Medicinal Plants and Natural Products Used in Cataract Management

Cataract is the leading reason of blindness worldwide and is defined by the presence of any lens opacities or loss of transparency. The most common symptoms of cataract are impaired vision, decreased contrast sensitivity, color disturbance, and glare. Oxidative stress is among the main mechanisms involved in the development of age-related cataract. Surgery through phacoemulsification and intraocular lens implantation is the most effective method for cataract treatment, however, there are chances of serious complications and irreversible loss of vision associated with the surgery. Natural compounds consisting of antioxidant or anti-inflammatory secondary metabolites can serve as potential leads for anticataract agents. In this review, we tried to document medicinal plants and plant-based natural products used for cataract treatment worldwide, which are gathered from available ethnopharmacological/ethnobotanical data. We have extensively explored a number of recognized databases like Scifinder, PubMed, Science Direct, Google Scholar, and Scopus by using keywords and phrases such as “cataract”, “blindness”, “traditional medicine”, “ethnopharmacology”, “ethnobotany”, “herbs”, “medicinal plants”, or other relevant terms, and summarized the plants/phytoconstituents that are evaluated in different models of cataract and also tabulated 44 plants that are traditionally used in cataract in various folklore medical practices. Moreover, we also categorized the plants according to scientific studies carried out in different cataract models with their mechanisms of action.


CATARACT: AN OVERVIEW
The crystalline lens lies behind the iris and represents the dynamic part of the eye's optical system, responsible for focusing the image onto the retina. Cataract is defined by the presence of any lens opacities or loss of transparency. The most common symptoms of cataract are impaired vision, decreased contrast sensitivity, color disturbance, and glare. Changes in the lens may also serve as markers for systemic health and aging in the over-all population (Song et al., 2014). According to the type of lens opacities, cataract is classified into three classical types: nuclear, posterior subcapsular, and cortical. These types can also be associated with each other and if untreated, they progress to total lens opacification. Some of the most common causes for cataract in adults are age, diabetes, steroid use, family history, or trauma. Congenital cataract has a significant prevalence, also.
Cataract is the foremost reason of blindness worldwide in spite of the technological advancements in eye surgery in the last two decades. In 2010, there were around 32 million blind people and 191 million were with poor vision. One in three blind people suffered from cataract (Khairallah et al., 2015). The World Health Organization (WHO) suggests that by 2020 the number of blind people will reach 90 million globally (Khairallah et al., 2015;Taylor, 2016). The strategy to fight this challenge is costly, aiming human resource, infrastructure development, and effective disease control. The latter is dependent on the characteristics of the specific disease. Prevalence of cataract increases with age, from 5% for patients of age 52-62 to 64% for patients over 70 years, in Europe (Prokofyeva et al., 2013). Age is a non-modifiable risk factor involved in the pathogenesis of cataract, hence the progressive aging of the population is an alarming issue. Identifying modifiable risk factors for cataract is imperative and may help to establish the preventive measures.
The surgical treatment for cataract consists of cataractous lens extraction and intraocular lens implant. It is the only current treatment available in order for patients to recover their visual function. This implies a significant cost and there is a significant lack of access to surgery, especially in the developing world. Despite good postoperative outcomes, complications are possible following cataract surgery. Studies have suggested that pseudophakia patients have a higher risk of retinal detachment. Endophthalmitis has also been reported in 0.12% of the operated cases (Toh et al., 2007). After the surgery, the mobility of the lens is lost and correcting glasses are usually necessary. This will only increase the expense and the discomfort for the patient and society. Medical treatment would be a desired alternative.
The most primitive written reference to cataract surgery was discovered in Sanskrit manuscripts dating back from the 5th century BCE. It was attributed to Sushruta, a well-known ancient plastic surgeon who described a procedure known as couching, in which the cataractous lens was displaced with a sharp tool to fall it into the vitreous cavity, clearing the visual axis, though the vision was significantly blurred as there were no corrective lenses or glasses (Uhr, 2003;Sachdev, 2017). Even at the time of Mesopotamia (ca. 3,000-4,000 BCE) records reveal that mysticism along with different animal products, vegetables, and minerals were utilized for the treatment of devil and spirits causing eye diseases. Hundreds of remedies were also described during the Greek era (ca. 460-375 BCE) for disorders of the eyes. Moreover, eye diseases are also described anatomically by Sushruta (as mentioned above), Galen and various medicinal and surgical procedures were described for the treatment of eye diseases (Duke-Elder, 1962;Albert and Edwards, 1996;Goodman, 1996). In 1748, the introduction of modern cataract surgery was done by Jacques Daviel in Paris, in which the cataractous lens is removed from the eye. Later on in 1753, Samuel Sharp of London presented the intracapsular procedure, wherein the whole lens was removed by an incision by put on thumb pressure. In 1867 silk sutures for cataract surgery was originally described by Henry Willard Williams of Boston (Uhr, 2003).

CATARACT -PATHOGENESIS
Various mechanisms have been associated with age-related cataract pathogenesis. Lens opacities may appear due to changes in the microarchitecture, caused by mutations, biomechanical, or physical changes.

Mutations
Despite cataract being a multifactorial disease, sometimes mutations alone can cause lens opacities and this usually leads to congenital or pediatric cataract. Studies have presented more and more evidence that genetic factors are also part of age related cataract pathogenesis, raising the probability of molecular genetic relations between lens development and aging (Hejtmancik and Kantorow, 2004). Out of around 42 genes and loci that have been found to underlie congenital forms of cataract, a few of them have been linked with age associated cataract: EPHA2 (encodes a member of ephrin receptor of protein-tyrosinekinases), CRYAA, CRYGS (both encode lens proteins), FYCO1 (encodes a scaffolding protein which is active in microtubule transport of autophagic vesicle), or TDRD7 (encodes an RNAbinding protein). The mutation p.Gly18Val in CRYGS results in a protein with normal structure in physiological conditions. The alterations in its structure occur after thermal or chemical injury. A similar mutation is Phe71Leu in CRYAA. The discovery of mutations in genes coding for TDRD7, EPHA2, and FYCO1 has provided the initial evidence for the functional importance of posttranscriptional mRNA regulation, ephrin signaling, and the autophagy pathway, respectively, in human lens transparency (Shiels and Hejtmancik, 2015).
Gene mutations underlying secondary forms of cataract could also play part in age related cataract formation. A mutation in gene on 17q of galactokinase 1 (GALK1) which is responsible for encoding of the first enzyme in galactose metabolism, trigger autosomal recessive GALK1 1-deficiency with hypergalactosemia and cataract as a result of galactitol accumulation and osmotic stress. A coding variation in GALK1 (p.A198V) generates enzyme instability associated with amplified risk of age-related cataract in the Japanese population (Okano et al., 2001).

Oxidative Stress
Oxidative stress is among the main mechanisms involved in the development of age-related cataract. Oxidative stress occurs when reactive compounds like the superoxide anion, hydroxyl radicals, and hydrogen peroxide are not neutralized by antioxidant enzymes and defense systems. Enzymes like catalase, SOD, and GPX are crucial for the homeostasis of the antioxidant system and ROS. When levels of ROS increase, this denatures the lens nucleic acids, proteins, and lipids, leading to mutations and cell apoptosis. Metabolic activities mostly take place in the lens epithelium. The lens epithelium uses the antioxidative enzymes in order to prevent damages caused by oxidative stress. Studies suggest that the highest concentration of SOD is in the lens epithelium (Rajkumar et al., 2013). These enzymes are also present in other parts of the lens and play a very important part in maintaining the lens clarity (Chang et al., 2013). SOD is responsible for converting superoxide anion into hydrogen peroxide, and then hydrogen peroxide is transformed into water by catalase or GPX. SOD enzyme activity is associated with cofactors like zinc, manganese, and copper. However, a decreased level of cofactors in cataractous lenses was not found. Experimental animal models show a decreased level of glutathione in the nucleus, therefore there is a higher susceptibility for oxidative damage and opacity formation (Giblin, 2000). Studies have shown that serum and aqueous humor levels of antioxidative enzymes are decreased in patients with cataract. However, there was no significant difference among different types of cataract and enzymes serum levels (Ohia et al., 2005;Wang et al., 2015).

Crystallins Problems
Crystallins, the major structural lens proteins have an imperative role in the lens transparency and acquire post-translational alterations during cataract formation, which lead to protein insolubility, aggregation and loss of lens transparency. Out of the three major crystallins, α-, β-, and γ-, α crystallins exhibit chaperone like activity, preventing them to aggregate. The chaperone activity is reduced in cataractous lenses. Prolonged hyperglycemic conditions increase the chances of crystallins deterioration (Reddy et al., 2014). Calcium activates calciumbinding proteins triggering changes in the shape and charge of the proteins. Elevated levels of calcium appear to induce proteolysis of crystallins by calpain, an intracellular cysteine protease. Activation of calpain, an intracellular cysteine protease, leads to proteolysis of the lens proteins. In order for calpains to activate, a high level of calcium is required (Obrosova et al., 2010). Studies demonstrate that the privation of an endogenous inhibitor of calpain, named calpastatin, could be linked to the initial changes that cause cataract (Nakajima et al., 2014). Some antioxidants have been reported to regulate calcium influx in selenite induced cataracts, for instance the flavonoid fraction of Brassica oleracea (Vibin et al., 2010).

Protein Structures
Alterations in the protein structure are also determined by UV exposure. Studies have shown that UVB generates more damage than UVA and that damages are prevented by the lens filters. After UV radiations, proteins suffer chemical reactions resulting in aggregations, decreasing the transparency of the lens (Cetinel et al., 2017). The crystalline lens is particularly exposed to phototoxic damage, because it absorbs most of UV radiation, together with cornea. The main association is with cortical cataract, most of the absorption occurring at the posterior surface of the lens. UV radiation can generate free radicals including oxygen-derived species, that cause lipid peroxydation of cellular membranes or can damage DNA directly (Youn et al., 2011). In vivo, induced cataract has no absolute threshold for UV exposure. UV induced cataract for in vivo exposure at UV-300 nm has a continuous dose-response function (Söderberg et al., 2016). UV radiation data from Eurosun library implied that rates of cataract were higher in regions with higher ambient UV-B radiation levels (Delcourt et al., 2014).

MEDICINAL PLANTS AND NATURAL PRODUCTS USED AGAINST CATARACT
Opacity of the lens is triggered by free radicals in most of the cases (Varma et al., 1984;Thiagarajan and Manikandan, 2013). Severe oxidative stress also leads to the protein modifications by free radicals, and several natural products from plants are helpful in the prevention of proteins insolubilization, which may delay the opacity of lenses (Bhadada et al., 2016b). Natural compounds constituting of antioxidant or anti-inflammatory secondary metabolites could be viewed as potentially optimal anticataract agents as antioxidant effect is among the major mechanisms for prevention of cataract in most of the cases, however, not all the plants possessing antioxidant potential could have anticataract properties. The role of plant polyphenols in anti-cataractogenic activities is also studied in the comprehensive manner either in vitro or in vivo (Rooban et al., 2009(Rooban et al., , 2011Kim et al., 2011c;Wang et al., 2011;Sasikala et al., 2013;Sunkireddy et al., 2013;Ferlemi et al., 2016).
Although there is substantial basic and applied research in the field of cataract management by natural products, mostly ethno-pharmacological/ethnobotanical research, there are not many review papers available about the activity analysis of natural products against different cataract models. One paper focused on antioxidant containing plants against cataract was found with 41 plants investigating anti-cataract activity (Thiagarajan and Manikandan, 2013). Although there are few ethnopharmacological surveys and their reviews available (Maregesi et al., 2017), there is no detailed review available on the activities of different plants extracts and natural products in cataract models.

METHODOLOGY AND HYPOTHESIS
In this work, we attempted to gather and document the widely scattered information from various preclinical investigations and ethnopharmacological reports. We searched several web databases namely, Scifinder, ScienceDirect, Pubmed, Scopus, and Google Scholar. Boolean information retrieval method (Pohl et al., 2010) was applied using plant name with "AND" operator as also done in some other systemic reviews (Tewari et al., 2017(Tewari et al., , 2018 followed by "cataract" and using other different keywords such as "cataract", "traditional medicine", "ethnobotany", "sodium selenite", and "ethnopharmacology".
The main research question we try to address in this paper is: "are medicinal plants/natural products used in various folk and traditional medicine of importance in the management of cataract?" and "what are the major preclinical in vitro/in vivo models that are used globally for the evaluation of cataract?". We hypothesize that plants used in ethnomedicine are not only of potential importance but also preclinical studies conducted on various models of cataract could result in the development of potential drug candidates in future. This could be very rewarding for the scientists and scholars working in this area and also very beneficial for the patients to take forward the preclinically effective plants for clinical studies.

RESULTS
Oxidative stress is involved in activation of MAPKs. Compounds resulted from the activation of MAPKs have been studied and were associated with cell apoptosis. The p38 MPAK was studied in vitro and it was shown that it is activated by hydrogen peroxide,  Alcoholic extract at an increasing concentration between 0 and 300 µg/mL (IC 50 106 ± 5.11 µg/mL) Exhibit significant inhibitory effects on aldose reductase (AR) in the rat lens in vitro.

Kumar et al., 2011
Allium cepa L. (Tuber/bulb) 50% diluted juice Prevention of selenite-induced cataract formation by increase in superoxide dismutase (SOD) and total antioxidant level and activities of glutathione peroxidase (GPX) in lens through instillation of juice in rat eyes.
(Tuber/bulb) Aqueous extract, 1 mL/kg body weight Free radical scavenging activity (FRSA), antioxidant properties and associated with increased TA level, SOD and GPX activities in the lens.
Aqueous extract at 1 and 10 mg/mL (IC 50 11.3 µg/mL)  Ethanolic extract (300 µg/mL) Increase in the activity of antioxidant enzymes and increase in the level of reduced glutathione in lens, reduces free radical generation. Anitha et al., 2011Anitha et al., , 2013 Vitex negundo L. (Leaves) Flavonoids Maintenance of antioxidant status, by inhibition of ROS generation/lipid peroxidation in lens.
Flavonoid fraction 2.5 µg/g body weight Improvement of total antioxidant capability in lens, prevention of protein oxidation and lipid peroxidation.

Sasikala et al., 2010
Origanum vulgare L. (Upper crust of beans) Hydroethanolic extract (70%), 2 g/kg Averts selenite-induced cataract through its antioxidant property.  induce cell apoptosis in lens epithelial cells and the antioxidant agents could reduce its effects. Inhibitors of p38 MAPK reduced ROS levels and apoptosis (Bai et al., 2015). Lipids peroxidation is also a reason of age related cataract. This process has a negative impact on lipid-lipid and lipid-protein interactions. Research has shown high levels of hydroperoxides, oxy derivatives, and diene conjugates of phospholipid fatty acids in the aqueous humor of cataract patients. Also, studies have reported high levels of oxidation products of linoleic acid in patients with early cataract (Bai et al., 2015). A schematic representation of oxidative stress mechanisms involved in cataract etiology and action mechanisms of several medicinal plants with conducted pharmacological studies for the treatment of cataract are presented in Figure 1.
Polyol pathway is associated with diabetic cataract. Enzymes implicated in the polyol pathway, sorbitol dehydrogenase and AR are responsible for the conversion of glucose to fructose. Sorbitol, an intermediate compound, was found to produce cell lesions by modifying the membrane permeability. Therefore, accumulation of sorbitol leads to osmotic stress, collapse, and liquefaction of lens fibers resulting in loss of lens transparency (Pollreisz and Schmidt-Erfurth, 2010;Hashim and Zarina, 2012). AR converts glucose to sorbitol, dependent to NADPH. As a consequence, the level of NADPH decreases, also having a negative impact on the glutathione activity and the antioxidant system. In vivo and in vitro studies have shown that by inhibiting the activity of AR, the progression to cataract in patients with diabetes is reduced (Kim et al., 2011a;Ramana, 2011). The glycosylation pathway has also been linked to diabetic cataract. Excessive glucose level induces the glycation of proteins, generating superoxide radicals and AGEs in the process. Recent studies suggest that there is interdependence between the oxidative stress and polyol pathway, through AR and iNOS, responsible for the nitric oxide production during oxidation (Snow et al., 2015;Li et al., 2017) (Figure 1).
Here, we present details of plants evaluated against cataract with discussion of their possible mechanism of action (Figure 1 and Tables 1-4). Some important chemical structures of the natural products that are used against cataract or found in plants used in the management of cataract are also presented at Figure 2 (not all chemical structures are presented). We categorized the plants based upon the models evaluated. Table 1 describes the natural products used against cataract evaluated on selenite/sodium selenite induced cataracts, in Table 2 natural products used against cataract on preventive photooxidative damage is described, Table 3 deals with the natural products used against cataract on sugar-induced lens opacity/Streptozotocin induced diabetic cataract/galactose or glucose induced/ZDF models, in Table 4 AGEs-BSA crosslinking inhibition assay and lens AR activity models are described, and Table 5 describes the natural products used against cataract on hydrogen peroxide and naphthalene induced cataract and other miscellaneous models.
Like in case of any other disease conditions, medicinal plants are being used in management of various eye ailments from ancient times. Medicinal plants are used in case of cataract, eye infections, conjunctivitis, eye dryness, and other eye disorders in many countries including India (Sandhu et al., 2011;Das et al., 2013;Rothe and Maheshwari, 2016), Bangladesh (Yusuf et al., 2006;Das et al., 2007Das et al., , 2013, Nepal (Manandhar, 2002;Acharya and Pokhrel, 2006;Gewali, 2011; Kadota et al., 1994 Morinda citrifolia L. (Fruits) Sequential water, ethanol, and chloroform extracts AR inhibition and free radical scavenging activity.

Gacche and Dhole, 2011b
Onoclea orientalis ( Watanabe et al., 2013), Sudan (Khalid et al., 2012), Tanzania (Maregesi et al., 2016), South Africa (Pendota et al., 2008), and many other regions of the world. The literature analysis revealed that the sugar-induced or diabetic cataract models were the highest used models which were applied for the evaluation of around 39.84% of the plants/natural products. It was followed by selenite/sodium selenite induced cataract which is another common model of evaluation of cataract, and it accounts for around 36.71% of the plants/natural products. AGE-BSA crosslinking inhibition assay was used for the evaluation of 10.93%, and hydrogen peroxide and naphthalene induced cataract was account for evaluation of around 9.38% of the plants (Figure 3). In most of the cases especially for the diabetic cataract models, it was found that different antioxidant parameters like soluble protein, reduced glutathione, superoxide dismutase, lipid peroxidation were used (Bhadada et al., 2016b). Inhibition of AR was found as the most common hypothesis in these models (Bhadada et al., 2016b). Uses of in silico studies were also found common in some studies to explore the binding mode of the phytochemicals with the aldose reductase enzyme (Bhadada et al., 2016b;Patil et al., 2016).
In most of the studies, rats or rat pups lens were utilized as the model (Bhadada et al., 2016b;El Okda et al., 2016;Ferlemi et al., 2016;Sreelakshmi and Abraham, 2016) and in some cases fresh goat eyeballs were also used (Patil et al., 2016). In vitro studies were also utilized in large number of experiments. In some studies lens crystalline turbidity assay was used by estimation of lens protein turbidity using homogenized decapsulated porcine lenses which were procured from the local slaughterhouses in some cases (Ferlemi et al., 2016;Liao et al., 2016). Some other important factors in cataractogenesis like UV radiation was also used by researchers, and it was also proposed that some compounds can protect γ-crystallin from UV radiation damage and can act as potential anticataract agents (Liao et al., 2016).
Many of the mentioned plants showed potent anticataract activity in in vitro and in vivo models. Vitex negundo and Vitis vinifera were the plants in which sufficient preclinical studies were conducted and they may be of potential clinical use. It is also interesting that Vitex negundo was also used in the folk medicine in India (Kulkarni et al., 2008). The genus Ocimum was also one such genus which is utilized in folk medicine and was scientifically validated for its anticataract potential. Some other interesting findings were the use of Pleurotus ostreatus extract that prevented cataract in 75% of the tested rats (Isai et al., 2009). In a clinical study, although not directly against cataract, silybin improved the peripheral nerve conduction velocity and was reported as an effective aldose reductase inhibitor that can improve the disorder of polyol pathway in non-insulin dependent diabetes patients and prevent chronic complications of diabetes (Zhang et al., 1995) like cataract.
The detailed list of medicinal plants used in the management of cataract as reported in many ethnopharmacological surveys is given in Table 6. Singh et al. (2012) had also listed the medicinal plants used in management of cataract, however, the mechanistic insight was not performed and plants used in the management of cataract available till 2011 were covered (Singh et al., 2012).
It was found that most of the surveys were conducted in different developing countries like Bangladesh, Chile, India, Nepal, and Tanzania (see Figure 4). Apart from the ethnobotanical surveys, several plants used in traditional medicine systems like Ayurveda were also found beneficial for cataract. One such good example of use of Ayurvedic formulation against cataract is the use of Triphala which showed good effect against cataract in in vitro and in vivo (Gupta et al., 2010a;Mahajan et al., 2011) studies and also was evaluated clinically and showed promising results (Bhati and Manjusha, 2015), however, more clinical studies are required involving larger patients for better scientific evidences. Plants used in Ayurveda like Momordica charantia, Eugenia jambolana, Pterocarpus marsupium, and Trigonella foenum-graecum prevented cataract development when observed in alloxan diabetic cataract model (Rathi et al., 2002;Vats et al., 2004).
Although, many plants have been utilized in various folklore medical practices, most of them are not scientifically validated. Moreover, some of these traditional practices may be harmful for the eyes as well. For instance, use of latex/sap of some Euphorbiaceae plants like Euphorbia hirta and Croton caudatus can be dangerous for eyes rather being beneficial. Moreover, sufficient care is obligatory while using the herbal medication for any of the eye diseases, as there is a case study that showed  that cataract or development of cataract was aggravated after treatment with some unrevealed herbal medication in a 11 years old patient with atopic dermatitis (Kang et al., 2008).
This survey reveals that selenite/sodium selenite induced cataracts was the preferred model in studies with natural products used against cataract, followed by sugar-induced  Ragasa et al., 2013;Garaniya and Bapodra, 2014;Maregesi et al., 2016 Aloe vera (L.) Burm. f.
One drop of leaf juice twice a day is used as eye drop Anthraquinones; aloe emodin and chrysophanol Tanzania Lee et al., 2013;Maregesi et al., 2017 Barleria prionitis L.
Juice of fresh leaves is used as eye drops.
Fresh leaves are squeezed and the juice is utilized as eye drops.
Oleanolic acid Chile Gusinde, 1936a,b;Silva and Stück, 1962 Breynia New stems are heated and the juice of the stem is received in a vessel and mixed with breast milk and Oxalis rosea Holocellulose; lignin and α-Cellulose Chile Gusinde, 1936a,b;Oliveira et al., 2016 Citrus limon (L.) Osbeck (Rutaceae) Salted lemon juice is used as eye drops.
Leaves are cooked and eaten for 2-4 weeks or till curing.
Fresh latex which was produced on detachment of leaf is applied daily until recovery.
Not described Tanzania Maregesi et al., 2016 Croton caudatus Geisel. (Euphorbiaceae) Gum/sap is mixed with mustard oil and applied to eyes.
Stem juice is given in the eye as a drop. Not described Chile Gusinde, 1936a,b Oxalis corniculata L.
Aerial parts are squeezed and the juice is used as eye drops 2 times daily till recovery.

Adenosine
Tanzania Fuentes et al., 2012;Maregesi et al., 2016 (Continued) Frontiers in Pharmacology | www.frontiersin.org Bubbles of 1-2 drops of the watery latex from the stem are blown gently into the affected eyes, 3 times a day for 4-5 days Isounedoside and grandifloric acid India Ismail et al., 1996;Dipankar, 2012 Typha angustifolia L.
New stems are applied on the eye Pentacosanoic acid; β-sitosterol; nonadecanol; naringenin; daucosterol; uracil typhaneoside; nicotinic acid; vanillic acid; succinic acid; thymine; stearic acid propanetriol ester Chile Gusinde, 1936a,b;Jia et al., 1986;Liao et al., 1990;Chen et al., 2008;Varghese et al., 2009;Shukla et al., 2013 Tridax procumbens (L.) L. ( lens opacity/diabetes induced cataract models, AGE-BSA cross-linking inhibition assay, lens aldose reductase activity models, and hydrogen peroxide-induced cataract, and other miscellaneous models. Diverse and sometimes complex phytochemicals present in numerous plants possess a broad spectrum of mechanisms for cataract treatment. One of the main mechanisms for the anticataract effect is the antioxidant effect (inhibitory effect on ROS formation). Several plants increase the activity of antioxidant enzymes as well. Some other important mechanisms involved are calpain inhibition, inhibition of lipid peroxidation, amelioration of calcium induced proteolysis, alteration in the protein profiles and the insolubilization of soluble proteins, attenuation in the inducible nitric oxide synthase expression, and AR inhibition.
For development of ocular drug delivery, various factors should be considered which affect the bioavailability of the ocular drugs. These factors include pH, structural forms of the drug, osmolarity, viscosity, tonicity, and the salt form of the drug (Goodman, 1996). Increasing scientific evidence clearly reveals that natural products have the potential to combat cataract at different levels but at the same time critical evaluation for the safety and toxicity profiles are required. Despite of potential evidence for the significance of natural products against cataract, the possible clinical trials are still lacking.

CONCLUSION
Ethnopharmacological evaluation of the medicinal plants used for cataract treatment could be a beneficial approach for the development of potential natural product-based therapies against cataract. In this work we have analyzed over 120 papers and found that around 44 medicinal plants/natural products are used for cataract management in different traditional and folk medicine systems. Possible mechanisms of around 118 plants/natural products (including repetition in different models) are also studied. It is interesting that most of the ethnobotanical survey studies are reported from many developing countries like Bangladesh, Chile, India, Nepal, and Tanzania. The medicinal plants are not only utilized in the folk medicine but many of the plants are also mentioned for cataract management in the traditional systems of medicine like in Ayurveda, traditional Chinese medicine and in Korean tradition medicine. However, it is still of utmost importance to document more comprehensively the plants utilized in the traditional medicine and rigorous preclinical and clinical studies are required to validate the use of such plants.
It was also notable that some combinations of plants were also used such as KIOM-79 which is a mixture of ethanol extract (80%) of parched Puerariae Radix, gingered Magnoliae Cortex, Glycyrrhizae Radix, and Euphorbiae Radix is used in Korean tradition medicine. Another such important combination formulation is 'Triphala' which is widely used Ayurvedic formulation in India containing fruits of Emblica officinalis Gaertn., Terminalia chebula Retz., and Terminalia belerica (Gaertn.) Roxb. However, many of the plants used in traditional medicines are not evaluated for their efficacy using rigorous scientific studies. Detailed mechanism-based in vitro and in vivo studies should be performed for the characterization of their possible pharmacological effects. On the other hand, evaluation of possible toxicity of these medicinal plants/natural products is also important as these medicines are directly applied in eyes and can have not just potential benefits but also harmful effects. Although there are numerous studies going on at preclinical level, clinical evidence for efficacy is still the need of the hour.

AUTHOR CONTRIBUTIONS
DT, OS, AM, DG, HD, JE, and AA drafted the initial manuscript. All authors improved, contributed, and agreed on the final version of the manuscript.