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Herbal molecules in eye diseases
Taiwan Journal of Ophthalmology xxx (2014) 1e7
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Review article
Herbal molecules in eye diseases Kai-On Chu a, b, Chi-Pui Pang a, * a b
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 February 2014 Received in revised form 18 March 2014 Accepted 21 March 2014 Available online xxx
The eyes are exposed to oxidative stress due to light absorption and the high metabolism rate of their tissue cells. Oxidative stress plays an important role in the pathogenesis of many major eye diseases, including ocular inflammation, neovascularization, age-related macular degeneration, glaucoma, and cataracts. Herbal molecules, such as lutein, zeaxanthin, omega-3 fatty acids, vitamin C, and vitamin E, have been tried as ocular aliments. Although there are many positive outcomes for preventive or even therapeutic uses for ocular diseases, the efficacy remains controversial. Nevertheless, traditional Chinese medicine remains the best choice of herbal molecules mining for ocular remedies. Copyright Ó 2014, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: antioxidants Chinese Medicine diseases herbal molecules ocular
1. Introduction Many herbal remedies have been applied for eye ailments for a long time, as recorded in different ancient and modern Chinese Pharmacopoeia. They can be used for treatment of night blindness, cataract, floaters, and glaucoma. The efficacy of these remedies is based on experiences and discrete clinical outcomes, without strictly passing through modern systematic scientific assessments including animal testing and clinical trials. Furthermore, the efficacies have also been reputed as having a large variation due to nonstandardized sources, qualities, combinations, and preparation methods of herbal remedies. Nevertheless, these long-documented historical remedies are a goldmine for natural products discovery. In order to overcome the problems of variations, defined herbal extracts and herbal molecules provide a better option for future development. The eye is a high metabolism organ and suffers from consistent photooxidation by light. The tissue cells of the eye are susceptible to oxidative damage.1 Although there are many pathological factors associated with ocular diseases such as age, genetic predisposition, oxidation stress, inflammation, tumorigenesis, angiogenesis, ischemia, and diabetes, oxidative stress seems to play a key role in the pathogenesis of ocular diseases.1e3 * Corresponding author. Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, 4/F, Hong Kong Eye Hospital, 147K, Argyle Street, Kowloon, Hong Kong. E-mail address: [email protected] (C.P. Pang).
Several risk factors have been attributed to age-related macular diseases (AMD) such as aging,4 cigarette smoking,5 sunlight exposure, high fat, low antioxidant intake,6 and genetic variants (e.g., polymorphism of complement factor H).7 All these risk factors are correlated with oxidative stress resulting in retinal tissue damage, including damage to photoreceptor cells, retinal pigment epithelium, and choroidal capillaries. Glaucoma causes progressive, irreversible loss of retinal ganglion cells, damage of the optic nerve, and loss of vision with and without increased intraocular pressure. Oxidative stress causes cytotoxic effects, retinal ganglion cell death,8 and trabecular meshwork damage which leads to obstruction of aqueous humor outflow, resulting in intraocular pressure elevation.9 Cataract is caused by opacity of the lens as a result of long-term light exposure. This photooxidation decomposes biological components of the lens,10 mainly crystallin. Oxidized thiol groups of crystalline molecules form disulfide bonds, which subsequently lead to crystalline aggregation and cataract formation.11 Diabetes causes oxidative stress increase to induce capillary cells and retinal microvasculature damages. Glyceraldehyde-3phosphate dehydrogenase impairment in diabetes also causes improper activation of major biochemical pathways, leading to the pathogenesis of diabetic retinopathy.12,13 Graves’ ophthalmopathy (GO) is characterized by protrusion of the eye ball, partly caused by hyperthyroidism. It affects 25e50% Graves’ patients. About 5% GO patients have a potential sight threatening disease.14 Many evidences indicate oxidative stress involvement in the pathogenesis of GO.15e17 Overproduction of
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thyroid hormones accelerates the basic metabolic rates and cellular oxidative metabolism in mitochondria resulting in reactive oxygen species (ROS) overproduction. This oxidative environment can subsequently stimulate retroocular fibroblasts cell proliferation18 leading to eye protrusion. The mechanism was supported by some findings that a higher 8-hydroxy-20 -deoxyguanoin (8-OHdG) level was found in urine of active GO patients (CAS > 3) and higher levels of 8-OHdG, malondialdehyde (MDA), superoxide anions, and hydrogen peroxides in GO orbital fibroblasts.3 Because oxidative stress plays an important role in the pathogenesis of these common eye diseases, many studies showed that herbal remedies possess various antioxidants which has potential use for eye protection. Many studies have investigated if the therapeutic or preventive effects of herbal molecules in cells, animal models, and clinical trials are related to antioxidation effects.19,20 2. Lutein and zeaxanthin Lutein and zeaxanthin belong to the xanthophyll family of carotenoids commonly found in tomatoes, Chinese wolfberry fruit, and carrots. They are isomers with a double bond difference (Fig. 1). Lutein has three chiral centers whereas zeaxanthin has two.21 The (3R,30 S) and (3S,30 R) stereoisomers of zeaxanthin are symmetrical and identical. Therefore, zeaxanthin has only three stereoisomeric forms. The principal natural form of zeaxanthin is (3R,30 R)zeaxanthin.22 Pyridinium bisretinoid products, A2-PE and A2E, are the byproducts derived from all-trans-retinal in the visual cycle (Fig. 2).23 Photooxidation of ARPE-19 is protected by zeaxanthin, which is more potent than alpha-tocopherol. Zeaxanthin can be potentiated by combining with alpha-tocopherol.24 In this case, zeaxanthin acts as a photo filter, absorbing photons so as to inhibit ROS and 5a-tocopherol-OOH generation. Ascorbic acid or alphatocopherol acts as antioxidant to regenerate zeaxanthin. The number of apoptotic rods and cones inversely correlated significantly with zeaxanthin and lutein concentration in the retina in a light-damaged quail eye, demonstrating that retinal zeaxanthin protects photoreceptors from light-induced damage.25,26 Zeaxanthin supplementation inhibited lipid peroxide, protecting DNA, electron transport complex III, nitrotyrosine, and mitochondrial superoxide dismutase from damage in diabetic rats.27 It also prevented vascular endothelial growth factor and intercellular adhesion molecule-1 expression from increasing in retinas of diabetic
patients.27 Lutein also protects retina from diabetes-induced oxidative stressed.28 Choroidal neovascularization in mice was significantly suppressed following 3 days of oral lutein pretreatment, in comparison with vehicle, in a laser-induced choroidal neovascularization animal model. Macrophage infiltration into the choroidal neovascular membrane, inflammation-related molecules expression including vascular endothelial growth factor, monocyte chemotactic protein-1, intercellular adhesion molecule-1, and IkB-a degradation, and NF-kB p65 translocation were suppressed.29 Lutein and zeaxanthin consumption was also found to be associated with a lower risk of AMD30 in the Age Related Eye Diseases Study. Dietary lutein or zeaxanthin can reduce the risk of agerelated macular degeneration, geographic atrophy, and large or extensive intermediate drusen, with odds ratios ¼ 0.65, 0.45, and 0.73, respectively.31 However, they were found to be positively associated with AMD progress (odds ratio ¼ 2.65, 95% confidence interval ¼ 1.13e6.22)32 in a prospective study with 7 years follow up. Therefore, the clinical effects of lutein or zeaxanthin in agerelated macular degeneration are controversial. 3. Omega-3 fatty acids Omega-3 fatty acids are long-chain polyunsaturated fatty acids that have a common final carbon-carbon double bond between the last third and fourth carbon of the fatty acid chain (Fig. 3). They are essential fatty acids, which mean essential for health maintenance. However, they must be obtained from diet, because the body cannot synthesize them. Common sources from plants include algal oil, flaxseed oil, and sea buckhorn seed.33 Docosahexaenoic acid (DHA), all-cis-docosa-4,7,10,13,16,19-hexaenoic acid [22:6(n-3)], has 22 carbons with six conjugated double bonds. Eicosapentaenoic acid (EPA), (5z, 8z, 11z, 14z, 17z)-eicosa-5,8,11,14,17-pentenoic acid [20:5 (n-3)], has 20 carbons and five conjugated double bonds. These omega-3 fatty acids are extensively studied in ocular health maintenance. DHA is the major fatty acid constituted in the outer segment disc membrane of retinal photoreceptors. The biophysical and biochemical properties of DHA can affect the integrity and function of the membrane through altering the permeability, fluidity, thickness, lipid phase properties, and activation of membrane-bound proteins, which subsequently affect the phototransduction and vision.34 Omega-3 fatty acids also act as antioxidants. Their polyunsaturated conjugated bonds provide a sink to absorb electrons
Fig. 1. Structure of (A) lutein; (B) zeaxanthin.
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Fig. 2. Visual cycle and A2E formation. A2E is formed from all-trans-retinal when it reacts with phosphatidylethanolamine in the visual cycle in the photoreceptor outer segments. Precursor A2-PE is formed. After a multi-step biological process, A2E is released following phosphate hydrolysis [23].
from reactive species. They remove electrons from free radicals through formation of peroxides, to protect cell membranes and other macromolecules from attack. It has been reported that omega-3 fatty acids prevented free radical-induced hemolysis,35 abnormal in vitro low-density lipoprotein oxidation,36 excessive superoxide anion generation,37,38 and oxidative stress within platelets.39 In addition, DHA also reduced caspase-3 expression and genomic DNA fragmentation in serum-starved PC-12 and Neuro-2A cells, thereby inhibiting the apoptosis of neuronal cells.40 DHA inhibited photoreceptor cell apoptosis, prolonged its survival in vitro,41 and promoted differentiation of developing photoreceptors.42 DHA treatment reduced Bax and increased bcl-2 expression, protected mitochondrial membrane structure, and preserved photoreceptors from apoptosis when the rat photoreceptors were exposed to paraquat in vitro.43 Several epidemiology studies examined the relationship between omega-3 fatty acids or fish intake with prevalence of agerelated macular degeneration. A systematic review with 88,974 people showed the amount of omega-3 fatty acids or fish consumption largely associated with decreased risk of age-related macular degeneration.6 Increased omega-3 fatty acids consumption correlated with decreased occurrence of late age-related macular degeneration development, with an odds ratio of 0.62 and 95% confidence interval 0.48e0.82. Consumption of fish more than twice a week was also associated with a decreased risk of occurrence of both early age-related macular degeneration (odds ratio ¼ 0.76) and late age-related macular degeneration (odds ratio ¼ 0.67).6 However, no randomized, control trials were reported and further investigation is needed to confirm the results. Another controlled clinical study demonstrated that omega-3 fatty acids have a beneficial on diabetic retinopathy.44 However, the study was limited by a small sample size. Also, no outcome of the progress of diabetic maculopathy has been mentioned.
O
HO
O
H O
-
.H
+
+
α 9
3
6
9 12
15
Fig. 3. Structure of omega-3 fatty acid.
1 CH3
18
ω
O
HO H
H
O
OH
O OH
Fig. 4. Oxidation of ascorbic acid.
4. Vitamin C and E Vitamin C (L-ascorbic acid) is a six-carbon lactone that is synthesized from glucose in the livers of most mammalian species, but not in humans and some primates who lack an enzyme, gulonolactone oxidase, which is essential for the synthesis of vitamin C.45 It is commonly available in citric fruits. Vitamin E is a family of alpha-, beta-, gamma-, and delta-tocopherols corresponding to four tocotrienols. Of these, alpha-tocopherol is the most extensively studied vitamin E, because it has the highest bioavailability and is the only form of vitamin E required by humans.46 It is found in wheat germ oil, sunflowers, and safflower oil. Ascorbic acid donates two electrons from a double bond between the second and the third carbon, to prevent the other compound from oxidation (Fig. 4).42 Vitamin E (Fig. 5) can protect cell membranes from lipid peroxidation by scavenging ROS and quenching the chain oxidation reaction.47 Owing to its low solubility, vitamin E is located in the interface between the cell membrane and the extracellular matrix space, facilitating membrane
OH H3C
CH3
H3C
O HO 1
HO
HO
O
H3C
CH3
H3C
H3C
CH3
CH3 CH3
Fig. 5. Structure of a-tocopherol.
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.
GS GSSG LOO
α−Toc-OH
LH
α−Toc-O
.
LOOH
NaDPH + H+
.
Vitamin C
Vitamin C GSH
NaSP+
Fig. 6. Mechanism of a-tocopherol quenching chain lipid peroxidation and regeneration.
protection. Vitamin C and vitamin E may form a recycling circuit. The oxidized form of vitamin E, i.e., tocotrienoxyl or tocopheroxyl radical can be regenerated to the reduced native state, tocotrienol and tocopherol, through oxidation of vitamin C and glutathione (Fig. 6).48,49 The National Health and Nutrition Examination Survey II study reported the amount of ascorbic acid consumption and its serum levels were inversely associated with the number of cataract cases.46,50 Supporting51,52 and conflicting results53e55 were also reported. Similarly, conflicting results were also found in vitamin E. A lower prevalence of cataracts was found in individuals with high vitamin E intake compared to controls,56,57 but no association was reported.51,58 Linxian studies found that individuals with multivitamins or mineral supplementation had a significant reduction of nuclear cataract prevalence by 43% compared to controls.59 In addition, the REACT Study showed that antioxidants given (vitamin C 750 mg; vitamin E 600 IU, and beta-carotene, 18 mg) daily for 3 years have a small but significant positive effect.60 However, the VECAT Study found that a supplement of 500 mg vitamin E daily over 4 years showed no clinically significant effect on the number of incidences and progression of nuclear or cortical cataracts.61 The AREDS Trial randomly gave 4629 participants oral antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg) or placebo daily; after an average of 6.3 years follow up, no statistically significant effect was found on the development or progression of age-related lens opacities (odds ratio ¼ 0.97, p ¼ 0.55).62 Therefore, the antioxidative effects of vitamins on cataracts remain to be further investigated. The association of age-related macular degeneration and antioxidative vitamins was also investigated. A higher dosage of oral vitamin C supplement, or a higher plasma level of vitamin C was associated with a lower incidence of AMD, but the results are not significant,63,64 or even without protection.65 Although serum levels of vitamin E in age-related macular degeneration patients were lower than those in age-matched controls,60,66 no protective effect of vitamin E supplementation was found.60,67 None of the vitamin C or E supplements showed prevention of early onset of age-related macular degeneration in three randomized, controlled trials.68
The Age-Related Eye Disease Study investigated antioxidant (beta-carotene, vitamin C, vitamin E, and zinc) supplement effects on the progression of advanced age-related maculopathy, showing an odds ratio of 0.68 with 99% confidence intervals of 0.49e0.93. People taking supplements were less likely to lose 15 or more letters of visual acuity.69 Based on this evidence, antioxidants may protect age-related macular degeneration from progression but not onset.
Fig. 7. Structure of isoliquiritigenin.
Fig. 8. Structure of epigallocatechin gallate.
5. Herbal molecules in our study Four herbal chemicals, isoliquiritigenin (ISL) (Fig. 7) from licorice, epigallocatechin gallate (EGCG) (Fig. 8) from green tea, resveratrol (Fig. 9) from grapes, and gambogic acid (Fig. 10) from the resin of Garcinia hanburyi, were screened on human umbilical vein endothelial cells to assess their effects on cell growth and migration. ISL, EGCG, and resveratrol at sub-cytotoxic levels (10, 50, and 10 mM, respectively), suppressed vascular endothelial growth factor-induced endothelial cells proliferation and migration, whereas gambogic acid showed toxicity even at nanomolar levels.70 The inhibition on endothelial cell migration by ISL and EGCG are even higher than that by bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor. Western blot analysis showed that these chemicals affected local adhesion kinase activation and pigment epithelial growth factor expression. Therefore, ISL, EGCG, and resveratrol could be potential candidates to treat ocular diseases with neovascularization, such as exudative age-related macular degeneration and proliferative diabetic retinopathy.70 ISL was further investigated for its anti-angiogenesis effect, because it appears as the most potent compound amongst them. It suppressed 100 ng/mL VEGF-induced neovascularization at 10 mM in an ex ovo chick chorioallantoic membrane (CAM) assay. It also suppressed silver nitrate-induced corneal neovascularization with
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the expression of stress-related genes, alpha B-crystallin, and heat shock proteins 70 and 90 alpha. Furthermore, pathological changes associated with dexamethasone were found to be smaller in Ginkgo biloba extract-treated or primed trabecular meshwork cells.74 Ginkgo biloba extract may be another choice for glaucoma treatment. 6. Nicotinamide Fig. 9. Structure of resveratrol.
5 mM topical application. Western blot showed that it suppressed VEGF, but upregulated PEDF expression at 10 mM in cell culture.71 Catechins, the active constituents of green tea, are reputed for their antioxidative, anti-inflammatory, and anti-angiogenic activities. We investigated the pharmacokinetics and in vivo effect on oxidation status of catechins in rat eyes after oral administration. Gallocatechin was dominant in the retina, and epigallocatechin was dominant in aqueous humor. Significant reductions in 8-epi-isoprostane levels were found in different tissue compartments, but not the choroid-sclera or plasma, indicating that catechins exerted antioxidative activities in these tissues and suggesting that these compounds could be used as potential drugs for oxidative ocular diseases associated with oxidative stress.72 In addition, many other studies showed that catechins can protect nerves in retina following ischemia/reperfusion insult.73 Catechins are nontoxic compounds, even for the fetus, although EGCG showed weak embryotoxicity. Therefore, they can be safely applied at high doses for long-term use. We also showed that catechins and green tea extract can suppress sodium iodate-induced oxidative retinal degeneration. Through direct free radical neutralization, anti-oxidative enzymes, glutathione peroxidase and superoxide dismutase, and apoptosis molecule, caspase 3, induction by the stress was prevented. Histology and fundus photography demonstrated that the retinal damage was protected after green tea extract administration 21 days after the oxidative insult. Green tea extract also protected endotoxin-induced ocular inflammation. The inflammation markers, monocyte chemoattractant protein-1, protein, tumor necrosis factor-alpha (TNF-a), and interleukin-6 concentration in the aqueous humor were significantly suppressed. Histology showed that immune cells infiltration in the anterior chamber is greatly reduced. The clinical features of inflammation in the anterior chamber were suppressed after green tea extract administration. We found that topical application of 5 mg Ginkgo biloba extract on corneas four times daily suppressed dexamethasone-induced intraocular pressure elevation and reduced the accumulation of extracellular materials within the cribriform layers of the trabecular meshwork associated with dexamethasone. In cultured human trabecular meshwork cells, Ginkgo biloba extract substantially reduced anti-Fas ligand-induced apoptosis and reduced dexamethasone-induced myocilin expression. It also modulated
OH
O H
CH3 H3C H3C
O H3C H3C
O
O H H3C
O
O CH3
Fig. 10. Structure of gambogic acid.
OH CH3
Nicotinamide is commonly found in red rice. Allopurinol and nicotinamide were given at a dose of 300 mg daily for 3 months, as oral antioxidants, for GO treatment. Eighty-two percent of GO patients showed improvement with these antioxidants compared to 27% of GO patients given placebo.62 This is supported by Hiromatsu, who showed that nicotinamide could inhibit orbital fibroblasts activation induced by interferon-g or TNF-a, because it could remove ROS that induced glycosaminoglycans accumulation by retroocular fibroblasts.75 7. Perspectives Following the improvement of our understanding on the pathogenesis of ocular diseases, we conclude that oxidative stress plays an important role in these diseases. However, the therapeutic effects of antioxidation of herbal molecules remain controversial. In fact, herbal molecules can interact with regulatory molecules in many pathways to modulate various biological effects.76 They also modulate gene expressions through epigenetic alteration, by direct molecular interaction, or change of redox status.77 Complicated pharmacodynamics and pharmacokinetics interactions of herbal molecules in conjunction with non-standardized herbal preparations and medical practice cause a large variation in therapeutic results. Recently, an exhaustive herbalome project has launched.78 It tries to isolate, identify, and characterize herbal preparations into defined mixtures or even molecules. Dehydrocorybulbine is an example molecule being isolated and identified as a novel analgesic from Corydalis yanhusuo under this project.79 With such huge project investment on herbal molecule mining, the therapeutic use of herbal molecules on ocular treatment could become realistic in the near future. Conflicts of interest All authors declare no conflicts of interest. References 1. Williams DL. Oxidative stress and the eye. Vet Clin North Am Small Anim Pract. 2008;38:179e192. vii. 2. Tsai CC, Cheng CY, Liu CY, Kao SC, Kau HC, Hsu WM, et al. Oxidative stress in patients with Graves’ ophthalmopathy: relationship between oxidative DNA damage and clinical evolution. Eye (Lond). 2009;23:1725e1730. 3. Tsai CC, Wu SB, Cheng CY, Kao SC, Kau HC, Chiou SH, et al. Increased oxidative DNA damage, lipid peroxidation, and reactive oxygen species in cultured orbital fibroblasts from patients with Graves’ ophthalmopathy: evidence that oxidative stress has a role in this disorder. Eye (Lond). 2010;24:1520e1525. 4. Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE, et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology. 2001;108:697e704. 5. Cong R, Zhou B, Sun Q, Gu H, Tang N, Wang B. Smoking and the risk of agerelated macular degeneration: a meta-analysis. Ann Epidemiol. 2008;18: 647e656. 6. Chong EW, Kreis AJ, Wong TY, Simpson JA, Guymer RH. Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis. Arch Ophthalmol. 2008;126: 826e833. 7. Thakkinstian A, Han P, McEvoy M, Smith W, Hoh J, Magnusson K, et al. Systematic review and meta-analysis of the association between complement factor H Y402H polymorphisms and age-related macular degeneration. Hum Mol Genet. 2006;15:2784e2790.
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Moderate intake of n-3 fatty acids is associated with stable erythrocyte resistance to oxidative stress in hypertriglyceridemic subjects. Am J Clin Nutr. 2001;74:449e456. 36. Wander RC, Du SH, Thomas DR. Influence of long-chain polyunsaturated fatty acids on oxidation of low density lipoprotein. Prostaglandins Leukot Essent Fatty Acids. 1998;59:143e151. 37. Chen LY, Lawson DL, Mehta JL. Reduction in human neutrophil superoxide anion generation by n-3 polyunsaturated fatty acids: role of cyclooxygenase products and endothelium-derived relaxing factor. Thromb Res. 1994;76: 317e322.
38. Luostarinen R, Saldeen T. Dietary fish oil decreases superoxide generation by human neutrophils: relation to cyclooxygenase pathway and lysosomal enzyme release. Prostaglandins Leukot Essent Fatty Acids. 1996;55:167e172. 39. Vericel E, Polette A, Bacot S, Calzada C, Lagarde M. Pro- and antioxidant activities of docosahexaenoic acid on human blood platelets. J Thromb Haemost. 2003;1:566e572. 40. Kim HY, Akbar M, Kim KY. Inhibition of neuronal apoptosis by polyunsaturated fatty acids. J Mol Neurosci. 2001;16:223e227. discussion 279e284. 41. Rotstein NP, Aveldano MI, Barrantes FJ, Politi LE. Docosahexaenoic acid is required for the survival of rat retinal photoreceptors in vitro. J Neurochem. 1996;66:1851e1859. 42. Rotstein NP, Politi LE, Aveldano MI. Docosahexaenoic acid promotes differentiation of developing photoreceptors in culture. Invest Ophthalmol Vis Sci. 1998;39:2750e2758. 43. Rotstein NP, Politi LE, German OL, Girotti R. Protective effect of docosahexaenoic acid on oxidative stress-induced apoptosis of retina photoreceptors. Invest Ophthalmol Vis Sci. 2003;44:2252e2259. 44. Sorokin EL, Smoliakova GP, Bachaldin IL. Clinical efficacy of eiconol in patients with diabetic retinopathy. Vestn Oftalmol. 1997;113:37e39. 45. Padayatty SJ, Katz A, Wang Y, Eck P, Kwon O, Lee JH. Vitamin C as an antioxidant: evaluation of its role in disease prevention. J Am Coll Nutr. 2003;22: 18e35. 46. Brigelius-Flohe R, Traber MG. Vitamin E: function and metabolism. FASEB J. 1999;13:1145e1155. 47. Traber MG, Atkinson J. Vitamin E, antioxidant and nothing more. Free Radic Biol Med. 2007;43:4e15. 48. Tsuchiya M, Asada A, Kasahara E, Sato EF, Shindo M, Inoue M. Antioxidant protection of propofol and its recycling in erythrocyte membranes. Am J Respir Crit Care Med. 2002;165:54e60. 49. Engin KN. Alpha-tocopherol: looking beyond an antioxidant. Mol Vis. 2009;15: 855e860. 50. Simon JA, Hudes ES. Serum ascorbic acid and other correlates of self-reported cataract among older Americans. J Clin Epidemiol. 1999;52:1207e1211. 51. Valero MP, Fletcher AE, De Stavola BL, Vioque J, Alepuz VC. Vitamin C is associated with reduced risk of cataract in a Mediterranean population. J Nutr. 2002;132:1299e1306. 52. Jacques PF, Chylack Jr LT, Hankinson SE, Khu PM, Rogers G, Friend J. Long-term nutrient intake and early age-related nuclear lens opacities. Arch Ophthalmol. 2001;119:1009e1019. 53. Foster PJ, Wong TY, Machin D, Johnson GJ, Seah SK. Risk factors for age-related cortical, nuclear, and posterior subcapsular cataracts. The Italian-American Cataract Study Group. Am J Epidemiol. 1991;133:541e553. 54. Vitale S, West S, Hallfrisch J, Alston C, Wang F, Moorman C. Plasma antioxidants and risk of cortical and nuclear cataract. Epidemiology. 1993;4:195e203. 55. Hankinson SE, Stampfer MJ, Seddon JM, Colditz GA, Rosner B, Speizer FE. Nutrient intake and cataract extraction in women: a prospective study. BMJ. 1992;305:335e339. 56. Leske MC, Wu SY, Hyman L, Sperduto R, Underwood B, Chylack LT. Biochemical factors in the lens opacities. Case-control study. The Lens Opacities CaseControl Study Group. Arch Ophthalmol. 1995;113:1113e1119. 57. Robertson JM, Donner AP, Trevithick JR. Vitamin E intake and risk of cataracts in humans. Ann N Y Acad Sci. 1989;570:372e382. 58. Chasan-Taber L, Willett WC, Seddon JM, Stampfer MJ, Rosner B, Colditz GA. A prospective study of vitamin supplement intake and cataract extraction among U.S. women. Epidemiology. 1999;10:679e684. 59. Sperduto RD, Hu TS, Milton RC, Zhao JL, Everett DF, Cheng QF. The Linxian cataract studies. Two nutrition intervention trials. Arch Ophthalmol. 1993;111: 1246e1253. 60. Chylack Jr LT, Brown NP, Bron A, Hurst M, Kopcke W, Thien U. The Roche European American Cataract Trial (REACT): a randomized clinical trial to investigate the efficacy of an oral antioxidant micronutrient mixture to slow progression of age-related cataract. Ophthalmic Epidemiol. 2002;9:49e80. 61. Garrett SK, McNeil JJ, Silagy C, Sinclair M, Thomas AP, Robman LP. Methodology of the VECAT study: vitamin E intervention in cataract and age-related maculopathy. Ophthalmic Epidemiol. 1999;6:195e208. 62. Age-Related Eye Disease Study Research Group. A randomized, placebocontrolled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001;119:1439e1452. 63. VandenLangenberg GM, Mares-Perlman JA, Klein R, Klein BE, Brady WE, Palta M. Associations between antioxidant and zinc intake and the 5-year incidence of early age-related maculopathy in the Beaver Dam Eye Study. Am J Epidemiol. 1998;148:204e214. 64. West S, Vitale S, Hallfrisch J, Munoz B, Muller D, Bressler S, et al. Are antioxidants or supplements protective for age-related macular degeneration? Arch Ophthalmol. 1994;112:222e227. 65. Smith W, Mitchell P, Webb K, Leeder SR. Dietary antioxidants and age-related maculopathy: the Blue Mountains Eye Study. Ophthalmology. 1999;106: 761e767. 66. Belda JI, Roma J, Vilela C, Puertas FJ, Diaz-Llopis M, Bosch-Morell F. Serum vitamin E levels negatively correlate with severity of age-related macular degeneration. Mech Ageing Dev. 1999;107:159e164. 67. Antioxidant status and neovascular age-related macular degeneration. Eye Disease Case-Control Study Group. Arch Ophthalmol. 1993;111:104e109.
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K.-O. Chu, C.-P. Pang / Taiwan Journal of Ophthalmology xxx (2014) 1e7 68. Evans JR, Henshaw K. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Syst Rev. 2008. CD000253. 69. Age-Related Eye Disease Study Research Group. A randomized, placebocontrolled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417e1436. 70. Cao L, Liu H, Lam DS, Yam GH, Pang CP. In vitro screening for angiostatic potential of herbal chemicals. Invest Ophthalmol Vis Sci. 2010;51:6658e6664. 71. Jhanji V, Liu H, Law K, Lee VY, Huang SF, Pang CP, et al. Isoliquiritigenin from licorice root suppressed neovascularisation in experimental ocular angiogenesis models. Br J Ophthalmol. 2011;95:1309e1315. 72. Chu KO, Chan KP, Wang CC, Chu CY, Li WY, Choy KW. Green tea catechins and their oxidative protection in the rat eye. J Agric Food Chem. 2010;58:1523e1534. 73. Zhang B, Safa R, Rusciano D, Osborne NN. Epigallocatechin gallate, an active ingredient from green tea, attenuates damaging influences to the retina caused by ischemia/reperfusion. Brain Res. 2007;1159:40e53.
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74. Jia LY, Sun L, Fan DS, Lam DS, Pang CP, Yam GH. Effect of topical Ginkgo biloba extract on steroid-induced changes in the trabecular meshwork and intraocular pressure. Arch Ophthalmol. 2008;126:1700e1706. 75. Hiromatsu Y, Yang D, Miyake I, Koga M, Kameo J, Sato M, et al. Nicotinamide decreases cytokine-induced activation of orbital fibroblasts from patients with thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 1998;83:121e 124. 76. Sutherland BA, Rahman RM, Appleton I. Mechanisms of action of green tea catechins, with a focus on ischemia-induced neurodegeneration. J Nutr Biochem. 2006;17:291e306. 77. Malireddy S, Kotha SR, Secor JD, Gurney TO, Abbott JL, Maulik G. Phytochemical antioxidants modulate mammalian cellular epigenome: implications in health and disease. Antioxid Redox Signal. 2012;17:327e339. 78. Zhang X, Liu Y, Guo Z, Feng J, Dong J, Fu Q. The herbalomeean attempt to globalize Chinese herbal medicine. Anal Bioanal Chem. 2012;402:573e581. 79. Zhang Y, Wang C, Wang L, Parks GS, Zhang X, Guo Z. A novel analgesic isolated from a traditional Chinese medicine. Curr Biol. 2014;24:117e123.
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Review article
Herbal molecules in eye diseases Kai-On Chu a, b, Chi-Pui Pang a, * a b
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 February 2014 Received in revised form 18 March 2014 Accepted 21 March 2014 Available online xxx
The eyes are exposed to oxidative stress due to light absorption and the high metabolism rate of their tissue cells. Oxidative stress plays an important role in the pathogenesis of many major eye diseases, including ocular inflammation, neovascularization, age-related macular degeneration, glaucoma, and cataracts. Herbal molecules, such as lutein, zeaxanthin, omega-3 fatty acids, vitamin C, and vitamin E, have been tried as ocular aliments. Although there are many positive outcomes for preventive or even therapeutic uses for ocular diseases, the efficacy remains controversial. Nevertheless, traditional Chinese medicine remains the best choice of herbal molecules mining for ocular remedies. Copyright Ó 2014, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: antioxidants Chinese Medicine diseases herbal molecules ocular
1. Introduction Many herbal remedies have been applied for eye ailments for a long time, as recorded in different ancient and modern Chinese Pharmacopoeia. They can be used for treatment of night blindness, cataract, floaters, and glaucoma. The efficacy of these remedies is based on experiences and discrete clinical outcomes, without strictly passing through modern systematic scientific assessments including animal testing and clinical trials. Furthermore, the efficacies have also been reputed as having a large variation due to nonstandardized sources, qualities, combinations, and preparation methods of herbal remedies. Nevertheless, these long-documented historical remedies are a goldmine for natural products discovery. In order to overcome the problems of variations, defined herbal extracts and herbal molecules provide a better option for future development. The eye is a high metabolism organ and suffers from consistent photooxidation by light. The tissue cells of the eye are susceptible to oxidative damage.1 Although there are many pathological factors associated with ocular diseases such as age, genetic predisposition, oxidation stress, inflammation, tumorigenesis, angiogenesis, ischemia, and diabetes, oxidative stress seems to play a key role in the pathogenesis of ocular diseases.1e3 * Corresponding author. Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, 4/F, Hong Kong Eye Hospital, 147K, Argyle Street, Kowloon, Hong Kong. E-mail address: [email protected] (C.P. Pang).
Several risk factors have been attributed to age-related macular diseases (AMD) such as aging,4 cigarette smoking,5 sunlight exposure, high fat, low antioxidant intake,6 and genetic variants (e.g., polymorphism of complement factor H).7 All these risk factors are correlated with oxidative stress resulting in retinal tissue damage, including damage to photoreceptor cells, retinal pigment epithelium, and choroidal capillaries. Glaucoma causes progressive, irreversible loss of retinal ganglion cells, damage of the optic nerve, and loss of vision with and without increased intraocular pressure. Oxidative stress causes cytotoxic effects, retinal ganglion cell death,8 and trabecular meshwork damage which leads to obstruction of aqueous humor outflow, resulting in intraocular pressure elevation.9 Cataract is caused by opacity of the lens as a result of long-term light exposure. This photooxidation decomposes biological components of the lens,10 mainly crystallin. Oxidized thiol groups of crystalline molecules form disulfide bonds, which subsequently lead to crystalline aggregation and cataract formation.11 Diabetes causes oxidative stress increase to induce capillary cells and retinal microvasculature damages. Glyceraldehyde-3phosphate dehydrogenase impairment in diabetes also causes improper activation of major biochemical pathways, leading to the pathogenesis of diabetic retinopathy.12,13 Graves’ ophthalmopathy (GO) is characterized by protrusion of the eye ball, partly caused by hyperthyroidism. It affects 25e50% Graves’ patients. About 5% GO patients have a potential sight threatening disease.14 Many evidences indicate oxidative stress involvement in the pathogenesis of GO.15e17 Overproduction of
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thyroid hormones accelerates the basic metabolic rates and cellular oxidative metabolism in mitochondria resulting in reactive oxygen species (ROS) overproduction. This oxidative environment can subsequently stimulate retroocular fibroblasts cell proliferation18 leading to eye protrusion. The mechanism was supported by some findings that a higher 8-hydroxy-20 -deoxyguanoin (8-OHdG) level was found in urine of active GO patients (CAS > 3) and higher levels of 8-OHdG, malondialdehyde (MDA), superoxide anions, and hydrogen peroxides in GO orbital fibroblasts.3 Because oxidative stress plays an important role in the pathogenesis of these common eye diseases, many studies showed that herbal remedies possess various antioxidants which has potential use for eye protection. Many studies have investigated if the therapeutic or preventive effects of herbal molecules in cells, animal models, and clinical trials are related to antioxidation effects.19,20 2. Lutein and zeaxanthin Lutein and zeaxanthin belong to the xanthophyll family of carotenoids commonly found in tomatoes, Chinese wolfberry fruit, and carrots. They are isomers with a double bond difference (Fig. 1). Lutein has three chiral centers whereas zeaxanthin has two.21 The (3R,30 S) and (3S,30 R) stereoisomers of zeaxanthin are symmetrical and identical. Therefore, zeaxanthin has only three stereoisomeric forms. The principal natural form of zeaxanthin is (3R,30 R)zeaxanthin.22 Pyridinium bisretinoid products, A2-PE and A2E, are the byproducts derived from all-trans-retinal in the visual cycle (Fig. 2).23 Photooxidation of ARPE-19 is protected by zeaxanthin, which is more potent than alpha-tocopherol. Zeaxanthin can be potentiated by combining with alpha-tocopherol.24 In this case, zeaxanthin acts as a photo filter, absorbing photons so as to inhibit ROS and 5a-tocopherol-OOH generation. Ascorbic acid or alphatocopherol acts as antioxidant to regenerate zeaxanthin. The number of apoptotic rods and cones inversely correlated significantly with zeaxanthin and lutein concentration in the retina in a light-damaged quail eye, demonstrating that retinal zeaxanthin protects photoreceptors from light-induced damage.25,26 Zeaxanthin supplementation inhibited lipid peroxide, protecting DNA, electron transport complex III, nitrotyrosine, and mitochondrial superoxide dismutase from damage in diabetic rats.27 It also prevented vascular endothelial growth factor and intercellular adhesion molecule-1 expression from increasing in retinas of diabetic
patients.27 Lutein also protects retina from diabetes-induced oxidative stressed.28 Choroidal neovascularization in mice was significantly suppressed following 3 days of oral lutein pretreatment, in comparison with vehicle, in a laser-induced choroidal neovascularization animal model. Macrophage infiltration into the choroidal neovascular membrane, inflammation-related molecules expression including vascular endothelial growth factor, monocyte chemotactic protein-1, intercellular adhesion molecule-1, and IkB-a degradation, and NF-kB p65 translocation were suppressed.29 Lutein and zeaxanthin consumption was also found to be associated with a lower risk of AMD30 in the Age Related Eye Diseases Study. Dietary lutein or zeaxanthin can reduce the risk of agerelated macular degeneration, geographic atrophy, and large or extensive intermediate drusen, with odds ratios ¼ 0.65, 0.45, and 0.73, respectively.31 However, they were found to be positively associated with AMD progress (odds ratio ¼ 2.65, 95% confidence interval ¼ 1.13e6.22)32 in a prospective study with 7 years follow up. Therefore, the clinical effects of lutein or zeaxanthin in agerelated macular degeneration are controversial. 3. Omega-3 fatty acids Omega-3 fatty acids are long-chain polyunsaturated fatty acids that have a common final carbon-carbon double bond between the last third and fourth carbon of the fatty acid chain (Fig. 3). They are essential fatty acids, which mean essential for health maintenance. However, they must be obtained from diet, because the body cannot synthesize them. Common sources from plants include algal oil, flaxseed oil, and sea buckhorn seed.33 Docosahexaenoic acid (DHA), all-cis-docosa-4,7,10,13,16,19-hexaenoic acid [22:6(n-3)], has 22 carbons with six conjugated double bonds. Eicosapentaenoic acid (EPA), (5z, 8z, 11z, 14z, 17z)-eicosa-5,8,11,14,17-pentenoic acid [20:5 (n-3)], has 20 carbons and five conjugated double bonds. These omega-3 fatty acids are extensively studied in ocular health maintenance. DHA is the major fatty acid constituted in the outer segment disc membrane of retinal photoreceptors. The biophysical and biochemical properties of DHA can affect the integrity and function of the membrane through altering the permeability, fluidity, thickness, lipid phase properties, and activation of membrane-bound proteins, which subsequently affect the phototransduction and vision.34 Omega-3 fatty acids also act as antioxidants. Their polyunsaturated conjugated bonds provide a sink to absorb electrons
Fig. 1. Structure of (A) lutein; (B) zeaxanthin.
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Fig. 2. Visual cycle and A2E formation. A2E is formed from all-trans-retinal when it reacts with phosphatidylethanolamine in the visual cycle in the photoreceptor outer segments. Precursor A2-PE is formed. After a multi-step biological process, A2E is released following phosphate hydrolysis [23].
from reactive species. They remove electrons from free radicals through formation of peroxides, to protect cell membranes and other macromolecules from attack. It has been reported that omega-3 fatty acids prevented free radical-induced hemolysis,35 abnormal in vitro low-density lipoprotein oxidation,36 excessive superoxide anion generation,37,38 and oxidative stress within platelets.39 In addition, DHA also reduced caspase-3 expression and genomic DNA fragmentation in serum-starved PC-12 and Neuro-2A cells, thereby inhibiting the apoptosis of neuronal cells.40 DHA inhibited photoreceptor cell apoptosis, prolonged its survival in vitro,41 and promoted differentiation of developing photoreceptors.42 DHA treatment reduced Bax and increased bcl-2 expression, protected mitochondrial membrane structure, and preserved photoreceptors from apoptosis when the rat photoreceptors were exposed to paraquat in vitro.43 Several epidemiology studies examined the relationship between omega-3 fatty acids or fish intake with prevalence of agerelated macular degeneration. A systematic review with 88,974 people showed the amount of omega-3 fatty acids or fish consumption largely associated with decreased risk of age-related macular degeneration.6 Increased omega-3 fatty acids consumption correlated with decreased occurrence of late age-related macular degeneration development, with an odds ratio of 0.62 and 95% confidence interval 0.48e0.82. Consumption of fish more than twice a week was also associated with a decreased risk of occurrence of both early age-related macular degeneration (odds ratio ¼ 0.76) and late age-related macular degeneration (odds ratio ¼ 0.67).6 However, no randomized, control trials were reported and further investigation is needed to confirm the results. Another controlled clinical study demonstrated that omega-3 fatty acids have a beneficial on diabetic retinopathy.44 However, the study was limited by a small sample size. Also, no outcome of the progress of diabetic maculopathy has been mentioned.
O
HO
O
H O
-
.H
+
+
α 9
3
6
9 12
15
Fig. 3. Structure of omega-3 fatty acid.
1 CH3
18
ω
O
HO H
H
O
OH
O OH
Fig. 4. Oxidation of ascorbic acid.
4. Vitamin C and E Vitamin C (L-ascorbic acid) is a six-carbon lactone that is synthesized from glucose in the livers of most mammalian species, but not in humans and some primates who lack an enzyme, gulonolactone oxidase, which is essential for the synthesis of vitamin C.45 It is commonly available in citric fruits. Vitamin E is a family of alpha-, beta-, gamma-, and delta-tocopherols corresponding to four tocotrienols. Of these, alpha-tocopherol is the most extensively studied vitamin E, because it has the highest bioavailability and is the only form of vitamin E required by humans.46 It is found in wheat germ oil, sunflowers, and safflower oil. Ascorbic acid donates two electrons from a double bond between the second and the third carbon, to prevent the other compound from oxidation (Fig. 4).42 Vitamin E (Fig. 5) can protect cell membranes from lipid peroxidation by scavenging ROS and quenching the chain oxidation reaction.47 Owing to its low solubility, vitamin E is located in the interface between the cell membrane and the extracellular matrix space, facilitating membrane
OH H3C
CH3
H3C
O HO 1
HO
HO
O
H3C
CH3
H3C
H3C
CH3
CH3 CH3
Fig. 5. Structure of a-tocopherol.
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.
GS GSSG LOO
α−Toc-OH
LH
α−Toc-O
.
LOOH
NaDPH + H+
.
Vitamin C
Vitamin C GSH
NaSP+
Fig. 6. Mechanism of a-tocopherol quenching chain lipid peroxidation and regeneration.
protection. Vitamin C and vitamin E may form a recycling circuit. The oxidized form of vitamin E, i.e., tocotrienoxyl or tocopheroxyl radical can be regenerated to the reduced native state, tocotrienol and tocopherol, through oxidation of vitamin C and glutathione (Fig. 6).48,49 The National Health and Nutrition Examination Survey II study reported the amount of ascorbic acid consumption and its serum levels were inversely associated with the number of cataract cases.46,50 Supporting51,52 and conflicting results53e55 were also reported. Similarly, conflicting results were also found in vitamin E. A lower prevalence of cataracts was found in individuals with high vitamin E intake compared to controls,56,57 but no association was reported.51,58 Linxian studies found that individuals with multivitamins or mineral supplementation had a significant reduction of nuclear cataract prevalence by 43% compared to controls.59 In addition, the REACT Study showed that antioxidants given (vitamin C 750 mg; vitamin E 600 IU, and beta-carotene, 18 mg) daily for 3 years have a small but significant positive effect.60 However, the VECAT Study found that a supplement of 500 mg vitamin E daily over 4 years showed no clinically significant effect on the number of incidences and progression of nuclear or cortical cataracts.61 The AREDS Trial randomly gave 4629 participants oral antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg) or placebo daily; after an average of 6.3 years follow up, no statistically significant effect was found on the development or progression of age-related lens opacities (odds ratio ¼ 0.97, p ¼ 0.55).62 Therefore, the antioxidative effects of vitamins on cataracts remain to be further investigated. The association of age-related macular degeneration and antioxidative vitamins was also investigated. A higher dosage of oral vitamin C supplement, or a higher plasma level of vitamin C was associated with a lower incidence of AMD, but the results are not significant,63,64 or even without protection.65 Although serum levels of vitamin E in age-related macular degeneration patients were lower than those in age-matched controls,60,66 no protective effect of vitamin E supplementation was found.60,67 None of the vitamin C or E supplements showed prevention of early onset of age-related macular degeneration in three randomized, controlled trials.68
The Age-Related Eye Disease Study investigated antioxidant (beta-carotene, vitamin C, vitamin E, and zinc) supplement effects on the progression of advanced age-related maculopathy, showing an odds ratio of 0.68 with 99% confidence intervals of 0.49e0.93. People taking supplements were less likely to lose 15 or more letters of visual acuity.69 Based on this evidence, antioxidants may protect age-related macular degeneration from progression but not onset.
Fig. 7. Structure of isoliquiritigenin.
Fig. 8. Structure of epigallocatechin gallate.
5. Herbal molecules in our study Four herbal chemicals, isoliquiritigenin (ISL) (Fig. 7) from licorice, epigallocatechin gallate (EGCG) (Fig. 8) from green tea, resveratrol (Fig. 9) from grapes, and gambogic acid (Fig. 10) from the resin of Garcinia hanburyi, were screened on human umbilical vein endothelial cells to assess their effects on cell growth and migration. ISL, EGCG, and resveratrol at sub-cytotoxic levels (10, 50, and 10 mM, respectively), suppressed vascular endothelial growth factor-induced endothelial cells proliferation and migration, whereas gambogic acid showed toxicity even at nanomolar levels.70 The inhibition on endothelial cell migration by ISL and EGCG are even higher than that by bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor. Western blot analysis showed that these chemicals affected local adhesion kinase activation and pigment epithelial growth factor expression. Therefore, ISL, EGCG, and resveratrol could be potential candidates to treat ocular diseases with neovascularization, such as exudative age-related macular degeneration and proliferative diabetic retinopathy.70 ISL was further investigated for its anti-angiogenesis effect, because it appears as the most potent compound amongst them. It suppressed 100 ng/mL VEGF-induced neovascularization at 10 mM in an ex ovo chick chorioallantoic membrane (CAM) assay. It also suppressed silver nitrate-induced corneal neovascularization with
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the expression of stress-related genes, alpha B-crystallin, and heat shock proteins 70 and 90 alpha. Furthermore, pathological changes associated with dexamethasone were found to be smaller in Ginkgo biloba extract-treated or primed trabecular meshwork cells.74 Ginkgo biloba extract may be another choice for glaucoma treatment. 6. Nicotinamide Fig. 9. Structure of resveratrol.
5 mM topical application. Western blot showed that it suppressed VEGF, but upregulated PEDF expression at 10 mM in cell culture.71 Catechins, the active constituents of green tea, are reputed for their antioxidative, anti-inflammatory, and anti-angiogenic activities. We investigated the pharmacokinetics and in vivo effect on oxidation status of catechins in rat eyes after oral administration. Gallocatechin was dominant in the retina, and epigallocatechin was dominant in aqueous humor. Significant reductions in 8-epi-isoprostane levels were found in different tissue compartments, but not the choroid-sclera or plasma, indicating that catechins exerted antioxidative activities in these tissues and suggesting that these compounds could be used as potential drugs for oxidative ocular diseases associated with oxidative stress.72 In addition, many other studies showed that catechins can protect nerves in retina following ischemia/reperfusion insult.73 Catechins are nontoxic compounds, even for the fetus, although EGCG showed weak embryotoxicity. Therefore, they can be safely applied at high doses for long-term use. We also showed that catechins and green tea extract can suppress sodium iodate-induced oxidative retinal degeneration. Through direct free radical neutralization, anti-oxidative enzymes, glutathione peroxidase and superoxide dismutase, and apoptosis molecule, caspase 3, induction by the stress was prevented. Histology and fundus photography demonstrated that the retinal damage was protected after green tea extract administration 21 days after the oxidative insult. Green tea extract also protected endotoxin-induced ocular inflammation. The inflammation markers, monocyte chemoattractant protein-1, protein, tumor necrosis factor-alpha (TNF-a), and interleukin-6 concentration in the aqueous humor were significantly suppressed. Histology showed that immune cells infiltration in the anterior chamber is greatly reduced. The clinical features of inflammation in the anterior chamber were suppressed after green tea extract administration. We found that topical application of 5 mg Ginkgo biloba extract on corneas four times daily suppressed dexamethasone-induced intraocular pressure elevation and reduced the accumulation of extracellular materials within the cribriform layers of the trabecular meshwork associated with dexamethasone. In cultured human trabecular meshwork cells, Ginkgo biloba extract substantially reduced anti-Fas ligand-induced apoptosis and reduced dexamethasone-induced myocilin expression. It also modulated
OH
O H
CH3 H3C H3C
O H3C H3C
O
O H H3C
O
O CH3
Fig. 10. Structure of gambogic acid.
OH CH3
Nicotinamide is commonly found in red rice. Allopurinol and nicotinamide were given at a dose of 300 mg daily for 3 months, as oral antioxidants, for GO treatment. Eighty-two percent of GO patients showed improvement with these antioxidants compared to 27% of GO patients given placebo.62 This is supported by Hiromatsu, who showed that nicotinamide could inhibit orbital fibroblasts activation induced by interferon-g or TNF-a, because it could remove ROS that induced glycosaminoglycans accumulation by retroocular fibroblasts.75 7. Perspectives Following the improvement of our understanding on the pathogenesis of ocular diseases, we conclude that oxidative stress plays an important role in these diseases. However, the therapeutic effects of antioxidation of herbal molecules remain controversial. In fact, herbal molecules can interact with regulatory molecules in many pathways to modulate various biological effects.76 They also modulate gene expressions through epigenetic alteration, by direct molecular interaction, or change of redox status.77 Complicated pharmacodynamics and pharmacokinetics interactions of herbal molecules in conjunction with non-standardized herbal preparations and medical practice cause a large variation in therapeutic results. Recently, an exhaustive herbalome project has launched.78 It tries to isolate, identify, and characterize herbal preparations into defined mixtures or even molecules. Dehydrocorybulbine is an example molecule being isolated and identified as a novel analgesic from Corydalis yanhusuo under this project.79 With such huge project investment on herbal molecule mining, the therapeutic use of herbal molecules on ocular treatment could become realistic in the near future. Conflicts of interest All authors declare no conflicts of interest. References 1. Williams DL. Oxidative stress and the eye. Vet Clin North Am Small Anim Pract. 2008;38:179e192. vii. 2. Tsai CC, Cheng CY, Liu CY, Kao SC, Kau HC, Hsu WM, et al. Oxidative stress in patients with Graves’ ophthalmopathy: relationship between oxidative DNA damage and clinical evolution. Eye (Lond). 2009;23:1725e1730. 3. Tsai CC, Wu SB, Cheng CY, Kao SC, Kau HC, Chiou SH, et al. Increased oxidative DNA damage, lipid peroxidation, and reactive oxygen species in cultured orbital fibroblasts from patients with Graves’ ophthalmopathy: evidence that oxidative stress has a role in this disorder. Eye (Lond). 2010;24:1520e1525. 4. Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE, et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology. 2001;108:697e704. 5. Cong R, Zhou B, Sun Q, Gu H, Tang N, Wang B. Smoking and the risk of agerelated macular degeneration: a meta-analysis. Ann Epidemiol. 2008;18: 647e656. 6. Chong EW, Kreis AJ, Wong TY, Simpson JA, Guymer RH. Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis. Arch Ophthalmol. 2008;126: 826e833. 7. Thakkinstian A, Han P, McEvoy M, Smith W, Hoh J, Magnusson K, et al. Systematic review and meta-analysis of the association between complement factor H Y402H polymorphisms and age-related macular degeneration. Hum Mol Genet. 2006;15:2784e2790.
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