Encyclopedia
Please note this is a comparison between Version 1 by Ramón Rodrigo and Version 2 by Lindsay Dong.
Natural antioxidants are present in low concentrations within cells. They reduce free radicals to provide a protection system against vascular diseases. They have a strong potential to inhibit oxidative stress (OS), lipid peroxidation and the oxidation of breakdown products. Natural antioxidants can function either individually or synergistically to remove free radicals generated during oxidative metabolism, thus maintaining the redox balance.
- oxidative stress
- reperfusion injury
- antioxidants
- ischemic stroke
- acute myocardial infarction
1. Introduction
Acute ischemic diseases, such as acute myocardial infarction (AMI) and ischemic stroke (IS), stand as major causes of death and disability worldwide [1]. Both conditions result from the occlusion of a vascular structure [2][3][2,3]. The acute management for them is the prompt restoration of blood flow to the tissue [4][5][4,5], thereby reducing the time of hypoperfusion to preserve organ function [6]. Paradoxically, the restoration of blood flow induces an important additional damage [7][8][7,8], which is a phenomenon known as ischemia–reperfusion injury (IRI). This phenomenon was first described by Jennings et al. [9], in relation to the myocardium in 1960, and by Ames et al. [10], in relation to the brain, in 1968. While cardiac ischemia/reperfusion is associated with necrosis, cardiomyocyte apoptosis, contractile dysfunction, and life-threatening ventricular arrhythmias, cerebral IRI induces an increase in trans-endothelial permeability and blood–brain barrier (BBB) damage [11]. While essential for restoring aerobic ATP production, the re-entry of oxygenated blood into ischemic tissue leads to elevated reactive oxygen species (ROS) production. This effect can induce oxidative modifications in nearly all types of biomolecules within cells, ultimately resulting in cell dysfunction. This phenomenon has been labeled the ‘oxygen paradox’ [12], wherein oxidative stress-mediated injury and ischemia reperfusion damage play pivotal roles. However, the pathophysiology of IRI involves a complex interplay of mechanisms, including oxidative stress (OS), endoplasmic reticulum stress, calcium overload, inflammatory response, disturbances in energy metabolism, apoptosis, and various forms of programmed cell death (e.g., necroptosis, autophagy, pyroptosis, patanatos, and ferroptosis) [1].
IRI also comprises other mechanisms, such as microvascular vasoconstriction, whereas endothelin in the vascular wall can increase in OS, contributing to the reduction in NO bioavailability and consequently leading to vascular dysfunction [13]. Also, IRI is characterized by tissue necrosis and leukocyte infiltration, especially neutrophils that are recruited to the ischemic site following reperfusion and, prior to extravasation, adhere to the endothelium.
Hypoxia-inducible factor-1α (HIF-1α), an oxygen-sensitive transcription factor that mediates adaptive metabolic responses to hypoxia, is activated in IRI by improving mitochondrial function and decreasing OS, thus accounting for protective cellular mechanisms [14][15]. HIF-1α activates the transcription of other genes which play an important role in a cell’s adaptive responses to hypoxia, such as vascular endothelial growth factor (VEGF), erythropoietin (EPO) and glucose transporter-1. Among them, VEGF is the most important angiogenetic factor in all steps of angiogenesis [15][16]. During ischemia reperfusion, VEGF activity decreases due to the increase in its antagonist soluble fms-like tyrosine kinase-1 (sFlt-1), which is a truncated form of the VEGF receptor fms-like tyrosine kinase-1 (Flt-1) lacking the transmembrane and cytoplasmic domains. Therefore, increased sFlt-1 results in a harmful effect on the heart following MI, and it has been positively related to the severity and mortality of these patients [16][17].
Also, microRNAs (miRs) have been shown to be involved in the regulation and pathogenesis of ischemia [17][18] and IRI in the heart [18][19] as well as in the central nervous system [19][20]. They are tissue-specific [20][21] and are capable of silencing target genes, and thus, among other functions, miRs regulate OS by targeting ROS producers, ROS pathways and antioxidant effectors. Their functionality varies across contexts; some miRs exhibit pro-oxidant effects, while others concurrently target genes with opposite redox regulatory functions [21][22].
The cellular oxidative status is determined by the equilibrium between ROS formation and the activity of various antioxidant systems [22][23]. The mechanisms of damage are mainly mediated by ROS-induced transcription factors such as nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1). During ischemia followed by reperfusion, ROS mediate NF-κB activation by phosphorylating the IκB (NF-κB inhibitor proteins family) subunit, thereby provoking its proteolytic digestion. Then, NF-κB is translocated into the nucleus, leading to the transcription of genes causing inflammation and apoptosis [23][24]. Also, ischemia reperfusion leads to c-Jun N-terminal kinase (JNK) phosphorylation, which is translocated into the nucleus, inducing the expression of inflammation and apoptosis-related genes and AP-1 activation.
The antioxidant defense system (ADS) is regulated by transcriptions factors, such as nuclear factor erythroid 2-related factor 2 (Nrf2), which is a critical regulator of the cellular stress response. It controls cellular defense responses against OS by modulating the expression of antioxidant enzymes at the transcriptional, post-transcriptional and post-translational levels [24][26]. The ADS operates through both enzymatic and non-enzymatic molecules. Key enzymes include superoxide dismutases (SODs), catalase (CAT), peroxiredoxins, thioredoxins, glutaredoxins, and glutathione peroxidases (GPXs). Non-enzymatic molecules can be classified as endogenous, such as reduced glutathione, and exogenous, including vitamin C, vitamin E, carotenoids, flavonoids, and polyphenols, among others [23][25][26][24,27,28]. It is noteworthy that natural antioxidants constitute a diverse group of exogenous molecules that can be considered as pharmacological resources due to their safety, availability, and potential pleiotropic benefits against oxidative challenges.
2. Natural Antioxidant Bioactive Molecules against Myocardial Infarction and Ischemic Stroke Injury
2.1. Phenolic Compounds
2.1.1. Polyphenols
Resveratrol
Resveratrol, also known as 3,5,4′-trihydroxy-trans-stilbene, is a phytoalexin produced in various plants in response to injury caused by pathogens or physical damage. This compound can scavenge ROS and prevent lipid peroxidation in various OS related diseases. Foods such as grape skins, blackberries, raspberries, blueberries and peanuts contain resveratrol, being also one of the main components of red wine [27][92].
Resveratrol exists in either cis- or trans-resveratrol isoforms, the trans-isomer being more active as an antioxidant than the diastereomeric mixture [28][93]. This compound is also characterized by a good absorption capacity and rapid metabolization in the body, mainly through the formation of sulfoxide and glucuronide conjugates, which are mainly eliminated in the urine. In general, resveratrol has been found to be well tolerated, and no significant toxic effects associated with its consumption have been reported [29][94].
Resveratrol has been the subject of numerous preclinical and clinical studies due to its beneficial effects on various diseases, demonstrating its ability to reduce both OS and inflammation in different OS-dependent pathologies, both in animal models and in humans. Resveratrol has been shown to have neuroprotective effects in both animal models and clinical studies of IS. This happens through a variety of mechanisms, mainly because of its antioxidant and anti-inflammatory capacities [30][95], among other mechanisms, some of them not fully elucidated. Resveratrol has been shown to promote neurogenesis while reducing neurotoxicity by modulating glial activity and signaling [31][96].
To understand its protective effect in brain IRI, it is relevant to consider the Nrf2 and antioxidant response elements (ARE) signaling pathway. Normally, Nrf2 is found interacting with Kelch-like ECH-associated protein 1 (Keap1), forming the Keap1–Nrf2 complex, which limits Nrf2-mediated gene expression [32][100].
This is precisely where resveratrol plays an important role, as it has been shown to ameliorate brain injury caused by OS due to brain ischemia reperfusion by regulating the expression of Nrf2 and HO-1. By activating the Nrf2/ARE pathway, resveratrol promotes intracellular antioxidant defense, reducing levels of OS and providing protection against brain damage in the context of ischemia reperfusion [33][101].
There is a variety of preclinical and clinical evidence regarding the beneficial effect of resveratrol following IS. In a study conducted in rodents, resveratrol demonstrated a remarkable ability to significantly decrease neurological deficit scores, reduce brain infarct size, mitigate neuronal injury and myeloperoxidase activity [34][102]. In the context of cerebral ischemia, increased expression levels of toll-like receptor 4 (TLR4), NF-κB p65, cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1 beta (IL-1β) were observed, but resveratrol was able to attenuate the activity of all these factors [34][102]. Thus, resveratrol exerts a beneficial effect by reducing inflammation, preserving the integrity of the BBB and protecting against brain damage in rats subjected to focal cerebral ischemia.
Interestingly, a study has highlighted the role of resveratrol preconditioning in providing a long-term window of tolerance to cerebral ischemia, extending up to 2 weeks in mice [35][103]. This preconditioning process has been shown to have a significant impact on bioenergetic efficiency through its effect on cellular pathways such as enhanced glycolysis, mitochondrial respiration efficiency, and increased energy production (increased tricarboxylic acid cycle) as well as regulated oxidative phosphorylation and pyruvate uptake [35][103].
In summary, resveratrol shows significant antioxidant action by activating SOD and downregulating MDA in brain IRI. Furthermore, its ability to regulate the Nrf2/ARE signaling pathway and increase the expression of antioxidant enzymes such as HO-1 and SOD translates into a neuroprotective effect that helps mitigate the damage caused by OS in the brain subjected to ischemia and subsequent reperfusion. These findings highlight the therapeutic potential of resveratrol in the treatment of OS and ischemia reperfusion-related brain conditions.
Regarding cardiac protection, resveratrol acts directly and indirectly on molecular pathways [36][105]. Decades ago, resveratrol was shown to be able to suppress low-density lipoprotein (LDL) oxidation in humans [37][106] as well as to reduce lipid peroxidation [38][107]. Since then, several studies have expanded the evidence supporting the potential of resveratrol to combat cardiovascular diseases, mainly by acting on OS and inflammation.
In relation to its involvement in OS, resveratrol plays a crucial role as a component of the ADS not only by acting as a free radical scavenger but also by increasing the activity of antioxidant enzymes and regulating genes related to redox balance, nitric oxide (NO) availability and mitochondrial functionality [39][108]. The stimulation of endothelial NO production is achieved by the upregulation of eNOS expression [40][109].
Furthermore, several studies have shown that resveratrol exerts certain effects through modifications in sphingolipids, a category of biological lipids with multiple cellular functions, including apoptosis, cell proliferation, OS, and inflammation. These lipids have attracted considerable interest as critical emerging determinants in the risk and development of cardiometabolic diseases. The resveratrol-mediated modulation of sphingolipid metabolism and signaling may represent an essential mechanism by which the compound exerts its effects, including the maintenance of oxidative balance [41][110].
Quercetin
Quercetin is a flavonoid that is widely found in commonly consumed foods such as fruit, vegetables, tea, and red wine. It is safe for human consumption, even in high doses [42][43][114,115]. This compound has a number of biological properties, including antioxidant, anti-inflammatory, anti-aggregating and anti-aging [44][116]. Quercetin has been extensively investigated for its effect on ameliorating OS. This compound has been found to have the ability to scavenge free radicals [45][117] and to induce the expression of the antioxidant enzyme HO-1, which in turn helps to reduce OS caused by the enzyme NOX [46][118]. In addition, it has been observed that quercetin can suppress the expression of NOX2, which is an isoform of the NOX system that plays an important role in the production of ROS, such as H2O2 [47][119]. The overproduction of NOX has been shown to contribute to neurotoxicity and cerebrovascular disease, and it has been implicated as a major source of ROS in the brain [48][120]. Regarding evidence in IS, a recent systematic review and meta-analysis aimed at evaluating the efficacy and possible mechanisms of quercetin in the treatment of focal cerebral ischemia showed that compared to the control group, the quercetin-administered groups exhibited a marked improvement in neurological function score and a significant effect on reducing infarct volume. In addition, it was shown that quercetin could alleviate BBB permeability and brain water content [49][123]. The mechanisms involved in quercetin’s action against focal cerebral ischemia are diverse and involve antioxidation, anti-apoptosis, anti-inflammation and a reduction in calcium overload [49][123]. One of the limitations of using quercetin in patients undergoing IS is that its effectiveness varies substantially depending on the type of source plant, the dose and the chemical properties after processing [50][126]. In humans, quercetin has low bioavailability, and it is noteworthy that it poorly crosses the BBB [51][127]. For this reason, studies have been conducted that aim to increase the bioavailability of quercetin in the brain, such as the use of nano-encapsulation and enzymatic modification, among other strategies. This compound has also been shown to reverse myocardial remodeling after myocardial ischemia. Studies in animal models have shown that quercetin can reduce ischemic–reperfusion injury in the heart and improve myocardial function. It has also been shown to inhibit myocardial fibrosis, increase mitochondrial energy metabolism, reduce inflammatory response and attenuate OS in the heart [52][53][129,130].Curcumin
Turmeric species, in particular Curcuma longa L., have been extensively studied and found to possess a wide range of pharmacological properties, including anti-inflammatory, anti-diabetic, anti-cancer, antiproliferative, antithrombotic, antioxidant, hypotensive, hypocholesterolemic, antirheumatic and antiviral effects, among many others [54][55][132,133]. The active compound in turmeric extract is curcumin, which is a lipophilic polyphenol with proven safety and good tolerance at high oral doses [56][134]. Curcumin has demonstrated synergistic therapeutic effects, enhancing the efficacy of other drugs and compounds, such as antibiotics, anti-inflammatories and polyphenols. Regarding myocardial IRI, curcumin has been shown to protect white matter after IS by inhibiting microglia/macrophage pyroptosis through the suppression of NF-κB and inhibition of the nucleotide-binding domain and leucine-rich repeat containing family pyrin domain containing 3 (NLRP3) inflammasome, thus reducing injury and improving functional outcomes in mice [57][135]. Furthermore, curcumin has been reported to decrease the expression of light chain 3 phosphatidylethanolamine conjugate (LC3-II) and HIF-1α while increasing P62 levels in an in vitro model of IRI [58][137]. LC3-II is a widely used marker to assess autophagy, which is a cellular process that plays a crucial role in the degradation and recycling of damaged or unneeded cellular components. On the other hand, HIF-1α is a transcription factor that is activated under conditions of hypoxia (low oxygen availability) and plays a role in the cellular response to oxygen deprivation. The reduced expression of LC3-II and HIF-1α, together with increased P62, results in decreased cell death and apoptosis. Curcumin also contributes to the protection of the cardiomyocytes through several mechanisms. It improves cardiac function after IRI by inhibiting extracellular matrix degradation and collagen synthesis through the transforming growth factor beta (TGFβ)/ mothers against decapentaplegic (Smad) signaling pathway. In addition, curcumin mitigates oxidative damage and reduces cardiomyocyte apoptosis through activation of the janus kinase (JAK) 2/signal transducers and activator of transcription (STAT) 3 pathway, thereby alleviating myocardial IRI.25.1.2. Phenolic Acids
Phenolic acids are compounds that have a carboxylic acid group and are present in a wide variety of foods of plant origin, such as the skin of fruits, grape seeds, tea, honey, peach, red wine, and the leaves of vegetables. They are usually found as amides, esters, or glycosides, and they are rarely in free form [59][144]. Phenolic acids are mainly divided into two subgroups: hydroxybenzoic acid and hydroxycinnamic acid [60][145]. These compounds are of interest since they possess considerable antioxidant activity. An in vivo study shows that treatment with Macrotyloma uniflorum seed extract, which is rich in phenolic acids such as p-coumaric acid and ferulic acid, exerts a significant cardioprotective effect in rats exposed to isoproterenol, probably due to the potent antioxidant activity of phenolic acids, which protect the myocardium from the harmful effects of isoproterenol [61][146].2.2. Carotenoids
5.2. Carotenoids
Carotenoids are lipophilic compounds that are found in a wide range of fruits, vegetables, and other natural sources. They serve important functions in plants, protecting chlorophyll and mitochondria, while in animals, they act as potent antioxidants and support various aspects of health [62][63][150,151]. Once consumed, carotenoids are absorbed in the intestines and transported to various tissues in the body through lipoproteins. One of the best-known carotenoids is beta-carotene, which is abundant in carrots, sweet potatoes, and green leafy vegetables. Beta-carotene is a precursor of vitamin A, which is a nutrient essential for vision, immune function and cell growth [63][151]. In humans, carotenoids play a crucial role as antioxidants, helping to neutralize harmful free radicals and protecting cells from oxidative damage. The consumption of carotenoid-rich foods has been associated with various health benefits, including a reduced risk of chronic diseases, such as cardiovascular disease, certain cancers, and age-related macular degeneration [64][152]. In conjunction with their antioxidant function, carotenoids have also been studied for their potential anti-inflammatory and immunomodulatory effects [64][152]. Carotenoids present in natural plant products have been shown to provide neuroprotection through a variety of mechanisms. Some of the main mechanisms by which carotenoids exert their neuroprotective effect include the following.-
Inhibition of neuroinflammation: Carotenoids have shown the ability to reduce inflammation in the central nervous system by inhibiting the production of pro-inflammatory cytokines and inflammatory cell activation.
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Regulation of microglial activation: Carotenoids can modulate the activity of microglial cells, which are immune cells in the central nervous system, helping to limit excessive inflammatory response.
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Protection against the excitotoxic pathway: Carotenoids may act as neuroprotective agents by preventing neuronal damage caused by excitotoxicity, which is a process that occurs when there is excessive overstimulation of glutamate receptors on neurons.
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Modulation of autophagy: Carotenoids can influence autophagy, which is a cellular process that plays a crucial role in the removal of damaged cellular components, thus helping to maintain the integrity of neurons.
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Reducing oxidative damage: Carotenoids are known for their potent antioxidant activity, enabling them to neutralize ROS and reduce cell damage caused by OS.
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Activation of defensive antioxidant enzymes: Carotenoids can also stimulate the activity of endogenous antioxidant enzymes in the brain, thereby enhancing the nervous system’s ability to counteract the effects of OS.
