Year: 2024

Probing an Outdated Diabetes Drug’s Insulin Resistance Lowering Abilities

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Thiazolidinediones (TZDs) are a class of drug that can be used to treat type 2 diabetes by reversing insulin resistance, one of the main hallmarks of the disease. While TZDs were extremely popular in the 1990s and early 2000s, they have fallen out of use among physicians in recent decades because unwanted side effects emerged, including weight gain and excess fluid accumulation in body tissues.

Now, researchers at University of California San Diego School of Medicine are exploring how to isolate the positive effects of these drugs, which could help yield new treatments that don’t come with the old side effects.

In a new study published in Nature Metabolism, the researchers discovered how one of the most well-known TZD drugs works at the molecular level and were able to replicate its positive effects in mice without giving them the drug itself.

“For decades, TZDs have been the only drugs we have that can reverse insulin resistance, but we seldom use them anymore because of their side effects profile,” said Jerrold Olefsky, MD, a professor of medicine and assistant vice chancellor for integrative research at UC San Diego Health Sciences.

“Impaired insulin sensitivity is the root cause of type 2 diabetes, so any treatment we can develop to safely restore this would be a major step forward for patients.”

The main driver of insulin resistance in type 2 diabetes is obesity. Obesity-related inflammation causes macrophages to accumulate in adipose tissue, where they can comprise up to 40% of the total number of cells in the tissue.

When adipose tissue is inflamed, these macrophages release tiny nanoparticles containing instructions for surrounding cells in the form of microRNAs. These microRNA-containing capsules, called exosomes, are released into the circulation and can travel through the bloodstream to be absorbed by other tissues, such as the liver and muscles. This can then lead to the varied metabolic changes associated with obesity, including insulin resistance.

To understand how TZD drugs, which restore insulin resistance, affect this exosome system, the researchers treated a group of obese mice with the TZD drug rosiglitazone. Those mice became more sensitive to insulin, but they also gained weight and retained excess fluid, known side effects of rosiglitazone.

However, by isolating exosomes from the adipose tissue macrophages of the mice who had received the drug and injecting them into another group of obese mice that had not received it, the researchers were able to deliver the positive effects of rosiglitazone without transferring the negative effects.

“The exosomes were just as effective in reversing insulin resistance as the drug itself but without the same side effects,” said Olefsky.

“This indicates that exosomes can ultimately link obesity-related inflammation and insulin resistance to diabetes. It also tells us that we may be able to leverage this system to boost insulin sensitivity.”

The researchers were also able to identify the specific microRNA within the exosomes that was responsible for the beneficial metabolic effects of rosiglitazone. This molecule, called miR-690, could eventually be leveraged into new therapies for type 2 diabetes.

“It’s likely not practical to develop exosomes themselves as a treatment because it would be difficult to produce and administer them, but learning what drives the beneficial effects of exosomes at the molecular level makes it possible to develop drugs that can mimic these effects,” said Olefsky. “There’s also plenty of precedent for using microRNAs themselves as drugs, so that’s the possibility we’re most excited about exploring for miR-690 going forward.”

Source: University of California – San Diego

Certain Gut Bacteria Assist in Immunotherapy for Milk Allergy

Gut Microbiome. Credit Darryl Leja National Human Genome Research Institute National Institutes Of Health

Researchers in Japan have discovered a link between gut bacteria and the success of milk-allergy oral immunotherapy. Published in the scientific journal Allergology International, the study found that Bifidobacterium – a genus of beneficial bacteria in the gut – was associated with a higher chance of successful treatment. The finding may help in the development of more effective oral immunotherapies, perhaps by combining them with probiotic supplements.

Many children have allergic reactions to certain milk proteins. Most grow out of it but some have to contend with lifelong allergy. Milk allergy can be improved by oral immunotherapy – taking small, increasing doses of milk. Unfortunately, while allergic reactions are controlled during treatment, in most cases, tolerance disappears soon after the treatment ends.

Gut bacteria are thought to help reduce allergic reactions to some foods, but little is known about the link between these bacteria and oral immunotherapy for milk allergy. Hiroshi Ohno led a team at the RIKEN Center for Integrative Medical Sciences to find out why. The researchers examined 32 children with cow’s milk allergy who received oral immunotherapy, with the first month being conducted in a hospital. “Oral immunotherapy is not without risk,” explains Ohno. “We closely monitored the children in the hospital, and in fact 4 children had such severe reactions to the milk that we could not allow them to continue the treatment.”

The remaining 28 children then completed an additional 12 months of treatment at home. Next, they avoided milk for two weeks, and were then tested on a double-blind, placebo-controlled food challenge to see if they could still tolerate milk without any allergic reactions. During the food challenge, children were initially given a tiny amount of placebo or milk (only 0.01mL) which was gradually increased every 20 minutes until they had an allergic reaction or until they could drink the final 30mL without a reaction.

The researchers focused their analyses on immunological and bacterial changes during the treatment and the relationship between gut bacteria and successful treatment—which was defined as showing milk tolerance that lasted beyond the treatment period by passing the food challenge. They found that during treatment, immunological markers for cow’s milk allergy improved, and bacteria in the gut changed. Nevertheless, after two weeks of avoiding milk, only 7 of the 28 children passed the food challenge, even though they had been able to drink milk safely at the end of the treatment.

To understand why the treatment worked for these seven children but not the others, the team looked for the clinical factors and types of gut bacteria that were related to successful treatment. Of the clinical factors, unsuccessful treatment was more likely in children who were being treated for eczema or asthma and in children who initially had higher levels of milk-protein antibodies. Among the gut bacteria, the presence of Bifidobacterium, a genus of beneficial bacteria in the Bifidobacteriaceae family was related to a higher chance of successful treatment. In fact, only children who passed the final food challenge showed an increasing trend in these bacteria over the course of treatment. When considering ways to improve oral immunotherapy, this is good news because while the first two factors are difficult to change, the types of bacteria in one’s gut are not set in stone.

“With this study, we have identified gut environmental factors that help establish immune tolerance against cow’s milk allergy via oral immunotherapy,” says Ohno. “The next step is to examine the mechanisms underlying this phenomenon and to develop ways to improve the effectiveness of oral immunotherapy, such as the addition of probiotic supplements.”

Source: RIKEN

Do More Mentally Challenging Jobs Protect against Cognitive Decline?

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The harder your brain works at your job, the less likely you may be to have memory and thinking problems later in life, according to a new study published in Neurology®, the medical journal of the American Academy of Neurology. This study does not prove that stimulating work prevents mild cognitive impairment. It only shows an association.

“We examined the demands of various jobs and found that cognitive stimulation at work during different stages in life – during your 30s, 40s, 50s and 60s – was linked to a reduced risk of mild cognitive impairment after the age of 70,” said study author Trine Holt Edwin, MD, PhD, of Oslo University Hospital in Norway.

“Our findings highlight the value of having a job that requires more complex thinking as a way to possibly maintain memory and thinking in old age.”

The study looked at 7000 people and 305 occupations in Norway. Researchers measured the degree of cognitive stimulation that participants experienced while on the job. They measured the degree of routine manual, routine cognitive, non-routine analytical, and non-routine interpersonal tasks, which are skill sets that different jobs demand.

Routine manual tasks demand speed, control over equipment, and often involve repetitive motions, typical of factory work. Routine cognitive tasks demand precision and accuracy of repetitive tasks, such as in bookkeeping and filing.

Non-routine analytical tasks involve analysing information, engaging in creative thinking and interpreting information for others. Non-routine interpersonal tasks include establishing and maintaining personal relationships, motivating others and coaching. Non-routine cognitive jobs include public relations and computer programming.

Researchers divided participants into four groups based on the degree of cognitive stimulation that they experienced in their jobs. The most common job for the group with the highest cognitive demands was teaching. The most common jobs for the group with the lowest cognitive demands were mail carriers and custodians.

After age 70, participants completed memory and thinking tests to assess whether they had mild cognitive impairment. Of those with the lowest cognitive demands, 42% were diagnosed with mild cognitive impairment, compared to 27% for those with the highest cognitive demands.

After adjustment for age, sex, education, income and lifestyle factors, the group with the lowest cognitive demands at work had a 66% higher risk of mild cognitive impairment compared to the group with the highest cognitive demands at work.

“These results indicate that both education and doing work that challenges your brain during your career play a crucial role in lowering the risk of cognitive impairment later in life,” Edwin said. “Further research is required to pinpoint the specific cognitively challenging occupational tasks that are most beneficial for maintaining thinking and memory skills.”

A limitation of the study was that even within identical job titles, individuals might perform different tasks and experience different cognitive demands.

Source: American Academy of Neurology

Genetic Predisposition for Muscle Strength may Predict Longer Lifespan

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A study conducted at the University of Jyväskylä showed that a genetic predisposition for higher muscle strength predicts a longer lifespan and a lower risk for developing common diseases. This study, published in The Journals of Gerontology: Series A, is the most comprehensive international study to date on hereditary muscle strength and its relationship to morbidity. The genome and health data of more than 340 000 Finns was used in the research.

Muscle strength, especially hand grip strength, can indicate an individual’s physiological resources to protect against age-related diseases and disabilities, as well as their ability to cope with them. Age-related loss of muscle strength is individual and influenced not only by lifestyle but also by genetics.

The study revealed that individuals with a genetic predisposition for higher muscle strength have a slightly lower risk for common noncommunicable diseases and premature mortality. It did not however predict better survival after acute adverse health events compared to the time before illness onset.  

“It seems that a genetic predisposition for higher muscle strength reflects more on an individual’s intrinsic ability to resist and protect oneself against pathological changes that occur during aging than the ability to recover or completely bounce back after severe adversity,” says doctoral researcher Päivi Herranen from the Faculty of Sport and Health Sciences. 

A unique study population  

Muscle strength is a multifactorial trait influenced by lifestyle and environmental factors but also by numerous genetic variants, each with a very small effect on muscle strength. In this study, the genetic predisposition for muscle strength was defined by constructing a polygenic score for muscle strength, which summarises the effects of hundreds of thousands of genetic variants into a single score. The polygenic score makes it possible to compare participants with an exceptionally high or low genetic predisposition for muscle strength, and to investigate associations with inherited muscle strength and other phenotypes, in this case, common diseases.  

“In this study, we were able to utilise both genetic information and health outcomes from over 340 000 Finnish men and women,” Herranen explains. “To our knowledge, this is the first study to investigate the association between a genetic predisposition for muscle strength and various diseases on this scale.” 

Further research on the effects of lifestyles is still needed 

Information about the genetic predisposition for muscle strength could be used alongside traditional risk assessment in identifying individuals who are at particularly high risk of common diseases and health adversities. However, further research on the topic is still needed. 

“Based on these results, we cannot say how lifestyle factors, such as physical activity, modify an individual’s intrinsic ability to resist diseases and whether their impact on health differs among individuals due to genetics,” Herranen notes. 

The study utilised the internationally unique FinnGen dataset, compiled through the collaboration of Finnish biobanks. The dataset consisted of 342 443 Finns who had given their consent and provided a biobank sample. The participants were aged 40 to 108 years, and 53% of them were women. The diagnoses selected for the study were based on the leading causes of death and the most significant noncommunicable diseases in Finland. Selected diagnoses included the most common cardiometabolic and pulmonary diseases, musculoskeletal and connective tissue diseases, falls and fractures, mental health and cognitive disorders, cancers, as well as overall mortality and mortality from cardiovascular diseases. 

Source: University of Jyväskylä

New Drug Shows Promise for Treating Rare and Aggressive Gliomas

MRI scan showing brain cancer. Credit: Michelle Monje, MD, PhD, Stanford University

An experimental drug may provide a new treatment option for some patients with rare incurable brain tumours, according to an analysis published in the Journal of Clinical Oncology.

Diffuse midline gliomas are diagnosed in about 800 people per year in the U.S., according to the Centers for Disease Control and Prevention.

A subset of particularly aggressive diffuse midline gliomas are caused by a H3 K27M mutation and the only effective treatment is radiation, as the location of the tumour in the brain makes surgery difficult. Even with radiation, relapse is virtually inevitable and more than 70% of patients with this subtype of brain tumour die from the cancer, according to the National Institutes of Health.

In the study, investigators analysed the results of five previous clinical trials testing the effectiveness of dordaviprone, an experimental drug which works by blocking a certain protein in tumours with the mutation.

The study included results from 50 patients (including four children) with H3 K27M–mutant diffuse midline gliomas and found that 30% of patients responded well to the drug. The most common side effect reported was fatigue, according to the study.

Now, the researchers are launching a trial at Northwestern Medicine hospitals to investigate the drug’s effectiveness in newly diagnosed patients.

Source: Northwestern University

Bacteria Behind Meningitis in Babies Explains Resurgence

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A milestone study led by University of Queensland researchers has identified the main types of E. coli bacteria that cause neonatal meningitis, and revealed why some infections recur despite being treated with antibiotics.

The study, published in eLife, discovered that about 50% of neonatal meningitis infections are caused by two types of E. coli.

E. coli is the most common cause of meningitis in babies born pre-term, but knowing which types allows us to test for those strains and treat them appropriately,” said Professor Mark Schembri, who led the study along with Dr Nhu Nguyen and Associate Professor Adam Irwin.

The study was the largest of its type, examining the genomes of 58 different E. coli bacteria across four continents and using samples collected over 46 years. It found that two types of the bacteria were responsible for the majority of neonatal infections.

Rapid diagnosis and monitoring are key

Associate Professor Irwin, who is also a paediatric infectious disease specialist at the Queensland Children’s Hospital, said speed is of the essence to prevent lasting damage.

“While antibiotics can be effective in treating the infection, this relies on rapid diagnosis. Also, antibiotics don’t always eliminate the bacteria – some of the babies we tracked showed signs of a complete recovery before suffering repeated invasive E. coli infections,” he said.

The researchers discovered the bacteria causing subsequent infections were the same as in the initial infection.

“It’s most likely that bacteria hide out in the intestinal microbiome,” Professor Schembri said. “This tells us we need to keep monitoring these babies after their first infection, as they are at a high risk of subsequent infection.”

Professor Schembri said the E. coli that can lead to meningitis also cause urinary tract infections and colonise the intestinal tract. “There is something about these types of E. coli that equips them to cause both infections,” he said.

“Our next step is to examine the bacteria’s pathway from the intestinal tract or urinary tract into the bloodstream, and then to the brain, so we can consider new ways to stop them.”

Source: University of Queensland

Tracing the Earliest Embryonic Formation of Faces

ES cells can now be used to induce structures with regionalised maxillary and mandibular primordia through the neural crest cell state, allowing for the recapitulation of jaw development in vitro. (POU3F3+ for maxillary and HAND2+ for mandibular)

CREDIT: KyotoU/Mototsugu Eiraku and Yusuke Seto

The highly complex shapes of animal faces originate from their respective transient neural crest cells. These embryonic pluripotent cells within the facial primordium – the early development form – may be necessary for forming proper facial structures. They migrate from their dorsal origin to the ventral craniofacial primordium and contribute to the cartilage, bones, and connective tissues. Analysing the molecular mechanisms in such early stages of development however poses many technical challenges.

Now, a group of Kyoto University researchers have produced neural crest cell-rich aggregates from human pluripotent stem cells and also developed a method to differentiate them in cell populations with a branchial arch-like gene expression pattern. Their research is published in Nature Communications.

“After the cell populations differentiate into precursors of maxillary and mandibular cells in response to external signalling factors, these populations spontaneously form patterns of the facial primordium,” explains Yusuke Seto of KyotoU’s Institute for Life and Medical Sciences.

This cartilage-like structure, reminiscent of Meckel’s cartilage, is formed locally within the aggregates.

“We aim to establish a model for studying early facial development by using the properties of human pluripotent stem cells to generate in vitro tissue resembling the bronchial arch of the primordial face,” adds Ryoma Ogihara, also of the Institute.

Researchers are examining the various developmental processes that cause interspecific and individual differences in facial structure to explain conditions such as craniofacial disorders.

“Using our in vitro model could help us better understand and control signal integration during the fate determination of the branchial arch and cartilage formation in the face and elsewhere. We hope our technology can contribute to the development of cellular materials for new regenerative medicine,” adds Mototsugu Eiraku, also of the Institute.

Source: University of Kyoto

Newly Found Retinal Cells may Paint a Complete Picture of Colour Vision

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Scientists have long wondered how the eye’s three cone photoreceptor types work together to allow humans to perceive color. In a new study in the Journal of Neuroscience, researchers at the University of Rochester used adaptive optics to identify rare retinal ganglion cells (RGCs) that could help fill in the gaps in existing theories of colour perception.

The retina has three types of cones to detect colour that are sensitive to either short, medium, or long wavelengths of light. Retinal ganglion cells transmit input from these cones to the central nervous system.

In the 1980s, David Williams, the William G. Allyn Professor of Medical Optics, helped map the “cardinal directions” that explain colour detection. However, there are differences in the way the eye detects colour and how colour appears to humans. Scientists suspected that while most RGCs follow the cardinal directions, they may work in tandem with small numbers of non-cardinal RGCs to create more complex perceptions.

Recently, a team of researchers from Rochester’s Center for Visual Science, the Institute of Optics, and the Flaum Eye Institute identified some of these elusive non-cardinal RGCs in the fovea that could explain how humans see red, green, blue, and yellow.

“We don’t really know anything for certain yet about these cells other than that they exist,” says Sara Patterson, a postdoctoral researcher at the Center for Visual Science who led the study. “There’s so much more that we have to learn about how their response properties operate, but they’re a compelling option as a missing link in how our retina processes color.”

Adaptive optics peer past the eye’s natural distorations

The team leveraged adaptive optics, which uses a deformable mirror to overcome light distortion and was first developed by astronomers to reduce image blur in ground-based telescopes. In the 1990s, Williams and his colleagues began applying adaptive optics to study the human eye. They created a camera that compensated for distortions caused by the eye’s natural aberrations, producing a clear image of individual photoreceptor cells.

“The optics of the eye’s lens are imperfect and really reduce the amount of resolution you can get with an ophthalmoscope,” says Patterson. “Adaptive optics detects and corrects for these aberrations and gives us a crystal-clear look into the eye. This gives us unprecedented access to the retinal ganglion cells, which are the sole source of visual information to the brain.”

Patterson says improving our understanding of the retina’s complex processes could ultimately help lead to better methods for restoring vision for people who have lost it.

“Humans have more than 20 ganglion cells and our models of human vision are only based on three,” says Patterson. “There’s so much going on in the retina that we don’t know about. This is one of the rare areas where engineering has totally outpaced visual basic science. People are out there with retinal prosthetics in their eyes right now, but if we knew what all those cells do, we could actually have retinal prosthetics drive ganglion cells in accordance with their actual functional roles.”

Source: University of Rochester

To Beat Lung Fibrosis, Researchers Turn to Body’s own Healing Powers

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The most common type of lung fibrosis is idiopathic – of unknown cause. Researchers are urgently trying to find ways to prevent or slow idiopathic pulmonary fibrosis (IPF) and related lung conditions, which can cause worsening shortness of breath, dry cough, and extreme fatigue. Average survival following diagnosis of IPF is just three to five years, and the disease has no cure.

A recent U-M study from a team led by Sean Fortier, MD and Marc Peters-Golden, MD at University of Michigan Medical School uncovers a pathway used during normal wound healing that has the potential to reverse IPF. They published their research in the Journal of Clinical Investigation.

Using a mouse model, they simulated IPF by administering bleomycin, a chemotherapy agent that causes cell injury and confirmed that the resulting lung scarring resolved itself over the span of about six weeks.

Because of this, “studying fibrosis is kind of tough,” said Fortier. “If we’re going to give experimental drugs to try and resolve fibrosis, we have to do it before it resolves on its own.

Otherwise, we will not be able to tell if the resolution was the action of the drug or natural repair mechanisms of the body.”

However, he said, “there’s actually a lot to learn about how the mouse gets better on its own. If we can learn the molecular mechanisms by which this occurs, we may uncover new targets for IPF.”

The process by which lung injury either leads to healing or fibrosis relies in part on what happens to fibroblasts – cells which forms connective tissue.

During injury or illness, fibroblasts are activated, becoming myofibroblasts that form scar tissue by secreting collagen. When the job is done, these fibroblasts must be deactivated, or de-differentiated, to go back to their quiet state or undergo programmed cell death and be cleared.

“This is the major distinction between normal wound healing and fibrosis – the persistence of activated myofibroblasts,” explained Fortier. That deactivation is controlled by molecular brakes. The study examined one of these brakes, called MKP1 – which the team found was expressed at lower levels in fibroblasts from patients with IPF.

By genetically eliminating MKP1 in fibroblasts of mice after establishing lung injury, the team saw that fibrosis continued uncontrolled.

“Instead of at day 63, seeing that nice resolution, you still see fibrosis,” said Fortier.

“We argued by contradiction: when you knock out this brake, fibrosis that would otherwise naturally disappear, persists and therefore MKP1 is necessary for spontaneous resolution of fibrosis.”

They performed several additional studies using CRISPR techniques to demonstrate how MKP1 applies the brakes, mainly by deactivating the enzyme p38α, which is implicated in a cell’s reaction to stress.

Furthermore, they demonstrated that neither of the two current FDA approved drugs for lung fibrosis, pirfenidone and nintedanib, are able to turn off myofibroblasts.

“That’s totally in keeping with the fact that they do slow the progression, but they don’t halt or reverse disease,” said Fortier.

Fortier hopes the discovery that this pathway reverses fibrosis leads to exploration of additional brakes on fibrosis.

“So much work on fibrosis has focused on how we can prevent it, but when a patient presents to my clinic with a dry cough, shortness of breath, and low oxygen as a result of underlying IPF, the scarring is already present. Of course, we’d love a way to prevent the scarring from getting worse, but the Holy Grail is to reverse it.”

Source: Michigan Medicine – University of Michigan

Epigenetic Changes Drive this Rare Malignant Paediatric Brain Tumour

A healthy neuron. Credit: NIH

A new study published in Life Science Alliance revealed how aberrant epigenetic regulation contributes to the development of atypical teratoid/rhabdoid (AT/RT) tumours, which mainly affect young children. There is an urgent need for more research in this area as current treatment options are ineffective against these highly malignant tumours.

Most tumours take a long time to develop as harmful mutations gradually accumulate in cells’ DNA over time. AT/RT tumours are a rare exception, because the inactivation of one gene gives rise to this highly aggressive form of brain cancer.

AT/RT tumours are rare central nervous system embryonic tumours that predominantly affect infants and young children.

On average, 73 people are diagnosed with AT/RT in the USA each year. However, AT/RT is the most common central nervous system tumour in children under one years old and accounts for 40-50% of diagnoses in this age group. The prognosis for AT/RT patients is grim, with a postoperative median survival of only 11-24 months.

The collaborative study conducted by Tampere University and Tampere University Hospital examined how aberrant DNA methylation distorts cellular developmental trajectories and thereby contributes to the formation of AT/RT. DNA methylation is a normal process of controlling expression whereby methyl groups are added to the DNA strand, adding epigenetic information.

The new study showed that DNA methylation interferes with the activity of multiple regulators, which usually regulate the differentiation and maturation of central nervous system cells during brain development. Disrupted cell differentiation promotes the abnormal, uncontrolled proliferation of cells that eventually form a tumour.

The study also found several genes that regulate cell differentiation or inhibit tumour development and are silenced in AT/RT together with increased DNA methylation.

“These results will provide deeper insights into the development of AT/RTs and their malignancy. In the future, the results will help to accelerate the discovery of new treatments for this aggressive brain tumour,” says senior author Docent Kirsi Rautajoki from Tampere University.

Source: Tampere University