Augusta University Discovers How Nrf2 Activator Preserves Sight in Retinal Degeneration Model

Augusta University Discovers How Nrf2 Activator Preserves Sight in Retinal Degeneration Model

AUGUSTA, Ga. (Dec. 6, 2017) – In an exciting breakthrough scientists have discovered that a common pain medication often prescribed for chronic pain  can help preserve vision in a model of severe, blinding retinal degeneration.

The vision preservation could activate one of the most powerful antioxidants in the human body known as Nrf2. This targets receptors to protect neurodegenerative diseases.

The drug is known as pentazocine, and is a receptor of sigma 1, a powerful natural antioxidant and Nrf2 activator.

“We are very, very pleased that we can now explore the mechanisms,”, mentioned Dr. Sylvia Smith, chair of the Department of Cellular Biology and Anatomy at the Medical College of Georgia at Augusta University and co-director of the James and Jean Culver Vision Discovery Institute at AU.

A new $1.14 million grant from the National Eye Institute is enabling research to explore the nrf2 protecting ability against sight-degrading conditions like retinitis pigmentosa, macular degeneration and glaucoma.

The protective power of activated Nrf2 through the Sigma 1 receptor (a well-established non-opioid pain receptor) is  an essential means to a healthy retina. Without the sigma 1 receptor, the Müller cells that support our photoreceptor cells are overpowered by oxidative stress (cellular damage) impacting oxygen supply and light to enable healthy vision.

The studies showing Pentazocine activating the sigma 1 receptor have been reported in the 2016  Journal Proceedings of the National Academy of Sciences.

 

How does it work?

The proteins Nrf2 and Keap1 and cul3, congregate quietly in the cell cytoplasm. Excess production of antioxidants by Nrf2 activation moves to the cell proteasome to be eliminated.

But if needed such as in a case of increased oxidative stressas manifest in conditions like retinitis pigmentosa and aging – Nrf2 and Keap1 response activates hundreds of natural antioxidants and cell protection genes.

“It can launch an almost amazing response to stress,” says Smith. “I think it’s arguably the most important antioxidant in cells.”

Dr. Bobby Thomas, neuroscientist in the MCG Department of Pharmacology and Toxicology, is a coinvestigator with Smith on these studies and also exploring the pathway in Parkinson’s disease.

Dr. Smith explains, “Millions of super metabolically active photoreceptor cells in the retina – some 125 million rods and 6 million cones – use a lot of oxygen constantly converting light into images. In the case of retinitis pigmentosa, it’s actually a genetic mutation that kills off the rods but their death creates so much oxidative stress that the cones also are lost in a “bystander” effect.

It’s the cones pentazocine appears to protect, which should enable individuals to maintain functional vision. Interestingly and inexplicably, the high oxidative stress increases the binding of pentazocine to the sigma 1 receptor.”

The studies are being done in mouse cone cells from the retina and the supportive Müller cells. Other collaborators include Dr. Graydon B. Gonsalvez, cell biologist in the MCG Department of Cellular Biology and Anatomy, and Dr. Alan Saul, neuroscientist and electrophysiologist in the MCG Department of Ophthalmology.

For further information contact http://www.augusta.edu/mcg/

1,2

1. Tang C, Li K, Yu Q, Jiang Q, Yao J, Cao C. Activation of Nrf2 by Ginsenoside Rh3 protects retinal pigment epithelium cells and retinal ganglion cells from UV. Free Radic Biol Med. February 2018. [PubMed]
2. Deliyanti D, Alrashdi S, Tan S, et al. Nrf2 Activation Is a Potential Therapeutic Approach to Attenuate Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 2018;59(2):815-825. [PubMed]

JOIN OUR COMMUNITY.

JOIN OUR COMMUNITY

Reach Us

Our mission is to provide an impartial review of the emerging research regarding Nrf2 activation.

We welcome the involvement of those who have published peer review studies in this field. 

Should you wish to contact us, please leave a message using the adjacent form. 

 

    Researching Nrf2? Leave us a message to collaborate

    New Protandim Study – International Formula Impact on Oxidative Stress

    New Protandim Study – International Formula Impact on Oxidative Stress

    LifeVantage Corporation announced a study on Protandim which was presented at the 2014 Experimental Biology Conference held April 26-30, 2014  in San Diego, California.

    Experimental Biology is an annual meeting attended by more than 14,000 scientists. The theme for 2014 was “Transforming the Future through Science.” The  Colorado State University study entitled Oxidative Stress is Decreased with Short-Term Protandim Use. The placebo-controlled double-blind study supplemented overweight/obese adults with ages from 45-69 for 30-days with LifeVantage’s Protandim international formula currently sold in Japan. The results indicated a significant reduction in markers of oxidative stress in subjects receiving this Protandim formulation.

    Dr. Shawn Talbott, LifeVantage Chief Science Officer of LifeVantage commented, “We are pleased to see clinical studies involving our unique products. This research will be added to our large and growing portfolio of scientific studies and builds on the growing collection of evidence supporting Nrf2 activation and oxidative stress reduction associated with Protandim. In addition, this study demonstrates that both of our formulations of Protandim are potent oxidative stress reducers. This allows us to offer people a powerful Nrf2 activator and oxidative stress reduction product in most jurisdictions.”

    Abstracts of the conference can be found at the Journal of the Federation of American Societies for Experimental Biology.Edit Post

    Rebecca Scalzo, Janelle Davis, Joseph Beals, Laurie Biela, Gregory Giordano, Hunter Paris Benjamin Miller, Karyn Hamilton, and Christopher Bell, (2014) Oxidative stress is decreased with short-term Protandim use when piperine is substituted for ashwagandha (LB399) FASEB J April 28:LB399.

    Other Protandim studies can be viewed at Protandim Pubmed Studies

    JOIN OUR COMMUNITY.

    JOIN OUR COMMUNITY

    Reach Us

    Our mission is to provide an impartial review of the emerging research regarding Nrf2 activation.

    We welcome the involvement of those who have published peer review studies in this field. 

    Should you wish to contact us, please leave a message using the adjacent form. 

     

      Researching Nrf2? Leave us a message to collaborate

      Reversal of persistent fibrosis in aging by targeting nox4-Nrf2 redox imbalance – Sciencemag.org

      Reversal of persistent fibrosis in aging by targeting nox4-Nrf2 redox imbalance – Sciencemag.org

      Emphysema and honeycomb fibrosis

      Emphysema and honeycomb fibrosis (Photo credit: Pulmonary Pathology)

      A brand new article in Sciencemag.org presents a study demonstrating how pathological fibrosis increases with age, but how NRF2 activation in mice was able to reverse the damage and repair lung capacity and fibrosis (scar tissue) resolution.

      This is a promising study because the current treatments of pathological  and cystic fibrosis are costly and very time consuming. Persistent fibrosis in lungs of aged mice was caused by the loss of cellular redox balance. The mice in the study with low NRF2 expression had a higher incidence of progressive lung disease. Tissues from human lung samples demonstrated this same Nox4-Nrf2 imbalance.

      The abstract concludes with the following promising statement. “The studies suggest that restoration of Nox4-Nrf2 redox balance in myofibroblasts may be a therapeutic strategy in age-associated fibrotic disorders, potentially able to resolve persistent fibrosis or even reverse its progression.”

       

      Further research on the topic of Nrf2 and Fibrosis:

       

      Nrf2 in alcoholic liver disease
      Sun J, Fu J, Li L, Chen C, Wang H, Hou Y, Xu Y and Pi J
      Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality of liver disorders and a major health issue globally. ALD refers to a spectrum of liver pathologies ranging from steatosis, steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Various mechanisms, including oxidative stress, protein and DNA modification, inflammation and impaired lipid metabolism, have been implicated in the pathogenesis of ALD. Further, reactive oxygen species (ROS) in particular, have been identified as a key component in the initiation and progression of ALD. Nuclear factor erythroid 2 like 2 (Nrf2) is a master regulator of the intracellular adaptive antioxidant response to oxidative stress, and aids in the detoxification of a variety of toxicants. Given its cytoprotective role, Nrf2 has been extensively studied as a therapeutic target for ALD. Paradoxically, however, emerging evidence have revealed that Nrf2 may be implicated in the progression of ALD. In this review, we summarize the role of Nrf2 in the development of ALD and discuss the underlying mechanisms. Clearly, more comprehensive studies with proper animal and cell models and in human are needed to verify the potential therapeutic role of Nrf2 in ALD.
      Protective effect of the ethanol extract from Ligusticum chuanxiong rhizome against streptozotocin-induced diabetic nephropathy in mice
      Yang WJ, Li YR, Gao H, Wu XY, Wang XL, Wang XN, Xiang L, Ren DM, Lou HX and Shen T
      Rhizome of Ligusticum chuanxiong Hort. (Abbreviated as LC) is a frequently prescribed component in plenty of traditional Chinese medicine (TCM) formulas which are used to treat diabetic nephropathy (DN). The aims of the present study are to investigate the protective effect of the ethanol extract of LC rhizome (EEL) against DN in vivo, evaluate its potential mechanism, and find the evidence supporting its enthopharmacological use as an anti-DN agent.
      Ramalin, an antioxidant compound derived from Antarctic lichen, prevents progression of liver fibrosis induced by dimethylnitrosamine (DNM) in rats
      Kim MK, Kim MA, Yim JH, Lee DH, Cho SK and Yang SG
      Hepatic fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM), primarily collagen, within the liver. Because reactive oxygen species (ROS) has been implicated in its pathogenesis, the use of antioxidants as a potential treatment has been broadly explored. Here, we investigated the hepatoprotective properties of ramalin (RM), a compound extracted from the Antarctic lichen Ramalina terebrata, against hepatic fibrosis in vitro and in vivo. RM suppressed hepatic stellate cell (HSC) activation in vitro without any significant signs of adverse effects on the cells tested, and the accumulation of ECM was dramatically reduced in the liver tissue. Oral administration of RM in rats noticeably improved the gross appearance of the liver with increased body and liver weight relative to the DMN injected rats, and all of the serum biochemical markers returned to the normal range. RM treatment have ameliorated hepatic fibrosis in rats induced by DMN by repressing α-smooth muscle actin (α-SMA) and upregulating heme oxygenase-1 (HO-1). In addition, RM significantly reduced collagen accumulation, and levels of malondialdehyde (MDA) and hydroxyproline (HP) in the liver tissue of DMN injected rats. The efficacy exerted by RM was through erythroid 2-related factor 2 (Nrf2) mediated antioxidant response proteins such as HO-1 and NAD(P)H quinone dehydrogenase 1 (NQO-1). Our results show the beneficial effect of RM against the progression of hepatic fibrosis.
      Protective effect of isochlorogenic acid B on liver fibrosis in non-alcoholic steatohepatitis of mice
      Liu X, Huang K, Niu Z, Mei D and Zhang B
      Liver fibrosis is a common symptom of non-alcoholic steatohepatitis (NASH) and a worldwide clinical issue. The miR-122/HIF-1α signalling pathway is believed to play an important role in the genesis of progressive fibrosis. Isochlorogenic acid B (ICAB), naturally isolated from Laggera alata, is verified to have antioxidative and hepatoprotective properties. The aim of this study was to investigate the effect of ICAB on liver fibrosis in NASH and its potential protective mechanisms. NASH was induced in a mouse model with a methionine- and choline-deficient (MCD) diet for 4 weeks, and ICAB was orally administered every day at three doses (5, 10 and 20 mg/kg). Pathological results indicated that ICAB significantly improved the pathological lesions of liver fibrosis. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic hydroxyproline (Hyp), cholesterol (CHO), triglyceride (TG) were also significantly decreased by ICAB. In addition, ICAB inhibited hepatic stellate cells (HSCs) activation and the expressions of hepatic genes involved in liver fibrosis including LOX, TGF-β1, MCP-1, COL1α1 and TIMP-1. ICAB also attenuated liver oxidative stress through Nrf2 signalling pathway. What's more, the decreased levels of miR-122 and over-expression of hepatic HIF-1α could be reversed by ICAB treatment. These results simultaneously confirmed that ICAB had a significant protective effect on fibrosis in NASH by inhibiting oxidative stress via Nrf2 and suppressing multiple profibrogenic factors through miR-122/HIF-1α signalling pathway. This article is protected by copyright. All rights reserved.
      Raf kinase inhibitor protein mediates myocardial fibrosis under conditions of enhanced myocardial oxidative stress
      Kazakov A, Hall RA, Werner C, Meier T, Trouvain A, Rodionycheva S, Nickel A, Lammert F, Maack C, Böhm M and Laufs U
      Fibrosis is a hallmark of maladaptive cardiac remodelling. Here we report that genome-wide quantitative trait locus (QTL) analyses in recombinant inbred mouse lines of C57BL/6 J and DBA2/J strains identified Raf Kinase Inhibitor Protein (RKIP) as genetic marker of fibrosis progression. C57BL/6 N-RKIP mice demonstrated diminished fibrosis induced by transverse aortic constriction (TAC) or CCl (carbon tetrachloride) treatment compared with wild-type controls. TAC-induced expression of collagen Iα2 mRNA, Ki67 fibroblasts and marker of oxidative stress 8-hydroxyguanosine (8-dOHG) fibroblasts as well as the number of fibrocytes in the peripheral blood and bone marrow were markedly reduced in C57BL/6 N-RKIP mice. RKIP-deficient cardiac fibroblasts demonstrated decreased migration and fibronectin production. This was accompanied by a two-fold increase of the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), the main transcriptional activator of antioxidative proteins, and reduced expression of its inactivators. To test the importance of oxidative stress for this signaling, C57BL/6 J mice were studied. C57BL/6 J, but not the C57BL/6 N-strain, is protected from TAC-induced oxidative stress due to mutation of the nicotinamide nucleotide transhydrogenase gene (Nnt). After TAC surgery, the hearts of Nnt-deficient C57BL/6 J-RKIP mice revealed diminished oxidative stress, increased left ventricular (LV) fibrosis and collagen Iα2 as well as enhanced basal nuclear expression of Nrf2. In human LV myocardium from both non-failing and failing hearts, RKIP-protein correlated negatively with the nuclear accumulation of Nrf2. In summary, under conditions of Nnt-dependent enhanced myocardial oxidative stress induced by TAC, RKIP plays a maladaptive role for fibrotic myocardial remodeling by suppressing the Nrf2-related beneficial effects.
      Silybin Alleviates Hepatic Steatosis and Fibrosis in NASH Mice by Inhibiting Oxidative Stress and Involvement with the Nf-κB Pathway
      Ou Q, Weng Y, Wang S, Zhao Y, Zhang F, Zhou J and Wu X
      Silybin is the major biologically active compound of silymarin, the standardized extract of the milk thistle (Silybum marianum). Increasing numbers of studies have shown that silybin can improve nonalcoholic steatohepatitis (NASH) in animal models and patients; however, the mechanisms underlying silybin's actions remain unclear.
      A novel Gallic acid derivative attenuates BLM-induced pulmonary fibrosis in mice
      Rong Y, Cao B, Liu B, Li W, Chen Y, Chen H, Liu Y and Liu T
      Idiopathic Pulmonary fibrosis is a disease with high morbidity and mortality. Therefore, the development of new drugs is imperative. Gallic acid derivative is a derivative of Gallic acid that can be extracted from Chinese herbal medicine. In previous experiments, we found that Gallic acid derivative played dual roles in inflammatory and antioxidant activities. Meanwhile, Gallic acid derivative could inhibit the proliferation of lung fibroblast. In the present study, we investigated the function of Gallic acid derivative in inhibiting lung fibrosis. 5 mg/kg of bleomycin was administered to mice by a single intratracheal instillation. Three dosages of Gallic acid derivative (75 mg/kg, 150 mg/kg, 300 mg/kg) and Pirfenidone (80 mg/kg) were given to mice for 21 day. Gallic acid derivative treatment significantly reduced lung histological changes and decreased inflammatory cell infiltration. The content of collagen decreased with the decrease of hydroxyproline level. Analogously, the expression of alpha smooth muscle actin was reduced. Gallic acid derivative enhanced the antioxidant status, but reduced the expression of interleukin 6, NADPH oxidase-4. Our study proved that Gallic acid derivative reduced inflammation activation to some extent and could exert its effects through transforming growth factor β1/Smad2 signaling pathway and balancing NOX4/Nrf2.
      Lipoic Acid Prevents High-Fat Diet-Induced Hepatic Steatosis in Goto Kakizaki Rats by Reducing Oxidative Stress Through Nrf2 Activation
      Sena CM, Cipriano MA, Botelho MF and Seiça RM
      Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, and oxidative stress in a model of type 2 diabetes fed with a high fat diet (HFD). Goto-Kakizaki rats were randomly divided into four groups. The first group received only a standard rat diet (control GK) including groups 2 (HFD), 3 (vehicle group), and 4 (α-LA group), which were given HFD, ad libitum during three months. Wistar rats are the non-diabetic control group. Carbohydrate and lipid metabolism, liver function, plasma and liver tissue malondialdehyde (MDA), liver GSH, tumor necrosis factor-α (TNF-α) and nuclear factor E2 (erythroid-derived 2)-related factor-2 (Nrf2) levels were assessed in the different groups. Liver function was assessed using quantitative hepatobiliary scintigraphy, serum aspartate, and alanine aminotransferases (AST, ALT), alkaline phosphatase, gamma-glutamyltranspeptidase, and bilirubin levels. Histopathologically steatosis and fibrosis were evaluated. Type 2 diabetic animals fed with HFD showed a marked hepatic steatosis and a diminished hepatic extraction fraction and both were fully prevented with α-LA. Plasma and liver tissue MDA and hepatic TNF-α levels were significantly higher in the HFD group when compared with the control group and significantly lower in the α-LA group. Systemic and hepatic cholesterol, triglycerides, and serum uric acid levels were higher in hyperlipidemic GK rats and fully prevented with α-LA. In addition, nuclear Nrf2 activity was significantly diminished in GK rats and significantly augmented after α-LA treatment. In conclusion, α-LA strikingly ameliorates steatosis in this animal model of diabetes fed with HFD by decrementing the inflammatory marker TNF-α and reducing oxidative stress. α-LA might be considered a useful therapeutic tool to prevent hepatic steatosis by incrementing antioxidant defense systems through Nrf2 and consequently decreasing oxidative stress and inflammation in type 2 diabetes.
      Sinapic acid ameliorates bleomycin-induced lung fibrosis in rats
      Raish M, Ahmad A, Ahmad Ansari M, Ahad A, Al-Jenoobi FI, Al-Mohizea AM, Khan A and Ali N
      Pulmonary fibrosis is a multifaceted disease with high mortality and morbidity, and it is commonly nonresponsive to conventional therapy.
      Tanshinone IIA activates nuclear factor-erythroid 2-related factor 2 to restrain pulmonary fibrosis via regulation of redox homeostasis and glutaminolysis
      An L, Peng LY, Sun NY, Yang YL, Zhang XW, Li B, Liu BL, Li P and Chen J
      Pulmonary fibrosis (PF) is characterized by myofibroblast activation through oxidative stress. However, the precise regulation of myofibroblast transdifferentiation remain largely uncharacterized.
      Beneficial effects of oltipraz, nuclear factor - erythroid - 2 - related factor 2 (Nrf2), on renal damage in unilateral ureteral obstruction rat model
      Polat EC, Besiroglu H, Ozcan L, Otunctemur A, Eruyar AT, Somay A, Ozbay N, Cekmen M, Eraldemir C and Ozbek E
      We investigated whether Oltipraz (OPZ) attenuated renal fibrosis in a unilateral ureteral obstruction (UUO) rat model.
      Polysaccharide FMP-1 from Morchella esculenta attenuates cellular oxidative damage in human alveolar epithelial A549 cells through PI3K/AKT/Nrf2/HO-1 pathway
      Li W, Cai ZN, Mehmood S, Wang Y, Pan WJ, Zhang WN, Lu YM and Chen Y
      Oxidative stress is considered to involve cell death in severe pulmonary diseases like idiopathic pulmonary fibrosis (IPF). Polysaccharide FMP-1 from Morchella esculenta can exert significant antioxidant activity. However, its effects on alveolar epithelial cells remain unperceived. Herein, the effects of FMP-1 against HO-induced oxidative damage in human alveolar epithelial A549 cells were investigated. FMP-1 could inhibit HO-induced cytochrome C and Caspase-3 release to prevent cell apoptosis via attenuation of MDA and ROS levels, and enhancement the enzymatic activities of SOD and T-AOC. Furthermore, the underlying molecular mechanisms were clarified. The phosphorylation of AKT and the nuclear translocation of Nrf2 were observed to be promoted by FMP-1 as well as the level of HO-1. These findings suggested that FMP-1 attenuate cellular oxidative stress through PI3K/AKT pathway, and FMP-1 could be explored as natural potential antioxidants to lower oxidative stress relevant to the progression of IPF.
      Uremia induces upregulation of cerebral tissue oxidative/inflammatory cascade, down-regulation of Nrf2 pathway and disruption of blood brain barrier
      Jing W, Jabbari B and Vaziri ND
      Chronic kidney disease (CKD) results in various central nervous systems (CNS) disorders including cognitive dysfunction, depression, anxiety, movement disorders, seizures and encephalopathy. Uremic retention products, oxidative stress, inflammation and impaired blood-brain barrier have been implicated as the major mediators of CKD-induced CNS disorders. However, mechanisms of CKD-induced cerebral tissue oxidative stress, inflammation and impaired blood brain barrier have not been fully elucidated and were explored. Male Sprague Dawley rats underwent sham operation or 5/6 nephrectomy and were observed for 10 weeks. Arterial pressure, body weight, and renal function were monitored. Under general anesthesia the animals' cerebral cortex was harvested. Nuclear translocations of NF-κB and Nrf2 and their key target gene products, neuronal, endothelial and inducible NO synthase (NOS) isoforms, markers of oxidative, nitrosative and myeloperoxidase reactions, fibrosis mediators and key protein constituents of capillary endothelial junctional complex were determined by Western blot analysis. The CKD rats exhibited reduced body weight, hypertension, elevated serum urea and creatinine concentrations. Compared to control group cerebral cortex of the CKD group showed activation (increased nuclear translocation) of NF-κB, elevation of pro-oxidant and pro-inflammatory molecules, diminished nuclear translocation of Nrf2 and expression of cytoprotective antioxidant molecules and depletion of the key protein constituents of endothelial junctional complex. In conclusion CKD results in the cerebral tissue activation of inflammatory and oxidative pathways, inhibition of antioxidant and cytoprotective system and erosion of cerebral capillary junctional complex, events that contribute to CNS dysfunction and impaired blood brain barrier.
      Exogenous Pancreatic Kallikrein Improves Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetes
      Wu M, Yang Y, Wang M, Zeng F, Li Q, Liu W, Guo S, He M, Wang Y, Huang J, Zhou L, Li Y, Hu J, Gong W and Zhang Z
      To evaluate the protective effects of exogenous pancreatic kallikrein (PKK) treatment on diabetic cardiomyopathy (DCM) and explore the underlying mechanisms. Streptozotocin (STZ)-induced diabetic rats, a type 1 diabetic model, were treated with either PKK or saline for 12 weeks. Non-diabetic rats were used as controls. PKK administration attenuated the mitochondria swelling, Z line misalignments, myofibrosis and interstitial collagen accumulation in diabetic myocardial tissue. The oxidative stress imbalance including increased nitrotyrosine, decreased anti-oxidative components such as nuclear receptor nuclear factor like 2 (Nrf2), glutathione peroxidase 1(GPx-1), catalase (CAT) and superoxide dismutase (SOD), were recovered in the heart of PKK-treated diabetic rats. In diabetic rats, protein expression of TGF-β1 and accumulation of collagen I in the heart tissues was decreased after PKK administration. Markers for inflammation were decreased in diabetic rats by PKK treatment. Compared to diabetic rats, PKK reversed the degradation of IκB-α, an inhibitive element of heterotrimer nuclear factor kappa B (NF-κB). The endothelial nitric oxide synthase (eNOS) protein and myocardial nitrate/nitrite were impaired in the heart of diabetic rats, which, however, were restored after PKK treatment. The sarcoplasmic reticulum Ca-ATPase 2 (SERCA2) and phospholamban (PLN) were mishandled in diabetic rats, while were rectified in PKK-treated diabetic rats. The plasma NT-proBNP level was increased in diabetic rats while was reduced with PKK treatment. PKK protects against DCM via reducing fibrosis, inflammation, and oxidative stress, promoting nitric oxide production, as well as restoring the function of the calcium channel.
      The -Antioxidant Response Element Signaling Pathway Controls Fibrosis and Autoimmunity in Scleroderma
      Kavian N, Mehlal S, Jeljeli M, Saidu NEB, Nicco C, Cerles O, Chouzenoux S, Cauvet A, Camus C, Ait-Djoudi M, Chéreau C, Kerdine-Römer S, Allanore Y and Batteux F
      Systemic sclerosis (SSc) is an autoimmune disease with fibrosis of the skin and internal organs and vascular alterations. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of the disease. Indeed, reactive oxygen species (ROS) trigger neoepitopes leading to a breach of immune tolerance and autoimmune responses, activate fibroblasts to proliferate and to produce excess of type I collagen. ROS also alter endothelial cells leading to vascular dysfunction. Glutathione (GSH) is the most potent antioxidant system in eukaryotic cells. Numerous studies have reported a defect in GSH in SSc animal models and humans, but the origin of this defect remains unknown. The transcription factor NRF2 is a key player in the antioxidant defense, as it can induce the transcription of antioxidant and cytoprotective genes, including GSH, through its interaction with the antioxidant response elements. In this work, we investigated whether NRF2 could be implicated in the pathogenesis of SSc, and if this pathway could represent a new therapeutic target in this orphan disease with no curative medicine. Skin biopsies from 11 patients and 10 controls were harvested, and skin fibroblasts were extracted. Experimental SSc was induced both in BALB/c and in mice by daily intradermal injections of hypochloric acid. In addition, diseased BALB/c mice were treated with an agonist, dimethyl fumarate, or placebo. A drop in and target genes mRNA levels was observed in skin fibroblasts of SSc patients compared to controls. Moreover, the pathway is also downregulated in skins and lungs of SSc mice. In addition, we observed that mice have a more severe form of SSc with increased fibrosis and inflammation compared to wild-type SSc mice. Diseased mice treated with the agonist dimethyl fumarate (DMF) exhibited reduced fibrosis and immune activation compared to untreated mice. The treatment of skin fibroblasts from SSc mice with DMF restores GSH intracellular content, decreases ROS production and cell proliferation. These results suggest that the pathway is highly dysregulated in human and SSc mice with deleterious consequences on fibrosis and inflammation and that Nrf2 modulation represents a therapeutic target in SSc.

      JOIN OUR COMMUNITY.

      Reach Us

      Our mission is to provide an impartial review of the emerging research regarding Nrf2 activation.

      We welcome the involvement of those who have published peer review studies in this field. 

      Should you wish to contact us, please leave a message using the adjacent form. 

       

        Researching Nrf2? Leave us a message to collaborate

        Inflammation: A Major Contributor to Disease and Aging. Can Nrf2 Help Reduce It?

        Inflammation: A Major Contributor to Disease and Aging. Can Nrf2 Help Reduce It?

        English: PET scan of a human brain with Alzhei...

        As the boomer generation ages, it is probable that there will be more posts such as the one I saw this week from a friend on Facebook. Their plea was for suggestions and recommendations for a good solution to help alleviate the pain they were experiencing from inflammation.

        Externally, inflammation can be recognized by redness, swelling and pain. Internally, it is a lot more difficult to recognize and may well go undetected for long periods of time.  The effects of inflammation can also range from minor to chronic. An example of a minor case of inflammation may include bacteria causing an infection such as from a splinter piercing the skin. The more serious chronic inflammation may be a common factor in many age-related diseases such as Diabetes, arthritis, heart disease, cancer or Alzheimer’s.

        There are over 500 results on Pubmed.gov when searching for NRF2 and inflammation. A couple of examples of the positive role that NRF2 had on inflammation.

        The first study we will highlight is one called “Transcription Factor Nrf2 Regulates Inflammation” which was published in the Journal of Molecular and Cellular Biology. This inflammation. study dates back to 2003 in which two groups of mice with pleurisy were tested. The one group was treated with a Nrf2 activator, cyclooxygenase 2 inhibitor NS-398 the other group was not treated.  The conclusion of the study shows that the mice with elevated NRF2 had less inflammation than the mice that were not treated.

        “Administration of 15d-PGJ into the pleural space of NS-398-treated wild-type mice largely counteracted both the decrease in PrxI and persistence of neutrophil recruitment. In contrast, these changes did not occur in the Nrf2-deficient mice. These results demonstrate that Nrf2 regulates the inflammation process downstream of 15d-PGJ by orchestrating the recruitment of inflammatory cells and regulating the gene expression within those cells.”

        The following study “Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis.” Published in the
        European Journal of Immunology. shows the interaction between NRF2 and the inflammation-causing protein called inflammasome.

        Quoting from the study, “Here we have identified the oxidative stress-responsive transcription factor NF-E2-related 2 (Nrf2) as an essential positive regulator of inflammasome activation and IL-1-mediated vascular inflammation. We show that cholesterol crystals, which accumulate in atherosclerotic plaques, represent an endogenous danger signal that activates Nrf2 and the NLRP3 inflammasome.”

        So, in response to my friend looking for solutions to their inflammation concerns, we suggest researching further in Pubmed and other reputable journals as well as getting the advice of a healthcare professional.

        Here are the latest Nrf2 Studies regarding inflammation: 

         

        Resveratrol ameliorates sepsis-induced acute kidney injury in a pediatric rat model via Nrf2 signaling pathway
        Wang Y, Feng F, Liu M, Xue J and Huang H
        Acute kidney injury (AKI) is a hyper-inflammation-induced abrupt loss of kidney function and has become a major public health problem. The cecal ligation and puncture (CLP) model of peritonitis in rat pups mimics the development of sepsis-induced pediatric AKI is pre-renal without morphological changes of the kidneys and high lethality. Resveratrol, a natural polyphenolic compound with low toxicity, has obvious anti-oxidant and anti-inflammatory properties. The present study aimed to determine whether resveratrol alleviates pediatric AKI and investigated the potential mechanism. Thus, a CLP model of 17-18 day-old rat pups was used to mimic the development of sepsis-induced AKI in children. In the group treated with resveratrol, renal injury induced by CLP was alleviated with downregulation of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and kidney injury molecule (KIM)-1 expression. Nuclear factor-erythroid-2-related factor 2 (Nrf2) signaling is known to effectively inhibit inflammation, the present study found that resveratrol reduced the lipopolysaccharide-induced inflammatory response in kidney cells and induced the activation of Nrf2 signaling, including accumulation of nuclear Nrf2 and increase of the expression of Nrf2 target genes heme oxygenase (HO)-1 and NAD(P)H dehydrogenase (quinone) 1 (NQO1); this was confirmed by the induction of the expression of HO-1 and NQO1 by treatment of resveratrol and . Of note, knockdown of Nrf2 effectively abrogated the downregulation of TNF-α, IL-1β and KIM-1 expression induced by resveratrol . These results suggested that resveratrol ameliorates sepsis-induced acute kidney injury in a pediatric model of AKI via the Nrf2 signaling pathway.
        Synergism between luteolin and sulforaphane in anti-inflammation
        Rakariyatham K, Wu X, Tang Z, Han Y, Wang Q and Xiao H
        Luteolin and sulforaphane are well-known food bioactives with anti-inflammatory properties. Herein, we determined their combinational effects in inhibiting inflammation in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Both luteolin and sulforaphane showed dose-dependent inhibition on LPS-induced production of nitric oxide (NO) in the macrophages. The combined treatments led to a stronger inhibition on NO production compared to the singular treatments. Isobologram analysis confirmed that the combined treatments produced a synergy. Western blotting and ELISA showed that the combined treatment reduced the expression levels of pro-inflammatory proteins involving NF-κB pathway, and STAT3 activation, which regulated expression of other inflammatory proteins such as iNOS, COX-2, IL-6, and IL-1β. Moreover, the combination treatments reduced reactive oxygen species in cells and increased the expression of Nrf2 and HO-1, which are cellular antioxidant proteins. In conclusion, our findings support the notion that certain bioactive food components may act synergistically to produce enhanced health effects such as anti-inflammation.
        Lipoic Acid Prevents High-Fat Diet-Induced Hepatic Steatosis in Goto Kakizaki Rats by Reducing Oxidative Stress Through Nrf2 Activation
        Sena CM, Cipriano MA, Botelho MF and Seiça RM
        Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, and oxidative stress in a model of type 2 diabetes fed with a high fat diet (HFD). Goto-Kakizaki rats were randomly divided into four groups. The first group received only a standard rat diet (control GK) including groups 2 (HFD), 3 (vehicle group), and 4 (α-LA group), which were given HFD, ad libitum during three months. Wistar rats are the non-diabetic control group. Carbohydrate and lipid metabolism, liver function, plasma and liver tissue malondialdehyde (MDA), liver GSH, tumor necrosis factor-α (TNF-α) and nuclear factor E2 (erythroid-derived 2)-related factor-2 (Nrf2) levels were assessed in the different groups. Liver function was assessed using quantitative hepatobiliary scintigraphy, serum aspartate, and alanine aminotransferases (AST, ALT), alkaline phosphatase, gamma-glutamyltranspeptidase, and bilirubin levels. Histopathologically steatosis and fibrosis were evaluated. Type 2 diabetic animals fed with HFD showed a marked hepatic steatosis and a diminished hepatic extraction fraction and both were fully prevented with α-LA. Plasma and liver tissue MDA and hepatic TNF-α levels were significantly higher in the HFD group when compared with the control group and significantly lower in the α-LA group. Systemic and hepatic cholesterol, triglycerides, and serum uric acid levels were higher in hyperlipidemic GK rats and fully prevented with α-LA. In addition, nuclear Nrf2 activity was significantly diminished in GK rats and significantly augmented after α-LA treatment. In conclusion, α-LA strikingly ameliorates steatosis in this animal model of diabetes fed with HFD by decrementing the inflammatory marker TNF-α and reducing oxidative stress. α-LA might be considered a useful therapeutic tool to prevent hepatic steatosis by incrementing antioxidant defense systems through Nrf2 and consequently decreasing oxidative stress and inflammation in type 2 diabetes.
        Interleukin-17D and Nrf2 mediate initial innate immune cell recruitment and restrict MCMV infection
        Seelige R, Saddawi-Konefka R, Adams NM, Picarda G, Sun JC, Benedict CA and Bui JD
        Innate immune cells quickly infiltrate the site of pathogen entry and not only stave off infection but also initiate antigen presentation and promote adaptive immunity. The recruitment of innate leukocytes has been well studied in the context of extracellular bacterial and fungal infection but less during viral infections. We have recently shown that the understudied cytokine Interleukin (IL)-17D can mediate neutrophil, natural killer (NK) cell and monocyte infiltration in sterile inflammation and cancer. Herein, we show that early immune cell accumulation at the peritoneal site of infection by mouse cytomegalovirus (MCMV) is mediated by IL-17D. Mice deficient in IL-17D or the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an inducer of IL-17D, featured an early decreased number of innate immune cells at the point of viral entry and were more susceptible to MCMV infection. Interestingly, we were able to artificially induce innate leukocyte infiltration by applying the Nrf2 activator tert-butylhydroquinone (tBHQ), which rendered mice less susceptible to MCMV infection. Our results implicate the Nrf2/IL-17D axis as a sensor of viral infection and suggest therapeutic benefit in boosting this pathway to promote innate antiviral responses.
        Taurine: A Regulator of Cellular Redox-Homeostasis and Skeletal Muscle Function
        Seidel U, Huebbe P and Rimbach G
        Taurine is a non-proteinogenic ß-aminosulfonic acid. Important dietary sources of taurine are fish and seafood. Taurine interacts with ion channels, stabilizes membranes and regulates the cell volume. These actions confirm its high concentrations in excitable tissues like retina, neurons and muscles. Retinal degeneration, cardiomyopathy as well as skeletal muscle malfunction are evident in taurin e deficient phenotypes. There is evidence that taurine counteracts lipid peroxidation and increases cellular antioxidant defense in response to inflammation. In activated neutrophils taurine reacts with hypochloric acid to taurine chloramine (TauCl), which triggers the Kelch-like ECH-associated protein 1-nuclear factor E2-related factor 1 (Keap1-Nrf2) pathway. Consequently, Nrf2 target genes such as heme oxygenase-1 (HMOX1) and catalase (CAT) are induced. Furthermore taurine may prevent an overload of reactive oxygen species (ROS) directly by an inhibition of ROS generation within the respiratory chain. Taurine affects mitochondrial bioenergetics and taurine deficient mice exhibit an impaired exercise performance. Moreover, some studies demonstrate that taurine enhances the glycogen repletion in the post-exercise recovery phase. In the case of taurine deficiency, many studies observed a phenotype known in muscle senescence and skeletal muscle disorders. Overall, taurine plays an important role in cellular redox homeostasis and skeletal muscle function. This article is protected by copyright. All rights reserved.
        Paeonol attenuates ligation-induced periodontitis in rats by inhibiting osteoclastogenesis via regulating Nrf2/NF-κB/NFATc1 signaling pathway
        Li J, Li Y, Pan S, Zhang L, He L and Niu Y
        Paeonol is a natural phenolic compound in Moutan Cortex with multiple biological functions, such as anti-inflammatory and anti-oxidant activity. Recent evidence has proven that persistent inflammation, oxidative stress, along with nuclear factor E2-related factor 2 (Nrf2) signaling dysfunction in periodontium are the possible causes of alveolar bone resorption, and ultimately lead to periodontitis. The present study was designed to explore the protective effects of paeonol on ligation-induced periodontitis in rats, and investigate the possible mechanism. We found that treatment with paeonol (40, 80 mg/kg, intraperitoneal injection) for 7 days remarkably decreased the expression of receptor activator of nuclear factor kappa-B ligand increased the expression of osteoprotegrin and inhibited the formation of osteoclasts. This function of paeonol might be correlated with its ability to reduce inflammatory factors (IL-1β, IL-6 and TNF-α) and alleviate oxidative stress (SOD, MDA, GSH and ROS) in gingival tissues. Besides, paeonol increased Nrf2 activity. Silence of Nrf2 using specific siRNA diminished the inhibitory effect of paeonol on NF-κB p65 activation and aftedexpression, suggesting that Nrf2 was essential for protective effect of paeonol. These results showed that paeonol protected against periodontitis-aggravated osteoclastogenesis and alveolar bone lesion via regulating Nrf2/NF-κB/NFATc1 signaling pathway.
        Skullcapflavone II inhibits osteoclastogenesis by regulating reactive oxygen species and attenuates the survival and resorption function of osteoclasts by modulating integrin signaling
        Lee J, Son HS, Lee HI, Lee GR, Jo YJ, Hong SE, Kim N, Kwon M, Kim NY, Kim HJ, Lee YJ, Seo EK and Jeong W
        Many bone diseases, such as osteoporosis and rheumatoid arthritis, are attributed to an increase in osteoclast number or activity; therefore, control of osteoclasts has significant clinical implications. This study shows how skullcapflavone II (SFII), a flavonoid with anti-inflammatory activity, regulates osteoclast differentiation, survival, and function. SFII inhibited osteoclastogenesis with decreased activation of MAPKs, Src, and cAMP response element-binding protein (CREB), which have been known to be redox sensitive. SFII decreased reactive oxygen species by scavenging them or activating nuclear factor-erythroid 2-related factor 2 (Nrf2), and its effects were partially reversed by hydrogen peroxide cotreatment or Nrf2 deficiency. In addition, SFII attenuated survival, migration, and bone resorption, with a decrease in the expression of integrin β, Src, and p130 Crk-associated substrate, and the activation of RhoA and Rac1 in differentiated osteoclasts. Furthermore, SFII inhibited osteoclast formation and bone loss in an inflammation- or ovariectomy-induced osteolytic mouse model. These findings suggest that SFII inhibits osteoclastogenesis through redox regulation of MAPKs, Src, and CREB and attenuates the survival and resorption function by modulating the integrin pathway in osteoclasts. SFII has therapeutic potential in the treatment and prevention of bone diseases caused by excessive osteoclast activity.-Lee, J., Son, H. S., Lee, H. I., Lee, G.-R., Jo, Y.-J., Hong, S.-E., Kim, N., Kwon, M., Kim, N. Y., Kim, H. J., Lee, Y. J., Seo, E. K., Jeong, W. Skullcapflavone II inhibits osteoclastogenesis by regulating reactive oxygen species and attenuates the survival and resorption function of osteoclasts by modulating integrin signaling.
        The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages
        Mylka V, Deckers J, Ratman D, De Cauwer L, Thommis J, De Rycke R, Impens F, Libert C, Tavernier J, Vanden Berghe W, Gevaert K and De Bosscher K
        Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorticoids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) modulator, exhibits an inflammation-suppressive effect, largely in the absence of detrimental side effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone (DEX) and CpdA, we looked for proteins oppositely regulated in bone marrow-derived macrophages using an unbiased proteomics approach. We found that the autophagy receptor SQSTM1 but not NR3C1 mediates the anti-inflammatory action of CpdA. CpdA drives SQSTM1 upregulation by recruiting the NFE2L2 transcription factor to its promoter. In contrast, the classic NR3C1 ligand dexamethasone recruits NR3C1 to the Sqstm1 promoter and other NFE2L2-controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA induce autophagy, with marked different autophagy characteristics and morphology. Suppression of LPS-induced Il6 and Ccl2 genes by CpdA in macrophages is hampered upon Sqstm1 silencing, confirming that SQSTM1 is essential for the anti-inflammatory capacity of CpdA, at least in this cell type. Together, these results demonstrate how off-target mechanisms of selective NR3C1 ligands may contribute to a more efficient anti-inflammatory therapy.
        Sinapic acid ameliorates bleomycin-induced lung fibrosis in rats
        Raish M, Ahmad A, Ahmad Ansari M, Ahad A, Al-Jenoobi FI, Al-Mohizea AM, Khan A and Ali N
        Pulmonary fibrosis is a multifaceted disease with high mortality and morbidity, and it is commonly nonresponsive to conventional therapy.
        Icariin and icaritin recover UVB-induced photoaging by stimulating Nrf2/ARE and reducing AP-1 and NF-κB signaling pathways: a comparative study on UVB-irradiated human keratinocytes
        Hwang E, Lin P, Ngo HTT, Gao W, Wang YS, Yu HS and Yi TH
        Icariin (ICA) and icaritin (ICT) exhibit many pharmacological functions including anti-osteoporosis, anti-cardiovascular, and anti-cancer activities; however, there are few comprehensive studies that track the detailed effects on UVB-induced photoaging. The recovery effects of ICA and ICT were investigated in UVB-irradiated human keratinocytes (HaCaTs). The results indicated that ICT and ICA showed strong radical scavenging activity, and the reactive oxygen species (ROS) scavenging activity of ICT was superior. UVB-induced matrix metalloproteinase-1 (MMP-1) expression was blocked by ICA via the inhibition of mitogen-activated protein kinase/activator protein 1 (MAPK/AP-1), which directly reduced extracellular matrix (ECM) degradation. ICT activated nuclear factor erythroid 2 related factor 2 (Nrf2) to improve the anti-oxidative stress capacity and suppress nuclear factor-κB (NF-κB) activation, decreasing vascular endothelial growth factor (VEGF) protein, and inflammatory cytokines induced ECM degrading enzyme secretion. Moreover, ICT was more advantageous to improve transforming growth factor beta 1 (TGF-β1) and procollagen type I expression than ICA, promoting the synthesis of collagen. Therefore, ICA and ICT have potential to treat UVB-induced oxidative stress, inflammation and photoaging, and will be posited as a novel strategy to alleviate photodamage.
        Oxidative stress responses in human bronchial epithelial cells exposed to cigarette smoke and vapor from tobacco- and nicotine-containing products
        Munakata S, Ishimori K, Kitamura N, Ishikawa S, Takanami Y and Ito S
        The use of novel tobacco- and nicotine-containing vapor products that do not combust tobacco leaves is on the rise worldwide. The emissions of these products typically contain lower numbers and levels of potentially harmful chemicals compared with conventional cigarette smoke. These vapor products may therefore elicit fewer adverse biological effects. We compared the effects of emissions from different types of such products, i.e., our proprietary novel tobacco vapor product (NTV), a commercially available heat-not-burn tobacco product (HnB), and e-cigarette (E-CIG), and a combustible cigarette in a human bronchial epithelial cell line. The aqueous extract (AqE) of the test product was prepared by bubbling the produced aerosol into medium. Cells were exposed to the AqEs of test products, and then glutathione oxidation, Nrf2 activation, and secretion of IL-8 and GM-CSF were examined. We found that all endpoints were similarly perturbed by exposure to each AqE, but the effective dose ranges were different between cigarette smoke and the tobacco- and nicotine-containing vapors. These results demonstrate that the employed assays detect differences between product exposures, and thus may be useful to understand the relative potential biological effects of tobacco- and nicotine-containing products.
        Effects of Ulinastatin on myocardial oxidative stress and inflammation in severely burned rats
        He F, Song Y, Ying WJ, Jin XY, Wang ZX, Su JD and Wang GY
        By constructing the severe burns model in rat, we explored the effects of different doses of Ulinastatin (UTI) on protecting myocardium from oxidative stress and inflammatory reaction.
        Molecular Mechanisms of Lithium Action: Switching the Light on Multiple Targets for Dementia Using Animal Models
        Kerr F, Bjedov I and Sofola-Adesakin O
        Lithium has long been used for the treatment of psychiatric disorders, due to its robust beneficial effect as a mood stabilizing drug. Lithium's effectiveness for improving neurological function is therefore well-described, stimulating the investigation of its potential use in several neurodegenerative conditions including Alzheimer's (AD), Parkinson's (PD) and Huntington's (HD) diseases. A narrow therapeutic window for these effects, however, has led to concerted efforts to understand the molecular mechanisms of lithium action in the brain, in order to develop more selective treatments that harness its neuroprotective potential whilst limiting contraindications. Animal models have proven pivotal in these studies, with lithium displaying advantageous effects on behavior across species, including worms (), zebrafish (), fruit flies () and rodents. Due to their susceptibility to genetic manipulation, functional genomic analyses in these model organisms have provided evidence for the main molecular determinants of lithium action, including inhibition of inositol monophosphatase (IMPA) and glycogen synthase kinase-3 (GSK-3). Accumulating pre-clinical evidence has indeed provided a basis for research into the therapeutic use of lithium for the treatment of dementia, an area of medical priority due to its increasing global impact and lack of disease-modifying drugs. Although lithium has been extensively described to prevent AD-associated amyloid and tau pathologies, this review article will focus on generic mechanisms by which lithium preserves neuronal function and improves memory in animal models of dementia. Of these, evidence from worms, flies and mice points to GSK-3 as the most robust mediator of lithium's neuro-protective effect, but it's interaction with downstream pathways, including Wnt/β-catenin, CREB/brain-derived neurotrophic factor (BDNF), nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and toll-like receptor 4 (TLR4)/nuclear factor-κB (NFκB), have identified multiple targets for development of drugs which harness lithium's neurogenic, cytoprotective, synaptic maintenance, anti-oxidant, anti-inflammatory and protein homeostasis properties, in addition to more potent and selective GSK-3 inhibitors. Lithium, therefore, has advantages as a multi-functional therapy to combat the complex molecular pathology of dementia. Animal studies will be vital, however, for comparative analyses to determine which of these defense mechanisms are most required to slow-down cognitive decline in dementia, and whether combination therapies can synergize systems to exploit lithium's neuro-protective power while avoiding deleterious toxicity.
        Triptriolide Alleviates Lipopolysaccharide-Induced Liver Injury by Nrf2 and NF-κB Signaling Pathways
        Yang YQ, Yan XT, Wang K, Tian RM, Lu ZY, Wu LL, Xu HT, Wu YS, Liu XS, Mao W, Xu P and Liu B
        Nrf2 (Nuclear Factor Erythroid 2 Related Factor 2) transcription factor not only regulates oxidative stress response, but also represses inflammation by regulating cytokines production and cross-talking with NF-κB signaling pathways. Nrf2 plays an essential role in liver injury induced by oxidative stress and inflammation. Triptriolide (T11) is a minor component of Hook F. (TwHF), which can be obtained by hydrolysis reaction of triptolide (T9). The major purpose of this study is to clarify the regulating effects of T11 on oxidative stress and inflammation and . LPS-stimulated RAW 264.7 cells were used to verify the regulating effects of T11 on oxidative stress (ROS and Nrf2 signaling pathway) and inflammatory cytokines production (TNF-α, IL-6 and IL-1β). The antioxidant responsive element (ARE) luciferase assay was employed to evaluate Nrf2 activation effect of T11 in HEK-293T cells. Lipopolysaccharides (LPS) induced acute liver injury (ALI) in BALB/c mice were used to study the protective effects (ALT, AST, MDA, SOD, histopathology and neutrophils/macrophages filtration) and the underlying protection mechanisms of ALI amelioration (Nrf2 and NF-κB signaling pathway) of T11. Firstly, the results showed that T11 can not only effectively decrease the productions of inflammatory cytokines (TNF-α, IL-6 and IL-1β), ROS and NO in LPS-stimulated RAW 264.7 cells, but also further significantly increase the activity of Nrf2 in HEK-293T cells. Secondly, the results suggested that T11 could dramatically decrease the oxidative stress responses (SOD and MDA) and inflammation (histopathology, neutrophils/macrophages filtration, TNF-α, IL-6 and IL-1β production) in LPS-induced ALI in BALB/c mice. Finally, the results implied that T11 could dramatically increase Nrf2 protein expression and decrease p-TAK1, p-IκBα and NF-κB protein expression both and In conclusion, our findings indicated that T11 could alleviate LPS induced oxidative stress and inflammation by regulating Nrf2 and NF-κB signaling pathways and , which offers a novel insights for the application of TwHF in clinical.
        Activation of Nrf2/HO-1 Pathway by Nardochinoid C Inhibits Inflammation and Oxidative Stress in Lipopolysaccharide-Stimulated Macrophages
        Luo JF, Shen XY, Lio CK, Dai Y, Cheng CS, Liu JX, Yao YD, Yu Y, Xie Y, Luo P, Yao XS, Liu ZQ and Zhou H
        The roots and rhizomes of have neuroprotection and cardiovascular protection effects. However, the specific mechanism of is not yet clear. Nardochinoid C (DC) is a new compound with new skeleton isolated from and this study for the first time explored the anti-inflammatory and anti-oxidant effect of DC. The results showed that DC significantly reduced the release of nitric oxide (NO) and prostaglandin E (PGE) in lipopolysaccharide (LPS)-activated RAW264.7 cells. The expression of pro-inflammatory proteins including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were also obviously inhibited by DC in LPS-activated RAW264.7 cells. Besides, the production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were also remarkably inhibited by DC in LPS-activated RAW264.7 cells. DC also suppressed inflammation indicators including COX-2, PGE, TNF-α, and IL-6 in LPS-stimulated THP-1 macrophages. Furthermore, DC inhibited the macrophage M1 phenotype and the production of reactive oxygen species (ROS) in LPS-activated RAW264.7 cells. Mechanism studies showed that DC mainly activated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, increased the level of anti-oxidant protein heme oxygenase-1 (HO-1) and thus produced the anti-inflammatory and anti-oxidant effects, which were abolished by Nrf2 siRNA and HO-1 inhibitor. These findings suggested that DC could be a new Nrf2 activator for the treatment and prevention of diseases related to inflammation and oxidative stress.

        JOIN OUR COMMUNITY.

        Reach Us

        Our mission is to provide an impartial review of the emerging research regarding Nrf2 activation.

        We welcome the involvement of those who have published peer review studies in this field. 

        Should you wish to contact us, please leave a message using the adjacent form. 

         

          Researching Nrf2? Leave us a message to collaborate

          Spring Cleaning Damaged Proteins with Nrf2: Good for Huntington’s Disease and Other Neurodegenerative Disorders?

          Spring Cleaning Damaged Proteins with Nrf2: Good for Huntington’s Disease and Other Neurodegenerative Disorders?

          English: Complete neuron cell diagram. Neurons...

          English: Complete neuron cell diagram. Neurons (also known as neurones and nerve cells) are electrically excitable cells in the nervous system that process and transmit information. In vertebrate animals, neurons are the core components of the brain, spinal cord and peripheral nerves. (Photo credit: Wikipedia)

          A new study supported by grants from NINDS and the National Institute on Aging as well as funding provided by the Taube/Koret Center, the National Science Foundation , the Huntington’s Disease Society of America, the Milton Wexler Award, and the Hillblom Foundation shows that activating a gene known as NRF2 helps clear damaged proteins which slows down or could possibly prevent Huntington’s disease.

          The study published in Nature Chemical Biology explains how important it is to quickly clear damaged proteins from neurons. Cell survival may be affected by the speed at which damaged proteins are removed. In Huntington’s disease and other neurodegenerative disorders, damaged proteins become misshaped and abnormal. They envelope neurons and damage or  kill the nearby brain cells. Healthy bodies are able to control quality and quantity of protein levels, as well as is able to detect malformed proteins and flush them be fore they can do any damage through a process called proteostasis.

          The study broke new ground in developing and using a technique called optical pulse-labeling to measure how quickly damaged proteins get removed. “Before this new technique, there was no way to look at individual neurons and their capacity to handle proteins. This method provides a real-time readout of how fast proteins are turned over in neurons and gives us a look at some of the mechanisms involved,” said Margaret Sutherland, Ph.D., program director at NINDS.

          The research studied the impact of different forms of huntingtin, the protein in Huntington’s disease on neuron death and the symptoms of the disease. The experiments showed that the mutant form of huntingtin caused more rat cells to die than the normal healthy form of the protein.

          To test this idea, the researchers activated Nrf2, a protein known to regulate protein processing. When Nrf2 was turned on, the mean lifetime of huntingtin was shortened, and the neuron lived longer. The researchers discovered that neuronal survival is directly correlated with the amount of time a neuron is exposed to the mutant huntingtin protein. Improving proteostasis in Huntington’s brains may improve neuronal survival and slow down or even prevent the the progression of the disease.

          “Nrf2 seems like a potentially exciting therapeutic target. It is profoundly neuroprotective in our Huntington’s model and it accelerates the clearance of mutant huntingtin,” said Dr. Steven Finkbeiner, senior author of the paper.

          “These findings provide evidence that our brains have powerful coping mechanisms to deal with disease-causing proteins. The fact that some of these diseases don’t cause symptoms we can detect until the fourth or fifth decade of life, even when the gene has been present since birth, suggests that those mechanisms are pretty good,” said Dr. Finkbeiner.
          Other NRF2 Huntington studies on Pubmed.org:

          Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin.

          JOIN OUR COMMUNITY.

          Reach Us

          Our mission is to provide an impartial review of the emerging research regarding Nrf2 activation.

          We welcome the involvement of those who have published peer review studies in this field. 

          Should you wish to contact us, please leave a message using the adjacent form. 

           

            Researching Nrf2? Leave us a message to collaborate

            A New Nrf2 and Diabetes Study Underway

            A New Nrf2 and Diabetes Study Underway

            Age-standardised disability-adjusted life year...

            The American Diabetes Journal has details on an interesting NRF2 study currently in progress. Diabetes is a huge concern to many individuals and families. According to statistics published by the American Diabetes Association  more than 25.8 million children and adults in the United States in 2010 have diabetes. That accounts for 8.3% of the population. A whopping 79 million people have pre-diabetic symptoms. In 2010, there were 1.9 million new cases of diabetes in people aged 20 years and older.

            Complications from Diabetes

            The following complications may occur as a result of diabetes.

            • Heart disease and stroke
            • High blood pressure
            • Blindness
            • Kidney disease
            • Nervous system disease (Neuropathy)
            • Amputation

            The following study is highlighted on the American Diabetes Association (ADA) website.

            Nrf2 activator to prevent diabetic cardiomyopathy

            The study is being conducted by: Cai, Lu , M.D., Ph.D. University of Louisville, Louisville, Kentucky. It focuses on both Type 1 And Type 2 Diabetes. The study started January 1, 2011 and is anticipated to end December 31, 2013.

            Background:

            Oxidative stress is associated with over 200 diseases, including diabetes. A diabetic’s heart is easily damaged from oxidative stress. Consuming antioxidants directly is not an effective enough protector of the heart. This study attempts to stimulate the body’s own production of several antioxidant genes/proteins in the heart through  a pathway known as the Nrf2 pathway. Nrf2 is the master regulator which turns on several antioxidant enzymes in the body.

            According to the website, Dr. Cai’s group showed that mice without Nrf2 are more easily damaged by diabetes than mice with higher levels of Nrf2. The group used a compound known as Dh404 as their NRF2 activator. Their hope is that results of this study will be conclusive to provide a new medication to protect the heart from diabetes. The researchers state that although this a new approach to diabetes treatment, their initial research shows it to be “a feasible project since we have shown the importance of Nrf2 in protecting a diabetic heart, and also have the compound (Dh404) to increase cardiac Nrf2 in animals.”

            To be more specific regarding protecting the heart, this project investigates the effects of NRF2 on diabetic myocardial complications (diabetic cardiomyopathy).  When the results are presented, there will be an answer to whether Nrf2 is capable of preventing diabetes-induced oxidative and nitrosative stress and the resulting progression of diabetic cardiomyopathy.

            The researchers  hope that if their findings are positive, that they might find or develop some dietary supplements to up-regulate cardiovascular levels of Nrf2. They further hope that this NRF2 up-regulation of genes and proteins in the heart will be able to prevent diabetes-induced cardiovascular diseases.

            Dr. Cai is motivated to find a cure due to the fact that many of his friends and family have been inflicted with Diabetes, including his mother in 1999 at the age of 59 years of age.

            Dr. Cai believes that diabetes (both type I and type II) will be prevented or at least delayed if an early diagnosis and treatment can be implemented as a result of these and future studies. It is his hope that hypertension, cardiomyopathy, and stroke will be prevented through the enhancement of endogenous and exogenous antioxidants.

            There are over 150 NRF2/Diabetic studies published on Pubmed.

            JOIN OUR COMMUNITY.

            Reach Us

            Our mission is to provide an impartial review of the emerging research regarding Nrf2 activation.

            We welcome the involvement of those who have published peer review studies in this field. 

            Should you wish to contact us, please leave a message using the adjacent form. 

             

              Researching Nrf2? Leave us a message to collaborate

              Pin It on Pinterest