Day: August 26, 2025

Categories : Metabolic Disorders NeurologyTags :

New Research Shows that Macrophages Help Prevent the Development of Neuropathy

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Source: Pixabay CC0

An increase in high-fat, high-fructose foods in people’s diets has contributed to a dramatic increase in type 2 diabetes. This, in turn, has led to an increase in peripheral neuropathy. About half of people with type 2 diabetes are affected, and of these, about half experience severe neuropathic pain.

The damage begins as axons from sensory neurons begin to retract and disappear from the tissues they innervate. New research from the lab of Clifford Woolf, MB, BCh, PhD, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, reveals that months before the damage occurs, immune cells flood into peripheral nerves in an apparent attempt to protect them. This surprising insight, published in Nature, could lead to strategies to prevent peripheral neuropathy or at least minimize and slow the onset of the damage.

Immune cells prevent nerve damage

A team led by Sara Hakim, PhD, a graduate student in the lab, created a mouse model of diabetes induced by a high-fat, high-fructose diet. The model showed that these mice developed all the major features of diabetes within eight to 12 weeks of starting the diet. At about six months, axons in the skin began to degenerate, indicating the presence of neuropathy.

“Diabetic neuropathy takes years, or even decades to develop in humans,” says Hakim, who is now at Vertex. “By using a mouse model in which symptoms slowly develop over months, we were able to catch the progression of the disease over time, and observe those early protective responses when the body is still trying to fight the disease.”

The researchers suspected that peripheral neuropathy is caused by the immune system, so used single-cell sequencing to detect changes in immune cells near sensory neuron axons in peripheral nerves.

One type of immune cell residing in nerves, a pro-inflammatory macrophage, began producing chemokines. These signaling molecules recruited a second population of circulating macrophages, which began infiltrating the nerve 12 weeks after the mice began the diet – as sensory symptoms were starting to appear but before nerve degeneration was seen.

Previously, macrophages were thought to have a pathogenic role in diabetes and were mainly reacting to axon loss. But Hakim, Woolf, and colleagues observed just the opposite.

“To our great surprise, when we blocked infiltration of macrophages into the nerve, neuropathy started getting worse, not better,” says Woolf. “The macrophages were protective. They slowed down the onset of neuropathy and reduced its impact.”

Potential strategies for peripheral neuropathy

The Woolf Lab is now exploring how the infiltrating macrophages protect against peripheral neuropathy. The next step would be to find a way to induce and sustain this protection and identify biomarkers that would flag those people with diabetes who are at risk.

One potential protective strategy might involve accelerating the recruitment of macrophages into nerves; another might involve mimicking their protective function by harnessing compounds they secrete, such as galectin 3.

“Since we could profile the cells and identify what genes they are expressing, we found a number of signalling molecules known to be protective,” says Woolf. “We can now go through that list and check to see which are most active.”

The latest work reinforces the idea that pain isn’t just a disease of neurons, but results from interactions between the nervous system and the immune system. In a study last year, the Woolf Lab discovered thousands of molecular interactions between pain-sensing neurons and different types of immune cells.

Now, the plot is thickening with this example of immune cells acting to prevent painful nerve damage. “We’ve now revealed a novel, slower protective effect of the immune system,” Woolf says.

Source: Boston Children’s Hospital

Categories : Cancer NeurologyTags :

Researchers Find TBI Link to Development of Malignant Brain Tumours

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Coup and contrecoup brain injury. Credit: Scientific Animations CC4.0

New research led by investigators at Mass General Brigham suggests a link between a history of traumatic brain injury (TBI) and risk of developing a malignant brain tumour. By evaluating data from 2000–2024 of more than 75 000 people with a history of mild, moderate or severe TBI, the team found the risk of developing a malignant brain tumour was significantly higher compared to people without a history of TBI. The results were published in JAMA Network Open.

“I see these results as alarming,” said co-senior author and corresponding author Saef Izzy, MD, FNCS, FAAN, a neurologist and head of the Immunology of CNS Injury Program at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system. “Our work over the past five years has shown that TBI is a chronic condition with lasting effects. Now, evidence of a potential increased risk of malignant brain tumours adds urgency to shift the focus from short-term recovery to lifelong vigilance.

“Alongside our earlier findings linking TBI and cardiovascular disease, this underscores the importance of long-term monitoring for anyone with a history of TBI.”

The team divided the severity of TBI between mild, moderate and severe, with participants suffering from incidents ranging from car accidents to falls. In the two categories of moderate and severe, 0.6% of people (87 out of 14 944) developed brain tumours within 3-to-5 years after the TBI, which was a higher percentage than controls. Mild cases of TBI, such as those caused by concussions, were not associated with an increased risk of tumour. The aim of the study was not to establish a cause-and-effect link between moderate-to-severe TBI and malignant tumours, but rather to explore whether an association exists. Determining causality and understanding the underlying mechanisms will require a dedicated translational study in the future.

A previous study showed veterans of the Iraq and Afghanistan wars who suffered TBI experienced an increased risk of brain tumours, but previous studies on civilian populations showed conflicting results. The collaborative team of researchers used an international disease classifying system known as ICD codes to exclude anyone in the study with a history of brain tumour, benign tumours, and risk factors such as radiation exposure.

Previous neurotrauma studies from Mass General Brigham have looked at patients with a history of TBI and found an association with the emergence of anxiety, depression, and other psychiatric, neurological, and cardiovascular diseases, but the current study focuses on malignant tumour development.

Future imaging studies could draw a connection between the location of the TBI and where tumours developed in the brains of participants. The team would like to further study patients with repeated injuries, such as falls. 

“While there is an increased risk of tumour from TBI, the overall risk remains low. Still, brain tumour is a devastating disease and often gets detected in later stages,” said lead author Sandro Marini, MD, a neurologist at Mass General Brigham. “Now, we’ve opened the door to monitor TBI patients more closely.”

Source: Mass General Brigham

Categories : GastrointestinalTags :

Research Uncovers Why IBD Causes Blood Clots – and How to Prevent Them

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Irritable bowel syndrome. Credit: Scientific Animations CC4.0

Rates of inflammatory bowel disease are rising, and there’s currently no cure. IBD can also be deadly: up to 8% of people with the disease develop blood clots, which can lead to heart attack and stroke. New research has uncovered why blood clotting malfunctions in IBD – and identified drugs that normalise blood clotting in human cells and animal models of IBD.

“We think we can leverage these findings to reduce inflammation and the risk of blood clots,” says senior author Aaron Petrey, PhD, assistant professor of microbiology and immunology at University of Utah Health, associate director of the U’s Molecular Medicine Program.  “This could be lifesaving.”
 
The results are published in Blood.

Clotting with the brakes off

Most research into IBD has focused on immune cells. But blood cells called platelets are another key contributor to IBD symptoms. In healthy people, platelets clump together into clots in response to injuries to stop bleeding, and don’t form clots otherwise. But in patients with IBD, platelets are on a hair trigger, ready to form clots at the slightest provocation.

Surprisingly, platelets from IBD patients weren’t clotting via the normal pathways that trigger clotting, says first author Rebecca Mellema, PhD, pathology postdoc. “It’s completely independent of what we would expect.”

“There’s an innate mechanism by blood vessels to tell platelets to stay quiet and not form a clot yet,” Petrey explains. “Once there’s injury or inflammation, that signal can switch over and tell them to form a clot. That’s the process that’s broken in IBD patients.”

IBD platelets appear to clot more often because they don’t have enough of a key protein called layilin, the researchers found. In healthy people, layilin acts as a molecular brake for clotting: it senses the difference between healthy and injured blood vessels and prevents platelets from clotting as long as blood vessels are intact.

But when the researchers deleted the layilin gene in mice, the brakes came off. Without layilin, platelets were extra sticky, forming clots when they shouldn’t.

The researchers also found that platelets from IBD patients only had about 60% of the layilin protein that they should, leaving them constantly on the verge of clotting. 

A promising drug target

Layilin prevents unwanted clotting by tamping down the activity of a clot-triggering molecule called Rac1. In mice without the layilin gene – and in people with IBD – Rac1 is always a little bit too active, which means platelets are too prone to forming clots.

But there’s good news. Drugs that prevent Rac1 activity are already in clinical trials for other conditions, and the researchers’ results suggest that these Rac1 inhibitors could be powerful therapeutics for IBD.

One Rac1 inhibitor reduced excessive clotting in human platelets in a dish. The inhibitor also decreased the level of tissue damage in the gut in a mouse model of IBD.

Promisingly, the drug decreased clotting in platelets from IBD patients even more strongly than it affected healthy cells. “We have shown a hyperactivation pathway in resting IBD patient platelets, but they’re also incredibly sensitive to treatment, moreso than those from a healthy person,” Mellema says.

Normalizing Rac1 activity might not only reduce the risk of heart attack and stroke—it could also help alleviate day-to-day IBD symptoms, the researchers say. Excessive clotting can block blood flow in the gut and make inflammation worse, which means that preventing clotting could reduce inflammation.

Unlike established anti-clotting drugs, the researchers say, Rac1 inhibitors shouldn’t lead to an increased risk of dangerous bleeding, which is a serious concern for IBD patients with chronic inflammation. Blocking Rac1 won’t interfere with other, independent pathways that can trigger platelet clotting, so the cells should still be able to form needed clots in response to injury. 

“We’re targeting a pathway that is not pre-activated in healthy people,” Petrey says. “So we can address that step of the pathway, and if there’s a significant injury, the platelets can overcome that inhibition.”

Other groups had been looking into the potential of Rac1 inhibitors to reduce inflammation in IBD. The new work emphasises the potential of these drugs to address multiple symptoms. “Paying more attention to what we can do to address these blood clotting risks could significantly improve patient lives,” Petrey says.

Source: University of Utah Health

Categories : GeneticsTags :

Like Likes Like: Partner Preferences May Be Explained by Genetics 

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Couple or siblings? New study may explain why we prefer partners who are similar to us. Photo by Daniil Onischenko on Unsplash

It is no secret that people are often drawn to romantic partners who seem similar to themselves. This tendency, called assortative mating, has been established in humans (Horwitz et al., 2023; Luo, 2017) as well as other species. Fish, for example, demonstrate the behaviour frequently (Jiang et al., 2013).  

Assortative mating has also recently been in focus on social media with the viral Siblings or Dating game, where people guess whether two individuals who look alike are related or a couple. 

The idea is well-founded in academic research. Humans have been observed to select partners with similar physical, personality, and demographic traits (Horwitz et al., 2023), which can impact the genetics of populations – creating subgroups that emphasise the presence of shared traits (Abdellaoui et al., 2015).  

But selecting a partner like ourselves may not be solely determined by personal choice. A new study soon to be published in Psychological Science suggests that assortative mating can be explained relatively simply by looking at the inheritance of preferred traits and corresponding preferences for those traits. 

Coauthors Kaitlyn Harper and Brendan Zietsch from the University of Queensland describe this scenario simply: If you are tall, you may have inherited tallness from one parent (say, your mother) and the preference for tallness in a romantic partner from your other parent (in this case, your father). The combination of those inherited traits means that you exist in the world as a tall person and are attracted to tall people.  

The idea that preference for a particular trait could lead to genetic correlations has been discussed in previous research but is a newer concept for evolutionary psychology, especially in the context of assortative mating.  

“The pieces were there, but they hadn’t been connected in this way before,” Harper said. “Agent-based modelling helped us connect the dots – by simulating populations, we could see that assortative mating naturally emerged without the need for additional assumptions or processes.” 

She added that this research wouldn’t have been possible without an interdisciplinary mindset. 

“The mechanism itself is familiar in evolutionary biology, but it wasn’t thought of as an explanation for assortative mating,” she said. “Making that connection only became possible when we looked across the two disciplines.” 

To test this theory, the authors ran an agent-based model where partners are chosen according to heritable traits and preferences over 100 generations. They included models with and without selection pressure on the number of offspring within each generation to assess how the theory stands up under more naturalistic conditions.  

They found that even with up to 10 preferences for traits in a partner, clear genetic correlations formed between traits and preferences for those traits, which resulted in the agents choosing partners similar to themselves. Models with selection pressure generated less-stable correlations, which the authors attribute to reduced variance in traits.  

“The power of this finding is in its parsimony – it shows that a phenomenon which has puzzled researchers for decades can be understood through an explanation that was hiding in plain sight,” Harper said. “And because the mechanism is so general, it can also apply to assortative mating in animals, where many of the explanations proposed for humans wouldn’t make sense.” 

Source: Association for Psychological Science

Categories : Cardiovascular DiseaseTags :

High-salt Diet Causes Brain Inflammation, Raising Blood Pressure

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Credit: Pixabay CC0

A new study from McGill University finds that a high-salt diet triggers brain inflammation that drives up blood pressure.

The research, led by Masha Prager-Khoutorsky in collaboration with an interdisciplinary team at McGill and the Research Institute of the McGill University Health Centre, suggests the brain may be a missing link in certain forms of hypertension traditionally attributed to the kidneys.

“This is new evidence that high blood pressure can originate in the brain, opening the door for developing treatments that act on the brain,” said Prager-Khoutorsky, associate professor in McGill’s Department of Physiology.

Hypertension affects two-thirds of people over 60 and contributes to 10 million deaths worldwide each year. Often symptomless, the condition increases the risk of heart disease, stroke and other serious health problems.

About one-third of patients don’t respond to standard medications, which primarily target the blood vessels and kidneys based on the long-standing view that hypertension begins there. The study, published in the journal Neuron, suggests the brain may also be a key driver of the condition, particularly in treatment-resistant cases.

How salt disrupts the brain

To mimic human eating patterns, rats were given water containing two per cent salt, comparable to a daily diet high in fast food and items like bacon, instant noodles and processed cheese.

The high-salt diet activated immune cells in a specific brain region, causing inflammation and a surge in the hormone vasopressin, which raises blood pressure. Researchers tracked these changes using cutting-edge brain imaging and lab techniques that only recently became available.

“The brain’s role in hypertension has largely been overlooked, in part because it’s harder to study,” Prager-Khoutorsky said. “But with new techniques, we’re able to see these changes in action.”

The researchers used rats instead of the more commonly studied mice because rats regulate salt and water more like humans. That makes the findings more likely to apply to people, noted Prager-Khoutorsky.

Next, the scientists plan to study whether similar processes are involved in other forms of hypertension.

Source: McGill University