Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2015

Open Access 01-12-2015 | Research article

Inhibitory effect of Samul-tang on retinal neovascularization in oxygen-induced retinopathy

Authors: Yun Mi Lee, Chan-Sik Kim, Kyuhyung Jo, Eun Jin Sohn, Jin Sook Kim, Junghyun Kim

Published in: BMC Complementary Medicine and Therapies | Issue 1/2015

Login to get access

Abstract

Background

Retinal neovascularization is a common cause of vision loss in proliferative diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration. Samul-tang (SMT) is a widely used traditional herbal medicine in East Asia and is also known as Shimotsu-to in Japanese and Si-Wu decoction in Chinese. This study was designed to evaluate the inhibitory effect of SMT on retinal pathogenic angiogenesis in a mouse model of oxygen-induced retinopathy (OIR).

Method

The mice were exposed to a 75 % concentration of oxygen for five days, starting on postnatal day 7 (P7-P12). The mice were then exposed to room air and were intraperitoneally injected with SMT (10 mg/kg or 50 mg/kg) once per day for five days (P12-P16). On P17, we measured retinal neovascularization and evaluated both the expression of angiogenesis-related proteins and changes in the gene expression level in the mRNA.

Results

SMT reduced the area of the central retina and reduced retinal neovascularization in OIR mice. The protein array revealed that SMT reduced the level of SDF-1 protein expression. Quantitative real-time PCR revealed that the HIF-1α, SDF-1, CXCR4 and VEGF mRNA levels in the retinas of OIR mice were elevated compared with those of normal control mice. However, SMT decreased the levels of HIF-1α, SDF-1, CXCR4 and VEGF mRNA in OIR mice.

Conclusion

We are the first to elucidate that SMT inhibits the retinal pathogenic angiogenesis induced by ischemic retinopathy in OIR mice. SMT significantly inhibited retinal neovascularization by downregulating HIF-1α, SDF-1, CXCR4 and VEGF. Based on the results of our study, SMT could be a useful herbal medicine for treating ischemic retinopathy.
Literature
1.
go back to reference Campochiaro PA. Ocular neovascularization. J Mol Med (Berl). 2013;91(3):311–21.CrossRef Campochiaro PA. Ocular neovascularization. J Mol Med (Berl). 2013;91(3):311–21.CrossRef
2.
go back to reference Wang W, Li Z, Sato T, Oshima Y. Tenomodulin inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy. Int J Mol Sci. 2012;13(11):15373–86.CrossRefPubMedPubMedCentral Wang W, Li Z, Sato T, Oshima Y. Tenomodulin inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy. Int J Mol Sci. 2012;13(11):15373–86.CrossRefPubMedPubMedCentral
4.
go back to reference Gariano RF, Gardner TW. Retinal angiogenesis in development and disease. Nature. 2005;438(7070):960–6.CrossRefPubMed Gariano RF, Gardner TW. Retinal angiogenesis in development and disease. Nature. 2005;438(7070):960–6.CrossRefPubMed
5.
go back to reference Tomao F, Papa A, Rossi L, Zaccarelli E, Caruso D, Zoratto F, et al. Angiogenesis and antiangiogenic agents in cervical cancer. Onco Targets Ther. 2014;7:2237–48.CrossRefPubMedPubMedCentral Tomao F, Papa A, Rossi L, Zaccarelli E, Caruso D, Zoratto F, et al. Angiogenesis and antiangiogenic agents in cervical cancer. Onco Targets Ther. 2014;7:2237–48.CrossRefPubMedPubMedCentral
6.
go back to reference Agrawal S, Joshi M, Christoforidis JB. Vitreous inflammation associated with intravitreal anti-VEGF pharmacotherapy. Mediators Inflamm. 2013;2013:943409.CrossRefPubMedPubMedCentral Agrawal S, Joshi M, Christoforidis JB. Vitreous inflammation associated with intravitreal anti-VEGF pharmacotherapy. Mediators Inflamm. 2013;2013:943409.CrossRefPubMedPubMedCentral
7.
go back to reference Zhang SX, Ma JX. Ocular neovascularization: implication of endogenous angiogenic inhibitors and potential therapy. Prog Retin Eye Res. 2007;26(1):1–37.CrossRefPubMed Zhang SX, Ma JX. Ocular neovascularization: implication of endogenous angiogenic inhibitors and potential therapy. Prog Retin Eye Res. 2007;26(1):1–37.CrossRefPubMed
8.
9.
go back to reference Liekens S, Schols D, Hatse S. CXCL12-CXCR4 axis in angiogenesis, metastasis and stem cell mobilization. Curr Pharm Des. 2010;16(35):3903–20.CrossRefPubMed Liekens S, Schols D, Hatse S. CXCL12-CXCR4 axis in angiogenesis, metastasis and stem cell mobilization. Curr Pharm Des. 2010;16(35):3903–20.CrossRefPubMed
10.
go back to reference De La Luz SM, Yang F, Narazaki M, Salvucci O, Davis D, Yarchoan R, et al. Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity. Blood. 2004;103(7):2452–9.CrossRef De La Luz SM, Yang F, Narazaki M, Salvucci O, Davis D, Yarchoan R, et al. Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity. Blood. 2004;103(7):2452–9.CrossRef
11.
go back to reference Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107(5):1761–7.CrossRefPubMed Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107(5):1761–7.CrossRefPubMed
12.
go back to reference Cai X, Chen Z, Pan X, Xia L, Chen P, Yang Y, et al. Inhibition of angiogenesis, fibrosis and thrombosis by tetramethylpyrazine: mechanisms contributing to the SDF-1/CXCR4 axis. PLoS One. 2014;9(2), e88176.CrossRefPubMedPubMedCentral Cai X, Chen Z, Pan X, Xia L, Chen P, Yang Y, et al. Inhibition of angiogenesis, fibrosis and thrombosis by tetramethylpyrazine: mechanisms contributing to the SDF-1/CXCR4 axis. PLoS One. 2014;9(2), e88176.CrossRefPubMedPubMedCentral
13.
go back to reference Salcedo R, Wasserman K, Young HA, Grimm MC, Howard OM, Anver MR, et al. Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol. 1999;154(4):1125–35.CrossRefPubMedPubMedCentral Salcedo R, Wasserman K, Young HA, Grimm MC, Howard OM, Anver MR, et al. Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol. 1999;154(4):1125–35.CrossRefPubMedPubMedCentral
14.
go back to reference Salcedo R, Oppenheim JJ, Salcedo R, Oppenheim JJ. Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation. 2003;10(3–4):359–70.CrossRefPubMed Salcedo R, Oppenheim JJ, Salcedo R, Oppenheim JJ. Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation. 2003;10(3–4):359–70.CrossRefPubMed
15.
go back to reference Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell. 2006;124(1):175–89.CrossRefPubMed Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell. 2006;124(1):175–89.CrossRefPubMed
16.
go back to reference Zhong Yi, Fang Ji, Xian Dai, Yan Jiu. Modern Study of the Medical Formula in Traditional Chinese Medicine Beijing Academy. Press, 1997. Zhong Yi, Fang Ji, Xian Dai, Yan Jiu. Modern Study of the Medical Formula in Traditional Chinese Medicine Beijing Academy. Press, 1997.
17.
go back to reference Chang-Seob Seo HH, Da-Young J, Ho Young L, Shin H-K. Evaluation of the immune-stimulating activity of Samul-tang, a traditional Korean herbal medicine, standardized by HPLC-PDA. J Korean Or Med. 2011;32(3):25–34. Chang-Seob Seo HH, Da-Young J, Ho Young L, Shin H-K. Evaluation of the immune-stimulating activity of Samul-tang, a traditional Korean herbal medicine, standardized by HPLC-PDA. J Korean Or Med. 2011;32(3):25–34.
18.
go back to reference Kojima S, Inaba K, Kobayashi S, Kimura M. Inhibitory effects of traditional Chinese medicine Shimotsu-to and its included crude fractions on adjuvant-induced chronic inflammation of mice. Biol Pharm Bull. 1996;19(1):47–52.CrossRefPubMed Kojima S, Inaba K, Kobayashi S, Kimura M. Inhibitory effects of traditional Chinese medicine Shimotsu-to and its included crude fractions on adjuvant-induced chronic inflammation of mice. Biol Pharm Bull. 1996;19(1):47–52.CrossRefPubMed
19.
go back to reference Jin Yeul Ma YBY, Hye Kyung HA, Dae Sun H, Hyun Kyoo S. Subacute toxicity study on Samul-tang in SD rats. Korean J Or Physiol Patholog. 2008;22(1):137–41. Jin Yeul Ma YBY, Hye Kyung HA, Dae Sun H, Hyun Kyoo S. Subacute toxicity study on Samul-tang in SD rats. Korean J Or Physiol Patholog. 2008;22(1):137–41.
20.
go back to reference Lee YM, Kim J, Jo K, Shin SD, Kim CS, Sohn EJ, et al. Ethyl pyruvate inhibits retinal pathogenic neovascularization by downregulating HMGB1 expression. J Diabetes Res. 2013;2013:245271.CrossRefPubMedPubMedCentral Lee YM, Kim J, Jo K, Shin SD, Kim CS, Sohn EJ, et al. Ethyl pyruvate inhibits retinal pathogenic neovascularization by downregulating HMGB1 expression. J Diabetes Res. 2013;2013:245271.CrossRefPubMedPubMedCentral
21.
go back to reference Yoo S-R, Jeong. Single oral dose toxicity evaluation of Samul-tang, a traditional herbal formula, in Crl:CD (SD) rats. J Korean Med. 2014;35(2):28–33.CrossRef Yoo S-R, Jeong. Single oral dose toxicity evaluation of Samul-tang, a traditional herbal formula, in Crl:CD (SD) rats. J Korean Med. 2014;35(2):28–33.CrossRef
22.
go back to reference Connor KM, Krah NM, Dennison RJ, Aderman CM, Chen J, Guerin KI, et al. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat Protoc. 2009;4(11):1565–73.CrossRefPubMedPubMedCentral Connor KM, Krah NM, Dennison RJ, Aderman CM, Chen J, Guerin KI, et al. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat Protoc. 2009;4(11):1565–73.CrossRefPubMedPubMedCentral
23.
go back to reference Smith LE, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R, et al. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci. 1994;35(1):101–11.PubMed Smith LE, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R, et al. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci. 1994;35(1):101–11.PubMed
24.
go back to reference Simpson DA, Murphy GM, Bhaduri T, Gardiner TA, Archer DB, Stitt AW. Expression of the VEGF gene family during retinal vaso-obliteration and hypoxia. Biochem Biophys Res Commun. 1999;262(2):333–40.CrossRefPubMed Simpson DA, Murphy GM, Bhaduri T, Gardiner TA, Archer DB, Stitt AW. Expression of the VEGF gene family during retinal vaso-obliteration and hypoxia. Biochem Biophys Res Commun. 1999;262(2):333–40.CrossRefPubMed
25.
go back to reference Gengrinovitch S, Greenberg SM, Cohen T, Gitay-Goren H, Rockwell P, Maione TE, et al. Platelet factor-4 inhibits the mitogenic activity of VEGF121 and VEGF165 using several concurrent mechanisms. J Biol Chem. 1995;270(25):15059–65. Gengrinovitch S, Greenberg SM, Cohen T, Gitay-Goren H, Rockwell P, Maione TE, et al. Platelet factor-4 inhibits the mitogenic activity of VEGF121 and VEGF165 using several concurrent mechanisms. J Biol Chem. 1995;270(25):15059–65.
26.
go back to reference Abu El-Asrar AM, Nawaz MI, Kangave D, Siddiquei MM, Ola MS, Opdenakker G. Angiogenesis regulatory factors in the vitreous from patients with proliferative diabetic retinopathy. Acta Diabetol. 2013;50(4):545–51.CrossRefPubMed Abu El-Asrar AM, Nawaz MI, Kangave D, Siddiquei MM, Ola MS, Opdenakker G. Angiogenesis regulatory factors in the vitreous from patients with proliferative diabetic retinopathy. Acta Diabetol. 2013;50(4):545–51.CrossRefPubMed
27.
go back to reference Park SW, Kim JH, Kim KE, Jeong MH, Park H, Park B, et al. Beta-lapachone inhibits pathological retinal neovascularization in oxygen-induced retinopathy via regulation of HIF-1alpha. J Cell Mol Med. 2014;18(5):875–84.CrossRefPubMedPubMedCentral Park SW, Kim JH, Kim KE, Jeong MH, Park H, Park B, et al. Beta-lapachone inhibits pathological retinal neovascularization in oxygen-induced retinopathy via regulation of HIF-1alpha. J Cell Mol Med. 2014;18(5):875–84.CrossRefPubMedPubMedCentral
28.
go back to reference Villalvilla A, Moro M, Arruza L, Redondo S, Fernandez-Cruz A, Fernandez-Durango R. Circulating endothelial progenitor cells are reduced in rat oxygen-induced retinopathy despite a retinal SDF-1/CXCR4 and VEGF proangiogenic response. Life Sci. 2012;91(7–8):264–70.CrossRefPubMed Villalvilla A, Moro M, Arruza L, Redondo S, Fernandez-Cruz A, Fernandez-Durango R. Circulating endothelial progenitor cells are reduced in rat oxygen-induced retinopathy despite a retinal SDF-1/CXCR4 and VEGF proangiogenic response. Life Sci. 2012;91(7–8):264–70.CrossRefPubMed
29.
go back to reference Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO. Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res. 2003;22(1):1–29.CrossRefPubMed Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO. Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res. 2003;22(1):1–29.CrossRefPubMed
30.
go back to reference Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A. 1995;92(23):10457–61.CrossRefPubMedPubMedCentral Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A. 1995;92(23):10457–61.CrossRefPubMedPubMedCentral
31.
go back to reference Mohamed Al-Shabrawey ME, Julian N, Amira O, Sylvia M, Amany T. Targeting neovascularization in ischemic retinopathy: recent advances. Expert Review of Ophthalmology. 2013;8(3):267–86.CrossRefPubMedPubMedCentral Mohamed Al-Shabrawey ME, Julian N, Amira O, Sylvia M, Amany T. Targeting neovascularization in ischemic retinopathy: recent advances. Expert Review of Ophthalmology. 2013;8(3):267–86.CrossRefPubMedPubMedCentral
32.
go back to reference Yoshida T, Zhang H, Iwase T, Shen J, Semenza GL, Campochiaro PA. Digoxin inhibits retinal ischemia-induced HIF-1alpha expression and ocular neovascularization. FASEB J. 2010;24(6):1759–67.CrossRefPubMedPubMedCentral Yoshida T, Zhang H, Iwase T, Shen J, Semenza GL, Campochiaro PA. Digoxin inhibits retinal ischemia-induced HIF-1alpha expression and ocular neovascularization. FASEB J. 2010;24(6):1759–67.CrossRefPubMedPubMedCentral
33.
go back to reference Butler JM, Guthrie SM, Koc M, Afzal A, Caballero S, Brooks HL, et al. SDF-1 is both necessary and sufficient to promote proliferative retinopathy. J Clin Invest. 2005;115(1):86–93.CrossRefPubMedPubMedCentral Butler JM, Guthrie SM, Koc M, Afzal A, Caballero S, Brooks HL, et al. SDF-1 is both necessary and sufficient to promote proliferative retinopathy. J Clin Invest. 2005;115(1):86–93.CrossRefPubMedPubMedCentral
34.
go back to reference Sonmez K, Drenser KA, Capone Jr A, Trese MT. Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity. Ophthalmology. 2008;115(6):1065–70. e1061.CrossRefPubMed Sonmez K, Drenser KA, Capone Jr A, Trese MT. Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity. Ophthalmology. 2008;115(6):1065–70. e1061.CrossRefPubMed
35.
go back to reference Lima e Silva R, Shen J, Hackett SF, Kachi S, Akiyama H, Kiuchi K, et al. The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization. FASEB J. 2007;21(12):3219–30.CrossRefPubMed Lima e Silva R, Shen J, Hackett SF, Kachi S, Akiyama H, Kiuchi K, et al. The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization. FASEB J. 2007;21(12):3219–30.CrossRefPubMed
36.
go back to reference Unoki N, Murakami T, Nishijima K, Ogino K, van Rooijen N, Yoshimura N. SDF-1/CXCR4 contributes to the activation of tip cells and microglia in retinal angiogenesis. Invest Ophthalmol Vis Sci. 2010;51(7):3362–71.CrossRefPubMed Unoki N, Murakami T, Nishijima K, Ogino K, van Rooijen N, Yoshimura N. SDF-1/CXCR4 contributes to the activation of tip cells and microglia in retinal angiogenesis. Invest Ophthalmol Vis Sci. 2010;51(7):3362–71.CrossRefPubMed
37.
go back to reference Nishigaki A, Okada H, Okamoto R, Sugiyama S, Miyazaki K, Yasuda K, et al. Concentrations of stromal cell-derived factor-1 and vascular endothelial growth factor in relation to the diameter of human follicles. Fertil Steril. 2011;95(2):742–6.CrossRefPubMed Nishigaki A, Okada H, Okamoto R, Sugiyama S, Miyazaki K, Yasuda K, et al. Concentrations of stromal cell-derived factor-1 and vascular endothelial growth factor in relation to the diameter of human follicles. Fertil Steril. 2011;95(2):742–6.CrossRefPubMed
38.
go back to reference Nishigaki A, Okada H, Okamoto R, Shimoi K, Miyashiro H, Yasuda K, et al. The concentration of human follicular fluid stromal cell-derived factor-1 is correlated with luteinization in follicles. Gynecol Endocrinol. 2013;29(3):230–4.CrossRefPubMed Nishigaki A, Okada H, Okamoto R, Shimoi K, Miyashiro H, Yasuda K, et al. The concentration of human follicular fluid stromal cell-derived factor-1 is correlated with luteinization in follicles. Gynecol Endocrinol. 2013;29(3):230–4.CrossRefPubMed
39.
go back to reference Lee HJ, Lee EO, Lee JH, Lee KS, Kim KH, Kim SH, et al. In vivo anti-cancer activity of Korean Angelica gigas and its major pyranocoumarin decursin. Am J Chin Med. 2009;37(1):127–42.CrossRefPubMed Lee HJ, Lee EO, Lee JH, Lee KS, Kim KH, Kim SH, et al. In vivo anti-cancer activity of Korean Angelica gigas and its major pyranocoumarin decursin. Am J Chin Med. 2009;37(1):127–42.CrossRefPubMed
40.
go back to reference Jung MH, Lee SH, Ahn EM, Lee YM. Decursin and decursinol angelate inhibit VEGF-induced angiogenesis via suppression of the VEGFR-2-signaling pathway. Carcinogenesis. 2009;30(4):655–61. Jung MH, Lee SH, Ahn EM, Lee YM. Decursin and decursinol angelate inhibit VEGF-induced angiogenesis via suppression of the VEGFR-2-signaling pathway. Carcinogenesis. 2009;30(4):655–61.
41.
go back to reference Kwak DH, Kim JK, Kim JY, Jeong HY, Keum KS, Han SH, et al. Anti-angiogenic activities of Cnidium officinale Makino and Tabanus bovinus. J Ethnopharmacol. 2002;81(3):373–9. Kwak DH, Kim JK, Kim JY, Jeong HY, Keum KS, Han SH, et al. Anti-angiogenic activities of Cnidium officinale Makino and Tabanus bovinus. J Ethnopharmacol. 2002;81(3):373–9.
42.
go back to reference Deng H, Yan C, Xiao T, Yuan D, Xu J. Total glucosides of Paeonia lactiflora Pall inhibit vascular endothelial growth factor-induced angiogenesis. J Ethnopharmacol. 2010;127(3):781–5.CrossRefPubMed Deng H, Yan C, Xiao T, Yuan D, Xu J. Total glucosides of Paeonia lactiflora Pall inhibit vascular endothelial growth factor-induced angiogenesis. J Ethnopharmacol. 2010;127(3):781–5.CrossRefPubMed
43.
go back to reference Wang YB, Liu YF, Lu XT, Yan FF, Wang B, Bai WW, et al. Rehmannia glutinosa extract activates endothelial progenitor cells in a rat model of myocardial infarction through a SDF-1 alpha/CXCR4 cascade. PLoS One. 2013;8(1), e54303.CrossRefPubMedPubMedCentral Wang YB, Liu YF, Lu XT, Yan FF, Wang B, Bai WW, et al. Rehmannia glutinosa extract activates endothelial progenitor cells in a rat model of myocardial infarction through a SDF-1 alpha/CXCR4 cascade. PLoS One. 2013;8(1), e54303.CrossRefPubMedPubMedCentral
Metadata
Title
Inhibitory effect of Samul-tang on retinal neovascularization in oxygen-induced retinopathy
Authors
Yun Mi Lee
Chan-Sik Kim
Kyuhyung Jo
Eun Jin Sohn
Jin Sook Kim
Junghyun Kim
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2015
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-015-0800-7

Other articles of this Issue 1/2015

BMC Complementary Medicine and Therapies 1/2015 Go to the issue