Publisher Health

In new peer-reviewed research published Nov. 3rd, 2022 in Nature Communications, Emily Spaulding, PhD. and Dustin Updike, PhD. reveal the homolog of a well-known human protein, Nucleolin, in the tiny, transparent roundworm, C. elegans.
Nucleolin is linked to human neurodegenerative disease and cancer. But the new finding challenges recent theories of the role structures inside the nucleus may play in such disorders — and surfaces a powerful new tool for researching the function of Nucleolin and how it does contribute to disease.
“Nucleolin is a multifunctional protein conserved across many animals, plants, and fungi, but previously thought to be absent in nematodes,” says Spaulding, a post-doctoral fellow in the Updike lab at Mount Desert Island Biological Laboratory. “It’s also associated with familial ALS and Alzheimer’s disease, and overall nucleolar dysfunction is linked to neurodegeneration.”
Their identification of the Nucleolin homolog (named NUCL-1) establishes C. elegans as a new discovery platform for neuronal functions of Nucleolin and the genetics of related neurodegeneration.
Nucleolin is found mainly in the nucleolus, the factory inside a cell’s nucleus where ribosomes are assembled. Unlike many other membrane-bound organelles inside cells, the nucleolus behaves like a large liquid droplet, also called a condensate.
Condensates form through liquid-to-liquid phase separation. Some imagine blobs of different densities forming inside a lava lamp, but exactly how this is achieved in living cells is unclear. Spaulding and Updike’s work shows that NUCL-1 is needed for phase separation in the C. elegans nucleolus.

In the battle of the sexes, women beat men in their ability to recover from kidney injury, but the reasons are not well understood.
A study led by Duke Health researchers provides some insights: Females, it turns out, have an advantage at the molecular level that protects them from a form of cell death that occurs in injured kidneys. This protection could be exploited as a potential therapeutic.
The findings appear online Nov. 8 in the journal Cell Reports.
“Kidney disease afflicts more than 850 million people worldwide every year, so it’s important to understand why female kidneys are more protected from these acute and chronic injuries,” said Tomokazu Souma, M.D., Ph.D., assistant professor in the Department of Medicine at Duke University School of Medicine. “Our study is a step toward identifying the causes and suggests that this female resilience could be therapeutically harnessed to improve kidney repair in both sexes.”
Souma and colleagues conducted studies in mice focusing on a form of cell death called ferroptosis, which was only recently discovered. This form of cell death is dependent on iron and oxidative stress. It has been identified as a key player in kidney diseases.
Using genetic and single-cell RNA transcriptomic analysis in mice, the researchers found that being female confers striking protection against ferroptosis through a particular pathway called nuclear factor erythroid 2-related factor 2, or NRF2.
In females, NRF2 is highly active, keeping cell death in check. In males, however, the sex hormone testosterone reduces the activity of NRF2, thus promoting ferroptosis and undermining cell resiliency in kidney injury.
Further experiments showed that chemically activating NRF2 protected male kidney cells from ferroptosis, demonstrating that NRF2 could be a potential therapeutic target to prevent failed renal repair after acute kidney injury.
“By identifying the mechanism in which the female hormonal environment protects and the male hormonal environment aggravates acute and chronic kidney injuries, we believe there is strong potential to boost the resilience of kidneys,” Souma said.
In addition to Souma, study authors include Shintaro Ide, Kana Ide, Koki Abe, Yoshihiko Kobayashi, Hiroki Kitai, Jennifer McKey, Sarah A. Strausser, Lori L. O’Brien, Aleksandra Tata, and Purushothama Rao Tata.
This study received support, in part, from the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK123097) and a Duke DST Spark Seed grant.
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Scientists investigating the mechanics of the early stages of lung cancer have identified a new potential treatment, which could also aid early detection of the disease.
Levels of a key protein — called TLR2 — in tumours was found to predict a patient’s survival after being diagnosed with lung cancer, a study shows.
A drug compound that activates TLR2 was tested in mice and was found to reduce tumour growth in the early stages of the disease.
With the five-year survival rate from late stage lung cancer only six per cent — compared with 50 per cent when diagnosed earlier — experts say the breakthrough could help spot the disease sooner and improve patient outcomes.
A group, led by researchers from the University of Edinburgh, discovered that TLR2 helps control some of the body’s defense mechanisms when cancerous mutations occur in cells.
The protein is linked with senescence, a process whereby cells stop growing and secrete a variety of chemicals and other proteins which collectively act as warning signals and defences against cancer.

Two novel and orally administered drugs can not only block the growth, but also shrink the size, of a tumour type found in the nervous system, new research has shown.
The tumours, schwannomas, most frequently grow on the nerves that bring hearing and balance information into the brain. Schwannomas are the most common nerve sheath tumour, and can occur in anyone but are also linked to a hereditary condition known as Neurofibromatosis Type II (NF2).
In NF2, where the function of the protein Merlin is lost in cells, patients frequently develop not only schwannomas, but also meningioma tumours associated with the brain and spinal cord.
The treatment of both tumour types is difficult, with surgery being the current mainstay but also carrying a high risk of damage to the surrounding normal nervous system tissue.
With an urgent need for new treatments, an international team of scientists focused on the Hippo signalling pathway, which normally controls organ size in human tissues and cells, but is dysregulated in multiple types of cancer.
Using a combination of patient-donor tumour cells from surgical resections and mouse models of schwannoma, the researchers showed that after just 21 days of the drugs being administered, tumour growth can be strongly and significantly reduced.

A year-long study of the dietary habits of 9,341 Australians has backed growing evidence that highly processed and refined foods are the leading contributor of rising obesity rates in the Western world.
The new study, in the latest issue of the journal Obesity conducted by the University of Sydney’s Charles Perkins Centre (CPC), was based on a national nutrition and physical activity survey undertaken by the Australian Bureau of Statistics (ABS), and further backs the ‘Protein Leverage Hypothesis’.
First put forward in 2005 by professors Raubenheimer and Stephen Simpson, the Protein Leverage Hypothesis argues that people overeat fats and carbohydrates because of the body’s strong appetite for protein, which the body actively favours over everything else. Because so much of modern diets consist of highly processed and refined foods — which are low in protein — people are driven to consume more energy-dense foods until they satisfy their protein demand.
Processed foods lack protein and drive craving
“As people consume more junk foods or highly processed and refined foods, they dilute their dietary protein and increase their risk of being overweight and obese, which we know increases the risk of chronic disease,” said lead author Dr Amanda Grech, a Postdoctoral Research Fellow at the CPC and the university’s School of Life and Environmental Sciences.
“It’s increasingly clear that our bodies eat to satisfy a protein target,” added Professor David Raubenheimer, the Leonard Ullmann Chair in Nutritional Ecology at the School of Life and Environmental Sciences. “But the problem is that the food in Western diets has increasingly less protein. So, you have to consume more of it to reach your protein target, which effectively elevates your daily energy intake.

Researchers have discovered the vital role of a hormone, that develops in men during puberty, in providing an early prediction of whether they could develop certain diseases in later life.
Scientists from the University of Nottingham have discovered that the novel insulin-like peptide hormone, called INSL3, is consistent over long periods of time and is an important early biomarker for prediction of age-linked disease. Their latest findings have been published today in Frontiers in Endocrinology.
INSL3 is made by the same cells in the testes that make testosterone, but unlike testosterone which fluctuates throughout a man’s life, INSL3 remains consistent, with the level at puberty remaining largely the same throughout a man’s life, decreasing only slightly into old age. This makes it the first clear and reliable predictive biomarker of age-related morbidity as compared to any other measurable parameters.
The results show that the level of INSL3 in blood correlates with a range of age-related illnesses, such as bone weakness, sexual dysfunction, diabetes, and cardiovascular disease.
The discovery of the consistent nature of this hormone is very significant as it means that a man with high INSL3 when young will still have high INSL3 when he is older. But someone with low INSL3 already at a young age, will have low INSL3 when older making him more likely to acquire typical age-related illnesses. This opens up exciting possibilities for predicting age-related illnesses and finding ways to prevent the onset of these diseases with early intervention.
The research was led by Professor Ravinder Anand-Ivell and Professor Richard Ivell and is the latest of three recent studies into this hormone. Professor Ravinder Anand-Ivell explains: “The holy grail of aging research is to reduce the fitness gap that appears as people age. Understanding why some people are more likely to develop disability and disease as they age is vital so that interventions can be found to ensure people not only live a long life but also a healthy life as they age. Our hormone discovery is an important step in understanding this and will pave the way for not only helping people individually but also helping to ease the care crisis we face as a society.”
The team analysed blood samples from 3,000 men from 8 regional centres in north, south, east, and west of Europe, including the UK, with two samples taken four years apart. The results showed that unlike testosterone, INSL3 remains at consistent levels in individuals
The study also showed that the normal male population, even when young and relatively healthy, still shows a wide variation between individuals in the concentration of INSL3 in the blood — almost 10-fold.
Professor Richard Ivell adds: “Now we know the important role this hormone plays in predicting disease and how it varies amongst men we are turning our attention to finding out what factors have the most influence on the level of INSL3 in the blood. Preliminary work suggests early life nutrition may play a role, but many other factors such as genetics or exposure to some environmental endocrine disruptors may play a part.”
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Watching violent TV during the preschool years can lead to later risks of psychological and academic impairment, the summer before middle school starts, according to a new study led by Linda Pagani, a professor at Université de Montréal’s School of Psycho-Education.
The study is published in the Journal of Developmental and Behavioral Pediatrics.
Before now, “it was unclear to what extent exposure to typical violent screen content in early childhood — a particularly critical time in brain development — can predict later psychological distress and academic risks,” said Pagani.
“The detection of early modifiable factors that influence a child’s later well-being is an important target for individual and community health initiatives, and psychological adjustment and academic motivation are essential elements in the successful transition to adolescence,” she added.
“So, we wanted to see the long-term effect of typical violent screen exposure in preschoolers on normal development, based on several key indicators of youth adjustment at age 12.”
To do this, Pagani and her team examined the violent screen content that parents reported their children viewing between ages three-and-a-half and four-and-a-half, and then conducted a follow-up when the children reached 12.

A new study by Portland State University researchers is the first to show that eating a diet exclusively high in saturated fats can reprogram the mouse immune system, making it better able to fight off infection but more susceptible to systemic inflammatory conditions, including sepsis. Brooke Napier, assistant professor of biology at PSU, led the study, which was published in eLife.
The ketogenic or “keto” diet is a popular high-fat diet used for weight loss or to control epileptic seizures. This study shows that when mice eat a ketogenic diet that is high in saturated fats it can have a significant impact on their immune system.
A previous study by Napier and colleagues found that mice fed a high-fat, high-sugar Western diet were more susceptible to sepsis and had a higher mortality rate than mice fed a standard diet. In the current study, the researchers found similar effects in mice fed a high-fat ketogenic diet, suggesting that dietary fat may play a role in sepsis.
The researchers focused on one particular fat found in the blood of the mice fed a ketogenic diet: palmitic acid, which is commonly found in animal fats and dairy products. Remarkably, mice fed a normal diet who were injected with palmitic acid also became more susceptible to sepsis.
“It was just exposure to this one saturated fat that made them more susceptible to sepsis mortality,” says Napier. “The idea that you could have a specific fat in your diet that would cause such a drastic outcome in disease is kind of incredible.”
Napier and her team next probed just how exactly high levels of palmitic acid could initiate sepsis. Their first clue came when they noticed that mice fed the Western diet, mice fed the ketogenic diet, and mice treated with palmitic acid all had high levels of inflammatory cytokines, immunological hormones that can cause fever and systemic inflammation during sepsis.

A new drug called Baxdrostat has been shown to significantly reduce high blood pressure (hypertension) in patients who may not respond to current treatments for the condition, according to results from a phase II trial led jointly by a Queen Mary University of London researcher and colleagues at CinCor Pharma, USA.
Published in the New England Journal of Medicine and presented at the American Heart Association Scientific Sessions conference, the trial results represent the first time that this long-sought new class of drugs to treat resistant hypertension has been developed and successfully tested.
The trial, conducted over 12 weeks, gave 248 patients either a once daily dose of Baxdrostat at varying amounts or a placebo. At entry to the trial, none of these patients’ blood pressure was controlled despite taking 3 or more medicines for high blood pressure. The doses of Baxdrostat, taken in addition to patients’ usual medicines, varied from 2mg, to 1mg, to 0.5mg. At the end of the 12 weeks, the group who received the highest amount of Baxdrostat saw a 20-point fall in blood pressure. There was an 11-point difference between this group and that which received the placebo treatment, a difference rarely seen in any single drug to reduce blood pressure.
Baxdrostat works by preventing the body from making aldosterone, a hormone which regulates the amount of salt in the body. Baxdrostat suppressed blood and urine levels of aldosterone. The study shows the drug causes a marked fall in blood pressure in patients whose hypertension is resistant to usual drugs, and that this type of hypertension is partly due to excess production of the aldosterone hormone.
The obstacle to development of such a drug has been matching the drug’s target — the enzyme which makes aldosterone — with another enzyme, which makes the essential steroid hormone, cortisol.
Professor Morris Brown, co-senior author of the study and Professor of Endocrine Hypertension at Queen Mary University of London, said: “The results of this first-of-its-kind drug are exciting, although more testing is required before we can draw comparisons with any existing medications. But Baxdrostat could potentially offer hope to many people who do not respond to traditional hypertension treatment.
“The effectiveness of older drugs in individual patients can vary substantially, whereas a hallmark of this new class is that it can be predicted to work well in the patients whose aldosterone hormone has made them resistant to older treatments.”
High blood pressure is the main cause of strokes, and a common cause of heart attacks and kidney failure. In most people with the condition, the cause is unknown, and they need life-long treatment through drugs.
High blood pressure is one of the most common conditions among adults in the UK — roughly a third of adults suffer from it. In recent years, it has become clear that in 5-10 per cent of people with it is a gene mutation in the adrenal glands, which results in excessive amounts of the steroid hormone, aldosterone, being produced. This amounts to potentially more than 500,000 people in the UK.
Aldosterone causes salt to be retained in the body, driving up the blood pressure. Patients with excessive aldosterone levels in the blood are resistant to treatment with the commonly used drugs for hypertension.
Professor Brown has been personally involved in work on the drug for over 10 years and advised both on the Baxdrostat trial, undertaken in the US, and the drug’s previous development. He worked closely with pharmaceutical firms responsible for developing the drug as well as start-ups that have licensed it.
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Researchers at the University of Maryland School of Medicine’s (UMSOM) Center for Precision Disease Modeling identified how a specific protein in SARS-CoV-2, the virus responsible for COVID-19, damages heart tissue. They then used a drug to reverse the toxic effects of that protein on the heart.
Their findings, based on research with fruit flies and mouse heart cells, were published on Sept. 30, 2022, in Communications Biology, a Nature journal.
People infected with COVID-19 are at a significantly higher risk for developing inflammation of the heart muscle, abnormal heart rhythms, blood clots, stroke, heart attacks, and heart failure for at least a year after infection, compared to those who have not been infected with the virus. Although scientists rapidly developed vaccines and medications to lessen the severity of COVID-19 disease, these therapies do not protect the heart or other organs from the damage that can be done by even a mild infection.
“To treat patients in the long run, we must first understand the mechanism behind what is causing the disease. Our research shows that individual SARS-CoV-2 proteins can each do major damage to specific tissues in the body — similar to what has been found for other viruses like HIV and Zika,” said senior author Zhe Han, PhD, Professor of Medicine and Director of the Center for Precision Disease Modeling at UMSOM. “By identifying these processes of injury in each tissue, we can test drugs to see whether any can reverse this damage; those drugs that show promise can then be further tested in clinical research studies.”
Last year, Dr. Han and his research team identified the most toxic SARS-CoV-2 proteins in studies using fruit flies and human cells. They found a promising drug selinexor reduced the toxicity of one of these proteins, but not the other one, known as Nsp6.
In their latest study, they found that Nsp6 turned out to be the most toxic SARS-CoV-2 protein in the fly heart. Next, they found that the Nsp6 protein hijacked the fruit fly’s cells in its heart to turn on the glycolysis process, which enables cells to burn the sugar glucose for energy. Typically, heart cells use fatty acids as an energy source, but switch over to sugar metabolism during heart failure as these cells to try to repair the damaged tissue. The researchers also found the Nsp6 protein did added damage by disrupting the cell’s powerhouse, called the mitochondria, which produces energy from sugar metabolism.
The team then blocked sugar metabolism in fruit flies and mouse heart cells using the drug 2-deoxy-D-glucose (2DG). They found that the drug reduced the heart and mitochondria damage caused by the Nsp6 viral protein.
“We know that some viruses hijack the infected animal’s cell machinery to change its metabolism to steal the cell’s energy source, so we suspect SARS-CoV-2 does something similar. The viruses can also use the byproducts of sugar metabolism as building blocks to make more viruses,” said Dr. Han. “So, we predict this drug that changes the metabolism in the heart back to what it was before infection would be bad for the virus, by both cutting off its energy supply and eliminating the pieces it needs to replicate.”
The researchers said that fortunately 2DG is inexpensive and is used regularly in laboratory research. Although 2DG has not been approved by the U.S. Food and Drug Administration to treat disease, the drug is currently in clinical trials for treatment of COVID-19 in India.
“Too many Americans who have recovered from COVID wind up with dangerous heart conditions weeks or months later, and we need to learn the fundamental reasons for why this is happening,” said Mark T. Gladwin, MD, Vice President for Medical Affairs at University of Maryland, Baltimore and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, UMSOM. “With this research elucidating the pathways of the Nsp6 protein, we can refine the treatments we target for future research with the ultimate aim of reversing further heart damage in these patients.”
This study was funded by the University of Maryland, Baltimore Institute for Clinical and Translational Research COVID-19 Accelerated Translational Incubator Pilot (ATIP) grant.
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Materials provided by University of Maryland School of Medicine. Original written by Vanessa McMains. Note: Content may be edited for style and length.