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Antioxidant Supplements to Prevent Mortality
Abstract
Are antioxidant supplements associated with higher or lower all-cause mortality?
Antioxidant supplements are not associated with lower all-cause mortality. Beta carotene, vitamin E, and higher doses of vitamin A may be associated with higher all-cause mortality.
... Despite the relatively stable relation between increased carotene intake and status and the risk of CVD, carotene intake has been shown to have little effect on cardiovascular disease (CVD) or lung cancer in randomized controlled trials (RCTs) (Voutilainen et al., 2006). According to meta-analyses, carotene supplements have been linked to an increased risk of death, especially in smokers (Bjelakovic et al., 2013), as a result, the data from retrospective trials and RCTs on the impact on CVD results has been inconsistent. The RCTs' design has been criticized (Riccioni et al., 2012, Stanner et al., 2004. ...
... Indeed, results were found in those with originally lower nutrient status in the only two carotene-containing, as conclusion, trials demonstrate a beneficial influence of supplementation (Blot et al., 1993, Hercberg et al., 2004. Bjelakovic et al. (2013) studies found that at larger doses, vitamins have little benefit or have a negative effect, however, as a result of these carotene trial results, health care organizations have advised against taking carotene supplements for the treatment of CVD or cancer. To better evaluate the impact of carotenoids on CVD risk, RCTs that consider the health and the nutritional status of participants entering trials are needed. ...
... It was classified as probable that foods containing carotenoids protected against cancer in the mouth, pharynx, and larynx, as well as lung cancer, whereas, this association is improbable for prostate cancer and nonmelanoma skin cancer. On the other hand, foods rich in lycopene are thought to protect against prostate cancer (Bjelakovic et al., 2013). ...
Carotenoids are widely distributed among naturally occurring plant pigments, with a high degree of structural variability and a broad range of biological functions. Because of their capacity to quench singlet oxygen and scavenge free radicals, they have antioxidant properties.
Carotenoids have been related to the prevention and treatment of a number of chronic diseases, including certain cancers, cardiovascular diseases, and eye diseases, as well as enhancement of immune system functions.
... In contrast to the findings from these observational studies, many interventional studies suggest neutral [15][16][17][18] or detrimental effects [19,20] on cardiovascular disease and mortality for antioxidant supplements. For example, a pooled analysis of randomized clinical trials (RCTs) failed to show that adequate vitamin E intake alone can lower the risk of all-cause mortality [18]. ...
... For example, a pooled analysis of randomized clinical trials (RCTs) failed to show that adequate vitamin E intake alone can lower the risk of all-cause mortality [18]. Some meta-analyses of RCTs even indicated that individuals supplemented with antioxidants such as beta-carotene, vitamin A, and vitamin E had increased risk of mortality [19,20]. Conclusions from RCTs can be limited by duration, dosage, and timing of antioxidant supplements [21]. ...
... For instance, in a meta-analysis which included 37,199 participants from six prospective cohorts, a higher circulating BioMed Research International α-tocopherol level was significantly associated with a lower risk of all-cause mortality [68]. However, other metaanalyses based on RCTs indicated reverse conclusions, especially for the highest supplement dosage (≥400 IU/d) [20,[69][70][71]. Significant heterogeneity between observational studies was observed for the effect estimates in the metaanalysis. ...
Background. Antioxidants attracted long-standing attention as promising preventive agents worldwide. Previous observational studies have reported that circulating antioxidants are associated with reduced mortality; however, randomized clinical trials indicate neutral or harmful impacts. The association of long-term circulating antioxidant exposure with longevity is still unclear. Objectives. We aim to determine whether long-term circulating antioxidant exposure is causally associated with longevity in the general population using the two-sample Mendelian randomization (MR) design. Methods. Genetic instruments for circulating antioxidants (ascorbate, lycopene, selenium, beta-carotene, and retinol) and antioxidant metabolites (ascorbate, alpha-tocopherol, gamma-tocopherol, and retinol) were identified from the largest up-to-date genome-wide association studies (GWASs). Summary statistics of these instruments with individual survival to the 90th vs. 60th percentile age (11,262 cases and 25,483 controls) and parental lifespan (N=1,012,240 individuals) were extracted. The causal effect was estimated using the inverse-variance weighted method in the main analysis and complemented by multiple sensitivity analyses to test the robustness of results. Results. We found that genetically determined higher concentration of circulating retinol (vitamin A) metabolite was casually associated with a higher odds of longevity (OR, 1.07; 95% CI, 1.02–1.13; P
... Despite the extensive research on the analytical and biochemical identification and characterization of β-carotene was initially believed to be protective against multiple chronic diseases, particularly cardiovascular disease and cancer, due to observations of associations of reduced risk of these diseases with a high dietary intake (with carrots as the primary dietary source of β-carotene) [13][14][15][16]. However, meta-analyses of subsequent intervention studies ruled out a role of β-carotene in suppressing non-communicable diseases affecting lifespan [17]. for example, dietary supplementation with purified β-carotene showed a dose-dependent increased risk of lung cancer for intakes higher than what can be obtained from food [18]. ...
... Various cell types involved in chronic inflammation can be found β-carotene was initially believed to be protective against multiple chronic diseases, particularly cardiovascular disease and cancer, due to observations of associations of reduced risk of these diseases with a high dietary intake (with carrots as the primary dietary source of β-carotene) [13][14][15][16]. However, meta-analyses of subsequent intervention studies ruled out a role of β-carotene in suppressing non-communicable diseases affecting lifespan [17]. for example, dietary supplementation with purified β-carotene showed a dose-dependent increased risk of lung cancer for intakes higher than what can be obtained from food [18]. ...
Polyacetylene phytochemicals are emerging as potentially responsible for the chemoprotective effects of consuming apiaceous vegetables. There is some evidence suggesting that polyacetylenes (PAs) impact carcinogenesis by influencing a wide variety of signalling pathways, which are important in regulating inflammation, apoptosis, cell cycle regulation, etc. Studies have shown a correlation between human dietary intake of PA-rich vegetables with a reduced risk of inflammation and cancer. PA supplementation can influence cell growth, gene expression and immunological responses, and has been shown to reduce the tumour number in rat and mouse models. Cancer chemoprevention by dietary PAs involves several mechanisms, including effects on inflammatory cytokines, the NF-κB pathway, antioxidant response elements, unfolded protein response (UPR) pathway, growth factor signalling, cell cycle progression and apoptosis. This review summarises the published research on falcarinol-type PA compounds and their mechanisms of action regarding cancer chemoprevention and also identifies some gaps in our current understanding of the health benefits of these PAs.
... Many proposed supplementary antioxidants are naturally occurring in fruits and vegetables so are consumed as part of a normal diet. However, it is unknown if the doses of vitamins consumed in food have any direct beneficial effects on vascular oxidative stress and cardiovascular disease [135]. ...
... While natural antioxidants have demonstrated potential in in vitro and in in vivo animal models, and even appear to be effective in short term human studies, no long term human study has yielded positive results to support antioxidant therapy in atherosclerosis [136]. Clinical trials investigating the use of dietary antioxidants such as vitamin E, beta carotene and higher doses of vitamin A to treat cardiovascular disease failed to demonstrate a protective effect [135]. Vitamin D supplementation also did not reduce the incidence of cardiovascular events in a large scale, randomised, placebo-controlled trial [137]. ...
Atherosclerosis is a chronic inflammatory disease of the vascular system and is the leading cause of cardiovascular diseases worldwide. Excessive generation of reactive oxygen species (ROS) leads to a state of oxidative stress which is a major risk factor for the development and progression of atherosclerosis. ROS are important for maintaining vascular health through their potent signalling properties. However, ROS also activate pro-atherogenic processes such as inflammation, endothelial dysfunction and altered lipid metabolism. As such, considerable efforts have been made to identify and characterise sources of oxidative stress in blood vessels. Major enzymatic sources of vascular ROS include NADPH oxidases, xanthine oxidase, nitric oxide synthases and mitochondrial electron transport chains. The production of ROS is balanced by ROS-scavenging antioxidant systems which may become dysfunctional in disease, contributing to oxidative stress. Changes in the expression and function of ROS sources and antioxidants have been observed in human atherosclerosis while in vitro and in vivo animal models have provided mechanistic insight into their functions. There is considerable interest in utilising antioxidant molecules to balance vascular oxidative stress, yet clinical trials are yet to demonstrate any atheroprotective effects of these molecules. Here we will review the contribution of ROS and oxidative stress to atherosclerosis and will discuss potential strategies to ameliorate these aspects of the disease.
... The latter above reported is likely the oldest strategy. Accordingly, a lot of antioxidants have been demonstrated to postpone the senescence process in vitro (Bjelakovic et al., 2013). However, the application of these promising findings, in vivo models (i.e., mice models) by using traditional antioxidants (e.g., C and E vitamins) have been scarcely translated in emerging therapies (Bjelakovic et al., 2013). ...
... Accordingly, a lot of antioxidants have been demonstrated to postpone the senescence process in vitro (Bjelakovic et al., 2013). However, the application of these promising findings, in vivo models (i.e., mice models) by using traditional antioxidants (e.g., C and E vitamins) have been scarcely translated in emerging therapies (Bjelakovic et al., 2013). Furthermore, results from human cohort studies also evidence the incapacity of such compounds to stop the ARD, even if discordant data have been detected varying the molecules analyzed (Kirkland and Tchkonia, 2017a). ...
It rates that in 2030, the cardiovascular diseases (CVD) will result in 40% of all deaths and rank as the leading cause. Thus, the research of appropriate therapies able to delay or retard their onset and progression is growing. Of particular interest is a new branch of the medical science, called anti-ageing medicine since CVD are the result of cardiovascular ageing. Senescent cells (SC) accumulate in cardiovascular system contributing to the onset of typical age-related cardiovascular conditions (i.e., atherosclerosis, medial aorta degeneration, vascular remodeling, stiffness). Such conditions progress in cardiovascular pathologies (i.e., heart failure, coronary artery disease, myocardial infarction, and aneurysms) by evocating the production of a proinflammatory and profibrotic senescence-associated secretory phenotype (SASP). Consequently, therapies able to specifically eliminate SC are in developing. The senotherapeutics represents an emerging anti-SC treatment, and comprises three therapeutic approaches: (a) molecules to selectively kill SC, defined senolytics; (b) compounds able in reducing evocated SC SASP, acting hence as SASP suppressors, or capable to change the senescent phenotype, called senomorphics; (c) inhibition of increase of the number of SC in the tissues. Here, it describes them and the emerging data about current investigations on their potential clinical application in CVD, stressing benefits and limitations, and suggesting potential solutions for applying them in near future as effective anti-CVD treatments.
... The authors argued that inhibiting ROS impaired physiological signaling events normally triggered in response to weight gain, rendering the animals insulin resistant and with deleterious ectopic lipid accumulation. Based on these and other negative results [220], the authors caution against antioxidants as a preventive therapy (before the actual oxidative insult is established) due to the relevance of the oxidative balance for maintaining homeostasis. Clinical trials using antioxidant therapies have failed to improve insulin resistance and other obesity-related disorders, and even induce adverse outcomes [220]. ...
... Based on these and other negative results [220], the authors caution against antioxidants as a preventive therapy (before the actual oxidative insult is established) due to the relevance of the oxidative balance for maintaining homeostasis. Clinical trials using antioxidant therapies have failed to improve insulin resistance and other obesity-related disorders, and even induce adverse outcomes [220]. Together with the controversial observations in animal studies, these results suggest that there is still no evidence to support the use of antioxidant therapy for the treatment of insulin resistance and other obesity-related metabolic disorders in individuals without nutrient deficiencies [221,222]. ...
Non-communicable diseases (NCDs), also known as chronic diseases, are long-lasting conditions that affect millions of people around the world. Different factors contribute to their genesis and progression; however they share common features, which are critical for the development of novel therapeutic strategies. A persistently altered inflammatory response is typically observed in many NCDs together with redox imbalance. Additionally, dysregulated proteostasis, mainly derived as a consequence of compromised autophagy, is a common feature of several chronic diseases. In this review, we discuss the crosstalk among inflammation, autophagy and oxidative stress, and how they participate in the progression of chronic diseases such as cancer, cardiovascular diseases, obesity and type II diabetes mellitus.
... However, some of the latest research findings advise against routine consumption of dietary antioxidant supplements. There are various reputable studies, including meta analyses, systematic reviews, observational studies, and human intervention trials which demonstrate no beneficial effect of multi-vitamin or multimineral antioxidant supplements on all-cause mortality, cancer, cardiovascular diseases (CVD), and cognitive functions (Angelo et al. 2015, Bjelakovic et al. 2013, Fortmann et al. 2013, Kuszak et al. 2016, Myung et al. 2013, Ye et al. 2013. Moreover, it was found that b-carotene, vitamin E, and possibly high doses of vitamin A supplements may be associated with higher all-cause mortality. ...
... This happens because b-carotene and vitamin E have been shown to be pro-oxidants in the human body when taken at high doses, at least in some populations (Vrolijk et al. 2015). Most supplements do not prevent non-communicable diseases (NCDs) or death (Angelo et al. 2015, Bjelakovic et al. 2013, Cohen 2016, Fortmann et al. 2013, Kuszak et al. 2016. This is especially true for the healthy general population with no obvious evidence of nutrient deficiency. ...
Evidence is building that consumption of large doses of dietary antioxidant supplements may not always render beneficial health effects and some may even have a negative effect. There are few reasons why this happens. Firstly, the role of free radicals causing various chronic diseases is not yet fully clear. There are also some beneficial actions conferred by free radicals in human physiology. Secondly, antioxidant capacity in the body coupled with immune system may resist the action of dietary antioxidants. Lastly, the dosage of antioxidants taken may be inappropriate. Some misconceptions about free radicals and antioxidants are discussed. In fact, low to moderate level of prooxidants might sometimes be better in stimulating the endogenous antioxidant enzyme defence system for overall human health. Consumption of natural foods rich in antioxidants such as fruits, vegetables, nuts, and grains, among others, may provide a better option for health promotion instead of taking high dosages of dietary antioxidant supplements.
... While the protective efficacy of vegetable intake against cancer has long been recognized (Williams 1898), the operationalization of this insight regarding public health has been held back by difficulties in identifying protective mechanisms/constituents (WCRF/AICR 2018). Specifically, it is our impression that the demonstration of the absence of protective effects in randomized controlled trials of vitamins A, C and E and β-carotene (Bjelakovic, Nikolova, and Gluud 2013) hampered confidence in recommendations to increase consumption of vegetables in general and carrots in particular. Such apparent contradictions may be a contributory factor regarding how several public health initiatives in this area have only partially met their objectives (Wallace et al. 2020). ...
Carrots are main dietary sources of several potential anti-cancer compounds, including polyacetylenes, while β-carotene has shown no benefits in controlled cancer trials. Accordingly, associations between carrot intake and cancer incidence were quantified, where necessary using α-carotene as a non-causal biomarker of carrot consumption, by searching for studies published before June 2022 reporting risk estimates for relationships of cancer incidence with carrot intake or α-carotene intake or α-carotene plasma concentration, supplemented with hand searches of included studies and reviews. Meta-analyses comparing highest and lowest reported intakes in prospective studies using a random-effects model estimated summary relative risks (RRs) with 95% confidence intervals (CIs), separately for carrot intake or α-carotene plasma concentration, and the corresponding dose-responses. Of 198 observational studies, in 50 prospective studies with 52000 cases recording carrot intake, the cancer-risk was substantially reduced (RR 0.90, 95% CI 0.87–0.94, p ˂ 0·00004). In 30 prospective studies with 9331 cases reporting plasma α-carotene levels, summary RR was 0.80 (0.72–0.89, p ˂ 0·00006). For both exposure types, inter-study heterogeneity was moderate, interaction with cancer types insignificant, and the dose-response significant (p ˂ 0·01). In conclusion, carrot consumption is robustly associated with decreased cancer-risk; carrot consumption should be encouraged, and the causal mechanisms further investigated.
... Indeed, several compounds have been shown to be harmful. Beta-carotene, vitamin E and high doses of vitamin A seem to increase mortality [78], while two RCTs showed that beta-carotene increased lung cancer in smokers [79,80]. Moreover, vitamin E increased prostate cancer in the SELECT study [81]. ...
Dietary (food) supplements (DSs) have seen a sharp increase in use and popularity in recent years. Information on DS consumption is vital for national nutrition monitoring. The objective of this study was to investigate whether DS intake was reported in the National Nutrition Surveys (NNSs) in all European countries. NNSs reporting DS use were retrieved via literature review (i.e., PubMed, Google Scholar, Scopus), scientific and organizational publications (EFSA), or open-published government and other official reports. Included were the European NNSs referring to adults, published in English, French, or German, post-2000. Out of the 53 European countries, 30 recorded DS intake. Among them, related findings on the percentage of DS intake were published in 21 cases, 5 of them written in the local language. DS use varied by nation, with Finland and Denmark having the greatest (over 50%) and Italy having the lowest percentage (5%). In terms of comprehensive reported data on DS consumption in Europe and the investigation of the contribution of DSs to total nutrient intake, there is a need for improvement. Common DS categories should be defined upon agreement among the involved scientific parties to allow for comparable data and estimations between surveys.
... Recent research has raised concerns about the routine consumption of antioxidant supplements. Several reputable studies, including meta-analyses, systematic reviews, observational studies, and human intervention trials, have shown that antioxidant multivitamin or multimineral supplements have no beneficial effect on all-cause mortality, cancer, cardiovascular disease, or cognitive function (31)(32)(33)(34)(35)(36). ...
Dietary supplements (DS) are manufactured products consisting of one or more dietary ingredients; they are intended to supplement the diet and provide additional nutrients or other beneficial compounds that are lacking or insufficient in a regular diet. Dietary supplements containing antioxidant compounds have been shown to have positive effects in various (pato)physiological processes, i.e., any condition that is fundamentally redox imbalanced (cardiovascular diseases, cancer, aging, intense exercise). The most common antioxidants in dietary supplements are clearly antioxidant micronutrients such as vitamin C, vitamin E, zinc, and selenium, but also various secondary plant compounds, including polyphenols and carotenoids. The dosage of antioxidants administered through dietary supplements may not always be optimal, so some dietary interventions through supplementation with antioxidant compounds have been shown to have an effect that it is limited, or completely absent. Therefore, any dietary supplementation should be done only under appropriate guidance from health care professionals to ensure that it is safe, effective, and appropriate for the individual's condition and needs.
... 23 There are numerous meta-analyses, systematic reviews, observational studies, and human intervention trials that demonstrate no beneficial effect of multi-vitamin or multi-mineral antioxidant supplements on all-cause mortality, cancer, CVD, and cognitive functions, among others. [24][25][26][27][28][29] Moreover, it was found that b-carotene, vitamin E, and possibly high doses of vitamin A supplements may be associated with higher all-cause mortality. 29 In reality, certain antioxidant supplements demonstrate positive effects and good efficacy. ...
Non-communicable diseases, such as cardiovascular disease, cancer, diabetes, obesity, and hypertension, represent the cause of 60% of all deaths around the globe. With proper diet and natural dietary antioxidant supplements, these diseases can be prevented by up to 40% according to the British Nutrition Foundation.
This book provides a comprehensive overview of the literature on the health benefits of natural dietary antioxidant supplements. It presents state-of-the-art research and information as well as the global regulations, labelling, and health claims of natural dietary antioxidant supplements.
Written by expert authors, the wealth of research is arranged by disease type rather than by supplement type making it much more useful to the reader. Filling a gap in the literature, the book is aimed at researchers and professionals working in food chemistry, nutrition, and health benefits.
... Despite unexpected wide use, harmful effects of antioxidants has been claimed in many papers, wherein high intake of β-carotene or vitamin E was associated with the risk of mortality (Huang et al. 2000;d'Uscio et al. 2003;Bjelakovic et al. 2013). Therefore, a promising alternative for ROS control in adipocytes favoring an increased demand. ...
Bacteria capable of producing electricity in intestinal microbiota have been discovered. However, no studies have explored butyric acid which generated by electrogenic bacteria on the host organism have significant physiological impacts on certain organs. We found that the capacity for electrical current generation by the commensal gut Leuconostoc mesenteroides EH-1 (L. mesenteroides EH-1) during glucose fermentation. The electricity production was essential for the gut colonization of L. mesenteroides EH-1 since the inhibition of electricity production by cyclophilin A inhibitor (TMN355) significantly diminished the number of bacteria attached to the human gut epithelial cell surface. The adipocyte differentiation contributes to the increased 4-hydroxy-2-nonenal (4-HNE), considered as a biomarker of reactive oxygen species (ROS). The effect of intestinal electrogenic microbiota in the high-fat diet (HFD)-induced 4-HNE and abdominal fat accumulation in mice was investigated in this study. The oral administration of glucose with a butyric acid-producing L. mesenteroides EH-1 bacterium attenuated the expression of 4-HNE and abdominal fat. The level of 4-HNE and abdominal fat depot were markedly increased in mice administered with cyclophilin A inhibitor-pretreated bacteria or GLPG-0974, an antagonist of free fatty acid receptor 2 (Ffar2). Our studies suggest a novel means by which the probiotic bacteria can modulate fat mass deposition and oxidative stress via the cyclophilin A-mediated electron production and the butyric acid-activated Ffar2 pathway.
... They may include various reactive species such as super oxide radicals, hydrogen peroxide, peroxyl radicals and various lipid peroxides. ROS can react with lipids, proteins, nucleic acids and various metabolic enzymes and can cause various diseases like atherosclerosis, respiratory disease, cancer, gout etc. Antioxidants can terminate these chain reactions by removing free radical intermediates and able to save the life of the cell by preventing its further oxidation [11]. ...
... Historically, the term vitamin A comprises retinol / retinyl esters, retinal isomers, and retinoic acid isomers, as well as provitamin A carotenoids and this term vitamin A is often incorrectly associated with antioxidant activity (reviewed in [7,8]). Recently, two reviews summarised and discussed this antioxidant activity [9, 10] and concluded that vitamin A, in the form of retinal and retinoic acid, as well as retinol and retinyl esters have no direct antioxidant activity in humans [10], contrary to what is often claimed. ...
... However, as shown by the mostly inconclusive placebocontrolled trials of vitamin C referred to in the article, the evidence for causality of vitamin C is equally weak as for any of the other vegetable and fruit constituents. Additionally, the article fails to refer to the important meta-analysis of mortality caused by vitamin C supplementation, by Bjelakovic et al. (6) or similar literature. This meta-analysis showed that, among 29 intervention trials with low risk of bias, 3,637 of 36,659 vitamin C-supplemented participants died (9.92%), while the mortality among 29,283 placebo-treated participants was only 9.28% (2,717 deaths). ...
... If BBS is found early or incidentally, the therapy is primarily conservative and includes treating the underlying malabsorption. Vitamin E supplementation usually takes months to show the benefits [1,12,17], and caution must be taken because high doses can surpass its antioxidant properties and begin to work as a pro-oxidant [25,26]. e application of MitoTEMPO [4] or melatonin [27] has been also shown to prevent the accumulation of the lipofuscin protein aggregate and may be a potential novel therapy of targeting antioxidants to mitochondria. ...
Background. Brown bowel syndrome (BBS) is a rare gastrointestinal condition, and vitamin E deficiency has been considered to be a main contributor. However, vitamin E deficiency has been found in only a few patients throughout the published literature studies and its cutoff lab value for diagnosis is not entirely clarified. Case Presentation. A 56-year-old female patient with a history of congenital bowel obstruction (repaired at birth) presented with bloating, abdominal pain, and chronic diarrhea. Endoscopy identified unremarkable gastrointestinal mucosa except a few small polyps in the colon. A partial obstruction was detected by a small bowel follow-through series and then confirmed by CT scan. The resected small bowel was significantly dilated with a thickened brown wall and extensive serosal adhesion. Microscopic examination revealed unremarkable mucosa, but dense granular brown pigments were identified in the cytoplasm of the smooth muscle cells in the muscularis propria. These deposits resulted to be lipofuscin, and BBS was diagnosed. The patient was asymptomatic at 9-month follow-up after surgery without vitamin E supplement. Conclusion. Mitochondrial damage with lipofuscin deposition is at the root of BBS pathogenesis. Any etiology associated with mitochondrial damage can cause this disease, and vitamin E deficiency is just one of them. Dysmotility from extensive serosal adhesion could be a possible etiology for this patient. Due to overlapping symptoms, lipofuscin deposition primarily in the muscularis propria, and unclear serum value of vitamin E, this syndrome is often missed in routine clinical practice from the superficial biopsy. A transmural biopsy is necessary for a definite diagnosis.
... Since 2007, the FDA has identified more than 1050 tainted dietary supplements (4) , and analyses continue to identify synthetic drugs as product adulterants (5) . An estimated 23 000 individuals visit emergency departments each year due to supplement-related adverse events (6) , and even when supplements do not cause problems, their benefits appear marginal (7)(8)(9)(10)(11)(12) . Nevertheless, more than 50 % of adults in the USA take at least one dietary supplement, and the industry has reached $40 billion in annual sales (2) . ...
More than 25 years have passed since the Dietary Supplement Health and Education Act of 1994 (DSHEA) classified dietary supplements as a subcategory of food, thereby exempting manufacturers from providing premarket evidence of product safety and efficacy. In this commentary, I discuss problems in the supplement industry through an examination of cases introduced or decided in U.S. federal courts between 2010 and 2019. More than half the cases located involved defendants charged with introducing misbranded food or drugs into interstate commerce. Contaminants included anabolic steroids, erectile dysfunction medications, weight-loss drugs, workout stimulants, and mind-altering substances. As the article points out, raw powders obtained in bulk quantities facilitate the practice of “home brewing” and the introduction of prescription drugs into dietary supplements.
... A number of randomized clinical trials have examined the effects of different antioxidants in humans, including Vitamin C, Wild-derived voles 550 mg/kg Decrease Selman et al., 2013 Vitamin E, Vitamin A, beta-carotene and selenium. A metaanalysis of 78 trials that included a total of 296,707 individuals showed no beneficial effect of any of the antioxidants for human longevity in control or disease populations (Bjelakovic et al., 2012(Bjelakovic et al., , 2013. In fact, treatment with Vitamin E or beta carotene resulted in a higher risk of all-cause mortality. ...
Aging is the greatest risk factor for a multitude of diseases including cardiovascular disease, neurodegeneration and cancer. Despite decades of research dedicated to understanding aging, the mechanisms underlying the aging process remain incompletely understood. The widely-accepted free radical theory of aging (FRTA) proposes that the accumulation of oxidative damage caused by reactive oxygen species (ROS) is one of the primary causes of aging. To define the relationship between ROS and aging, there have been two main approaches: comparative studies that measure outcomes related to ROS across species with different lifespans, and experimental studies that modulate ROS levels within a single species using either a genetic or pharmacologic approach. Comparative studies have shown that levels of ROS and oxidative damage are inversely correlated with lifespan. While these studies in general support the FRTA, this type of experiment can only demonstrate correlation, not causation. Experimental studies involving the manipulation of ROS levels in model organisms have generally shown that interventions that increase ROS tend to decrease lifespan, while interventions that decrease ROS tend to increase lifespan. However, there are also multiple examples in which the opposite is observed: increasing ROS levels results in extended longevity, and decreasing ROS levels results in shortened lifespan. While these studies contradict the predictions of the FRTA, these experiments have been performed in a very limited number of species, all of which have a relatively short lifespan. Overall, the data suggest that the relationship between ROS and lifespan is complex, and that ROS can have both beneficial or detrimental effects on longevity depending on the species and conditions. Accordingly, the relationship between ROS and aging is difficult to generalize across the tree of life.
... Increased ROS levels correlated with Uncoupling Protein 1 (UCP1) activation in subcutaneous WAT and higher energy expenditure (Han et al., 2016). These disparate features of mice that lack the Prdx3 and MnSOD genes coupled with therapeutic shortcomings of antioxidant therapies in human clinical trials (Fusco et al., 2007;Bjelakovic et al., 2013Bjelakovic et al., , 2014 suggest a more complex interaction of metabolism and redox balance in WAT. ...
Overnutrition and sedentary activity reinforce the growing trend of worldwide obesity, insulin resistance, and type 2 diabetes. However, we have limited insight into how food intake generates sophisticated metabolic perturbations associated with obesity. Accumulation of mitochondrial oxidative stress contributes to the metabolic changes in obesity, but the mechanisms and significance are unclear. In white adipose tissue (WAT), mitochondrial oxidative stress, and the generation of reactive oxygen species (ROS) impact the endocrine and metabolic function of fat cells. The central role of mitochondria in nutrient handling suggests pharmacological targeting of pathological oxidative stress likely improves the metabolic profile of obesity. This review will summarize the critical pathogenic mechanisms of obesity-driven oxidative stress in WAT.
... In order to alleviate and prevent situations of oxidative stress, many people take antioxidant supplements orally, containing mostly vitamins. However, the efficacy of this treatment has been often criticized because of the low bioavailability of molecules, which really exerts a therapeutic effect [12][13][14]. In fact, most of the vitamins are degraded once ingested, or they do not reach the desired target because of unfavorable biodistribution or absorption limits [15]. ...
Reactive oxygen and nitrogen species (RONS) are produced endogenously in our body, or introduced through external factors, such as pollution, cigarette smoke, and excessive sunlight exposure. In normal conditions, there is a physiological balance between pro-oxidant species and antioxidant molecules that are able to counteract the detrimental effect of the former. Nevertheless, when this homeostasis is disrupted, the resulting oxidative stress can lead to several pathological conditions, from inflammation to cancer and neurodegenerative diseases. In this review, we report on the recent developments of different polymeric formulations that are able to reduce the oxidative stress, from natural extracts, to films and hydrogels, and finally to nanoparticles (NPs).
... The first strategy is to exploit the antioxidant properties of CHMs to reduce excessive intracellular ROS and to antagonize ROS-induced protumorigenic effects on normal cells. However, many clinical trials have inconsistently concluded that antioxidant supplements are beneficial for preventing tumors; furthermore, the long-term use of certain antioxidant supplements may even increase the incidence of some tumors and overall mortality [3,145]. Moreover, recent studies have shown that antioxidants can promote carcinoma proliferation and distant metastasis in vivo [6,146]. ...
Recently, reactive oxygen species (ROS), a class of highly bioactive molecules, have been extensively studied in cancers. Cancer cells typically exhibit higher levels of basal ROS than normal cells, primarily due to their increased metabolism, oncogene activation, and mitochondrial dysfunction. This moderate increase in ROS levels facilitates cancer initiation, development, and progression; however, excessive ROS concentrations can lead to various types of cell death. Therefore, therapeutic strategies that either increase intracellular ROS to toxic levels or, conversely, decrease the levels of ROS may be effective in treating cancers via ROS regulation. Chinese herbal medicine (CHM) is a major type of natural medicine and has greatly contributed to human health. CHMs have been increasingly used for adjuvant clinical treatment of tumors. Although their mechanism of action is unclear, CHMs can execute a variety of anticancer effects by regulating intracellular ROS. In this review, we summarize the dual roles of ROS in cancers, present a comprehensive analysis of and update the role of CHM—especially its active compounds and ingredients—in the prevention and treatment of cancers via ROS regulation and emphasize precautions and strategies for the use of CHM in future research and clinical trials.
... Vitamin E administered at a daily dose of 800 IU/day improves liver histology in nondiabetic adults with biopsy-proven NASH [130] and therefore may be considered for treating these patients. However, concerns have been raised on the long-term safety of vitamin E [131] and the lack of data in patients with T2DM and cirrhosis, thus, is not recommended in these groups. Moreover, current evidence suggests that vitamin E supplementation has no role for the treatment/prevention of CV disease [132]. ...
New evidence suggests that non-alcoholic fatty liver disease (NAFLD) has a strong multifaceted relationship with diabetes and metabolic syndrome, and is associated with increased risk of cardiovascular events, regardless of traditional risk factors, such as hypertension, diabetes, dyslipidemia, and obesity. Given the pandemic-level rise of NAFLD-in parallel with the increasing prevalence of obesity and other components of the metabolic syndrome-and its association with poor cardiovascular outcomes, the question of how to manage NAFLD properly, in order to reduce the burden of associated incident cardiovascular events, is both timely and highly relevant. This review aims to summarize the current knowledge of the association between NAFLD and cardiovascular disease, and also to discuss possible clinical strategies for cardiovascular risk assessment, as well as the spectrum of available therapeutic strategies for the prevention and treatment of NAFLD and its downstream events.
... Среди этих мужчин чаще наблюдались случаи аденокарциномы предстательной железы и рака мочевого пузыря [10]. Отмечено, что прием альфа-токоферола, ретинола и бета-каротина увеличивал смертность от онкологических заболеваний на 4 % среди тех участников исследования, кто принимал данные антиоксиданты, по сравнению с теми, кто их не употреблял [13]. ...
This review analyzes the literature on the effects of certain drugs with antioxidant properties on the risk of developing malignant neoplasias, as well as on their growth and metastasis. Antioxidants are able to protect not only normal cells from the alterative effect of free radicals, but also tumor cells, thereby stimulating their survival and growth. There are data showing that in cells of certain malignant tumors, concentrations of endogenous antioxidant proteins are increasing. The synthesis of these proteins is determined by the cellular signaling pathway KEAP1/NRF2/ARE, it was revealed that oncogenes are involved in the regulation of this signaling pathway. The p53 protein, which activates apoptosis in diseased cells, can be inactivated by antioxidants, which in turn can stimulate the survival and growth of malignant tumor cells. Currently, there is a sufficient amount of information about the effect on tumor growth of certain drugs of various pharmacological groups with antioxidant properties, such as the widely used mucolytic N-acetylcysteine, antidiabetic drugs inhibitors of DPP4 (saxagliptin, sitagliptin), alpha lipoic acid used in the treatment of neuropathies of various origins, as well as vitamins A and E. development of malignant neoplasias in at-risk patients (smokers, patients with chronic obstructive pulmonary disease and diabetes mellitus ). As well as they can complicate the course of existing cancers.
... 29 The present findings of a strong inverse serum vitamin E-mortality association stand in stark contrast to the results of controlled trials showing a lack of beneficial effects, and possible adverse effects, for vitamin E supplementation, particularly for the highest supplementation dosages (ie, ≥400 IU/ day). 25,[30][31][32][33] One meta-analysis of antioxidant supplementation trials, for example, showed that vitamin E used alone did not significantly impact overall mortality (relative risk=1.02; 95% CI, 0.98-1.05). ...
Rationale:
Although there has been a long-standing interest in the human health effects of vitamin E, a comprehensive analysis of the association between circulating vitamin E and long-term mortality has not been conducted.
Objective:
Determine whether serum α-tocopherol (the predominant form of vitamin E) is related to long-term overall and cause-specific mortality and elucidate the dose-response relationships with better quantification of the associations.
Methods and results:
We conducted a biochemical analysis of 29 092 participants in the ATBC Study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention) that originally tested vitamin E and β-carotene supplementation. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and during a 30-year follow-up we identified 23 787 deaths, including deaths from cardiovascular disease (9867), cancer (7687), respiratory disease (2161), diabetes mellitus (119), injuries and accidents (1255), and other causes (2698). After adjusting for major risk factors, we found that men with higher serum α-tocopherol had significantly lower all-cause mortality (hazard ratios=0.83, 0.79, 0.75, and 0.78 for quintile 2 (Q2)-Q5 versus Q1, respectively; Ptrend<0.0001), and significantly decreased mortality from cardiovascular disease, heart disease, stroke, cancer, respiratory disease, and other causes, with risk reductions from 17% to 47% for the highest versus lowest quintile. The α-tocopherol association with overall mortality was similar across subgroups of smoking intensity, years of smoking, alcohol consumption, trial supplementation, and duration of follow-up. The association was, however, significantly modified by baseline age and body mass index, with stronger inverse associations for younger men and men with a lower body mass index ( Pinteraction≤0.006).
Conclusions:
In this long-term prospective cohort study, higher baseline serum α-tocopherol biochemical status was associated with lower risk of overall mortality and mortality from all major causes. Our data support the long-term health benefits of higher serum α-tocopherol for overall and chronic disease mortality and should be replicated in other more diverse populations.
... Vitamins C, D, and E and beta carotene have failed to reduce events in appropriately conducted and powered clinical trials. [18][19][20] The powerful antioxidant succinobucol partitions into lipoprotein particles and effectively prevents LDL oxidation in vitro. Yet, the large ARISE trial (Aggressive Reduction of Inflammation Stops Events) did not meet its primary end point. ...
Many measures can control lipid risk factors for atherosclerosis. Yet, even with excellent control of dyslipidemia, other sources of risk remain. Hence, we must look beyond lipids to address residual risk. Lifestyle measures should form the foundation of cardiovascular risk control. Many pharmacological interventions targeting oxidation have proven disappointing. A large program tested inhibition of a LpPLA2 (lipoprotein-associated phospholipase A2), culminating in 2 large-scale clinical trials that did not meet their primary end points. A variety of antioxidants have not shown benefit in clinical trials. Numerous laboratory and clinical studies have inculpated inflammatory pathways in the pathogenesis of atherosclerotic events. The p38 MAPK (mitogen-activated protein kinase) inhibitor losmapimod and an inhibitor of a leukocyte adhesion molecule, P-selectin, did not alter adverse events in trials. Low-dose methotrexate, despite the promising observational studies, did not lower biomarkers of inflammation or alter cardiovascular outcomes in the CIRT (cardiovascular inflammation reduction trial). Four large-scale investigations underway will determine colchicine's ability to reduce recurrent events in secondary prevention. The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) showed that an antibody that neutralizes IL (interleukin)-1β can reduce recurrent cardiovascular events in secondary prevention. The success of CANTOS points to the pathway that leads from the NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) inflammasome through IL-1β to IL-6 as an attractive target for further study and clinical development beyond lipid therapies to address the unacceptable burden of risk that remains despite our best current care in secondary prevention.
... In contrast to the life span extending effects of ketosis, which we have attributed largely to its effects of reducing the cytoplasmic free [NADP + ]/[NADPH] and oxidizing the cytoplasmic free [NAD + ]/[NADH], administration of antioxidants, such as vitamin C and E, in large multicenter trials have resulted in an increase in all-cause mortality (92). Therefore, administration of these so-called antioxidants, without proper understanding of cellular redox state appears to be without benefit and could even be associated with negative health outcomes. ...
Nucleotide coenzymes dot the map of metabolic pathways providing energy to drive the reactions of the pathway and play an important role in regulating and controlling energy metabolism through their shared potential energy, which is widely unobserved due to the paradox that the energy in the coenzyme pools cannot be determined from the concentration of the coenzyme couples. The potential energy of the nucleotide couples in the mitochondria or the cytoplasm is expressed in the enzyme reactions in which they take part. The energy in these couples, [NAD+]/[NADH], [NADP+]/[NADPH], [acetyl CoA]/[CoA], and [ATP]/[ADP]x[Pi], regulates energy metabolism. The energy contained in the couples can be altered by suppling energy equivalents in the form of ketones, such as, D‐β‐hydroxybutyrate to overcome insulin resistance, to restore antioxidants capacity, to form potential treatments for Alzheimer's and Parkinson's diseases, to enhance life span, and to increase physiological performance. © 2019 IUBMB Life, 9999(9999):1–15, 2019
... Generation of free radicals is a continuous process leading to cell damage or death through the oxidation of different cell components, such as lipids in cell membranes, proteins and DNA ( Figure 2) inside the cell (Halliwell, 1994a,b;Lushchak, 2014). A balance between oxidants and antioxidants is therefore crucial to reduce the risk of chronic diseases associated with a high level of oxidants (Bjelakovic et al., 2013). An imbalance between the production of free radicals or oxidants (including reactive oxygen species abbreviated as ROS) and the levels of antioxidants is referred to as oxidative stress and is associated with a number of serious chronic diseases globally (Kohen and Nyska, 2002). ...
... These findings indicate that the myokines, which induced during strength training are crucial for muscle adaptation after exercise. While associations of ROS/antioxidants also have been the focus of a number of diet based health interventions, it remains that most large clinical studies of anti-oxidants have not demonstrated major health benefits (37,38), suggesting that moderating ROS cannot explain the health benefits of exercise. ...
Substantial evidence exists indicating that inactivity contributes to the progression of chronic disease, and conversely, that regular physical activity can both prevent the onset of disease as well as delay the progression of existing disease. To that end “exercise as medicine” has been advocated in the broad context as general medical care, but also in the specific context as a therapeutic, to be considered in much the same way as other drugs. As there are non-responders to many medications, there also are non-responders to exercise; individual who participate but do not demonstrate appreciable improvement/benefit. In some settings, the stress induced by exercise may aggravate an underlying condition, rather than attenuate chronic disease. As personalized medicine evolves with ready access to genetic information, so too will the incorporation of exercise in the context of those individual genetics. The focus of this brief review is to distinguish between the inherent capacity to perform, as compared to adaptive response to active exercise training in relation to cardiovascular health and peripheral arterial disease.
... Generation of free radicals is a continuous process leading to cell damage or death through the oxidation of different cell components, such as lipids in cell membranes, proteins and DNA ( Figure 2) inside the cell (Halliwell, 1994a,b;Lushchak, 2014). A balance between oxidants and antioxidants is therefore crucial to reduce the risk of chronic diseases associated with a high level of oxidants (Bjelakovic et al., 2013). An imbalance between the production of free radicals or oxidants (including reactive oxygen species abbreviated as ROS) and the levels of antioxidants is referred to as oxidative stress and is associated with a number of serious chronic diseases globally (Kohen and Nyska, 2002). ...
Ferulic acid (FA) and p‐coumaric acid (pCA) are the most abundant phenolic acids in cereals contributing 70–80% of the total phenolic acid pool (Harris and Hartley, 1980; Van Hung, 2016). They have roles in human health and nutrition (Van Hung, 2016) and cell wall cross‐linking in planta (de O Buanafina, 2009). These compounds are mainly bound to arabinoxylan polysaccharides and lignin polymers in cereals (Molinari et al., 2013). Such linkages may affect properties of the cell wall including adhesion and rigidity (Barrière et al., 2004), and might also limit the availability of wall polysaccharides in downstream processes due to the formation of polysaccharide–polysaccharide and polysaccharide–lignin complexes (Iiyama et al., 1990; Jung et al., 2012). Biosynthetic pathways that lead to the production of these phenolic compounds and their incorporation into the plant cell walls are complicated and there is still much to be understood. This article will cover the applications of cell wall‐bound phenolic acids, focusing on health benefits, and will discuss the possible routes currently thought to exist for the generation and incorporation of these compounds into the cell wall.
... Allied with previous literature (Paulsen et al. 2014;Bjørnsen et al. 2016), the present work supports the recent notion that, instead of detrimental, ROS produced by exercise are complex signaling molecules related to chronic muscle adaptation (Powers et al. 2010;Gomes et al. 2012). In addition, there is some evidence that the overconsumption of synthetic antioxidants may be associated with higher all-cause mortality (Bjelakovic et al. 2013). ...
This was a placebo-controlled randomized study that aimed to investigate the effects of strength training (ST) combined with antioxidant supplementation on muscle performance and thickness. Forty-two women (age, 23.8 ± 2.7 years; body mass, 58.7 ± 11.0 kg; height, 1.63 ± 0.1 m) were allocated into 3 groups: vitamins (n = 15), placebo (n = 12), or control (n = 15). The vitamins and placebo groups underwent an ST program, twice a week, for 10 weeks. The vitamins group was supplemented with vitamins C (1 g/day) and E (400 IU/day) during the ST period. Before and after training, peak torque (PT) and total work (TW) were measured on an isokinetic dynamometer, and quadriceps muscle thickness (MT) was assessed by ultrasound. Mixed-factor ANOVA was used to analyze data and showed a significant group × time interaction for PT and TW. Both the vitamins (37.2 ± 5.4 to 40.3 ± 5.6 mm) and placebo (39.7 ± 5.2 to 42.5 ± 5.6 mm) groups increased MT after the intervention (P < 0.05) with no difference between them. The vitamins (146.0 ± 29.1 to 170.1 ± 30.3 N·m) and placebo (158.9 ± 22.4 to 182.7 ± 23.2 N·m) groups increased PT after training (P < 0.05) and PT was higher in the placebo compared with the control group (P = 0.01). The vitamins (2068.3 ± 401.2 to 2295.5 ± 426.8 J) and placebo (2165.1 ± 369.5 to 2480.8 ± 241.3 J) groups increased TW after training (P < 0.05) and TW was higher in the placebo compared with the control group (P = 0.01). Thus, chronic antioxidant supplementation may attenuate peak torque and total work improvement in young women after 10 weeks of ST.
... Allied with previous literature (Paulsen et al. 2014;Bjørnsen et al. 2016), the present work supports the recent notion that, instead of detrimental, ROS produced by exercise are complex signaling molecules related to chronic muscle adaptation (Powers et al. 2010;Gomes et al. 2012). In addition, there is some evidence that the overconsumption of synthetic antioxidants may be associated with higher all-cause mortality (Bjelakovic et al. 2013). ...
... Observational epidemiologic studies provide evidence of the inverse association between carotenoid-containing fruits and vegetables or serum carotenoid levels with risk for various chronic diseases, including lung, gastrointestinal tract, pancreas, breast and prostate cancers, heart disease, and age-related macular degeneration [1][2][3][4][5][6][7]. Actually, a causal association has been examined by a variety of meta-analysis studies and intervention trials performed with specific carotenoids, including β- carotene, lycopene, lutein and zeaxanthin [8][9][10]. The quest for that causal association is sustained by some reasons. ...
Metabolism of the carotenoids in humans is often reserved to bioconversion of provitamin A carotenoids in retinoids and oxidative/degradative products arising from enzymatic eccentric cleavage, yielding apo-carotenoids. Nevertheless, additional metabolic routes should be available, and some of the structures of those metabolites have only been anticipated. The identification of carotenoids and their metabolites is commonly performed by HPLC coupled to MS. The acquisition of MS data in different instrumental modes and hardware configurations allows the detailed structural description of the target compound. Indeed, the MS data of carotenoids and their metabolites available in literature could be collected in a database to automatically perform a screening of the theoretical MS data included in the database with the MS experimental values. This review describes the required fundamentals for a systematic pursuit of carotenoids and their metabolites. Highlights on the use of appropriate hyphenated HPLC-MS systems and the requirements for the identification are discussed, while the application of software tools to apply filtering rules and the implementation of post-processing workflow, which uses two orthogonal criteria for the identification from the mass spectra data, are described.
... However, these findings have been hardly translated in promising findings, in vivo models, since no "usual" antioxidant (e.g., C and E vitamins) consistently increases lifespan or healthspan in mice models [31]. Moreover, data derived from human cohorts further suggest the inability of such compounds to prevent the major ARDs, even if consistent differences can be observed depending on the molecule tested [32]. Interesting preclinical findings have been reported for both senolytics and SASP-suppressing compounds. ...
Vascular endothelial cells form a single layer of flat cells that line the inner surface of blood vessels, extending from large vessels to the microvasculature of various organs. These cells are crucial metabolic and endocrine components of the body, playing vital roles in maintaining circulatory stability, regulating vascular tone, and preventing coagulation and thrombosis. Endothelial cell injury is regarded as a pivotal initiating factor in the pathogenesis of various diseases, triggered by multiple factors, including infection, inflammation, and hemodynamic changes, which significantly compromise vascular integrity and function. This review examines the causes, underlying molecular mechanisms, and potential therapeutic approaches for endothelial cell injury, focusing specifically on endothelial damage in cardiac ischemia/reperfusion (I/R) injury, sepsis, and diabetes. It delves into the intricate signaling pathways involved in endothelial cell injury, emphasizing the roles of oxidative stress, mitochondrial dysfunction, inflammatory mediators, and barrier damage. Current treatment strategies—ranging from pharmacological interventions to regenerative approaches and lifestyle modifications—face ongoing challenges and limitations. Overall, this review highlights the importance of understanding endothelial cell injury within the context of various diseases and the necessity for innovative therapeutic methods to improve patient outcomes.
Carotene-rich vegetables like carrots have been consistently associated with lowered cancer risk in observational studies ⁽¹⁾ . Beta-carotene, a phytochemical found in fruits and vegetables, is known for its antioxidant properties. In rodent trials, supplementation with carrot (containing both carotenes and polyacetylenes) significantly reduced tumour numbers in the APC Min/+ mouse model ⁽²⁾ . However, human intervention trials with pure beta-carotene showed more adverse effects than benefits ⁽³⁾ . This study aimed to investigate the impact of beta- and alpha-carotene supplementation (without polyacetylenes) on colorectal cancer using the APC Min/+ mouse model, which spontaneously develops intestinal tumours and an enlarged liver ⁽⁴⁾ .
APC Min/+ mice were fed either a daily supplement of 10mg/kg mouse of a polyacetylene-free extract from carrots containing a beta- and alpha-carotene mixture, in a dose corresponding to the beneficial carrot supplementation, or the control diet, with a very low beta-carotene content (providing approx. 0.02mg/kg mouse/day). The 8-week supplementation commenced at 5 weeks of age. Tumour quantification in the small intestines of APC Min/+ mice was performed by histology of the entire small intestine, with one slide per 0.3mm, using the H&E staining method and Imagescope software.
Supplementation with carotenes had no significant effect on the total number of tumours (≥0.5 mm), showing no discernible difference between the control (n = 6) (20.5, 95% CI [14.69, 26.31]) and treatment (n = 8) (24.5, [19.21, 29.79]) group (P = 0.237). However, the liver weight, in % of body weight, showed a significant 25% decrease in the treatment group (n = 7) (4.78 95% CI [4.45, 5.15]) compared to controls (6.42, [5.71, 7.13]) (P<0.0003), reaching a level comparable with wildtype mice (4.48, [4.13, 4.83].
These findings confirm the results from the human intervention trials by indicating that beta- and alpha-carotene do not confer any benefit for cancer prevention, while the decrease in liver weight suggests a potential beneficial effect on another aspect of liver health. Additional research is necessary to fully understand these relationships and uncover the underlying mechanisms behind these results. Specifically, beta-and alpha-carotene from carrots do not provide the reduction in tumour numbers in a mouse model of colon cancer found when feeding the corresponding dose of freeze-dried carrot. However, the carotenes significantly attenuate the liver enlargement also seen in this model.
Oxidative stress is a key driver of carcinogenesis, and antioxidants play a critical role in maintaining redox homeostasis and preserving cellular integrity. While antioxidants hold promise as chemopreventive agents and adjunctive therapies in cancer treatment, their dualistic nature complicates their use in clinical practice. Personalised approaches are needed to optimise the efficacy and safety of antioxidant-based interventions, taking into account such factors as the tumour type, stage, genetic background, and redox environment.
In this chapter, we aim to elucidate the importance of selected antioxidants in carcinogenesis and cancer therapy by synthesising evidence from epidemiological studies, preclinical research, and clinical trials. By delineating the multiple roles of antioxidants in modulating key pathways involved in cancer development and treatment response, we aim to provide insights into the rational use of personalised antioxidant-based interventions aimed at reducing cancer incidence and improving therapeutic outcomes.
Preclinical research has elucidated the molecular mechanisms by which antioxidants modulate key pathways involved in carcinogenesis, including DNA damage repair, inflammation, angiogenesis, and metastasis. In addition, clinical trials have investigated the efficacy of antioxidant supplementation in cancer prevention and therapy, with mixed results depending on such factors as the antioxidant type, dosage, timing, and patient population. Controversies remain regarding the optimal use of antioxidants in cancer therapy, as high doses may potentially interfere with the cytotoxic effects of anti-cancer treatments and promote tumour growth in certain contexts. In addition, emerging antioxidant compounds with potential anti-cancer properties are being actively investigated as novel therapeutic agents.
This chapter provides an overview of the importance of selected antioxidants in carcinogenesis and cancer therapy. Oxidative stress is a key driver of carcinogenesis, and antioxidants play a critical role in maintaining redox homeostasis and preserving cellular integrity. While antioxidants hold promise as chemopreventive agents and adjunctive therapies in cancer treatment, their dualistic nature complicates their use in clinical practice.
Nesta coletânea de fôlego, os organizadores e autores oferecem uma poderosa ferramenta de trabalho aos pesquisadores e interessados na epidemiologia nutricional brasileira. Ampliando os horizontes tradicionais desse campo de estudo, o livro vai além de avaliação de dietas e da relação entre alimentação e doenças crônicas não transmissíveis. Os 38 capítulos desta segunda edição revista e ampliada contemplam métodos e análises que abrangem antigos e atuais problemas nutricionais brasileiros, com engajamento propositivo na solução de problemas. Simultaneamente, manual técnico da complexa área da avaliação nutricional e rigorosa enciclopédia nutricional brasileira, este compêndio de enfoque amplo e multidisciplinar reúne os principais investigadores na área de nutrição e saúde pública no Brasil e surge como leitura fundamental para os estudos de nutrição e saúde coletiva.
Atherosclerosis, formed by fibrofatty lesions in the artery wall, underpins myocardial infarctions, strokes and disabling peripheral artery diseases. Inflammation with multiple maladaptive roles runs through atherosclerotic inception, propagation, and complications. Given degree of inflammation differing among atherosclerotics, inflammation-targeted nanomedicine may produce individualized monitoring and manipulation of inflammatory regulators beyond traditionally slowing down atherosclerosis progression. Equipped with biomimetic membrane, microenvironment-responsive and targeting structures, nanomedicines could escape from the innate immune system and autonomously navigate to targeted lesions, thereby muting inflammation in atherosclerotic sites. Moreover, nanoparticles’ advantages go beyond advancing pharmacology. The optimal physicochemical properties of nanoparticles favor noninvasive imaging function to provide diagnostic and prognostic information of atherosclerotic plaques. Despite efficacious ability of the preclinical anti-inflammation nanotherapeutics to reduce atherosclerotic risks, future translation of inflammation-targeted nanomedicines requires to comprehensively refine the strategies that the nanomedicines forestall inflammatory pathways via systemic exposure, drug-cell interactions, and endothelial barrier reconstruction. In this review, we outline the development of diverse nanomedicines to specifically identify pathophysiological changes and combat advanced atherosclerosis along with dynamically tracing inflammatory markers. Finally, challenges and opportunities of inflammation-targeted nanomedicines are highlighted to pave avenues toward personalized medicine for atherosclerosis to stem the growing global burden of cardiovascular diseases.
Introduction:
Atherosclerosis can be considered a chronic inflammatory process that stands out as a dominant cause of cardiovascular disease (CVD). Since blood lipids are the leading risk factor for atherosclerosis development, lowering low-density lipoprotein cholesterol (LDL-C) and other apolipoprotein B-containing lipoproteins reduces the risk of future cardiovascular events. However, there has been significant progress in developing lipid-lowering drugs for aggressive management of dyslipidemia, the rates of CVD events remain unacceptably high, so there is great need to identify novel therapeutic pathways targeting the atherosclerosis process.
Areas covered:
We discussed the current guidelines on CVD prevention, the role of novel lipid-lowering drugs, as well as emerging drugs for atherosclerosis, emphasizing the current data on compounds targeting inflammatory and oxidant pathways.
Expert opinion:
Although novel lipid-lowering drugs all showed their therapeutic efficacy in LDL-C lowering, data regarding their impact on cardiovascular outcomes is still inconclusive. On the other hand, some of the agents targeting inflammatory pathways, especially colchicine, showed promising results in terms of reducing CVD events. In contrast, those pointed at oxidant pathways failed to do so. Finally, exploring ways of targeting new therapeutic venues, such as adaptive immunity and clonal hematopoiesis, is a goal in the future.
Non-alcoholic fatty liver disease presents a number of ethical dilemmas. These relate to the potential harms of diagnosing the disease in health, diagnosing a condition for which there is no effective treatment, and variability in specialists’ attitudes to discussing and managing obesity. Erroneous homogenisation of a patient group that is extremely varied in terms of risk factors such as ethnic background, socioeconomic status, and genetic predisposition may result in inappropriate uniformity of approach when counselling patients as to underlying causes. This article will explore these challenges from the perspective of the gastroenterologist or hepatologist who must navigate them. Each section starts with questions posed by patients or comments made by doctors. Caution is suggested before widespread population-based screening is established, and the need for good adherence to referral algorithms is emphasised. Physicians are urged to engage with the condition’s hidden complexities and reflect on their own communication strategies.
https://www.emjreviews.com/hepatology/article/the-challenging-ethical-landscape-of-non-alcoholic-fatty-liver-disease/?msclkid=5c30ee40befa11ecb7f7ac2dac4465e5
Chemogenetics refers to experimental systems that dynamically regulate the activity of a recombinant protein by providing or withholding the protein's specific biochemical stimulus. Chemogenetic tools permit precise dynamic control of specific signaling molecules to delineate the roles of those molecules in physiology and disease. Yeast d-amino acid oxidase (DAAO) enables chemogenetic manipulation of intracellular redox balance by generating hydrogen peroxide only in the presence of d-amino acids. Advances in biosensors have allowed the precise quantitation of these signaling molecules. The combination of chemogenetic approaches with biosensor methodologies has opened up new lines of investigation, allowing the analysis of intracellular redox pathways that modulate physiological and pathological cell responses. We anticipate that newly developed transgenic chemogenetic models will permit dynamic modulation of cellular redox balance in diverse cells and tissues and will facilitate the identification and validation of novel therapeutic targets involved in both physiological redox pathways and pathological oxidative stress.
Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
La trans-différenciation des cellules musculaires lisses vasculaires (CMLV) joue un rôle clé dans l’initiation et la progression des lésions athéromateuses et du phénomène de re-sténose post-angioplastie. Les travaux de notre équipe ont démontré que l’expression de novo de l’Adenylyl Cyclase (AC) 8 participe à la trans-différenciation des CMLV. Chez l’Homme, l’AC8, absente de la paroi artérielle saine, est détectée dans les lésions athéromateuses. Cependant, de nombreux travaux montrent le rôle vasculoprotecteur de la voie de signalisation AMPc. Les AC8 des CMLV de rat trans-différenciées sont issues de 4 variants d’épissage : les AC8E-H. Ils sont tous amputés des 5 premiers domaines transmembranaires par rapport à l’AC8 pleine-taille (AC8A) et exercent un effet dominant-négatif en s’hétérodimérisant avec les AC endogènes fonctionnelles. Les motifs peptidiques impliqués dans l’hétérodimérisation de l’AC8E avec ces AC partenaires ont été identifiés par PEPscan. Ceci a permis de concevoir 10 peptides candidats en vue d’inhiber l’hétérodimérisation de l’AC8E avec les AC3 et AC6 en vue de restaurer une capacité normale des CMLV à produire de l’AMPc. Parallèlement, la modélisation des structures 3D des AC3, AC8A et AC8E positionne les domaines N-terminal et C1b de façon symétrique autour de la région hélicoïdale des AC. Cette architecture, en accord avec les données biochimiques, révèle comment ces 2 domaines régulent la conformation du site catalytique, et donc son activité. Le complexe AC8E/AC3, en cours de modélisation, permettra d’évaluer l’efficacité d’interférence des peptides candidats et de les optimiser.
Students encounter antioxidants in many areas of their daily life. Antioxidants play a crucial role in cosmetics, in nutritional or dietary supplements, as additives for the preservation of food, and as a natural component in fruit and vegetables. Accordingly, antioxidants are believed to promote health through the prevention of oxidative stress by scavenging free radicals. The underlying oxidation and reduction processes of antioxidants are a central topic of chemistry classes. Additionally, antioxidants can be linked to aspects of sustainability. In this paper, the model substance chosen to demonstrate these aspects of antioxidants is hydroxytyrosol. Hydroxytyrosol is a natural, highly effective antioxidant, which is produced, for example, in olive trees and can be found in high concentrations in olive mill wastewater, which is potentially hazardous to the environment. In the first experiment, WELL-plate experiments are used to show the principal properties of antioxidants, both as reducing agents and radical scavengers, for the example of hydroxytyrosol. The experiments are based on the oxygen radical absorbance capacity (ORAC) test, which is widely applied in the food industry. In a second experiment, the properties of antioxidants are demonstrated using alginate balls as reaction vessels to produce a luminous bubble tea. Furthermore, the school-student-friendly extraction of hydroxytyrosol is presented.
Although several electrogenic bacteria have been identified, the physiological effect of electricity generated by bacteria on host health remains elusive. We found that probiotic Leuconostoc mesenteroides (L. mesenteroides) can metabolize linoleic acid to yield electricity via an intracellular cyclophilin A-dependent pathway. Inhibition of cyclophilin A significantly abolished bacterial electricity and lowered the adhesion of L. mesenteroides to the human gut epithelial cell line. Butyrate from L. mesenteroides in the presence of linoleic acid were detectable and mediated free fatty acid receptor 2 (Ffar2) to reduce the lipid contents in differentiating 3T3-L1 adipocytes. Oral administration of L. mesenteroides plus linoleic acid remarkably reduced high-fat-diet (HFD)-induced formation of 4-hydroxy-2-nonenal (4-HNE), a reactive oxygen species (ROS) biomarker, and decreased abdominal fat mass in mice. The reduction of 4-HNE and abdominal fat mass was reversed when cyclophilin A inhibitor-pretreated bacteria were administered to mice. Our studies present a novel mechanism of reducing abdominal fat mass by electrogenic L. mesenteroides which may yield electrons to enhance colonization and sustain high amounts of butyrate to limit ROS during adipocyte differentiation.
Objective
Numerous epidemiological studies show an increased prevalence of metabolic diseases related to oxidation stress causing cell damage. Antioxidant supplementation is then useful to protect against the oxidative stress mediated disease development, and has become an increasingly popular practice. In this review, a selection of clinical and in vitro studies on vitamin C and E supplementation and the evaluation of their beneficial or negative effects are analyzed.
Results
Clinical studies and supplementation trials show a correlation between antioxidants and metabolic improvement in different diseases such as cancer, cardiovascular disease, diabetes, obesity. Vitamin C (ascorbic acid) and E (α-tocopherol) appear to be among the most commonly used antioxidants. However, taking antioxidant supplements in high doses can be harmful. In some studies, little supportive evidence has been provided on substantial protection against chronic diseases by antioxidants. In addition, previous studies have revealed negative effects of antioxidant supplements such as pro-oxidant activities in particular conditions including their dosage and the body oxidant/ antioxidant status.
Conclusion
Antioxidant supplements should be used with caution.
Les maladies cardiovasculaires représentent la première cause de mortalité en France avec une prévalence encore plus importante à La Réunion. La plupart des décès sont attribuables aux cardiopathies ischémiques due à la rupture d'une plaque d'athérosclérose et à la formation d'un caillot entrainant une ischémie cardiaque. L'oxydation des lipoprotéines de basse densité (LDL) et la dysfonction de l'endothélium représentent des étapes importantes dans la déstabilisation de la plaque, d'où l’intérêt de rechercher un traitement capable de diminuer l'oxydation des LDL ou de protéger les cellules endothéliales de leurs effets cytotoxiques. Les polyphénols sont des molécules antioxydantes très présentes dans le règne végétal. Des études préliminaires du laboratoire sur des adipocytes humain on montré que des extraits riches en polyphénols d'Antirhea borbonica et de Doratoxylon apetalum, deux espèces respectivement endémique et indigène de l'Île de La Réunion, possédaient des propriétés antioxydantes et anti-inflammatoires (Marimoutou, M et al. 2015). Le But de cette thèse était, dans un premier temps, de tester les capacités antioxydantes et cytoprotectrices d'extraits riches en polyphénols de ces deux espèces sur des cellules endothéliales. Puis dans un second temps nous avons testé l'extrait de Doratoxylon apetalum sur un modèle murin d'athérosclérose (souris ApoE KO) pour évaluer son effet anti-inflammatoire sur les plaques d'athérome.
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Our systematic review has demonstrated that antioxidant supplements may increase mortality. We have now updated this review.
To assess the beneficial and harmful effects of antioxidant supplements for prevention of mortality in adults.
We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science to February 2011. We scanned bibliographies of relevant publications and asked pharmaceutical companies for additional trials.
We included all primary and secondary prevention randomised clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention.
Three authors extracted data. Random-effects and fixed-effect model meta-analyses were conducted. Risk of bias was considered in order to minimise the risk of systematic errors. Trial sequential analyses were conducted to minimise the risk of random errors. Random-effects model meta-regression analyses were performed to assess sources of intertrial heterogeneity.
Seventy-eight randomised trials with 296,707 participants were included. Fifty-six trials including 244,056 participants had low risk of bias. Twenty-six trials included 215,900 healthy participants. Fifty-two trials included 80,807 participants with various diseases in a stable phase. The mean age was 63 years (range 18 to 103 years). The mean proportion of women was 46%. Of the 78 trials, 46 used the parallel-group design, 30 the factorial design, and 2 the cross-over design. All antioxidants were administered orally, either alone or in combination with vitamins, minerals, or other interventions. The duration of supplementation varied from 28 days to 12 years (mean duration 3 years; median duration 2 years). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects model meta-analysis (21,484 dead/183,749 (11.7%) versus 11,479 dead/112,958 (10.2%); 78 trials, relative risk (RR) 1.02, 95% confidence interval (CI) 0.98 to 1.05) but significantly increased mortality in a fixed-effect model (RR 1.03, 95% CI 1.01 to 1.05). Heterogeneity was low with an I(2)- of 12%. In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. Meta-regression analysis did not find a significant difference in the estimated intervention effect in the primary prevention and the secondary prevention trials. In the 56 trials with a low risk of bias, the antioxidant supplements significantly increased mortality (18,833 dead/146,320 (12.9%) versus 10,320 dead/97,736 (10.6%); RR 1.04, 95% CI 1.01 to 1.07). This effect was confirmed by trial sequential analysis. Excluding factorial trials with potential confounding showed that 38 trials with low risk of bias demonstrated a significant increase in mortality (2822 dead/26,903 (10.5%) versus 2473 dead/26,052 (9.5%); RR 1.10, 95% CI 1.05 to 1.15). In trials with low risk of bias, beta-carotene (13,202 dead/96,003 (13.8%) versus 8556 dead/77,003 (11.1%); 26 trials, RR 1.05, 95% CI 1.01 to 1.09) and vitamin E (11,689 dead/97,523 (12.0%) versus 7561 dead/73,721 (10.3%); 46 trials, RR 1.03, 95% CI 1.00 to 1.05) significantly increased mortality, whereas vitamin A (3444 dead/24,596 (14.0%) versus 2249 dead/16,548 (13.6%); 12 trials, RR 1.07, 95% CI 0.97 to 1.18), vitamin C (3637 dead/36,659 (9.9%) versus 2717 dead/29,283 (9.3%); 29 trials, RR 1.02, 95% CI 0.98 to 1.07), and selenium (2670 dead/39,779 (6.7%) versus 1468 dead/22,961 (6.4%); 17 trials, RR 0.97, 95% CI 0.91 to 1.03) did not significantly affect mortality. In univariate meta-regression analysis, the dose of vitamin A was significantly associated with increased mortality (RR 1.0006, 95% CI 1.0002 to 1.001, P = 0.002).
We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.
An imbalance between oxidants and antioxidants in favour of the oxidants, potentially leading to damage, is termed 'oxidative stress'. Oxidants are formed as a normal product of aerobic metabolism but can be produced at elevated rates under pathophysiological conditions. Antioxidant defense involves several strategies, both enzymatic and non-enzymatic. In the lipid phase, tocopherols and carotenes as well as oxy-carotenoids are of interest, as are vitamin A and ubiquinols. In the aqueous phase, there are ascorbate, glutathione and other compounds. In addition to the cytosol, the nuclear and mitochondrial matrices and extracellular fluids are protected. Overall, these low molecular mass antioxidant molecules add significantly to the defense provided by the enzymes superoxide dismutase, catalase and glutathione peroxidases.
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