Nrf2 Overview

Nrf2 in plain English

There are many scientific articles explaining in great detail and using long scientific words that are difficult to understand. If you’d like one of those articles click here.

For the rest of you still reading, here is a quick overview of what Nrf2 is and why there is such a buzz around the topic.

When the body is “in tune” it regulates itself in “miraculous” ways. Similar to the regulator that governs your air conditioning and heating in your home. Your body has it’s own “perfect environment” and up-regulates or down-regulates its own genes to keep itself in harmony just like if the house is too cold the heating switches on until the correct temperature is reached or vice versa with the air-conditioning. So if the body requires more enzymes to fight an illness it knows to produce the right amount of “survival” genes to fight that particular illness.

This all works well and good, until it doesn’t. Like when the heating unit gets old, or perhaps the filter is clogged up. Perhaps it gets inefficient with age and is unable to detect the “ideal temperature”. The body likewise gets out of sync through various factors, such as illness or disease, stress, pollution and toxins, inadequate nutrition and so forth.

These stressors result in malfunction, aging and disease as well as inflammation and fibrosis (scar tissue). The body is unable to up-regulate or down-regulate the survival genes like it could before. Cell damage (oxidative stress) occurs, and that’s when things become overwhelming. Another analogy that I have found useful is like when the garbage removal service personnel go on strike and garbage stats piling up in homes and the streets of a city. Pretty gross, right?  Well that’s similar to the garbage that piles up in the body when it is out of sync. And to make matters worse, sometimes it goes silently undetected causing multiple years of damage before it manifests itself.

So what has this to do with Nrf2?

Each cell in the body has its own regulation unit. Various pathways govern the efficient operation of the unit. One of those pathways (the Nrf2 pathways) ensures the body maintains the correct amount and balance of the survival genes. When the body is young and healthy, it works well, like a brand new air-conditioner. The trouble is that in our early twenties aging begins to set in. And as our bodies begin that aging process, the regulator gets less efficient. The older one gets the more the body becomes overwhelmed with cell damage, illness, disease and its resulting inflammation and fibrosis. As mentioned earlier much of this goes on unnoticed, but at some point the warning signs begin to appear. This is manifest with lower Nrf2 activation in the cells.

So what can be done to improve the situation?

Traditionally the health solution touted by health care companies has been to push supplements such as vitamins and antioxidants, and while they may be important for overall nutrition, they are inadequate to slow down the damage resulting from inefficient Nrf2 activation in the cells. Perhaps they are like using a small paper fan to keep the whole house cool. When Dr. Joe McCord discovered this Nrf2 pathway and also the mechanism to trigger the mechanism back into a finely tuned condition again, a new tool was discovered to fight malfunction, aging and disease in the body. This tool became known as “Nrf2 activation”.

There are many foods are Nrf2 activators. The Nrf2 Activators section of this site display the latest/top scientific papers referenced from Pubmed.

Regarding supplements to activate Nrf2, sometimes it is more practical to take a supplement and more cost effective to buy a supplement.

The product with the most scientific research on Pubmed that Dr. McCord developed to activate Nrf2  (called Protandim), and there have been over 25 studies published on the effectiveness of this particular supplement on all kinds of disease and aging conditions. There are other supplements and pharmaceutical drugs on the market, but Protandim is the leader in scientific research at this point in time.  Here is a summary page of the studies of Protandim on Pubmed.

To summarize then,

Nrf2 activation is a field of research capturing the imagination of the medical world. It is the subject of full conferences attended by reputable scientists and organizations worldwide. Universities are also studying the effects of Nrf2 activators on health conditions.

In a study published by Washington State University, they state that ” While no doubt it is too early to make a conclusion, it is difficult to escape the suggestion,
from Tables i and 4 (see the full study), that we may be on the verge of a new literature on health effects of Nrf2
 which may well become the most extraordinary therapeutic and most extraordinary
preventive breakthrough in the history of medicine. It is our opinion that raising Nrf2 is likely to be the most important health promoting
 approach into the foreseeable future.”

This site is here to educate on the topic of Nrf2, but we leave the conclusion of whether it is right for you to discuss with a medical professional whio understands and is familiar with your unique situation.

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 https://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]

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    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

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      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:

       

      Costunolide inhibits pulmonary fibrosis via regulating NF-kB and TGF-β/Smad/Nrf-NOX signaling pathways
      Liu B, Rong Y, Sun D, Li W, Chen H, Cao B and Wang T
      Specific study about the inhibitory effect of costunolide (CN) and relevant mechanism is of great significance for the treatment of pulmonary fibrosis. Here, the pharmacological activity of costunolide on the treatment of pulmonary fibrosis was investigated in vivo and in vitro. The in vivo mice study, mice were received intratracheal injection of bleomycin (BLM, 5 mg/kg) on 0 day to obtain BLM-induced pulmonary fibrosis firstly. From 2 day to 21 day, mice were orally administered with different dose of CN (low dose(CNL): 10 mg/kg, high dose(CNH): 20 mg/kg) and pirfenidone (PFD)(positive control, 50 mg/kg). The in vitro cells model, cells were incubated with recombinant human TGF-β1 for 24 h to get TGF-β-induced pulmonary fibrosis. Cells were treated differently for 24 h and divided into five groups. Then, the activity of CN was evaluated by the expression level of related protein and the factors of oxidative stress in vivo and in vitro, and the mechanism was tested from the involved channel protein aspect. As a result, from the comparison of multiple factors (α-SMA, collagen type I/III, HYP, MDA, SOD) between pirfenidone group and CN group, it revealed the beneficial effects of CN against BLM-induced and TGF-β-induced pulmonary fibrosis. In addition, our study also proved that CN exerted its effects through suppressing the NF-kB dependent inflammation and regulated TGF-β/Smad/ NOX-Nrf signaling pathways. In conclusion, CN could be a potential theraputic candidate for the treatment pulmonary fibrosis in the future.
      Mitoquinone ameliorates pressure overload-induced cardiac fibrosis and left ventricular dysfunction in mice
      Goh KY, He L, Song J, Jinno M, Rogers AJ, Sethu P, Halade GV, Rajasekaran NS, Liu X, Prabhu SD, Darley-Usmar V, Wende AR and Zhou L
      Increasing evidence indicates that mitochondrial-associated redox signaling contributes to the pathophysiology of heart failure (HF). The mitochondrial-targeted antioxidant, mitoquinone (MitoQ), is capable of modifying mitochondrial signaling and has shown beneficial effects on HF-dependent mitochondrial dysfunction. However, the potential therapeutic impact of MitoQ-based mitochondrial therapies for HF in response to pressure overload is reliant upon demonstration of improved cardiac contractile function and suppression of deleterious cardiac remodeling. Using a new (patho)physiologically relevant model of pressure overload-induced HF we tested the hypothesis that MitoQ is capable of ameliorating cardiac contractile dysfunction and suppressing fibrosis. To test this C57BL/6J mice were subjected to left ventricular (LV) pressure overload by ascending aortic constriction (AAC) followed by MitoQ treatment (2 µmol) for 7 consecutive days. Doppler echocardiography showed that AAC caused severe LV dysfunction and hypertrophic remodeling. MitoQ attenuated pressure overload-induced apoptosis, hypertrophic remodeling, fibrosis and LV dysfunction. Profibrogenic transforming growth factor-β1 (TGF-β1) and NADPH oxidase 4 (NOX4, a major modulator of fibrosis related redox signaling) expression increased markedly after AAC. MitoQ blunted TGF-β1 and NOX4 upregulation and the downstream ACC-dependent fibrotic gene expressions. In addition, MitoQ prevented Nrf2 downregulation and activation of TGF-β1-mediated profibrogenic signaling in cardiac fibroblasts (CF). Finally, MitoQ ameliorated the dysregulation of cardiac remodeling-associated long noncoding RNAs (lncRNAs) in AAC myocardium, phenylephrine-treated cardiomyocytes, and TGF-β1-treated CF. The present study demonstrates for the first time that MitoQ improves cardiac hypertrophic remodeling, fibrosis, LV dysfunction and dysregulation of lncRNAs in pressure overload hearts, by inhibiting the interplay between TGF-β1 and mitochondrial associated redox signaling.
      Adropin protects against liver injury in nonalcoholic steatohepatitis via the Nrf2 mediated antioxidant capacity
      Chen X, Xue H, Fang W, Chen K, Chen S, Yang W, Shen T, Chen X, Zhang P and Ling W
      Adropin, a secretory signal peptide, has shown beneficial effects on improving glucose homeostasis and dyslipidemia. However, whether this peptide affects nonalcoholic steatohepatitis (NASH) has remained unclear. In this study, the serum adropin levels, liver injury and oxidative stress were measured in diet-induced NASH mice. Adropin knock-out mice and palmitate treated primary hepatic cells were used to investigate the influence of adropin on liver injury. Our results show that serum adropin levels were decreased and negatively correlated with liver injury in NASH mice. Knockout of adropin significantly exacerbated hepatic steatosis, inflammatory responses and fibrosis in mice after either methionine-choline deficient diet (MCD) or western diet (WD) feeding. And the treatment with adropin bioactive peptides ameliorated NASH progression in mice. Adropin alleviated hepatocyte injury by upregulating the expression of Gclc, Gclm, and Gpx1 in a manner dependent on Nrf2 transcriptional activity and by increasing the glutathione (GSH) levels. And adropin significantly increased CBP expression and promoted its binding with Nrf2, which enhanced Nrf2 transcriptional activity. Furthermore, AAV8-mediated overexpression of hepatic Nrf2 expression functionally restored the liver injury induced by adropin-deficiency MCD-fed mice. These findings provide evidence that adropin activates Nrf2 signaling and plays a protective role in liver injury of NASH and therefore might represent a novel target for the prevention and treatment of NASH.
      Progress of small ubiquitin-related modifiers in kidney diseases
      Li O, Ma Q, Li F, Cai GY, Chen XM and Hong Q
      Small ubiquitin-related modifiers (SUMOs) are a group of post-translational modification proteins extensively expressed in eukaryotes. Abnormal SUMOylation can lead to the development of various diseases. This article summarizes the progress on research of the role of SUMOs in various types of kidney diseases to further increase the understanding of the regulatory functions of SUMOylation in the pathogenesis of kidney diseases.
      SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart
      Li C, Zhang J, Xue M, Li X, Han F, Liu X, Xu L, Lu Y, Cheng Y, Li T, Yu X, Sun B and Chen L
      Hyperglycaemia associated with myocardial oxidative stress and fibrosis is the main cause of diabetic cardiomyopathy. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor has recently been reported to improve glycaemic control in patients with type 2 diabetes in an insulin-independent manner. The aim of this study was to investigate the effect of empagliflozin on myocardium injury and the potential mechanism in type 2 diabetic KK-Ay mice.
      Poricoic acid A enhances melatonin inhibition of AKI-to-CKD transition by regulating Gas6/AxlNFκB/Nrf2 axis
      Chen DQ, Feng YL, Chen L, Liu JR, Wang M, Vaziri ND and Zhao YY
      Renal ischemia-reperfusion injury (IRI) is a complex syndrome, which causes chronic kidney disease (CKD) after recovery from IRI-mediated acute kidney injury (AKI). There is no single therapy that could effectively prevent the renal injury after ischemia. In this study, the effects of melatonin or poricoic acid A (PAA) and their combination were investigated in protecting against AKI-to-CKD transition in rats and hypoxia/reoxygenation (H/R)-induced injury in cultured renal NRK-52E cells. Melatonin and PAA significantly reduced the magnitude of rise in serum creatinine and urea levels in IRI rats at days 3 and 14. Our results further showed that treatment with melatonin and PAA ameliorated renal fibrosis and podocyte injury by attenuating oxidative stress and inflammation via regulation of nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) pathways in IRI rats. Melatonin and PAA protected against AKI-to-CKD transition by regulating growth arrest-specific 6 (Gas6)/AxlNFκB/Nrf2 signaling cascade. Melatonin and PAA initiallyupregulated Gas6/Axl signaling to reduce oxidative stress and inflammation in AKI and subsequently downregulated Gas6/Axl signaling to attenuate renal fibrosis and progression to CKD. Melatonin and PAA inhibited expression of extracellular matrix proteins. Poricoic acid A enhances melatonin-mediated inhibition of AKI-to-CKD transition by the regulating Gas6/AxlNFκB/Nrf2 signaling cascade. Notably, our study first identified Axl as a promising therapeutic target for prevention of AKI-to-CKD transition.
      High-Dose Paraquat Induces Human Bronchial 16HBE Cell Death and Aggravates Acute Lung Intoxication in Mice by Regulating Keap1/p65/Nrf2 Signal Pathway
      Yao J, Zhang J, Tai W, Deng S, Li T, Wu W, Pu L, Fan D, Lei W, Zhang T and Dong Z
      Paraquat (PQ) intoxication seriously endangers human beings' health, however, the underlying mechanisms are still unclear. Here we found that PQ inhibits human bronchial 16HBE cell proliferation and promotes cell apoptosis, necrosis as well as ROS generation in a dose dependent manner. Of note, low-dose PQ (50 μM) induces cell autophagy, increases Nrf2 as well as p65 levels and has little impacts on Keap1, while high-dose PQ (500 μM) inhibits autophagy, upregulates Keap1 as well as downregulates p65 and Nrf2. In addition, we verified that p65 overexpression increases Nrf2 and its downstream targets in 16HBE cells, which are reversed by synergistically knocking down Nrf2. Our further results showed that high-dose PQ's effects on cell proliferation, apoptosis, ROS levels and autophagy are reversed by p65 overexpression. Besides, the protective effects of overexpressed p65 on high-dose PQ (500 μM) treated 16HBE cells are abrogated by synergistically knocking down Nrf2. In vivo experiments also showed that high-dose PQ promotes inflammatory cytokines secretion, lung fibrosis and cell apoptosis, inhibits cell proliferation in mice models by regulating Keap1/p65/Nrf2 signal pathway. Therefore, we concluded that high-dose PQ (500 μM) inhibits 16HBE cell proliferation and autophagy, promotes cell death and mice lung fibrosis by regulating Keap1/p65/Nrf2 signal pathway.
      Ligustrazin increases lung cell autophagy and ameliorates paraquat-induced pulmonary fibrosis by inhibiting PI3K/Akt/mTOR and hedgehog signalling via increasing miR-193a expression
      Liu MW, Su MX, Tang DY, Hao L, Xun XH and Huang YQ
      Reactive oxygen species (ROS) levels largely determine pulmonary fibrosis. Antioxidants have been found to ameliorate lung fibrosis after long-term paraquat (PQ) exposure. The effects of antioxidants, however, on the signalling pathways involved in PQ-induced lung fibrosis have not yet been investigated sufficiently. Here, we examined the impacts of ligustrazin on lung fibrosis, in particular ROS-related autophagy and pro-fibrotic signalling pathways, using a murine model of PQ-induced lung fibrosis.
      Exercise promotes a cardioprotective gene program in resident cardiac fibroblasts
      Lighthouse JK, Burke RM, Velasquez LS, Dirkx RA, Aiezza A, Moravec CS, Alexis JD, Rosenberg A and Small EM
      Exercise and heart disease both induce cardiac remodeling, but only disease causes fibrosis and compromises heart function. The cardioprotective benefits of exercise have been attributed to changes in cardiomyocyte physiology, but the impact of exercise on cardiac fibroblasts (CFs) is unknown. Here, RNA-sequencing reveals rapid divergence of CF transcriptional programs during exercise and disease. Among the differentially expressed programs, NRF2-dependent antioxidant genes - including metallothioneins (Mt1 and Mt2) - are induced in CFs during exercise and suppressed by TGF-β/p38 signaling in disease. In vivo, mice lacking Mt1/2 exhibit signs of cardiac dysfunction in exercise, including cardiac fibrosis, vascular rarefaction, and functional decline. Mechanistically, exogenous MTs derived from fibroblasts are taken up by cultured cardiomyocytes, reducing oxidative damage-dependent cell death. Importantly, suppression of MT expression is conserved in human heart failure. Taken together, this study defines the acute transcriptional response of CFs to exercise and disease and reveals a cardioprotective mechanism that is lost in disease.
      Notoginsenoside R1 Protects db/db Mice against Diabetic Nephropathy via Upregulation of Nrf2-Mediated HO-1 Expression
      Zhang B, Zhang X, Zhang C, Shen Q, Sun G and Sun X
      Diabetic nephropathy (DN) is a leading cause of end-stage renal failure, and no effective treatment is available. Notoginsenoside R1 (NGR1) is a novel saponin that is derived from , and our previous studies showed the cardioprotective and neuroprotective effects of NGR1. However, its role in protecting against DN remains unexplored. Herein, we established an experimental model in / mice and HK-2 cells exposed to advanced glycation end products (AGEs). The in vivo investigation showed that NGR1 treatment increased serum lipid, β2-microglobulin, serum creatinine, and blood urea nitrogen levels of / mice. NGR1 attenuated histological abnormalities of kidney, as evidenced by reducing the glomerular volume and fibrosis in diabetic kidneys. In vitro, NGR1 treatment was further found to decrease AGE-induced mitochondria injury, limit an increase in reactive oxygen species (ROS), and reduce apoptosis in HK-2 cells. Mechanistically, NGR1 promoted nucleus nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expressions to eliminate ROS that induced apoptosis and transforming growth factor beta (TGF-β) signaling. In summary, these observations demonstrate that NGR1 exerts renoprotective effects against DN through the inhibition of apoptosis and renal fibrosis caused by oxidative stress. NGR1 might be a potential therapeutic medicine for the treatment of DN.
      SVIP alleviates CCl-induced liver fibrosis via activating autophagy and protecting hepatocytes
      Jia D, Wang YY, Wang P, Huang Y, Liang DY, Wang D, Cheng C, Zhang C, Guo L, Liang P, Wang Y, Jia Y and Li C
      Prolonged parenchymal cell death leads to activation of fibrogenic cells and extracellular matrix accumulation and eventually liver fibrosis. Autophagy, a major catabolic process of intracellular degradation and recycling, participates in hepatic fibrosis. However, the precise role of autophagy in the pathogenesis of hepatic fibrosis is controversial. The present study aims to investigate the key role of small VCP/p97 interacting protein (SVIP) against CCl-induced hepatic fibrosis via activating autophagy. Autophagy could be activated by SVIP in HepG2 cells, but starvation cannot increase SVIP expression in vitro and in vivo. Moreover, SVIP expression, in agreement with autophagic activity and the volume of lipid droplets, first increases and then decreases during the progression of liver fibrosis with CCl treatment in vivo and in vivo. Further, overexpression of SVIP can protect HepG2 cells from the toxicity of CCl, which could be enhanced by starvation. Finally, starvation keeps SVIP and autophagy at such high levels in the rat livers that markedly delays the progress of hepatic fibrosis. Probably, the protective effect of SVIP is associated with stabilizing nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) and transcription factor EB (TFEB). The current study provides insight into the biological role of SVIP and autophagy in regulating hepatic fibrosis, targeting SVIP might be a novel therapeutic strategy in the future.
      Irisin attenuates angiotensin II-induced cardiac fibrosis via Nrf2 mediated inhibition of ROS/ TGFβ1/Smad2/3 signaling axis
      Chen RR, Fan XH, Chen G, Zeng GW, Xue YG, Liu XT and Wang CY
      Angiotensin II-related cardiac fibrosis is one of the key pathological changes of the hypertrophied left ventricle in various heart disease. Irisin was recently reported to confer cardio-protective and anti-oxidative effects, while whether it can reverse the renin-angiotensin-aldosterone system(RAAS) activation related(angiotensin II-induced) cardiac fibrosis is unknown. In this study, we found that angiotensin II-induced cardiac dysfunction and fibrotic responses were dampened by irisin treatment in mice. Mechanistically, angiotensin II induced robust ROS generation, which in turn triggered activation of pro-fibrotic TGFβ1-Smad2/3 signaling and subsequent collagen synthesis and fibroblast-myofibroblast transformation in cardiac fibroblasts. In contrast, Irisin treatment suppressed angiotensin II-induced ROS generation, TGFβ1 activation, collagen synthesis and fibroblast-myofibroblast transformation, the effects of which was accompanied by Nrf2 activation and also abolished by a Nrf2 targeted siRNA. Taken together, we here identified irisin as a promising anti-fibrotic therapeutic for angiotensin II-related cardiac fibrosis.
      Novel Curcumin C66 That Protects Diabetes-Induced Aortic Damage Was Associated with Suppressing JNK2 and Upregulating Nrf2 Expression and Function
      Li C, Miao X, Wang S, Adhikari BK, Wang X, Sun J, Liu Q, Tong Q and Wang Y
      Diabetes-related cardiovascular diseases are leading causes of the mortality worldwide. Our previous study has explored the protective effect of curcumin analogue C66 on diabetes-induced pathogenic changes of the aorta. In the present study, we sought to reveal the underlying protective mechanisms of C66. Diabetes was induced in male WT and JNK2 mice with a single intraperitoneal injection of streptozotocin. Diabetic mice and age-matched nondiabetic mice were randomly treated with either vehicle (WT, WT DM, JNK2, and JNK2DM) or C66 (WT + C66, WT DM + C66, JNK2 + C66, and JNK2DM + C66) for three months. Aortic oxidative stress, cell apoptosis, inflammatory changes, fibrosis, and Nrf2 expression and function were assessed by immunohistochemical staining for the protein level and real-time PCR method for mRNA level. The results suggested that either C66 treatment or JNK2 deletion can reverse diabetes-induced aortic oxidative stress, cell apoptosis, inflammation, and fibrosis. Nrf2 was also found to be activated either by C66 or JNK2 deletion. However, C66 had no extra effect on diabetic aortic damage or Nrf2 activation without JNK2. These results suggest that diabetes-induced pathological changes in the aorta can be protected by C66 mainly via inhibition of JNK2 and accompanied by the upregulation of Nrf2 expression and function.
      Xiaochaihutang Inhibits the Activation of Hepatic Stellate Cell Line T6 Through the Nrf2 Pathway
      Hu R, Jia WY, Xu SF, Zhu ZW, Xiao Z, Yu SY and Li J
      Xiaochaihutang (XCHT) is one of classic prescriptions in Treatise on Febrile Diseases in China which was reported to have the effect of anti-hepatic fibrosis . Activation of hepatic stellate cells (HSCs) is now well established as a central driver of fibrosis in liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important element for anti-oxidative damage which is one of the key factors responsible for occurrence. This study was to investigate the effect of XCHT compound serum on HSCs activation and focus on the Nrf2 pathway. Rats in treatment groups were given the appropriate doses of XCHT granules (5 g/kg) and Silybin (50 mg/kg) for 6 days, and the serum were obtained. The compound serum was used to intervene HSCs. The results found that XCHT compound serum significantly inhibited the proliferation of HSCT6 cells. The number of α-SMA positive stained cells in HSCT6 cells and the content of Collagen type I (collagen-I) in supernatant were significantly decreased indicating suppression of activated HSCs. Compared with the control group, the nuclear transcription of Nrf2 and the expressions of Nqo1, GCLC, and GCLM were significantly increased in XCHT group. However, the effects of XCHT were inhibited in Nrf2-siRNA transfected HSCT6 cells. These studies demonstrated that XCHT could inhibit HSCT6 cell proliferation and activation. The mechanism might be related to up-regulation of the Nrf2 pathway against oxidative stress.
      Role of Nrf2 and Its Activators in Respiratory Diseases
      Liu Q, Gao Y and Ci X
      Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidant response element- (ARE-) driven cytoprotective protein expression. The activation of Nrf2 signaling plays an essential role in preventing cells and tissues from injury induced by oxidative stress. Under the unstressed conditions, natural inhibitor of Nrf2, Kelch-like ECH-associated protein 1 (Keap1), traps Nrf2 in the cytoplasm and promotes the degradation of Nrf2 by the 26S proteasome. Nevertheless, stresses including highly oxidative microenvironments, impair the ability of Keap1 to target Nrf2 for ubiquitination and degradation, and induce newly synthesized Nrf2 to translocate to the nucleus to bind with ARE. Due to constant exposure to external environments, including diverse pollutants and other oxidants, the redox balance maintained by Nrf2 is fairly important to the airways. To date, researchers have discovered that Nrf2 deletion results in high susceptibility and severity of insults in various models of respiratory diseases, including bronchopulmonary dysplasia (BPD), respiratory infections, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and lung cancer. Conversely, Nrf2 activation confers protective effects on these lung disorders. In the present review, we summarize Nrf2 involvement in the pathogenesis of the above respiratory diseases that have been identified by experimental models and human studies and describe the protective effects of Nrf2 inducers on these diseases.

      JOIN OUR COMMUNITY.

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      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: 

         

        IPSE, a urogenital parasite-derived immunomodulatory protein, ameliorates ifosfamide-induced hemorrhagic cystitis through downregulation of pro-inflammatory pathways
        Mbanefo EC, Le L, Zee R, Banskota N, Ishida K, Pennington LF, Odegaard JI, Jardetzky TS, Alouffi A, Falcone FH and Hsieh MH
        Ifosfamide and other oxazaphosphorines can result in hemorrhagic cystitis, a constellation of complications caused by acrolein metabolites. We previously showed that a single dose of IPSE (Interleukin-4-inducing principle from Schistosoma eggs), a schistosome-derived host modulatory protein, can ameliorate ifosfamide-related cystitis; however, the mechanisms underlying this urotoxicity and its prevention are not fully understood. To provide insights into IPSE's protective mechanism, we undertook transcriptional profiling of bladders from ifosfamide-treated mice, with or without pretreatment with IPSE or IPSE-NLS (a mutant of IPSE lacking nuclear localization sequence). Ifosfamide treatment upregulated a range of proinflammatory genes. The IL-1β-TNFα-IL-6 proinflammatory cascade via NFκB and STAT3 pathways was identified as the key driver of inflammation. The NRF2-mediated oxidative stress response pathway, which regulates heme homoeostasis and expression of antioxidant enzymes, was highly activated. Anti-inflammatory cascades, namely Wnt, Hedgehog and PPAR pathways, were downregulated. IPSE drove significant downregulation of major proinflammatory pathways including the IL-1β-TNFα-IL-6 pathways, interferon signaling, and reduction in oxidative stress. IPSE-NLS reduced inflammation but not oxidative stress. Taken together, we have identified signatures of acute-phase inflammation and oxidative stress in ifosfamide-injured bladder, which are reversed by pretreatment with IPSE. This work revealed several pathways that could be therapeutically targeted to prevent ifosfamide-induced hemorrhagic cystitis.
        Poricoic acid A enhances melatonin inhibition of AKI-to-CKD transition by regulating Gas6/AxlNFκB/Nrf2 axis
        Chen DQ, Feng YL, Chen L, Liu JR, Wang M, Vaziri ND and Zhao YY
        Renal ischemia-reperfusion injury (IRI) is a complex syndrome, which causes chronic kidney disease (CKD) after recovery from IRI-mediated acute kidney injury (AKI). There is no single therapy that could effectively prevent the renal injury after ischemia. In this study, the effects of melatonin or poricoic acid A (PAA) and their combination were investigated in protecting against AKI-to-CKD transition in rats and hypoxia/reoxygenation (H/R)-induced injury in cultured renal NRK-52E cells. Melatonin and PAA significantly reduced the magnitude of rise in serum creatinine and urea levels in IRI rats at days 3 and 14. Our results further showed that treatment with melatonin and PAA ameliorated renal fibrosis and podocyte injury by attenuating oxidative stress and inflammation via regulation of nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) pathways in IRI rats. Melatonin and PAA protected against AKI-to-CKD transition by regulating growth arrest-specific 6 (Gas6)/AxlNFκB/Nrf2 signaling cascade. Melatonin and PAA initiallyupregulated Gas6/Axl signaling to reduce oxidative stress and inflammation in AKI and subsequently downregulated Gas6/Axl signaling to attenuate renal fibrosis and progression to CKD. Melatonin and PAA inhibited expression of extracellular matrix proteins. Poricoic acid A enhances melatonin-mediated inhibition of AKI-to-CKD transition by the regulating Gas6/AxlNFκB/Nrf2 signaling cascade. Notably, our study first identified Axl as a promising therapeutic target for prevention of AKI-to-CKD transition.
        Helicobacter pylori infection promotes autophagy through Nrf2-mediated heme oxygenase upregulation in human gastric cancer cells
        Paik JY, Lee HG, Piao JY, Kim SJ, Kim DH, Na HK and Surh YJ
        It has been reported that Helicobacter pylori (H. pylori) infection is one of the primary causes of gastritis and peptic ulcer diseases. More than 50% of the world's population is supposed to be infected by this bacterium. However, 90% of infected patients are asymptomatic, suggesting the existence of host defense mechanisms. Nrf2 is a transcription factors that plays a key role in cellular defence against oxidative stress and inflammation. Autophagy, an autodigestive process that degrades cellular organelles and proteins, plays an important role in maintaining cellular homeostasis. To investigate the molecular mechanisms responsible for cellular adaptive response to H. pylori induced gastric inflammation, human gastric epithelial cells and mice were infected with H. pylori. H. pylori infection induced expression of microtubule-associated light chain3 (LC3), an autophagic marker, through accumulation of reactive oxygen species and subsequently Nrf2 nuclear translocation in AGS cells. Furthermore, Nrf2-induced LC3 up-regulation was mediated by heme oxygenase-1 and its by-product, carbon monoxide. Taken together, Nrf2 may be considered to play a role in cellular adaptive response to H. pylori-induced gastritis by inducing autophagy.
        A chalcone derivative suppresses the induction of TSLP in mice and human keratinocytes and attenuates OVA-induced antibody production in mice
        Segawa R, Shiraki M, Sudo S, Shigeeda K, Saito T, Mizuno N, Moriya T, Yonezawa T, Woo JT, Hiratsuka M and Hirasawa N
        Thymic stromal lymphopoietin (TSLP) is a key epithelial-derived factor that aggravates allergic diseases. Therefore, TSLP inhibitors are candidate compounds for the treatment of allergic diseases. Previously, we reported that KCMH-1, a mouse keratinocyte cell line, constitutively produces TSLP. In this study, we tried to identify inhibitors of TSLP by screening 2169 compounds in KCMH-1 cells and found one such chalcone derivative (code no. 16D10). 16D10 inhibited TSLP expression and TSLP promoter activation in HaCaT cells, a human keratinocyte cell line. Although nuclear factor kappa-B (NF-κB) is a key transcription factor for the induction of TSLP, 16D10 did not inhibit the activation pathway of NF-κB, such as degradation of inhibitor of κB (IκB) and p65 nuclear translocation. 16D10 activated the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system, although this system was not involved in the inhibitory effect of 16D10. 16D10 also inhibited TSLP production in a lipopolysaccharide (LPS)- or ovalbumin (OVA)-induced air-pouch-type inflammation model. Further, repeated 16D10 administration diminished serum immunoglobulin G1 (IgG1) and IgE concentration in an OVA-induced air-pouch-type sensitization model. Taken together, these results indicate that 16D10 is an inhibitor of TSLP production and has an anti-allergic effect. This inhibitory effect is independent of the activation of NF-κB and the Keap1-Nrf2 system. Therefore, 16D10 could be a new type of candidate drug for allergic diseases.
        High-Dose Paraquat Induces Human Bronchial 16HBE Cell Death and Aggravates Acute Lung Intoxication in Mice by Regulating Keap1/p65/Nrf2 Signal Pathway
        Yao J, Zhang J, Tai W, Deng S, Li T, Wu W, Pu L, Fan D, Lei W, Zhang T and Dong Z
        Paraquat (PQ) intoxication seriously endangers human beings' health, however, the underlying mechanisms are still unclear. Here we found that PQ inhibits human bronchial 16HBE cell proliferation and promotes cell apoptosis, necrosis as well as ROS generation in a dose dependent manner. Of note, low-dose PQ (50 μM) induces cell autophagy, increases Nrf2 as well as p65 levels and has little impacts on Keap1, while high-dose PQ (500 μM) inhibits autophagy, upregulates Keap1 as well as downregulates p65 and Nrf2. In addition, we verified that p65 overexpression increases Nrf2 and its downstream targets in 16HBE cells, which are reversed by synergistically knocking down Nrf2. Our further results showed that high-dose PQ's effects on cell proliferation, apoptosis, ROS levels and autophagy are reversed by p65 overexpression. Besides, the protective effects of overexpressed p65 on high-dose PQ (500 μM) treated 16HBE cells are abrogated by synergistically knocking down Nrf2. In vivo experiments also showed that high-dose PQ promotes inflammatory cytokines secretion, lung fibrosis and cell apoptosis, inhibits cell proliferation in mice models by regulating Keap1/p65/Nrf2 signal pathway. Therefore, we concluded that high-dose PQ (500 μM) inhibits 16HBE cell proliferation and autophagy, promotes cell death and mice lung fibrosis by regulating Keap1/p65/Nrf2 signal pathway.
        Lycopene attenuates aluminum-induced hippocampal lesions by inhibiting oxidative stress-mediated inflammation and apoptosis in the rat
        Cao Z, Wang P, Gao X, Shao B, Zhao S and Li Y
        Aluminum (Al) causes hippocampal lesions by oxidative stress, which is widely accepted as the primary pathogenesis of Al neurotoxicity. Lycopene (LYC), a naturally carotenoid, has received extensive attention due to its antioxidant effect. In this study, the neuroprotective effects and mechanisms of LYC against aluminum chloride (AlCl)-induced hippocampal lesions were explored. First, oral administration of LYC (4 mg/kg) alleviated AlCl-induced (150 mg/kg) cognition impairment and histopathological changes of the hippocampus in rats. Then, LYC significantly attenuated AlCl-induced oxidative stress, presenting as the reduced reactive oxygen species, malondialdehyde and 8-hydroxy-2'-deoxyguanosine levels, and increased glutathione level and superoxide dismutase activity. Moreover, LYC also protected the hippocampus from AlCl-induced apoptosis and neuroinflammation, as assessed by protein levels of p53, Bcl-2-associated X protein (Bax), B-cell lymphoma gene 2 (Bcl-2), Cytochrome c (Cyt c), cleaved caspase-3 and nuclear factor kappa B, as well as the mRNA levels of Bax, Bcl-2, tumor necrosis factor alpha, interleukin-6 and interleukin-1 beta. Finally, LYC increased nuclear factor-erythroid-2-related factor 2 (Nrf2) nuclear translocation and its downstream gene expression, including heme oxygenase-1, NAD(P)H: quinone oxidoreductase 1, glutamate cysteine ligase catalytic subunit and superoxide dismutase 1, which were involved in antioxidant, anti-apoptosis, and anti-inflammation. Overall, our findings demonstrate LYC attenuates Al-induced hippocampal lesions by inhibiting oxidative stress-mediated inflammation and apoptosis in the rat.
        Genetic risk score combining six genetic variants associated with the cellular NRF2 expression levels correlates with Type 2 diabetes in the human population
        Shin JH, Lee KM, Shin J, Kang KD, Nho CW and Cho YS
        Type 2 diabetes (T2D) is known as an inflammatory disease. NRF2 (Nuclear Factor Erythroid 2 Like2) encodes a transcription factor that binds to antioxidant response elements (AREs) and regulates the expression of genes involved in many antioxidant responses.
        BML-111 accelerates the resolution of inflammation by modulating the Nrf2/HO-1 and NF-κB pathways in rats with ventilator-induced lung injury
        Xu J, Li HB, Chen L, Wang YX, Lu S, Li SN, Cui SN, Xiao HR, Qin L, Hu H, Yao S and Shang Y
        The timely resolution of pulmonary inflammation coordinated by endogenous pro-resolving mediators helps limit lung tissue injury, but few endogenous pro-resolving mediators that are normally operative during acute inflammation. The protective effects of BML-111 (5(S)-6(R)-7-trihydroxyheptanoic acid methyl ester), a potent commercially available anti-inflammatory and pro-resolving mediator, on ventilation-induced lung injury (VILI) have been extensively studied, but its characteristics as a pro-resolving mediator have not. Here, anesthetized Sprague-Dawley rats were ventilated with a high tidal volume (20 mL/kg, HV) for 1 h and randomly allocated to recover for 6, 12, 24, 48, 72, 96 or 168 h; BML-111 was administered at the peak of inflammation to evaluate its pro-resolving effect on VILI. The one-hour HV induced a maximal pulmonary inflammatory response at 12 h that was largely resolved by 72 h. BML-111 largely resolved the maximal inflammatory response at 48 h; the resolution interval (Ri) was shortened by 26 h. Similarly, HV elicited a time course of changes in histopathology and pulmonary edema, and BML-111 alleviates these changes. Mechanistically, neutrophil apoptosis was significantly increased in BML-111-treated rats subjected to HV. The apoptosis inhibitor z-VAD-fmk partially reversed the proapoptotic actions of BML-111 on neutrophil and the resolving effects of BML-111 on VILI but had no effect alone. Importantly, the HV treatment activated the nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1) and NF-κB signaling pathways in the lung tissue, and BML-111 further induced Nrf2 and HO-1 expression but inhibited the NF-κB pathway. Intriguingly, when we inhibited the Nrf2/HO-1 pathway with the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX), Nrf2 expression was further increased, but the inhibitory effects of BML-111 on the NF-κB pathway and on the subsequent inflammatory response, and the proapoptotic actions on neutrophil were reversed. The results suggest that BML-111 promotes the resolution of HV-induced inflammation to mitigate VILI in rats, perhaps by modulating the Nrf2/HO-1 and NF-κB pathways and subsequently increasing neutrophil apoptosis.
        PCB 126 induces monocyte/macrophage polarization and inflammation through AhR and NF-κB pathways
        Wang C, Petriello MC, Zhu B and Hennig B
        Polychlorinated biphenyls (PCBs) are persistent organic pollutants that contribute to inflammatory diseases such as atherosclerosis, and macrophages play a key role in the overall inflammatory response. Depending on specific environmental stimuli, macrophages can be polarized either to pro-inflammatory (e.g., M1) or anti-inflammatory (e.g., M2) phenotypes. We hypothesize that dioxin-like PCBs can contribute to macrophage polarization associated with inflammation. To test this hypothesis, human monocytes (THP-1) were differentiated to macrophages and subsequently exposed to PCB 126. Exposure to PCB 126, but not to PCB 153 or 118, significantly induced the expression of inflammatory cytokines, including TNFα and IL-1β, suggesting polarization to the pro-inflammatory M1 phenotype. Additionally, monocyte chemoattractant protein-1 (MCP-1) was increased in PCB 126-activated macrophages, suggesting induction of chemokines which regulate immune cell recruitment and infiltration of monocytes/macrophages into vascular tissues. In addition, oxidative stress sensitive markers including nuclear factor (erythroid-derived 2)-like 2 (NFE2L2; Nrf2) and down-stream genes, such as heme oxygenase 1 (HMOX1) and NAD(P)H quinone oxidoreductase 1 (NQO1), were induced following PCB 126 exposure. Since dioxin-like PCBs may elicit inflammatory cascades through multiple mechanisms, we then pretreated macrophages with both aryl hydrocarbon receptor (AhR) and NF-κB antagonists prior to PCB treatment. The NF-κB antagonist BMS-345541 significantly decreased mRNA and protein levels of multiple cytokines by approximately 50% compared to PCB treatment alone, but the AhR antagonist CH-223191 was protective to a lesser degree. Our data demonstrate the involvement of PCB 126 in macrophage polarization and inflammation, indicating another important role of dioxin-like PCBs in the pathology of atherosclerosis.
        Mangiferin alleviates arsenic induced oxidative lung injury via upregulation of the Nrf2-HO1 axis
        Mahalanobish S, Saha S, Dutta S and Sil PC
        Arsenic contaminated drinking water consumption is a serious health issue around the world. Chronic inorganic arsenic exposure has been associated with respiratory dysfunctions. It exerts various detrimental effects, disrupting normal cellular homeostasis and turning on severe pulmonary complications. This study elucidated the role of mangiferin, a natural xanthone, against arsenic induced lung toxicity. Chronic exposure of sodium arsenite (NaAsO) at 10 mg/kg bw for 3 months abruptly increased the LDH release in broncho-alveolar lavage fluid, generated reactive oxygen species (ROS), impaired the antioxidant defense and distorted the alveoli architecture. It caused significant inflammatory outburst and promoted the apoptotic mode of cell death via upregulating the expressions of various proapoptotic molecules related to mitochondrial, extra-mitochondrial and ER stress mediated apoptotic pathway. Activation of inflammatory cascade led to disruption of alveolar capillary barrier and impaired Na/K-ATPase function that led to detaining of alveolar fluid clearance activity. Mangiferin due to its anti-inflammatory activity suppressed this inflammation and reduced inflammatory cell infiltration in lung tissue. It significantly restored the antioxidant balance and inhibited apoptosis in lung via upregulating Nrf2-HO1 axis.
        Aloin reduces inflammatory gene iNOS via inhibition activity and p-STAT-1 and NF-κB
        Lee W, Yang S, Lee C, Park EK, Kim KM, Ku SK and Bae JS
        Aloin is the major anthraquinone glycoside obtained from the Aloe species and exhibits anti-inflammatory and anti-oxidative activities. Here, we aimed to determine the effects of aloin on heme oxygenase-1 (HO-1) induction and on the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX) 2 in lipopolysaccharide (LPS)-activated human umbilical vein endothelial cells (HUVECs). To the end, aloin was tested whether aloin reduces iNOS protein expression and inflammatory markers (interleukin (IL)-1β and tumor necrosis factor (TNF)-α) in LPS-treated mice lung tissue. The results indicated that aloin affected HO-1 induction and reduced LPS-activated NF-κB-luciferase activity showed to preferential inhibition of iNOS/NO and COX-2/PGE2 that was partly related to inhibition of STAT-1 phosphorylation. In particular, aloin induced translocation of Nrf2 from cytosol into the nucleus by an increased Nrf2-ARE binding activity, and reduced IL-1β production in LPS-activated HUVECs. The reduced expression of iNOS/NO by aloin was reversed by siHO-1RNA-transfection. In LPS-treated mice, aloin significantly reduced iNOS protein in lung tissues, and TNF-α levels in the BALF. We concluded that aloin may be beneficial for treatment of lung injury.
        CX3CR1-deficient microglia shows impaired signalling of the transcription factor NRF2: Implications in tauopathies
        Castro-Sánchez S, García-Yagüe ÁJ, Kügler S and Lastres-Becker I
        TAU protein aggregation is the main characteristic of neurodegenerative diseases known as tauopathies. Low-grade chronic inflammation is also another hallmark that indicates crosstalk between damaged neurons and glial cells. Previously, we have demonstrated that neurons overexpressing TAU release CX3CL1, which activates the transcription factor NRF2 signalling to limit over-activation in microglial cells in vitro and in vivo. However, the connection between CX3CL1/CX3CR1 and NRF2 system and its functional implications in microglia are poorly described. We evaluated CX3CR1/NRF2 axis in the context of tauopathies and its implication in neuroinflammation. Regarding the molecular mechanisms that connect CX3CL1/CX3CR1 and NRF2 systems, we observed that in primary microglia from Cx3cr1 mice the mRNA levels of Nrf2 and its related genes were significantly decreased, establishing a direct linking between both systems. To determine functional relevance of CX3CR1, migration and phagocytosis assays were evaluated. CX3CR1-deficient microglia showed impaired cell migration and deficiency of phagocytosis, as previously described for NRF2-deficient microglia, reinforcing the idea of the relevance of the CX3CL1/CX3CR1 axis in these events. The importance of these findings was evident in a tauopathy mouse model where the effects of sulforaphane (SFN), an NRF2 inducer, were examined on neuroinflammation in Cx3cr1 and Cx3cr1 mice. Interestingly, the treatment with SFN was able to modulate astrogliosis but failed to reduce microgliosis in Cx3cr1 mice. These findings suggest an essential role of the CX3CR1/NRF2 axis in microglial function and in tauopathies. Therefore, polymorphisms with loss of function in CX3CR1 or NRF2 have to be taken into account for the development of therapeutic strategies.
        Ambient PM2.5 caused depressive-like responses through Nrf2/NLRP3 signaling pathway modulating inflammation
        Chu C, Zhang H, Cui S, Han B, Zhou L, Zhang N, Su X, Niu Y, Chen W, Chen R, Zhang R and Zheng Y
        PM2.5 pollution has been associated with numerous adverse effects including cardiovascular, respiratory and metabolic diseases as well as emotional disorders. However, the potential mechanism has not known clearly. Twenty-four rats were divided into 3 groups and exposed to various airs: filtered air (FA), unfiltered air (UA) and concentrated PM2.5 air (CA), respectively. Thirty wild type (WT) and 30 Nrf2 knockout (KO) mice were divided into 2 groups and exposed to FA and UA, respectively. The changes of neurobehavioral function, neurotransmitter secretion, toxic elements deposition, oxidative stress and the inflammation in prefrontal cortex were investigated during 9-12 weeks with/without PM2.5 exposure. Results showed that CA rats and KO-UA mice emerged obviously depressive-like responses. Li, Be, Al, Cr, Co, Ni, Se, Cd, Ba, Ti and Pb could deposit in the prefrontal cortex of rats after PM2.5 exposure. The neurotransmitters were significantly disorder in prefrontal cortex of CA rats. The NLRP3 signaling pathway was more activated in Nrf2 than WT mice after PM2.5 exposure for 9 weeks. Nrf2/ NLRP3 signaling pathway modulating the inflammation might play an important role in the depression induced by ambient PM2.5.
        Tomato Powder Modulates NF-B, mTOR, and Nrf2 Pathways during Aging in Healthy Rats
        Sahin K, Orhan C, Tuzcu M, Tastan H, Bilir B, Sahin N, Oner DA and Kucuk O
        In the present study, we aimed to investigate the effects of tomato powder (TP) on glucose and lipid metabolism, as well as oxidative stress and the NF-B, mTOR, and Nrf2 pathways during the aging process in healthy rats.
        Strigolactone GR24 upregulates target genes of the cytoprotective transcription factor Nrf2 in skeletal muscle
        Modi SR and Kokkola T
        GR24 is a synthetic strigolactone analog, demonstrated to regulate the development of plants and arbuscular mycorrhizal fungi. GR24 possesses anti-cancer and anti-apoptotic properties, enhances insulin sensitivity and mitochondrial biogenesis in skeletal myotubes, inhibits adipogenesis, decreases inflammation in adipocytes and macrophages and downregulates the expression of hepatic gluconeogenic enzymes. Transcription factor Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) is a master regulator of antioxidant response, regulating a multitude of genes involved in cellular stress responses and anti-inflammatory pathways, thus maintaining cellular redox homeostasis. Nrf2 activation reduces the deleterious effects of mitochondrial toxins and has multiple roles in promoting mitochondrial function and dynamics. We studied the role of GR24 on gene expression in rat L6 skeletal muscle cells which were differentiated into myotubes. The myotubes were treated with GR24 and analyzed by microarray gene expression profiling. GR24 upregulated the cytoprotective transcription factor Nrf2 and its target genes, activating antioxidant defences, suggesting that GR24 may protect skeletal muscle from the toxic effects of oxidative stress.

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