Vitamins as Nrf2 Activators
Vitamins have often been referred to as "direct antioxidants". Dr. Joe McCord in an ABC primetime video mentioned that they were not good enough on their own to fight the enormous battle against free radical damage.
So when are vitamins effective in the fight against free radicals?Vitamins as direct antioxidants eliminate free radicals on a 1:1 basis. In other words, one molecule of a vitamin eliminates one free radical if it is purely acting as a direct antioxidant. However when that vitamin becomes a Nrf2 activator, it turns on the switch to the body's own antioxidant defenses and neutralizes free radicals more like a 1:1,000,000 ratio every second.
Below are the latest 15 Pubmed studies referencing vitamis and Nrf2 activation.
Cellular stress and AMPK activation as a common mechanism of action linking the effects of metformin and diverse compounds that alleviate accelerated aging defects in Hutchinson-Gilford progeria syndrome
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by an accelerated aging phenotype that typically leads to death via stroke or myocardial infarction at approximately 14.6 years of age. Most cases of HGPS have been linked to the extensive use of a cryptic splice donor site located in the LMNA gene due to a de novo mutation, generating a truncated and toxic protein known as progerin. Progerin accumulation in the nuclear membrane and within the nucleus distorts the nuclear architecture and negatively effects nuclear processes including DNA replication and repair, leading to accelerated cellular aging and premature senescence. The serine-arginine rich splicing factor SRSF1 (also known as ASF/SF2) has recently been shown to modulate alternative splicing of the LMNA gene, with SRSF1 inhibition significantly reducing progerin at both the mRNA and protein levels. In 2014, we hypothesized for the first time that compounds including metformin that induce activation of AMP-activated protein kinase (AMPK), a master metabolic regulator activated by cellular stress (e.g. increases in intracellular calcium, reactive oxygen species, and/or an AMP(ADP)/ATP ratio increase, etc.), will beneficially alter gene splicing in progeria cells by inhibiting SRSF1, thus lowering progerin levels and altering the LMNA pre-mRNA splicing ratio. Recent evidence has substantiated this hypothesis, with metformin significantly reducing the mRNA and protein levels of both SRSF1 and progerin, activating AMPK, and alleviating pathological defects in HGPS cells. Metformin has also recently been shown to beneficially alter gene splicing in normal humans. Interestingly, several chemically distinct compounds, including rapamycin, methylene blue, all-trans retinoic acid, MG132, 1α,25-dihydroxyvitamin D3, sulforaphane, and oltipraz have each been shown to alleviate accelerated aging defects in patient-derived HGPS cells. Each of these compounds has also been independently shown to induce AMPK activation. Because these compounds improve accelerated aging defects in HGPS cells either by enhancing mitochondrial functionality, increasing Nrf2 activity, inducing autophagy, or by altering gene splicing and because AMPK activation beneficially modulates each of the aforementioned processes, it is our hypothesis that cellular stress-induced AMPK activation represents an indirect yet common mechanism of action linking such chemically diverse compounds with the beneficial effects of those compounds observed in HGPS cells. As normal humans also produce progerin at much lower levels through a similar mechanism, compounds that safely induce AMPK activation may have wide-ranging implications for both normal and pathological aging.
Therapeutic Effects of Pretreatment with Tocovid on Oxidative Stress in Postischemic Mice Brain
Dietary supplement is an attempt to reduce the risk of ischemic stroke in high-risk population. A new mixed vitamin E-Tocovid that mainly contains tocotrienols other than tocopherol, attenuated the progression of white matter lesions by oral in humans. However, the effect of Tocovid on ischemic stroke has not been examined. In the present study, we assessed the therapeutic effects of Tocovid pretreatment on transient middle cerebral artery occlusion (tMCAO) in mice.
Oxidative stress and NF-κB signaling are involved in LPS induced pulmonary dysplasia in chick embryos
Inflammation or dysbacteriosis-derived lipopolysaccharides (LPS) adversely influence the embryonic development of respiratory system. However, the precise pathological mechanisms still remain to be elucidated. In this study, we demonstrated that LPS exposure caused lung maldevelopment in chick embryos, including higher embryo mortality, increased thickness of alveolar gas exchange zone, and accumulation of PAS immature pulmonary cells, accompanied with reduced expression of alveolar epithelial cell markers and lamellar body count. Upon LPS exposure, pulmonary cell proliferation was significantly altered and cell apoptosis was inhibited as well, indicating a delayed progress of pulmonary development. LPS treatment also resulted in reduced CAV-1 expression and up-regulation of Collagen I, suggesting increased lung fibrosis, which was verified by Masson staining. Moreover, LPS induced enhanced Nrf2 expression in E18 lungs, and the increased reactive oxygen species (ROS) production was confirmed in MLE-12 cells in vitro. Antioxidant vitamin C restored the LPS induced down-regulation of ABCA3, SP-C and GATA-6 in MLE-12 cells. Furthermore, LPS induced activation of NF-κB signaling in MLE-12 cells, and the LPS-induced decrease in SP-C expression was partially abrogated by blocking NF-κB signaling with Bay-11-7082. Bay-11-7082 also inhibited LPS-induced increases of ROS and Nrf2 expression. Taken together, we have demonstrated that oxidative stress and NF-κB signaling are involved in LPS induced disruption of pulmonary cell development in chick embryos.
A Novel Peptide, Nicotinyl⁻Isoleucine⁻Valine⁻Histidine (NA⁻IVH), Promotes Antioxidant Gene Expression and Wound Healing in HaCaT Cells
Nicotinamide (NA), a water-soluble vitamin B₃, has been shown to exert cellular-protective effects against reactive oxygen species (ROS). In order to improve the cellular-protective effects of NA, we synthesized a novel compound, nicotinyl⁻isoleucine⁻valine⁻histidine (NA⁻IVH), by combining NA with jellyfish peptides' IVH. In the present study, we examined the cellular-protective effects of the novel synthetic nicotinyl-peptide, NA⁻IVH. We found that NA⁻IVH enhances the radical scavenging activity with a robust increase of the nuclear factor (erythroid-derived 2)-like factor (Nrf2) expression in human HaCaT keratinocytes. In addition, NA⁻IVH protected the cells from hydrogen peroxide (H₂O₂)-induced cell death. Interestingly, NA⁻IVH exhibited an improved wound-healing effect in a high glucose condition, possibly through the regulation of reactive oxygen species (ROS). Collectively, our results imply that a novel nicotinyl-peptide, NA⁻IVH, has a wound-healing effect in a hyperglycemic condition, possibly by modulating excessive ROS.
Effects and Mechanism of Nicotinamide Against UVA- and/or UVB-mediated DNA Damages in Normal Melanocytes
Melanoma incidences are increasing rapidly, and ultraviolet (UV) radiation from the sun is believed to be its major contributing factor. UV exposure causes DNA damage in skin which may initiate cutaneous skin cancers including melanoma. Melanoma arises from melanocytes, the melanin-producing skin cells, following genetic dysregulations resulting into hyperproliferative phenotype and neoplastic transformation. Both UVA and UVB exposure to the skin are believed to trigger melanocytic hyperplasia and melanomagenesis. Melanocytes by themselves are deficient in repair of oxidative DNA damage and UV-induced photoproducts. Nicotinamide, an active form of Vitamin B3 and a critical component of the human body's defense system has been shown to prevent certain cancers including nonmelanoma skin cancers. However, the mechanism of nicotinamide's protective effects is not well understood. Here, we investigated potential protective effects and mechanism of nicotinamide against UVA- and/or UVB- induced damage in normal human epidermal melanocytes. Our data demonstrated an appreciable protective effect of nicotinamide against UVA- and/or UVB- induced DNA damage in melanocytes by decreasing both cyclobutane pyrimidine dimers and 8-hydroxy-2'-deoxyguanine levels. We found that the photoprotective response of nicotinamide was associated with activation of nucleotide excision repair and NRF2. Further studies are needed to validate our findings in in vivo models. This article is protected by copyright. All rights reserved.
Di-(2-ethylhexyl) phthalate (DEHP)-induced testicular toxicity through Nrf2-mediated Notch1 signaling pathway in Sprague-Dawley rats
Di-(2-ethylhexyl) phthalate (DEHP) is an environmental endocrine disruptor widely used in China that is harmful to the male reproductive system. Many studies have shown that DEHP causes testicular toxicity through oxidative stress, but the specific mechanism is unknown. Because the Notch pathway is a key mechanism for regulating cell growth and proliferation, we investigated whether Notch is involved in DEHP-induced testicular toxicity and whether vitamins E and C could rescue testicular impairment in Sprague-Dawley (SD) rats. Compared with the control group, we found that DEHP exposure induced testicular toxicity through oxidative stress injury, and it decreased the testosterone level (P < .01) and upregulated nuclear factor-erythroid 2 related factor (Nrf2) expression (P < .01). Therefore, because oxidative stress might be the initiating factor of DEHP-induced testicular toxicity, treatment with the antioxidant vitamins E and C activated the Notch1 signaling pathway in the testis and in Leydig cells. Treatment with vitamins E and C normalized the oxidative stress state after DEHP exposure and restored testicular development to be similar to the control group. In summary, antioxidant vitamins E and C may be used to treat DEHP-induced testicular toxicity.
Vitamin E alleviates phoxim-induced toxic effects on intestinal oxidative stress, barrier function, and morphological changes in rats
Phoxim is an organic phosphorus pesticide that remains easily in the environment, such as human food and animal feed. The objective of this study was to explore the effect of vitamin E on phoxim-induced oxidative stress in the intestinal tissues of Sprague-Dawley (SD) rats. Forty-eight Sprague-Dawley rats were randomly assigned to a control group and three treatment groups: treatment group 1 (phoxim: 20 mg/kg·BW), treatment group 2 (phoxim: 180 mg/kg·BW), and treatment 3 (vitamin E + phoxim: 200 mg/kg·BW + 180 mg/kg·BW). Phoxim was given by gavage administration once a day for 28 days. The results showed that phoxim significantly reduced jejunum villus height in rats (P < 0.05), and decreased the mRNA expression of junction protein genes of rats, including Occlidin and Claudin-4 (P < 0.05). Phoxim reduced GSH content and T-AOC level in the intestinal mucosa (P < 0.05). The mRNA expression levels of oxidative stress-related genes (Nrf2 and GPx2) were decreased. The mRNA expression of SOD was significantly increased. In addition, phoxim increased the level of interleukin-6 (IL-6) in jejunum mucosa and significantly reduced the level of IL-8 in ileum mucosas, while significantly increased TNF-α secretion. The mRNA expression levels of IL-1β, IL-6, and IL-8 were significantly decreased, and mRNA expression of TNF-α was significantly increased (P < 0.05). Phoxim also increased the DNA expression of total cecal bacteria and Escherichia coli, inhibited the DNA expression of Lactobacillus and destroyed the intestinal barrier. Two hundred milligrams per kilogram BW vitamin E reduced the effect of phoxim on intestinal structure, alleviated the oxidative stress in intestinal tissue, and decreased the level of TNF-α. The mRNA expressions of antioxidative stress genes (SOD and GPx2) were significantly increased. The DNA expression level of Lactobacillus was significantly increased. In conclusion, vitamin E helped reduce the toxicity of organophosphate pesticides, such as phoxim on rat intestinal tissue.
Differential Effects of Vitamin C or Protandim on Skeletal Muscle Adaptation to Exercise
Maintaining proteostasis is a key mechanism for preserving cell function. Exercise-stimulated proteostasis is regulated, in part, by redox-sensitive signaling. Several studies suggest that supplementation with exogenous antioxidants blunts exercise-induced cellular adaptations, though this conclusion lacks consensus. Our group uses a fundamentally different approach to maintain redox balance by treatment with bioactive phytochemicals to activate the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and downstream endogenous antioxidant pathways. We hypothesized that VitC would interfere with redox-sensitive proteostatic mechanisms in skeletal muscle while phytochemical treatment would permit proteostatic maintenance. We measured protein and DNA synthesis in skeletal muscle from high-volume voluntary wheel running rats. While phytochemical treatment permitted mitochondrial and other proteostatic adaptations to exercise, VitC treatment did not. During an in vitro oxidative challenge, phytochemical treatment helped maintain proteostasis, including the mitochondrial fraction, while VitC did not. Our findings support the conclusion that VitC can blunt some of the beneficial adaptations to exercise. We propose that regulation of endogenous antioxidants represents a novel approach to maintain redox balance while still permitting redox-sensitive proteostatic adaptations.
Effects of nutritional state, aging and high chronic intake of sucrose on brain protein synthesis in rats: modulation of it by rutin and other micronutrients
Little is still known about brain protein synthesis. In order to increase our knowledge of it, we aimed to modulate brain protein synthesis rates through aging, variations in nutritional state (fed state vs. fasted state), high sucrose diet and micronutrient supplementation. Four groups of 16 month-old male rats were fed for five months with a diet containing either 13% or 62% sucrose (wheat starch was replaced with sucrose), supplemented or not with rutin (5 g kg-1 diet), vitamin E (4×), A (2×), D (5×), selenium (10×) and zinc (+44%) and compared with an adult control group. We measured cerebellum protein synthesis and hippocampus gene expression of antioxidant enzymes, inflammatory cytokines and transcription factors. We showed that cerebellum protein synthesis was unchanged by the nutritional state, decreased during aging (-8%), and restored to the adult level by micronutrient supplementation. Sucrose diet did not change protein synthesis but reduced the protein content. Micronutrient supplementation had no effect in sucrose fed rats. Hippocampus gene expressions were affected by age (an increase of TNF-α), sucrose treatment (an increase of IL-1β and IL-6), and micronutrient supplementation (a decrease of heme oxygenase, catalase, glutathione peroxidase, TNF-α, and Nrf2). We noted that cerebellum protein synthesis and hippocampus TNF-α gene expression were modulated by the same factors: they were affected by aging and micronutrient supplementation and unchanged by feeding and by high sucrose diet.
Proteome-wide changes in primary skin keratinocytes exposed to diesel particulate extract-A role for antioxidants in skin health
Skin acts as a protective barrier against direct contact with pollutants but inhalation and systemic exposure have indirect effect on keratinocytes. Exposure to diesel exhaust has been linked to increased oxidative stress.
Vitamin A pretreatment protects NO-induced bovine mammary epithelial cells from oxidative stress by modulating Nrf2 and NF-κB signaling pathways
It is known that physiological overproduction of nitric oxide (NO) contributes to oxidative stress and inflammation. Our published studies indicated that vitamin A (VA) reduces NO-induced oxidative stress in bovine mammary epithelial cells (BMECs) by increasing antioxidant enzyme activities. However, the precise mechanism is unclear. The present study was conducted to examine the protective effects of VA on NO-induced damage to BMECs in vitro using diethylenetriamine nitric oxide (DETA-NO) as the NO donor and to explore the intracellular signaling mechanisms of VA that involve nuclear factor erythroid 2-related factor (Nrf2) and nuclear factor kappa-B (NF-κB). Subconfluent BMECs were divided into 10 treatment groups with 6 replicates per treatment and were cultured with dimethyl sulfoxide (DMSO, vehicle negative control) or 0, 0.05, 0.1, 0.2, 0.5, 1, 2, 3, or 4 μg/mL of VA for 24 h and then incubated in the absence or presence of DETA-NO (1,000 μmol/liter) and VA for an additional 6 h. The results showed that exposure to DETA alone decreased cell proliferation compared with the negative control. Pretreatment with VA promoted the proliferation of BMECs, increased the activities of antioxidative enzymes including selenoprotein glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) and their gene and protein expression but decreased NO and interleukin 1 (IL-1) contents in a quadratic manner (P < 0.05). In addition, the expression of mRNA and protein of factors that are related to NF-κB or Nrf2 signaling pathways in BMECs were regulated by VA in a quadratic dose-dependent manner; VA at a concentration of 1 μg/mL exhibited the strongest effect. Together, these results suggest that VA promotes antioxidant functions of BMECs by regulating the synthesis of selenoproteins including GPx and TrxR and by reducing concentrations of IL-1 and NO in vitro by modulating Nrf2 and NF-κB signaling pathways.
Acute exposure of ozone induced pulmonary injury and the protective role of vitamin E through the Nrf2 pathway in Balb/c mice
Ozone (O) in the lower atmosphere is generally derived from various sources of human activity. It has become a major air pollutant in China and has been shown to adversely affect the health of humans and animals. We undertook a study to ascertain the molecular mechanism of ozone induced lung injury in mice and tried to demonstrate the protective mechanism of vitamin E. In this study, mice were exposed to clean air and three different concentrations of ozone. Oxidative stress (reactive oxygen species and malondialdehyde) and Th cytokines in the lung, serum IgE, as well as histopathological examination and the airway hyper-responsiveness (AHR) test were used to reflect inflammation and damage to the lungs of ozone-exposed mice. We then chose an effective concentration of ozone and combined treatment with vitamin E (VE) to explore the underlying mechanism of ozone-induced lung damage. The results of immunological and inflammatory biomarkers (total-immunoglobulin (Ig) E and Th cytokines) as well as histopathological examination and AHR assessment supported the notion that high doses of ozone (>0.5 ppm) could induce inflammation and lung injury in mice and that this induction was counteracted by concurrent administration of VE. The elimination of oxidative stress, the reduced Th2 responses and Ig production, and the relief of lung damage were proposed to explain the molecular mechanism of ozone induced lung injury. We also showed that VE, an antioxidant that enhanced the expression of Nrf2 and up-regulated the antioxidant genes HO-1 and NQO1, could decrease the levels of oxidative stress and alleviate ozone-induced lung injury.
L-Ascorbic Acid and α-Tocopherol Reduces Hepatotoxicity Associated with Arsenic Trioxide Chemotherapy by Modulating Nrf2 and Bcl2 Transcription Factors in Chang liver Cells
Arsenic trioxide (AsO) is a promising new regimen for the treatment of acute promyelocytic leukemia (APL). The induction of oxidative stress mediated by reactive oxygen species (ROS) and excessive intracellular calcium influx are the main reasons behind AsO toxicity. Since liver is the major organ for xenobiotic metabolism, it is always under stress. Antioxidant vitamins such as L-Ascorbic acid (L-AA) and α-Tocopherol (α-TOC) have been proposed to have beneficial effects against a variety of pathological conditions and are known by their free radical scavenging properties. The present study evaluates the curative efficacy of L-AA and α-TOC against AsO toxicity using immortalized human Chang liver cells. Our results suggest that L-AA (100 µM) and α-TOC (50 µM) recovered AsO (10 µM) cytotoxicity. Furthermore, AsO treatment showed an increase in lipid peroxidation and depletion in antioxidant status, mitochondrial trans membrane potential and values of total antioxidant capacity. Cotreatment of antioxidant vitamins with AsO resulted in a significant reversal of oxidative stress markers. Our findings substantiate the effect of antioxidant vitamins in protecting the hepatocytes from oxidative stress which may be attributed through Nrf2 (Nuclear factor erythroid 2-related factor 2) mediated upregulation of Bcl2 (B-cell lymphoma 2) expression.
Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration
Ferroptosis is a newly described form of regulated cell death, distinct from apoptosis, necroptosis and other forms of cell death. Ferroptosis is induced by disruption of glutathione synthesis or inhibition of glutathione peroxidase 4, exacerbated by iron, and prevented by radical scavengers such as ferrostatin-1, liproxstatin-1, and endogenous vitamin E. Ferroptosis terminates with mitochondrial dysfunction and toxic lipid peroxidation. Although conclusive identification of ferroptosis is challenging, several salient and very well established features of neurodegenerative diseases are consistent with ferroptosis, including lipid peroxidation, mitochondrial disruption and iron dysregulation. Accordingly, interest in the role of ferroptosis in neurodegeneration is escalating and specific evidence is rapidly emerging. One aspect that has thus far received little attention is the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). This transcription factor regulates hundreds of genes, of which many are either directly or indirectly involved in modulating ferroptosis, including metabolism of glutathione, iron and lipids, and mitochondrial function. This potentially positions Nrf2 as a key deterministic component modulating the onset and outcomes of ferroptotic stress. The minimal direct evidence currently available is consistent with this and indicates that Nrf2 may be critical for protection against ferroptosis. In contrast, abundant evidence demonstrates that enhancing Nrf2 signaling is potently neuroprotective in models of neurodegeneration, although the exact mechanism by which this is achieved is unclear. Further studies are required to determine to extent to which the neuroprotective effects of Nrf2 activation involve the prevention of ferroptosis.
Antifatigue Potential Activity of in Acute Excise-Treated and Chronic Fatigue Syndrome in Mice via Regulation of Nrf2-Mediated Oxidative Stress
(SI), a precious edible fungus, contains 35.22% of total sugar, 18.33% of total protein, 24 types of fatty acid, 16 types of amino acid, and 8 types of minerals. Encouragingly, it is rich in potential antioxidants such as total polyphenols (0.41%), total sterols (3.16%), and vitamins (0.44%). In the present study, the antifatigue properties of SI and its potential mechanisms of action were explored by the experiments on acute excise-treated mice and chronic fatigue syndrome (CFS) mice. SI (0.25, 0.5, and 1 g/kg) significantly enhanced exercise tolerance in the weight-loaded forced swimming test (FST) and rota-rod test (RRT) and reduced the immobility in the tail suspension test on CFS mice. SI markedly increased the levels of glycogen in the liver and adenosine triphosphate (ATP) in the liver and muscle and decreased the lactic acid (LD) and blood urea nitrogen (BUN) content in both acute swimming-treated mice and CFS mice. SI improved the endogenous cellular antioxidant enzyme contents in the two mouse models by improving the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels in serum, liver, and muscle, respectively. In CFS mice, the enhanced expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2), SOD1, SOD2, heme oxygenase-1 (HO-1), and catalase (CAT) in the liver were observed after a 32-day SI administration. Our data indicated that SI possessed antifatigue activity, which may be related to its ability to normalize energy metabolism and Nrf2-mediated oxidative stress. Consequently, SI can be expected to serve as a novel natural antifatigue supplement in health foods.