Persimmon (Diospyros Kaki) Leaves Extract (PLE): A Potential Drug for Eye-Related diseases
Ramsha Afzal1, Sualiha Afzal2 and Asad ul-Haq3,4*
1Department of Ophthalmology, The Catholic University of Korea, South Korea
2Pharmacology Unit, Western Sydney University, Australia
3Department of Internal Medicine, Soonchunhyang University Seoul, Korea
4Probiotics Microbiome Convergence Center, Soonchunhyang University, Korea
Submission: February 22, 2022; Published: March 09, 2022
*Corresponding author: Asad ul Haq, Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, 59, Daesagwan-ro, Yongsan-gu, Seoul 04401, Republic of Korea.
How to cite this article:Ramsha A, Sualiha A, Asad u-H. Persimmon (Diospyros Kaki) Leaves Extract (PLE): A Potential Drug for Eye-Related Diseases. Glob J Pharmaceu Sci. 2022; 9(4): 555768. DOI: 10.19080/GJPPS.2022.09.555768.
Abstract
Persimmon (Diospyros kaki) leaves have been used as a traditional or local medicine for multiple diseases in different eastern countries (Japan, Korea, India, and China) for centuries. In the recent past, several studies have used persimmon leaves extract (PLE) against different eye-related diseases. In this review, we discussed the ethnopharmacological use, therapeutic potentials and future opportunities for research using PLE for different ocular disorders based on the latest research. The pieces of information regarding PLE were collected using Pubmed, ACS, Elsevier, EMBASE, Web of Science, CNKI and different books. It can be concluded from this review that PLE probably have therapeutic potential against inflammation and oxidative stress induced disorders like dry eye disease (DED), corneal neurovascularization (CoNV), glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and edema. However, further investigations are required to discover exact biological compounds involved in the pharmacological effects against the aforementioned diseases. Furthermore, clinical trials are needed to be performed before integrating PLE for medicinal use
Keywords: Cell viability; Cornea; Retina; Na+/K+-ATPase; Glaucoma; Oxidative stress; Inflammation; Diospyros kaki (D.Kaki), Persimmons leaves; Dry eye disease; Corneal neurovascularization; Glaucoma; Age-related macular degeneration; Diabetic retinopathy; Edema
Abbreviations: PLE: Persimmon Leaves Extract; DED: Dry Eye Disease; CoNV: Corneal Neurovascularization; AMD: Age-Related Macular Degeneration; DR: Diabetic Retinopathy; VEGF: Vascular Endothelial Growth Factor; ROS: Reactive Oxygen Species; TBUT: Tear Breakup Time; RGC: Retinal Ganglion Cells; IOP: Increased Intraocular Pressure; BRB: Blood-Retinal Barrier
Introduction
Persimmon tree (Family: Ebenaceae, Genus: Diospyros, Specie: kaki or (D.Kaki)) has been cultivated throughout Asian countries (Korea, China, Japan and India) and used as sources of fruit and traditional medicine for centuries [1,2]. Because of its delicious taste and high nutritional values, Persimmon fruit is commonly used in a diet (as a fruit or in teas). Persimmon leaves extract (PLE) have been used as a traditional and/or herbal medicine against internal haemorrhage, ischemia, stroke, angina, paralysis, burns, constipation, and frostbite. PLE has largely been used in cosmetics as they contain anti-ageing compounds, and the compounds present in bark prevent melanin biosynthesis [3]. (D.Kaki) have more nutritional benefits as compared to apples [4]. PLE has anti-atherosclerotic, antidiabetic, anti-inflammatory, and anti-neurodegenerative properties [1,5-9]. Recent studies have shown that persimmons are rich in flavonoids and terpenoids [10] with other compounds like tannins, coumarins, ionones, fatty acids and naphthoquinones [11-16]. The flavonoids like quercetin and iso-quercetin in PLE are responsible for their anti-inflammatory effects [4]. These dietary flavonoids inhibit tumour necrosis factor-alpha (TNF-α) [17], vascular endothelial growth factor (VEGF) [18] interleukin-1beta (IL-1β), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) [19,20] that are known to be pro-inflammatory and pro-angiogenic cytokines. (D.Kaki)’s antioxidant activity is mainly linked to the presence of high molecular weight tannins that reduce the risk of cardiovascular diseases, hypertension, diabetes,and leukemia [21-23]. Along with that, terpenoids present in PLE are reported to suppress stimulus-induced superoxide generation and tyrosyl phosphorylation [24]. Antioxidant and antiinflammatory properties of PLE are crucial to maintain eye health. So, many researchers are interested in PLE to check its effects on different eye diseases. The eye is the one’s window to the outside world and it is the most sensitive organ of the human body. Among two important parts of the eye, the cornea is a clear front of the eye while the retina is located at the back. The cornea controls and focuses the light that enters the eye. The retina is a nerve layer at the posterior part of the eye that detects light and generates electrical impulses that are transmitted to the brain via the optic nerve [25]. The retina is made up of millions of light-sensitive cells called rods and cones that help to convert light into signals that the brain perceives as images. Any changes or disruption in the function of the cornea or retina can cause serious damage.
In the recent past, many scientists have tried to use PLE for different eye diseases like dry eye disease (DED), corneal neurovascularization (CoNV), glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and edema. So, the purpose of this review was to evaluate pharmaceutical, medicinal and ethnopharmacological applications of PLE for eye diseases. We expect that with more detailed investigations and clinical trials, the PLE can be a potential drug against different ocular abnormalities.
Factors Causing Ocular Disorders
Oxidative stress
Oxidative stress refers to cellular and molecular damage caused by reactive oxygen species (ROS). It has a major contribution in corneal as well as retinal diseases. Oxidative stress leads to ocular aging process and initiate or develop corneal injury [26]. Many corneal dystrophies are linked to oxidative stress. Oxygen is continuously required during the visual process [27]. The retina, which is made up of specialized neurons and retinal ganglion cells, is one of the body’s most oxygen-consuming tissues (RGCs) [28]. High oxygen consumption causes oxidative stress-induced retinal damage and induces a high risk of ROS accumulation in the retina which in turn raise a potential risk for retinal disorders or retinal damage [29-32]. It is already reported that patients with retinal degenerations exhibit high ROS levels vs low levels of anti-oxidative proteins compared to healthy patients [33]. Antioxidants are long been used and prescribed for better eye health [34] and are associated with a reduced risk for developing retinal degeneration [35].
Inflammation
Ocular inflammation is considered one of the leading factors for visual impairment. Some corneal [36] and most of the retinal disorders are linked to inflammation [37-40]. Despite significant progress in clinical care and understanding pathophysiological mechanisms, there is still a significant unmet medical need relating to ocular disorders. Many antioxidants and anti-inflammatory drugs are being used to treat these disorders but most of them are coupled with multiple side effects. So, there is a dire need to develop some drugs that can protect the eye without any harm.
Role of PLE Against Different Eye Diseases
Recently, different groups of scientists have studied the effect of PLE on the different eye diseases. Here, we will briefly discuss the eye diseases (DED, CoNV, AMD, DR, edema and glaucoma) and the role of PLE as potential drugs.
DED
With each blink of eye, tears spread on the cornea to provide lubrication and wash off any foreign object to keep the eye clean. DED is a serious condition that develops if a person doesn’t have enough quality tears to lubricate the cornea. It is an inflammatory condition with many resemblances to autoimmune diseases [41,42] that is a common problem of all ages. DED is characterized by inflammation of the ocular surface and lacrimal glands along with symptoms of discomfort, visual disruption and tear film instability [43]. Inflammatory cytokines are increased in DED conditions [44] that triggers apoptosis and apoptotic cells are found in dry eye animal models [45,46]. So, DED can be treated by inhibiting corneal inflammation [47]. Commonly used ocular drugs are unable to provide immediate and complete relief. Based on data from the National Health and Wellness Survey, 6.8 per cent of the United States adult population (approximately 16.4 million people) have been diagnosed with DED. PLE application regulated the key factors for the healthy eye like tear volume, tear breakup time (TBUT) and corneal epithelium lining in the dry eye mouse model. There were less apoptotic cells and the expression levels of apoptosis inducing inflammatory cytokines (IL-1α, IL-1β, TNF-α, MCP-1, and IL-6) were also decreased. So, PLE treatment not only helps the cornea to survive against degradation but also help cells to proliferate in a regular manner [48].
Corneal neurovascularization (CoNV)
CoNV is defined as the invasion of new blood vessels into the cornea and occurs as a result of inflammation of the cornea or imbalance between angiogenic and anti-angiogenic factors [49-52]. Under inflammatory conditions, corneal cells produce angiogenic factors like VEGF [53], which upregulates the production of MMPs [54,55] and stimulates blood vessel formation. The CoNV disrupts the corneal clarity leading to vision loss in many cases. Anti-inflammatory, anti-VEGF agents and MMP inhibitors are long been used to treat CoNV. All these drugs proved beneficial for a short period and has severe side effects [56]. When PLE was applied to the injured eye representing CoNV eye model, the protein expression level of angiogenic and inflammatory proteins (VEGF, MMP, IL-6, FGF) decreased significantly [57]. It is reported that the flavonoids could be the active compounds that exert these anti-inflammatory and anti-angiogenesis effects [58].
Glaucoma
Another lethal ocular disorder is glaucoma that affects the optic nerve [59], which is made up of a bundle of Retinal Ganglion cells (RGC) axons in the retina. The main cause of glaucoma is the flushing of aqueous humour that leads to increased intraocular pressure (IOP) [60,61]. One of the obstacles in preventing the etiology of glaucoma is protecting RGCs, and significant efforts have been made in scientific and clinical research to minimize RGC degradation [62]. PLE is shown to reduced IOP [63]. The studies show that PLE reduce glaucoma symptoms in animal models of glaucoma and play a protective role against RGCs death through its anti-oxidative and anti-inflammatory properties [64].
Age related macular degeneration (AMD)
AMD is known to be one of the leading cause of retinal degeneration and blindness [65]. It is a multifactorial disease including aging, environmental factors and genetic susceptibility [66]. Chorionic inflammation and oxidative stress are known to be the root cause of AMD and vision loss worldwide [67]. Antioxidants are long been used to treat retinal disorders [34]. D.Kaki fruit and leaves was proven to have antioxidant activities [21,68]. So, when PLE applied to the mouse model that represent retinal degeneration it ameliorates the symptoms [69].
Diabetic retinopathy (DR)
DR is an inflammation of macula triggered by blood-retinal barrier (BRB) breakage in diabetic patients [70]. Oxidative stress because of ROS accumulation and inflammatory cytokines plays a major role in pathogenesis of DR [71-73] The studies have demonstrated that SPARC-like protein 1 precursor (SPARCL1) is overexpressed in DR [74,75]. However, downregulation of this protein was observed in diabetic patients treated with PLE [76]. So, probably, PLE can be treated against DR disease
Edema
Corneal edema also known as the swelling of cornea it occurs because of fluid buildup in cornea. It results in loss of transparency and known to be the sign of acute corneal disorders. Damage of corneal epithelium or endothelium contributes to this. Ouabain (OU), a known Na+ /K+ -ATPae inhibitor, is reported to causes edema in human and rabbit eye models [77,78]. When PLE was applied to cells under the influence of OU, enzymatic activity and protein level of Na+ /K+ -ATPae was increased [79]. IOP also contributes to corneal edema [80,81], and a recent study showed PLE as an IOP lowering agent [63]. All these above-mentioned diseases seriously damage the eye. It is critical to diagnose the factors contributing to these conditions to treat them for the sake of healthy vision. So, the studies discusses here demonstrate that PLE can be a potential agent to prevent many corneal and retinal disorders.
Conclusions
It can be concluded from this review that PLE has the potential to be a candidate for the treatment of ocular diseases like DED, CoNV, glaucoma, AMD, DR and edema. However, further detailed studies including the identification of specific compounds responsible for these effects as well as the clinical trials on all age groups are needed before using PLE as an ocular drug.
Funding
The authors received no funding for this study.
References
- Funayama S, Hikino H (1979) Hypotensive principles of Diospyros kaki Chemical & pharmaceutical bulletin 27(11): 2865-2868.
- Xie C, Xie Z, Xu X, Yang D (2015) Persimmon (Diospyros kaki L.) leaves: A review on traditional uses, phytochemistry and pharmacological properties. Journal of Ethnopharmacology 163: 229-240.
- Ohguchi K, Nakajima C, Oyama M, Iinuma M, Itoh T, et al. (2010) Inhibitory effects of flavonoid glycosides isolated from the peel of Japanese persimmon (Diospyros kaki 'Fuyu') on melanin biosynthesis. Biological & pharmaceutical bulletin 33(1): 122-124.
- Gorinstein S, Zachwieja Z, Folta M, Barton H, Piotrowicz J, et al. (2001) Comparative contents of dietary fiber, total phenolics, and minerals in persimmons and apples. Journal of agricultural and food chemistry 49(2): 952-957.
- Bei W, Zang L, Guo J, Peng W, Xu A, et al. (2009) Neuroprotective effects of a standardized flavonoid extract from Diospyros kaki J Ethnopharmacol 126(1): 134-142.
- Kim HH, Kim DS, Kim SW, Lim SH, Kim DK, et al. (2013) Inhibitory effects of Diospyros kaki in a model of allergic inflammation: role of cAMP, calcium and nuclear factor-κ International journal of molecular medicine 32(4): 945-951.
- Izuchi R, Takahashi H, Inada Y (2009) Preparing a carotenoid polyphenol-enriched extract from the peel of persimmon, Diospyros kakif. Bioscience, biotechnology, and biochemistry 73(12): 2793-2795.
- Son JE, Hwang MK, Lee E, Seo SG, Kim JE, et al. (2013) Persimmon peel extract attenuates PDGF-BB-induced human aortic smooth muscle cell migration and invasion through inhibition of c-Src activity. Food chemistry 141(4): 3309-3316.
- Al Ishaq RK, Abotaleb M, Kubatka P, Kajo K, Büsselberg D (2019) Flavonoids and Their Anti-Diabetic Effects: Cellular Mechanisms and Effects to Improve Blood Sugar Levels. Biomolecules 9 (9).
- Thuong PT, Lee CH, Dao TT, Nguyen PH, Kim WG, et al. (2008) Triterpenoids from the Leaves of Diospyros kaki (Persimmon) and Their Inhibitory Effects on Protein Tyrosine Phosphatase 1B. Journal of Natural Products 71(10): 1775-1778.
- Matsuo T, Ito S (1978) The Chemical Structure of Kaki-tannin from Immature Fruit of the Persimmon (Diospyros kaki ). Agricultural and Biological Chemistry 42(9): 1637-1643.
- Bawazeer S, Rauf A (2021) In Vivo Anti-inflammatory, Analgesic, and Sedative Studies of the Extract and Naphthoquinone Isolated from Diospyros kaki (Persimmon). ACS Omega 6(14): 9852-9856.
- Yoshimura M, Mochizuki A, Amakura Y (2021) Identification of Phenolic Constituents and Inhibitory Activity of Persimmon Calyx and Shiteito against Tumor Cell Proliferation. Chemical and Pharmaceutical Bulletin 69(1): 32-39.
- Wang L, Xu ML, Rasmussen SK, Wang MH (2011) Vomifoliol 9-O-α-arabinofuranosyl (1→6)-β-d-glucopyranoside from the leaves of Diospyros Kaki stimulates the glucose uptake in HepG2 and 3T3-L1 cells. Carbohydrate Research 346(10): 1212-1216.
- Hitaka Y, Nakano A, Tsukigawa K, Manabe H, Nakamura H, et al. (2013) Characterization of Carotenoid Fatty Acid Esters from the Peels of the Persimmon Diospyros kaki. Chemical and Pharmaceutical Bulletin 61(6): 666-669.
- Kwon J, Park JE, Lee JS, Lee JH, Hwang H (2021) Chemical Constituents of the Leaves of Diospyros kaki (Persimmon). Plants, 10(10): 2032.
- Nair MP, Mahajan S, Reynolds JL, Aalinkeel R, Nair H, et al. (2006) The flavonoid quercetin inhibits proinflammatory cytokine (tumor necrosis factor alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the NF-kappa beta system. Clinical and vaccine immunology: CVI 13(3): 319-328.
- Freitas S, Costa S, Azevedo C, Carvalho G, Freire S, et al. (2011) Flavonoids inhibit angiogenic cytokine production by human glioma cells. Phytotherapy research: PTR 25(6): 916-921.
- Ende C, Gebhardt R (2004) Inhibition of matrix metalloproteinase-2 and -9 activities by selected flavonoids. Planta medica 70(10): 1006-1008.
- In Hwan P, Eun JK, Soo JL, Sang HL, Dai NN (2011) Quercetin with Antioxidant Activity Inhibits Matrix Metalloproteinase-2 and -9 in HT1080 Cell Line. J Cancer Prev 16(3): 223-230.
- Gu HF, Li C, Xu YJ, Hu W, Chen M, et al. (2008) Structural features and antioxidant activity of tannin from persimmon pulp. 41(2): 208-217.
- Chen XN, Fan JF, Yue X, Wu XR, Li LT (2008) Radical scavenging activity and phenolic compounds in persimmon (Diospyros kaki cv. Mopan). Journal of food science 73(1): C24-C28.
- Achiwa Y, Hibasami H, Katsuzaki H, Imai K, Komiya T (1997) Inhibitory effects of persimmon (Diospyros kaki) extract and related polyphenol compounds on growth of human lymphoid leukemia cells. Bioscience, biotechnology, and biochemistry 61(7): 1099-1101.
- Chen G, Lu H, Wang C, Yamashita K, Manabe M, et al. (2002) Effect of five triterpenoid compounds isolated from leaves of Diospyros kaki on stimulus-induced superoxide generation and tyrosyl phosphorylation in human polymorphonuclear leukocytes. Clinica chimica acta. International journal of clinical chemistry 320(1-2): 11-16.
- Wässle H (2004) Parallel processing in the mammalian retina. Nature reviews. 5(10): 747-757.
- Cejka C, Cejkova J (2015) Oxidative Stress to the Cornea, Changes in Corneal Optical Properties, and Advances in Treatment of Corneal Oxidative Injuries. Oxidative Medicine and Cellular Longevity 591530.
- Anderson B (1968) Ocular effects of changes in oxygen and carbon dioxide tension. Transactions of the American Ophthalmological Society 66: 423-474.
- Yu DY, Cringle SJ (2001) Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease. Progress in retinal and eye research 20(2): 175-208.
- Beatty S, Koh H, Phil M, Henson D, Boulton M (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Survey of ophthalmology 45(2): 115-134.
- Campochiaro PA, Strauss RW, Lu L, Hafiz G, Wolfson Y, et al. (2015) Is There Excess Oxidative Stress and Damage in Eyes of Patients with Retinitis Pigmentosa? Antioxidants & redox signaling 23(7): 643-648.
- Kowluru RA, Kowluru A, Mishra M, Kumar B (2015) Oxidative stress and epigenetic modifications in the pathogenesis of diabetic retinopathy. Prog Retin Eye Res 48: 40-61.
- Pinazo-Durán, MD, Zanón-Moreno V, Gallego-Pinazo R, García-Medina JJ ( 2015) Oxidative stress and mitochondrial failure in the pathogenesis of glaucoma neurodegeneration. Progress in brain research 220: 127-153.
- Dănulescu R, Costin D (2012) Use of blood markers in early diagnosis of oxidative stress in age related macular degeneration. Rev Med chir Med Nat Iasi 116(4): 1136-11342.
- Grover AK, Samson SE (2014) Antioxidants and vision health: facts and fiction. Mol Cell Biochem 388(1-2): 173-183.
- Zampatti S, Ricci F, Cusumano A, Marsella LT, Novelli G, et al. (2014) Review of nutrient actions on age-related macular degeneration. Nutr Res 34(2): 95-105.
- Galvis V, Sherwin T, Tello A, Merayo J, Barrera R, et al. (2015) Keratoconus: an inflammatory disorder? Eye 29(7): 843-859.
- Joussen, AM, Poulaki V, Le ML, Koizumi K, Esser C, et al. (2004) A central role for inflammation in the pathogenesis of diabetic retinopathy 18(12): 1450-1452.
- Ehlers JP, Fekrat S (2011) Retinal vein occlusion: beyond the acute event. Survey of ophthalmology 56(4): 281-299.
- Yoshida N, Ikeda Y, Notomi S, Ishikawa K, Murakami Y, et al. (2013) Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology 120(1): 100-105.
- Buschini E, Piras A, Nuzzi, R, Vercelli A (2011) Age related macular degeneration and drusen: neuroinflammation in the retina. Progress in neurobiology 95(1): 14-25.
- Stern ME, Schaumburg CS, Pflugfelder SC (2013) Dry eye as a mucosal autoimmune disease. International reviews of immunology 32(1): 19-41.
- Stevenson W, Chauhan SK, Dana R (2012) Dry eye disease: an immune-mediated ocular surface disorder. Arch ophthalmol 130(1): 90-100.
- The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul surf 5(2): 75-92.
- Calonge M, Enríquez-de-Salamanca A, Diebold Y, González-García MJ, Reinoso R, et al. (2010) Dry eye disease as an inflammatory disorder. Ocular immunology and inflammation 18(4): 244-253.
- Strong B, Farley W, Stern ME, Pflugfelder SC (2005) Topical cyclosporine inhibits conjunctival epithelial apoptosis in experimental murine keratoconjunctivitis sicca. Cornea 24(1): 80-85.
- Yeh S, Song XJ, Farley W, Li DQ, Stern ME (2003) Apoptosis of ocular surface cells in experimentally induced dry eye. Invest ophthalmol Vis sci 44(1): 124-129.
- Yagci A, Gurdal C (2014) The role and treatment of inflammation in dry eye disease. Int ophthalmol 34(6): 1291-301.
- Kim KA, Hyun LC, Jung SH, Yang SJ (2016) The leaves of Diospyros kaki exert beneficial effects on a benzalkonium chloride-induced murine dry eye model. Mol vis 22: 284-293.
- Chuang YL, Fang HW, Ajitsaria A, Chen KH, Su CY, et al. (2019) Development of Kaempferol-Loaded Gelatin Nanoparticles for the Treatment of Corneal Neovascularization in Mice. Pharmaceutics 11(12): 635.
- Zhang Y, He B, Liu K, Ning L, Luo D, et al. (2017) A novel peptide specifically binding to VEGF receptor suppresses angiogenesis in vitro and in vivo. Signal transduction and targeted therapy 2: 17010.
- Chang J H, Gabison EE, Kato T, Azar DT (2001) Corneal neovascularization. Current opinion in ophthalmology 12(4): 242-9.
- Sharif Z, Sharif W (2019) Corneal neovascularization: updates on pathophysiology, investigations & management. Romanian journal of ophthalmology 63(1): 15-22.
- Philipp W, Speicher L, Humpel C (2000) Expression of Vascular Endothelial Growth Factor and Its Receptors in Inflamed and Vascularized Human Corneas. Investigative ophthalmology & visual science 41(9): 2514-2522.
- Dias, S, Hattori K, Zhu Z, Heissig B, Choy M, et al. (2000) Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J clin invest 106(4): 511-521.
- Wang H, Keiser JA (1998) Vascular endothelial growth factor upregulates the expression of matrix metalloproteinases in vascular smooth muscle cells: role of flt-1. Circ Res 83(8): 832-840.
- Gupta D, Illingworth C (2011) Treatments for corneal neovascularization: a review. Cornea 30(8): 927-38.
- Yang SJ, Jo H, Kim KA, Ahn HR, Kang SW (2016) Diospyros kaki Extract Inhibits Alkali Burn-Induced Corneal Neovascularization. Journal of medicinal food 19(1): 106-109.
- Wu WB, Hung DK, Chang FW, Ong ET, Chen BH (2012) Anti-inflammatory and anti-angiogenic effects of flavonoids isolated from Lycium barbarum Linnaeus on human umbilical vein endothelial cells. Food & function 3(10): 1068-1081.
- Quigley HA, Addicks EM, Green WR, Maumenee AE (1981) Optic Nerve Damage in Human Glaucoma: II. The Site of Injury and Susceptibility to Damage. Archives of Ophthalmology 99(4): 635-649.
- Guo L, Moss SE, Alexander RA, Ali RR, Fitzke FW (2005) Retinal ganglion cell apoptosis in glaucoma is related to intraocular pressure and IOP-induced effects on extracellular matrix. Investigative ophthalmology & visual science 46(1): 175-182.
- Ventura LM, Feuer WJ, Porciatti V (2012) Progressive loss of retinal ganglion cell function is hindered with IOP-lowering treatment in early glaucoma. Investigative ophthalmology & visual science 53(2): 659-663.
- Shen J, Wang Y, Yao K (2021) Protection of retinal ganglion cells in glaucoma: Current status and future. Experimental eye research 205: 108506.
- Ahn HR, Yang JW, Kim JY, Lee CY, Kim TJ, et al. (2019) The Intraocular Pressure-Lowering Effect of Persimmon leaves (Diospyros kaki) in a Mouse Model of Glaucoma. International journal of molecular sciences 20(21).
- Ryul Ahn H, Kim KA, Kang SW, Lee JY, Kim TJ (2017) Persimmon Leaves (Diospyros kaki) Extract Protects Optic Nerve Crush-Induced Retinal Degeneration. Scientific reports 7: 46449.
- Fletcher AE (2010) Free radicals, antioxidants and eye diseases: evidence from epidemiological studies on cataract and age-related macular degeneration. Ophthalmic research 44(3): 191-198.
- Armstrong RA, Mousavi M (2015) Overview of Risk Factors for Age-Related Macular Degeneration (AMD). Journal of stem cells 10(3): 171-191.
- Masuda T, Shimazawa M, Hara H (2017) Retinal Diseases Associated with Oxidative Stress and the Effects of a Free Radical Scavenger (Edaravone). Oxid Med Cell Longev 9208489.
- Lee JH, Lee YB, Seo WD, Kang ST, Lim JW, et al. (2012) Comparative Studies of Antioxidant Activities and Nutritional Constituents of Persimmon Juice (Diospyros kaki cv. Gapjubaekmok). Preventive nutrition and food science 17(2): 141-151.
- Kim KA, Kang SW, Ahn HR, Song Y, Yang SJ, et al. (2015) Leaves of Persimmon (Diospyros kaki) Ameliorate N-Methyl-N-nitrosourea (MNU)-Induced Retinal Degeneration in Mice. Journal of agricultural and food chemistry 63(35): 7750-7759.
- Romero Aroca P, Baget Bernaldiz M, Pareja Rios A, Lopez Galvez M, Navarro Gil R (2016) Diabetic Macular Edema Pathophysiology Vasogenic versus Inflammatory. Journal of diabetes research 2156273.
- Koleva Georgieva DN, Sivkova NP, Terzieva D (2011) Serum inflammatory cytokines IL-1beta, IL-6, TNF-alpha and VEGF have influence on the development of diabetic retinopathy. Folia medica 53(2): 44-50.
- Boss JD, Singh PK, Pandya HK, Tosi J, Kim C, et al. (2017) Assessment of Neurotrophins and Inflammatory Mediators in Vitreous of Patients with Diabetic Retinopathy. Investigative ophthalmology & visual science 58(12): 5594-5603.
- Kang Q, Yang C (2020) Oxidative stress and diabetic retinopathy Molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biology 37: 101799.
- Watanabe K, Okamoto F, Yokoo T, Iida KT, Suzuki H, et al. (2009) SPARC is a major secretory gene expressed and involved in the development of proliferative diabetic retinopathy. Journal of atherosclerosis and thrombosis 16(2): 69-76.
- Chee CS, Chang KM, Loke MF, Angela Loo VP, Subrayan V (2016) Association of potential salivary biomarkers with diabetic retinopathy and its severity in type-2 diabetes mellitus: a proteomic analysis by mass spectrometry. PeerJ 4: e2022.
- Mohd MK, Bao Quoc T, Yoon Jin J, Soo Hyun P, William EF, et al. (2017) Assessment of the Therapeutic Potential of Persimmon Leaf Extract on Prediabetic Subjects. Mol Cells 40(7): 466-475.
- Geroski DH, Kies JC, Edelhauser HF (1984) The effects of ouabain on endothelial function in human and rabbit corneas. Current Eye Research 3(2): 331-338.
- Trenberth SM, Mishima S (1968) The Effect of Ouabain on the Rabbit Corneal Endothelium. Investigative ophthalmology & visual science 7(1): 44-52.
- Afzal R, Hwang HB (2022) Persimmon Leaves (Diospyros kaki) Extract Enhances the Viability of Human Corneal Endothelial Cells by Improving Na (+)-K (+)-ATPase Activity. Pharmaceuticals (Basel, Switzerland) 15: 1.
- Melamed S, Ben Sira I, Ben Shaul Y (1980) Corneal endothelial changes under induced intraocular pressure elevation: a scanning and transmission electron microscopic study in rabbits. The British journal of ophthalmology 64(3): 164-169.
- Neuburger M, Maier P, Böhringer D, Reinhard TJFJ (2013) The impact of corneal edema on intraocular pressure measurements using goldmann applanation tonometry, Tono Pen XL, iCare, and ORA an in vitro model. Journal of glaucoma 22(7): 584-590.