- Email: [email protected]
Quercetin and Glaucoma
11 Quercetin and Glaucoma Naoya Miyamoto*, Kimitoshi Kohno† *MI YAMO TO EY E C LINIC , FUK UOK A, JAPAN † KURATE HOSPITAL, FUKUOKA, JAPAN
CHAPTER OUTLINE Introduction .................................................................................................................................. 189 Oxidative Stress ........................................................................................................................... 190 Oxidative Stress and Transcription ............................................................................................. 191 Oxidative Stress and Glaucoma .................................................................................................. 192 Oxidative Stress and TM .............................................................................................................. 193 Quercetin and Glaucoma ............................................................................................................. 194 Conclusions ................................................................................................................................... 197 Summary Points ........................................................................................................................... 197 References .................................................................................................................................... 198
List of Abbreviations H2O2 HO-1 IOP Nrf2 POAG PRDX RGC ROS TM
hydrogen peroxide heme oxygenase 1 intraocular pressure nuclear factor-like 2 (erythroid-derived 2) primary open angle glaucoma peroxiredoxin retinal ganglion cell reactive oxygen species trabecular meshwork
Introduction Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs)1 and their axons.2 Glaucoma is a leading cause of irreversible blindness and it has been predicted that 79.6 million people worldwide will suffer with glaucoma by 2020.3 Elevated intraocular pressure (IOP), caused by a reduction in aqueous outflow, is a major risk factor in the development of glaucoma4 and the progression of glaucomatous damage to the optic nerve.5 IOP elevation and visual field damage are reported to be proportional to the DNA oxidative damage found in the human trabecular meshwork.6 This finding forms the basis for the role of oxidative stress in pathogenesis of glaucoma, and provides new insight into the molecular mechanisms involved. Handbook of Nutrition, Diet, and the Eye. https://doi.org/10.1016/B978-0-12-815245-4.00011-9 © 2019 Elsevier Inc. All rights reserved.
189
190
HANDBOOK OF NUTRITION, DIET, AND THE EYE
Flavonoids such as quercetin can protect cells from oxidative stress.7, 8 Quercetin is one of the most widely distributed flavonoids.9 It has been shown that certain flavonoids can induce antioxidant responsive element-dependent gene expression through the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2).10 Most importantly, oxidative stress plays an important role in the pathogenesis of multiple ocular diseases, including glaucoma.11
Oxidative Stress Under physiological conditions, there is a state of equilibrium between the endogenous production of free radicals and their neutralization capacity (“scavenging” activity). When damage ensues, this condition is known as oxidative stress. More than 90% of the oxygen is consumed by mitochondria in aerobic organisms. Under normal physiological conditions, about 1%5% of the oxygen consumed by mitochondria is converted to reactive oxygen species (ROS), including superoxide anions, hydrogen peroxide (H2O2), and hydroxyl radicals.12 Mitochondrial respiratory function declines with age13 and this increases the production of ROS and free radicals in mitochondria. Consequently, ROS production essentially depends on mitochondrial function and on the levels of antioxidant defenses.14 Free radicals are neutralized by three major antioxidant systems in mammalian cells, superoxide dismutase/catalase, glutathione, and peroxiredoxin (PRDX) (Fig. 1).15 Oxidative stresses are neutralized by numerous molecules that are either endogenously produced, such as glutathione, or are a part of dietary consumption, such as flavonoids, vitamins C and E. This mechanism is believed to be involved in the etiopathogenesis of many degenerative diseases (Fig. 2). Both vitamin C and glutathione operate in fluids outside the cell and within the cell,16 whereas vitamin E prevents endogenous mitochondrial
FIG. 1 Scheme for intracellular generation of reactive oxygen species (ROS). O 2 is dismutated to H2O2, which can • generate OH. Cell resistance to oxidative stress and repair depends in large part on removal of H2O2 and reduction of • phospholipid hydroperoxides (there is no specific scavenger for OH). H2O2 can be removed by multiple enzymes, including catalase, GSH peroxidases, and all PRDXs.
Chapter 11 • Quercetin and Glaucoma 191
FIG. 2 Systemic and ocular diseases due to oxidative stress.
production of ROS.17 This may be important in maintaining cellular homeostasis, which is relevant to the etiology of primary open angle glaucoma (POAG).18 It have been shown that canonical wnt signaling regulates extracellular matrix expression in the trabecular meshwork and is implicated in the pathology of POAG.19, 20 It has been also reported that wnt signaling is activated by oxidative stress and plays a critical role in the growth of fibroblasts/myofibroblasts and microvascular endothelial cells involved in wound healing/ scarring by regulating the expression of collagen.21–23
Oxidative Stress and Transcription ROS, including H2O2, are toxic and potent inducers of oxidative damage, but they have been shown to also function as necessary second messengers in various signal transduction pathways. Knowledge of the molecular links between stress signaling pathways and transcription factors is essential for understanding the complexity of the genomic response. Many transcription factors are activated by oxidative stress, which induces the expression of target genes such as cellular antioxidant molecules for defense and survival (Fig. 3). The genomic response system is thought to decline during aging, suggesting that the dysfunction of antioxidant systems induces various age-related diseases. It is well known that Nrf2 is a master transcription factor involved in stress responses, including oxidative stress. Many transcription factors activated by oxidative stress have been identified, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), activating transcription factor 4 (ATF4), and nuclear respiratory factor 1 (Nrf1). Recently, Nrf2 regulatory factors and the interacting molecules have been identified.24 Mechanistic details of the total genomic response are essential to facilitate the development of glaucoma treatments.
192
HANDBOOK OF NUTRITION, DIET, AND THE EYE
FIG. 3 Hydrogen peroxide is a metabolic byproduct or common mediator for signal transduction.
Oxidative Stress and Glaucoma Elevated IOP is the most important risk factor for glaucoma. High IOP usually occurs as a result of an increase in the aqueous humor outflow resistance of the TM. The TM, which comprises endothelial-like cells, is composed of trabecular beams made of extracellular matrix (ECM) elements, including fibronectin, laminin, and collagens.25 The TM cells are critical for the maintenance of the aqueous humor outflow pathway. TM abnormalities are the most common pathogenesis of glaucoma. The pathogenic role of oxidative stress in increasing IOP is supported by various studies. The TM is the most sensitive tissue to oxidative damage in the anterior chamber.26 Oxidative stress to the TM can cause much damage, such as reduction of TM mitochondrial respiratory activity, leading to growth arrest,27 and can affect ECM structure28 such as ECM accumulation,29 including DNA damage of TM cells.30 Cell death due to oxidative stress may cause further free radical attacks and the loss of function or altered function of TM cells, leading to even more oxidative stress and beginning a vicious cycle.31 At least, ROS alter the morphology, function, and drainage of the anterior chamber filter channel that eventually leads to an increase in IOP.32 A recent study reported that patients with POAG have pathological changes in the TM, including a reduced number of human TM cells (HTMCs), an accumulation of ECM, and cytoskeletal changes.33 It has recently been demonstrated that oxidative damage to the TM may serve an important role in the development of POAG.34 It has been reported that the expression of antioxidants, including superoxide dismutase-1 (SOD1) and glutathione (GSH), is increased in TM of patients with primary open angle glaucoma (POAG).35
Chapter 11 • Quercetin and Glaucoma 193
Growing evidence supports the involvement of oxidative stress as a common component of neurodegenerative glaucoma in different subcellular compartments of RGCs.36, 37 In addition to the evidence of a direct cytotoxicity leading to RGC death, ROS may also act as a second messenger to modulate protein function, by redox modifications of downstream enzymatic oxidation of specific amino acid residues.38 Studies provide increasing evidence, which supports the association of ROS with different aspects of the neurodegenerative process.39, 40 Oxidative protein modifications during neurodegenerative glaucoma increase neuronal susceptibility to damage and also lead to glial dysfunction.41 Oxidative stress induced dysfunctional glial cells may contribute to spreading neuronal damage by secondary degeneration.42 Oxidative stress also promotes the accumulation of advanced glycation end products in glaucomatous tissues.43
Oxidative Stress and TM It has been suggested that age-and disease-related loss of trabecular meshwork cells, followed by substitution with extracellular matrix, contributes to an increased resistance to aqueous outflow and to the subsequent increase in IOP found in POAG patients.44, 45 With age, resistance increases and alterations of the extracellular matrix in the juxtacanalicular region occur.46 The loss or altered functionality of human TM cells may be the result of an increase in oxidative stress.47 Resistance to aqueous humor outflow increases in the presence of high levels of H2O2 in eyes with glutathione (GSH)-depleted TM.48 Moreover, the specific activity of superoxide dismutase demonstrates an age-dependent decline in normal human TM collected from cadavers.47 The H2O2 effect on the adhesion of TM cells to the extracellular matrix proteins results in rearrangement of cytoskeletal structures that may induce a decrease in TM cell adhesion, cell loss, and compromised TM integrity.49 Oxidative stress can also influence biological reactions of human TM cells, and may contribute to the changes observed in aging and in POAG.50 These changes may include trabecular thickening and trabecular fusion.51 Oxidative damage to the DNA of TM cells is significantly higher in affected patients than in age-matched control subjects, as demonstrated by analysis of 8-hydroxyguanosine (8-OH-dG), the most common oxidatively modified nucleotide.52 Additional studies report a significant correlation among 8-OH-dG levels in the TM, increased IOP, and visual field damage.53 The importance of oxidative damage in POAG has been further substantiated by the findings that glaucoma affected patients have a significant depletion of total antioxidant potential in the aqueous humor,54 an increase in serum antibodies against glutathione S-transferase,55 a decrease in plasma glutathione levels,56 and an increase of lipid peroxidation products in the plasma,57 when compared with nonaffected individuals. These findings provide the basis for a possible role of oxidative stress in the pathogenesis of glaucoma and provide new insight into the molecular mechanisms involved in this blinding disease.58 This pathogenic mechanism plays a fundamental role in POAG, in which TM pathological changes, mainly including oxidative DNA damage, trigger the “glaucomatous cascade.”
194
HANDBOOK OF NUTRITION, DIET, AND THE EYE
Quercetin and Glaucoma Flavonoids comprise a large family of plant-derived polyphenolic compounds widely distributed in fruits and vegetables, and therefore regularly consumed in the human diet.59, 60 They are particularly abundant in beverages derived from plants such as tea, cocoa, and red wine. Flavonoids are believed to exert protective as well as beneficial effects on multiple disease states, including cancer, cardiovascular disease, and neurodegenerative disorders.59, 60 The physiological benefits of flavonoids are generally thought to be derived from their antioxidant and free radical scavenging properties.61 Accordingly, flavonoids may also have therapeutic potential in ocular diseases including glaucoma. Flavonoids such as quercetin, catechins, and kaempferol are better antioxidants than vitamin C and vitamin E.62 Quercetin (3,5,7,30 ,40 -pentahydroxy flavone) is one of the most widely distributed flavonoids, present in fruit, vegetables, and many other dietary sources (apples, onions, tomatoes) (Fig. 4). Among the flavonoids, quercetin has numerous beneficial effects, including antiinflammatory,63 antiapoptosis,64 antiischemic,65 antioxidative stress,66 antiendoplasmic reticulum (ER) stress,67 in addition to promoting mitochondrial biogenesis.68 Flavonoids can induce the expression of phase-2 proteins that function to enhance the cell’s natural defenses against oxidative stress. Phase-2 proteins catalyze several different reactions, which neutralize ROS and increase the intracellular concentrations of antioxidants such as glutathione.69 Among these phase-2 proteins are some of the key enzymes
FIG. 4 (A) Chemical structure of quercetin. (B) Quercetin is the main representative of the flavonol class and a polyphenolic antioxidant found in a variety of fruits and vegetables. It is highly concentrated in onions, green tea, apples, grapes (red wine), and in soybeans.
Chapter 11 • Quercetin and Glaucoma 195
involved in glutathione metabolism (glutathione S-transferase [GSH] and glutamate cysteine ligase) and other antioxidant enzymes, including heme oxygenase 1 (HO-1).69 Overexpression of HO-1 in cells resulted in a marked reduction in injury and cytotoxicity induced by oxidative stress.70 Quercetin prevented H2O2-induced apoptosis via antioxidant activity and HO-1 gene expression in macrophages.4 It is reported that quercetin decreased oxidative stress, NF-κB activation, and inducible nitric oxide synthase (iNOS) overexpression in livers of streptozotocin-induced diabetic rats.71 Several transcription factors are activated under oxidative stress induced by H2O2 and inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β). Among them, both NF-kB and Nrf2 are well-known transcription factors related to oxidative stress.72, 73 Peroxiredoxins (PRDXs) can eliminate H2O2 efficiently and participate in many physiological processes such as signal transduction and apoptosis.74 There are six distinct members of this family located in various subcellular compartments. PRDX1, 2, and 6 are in the cytoplasm, and PRDX3 is found in mitochondria. PRDX4 is in endoplasmic reticulum and is secreted. PRDX5 is found in various compartments (Table 1). It has been previously shown that oxidative stress induces PRDX1 and PRDX5 through the activation of Ets1.75 Furthermore, PRDX2 expression is regulated by the transcription factor Foxo3a via treatment with the antiglaucoma agents nipradilol and timolol.76 Chhunchha et al. have recently showed that specific loss of PRDX6 in aging or in glaucomatous TM cells caused ROS accumulation and pathobiological changes in TM cells.77 Miyamoto et al. (2011)78 found that the Nrf2/NRF1 transcription pathway was also involved in the expression of both the PRDX3 and PRDX5 genes. Nrf2, a basic leucine zipper transcription factor, is essential for the inducible and constitutive expression of several phase II detoxification proteins including those required for mitochondrial respiratory function.79 NRF1 was found to act on many nuclear genes required for mitochondrial respiratory function.80 This primary function was confirmed by disrupting the Nrf1 gene in mice, resulting in a phenotype of peri-implantation lethality, and a striking decrease in the mitochondrial DNA content of Nrf1-null blastocysts.81 Table 1 Cellular H2O2 Levels are Controlled Sequentially by Peroxiredoxins (PRDXs) Human Gene
Amino Acid
Localization
PRDX1 PRDX2 PRDX3 PRDX4 PRDX5 PRDX6
199 198 256 271 214 224
Cytoplasm nucleus Cytoplasm cellular membrane Mitochondria Cytoplasm golgi body secretion Mitochondria peroxisome cytoplasm Cytoplasm
aa aa aa (cleaved at 63–64 aa) aa (cleaved at 36–37 aa) aa (cleaved at 52–53 aa) aa
Peroxiredoxins (PRDXs) are a family of small (22–27 kDa) nonselenium peroxidases currently thought to be composed of six mammalian isoforms. Although their individual roles in cellular redox regulation and antioxidant protection are quite distinct, they all catalyze peroxide reduction of H2O2, organic hydroperoxides, and peroxynitrite. They are found to be expressed ubiquitously and in high levels, suggesting that they are both an ancient and important enzyme family. PRDXs can be divided into three major subclasses: typical 2-cysteine (2-Cys) PRDXs (PRDX1-4), atypical 2-Cys PRDXs (PRDX-5), and 1-Cys PRDXs (PRDX-6).
196
HANDBOOK OF NUTRITION, DIET, AND THE EYE
One specific ROS, H2O2, is produced by mitochondria. Since peroxiredoxins (PRDXs) can eliminate H2O2 efficiently, mitochondrial PRDX3 may protect mitochondrial DNA from ROS damage.82, 83 We have previously reported that a member of the high mobility group protein family, mtTFA, can recognize oxidatively damaged DNA. Furthermore, it has been shown that mtTFA binds to mitochondrial DNA (mtDNA) in the same way that histones bind to nuclear DNA.84 Because mtTFA is not protected by chromatin proteins like histones, it is highly sensitive to oxidative stress. mtTFA may protect mtDNA, acting as a preserver of mitochondrial function.85, 86 Miyamoto et al. (2011)78 reported that quercetin induced mtTFA protein expression and protected against H2O2 toxicity. This indicates that quercetin may protect mitochondria from oxidative stress through the induction of both mtTFA and PRDX3 (Fig. 5). Quercetin inhibits the activation of caspase 3, and abolishes the H2O2-dependent induction of apoptosis-associated proteins such as Bcl2.87 This also suggests that quercetin inhibits the mitochondrial apoptotic pathway induced by various stresses. It has been reported that mitochondria play an important role in the pathogenesis of glaucoma, suggesting that various strategies targeting mitochondrial protection might provide a promising way to delay the onset and/or progression of glaucoma. Quercetin is now recognized as promising agent in human health and can modulate pathways associated with intramitochondrial redox status and subsequently mitochondria-induced apoptosis.88, 89 The endothelium plays a key role in maintenance of anterior chamber homeostasis and is also involved in glaucoma pathogenesis.90 The expression of PRDX proteins was
FIG. 5 Scheme for protective effect of quercetin. Quercetin protects the trabecular meshwork (TM) cells by the modulation of an oxidative stress-protective pathway involving control of PRDX3, PRDX5, and mtTFA expression by the transcription factors Nrf2 and NRF1.
Chapter 11 • Quercetin and Glaucoma 197
investigated in Fuchs’ endothelial dystrophy and the expression of PRDX2, 3, and 5 was significantly downregulated.91 It has been reported that PRDX3 oxidation is found in TNF-α treated cells and is the early event of apoptosis. This leads to an increase of H2O2, which modulates the progression of apoptosis.92 These data indicate that the expression of PRDXs in endothelial cells may also be related to glaucoma pathogenesis. PRDX6 reduces oxidative stress and TGF-β induced abnormalities of TM cells.93 TGF-β is a fibrogenic cytokine, which increases ROS production,94 indicating that our study may be relevant to the physiology and pathophysiology of the outflow pathway in glaucoma. Glaucoma is a progressive neuropathy characterized by the loss of RGCs.95 Strategies that delay or halt RGC loss have been recognized as potentially helpful for rescuing vision in glaucoma. Therefore, many studies have evaluated neuroprotection for glaucoma and many neuroprotective agents have been identified, such as N-methyl-D-aspartate (NMDA) receptor antagonists (memantine, brimonidine), glutamate release inhibitors (bis(7)-tacrine),96 calcium channel blockers (cilnidipine, lomerizine),97 neurotrophins (brain-derived neurotrophic factor, neurotrophic factor),98 antioxidants (astaxanthin, flavonoids),99 and others. Recently, it was reported that quercetin preserved RGCs function and prevented RGCs apoptosis in a rat model of chronic glaucoma in vivo and in hypoxia-induced RGCs apoptosis in vitro. The mechanism involved ameliorating mitochondrial function and preventing mitochondria-mediated apoptosis.100
Conclusions On the basis of the previous reports, it remains to be resolved whether oxidative stress is a principal cause of ocular diseases including glaucoma. However, the involvement of oxidative stress has certainly been confirmed in a spectrum of damaging processes. Oxidative stress plays an important role in glaucoma pathogenesis, affecting the trabecular meshwork cells, RGCs, and the optic nerve head. As the pharmacological properties of quercetin specifically target the factors involved in glaucomatous disease (oxidative stress and impairment of mitochondrial functions in trabecular meshwork cells, RGCs), quercetin could theoretically be beneficial for glaucoma. This is certainly supported by solid data, but definitive proof is still required. Indeed, several factors are known to play a role in these processes, but many more remain to be elucidated. Further research in this area will help to understand the physiopathology of glaucoma and to develop new approaches for its prevention and treatment.
Summary Points • •
Oxidative stress plays an important role in glaucoma pathogenesis, affecting the trabecular meshwork cells, retinal ganglion cells, and the optic nerve head. Many transcription factors are activated by oxidative stress, which induces the expression of target genes such as cellular antioxidant molecules for defense and survival.
198
• • • • •
HANDBOOK OF NUTRITION, DIET, AND THE EYE
Mechanistic details of the total genomic response are essential to facilitate the development of glaucoma treatments. The loss of function or altered function of human TM cells may be the result of an increase in oxidative stress. Flavonoids are believed to exert protective as well as beneficial effects on multiple disease states. Quercetin, one of the flavonoids, can protect TM cells from oxidative stress. Quercetin induces the expression of antioxidant proteins and protects trabecular meshwork cells from oxidative stress.
References 1. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014;311:1901–1911. 2. Vasudevan SK, Gupta V, Crowston JG. Neuroprotection in glaucoma. Indian J Ophthalmol. 2011;59 (suppl):S102–S113. 3. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262–267. 4. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:714–720. 5. Leske MC, Heiji A, Hussein M, Bengtsson B, Hyman L, Komaroff E. Factors for glaucoma progression and effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121:48–56. 6. Sacca` SC, Pascotto A, Camicione P, Capris P, Izzotti A. Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol. 2005;123:458–463. 7. Chow JM, Shen SC, Huan SK, Lin HY, Chen YC. Quercetin, but not rutin and quercetin, prevention of H2O2-induced apoptosis via anti-oxidant activity and heme oxygenase 1 gene expression in macrophages. Biochem Pharmacol. 2005;69:1839–1851. 8. Kook D, Wolf AH, Yu AL, et al. The protective effect of quercetin against oxidative stress in the human RPE in vitro. Invest Ophthalmol Vis Sci. 2008;49:1712–1720. 9. Pawlikowska-Pawlega B, Guszecki WI, Misiak LE, Gawron A. The study of the quercetin action on human erythrocyte membranes. Biochem Pharmecol. 2003;66:605–612. 10. Johnson J, Maher P, Hanneken A. The flavonoid, eriodictyol, induces long-term protection in ARPE19 cells through its effects on Nrf2 activation and phase II gene expression. Invest Ophthalmol Vis Sci. 2009;50:2398–2406. 11. Sacca` SC, Izzotti A, Rossi P, Traverso C. Glaucomatous outflow pathway and oxidative stress. Exp Eye Res. 2007;84:389–399. 12. Trounce I, Byrne E, Marzuki S. Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing. Lancet. 1989;1:637–639. 13. Yen TC, Chen YS, King KL, Yeh SH, Wei YH. Liver mitochondrial respiratory functions decline with age. Biochem Biophy Res Commun. 1989;165:994–1003. 14. Camougrand N, Rigoulet M. Aging and oxidative stress: studies of some genes involved both in aging and in response to oxidative stress. Respir Physiol. 2001;128:393–401. 15. Rhee SG, Kang SW, Jeong W, Chang TS, Yang KS, Woo HA. Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. Curr Opin Cell Biol. 2005;17:183–189.
Chapter 11 • Quercetin and Glaucoma 199
16. Cardoso SM, Pereira C, Oliveira CR. The protective effect of vitamin E, idebenone and reduced glutathione on free radical mediated injury in rat brain synaptosomes. Biochem Biophys Res Commun. 1998;246:703–710. 17. Southam E, Thomas PK, King RH, Goss-Sampson MA, Muller DP. Experimental vitamin E deficiency in rats. Morphological and functional evidence of abnormal axonal transport secondary to free radical damage. Brain. 1991;114:915–936. 18. Veach J. Functional dichotomy: glutathione and vitamin E in homeostasis relevant to primary openangle glaucoma. Br J Nutr. 2004;91:809–829. 19. Villarreal Jr G, Chatterjee A, Oh SS, Oh DJ, Kang MH, Rhee DJ. Canonical wnt signaling regulates extracellular matrix expression in the trabecular meshwork cells. Invest Ophthalmol Vis Sci. 2014;55:7433–7440. 20. Webber HC, Bermudez JY, Sethi A, Clark AF, Mao W. Crosstalk between TGFβ and Wnt signaling pathways in the trabecular meshwork. Exp Eye Res. 2016;148:97–102. 21. Yasuniwa Y, Izumi H, Wang KY, et al. Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway. Plos One. 2010;5. e15330. 22. Kuma A, Yamada S, Wang KY, et al. Role of WNT10A-expression kidney fibroblasts in acute interstitial nephritis. Plos One. 2014;23. e103240. 23. Wang KY, Yamada S, Izumi H, et al. Critical in vivo roles of WNT10A in wound healing by regulating collagen expression/synthesis in WNT10A-dificient mice. Plos One. 2018;13. e0195156. 24. Papp D, Lenti K, Mo´dos D, et al. The NRF2-related interactome and regulome contain multifunctional proteins and fine-tuned autoregulatory loops. FEBS Lett. 2012;586:1795–1802. 25. Yue BY. The extracellular matrix and its modulation in the trabecular meshwork. Surv Ophthalmol. 1996;40:379–390. 26. Izzotti A, Sacca` SC, Longobardi M, Cartiglia C. Sensitivity of ocular anterior chamber tissues to oxidative damage and its relevance to the pathogenesis of glaucoma. Invest Ophthalmol Vis Sci. 2009;50:5251–5258. 27. Clopton DA, Saltman P. Low-level oxidative stress causes cell-cycle specific arrest in cultured cells. Biochem Biophys Res Commun. 1995;210:189–196. 28. Knepper PA, Goossens W, Palmberg PF. Glycosaminoglycan stratification of the juxtacanalicular tissue in normal and primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1996;37:2414–2425. 29. Knepper PA, Goossens W, Hvizd M, Palmberg PF. Glycosaminoglycans of the human trabecular meshwork in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1996;37:1360–1367. 30. Izzotti A, Longobardi M, Cartiglia C, Sacca` SC. Mitochondrial damage in the trabecular meshwork occurs only in primary open-angle glaucoma and in pseudoexfoliative glaucoma. PLoS One. 2011;6(1). e14567. 31. De La Paz MA, Epstein DL. Effect of age on superoxide dismutase activity of human trabecular meshwork. Invest Ophthalmol Vis Sci. 1996;37:1849–1853. 32. Sacca` SC, Pascotto A, Camicione P, Capris P, Izzotti A. Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol. 2005;123:458–463. 33. Chrysostomou V, Rezania F, Trounce IA, Crowston JG. Oxidative stress and mitochondrial dysfunction in glaucoma. Curr Opin Pharmacol. 2013;13:12–15. 34. Zhao J, Wang S, Zhong W, Yang B, Sun L, Zheng Y. Oxidative stress in the trabecular meshwork (review). Int J Mol Med. 2016;38:995–1002. 35. Ghanem AA, Arafa LF, El-Baz A. Oxidative stress markers in patients with primary open-angle glaucoma. Curr Eye Res. 2010;35:295–301.
200
HANDBOOK OF NUTRITION, DIET, AND THE EYE
36. Ganapathy PS, White RE, Ha Y, et al. The role of N-methyl-D-aspartate receptor activation in homocysteine-induced death of retinal ganglion cells. Invest Ophthalmol Vis Sci. 2011;52:5515–5524. 37. Li GY, Fan B, Su GF. Acute energy reduction induces caspase-dependent apoptosis and activates p53 in retinal ganglion cells (RGC-5). Exp Eye Res. 2009;89:581–589. 38. Williams D, Norman G, Khoury C, et al. Evidence for a second messenger function of dUTP during Bax mediated apoptosis of yeast and mammalian cells. Biochim Biophys Acta. 2011;1813:315–321. 39. Kaur H, Chauhan S, Sandhir R. Protective effect of lycopene on oxidative stress and cognitive decline in rotenone induced model of Parkinson’s disease. Neurochem Res. 2011;36:1435–1443. 40. Wang F, Zhai H, Huang L, et al. Aspirin protects dopaminergic neurons against lipopolysaccharideinduced neurotoxicity in primary midbrain cultures. J Mol Neurosci. 2012;46:153–161. langer M, et al. Amyloid-beta aggregates cause alterations of astrocytic met41. Allaman I, Gavillet M, Be abolic phenotype: impact on neuronal viability. J Neurosci. 2010;30:3326–3338. 42. Fitzgerald M, Bartlett CA, Payne SC, et al. Near infrared light reduces oxidative stress and preserves function in CNS tissue vulnerable to secondary degeneration following partial transection of the optic nerve. J Neurotrauma. 2010;27:2107–2119. 43. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107:1058–1070. 44. Alvarado J, Murphy C, Polansky J, Juster R. Age-related changes in trabecular meshwork cellularity. Invest Ophthalmol Vis Sci. 1981;21:714–727. € tjen-Drecoll E. Morphological changes in glaucomatous eyes and the role of TGFbeta2 for the 45. Lu pathogenesis of the disease. Exp Eye Res. 2005;81:1–4. 46. Tian B, Geiger B, Epstein DL, Kaufman PL. Cytoskeletal involvement in the regulation of aqueous humor outflow. Invest Ophthalmol Vis Sci. 2000;41:619–623. 47. De La Paz MA, Epstein DL. Effect of age on superoxide dismutase activity of human trabecular meshwork. Invest Ophthalmol Vis Sci. 1996;37:1849–1853. 48. Kahn MG, Giblin FJ, Epstein DL. Glutathione in calf trabecular meshwork and its relation to aqueous humor outflow facility. Invest Ophthalmol Vis Sci. 1983;24:1283–1287. 49. Zhou L, Li Y, Yue BY. Oxidative stress affects cytoskeletal structure and cell-matrix interactions in cells from an ocular tissue: the trabecular meshwork. J Cell Physiol. 1999;180:182–189. 50. Tamm ER, Russell P, Johnson DH, Piatigorsky J. Human and monkey trabecular meshwork accumulate alpha B-crystallin in response to heat shock and oxidative stress. Invest Ophthalmol Vis Sci. 1996;37:2402–2413. 51. Hogg P, Calthorpe M, Batterbury M, Grierson I. Aqueous humor stimulates the migration of human trabecular meshwork cells in vitro. Invest Ophthalmol Vis Sci. 2000;41:1091–1098. 52. Izzotti A, Sacca` SC, Cartiglia C, De Flora S. Oxidative deoxyribonucleic acid damage in the eyes of glaucoma patients. Am J Med. 2003;114:638–646. 53. Sacca` SC, Pascotto A, Camicione P, Capris P, Izzotti A. Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol. 2005;123:458–463. 54. Ferreira SM, Lerner SF, Brunzini R, Evelson PA, Llesuy SF. Oxidative stress markers in aqueous humor of glaucoma patients. Am J Ophthalmol. 2004;137:62–69. 55. Yang J, Tezel G, Patil RV, Romano C, Wax MB. Serum autoantibody against glutathione S-transferase in patients with glaucoma. Invest Ophthalmol Vis Sci. 2001;42:1273–1276. 56. Gherghel D, Griffiths HR, Hilton EJ, Cunliffe IA, Hosking SL. Systemic reduction in glutathione levels occurs in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2005;46:877–883. 57. Yildirim O, Ateş NA, Ercan B, et al. Role of oxidative stress enzymes in open-angle glaucoma. Eye. 2005;19:580–583. 58. Izzotti A, Bagnis A, Sacca` SC. The role of oxidative stress in glaucoma. Mutat Res. 2006;612:105–114.
Chapter 11 • Quercetin and Glaucoma 201
59. Middleton E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev. 2000;52:673–751. 60. Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr. 2002;22:19–34. 61. Ishige K, Schubert D, Sagara Y. Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med. 2001;30:433–446. 62. Noroozi M, Angerson WJ, Lean ME. Effects of flavonoids and vitamin C on oxidative DNA damage to human lymphocytes. Am J Clin Nutr. 1998;67:1210–1218. 63. Periasamy R, Kalal IG, Krishnaswamy R, Viswanadha V. Quercetin protects human peripheral blood mononuclear cells from OTA-induced oxidative stress, genotoxicity, and inflammation. Environ Toxicol. 2016;31:855–865. 64. Ben Salem I, Boussabbeh M, Graiet I, Rhouma A, Bacha H, Essefi SA. Quercetin protects HCT116 cells from Dichlorvos-induced oxidative stress and apoptosis. Cell Stress Chaperones. 2016;21:179–186. € lc¸in I, Karago € z B, Soslu R. Quercetin protects rat skeletal muscle from ischemia 65. Ekinci Akdemir FN, Gu reperfusion injury. J Enzyme Inhib Med Chem. 2016;31:162–166. 66. Xu XR, Yu HT, Yang Y, Hang L, Yang XW, Ding SH. Quercetin phospholipid complex significantly protects against oxidative injury in ARPE-19 cells associated with activation of Nrf2 pathway. Eur J Pharmacol. 2016;770:1–8. 67. Ben Salem I, Prola A, Boussabbeh M, et al. Crocin and Quercetin protect HCT116 and HEK293 cells from Zearalenone-induced apoptosis by reducing endoplasmic reticulum stress. Cell Stress Chaperones. 2015;20:927–938. 68. Sharma DR, Sunkaria A, Wani WY, et al. Quercetin protects against aluminium induced oxidative stress and promotes mitochondrial biogenesis via activation of the PGC-1α signaling pathway. Neurotoxicology. 2015;51:116–137. 69. Talalay P. Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors. 2000;12:1–4. 70. Taille C, El-Benna J, Lanone S, et al. Induction of heme oxygenase-1 inhibits NAD(P)H oxidase activity by down-regulating cytochrome b558 expression via the reduction of heme availability. J Biol Chem. 2004;279:28681–28688. 71. Dias AS, Porawski M, Alonso M, Marroni N, Collado PS, Gonza´lez-Gallego J. Quercetin decreases oxidative stress, NF-kappa B activation, and iNOS overexpression in liver of streptozotocin-induced diabetic rats. J Nutr. 2005;135:2299–2304. 72. Gloire G, Legrand-Poels S, Piette J. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol. 2006;72:1493–1505. 73. Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284:13291–13295. 74. Ola´hova´ M, Taylor SR, Khazaipoul S, et al. A redox-sensitive peroxiredoxin that is important for longevity has tissue- and stress-specific roles in stress resistance. Proc Natl Acad Sci U S A. 2008;105:19839–19844. 75. Shiota M, Izumi H, Miyamoto N, et al. Ets regulates peroxiredoxin1 and 5 expressions through their interaction with the high-mobility group protein B1. Cancer Sci. 2008;99:1950–1959. 76. Miyamoto N, Izumi H, Miyamoto R, et al. Nipradilol and timolol induce Foxo3a and peroxiredoxin 2 expression and protect trabecular meshwork cells from oxidative stress. Invest Ophthalmol Vis Sci. 2008;50:2777–2784. 77. Chhunchha B, Singh P, Stamer WD, Singh DP. Prdx6 retards senescence and restores trabecular meshwork cell health by regulating reactive oxygen species. Cell Death Discov. 2017;11(3):17060. 78. Miyamoto N, Izumi H, Miyamoto R, et al. Quercetin induces the expression of peroxiredoxins 3 and 5 via the Nrf2/NRF1 transcription pathway. Invest Ophthalmol Vis Sci. 2011;52:1055–1063.
202
HANDBOOK OF NUTRITION, DIET, AND THE EYE
79. Ishii T, Itoh K, Takahashi S, et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem. 2000;275:16023–16029. 80. Scarpulla R. Transcriptional activators and coactivators in the nuclear control of mitochondrial function in mammalian cells. Gene. 2002;286:81–89. 81. Huo L, Scarpulla RC. Mitochondrial DNA instability and peri-implantation lethality associated with targeted disruption of nuclear respiratory factor 1 in mice. Mol Cell Biol. 2001;21:644–654. 82. Noh YH, Baek JY, Jeong W, Rhee SG, Chang TS. Sulfiredoxin translocation into mitochondria plays a crucial role in reducing hyper-oxidized peroxiredoxin III. J Biol Chem. 2009;284:8470–8477. 83. Wood ZA, Poole LB, Karplus PA. Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science. 2003;300:650–653. 84. Yoshida Y, Izumi H, Torigoe T, et al. P53 physically interacts with mitochondrial transcription factor A and differentially regulates binding to damaged DNA. Cancer Res. 2003;63:3729–3734. 85. Kanki T, Ohgaki K, Gaspari M, et al. Architectural role of mitochondrial transcription factor A in maintenance of human mitochondrial DNA. Mol Cell Biol. 2004;24:9823–9834. 86. Larsson NG, Wang J, Wilhelmsson H, et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet. 1998;18:231–236. 87. Park C, So HS, Shin CH, et al. Quercetin protects the hydrogen peroxide-induced apoptosis via inhibition of mitochondrial dysfunction in H9c2 cardiomyoblast cells. Biochem Pharmacol. 2003;66:1287–1295. 88. De Oliveira MR, Nabavi SM, Braidy N, Setzer WN, Ahmed T, Nabavi SF. Quercetin and mitochondria: a mechanistic view. Biotechnol Adv. 2016;34:532–549. 89. Kamel K, Farrell M, O’Brien C. Mitochondrial dysfunction in ocular disease: focus on glaucoma. Mitochondrion. 2017;35:44–53. €ger-Mayrl G, Hommer A, Schmetterer L. Endothelial dysfunction in 90. Resch H, Garhofer G, Fuchsja glaucoma. Acta Ophthalmol. 2009;87:4–12. 91. Jurkunas UV, Rawe I, Bitar MS, et al. Decreased expression of peroxiredoxins in Fuchs’ endothelial dystrophy. Invest Ophthalmol Vis Sci. 2008;49:956–2963. 92. Cox AG, Pullar JM, Hughes G, Ledgerwood EC, Hampton MB. Oxidation of mitochondrial peroxiredoxin 3 during the initiation of receptor-mediated apoptosis. Free Radic Biol Med. 2008;44:1001–1009. 93. Liu RM, Choi J, Wu JH, et al. Oxidative modification of nuclear mitogen-activated protein kinase phosphatase 1 is involved in transforming growth factor beta1-induced expression of plasminogen activator inhibitor 1 in fibroblasts. J Biol Chem. 2010;285:16239–16247. 94. Liu RM, Gaston Pravia KA. Oxidative stress and glutathione in TGF-beta-mediated fibrogenesis. Free Radic Biol Med. 2010;48:1–15. 95. Calkins DJ. Critical pathogenic events underlying progression of neurodegeneration in glaucoma. Prog Retin Eye Res. 2012;31:702–719. 96. Fang JH, Wang XH, Xu ZR, Jiang FG. Neuroprotective effects of bis(7)-tacrine against glutamateinduced retinal ganglion cells damage. BMC Neurosci. 2010;11:31. 97. Fitzgerald M, Payne SC, Bartlett CA, Evill L, Harvey AR, Dunlop SA. Secondary retinal ganglion cell death and the neuroprotective effects of the calcium channel blocker lomerizine. Invest Ophthalmol Vis Sci. 2009;50:5456–5462. 98. Pease ME, Zack DJ, Berlinicke C, et al. Effect of CNTF on retinal ganglion cell survival in experimental glaucoma. Invest Ophthalmol Vis Sci. 2009;50:2194–2200. 99. Yamagishi R, Aihara M. Neuroprotective effect of astaxanthin against rat retinal ganglion cell death under various stresses that induce apoptosis and necrosis. Mol Vis. 2014;20:1796–1805. 100. Gao FJ, Zhang SH, Xu P, et al. Quercetin declines apoptosis, ameliorates mitochondrial function and improves retinal ganglion cell survival and function in in vivo model of glaucoma in rat and retinal ganglion cell culture in vitro. Front Mol Neurosci. 2017;10:285.
CHAPTER OUTLINE Introduction .................................................................................................................................. 189 Oxidative Stress ........................................................................................................................... 190 Oxidative Stress and Transcription ............................................................................................. 191 Oxidative Stress and Glaucoma .................................................................................................. 192 Oxidative Stress and TM .............................................................................................................. 193 Quercetin and Glaucoma ............................................................................................................. 194 Conclusions ................................................................................................................................... 197 Summary Points ........................................................................................................................... 197 References .................................................................................................................................... 198
List of Abbreviations H2O2 HO-1 IOP Nrf2 POAG PRDX RGC ROS TM
hydrogen peroxide heme oxygenase 1 intraocular pressure nuclear factor-like 2 (erythroid-derived 2) primary open angle glaucoma peroxiredoxin retinal ganglion cell reactive oxygen species trabecular meshwork
Introduction Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs)1 and their axons.2 Glaucoma is a leading cause of irreversible blindness and it has been predicted that 79.6 million people worldwide will suffer with glaucoma by 2020.3 Elevated intraocular pressure (IOP), caused by a reduction in aqueous outflow, is a major risk factor in the development of glaucoma4 and the progression of glaucomatous damage to the optic nerve.5 IOP elevation and visual field damage are reported to be proportional to the DNA oxidative damage found in the human trabecular meshwork.6 This finding forms the basis for the role of oxidative stress in pathogenesis of glaucoma, and provides new insight into the molecular mechanisms involved. Handbook of Nutrition, Diet, and the Eye. https://doi.org/10.1016/B978-0-12-815245-4.00011-9 © 2019 Elsevier Inc. All rights reserved.
189
190
HANDBOOK OF NUTRITION, DIET, AND THE EYE
Flavonoids such as quercetin can protect cells from oxidative stress.7, 8 Quercetin is one of the most widely distributed flavonoids.9 It has been shown that certain flavonoids can induce antioxidant responsive element-dependent gene expression through the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2).10 Most importantly, oxidative stress plays an important role in the pathogenesis of multiple ocular diseases, including glaucoma.11
Oxidative Stress Under physiological conditions, there is a state of equilibrium between the endogenous production of free radicals and their neutralization capacity (“scavenging” activity). When damage ensues, this condition is known as oxidative stress. More than 90% of the oxygen is consumed by mitochondria in aerobic organisms. Under normal physiological conditions, about 1%5% of the oxygen consumed by mitochondria is converted to reactive oxygen species (ROS), including superoxide anions, hydrogen peroxide (H2O2), and hydroxyl radicals.12 Mitochondrial respiratory function declines with age13 and this increases the production of ROS and free radicals in mitochondria. Consequently, ROS production essentially depends on mitochondrial function and on the levels of antioxidant defenses.14 Free radicals are neutralized by three major antioxidant systems in mammalian cells, superoxide dismutase/catalase, glutathione, and peroxiredoxin (PRDX) (Fig. 1).15 Oxidative stresses are neutralized by numerous molecules that are either endogenously produced, such as glutathione, or are a part of dietary consumption, such as flavonoids, vitamins C and E. This mechanism is believed to be involved in the etiopathogenesis of many degenerative diseases (Fig. 2). Both vitamin C and glutathione operate in fluids outside the cell and within the cell,16 whereas vitamin E prevents endogenous mitochondrial
FIG. 1 Scheme for intracellular generation of reactive oxygen species (ROS). O 2 is dismutated to H2O2, which can • generate OH. Cell resistance to oxidative stress and repair depends in large part on removal of H2O2 and reduction of • phospholipid hydroperoxides (there is no specific scavenger for OH). H2O2 can be removed by multiple enzymes, including catalase, GSH peroxidases, and all PRDXs.
Chapter 11 • Quercetin and Glaucoma 191
FIG. 2 Systemic and ocular diseases due to oxidative stress.
production of ROS.17 This may be important in maintaining cellular homeostasis, which is relevant to the etiology of primary open angle glaucoma (POAG).18 It have been shown that canonical wnt signaling regulates extracellular matrix expression in the trabecular meshwork and is implicated in the pathology of POAG.19, 20 It has been also reported that wnt signaling is activated by oxidative stress and plays a critical role in the growth of fibroblasts/myofibroblasts and microvascular endothelial cells involved in wound healing/ scarring by regulating the expression of collagen.21–23
Oxidative Stress and Transcription ROS, including H2O2, are toxic and potent inducers of oxidative damage, but they have been shown to also function as necessary second messengers in various signal transduction pathways. Knowledge of the molecular links between stress signaling pathways and transcription factors is essential for understanding the complexity of the genomic response. Many transcription factors are activated by oxidative stress, which induces the expression of target genes such as cellular antioxidant molecules for defense and survival (Fig. 3). The genomic response system is thought to decline during aging, suggesting that the dysfunction of antioxidant systems induces various age-related diseases. It is well known that Nrf2 is a master transcription factor involved in stress responses, including oxidative stress. Many transcription factors activated by oxidative stress have been identified, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), activating transcription factor 4 (ATF4), and nuclear respiratory factor 1 (Nrf1). Recently, Nrf2 regulatory factors and the interacting molecules have been identified.24 Mechanistic details of the total genomic response are essential to facilitate the development of glaucoma treatments.
192
HANDBOOK OF NUTRITION, DIET, AND THE EYE
FIG. 3 Hydrogen peroxide is a metabolic byproduct or common mediator for signal transduction.
Oxidative Stress and Glaucoma Elevated IOP is the most important risk factor for glaucoma. High IOP usually occurs as a result of an increase in the aqueous humor outflow resistance of the TM. The TM, which comprises endothelial-like cells, is composed of trabecular beams made of extracellular matrix (ECM) elements, including fibronectin, laminin, and collagens.25 The TM cells are critical for the maintenance of the aqueous humor outflow pathway. TM abnormalities are the most common pathogenesis of glaucoma. The pathogenic role of oxidative stress in increasing IOP is supported by various studies. The TM is the most sensitive tissue to oxidative damage in the anterior chamber.26 Oxidative stress to the TM can cause much damage, such as reduction of TM mitochondrial respiratory activity, leading to growth arrest,27 and can affect ECM structure28 such as ECM accumulation,29 including DNA damage of TM cells.30 Cell death due to oxidative stress may cause further free radical attacks and the loss of function or altered function of TM cells, leading to even more oxidative stress and beginning a vicious cycle.31 At least, ROS alter the morphology, function, and drainage of the anterior chamber filter channel that eventually leads to an increase in IOP.32 A recent study reported that patients with POAG have pathological changes in the TM, including a reduced number of human TM cells (HTMCs), an accumulation of ECM, and cytoskeletal changes.33 It has recently been demonstrated that oxidative damage to the TM may serve an important role in the development of POAG.34 It has been reported that the expression of antioxidants, including superoxide dismutase-1 (SOD1) and glutathione (GSH), is increased in TM of patients with primary open angle glaucoma (POAG).35
Chapter 11 • Quercetin and Glaucoma 193
Growing evidence supports the involvement of oxidative stress as a common component of neurodegenerative glaucoma in different subcellular compartments of RGCs.36, 37 In addition to the evidence of a direct cytotoxicity leading to RGC death, ROS may also act as a second messenger to modulate protein function, by redox modifications of downstream enzymatic oxidation of specific amino acid residues.38 Studies provide increasing evidence, which supports the association of ROS with different aspects of the neurodegenerative process.39, 40 Oxidative protein modifications during neurodegenerative glaucoma increase neuronal susceptibility to damage and also lead to glial dysfunction.41 Oxidative stress induced dysfunctional glial cells may contribute to spreading neuronal damage by secondary degeneration.42 Oxidative stress also promotes the accumulation of advanced glycation end products in glaucomatous tissues.43
Oxidative Stress and TM It has been suggested that age-and disease-related loss of trabecular meshwork cells, followed by substitution with extracellular matrix, contributes to an increased resistance to aqueous outflow and to the subsequent increase in IOP found in POAG patients.44, 45 With age, resistance increases and alterations of the extracellular matrix in the juxtacanalicular region occur.46 The loss or altered functionality of human TM cells may be the result of an increase in oxidative stress.47 Resistance to aqueous humor outflow increases in the presence of high levels of H2O2 in eyes with glutathione (GSH)-depleted TM.48 Moreover, the specific activity of superoxide dismutase demonstrates an age-dependent decline in normal human TM collected from cadavers.47 The H2O2 effect on the adhesion of TM cells to the extracellular matrix proteins results in rearrangement of cytoskeletal structures that may induce a decrease in TM cell adhesion, cell loss, and compromised TM integrity.49 Oxidative stress can also influence biological reactions of human TM cells, and may contribute to the changes observed in aging and in POAG.50 These changes may include trabecular thickening and trabecular fusion.51 Oxidative damage to the DNA of TM cells is significantly higher in affected patients than in age-matched control subjects, as demonstrated by analysis of 8-hydroxyguanosine (8-OH-dG), the most common oxidatively modified nucleotide.52 Additional studies report a significant correlation among 8-OH-dG levels in the TM, increased IOP, and visual field damage.53 The importance of oxidative damage in POAG has been further substantiated by the findings that glaucoma affected patients have a significant depletion of total antioxidant potential in the aqueous humor,54 an increase in serum antibodies against glutathione S-transferase,55 a decrease in plasma glutathione levels,56 and an increase of lipid peroxidation products in the plasma,57 when compared with nonaffected individuals. These findings provide the basis for a possible role of oxidative stress in the pathogenesis of glaucoma and provide new insight into the molecular mechanisms involved in this blinding disease.58 This pathogenic mechanism plays a fundamental role in POAG, in which TM pathological changes, mainly including oxidative DNA damage, trigger the “glaucomatous cascade.”
194
HANDBOOK OF NUTRITION, DIET, AND THE EYE
Quercetin and Glaucoma Flavonoids comprise a large family of plant-derived polyphenolic compounds widely distributed in fruits and vegetables, and therefore regularly consumed in the human diet.59, 60 They are particularly abundant in beverages derived from plants such as tea, cocoa, and red wine. Flavonoids are believed to exert protective as well as beneficial effects on multiple disease states, including cancer, cardiovascular disease, and neurodegenerative disorders.59, 60 The physiological benefits of flavonoids are generally thought to be derived from their antioxidant and free radical scavenging properties.61 Accordingly, flavonoids may also have therapeutic potential in ocular diseases including glaucoma. Flavonoids such as quercetin, catechins, and kaempferol are better antioxidants than vitamin C and vitamin E.62 Quercetin (3,5,7,30 ,40 -pentahydroxy flavone) is one of the most widely distributed flavonoids, present in fruit, vegetables, and many other dietary sources (apples, onions, tomatoes) (Fig. 4). Among the flavonoids, quercetin has numerous beneficial effects, including antiinflammatory,63 antiapoptosis,64 antiischemic,65 antioxidative stress,66 antiendoplasmic reticulum (ER) stress,67 in addition to promoting mitochondrial biogenesis.68 Flavonoids can induce the expression of phase-2 proteins that function to enhance the cell’s natural defenses against oxidative stress. Phase-2 proteins catalyze several different reactions, which neutralize ROS and increase the intracellular concentrations of antioxidants such as glutathione.69 Among these phase-2 proteins are some of the key enzymes
FIG. 4 (A) Chemical structure of quercetin. (B) Quercetin is the main representative of the flavonol class and a polyphenolic antioxidant found in a variety of fruits and vegetables. It is highly concentrated in onions, green tea, apples, grapes (red wine), and in soybeans.
Chapter 11 • Quercetin and Glaucoma 195
involved in glutathione metabolism (glutathione S-transferase [GSH] and glutamate cysteine ligase) and other antioxidant enzymes, including heme oxygenase 1 (HO-1).69 Overexpression of HO-1 in cells resulted in a marked reduction in injury and cytotoxicity induced by oxidative stress.70 Quercetin prevented H2O2-induced apoptosis via antioxidant activity and HO-1 gene expression in macrophages.4 It is reported that quercetin decreased oxidative stress, NF-κB activation, and inducible nitric oxide synthase (iNOS) overexpression in livers of streptozotocin-induced diabetic rats.71 Several transcription factors are activated under oxidative stress induced by H2O2 and inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β). Among them, both NF-kB and Nrf2 are well-known transcription factors related to oxidative stress.72, 73 Peroxiredoxins (PRDXs) can eliminate H2O2 efficiently and participate in many physiological processes such as signal transduction and apoptosis.74 There are six distinct members of this family located in various subcellular compartments. PRDX1, 2, and 6 are in the cytoplasm, and PRDX3 is found in mitochondria. PRDX4 is in endoplasmic reticulum and is secreted. PRDX5 is found in various compartments (Table 1). It has been previously shown that oxidative stress induces PRDX1 and PRDX5 through the activation of Ets1.75 Furthermore, PRDX2 expression is regulated by the transcription factor Foxo3a via treatment with the antiglaucoma agents nipradilol and timolol.76 Chhunchha et al. have recently showed that specific loss of PRDX6 in aging or in glaucomatous TM cells caused ROS accumulation and pathobiological changes in TM cells.77 Miyamoto et al. (2011)78 found that the Nrf2/NRF1 transcription pathway was also involved in the expression of both the PRDX3 and PRDX5 genes. Nrf2, a basic leucine zipper transcription factor, is essential for the inducible and constitutive expression of several phase II detoxification proteins including those required for mitochondrial respiratory function.79 NRF1 was found to act on many nuclear genes required for mitochondrial respiratory function.80 This primary function was confirmed by disrupting the Nrf1 gene in mice, resulting in a phenotype of peri-implantation lethality, and a striking decrease in the mitochondrial DNA content of Nrf1-null blastocysts.81 Table 1 Cellular H2O2 Levels are Controlled Sequentially by Peroxiredoxins (PRDXs) Human Gene
Amino Acid
Localization
PRDX1 PRDX2 PRDX3 PRDX4 PRDX5 PRDX6
199 198 256 271 214 224
Cytoplasm nucleus Cytoplasm cellular membrane Mitochondria Cytoplasm golgi body secretion Mitochondria peroxisome cytoplasm Cytoplasm
aa aa aa (cleaved at 63–64 aa) aa (cleaved at 36–37 aa) aa (cleaved at 52–53 aa) aa
Peroxiredoxins (PRDXs) are a family of small (22–27 kDa) nonselenium peroxidases currently thought to be composed of six mammalian isoforms. Although their individual roles in cellular redox regulation and antioxidant protection are quite distinct, they all catalyze peroxide reduction of H2O2, organic hydroperoxides, and peroxynitrite. They are found to be expressed ubiquitously and in high levels, suggesting that they are both an ancient and important enzyme family. PRDXs can be divided into three major subclasses: typical 2-cysteine (2-Cys) PRDXs (PRDX1-4), atypical 2-Cys PRDXs (PRDX-5), and 1-Cys PRDXs (PRDX-6).
196
HANDBOOK OF NUTRITION, DIET, AND THE EYE
One specific ROS, H2O2, is produced by mitochondria. Since peroxiredoxins (PRDXs) can eliminate H2O2 efficiently, mitochondrial PRDX3 may protect mitochondrial DNA from ROS damage.82, 83 We have previously reported that a member of the high mobility group protein family, mtTFA, can recognize oxidatively damaged DNA. Furthermore, it has been shown that mtTFA binds to mitochondrial DNA (mtDNA) in the same way that histones bind to nuclear DNA.84 Because mtTFA is not protected by chromatin proteins like histones, it is highly sensitive to oxidative stress. mtTFA may protect mtDNA, acting as a preserver of mitochondrial function.85, 86 Miyamoto et al. (2011)78 reported that quercetin induced mtTFA protein expression and protected against H2O2 toxicity. This indicates that quercetin may protect mitochondria from oxidative stress through the induction of both mtTFA and PRDX3 (Fig. 5). Quercetin inhibits the activation of caspase 3, and abolishes the H2O2-dependent induction of apoptosis-associated proteins such as Bcl2.87 This also suggests that quercetin inhibits the mitochondrial apoptotic pathway induced by various stresses. It has been reported that mitochondria play an important role in the pathogenesis of glaucoma, suggesting that various strategies targeting mitochondrial protection might provide a promising way to delay the onset and/or progression of glaucoma. Quercetin is now recognized as promising agent in human health and can modulate pathways associated with intramitochondrial redox status and subsequently mitochondria-induced apoptosis.88, 89 The endothelium plays a key role in maintenance of anterior chamber homeostasis and is also involved in glaucoma pathogenesis.90 The expression of PRDX proteins was
FIG. 5 Scheme for protective effect of quercetin. Quercetin protects the trabecular meshwork (TM) cells by the modulation of an oxidative stress-protective pathway involving control of PRDX3, PRDX5, and mtTFA expression by the transcription factors Nrf2 and NRF1.
Chapter 11 • Quercetin and Glaucoma 197
investigated in Fuchs’ endothelial dystrophy and the expression of PRDX2, 3, and 5 was significantly downregulated.91 It has been reported that PRDX3 oxidation is found in TNF-α treated cells and is the early event of apoptosis. This leads to an increase of H2O2, which modulates the progression of apoptosis.92 These data indicate that the expression of PRDXs in endothelial cells may also be related to glaucoma pathogenesis. PRDX6 reduces oxidative stress and TGF-β induced abnormalities of TM cells.93 TGF-β is a fibrogenic cytokine, which increases ROS production,94 indicating that our study may be relevant to the physiology and pathophysiology of the outflow pathway in glaucoma. Glaucoma is a progressive neuropathy characterized by the loss of RGCs.95 Strategies that delay or halt RGC loss have been recognized as potentially helpful for rescuing vision in glaucoma. Therefore, many studies have evaluated neuroprotection for glaucoma and many neuroprotective agents have been identified, such as N-methyl-D-aspartate (NMDA) receptor antagonists (memantine, brimonidine), glutamate release inhibitors (bis(7)-tacrine),96 calcium channel blockers (cilnidipine, lomerizine),97 neurotrophins (brain-derived neurotrophic factor, neurotrophic factor),98 antioxidants (astaxanthin, flavonoids),99 and others. Recently, it was reported that quercetin preserved RGCs function and prevented RGCs apoptosis in a rat model of chronic glaucoma in vivo and in hypoxia-induced RGCs apoptosis in vitro. The mechanism involved ameliorating mitochondrial function and preventing mitochondria-mediated apoptosis.100
Conclusions On the basis of the previous reports, it remains to be resolved whether oxidative stress is a principal cause of ocular diseases including glaucoma. However, the involvement of oxidative stress has certainly been confirmed in a spectrum of damaging processes. Oxidative stress plays an important role in glaucoma pathogenesis, affecting the trabecular meshwork cells, RGCs, and the optic nerve head. As the pharmacological properties of quercetin specifically target the factors involved in glaucomatous disease (oxidative stress and impairment of mitochondrial functions in trabecular meshwork cells, RGCs), quercetin could theoretically be beneficial for glaucoma. This is certainly supported by solid data, but definitive proof is still required. Indeed, several factors are known to play a role in these processes, but many more remain to be elucidated. Further research in this area will help to understand the physiopathology of glaucoma and to develop new approaches for its prevention and treatment.
Summary Points • •
Oxidative stress plays an important role in glaucoma pathogenesis, affecting the trabecular meshwork cells, retinal ganglion cells, and the optic nerve head. Many transcription factors are activated by oxidative stress, which induces the expression of target genes such as cellular antioxidant molecules for defense and survival.
198
• • • • •
HANDBOOK OF NUTRITION, DIET, AND THE EYE
Mechanistic details of the total genomic response are essential to facilitate the development of glaucoma treatments. The loss of function or altered function of human TM cells may be the result of an increase in oxidative stress. Flavonoids are believed to exert protective as well as beneficial effects on multiple disease states. Quercetin, one of the flavonoids, can protect TM cells from oxidative stress. Quercetin induces the expression of antioxidant proteins and protects trabecular meshwork cells from oxidative stress.
References 1. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014;311:1901–1911. 2. Vasudevan SK, Gupta V, Crowston JG. Neuroprotection in glaucoma. Indian J Ophthalmol. 2011;59 (suppl):S102–S113. 3. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262–267. 4. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:714–720. 5. Leske MC, Heiji A, Hussein M, Bengtsson B, Hyman L, Komaroff E. Factors for glaucoma progression and effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121:48–56. 6. Sacca` SC, Pascotto A, Camicione P, Capris P, Izzotti A. Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol. 2005;123:458–463. 7. Chow JM, Shen SC, Huan SK, Lin HY, Chen YC. Quercetin, but not rutin and quercetin, prevention of H2O2-induced apoptosis via anti-oxidant activity and heme oxygenase 1 gene expression in macrophages. Biochem Pharmacol. 2005;69:1839–1851. 8. Kook D, Wolf AH, Yu AL, et al. The protective effect of quercetin against oxidative stress in the human RPE in vitro. Invest Ophthalmol Vis Sci. 2008;49:1712–1720. 9. Pawlikowska-Pawlega B, Guszecki WI, Misiak LE, Gawron A. The study of the quercetin action on human erythrocyte membranes. Biochem Pharmecol. 2003;66:605–612. 10. Johnson J, Maher P, Hanneken A. The flavonoid, eriodictyol, induces long-term protection in ARPE19 cells through its effects on Nrf2 activation and phase II gene expression. Invest Ophthalmol Vis Sci. 2009;50:2398–2406. 11. Sacca` SC, Izzotti A, Rossi P, Traverso C. Glaucomatous outflow pathway and oxidative stress. Exp Eye Res. 2007;84:389–399. 12. Trounce I, Byrne E, Marzuki S. Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing. Lancet. 1989;1:637–639. 13. Yen TC, Chen YS, King KL, Yeh SH, Wei YH. Liver mitochondrial respiratory functions decline with age. Biochem Biophy Res Commun. 1989;165:994–1003. 14. Camougrand N, Rigoulet M. Aging and oxidative stress: studies of some genes involved both in aging and in response to oxidative stress. Respir Physiol. 2001;128:393–401. 15. Rhee SG, Kang SW, Jeong W, Chang TS, Yang KS, Woo HA. Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. Curr Opin Cell Biol. 2005;17:183–189.
Chapter 11 • Quercetin and Glaucoma 199
16. Cardoso SM, Pereira C, Oliveira CR. The protective effect of vitamin E, idebenone and reduced glutathione on free radical mediated injury in rat brain synaptosomes. Biochem Biophys Res Commun. 1998;246:703–710. 17. Southam E, Thomas PK, King RH, Goss-Sampson MA, Muller DP. Experimental vitamin E deficiency in rats. Morphological and functional evidence of abnormal axonal transport secondary to free radical damage. Brain. 1991;114:915–936. 18. Veach J. Functional dichotomy: glutathione and vitamin E in homeostasis relevant to primary openangle glaucoma. Br J Nutr. 2004;91:809–829. 19. Villarreal Jr G, Chatterjee A, Oh SS, Oh DJ, Kang MH, Rhee DJ. Canonical wnt signaling regulates extracellular matrix expression in the trabecular meshwork cells. Invest Ophthalmol Vis Sci. 2014;55:7433–7440. 20. Webber HC, Bermudez JY, Sethi A, Clark AF, Mao W. Crosstalk between TGFβ and Wnt signaling pathways in the trabecular meshwork. Exp Eye Res. 2016;148:97–102. 21. Yasuniwa Y, Izumi H, Wang KY, et al. Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway. Plos One. 2010;5. e15330. 22. Kuma A, Yamada S, Wang KY, et al. Role of WNT10A-expression kidney fibroblasts in acute interstitial nephritis. Plos One. 2014;23. e103240. 23. Wang KY, Yamada S, Izumi H, et al. Critical in vivo roles of WNT10A in wound healing by regulating collagen expression/synthesis in WNT10A-dificient mice. Plos One. 2018;13. e0195156. 24. Papp D, Lenti K, Mo´dos D, et al. The NRF2-related interactome and regulome contain multifunctional proteins and fine-tuned autoregulatory loops. FEBS Lett. 2012;586:1795–1802. 25. Yue BY. The extracellular matrix and its modulation in the trabecular meshwork. Surv Ophthalmol. 1996;40:379–390. 26. Izzotti A, Sacca` SC, Longobardi M, Cartiglia C. Sensitivity of ocular anterior chamber tissues to oxidative damage and its relevance to the pathogenesis of glaucoma. Invest Ophthalmol Vis Sci. 2009;50:5251–5258. 27. Clopton DA, Saltman P. Low-level oxidative stress causes cell-cycle specific arrest in cultured cells. Biochem Biophys Res Commun. 1995;210:189–196. 28. Knepper PA, Goossens W, Palmberg PF. Glycosaminoglycan stratification of the juxtacanalicular tissue in normal and primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1996;37:2414–2425. 29. Knepper PA, Goossens W, Hvizd M, Palmberg PF. Glycosaminoglycans of the human trabecular meshwork in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1996;37:1360–1367. 30. Izzotti A, Longobardi M, Cartiglia C, Sacca` SC. Mitochondrial damage in the trabecular meshwork occurs only in primary open-angle glaucoma and in pseudoexfoliative glaucoma. PLoS One. 2011;6(1). e14567. 31. De La Paz MA, Epstein DL. Effect of age on superoxide dismutase activity of human trabecular meshwork. Invest Ophthalmol Vis Sci. 1996;37:1849–1853. 32. Sacca` SC, Pascotto A, Camicione P, Capris P, Izzotti A. Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol. 2005;123:458–463. 33. Chrysostomou V, Rezania F, Trounce IA, Crowston JG. Oxidative stress and mitochondrial dysfunction in glaucoma. Curr Opin Pharmacol. 2013;13:12–15. 34. Zhao J, Wang S, Zhong W, Yang B, Sun L, Zheng Y. Oxidative stress in the trabecular meshwork (review). Int J Mol Med. 2016;38:995–1002. 35. Ghanem AA, Arafa LF, El-Baz A. Oxidative stress markers in patients with primary open-angle glaucoma. Curr Eye Res. 2010;35:295–301.
200
HANDBOOK OF NUTRITION, DIET, AND THE EYE
36. Ganapathy PS, White RE, Ha Y, et al. The role of N-methyl-D-aspartate receptor activation in homocysteine-induced death of retinal ganglion cells. Invest Ophthalmol Vis Sci. 2011;52:5515–5524. 37. Li GY, Fan B, Su GF. Acute energy reduction induces caspase-dependent apoptosis and activates p53 in retinal ganglion cells (RGC-5). Exp Eye Res. 2009;89:581–589. 38. Williams D, Norman G, Khoury C, et al. Evidence for a second messenger function of dUTP during Bax mediated apoptosis of yeast and mammalian cells. Biochim Biophys Acta. 2011;1813:315–321. 39. Kaur H, Chauhan S, Sandhir R. Protective effect of lycopene on oxidative stress and cognitive decline in rotenone induced model of Parkinson’s disease. Neurochem Res. 2011;36:1435–1443. 40. Wang F, Zhai H, Huang L, et al. Aspirin protects dopaminergic neurons against lipopolysaccharideinduced neurotoxicity in primary midbrain cultures. J Mol Neurosci. 2012;46:153–161. langer M, et al. Amyloid-beta aggregates cause alterations of astrocytic met41. Allaman I, Gavillet M, Be abolic phenotype: impact on neuronal viability. J Neurosci. 2010;30:3326–3338. 42. Fitzgerald M, Bartlett CA, Payne SC, et al. Near infrared light reduces oxidative stress and preserves function in CNS tissue vulnerable to secondary degeneration following partial transection of the optic nerve. J Neurotrauma. 2010;27:2107–2119. 43. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107:1058–1070. 44. Alvarado J, Murphy C, Polansky J, Juster R. Age-related changes in trabecular meshwork cellularity. Invest Ophthalmol Vis Sci. 1981;21:714–727. € tjen-Drecoll E. Morphological changes in glaucomatous eyes and the role of TGFbeta2 for the 45. Lu pathogenesis of the disease. Exp Eye Res. 2005;81:1–4. 46. Tian B, Geiger B, Epstein DL, Kaufman PL. Cytoskeletal involvement in the regulation of aqueous humor outflow. Invest Ophthalmol Vis Sci. 2000;41:619–623. 47. De La Paz MA, Epstein DL. Effect of age on superoxide dismutase activity of human trabecular meshwork. Invest Ophthalmol Vis Sci. 1996;37:1849–1853. 48. Kahn MG, Giblin FJ, Epstein DL. Glutathione in calf trabecular meshwork and its relation to aqueous humor outflow facility. Invest Ophthalmol Vis Sci. 1983;24:1283–1287. 49. Zhou L, Li Y, Yue BY. Oxidative stress affects cytoskeletal structure and cell-matrix interactions in cells from an ocular tissue: the trabecular meshwork. J Cell Physiol. 1999;180:182–189. 50. Tamm ER, Russell P, Johnson DH, Piatigorsky J. Human and monkey trabecular meshwork accumulate alpha B-crystallin in response to heat shock and oxidative stress. Invest Ophthalmol Vis Sci. 1996;37:2402–2413. 51. Hogg P, Calthorpe M, Batterbury M, Grierson I. Aqueous humor stimulates the migration of human trabecular meshwork cells in vitro. Invest Ophthalmol Vis Sci. 2000;41:1091–1098. 52. Izzotti A, Sacca` SC, Cartiglia C, De Flora S. Oxidative deoxyribonucleic acid damage in the eyes of glaucoma patients. Am J Med. 2003;114:638–646. 53. Sacca` SC, Pascotto A, Camicione P, Capris P, Izzotti A. Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol. 2005;123:458–463. 54. Ferreira SM, Lerner SF, Brunzini R, Evelson PA, Llesuy SF. Oxidative stress markers in aqueous humor of glaucoma patients. Am J Ophthalmol. 2004;137:62–69. 55. Yang J, Tezel G, Patil RV, Romano C, Wax MB. Serum autoantibody against glutathione S-transferase in patients with glaucoma. Invest Ophthalmol Vis Sci. 2001;42:1273–1276. 56. Gherghel D, Griffiths HR, Hilton EJ, Cunliffe IA, Hosking SL. Systemic reduction in glutathione levels occurs in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2005;46:877–883. 57. Yildirim O, Ateş NA, Ercan B, et al. Role of oxidative stress enzymes in open-angle glaucoma. Eye. 2005;19:580–583. 58. Izzotti A, Bagnis A, Sacca` SC. The role of oxidative stress in glaucoma. Mutat Res. 2006;612:105–114.
Chapter 11 • Quercetin and Glaucoma 201
59. Middleton E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev. 2000;52:673–751. 60. Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr. 2002;22:19–34. 61. Ishige K, Schubert D, Sagara Y. Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med. 2001;30:433–446. 62. Noroozi M, Angerson WJ, Lean ME. Effects of flavonoids and vitamin C on oxidative DNA damage to human lymphocytes. Am J Clin Nutr. 1998;67:1210–1218. 63. Periasamy R, Kalal IG, Krishnaswamy R, Viswanadha V. Quercetin protects human peripheral blood mononuclear cells from OTA-induced oxidative stress, genotoxicity, and inflammation. Environ Toxicol. 2016;31:855–865. 64. Ben Salem I, Boussabbeh M, Graiet I, Rhouma A, Bacha H, Essefi SA. Quercetin protects HCT116 cells from Dichlorvos-induced oxidative stress and apoptosis. Cell Stress Chaperones. 2016;21:179–186. € lc¸in I, Karago € z B, Soslu R. Quercetin protects rat skeletal muscle from ischemia 65. Ekinci Akdemir FN, Gu reperfusion injury. J Enzyme Inhib Med Chem. 2016;31:162–166. 66. Xu XR, Yu HT, Yang Y, Hang L, Yang XW, Ding SH. Quercetin phospholipid complex significantly protects against oxidative injury in ARPE-19 cells associated with activation of Nrf2 pathway. Eur J Pharmacol. 2016;770:1–8. 67. Ben Salem I, Prola A, Boussabbeh M, et al. Crocin and Quercetin protect HCT116 and HEK293 cells from Zearalenone-induced apoptosis by reducing endoplasmic reticulum stress. Cell Stress Chaperones. 2015;20:927–938. 68. Sharma DR, Sunkaria A, Wani WY, et al. Quercetin protects against aluminium induced oxidative stress and promotes mitochondrial biogenesis via activation of the PGC-1α signaling pathway. Neurotoxicology. 2015;51:116–137. 69. Talalay P. Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors. 2000;12:1–4. 70. Taille C, El-Benna J, Lanone S, et al. Induction of heme oxygenase-1 inhibits NAD(P)H oxidase activity by down-regulating cytochrome b558 expression via the reduction of heme availability. J Biol Chem. 2004;279:28681–28688. 71. Dias AS, Porawski M, Alonso M, Marroni N, Collado PS, Gonza´lez-Gallego J. Quercetin decreases oxidative stress, NF-kappa B activation, and iNOS overexpression in liver of streptozotocin-induced diabetic rats. J Nutr. 2005;135:2299–2304. 72. Gloire G, Legrand-Poels S, Piette J. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol. 2006;72:1493–1505. 73. Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284:13291–13295. 74. Ola´hova´ M, Taylor SR, Khazaipoul S, et al. A redox-sensitive peroxiredoxin that is important for longevity has tissue- and stress-specific roles in stress resistance. Proc Natl Acad Sci U S A. 2008;105:19839–19844. 75. Shiota M, Izumi H, Miyamoto N, et al. Ets regulates peroxiredoxin1 and 5 expressions through their interaction with the high-mobility group protein B1. Cancer Sci. 2008;99:1950–1959. 76. Miyamoto N, Izumi H, Miyamoto R, et al. Nipradilol and timolol induce Foxo3a and peroxiredoxin 2 expression and protect trabecular meshwork cells from oxidative stress. Invest Ophthalmol Vis Sci. 2008;50:2777–2784. 77. Chhunchha B, Singh P, Stamer WD, Singh DP. Prdx6 retards senescence and restores trabecular meshwork cell health by regulating reactive oxygen species. Cell Death Discov. 2017;11(3):17060. 78. Miyamoto N, Izumi H, Miyamoto R, et al. Quercetin induces the expression of peroxiredoxins 3 and 5 via the Nrf2/NRF1 transcription pathway. Invest Ophthalmol Vis Sci. 2011;52:1055–1063.
202
HANDBOOK OF NUTRITION, DIET, AND THE EYE
79. Ishii T, Itoh K, Takahashi S, et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem. 2000;275:16023–16029. 80. Scarpulla R. Transcriptional activators and coactivators in the nuclear control of mitochondrial function in mammalian cells. Gene. 2002;286:81–89. 81. Huo L, Scarpulla RC. Mitochondrial DNA instability and peri-implantation lethality associated with targeted disruption of nuclear respiratory factor 1 in mice. Mol Cell Biol. 2001;21:644–654. 82. Noh YH, Baek JY, Jeong W, Rhee SG, Chang TS. Sulfiredoxin translocation into mitochondria plays a crucial role in reducing hyper-oxidized peroxiredoxin III. J Biol Chem. 2009;284:8470–8477. 83. Wood ZA, Poole LB, Karplus PA. Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science. 2003;300:650–653. 84. Yoshida Y, Izumi H, Torigoe T, et al. P53 physically interacts with mitochondrial transcription factor A and differentially regulates binding to damaged DNA. Cancer Res. 2003;63:3729–3734. 85. Kanki T, Ohgaki K, Gaspari M, et al. Architectural role of mitochondrial transcription factor A in maintenance of human mitochondrial DNA. Mol Cell Biol. 2004;24:9823–9834. 86. Larsson NG, Wang J, Wilhelmsson H, et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet. 1998;18:231–236. 87. Park C, So HS, Shin CH, et al. Quercetin protects the hydrogen peroxide-induced apoptosis via inhibition of mitochondrial dysfunction in H9c2 cardiomyoblast cells. Biochem Pharmacol. 2003;66:1287–1295. 88. De Oliveira MR, Nabavi SM, Braidy N, Setzer WN, Ahmed T, Nabavi SF. Quercetin and mitochondria: a mechanistic view. Biotechnol Adv. 2016;34:532–549. 89. Kamel K, Farrell M, O’Brien C. Mitochondrial dysfunction in ocular disease: focus on glaucoma. Mitochondrion. 2017;35:44–53. €ger-Mayrl G, Hommer A, Schmetterer L. Endothelial dysfunction in 90. Resch H, Garhofer G, Fuchsja glaucoma. Acta Ophthalmol. 2009;87:4–12. 91. Jurkunas UV, Rawe I, Bitar MS, et al. Decreased expression of peroxiredoxins in Fuchs’ endothelial dystrophy. Invest Ophthalmol Vis Sci. 2008;49:956–2963. 92. Cox AG, Pullar JM, Hughes G, Ledgerwood EC, Hampton MB. Oxidation of mitochondrial peroxiredoxin 3 during the initiation of receptor-mediated apoptosis. Free Radic Biol Med. 2008;44:1001–1009. 93. Liu RM, Choi J, Wu JH, et al. Oxidative modification of nuclear mitogen-activated protein kinase phosphatase 1 is involved in transforming growth factor beta1-induced expression of plasminogen activator inhibitor 1 in fibroblasts. J Biol Chem. 2010;285:16239–16247. 94. Liu RM, Gaston Pravia KA. Oxidative stress and glutathione in TGF-beta-mediated fibrogenesis. Free Radic Biol Med. 2010;48:1–15. 95. Calkins DJ. Critical pathogenic events underlying progression of neurodegeneration in glaucoma. Prog Retin Eye Res. 2012;31:702–719. 96. Fang JH, Wang XH, Xu ZR, Jiang FG. Neuroprotective effects of bis(7)-tacrine against glutamateinduced retinal ganglion cells damage. BMC Neurosci. 2010;11:31. 97. Fitzgerald M, Payne SC, Bartlett CA, Evill L, Harvey AR, Dunlop SA. Secondary retinal ganglion cell death and the neuroprotective effects of the calcium channel blocker lomerizine. Invest Ophthalmol Vis Sci. 2009;50:5456–5462. 98. Pease ME, Zack DJ, Berlinicke C, et al. Effect of CNTF on retinal ganglion cell survival in experimental glaucoma. Invest Ophthalmol Vis Sci. 2009;50:2194–2200. 99. Yamagishi R, Aihara M. Neuroprotective effect of astaxanthin against rat retinal ganglion cell death under various stresses that induce apoptosis and necrosis. Mol Vis. 2014;20:1796–1805. 100. Gao FJ, Zhang SH, Xu P, et al. Quercetin declines apoptosis, ameliorates mitochondrial function and improves retinal ganglion cell survival and function in in vivo model of glaucoma in rat and retinal ganglion cell culture in vitro. Front Mol Neurosci. 2017;10:285.