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Many common illnesses such as arteriosclerosis and diabetes or neurodegenerative diseases such as Alzheimer’s are associated with inflammatory processes. Gaining a better understanding of these processes is therefore an important stepping stone toward the development of new therapeutic approaches. Specific immune cells known as neutrophils play a decisive role in the initiation and maintenance of inflammatory processes in blood and tissue. In the course of their activation, these neutrophils already begin to release pro-inflammatory messengers into blood vessels, signaling to the body that the immune system must redouble its efforts.
A team led by Professor Markus Sperandio at LMU’s Institute of Cardiovascular Physiology and Pathophysiology has now discovered the molecular mechanisms by which neutrophils release certain messengers known as alarmins in a very early phase of the immune response.
As the researchers report in the journal Nature Immunology, the release of these alarmins from the cell interior occurs through gasdermin D pores in the cell membrane of the neutrophils, which are formed by activation of the so-called NLRP3 inflammasome. It was already known that immune cells can form these pores after extended periods of activation. However, the LMU team, supported by partners in Germany and Switzerland, has now been able to demonstrate for the first time that the pore formation and alarmin release take place in the blood circulation and not just later in the tissue.
Rapid and reversible pore formation
The research team also discovered that the process is not only fast, but reversible. That is to say, the neutrophils can remove the formed pores again in a matter of minutes. This prevents the cell death that would otherwise set in, as is often observed after activation of the NLRP3 inflammasome and subsequent pore formation.
The research thus expands our knowledge of how the NLRP3 inflammasome works and opens up the possibility of therapeutically influencing inflammatory processes at a very early stage through modulation of the mechanisms involved in alarmin release.

LMU researchers have identified a signaling pathway by which aspirin can inhibit colorectal cancer.
Colorectal cancer (bowel cancer) is the third most common form of cancer worldwide, with around 1.9 million newly diagnosed cases and 900,000 deaths every year. Therefore, preventive substances represent an urgent clinical need. Aspirin/acetylsalicylic acid has proven to be one of the most promising candidates for the prevention of colorectal cancer. Among other findings, studies have shown that when patients with cardiovascular diseases took low doses of aspirin over several years, it reduced their risk of colorectal cancer. Furthermore, aspirin can inhibit the progression of colorectal cancer. Now a team led by Heiko Hermeking, Professor of Experimental and Molecular Pathology at LMU, has investigated which molecular mechanisms mediate these effects.
As the researchers report in the journal Cell Death and Disease, aspirin induces the production of two tumor-suppressive microRNA molecules (miRNAs) called miR-34a and miR-34b/c. To do this, aspirin binds to and activates the enzyme AMPK, which in turn alters the transcription factor NRF2 such that it migrates into the cell nucleus and activates the expression of the miR-34 genes. For this activation to succeed, aspirin additionally suppresses the oncogene product c-MYC, which otherwise inhibits NRF2.
Overall, the results show that the miR-34 genes are necessary for mediating the inhibiting effect of aspirin on colorectal cancer cells. Aspirin was thus unable to prevent migration, invasion, and metastasis in miR-34-deficient cancer cells. It was already known that the miR-34 genes are induced by the transcription factor p53 and mediate its effects. “Our results show, however, that activation of the miR-34 genes by aspirin takes place independently of the p53 signaling pathway,” says Hermeking. “This is important because the p53-encoding gene is the most commonly inactivated tumor suppressor gene in colorectal cancer. In most other kinds of cancer, moreover, p53 is inactivated by mutations or viruses in the majority of cases. Aspirin could therefore be employed therapeutically in such cases in the future.”

Metabolites called nucleotides are the building blocks of DNA and can impact cancer’s sensitivity or resistance to chemotherapy and radiation in brain cancer.
Findings from researchers at the University of Michigan Health Rogel Cancer Center, published in Cancer Discovery, show how a specific nucleotide metabolite, called GTP, controls responses to radiation and chemotherapy in an unexpected way.
“We learned that if you increase a cell’s GTP levels, it makes it really resistant to radiation or chemotherapy. Lowering GTP levels, the cell becomes much more sensitive,” said Daniel Wahl, M.D., Ph.D., associate professor of radiation oncology at Michigan Medicine and senior author of this paper.
Researchers have long known that levels of nucleotides like GTP control how fast DNA damage is repaired, which in turn controls sensitivity to therapies.
Researchers previously thought that this only happened because nucleotides are the building blocks that form DNA. But these findings uncover an entirely new way that nucleotides control DNA repair.
“GTP impacts resistance or sensitivity to treatment not just because it’s a building block of DNA, as we previously thought,” Wahl continued.
“Instead of only affecting the physical structure of the DNA, it also acts as a signaler. The levels of GTP turn on a signaling pathway and give cells instructions to repair damaged DNA.”
What’s more, Wahl and collaborator Weihua Zhou, Ph.D., found this to be true for normal tissue in addition to cancer cells.

Most people who have pulled an all-nighter are all too familiar with that “tired and wired” feeling. Although the body is physically exhausted, the brain feels slap-happy, loopy and almost giddy.
Now, Northwestern University neurobiologists are the first to uncover what produces this punch-drunk effect. In a new study, researchers induced mild, acute sleep deprivation in mice and then examined their behaviors and brain activity. Not only did dopamine release increase during the acute sleep loss period, synaptic plasticity also was enhanced — literally rewiring the brain to maintain the bubbly mood for the next few days.
These new findings could help researchers better understand how mood states transition naturally. It also could lead to a more complete understanding of how fast-acting antidepressants (like ketamine) work and help researchers identify previously unknown targets for new antidepressant medications.
The research will be published online on Thursday (Nov. 2) in the journal Neuron. Northwestern postdoctoral fellow Mingzheng Wu is the paper’s first author, and Professor Yevgenia Kozorovitskiy is the corresponding author.
“Chronic sleep loss is well studied, and it’s uniformly detrimental effects are widely documented,” Kozorovitskiy said. “But brief sleep loss — like the equivalent of a student pulling an all-nighter before an exam — is less understood. We found that sleep loss induces a potent antidepressant effect and rewires the brain. This is an important reminder of how our casual activities, such as a sleepless night, can fundamentally alter the brain in as little as a few hours.”
An expert in neuroplasticity, Kozorovitskiy is an associate professor of neurobiology and the Irving M. Klotz Professor at Northwestern’s Weinberg College of Arts and Sciences.
Signs of sleep loss
Scientists long have known that acute perturbations in sleep are associated with altered mental states and behaviors. Alterations of sleep and circadian rhythms in patients, for example, can trigger mania or occasionally reverse depressive episodes.

Women who receive a false positive mammography result are more likely to develop breast cancer over the subsequent 20 years, report researchers from Karolinska Institutet in a study published in JAMA Oncology. The risk is highest for women aged between 60 and 75 and who have low breast density.
In global terms, breast cancer is the most common form of cancer among women, and screening is an important tool for catching women with a tumour at the earliest possible stage. In Sweden, all women between 40 and 74 are invited for screening at 18 to 24-month intervals.
At each screening visit, approximately three per cent of the women who undergo screening have a false positive result, which means that they are recalled for further examination without any cancer diagnosis. False-positive mammography results can cause psychological anxiety and influence screening attendance. Previous studies indicated that false-positive mammography results were associated with a short-term increased risk of breast cancer.
The new study shows that women with false-positive results are more likely to develop breast cancer than other women over the subsequent 20 years, facing, on average, a 60 per cent increased risk, suggesting the increased risk is long-term. In this study, the researchers identified 45,213 women with an initial false positive result and 452,130 women of the same age who were not recalled, all of whom attended the mammography screening program in Stockholm. Additionally, the researchers included 12,243 women with information on mammographic density from the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) study.
“The elevated risk was higher in women in the 60-75 age-bracket than in the 40-49 age-bracket, and in women with low rather than high mammographic density,” says Xinhe Mao, postdoctoral researcher at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet in Sweden. “The risk was also highest in the four to six years following a false positive result.”
“It’s important to accentuate a long-term awareness of breast cancer in women who get false positive mammography results,” says Mao. “It might be beneficial to draw up personal monitoring programmes for these women with careful follow-ups over the years immediately following.”
The study formed part of Xinhe Mao’s doctoral thesis, and she will now continue her research with the aim to motivate more women to undergo regular mammography screening.
“Radiology and breast cancer screening are currently in a phase of rapid development, partly thanks to the use of AI,” says the study’s last author Professor Kamila Czene at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. “Our published paper is part of the general efforts to achieve better screening results and increase the screening programme uptake.”
The study was financed by the Swedish Research Council, the Swedish Cancer Society, Region Stockholm, the Swedish Research Council for Health, Working Life and Welfare (FORTE) and the China Scholarship Council.

Practicing mindfulness focused on healthy eating can be good for the heart, a new study shows, because it improves self-awareness and helps people stick to a heart-healthy diet.
When people who had elevated blood pressure participated in an eight-week mindfulness-based blood pressure reduction program for the study, they significantly improved their scores on measures of self-awareness and adherence to a heart-healthy diet compared to a control group. The results were published in JAMA Network Open.
“Participants in the program showed significant improvement in adherence to a heart-healthy diet, which is one of the biggest drivers of blood pressure, as well as significant improvements in self-awareness, which appears to influence healthy eating habits,” said lead study author Eric B. Loucks, an associate professor of epidemiology, behavioral and social sciences, and director of the Mindfulness Center at Brown University.
Loucks said the study helps explain the mechanism by which a customized mindfulness training program adapted toward improving diet can affect blood pressure.
“Improvements in our self-awareness, of how different foods make us feel, of how our body feels in general, as well as our thoughts, emotions and physical sensations around eating healthy as well as unhealthy food, can influence people’s dietary choices,” he said.
High blood pressure, a major cause of cardiovascular disease, is the single most important risk factor for early death worldwide, according to a recent report by the World Health Organization, leading to an estimated 10.8 million avoidable deaths every year. The important thing to note about those avoidable deaths, Loucks said, is that there is ample research supporting effective strategies to control and prevent hypertension.
“Almost everyone has the power to control blood pressure through changes in diet and physical activity, adherence to antihypertensive medications, minimizing alcohol intake and monitoring stress reactivity,” he said.

Major depressive disorder (MDD) is a widespread mental health condition that for many is disabling. It has long been appreciated that MDD has genetic as well as environmental influences. In a new study in Biological Psychiatry, published by Elsevier, researchers identify a gene that interacted with stress to mediate aspects of treatment-resistant MDD in an animal model.
Jing Zhang, PhD, at Fujian Medical University and senior author of the study, said, “Emerging evidence suggests that MDD is a consequence of the co-work of genetic risks and environmental factors, so it is crucial to explore how stress exposure and risk genes co-contribute to the pathogenesis of MDD.”
To do that, the authors used a mouse model of stress-induced depression called chronic social defeat stress (CSDS) in which mice are exposed to aggressor mice daily for two weeks. They focused on a gene called LHPP, which interacts with other signaling molecules at neuronal synapses. Increased expression of LHPP in the stressed mice aggravated the depression-like behaviors by decreasing expression of BDNF and PSD95 by dephosphorylating two protein kinases, CaMKIIα and ERK, under stress exposure.
Dr. Zhang noted, “Interestingly, LHPP mutations (E56K, S57L) in humans can enhance CaMKIIα/ERK-BDNF/PSD95 signaling, which suggests that carrying LHPP mutations may have an antidepressant effect in the population.”
MDD is an extremely heterogeneous condition. Differences in the types of depression experienced by people influence the way they respond to treatment. A large subgroup of people with depression fail to respond to standard antidepressant medications and have “treatment-resistant” symptoms of depression. These patients often respond to different medications, such as ketamine or esketamine, or to electroconvulsive therapy. Notably, esketamine markedly alleviated LHPP-induced depression-like behaviors, whereas the traditional drug fluoxetine did not, suggesting that the mechanism might underlie some types of treatment-resistant depression.
John Krystal, MD, Editor of Biological Psychiatry, said of the work, “We have limited understanding of the neurobiology of treatment-resistant forms of depression. This study identifies a depression risk mechanism for stress-related behaviors that fail to respond to a standard antidepressant but respond well to ketamine. This may suggest that the risk mechanisms associated with the LHPP gene shed light on the poorly understood biology of treatment-resistant forms of depression.”
Dr. Zhang added, “Together, our findings identify LHPP as an essential player driving stress-induced depression, implying targeting LHPP as an effective strategy in MDD therapeutics in the future.”

The Latest NewsThe number of high school students who reported using e-cigarettes fell to 10 percent in the spring of this year from 14 percent last year, according to the results of an annual survey released on Thursday by federal health agencies.Vaping rose slightly among middle school students, to 4.6 percent this year from 3.3 percent in 2022. The use of traditional cigarettes among high school students remained at a record low of less than 2 percent.The decline in high school vaping rates was “encouraging,” said Linda Neff, an official with the Centers for Disease Control and Prevention and the lead author on the latest survey report. But she said the results for older teenagers were tempered by very small increases in middle school students reporting tobacco use.Puff Bar e-cigarettes.Jenna Schoenefeld for The New York TimesWhat’s Behind the Numbers: Flavor bans may have had an effect.One thing is clear about underage e-cigarette use: Adolescents like flavors. About 90 percent of the students who reported vaping said they used flavored products, citing favorites that tasted like fruit and candy.Teenagers identified Elf Bar and Esco Bar as their favorite brands, well-known for flavors such as strawberry kiwi and watermelon ice.Public health advocates in California recognized the allure, leading to a yearslong fight to pass a ban on flavored tobacco products, which took effect in December. It quickly led to falling sales, according to data from the C.D.C. Foundation. From December 2022 to June of this year, flavored e-cigarette sales fell by nearly 70 percent, to 179,000 from about 575,000 vapes or refills.The ban no doubt made it harder for young people to buy vapes in California, where you must be 21 to buy tobacco products.Public health experts also linked other state and local flavor bans and education campaigns to the falling high school vaping rate, which is the lowest in nearly a decade. And a few years ago, under public pressure, Juul, which had once been the most popular brand, withdrew most of its flavors from the market.The survey was given in about 180 schools nationwide, and was released by the C.D.C. and the Food and Drug Administration. It reported on e-cigarette use in the last 30 days but did not include any state-specific information.In all, about 2.1 million middle and high school students reported using e-cigarettes, down from 2.5 million last year. But surveys conducted during a few previous years since the peak of the vaping crisis in 2019 have carried notes of caution about drawing strict comparisons year-to-year because of pandemic conditions when students were in and out of school.Why It Matters: Studies identify health risks of vaping for teenagers.Federal officials who regulate e-cigarettes see their use as an aid in helping adult smokers quit traditional cigarettes, given the well-known cancer risks.But e-cigarette use has become wildly popular among nonsmokers. About 40 percent of people who use e-cigarettes are under 25, including many who started when Juul was first introduced. A majority of those young people never smoked before vaping, according to the C.D.C.The health effects are well known by now. One recent University of Southern California study noted the toxicity of the chemicals in e-cigarettes and sent questionnaires to adolescents who vaped. It found significant increases in wheezing, shortness of breath and bronchitis symptoms. And many experts have expressed concerns about the effect of nicotine addiction on the adolescent’s developing brain.What’s Next: A proposed menthol ban and heightened enforcement of illegal imports.The F.D.A. is moving toward a ban on menthol cigarettes and is advancing a proposal to drastically cut nicotine levels in cigarettes. That has led legacy tobacco companies to embrace e-cigarette sales as the way forward in the marketplace to offset overall declining cigarette sales.Yet those companies — along with many lawmakers in Congress and antismoking groups — say they have been dismayed with what they consider lax enforcement by the F.D.A. While the agency has authorized about two dozen vaping products for sale, thousands of illicit candy-colored flavored vapes have flooded the country and are top sellers.The F.D.A. said it would press ahead with its enforcement efforts, including its import ban on Elf Bar and Esco Bar products and fines on retailers who continue to sell them. The agency has issued warning letters to makers of those vapes and many others.Brian King, the F.D.A.’s tobacco division chief, welcomed the findings, but said: “We can’t rest on our laurels. There’s more work to be done to build on this progress.”Dr. Neff said her agency needed to better understand why there was a small but significant increase in middle school use of any tobacco product, to 6.6 percent this year from 4.5 percent last year.“Our work is far from done,” Dr. Neff said.Other researchers noted that the combined general use of tobacco products by middle and high school students barely fell, to 10 percent this year from 11 percent last year. “On balance, it’s no change in the overall youth tobacco use,” said Karen Knudsen, chief executive of the American Cancer Society. “And that’s concerning.”

Published43 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesThe boss and three other officials of an Indonesian firm whose cough syrup was linked to the deaths of over 200 children have been sentenced to jail.They were handed two-year prison sentences and fined 1bn Indonesian rupiah ($63,029; £51,7130) each.The firm, Afi Farma, was accused of producing cough syrups containing excess amounts of toxic substances.The company’s lawyer said they denied negligence and the firm was considering whether to appeal.Prosecutors had been seeking a prison sentence of seven to nine years for Afi Farma’s chief executive, Prasetya Harahap, and seven years each for the other defendants.The Public Prosecutor said that between October 2021 and February 2022 the company received two batches of propylene glycol, which is used for making cough syrup.These batches contained 96% to 99% ethylene glycol, the prosecutor said. Both substances can be used as additives to solvents. While, propylene glycol is non-toxic and widely used in medicines, cosmetics and food, ethylene glycol is toxic and used in paint, pens and brake fluid.The company did not test the ingredients used in the cough syrup and instead relied on quality and safety certificates from its supplier, prosecutors said.Afi Farma’s lawyer, Samsul Hidayat, told the BBC that Indonesia’s drug regulator did not require drug makers to carry out rigorous testing of ingredients.The judge in the Kediri District Court, East Java, found the four defendants guilty of intentionally producing pharmaceutical goods that did not meet safety standards.The case comes as efforts grow worldwide to tighten the oversight of drug supply chains after the poisonings.Since 2022, more than 200 Indonesian children, most of whom were under the age of five, have died of acute kidney injury linked to contaminated cough syrup. About 100 deaths have been reported in The Gambia and Uzbekistan.The World Health Organization (WHO) has issued warnings about six cough syrups made in India and Indonesia.More on this storyIndia makes cough syrup testing mandatory for exportsPublished23 MayTears of relief over Indonesia syrup deaths lawsuitPublished21 MarchSyrup medicine deaths devastate IndonesiaPublished30 October 2022Why drugs made in India are sparking safety concernsPublished17 October 2022WHO issues alert over another India-made cough syrupPublished26 April

Published7 hours agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy Michelle RobertsDigital health editorThe Covid pandemic may have impacted brain health in people in the UK aged 50 and over, according to a new study. More than 3,000 volunteers completed yearly questionnaires and online cognitive tests to measure changes in memory, and other faculties, as the pandemic unfolded. The results revealed a decline, irrespective of Covid infection.Stress, loneliness and alcohol consumption may explain some of the findings, experts say. Coping with Covid fears, worries and uncertainties and disruption to routines may have had a “real, lasting impact” on brain health, they say. Covid: How might the pandemic have affected your brain?Covid brain fog more common two years on, study suggestsThe rate of the drop in cognitive function was accelerated during the first year of the pandemic, when lockdowns occurred, the study found.For memory issues, the decline continued into the second year. People who already had some mild memory problems before the pandemic began had the worst overall decline.Image source, Science Photo LibraryThe study, called PROTECT – published in The Lancet Healthy Longevity – was set up to help understand how healthy brains age and why some people develop dementia. It uses brain-training games to check memory skills and reasoning, while the questionnaire looks for possible risk factors that could harm brain health.The plan is to keep the study running in the future to see how participants fare, and what lessons can be learned to help others.Based on the current findings, lead investigator Prof Anne Corbett, from the University of Exeter and previously King’s College London, says pandemic conditions may have hastened brain decline.”Our findings suggest that lockdowns and other restrictions we experienced during the pandemic have had a real, lasting impact on brain health in people aged 50 or over, even after the lockdowns ended. “This raises the important question of whether people are at a potentially higher risk of cognitive decline which can lead to dementia. “It is now more important than ever to make sure we are supporting people with early cognitive decline, especially because there are things they can do to reduce their risk of dementia later on. “So if you are concerned about your memory, the best thing to do is to make an appointment with your GP and get an assessment.”Dr Dorina Cadar, a dementia expert from Brighton and Sussex Medical School, said the effect of the pandemic on the general population had been “catastrophic”. “Many of the long-term consequences of Covid-19, or the restriction measures implemented around the world, remain unknown,”She recommended more research, and said although the findings could not prove cause and effect, there is mounting evidence that some of the factors described, such as social isolation, can negatively impact brain health. Dr Susan Mitchell from Alzheimer’s Research UK said: “While our genetics play an important role in the health of our brains as we age, we know that a range of health and lifestyle factors can impact our brain health. “Sadly, there’s no sure-fire way to prevent dementia yet, but meanwhile, taking care of our brains can at least help stack the odds in our favour. It’s never too early or too late to think about adopting healthy habits, which includes looking after your heart health, keeping connected and staying sharp.”More on this storyBrain fog after Covid linked to blood clots – studyPublished31 AugustBrain changes seen after mild CovidPublished7 March 2022Related Internet LinksPROTECT studyThe Lancet Healthy LongevityThe BBC is not responsible for the content of external sites.