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]

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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.”

 

 

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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 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 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.

 

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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.

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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.

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