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Review

Exploring Oxidative Stress in Disease and Its Connection with Adenosine

by
Ana Salomé Correia
1,2,3 and
Nuno Vale
1,2,4,*
1
PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
2
CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
3
Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
4
Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
*
Author to whom correspondence should be addressed.
Oxygen 2024, 4(3), 325-337; https://doi.org/10.3390/oxygen4030019
Submission received: 18 July 2024 / Revised: 30 July 2024 / Accepted: 15 August 2024 / Published: 19 August 2024
Browse Figure
Versions Notes

Abstract

:
Oxidative stress, characterized by an imbalance between the production of reactive oxygen species and the body’s antioxidant defenses, plays an important role in the pathogenesis of various health conditions, including cancer and neurological disorders. For example, excessive ROS can lead to mutations, genomic instability, and uncontrolled cell proliferation in cancer. In neurological disorders, oxidative stress contributes to neuronal damage, inflammation, and the progression of diseases such as Alzheimer’s and Parkinson’s diseases. Adenosine, a nucleoside involved in energy transfer and signal transduction, is crucial to maintaining cellular homeostasis. Its role extends to modulating oxidative stress. Adenosine receptors are implicated in various physiological processes and in the pathophysiology of diseases. The interplay between oxidative stress and adenosine signaling is complex and critical. Adenosine can modulate oxidative stress responses, providing therapeutic potential for conditions where oxidative stress is a key player. Understanding this connection opens up avenues for novel therapeutic strategies targeting adenosine receptors to mitigate oxidative damage.

1. Introduction

Oxidative stress is a biological process triggered by an imbalance between the generation of free radicals, especially reactive oxygen species (ROS), and the body’s ability to neutralize these harmful compounds with antioxidants. This balance is crucial for maintaining normal cellular functions, as antioxidants detoxify reactive species produced during various metabolic reactions. Factors such as smoking and ultraviolet (UV) radiation can exacerbate this imbalance, leading to increased oxidative stress and potential cellular damage [1,2].
While ROS function as essential signaling molecules at normal levels, their overproduction during oxidative stress can cause significant cellular damage. This damage results from harmful interactions with proteins, lipids, and DNA, contributing to the development of numerous oxidative stress-related conditions. These conditions encompass cancer, metabolic disorders like diabetes and obesity, as well as neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [3].
Adenosine, an essential endogenous component, exerts its influence through activation of four receptors: A1, A2A, A2B, and A3. This nucleoside is widely distributed across organs and tissues, thereby eliciting diverse physiological and pathological effects. Its impact spans the central nervous, cardiovascular, and immune systems, highlighting its role in regulating various bodily functions. The expression profiles of adenosine receptors exhibit heterogeneity among different cell types, underscoring their potential role as diagnostic markers of diseases and promising targets for innovative pharmaceutical interventions [4].
Adenosine exhibits protective effects against oxidative stress by functioning as an antioxidant. It scavenges ROS, thereby shielding cells from oxidative damage [5]. Moreover, adenosine regulates the activity of enzymes and signaling pathways crucial for the cellular response to oxidative stress [6].
This review aims to explore the role of oxidative stress in disease while also examining the involvement of adenosine in this context. A comprehensive study of these topics is essential for advancing treatment approaches and deepening our understanding of these mechanisms.

2. Oxidative Stress: Mechanisms, Effects, and the Role of Antioxidants

Oxidative stress is characterized by disturbances between the levels of ROS and a biological system’s ability to detoxify these reactive products [2] (Table 1). ROS include superoxide radicals (O2•−), hydrogen peroxide (H2O2), hydroxyl radicals (•OH), and singlet oxygen (1O2) [2].
ROS are well recognized as critical second messenger signaling molecules in cell biology and physiology. Table 2 presents the physiological effects of ROS.
Focusing on H2O2, it is the primary ROS involved in the redox-dependent control of biological activities. This molecule modulates signal transmission, cell metabolism, and stress responses, as well as other physiological processes [24]. Other enzymes decompose H2O2; for example, peroxiredoxins (Prxs), distributed across various cellular compartments, reduce H2O2 and organic hydroperoxides to water and alcohols through a conserved cysteine residue [25]. Myeloperoxidase (MPO), present in neutrophils, converts H2O2 into hypochlorous acid during immune responses [26]. H2O2 is produced by the NAD(P)H oxidases (NOX)/SOD system and enters cells through simple diffusion and facilitated diffusion via aquaporin water channels. The most well-understood mechanism by which H2O2 mediates cellular signaling is through the reversible oxidation of specific cysteine (Cys) residues. This process primarily involves redox-sensitive proteins with metabolic regulatory roles. By entering the cell, H2O2 initiates ROS signaling by oxidizing critical redox-sensitive Cys residues in signaling proteins. The primary targets of H2O2 include transcription factors and protein tyrosine phosphatases [27]. Indeed, in redox-sensitive proteins, Cys residues play a crucial role. Under physiological pH, these residues are partially ionized, meaning they have a charge due to the presence of the thiol (-SH) group. Upon oxidation by H2O2, they form sulfenic acids or their salts, which are highly reactive and can lead to the formation of intra- or intermolecular disulfide bonds in the presence of other thiolates. This sulfenylation process can take place either within the same molecule or between different molecules, with a preference for GSH to create glutathionylated intermediates. These redox modifications induce changes in the functions of target proteins and are reversible through the action of antioxidative systems such as Trx or GSH, which can reduce the modified cysteine residues back to their original state. However, under excessive concentrations of H2O2, sulfenic acid intermediates may undergo further oxidation to form sulfinic and sulfonic acids. These modifications are typically irreversible and can lead to significant changes in protein structure and function [28].
Whether H2O2 functions as a signaling molecule or causes oxidative damage to biomolecules, resulting in oxidative stress, is determined by the cellular context, its local concentration, and the dynamics of its production and elimination [29]. Indeed, in contrast to healthy levels, high H2O2 concentrations produce oxidative stress via non-specific protein oxidation and biomolecule damage, such as oxidative DNA damage [24]. Exposure to H2O2 is a common method for inducing oxidative stress in biological models. The Fenton reaction between H2O2 and Fe2+ ions produces the extremely reactive OH radical, which is regarded to be the primary cause of oxidative damage [30]. In fact, H2O2 has been utilized in medicine for over a century. In surgery, it is valued as an effective irrigation solution because of its hemostatic and antimicrobial properties. However, concerns about its safety arise from its cytotoxic effects at higher concentrations [31]. When the body metabolizes toxic substances like alcohol, it can result in the heightened formation of ROS that can inflict damage on liver cells. The excessive production of ROS in the liver is a key factor in alcohol poisoning, causing a severe depletion of the liver’s natural antioxidant defenses [32]. ATG4, a crucial gene in the autophagy pathway, has been identified as a direct target for oxidation by H2O2 during periods of starvation. The presence of excess H2O2 can oxidize ATG4, enhancing its activity. This oxidation of ATG4 facilitates the lipidation of LC3/ATG8, which is essential for initiating autophagy [32].

3. ROS and Disease

ROS overproduction is linked to the onset of various human diseases, including cancer, neurological disorders, cardiovascular diseases and metabolic diseases such as diabetes. Excessive ROS levels are also associated with processes like inflammation and aging [33]. In this section, an overview of the connection between ROS and different diseases will be presented.
The metabolic reprogramming of cancer cells facilitates the production of ROS at significantly higher levels compared to normal cells [34]. Nevertheless, many chemotherapy drugs increase the levels of ROS within cells, disrupting the redox balance in cancer cells. In fact, it is well established that these drugs exert their anticancer effects primarily by inducing oxidative stress and causing ROS-mediated damage to cancer cells [35]. Indeed, in cancer, ROS significantly modulate various critical processes, including genome instability, proliferation, immortalization, angiogenesis, epithelial–mesenchymal transition, and metastasis [36]. The intense metabolic activity in cancer cells leads to the excessive production of metabolites, which disrupts the balance between oxidative stress and redox homeostasis. This imbalance causes a significant accumulation of ROS within cancer cells. While moderate levels of ROS can enhance tumor growth by promoting cellular signaling pathways and gene expression related to these processes, excessively high levels of ROS can overwhelm the cell’s antioxidant defenses, leading to oxidative damage and triggering cell death. Thus, ROS can both promote and inhibit cancer, depending on their concentration within the cells [34]. In fact, in numerous cancer cells, consistently elevated H2O2-dependent signaling pathways are integral to processes such as cell differentiation, growth, and survival. Nevertheless, excessive H2O2 can cause cells to undergo cell cycle arrest or apoptosis. To balance this dual nature of H2O2, strong cellular antioxidant systems are vital for sustaining redox equilibrium. Cancer cells often enhance their oxidative stress defense mechanisms through the activation of the transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2) [28]. The inhibition of NRF2 increases ROS levels, a process that can impair tumorigenesis. Oncogenes such as K-RAS and c-MYC, which induce intracellular ROS, have been shown to stabilize NRF2 [37]. P53, the well-known tumor suppressor gene, also plays role in managing oxidative stress, acting as both a prooxidant and an antioxidant. These seemingly opposing functions of p53 in regulating the redox balance are likely influenced by the specific conditions of the cells, which can be either under stress or not [38]. For example, inactivating p53 reduced ROS production in cells exposed to patulin in vitro, indicating its role in promoting oxidative stress [38,39]. Conversely, inhibiting p53 led to prolonged activation of JNK (c-Jun N-terminal kinase), which elevates ROS levels, whereas activating p53 suppressed JNK activity [38,40,41].
The central nervous system relies heavily on mitochondria to meet its high energy demands, given its rapid metabolic rate. This need for energy is satisfied through ATP production via the electron transport chain and oxidative phosphorylation. As a result, neurons and glial cells produce considerable amounts of ROS, which is linked to the pathogenesis of several neurological disorders, such as AD, PD, amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD) [42].

3.1. In Alzheimer’s Disease

AD is marked by the abnormal deposition of amyloid β (Aβ) peptides and the intracellular accumulation of neurofibrillary tangles composed of hyperphosphorylated τ proteins, leading to dementia. The brains of AD patients exhibit significant oxidative damage, closely linked to the excessive accumulation of Aβ and the formation of neurofibrillary tangles [43,44]. In AD, one of the most prevalent issues within the mitochondrial electron transport chain is the deficiency of cytochrome c oxidase, which leads to increased ROS production, depletion of energy reserves, and impaired energy metabolism [45,46]. Moreover, ROS inhibits phosphatase 2A (PP2A), which promotes the activation of glycogen synthase kinase 3β, a kinase that plays a crucial role in Tau phosphorylation [46,47]. Oxidative stress also triggers the formation of stress granules, which are dense accumulations of proteins and untranslated mRNAs that appear in the cytoplasm under stress conditions [48,49]. Under pathological conditions such as AD, these stress granules can transform into persistent aggregates. Stress granules induced by acute stress have a protective role and help reduce apoptosis. In contrast, in AD, stress granules disrupt neuronal function by sequestering essential proteins, including ribonucleoproteins, thereby exacerbating the disease [48,50]. Additionally, endoplasmic reticulum (ER) stress (buildup of improperly folded or unfolded proteins within the ER, triggered by various factors like exposure to toxins, inflammatory cytokines, and mutations in proteins that disrupts the ER’s normal functioning) is pronounced in AD. In this disease, postmortem analyses reveal significantly higher levels of ER stress markers, such as PERK and eIF2α, in brain tissues compared to those of age-matched healthy individuals [51]. A recent study discovered that patients with AD and 3 × Tg mice exhibited decreased expression of NRF2 and increased expression of the ROS marker NADPH oxidase 4 (NOX4). This deficiency in NRF2 led to ferroptosis-dependent oxidative stress, characterized by an increase in ROS and a decrease in heme oxygenase-1 and glutathione peroxidase 4, along with an increase in cystine/glutamate transporter expression. Furthermore, this deficiency resulted in findings such as elevated lipid peroxidation and DNA oxidation in mouse astrocytes. This suggests that NRF2 deficiency contributes to ferroptosis in astrocytes through oxidative stress mechanisms in AD [51]. Another study also revealed that in response to ROS, two encapsulated therapeutic aggregation-induced emission molecules are released to start a self-enhanced therapy program. One molecule stops the formation of Aβ fibrils, breaks down existing fibrils, and prevents them from forming again. The other molecule scavenges ROS and reduces inflammation, restoring the brain’s redox balance. Together, these molecules reversed neurotoxicity and improved behavior and cognition in a mice model of AD [52]. Also, many studies have highlighted the beneficial antioxidant effects of natural flavonoids, which are able to inhibit the aggregation of Aβ and hyperphosphorylation of Tau proteins by activating NRF2; for example, exhibiting neuroprotective effects in AD [53].

3.2. In Parkinson’s Disease

In PD, the decline of dopaminergic neurons is also closely linked to oxidative stress. Disruptions in the normal redox balance within neurons, driven by various biological processes, can result in neuronal death. Indeed, both oxidative and nitrative damages are evident in the substantia nigra of PD patients. This brain region, which experiences a significant reduction in dopaminergic neurons, is particularly vulnerable [54]. ALS, characterized by the degeneration of lower motor neurons in the spinal cord and upper motor neurons in the cerebral cortex, is also connected to oxidative stress. Indeed, one established cause of ALS pathogenesis is oxidative stress, which has been consistently observed in patients and in cellular and animal models, inducing mitochondrial dysfunction and leading to the loss of motor neurons [55]. HD is also a neurodegenerative disorder, caused by an expanded polyglutamine sequence within the huntingtin protein, which exerts harmful effects through various mechanisms, including altered gene expression. The key characteristics of HD include heightened oxidative stress and disrupted redox homeostasis. The disease is associated with compromised antioxidant defenses, which involve both antioxidant compounds and enzymes that neutralize or repair oxidative damage. Additionally, HD is marked by impaired mitochondrial function, which results in deficient energy production and increased generation of ROS within cells [56].

3.3. In Cardiovascular Diseases and Diabetes

Cardiovascular diseases are the foremost cause of death worldwide, with oxidative stress also being a key factor in its progression. Elevated ROS levels decrease nitric oxide availability, leading to vasoconstriction and subsequently to arterial hypertension. ROS also disrupt calcium handling in the myocardium, causing arrhythmias, and contribute to cardiac remodeling through hypertrophic signaling and apoptosis induction. Additionally, ROS are implicated in the formation of atherosclerotic plaques [57]. In the context of diabetes, oxidative stress is also a critical determinant of the disease’s pathogenesis and its associated complications. Diabetes exacerbates oxidative stress through chronic hyperglycemia and mitochondrial dysfunction, which increase ROS production. The resultant oxidative burden adversely affects the Langerhans β cell function and insulin sensitivity, leading to impaired glucose regulation. Additionally, oxidative stress inflicts damage to blood vessels and compromises endothelial function, thereby contributing to diabetic vascular complications like retinopathy, nephropathy, and cardiovascular diseases [58].
A comprehensive understanding of the mechanisms by which ROS and antioxidants operate, including the contexts and conditions under which they are most effective, could lead to more rational and targeted pharmacological strategies, leading to improved clinical outcomes and greater success in treating various oxidative stress-related diseases [59].

4. The Interplay between Adenosine and ROS

4.1. An Overview of Adenosine

Adenosine, a naturally occurring nucleoside derived from purine, is found throughout nearly all the tissues in the body (Figure 1).
Adenosine influences a range of physiological processes by binding to four distinct G-protein coupled receptors (GPCRs): A1, A2A, A2B, and A3. The A1 and A3 receptors are associated with the Gi and Go protein families, whereas the A2A and A2B receptors are linked to the Gs protein family. These receptors are significant pharmacological targets for the treatment of various human conditions, such as neurological disorders [60]. This molecule has several functions, like the modulation of neuronal plasticity, learning, memory and motor function [61].
Inside the cell, adenosine is generated through either the dephosphorylation of AMP by 5′-nucleotidase or the hydrolytic cleavage of S-adenosylhomocysteine, facilitated by enzymes that convert S-adenosylhomocysteine into adenosine and homocysteine. Outside the cell, adenosine is derived from adenine nucleotides like adenosine triphosphate (ATP) or adenosine diphosphate (ADP), which are released and then processed by a series of ectonucleotidases. These ectonucleotidases catalyze the sequential hydrolysis of ATP or ADP, resulting in the formation of adenosine [62]. Extracellularly, the activation of the adenosine receptors leads to the adenosine’s biological activities [63].
Adenosine differs from other neurotransmitters in several key ways. It is not stored in synaptic vesicles and does not act exclusively at synapses. Instead, its release and uptake are facilitated by nucleoside transporters, with the direction of transport determined by the concentration gradient between the cytoplasm and the extracellular space. As a result, adenosine is regarded as a neuromodulator. It can regulate neurotransmitter release presynaptically, cause hyperpolarization or depolarization of neurons postsynaptically, and exert regulatory effects on glial cells nonsynaptically [64].
Adenosine plays a crucial role in treating several diseases, such as CNS and cardiovascular disorders, with its mechanisms varying based on the disease type, affected areas, and the distribution of adenosine receptors. Indeed, dysfunctions in adenosine receptors are implicated in the pathogenesis of disorders such as AD and epilepsy [65]. For example, caffeine, a non-specific adenosine receptor antagonist, seems to have beneficial effect on AD, highlighting that adenosine also worsens the AD pathological state [66]. Table 3 provides a summary of some recent studies highlighting diseases associated with adenosine dysfunction.
However, while adenosine can sometimes have harmful effects in certain pathological conditions, it is also broadly recognized as a protective agent that mitigates tissue damage and stress. Notably, adenosine exhibits significant immune-regulatory properties, predominantly acting as an anti-inflammatory mediator. However, in some situations, it may suppress antitumor and antibacterial responses, potentially facilitating the progression of cancer and sepsis [77]. In fact, in cancer, extensive evidence shows that the transformation of pro-inflammatory extracellular ATP into immunosuppressive extracellular adenosine promotes cancer progression and enables the evasion of antitumor immunity [78].
Modulating adenosine metabolism and receptor signaling could be an effective treatment strategy for a range of human diseases. Research has demonstrated that numerous drugs benefit patients by targeting adenosine signaling pathways. Examples include A2A adenosine receptor modulators like istradefylline and regadenoson, which have shown positive therapeutic effects [79]. Istradefylline exerts its anti-Parkinsonian effects by acting as an antagonist to the adenosine A2A receptor [80]. Regadenoson, approved as a pharmacologic stress agent for radionuclide myocardial perfusion imaging in patients who cannot undergo sufficient exercise stress, functions as an A2A receptor agonist [81].
Understanding adenosine can lead to groundbreaking insights in medicine and biology. By delving into its complex mechanisms, scientists aim to implement innovative therapies and interventions.

4.2. Adenosine and Oxidative Stress

Adenosine has been shown to have protective effects against oxidative stress. It can act as an antioxidant, scavenging ROS and protecting cells from damage caused by oxidative stress [5]. Additionally, adenosine can modulate the activity of various enzymes and signaling pathways involved in the cellular response to oxidative stress [6]. Adenosine functions as a true oxygen sensor. ROS production occurs under both hypoxic and hyperoxic conditions. In response to hypoxia, adenosine is significantly released by endothelial through the HIF (hypoxia-inducible factor) pathway [82]. Conversely, in cases of hyperoxia, the vasoconstriction resulting from a decrease in the plasma adenosine levels helps protect organs from excessive oxygen and ROS production [83].
During oxidative stress, activating adenosine receptors has been demonstrated to shield against oxidative damage due to their protective properties. Nonetheless, the specific subtype selectivity and signaling mechanisms of the adenosine A1 receptor in safeguarding the heart during oxidative stress have remained unclear. In a study, it was observed that stimulation of A1Rs with N6-cyclopentyladenosine, a specific A1 receptor agonist, reduced the production ROS as well as causing a decrease in apoptosis induced by H2O2. Additionally, this increased the synthesis of antioxidant enzymes and antiapoptotic proteins [84]. Furthermore, another study revealed that adenosine mitigated the adverse impacts of oxidative stress and mitochondrial dysfunction by modulating mitochondrial function and biogenesis in fibroblasts derived from a patient with Friedreich’s ataxia [85]. Additionally, another research study demonstrated that caffeine, either alone or in conjunction with an adenosine A2A receptor antagonist, inhibited apoptosis, fostered proliferation, and mitigated oxidative stress. However, the beneficial effects of caffeine were compromised in the presence of an A2A receptor agonist. Knockdown of the receptor yielded similar results to caffeine treatment, indicating the pivotal role of this receptor in mediating these effects [86]. Another antagonist of A2A receptors, RAD11, also alleviated liver damage induced by lipid accumulation-mediated oxidative stress in cases of hepatic fibrosis [87]. Other research highlighted that aging in A1 receptor +/+ mice is linked to increased oxidative stress, characterized by enhanced NADPH oxidase-derived O2− formation and elevated NADPH oxidase isoform 2 (NOX2) protein expression in the pancreas and visceral adipose tissue. These findings underscored the role of A1 receptors in modulating oxidative stress during aging, influencing metabolic and endocrine functions [88]. In the context of glaucoma, oxidative stress also plays a critical role in retinal cell death triggered by elevated pressure. Blocking adenosine A2A receptors in microglia effectively mitigated this oxidative stress response. Specifically, inhibiting these receptors prevented an increase in ROS and morphological alterations in microglia induced by elevated pressure. This suggests that targeting A2A receptors in microglia could be a promising strategy for controlling oxidative stress and protecting retinal cells from damage in glaucoma [89]. Another recent study revealed that naringin, a potential nutraceutical agent, may mitigate neurodegeneration associated with PD by inhibiting adenosine A2A receptors [90]. Moreover, other research demonstrated that the A2A adenosine receptor agonist-treated group exhibited reduced oxidative stress and inflammation, highlighting the positive impact of A2AR activation in managing diabetes-induced osteoporosis, evidenced by notable enhancements in the bone microarchitecture [91].
In sum, these studies demonstrate that adenosine and its receptors are crucial in protecting against oxidative stress in conditions such as cardiovascular diseases. Modulating adenosine receptors, particularly A1 and A2A, shows promise for reducing oxidative damage and improving cellular resilience. Future research should explore the mechanisms and broader applications of adenosine receptor modulation in oxidative stress-related diseases.

Author Contributions

Conceptualization, N.V. and A.S.C.; formal analysis, A.S.C. and N.V.; writing—original draft preparation, A.S.C.; writing—review and editing, A.S.C. and N.V.; supervision, N.V.; project administration, N.V.; funding acquisition, N.V. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financed by the FEDER—Fundo Europeu de Desenvolvimento Regional through the COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through the FCT—Fundação para a Ciência e a Tecnologia, in a framework of the projects in CINTESIS, R&D Unit (reference UIDB/4255/2020) and within the scope of the project “RISE—LA/P/0053/2020. Nuno Vale also thanks support from FCT and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004 and CHAIR in Onco-Innovation at FMUP.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

A.S.C. acknowledges the FCT for funding her PhD grant (SFRH/BD/146093/2019).

Conflicts of Interest

The authors declare no conflicts of interest.

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Oxygen 04 00019 g001
Figure 1. Molecular structure of adenosine.
Figure 1. Molecular structure of adenosine.
Oxygen 04 00019 g001
Table 1. Principal existent antioxidants and brief descriptions of them.
Table 1. Principal existent antioxidants and brief descriptions of them.
CategoryAntioxidantBrief DescriptionReference
ExogenousVitamin CProtects cellular structures from free radical damage[7]
Vitamin EProtects cell membranes from oxidative damage[8]
SeleniumComponent of some selenoproteins, glutathione peroxidase, thioredoxin reductase and other peroxidases [9]
PolyphenolsDirect scavenging of free radicals[10]
ZincSupports the activity of antioxidant enzymes such as superoxide dismutase (SOD) and inhibits nicotinamide adenine dinucleotide phosphate oxidase (NADPH-Oxidase) [11]
EndogenousSODEnzyme found in nearly all living cells; converts superoxide radicals to H2O2 and oxygen [12]
CatalaseLocated in the peroxysomes, converts H2O2 to water and oxygen [13]
Glutathione (GSH)Removal of harmful ROS and reactive nitrogen species (RNS), acting as the primary antioxidant in cells [14]
Glutathione Peroxidase (GPx)Reduces H2O2 or organic hydroperoxides to water and corresponding alcohols; uses GSH as a substrate [15]
ThioredoxinFacilitates the reduction of other proteins through its disulfide reductase activity [16]
Table 2. Overview of the physiological effects of ROS.
Table 2. Overview of the physiological effects of ROS.
ProcessBeneficial Effects of ROSReference
Cell SignalingAct as signaling molecules that help regulate various cellular functions, including growth, differentiation, and cell death [17]
Immune ResponseProduced by immune cells to kill pathogens [18]
Cell ProliferationLow levels promote cell division and proliferation [19]
HormesisInduce adaptive responses at low concentrations, enhancing cellular stress resistance and longevity [20]
Vascular FunctionInvolved in the regulation of vascular tone and blood pressure by modulating the activity of endothelial cells [21]
Wound HealingPlay a role in the signaling processes that initiate and sustain the healing of damaged tissues [22]
NeurotransmissionContribute to the modulation of synaptic plasticity and are involved in the signaling pathways in neurons [23]
Table 3. Overview of some recent studies highlighting diseases associated with adenosine dysfunction.
Table 3. Overview of some recent studies highlighting diseases associated with adenosine dysfunction.
DiseaseConnection to Adenosine Reference
Cardiovascular diseasesBlocking endothelial A2A receptor suppresses atherosclerosis in vivo by inhibiting CREB-ALK5-mediated endothelial-to-mesenchymal transition.
Activating the adenosine A2B receptor alleviates myocardial ischemia–reperfusion injury by suppressing endoplasmic reticulum stress and restoring autophagy flux.		[67,68,69]
EpilepsyThe motor nerve-derived factor-agrin/low-density lipoprotein receptor related protein pathway in hippocampal astrocytes suppresses the development of temporal lobe epilepsy via adenosine signaling.
Transplanting mesenchymal stem cells modified with the adenosine kinase gene reduces seizure severity and mitigates associated cognitive impairment in a rat model of temporal lobe epilepsy.		[70,71]
CancerInhibiting the A2A receptor enhances the anti-tumor effectiveness of anti- programmed death 1 (PD1) treatment in murine hepatobiliary cancers.
Adenosine enhances programmed death ligand 1 (PD-L1) expression in cervical cancer-derived mesenchymal stromal cells by interacting with A2AR/A2BR and promoting the production of transforming growth factor beta 1 (TGF-β1).		[72,73]
Neurological diseasesEarly upregulation of A2AR in the presence of ongoing amyloid pathology exacerbates memory impairments in APP/PS1 mice.
KW6002, an adenosine A2A receptor antagonist, mitigates brain damage and neuronal apoptosis induced by A53T mutant alpha-synuclein in Parkinson’s disease mice by enhancing autophagic flux.		[74,75]
DiabetesGDF15 shields insulin-producing beta cells from pro-inflammatory cytokines and metabolic stress by enhancing the deamination process of intracellular adenosine.
Equilibrative nucleoside transporter-2 (ENT2) activity in glomerular cells is tightly regulated by the insulin/PI3K pathway, which enhances its activity. Conversely, deficient insulin signaling diminishes ENT2 activity, leading to elevated extracellular adenosine levels. This impairment in adenosine uptake is implicated in renal alterations, frequently observed in diabetes.		[76]
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Correia, A.S.; Vale, N. Exploring Oxidative Stress in Disease and Its Connection with Adenosine. Oxygen 2024, 4, 325-337. https://doi.org/10.3390/oxygen4030019

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Correia AS, Vale N. Exploring Oxidative Stress in Disease and Its Connection with Adenosine. Oxygen. 2024; 4(3):325-337. https://doi.org/10.3390/oxygen4030019

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Correia, Ana Salomé, and Nuno Vale. 2024. "Exploring Oxidative Stress in Disease and Its Connection with Adenosine" Oxygen 4, no. 3: 325-337. https://doi.org/10.3390/oxygen4030019

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