Exogenous foods that activate the NRF2 protein: Systematic review

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The objective of this research was to identify studies on exogenous foods that activate the NRF2 protein in the scientific literature. Methods A literature review aimed at identifying manuscripts on NRF2 activation with exogenous foods and its human benefits was conducted. The systematic review spanned English and Spanish articles from MEDLINE, PubMed, SciELO, and Scopus repositories until August 2023. All authors participated in search, analysis, and selection. Inclusion criteria prioritized NRF2-activating foods and their benefits, with exclusion criteria for irrelevant articles in other languages. Stringent filters were applied in stages—initial title search, abstract review, and thorough reading of remaining articles—to minimize bias and ensure relevance to the study’s objective. Results A total of 25 articles were analyzed, which discussed the adaptive mechanism of NRF2 and its role in hormone dose response, the effects of certain foods and health benefits associated with NRF2 activation Conclusions The studies support the notion that NRF2 activation plays a fundamental role in promoting health in various spheres, underscoring the relevance of factors such as diet, natural components, and antioxidant supplementation in defending against oxidative stress and its implications for overall well-being. For future research on this topic, it is important to analyze how the population stands regarding the consumption of exogenous foods that activate NRF2, to understand both the consumption, quantity, and frequency of certain foods and whether they are doing so correctly. 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F1000Research 2024, 13 :278 ( https://doi.org/10.12688/f1000research.143351.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review Exogenous foods that activate the NRF2 protein: Systematic review [version 1; peer review: 1 not approved] Ambrocio Teodoro Esteves Pairazaman https://orcid.org/0000-0003-4168-0850 1 , Emma Caldas Herrera 2 , Jesus Collanque Pinto 3 , [...] Flor Lidia Bustamante Fustamante 3 , José Rincón Chavez 3 , Carmela Gelida Barboza Justiniano 4 , Pamela Belen Esteves Cardenas 5 , Patricia Mariane Grados Alva 1 , Elmer Oyarce Alvarado 3 Ambrocio Teodoro Esteves Pairazaman https://orcid.org/0000-0003-4168-0850 1 , Emma Caldas Herrera 2 , [...] Jesus Collanque Pinto 3 , Flor Lidia Bustamante Fustamante 3 , José Rincón Chavez 3 , Carmela Gelida Barboza Justiniano 4 , Pamela Belen Esteves Cardenas 5 , Patricia Mariane Grados Alva 1 , Elmer Oyarce Alvarado 3 PUBLISHED 16 Apr 2024 Author details Author details 1 Universidad Hipócrates, Acapulco, Mexico 2 Sanidad de la Policía Nacional del Peru, Lima, Peru 3 Universidad Norbert Wiener, Lima, Peru 4 Universidad Peruana Cayetano Heredia, Lima District, Lima Region, Peru 5 Universidad Cesar Vallejo, Trujillo, La Libertad, Peru Ambrocio Teodoro Esteves Pairazaman Roles: Conceptualization, Funding Acquisition, Investigation, Supervision, Visualization, Writing – Original Draft Preparation Emma Caldas Herrera Roles: Methodology, Visualization, Writing – Review & Editing Jesus Collanque Pinto Roles: Resources, Validation, Writing – Review & Editing Flor Lidia Bustamante Fustamante Roles: Formal Analysis, Visualization, Writing – Review & Editing José Rincón Chavez Roles: Formal Analysis, Visualization, Writing – Review & Editing Carmela Gelida Barboza Justiniano Roles: Formal Analysis, Visualization Pamela Belen Esteves Cardenas Roles: Formal Analysis, Writing – Review & Editing Patricia Mariane Grados Alva Roles: Investigation, Methodology, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Elmer Oyarce Alvarado Roles: Methodology, Visualization, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background The activation of the Nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway, whether through natural compounds, diet, or supplements, plays a crucial role in protecting against oxidative stress and promoting health in various aspects. The objective of this research was to identify studies on exogenous foods that activate the NRF2 protein in the scientific literature. Methods A literature review aimed at identifying manuscripts on NRF2 activation with exogenous foods and its human benefits was conducted. The systematic review spanned English and Spanish articles from MEDLINE, PubMed, SciELO, and Scopus repositories until August 2023. All authors participated in search, analysis, and selection. Inclusion criteria prioritized NRF2-activating foods and their benefits, with exclusion criteria for irrelevant articles in other languages. Stringent filters were applied in stages—initial title search, abstract review, and thorough reading of remaining articles—to minimize bias and ensure relevance to the study’s objective. Results A total of 25 articles were analyzed, which discussed the adaptive mechanism of NRF2 and its role in hormone dose response, the effects of certain foods and health benefits associated with NRF2 activation Conclusions The studies support the notion that NRF2 activation plays a fundamental role in promoting health in various spheres, underscoring the relevance of factors such as diet, natural components, and antioxidant supplementation in defending against oxidative stress and its implications for overall well-being. For future research on this topic, it is important to analyze how the population stands regarding the consumption of exogenous foods that activate NRF2, to understand both the consumption, quantity, and frequency of certain foods and whether they are doing so correctly. READ ALL READ LESS Keywords NRF2, activation, antioxidant, food, protein Corresponding Author(s) Ambrocio Teodoro Esteves Pairazaman ( [email protected] ) Close Corresponding author: Ambrocio Teodoro Esteves Pairazaman Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2024 Esteves Pairazaman AT et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Esteves Pairazaman AT, Caldas Herrera E, Collanque Pinto J et al. Exogenous foods that activate the NRF2 protein: Systematic review [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :278 ( https://doi.org/10.12688/f1000research.143351.1 ) First published: 16 Apr 2024, 13 :278 ( https://doi.org/10.12688/f1000research.143351.1 ) Latest published: 16 Apr 2024, 13 :278 ( https://doi.org/10.12688/f1000research.143351.1 ) Introduction Aging is a complex process that involves a combination of genetically programmed development and degenerative changes caused by the accumulation of stress. It is not entirely clear whether cellular senescence is the sole factor associated with aging. 1 , 2 Theories of aging, such as programmed degeneration, evolutionarily favored aging, or cumulative aging, implicate the formation of free radicals. Some older organisms produce more reactive oxygen species (ROS) than younger organisms. Under healthy living conditions, cumulative changes in lifespan limits have resulted in an average life expectancy at birth of around 85 years, with the maximum reaching 122 years. These boundaries have expanded over the last 2,000 years due to progressive improvements in living conditions. Life expectancy at birth has grown from around 30 years in ancient Rome to over 80 years in today’s developed countries. Surprisingly, life expectancy has nearly doubled in the last century. 3 Considering this, it can be said that oxidative stress increasingly plays a fundamental role in aging and various age-associated physiopathological conditions. 4 Skin degeneration can be divided into two conditions: intrinsic and extrinsic. Intrinsic aging is described as natural aging, while extrinsic aging is caused by environmental factors such as ultraviolet rays, tobacco, wind, and exposure to harmful substances. When cells are stimulated by various external factors, several ROS reactions are triggered in the body. 5 The human body requires a significant amount of energy to maintain homeostasis and autonomous function. Cellular homeostasis is maintained by using mitochondria to generate large amounts of adenosine triphosphate (ATP). However, during this process, mitochondria inadvertently produce ROS, disrupting normal cellular function. This occurs mainly when unpaired electrons leave the electron transport chain (ETC) and react with molecular oxygen to form superoxide. This ROS radical is commonly eliminated by various antioxidant enzymes, including reduced glutathione, vitamins C and E, bilirubin, and urate. Non-catalytic antioxidant proteins such as thioredoxin, glutaredoxin, and metallothionein, as well as enzymes like superoxide dismutase, catalase, peroxidase, and glutathione peroxidase, play important roles. Glutathione serves as a primary antioxidant to reduce oxidative stress caused by ROS. 6 , 7 The primary transcription factor responsible for initiating the response to oxidative stress is called factor 2, which is closely related to Nuclear factor erythroid 2-related factor 2 (NRF2). This protein consists of 605 amino acids, and it is within NRF2 that we find erythroid 2 factor, a human transcription factor that regulates the expression of various key components for mitochondrial function and aids in cellular cytoprotection with its effects. 8 Under normal circumstances, NRF2 is retained within the cytosol through interaction with its inhibitory binding partner Kelch-like ECH-associated protein 1 (Keap1), and NRF2 activity is thereby inhibited. 9 However, when it dissociates from Keap1, NRF2 engages in antioxidant protein activity with a protective function, inhibiting oxidative stress. NRF2 also possesses the ability to repair damaged mitochondrial function, reduce endoplasmic reticulum stress to prevent an inflammatory response, and enhance neuronal network regeneration, thereby reducing causes of cellular oxygen and glucose deprivation. This injury has a significant protective effect on cerebral ischemia-reperfusion in animals. 10 NRF2 mediates the antioxidant defense network and efficiently interacts with other transcription factors, not only synergizing with these proteins to enhance biopersistence through a dose-dependent graded process but also adjusting the quantitative dose-response characteristics of hormetic responses to subtoxic or below-threshold doses of various stressors that directly and immediately disrupt cellular homeostasis. 11 Therefore, the primary objective of this study was to investigate the fundamental role of exogenous foods in activating the NRF2 protein and how the genetic expression of the human body subsequently diminishes the signs of progressive internal and external aging through the human genome. All of this occurs with the activation of antioxidants that help combat oxidative stress, which is the predominant factor in aging and various forms of physiopathology commonly associated with aging. 12 , 13 Methods To develop the research, a scientific search related to the topic of exogenous foods that activate the NRF2 protein in scientific production was conducted. This method aims to identify, interpret, and evaluate various studies conducted by researchers on a specific topic or field, 14 with the intention of “providing the researcher and the reader with clarifying information on a particular subject”. 15 Based on this, the research question for the review was formulated: What are the exogenous foods that activate the NRF2 protein addressed in research articles? This study involved a thorough review of the scientific literature related to exogenous foods that activate the NRF2 protein and their effects within the human body. To carry out this review, the procedures described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 16 , 36 were followed, specifically designed to ensure rigorous systematic reviews. Initial search The first step in the systematic review process was to conduct initial searches in January 2023 in the MEDLINE (RRID:SCR_002185), PubMed (RRID:SCR_004846), SciELO , and Scopus (RRID:SCR_022559) databases. All databases were searched until 30 August 2023. These searches yielded a total of 34,212 manuscripts to be analyzed on the research topic. Systematic search The search was conducted, taking into account works published from 2020 to 2023, in the MEDLINE , PubMed , SciELO , and Scopus databases, resulting in a total of 34,212 works found. The combination of terms that yielded the best results in the search engines was as follows: (“alimentos activadores del NRF2”; “NRF2-activating foods”; “NRF2” AND “foods” AND “medicine” “Alimentos” AND “NRF2”), or the search strategy was adapted according to the specific requirements of each database. Specifically, 29,080 results were obtained from the five databases. Before proceeding to the article selection, inclusion and exclusion criteria were defined. Eligibility criteria Inclusion criteria • Empirical studies and systematic reviews addressing foods that activate the NRF2 protein, their antioxidant properties, direct activation benefits, among other relevant aspects. • Studies published in Spanish and English. • Studies published in the period from 2020 to 2023 up to the cutoff date of our review (February 2023). Exclusion criteria • Studies that did not specifically address foods that activate NRF2 and their benefits. • Studies that solely focused on NRF2 benefits without addressing the topic of foods that may help in its activation. • Studies that were not accessible in full text. Study selection process The selection of studies was carried out in three stages: a first stage based on reading the titles, a second stage based on reading the abstracts, and a third stage based on a thorough review of the articles chosen in the first stage. The selection was independently performed by five researchers, and disagreements were resolved through consensus. Ultimately, 25 articles met the inclusion criteria and were chosen for a systematic review. Data items Systematic reviews were conducted with the aim of identifying data related to food-mediated NRF2 protein activation, focusing on its antioxidant properties and direct benefits. The outcomes sought are listed and defined below: • Antioxidant Properties of Foods. • Measurement of the antioxidant capacity of foods that activate NRF2. • Search for data on antioxidant capacity in different studies and analyses. • Direct Benefits of NRF2 Activation. • Type of food, frequency of consumption, dosage. • We assumed inclusion of outcomes consistent with each outcome domain in each study, unless otherwise stated in the specific research methods. • In the absence of clear information, studies were considered not to address the variable in question. Study risk of bias assessment The procedure for determining the suitability of an article began with a review of the titles of each research project, where it was assessed whether the article addressed the topic. After this first filter, all results were read and evaluated for their agreement with the search variable. Finally, a thorough review of the entire content of the manuscript was carried out for inclusion in the article. The filtering process was carried out by nine of the authors, and each author individually reviewed the registered and retrieved documents. It is essential to note that the distribution of tasks was carried out equally, considering the number of articles among the authors. Although each article was subject to individual review and analysis, in the end, all writers collaborated to create a comprehensive compilation. Effect measures Each author conducted a thorough review of the content of each manuscript, assessing in detail the variable “activation of NRF2 by exogenous foods”. The methodology employed, data collected and preliminary interpretations were considered. Individual analysis facilitated a thorough exploration of each manuscript, ensuring a diversity of perspectives and experiences in the interpretation of the data . Synthesis methods Systematic data collection was carried out for each article, including information on authors, year, abstract, type of research and key findings. After this phase, all papers that included the study variable in their abstracts or findings were analyzed in detail. Priority was given to selecting data from those articles that specifically addressed foods that activate NRF2. Reporting bias assessment In order to ensure the cohesion and integration of the various studies, a collaborative review phase was carried out. During this stage, the different methodologies and findings were compiled and compared. Constructive discussions and debates were encouraged to resolve potential disagreements and ensure that the final interpretation was robust and well-supported. The process concluded with the creation of a final compilation incorporating the data and conclusions drawn by consensus from the various analyses . Certainty assessment The data were analyzed according to each author’s individual criteria and filtered according to their relevance to the results. It is important to note that this process was shared with all authors, culminating in a final consensus for selection. This method was used to assess the reliability of the papers analyzed . Results We analyzed 25 articles that met the inclusion criteria ( Figure 1 ), indicating that we included all research that talked about foods or supplements that activate the NRF2 protein, as well as their benefits and properties that they have in people’s bodies. All works that address the aforementioned topic were taken into account, regardless of the methodology used, population and/or instrument. Figure 1. Flowchart of manuscript inclusion and exclusion according to the PRISMA 2020 method. According to the 25 articles analyzed, it was found that ( Table 1 ): Table 1. Articles filtered and analyzed by authors. N° Authors Article Title Study Type Authors Article Title Results 1 Calabrese y Kozumbo. 11 The hormetic dose-response mechanism: NRF2 activation Systematic Review Article The adaptive mechanism of Nrf2 explains the ubiquity of the hormone dose response and supports the preservation of fundamental hormonal properties. Since Nrf2 is highly conserved and exhibits various moderately stimulatory responses, assimilation efficiency is enhanced. 2 Lin X, et al. 17 Curcumin attenuates oxidative stress in RAW264.7 cells by increasing the activity of antioxidant enzymes and activating the NRF2-Keap1 Mixed-Methods Experimental Study The results indicated that curcumin demonstrated its ability to counteract the harmful effects of oxidants. It achieved this by enhancing the activity of antioxidant enzymes and activating the Nrf2-Keap1 signaling pathway. These findings suggested that curcumin had the potential not only to strengthen the antioxidant capacity of macrophages but also to promote their cellular survival in oxidative stress situations. 3 Ji, et al. 1 Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases Mixed-Methods Experimental Study They analyzed both intrinsic and extrinsic components exerting inhibitory influence on cellular regeneration and orientation. Key elements in this context were highlighted with the intervention of NRF2. Additionally, they explored various therapeutic approaches to address degeneration-related diseases, including cellular reprogramming, exclusion of senescent stem cells, and reduction of the senescence-associated secretory phenotype (SASP) effect, among others. These restorative approaches have proven to be promising in the treatment of specific diseases associated with cellular degeneration. 4 Qian, et al. 18 Seeds of Ginkgo biloba L. inhibit oxidative stress and inflammation induced by cigarette smoke in COPD rats through the NRF2 pathway Quantitative Experimental Study As a traditional medicine, Ginkgo biloba L. (Gbs) seeds have long been used to treat cough or asthma. However, the research was designed to explore the protective effects of Gbs on antioxidants, revealing that Gbs altered the expressions of Nrf2 and inhibited oxidative stress. 5 Zhang, et al. 19 A diarylheptanoid compound from Alpinia officinarum Hance ameliorates high glucose-induced insulin resistance by regulating PI3K/AKT-NRF2-GSK3β signaling pathways in HepG2 cells Quantitative Pre-Experimental Study Alpinia officinarum Hance is a natural perennial medicinal herb traditionally used to treat colds, stomach pains, and diabetes for thousands of years. However, a diarylheptanoid isolated from the rhizome of A. officinarum is safe and has antioxidant effects. The study of DPH5 enhances antioxidant capacity by activating the Nrf2/HO-1 elements, including increased expression of Nrf2, HO-1, SOD, NQO1, and GSH-Px, and reducing levels of MDA, ROS, and JNK, thereby improving oxidative stress. 6 Islam, et al. 20 Clerodendrum viscosum leaves attenuate lead-induced neurotoxicity through upregulation of BDNF-Akt-NRF2 pathway in mice Quantitative Experimental Study Clerodendrum viscosum harbors a wide range of secondary metabolites known for their potent anti-proliferative and antioxidant activity. It was revealed that supplementation with this plant stimulated the expression of BDNF and neurochemicals, in addition to strengthening the antioxidant system. These effects were achieved through positive regulation of the Nrf2 pathway in mice exposed to elevated levels of lead (Pb). These findings suggest that Clerodendrum viscosum could play a significant role in promoting health and neuronal protection in environments with Pb exposure. 7 George, et al. 6 Role of NRF2 in aging, Alzheimer's and other neurodegenerative diseases Quantitative Experimental Study Altered Nrf2 is primarily associated with aging and neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, stroke, multiple sclerosis, etc. P62 is both a competitive inhibitor of Nrf2 at the Keap1 binding site and a downstream protein in the Nrf2 pathway involved in autophagy. Activators of P62 currently under investigation include trehalose, rapamycin, curcumin, and resveratrol. 8 Sun, et al. 10 The Role of NRF2 in Relieving Cerebral Ischemia-Reperfusion Injury Quantitative Experimental Study New studies show that activated Nrf2 can not only effectively inhibit oxidative stress but also remedy damaged mitochondria, reduce ER stress, prevent inflammatory reactions, inhibit apoptosis of nerve cells, and improve nervous function. It enhances remodeling, producing a significant protective effect, attenuates damage caused by cellular hypoxia, and glucose deficiency in animal brains. The mechanisms underlying its potential pharmacological effects in mitigating cerebral ischemia/reperfusion injury are being explored and developed. 9 Li, et al. 8 Water extract from Herpetospermum pedunculosum attenuates oxidative stress and ferroptosis induced by acetaminophen via regulating NRF2 and NF-κB pathways Quantitative Experimental Study Seeds of Herpetospermum pedunculosum are a traditional Tibetan medicine with a hepatoprotective effect and the ability to inhibit ROS accumulation. Through a study, it was indicated that this exogenous food, Herpetospermum pedunculosum seeds, alleviates oxidative stress and ferroptosis by activating the Nrf2 signaling pathway and inhibiting the NF-κB-mediated pathway. 10 Liu, et al. 21 Seaweed-Derived Polysaccharides Attenuate Heat Stress-Induced Splenic Oxidative Stress and Inflammatory Response via Regulating NRF2 and NF-κB Signaling Pathways Quantitative Experimental Study They evaluated the enhancing effect of polysaccharides (SDP) derived from algae (Enteromorpha prolifera) on heat stress-induced oxidative stress and the immune organ (spleen) inflammatory response using an animal model (Gallus gallus domesticus). In total, 144 animals were used, indicating that SDP improved antioxidant capacity. Additionally, it alleviated heat stress-induced splenic inflammation by suppressing nuclear factor kappa B (NF-κB) p65 signaling. These findings suggest that it can be used as a food to mitigate oxidative stress due to its antioxidant and anti-inflammatory effects 11 Abrescia, et al. 22 Modulatory role of dietary polyunsaturated fatty acids in NRF2-mediated redox homeostasis Review Article In a previous study, the role of polyunsaturated fatty acids in cellular signaling was explored, playing a significant role in various signaling pathways. Among these, the activation of the erythroid 2-related factor 2 (Nrf2) pathway was highlighted, considered a key mechanism in maintaining redox, metabolic, and protein homeostasis, as well as regulating the inflammatory response 12 Felgus, et al. 23 The Effects of Blueberry Phytochemicals on Cell Models of Inflammation and Oxidative Stress Systematic Review Article Furthermore, the study investigated how certain polyunsaturated fatty acids present in animal-derived foods may possess antioxidant properties by activating the Nrf2 pathway. For example, the ingestion of n-3 polyunsaturated fatty acids, also known as ω-3, through the consumption of fish or fish oil (FO), was shown to prevent or improve oxidative stress-related disorders and other associated health problems. These findings suggest that the incorporation of n-3 polyunsaturated fatty acids into the diet could play a crucial role in protecting against oxidative stress and its negative consequences 13 Martemucci, et al. 3 Oxidative stress, aging, antioxidant supplementation and their impact on human health: An overview. Review Article Results from cell culture-based studies provided solid and consistent evidence that blueberry phytochemicals have anti-inflammatory and antioxidant properties. These findings support and explain the health benefits associated with blueberry consumption by helping combat oxidative stress and reduce inflammation in the human body. 14 Farshbaf, et al. 24 Clinical Efficacy of Curcumin and Vitamin E on Inflammatory-Oxidative Stress Biomarkers and Primary Symptoms of Menopause in Healthy Postmenopausal Women: A Triple-Blind Randomized Controlled Trial Review Article Oxidative stress (OS) is a primary mechanism of cellular aging and increased vulnerability, leading to various age-related non-infectious ailments, including genomic imbalance, telomere reduction, epigenetic components, homeostatically reduced proteome, altered mitochondrial function, metabolic instability, intercellular signaling defects, and a growing dysregulation in nutrient sensing. These events and their interactions are regulated by the Mediterranean diet, dietary antioxidants (broccoli, spinach, sunflower seeds), and caloric restriction. 15 Mohammadrezaei, et al. 25 Effects of hemp seed alone and combined with aerobic exercise on metabolic parameters, oxidative stress, and neurotrophic factors in young sedentary men Review Article The results were positive, indicating that both curcumin and vitamin E had a beneficial effect on improving oxidative stress biomarkers. These findings suggest that the combination of curcumin and vitamin E could be a promising treatment option to address the effects of oxidative stress and menopausal symptoms in postmenopausal women 16 Shirvani, et al. 26 Oregano (Origanum vulgare) Consumption Reduces Oxidative Stress and Markers of Muscle Damage after Combat Readiness Tests in Soldiers Quantitative Experimental Study They examined the effects of hemp seed and aerobic exercise on metabolic contrasts, oxidative stress, and neurotrophic elements in young males. The results of this trial indicated that aerobic exercise combined with hemp seed consumption can improve oxidative stress indices and brain-derived neurotrophic factor among sedentary young men. 17 Kobayashi, et al. 27 Effects of Coffee Intake on Oxidative Stress During Aging-related Alterations in Periodontal Tissue Quantitative Experimental Study The results indicated that oregano supplementation had the potential to reduce muscle damage and increase antioxidant capacity after completing the Army Preparation Test. These findings suggest that including oregano as part of the dietary strategy could be beneficial for enhancing physical readiness and facilitating recovery in military recruits. 18 Zhao, et al. 28 Resveratrol Attenuates Heat Stress-Induced Impairment of Meat Quality in Broilers by Regulating the NRF2 Signaling Pathway Quantitative Experimental Study They established the anti-aging effects of caffeine consumption based on periodontal oxidative stress and alveolar bone loss in rats. Consequently, continuous consumption of coffee at 1.36% prevented age-related oxidative stress in periodontal tissues and alveolar bone loss in rats, possibly by positively regulating the Nrf2 signaling pathway. 19 Hongyan, et al. 29 Resveratrol Alleviates Inflammation and ER Stress Through SIRT1/NRF2 to Delay Ovarian Aging in a Short-Lived Fish Quantitative Experimental Study Analyses have shown that dietary resveratrol (RES) enhances muscle efficiency in heat-stressed broiler chickens, but much is still unclear. Therefore, the primary objective of the study was to investigate the effect of RES on muscle quality in broiler chickens, the muscular antioxidant stage, and the mechanism of action under heat stress conditions. The study demonstrated that RES could improve the muscle antioxidant capacity in broiler chickens under heat stress by activating the Nrf2 signaling pathway. 20 Pistol, et al. 30 Grape seed meal by-product is able to counteract oxidative stress induced by lipopolysaccharide and dextran sulphate in IPEC cells and piglets after weaning Mixed-Methods Study The results revealed that the age-related activity of β-galactosidase and the accumulation of lipofuscin in the ovaries increased over time as the fish aged. However, resveratrol treatment had a notable effect in reversing these age-related changes. Additionally, resveratrol prolonged the period of activity of the nuclear antigen of cell proliferation and increased the proportion of oocytes in primary anagen stages and vitellogenic pits. Moreover, it reduced the number of ducts in the fish ovaries at 6, 9, and 12 months of age. These results highlight the protective effect of resveratrol on ovarian aging, suggesting its ability to delay this process and deserving special attention in the context of aging-related research and reproductive health. 21 Chan, et al. 31 Fermented pomegranate extracts protect against oxidative stress and aging of skin Quantitative Experimental Study The Punica granatum, or commonly known as pomegranate, can improve the anti-inflammatory effect and skin condition (stromal keratitis). Fermentation is a biotechnology that simply benefits health by producing antioxidants. However, the anti-aging effects of fermented pomegranate extract on the skin are still unclear. The study revealed positive effects as an effective supplement and cosmetic mixture in vivo. 22 Liang, et al. 32 Culture salinity modulates NRF2 antioxidant signaling pathway and immune response of juvenile Genetically Improved Farmed Tilapia (GIFT) (Oreochromis niloticus) under different dietary protein levels Quantitative Study They analyzed the effect of protein level in the diet and the level of cultivated salt on the health stage of transgenic tilapia fry. The results showed that appropriate protein levels suppressed the intestinal expression of proinflammatory genes, including interleukin 1β (IL-1β) mRNA, interleukin 8, and TNF-α factor at both salt levels. Therefore, appropriate protein levels and a cultivation salinity of 8‰ are crucial for maintaining the health of GIFT juveniles by enhancing antioxidant and immune capacity. 23 Keshani, et al. 33 The Effect of Genetically Modified Food on Infertility Indices: A Systematic Review Study Review Article The results of this research indicated that transgenic products showed no adverse effects on infertility indices, such as sperm head morphology, motility, sperm abnormalities, and fertility rates. It was also observed that these transgenic products also possessed antioxidant properties that could be related to the activation of the NRF2 pathway. These findings suggest that genetically modified crops, specifically transgenic soy and corn, did not have negative impacts on reproductive health in relation to the evaluated parameters and, moreover, could have a beneficial antioxidant effect related to the NRF2 pathway. 24 Bykowska, et al. 34 Emerging Trends in Research on Food Compounds and Women’s Fertility: A Systematic Review Review Article A review of the last five years (2020-2015) listed foods associated with higher fertility rates, such as caffeine, fatty acids, vitamin D, as well as the effects of fish, dairy, and soy intake, which resulted in the activation of the NRF2 protein and favored women's fertility. 25 Steiner, et al. 35 The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial Quantitative Study The results indicated that, in the case of men with male infertility, antioxidants (vitamin C, vitamin E, selenium, l-carnitine, zinc, and lycopene) did not show significant improvements in semen parameters or sperm DNA integrity. However, they observed that some of these antioxidants had the ability to internally activate the NRF2 pathway. These findings suggest that while antioxidants did not have a positive impact on male fertility in terms of semen parameters and sperm DNA integrity, some of them may play a role in the activation of the NRF2 pathway, which could have implications for other aspects of health and cellular protection. The analyzed studies underscore the significance of the NRF2 signaling pathway in safeguarding against oxidative stress and its crucial role in various facets of health and cellular protection. This adaptive pathway is pivotal in responding to hormonal doses, supporting essential hormonal properties. The conservation of NRF2 and its moderately stimulating responses are key factors amplifying its assimilation efficiency, as indicated by Calabrese and Kozumbo. 11 Previous research has illuminated the impact of NRF2 protein activation on health promotion in diverse areas. Hongyan, et al., 29 illustrated that resveratrol can delay ovarian aging and enhance reproductive health. Conversely, Pistol, et al., 30 explored the beneficial effects of grape seed flour by-products in neutralizing prooxidant effects, suggesting significant health implications for oxidative stress prevention. Chan, et al., 31 emphasized the positive effects of fermented pomegranate extract on the skin, potentially applicable in skincare and overall health. Liang, et al., 32 addressed the importance of diet and salinity in the health of transgenic tilapia fry, underscoring the relevance of adequate protein and salinity levels in maintaining health through improved antioxidant and immune capacity. Additionally, Bykowska, et al., 34 examined foods associated with higher birth rates, highlighting NRF2 protein activation as a beneficial factor. Collectively, these studies offer valuable insights into how NRF2 activation contributes to health promotion in various domains. Authors such as Lin et al. 17 and Zhang et al. 19 emphasize the NRF2 signaling pathway in the antioxidant response and cellular protection. They demonstrate how curcumin and extracts from medicinal plants like Alpinia officinarum can activate this pathway, reinforcing antioxidant defenses in the body. These results suggest that natural compounds can be valuable tools in preventing oxidative stress. Ji et al. 1 and Martemucci et al. 3 explore therapeutic approaches for diseases related to cellular degeneration and aging. They discuss cellular reprogramming and the inclusion of antioxidants in the diet as strategies to counteract the harmful effects of oxidative stress and degeneration. Abrescia et al. 22 discuss the role of polyunsaturated fatty acids in cellular signaling, intertwining with research on dietary antioxidants. These fatty acids, found in foods like fish, exhibit antioxidant properties and activate the NRF2 pathway, supporting the idea that diet plays a crucial role in protection against oxidative stress. Supplementation with antioxidants, such as vitamin E and curcumin, is addressed in several studies (Farshbaf et al., 24) and (George et al., 6). These antioxidants show beneficial effects in improving oxidative stress biomarkers, suggesting their utility in protecting against oxidative damage. The use of exogenous foods with antioxidant properties is highlighted in research such as that of Li et al. 8 and Zhao et al. 28 Both Herpetospermum pedunculosum seeds and dietary resveratrol activate the NRF2 signaling pathway, alleviating oxidative stress and emphasizing the relevance of food choices in oxidative stress prevention. Regarding reproductive health, studies by Steiner et al. 35 and Keshani et al. 33 explore the effects of antioxidants and genetically modified foods on fertility. Although improvements in fertility parameters are not always observed, some of these compounds activate the NRF2 pathway, suggesting implications for other aspects of health. Qian et al. 18 conducted research focused on the protective effects of Ginkgo biloba seeds in relation to oxidative stress. Findings indicated that these seeds had the ability to modify NRF2 expressions and inhibit oxidative stress, highlighting the possibility that natural compounds could significantly impact the activation of this pathway and cellular protection. Islam et al. 20 explored the beneficial effects of Clerodendrum viscosum, a medicinal plant in Ayurveda. Their study demonstrated how this plant could strengthen the antioxidant system by stimulating the NRF2 pathway, suggesting its potential in promoting health and neuronal protection, especially in environments exposed to harmful substances such as lead. In the context of mitigating cerebral ischemia/reperfusion injury, Sun et al. 10 investigated the activation of NRF2. Results indicated that activated NRF2 had a protective effect by preventing inflammatory reactions, inhibiting nerve cell apoptosis, and improving nerve function, emphasizing the crucial role of this pathway in cerebral protection. Liu et al. 21 evaluated the effects of polysaccharides derived from algae on oxidative stress and inflammatory response. Their study demonstrated how these polysaccharides improved antioxidant capacity and reduced the inflammatory response by suppressing NF-κB p65 signaling, suggesting their utility in reducing oxidative stress and inflammation. On the other hand, Felgus et al. 23 focused on the health benefits associated with blueberry consumption, particularly in mitigating oxidative stress. Their review highlighted how blueberry phytochemicals possessed antioxidant and anti-inflammatory properties, supporting the health benefits of this food. Shirvani et al. 26 conducted research on oregano supplementation in soldiers subjected to extreme physical conditions. Their study suggested that oregano could reduce muscle damage and increase antioxidant capacity, which could be beneficial for improving physical readiness in high-stress situations. Meanwhile, Kobayashi et al. 27 established an interesting connection between caffeine and age-related oxidative stress prevention in periodontal tissues and alveolar bone loss in rats. Their study emphasized how coffee consumption could positively regulate the NRF2 signaling pathway, supporting the idea that certain foods and beverages could have protective effects. Zhao et al. 28 investigated the effects of dietary resveratrol on muscle quality in broiler chickens under heat stress. Results suggested that resveratrol could enhance muscle antioxidant capacity by activating the NRF2 pathway, highlighting its utility in protection against oxidative stress. Lastly, the importance of physical activity and antioxidant supplementation in overall health is discussed. Studies like that of Mohammadrezaei et al. 25 highlight how the combination of aerobic exercise and the consumption of certain foods can improve antioxidant capacity and overall health. Discussion The analyzed studies underscore the fundamental relevance of the NRF2 signaling pathway in protection against oxidative stress and its profound impact on various aspects of health and cellular defense. This adaptive pathway emerges as an essential pillar in hormone response and support of basic hormonal functions, as indicated by Calabrese and Kozumbo. 11 Furthermore, the preservation of NRF2 and its moderate stimulating responses have been observed as crucial components that enhance its assimilation efficiency. Particularly, significant results from various studies have been highlighted. Hongyan, et al. 29 revealed how resveratrol has the ability to delay ovarian aging and improve reproductive health, suggesting a key role of NRF2 in reproductive health. On the other hand, Pistol, et al. 30 explored the benefits of grape seed flour by-products in neutralizing prooxidant effects, pointing to significant implications for health and oxidative stress prevention. Additionally, Chan, et al. 31 emphasized how fermented pomegranate extract may have positive effects on the skin and possibly on overall skin-related health. The study by Liang, et al. 32 underscores the relevance of diet and salinity in the health of transgenic tilapia fry, emphasizing the importance of maintaining adequate levels of protein and salinity to enhance antioxidant and immune capacity. Furthermore, Bykowska, et al. 34 examined the relationship between NRF2 protein activation and women’s fertility through foods associated with higher birth rates. Additionally, previous studies have demonstrated how natural compounds such as curcumin and extracts from medicinal plants can activate the NRF2 pathway, strengthening antioxidant defenses and suggesting the relevance of incorporating natural foods in oxidative stress prevention. Therapeutic approaches to address diseases related to cellular degeneration and aging, such as cellular reprogramming and the inclusion of antioxidants in the diet, have also been explored. Polyunsaturated fatty acids found in foods like fish have also been shown to possess antioxidant properties and the ability to activate the NRF2 pathway, emphasizing the importance of diet in protection against oxidative stress. Antioxidant supplementation, such as vitamin E and curcumin, has shown beneficial effects in improving oxidative stress biomarkers. Regarding reproductive health, the effects of antioxidants and genetically modified foods have been explored, highlighting that some of these compounds activate the NRF2 pathway, which could have implications beyond fertility. Finally, the relationship between caffeine and age-related oxidative stress prevention has been highlighted, as well as the potential of resveratrol in enhancing antioxidant capacity in various conditions, including thermal stress. Conclusions Taken together, these studies support the notion that NRF2 activation through food intake plays a crucial role in promoting health in a variety of areas, emphasizing the importance of diet, natural compounds, and antioxidant supplementation in protection against oxidative stress and its implications for overall health. Author roles Ambrocio Teodoro Esteves Pairazaman: Conceptualization, Investigation, Supervision, Funding acquisition, Visualization and Writing – original draft Emma Caldas Herrera: Methodology, Visualization and Writing – Review & Editing Jesus Collanque Pinto: Resources, Validation and Writing – Review & Editing Flor Lidia Bustamante Fustamante: Formal analysis, Visualization and Writing – Review & Editing José Rincón Chavez: Formal analysis, Visualization and Writing – Review & Editing Carmela Gelida Barboza Justiniano: Visualization and Formal Analysis Pamela Belen Esteves Cardenas: Formal analysis and Writing – Review & Editing Patricia Mariane Grados Alva: Investigation, Methodology, Validation, Visualization, Writing – Original Draft Preparation and Writing – Review & Editing Elmer Oyarce Alvarado: Methodology, Visualization and Writing – Review & Editing Data availability Underlying data All data underlying the results are available as part of the article and no additional source data are required. 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Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 16 Apr 2024 ADD YOUR COMMENT Comment Author details Author details 1 Universidad Hipócrates, Acapulco, Mexico 2 Sanidad de la Policía Nacional del Peru, Lima, Peru 3 Universidad Norbert Wiener, Lima, Peru 4 Universidad Peruana Cayetano Heredia, Lima District, Lima Region, Peru 5 Universidad Cesar Vallejo, Trujillo, La Libertad, Peru Ambrocio Teodoro Esteves Pairazaman Roles: Conceptualization, Funding Acquisition, Investigation, Supervision, Visualization, Writing – Original Draft Preparation Emma Caldas Herrera Roles: Methodology, Visualization, Writing – Review & Editing Jesus Collanque Pinto Roles: Resources, Validation, Writing – Review & Editing Flor Lidia Bustamante Fustamante Roles: Formal Analysis, Visualization, Writing – Review & Editing José Rincón Chavez Roles: Formal Analysis, Visualization, Writing – Review & Editing Carmela Gelida Barboza Justiniano Roles: Formal Analysis, Visualization Pamela Belen Esteves Cardenas Roles: Formal Analysis, Writing – Review & Editing Patricia Mariane Grados Alva Roles: Investigation, Methodology, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Elmer Oyarce Alvarado Roles: Methodology, Visualization, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 16 Apr 2024, 13:278 https://doi.org/10.12688/f1000research.143351.1 Copyright © 2024 Esteves Pairazaman AT et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Esteves Pairazaman AT, Caldas Herrera E, Collanque Pinto J et al. Exogenous foods that activate the NRF2 protein: Systematic review [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :278 ( https://doi.org/10.12688/f1000research.143351.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 16 Apr 2024 Views 0 Cite How to cite this report: Russo GL. Reviewer Report For: Exogenous foods that activate the NRF2 protein: Systematic review [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :278 ( https://doi.org/10.5256/f1000research.156999.r290805 ) The direct URL for this report is: https://f1000research.com/articles/13-278/v1#referee-response-290805 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 28 Jun 2024 Gian Luigi Russo , Institute of Food Science, National Research Council, Avellino, Italy Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.156999.r290805 I read with great attention and interest the work by Ambrocio Teodoro Esteves Pairazaman et al. The scope of the systematic review is to assess the role of foods in activating the NRF2 system of antioxidant response. Although the ... Continue reading READ ALL I read with great attention and interest the work by Ambrocio Teodoro Esteves Pairazaman et al. The scope of the systematic review is to assess the role of foods in activating the NRF2 system of antioxidant response. Although the topic is of great interest, leading me to accept the current revision, I must admit that, in my opinion, the authors fail to achieve their objective. If the main question to be answered was: “What are the exogenous foods that activate the NRF2 protein addressed in research articles?” (page 3 of 15), this is not clearly answered in the article. While I am not an expert in systematic reviews, it seems the main issue lies in the method used to select the 25 articles that met the inclusion criteria. Notably, about 30% of these articles are reviews, not original research. Additionally, the articles include studies where single compounds were tested alongside others using extracts, making it difficult to discern a functional relationship between specific food agents and their effects on the NRF2 pathway. The Results section does little to aid comprehension, as it is limited to brief descriptions of each article retrieved. Instead, it was expected that the authors would attempt to identify common modes of action triggered by specific classes of compounds in particular food groups that activate the NRF2 pathway. The functional relationship (if any) between the measurement of the antioxidant capacity of foods and the activation of NRF2 remains unclear (page 4 of 15). Finally, the article does not sufficiently address the concentrations of the putative agents used to stimulate NRF2. This is crucial since NRF2 activation is not always or exclusively associated with beneficial effects. Overall, after reading the article, I, and presumably other readers, are left with the unresolved question of which foods and their portions should be consumed to maintain an activating level of NRF2 activity. Other comments: - The Discussion section largely duplicates the Results and needs revision. - A clear definition of “exogenous” food should be provided. - An explanation of why only studies published in Spanish and English were considered, excluding other languages, should be given. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are the conclusions drawn adequately supported by the results presented in the review? No If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: Keywords : phytochemicals; polyphenols; botanicals; disease prevention; health; cancer; chemoprevention; antioxidant; protein kinases; cell division cycle; apoptosis; senescence; autophagy. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Russo GL. Reviewer Report For: Exogenous foods that activate the NRF2 protein: Systematic review [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :278 ( https://doi.org/10.5256/f1000research.156999.r290805 ) The direct URL for this report is: https://f1000research.com/articles/13-278/v1#referee-response-290805 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 16 Apr 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 Version 1 16 Apr 24 read Gian Luigi Russo , Institute of Food Science, National Research Council, Avellino, Italy Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Russo G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 28 Jun 2024 | for Version 1 Gian Luigi Russo , Institute of Food Science, National Research Council, Avellino, Italy 0 Views copyright © 2024 Russo G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I read with great attention and interest the work by Ambrocio Teodoro Esteves Pairazaman et al. The scope of the systematic review is to assess the role of foods in activating the NRF2 system of antioxidant response. Although the topic is of great interest, leading me to accept the current revision, I must admit that, in my opinion, the authors fail to achieve their objective. If the main question to be answered was: “What are the exogenous foods that activate the NRF2 protein addressed in research articles?” (page 3 of 15), this is not clearly answered in the article. While I am not an expert in systematic reviews, it seems the main issue lies in the method used to select the 25 articles that met the inclusion criteria. Notably, about 30% of these articles are reviews, not original research. Additionally, the articles include studies where single compounds were tested alongside others using extracts, making it difficult to discern a functional relationship between specific food agents and their effects on the NRF2 pathway. The Results section does little to aid comprehension, as it is limited to brief descriptions of each article retrieved. Instead, it was expected that the authors would attempt to identify common modes of action triggered by specific classes of compounds in particular food groups that activate the NRF2 pathway. The functional relationship (if any) between the measurement of the antioxidant capacity of foods and the activation of NRF2 remains unclear (page 4 of 15). Finally, the article does not sufficiently address the concentrations of the putative agents used to stimulate NRF2. This is crucial since NRF2 activation is not always or exclusively associated with beneficial effects. Overall, after reading the article, I, and presumably other readers, are left with the unresolved question of which foods and their portions should be consumed to maintain an activating level of NRF2 activity. Other comments: - The Discussion section largely duplicates the Results and needs revision. - A clear definition of “exogenous” food should be provided. - An explanation of why only studies published in Spanish and English were considered, excluding other languages, should be given. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are the conclusions drawn adequately supported by the results presented in the review? No If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise Keywords : phytochemicals; polyphenols; botanicals; disease prevention; health; cancer; chemoprevention; antioxidant; protein kinases; cell division cycle; apoptosis; senescence; autophagy. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Russo GL. Peer Review Report For: Exogenous foods that activate the NRF2 protein: Systematic review [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :278 ( https://doi.org/10.5256/f1000research.156999.r290805) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-278/v1#referee-response-290805 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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