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Bronchial constriction is what makes many lung diseases like asthma so dangerous. Researchers have discovered a new signalling pathway that causes the airways to widen.
Inhalation therapy for asthma and other obstructive lung diseases often loses its effect following prolonged use. A research team led by Professor Daniela Wenzel from the Department of Systems Physiology at Ruhr University Bochum, Germany, has now shown an alternative signalling pathway through which the body’s own cannabinoids cause the bronchial tubes to dilate. This gives rise to hope for alternative treatment options. Asthma is evidently also associated with a deficiency of these cannabinoids in the bronchial tubes, which could be one of the causes of the disease.
Bronchial tubes dilated by the body’s own cannabinoids
Obstructive lung diseases are the third most common cause of death worldwide. They include chronic obstructive pulmonary disease (COPD), which affects many smokers, as well as bronchial asthma. During an asthma attack, the bronchial tubes contract so violently that it is no longer possible to exhale — and this can be life-threatening. “Asthma is an inflammatory process, but what is fatal is the constriction of the bronchial tubes,” explains Annika Simon, lead author of the study. “This is why we are very much interested in the regulation of this constriction.”
In a previous study, the researchers had likewise focused on the body’s own cannabinoid system, specifically on its effect in the blood vessels of the lungs. The best known endogenous cannabinoid is anandamide. “Since our results show that anandamide dilates the bronchial tubes, we wanted to understand the exact mechanism behind it,” explains Daniela Wenzel.
Enzyme degrades cannabinoid
It quickly emerged that the two best-known receptors for anandamide (CB1 and CB2) are irrelevant for this regulation. Therefore, there must be an alternative signalling pathway through which the messenger substance anandamide acts on the bronchial tubes.
Daniela Wenzel and her team showed that this alternative pathway uses an enzyme called fatty acid amide hydrolase (FAAH). FAAH degrades anandamide, producing e.g. arachidonic acid, which in turn is converted to prostaglandin E2. “We know that prostaglandin E2 can dilate the bronchial tubes,” points out Annika Simon. Prostaglandin E2 acts via certain receptors and leads to an increase in the messenger substance cAMP (cyclic adenosine monophosphate). “It is precisely this, the increase in cAMP, that is targeted by well-established inhalation medications against asthma,” says Daniela Wenzel. So, the goal is the same, but the path is different.
Anandamide deficiency in asthma
Wenzel and her team gradually deciphered the signalling pathway. They revealed that the enzyme FAAH is located both in the smooth muscle of the bronchial tubes and in the ciliated epithelium. The increase in cAMP after anandamide administration could be detected both in the mouse model and in human bronchial cells. In order to find out whether anandamide could also works in asthma patients, the team used a disease model in mice where certain substances can be used to create artificial asthma. In these animals, too, the administration of anandamide led to a widening of the bronchial tubes. “This means that asthma doesn’t result in resistance to anandamide,” explains Daniela Wenzel. Moreover, the researchers found that asthmatic animals have less anandamide and other endocannabinoids in their bronchial system than healthy animals. “Therefore, it’s possible that this anandamide deficiency is one of the causes of bronchial asthma,” concludes Daniela Wenzel.
The discovery of the new signalling pathway could also open up new possibilities for intervening in the disease process. “But there’s still a long way to go, and it will certainly take several years,” stresses Daniela Wenzel. She expressly warns patients not to undertake experiments with cannabis plants. “We can’t draw any direct conclusions regarding plant cannabinoids from the findings on endogenous cannabinoids. Exactly which other ingredients are found in cannabis plants besides the known cannabinoids is entirely unclear. Plus, the plants sometimes contain harmful substances.” Nevertheless, the findings of this study are already pointing towards a better understanding of the body’s own cannabinoid system, which could lead to new treatment options for lung diseases in a few years’ time.
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Materials provided by Ruhr-University Bochum. Original written by Meike Drießen. Note: Content may be edited for style and length.

Mitochondria are primarily known as the powerhouse of the cell. However, these cellular organelles are required not only for providing energy: Professor Konstanze Winklhofer and her group at the Faculty of Medicine at Ruhr University Bochum, Germany, recently discovered that mitochondria play an important role in signal transduction in innate immune pathways. They regulate a signalling pathway that helps to eliminate pathogens, but can cause damage through inflammation upon overactivation.Protection from bacteria and virusesCertain cytokines but also intracellular pathogens, such as viruses and some bacteria, activate the transcription factor NF-κB, which regulates the expression of various genes. “Depending on the stimulus and the cell type, NF-κB activation results in protection from cell death and increased synthesis of proteins required for the elimination of bacteria or viruses,” explains Konstanze Winklhofer. However, upon excessive and prolonged activation, this basically protective pathway can cause chronic inflammation. “Hence, a fine-tuned regulation of these signalling processes is of great medical relevance, in order to prevent pathophysiological conditions caused by either inefficient or overshooting NF-κB activation.”Two advantages of mitochondria: they are mobile and have a large surface areaThe new study has revealed that mitochondria play a crucial role in the regulation of the NF-κB signalling pathway. Within minutes after pathway activation, a signalling platform assembles at the outer mitochondrial membrane, resulting in the activation of NF-κB. “This allows signal amplification, based on the large surface of mitochondria,” says Konstanze Winklhofer. “Moreover, mitochondria have another capacity that qualifies them as organelles for signal transduction: they are mobile and can dock onto motor proteins in the cell.” The research team observed that mitochondria escort the activated transcription factor NF-κB to the nuclear membrane, thus facilitating the translocation of NF-κB into the nucleus.
However, mitochondria are not only involved in the efficient activation of the NF-κB signalling pathway; they also contribute to the deactivation and thus regulation of the signal. This is accomplished by an enzyme located at the outer mitochondrial membrane, which counteracts ubiquitination, a posttranslational modification required for NF-κB activation.Why Parkinson’s disease patients are more susceptible to some infectionsTwo genes causally linked to Parkinson’s disease are involved in the mitochondrial regulation of the NF-κB signalling pathway: PINK1 and Parkin. “Our findings explain why mutations resulting in a loss of PINK1 or Parkin function promote neuronal cell death under stress conditions,” points out Konstanze Winklhofer. “Remarkably, our findings show that Parkinson’s disease patients with mutations in the PINK1 or Parkin gene show an increased vulnerability to various infections caused by intracellular pathogens. Thus, our study also helps to gain a better understanding of the interfaces between the nervous and immune system.”
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Materials provided by Ruhr-University Bochum. Original written by Meike Drießen. Note: Content may be edited for style and length.

Researchers at Karolinska Institutet in Sweden have shown that patients with acute COVID-19 infection have increased levels of the cytokine IL-26 in their blood. Moreover, high IL-26 levels correlate with an exaggerated inflammatory response that signifies severe cases of the disease. The findings, which are presented in Frontiers in Immunology, indicate that IL-26 is a potential biomarker for severe COVID-19.
Vaccines for SARS-CoV-2 have proved effective at reducing the number of cases of severe COVID-19. However, the emergence of new viral variants, limited distribution of the vaccine and declining immunity are problems that drive scientists to find more efficacious treatments for the disease.
“We need to understand more about underlying immunological mechanisms in order to find better treatments. There is also a need for improved diagnostics in COVID 19-patients,” says Eduardo Cardenas, postdoc researcher at the Institute of Environmental Medicine, Karolinska Institutet, and principal author of the new pilot study.
The researchers have tried, for the first time, to ascertain whether immune signalling via the cytokine interleukin-26 (IL-26) is involved in severe COVID-19.
“We already know that IL-26 is engaged in mobilising immune cells that combat bacterial infections in the lungs and also in chronic respiratory disease in humans,” says the study’s last author Anders Lindén, consultant and professor at the Institute of Environmental Medicine, Karolinska Institutet. “What’s more, IL-26 has antiviral and antibacterial effects.”
To study how the molecule is involved in COVID-19, the scientists recruited 49 patients who had been hospitalised with SARS-CoV-2-infection, 44 of whom had severe symptoms and needed oxygen therapy. The patients were recruited at a hospital in Stockholm from June 2020 to January 2021. A control group of 27 healthy individuals was also recruited during the same period. The researchers then measured levels of IL-26 protein and other inflammatory compounds in the blood.
“We can show for the first time that blood levels of the cytokine IL-26 are much higher in patients with COVID-19 than in healthy controls,” says Dr Cardenas.
The researchers could also see that the increase was associated with the so-called cytokine storm — an excessive and dangerous inflammatory response that signifies severe cases of COVID-19.
“Our discovery gives us a potential biomarker for severe COVID-19, but given the antiviral effects of IL-26, we may also have identified a new therapeutic target,” says Professor Lindén.
According to Dr Cardenas, the results are promising but are preliminary and warrant further study with a larger patient cohort.
“Such a study is on the way and can give more information on the clinical value of measuring IL-26 in COVID-patients, such as whether the levels reflect the severity of the disease.
The study was financed by the Swedish Research Council and the Swedish Heart-Lung Foundation.
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Materials provided by Karolinska Institutet. Note: Content may be edited for style and length.

Cancer that splits and develops in new organs around the body becomes significantly more difficult to fight. Now, researchers at Chalmers University of Technology, Sweden, have shown that these metastatic cancers, that spread from the original, adapt their metabolism to the tissue in which they grow. The discovery represents a breakthrough for the understanding of metastatic cancer and is an important piece of the puzzle in the search for more effective treatments.
Metabolism in the human body can be likened to its internal engine. It is a prerequisite for our cells to grow and receive energy. Therefore, it is also an important target for cancer treatments, where the focus is on stopping the progress of cancer cells.
In a new study, which was recently presented in the scientific journal PNAS, researchers in Systems and Synthetic Biology at Chalmers have examined how metabolism works in cancer cells that have spread via metastases — also called secondary tumors — to new organs. The study gave the researchers new insights into how the metastases adapt to their new environment.
“Obviously, the local environment affects the cancer cells more than previously known. The metastatic tumours should show the same metabolic properties no matter where in the body they are located, but we discovered that the cancer cells largely adapted their metabolism to the new tissue in order to continue to develop and grow. This is important knowledge, which shows that we cannot consider the metastases as their original tumors,” says Fariba Roshanzamir, PhD in Systems and Synthetic Biology at Chalmers and the study’s lead author.
Tools for inhibiting cancer metabolism
Fariba Roshanzamir works in Professor Jens Nielsen’s research group at Chalmers and has, together with Swedish and international colleagues, been able to establish the groundbreaking results. The study focused primarily on so-called triple-negative breast cancer — a severe breast cancer that is difficult to treat with drugs — but the conclusions can, according to the researchers, be applied to all types of metastatic cancer. This opens new doors to develop more effective treatments.
“If we manage to shut down the metabolism in a tumour, it will stop working and this study provides important keys to better understand what to target. Selecting metabolic inhibitors that specifically target the metastases in the organs to which the tumour has spread, rather than treating them as their original tumours, is of great importance to be able to find good strategies for treatments in the future,” she says.
New view of the properties of metastases
Today, the spread of cancer to new organs is one of the leading causes of death in cancer patients. Jens Nielsen, Professor of Systems and Synthetic Biology at Chalmers University of Technology and one of the study’s authors, hopes that it will lead to a new view of the properties and behavior of metastases.
“This is a breakthrough in terms of our understanding of metastatic cancer and an important step on the way to more individualised drugs,” he says.
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Materials provided by Chalmers University of Technology. Original written by Ulrika Ernström. Note: Content may be edited for style and length.

Fungi in the soil cause a significant number of serious lung infections in 48 out of 50 states and the District of Columbia, including many areas long thought to be free of deadly environmental fungi, according to a study by researchers at Washington University School of Medicine in St. Louis.
Studies from the 1950s and 60s indicated that fungal lung infections were a problem only in certain parts of the country. The new study, available online in Clinical Infectious Diseases, shows that is no longer the case. Doctors who rely on outdated maps of disease-causing fungi may miss the signs of a fungal lung infection, resulting in delayed or incorrect diagnoses, the researchers said.
“Every few weeks I get a call from a doctor in the Boston area — a different doctor every time — about a case they can’t solve,” said senior author Andrej Spec, MD, an associate professor of medicine and a specialist in fungal infections. “They always start by saying, ‘We don’t have histo here, but it really kind of looks like histo.’ I say, ‘You guys call me all the time about this. You do have histo.'”
Histoplasma, or histo, is one of the three main species of soil fungi that cause lung infections in the U.S. Historically, Histoplasma was found in the Midwest and parts of the East, Coccidioides in the Southwest, and Blastomyces in the Midwest and the South. But a growing number of case reports and anecdotes suggest that all three have expanded out of their traditional ranges in recent decades, most likely due to climate change.
People develop fungal lung infections after breathing in spores from fungi in the soil. The spores become airborne when the ground is disturbed by farming, landscaping, construction or even just by people walking around in fungi-rich environments such as caves. Most healthy adults and children can fight off a fungal infection handily, but infants, older adults and people with compromised immune systems may develop fever, cough, fatigue and other symptoms. Fungal lung infections easily can be mistaken for bacterial or viral lung infections such as COVID-19, bacterial pneumonia and tuberculosis.
“People with fungal lung infection often spend weeks trying to get the right diagnosis and appropriate treatment, and the whole time they’re feeling terrible,” said lead author Patrick B. Mazi, MD, a clinical fellow in infectious diseases. “They usually have multiple health-care visits with multiple opportunities for testing and diagnosis, but the doctor just doesn’t consider a fungal infection until they’ve exhausted all other possibilities.”
Spec, Mazi and colleagues set out to determine where soil fungi are sickening people today. The Centers for Disease Control and Prevention (CDC) last revised its maps of disease-causing fungi in 1969.
The researchers calculated the number of fungal lung infections nationwide from 2007 to 2016 using Medicare fee-for-service claims from all 50 states and the District of Columbia. Using the patients’ home addresses to identify counties of residence, they calculated the number of cases per 100,000 person-years for each county. (Person-years are a way to correct for the fact that counties can have wildly different population sizes; one person on Medicare for one year is one person-year). Counties with more than 100 cases caused by Histoplasma or Coccidioides, or 50 cases caused by Blastomyces, per 100,000 person-years were defined as having a meaningful number of fungal lung infections.
Of the 3,143 counties in the U.S., 1,806 had meaningful numbers of lung infections caused by Histoplasma, 339 of Coccidioides and 547 of Blastomyces. These counties were distributed across the majority of the U.S. Across the 50 states plus DC, 94% had at least one county with a problem with Histoplasma lung infections, 69% with Coccidioides and 78% with Blastomyces.
“Fungal infections are much more common than people realize, and they’re spreading,” Spec said. “The scientific community has underinvested in studying and developing treatments for fungal infections. I think that’s beginning to change, but slowly. It’s important for the medical community to realize these fungi are essentially everywhere these days and that we need to take them seriously and include them in considering diagnoses.”

The number of U.S. adult handgun owners carrying a loaded handgun on their person doubled from 2015 to 2019, according to new research led by the University of Washington.
Data come from the 2019 National Firearms Survey (NFS), an online survey of U.S. adults living in households with firearms, including nearly 2,400 handgun owners. Compared to estimates from prior UW-led research, the new study suggests that in 2019 approximately 16 million adult handgun owners had carried a loaded handgun on their person in the past month (up from 9 million in 2015) and 6 million carried every day (twice as many as carried daily in 2015).
Published Nov. 16 in the American Journal of Public Health, the study also found that a larger proportion of handgun owners carried handguns in states with less restrictive carrying regulations: In these states, approximately one-third of handgun owners reported carrying in the past month, whereas in states with more restrictive regulations, only about one-fifth did.
“Between increases in the number of people who own handguns and the number of people who carry every day, there has been a striking increase in handgun carrying in the U.S.,” said lead author Dr. Ali Rowhani-Rahbar, a professor of epidemiology and Bartley Dobb Professor for the Study and Prevention of Violence at the UW.
Among the other findings reported in the new study: About 7 in 10 handgun owners said they carried a loaded handgun as protection against another person, dwarfing the number who said they carried as protection against an animal, for example, or for work 4 in 5 handgun owners who reported carrying were male, 3 in 4 were white, and a majority were between the ages of 18 and 44Researchers pointed to some limitations of the study: Respondents were asked if they carried, and how often, but not where. It is possible that a person residing in a state with one type of permitting restrictions (or none) could have carried their handgun in another state with different laws. The study also did not ask whether the respondent carried a handgun openly or concealed.
While the data are from 2019, researchers say the findings are timely, following the U.S. Supreme Court ruling in June that struck down a New York state handgun-carrying law. States, in general, have become less restrictive over the years regarding handgun carrying — more than 20 do not require permits to carry today, compared to only one such state in 1990. The differences highlighted in this study suggest that this behavior may be responsive to the types of laws governing carrying that pertain in a state.
“The Supreme Court ruling has already resulted in some states’ loosening of laws related to handgun carrying,” Rowhani-Rahbar said. “In light of that ruling, our study reinforces the importance of studying the implications of handgun carrying for public health and public safety.”
The study was funded by the Joyce Foundation and the New Venture Fund. Co-authors were Amy Gallagher, now of the Centers for Disease Control and Prevention, previously of the Firearm Injury & Policy Research Program at the UW; Deborah Azrael of Harvard University; and Matthew Miller of Northeastern University.
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Materials provided by University of Washington. Original written by Kim Eckart. Note: Content may be edited for style and length.

Johns Hopkins Medicine researchers have revamped an anti-cancer drug to better target cancer cells and leave healthy tissues unharmed. Scientists have dubbed this type of targeted approach a “prodrug” — a medicine designed to release its payload in a particular area of the body and in no other areas. The Johns Hopkins-discovered prodrug, called DRP-104 (sirpiglenastat), is in early-stage clinical trials in people with advanced solid tumors. The newly published studies in mice show that the augmented drug preferentially eliminates cancer cells but does not harm healthy cells.
A report of their experiments is published November 16 in Science Advances.
“Our goal was to modify an old cancer drug that had shown robust efficacy but was too toxic, especially to the gut, to be developed clinically. To do this, we used a prodrug approach. What is unique about our approach is that we utilized a novel chemistry design to create a prodrug that was simultaneously bio-activated in cancer cells but bio-inactivated in healthy tissues such as the gut. This preferential targeting of the payload to cancer cells is now enabling this efficacious class of drugs to be reevaluated safely in people,” says study author Barbara Slusher, Ph.D., M.A.S., director of the Johns Hopkins Drug Discovery Program and professor of neurology, pharmacology and molecular sciences, psychiatry, neuroscience, medicine and oncology at the Johns Hopkins University School of Medicine.
The newly modified prodrug takes advantage of a common property of cancer cells: a voracious appetite for an amino acid called glutamine, which is a critical building block for proteins, lipids and nucleotides, as well as for energy formation. Rapidly growing cancer cells use a tremendous amount of glutamine, a phenomenon called “glutamine addiction,” but other healthy cells with rapid turnover, like those lining the gut, also rely on glutamine.
Co-author Rana Rais, Ph.D., an associate professor of neurology and pharmacology, says, “DRP-104 is a tumor-targeted prodrug of the glutamine mimic drug called DON (6-Diazo-5-Oxo-L-norleucine), which inhibits multiple glutamine-utilizing enzymes in cancer cells. Many early studies of DON showed it was robustly efficacious in people and mice, but its development was halted due to its toxicity to normal tissues, especially the gut.”
Development of this promising class of drugs did not resume until Slusher, Rais and team decided to make chemical modifications to DON.

People with neurologic diseases like headache, dementia, multiple sclerosis (MS) and Parkinson’s disease may experience worsening symptoms due to climate change, according to a scoping review of research published in the November 16, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology. The review also found that stroke may become more prevalent due to climate change.
“Although the international community seeks to reduce global temperature rise to under 2.7 ºF before 2100, irreversible environmental changes have already occurred, and as the planet warms these changes will continue to occur,” said review author Andrew Dhawan, MD, DPhil, of Cleveland Clinic in Ohio and a member of the American Academy of Neurology. “As we witness the effects of a warming planet on human health, it is imperative that neurologists anticipate how neurologic disease may change.”
For the review, researchers looked at studies published on climate change, pollutants, temperature extremes and neurologic disease between 1990 and 2022. They identified 364 relevant studies in three categories, including 289 studies on the impact of pollution, 38 studies on extreme weather events and temperature fluctuations and 37 studies on emerging neuroinfectious diseases. They included only studies on adults, not children.
The studies highlighted the relationships between temperature variability and worsening neurologic symptoms, warming climates and tick- and mosquito-borne infections, as well as airborne pollutants and cerebrovascular disease rate and severity.
The review showed extreme weather events and temperature fluctuations were associated with stroke incidence and severity, migraine headaches, hospitalization in dementia patients, and worsening of MS.
It showed for emerging neuroinfectious diseases like West Nile virus, meningococcal meningitis and tick-borne encephalitis, climate change expanded the favorable conditions beyond the traditional geographic areas, and these diseases carried by animals and insects pose the risk of disease in new populations.
The review also showed exposure to airborne pollutants, especially nitrates and fine particulate matter, also known as PM 2.5, pollutant particles of less than 2.5 microns in diameter, was associated with stroke incidence and severity, headaches, dementia risk, Parkinson’s disease, and worsening of MS.
“Climate change poses many challenges for humanity, some of which are not well-studied,” said Dhawan. “For example, our review did not find any articles related to effects on neurologic health from food and water insecurity, yet these are clearly linked to neurologic health and climate change. More studies are needed on ways to reduce neuroinfectious disease transmission, how air pollution affects the nervous system, and how to improve delivery of neurologic care in the face of climate-related disruptions.”
A limitation is that the studies were conducted in resource-rich regions of the world, suggesting that the results may not apply in regions with fewer resources where such changes may be even more likely to occur.
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Materials provided by American Academy of Neurology. Note: Content may be edited for style and length.

People who have a COVID-19 infection are more likely to develop seizures or epilepsy within the next six months than people who have an influenza infection, according to a study published in the November 16, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology. The increased risk was more noticeable in children than adults. It was also more noticeable in people who did not need hospitalization for COVID-19 infections.
“While the overall risk of developing seizures or epilepsy was low — less than 1% of all people with COVID-19, given the large number of people who have been infected with COVID-19, this could result in increases in the number of people with seizures and epilepsy,” said study author Arjune Sen, MD, PhD, of the University of Oxford in England. “In addition, the increased risk of seizures and epilepsy in children gives us another reason to try to prevent COVID-19 infections in kids.”
For the study, researchers looked at a health records network for people with COVID-19 infections. They were matched to people who were diagnosed with influenza during the same time period and who were similar in age, sex and other factors, such as other medical conditions. None of the participants had previously been diagnosed with epilepsy or recurrent seizures. The researchers then looked to see whether people developed epilepsy or seizures in the following six months.
There were 152,754 people in each of the COVID-19 and influenza groups.
People who had COVID-19 were 55% more likely to develop epilepsy or seizures over the next six months than people who had influenza. The rate of new cases of epilepsy or seizures was 0.94% in the people who had COVID-19, compared to 0.60% in those who had influenza.
“People should interpret these results cautiously since the overall risk is low,” Sen said. “We do, however, recommend that health care professionals pay particular attention to individuals who may have more subtle features of seizures, such as focal aware seizures, where people are alert and aware of what is going on, especially in the three months following a less severe COVID-19 infection.”
A limitation of the study was that researchers were unable to identify which specific virus variants people were infected with, which could have influenced results.
The study was supported by the British National Institute for Health and Care Research Oxford Health Biomedical Research Centre.
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Materials provided by American Academy of Neurology. Note: Content may be edited for style and length.