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Endocrine, Metabolic & Immune Disorders - Drug Targets

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ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

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Research Article

Taxifolin Shows Anticataractogenesis and Attenuates Diabetic Retinopathy in STZ-Diabetic Rats via Suppression of Aldose Reductase, Oxidative Stress, and MAPK Signaling Pathway

Author(s): Fei Liu, Ying Ma and Yanli Xu*

Volume 20, Issue 4, 2020

Page: [599 - 608] Pages: 10

DOI: 10.2174/1871530319666191018122821

Price: $65

Abstract

Background: Due to the increased prevalence of diabetes-associated complications of the eye like diabetic retinopathy and cataract, the need for a novel therapeutic agent is urgent. Due to the advantages that the polyphenolic compounds enjoy in diabetes and associated complications, we postulated that Taxifolin (TXF), a poly-phenolic flavanol, could show anti-retinopathic and anti-cataract effect in diabetes-induced rats.

Methods: TXF at a dose of 10, 25, and 50 mg/kg was given by oral route to STZ mediated diabetic rats for a time period of 10 weeks. The opacity of lens was studied after every 7 days of treatment till 10 weeks; evaluation of the severity of cataract and changes in the histology of lens as well as retina was done. Tissue homogenates of lens isolated after the end of the study were evaluated for markers of oxidative stress, levels of aldose reductase, p38MAPK, VEGF, and ERK1/2.

Results: Outcomes suggested that TXF improved retinopathy and cataract in diabetes-induced rats. The treatment of TXF also improved the status of oxidative stress and inhibited the levels of p38MAPK, VEGF, and ERK1/2. The treatment also improved the lens opacity in diabetic rats. The results suggest that the protective effect of TXF against cataract and retinopathy may be due to the anti-oxidative potential of TXF and its inhibiting effect on VEGF, ERK1/2, p38MAPK, and aldose reductase.

Conclusion: The study confirms that TXF is a potential candidate showing a protective effect against diabetic induced retinopathy and cataract.

Keywords: Taxifolin, diabetes, diabetic retinopathy, cataract, p38MAPK, VEGF, ERK1/2.

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Graphical Abstract

[1]
Gürler, B.; Vural, H.; Yilmaz, N.; Oguz, H.; Satici, A.; Aksoy, N. The role of oxidative stress in diabetic retinopathy. Eye (Lond.), 2000, 14(Pt. 5), 730-735.
[http://dx.doi.org/10.1038/eye.2000.193] [PMID: 11116694]
[2]
Kowluru, R.A. Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes, 2003, 52(3), 818-823.
[http://dx.doi.org/10.2337/diabetes.52.3.818] [PMID: 12606525]
[3]
Madsen-Bouterse, S.A.; Kowluru, R.A. Oxidative stress and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Rev. Endocr. Metab. Disord., 2008, 9(4), 315-327.
[http://dx.doi.org/10.1007/s11154-008-9090-4] [PMID: 18654858]
[4]
Kowluru, R.A.; Abbas, S.N. Diabetes-induced mitochondrial dysfunction in the retina. Invest. Ophthalmol. Vis. Sci., 2003, 44(12), 5327-5334.
[http://dx.doi.org/10.1167/iovs.03-0353] [PMID: 14638734]
[5]
Klettner, A.; Roider, J. Constitutive and oxidative-stress-induced expression of VEGF in the RPE are differently regulated by different Mitogen-activated protein kinases. Graefes Arch. Clin. Exp. Ophthalmol., 2009, 247(11), 1487-1492.
[http://dx.doi.org/10.1007/s00417-009-1139-x] [PMID: 19603178]
[6]
Kowluru, R.A.; Chan, P.S. Oxidative stress and diabetic retinopathy. Exp. Diabetes Res., 2007, 2007, 1-12.
[7]
Obrosova, I.G.; Pacher, P.; Szabó, C.; Zsengeller, Z.; Hirooka, H.; Stevens, M.J.; Yorek, M.A. Aldose reductase inhibition counteracts oxidative-nitrosative stress and poly(ADP-ribose) polymerase activation in tissue sites for diabetes complications. Diabetes, 2005, 54(1), 234-242.
[http://dx.doi.org/10.2337/diabetes.54.1.234] [PMID: 15616034]
[8]
Pandita, NS; Vaidya, AS Therapeutic potential of plant phenolics for the management of diabetic retinopathy. Pharm. Crops, 2014, 5(1) M3. , 29-38.
[http://dx.doi.org/10.2174/2210290601405010029]
[9]
Thiraphatthanavong, P.; Wattanathorn, J.; Muchimapura, S. Preventive effect of Zea mays L. (purple waxy corn) on experimental diabetic cataract. BioMed Res. Int., 2014, 2014, 1-8.
[10]
Stefek, M. Natural flavonoids as potential multifunctional agents in prevention of diabetic cataract. Interdiscip. Toxicol., 2011, 4(2), 69-77.
[http://dx.doi.org/10.2478/v10102-011-0013-y] [PMID: 21753902]
[11]
Arikan, S.; Ersan, I.; Karaca, T.; Kara, S.; Gencer, B.; Karaboga, I.; Hasan Ali, T. Quercetin protects the retina by reducing apoptosis due to ischemia-reperfusion injury in a rat model. Arq. Bras. Oftalmol., 2015, 78(2), 100-104.
[http://dx.doi.org/10.5935/0004-2749.20150026] [PMID: 25945531]
[12]
Xie, X.; Feng, J.; Kang, Z.; Zhang, S.; Zhang, L.; Zhang, Y.; Li, X.; Tang, Y. Taxifolin protects RPE cells against oxidative stress-induced apoptosis. Mol. Vis., 2017, 23, 520-528.
[PMID: 28761325]
[13]
Topal, F.; Nar, M.; Gocer, H.; Kalin, P.; Kocyigit, U.M.; Gülçin, İ.; Alwasel, S.H. Antioxidant activity of taxifolin: an activity-structure relationship. J. Enzyme Inhib. Med. Chem., 2016, 31(4), 674-683.
[http://dx.doi.org/10.3109/14756366.2015.1057723] [PMID: 26147349]
[14]
Schauss, A.G.; Tselyico, S.S.; Kuznetsova, V.A.; Yegorova, I. Toxicological and genotoxicity assessment of a dihydroquercetin-rich dahurian larch tree (Larix gmelinii Rupr) extract (Lavitol). Int. J. Toxicol., 2015, 34(2), 162-181.
[http://dx.doi.org/10.1177/1091581815576975] [PMID: 25850419]
[15]
Slimestad, R.; Fossen, T.; Vågen, I.M. Onions: a source of unique dietary flavonoids. J. Agric. Food Chem., 2007, 55(25), 10067-10080.
[http://dx.doi.org/10.1021/jf0712503] [PMID: 17997520]
[16]
Oi, N.; Chen, H.; Ok Kim, M.; Lubet, R.A.; Bode, A.M.; Dong, Z. Taxifolin suppresses UV-induced skin carcinogenesis by targeting EGFR and PI3K. Cancer Prev. Res. (Phila.), 2012, 5(9), 1103-1114.
[http://dx.doi.org/10.1158/1940-6207.CAPR-11-0397] [PMID: 22805054]
[17]
Gupta, M.B.; Bhalla, T.N.; Gupta, G.P.; Mitra, C.R.; Bhargava, K.P. Anti-inflammatory activity of taxifolin. Jpn. J. Pharmacol., 1971, 21(3), 377-382.
[http://dx.doi.org/10.1254/jjp.21.377] [PMID: 4254191]
[18]
Sun, X.; Chen, R.C.; Yang, Z.H.; Sun, G.B.; Wang, M.; Ma, X.J.; Yang, L.J.; Sun, X.B. Taxifolin prevents diabetic cardiomyopathy in vivo and in vitro by inhibition of oxidative stress and cell apoptosis. Food Chem. Toxicol., 2014, 63, 221-232.
[http://dx.doi.org/10.1016/j.fct.2013.11.013] [PMID: 24269735]
[19]
Gocer, H.; Topal, F.; Topal, M.; Küçük, M.; Teke, D.; Gülçin, İ.; Alwasel, S.H.; Supuran, C.T. Acetylcholinesterase and carbonic anhydrase isoenzymes I and II inhibition profiles of taxifolin. J. Enzyme Inhib. Med. Chem., 2016, 31(3), 441-447.
[PMID: 25893707]
[20]
Zhao, M.; Chen, J.; Zhu, P.; Fujino, M.; Takahara, T.; Toyama, S.; Tomita, A.; Zhao, L.; Yang, Z.; Hei, M.; Zhong, L.; Zhuang, J.; Kimura, S.; Li, X.K. Dihydroquercetin (DHQ) ameliorated concanavalin A-induced mouse experimental fulminant hepatitis and enhanced HO-1 expression through MAPK/Nrf2 antioxidant pathway in RAW cells. Int. Immunopharmacol., 2015, 28(2), 938-944.
[http://dx.doi.org/10.1016/j.intimp.2015.04.032] [PMID: 25916679]
[21]
Guo, H.; Zhang, X.; Cui, Y.; Zhou, H.; Xu, D.; Shan, T.; Zhang, F.; Guo, Y.; Chen, Y.; Wu, D. Taxifolin protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload. Toxicol. Appl. Pharmacol., 2015, 287(2), 168-177.
[http://dx.doi.org/10.1016/j.taap.2015.06.002] [PMID: 26051872]
[22]
Dok-Go, H.; Lee, K.H.; Kim, H.J.; Lee, E.H.; Lee, J.; Song, Y.S.; Lee, Y-H.; Jin, C.; Lee, Y.S.; Cho, J. Neuroprotective effects of antioxidative flavonoids, quercetin, (+)-dihydroquercetin and quercetin 3-methyl ether, isolated from Opuntia ficus-indica var. saboten. Brain Res., 2003, 965(1-2), 130-136.
[http://dx.doi.org/10.1016/S0006-8993(02)04150-1] [PMID: 12591129]
[23]
Wang, Y.H.; Wang, W.Y.; Chang, C.C.; Liou, K.T.; Sung, Y.J.; Liao, J.F.; Chen, C.F.; Chang, S.; Hou, Y.C.; Chou, Y.C.; Shen, Y.C. Taxifolin ameliorates cerebral ischemia-reperfusion injury in rats through its anti-oxidative effect and modulation of NF-kappa B activation. J. Biomed. Sci., 2006, 13(1), 127-141.
[http://dx.doi.org/10.1007/s11373-005-9031-0] [PMID: 16283433]
[24]
Manigandan, K.; Manimaran, D.; Jayaraj, R.L.; Elangovan, N.; Dhivya, V.; Kaphle, A. Taxifolin curbs NF-κB-mediated Wnt/β-catenin signaling via up-regulating Nrf2 pathway in experimental colon carcinogenesis. Biochimie, 2015, 119, 103-112.
[http://dx.doi.org/10.1016/j.biochi.2015.10.014] [PMID: 26482805]
[25]
Xie, X.; Feng, J.; Kang, Z.; Zhang, S.; Zhang, L.; Zhang, Y.; Li, X.; Tang, Y. Taxifolin protects RPE cells against oxidative stress-induced apoptosis. Mol. Vis., 2017, 23, 520-528.
[PMID: 28761325]
[26]
Yazdi, H.B.; Hojati, V.; Shiravi, A.; Hosseinian, S.; Vaezi, G.; Hadjzadeh, M.A. Liver Dysfunction and Oxidative Stress in Streptozotocin-Induced Diabetic Rats: Protective Role of Artemisia Turanica. J. Pharmacopuncture, 2019, 22(2), 109-114.
[PMID: 31338251]
[27]
Suryanarayana, P.; Saraswat, M.; Mrudula, T.; Krishna, T.P.; Krishnaswamy, K.; Reddy, G.B. Curcumin and turmeric delay streptozotocin-induced diabetic cataract in rats. Invest. Ophthalmol. Vis. Sci., 2005, 46(6), 2092-2099.
[http://dx.doi.org/10.1167/iovs.04-1304] [PMID: 15914628]
[28]
Ohkawa, H.; Ohishi, N.; Yagi, K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem., 1979, 95(2), 351-358.
[http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID: 36810]
[29]
Sun, Y.; Oberley, L.W.; Li, Y. A simple method for clinical assay of superoxide dismutase. Clin. Chem., 1988, 34(3), 497-500.
[PMID: 3349599]
[30]
Góth, L. A simple method for determination of serum catalase activity and revision of reference range. Clin. Chim. Acta, 1991, 196(2-3), 143-151.
[http://dx.doi.org/10.1016/0009-8981(91)90067-M] [PMID: 2029780]
[31]
Rotruck, J.T.; Pope, A.L.; Ganther, H.E.; Swanson, A.B.; Hafeman, D.G.; Hoekstra, W.G. Selenium: biochemical role as a component of glutathione peroxidase. Science, 1973, 179(4073), 588-590.
[http://dx.doi.org/10.1126/science.179.4073.588] [PMID: 4686466]
[32]
Patel, M.; Mishra, S. Aldose reductase inhibitory activity and anticataract potential of some traditionally acclaimed antidiabetic medicinal plants. Orient. Pharm. Exp. Med., 2009, 9(3), 245-251.
[http://dx.doi.org/10.3742/OPEM.2009.9.3.245]
[33]
Agarwal, R.; Iezhitsa, I.; Awaludin, N.A.; Ahmad Fisol, N.F.; Bakar, N.S.; Agarwal, P.; Abdul Rahman, T.H.; Spasov, A.; Ozerov, A.; Mohamed Ahmed Salama, M.S.; Mohd Ismail, N. Effects of magnesium taurate on the onset and progression of galactose-induced experimental cataract: in vivo and in vitro evaluation. Exp. Eye Res., 2013, 110, 35-43.
[http://dx.doi.org/10.1016/j.exer.2013.02.011] [PMID: 23428743]
[34]
Pollreisz, A.; Schmidt-Erfurth, U. Diabetic cataract-pathogenesis, epidemiology and treatment. J. Ophthalmol., 2010, 2010 608751
[http://dx.doi.org/10.1155/2010/608751]
[35]
Anderson, R.E.; Rapp, L.M.; Wiegand, R.D. Lipid peroxidation and retinal degeneration. Curr. Eye Res., 1984, 3(1), 223-227.
[http://dx.doi.org/10.3109/02713688408997203] [PMID: 6606531]
[36]
Ozmen, B.; Ozmen, D.; Erkin, E.; Güner, I.; Habif, S.; Bayindir, O. Lens superoxide dismutase and catalase activities in diabetic cataract. Clin. Biochem., 2002, 35(1), 69-72.
[http://dx.doi.org/10.1016/S0009-9120(01)00284-3] [PMID: 11937081]
[37]
Halliwell, B. Free radicals, antioxidants, and human disease: curiosity, cause, or consequence? Lancet, 1994, 344(8924), 721-724.
[http://dx.doi.org/10.1016/S0140-6736(94)92211-X] [PMID: 7915779]
[38]
Mullarkey, C.J.; Edelstein, D.; Brownlee, M. Free radical generation by early glycation products: a mechanism for accelerated atherogenesis in diabetes. Biochem. Biophys. Res. Commun., 1990, 173(3), 932-939.
[http://dx.doi.org/10.1016/S0006-291X(05)80875-7] [PMID: 2176495]
[39]
Morgan, P.E.; Dean, R.T.; Davies, M.J. Inactivation of cellular enzymes by carbonyls and protein-bound glycation/glycoxidation products. Arch. Biochem. Biophys., 2002, 403(2), 259-269.
[http://dx.doi.org/10.1016/S0003-9861(02)00222-9] [PMID: 12139975]
[40]
Murphy, M.P. How mitochondria produce reactive oxygen species. Biochem. J., 2009, 417(1), 1-13.
[http://dx.doi.org/10.1042/BJ20081386] [PMID: 19061483]
[41]
Drel, V.R.; Pacher, P.; Ali, T.K.; Shin, J.; Julius, U.; El-Remessy, A.B.; Obrosova, I.G. Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis. Int. J. Mol. Med., 2008, 21(6), 667-676.
[http://dx.doi.org/10.3892/ijmm.21.6.667] [PMID: 18506358]
[42]
Chung, S.S.; Ho, E.C.; Lam, K.S.; Chung, S.K. Contribution of polyol pathway to diabetes-induced oxidative stress. J. Am. Soc. Nephrol., 2003, 14(8)(Suppl. 3), S233-S236.
[http://dx.doi.org/10.1097/01.ASN.0000077408.15865.06] [PMID: 12874437]
[43]
Obrosova, I.G.; Kador, P.F. Aldose reductase / polyol inhibitors for diabetic retinopathy. Curr. Pharm. Biotechnol., 2011, 12(3), 373-385.
[http://dx.doi.org/10.2174/138920111794480642] [PMID: 20939801]
[44]
Kinoshita, J.H.; Fukushi, S.; Kador, P.; Merola, L.O. Aldose reductase in diabetic complications of the eye. Metabolism, 1979, 28(4)(Suppl. 1), 462-469.
[http://dx.doi.org/10.1016/0026-0495(79)90057-X] [PMID: 45423]
[45]
Kinoshita, J.H.; Kador, P.; Catiles, M. Aldose reductase in diabetic cataracts. JAMA, 1981, 246(3), 257-261.
[http://dx.doi.org/10.1001/jama.1981.03320030049032] [PMID: 6787220]
[46]
Sun, W.; Oates, P.J.; Coutcher, J.B.; Gerhardinger, C.; Lorenzi, M. A selective aldose reductase inhibitor of a new structural class prevents or reverses early retinal abnormalities in experimental diabetic retinopathy. Diabetes, 2006, 55(10), 2757-2762.
[http://dx.doi.org/10.2337/db06-0138] [PMID: 17003340]
[47]
Roy, S.; Kern, T.S.; Song, B.; Stuebe, C. Mechanistic insights into pathological changes in the diabetic retina: implications for targeting diabetic retinopathy. Am. J. Pathol., 2017, 187(1), 9-19.
[http://dx.doi.org/10.1016/j.ajpath.2016.08.022] [PMID: 27846381]
[48]
Zatechka, D.S., Jr; Kador, P.F.; Garcia-Castiñeiras, S.; Lou, M.F. Diabetes can alter the signal transduction pathways in the lens of rats. Diabetes, 2003, 52(4), 1014-1022.
[http://dx.doi.org/10.2337/diabetes.52.4.1014] [PMID: 12663474]
[49]
Krysan, K.; Lou, M.F. Regulation of human thioltransferase (hTTase) gene by AP-1 transcription factor under oxidative stress. Invest. Ophthalmol. Vis. Sci., 2002, 43(6), 1876-1883.
[PMID: 12036993]
[50]
Purves, T.; Middlemas, A.; Agthong, S.; Jude, E.B.; Boulton, A.J.; Fernyhough, P.; Tomlinson, D.R. A role for mitogen-activated protein kinases in the etiology of diabetic neuropathy. FASEB J., 2001, 15(13), 2508-2514.
[http://dx.doi.org/10.1096/fj.01-0253hyp] [PMID: 11689477]
[51]
Du, Y.; Tang, J.; Li, G.; Berti-Mattera, L.; Lee, C.A.; Bartkowski, D.; Gale, D.; Monahan, J.; Niesman, M.R.; Alton, G.; Kern, T.S. Effects of p38 MAPK inhibition on early stages of diabetic retinopathy and sensory nerve function. Invest. Ophthalmol. Vis. Sci., 2010, 51(4), 2158-2164.
[http://dx.doi.org/10.1167/iovs.09-3674] [PMID: 20071676]
[52]
Gupta, N.; Mansoor, S.; Sharma, A.; Sapkal, A.; Sheth, J.; Falatoonzadeh, P.; Kuppermann, B.; Kenney, M. Diabetic retinopathy and VEGF. Open Ophthalmol. J., 2013, 7, 4-10.
[http://dx.doi.org/10.2174/1874364101307010004] [PMID: 23459241]
[53]
Stefek, M. Natural flavonoids as potential multifunctional agents in prevention of diabetic cataract. Interdiscip. Toxicol., 2011, 4(2), 69-77.
[http://dx.doi.org/10.2478/v10102-011-0013-y] [PMID: 21753902]
[54]
Ghosh, D.; Konishi, T. Anthocyanins and anthocyanin-rich extracts: role in diabetes and eye function. Asia Pac. J. Clin. Nutr., 2007, 16(2), 200-208.
[PMID: 17468073]

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