Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more
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Department of Dermatology

The future of your face is plastic

Prolific drug discoverer and repurposer Jack Arbiser is at it again. Arbiser, an Emory dermatologist, has identified a new (but old) compound as a treatment for rosacea, a common skin condition, according to New York cosmetic dermatology doctors involving redness and visible blood vessels on the face. Severe rosacea can lead to itching, pain, or thickening of the skin.

The compound is remarkable for two reasons: it is the same as Irganox 1010, an antioxidant plastic stabilizer used in industry for years, and it is a proteasome inhibitor.

The proteasome is the cell’s garbage disposal, and many kinds of proteins get tagged and thrown into it. Interfering with the disposal inhibits the inflammatory NFkB pathway. Oncologists may be familiar with the proteasome inhibitor bortezomib (a blockbuster drug known commercially as Velcade), used to treat multiple myeloma.

Arbiser has founded a company called Accuitis to develop the compound, called ACU-D1. Accuitis was funded by the Georgia Research Alliance. Accuitis’ web site notes that the compound “has the advantage of extensive toxicology testing in multiple animal species, as well as a safe record of human exposure for over 30 years.”

“ACU-D1 is a cream that works through a new mechanism of action that no current rosacea medications work through,” Arbiser told Dermatology Times. “Given the fact that there are no truly great treatments for rosacea, we are hoping that in the future our compound will be a first-in-class drug and become first-line therapy for rosacea.”

The results of a clinical trial for ACU-D1, conducted at the University of Louisville in Kentucky and Forefront Dermatology in San Antonio, were recently published in Journal of Drug in Dermatology.

This was a first-in-human study with 40 participants, lasting 12 weeks. It was not powered for a pivotal evaluation of ACU-D1’s efficacy. However, the drug showed a pronounced effect on people with severe rosacea. The trial used a Canfield imaging system imaging as a way of measuring skin irritation objectively, separately from the opinions of the investigators.

Canfield imaging of the face. From left to right: baseline, week 4, week 12

The drug appears to take effect after a couple weeks, showing maximum efficacy at one month. It also shows positive effects on redness, which is rare for a skin medication, Arbiser says. Few adverse effects were reported.

Arbiser says ACU-D1 could be an alternative to antibiotics, a common systemic treatment for rosacea. (Rosacea is partly an inflammatory response to microbes in the skin.) He is interested in studying ACU-D1’s efficacy for other inflammatory skin conditions such as eczema and psoriasis.

Now, plastic and cosmetic surgery such as TipLyft is common in treating a skin condition or a blunt from an accident. It helps to know that individuals can get treatments like these.

Posted on August 27, 2021 by Quinn Eastman in Cancer, Immunology Leave a comment

Beyond birthmarks and beta blockers, to cancer prevention

Ahead of this week’s Morningside Center conference on repurposing drugs, we wanted to highlight a recent paper in NPJ Precision Oncology by dermatologist Jack Arbiser. It may represent a new chapter in the story of the beta-blocker propranolol.

Infantile hemangioma (stock photo)

Several years ago, doctors in France accidentally discovered that propranolol is effective against hemangiomas: bright red birthmarks made of extra blood vessels, which appear in infancy. Hemangiomas often don’t need treatment and regress naturally, but some can lead to complications because they compromise other organs. Infants receiving propranolol require close monitoring to ensure that they do not suffer from side effects related to propranolol’s beta blocker activity, such as slower heart rate or low blood sugar.

Arbiser’s lab showed that only one of two mirror-image forms of propranolol is active against endothelial or hemangioma cells, but it is the inactive one, as far as being a beta-blocker. Many researchers were already looking at repurposing propranolol based on its anti-cancer properties. The insight could be a way to avoid beta-blocker side effects, even beyond hemangiomas to malignant tumors. Check out the Office of Technology Transfer’s feature on this topic. Read more

Posted on November 12, 2019 by Quinn Eastman in Cancer Leave a comment

Fighting cancer with combinatorial imagination

In his undergraduate days, Winship Cancer Institute dermatologist and cancer researcher Jack Arbiser was an organic chemist. That may be why he recognized an organic synthesis reagent based on the metal palladium as a potential anti-cancer drug.

We’re talking about Tris-DBA-palladium. Arbiser and colleagues showed in a 2008 Clinical Cancer Research paper that this deep purple stuff (see photo) is active against melanoma, and since then, against other types of cancer such as pancreatic cancer, multiple myeloma, and CLL leukemia.

Tris-DBA-PD has a deep purple color. The palladium atoms can be seen in the diagram as two blue balls at the center. From Wikipedia.

Since it’s used in organic synthesis, you might expect Tris-DBA-palladium not to be very soluble in water. A new paper in Scientific Reports demonstrates that this issue can be addressed by hooking up the reagent to nanoparticles made of hyaluronic acid, which targets tumor cells. They are effective against melanoma in mice, the paper shows.

“We have already demonstrated that Tris DBA palladium by itself has activity against melanoma in mice,” Arbiser writes (in his VA grant summary). “However, we believe that we can make Tris DBA palladium into an even more powerful drug by adding it to nanoparticles that are guided to the tumor.”

In an email to Lab Land, Arbiser says he arrived at Tris-DBA-palladium by using his chemist’s imagination, in a “your chocolate landed in my peanut butter” kind of way.

“I got the idea for looking at this compound because it is a complex of Pd with a curcumin-like structure, and I figured it might have the characteristics of platinum and curcumin together,” he says. Read more

Posted on March 6, 2019 by Quinn Eastman in Cancer Leave a comment

From stinging to soothing: fire ant venom may lead to skin treatments

Compounds derived from fire ant venom can reduce skin thickening and inflammation in a mouse model of psoriasis, Emory and Case Western scientists have shown.

The results were published on Sept. 11 in Scientific Reports.

Update: When this paper was published, Lab Land received an email providing anecdotal support for effectiveness in humans. “I have suffered with psoriasis all my life and in 2015, I went on an expedition to Central America. I got eaten alive by fire ants, as they managed to get into my socks. My psoriasis however got better for a time, and as somebody who has directly experienced fire ant venom, I strongly believe that there is a correlation between it and psoriasis.”

The findings could lead to new treatments for psoriasis, a common autoimmune skin disease. Topical steroids are now most frequently used for mild to moderate psoriasis, but they have side effects such as skin thinning and easy bruising.

Solenopsins are the main toxic components of fire ant venom. They chemically resemble ceramides, which are lipid-like molecules essential for maintaining for the barrier function of the skin. Ceramides can be found in many skin care products.

Ceramides can act as a double-edged sword, says lead author Jack Arbiser, MD, PhD, professor of dermatology at Emory University School of Medicine. Under certain conditions they can be converted by cells into S1P (sphingosine-1-phosphate), an inflammatory molecule.

Arbiser and his colleagues devised two solenopsin analogs that look like ceramides, but can’t be degraded into S1P. They then tested them in a mouse model of psoriasis, applying the compounds in a one percent skin cream for 28 days. Read more

Posted on September 15, 2017 by Quinn Eastman in Immunology Leave a comment

Opioid abuse medicine can control genetic skin disease

Evidence is emerging that naltrexone, a medicine used to treat opioid and alcohol abuse, can also control a genetic skin disease that causes painful, itchy rashes and blisters.

Two separate brief reports last week in JAMA Dermatology, from Emory and Cleveland Clinic investigators, describe the treatment of six patients with Hailey-Hailey disease.

Dermatologist Ron Feldman, MD, PhD is the senior author on the Emory report, which says:

“Low-dose naltrexone has been widely touted on social media platforms, including multiple YouTube videos, as an anecdotal treatment for patients with HHD, with surprisingly no published evidence until this year.”

Feldman tells Lab Land: “We decided to try it based on the patients; we had no clue about low-dose naltrexone until we met one of the patients with Hailey-Hailey disease, who came in asking for this therapy based on social media.”

At Emory, each of the three patients had tried at least four prior treatments, such as antibiotics and corticosteroids, but all were unsuccessful in controlling the disease. Read more

Posted on August 7, 2017 by Quinn Eastman in Immunology 1 Comment

Rescuing existing antibiotics with adjuvants

One of the speakers at Thursday’s Antibiotic Resistance Center symposium, Gerald Wright from McMaster University, made the case for fighting antibiotic resistance by combining known antibiotics with non-antibiotic drugs that are used to treat other conditions, which he called adjuvants.

As an example, he cited this paper, in which his lab showed that loperamide, known commercially as the anti-diarrheal Immodium, can make bacteria sensitive to tetracycline-type antibiotics.

Wright said that other commercial drugs and compounds in pharmaceutical companies’ libraries could have similar synergistic effects when combined with existing antibiotics. Most drug-like compounds aimed at human physiology follow “Lipinski’s rule of five“, but the same rules don’t apply to bacteria, he said. What might be a more rewarding place to look for more anti-bacterial compounds? Natural products from fungi and plants, Wright proposed.

“I made a little fist-pump when he said that,” says Emory ethnobotanist Cassandra Quave, whose laboratory specializing in looking for anti-bacterial activities in medicinal plants.

Medical thnobotanist Cassandra Quave collecting plant specimens in Italy.

Medical ethnobotanist Cassandra Quave collecting plant specimens in Italy

Indeed, many of the points he made on strategies to overcome antibiotic resistance could apply to Quave’s approach. She and her colleagues have been investigating compounds that can disrupt biofilms, thus enhancing antibiotic activity. More at eScienceCommons and at her lab’s site.

Posted on January 15, 2016 by Quinn Eastman in Uncategorized Leave a comment

Honokiol, Jack of all trades

Emory dermatologist Jack Arbiser discovered the anti-angiogenic properties of honokiol, a compound derived from magnolia cones, more than a decade ago. Since then, honokiol has been found to have anti-inflammatory, anti-oxidant and anticancer properties.

A paper published Tuesday in Nature Communications from researchers at the University of Chicago shows that honokiol inhibits the mitochondrial enzyme Sirt3, which has connections to longevity. Manesh Gupta and colleagues demonstrate that honokiol can block cardiac hypertrophy in mice, a finding with possible relevance for the treatment of heart failure.

Sirt3 has been linked both genetically to human life span, and until now, the only way to increase levels of Sirt3 was old-fashioned calorie restriction and/or endurance exercise.

The authors write: It is believed that Sirt3 does not play a role in embryonic development, but rather it fine tunes the activity of mitochondrial substrates by lysine deacetylation to protect cells from stress… To the best of our knowledge, this is the first report describing a pharmacological activator of Sirt3.

 

Posted on April 15, 2015 by Quinn Eastman in Cancer, Heart Leave a comment

Nox4 inhibitor expands its reach to A-T

Emory dermatologist Jack Arbiser has been investigating (and recently patented) inhibitors of the enzyme Nox4 as potential anti-cancer drugs.

Nox4 has emerged as a potential therapeutic target in ataxia-telangiectasia, a rare multifaceted genetic disorder that leads to neurological problems, a weakened immune system and an increased risk of cancer. Ataxia-telangiectasia (or A-T) is caused by a defect in ATM, a sensor responsible for managing cells’ responses to DNA damage and other kinds of stress.

In a February PNAS paper, researchers at the National Cancer Institute led by William Bonner report that a Nox4 inhibitor can dial back oxidative stress and DNA damage in ataxia-telangiectasia cells, and can reduce cancer rates in a mouse model of the disease. Nox4 was activated in cells and tissue samples obtained from A-T patients.

The Nox4 inhibitor the NCI team used, fulvene-5, was originally identified by Arbiser in a 2009 Journal of Clinical Investigation paper as a possible treatment for hemangiomas, a common tumor in infants that emerges from blood vessels.

David Lambeth, an expert on the NADPH oxidase family of enzymes, and his team recently described Nox4 as an “hydrogen peroxide-generating oxygen sensor.”

 

Posted on February 12, 2015 by Quinn Eastman in Cancer Leave a comment

Magnanimous magnolias keep on giving

Honokiol, the versatile compound found by Emory dermatologist Jack Arbiser in the cones of magnolia trees, makes a surprise appearance in a recent paper in Nature Medicine.

Jack Arbiser, MD, PhD, and colleagues originally isolated honokiol from magnolia cones. It can also be found in herbal teas.

The paper, from Sabrina Diano, Tamas Horvath and colleagues at Yale, probes the role of reactive oxygen species (ROS) in the hypothalamus, a part of the brain that regulates appetite. In the paper, Horvath’s laboratory uses honokiol as a super-antioxidant, mopping up ROS that suppress appetite. Arbiser initiated the collaboration with Horvath after finding, while working with Emory free radical expert Sergei Dikalov, how effective honokiol is at neutralizing ROS.

The paper is intriguing partly because it’s an example of a situation where ROS, often thought to be harmful because of their links to aging and several diseases, are actually beneficial. In this case, they provide a signal to stop eating. A recent paper from Andrew Neish’s lab at Emory provides another example, where probiotic bacteria stimulate production of ROS, which promote healing of the intestine.

Arbiser notes that since honokiol can increase appetite, the compound may be helpful in situations where doctors want patients to eat more.

“This might be particularly valuable in patients who are nutritionally deficient due to chemotherapy and provides a rationale for adding honokiol to chemotherapy regimens,” he writes.

Satiety producing neurons in the hypothalamus

A note of caution: in the Nature Medicine paper, honokiol is infused directly into the brain.

Honokiol has been shown to counteract inflammation and slow the growth of blood vessels (important in fighting cancer). Collaborating with Arbiser, Emory endocrinologist Neale Weitzmann has recently found that honokiol stimulates osteoblasts, the cells that build bone, suggesting that it could reduce bone loss in osteoporosis.

Posted on September 7, 2011 by Quinn Eastman in Cancer Leave a comment