1. Introduction

Glaucoma is an ocular disease that is characterized by the progressive loss of optic nerve fibers, which results in visual field defects. Glaucoma sits at the top among the causes of irreversible blindness worldwide [1]. Predisposing factors include heredity, gender, race, trauma, and steroid use [2]. Obstructive sleep apnea has also been implicated in glaucoma [3]. Glaucoma can either be primary or secondary ^[4][5][6][4–6]. Glaucoma is diagnosed using tests such as tonometry ^[7][8][7,8], visual field measurement, and direct observation. Glaucoma morbidity costs USD 3 billion annually in the USA alone [9]. Varma et al. projected glaucoma to have a worldwide prevalence of above 79 million by 2020 [10].

Topical drugs, lasers, and surgery are used to manage glaucoma [5]. The only modifiable factor that is currently clinically considered when treating glaucoma to avoid progression is intraocular pressure (IOP) [7]. IOP is the most important risk factor in the development and worsening of this disease. The diagnosis of glaucoma is typically based on IOP in the presence of optic nerve fiber layer thinning, glaucomatous optic nerve cupping, and visual field loss [8].

Nutritional supplements have been proposed in the past years to offer neuroprotection and anti-oxidative factors to help slow down glaucomatous progressive loss. Nutrients have been used in medicine in the form of supplements for the proper function of body systems [11]. Most nutritional elements are typically found in a healthy diet ^[12][13][12,13] and are favored in the presence of non-dietary sources, including the environment [14]. This approach is now being termed as “Nutraceuticals” [15]. Natural immunity largely depends on the availability of a nutrient-rich diet ^[16][17][16,17]. A complex relationship exists between nutrients and infectious processes ^[18][19][20][18–20]. The knowledge of nutrients in ophthalmic medicine is limited, but the current literature seems to be expanding in this interesting field [21]. Nutritional factors have been implicated in multiple oculo-visual diseases ^[22][23][24][22–24]. A thorough understanding of the molecular mechanisms and pathways involved in nutrients can be useful for considering this supplementary therapy in a routine clinical setting when managing glaucoma and other ophthalmologic conditions.

2. Nutritional Factors: Benefits in Glaucoma and Ophthalmologic Pathologies

2.1. Glutathione

Glutathione is an organosulfur molecule that derives from the family of thiols. It is a very potent antioxidant that can be found all over the body. It is a tri-peptide comprising the amino acids cysteine, glutamate, and glutamic acid and has similar concentrations to glucose and cholesterol. The glutathione molecule is produced within the cytoplasm. It is present in the body in either an initial reduced or oxidized state; the reduced form is about 100 times more abundant than the oxidized form in resting cells. This abundance drops 10-fold in the presence of oxidative stress ^[25][42]. This ratio is referred to as the redox number of the cell.

Glutathione generally prevents damage from oxidative stress that is triggered by free radicals, oxides, and toxic xenobiotics ^[26][43]. It facilitates the replenishment of depleted ascorbic acid, tocopherols, and tocotrienols. This substance catalyzes the outward movement of mercury out of neurons and regulates cell apoptosis.

2.2. Minocycline

Minocycline is a second-generation tetracycline-class antibiotic. It is used for both infective and non-infective conditions and also has apoptotic applications. It was created in 1967 as a semi-synthetic broad-spectrum antibiotic. Minocycline works by binding to the 30s ribosome of organisms, stopping such organisms from replicating or growing. This substance is thus bacteriostatic. Minocycline is more easily absorbed into the skin and the central nervous system than other tetracyclines. It has also been shown to have anti-inflammatory properties ^[27][49].

Minocycline binds to the 30s ribosome receptors in the cells of prokaryotes, stopping the activities of transfer RNA molecules that help with protein synthesis. This halts cell growth and results in a bacteriostatic effect. Minocycline is very fat-soluble and is therefore easily absorbed all over the human body. It can be administered orally and intravenously. Minocycline is useful for managing many antibacterial-resistant infections ^[28][29][50,51].

Minocycline has primarily been used for decades for its effects on both Gram-positive and Gram-negative bacterial action ^[28][50]. Studies have reported that it can induce neuroprotection in rats that are undergoing temporary middle cerebral artery occlusion ^[30][52]. IV minocycline has also been found to be potent against multiple multi-resistant drug organisms ^[29][51]. Garner et al. reported the benefits of minocycline for acne vulgaris ^[31][53].

2.3. Spermidine

Spermidine is a naturally occurring polyamine in the cells of organisms. They are known to mediate anti-aging processes but tend to be limited by the increasing age of the organism ^[32][57]. Polyamines are commonly occurring, positively charged compounds. It was originally derived from semen, hence the origin of this name. The chemical formula is C7H19N3. Spermidine is derived from putrescine in a reaction catalyzed by spermidine synthase. Dietary sources include proteins such as soy, legumes, and grains.

Increased dietary supplementation with spermidine has been shown to improve overall health ^[33][58]. Spermidine blocks the enzyme that catalyzes nitric oxide synthesis, aids DNA formation, and regulates the growth of other polyamines such as spermine and thermospermine. The official IUPAC name of this substance is N-(3-aminopropyl)butane-1,4-diamine. The antiaging abilities of spermidine are mediated by multiple pathways, including autophagy ^[34][59], hypusination ^[35][60], and the stabilization of melanogenesis ^[36][61].

The potential benefits of spermidine in ocular diseases are far-reaching ^[37][65]. The defective mitochondrial oxidation of substrates, which is mediated by spermidine, is one of the pathophysiology channels that is seen in glaucoma ^[38][66]. Buisset et al. ^[39][67] reported a reduction in spermine levels in the eyes of patients with open-angle glaucoma. Spermine is a derivative of spermidine. Other studies have equally reported reduced spermidine levels in glaucomatous eyes ^[38][66]. Lillo et al. reported, however, elevated levels of spermidine in the aqueous humor of open-angle glaucoma patients [68]. Wang et al. also reported reduced levels of spermidine to be implicated in glaucomatous damage ^[40][69].

2.4. Fisetin

Fisetin is a flavonol, which is part of a group of compounds known as polyphenols. It is derived from common fruits and vegetables such as apples, onions, and cucumbers. It is also found in eudicotyledon trees and shrubs. It has a distinctive yellowing effect and is therefore used as a dye. The biochemical precursor is phenylalanine. Like resveratrol, studies have shown that fisetin can prolong the life of lower animals ^[41][70].

Fisetin has multiple beneficial pathways that can help in disease reduction. These include neuroprotective and anti-angiogenic properties. The anti-proliferative abilities of this substance work at interfering with the cell cycle through multiple channels. It inhibits the PI3K/Akt and mTOR pathways in humans and is therefore important for managing prostate cancer ^[42][71]. The anti-carcinogenic activity of fisetin may be because it is a topoisomerase inhibitor ^[43][72]. It also mediates its anti-cancer properties by senolysis, which is said to be twice as potent as quercetin ^[44][73]. Fisetin inhibits colon cancer cells by suppressing COx2 and Wnt/EGFR/NF-kappaB signaling pathways. Fisetin also suppresses the p38 MAPK-dependent NF-kB signal pathways, leading to a downregulation of the urokinase plasminogen activator ^[45][74].

Fisetin essentially has a wide range of anti-cancer capabilities ^[46][75] in addition to other chronic diseases ^[47][76]; it also has anti-inflammatory and neurotrophic abilities ^[48][77]. Kubina et al. reported cytotoxic activity of fisetin against cancer cells ^[49][78]. Lall et al. also attributed its anti-carcinogenic properties to apoptotic cell cycle dysregulation ^[50][79]. Fisetin has been shown to prevent the growth and spread of cancers of the breast, cervix, and colon ^{[51][52][53][54]}[80–83]. Prostrate-specific antigen levels in athymic nude mice were found to be reduced after treatment with fisetin supplements ^[55][84].

2.5. Omega-3

Omega-3 polyunsaturated fatty acids are termed with this name based on structural features. Fatty acids possess a carboxylic chain on one end, which is designated as ‘alpha’; meanwhile, a methyl group exists at the ‘omega end’. For omega-3s, the cis double bonds are first separated by a methylene group on the third carbon atom of the omega end.

Omega-3s are a group of polyenoic fatty acids (FAs) that includes both long-chain and short chain substrates, such as:

• DHA {cis-4,cis-7,cis-10,cis-13,cis-16,cis-19- docosahexaenoic acid};
• DPA {cis-7,cis-10,cis-13,cis-16,cis-19- docosapentaenoic acid};
• EPA {cis-5,cis-8,cis-11,cis-14,cis-17- eicosapentaenoic acid}; as well as
• SDA: stearidonic acid {cis-6,cis-9,cis-12,cis-15- octadecatetraenoic acid} and;
• Short-chain ALA: alpha-linolenic acid {cis-9,cis-12,cis-15-octadecatrienoic acid}.

They are mainly found in oils derived from the liver and integument of aquatic mammals. However, plant-like organisms such as microalgae and other forbs have been theorized to synthesize compounds with similar biochemical structures. Dietary sources from oily fish (cod, anchovies, salmon, herring, mackerel, etc.) can provide modest levels of EPA and DHA ^[56][89]. ALA is obtained from flaxseed and nuts ^[57][90]. Numerous biological properties of polyunsaturated fatty acids are yielded via lipid mediators of fatty acid oxygenases, which include cytochrome P450 mono-oxygenases, cyclo-oxygenase, and lipo-oxygenase enzymes ^[58][91].

Long-chain polyunsaturated FAs, especially DHA and EPA, possess anti-inflammatory effects. Omega-3 FAs lend an anti-inflammatory effect via inhibition of the phospholipase A2 released from stressed or injured/inflamed tissue. In addition, these substances compete with eicosanoid formation that is caused by omega-6 arachidonic. This subsequently results in reduced production of the eicosanoids (i.e., prostacyclin, cytokines, leukotrienes, and prostaglandin-E1) ^[58][91]. Vaso-protective and cardioprotective effects of dietary omega-3 FA intake may be attributed to the cytochrome P-dependent mechanisms of EPA and DHA ^[59][92].

2.6. Rapamycin

Rapamycin is a macrolide (polyketide) compound derived from Streptomyces hygroscopicus. Rapamycin (RAPA) is a specific inhibitor of the mTORC1 signaling pathway. This substance modulates neuroglial proliferation via the inhibition of ‘pro-proliferative’ mTORC-1 signaling ^[60][113]. The depicted benefits applicable in neoplastic and degenerative diseases are provided by the antioxidant properties via the enzymatic inhibition of nitric oxide synthase and de-catalyzation of the release of ‘free’ reactive oxygen species (ROS). The macrolide chemical structure of rapamycin provides antimicrobial (antibacterial and antifungal), anti-inflammatory, and immunomodulatory properties ^[61][115]. By hindering the activation of activator protein 1 and nuclear factor kappa B (NF-kB), which mediate the induction of cyclo-oxygenase-2 (COX-2) enzyme and other inflammatory cytokines, mTOR inhibition consequently reduces inflammatory responses at the cellular level.

RAPA promotes immunomodulation via the inhibition of macrophage cell function and cellular migration following exposure; it also possesses several immunosuppressive properties. RAPA acts on interleukin-2 (IL-2) and costimulatory signaling pathways, thus attenuating the immune response. mTOR governs the cellular pathways of apoptosis, autophagy, and necroptosis ^[60][113]. Inhibition of mTOR by rapamycin suppresses the immune response by preventing cell cycle progression from the G1 phase to S phase, thereby blocking proliferation ^[62][114].

RAPA has gained clinical significance in the field of anti-aging medicine based on animal-based research outcomes, which have suggested that a dose-specific effect on lifespan extension can be elicited following acute administration of the mTOR inhibitor during early stages of life ^[61][115]. RAPA has also been reported to yield benefits in the setting of neurodegenerative disease management. It has been suggested that this effect occurs as a product of cellular autophagy modulation ^[63][116]. The potential value for understanding Alzheimer’s disease has been linked to the possible mechanisms of autonomic neuron mitochondrial dysfunction, known as mitophagy ^[63][116], and other related neuroinflammatory processes. mTOR inhibitions via RAPA and related analogs have been linked to increased survival rates among patients with metastatic renal malignancies ^[64][117]. The pathway of mTOR inhibition may also provide novel strategies for managing autosomal dominant polycystic kidneys ^[65][118]. Evidence-based data also recommends mTOR inhibition for managing tuberous sclerosis complex-associated epilepsy ^[66][119]. The mechanistic role of RAPA has shown potentially promising results for managing a wide range of hepatic pathologies ^[67][120]. RAPA is also widely used to prevent organ transplant rejection.

2.7. Metformin

Metformin is a biguanide compound originally derived from Galega officinalis (G. Officinalis), the French lilac ^[68][133]. Hepatic transport of metformin occurs via the hepatic portal vein following intestinal absorption.

OCT1 is a hepatic uptake transporter. OCT1 and PMAT are also reported to play combined roles in the intestinal accumulation of metformin. The exact biochemistry of intestinal OCT1 remains unclear; however, PMAT has been known to be expressed in the apical membrane of enterocytes. Metformin is hypothesized to primarily act on hepatic metabolism. Metformin acts via adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. The therapeutic effects have been linked to OCT1 activation of AMPK.

Metformin exerts its effects of glycemic control by acting on the liver via AMPK activation and by inhibiting hepatic glucose production (HGP)/gluconeogenesis ^[69][134]; it also improves muscular and hepatic absorption of glucose substrates. Due to its favorable safety profile, metformin is considered an essential oral antidiabetic for managing diabetes mellitus type II (NIDDM). For non-diabetic subjects, it has been found to attain significant plasma concentrations within three hours of administration. Serum concentrations reach nearly two-fold values in diabetic individuals who are on consistent daily doses of about one gram of metformin. The weight loss-inducing effect ^[69][134] is also suggested to modulate cardiovascular risk factors among individuals with NIDDM.

Mitochondria-targeted therapy via metformin has been considered a potential strategy for reducing oxygen demand and consumption in neoplastic lesions ^[70][135]. The anti-proliferative attributes of metformin have been established via the inhibition of breast cancer cells in vitro as well ^[71][136]. Metformin has also found versatile applications in obstetrics and gynecology. This substance has gained attention for managing gestational diabetes and polycystic ovarian syndrome ^[72][137].

2.8. Alpha-Ketoglutarate

Alpha-ketoglutarate (aKG) is a precursor of glutamate and glutamine. Glutamate is yielded by adding an amino group to the aKG molecule. The conversion of aKG to glutamine within the plasma membrane is catalyzed by glutamate dehydrogenase (GDH) and glutamine synthetase (GS) via the addition of a nitrogen group. aKG is an intermediate metabolite substrate of the tricarboxylic acid cycle (TAC, which is essential for cellular metabolism ^[73][144].

aKG possesses a strong affinity for reactive oxygen species (ROS) released from the mitochondria, especially hydrogen peroxide, which it reacts with as a result of the conversion of succinate, carbon dioxide, and water, subsequently leading to its elimination ^[74][145]. Excess-free/unbounded ROS such as superoxide anions, hydrogen peroxide, etc., inhibit normal deoxyribonucleic acid (DNA) synthesis. They consequently cause damage to the cytoskeleton and tissue integrity. aKG is thus a potent antioxidant that enables tissue repair.

aKG administration has been correlated with increased bone among aged experimental animals ^[75][143]. The use of this substance has also been associated with improved potency in the bone marrow-derived stem cells (MSCs) obtained from senescent mice ^[76][146]. aKG supplementation has been linked with improved cardiac function in mice with pre-existing myocardial dysfunction ^[77][147]. aKG supplementation has been reported to suppress the growth of colorectal cancer tumor models via inhibited Wnt signaling mechanisms ^[78][148]. aKG-dependent circular RNA (circFTO) has been reported to have pro-angiogenetic effects and impair the blood–retinal barrier in DR. aKG-modulation strategies targeting at-risk tissues may thus potentially help regulate DR progression ^[79][80][149,150]. The aKG dehydrogenase complexes play a key role in intracellular glucose metabolism ^[81][151]. Studies have also suggested that the antioxidant effects of aKG include reduced cataractogenesis in experimental animal models ^[82][152].

2.9. Vitamin B3 (Niacin)

Niacin (also known as nicotinic acid) is an essential, water-soluble form of vitamin B3 with contrasting effects when used at various dosages. This organic compound is a pyridine derivative with a carboxyl group at the 3-position. Niacin is a precursor to NAD+/NADH and NADP+/NADPH, both of which are required for metabolic functions in living cells. It is involved in both DNA repair and adrenal gland steroid hormone production. Niacin has been confirmed to cause mild-to-moderate serum aminotransferase elevations.

Niacin is a cofactor in over 400 biochemical reactions in the body, including in metabolic processes. Julius ^[83][153] concluded that niacin plays a role as a replacement for statin and/or as an important additive in statin-intolerant patients. Patients with elevated triglyceride and low HDL cholesterol levels, in addition to patients with elevated lipoprotein (a) concentrations, can possibly reap benefits from using niacin. Xu and Jiang ^[84][154] published a study about the psychiatric manifestations of niacin deficiency and found that schizophrenia patients can benefit from niacin augmentation.

2.10. Vitamin D

Vitamin D (ergocalciferol) is a fat-soluble vitamin that is a member of the calciferols, and it essentially functions as a hormone. Vitamin D was discovered to be crucial to the prevention of rickets. It is denoted as the most important vitamin and is derived as a benefit from normal levels of exposure to sunlight. Vitamin D is produced in the epidermis of animals due to the precursor molecule 7-dehydrocholesterol absorbing light quanta. Vitamin D needs to be converted to 1,25-dihydroxycholecalciferol, which is its active form. This transformation takes place in two steps: Cholecalciferol is hydroxylated to 25-hydroxycholecalciferol in the liver by the enzyme 25-hydroxylase. Then, within the kidney, 25-hydroxycholecalciferol acts as a substrate for 1-alpha-hydroxylase, resulting in the biologically active form 1,25-dihydroxycholecalciferol.

Vitamin D is a long-known vitamin that aids in the body’s absorption and storage of calcium and phosphorus. These two nutrients are especially important for bone formation. In oncology, researchers ^[85][157] have identified that vitamin D metabolism is important in the management of cancer patients. A growing body of evidence points to the dysregulation of vitamin D metabolism and functions in many cancer types, which confers resistance to the antitumorigenic effects of vitamin D and aids in the growth and development of cancer. It has also been reported in several studies that vitamin D can serve as an adjunct therapy in SARS-CoV2 virus infections ^[86][158]. Studies have shown that this vitamin can increase cellular immunity and induce antimicrobial peptides, hence reducing the severity of viral infection ^[87][159]. The mechanisms involved include elevating the levels of anti-inflammatory cytokines while lowering the levels of proinflammatory cytokines. It is also indicated as a therapeutic option in the management of diabetes mellitus ^[88][89][160,161] and skin diseases ^[90][162].

2.11. Zeaxanthin

Zeaxanthin is a carotenoid molecule with a conjugated double-bond system, which gives it its characteristic yellow color. It consists of a central chain of 40 carbon atoms, with two hydroxyl groups (-OH) on either end. Zeaxanthin melts at about 215–216 °C. It is insoluble in water, but it is soluble in polar organic solvents such as ethanol, acetone, and chloroform. Zeaxanthin is synthesized through the methylerythritol phosphate (MEP) pathway, also known as the non-mevalonate pathway, which is an alternative biosynthetic pathway for isoprenoid compounds in bacteria, plants, and algae. The MEP pathway involves seven enzymatic steps that convert pyruvate and glyceraldehyde-3-phosphate to isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), the precursors for carotenoid synthesis. It can be converted to other carotenoids through a variety of metabolic pathways. For example, zeaxanthin can be converted to violaxanthin, antheraxanthin, and neoxanthin through a series of enzyme-catalyzed reactions that are known as the xanthophyll cycle. This cycle plays a crucial role in regulating the amount of light absorbed by chloroplasts in plants, which helps protect them from excess light and prevents photodamage. Zeaxanthin has strong absorption in the blue-green region of the visible spectrum and reflects yellow light. It exists in two isomeric forms: (3R,3’R)-zeaxanthin and (3R,3’S)-zeaxanthin, which differs only in the orientation of the hydroxyl groups on the end rings.

Zeaxanthin possesses anti-inflammatory effects that can reduce the risk of chronic diseases such as heart disease, cancer, and arthritis. It enhances the activity of white blood cells, which play a crucial role in fighting infections and diseases. Furthermore, zeaxanthin improves cognitive and cardiovascular health by reducing oxidative stress and inflammation. Some studies have suggested that zeaxanthin has benefits for skin health. A double-blind, placebo-controlled study found that supplementation with a combination of zeaxanthin and other carotenoids improved skin hydration and elasticity in healthy middle-aged women ^[91][167]. Another study found that zeaxanthin reduced the number of sunburned cells in the skin after UV irradiation in mice ^[92][168]. A study in healthy elderly men found that supplementation with lutein and zeaxanthin improved immune function by increasing the activity of natural killer cells ^[93][169]. Moreso found that zeaxanthin reduced cognitive decline in mice with Alzheimer’s disease ^[94][170]. Kishimoto et al. conducted a clinical trial and reported that supplementation with lutein and zeaxanthin reduced oxidized LDL cholesterol levels in people with metabolic syndrome ^[95][171].

2.12. Lutein

Lutein is a carotenoid pigment that is naturally found in various fruits and vegetables, particularly in leafy green vegetables such as spinach and kale ^[96][179]. It is a yellow-to-orange colored pigment that is insoluble in water but soluble in organic solvents such as ethanol, hexane, and chloroform. Lutein is known for its antioxidant ^[97][98][180,181] and anti-inflammatory properties ^[99][182], and it has been associated with numerous health benefits, particularly for eye health. It is one of the major carotenoids found in the human retina and is believed to protect the eye from age-related macular degeneration and other eye diseases. Overall, lutein has several biological properties that make it a beneficial compound for human health, particularly for eye health, skin health, and cognitive function ^[100][101][183,184].

Lutein is a powerful antioxidant that can neutralize free radicals and reactive oxygen species, which can cause oxidative damage to cells and tissues. It can help protect cells from oxidative stress and reduce the risk of chronic diseases such as cancer, cardiovascular disease, and neurodegenerative disorders ^[102][185]. Chronic inflammation is associated with numerous health problems, including arthritis, asthma, and heart disease. The anti-inflammatory properties of this substance can help prevent and manage these conditions ^[103][104][186,187]. Lutein has been shown to regulate the expression of genes involved in inflammation, oxidative stress, and other biological processes. It has been reported to upregulate the expression of antioxidant enzymes such as superoxide dismutase and catalase. Lutein modulates signal transduction pathways that are involved in inflammation, oxidative stress, and cell proliferation ^[105][188]. This compound inhibits the activation of nuclear factor kappa B (NF-kB), a transcription factor involved in the expression of pro-inflammatory cytokines ^[106][107][189,190]. Lutein is implicated in the modulation of lipid metabolism, which may contribute to its beneficial effects on skin health. It can increase the expression of genes involved in lipid synthesis and may also inhibit the expression of genes involved in lipid oxidation ^[108][191].

2.13. Resveratrol

Resveratrol is a polyphenol that is naturally known to have a trans-stilbene structure, which was described when it was found in its natural state in red wine. This compound has two phenolic rings that are bonded together. The structure of resveratrol is made by the combination of two phenolic rings that are doubly bonded by a styrene bond that is doubled; this forms 3,5,4′-trihydroxystilbene with a molecular weight of 228.25 g/mol. This double bond is responsible for the isometric cis and trans forms of resveratrol. It is key to know that the trans isomer is the most stable form, and this is responsible for its medicinal or therapeutic effects because this isomer enhances its ability to bind to many biological molecules ^[109][197].

The benefits of resveratrol were first discovered after the “French Paradox”. Studies regarding this situation reported that red wine was a cardio-protective supplement for individuals in the Northern part of France, in which diets were high in saturated fat but mortality was low from heart diseases in comparison to other countries with a similarly high intake of fat in the diets. Studies have shown that phenolic compounds found in grapes and red wines exhibit a protective effect against diseases ^[110][111][198,199].

Resveratrol has unique chemical and physical features, which enhance its ability to cross cell membranes passively as well as interact with the membranes of cell receptors. This is responsible for its interaction with intracellular and extracellular molecules. The mode of action at the cellular level is initiated by signals from pathways in relation to the membranes of cells, triggering intracellular mechanisms or expressing itself in the core of the nucleus. Diseases such as cardiovascular problems, neurodegenerative diseases, cancers, and diabetes involve oxidative damage in their pathogenesis. Resveratrol is known to have antioxidant activity by disrupting the state of respiratory processes in the mitochondria, as found in a study conducted on rat brain mitochondria. It has also been found to initiate competitive substrate inhibition on coenzyme Q by reducing the concentration of complex III ^[112][200]. Resveratrol is also known to have phytoestrogen properties in that it binds the estrogen alpha receptors and beta receptors (ER-alpha and ER-beta). Studies have shown that ER-α is stereo-selective and has more affinity for the trans-isomer of resveratrol.

Resveratrol is a potent antioxidant. Studies have shown that its derivatives have a powerful inhibiting effect on inhibiting low-density protein induced by copper ions ^[113][201]. Resveratrol has also shown anticancer effects in in vitro and in vivo studies, where the evidence indicates that resveratrol inhibits initiation, promotion, and progression (carcinogenesis stages) ^{[114][115][116]}[202–204]. Evidence from several other studies has shown that resveratrol displays therapeutic properties that are of medical importance, which include anti-inflammatory and anti-proliferative effects ^[117][118][205,206].

2.14. Pyruvate

Pyruvate in the mitochondria is responsible for the mitochondrial pyruvate carriers, which mediate pyruvate import into the mitochondria. This is important in the major oxidative processes in the mitochondria such as the tricarboxylic cycle and oxidative phosphorylation. Inhibiting this process of pyruvate carrier-mediated pyruvate transport has been found to be beneficial and protective in neurodegenerative diseases such as Parkinson’s disease ^[119][216]. Pyruvate biochemical constituent is a 2-oxo monocarboxylic acid anion that is the conjugate base of pyruvic acid, which is an important metabolic product for energy-producing biochemical pathways. Pyruvate is the end product of glycolysis, and in a state of hypoxia, it can be metabolized to form lactate anaerobically. Pyruvate is a precursor of acetyl-coenzyme A (AcetylCoA) and oxaloacetate, which are involved in the tricarboxylic acid (TCA) cycle ^[120][217].

Pyruvate is one of the end products of glycolysis, and the transport mechanism that enhances pyruvate transport into the mitochondria is known as the mitochondrial pyruvate carrier. This is important in major oxidative processes in the mitochondria, such as the tricarboxylic acid cycle and in commonly biochemical reactions such as oxidative phosphorylation. This biochemical compound has been known to be protective against neurodegenerative diseases such as Parkinson’s disease ^[121][218]. Pyruvate is a major molecule that is important for several aspects of cellular and human metabolism. Pyruvate formed from glycolysis is the outcome of cellular cytoplasmic addition that is ferried to the mitochondria as one of the major sources of energy in the tricarboxylic acid cycle. Pyruvate is a cornerstone for ATP generation in the mitochondria and for making many of the major pathways intersecting the citric acid cycle effective ^[122][219]. The availability of pyruvate in the cytosol depends on the availability of enzymes such as pyruvate kinase, lactate dehydrogenase, and alanine aminotransferase. Cytosolic pyruvate needs to be actively moved into the mitochondrial matrix once formed, and the means of intermembrane transportation is through the mitochondrial pyruvate carrier (MPC) ^[122][219]. It is a known biochemical fact that the mitochondrial inner membrane is impermeable to ionic molecules even though other biochemical molecules and pyruvate can freely diffuse from the cytoplasm through porins ^[123][124][220,221]. The MPC found in humans is formed by two very similar subunits, which are known as MPC1 and MPC2. Their stoichiometry and physiological control and regulations are not well understood.

2.15. Vitamin A

Vitamin A (retinol) is a fat-soluble nutrient. It has been proven to have a neuroprotective capacity. This function is associated with the all-trans form of retinol, which has been shown in experimental studies conducted on rats ^[125][228]. It is known to have diverse characteristic neuroprotective potentials, although high doses of vitamin A (retinol) can be harmful and responsible for raised intracranial pressure, anorexia, and congenital malformations in early pregnancy ^[126][229]. According to the International Union of Biochemistry and Molecular Biology (IUBMB), retinol and other compounds such as retinoic acid and retinoic aldehyde are classified as retinoids. Retinoids are all derivatives of vitamin A, which could be natural or synthetic forms of vitamin A that do not have an aromatic portion of β-ionone ^[127][230].

Several physiological processes have shown the vital roles of vitamin A, including growth, tissue development at the embryogenic stage, proper development and functioning of the reproductive organs, proper functioning of the immune system, and the commonly known function of enhancing vision in the eyes. As a lipid-soluble vitamin, retinol stimulates retinoid receptors (RARs), the stimulation of which initiates the differentiation of cells as well as induction cell death of tumorigenic or cancerous cells, hence hindering the development of cancers. Because of the insolubility in body fluids, retinol is transported by specialized proteins known as retinol-binding proteins (RBP) through a complex involvement with transthyretin ^[128][231]. Cytosolic retinol-binding protein (CRBP) is in the cytoplasm and is known to have a high affinity for retinol. CRPB has two subtypes of receptors known as CRPB I and CRPBII ^[129][232]. Several studies have shown that the antioxidant properties of retinol exist through the mechanism of blocking the voltage-gated calcium channels, and this single mechanism is neuroprotective despite the fact that retinol has many biological effects ^[130][131][233,234].

2.16. Vitamin B1

Vitamin B1, also known as thiamine, is a water-soluble vitamin made up of two heterocyclic rings, which include a thaizole and pyrimidine ring interconnected with methylene. Thiamine is relatively stable in acidic solutions but reacts to heat, oxygen, and light. Biologically, thiamine is an important coenzyme for the completion of processes such as converting pyruvate to acetyl-CoA in the citric acid cycle to produce ATP, carbon dioxide, and other reducing agents. As a coenzyme in this process, thiamine is present in its active form, thiamine pyrophosphate (TPP).

The benefits of thiamine in medical disorders include its use in treating Wernicke–Korsakoff Syndrome. High doses of thiamine supplementation have been shown to improve cognitive function and reduce further neurological damage ^[132][240]. Heart failure has been linked to thiamine deficiency. A study by Rauchhaus et al. concluded that thiamine supplementation improved left ventricular ejection fraction and exercise capacity in heart failure patients with thiamine deficiency ^[133][241]. Day et al. reported that treating patients with alcohol withdrawal symptoms with thiamine produced positive results as it reduced the severity of symptoms ^[134][242].

Thiamine supplementation has been shown to improve visual function and reduce the risk of disease progression in patients with early-stage age-related macular degeneration, as supported by the observed reduction in oxidative stress markers in the retina ^[135][136][243,244]. When thiamine is supplied in the right doses, it has been shown to help reduce the risk of developing diabetic retinopathy ^[137][245]. Thiamine has also been shown to reduce the incidence, severity, and intensity of cataracts ^[138][246]. In a study conducted by Lee et al., a connection was found between thiamine intake and a reduction in disease progression for glaucoma patients with normal tension glaucoma ^[139][247].

2.17. Vitamin B2 (Riboflavin)

Riboflavin is a water-soluble vitamin that is relatively stable in heat and acid but sensitive to light. It serves as an important coenzyme in various metabolic processes such as in the conversion of food into energy and in the production of amino acids and fatty acids. Riboflavin shows an important role in cell repair and growth, considering that it helps eliminate free radicals that are capable of cell damage and that are capable of developing chronic diseases.

Riboflavin is a precursor for coenzymes such as flavin mononucleotide and flavin adenine dinucleotide, which serve as electron carriers that are important for metabolic pathways. It is also involved in the metabolism of iron to produce hemoglobin as it converts iron from its ferric state to ferrous, which is the active form in red blood cells (RBCs). Riboflavin is actively involved in the synthesis of opsin, which combines to form rhodopsin, a visual pigment required for low-light vision.

2.18. Vitamin B9

Vitamin B9, also known as folate, is a water-soluble vitamin and is one of eight essential B vitamins ^[140][254]. The chemical structure is similar to that of folic acid. Folate can be obtained from dietary sources, chiefly green leafy vegetables, as well as several animal sources (meat, eggs, etc.). The body easily absorbs synthesized sources of supplemental folic acid in greater amounts than it does from food-derived folate ^[141][255]. Within the body, oral vitamin B9 undergoes hepatic activation into tetrahydrofolate ^[142][256]. The primary route of excretion is via the kidneys.

Folate is key in the methylation processes, including in vitamin B12-associated methionine and homocysteine protein synthesis ^[143][257]. It also synergizes cobalamin to promote hematopoiesis (especially erythropoiesis) ^[144][258]. Via its role in DNA synthesis, vitamin B9 is essential for appropriate embryogenesis and fetal development ^[145][259].

2.19. Vitamin C

Vitamin C is a water-soluble nutrient. It is a powerful component and catalyst for forming many neurotransmitters and it is a potent antioxidant ^[146][301]. While some animals can produce this vitamin autonomously, most mammals generally obtain their source from their diet due to the absence of the enzyme gluconolactone oxidase ^[147][302]. Vitamin C is easily destroyed by prolonged cooking. It is especially important for wound healing and collagen synthesis. A deficiency of vitamin C (hypovitaminosis) results in scurvy ^[148][303], a condition characterized by poor wound healing and a general breakdown of body tissues ^[149][304]. This condition may eventually become fatal if not properly managed ^[150][305]. A review by Maekawa et al. suggested that large concentrations of vitamin C in the blood, achieved through intravenous administration, exerted anti-cancer effects through oxidative mechanisms ^[151][306]. Gokce et al. have suggested that vitamin C deficiency is linked to body hair loss ^[152][307]. The exact mechanism is not yet understood. However, vitamin C is an established reproductive health supplement for men as clinical trials have shown improved sperm motility with vitamin C supplementation ^[153][154][308,309]. Marrof et al. showed that vitamin C may play a role in ameliorating symptoms of atopic dermatitis ^[155][310].

2.20. Vitamin E

Vitamin E is a fat-soluble nutrient. These substances are from the classes of tocopherols (α, β, δ, γ isoforms) and trienols (α, β, δ, γ isoforms) ^[156][157][319,320]. It is a known antioxidant ^[158][321], immunomodulator ^[159][322], and antiplatelet compound ^[160][323]. The fat solubility of this vitamin means that it can easily be stored in body fat. Deficiencies in vitamin E are thus relatively rare ^[161][324]. Vitamin E has been widely reported to ameliorate immunosenescent changes ^[162][163][325,326]. Supplementation in the elderly with this substance has been shown to reduce the risk of respiratory complications in nursing homes ^[164][327]. Vitamin E also has effects on human reproductive health; an experimental study found that it increased sexual desire and satisfaction when administered together with ginseng in women ^[165][328]. It also has positive interactions in ameliorating certain skin disorders ^[166][329] and in cardiovascular medicine ^[167][330].

2.21. Citicoline

Citicoline is an isomeric form of choline, which is an intermediate metabolite of phospholipid synthesis within the cell membrane. Following administration, cytidine and choline are liberated from citicoline. It efficiently crosses the blood–brain barrier and reaches the CNS. Within the neuronal cell membrane, citicoline also serves as a choline donor in the pathway of neurotransmitter (acetylcholine) synthesis and activates biosynthesis of structural phospholipids, thus increasing brain metabolism ^[168][169][339,340].

Citicoline has been suggested to serve a neuroprotective function in ischemic diseases and reverse neural senescence in animal models. Citicoline has been reported to inhibit mechanisms of apoptosis that are associated with cerebral ischemia ^[170][341]. Its pharmacological characteristics and mechanisms suggest that the nutrient may be indicated for preserving motor function in the setting of cerebro-vascular disease, management of moderate-to-severe concussive head trauma, and cognitive disorders that follow post-concussion syndrome. Studies including patients who were managed with citicoline after suffering head trauma reported accelerated recovery from post-traumatic coma and other associated neurological deficits. Toxicological findings purport that citicoline demonstrates good safety profiles among human subjects ^[171][172][342,343].

2.22. Quercetin

Quercetin in an abundant flavonoid. It has strong antioxidative, anti-inflammatory, and neuroprotective functions in the body. It also has an anti-neoplastic and immunomodulatory agent. The literature has shown that is has been considered in multiple ocular conditions ^{[173][174][175]}[349–351]. The antioxidative action by this substance is believed to be due to its donation of hydrogen ions to stabilize free radicals ^[176][352]. It also possesses an enhanced radical-scavenging activity ^[177][353]. Quercetin has also been shown to block the production of vascular endothelial growth factor in cancer models ^[178][354].

2.23. Eyebright

Eyebright (Euphrasia officinalis) is a plant that has been utilized in contemporary eye care medication for decades ^[179][364. Three extracts have been isolated from the leaves of this plant, namely ethanol, ethyl acetate, and heptane ^[180][365]. Studies have shown that euphrasia successfully reduced glycemic levels to baseline in rats, which had been previously induced using alloxan ^[181][366]. Blazics et al. were also able to show that euphrasia extracts had significant antioxidant properties ^[182][367]. Stoss et al. reported that eyebright eyedrop formulations were efficient in ameliorating conjunctivitis indices in a human population, as reported by ^[183][368].

Numerous studies have shown that the combination of factors and nutrients that function in synergy can provide an enhanced clinical outcome. Dolgova et al. examined the effect of a nutrient complex (Focus Forte) on POAG patients and reported an improvement in retina function ^[184][369]. Another study also reported therapeutic effects of nutrient-based combination therapies on a mouse model with elevated IOP. The study concluded that retinal ganglion cell loss was significantly reduced, thereby preventing visual dysfunction; thus, the authors recommended the use of the test mixture of forskolin, homotaurine, spearmint, and B vitamins in glaucoma management ^[185][370].