Year: 2021

Categories : NeurologyTags :

Human Neurons Differ From Animal Ones in a Surprising Way

On By ModernMedia
A healthy neuron. Credit: National Institutes of Health

Human Neurons Differ From Animal Ones in a Surprising WayIn a surprising new finding published in Nature, neuroscientists have shown that human neurons have a much smaller number of ion channels than expected, compared to the neurons of other mammals.

Ion channels are integral membrane proteins that contain pathways through which ions can flow. By shifting between closed and open conformational states (‘gating’ process), they control passive ion flow through the plasma membrane. 

The researchers hypothesise that lower channel density may have helped the human brain evolve energy efficiency, letting it divert resources elsewhere.

“If the brain can save energy by reducing the density of ion channels, it can spend that energy on other neuronal or circuit processes,” said senior author Mark Harnett, an associate professor of brain and cognitive sciences.

Analysing neurons from 10 different mammals, the researchers identified a “building plan” that holds true for every examined species — save humans. They found that as the size of neurons increases, the density of channels found in the neurons also increases.

However, human neurons proved to be a striking exception to this rule.

“Previous comparative studies established that the human brain is built like other mammalian brains, so we were surprised to find strong evidence that human neurons are special,” said lead author and former MIT graduate student Lou Beaulieu-Laroche.

Neurons in the mammalian brain can receive electrical signals from thousands of other cells, and that input determines whether or not they will fire an electrical impulse called an action potential. In 2018, Prof Harnett and Beaulieu-Laroche discovered that human and rat neurons differ in some of their electrical properties, primarily in dendrites.

One of the findings from that study was that human neurons had a lower density of ion channels than neurons in the rat brain. The researchers were surprised by this observation, as ion channel density was generally assumed to be constant across species. In their new study, Harnett and Beaulieu-Laroche decided to compare neurons from several different mammalian species to see if they could find any patterns that governed the expression of ion channels. They studied two types of voltage-gated potassium channels and the HCN channel, which conducts both potassium and sodium, in layer 5 pyramidal neurons, a type of excitatory neurons found in the brain’s cortex.

They were able to obtain brain tissue from a range of 10 mammalian species, including human tissue removed from patients with epilepsy during brain surgery. This variety allowed the researchers to cover a range of cortical thicknesses and neuron sizes across the mammalian kingdom.

In nearly every mammalian species the researchers examined, the density of ion channels increased as the size of the neurons went up. Human neurons bucked this trend, having a much lower density of ion channels than expected.

The increase in channel density across species was a surprise, Prof Harnett explained, because the more channels there are, the more energy is required to pump ions in and out of the cell. However, it started to make sense once the researchers began thinking about the number of channels in the overall volume of the cortex, he said.

In the tiny brain of the Etruscan shrew, which is packed with very small neurons, there are more neurons in a given volume of tissue than in the same volume of tissue from the rabbit brain, which has much larger neurons. But because the rabbit neurons have a higher density of ion channels, the density of channels in a given volume of tissue is the same in both species, or any of the nonhuman species the researchers analysed.

“This building plan is consistent across nine different mammalian species,” Prof Harnett said. “What it looks like the cortex is trying to do is keep the numbers of ion channels per unit volume the same across all the species. This means that for a given volume of cortex, the energetic cost is the same, at least for ion channels.”

The human brain represents a striking deviation from this building plan, however. Instead of increased density of ion channels, the researchers found a dramatic decrease in the expected density of ion channels for a given volume of brain tissue.

The researchers believe this lower density may have evolved as a way to expend less energy on pumping ions, which allows the brain to use that energy for something else, like creating more complicated synaptic connections between neurons or firing action potentials at a higher rate.

“We think that humans have evolved out of this building plan that was previously restricting the size of cortex, and they figured out a way to become more energetically efficient, so you spend less ATP per volume compared to other species,” Prof Harnett said.

He now hopes to study where that extra energy might be going, and whether there are specific gene mutations that help neurons of the human cortex achieve this high efficiency. The researchers are also interested in exploring whether primate species that are more closely related to humans show similar decreases in ion channel density.

Source: Massachusetts Institute of Technology

Categories : HIVTags :

Major Mechanism for Chronic Inflammation in HIV Uncovered

On By ModernMedia
HIV invading a human cell
HIV invading a human cell: Credit NIH

In a groundbreaking study of people living with HIV, scientists found that neutrophils play a role in impaired T cell functions and counts, as well as the associated chronic inflammation that is common with the virus.

Neutrophils make up 60–80% of circulating immune cells in the blood. However, these white blood cells are extremely short-lived and cannot be frozen and thawed like other immune cells, making examining them extremely difficult, said study lead Shokrollah Elahi.

“Neutrophils live for hours to a day or two maximum,” Elahi said. “The body produces a lot of neutrophils, and they do their job and then they die and have to be regenerated in the bone marrow. But despite the fact that neutrophils are the most abundant white blood cells in the blood circulation, their role in the context of HIV has not been very well defined.”

In the study, published in the journal PLOS Biology, researchers examined fresh blood samples of 116 people living with HIV and 60 non-infected individuals. They ran comprehensive sequencing on all the genes expressed in the neutrophils from both groups to determine any differences between them.

“We found that not all HIV-infected individuals have similar types of neutrophils,” said Elahi. “As the HIV disease progresses, neutrophils become more activated and more potent, and in turn activate the body’s T cells, which likely causes some of the problems associated with HIV infection such as inflammation and rapid aging.”

Elahi said neutrophils act like an early alarm system: in response to pathogens, they release proteins to signal other immune cells to the danger. This activation can be high or low, or more or less potent, depending on the severity of the danger and the reaction of other immune cells.

One of these proteins is galectin-9, which Elahi previously linked to severe inflammation and cytokine storms in COVID patients. Elahi’s team reported that when neutrophils sense a danger such as an infection, they become stressed and release the galectin-9. As the protein begins to saturate the blood, it can interact with different immune cells. For example, the team found that galectin-9 reacted strongly with T cells and made them more susceptible to HIV infection, causing a cascading effect that leads to a hyper-immune response and inflammation.

Elahi’s prior work showed that patients with HIV and some forms of cancer had elevated levels of galectin-9 in their blood, but now he was able to identify the major source of the protein.

“We found for the very first time that the neutrophil membrane, through a complex mechanism, is covered like a blanket with galectin-9,” he said. “When neutrophils become highly activated, the secretion of galectin-9 can activate T cells through interaction with another molecule called CD44, which then promotes chronic inflammation in HIV patients.”

This ‘alarm’ reaction of shedding proteins such as galectin-9 was linked to oxidative stress, which is believed to play a role in the development of diseases including Parkinson’s, Alzheimer’s, cancer, heart failure and autism.

Based on his findings, Elahi said preventing galectin-9 shedding might be a powerful tool in reducing many of the negative effects of HIV infection. His team has already made some progress in reducing oxidative stress by using an organic antioxidant compound called phloretin and vitamin C.

“We have been looking at phloretin and vitamin C in the lab and our data are very promising,” Elahi said. “We know that both are good at reducing galectin-9 shedding, so we believe they can prevent the hyper-activation of neutrophils. We hope that our results will spark renewed investigation into the role of neutrophils in T cell activation in other acute and chronic conditions.”

Elahi noted the importance of immediate screening tests for HIV or at-risk people, saying: “If the virus is caught early and they can go on antiretroviral therapy, then it stops disease progression and reduces many of the complications associated with advanced HIV.”

Source: University of Alberta Faculty of Medicine & Dentistry

Categories : Gender Medical Research & TechnologyTags :

Biological Research Often Incorrectly Reports Sex Differences

On By ModernMedia
Photo by Tim Mossholder on Unsplash

An analysis of published studies from a range of biological specialties shows that when data are reported by sex, critical statistical analyses are often missing and the findings are likely to be reported in misleading ways.

The analysis was published in the journal eLife.

“We found that when researchers report that males and females respond differently to a manipulation such as a drug treatment, 70% of the time the researchers have not actually compared those responses statistically at all,” said senior author Donna Maney, a professor of neuroscience in Emory’s Department of Psychology. “In other words, an alarming percentage of claims of sex differences are not backed by sufficient evidence.”

In the articles lacking the proper evidence, she added, sex-specific effects were claimed almost 90% of the time. In contrast, authors that tested statistically for sex-specific effects only reported them 63% of the time.

”Our results suggest that researchers are predisposed to finding sex differences and that sex-specific effects are likely over-reported in the literature,” Prof Maney said.

The problem is so pervasive not even her own work was safe. “Once I realised how prevalent it is, I went back and checked my own published articles and there it was,” she said. “I myself have claimed a sex difference without comparing males and females statistically.”

Prof Maney stressed that the problem should not be discounted; it is becoming increasingly serious, she said, because of mounting pressure from funding agencies and journals to study both sexes, and interest from the medical community to develop sex-specific treatments.

Better training and oversight are needed to ensure scientific rigor in research on sex differences, the authors wrote: “We call upon funding agencies, journal editors and our colleagues to raise the bar when it comes to testing for and reporting sex differences.”

Historically, biomedical research has often included just one sex, usually biased toward males. In recent decades, laws have been passed requiring US medical research to include females in clinical trials and report the sex of human participants or animal subjects.

“If you’re trying to model anything relevant to a general population, you should include both sexes,” Prof Maney explained. “There are a lot of ways that animals can vary, and sex is one of them. Leaving out half of the population makes a study less rigorous.”

As more studies consider sex-based differences, Maney adds, it is important to ensure that the methods underlying their analyses are sound.

For the analysis, Prof Maney and co-author Yesenia Garcia-Sifuentes, PhD candidate, looked at 147 studies published in 2019 to see what is used for evidence of sex differences. The studies ranged across nine different biological disciplines, including field studies on giraffes and immune responses in humans.

The studies that were analysed all included both males and females and separated the data by sex. Garcia-Sifuentes and Prof Maney found that the sexes were compared, either statistically or by assertion, in 80% of the articles. Of those articles, sex differences were reported in 70% of them and of those treated as a major finding in about half.

Statistical errors were seen in some studies, with a significant difference for one sex but not the other counted as a difference between them.  The problem with that approach is that the statistical tests conducted on each sex can’t give “yes” or “no” answers about whether the treatment had an effect.

“Comparing the outcome of two independent tests is like comparing a ‘maybe so’ with an ‘I don’t know’ or ‘too soon to tell,'” Maney explains. “You’re just guessing. To show actual evidence that the response to treatment differed between females and males, you need to show statistically that the effect of treatment depended on sex. That is, to claim a ‘sex-specific’ effect, you must demonstrate that the effect in one sex was statistically different from the effect in the other.”

Conversely, their analysis also encountered strategies that could mask sex differences, such as pooling data from males and females without testing for a difference.

“At this moment in history, the stakes are high,” Maney says. “Misreported findings may affect health care decisions in dangerous ways. Particularly in cases where sex-based differences may be used to determine what treatment someone gets for a particular condition, we need to proceed cautiously. We need to hold ourselves to a very high standard when it comes to scientific rigor.”

Source: EurekAlert!

Categories : Diseases, Syndromes and Conditions New Compounds and TreatmentsTags :

An End to The ‘Therapeutic Drought’ in Atopic Dermatitis

On By ModernMedia
Source: NCI

The end of a longstanding “therapeutic drought” in atopic dermatitis (AD) is in sight as improved understanding of the pathogenesis and pathophysiology has stoked development of multiple drug candidates, according to a leading expert in the field.

“We did have treatments like cyclosporine, that are not specific as we know, and they are not treatments we can give our patients for long-term disease control,” said Emma Guttman-Yassky, MD, of the Icahn School of Medicine at Mount Sinai, during the Inflammatory Skin Diseases Summit.

She said that overcoming this drought was not easy, mostly because “we didn’t have enough understanding of the disease and its pathogenesis, really preventing therapeutic development for patients with atopic dermatitis,” she said.

New AD therapies built on the trail made for psoriasis treatment, starting with basic studies that produced insights into pathogenesis, leading to hypotheses that eventually could be tested in clinical trials, she said. Progress was accompanied by many failures in early stages of therapeutic development in psoriasis.

“One failure that I remember very vividly from psoriasis was the failure of interferon-gamma targeting,” Dr Guttman-Yassky recounted. “In atopic dermatitis, we also had our share of this type of failure, but these failures really helped shape therapeutic directions for all the diseases we are now targeting, including atopic dermatitis.”

This rocky development has led to recognition that AD is a complex disease involving multiple pathogenetic components, including barrier dysfunction, immune abnormalities, disruption of the dermal microbiome, and the peripheral and central nervous systems that play a central role in itch and other disease manifestations.

“Of all the major components involved in AD pathogenesis, immune targeting is the most tractable,” said Dr Guttman-Yassky. “Immune abnormalities are the most important because they perpetuate the disease phenotype of atopic dermatitis, from the nonlesional skin to acute disease and chronic lesions.”

In contrast to psoriasis, AD is a more heterogeneous disease with multiple clinical phenotypes that correlate with differences in immune polarisation and barrier dysfunction. All of the phenotypes exhibit activation of the type 2 inflammatory pathway as a common feature. Across the spectrum of clinical phenotypes, additional cytokine targeting may be required to achieve disease control.

Understanding that AD arises from systemic inflammation has also helped therapy development. Several studies have suggested that, compared to psoriasis, AD is associated with higher levels of immune activation. Blood samples of patients with AD have shown increased levels of activated T cells, circulatory cytokines, and cardiovascular markers.
The accumulation of new insights into AD pathogenesis added no fewer than a dozen viable therapeutic candidates to the pipeline. Dupilumab (Dupixent) led the way in providing the proof of principle that Th2-specific targeting reverses key pathogenetic factors that drive the disease process in AD.

Dr Guttman-Yassky pointed out how targeting Th2 inflammation with dupilumab led to reversal of barrier defects and lichenisation typical of AD as early as 4 weeks, and that by 16 weeks lesional and nonlesional skin looked similar. Furthermore, markers of epidermal hyperplasia and proliferation were “completely wiped out.”

Dr Guttman-Yassky highlighted several key classes of AD drug candidates with potential to build on the success of targeting inflammation: Interleukin-13 inhibition, OX40 inhibition and JAK/STAT inhibition, which showed promising results.

“With these types of response rates, our treatment goals for our patients are evolving,” said Dr Guttman-Yassky.

Source: MedPage Today

Categories : Cardiovascular DiseaseTags :

Vascular Damage in Diabetes Arises from Red Blood Cell Changes

On By ModernMedia
Photo by National Cancer Institute on Unsplash

Altered function of the red blood cells leads to vascular damage in type 2 diabetes, and new research shows that this effect is caused by low levels of an important red blood cell molecule. 

Patients with type 2 diabetes have an increased risk of cardiovascular disease, and type 2 diabetes may over time damage blood vessels, raising the risk for heart attack and stroke. However, the disease mechanisms underlying cardiovascular injury in type 2 diabetes are largely unknown and treatments to prevent such injuries are lacking.

Research has shown that red blood cells become dysfunctional in type 2 diabetes and can act as mediators of vascular complications. In this study, published in Diabetes, researchers examined cells from patients with type 2 diabetes and mice to see if molecular changes in the red blood cells could explain these harmful effects in type 2 diabetes.

The researchers found that levels of the small molecule microRNA-210 were markedly reduced in red blood cells from 36 patients with type 2 diabetes compared to healthy controls. Micro-RNAs belong to a group of molecules that serve as regulators of vascular function in diabetes and other conditions. The reduction in microRNA-210 caused alterations in specific vascular protein levels, and impaired blood vessel endothelial cell function. In laboratory experiments, restoration of microRNA-210 levels in red blood cells prevented the development of vascular injury via specific molecular changes.

“The findings demonstrate a previously unrecognised cause of vascular injury in type 2 diabetes,” said Zhichao Zhou, researcher at the Department of Medicine, Solna, Karolinska Institutet. “We hope that the results will pave the way for new therapies that increase red blood cell microRNA-210 levels and thereby prevent vascular injury in patients with type 2 diabetes.”

Source: Karolinska Institutet

Categories : General Interest Mental HealthTags :

No Evidence of Videogame and Violence Link in the Real World

On By ModernMedia

New research finds no evidence that violence increases after the release of a new video game.

Violent video games like Call of Duty are often linked by the media and public to real-life violence, although there is limited evidence to support the link. Debate on the topic generally intensifies after mass public shootings, with some commentators linking these violent acts to the perpetrators’ interests in violent video games. But different factors have been pointed out as more likely explanations, such as mental health issues and/or easy access to guns.

Before governments introduce any policies restricting access to violent video games, it is important to establish whether violent video games do indeed increase players’ violence in the real world.

Taking data from the US, Dr Agne Suziedelyte at University of London, provides evidence of the effects of violent video game releases on the violent behaviour of children. Dr Suziedelyte examined the effects of violent video games on two types of violence: aggression against other people, and destruction of objects or property.

Appearing in the Journal of Economic Behavior & Organization, the study focused on boys aged 8 to 18 years: the group most likely to play violent video games.

By using econometric methods which identify plausibly causal effects of violent video games on violence, rather than only associations, Dr Suziedelyte found no evidence that violence against other people increases after the release of a new violent video game. Parents reported, however, that children were more likely to destroy things after playing violent video games.

Dr Suziedelyte said: “Taken together, these results suggest that violent video games may agitate children, but this agitation does not translate into violence against other people — which is the type of violence which we care about most.

“A likely explanation for my results is that video game playing usually takes place at home, where opportunities to engage in violence are lower. This ‘incapacitation’ effect is especially important for violence-prone boys who may be especially attracted to violent video games.

“Therefore, policies that place restrictions on video game sales to minors are unlikely to reduce violence.

Source: City University London

Categories : Mental HealthTags :

Social Media Overuse Impacts Easily Distracted People Harder

On By ModernMedia
Photo by Tracy le Blanc from Pexels
Photo by Tracy le Blanc from Pexels

People who are easily distracted are more susceptible to psychological distress and mental health issues from high levels of social media use, according to a study published in the Journal of Affective Disorders. The study tracked the phone data of 69 participants ranging from 18 to 58 year-olds to see their usage of popular apps including Instagram and Reddit over a week period.

Using an eye gaze test, the researchers tracked participants’ levels of distraction and inattention. The Depression Anxiety Stress Scale, a well-known psychological scale, was used to measure and quantify measures of distress.

Lead researcher Tamsin Mahalingham, Master’s student at Curtin University, said that the results showed a strong connection with low levels of attention control and high social media use negatively impacting mental health.

“Past research has flagged concerns about the negative mental health effects from high levels of social media use, but there isn’t clear evidence about why this is, or who might be most at risk,” Miss Mahalingham said.

“Our findings suggest that if you are a very distractable person, high levels of social media use may be particularly bad for your mental health. Study results revealed that those who showed lower levels of attention control were particularly at risk of negative mental health effects of heavy social media use.”

“This inability to stay focussed may lead to exposure to more irrelevant and distracting information and potentially longer durations of social media use. On the other hand, those with higher levels of attention control may be able to more easily ignore irrelevant and potentially damaging information in news feeds such as advertising.”

Supervising researcher, Dr Patrick Clarke, said that the increased follow-on effects of greater social media use that could negatively impact emotional wellbeing.

“Social media apps are designed to draw us in and keep us engaged and the longer we spend on social media, the more we can be exposed to including negative content, or content leading to self-comparison to unattainable ideals, like those often illustrated by influencers,” Dr. Clarke said.

“More time on social media also means less time doing other, possibly more important or more productive tasks, which can also increase feelings of depression and anxiety.

“Our research helps to understand who is most at risk from the adverse mental health effects of social media use and suggests that improving attention may minimize those risks.”

Source: Curtin University

Categories : Ethics and LawTags :

Healthcare Organisations Urge Review of Culpable Homicide Law

On By ModernMedia
Photo by Tingey Injury Law Firm on Unsplash

Nine of South Africa’s leading healthcare organisations have joined together in urging the Government to begin a review of culpable homicide law and its application in a healthcare setting.

In a letter to the Minister of Justice and Correctional Services, Hon Ronald Lamola, the coalition said there is a very low threshold in South African law for blameworthiness when a patient dies while under medical care, which has resulted in errors of judgement in complex healthcare environments being criminalised, and healthcare professionals being convicted regardless of their intent.

The joint letter calls for the review to be carried out by the South Africa Law Reform Commission, due to the complexity of criminal law in a healthcare setting and the importance of achieving a long-term solution for healthcare professionals and patients alike.

The letter says: “It is hard to see who benefits from the current system. As well as families losing a loved one through tragic circumstances, doctors risk losing their career and liberty, and the fear of criminal charges also has a negative knock-on effect on patient care. The current system stands in the way of patients receiving an early apology and a full explanation of events, and thereby denies closure.

In a recent survey of 500 doctors, 88% are worried about investigations after an adverse patient outcome, and 90% think the prospect of criminal investigation affects their mental health. Due to the prospect of criminal investigation means nearly half of all doctors in South Africa have considered leaving the profession. The letter further notes that  4 in 5 doctors surveyed think the criminal justice system in South Africa has an inadequate understanding of medical practice.

Pointing out the need for a “long-term solution”, they write: “Healthcare professionals need to be held accountable, however, criminalising errors of judgement – particularly in this fast moving and complex healthcare environment – seems unreasonably severe. Criminalisation in the absence of any clear intention to cause harm is overly punitive, leaving healthcare professionals vulnerable to criminal charges. Lessons can be learned from other jurisdictions – for example, in Scotland, where charges are only brought against doctors if an act is proved to be intentional, reckless, or grossly careless.

“Our organisations are committed to the highest level of safety for all patients in South Africa. This will however require replacing the current culture of blame and fear with one of learning, where healthcare professionals feel able to apologise and learn from mistakes, which will help to reduce the number of errors and thus enable progress on improving patient safety. When healthcare professionals are allowed and supported to learn from mistakes, lessons are learnt, and patients are better protected in the future.

Highlighting the complexity of these matters, “Patients and clinicians want the same thing, for those in need to receive the best care,” the letter concludes.

The letter was signed by Medical Protection Society, Association of Surgeons of South Africa, Federation of South Africa Surgeons, Radiological Society of South Africa, South African Medical Association, South African Medico-Legal Association, South African Private Practitioners Forum, South African Society of Anaesthesiologists and South African Society of Obstetricians and Gynaecologists.

Source: Medical Protection Society

Categories : Cancer Metabolic DisordersTags :

Dasatinib May Have Potential as an Antidiabetic Drug

On By ModernMedia
Photo by Photomix Company from Pexels

Dasatinib, a drug that often is used to treat certain types of leukaemia, may have significant potential as an antidiabetic drug, according to new research published in Mayo Clinic Proceedings.

Dasatinib is a tyrosine kinase inhibitor used to treat tumours and malignant tissue, as well as chronic myelogenous leukaemia. Dasatinib is a senolytic drug, which target senescent cells that accumulate in many ageing tissues and at sites of pathology in chronic diseases. Senolytic drugs appear to delay, prevent or alleviate age-related changes, chronic diseases and geriatric syndromes in animal studies.

“Our findings suggest that dasatinib or related senolytic drugs may become diabetic therapies,” said senior author Robert Pignolo, MD, PhD. “More study is needed to determine whether these findings also are observed in patients with type 2 diabetes mellitus but without underlying malignant disease.”

Researchers used records for a total of 9.3 million individuals from 1994 to 2019 who were screened for use of either dasatinib or imatinib, another tyrosine kinase inhibitor that was approved for treatment of a type of leukemia in 2001 but with weak senolytic activity. Of those patients, 279 were treated with imatinib and 118 with dasatinib, and after further screening, a total of 48 patients were included in the study.
The findings show that dasatinib lowers serum glucose in patients with pre-existing type 2 diabetes to a greater extent than imatinib and comparable to first-line diabetic medications such as metformin and sulfonylureas.

More work is needed to determine whether the antidiabetic effect of dasatinib is due largely to its senolytic properties, explained Dr Pignolo. If it is, the effectiveness of combining dasatinib with another senolytic drug such as quercetin may be greater than with dasatinib alone.

“This study was really the first proof-of-concept that a senolytic drug may have substantial long-term beneficial effects in humans,” Dr Pignolo says. “According to research in animal models, it is not necessary to give senolytic drugs continuously, and so patients may need only take a drug such as dasatinib every few weeks, reducing possible side effects.”

Source: EurekAlert!

Categories : Injury & TraumaTags :

Exploring how Ischaemia-reperfusion Injuries Heal

On By ModernMedia
Source: Wikimedia CC0

Researchers from Japan have discovered the role of interleukin-36 receptor antagonists in healing skin wounds from ischaemia-reperfusion injuries.

Ischaemia is a medical condition in which the blood supply is cut off to different parts of the body. In patients who are bed-ridden, ischemia can manifest as pressure ulcers. Else, it could be the Raynaud’s phenomenon in someone under severe stress. Ischaemia, from the Latin “staunching of blood”, is a condition can be rescued by blood reperfusion to the affected areas. However, ischaemia-reperfusion (I/R) injuries where tissue damage caused by blood returning to tissues after a period of oxygen deprivation, are a risk.

Skin-based I/R injuries can be exacerbated by inherited immunological mechanisms, for instance in patients who are otherwise showing signs of slow wound healing. To understand the immunological mechanisms underlying the development of this condition better, decided to narrow down their investigation to interleukin-36 receptor antagonist (IL-36Ra), a protein that plays a pivotal immunomodulatory role in wound healing.

Lead researcher Mr Yoshihito Tanaka from Fujita Health University School of Medicine explained the motivation behind the research, “We wanted to understand the immunological mechanisms involved in the healing of wounds from cutaneous ischaemia-reperfusion injuries, such as pressure ulcers and Raynaud’s phenomenon, to narrow down possible therapeutic targets. Drawing from experience, IL-36Ra appeared to be a promising candidate for kickstarting our investigation.”

The scientists used mice knocked out for the IL-36Ra receptor, and induced cutaneous I/R injuries in the knockout and control mice. Then, they studied corresponding immunological responses in both groups of animals, including wound healing time, infiltration of neutrophils/macrophages  to the site of the wounds, apoptotic skin cells, and activation of other unwanted immunological defense mechanisms. Their findings appear in the Journal of The European Academy of Dermatology and Venereology.

They found that the absence of IL-36Ra, indeed, significantly slows down wound healing in cutaneous I/R injuries, through increased apoptosis, or ‘suicide’ of useful skins cells, excessive recruitment of inflammatory cells, and employment of unnecessary proinflammatory mechanisms.

Additionally, they demonstrated the role of Cl-amidine, a protein-arginine deiminase inhibitor as effective in normalizing exacerbated I/R injury in IL-36Ra mice. Based on these observations, the scientists assert their findings are the first conclusive report of the involvement of IL-36Ra in cutaneous I/R injury.

The researchers believe IL-36Ra is a good therapeutic candidate against cutaneous I/R injuries. As Mr. Tanaka optimistically adds, “Our research may lead to the development of therapeutic agents for wound healing of various other refractory skin diseases too.”

The quest for novel therapeutic targets in skin wound healing might just have been empowered by these findings of the team and the future indeed looks brighter for alleviating the painful burden of cutaneous I/R injuries.

Source: Fujita Health University School of Medicine