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.
Calcitriol inhibits ROS-NLRP3-IL-1β signaling axis via activation of Nrf2-antioxidant signaling in hyperosmotic stress stimulated human corneal epithelial cells
Dai Y, Zhang J, Xiang J, Li Y, Wu D and Xu J
The activation of ROS-NLRP3-IL-1β signaling axis induced by hyperosmotic stress (HS) has been recognized as a key priming stage of epithelial inflammation in dry eye pathogenesis. The current study aims to investigate whether calcitriol, the active metabolite of vitamin D, could protect cells against HS-induced inflammation through modulating this critical step.
Diterpenoids from the Chinese liverwort Frullania hamatiloba and their Nrf2 inducing activities
Qiao YN, Sun Y, Shen T, Zhang JZ, Zhou JC, Li Y, Chen W, Ren ZJ, Li YL, Wang X and Lou HX
Six previously undescribed labdane diterpenoids, frullanians A-F, along with five known diterpenoids, were isolated from the Chinese liverwort Frullania hamatiloba Stephani. Their structures were determined using NMR data, electronic circular dichroism (ECD) calculations as well as the single crystal X-ray diffraction measurement. NAD(P)H: QR (quinone reductase) assay demonstrated that frullanian D and four known compounds displayed antioxidant effect mediated via Nrf2 (Nuclear factor-erythroid 2-related factor 2) induction. Further investigation of the most bioactive frullanian D in MOVAS cells revealed that it ameliorated HO-induced oxidative insults without toxicity by increasing cell viability, attenuating morphological changes, and reducing intracellular ROS production. In addition, frullanian D promoted the nuclear translocation of Nrf2 and upregulated the expressions of antioxidant proteins NQO1 (NAD(P)H quinone oxidoreductase 1) and γ-GCS (γ-glutamyl cysteine synthetase). Docking analysis using MOE software further supported the activation of the Nrf2 pathway by frullanian D.
DHA and vitamin E antagonized the Aβ-mediated neuron oxidative damage through activation of Nrf2 signaling pathways and regulation of CD36, SRB1 and FABP5 expression in PC12 cells
Huang X, Zhen J, Dong S, Zhang H, Van Halm-Lutterodt N and Yuan L
The present study was designed to explore the neuroprotective effects of docosahexaenoic acid (DHA) and/or vitamin E (VE) in vitro. The PC12 cells were pretreated with DHA and/or VE for 4 h, followed by 50 μmol L-1 Aβ25-35 treatments for another 48 h. The cells were then collected and used for the measurements of oxidative stress parameters. Real time-PCR and western blot were applied to measure fatty acid transporters, Nrf2 and its downstream antioxidant targets' gene and protein expression. Our results indicated that the Aβ25-35 treatment inhibited cellular growth, increased intracellular ROS generation and decreased the mitochondrial membrane potential. The Aβ25-35 treatment decreased the total antioxidant capacity (T-AOC), whereas it increased the MDA levels in neuron cells. Pretreatment of cells with VE or DHA could antagonize the Aβ25-35-mediated cell growth inhibition and mitochondrial membrane potential decline. Activation of the Nrf2 signaling pathway and regulation of CD36, SRB1 and FABP5 expression were observed in DHA- and DHA + VE-pretreated cells. Our results indicated a synergistic effect of DHA and VE in antagonizing the oxidative damage caused by Aβ25-35 in the PC12 cells. The results of the present study will shed light on the application of nutritional intervention for DHA and VE in preventing neuronal damage-related diseases.
Vitamin A deficiency impairs intestinal physical barrier function of fish
Jiang WD, Zhou XQ, Zhang L, Liu Y, Wu P, Jiang J, Kuang SY, Tang L, Tang WN, Zhang YA, Shi HQ and Feng L
The present study was the first to investigate the effects of dietary vitamin A (VA) on the intestinal physical barrier function associated with oxidation, antioxidant system, apoptosis and cell-cellular tight junction (TJ) in the proximal (PI), mid (MI) and distal (DI) intestines of young grass carp (Ctenopharyngodon idella). Fish were fed graded levels of dietary VA for 10 weeks, and then a challenge test using an injection of Aeromonas hydrophila was conducted for 14 days. Results indicated that dietary VA deficiency caused oxidative damage to fish intestine partly by the reduced non-enzymatic antioxidant components glutathione (GSH) and VA contents as well as reduced antioxidant enzyme activities [not including manganese superoxide dismutase (MnSOD)]. Further results observed that the decreased antioxidant enzyme activities by VA deficiency were partly related to the down-regulation of their corresponding mRNA levels which were regulated by the down-regulation of NF-E2-related factor 2 (Nrf2) mRNA levels and up-regulation of kelch-like-ECH-associated protein (Keap1a) (rather than Keap1b) mRNA levels in three intestinal segments of fish. Meanwhile, VA deficiency up-regulated the mRNA levels of the apoptosis signalling [caspase-3, caspase-8, caspase-9 (rather than caspase-7)] associated with the inhibition of the target of rapamycin (TOR) signalling pathway in three intestinal segments of fish. Additionally, VA deficiency decreased the mRNA levels of TJ complexes [claudin-b, claudin-c, claudin-3, claudin-12, claudin-15a, occludin and zonula occludens-1 (ZO-1) in the PI, MI and DI, as well as claudin-7 and claudin-11a in the MI and DI] linked to the up-regulation of myosin light chain kinase (MLCK) signalling. These results suggested that VA deficiency impaired structural integrity in three intestinal segments of fish. Meanwhile, excessive VA also showed similar negative effects on these indexes. Taken together, the current study firstly demonstrated that VA deficiency impaired physical barrier functions associated with impaired antioxidant capacity, aggravated cell apoptosis and disrupted TJ complexes in the PI, MI and DI, but different segments performed different actions in fish. Based on protecting fish against protein oxidation, the optimal VA levels for grass carp were estimated to be 2622 IU/kg diet.
Dietary antioxidant for disease prevention corroborated by the Nrf2 pathway
Hegazy AM, El-Sayed EM, Ibrahim KS and Abdel-Azeem AS
Dietary antioxidants are widely distributed in various types of our food. They are strongly associated with reduced risk of many chronic diseases such as atherosclerosis, cancer, and Alzheimer's diseases. They include vitamins such as vitamins A, E, C, and carotenoids. Also, some minerals like; zinc, manganese, copper, iron, and selenium are essential for the activity of antioxidant enzymes. Furthermore, dietary polyphenols and flavonoids are considered as potent antioxidant compounds. Vegetables, fruits, and edible herbs are the richest sources of such antioxidants. Antioxidants reduce oxidative stress, either directly by reducing reactive species or indirectly by enhancing the body antioxidant defense mechanisms in different ways. These may include upregulating gene expression of some antioxidant enzymes via a nuclear factor erythroid 2 related factor2 pathway. Administration of a mixture of antioxidants is beneficial since they act synergistically in various phases. The aims of this review are to summarize the different antioxidants from dietary sources and their role in the prevention of different diseases.
Spermatogenesis dysfunction induced by PM from automobile exhaust via the ROS-mediated MAPK signaling pathway
Liu B, Wu SD, Shen LJ, Zhao TX, Wei Y, Tang XL, Long CL, Zhou Y, He DW, Lin T and Wei GH
Long-term exposure to particulate matter 2.5 (PM) from automobile exhaust impairs spermatogenesis through oxidative stress injury, but the underlying mechanism is unknown. To investigate the toxic mechanism of PM-induced spermatogenesis impairment, we focused on the MAPK signaling pathway. We also examined the effects of treatment with vitamins C and E on spermatogenic function. Male SD rats were divided randomly into three groups: control (0.9% sterilized saline), PM exposure (20 mg/kg.b.w.), and PM exposure (20 mg/kg.b.w.) with vitamin intervention (vitamin C, 100 mg/kg.b.w.; vitamin E, 50 mg/kg.b.w.). Male rats showed a marked decline in fertility and decreased sperm quality after PM exposure. The expression of SOD and Nrf2 was significantly decreased, and that of MDA was increased markedly. The expression of blood-testis barrier-associated proteins, such as ZO-1, occludin, connexin 43, and β-catenin, was significantly decreased, the Bcl-2/Bax ratio was downregulated, and the cleaved caspase-3 level was increased. Phosphorylation of MAPKs, including ERKs, JNKs, and p38, was upregulated. Treatment with vitamins C and E reversed the damage induced by PM exposure. These results suggest that PM from automobile exhaust disrupted spermatogenesis via ROS-mediated MAPK pathways, and that a combined vitamin C and E intervention effectively mitigated toxicity in the male reproductive system.
The dental monomer 2-hydroxyethyl methacrylate (HEMA) causes transcriptionally regulated adaptation partially initiated by electrophilic stress
Becher R, Valen H, Olderbø BP, Bølling AK and Samuelsen JT
Cellular responses including cell death are induced by in vitro exposure to the un-polymerized dental monomer 2-hydroxyethyl methacrylate (HEMA). Activation of the Nrf2/ARE signaling pathway has been suggested to mediate the cellular responses. Activation of this pathway may occur either indirectly through generation of increased oxidative stress or through direct binding to cysteine thiols due to the electrophilic properties of HEMA. The objective of this study was to elucidate the potential mechanism of Nrf2/ARE pathway activation after HEMA exposure.
Vitamin D Protects Against Alcohol-Induced Liver Cell Injury Within an NRF2-ALDH2 Feedback Loop
Zhang H, Xue L, Li B, Zhang Z and Tao S
Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. Oxidative stress induced during the alcohol metabolism plays a crucial role in ALD, and clinical evidence demonstrates the prevalence and risks of vitamin D (VD) deficiency in ALD. This study aims to explore the mechanism of VD administration to ameliorate alcohol-induced cell injury.
Vitamin D protects against particles-caused lung injury through induction of autophagy in an Nrf2-dependent manner
Tao S, Zhang H, Xue L, Jiang X, Wang H, Li B, Tian H and Zhang Z
Fine particulate matter is a well-known air pollutant threatening public health. Studies have confirmed long-term exposure to the particles could decrease the pulmonary function, induce asthma exacerbation, and chronic obstructive pulmonary disease, as well as increase the incidence and mortality of lung cancer. A clinical study has explored that the prevalence and risks of vitamin D (VD) deficiency in various chronic disease and toxins induced tissue damage. Our current study aimed to explore the mechanism and further therapeutic potential of VD administration to ameliorate fine particles exposure induced pulmonary damage in vivo and in vitro. To elucidate the effects and mechanisms of VD in particles-induced pulmonary damage, a murine model was established with fine particles intratracheal instillation along with VD intramuscular injection. Our study demonstrated that treatment with VD attenuated particles-induced pulmonary damage and promoted tissue repair by repressing of TGFβ1 signaling pathway and upregulation of MMP9 expression. VD treatment could also regulate the autophagy-related signals along with activation of Nrf2 transcription factor. Furthermore, the results from the in vitro study demonstrated that VD protected against particles-induced cells' damage through the induction of autophagy in an Nrf2-dependent manner. VD treatment caused the degradation of P62 and its bound Keap1, which decreased the Nrf2 ubiquitination and increasing its protein stability. Our work explored a novel potential mechanism in the protection of VD in particles-induced pulmonary injury and tissue repair, and could further bring insights into exploring antifine particles exposure caused inflammation among other natural products and contributes to inflammation disease medical therapies.
CQPC11 Isolated from Sichuan Pickled Cabbages Antagonizes d-galactose-Induced Oxidation and Aging in Mice
Qian Y, Zhang J, Zhou X, Yi R, Mu J, Long X, Pan Y, Zhao X and Liu W
Chinese pickled cabbage is a traditional fermented food that contains abundant microbes produced during the process of fermentation. In this work, an in vivo animal study was conducted to investigate the effects of a newly isolated lactic acid bacterium ( CQPC11, LP-CQPC11) on d-galactose-induced oxidation and aging in mice. Analysis of the serum and tissue samples of these mice using molecular biology approaches showed that LP-CQPC11 suppressed the decrease in thymus, brain, heart, liver, spleen, and kidney indices caused by oxidation and aging. Furthermore, LP-CQPC11 increased the levels of SOD (superoxide dismutase), GSH-Px (glutathione peroxidase), and GSH (glutathione), whereas it reduced the levels of NO (nitric oxide) and MDA (malondialdehyde) in the serum, liver, and spleen of oxidation and aging mouse models. Pathological observation indicated that LP-CQPC11 alleviated the damage caused by oxidation and aging on the liver and spleen of mice. qPCR analysis indicated that LP-CQPC11 effectively upregulated the expression of (neuronal nitric oxide synthase), (endothelial nitric oxide synthase), (cuprozinc-superoxide dismutase), (manganese superoxide dismutase), (catalase), (heme oxygenase-1), (nuclear factor-erythroid 2 related factor 2), γ (γ-glutamylcysteine synthetase), and (NAD(P)H dehydrogenase [quinone] 1), but downregulated the expression of (inducible nitric oxide synthase) in the mouse liver and spleen. Western blot analysis showed that LP-CQPC11 effectively upregulated SOD1 (), SOD2 (), CAT, GSH1 (c-glutamylcysteine synthetase), and GSH2 (glutathione synthetase) protein expression in mouse liver and spleen tissues. These findings suggest that LP-CQPC11 can effectively prevent d-galactose-induced oxidation and aging in mice, and the effect is even better than that of the commonly used subsp. (LDSB) and vitamin C in the industry. Thus, LP-CQPC11 may be potentially employed as a probiotic strain.
Dimethyl fumarate and vitamin D derivatives cooperatively enhance VDR and Nrf2 signaling in differentiating AML cells in vitro and inhibit leukemia progression in a xenograft mouse model
Nachliely M, Trachtenberg A, Khalfin B, Nalbandyan K, Cohen-Lahav M, Yasuda K, Sakaki T, Kutner A and Danilenko M
Acute myeloid leukemia (AML) is one of the deadliest hematological malignancies without effective treatment for most patients. Vitamin D derivatives (VDDs) - active metabolites 1α,25-dihydroxyvitamin D (1,25D2) and 1α,25-dihydroxyvitamin D (1,25D3) and their analogs - are differentiation-inducing agents which have potential for the therapy of AML. However, calcemic toxicity of VDDs limits their clinical use at doses effective against cancer cells in vivo. Here, we demonstrate that in AML cell cultures, moderate pro-differentiation effects of low concentrations of VDDs can be synergistically enhanced by structurally distinct compounds known to activate the transcription factor Nuclear Factor (Erythroid-derived 2)-Like 2 (NFE2L2 or Nrf2). Particularly, dimethyl fumarate (DMF), which is clinically approved for the treatment of multiple sclerosis and psoriasis, strongly cooperated with 1,25D3, PRI-5100 (19-nor-1,25D2; paricalcitol) and PRI-5202 (a double-point modified 19-nor analog of 1,25D2). The pro-differentiation synergy between VDDs (1,25D3 or PRI-5202) and Nrf2 activators (DMF, tert-butylhydroquinone or carnosic acid) was associated with a cooperative upregulation of the protein levels of the vitamin D receptor (VDR) and Nrf2 as well as increased mRNA expression of their respective target genes. These data support the notion that VDDs and Nrf2 activators synergize in inducing myeloid cell differentiation through the cooperative activation of the VDR and Nrf2/antioxidant response element signaling pathways. We have previously reported that PRI-5202 is more potent by approximately two orders of magnitude than 1,25D3 as a differentiation inducer in AML cell lines. In this study, we found that PRI-5202 was also at least 5-fold less calcemic in healthy mice compared to both its direct precursor PRI-1907 and 1,25D3. In addition, PRI-5202 was remarkably more resistant against degradation by the human 25-hydroxyvitamin D-24-hydroxylase than both 1,25D2 and 1,25D3. Importantly, using a xenograft mouse model we demonstrated that co-administration of PRI-5202 and DMF resulted in a marked cooperative inhibition of human AML tumor growth without inducing treatment toxicity. Collectively, our findings provide a rationale for clinical testing of low-toxic VDD/DMF combinations as a novel approach for differentiation therapy of AML.
MiR-145-modulated SOX9-mediated hypospadias through acting on mitogen-activated protein kinase signaling pathway
Shang Y, Kang Y, Sun J, Wei P, Yang J and Zhang H
This study primarily explored how miR-145, mitogen-activated protein kinase (MAPK) signaling and a downstream transcription factor (i.e., SOX9) mediated development of hypospadias. The hypospadias tissues and preputial tissues were isolated from pediatric inpatients postoperatively. Simultaneously, the rat models of hypospadias were established, and spermatogonial stem cells were separated. The expressions of proteins that symbolized cell apoptosis and oxidative stress were quantified via western blot analysis. Furthermore, the apoptosis, proliferation, and viability of cells were evaluated by means of flow cytometry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays. The results of microarray indicated miR-145 as a differentially expressed biomarker between hypospadias tissues and normal tissues (p < 0.05). Moreover, rat models of hypospadias were observed with markedly lower vitamins A and E levels, reduced expressions of proteins relevant to oxidative stress (i.e., Nrf2, HO-1, Gpx, and SOD-1), as well as enhanced Bax and cleaved caspase-3 expressions ( p < 0.05). Furthermore, SOX9 was found to be targeted by miR-145, and it was also modified by phosphorylated extracellular-regulated kinase (p-ERK), a portion of MAPK signaling ( p < 0.05). The p-ERK was significantly regulated after altering the expression of miR-145 ( p < 0.05). Moreover, activation of p-ERK and transfection of pcDNA-SOX9 could cause higher expression of apoptins and larger apoptotic proportion of cells ( p < 0.05), yet transfection of miR-145 mimic led to improved cell apoptosis and depressed cell viability ( p < 0.05). In conclusion, SOX9, which was regulated by both miR-145 and miR-145/MAPK signaling, could be involved in the pathogenesis of hypospadias.
Black Sesame Seeds Ethanol Extract Ameliorates Hepatic Lipid Accumulation, Oxidative Stress, and Insulin Resistance in Fructose-Induced Nonalcoholic Fatty Liver Disease
Yang Y, Wang J, Zhang Y, Li J and Sun W
The aim of the present study was to investigate the effect of black sesame seeds ethanol extract (BSSEE) against nonalcoholic fatty liver disease (NAFLD) in fructose-fed mice. Mice were fed a standard diet without or with 30% fructose in drinking water for 8 consecutive weeks, while mice in three BSSEE tested groups received different doses of BSSEE (0.5, 1, and 2 mL/kg) once a day from the fifth week to the eighth week. Administration of BSSEE dose-dependently exerted antiobesity and protective effect against metabolism disorder in fructose-fed mice. Histological examinations indicated that administration of BSSEE obviously reduced hepatic lipid accumulation. Insulin tolerance test (ITT) and glucose tolerance test (GTT) along with decreases of serum insulin and glucose levels by BSSEE treatment suggested the improvement of body insulin resistance, and administration of 1 and 2 mL/kg BSSEE mitigated liver insulin resistance as the evidence of downregulated expression of phospho-JNK1/2/3, phospho-NF-κB p65, phospho-IRS1, and phospho-IKK alpha/beta, up-regulated XBP1 expression, and reductions of TNF-α and IL-6 levels. In addition, BSSEE treatment ameliorated hepatic oxidative stress through increasing GSH, vitamin C, and Nrf2 levels, decreasing MDA and NO levels, and enhancing SOD, CAT, and GSH-Px activities. These results demonstrated that BSSEE showed protective effects against NAFLD-related metabolic diseases in fructose-fed mice. Therefore, BSSEE may be a potent dietary supplement to ameliorate the diseases.
Nociceptive behavior induced by chemotherapeutic paclitaxel and beneficial role of antioxidative pathways
Miao H, Xu J, Xu D, Ma X, Zhao X and Liu L
Paclitaxel is used for the treatment of several types of cancers. However, one of the significant limiting complications of paclitaxel is painful peripheral neuropathy during its therapy. In this study we examined the engagement of antioxidative signal pathway of the dorsal root ganglion (DRG) in mechanical and thermal hypersensitivity evoked by paclitaxel. Behavioral test was performed to determine mechanical and thermal sensitivity in rats. Western Blot analysis and ELISA were used to examine expression of Nrf2-antioxidant response element (ARE) and superoxide dismutases (SOD); and the levels of products of oxidative stress in the DRG. Our results show that paclitaxel increased mechanical and thermal sensitivity as compared with vehicle control animals. Paclitaxel also impaired Nrf2-ARE and SOD in the DRG and amplified products of oxidative stress, namely 8-isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine. Systemic administration of SOD mimetic using tempol, antioxidant vitamin C or blocking oxidative pathway using NADPH oxidase inhibitor (GKT137831) attenuated mechanical and thermal hypersensitivity induced by paclitaxel. This inhibitory effect was accompanied with decreases of proinflammatory cytokines (PICs) such as IL-1beta, IL-6 and TNF-alpha in the DRG. In conclusion, the data revealed impairment of Nrf2-ARE and heightened oxidative and PIC signals in the DRG of paclitaxel rats, leading to neuropathic pain. Balancing of reactive oxygen species by supplying antioxidants and/or inhibiting NADPH oxidase appears significant to yield beneficial effects in neuropathic pain conditions after chemotherapeutic paclitaxel.
Anti-inflammatory Activity of Tocotrienols in Age-related Pathologies: A SASPected Involvement of Cellular Senescence
Malavolta M, Pierpaoli E, Giacconi R, Basso A, Cardelli M, Piacenza F and Provinciali M
Tocotrienols (T3) have been shown to represent a very important part of the vitamin E family since they have opened new opportunities to prevent or treat a multitude of age-related chronic diseases. The beneficial effects of T3 include the amelioration of lipid profile, the promotion of Nrf2 mediated cytoprotective activity and the suppression of inflammation. All these effects may be the consequence of the ability of T3 to target multiple pathways. We here propose that these effects may be the result of a single target of T3, namely senescent cells. Indeed, T3 may act by a direct suppression of the senescence-associated secretory phenotype (SASP) produced by senescent cells, mediated by inhibition of NF-kB and mTOR, or may potentially remove the origin of the SASP trough senolysis (selective death of senescent cells). Further studies addressed to investigate the impact of T3 on cellular senescence "in vitro" as well as in experimental models of age-related diseases "in vivo" are clearly encouraged.

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