3):238–46. doi:10.3109/02713683.2010.539760.CrossRefPubMed Peng PH, Chao HM, Juan SH, Chen CF, Liu JH, Ko ML. Pharmacological preconditioning by low dose cobalt protoporphyrin induces heme oxygenase-1 overexpression and alleviates retinal ischemia-reperfusion injury in rats. Curr Eye Res. 2011;36(3):238–46. doi:10.​3109/​02713683.​2010.​539760.CrossRefPubMed
4.
go back to reference Wurm A, Iandiev I, Uhlmann S, Wiedemann P, Reichenbach A, Bringmann A, et al. Effects of ischemia-reperfusion on physiological properties of Müller glial cells in the porcine retina. Invest Ophthalmol Vis Sci. 2011;52(6):3360–7. doi:10.1167/iovs.10-6901.CrossRefPubMed Wurm A, Iandiev I, Uhlmann S, Wiedemann P, Reichenbach A, Bringmann A, et al. Effects of ischemia-reperfusion on physiological properties of Müller glial cells in the porcine retina. Invest Ophthalmol Vis Sci. 2011;52(6):3360–7. doi:10.​1167/​iovs.​10-6901.CrossRefPubMed
5.
go back to reference Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol. 2004;122(4):598–614.CrossRefPubMed Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol. 2004;122(4):598–614.CrossRefPubMed
7.
go back to reference Liu JH, Wann H, Chen MM, Pan WH, Chen YC, Liu CM, et al. Baicalein significantly protects human retinal pigment epithelium cells against H2 O2 -induced oxidative stress by scavenging reactive oxygen species and downregulating the expression of matrix metalloproteinase-9 and vascular endothelial growth factor. J Ocul Pharmacol Ther. 2010;26(5):421–9. doi:10.1089/jop.2010.0063.CrossRefPubMed Liu JH, Wann H, Chen MM, Pan WH, Chen YC, Liu CM, et al. Baicalein significantly protects human retinal pigment epithelium cells against H2 O2 -induced oxidative stress by scavenging reactive oxygen species and downregulating the expression of matrix metalloproteinase-9 and vascular endothelial growth factor. J Ocul Pharmacol Ther. 2010;26(5):421–9. doi:10.​1089/​jop.​2010.​0063.CrossRefPubMed
8.
9.
go back to reference Li W, Liu J, Zhao Y. PKM2 inhibitor shikonin suppresses TPA-induced mitochondrial malfunction and proliferation of skin epidermal JB6 cells. Mol Carcinog. 2014 May;53(5):403–12. doi:10.1002/mc.21988.CrossRefPubMed Li W, Liu J, Zhao Y. PKM2 inhibitor shikonin suppresses TPA-induced mitochondrial malfunction and proliferation of skin epidermal JB6 cells. Mol Carcinog. 2014 May;53(5):403–12. doi:10.​1002/​mc.​21988.CrossRefPubMed
10.
go back to reference Fu C, Xia Z, Liu Y, Lu H, Zhang Z, Wang Y, et al. Qualitative analysis of major constituents from Xue fu Zhu Yu decoction using ultra high performance liquid chromatography with hybrid ion trap time-of-flight mass spectrometry. J Sep Sci. 2016;39(17):3457–68. doi:10.1002/jssc.201600083.CrossRefPubMed Fu C, Xia Z, Liu Y, Lu H, Zhang Z, Wang Y, et al. Qualitative analysis of major constituents from Xue fu Zhu Yu decoction using ultra high performance liquid chromatography with hybrid ion trap time-of-flight mass spectrometry. J Sep Sci. 2016;39(17):3457–68. doi:10.​1002/​jssc.​201600083.CrossRefPubMed
11.
go back to reference Lee JJ, Hsu WH, Yen TL, Chang NC, Luo YJ, Hsiao G, et al. Traditional Chinese medicine, Xue-fu-Zhu-Yu decoction, potentiates tissue plasminogen activator against thromboembolic stroke in rats. J Ethnopharmacol. 2011;134(3):824–30. doi:10.1016/j.jep.2011.01.033.CrossRefPubMed Lee JJ, Hsu WH, Yen TL, Chang NC, Luo YJ, Hsiao G, et al. Traditional Chinese medicine, Xue-fu-Zhu-Yu decoction, potentiates tissue plasminogen activator against thromboembolic stroke in rats. J Ethnopharmacol. 2011;134(3):824–30. doi:10.​1016/​j.​jep.​2011.​01.​033.CrossRefPubMed
14.
go back to reference Chao HM, Lin DE, Chang Y, Hsu WM, Lee SM, Lee FL, et al. Ferulic acid, but not tetramethylpyrazine, significantly attenuates retinal ischemia/reperfusion-induced alterations by acting as a hydroxyl radical scavenger. J Ocul Pharmacol Ther. 2008b;24(5):461–72. doi:10.1177/0960327108092294.CrossRefPubMed Chao HM, Lin DE, Chang Y, Hsu WM, Lee SM, Lee FL, et al. Ferulic acid, but not tetramethylpyrazine, significantly attenuates retinal ischemia/reperfusion-induced alterations by acting as a hydroxyl radical scavenger. J Ocul Pharmacol Ther. 2008b;24(5):461–72. doi:10.​1177/​0960327108092294​.CrossRefPubMed
15.
16.
17.
go back to reference Liu L, Duan JA, Tang Y, Guo J, Yang N, Ma H, et al. Taoren–Honghua herb pair and its main components promoting blood circulation through influencing on hemorheology, plasma coagulation and platelet aggregation. J Ethnopharmacol. 2012;139(2):381–7. doi:10.1016/j.jep.2011.11.016.CrossRefPubMed Liu L, Duan JA, Tang Y, Guo J, Yang N, Ma H, et al. Taoren–Honghua herb pair and its main components promoting blood circulation through influencing on hemorheology, plasma coagulation and platelet aggregation. J Ethnopharmacol. 2012;139(2):381–7. doi:10.​1016/​j.​jep.​2011.​11.​016.CrossRefPubMed
18.
20.
go back to reference Cheong CU, Yeh CS, Hsieh YW, Lee YR, Lin MY, Chen CY, et al. Protective effects of Costunolide against hydrogen peroxide-induced injury in PC12 cells. Molecules. 2016 Jul 9;21(7):898–907. doi:10.3390/molecules21070898.CrossRef Cheong CU, Yeh CS, Hsieh YW, Lee YR, Lin MY, Chen CY, et al. Protective effects of Costunolide against hydrogen peroxide-induced injury in PC12 cells. Molecules. 2016 Jul 9;21(7):898–907. doi:10.​3390/​molecules2107089​8.CrossRef
23.
go back to reference Lim JH, Kim TW, Park SJ, Song IB, Kim MS, Kwon HJ, et al. Protective effects of Platycodon grandiflorum aqueous extract on thioacetamide-induced fulminant hepatic failure in mice. J Toxicol Pathol. 2011;24(4):223–8. doi:10.1293/tox.24.223.CrossRefPubMed Lim JH, Kim TW, Park SJ, Song IB, Kim MS, Kwon HJ, et al. Protective effects of Platycodon grandiflorum aqueous extract on thioacetamide-induced fulminant hepatic failure in mice. J Toxicol Pathol. 2011;24(4):223–8. doi:10.​1293/​tox.​24.​223.CrossRefPubMed
24.
go back to reference Chen YQ, Pan WH, Liu JH, Chen MM, Liu CM, Yeh MY, et al. The effects and underlying mechanisms of S-allyl l-cysteine treatment of the retina after ischemia/reperfusion. J Ocul Pharmacol Ther. 2012;28(2):110–7. doi:10.1089/jop.2011.0099.CrossRefPubMed Chen YQ, Pan WH, Liu JH, Chen MM, Liu CM, Yeh MY, et al. The effects and underlying mechanisms of S-allyl l-cysteine treatment of the retina after ischemia/reperfusion. J Ocul Pharmacol Ther. 2012;28(2):110–7. doi:10.​1089/​jop.​2011.​0099.CrossRefPubMed
25.
28.
29.
go back to reference Nishibuchi G, Shibata Y, Hayakawa T, Hayakawa N, Ohtani Y, Sinmyozu K, et al. Physical and functional interactions between the histone H3K4 demethylase KDM5A and the nucleosome remodeling and deacetylase (NuRD) complex. J Biol Chem. 2014 Oct 17;289(42):28956–70. doi:10.1074/jbc.M114.573725.CrossRefPubMedPubMedCentral Nishibuchi G, Shibata Y, Hayakawa T, Hayakawa N, Ohtani Y, Sinmyozu K, et al. Physical and functional interactions between the histone H3K4 demethylase KDM5A and the nucleosome remodeling and deacetylase (NuRD) complex. J Biol Chem. 2014 Oct 17;289(42):28956–70. doi:10.​1074/​jbc.​M114.​573725.CrossRefPubMedPubMedCentral
30.
go back to reference Horton JR, Engstrom A, Zoeller EL, Liu X, Shanks JR, Zhang X, et al. Characterization of a linked Jumonji domain of the KDM5/JARID1 family of histone H3 lysine 4 demethylases. J Biol Chem. 2016 Feb 5;291(6):2631–46. doi:10.1074/jbc.M115.698449.CrossRefPubMed Horton JR, Engstrom A, Zoeller EL, Liu X, Shanks JR, Zhang X, et al. Characterization of a linked Jumonji domain of the KDM5/JARID1 family of histone H3 lysine 4 demethylases. J Biol Chem. 2016 Feb 5;291(6):2631–46. doi:10.​1074/​jbc.​M115.​698449.CrossRefPubMed
31.
32.
go back to reference Imamura, K., Tanaka, T. Pyruvate kinase isozymes from rat. In: Willis, AW, editor. Methods in Enzymology. Academic Press; 1982. p. 150-165. Imamura, K., Tanaka, T. Pyruvate kinase isozymes from rat. In: Willis, AW, editor. Methods in Enzymology. Academic Press; 1982. p. 150-165.
37.
go back to reference Kim SH, Park HS, Hong MJ, Yoo JY, Lee H, Lee JA, et al. Tongqiaohuoxue decoction ameliorates obesity-induced inflammation and the prothrombotic state by regulating adiponectin and plasminogen activator inhibitor-1. J Ethnopharmacol. 2016 Nov 4;192:201–9. doi:10.1016/j.jep.2016.07.023.CrossRefPubMed Kim SH, Park HS, Hong MJ, Yoo JY, Lee H, Lee JA, et al. Tongqiaohuoxue decoction ameliorates obesity-induced inflammation and the prothrombotic state by regulating adiponectin and plasminogen activator inhibitor-1. J Ethnopharmacol. 2016 Nov 4;192:201–9. doi:10.​1016/​j.​jep.​2016.​07.​023.CrossRefPubMed
39.
go back to reference Stockton RA, Slaughter MM. B-wave of the electroretinogram. A reflection of ON bipolar cell activity. J Gen Physiol. 1989;93(1):101–22. PMCID: PMC2216200 CrossRefPubMed Stockton RA, Slaughter MM. B-wave of the electroretinogram. A reflection of ON bipolar cell activity. J Gen Physiol. 1989;93(1):101–22. PMCID: PMC2216200 CrossRefPubMed
41.
go back to reference Hayreh SS, Jonas JB. Optic disk and retinal nerve fiber layer damage after transient central retinal artery occlusion: an experimental study in rhesus monkeys. Am J Ophthalmol. 2000;129:786–95. PMID: 10926989 CrossRefPubMed Hayreh SS, Jonas JB. Optic disk and retinal nerve fiber layer damage after transient central retinal artery occlusion: an experimental study in rhesus monkeys. Am J Ophthalmol. 2000;129:786–95. PMID: 10926989 CrossRefPubMed
42.
go back to reference Hayreh SS, Zimmerman MB, Kimura A, Sanon A. Central retinal artery occlusion. Retinal survival time. Exp. Eye Res. 2004;78:723–36. PMID: 15106952 CrossRef Hayreh SS, Zimmerman MB, Kimura A, Sanon A. Central retinal artery occlusion. Retinal survival time. Exp. Eye Res. 2004;78:723–36. PMID: 15106952 CrossRef
44.
go back to reference Hsu TK, Chen SJ, Lei J, Wu Z, Lin CC, Chen MM, et al. Embolus-induced branch retinal artery occlusion with a presenting best-corrected visual acuity of <6/12 and visual field defect: yag embolectomy safely restores arteriolar perfusion and/or visual function. Retin Cases Brief Rep. 2013;7(3):210–6. doi:10.1097/ICB.0b013e3182852370.CrossRefPubMed Hsu TK, Chen SJ, Lei J, Wu Z, Lin CC, Chen MM, et al. Embolus-induced branch retinal artery occlusion with a presenting best-corrected visual acuity of <6/12 and visual field defect: yag embolectomy safely restores arteriolar perfusion and/or visual function. Retin Cases Brief Rep. 2013;7(3):210–6. doi:10.​1097/​ICB.​0b013e3182852370​.CrossRefPubMed
45.
go back to reference Hernandez C, Simo R. Somatostatin replacement: a new strategy for treating diabetic retinopathy. Curr Med Chem. 2013;20(26):3251–7. PMID: 23745546 CrossRefPubMed Hernandez C, Simo R. Somatostatin replacement: a new strategy for treating diabetic retinopathy. Curr Med Chem. 2013;20(26):3251–7. PMID: 23745546 CrossRefPubMed
Metadata
Title
Xue-fu-Zhu-Yu decoction protects rats against retinal ischemia by downregulation of HIF-1α and VEGF via inhibition of RBP2 and PKM2
Authors
Shu-Qiu Tan
Xue Geng
Jorn-Hon Liu
Wynn Hwai-Tzong Pan
Li-Xiang Wang
Hui-Kang Liu
Lei Hu
Hsiao-Ming Chao
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2017
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-017-1857-2

Other articles of this Issue 1/2017

BMC Complementary Medicine and Therapies 1/2017 Go to the issue