4.1. Broccoli
The
Brassica Oleracea, belonging to the vegetable
Brassicaceae family, is popularly known as broccoli (Italian variety), brecol (spanish) and ka-i-lan or kale (Chinese variety) with the new food baby broccoli or tenderstem being a mix between the traditional broccoli and the kale. This family of natural foods constitutes a group of vegetables including the following: cabbage, broccoli, cauliflower, red cabbage, Brussels sprouts, radish, turnip, and others, all of them important sources of micronutrients and fiber [
62]. The green broccoli (Calabrese) is the most common variety of this plant, sized 10–20 cm, weighing 500 g, with dark green and light green stems and buds from chlorophyll pigment. The broccoli contains high levels of water, carotenes (beta-carotene, lutein), vitamins (A, B, C, E), isothiocyanates, fatty acids (linoleic acid, palmitic acid) and diverse minerals (calcium, iron, magnesium, potassium, phosphorus, sodium). Additionally, amino acids (tyrosine, aspartic acid, glutamic acid, proline, valine) were found in larger concentrations. Even more, broccoli sprouts, have been implicated in many biological activities such as antiapoptotic, anti-inflammatory, antioxidant, antimicrobial, as well as neuroprotectant properties, as recently reviewed [
63,
64,
65]. The ethyl acetate fraction of broccoli florets was reported to exert potent antioxidant and anti-inflammatory effects, by inhibiting nitric oxide release, counteracting the ROS and nuclear factor-κB activation in a dose-dependent manner, concluding that broccoli can be utilized as a dietary supplement to improve nutrition as well as for the adjunctive intervention in chronic inflammation [
66]. The pro-apoptotic function of broccoli has been previously demonstrated in different cancers [
67,
68,
69]. In this concern, the effects of the bio-accessible fraction of broccoli, kale, mustard, and radish, were evaluated on colon cancer cells, showing its usefulness to reduce this disease in combination with a balanced diet. However, a review about the targets and mechanism on breast cancer reported the contradictory roles of sulforaphane derivatives in breast cancer therapy [
70]. The effects of the broccoli isothiocyanates, amino acid compounds that are detoxified by conjugation with glutathione, have also been reviewed in both in vitro and in vivo models of acute and chronic neurodegenerative diseases [
71]. Similarly, the sulphoraphane (glucoraphanin), a phytocompound belonging to the isothiocyanate family with a role in preventing vascular complications in diabetes [
72], also demonstrated important benefits for neurodegenerative disorders [
73].
Nowadays, AMD in the dry and wet clinical types is the first cause of blindness among the elder population [
2,
5,
6,
42,
56]. It has been estimated that early AMD cases will augment to approximately 17.8 million in 2050 [
74]. Increasing the consumption of specific nutrients may be an effective intervention to vision care in AMD as well as in other sight-threatening ocular diseases. Among these nutrients, the xanthophyll pigments lutein and zeaxanthin and its metabolic by-products, were identified in the macula in 1985, at the highest concentrations of the whole human body, suggesting pivotal roles for these carotenoids in the retina [
75]. In fact, lutein and zeaxantin have been proved to anatomically and functionally protecting the macula against photo-oxidative attack [
76]. The Age-Related Eye Disease Study (AREDS) concluded that the daily intake of 10 mg of lutein and 2 mg of zeaxantin alone or in combination with docosahexaenoic acid (DHA) (350 mg/day) and eicosapentaenoic acid (EPA) (650 mg/day) to the original AREDS supplement formula composed by vitamin C, vitamin E, beta carotene, zinc oxide and cupric oxide [
77], except the beta carotene, demonstrated efficacy in the prevention of AMD progression to advanced forms in right risk eyes [
78]. The question arose as to whether it is possible to identify individuals at risk of AMD based on the findings of their central macular pigment optical density (MPOD) levels. In this concern, Berstein et al. [
79] concluded that a central MPOD below 0.2 d.u. should be taken as low levels, 0.2–0.5. d.u. as mild levels and more than 0.5 as high levels.
To improve knowledge of the effects of the intake of broccoli on ocular health our group performed a pilot intervention study involving 14 voluntaries age/sex-matched, divided into: (1) healthy participants consuming a daily amount of 375 g of broccoli, which is equivalent to 10 g of lutein [
77], according to a strict menu plan lasting for 4 consecutive weeks, (BG;
n = 7), and (2) healthy participants no broccoli consumers, as the control group (CG;
n = 7). We determined plasma total antioxidant capacity (TAC), by enzymatic-colorimetric assays, as previously published [
6,
7,
8,
9,
10,
11] and MPOD determined from retinographies from the right eye (RE) and left eye (LE) collected with the VISUCAM 500
® (Carl Zeiss Meditec Iberia, Tres Cantos, Madrid, Spain). This tool was gently rendered by Carl Zeiss Meditec Iberia (Tres Cantos, Madrid, Spain). As previously, reported [
80]. An important requirement was to respect the way of cooking to avoid loss of the broccoli properties, including not eating the broccoli boiled, fried, or steamed and not using oven and microwave, according to the Yu et al., reports on the impact of home food preparation on the availability of antioxidants and other bioactivities in broccoli [
81]. Volunteers were instructed not to smoke and not to abuse alcohol. We also advised the participants to avoid eating citrus (lemon, tangerine, orange, kiwi), carrots, spinach, or beans. Data showed an improvement of the subjective criteria on visual function in the activities of daily living. A significant increment in the MPOD in the retinographies of the RE from the BG (
Figure 1) by an average of 30% more than their counterparts not assigned to the broccoli course.
Moreover, it was also found a significant increase in plasma TAC in the BG (baseline: 1.231 ± 0.120 mM; end-of-study: 1.858 ± 0.393 mM; p = 0.002). This study mainly suggests that the broccoli intake improved the antioxidant load and the MPOD associated with lutein dietary supplementation, thus helping in protect the macula against oxidative injury.
In summary, the biochemical and physicochemical characteristics of broccoli make this food optimal to fight against age-related chronic inflammatory and/or neurodegenerative disorders, to better eye and vision care, as widely suggested [
62,
63,
64,
65,
66,
72,
73,
80,
81,
82,
83,
84,
85].
4.2. Saffron
The
Crocus Sativus is a plant that provides a spice, saffron, which has been classically used in food preparation, being the most expensive spice in the world [
86]. Etymologically saffron comes from the Arabic term za’farān (yellow) as well as from the Persian za’ferân (golden stigmas), the Latin word safranum and the Spanish azafrán. Since ancient times, medicinal properties have been attributed to this species because it has more than 100 metabolites in the composition of its stigmas, including crocin isomers, zeaxanthin, lycopene and vitamin B12, among others [
87].
Major saffron components are crocin and crocetin (that gives the yellow color to the stigmas), picrocrocin (that contributes to the bittersweet flavor), kaempferol (from the crocus sativus petals) and safranal (which lends the fragrance to the spice, also contributing to the flavor) [
86,
87,
88]. However, the main therapeutic activities of saffron are due to its main bioactive components, the carotenoids crocetin and crocin [
88]. Crocin is hydrolyzed to crocetin when absorption occurs in the intestine [
89], and once in the blood it can be transported to different tissues and can even cross the blood-brain barrier reaching tissues of the central nervous system [
90]. This spice has been used in traditional medicine as anti-ischemic, hypolipidemic, anti-hypertensive, anxiolytic, antidiabetic, antidepressant, anticancer, and cardioprotective [
91,
92]. It has been possible due to the various properties attributed to crocetin as an anti-inflammatory, anti-apoptotic and antioxidant [
92]. Antioxidant activities are due to their ability to scavenge free radicals [
93], their capacity to decrease telomerase activity and to increase proapoptotic effects in cancer cells. In addition, the anti-inflammatory effect is due to the regulation of genes that control the release of proinflammatory cytokines, adhesion molecules and proinflammatory enzymes by glial cells, as well as modulation of inflammatory pathways (e.g., nuclear factor-κB) [
94].
The beneficial effects of saffron have been demonstrated in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, where it has been shown to exert a certain neuroprotective effect [
95,
96]. In addition, in neurodegenerative diseases of the eye, saffron may also have these beneficial effects [
94].
In AMD, it has been shown that in the early stages of the disease, saffron can improve visual function by reversing the damage to photoreceptors and bipolar cells caused by oxidative stress [
97]. In addition, daily supplementation with saffron improved retinal changes observed with optical coherence tomography and electroretinogram in patients with both dry and wet AMD [
98].
In DR, saffron can reduce insulin resistance in pre-diabetic patients [
99]. In vitro models of diabetes have shown that saffron can control microglia activation. In addition, crocin supplementation decreases macular thickness improving visual acuity in patients with diabetic macular edema probably by its anti-inflammatory effects [
100].
In glaucoma, there are two studies in patients on the possible hypotensive effect of saffron that show contradictory results. In patients with primary open-angle glaucoma, using a dose of 1g twice a week, no hypotensive effect was observed [
101]. However, in another study using a dose of 30 mg per day, a decrease in intraocular pressure (IOP) was found [
102]. Our group recently analyzed the anti-inflammatory and neuroprotective effect of saffron in a mouse model of chronic ocular hypertension (OHT) [
103]. We found that saffron extract (standardized to 3% crocin content) resulted in a reduction in both the number and signs of microglial cell activation (
Figure 2A,B) as well as a down-regulation of the purinergic receptor P2RY12a, a marker of inflammation-related non-activated microglia. In addition, saffron also prevented the retinal ganglion cells (RGCs) death that occurred in chronic hypertensive eyes (
Figure 2C,D), postulating that this neuroprotective effect of saffron could be due to its anti-inflammatory and antioxidant properties [
103].
4.3. Tigernut-Chufa de Valencia
The
Cyperus Esculentus is a herbaceous, perennial, fasciculate-rooted plant found across the world, but distributed mostly in Egypt, Nigeria and Spain. Additionally known as “Juncia Avellanada” and tigernut (TN), it has a highly developed rhizomatic system with the tubers produced at the apical ends of the rhizomes [
104]. It is known that only one specimen can produce hundreds or thousands of tubers through a growing season. According to the macroscopic characteristics three main tuber types have been described: brown, black and yellow [
105]. Over the last decades, substantial research has evidenced that TN is a good source of oil, and its by-products are rich in various nutrients and bioactive compounds [
105,
106]. The available data reveals that tubers are rich in essential dietary constituents such as proteins (3.28–8.45%), fats (22.14–44.92%), fibers (8.26–15.47%) and ashes (1.60–2.60%). The lipid profiling interestingly revealed that TN oil has a similar fatty acid composition to olive oil [
107].
The TN finds the Mediterranean climate of Valencia particularly favorable for its cultivation and development. In this area, it is known as
chufa de Valencia. It was introduced in the Valencian region in the 8th century CE, a multi-cultural period lasting 711–1492 in which Christians, Jews and Muslims created a high degree of civilization in Spain and Europe. The curative properties of the
chufa de Valencia date from 1297 [
108]. Arnau de Vilanova (1232–1311), a famous physician and theologian of this time, prescribed eating
chufa de Valencia to alleviate different disorders [
109]. The Valencian botanist Cavanilles (1745–1804) reflected in his works from 1795, the cultivation of the TN in the town of Alboraya (Valencia, Spain) [
110]. The
chufa de Valencia is dark brown, sized 0.9-1.6 cm long and 0.7–1.1 cm wide. According to the shape, two types are distinguished: the elongated (
chufa llargueta) and the rounded (
chufa armela). The
chufa de Valencia is a historical gastronomic and cultural wholesome brown tuber crop, with outstanding nutritional properties. This fresh functional food consists in carbohydrates 18%, fats 17% (including ω6/ω9 fatty acids), proteins 8%, fiber 13%, oligoelements (calcium, copper, iron, magnesium, phosphorus, potassium, zinc) and vitamins (C, E), providing 460 kcal/100 g [
111]. It is also extensively used to prepare a cold beverage, known as “horchata de chufa” typical to Valencia [
112].
Several epidemiologic and experimental studies pointed out the wide variety of therapeutic benefits of TN, such as cardioprotector, antioxidant, anti-inflammatory and neuroprotectant [
113,
114]. The TN also contributes to lowering total cholesterol and triglycerides, stabilizes glycemic profile, provides amino acids, vitamins, minerals, and fiber. Its salt content is low, and it does not contain lactose or fructose. Thus, the TN and its derivatives (
horchata, flours, oils, spices, etc.) constitute a very complete food, as they offer large proportions of vitamins and minerals (such as vitamins C and E), lipids and oleic acid which are useful for the control of cholesterol and triglycerides [
115,
116]. As for the presence of vitamin E, it is important to highlight its importance as it is an essential vitamin, not synthesized by the body, but necessary for its proper functioning, and therefore must be included in the diet [
117]. In addition to being one of the major antioxidants, vitamin E has the ability to scavenge free radicals, which reduces the risk of cancer and prevents the progression of pre-cancerous lesions [
118,
119].
Among the most prevalent eye diseases are ocular surface disorders. DED defines the pathology of the ocular surface that induces tear-film deficiency and dry eyes [
120]. The term includes complex diseases that affect the eyelids, lacrimal glands, conjunctiva, cornea and the tear film, with very high global prevalence, affecting both genders and people aged 60 years and above. The signs and symptoms range from mild redness, foreign body sensation, photophobia, and/or blurred vision, to intense and diffuse hyperemia, epiphora, continuous sensations of itchiness, stinging and burning, as well as visual impairment. First-line therapy includes eye drops of artificial tears, lubricant gels and ointments. The imbalance between prooxidant and antioxidant sources damages the ocular surface structures [
121,
122]. It has also been assumed that chronic inflammation is involved in OSD/DED, as demonstrated by the release of pro-inflammatory mediators and the positive response to the oral supplementation with antioxidants and essential fatty acids [
123,
124]. In this concern, anti-inflammatory eye drops can also be prescribed [
125,
126]. In spite of this, further research is needed to improve the eyes and the quality of life of patients affected by DED.
In this concern, our group conducted one study in the past years (2016–2018) about the role of the daily intake of chufa de Valencia in eye health, with the main purpose of evaluating its effects on DED by integrating clinical and biochemical data. A pilot study on 20 women aged 45–70 years, office employees of the administration services of the University of Valencia, with the common characteristic of working with computers during the workday were included in the study and classified as: (1) women working with computers assigned to a daily ration of 30 g of fresh chufa de Valencia, kindly given by the Regulatory Council of the Designation of Origin Chufa de Valencia (Alboraya, Valencia, Spain) during 3 consecutive months (n = 10; ChG) and (2) women working with computers without consuming the tuber (n = 10; CG). A personal interview including the ocular surface disorder questionnaire (OSDI; Allergan Inc., Irvine, CA, USA) to discriminate between normal-mild-moderate-severe DED, and ocular examination (best corrected visual acuity, the spontaneous number of closing eyelids in 1 min: blinking frequency that in normal conditions 9–12/min; quantitative Schirmer test, to evaluate the amount of wetting the strip located on the inferior inner eyelid during 5 min, that in normal conditions is more than 10 mm; qualitative break up time test (BUT), the time interval between last blink and the appearance of first dry spot over the cornea, that in normal conditions is more than 5 s), were carried out for all women participants. One important point of this study was to ensure compliance with the supplement food by the participants, which is essential to optimize the effectiveness of the nutritional intervention. Average duration of computer uses during the workday was 5.8 ± 2 h with similar type of screen and computer for the two groups of participants. Tear samples from the inferior eyelid lacrimal meniscus were collected with capillaire microtubes, labeled and stored at −80 °C until processing.
Mean age of participants was 55.4 ± 6.2 years. The OSDI questionnaire revealed that 68.4% of the ChG had moderate dry eyes at baseline and the same participants had mild-to-moderate dry eyes at the end of study (61.6%). All volunteers displayed signs and symptoms of DED, ranging from redness, grittiness, itchiness, foreign body sensation, burning, stinging and blurred vision. Eye discomfort, visual impairment, and reduction of the quality of life related to the eyes and vision, were referred by the volunteers at the onset of this study. However, a noticeable reduction of the signs, symptoms and subjective sensations was recorded at the end of the food supplementation. The blinking frequency was significantly and positively reduced in the ChG after the oral intake period as compared to the non-supplemented employers (
p = 0.042). The BUT test was significantly higher in the ChG at the end of study (RE: 7.4 ± 0.7 s, vs. 9.8 ± 0.4 s;
p = 0.011; LE: 7.5 ± 0.7 s vs. 9.7 ± 0.4 s,
p = 0.016). Additionally, the ChG showed higher Schirmer test marks at end-of-study, as compared to baseline (RE: 7.1 ± 0.7 mm vs. 10.5 ± 0.9 mm,
p = 0.002; LE: 7.0 ± 0.6 mm vs. 12.9 ± 1.8 mm,
p = 0.001), as reflected in
Figure 3. In addition, no adverse effects were reported in relation to the supplementation in the assigned participants to this regime. In contrast, all participants declared to be satisfied with the organoleptic properties of the intake of
chufa de Valencia.
In conclusion, the daily intake of 30 g. of chufa de Valencia improved the amount and stability of the tear film, decreasing the signs, symptoms, and subjective sensations of the DED patients.
As reflected in the anterior subsection (3.1 Broccoli) of this review, AMD refers to the chronic, progressive degeneration of the macula, a common eye disorder affecting people aged 60 years and more [
1,
2,
3,
6,
36,
37,
38,
77,
78,
79]. Up to 200 million people worldwide currently have AMD which is caused by complex interactions between aging comorbidities and genetics with the environmental factors, and other unknown situations [
1,
2,
3,
6]. The clinical AMD forms, dry and wet, can be clinically distinguished, with the dry AMD accounting for 90% of all cases. AMD progressively leads to central vision loss and reduced quality of life in the affected individuals.
We performed onr more pilot study on 30 healthy volunteers (12 men and 18 women) aged 44–51 years to evaluate the effects of the daily intake of fresh chufa de Valencia on the antioxidant status as well as in the MDOP measurement. As in the previous work, the tubers were gently donated by the Regulatory Council of the Designation of Origin Chufa de Valencia (Alboraya, Valencia, Spain). Each participant consumed a daily ration of 30 g of fresh chufa de Valencia during 3 consecutive months. It was not permitted to eat spinach, broccoli, pumpkin, carrots, citric, horchata or oral/topical nutraceutics, during the study course. The MPOD was done at baseline and at end of follow-up. Retinographies from the RE/LE were collected with the VISUCAM 500® (Carl Zeiss Meditec Iberia, Tres Cantos, Madrid, Spain). Blood samples were collected from the antecubital vein, that were centrifuged to separate blood and plasma. The latter was aliquoted and frozen at −80 °C until processing to determinate the malondialdehyde (MDA)/thiobarbituric acid reactive substances (TBARS) and TAC, by enzymatic-colorimetric methods.
The
chufa de Valencia daily core regimen induced a significant increase in the MPOD as reflected in the retinographies from baseline to end-of-study (
Figure 4).
Additionally, a significant improvement of the plasmatic TAC values (
p = 0.032) and a significant reduction in parallel of the plasmatic MDA/TBARS (
p = 0.017) at the end of follow-up was clearly detected (
Figure 5). From this latter study, we concluded that the daily intake of fresh
chufa de Valencia mitigated the oxidative stress by means of its antioxidant effects, as well as protected the macula by increasing the MPOD in healthy subjects.
These findings suggest that a regular chufa de Valencia intake may serve as a dietary prophylaxis adjunctive intervention for patients at risk of AMD and vision loss.
4.4. Walnuts
Walnut is the fruit of the juglans tree (
Juglandaceae family), with strong, outspread branches, native probably from Persia (
Juglans Regia). The walnuts are the round seeds of that tree, available in a range of distinct sizes and colors, and usually consumed as a nut when the hard shell has been wide open and discarded. Walnuts are a rich source of bioactive nutritional components that has the ability to modulate multiple metabolic pathways that contribute to protection against many chronic diseases, including those that affect the optic nerve, the retina and the ocular microcirculation. Most of these bioactives have a synergistic effect, acting in the protection of the physiological metabolic and vascular pathways [
125]. Walnuts have high contents of polyphenols, phytosterols, Υ-tocopherol, and mainly α-linolenic acid (ALA), in addition to minerals [
125], as listed in
Table 1 for the
Juglans Californica, being the general properties antioxidant, anti-inflammatory, neuroprotection, anti-thrombotic, anti-arrhythmic, cardiovascular protection, cholesterol-lowering and improve gut microbiota.
Human clinical trials have suggested an association of walnut consumption with better cognitive performance and memory improvement in adults, with beneficial effects on memory, learning, motor coordination, anxiety, and locomotor activity [
126,
127,
128]. These studies also concluded on the benefits of a walnut-enriched diet in brain disorders and other chronic diseases [
126,
127,
128,
129]. The additive effect of the essential components of walnuts is proven, with protective action against the events related to oxidative stress and inflammation present in different chronic diseases [
125,
130]. All these positive health effects can be obtained in different eye diseases, such as glaucoma, DR and age-AMD [
131], chronic pathologies with a degenerative character for the ocular structures, which share common pathophysiological mechanisms, characterized by the presence of events related to oxidative stress and inflammation. Likewise, in recent decades, with the increase in life expectancy and the progressive growth of the population with its consequent aging, we have noticed a significant increase in the incidence of chronic neurodegenerative disorders, as in the case of AMD. Its socio-economic consequences are evident, both in terms of the decrease in the quality of life of those affected and in terms of a considerable pressing in the health care system and increased financial burden.
Recent experimental evidence suggests that the main
polyphenols of walnuts, ellagitannins and their metabolites (
urolithins), have beneficial properties against the oxidation processes of cellular components and in the inflammation pathways, in addition to positively influencing the intestinal microbiome [
125,
132].
Phytosterols have proven antioxidant properties and are partly responsible for their cholesterol-lowering effect. They are powerful free radical scavengers, acting to reduce pro-inflammatory eicosanoids, and then mitigating the inflammatory response [
130,
131].
The metabolism of ALA—the vegetable ω3 fatty acid—gives rise to vasodilator and anti-inflammatory
oxylipins, which can be the basis for a protective action on the function of capillary endothelial cells. Its neuroprotective capacity has also been described on brain function, inducing vasodilation of the cerebral arteries with improved irrigation and contributing to phenomena related to neuroplasticity. These effects could also be observed in the retina and the optic nerve [
133,
134,
135,
136,
137,
138]. Interestingly, in addition to its already known anti-arrhythmic potential, ALA can exert other beneficial effects on cardiovascular function, through an anti-thrombotic, anti-inflammatory, and cholesterol-lowering action. The latter are considered protective factors against atherosclerosis [
137]. On the ocular tissues, its vasculoprotective action could contribute to an improved endothelial function in the microcirculation of the retina, the cribriform plate and the choriocapillaries [
137,
138].
Finally, walnuts are also rich in Υ-tocopherol—a form of vitamin E—as we have explained before, a powerful antioxidant with anti-inflammatory properties, with protective and preventive action in macular diseases, such as AMD [
139]. Non-sodium minerals such as potassium, calcium and magnesium, shared by all nuts, and especially in walnuts, also have a protective effect on cardio-metabolic risk, as confirmed by recent evidence [
138,
139].
Primary prevention in many of these neurodegenerative diseases is crucial from the point of view of public health and could be achieved early in life by introducing a healthy diet, rich in antioxidant and anti-inflammatory phytochemicals, as is the case with dietary supplementation with walnuts, as for its nutritional value for ocular chronic diseases.