Publisher Health

Researchers at Baylor College of Medicine and collaborating institutions discovered that the rheumatoid arthritis drug auranofin can potentially be repurposed to improve diabetes-associated symptoms. The study, which was conducted in mice, appeared today in the journal Cell Metabolism.
Although scientists have identified definitive associations between inflammation in white adipose tissue and insulin resistance in humans and rodents, broad anti-inflammatory treatments lack durable clinical efficacy on diabetes. In the current study, the researchers explored in more detail this association between inflammation and diabetes by looking for existing drugs that might affect both conditions.
“We computationally screened a small-molecule dataset and identified auranofin, an FDA-approved drug that has been used to treat rheumatoid arthritis, a condition involving inflammation,” said first and co-corresponding author Dr. Aaron R. Cox, instructor of medicine-endocrinology, diabetes and metabolism at Baylor. “Auranofin exerts anti-inflammatory properties, which many people suspected would be beneficial in obesity and diabetes; however, nothing was really known about how it might affect metabolism.”
The team evaluated the metabolic effects of auranofin in a mouse model of diabetes in which the animals consume a high-fat diet.
“We discovered that auranofin has anti-inflammatory and anti-diabetic effects that are independent from each other,” said co-corresponding author Dr. Sean Hartig, associate professor of medicine-endocrinology, diabetes and metabolism and molecular and cellular biology at Baylor. Hartig also is a member of Baylor’s Dan L Duncan Comprehensive Cancer Center. “Auranofin improved insulin sensitivity, or the body’s ability to respond to insulin to keep blood sugar at healthy levels. The drug also normalized obesity-associated changes such as hyperinsulinemia — blood insulin levels that are higher than normal — in the mouse model. In addition, we found that auranofin accumulation in white adipose tissue reduced inflammatory responses without altering body composition in obese mice.”
Looking into the mechanism of these metabolic changes, the team discovered that the anti-diabetic effects of auranofin involved reduction of leptin levels. Leptin is a hormone whose levels markedly increase in obesity, contributing to insulin resistance and diabetes. In addition, auranofin restored white adipose tissue’s ability to respond to catecholamines, which are signals that increase metabolic activities in adipose tissue, triggering the burning of lipids at a higher rate.
“These changes coupled together contribute to the overall improvement in insulin sensitivity of the mice, leading to blood glucose control, which is the ultimate goal of diabetes treatments,” Cox said. “High levels of glucose in the blood are detrimental to many tissues in the body. Uncontrolled, diabetes can lead to organ failure.”
“We are very excited about these findings; however, more research will be needed to determine an effective strategy to translate them to the clinic,” said Hartig.
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Materials provided by Baylor College of Medicine. Original written by Aaron Nieto. Note: Content may be edited for style and length.

The microenvironment surrounding tumours in HER2+ breast cancer protects them and helps them develop resistance to the most widely used treatment, the monoclonal antibody trastuzumab. And a particular type of cell in this microenvironment, fibroblasts, plays a key role in this process. These cells have the ability to block the immune system and thereby protect the tumour. Finding a way to overcome this boosts the treatment’s capacity to kill tumour cells.
Specifically, it is the presence of TGF-beta-activated fibroblasts, which express a molecule called FAP, that protects the tumour from the action of immune cells. Trastuzumab has the ability to target cancer cells that present high levels of the HER2 protein, and when it binds to the cancer, it activates a strong immune response, which is a major contributor to its efficacy against the tumour. However, in many tumours, the immune system is unable to break through the microenvironment surrounding the tumour to eliminate it. This leads to treatment resistance and increases the capacity of this type of cancer to evade the drug and proliferate further. This mechanism was discovered by a team of researchers from the IMIM-Hospital del Mar and the CIBER Cancer Research Centre (CIBERONC) in a study that has been published in the journal Nature Communications.
The authors have also identified a way to overcome the tumour’s ability to protect itself and allow the immune system to act on the tumour cells. Using an ex vivo model, i.e., a model that includes living cells from breast cancer patients, the researchers have shown that by targeting the fibroblast-expressed FAP molecules with immunotherapy, this ability to prevent access by immune cells can be reversed. “When this molecule, FAP-IL2v, is added to a tumour recreated ex vivo that contains this treatment-resistant microenvironment, in contact with immune cells, trastuzumab’s effectiveness is restored,” states Dr. Alexandre Calon, senior author of the research and head of the Translational Research in Tumour Microenvironment Laboratory at the IMIM-Hospital del Mar. It should be noted that the model generated uses human cells and is also applicable to other types of tumours.
The study has validated the results with three cohorts of patients and more than 120 samples. In all of them, the levels of fibroblast activation were found to be directly related to the immune system’s ability to act on the tumour. The higher the levels, the greater the difficulty in accessing and eliminating tumour cells despite the action of trastuzumab. Dr. Calon emphasised that this facilitates a better selection of patients who will benefit from FAP-IL2v treatment aimed at deactivating the action of the tumour microenvironment. “If we filter people based on these characteristics, we can isolate a population of treatment-resistant patients who can be targeted with this molecule to restore the effectiveness of the breast cancer therapy,” he explains.
There are already drugs available that can be used to achieve this effect, although further studies must be carried out to evaluate their application in patients, as Dr. Joan Albanell, head of the Oncology Department at the Hospital del Mar, Director of the Cancer Research Programme at the IMIM-Hospital del Mar and co-author of the study, points out. “The study identifies tumours in which anti-HER2 therapy resistance is caused primarily by one type of fibroblast rather than other causes. This important discovery should be used to design clinical trials with drugs that overcome this resistance only for those patients in whom this resistance is operative. This is where we need to move towards precision oncology,” adds Dr Albanell.
The work was carried out in collaboration with researchers from the Barcelona Institute for Research in Biomedicine (IRB) and the Institute for Bioengineering of Catalonia (IBEC), as well as the INCLIVA Health Research Institute in Valencia, and with the support of the Cellex Private Foundation, the Carlos III Health Institute and the Spanish Association Against Cancer.
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Cancer cells use an unusual mechanism to migrate into new tissue and form metastases there. The same process probably also keeps some immune cells on their toes. This is the result of a recent study led by the University of Bonn. According to the study, certain structures, the centrioles, increase in number. This makes it easier for them to maintain their direction and thus migrate more quickly to the lymph nodes, where they activate other immune cells. The results have now been published in the Journal of Cell Biology.
Like the police, the immune system relies on division of labor. First of all, there are the dendritic cells. They search the tissue around the clock for traces of suspicious intruders, called antigens. If they are successful, they rush to the lymphatic vessels and from there to the draining lymph nodes. There they present their findings to a powerful search team, the T cells. These endogenous troops now know which enemy to fight.
This attack must take place before the invaders cause major damage or multiply too much. It is therefore important that dendritic cells migrate as quickly as possible to the briefing in the lymph node. “We have discovered a mechanism that helps them doing this,” explains Prof. Dr. Eva Kiermaier from the LIMES Institute (Life and Medical Sciences) at the University of Bonn. “To do so, they form more of certain structures called centrosomes. These help them maintain their direction for longer and thus reach the lymphatic vessels more quickly.”
Important function in cell division
Centrosomes belong to the organelles — these are molecular complexes that are responsible for specific tasks in cells, much like the organs in the body. Normally, there is exactly one centrosome in each human cell. Shortly before cell division, it doubles. The two copies migrate to opposite poles of the cell and stretch a bundle of fibers between them, the microtubules. With them, they pull the chromosomes (which have also doubled) apart during division. Each of the resulting daughter cells thus receives a complete set of genetic material as well as one of the two centrosomes.
“However, centrosomes are also responsible for organizing the cytoskeleton during cell migration,” emphasizes Kiermaier, who was brought to the Rhine from Lower Austria (IST Austria, Klosterneuburg) in 2017 through the returnee program of the state of North Rhine-Westphalia. “By this we mean fiber-like structural proteins that give the cell its shape and provide it with stability.” The cytoskeleton also decides where “front” and “back” are in a cell. And that, in turn, affects its direction of movement. “We have now been able to show that dendritic cells form multiple centrosomes as soon as they come into contact with an antigen,” says Ann-Kathrin Weier. The PhD student at the LIMES Institute shares first authorship of the publication with her colleague Mirka Homrich. Both performed important parts of the experiments.
Staying the course longer to reach the destination more quickly
Dendritic cells have a problem: they do not know where the next lymphatic vessel is via which they can reach the lymph node. In their search, they proceed according to the strategy of “trial and error”: they run in one direction for a short while and then change it if they have not encountered a vessel in the process. “The more centrosomes they have, the longer they stay on course before continuing to search in a different direction,” says Mirka Homrich. “We were able to show in computer simulations that this allows them to find the lymphatic vessels much faster than they normally would.” In the process, the proliferation of centrosomes adjusts their staying power just right — so they don’t stick too stubbornly to their direction. This would increase the risk of them going astray and getting completely lost.
The mechanism identified in the study was previously completely unknown in healthy cells. Cancer cells were assumed to use it to form metastases. However, the multiplied centrosomes must not be freely distributed inside the cells. Otherwise, they would severely disrupt functions such as cell division. In both tumor and dendritic cells, the organelles therefore congregate at a single site — they cluster. “There are now agents that disrupt this clustering of centrosomes,” says Kiermaier, who is also a member of the ImmunoSensation2 Cluster of Excellence and the Transdisciplinary Research Area “Life and Health” at the University of Bonn. “As a result, the cancer cells can no longer divide correctly, but die.”
However, it is also possible that these substances interfere with the immune system — after all, the centrosomes cluster there as well. “We’ve tested several of these agents in cell cultures,” she says. “We’ve actually found evidence that they could significantly impair the effectiveness of the immune defense.” If that will be confirmed in clinical trials, it would be bad news as there could be considerable side effects if the active substances were used in cancer therapy.
Participating institutions: In addition to the University of Bonn, the Charles University in Vestec, Czech Republic, and the Institutes of Science and Technology in Austria and Spain were involved in the work.
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NKCC1 is a human chloride transporter that has the ability to transport sodium, potassium, and chloride from the exterior into cells. In the kidney, for example, NKCC1 type proteins ensure that these ions are reabsorbed from the urine, and generally NKCC1 is important for osmotic cell volume regulation. In brain, NKCC1 and related proteins are important for chloride gradients that are vital for the electrical signaling in neuronal networks.
Using cryo-electron microscopy (cryo-EM), a team from Poul Nissen’s laboratory with colleagues from the Fenton and Hartmann laboratories at Aarhus University (AU) and the Lindorff-Larsen laboratory at University of Copenhagen (KU) have determined the three-dimensional atomic structure of NKCC1 (a so-called Na+- K+- 2 Cl- cotransporter) and investigated its function.
Insights into the three-dimensional atomic structure and dynamics of NKCC1 including the bound ions, lipids and water molecules as well as ion transport studies in cells provide important new information on NKCC1 function, which is driven by the sodium gradient established by the sodium-potassium pump.
The studies that the team present in an article in EMBO Journal reveal a surprising mechanism for release of the ions into the cell that begins with one of the two bound chloride ions, and only then the sodium ion and finally the other chloride and the potassium ion. The researchers will now continue to try to identify novel compounds that interfere with NKCC1 function and that may help in for example kidney and brain disorders.
The project was highly challenging from the very beginning and was started almost 10 years ago as a collaboration between the Nissen and Fenton laboratories. First-author and PhD student Caroline Neumann (now graduated) and colleagues from the Nissen laboratory undertook important collaborations with Prof. Rune Hartman’s laboratory (AU) to establish an advanced expression system for efficient protein production, and with Prof. Robert Fenton’s laboratory (Dept. of Biomedicine, AU) for functional studies of the transporter in mammalian cells. Finally, a collaboration was initiated with Prof. Kresten Lindorff-Larsen’s group from the University of Copenhagen for the computational simulations of the NKCC1 dynamics and ion release.
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Materials provided by Aarhus University. Original written by Lisbeth Heilesen. Note: Content may be edited for style and length.

Pathological processes are usually characterised by altered gene activity in the cells affected. So, gaining an accurate picture of gene activity can provide the key to the development of new, targeted therapies. Whether these therapies then work as we would want them to can also be verified by looking at genes and the processes they initiate.
It is no wonder that research is focused on methods and techniques that provide detailed information about the genetic activity of individual cells. A research team at the University of Würzburg (JMU) has now developed a technique that is a significant improvement on the methods used to date. Scientists from the Institute for Molecular Infection Biology (IMIB) and the Helmholtz Institute for RNA-based Infection Research (HIRI) were involved. They have presented the results of their work in the current issue of the journal Nucleic Acids Research.
Analysis of a synthetic transcriptome
“We have developed a technique that can be used to analyse the translational landscape of a fully customisable synthetic transcriptome, in other words one outside the cell,” is how Jörg Vogel explains the central outcome of the study. Vogel heads the Institute for Molecular Infection Biology at JMU and is also the Director of HIRI as well as the principal author of the study. The new technique has been given the scientific name INRI-seq, which is short for in vitro Ribo-seq.
A transcriptome is a collection of all the genes that are active in a cell at a given point in time. It consists of the sum of the existing mRNA — the transporters of the blueprints for proteins from the cell nucleus to the ribosomes. Ribosomes are the “protein factories” of the cell; this is where translation of the nucleotide sequence of the mRNA into the amino acid sequence of a protein takes place.
Refinement of comparable methods
In principle, INRI-seq is a refinement of comparable methods that pursue the same goal but provide less accurate results or have other disadvantages. For example, RNA sequencing (RNA-seq) determines the concentration of mRNA in cells, allowing conclusions to be drawn about their active genes. However, the final protein abundance does not always correlate with the respective mRNA concentrations.

In a set of identical twins, investigators led by researchers at Massachusetts General Hospital (MGH) and Children’s Hospital Philadelphia (CHOP) have identified a mitochondrial disease not previously reported.
Diseases that affect mitochondria — specialized compartments within cells that contain their own DNA and convert the food we eat into energy needed to sustain life — typically interfere with mitochondrial function, but in these two patients, mitochondria were hyperactive.
So, as reported in the New England Journal of Medicine, even though the siblings were eating far more calories than needed, their body weights remained very low.
“This is a highly unusual mitochondrial phenotype. There are more than 300 rare genetic mitochondrial diseases, and nearly all of them are associated with an interruption of mitochondria,” says senior author Vamsi K. Mootha, MD, a Professor of Systems Biology and Medicine at MGH.
Genome sequencing revealed a mutation in an enzyme called the mitochondrial ATP synthase, which is required by cells to generate the energy storage molecule ATP.
Experiments indicated that this mutation creates “leaky” mitochondria that dissipate energy — a process called mitochondrial uncoupling.
“We propose a new name — mitochondrial uncoupling syndrome — that presents with hypermetabolism and uncoupled mitochondria,” says Mootha. “These cases are very important for the field of rare disease genetics, mitochondrial biology, and metabolism.”
The authors note that additional studies on mitochondrial uncoupling syndromes may provide insights into differences in energy metabolism in the general population.
“These twins represent the first disorder of mitochondrial uncoupling where we have been able to find the genetic cause,” said Rebecca D. Ganetzky, MD, an attending physician in Mitochondrial Medicine program at CHOP and co-author of the study.
“By discovering that pathogenic variants in the ATP synthase itself can cause mitochondrial uncoupling, these twins may be the first identified patients in a whole class of diseases of mitochondrial coupling.”
Additional co-authors include Andrew L. Markhard, BA, Irene Yee, BS, Sheila Clever, MSc, Alan Cahill, PhD, Hardik Shah, MS, Zenon Grabarek, PhD, and Tsz-Leung To, PhD.
This work was supported by the National Institutes of Health and others.
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Orthopaedics faculty at LSU Health New Orleans participated in a study comparing two antisepsis aqueous solutions in reducing the risk of infection in patients requiring surgery for open fractures. In the largest known randomized-controlled trial, the research team found that contrary to current international recommendations, chlorhexidine gluconate was not superior to povidone-iodine in an alcohol or aqueous solution in preventing surgical site infection. The results suggesting health care practitioners can select either aqueous-based antisepsis solution when treating open fractures on the basis of solution availability, patient contraindications, or product cost are published in The Lancet, available here.
Robert Zura, MD, Professor and Head of Orthopaedics, and Jessica Rivera, MD, PhD, Associate Professor of Orthopaedics, at LSU Health New Orleans School of Medicine, are also co-authors on the paper.
The authors highlight WHO estimates of millions of patients worldwide each year who have surgical site infections. The inherent risk of using fracture fixation in a contaminated or dirty wound is realized in about 10% of open fractures developing surgical site infections. Orthopaedic surgical procedures have the highest infection rate, greater than 20% for severe open tibia shaft fractures.
Previous reviews of general surgery, obstetrics and gynecology trials suggested the superiority of chlorhexidine over iodine. The Aqueous-PREP multiple-period, cluster-randomized,
crossover trial included 14 hospitals in Canada, Spain and the United States and 1,638 adults who underwent surgery for an open extremity fracture. It found that the odds of surgical site infection or unplanned fracture-related reoperations did not differ between patients assigned to receive skin antisepsis with aqueous 10% povidone or aqueous 4% chlorhexidine gluconate. The authors wrote, “Our findings contrast the superiority of chlorhexidine in alcohol that has been shown in clean or clean-contaminated surgery.”
The authors note their findings could have particular relevance to low- and middle-income countries, where both antiseptic solutions might not be readily available or procuring both products is unnecessarily costly.
They conclude, “Our findings are not only relevant to the management of open fractures but might also be applicable to the surgical treatment of other traumatic wounds.”
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Individuals with Down syndrome have less-frequent viral infections, but when present, these infections lead to more severe disease. New findings publishing on October 14 in the journal Immunity show that this is caused by increased expression of an antiviral cytokine type I interferon (IFN-I), which is partially coded for by chromosome 21. Elevated IFN-I levels lead to hyperactivity of the immune response initially, but the body overcorrects for this to reduce inflammation, leading to increased vulnerability later in the viral attack.
“Usually too much inflammation means autoimmune disease, and immune suppression usually means susceptibility to infections,” says senior study author Dusan Bogunovic of the Icahn School of Medicine at Mount Sinai. “What is unusual is that individuals with Down syndrome are both inflamed and immunosuppressed, a paradox of sorts. Here, we discovered how this is possible.”
Down syndrome is typically caused by triplication of chromosome 21. This syndrome affects multiple organ systems, causing a mixed clinical presentation that includes intellectual disability, developmental delays, congenital heart and gastrointestinal abnormalities, and Alzheimer’s disease in older individuals.
Recently, it has become clear that atypical antiviral responses are another important feature of Down syndrome. Increased rates of hospitalization of people with Down syndrome have been documented for influenza A virus, respiratory syncytial virus, and severe acute respiratory syndrome due to coronavirus (SARS-CoV-2) infections.
While people with Down syndrome show clear signs of immune disturbance, it has yet to be elucidated how a supernumerary chromosome 21 leads to dysregulation of viral defenses. To address this knowledge gap, the researchers compared fibroblasts and white blood cells derived from individuals with and without Down syndrome, at both the mRNA and protein levels. They focused on the potent antiviral cytokine IFN-I receptor subunits IFNAR1 and IFNAR2, which are located on chromosome 21.
The researchers found that increased IFNAR2 expression was sufficient for the hypersensitivity to IFN-I observed in Down syndrome, independent of trisomy 21. But subsequently, the hyper-active IFN-I signaling cascade triggered excessive negative feedback via a protein called USP18, which is a potent IFNAR negative regulator. This process, in turn, suppressed further responses to IFN-I and antiviral responses. Taken together, the findings unveil oscillations of hyper- and hypo-responses to IFN-I in Down syndrome, predisposing to both lower incidence of viral disease and increased infection-related morbidity and mortality.
“We have a lot more to do to completely understand the complexities of the immune system in Down syndrome,” says first author Louise Malle of the Icahn School of Medicine at Mount Sinai. “We have here, in part, explained the susceptibility to severe viral disease, but this is only the tip of the iceberg.”
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Pain has been long recognized as one of evolution’s most reliable tools to detect the presence of harm and signal that something is wrong — an alert system that tells us to pause and pay attention to our bodies.
But what if pain is more than just a mere alarm bell? What if pain is in itself a form of protection?
A new study led by researchers at Harvard Medical School suggests that may well be the case in mice.
The research, published Oct. 14 in Cell, shows that pain neurons in the mouse gut regulate the presence of protective mucus under normal conditions and stimulate intestinal cells to release more mucus during states of inflammation.
The work details the steps of a complex signaling cascade, showing that pain neurons engage in direct crosstalk with mucus-containing gut cells, known as goblet cells.
“It turns out that pain may protect us in more direct ways than its classic job to detect potential harm and dispatch signals to the brain. Our work shows how pain-mediating nerves in the gut talk to nearby epithelial cells that line the intestines,” said study senior investigator Isaac Chiu, associate professor of immunobiology in the Blavatnik Institute at HMS. “This means that the nervous system has a major role in the gut beyond just giving us an unpleasant sensation and that it’s a key player in gut barrier maintenance and a protective mechanism during inflammation.”
A direct conversation

Often referred to as smart materials, temperature-responsive or thermoresponsive polymers are gaining attention for their ability to respond to external temperature changes, allowing for an extensive range of applications. Making this smart material even smarter by improving the flexibility of its response to temperature, Osaka Metropolitan University scientists have developed a novel polymer, the thermoresponsiveness of which can easily be regulated by changing the type and mixing ratio of ionic species. Their findings were published in Macromolecules.
Polymers that exhibit temperature-related change in their physicochemical properties are called thermoresponsive polymers. They include two types: polymers with lower critical solution temperatures (LCST) and polymers with upper critical solution temperatures (UCST). Above a certain temperature, the former are insoluble, whereas the latter are soluble. In LCST-type thermoresponsive polymers, as the temperature increases, the polymer-solvent interaction decreases and the polymer-polymer interaction becomes dominant, leading to precipitation of polymers from the solvent. Conversely, in UCST-type thermoresponsive polymers, as the temperature increases, the polymer-polymer interaction decreases and the polymer-solvent interaction becomes dominant, resulting in dissolution. This indicates the affinity between the polymer and the solvent as an important factor in most thermoresponsive polymers.
Conventionally, the polymer-solvent interaction is used to regulate thermoresponsiveness in designing thermoresponsive polymers. However, attention has recently focused on a new technique that regulates thermoresponsiveness by adding a third component. This technique often uses organic solvents, but to develop materials such as those for drug delivery systems, it is necessary that water, which is harmless to the human body, be used as the solvent.
The research team led by Professor Atsushi Harada from the Graduate School of Engineering at Osaka Metropolitan University used water as the solvent and developed an LCST-type thermoresponsive polymer by adding alkaline earth metal ions — which are divalent cations — to polymers and aqueous solutions. They succeeded in regulating thermoresponsive properties, simply by changing the species and mixing ratio of the ions. This is different from the conventional technique that can only regulate thermoresponsiveness by changing the structure of the polymers.
“We have developed a novel polymer that exhibits thermoresponsiveness in the presence of certain ions,” concluded Professor Harada. “We expect that it will be applied as an analytical reagent for metal ion-sensing devices and as a material for drug delivery systems.”
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