Part 1: Polyphenols And Visual Health: Potential Effects On Degenerative Retinal Diseases
Mar 23, 2022
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Abstract: Dietary polyphenols are a group of natural compounds that have been proposed to have beneficial effects on human health. They were first known for their antioxidant properties, but several studies over the years have shown that these compounds can exert protective effects against chronic diseases. Nonetheless, the mechanisms underlying these potential benefits are still uncertain and contradictory effects have been reported. In this review, we analyze the potential effects of polyphenol compounds on some visual diseases, with a special focus on retinal degenerative diseases. Current effective therapies for the treatment of such retinal diseases are lacking and new strategies need to be developed. For this reason, there is currently a renewed interest in finding novel ligands (or known ligands with previously unexpected features) that could bind to retinal photoreceptors and modulate their molecular properties. Some polyphenols, especially flavonoids (e.g., quercetin and tannic acid), could attenuate light-induced receptor damage and promote visual health benefits. Recent evidence suggests that certain flavonoids could help stabilize the correctly folded conformation of the visual photoreceptor protein rhodopsin and offset the deleterious effect of retinitis pigmentosa mutations. In this regard, certain polyphenols, like the flavonoids mentioned before, have been shown to improve the stability, expression, regeneration, and folding of rhodopsin mutants in experimental in vitro studies. Moreover, these compounds appear to improve the integration of the receptor into the cell membrane while acting against oxidative stress at the same time. We anticipate that polyphenol compounds can be used to target visual photoreceptor proteins, such as rhodopsin, in a way that has only been recently proposed and that these can be used in novel approaches for the treatment of retinal degenerative diseases like retinitis pigmentosa; however, studies in this field are limited and further research is needed in order to properly characterize the effects of these compounds on retinal degenerative diseases through the proposed mechanisms.
Keywords: flavonoids; retinal degenerative diseases; retinitis pigmentosa; protein folding; ligand binding; rhodopsin
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1. Introduction
Different studies have reported that dietary polyphenols exert protective and beneficial effects against chronic diseases such as neurodegenerative and cardiovascular diseases, cancer, and diabetes [1]; however, the mechanisms underlying these benefits are far from being completely understood and more research is needed in order to define them. Despite all the benefits polyphenols can provide, there are some important aspects that have to be taken into account when discussing their physiological effects. These compounds have low oral bioavailability and other properties like their physicochemical stability, gastrointestinal absorption, and metabolism are important to ensure an effective action [2,3].
Despite the existent gap of knowledge in their action mechanism, the World Health Organization has recommended increasing the intake of fruit, vegetables, and fiber due to the high number of plant-derived components [4] with polyphenols having an important role, since they may confer health benefits related to non-communicable diseases(NCDs)[5,6]. Although associating polyphenols with specific diseases is challenging [7], some promising results have been obtained in different observational studies regarding polyphenols and certain NCDs [8,9], including some visual diseases. For this reason, the implication of polyphenols in health and disease states needs to be studied and better defined because of the expected positive impact on human health.
The main purpose of this review is to provide a synthetic account of some of the potential health benefits that polyphenols can have to improve human quality of life and to ameliorate the progression of some diseases, with a special emphasis on visual disorders. The use of a number of ubiquitous polyphenolic compounds is investigated here as potential treatments for a wide range of pathological conditions. Herein, we focus on the effects of these compounds on retinal functioning and particularly on their potential use to counteract retinal protein mutations, like those associated with retinal degenerative diseases like retinitis pigmentosa(RP). There is a clear need for more clinical trials to unravel their physiological significance as only a small number of studies have been conducted on the effects of polyphenols in human vision and their results need further validation.
2. Methods
This article is a literature review of the effect polyphenols can exert on some visual diseases, especially their impact on retinal degenerative diseases. Given the new properties that have been given to polyphenols over the years, the main purpose of our research is to show that these compounds may have positive effects on human visual health and also encourage researchers to inquire into this field. The different studies in this review (randomized control trials, meta-analysis, reviews, and experimental and observational studies) were identified by searching the PubMed and Cochrane databases up to and including February 2021. The following medical subject heading keywords were used: "polyphenols", "flavonoids", "retinal degenerative diseases", and"retinitis pigmentosa". Relevant papers were identified and selected independently by two authors following the inclusion criteria, i.e., original full-text articles that were written in English (including clinical and preclinical studies). On the other hand, the exclusion criteria included papers and articles written in other languages than English.
3. Polyphenols as Repurposed Drugs
Polyphenols or dietary phenolic compounds are known as the largest group of phytochemicals [10] and are a group of natural compounds sharing common structural features (Figure 1). Currently, there is a renewed interest in this wide family of natural compounds due to the potential roles regarding human health and disease states. Different lines of evidence, derived from sustained work in the last several years, provide support for an important role for polyphenols both in helping maintain a healthy lifestyle and in the prevention of prevalent diseases like cancer, cardiovascular and neurodegenerative diseases [11-13]. Specifically, several studies have suggested that the consumption of different polyphenols from natural sources such as fruit and vegetables can contribute to preserving vision and can even reverse visual impairment in certain visual disorders [14,15].
![es of representative and abundant polyphenols from different subfamilies. Quercetin is a typical flavonoid found in many products. Resveratrol is a natural polyphenolic phytoalexin. Curcumin is derived from the rhizome of turmeric and is usually found in its keto form. Finally, daidzein is one of the most common isoflavones. The polyphenol superfamily includes a large number of sub-families, among which we can find flavonoids, phenolic acids, stilbenes, and lignans [16]. In fact, they constitute a group of natural products in the plant kingdom that is one of the most numerous and ubiquitously distributed. One of the most studied groups, from these different sub-classes, is that of flavonoids, comprising over 4000 members [17]. Flavonoids have a characteristic structure of a 15-carbon skeleton of a chromane ring attached to another aromatic ring [18]. The biosynthesis of these complex polyphenols is linked to primary metabolism [10]. Flavonoids are stored, in their native state, in plants as glycoside and non-glycosylated conjugates and can be absorbed by the small intestine and readily metabolized, once ingested, by phase II enzymes. After this biochemical process, the resulting moieties can enter systemic circulation [19,20]. It should be noted that not all flavonoids are absorbed by the small intestine. A large number of them enter the large intestine, where the deconjugated metabolites are degraded by the colonic microbiota into molecules like phenolic acids that can be easily absorbed [19]. One of the main proposed biological actions of polyphenols is associated with their antioxidant power within living cells; however, detailed investigations indicate that these effects, in many tissues, may not be as relevant as previously suggested. This is due to the fact that in many tissues it is difficult for these compounds to reach the threshold concentration needed to exert any significant biological effect [21,22]. Nonetheless, recent studies have suggested that polyphenols may have significant effects on human health, such as anti-inflammatory, anti-microbial, and tumor-suppressing properties [23–25]. The diversity of polyphenolic compounds of natural origin, their chemical lability, and their complex bioavailability patterns consequently necessitates stringent evaluation of the physiological effects of these compounds, and such evaluations are not always available. These evaluations are absolutely needed for later use in therapeutic applications. 4. Implications and Potential Benefits of Polyphenols on Human Health As already discussed, polyphenols have been well characterized for their antioxidant effects, but their physiological relevance has been questioned due to the limited bioavailability that renders relatively low concentrations which may hamper achieving significant Figure 1. Structures of representative and abundant polyphenols from different subfamilies. Quercetin is a typical flavonoid found in many products. Resveratrol is a natural polyphenolic phytoalexin. Curcumin is derived from the rhizome of turmeric and is usually found in its keto form. Finally, daidzein is one of the most common isoflavones](/Content/uploads/2022842169/20220323103717b1b02e19a56a4000a29040e34368b70b.png "es of representative and abundant polyphenols from different subfamilies. Quercetin is a typical flavonoid found in many products. Resveratrol is a natural polyphenolic phytoalexin. Curcumin is derived from the rhizome of turmeric and is usually found in its keto form. Finally, daidzein is one of the most common isoflavones. The polyphenol superfamily includes a large number of sub-families, among which we can find flavonoids, phenolic acids, stilbenes, and lignans [16]. In fact, they constitute a group of natural products in the plant kingdom that is one of the most numerous and ubiquitously distributed. One of the most studied groups, from these different sub-classes, is that of flavonoids, comprising over 4000 members [17]. Flavonoids have a characteristic structure of a 15-carbon skeleton of a chromane ring attached to another aromatic ring [18]. The biosynthesis of these complex polyphenols is linked to primary metabolism [10]. Flavonoids are stored, in their native state, in plants as glycoside and non-glycosylated conjugates and can be absorbed by the small intestine and readily metabolized, once ingested, by phase II enzymes. After this biochemical process, the resulting moieties can enter systemic circulation [19,20]. It should be noted that not all flavonoids are absorbed by the small intestine. A large number of them enter the large intestine, where the deconjugated metabolites are degraded by the colonic microbiota into molecules like phenolic acids that can be easily absorbed [19]. One of the main proposed biological actions of polyphenols is associated with their antioxidant power within living cells; however, detailed investigations indicate that these effects, in many tissues, may not be as relevant as previously suggested. This is due to the fact that in many tissues it is difficult for these compounds to reach the threshold concentration needed to exert any significant biological effect [21,22]. Nonetheless, recent studies have suggested that polyphenols may have significant effects on human health, such as anti-inflammatory, anti-microbial, and tumor-suppressing properties [23–25]. The diversity of polyphenolic compounds of natural origin, their chemical lability, and their complex bioavailability patterns consequently necessitates stringent evaluation of the physiological effects of these compounds, and such evaluations are not always available. These evaluations are absolutely needed for later use in therapeutic applications. 4. Implications and Potential Benefits of Polyphenols on Human Health As already discussed, polyphenols have been well characterized for their antioxidant effects, but their physiological relevance has been questioned due to the limited bioavailability that renders relatively low concentrations which may hamper achieving significant Figure 1. Structures of representative and abundant polyphenols from different subfamilies. Quercetin is a typical flavonoid found in many products. Resveratrol is a natural polyphenolic phytoalexin. Curcumin is derived from the rhizome of turmeric and is usually found in its keto form. Finally, daidzein is one of the most common isoflavones")
The polyphenol superfamily includes a large number of subfamilies, among which we can find flavonoids, phenolic acids, stilbenes, and lignans [16]. In fact, they constitute a group of natural products in the plant kingdom that is one of the most numerous and ubiquitously distributed. One of the most studied groups, from these different sub-classes, is that of flavonoids, comprising over 4000 members [17]. Flavonoids have a characteristic structure of a 15-carbon skeleton of a chromane ring attached to another aromatic ring [18]The biosynthesis of these complex polyphenols is linked to primary metabolism [10]. Flavonoids are stored, in their native state, in plants as glycoside and non-glycosylated conjugates and can be absorbed by the small intestine and readily metabolized, once ingested, by phase I enzymes. After this biochemical process, the resulting moieties can enter systemic circulation [19,20].
It should be noted that not all flavonoids are absorbed by the small intestine. A large number of them enter the large intestine, where the deconjugated metabolites are degraded by the colonic microbiota into molecules like phenolic acids that can be easily absorbed [19].
One of the main proposed biological actions of polyphenols is associated with their antioxidant power within living cells; however, detailed investigations indicate that these effects, in many tissues, may not be as relevant as previously suggested. This is due to the fact that in many tissues it is difficult for these compounds to reach the threshold concentration needed to exert any significant biological effect [21,22]. Nonetheless, recent studies have suggested that polyphenols may have significant effects on human health, such as anti-inflammatory, anti-microbial, and tumor-suppressing properties [23-25]. The diversity of polyphenolic compounds of natural origin, their chemical lability, and their complex bioavailability patterns consequently necessitate a stringent evaluation of the physiological effects of these compounds, and such evaluations are not always available. These evaluations are absolutely needed for later use in therapeutic applications.
4. Implications and Potential Benefits of Polyphenols on Human Health
As already discussed, polyphenols have been well characterized for their antioxidant effects, but their physiological relevance has been questioned due to the limited bioavailability that renders relatively low concentrations which may hamper achieving significant in vivo effects [21,22]; however, different alternative molecular mechanisms in which polyphenols appear to have a role have been identified and this gives these compounds
another set of properties that may represent benefits for human health. These include different actions both at the intra- and inter-cellular signaling pathways levels, like, for example, regulating nuclear transcription factors and fat metabolism and modulating the synthesis of inflammatory mediators like cytokines, tumor necrosis factor αx, interleukin-1β, and interleukin-6 [26,27]. As a general overview, different studied flavonoids have been shown to play different roles in cellular processes, such as increasing insulin secretion, reducing apoptosis, promoting β-cell proliferation, and reducing inflammation and oxidative stress in some cells [28]. All these effects play a role in different processes, such as glucoregulation, and show that flavonoids can have favorable effects on diabetes and obesity prevention and control [29-31].
Despite all the potential beneficial effects of polyphenols proposed to date, a key aspect to consider concerns the effective concentration in the human body of these compounds and the amount of natural food that needs to be consumed to reach such a concentration. In many cases, the required polyphenol quantity needed to exert a certain physiological function can be attained by the consumption of common foods in appropriate amounts in a normal diet, and, in such cases, toxicity is avoided. In other cases, where the potential beneficial effects can be foreseen, the consumption of polyphenol-containing foods has to be increased and in principle, no adverse effects are expected if this increase is carefully planned. Finally, if the physiologically active concentration cannot be reached with common food ingestion, then dietary supplementation or pharmacological approaches may be necessary. This can lead to an increase in adverse secondary effects that would require a strict follow-up of the intake and proper control of the dose regime [30].
Polyphenols are mainly provided by the intake of different food sources, such as coffee, tea, cocoa, and apples and they have been associated with several potential health benefits [56,11,14,32-36]. In fact, polyphenols have been mechanistically involved in glucose metabolism, platelet function, endothelial function, blood pressure, inflammation, and cholesterol levels, among others [37,38]. This variety of cellular functions that may be affected by the action of polyphenols provides an excellent platform for the development of effective health prevention strategies as well as novel therapeutic approaches not only for prevalent NCDs but even for genetic hereditary rare pathological conditions [5,6]. Some of the evidence regarding the beneficial effect of polyphenols on human health comes from observational studies and this implies taking several factors into consideration when extracting meaningful conclusions when interpreting experimental data. For example, a high intake of polyphenols from different foods may be balanced by a reduced intake of otherwise potentially harmful foods of an animal origin; however, observational studies can be helpful in many cases, e.g.,in the formulation of hypotheses that will then be included into controlled intervention studies. In fact, observational studies regarding this matter should be complemented and supported by rigorous and wide clinical studies that evaluate the hypothesis that dietary phenolics have a positive role in improving human health and preventing disease states [28].
In addition to all the effects on cardiometabolic health, polyphenols are also thought to have a beneficial role in cognitive function. For example, some longitudinal studies show that regular dietary chocolate consumption can reduce the risk of cognitive decline 39,40. Studies of other food sources like tea show that its consumption can help lower the risk of cognitive impairment, reduce the risk of depression, and have protective effects against some diseases like Parkinson's disease [41-44].
From all polyphenol types, dietary flavonoids can also have beneficial effects in retinal degenerative diseases like retinitis pigmentosa, where mutations in retinal proteins can cause photoreceptor cell death and vision loss, eventually leading to blindness. In fact, the flavonoid quercetin was found to have an effect on the conformational stability and function of the visual G protein-coupled receptor(GPCR) rhodopsin (Rho)[45]. These results suggest that quercetin can have a positive effect on the stability and conformational properties of the G90V Rho RP mutant. These results emphasize that other roles, in addition to their established antioxidant effect, can be envisaged for flavonoids and other polyphenols. The effect on retinal Rho suggests an effect at the receptor level that deserves further investigation. These results open a new frame of possibilities to use this and other flavonoids, possibly in combination with specific retinoids, in order to treat retinal degeneration associated with RP. This strategy could also be used to overcome the mutational effect associated with different pathological conditions in other members of the GPCR superfamily [45].
Polyphenolic compounds, and particularly flavonoids, are good prospects for treating or ameliorating the progression of human diseases, in addition to their established antioxidant potential that is considered important as part of a healthy lifestyle.
