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Tag: Charité – Universitätsmedizin Berlin

  • New factor in excess body weight discovered

    New factor in excess body weight discovered

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    Newswise — What determines whether we become overweight? Aside from lifestyle, predisposition plays a role, but genes cannot fully explain the inherited propensity to accumulate excess weight. A new study by Charité – Universitätsmedizin Berlin in Science Translational Medicine* shows that a kind of formatting of the DNA code in one gene that is associated with satiety is implicated in a slightly elevated risk of excess body weight – at least in women. This “epigenetic marking” is established early on during the embryonic stage.

    People who are overweight, especially those who are severely overweight, are at increased risk of a number of serious diseases such as cardiovascular disease, diabetes, and cancer. It is a growing health issue. All over the world, the number of overweight people is increasing. In the European Region, two out of three adults (59 percent) are overweight or obese, according to the World Health Organization.

    But what determines whether people will become overweight? Genetic predisposition plays a major role, alongside lifestyle. The similarity of the body mass index (BMI) in identical twins ranges from 40 to 70 percent. Even identical twins raised in different families still show the same significant similarity. Scientists have identified several genetic variants that influence a person’s body weight – and with it, the risk of developing obesity. But even taken all together, they cannot explain the heritability that has been observed. Researchers began to suspect there must be additional non-genetic factors that affect a person’s propensity to gain excess weight.

    Satiety gene is not altered, but formatted

    Researchers led by Prof. Peter Kühnen, Director of the Department of Pediatric Endocrinology at Charité, have now identified one such factor in their recent study. According to their findings, women’s risk of being overweight increases by about 44 percent if there are an especially large number of methyl groups adhering to the POMC (pro-opiomelanocortin) gene, which is responsible for the feeling of satiety. Methyl groups are tiny chemical units the body uses to mark the letters in the DNA code to activate or deactivate genes without modifying the sequence of letters in the DNA. In other words, the effect is much like highlighting a section of a text without rewriting the text itself. This type of “DNA formatting” is known as epigenetic marking.

    For their study, the team of researchers analyzed the “formatting” of the POMC gene in more than 1,100 people. They found more methyl groups attached to the satiety gene in obese women with a BMI of over 35 than in women with normal body weight. “A 44 percent increase in the risk of obesity is about the same as the effect that has been observed for individual gene variants as well,” says Kühnen. “By comparison, socioeconomic factors have a much stronger effect. They can increase the risk by a factor of two to three. As for why the methylation effect only shows up in women, we don’t know yet.”

    The POMC gene is “formatted” very early on during embryonic development, as the researchers showed by comparing methylation patterns in more than 15 sets each of identical and fraternal twins. While the “formatting” of the satiety gene was the same in most of the identical twins, there was hardly any correlation in the fraternal twins. “This indicates that the epigenetic marking of the POMC gene is established shortly after the egg and sperm cells merge, before the fertilized egg divides into two twin embryos,” explains Lara Lechner, the study’s first author, who works at the Department of Pediatric Endocrinology. This means the very early stage of pregnancy is crucial.

    What influences formatting?

    But what influences how much methylation the satiety gene undergoes – and thus, the risk that a person will become overweight? Past studies indicated that the presence or absence of certain nutrients that supply methyl groups could have an effect on epigenetic processes. These nutrients include betaine, methionine, and folic acid, all of which are typically absorbed through a person’s diet. A newly developed method involving individual human stem cells allowed the Charité researchers to simulate in the lab how the methylation pattern is determined during embryonic development and how nutrients affect it.

    “On the one hand, our studies and others as well show that folic acid, betaine, and other nutrients have a limited effect on the extent of methylation,” Kühnen notes. “We’ve observed that the ‘DNA formatting system’ is very stable on the whole, with cells compensating for minor fluctuations in the nutrient supply. On the other hand, there are indications that the variability of this ‘formatting’ develops at random. That means that it is not possible – not yet, at any rate – to externally influence whether a person has more or less methylation in the POMC region.”

    Medications may help

    At least in theory, women who are at elevated risk of developing obesity due to methylation of the POMC gene could receive medications to help them lose weight, as initial studies of four severely obese women and one man with this exact type of “formatting” of the satiety gene suggest. The subjects were given a specific drug that curbs the feeling of hunger and has already been approved to treat obese patients with a mutation of the POMC gene. Within three months after starting treatment, all five patients experienced less hunger. They lost an average of seven kilograms, or about five percent of their body weight. Some of them continued the treatment and continued to lose weight.

    “These findings show, for a start, that a POMC gene that has undergone epigenetic changes can in fact potentially be addressed through medication,” Kühnen says. “Further large controlled studies will be needed to show whether treatment with this drug would also be effective over a longer period, and if so, how effective and how safe this type of treatment is. Overall, though, a medication like this would still need to be just one piece of a holistic treatment strategy.”

     

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  • Cystic fibrosis drug could help treat pneumonia

    Cystic fibrosis drug could help treat pneumonia

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    Newswise — Pathogens such as SARS-CoV-2 and pneumococcus can cause severe pneumonia. If the airways then fill with fluid, the patient risks developing acute respiratory distress syndrome. Researchers at Charité – Universitätsmedizin Berlin have now discovered the molecular mechanisms that trigger fluid accumulation in the lungs. This also led them to discover a potential new therapy: A cystic fibrosis drug proved effective in their laboratory experiments, raising hope that this could be used to treat pneumonia regardless of the pathogen that caused it. The study has been published in the journal Science Translational Medicine*.

    Pneumonia is the most common cause of fluid buildup in the lungs. This condition, known as pulmonary edema, results in parts of the airspaces filling with fluid instead of air, which prevents them from doing their job of exchanging gases. Patients struggle to breath and their body can’t get enough oxygen. The diagnosis is acute respiratory distress syndrome, or ARDS. “Despite cutting-edge medical procedures, roughly 40 percent of patients with ARDS die in intensive care. The problem is that antibiotics, antivirals, and immune modulating therapies rarely work well enough,” says study leader Prof. Dr. Wolfgang Kuebler, Director of the Institute of Physiology at Charité. “That’s why we took a very different approach in our study. Instead of focusing on the pathogen, we focused on strengthening the barrier function of the blood vessels in the lungs.” This makes sense, as they are the source of the fluid in pulmonary edema. The lung vessels become permeable, allowing fluid from the blood to flow into the surrounding tissue – and thereby flood the airspaces. 

    But what actually causes this? What are the underlying molecular mechanisms? A Charité research team led by Prof. Kuebler set out to answer these questions. They performed experiments using cells, lung tissue, and isolated lungs. The study centered on the CFTR chloride channel, which scientists know is mainly found in the mucosal cells of our airways. There, it plays a major role in keeping our mucus thin so it can drain away easily. The researchers have now shown for the first time that cells in the blood vessels of the lungs also have CFTR and that its presence is drastically reduced in pneumonia. 

    To find out what role CFTR plays in the pulmonary vessels and what is happening at the molecular level when the chloride channel is lost, the researchers blocked the channel with an inhibitor and dictated the number of chloride ions in the cells. They then used a special imaging technique known as immunofluorescence imaging: “We saw that inhibiting CFTR triggered a molecular cascade that ultimately causes the lung’s blood vessels to begin leaking,” says Dr. Lasti Erfinanda, who also works at the Institute of Physiology and is the study’s lead author. “So CFTR actually does play a very key role in the development of pulmonary edema.” 

    The study findings indicate that the loss of CFTR causes chloride to accumulate in the cells because it stops being transported out of them. The excess chloride triggers signaling that ends with an uncontrolled flow of calcium into the cells via a calcium channel. “The increased calcium concentration then causes the vascular cells to contract – much like the effect that calcium has on muscle cells,” explains Prof. Kuebler. “This results in gaps between the cells – which allows fluid to spill out of the blood vessels. Chloride channels are therefore crucial in maintaining the barrier function of the pulmonary vessels.” 
     
    The research team then addressed another question: How could they attenuate or prevent the pneumonia-induced loss of chloride channels in the pulmonary vessels? To answer this, the researchers used a therapeutic agent that is classed as a CFTR modulator and currently used to treat cystic fibrosis. In cystic fibrosis patients, a genetic mutation prevents the CFTR chloride channel from working properly in the mucosal cells of the airways, resulting in very viscous mucus. “Ivacaftor is a drug that increases the chances of the chloride channel opening, which helps the mucus to flow through the airways,” says Dr. Erfinanda. “We wanted to see if it would also have a positive effect on the cells in the blood vessels of the lungs.” 

    Ivacaftor did make the chloride channels more stable: it led to less degradation in the channels than that typically caused by the lung’s inflammatory processes. Experiments on animal models showed the same effect: treatment with ivacaftor increased the probability of surviving severe pneumonia, reduced lung injury, and resulted in much milder symptoms and a much better general condition than without the drug. “We really weren’t expecting it to work so well,” says Prof. Kuebler. “We hope our findings will pave the way for clinical trials to test the efficacy of CFTR modulators in pneumonia patients. If this promising, pathogen-independent therapy finds its way into clinical practice, it could benefit a huge number of patients and prevent pneumonia from becoming life-threatening – even in the case of unknown pathogens.” 

    Prof. Kuebler and his team are now planning research projects aimed at developing other potential therapies based on the CFTR signaling pathway. They are also going to research which patients have an elevated risk of developing ARDS, so they can provide these patients with preventive, personalized treatment.

     

    *Erfinanda L et al. Loss of endothelial CFTR drives barrier failure and edema formation in lung infection and can be targeted by CFTR potentiation. Science Translational Medicine 2022 Dec 07. doi: 10.1126/scitranslmed.abg8577ggf.

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  • Research team discovers central functions of innate immune cells

    Research team discovers central functions of innate immune cells

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    Newswise — Inflammation and increased mucus production are typical symptoms of worm infections and allergies. This immune response involves our innate immune cells, but their exact functions are not yet fully understood. A research team from Charité – Universitätsmedizin Berlin has now shed light on the key tasks that these cells perform. In the study, which has been published in the journal Nature*, the researchers also identify potential therapeutic approaches for the treatment of allergies.

    The human immune system is made up of two interconnected branches: the adaptive immune system, which learns something new with every infection and constantly develops over the course of a lifetime, and the innate immune system, which is less specialized but reacts particularly quickly and effectively. The cells of the innate immune system are located in the mucous membranes of the respiratory tract and the intestine, where they form a first line of defense at the point of entry for pathogens. These cells include group 2 innate lymphoid cells (ILC2s for short), which are active in the intestine in the case of parasitic diseases, and in the respiratory tract in the case of allergies.

    “Innate lymphoid cells were discovered a decade or so ago and we already know a lot about them, but their exact function in the machinery of the immune system is not yet completely understood,” explains Dr. Christoph Klose, who heads the Emmy Noether Independent Junior Research Group on the regulation of type 2 immune responses by neuropeptides and neurotransmitters at the Institute of Microbiology, Infectious Diseases and Immunology at Charité. “There is a group of adaptive immune cells – namely the T cells – that carry out some similar functions as part of the type 2 immune response, so it was previously thought that the role of ILC2s may be redundant and could be easily taken over by the T cells.”

    However, the recently published study has now disproved this theory. Using an animal model and state-of-the-art molecular methods such as single-cell sequencing, which allows scientists to zoom into individual cells and analyze their molecular state, they have shed light on the central functions of ILC2s. “A certain type of immune cells called eosinophils were not able to develop properly when ILC2s were absent,” explains Dr. Klose. “This relationship was previously unknown and came as a big surprise.” Eosinophils are involved in inflammatory processes in the tissue. The scientists also found that ILC2s have a major effect on the ability of epithelial cells to promote mucus production and expel parasites, such as worms, from the body. “The absence of ILC2s was clearly noticeable in our tests examining the immune response to worm infections. There was only limited mucus production in the tissue and the parasites could no longer be combated effectively,” says Dr. Klose, summarizing the results of the study.

    In further experiments, the researchers examined the symptoms of allergic asthma and found that these improved when ILC2s were absent. “This could be a starting point for future studies aimed at developing potential allergy therapies,” says Dr. Klose. “With our study, we were able to show that group 2 innate lymphoid cells are essential cogs in the machinery of the immune system and cannot be replaced without compromising the immune response.” In future research projects, Dr. Klose and his team would like to investigate whether the innate lymphoid cells regulate other aspects of the immune response.

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