Antioxidant Paradox Research Articles

Cardioprotective antihyperglycemic drugs ameliorate endoplasmic reticulum stress.

Cellular stress, notably oxidative, inflammatory, and endoplasmic reticulum (ER) stress, is implicated in the pathogenesis of cardiovascular disease. Modifiable risk factors for cardiovascular disease such as diabetes, hypercholesterolemia, saturated fat consumption, hypertension, and cigarette smoking cause ER stress whereas currently known cardioprotective drugs with diverse pharmacodynamics share a common pleiotropic effect of reducing ER stress. Selective targeting of oxidative stress with known antioxidative vitamins has been ineffective in reducing cardiovascular risk. This "antioxidant paradox" is partially attributed to the unexpected aggravation of ER stress by the antioxidative agents used. In contrast, some of the contemporary antihyperglycemic drugs inhibit both oxidative stress and ER stress in human coronary artery endothelial cells. Unlike sulfonylureas, meglitinides, α glucosidase inhibitors, and thiazolidinediones, metformin, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors are the only antihyperglycemic drugs that reduce ER stress caused by pharmacological agents (tunicamycin) or hyperglycemic conditions. Clinical trials with selective ER stress modifiers are needed to test the suitability of ER stress as a therapeutic target for cardiovascular disease.

SOD2 in platelets: with age comes responsibility

SOD2 in platelets: with age comes responsibility

Antioxidant Paradox in Male Infertility: 'A Blind Eye' on Inflammation.

The pathophysiology of male infertility involves various interlinked endogenous pathways. About 50% of the cases of infertility in men are idiopathic, and oxidative stress (OS) reportedly serves as a central mechanism in impairing male fertility parameters. The endogenous antioxidant system operates to conserve the seminal redox homeostasis required for normal male reproduction. OS strikes when a generation of seminal reactive oxygen species (ROS) overwhelms endogenous antioxidant capacity. Thus, antioxidant treatment finds remarkable relevance in the case of idiopathic male infertility or subfertility. However, due to lack of proper detection of OS in male infertility, use of antioxidant(s) in some cases may be arbitrary or lead to overuse and induction of ‘reductive stress’. Moreover, inflammation is closely linked to OS and may establish a vicious loop that is capable of disruption to male reproductive tissues. The result is exaggeration of cellular damage and disruption of male reproductive tissues. Therefore, limitations of antioxidant therapy in treating male infertility are the failure in the selection of specific treatments targeting inflammation and OS simultaneously, two of the core mechanisms of male infertility. The present review aims to elucidate the antioxidant paradox in male infertility treatment, from the viewpoints of both induction of reductive stress as well as overlooking the inflammatory consequences.

Impact of dietary supplements based on L-carnitine on free-radical processes in model systems

Introduction. According to the results of numerous studies and meta-analyses, the effectiveness of male infertility therapy with micronutrients-antioxidants in various variants remains low, especially concerning the increase in live-birth rates and the incidence of clinical pregnancy. This may be due to both the empirical nature of such therapy with an imbalance of ejaculate redox systems, and an overdose of individual ingredients of antioxidant complexes.Purpose of the study. To evaluate the antioxidant activity of complex preparation based on L-carnitine for the treatment of male infertility in an experimental model system.Materials and methods. The dietary supplements «AndroDoz®» («Nizhfarm» JSC, Russian Federation) and «Proxeed® plus» (Sigma-Tau Pharmaceuticals Inc., Italy) were tested. The antioxidant properties of the preparations were determined in vitro by recording chemiluminescence in model systems generating reactive oxygen species using the «LKB-Wallac 1256 chemiluminometer» (Wallac Oy/PerkinElmer®, Finland). Chemiluminescence was evaluated by the light sum and the maximum amplitude of the glow, the antioxidant activity in the biological environment was studied when adding drugs to chicken yolk lipids similar to blood lipoprotein complexes.Results. The introduction of «AndroDoz®» and «Proxeed® plus» into the incubation medium in an amount comparable to the physiological level of L-carnitine in seminal plasma, inhibited the luminescence of the model system. At the same time, if «Proxeed® plus» almost completely inhibited the formation of radicals, then an equivalent dose of «AndroDoz®» reduced the intensity of chemiluminescence by 60%. Approximately in the same proportions, the preparations suppressed the intensity of lipid peroxidation processes in a model system with lipoprotein complexes similar to blood lipids, that is, the antioxidant activity was preserved in the biological environment. A decrease in the value of the chemiluminescence light sum was also found against the background of the use of these dietary supplements, which may indicate their protective effect on biological membranes, including subcellular structures of spermatozoa.Conclusion. The combined dietary supplements used in the study have a high antioxidant potential. The preparation «Proxeed® plus» can completely suppress the processes of lipoperoxidation with the possible development of a deficiency of free radicals that provide vital processes. The preparation «AndroDoz®» has a milder effect on free-radical phenomena probably due to a lower content of active ingredients and a balanced composition, which reduces the risk of complications in the form of an «antioxidant paradox» or reductive stress.

Redox Balance in Male Infertility: Excellence through Moderation-"Μέτρον ἄριστον".

Male infertility, a relatively common and multifactorial medical condition, affects approximately 15% of couples globally. Based on WHO estimates, a staggering 190 million people struggle with this health condition, and male factor is the sole or contributing factor in roughly 20–50% of these cases. Nowadays, urologists are confronted with a wide spectrum of conditions ranging from the typical infertile male to more complex cases of either unexplained or idiopathic male infertility, requiring a specific patient-tailored diagnostic approach and management. Strikingly enough, no identifiable cause in routine workup can be found in 30% to 50% of infertile males. The medical term male oxidative stress infertility (MOSI) was recently coined to describe infertile men with abnormal sperm parameters and oxidative stress (OS), including those previously classified as having idiopathic infertility. OS is a critical component of male infertility, entailing an imbalance between reactive oxygen species (ROS) and antioxidants. ROS abundance has been implicated in sperm abnormalities, while the exact impact on fertilization and pregnancy has long been a subject of considerable debate. In an attempt to counteract the deleterious effects of OS, urologists resorted to antioxidant supplementation. Mounting evidence indicates that indiscriminate consumption of antioxidants has led in some cases to sperm cell damage through a reductive-stress-induced state. The “antioxidant paradox”, one of the biggest andrological challenges, remains a lurking danger that needs to be carefully avoided and thoroughly investigated. For that reason, oxidation-reduction potential (ORP) emerged as a viable ancillary tool to basic semen analysis, measuring the overall balance between oxidants and antioxidants (reductants). A novel biomarker, the Male infertility Oxidative System (MiOXSYS®), is a paradigm shift towards that goal, offering a quantification of OS via a quick, reliable, and reproducible measurement of the ORP. Moderation or “Μέτρον” according to the ancient Greeks is the key to successfully safeguarding redox balance, with MiOXSYS® earnestly claiming its position as a guarantor of homeostasis in the intracellular redox milieu. In the present paper, we aim to offer a narrative summary of evidence relevant to redox regulation in male reproduction, analyze the impact of OS and reductive stress on sperm function, and shed light on the “antioxidant paradox” phenomenon. Finally, we examine the most up-to-date scientific literature regarding ORP and its measurement by the recently developed MiOXSYS® assay.

Administration of Antioxidants in Infertile Male: When it may have a Detrimental Effect?

Significant advances in the field of male infertility have been witnessed during the last years. Given the well-known detrimental effects of reactive oxygen species (ROS), the administration of antioxidants has emerged as a promising solution for oxidative stress (OS)-induced male infertility. Nevertheless, this perception seems largely oversimplified, and the existing literature fails to recognize a notable superiority of the excessive use of these widely available nutritional compounds. Taking into consideration that several trials have shed light on the so-called "antioxidant paradox" phenomenon, we recognize that over-the-counter consumption of such supplements might be harmful. The relevant studies indexed in PubMed, Google Scholar and Scopus databases, published until September 2019 were identified and reported. In this setting, we acknowledge that there is an urgent need for more elaborate studies in the future that will efficiently elucidate the risks and benefits of antioxidants on semen parameters and their impact on fertility potential.

The excessive use of antioxidant therapy: A possible cause of male infertility?

Reactive oxygen species and oxidative stress are closely associated with various pathologies such as neurodegenerative diseases, ageing and male infertility. Hence, antioxidants such as vitamin C, vitamin E, N-acetyl cysteine, L-carnitine and folic acid are regularly used in various treatment regimens to protect cells from the damage induced by free radicals. However, given their over-the-counter availability at unnaturally high concentrations and also the fact that they are commonly added to various food products, patients may run a risk of consuming excessive dosages of these compounds, which may then be toxic. The few studies that have assessed antioxidant overuse and the associated adverse effects found that large doses of dietary antioxidant supplements have varying-if any-therapeutic effects even though free radicals clearly damage cells-a phenomenon that has been termed the "antioxidant paradox." Furthermore, overuse of antioxidants such as vitamin C, vitamin E, N-acetyl cysteine may lead to reductive stress, which is reported to be as dangerous to cells as oxidative stress and can be the cause of diseases such as cancer or cardiomyopathy. Therefore, we feel that there is a need for more elaborate research to establish the clear benefits and risks involved in antioxidant therapy for male infertility.

Bio-accessible milk casein derived tripeptide (LLY) mediates overlapping anti- inflammatory and anti-oxidative effects under cellular (Caco-2) and in vivo milieu

Inflammation and oxidative stress are closely linked patho-physiological processes which occur concurrently in many diseased conditions. Recently, interdependence between these two processes explains the antioxidant paradox associated with failure to select appropriate agents required for prevention of diseases known to be induced by oxidative stress. Present study established the overlapping anti-inflammatory and anti-oxidative potential along with bio-accessibility of milk casein derived tripeptide (LLY). Tripeptide exhibited anti-inflammatory response under ex vivo conditions by suppressing (P<.01) mice splenocytes proliferation and modulating their cytokines (IFN-γ, IL-10 and TGF-β) with improved phagocytosis of peritoneal macrophages. Conversely, tripeptide displayed extraordinary radical scavenging ability and cellular anti-oxidative potential using chemical assays and H2O2 induced oxidative stress model on Caco-2 cells. Under cellular assessment, on one hand tripeptide inhibited (P<.01) intracellular ROS generation and reduced MDA and protein carbonyls but on the other also increased (P<.01) the activity of anti-oxidative enzyme, catalase without much effect on SOD and GPx. This anti-oxidative potential was further established by studying relative expression of genes (Nrf-2 and Keap1) and Nrf-2 nuclear translocation associated with anti-oxidative signaling in Caco-2 cells. Bio-accessibility of tripeptide and its intact transport across Caco-2 cell monolayer was also found to be 1.72±0.22% through PepT1 mediated transport mechanism. Besides, tripeptide displayed strong anti-oxidative and anti-inflammatory potential under in vivo conditions in mice against ethanol induced oxidative stress by elevating (P<.01) liver GSH content and by decreasing (P<.01) the activities of anti-oxidative enzymes, MDA along with reduced expression of CYP2E1, PPAR-α, TNF-α and COX-2 genes than ethanol control.

Does serum bilirubin prevent cardiovascular disease?

Bilirubin possesses potent antioxidant, anti-inflammatory, anti-platelet, anti-hypercholesterolemic and anti-adiposity properties. Cross-sectional studies have demonstrated negative associations between serum bilirubin and metabolic syndrome (MetS), diabetes and atherosclerotic cardiovascular diseases (CVDs). However, longitudinal studies show conflicting results. Serum bilirubin levels are determined both genetically and environmentally, and fluctuate throughout one’s life. Longitudinal data suggest that some genetically hyperbilirubinemic individuals may have a lower CVD risk than the general population. However, the reverse may be also true; that is, postnatal metabolic or atherosclerotic diseases may cause oxidative stress and reduce serum bilirubin levels. Therefore, baseline serum bilirubin levels may not always be associated with future metabolic or atherosclerotic diseases. This situation resembles a phenomenon called antioxidant paradox; that is, randomized controlled trials have failed to confirm a role for antioxidant supplementation in CVD prevention, although oxidative stress is involved in the pathogenesis of CVD. Further prospective studies are required to confirm whether serum bilirubin prevents metabolic and atherosclerotic diseases.

Does the Interdependence between Oxidative Stress and Inflammation Explain the Antioxidant Paradox?

Oxidative stress has been implicated in many chronic diseases. However, antioxidant trials are so far largely unsuccessful as a preventive or curative measure. Chronic low-grade inflammatory process, on the other hand, plays a central role in the pathogenesis of a number of chronic diseases. Oxidative stress and inflammation are closely related pathophysiological processes, one of which can be easily induced by another. Thus, both processes are simultaneously found in many pathological conditions. Therefore, the failure of antioxidant trials might result from failure to select appropriate agents that specifically target both inflammation and oxidative stress or failure to use both antioxidants and anti-inflammatory agents simultaneously or use of nonselective agents that block some of the oxidative and/or inflammatory pathways but exaggerate the others. To examine whether the interdependence between oxidative stress and inflammation can explain the antioxidant paradox we discussed in the present review the basic aspects of oxidative stress and inflammation and their relationship and dependence.

The antioxidant paradox: what are antioxidants and how should they be used in a therapeutic context for cancer.

So-called antioxidants have yet to make a clinical impact on the treatment of human cancer. The reasons for this failure are several. First, many agents that are called antioxidants are truly antioxidants at a given dose, but this dose may not have been given in clinical trials. Second, many agents are not antioxidants at all. Third, not all tumors use reactive oxygen as a signaling mechanism. Finally, reactive oxygen inhibition is often insufficient to kill or regress a tumor cell by itself, but requires sequential introduction of a therapeutic agent for maximal effect. We hope to provide a framework for the logical use of these agents in cancer.

The antioxidant paradox: less paradoxical now?

The term 'antioxidant paradox' is often used to refer to the observation that oxygen radicals and other reactive oxygen species are involved in several human diseases, but giving large doses of dietary antioxidant supplements to human subjects has, in most studies, demonstrated little or no preventative or therapeutic effect. Why should this be? First, the role of reactive oxygen species in the origin and/or progression of most human diseases is unclear, although they are probably important in cancer, neurodegenerative diseases and perhaps some others. Second, the endogenous antioxidant defences in the human body are complex, interlocking and carefully regulated. The body's 'total antioxidant capacity' seems unresponsive to high doses of dietary antioxidants, so that the amount of oxidative damage to key biomolecules is rarely changed. Indeed, manipulation of endogenous antioxidant levels (e.g. by supplying weak pro-oxidants) may be a more useful approach to treatment and prevention of diseases in which reactive oxygen species are important than is consumption of large doses of dietary antioxidants.

The Antioxidant Paradox in Diabetes Mellitus

There is ample empiric evidence to indicate that oxidative stress contributes to the pathogenesis of coronary artery disease and has a key role in the onset and progression of diabetes and its complications. Diabetes leads to depletion of the cellular antioxidant defense system and is associated with an increase in the production of free radicals. Oxidative stress can be the result of multiple pathways. Some of these are related to substrate-driven overproduction of mitochondrial reactive oxygen species, advanced glycation end product formation, glucose autoxidation, and depletion of micronutrients and cellular elements with antioxidative properties. There are numerous observational studies in the literature showing a beneficial outcome of the consumption of antioxidant vitamins. However, the interventional trials portray a different picture. The divide between the robust experimental evidence of the pathogenetic role of increased oxidative load in diabetes and the overwhelming failure of antioxidants to show any health benefits in clinical trials may well be characterized as the "antioxidant paradox."

Leukocytes and oxidative stress: dilemma for sperm function and male fertility

Spermatozoa are constantly exposed to the interphase between oxidation through high amounts of reactive oxygen species (ROS) and leukocytes, and reduction by means of scavengers and antioxidants. Considering the very special functions as being the only cells with such high polarization and exerting their functions outside the body, even in a different individual, the female genital tract, the membranes of these cells are chemically composed of an extraordinary high amount of polyunsaturated fatty acids. This in turn, renders them very susceptible to oxidative stress, which is defined as an imbalance between oxidation and reduction towards the oxidative status. As a result, ROS deriving from both leukocytes and the male germ cells themselves cause a process called 'lipid peroxidation' and other damages to the sperm cell. On the other hand, a certain limited amount of ROS is essential in order to trigger vital physiological reactions in cells, including capacitation or the acrosome reaction in sperm. The treatment of patients with antioxidants to compensate the oxidative status caused by oxidative stress is highly debated as uncontrolled antioxidative treatment might derail the system towards the reduced status, which is also unphysiological and can even induce cancer. This paradox is called the 'antioxidant paradox'. Therefore, a proper andrological diagnostic work-up, including the evaluation of ROS levels and the antioxidant capacity of the semen, has to be carried out beforehand, aimed at keeping the fine balance between oxidation and scavenging of vital amounts of ROS.

Evolutionary inspirations for drug discovery

Conceptual innovations are needed to address the challenge of 'more investments, fewer drugs' in the pharmaceutical industry. Since the publication of The Origin of Species by Charles Darwin 150 years ago, evolution has been a central concept in biology. In this article, we show that evolutionary concepts are also helpful to streamline the drug-discovery pipeline through facilitating the discovery of targets and drug candidates. Furthermore, the antioxidant paradox can be addressed by an evolutionary methodology. Through examining the evolved biological roles of natural polyphenols (which dominate current antioxidant drug discovery), we reveal that polyphenols (particularly flavonoids) are not evolved for scavenging free radicals. This finding provides new clues to understanding why the strong in vitro antioxidant activities of polyphenols cannot be translated into in vivo effects. Polyphenols have evolved a superior ability to bind various proteins, so we also argue that they are good starting points for multi-target drugs.

The antioxidant paradox: Damage and defence

Over the last three decades, a considerable body of evidence has accumulated to suggest that a key factor in the development of both cancer and coronary heart disease is damage to tissues or plasma lipoproteins caused by free radicals. The majority of radicals that damage tissues are reactive oxygen species, and compounds that can quench potentially damaging radical chain reactions are therefore generally referred to as antioxidants. Epidemiological studies have shown a negative correlation between intakes of antioxidants (especially vitamin E and -carotene) and the incidence of cancer and coronary heart disease, and a positive correlation between markers of radical damage and disease. At the molecular level, there are sound theories to explain how radical damage can lead to cancer and coronary heart disease, and how antioxidants may provide protection. However, the results of intervention trials of vitamin E and -carotene have been, at best, disappointing; indeed, many trials have shown increased death among people taking supposedly protective antioxidant supplements. This is the antioxidant paradox.

Classical Anti-oxidants (Scavengers) versus Biological Anti-oxidants (Suppressors of ROS Generation): ANovel Way to Explain the Anti-oxidant Paradox

Metabolic Syndrome and Related DisordersVol. 2, No. 3 ReviewClassical Anti-oxidants (Scavengers) versus Biological Anti-oxidants (Suppressors of ROS Generation): ANovel Way to Explain the Anti-oxidant ParadoxParesh Dandona, Sandeep Dhindsa, Ahmad Aljada, and Ajay ChaudhuriParesh DandonaSearch for more papers by this author, Sandeep DhindsaSearch for more papers by this author, Ahmad AljadaSearch for more papers by this author, and Ajay ChaudhuriSearch for more papers by this authorPublished Online:13 May 2005https://doi.org/10.1089/met.2004.2.155AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byCarvedilol Exerts Neuroprotective Effect on Rat Model of Diabetic Neuropathy13 April 2021 | Frontiers in Pharmacology, Vol. 12Patients with multiple sclerosis show increased oxidative stress markers and somatic telomere length shortening26 November 2014 | Molecular and Cellular Biochemistry, Vol. 400, No. 1-2Antioxidant activity of carvedilol in cardiovascular diseaseJournal of Hypertension, Vol. 25, No. 4 Volume 2Issue 3Sep 2004 InformationCopyright 2004, Mary Ann Liebert, Inc.To cite this article:Paresh Dandona, Sandeep Dhindsa, Ahmad Aljada, and Ajay Chaudhuri.Classical Anti-oxidants (Scavengers) versus Biological Anti-oxidants (Suppressors of ROS Generation): ANovel Way to Explain the Anti-oxidant Paradox.Metabolic Syndrome and Related Disorders.Sep 2004.155-159.http://doi.org/10.1089/met.2004.2.155Published in Volume: 2 Issue 3: May 13, 2005PDF download

Reoxygenation injury and antioxidant protection: A tale of two paradoxes

Under certain circumstances, added antioxidants can protect tissues against reoxygenation injury after ischemia. Yet reperfusing blood carries many antioxidants with it. The implications of this “antioxidant paradox” are discussed.