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International research team led by Goethe University debunks concept popular for decades
Contrary to a concept propagated for almost 30 years, specialized pro-resolving lipid mediators, which our body forms from polyunsaturated omega-3 fatty acids, evidently do not actively stop inflammation. Although such resolvins or lipoxins can be produced under laboratory conditions, it is highly probably that they play no physiological role whatsoever. This is corroborated by a review undertaken by an international research team led by Professor Dieter Steinhilber from Goethe University, Frankfurt. The starting point for this work, which has caused quite a stir in the academic community, was experimental findings by the Research Training Group “Resolution of inflammation – Mediators, signalling and therapeutic options" at Goethe University.
FRANKFURT. Inflammation is the result of an active defence reaction by our immune system. It mostly disappears by itself. It was once assumed to be a passive process because the immune cells involved, having done their work, gradually die off or migrate. Today, we know that our body also actively controls the resolution of inflammation. To this end, certain cells of the innate immune system, known as M1 macrophages, which are pro-inflammatory and in the first instance serve as a defence mechanism, transform into M2 macrophages, which are anti-inflammatory and primarily help to heal wounds.
In the past, the formation of specialized pro-resolving lipid mediators (SPMs) was considered an important molecular effect of this transformation. Since their discovery in 1984, they have given an ever-growing group of “resolutionists" worldwide reason to hope that it would one day be possible to intervene therapeutically in inflammatory processes by means of synthetic “inflammation resolvers" (resolvins).
The drugs against inflammation and its symptoms that are currently available – such as acetylsalicylic acid and COX-2 inhibitors – act, by contrast, as antagonists to certain arachidonic acid metabolism reactions, which generate pro-inflammatory tissue hormones. These include thromboxane and prostaglandins on the one hand and leukotrienes on the other. Only two metabolism steps away from arachidonic acid, those SPMs are also produced to which an anti-inflammatory effect has so far been attributed.
Indeed, a doctoral thesis in the Research Training Group “Resolution of inflammation – Mediators, signalling and therapeutic options" established at Goethe University in 2017 showed that the anti-inflammatory macrophages form the two enzymes needed to produce SPMs. However, only under non-physiological conditions – the researchers added stimulators that increased the calcium permeability of the macrophage membrane (ionophores) – could tiny amounts of SPMs be detected. Even when, as another study demonstrated, pre-treated substrates of these enzymes were added to cell cultures of certain white blood cells (neutrophilic leukocytes), these substrates were hardly converted to lipoxins and resolvins.
Further suspicion was triggered by earlier work on SPM receptors by Professor Stefan Offermanns, who, like Professor Dieter Steinhilber, is project leader in the Collaborative Research Centre “Signalling by fatty acid derivatives and sphingolipids in health and disease" hosted by Goethe University. In his study, no effect of lipoxin A via the corresponding G protein-coupled receptor could be identified. Lipid mediators transmit their signals via these receptors. Moreover, in the blood plasma of healthy volunteers, SPMs could at best be found in the single-digit picogramme range, even when using the most sensitive and selective methods (coupling of chromatography and mass spectrometry).
On the basis of these findings, Steinhilber's research team combed through all the papers on SPMs published so far. This review endorsed their dismantling of the SPM concept: human leukocytes, to which macrophages also belong, can at best synthesize small amounts of SPMs. These amounts are so tiny that they cannot be reliably quantified even with state-of-the-art analytics. There is no correlation between SPM synthesis and the resolution of an inflammatory reaction nor with a targeted intake of polyunsaturated omega-3 fatty acids. To date, there is no valid evidence of functional SPM receptors.
“Insiders have known for a long time that the SPM concept was questionable," says Steinhilber. “But until now no one has taken the trouble to gather all the doubts together." There had to be another mechanism of active inflammation resolution, he says. “Because the transformation of pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages clearly goes hand in hand with a change in the lipid and cytokine profile."
“The search for the molecular signals that our body uses to actively prevent excessive or chronic inflammation continues to be exciting," says Professor Bernhard Brüne, Vice President of Goethe University and spokesperson for the Research Training Group. “It's a source of motivation for our future research."
Publication: Nils Helge Schebb, Hartmut Kühn, Astrid S. Kahnt, Katharina M. Rund, Valerie B. O'Donnell, Nicolas Flamand, Marc Peters-Golden, Per-Johan Jakobsson, Karsten H. Weylandt, Nadine Rohwer, Robert C. Murphy, Gerd Geisslinger, Garret A. FitzGerald, Julien Hanson, Claes Dahlgren, Mohamad Wessam Alnouri, Stefan Offermanns, Dieter Steinhilber: Formation, Signalling and Occurrence of Specialized Pro-Resolving Lipid Mediators – What is the Evidence so far? Frontiers in Pharmacology (2022) https://doi.org/10.3389/fphar.2022.838782
Professor Dieter Steinhilber
Institute of Pharmaceutical Chemistry
Goethe University Frankfurt, Germany
Tel.: +49 (0)69 798-29324
Cell culture studies in Frankfurt and Canterbury previously showed effects of Aprotinin against SARS-CoV-2
A clinical study from Spain recently confirmed laboratory experiments made by researchers of Goethe University Frankfurt and University of Kent who showed that the protease inhibitor aprotinin prevented cells to be infected by SARS-CoV2. The authors of the clinical study report that patients receiving an aprotinin aerosol could be discharged from hospital significantly earlier.
FRANKFURT. SARS-CoV-2, the coronavirus that causes COVID-19, needs its spike proteins to dock onto proteins (ACE receptors) on the surface of the host cells. Before this docking is possible, parts of the spike protein have to be cleaved by host cell's enzymes called proteases. In 2020, a scientific team led by Professor Jindrich Cinatl (Goethe University Frankfurt, Germany), Professor Martin Michaelis and Professor Mark Wass (both University of Kent, UK), conducted cell culture experiments and found that aprotinin, a protease inhibitor, could inhibit virus replications by preventing SARS-CoV-2 entry into host cells.
In a more recent study, the research consortium further showed that aprotinin is also effective against the Delta and Omicron variants.
Now, a Spanish research consortium has published the findings of a phase III clinical study investigating the use of an aprotinin aerosol in COVID-19 patients. Among other improvements, aprotinin treatment reduced the length of hospital stays by five days.
Professor Jindrich Cinatl, Goethe University Frankfurt, said: “This shows how scientific collaborations work even without a direct relationship between researchers. I am very glad that our cell culture study inspired this successful clinical trial".
Professor Martin Michaelis, University of
Kent, said: “Our cell culture data looked very convincing. It is exciting that
aprotinin has now also been shown to be effective against COVID-19 in
Spanish study: Francisco Javier Redondo-Calvo et. al.: Aprotinin treatment against SARS-CoV-2: A randomized phase III study to evaluate the safety and efficacy of a pan-protease inhibitor for moderate COVID-19. Eur. J. Clin. Invest. (2022) https://doi.org/10.1111/eci.13776
about the studies of Goethe University and University of Kent:
1) The drug aprotinin inhibits entry of SARS-CoV2 in host cells https://aktuelles.uni-frankfurt.de/englisch/the-drug-aprotinin-inhibits-entry-of-sars-cov2-in-host-cells/
2) Researchers of the University of Kent and Goethe-University find explanation why the Omicron variant causes less severe disease https://aktuelles.uni-frankfurt.de/englisch/researchers-of-the-university-of-kent-and-goethe-university-find-explanation-why-the-omicron-variant-causes-less-severe-disease/
Professor Jindrich Cinatl
Institute of Medical Virology
University Hospital Frankfurt and Goethe University Frankfurt
Phone.: +49 (0) 69 6301-6409
Online program promotes exercise and maintains well-being during pandemic
Interactive training programs for use at home can make the restrictions during a lockdown more bearable. The live-streaming of sports offerings allows for a significant increase in physical activity, revealed a research team from ten countries headed by the Institute of Sport Science at Goethe University Frankfurt. At the same time well-being improved compared to an inactive control group. One year previously, the team had described the negative impacts of coronavirus restrictions on exercise and well-being.
FRANKFURT. People were about 40 per cent less active during the first lockdown in the spring of 2020. This has been revealed by an international study headed by Goethe University Frankfurt. Psychological well-being also declined, with the proportion of people at risk of depression increasing threefold. In order to cushion the effects of this negative development, the research team designed an online training program for use at home and studied whether the physical activity that is so important to general health could be maintained during a lockdown. The results of the study were recently published in the British Journal of Sports Medicine.
Of 763 healthy subjects from nine countries on four continents, half trained for four weeks using a live-stream program, the others formed the control group. Those training could select from a number of daily workouts – for example with the focus on strength, endurance, balance or relaxation. Professional trainers actively accompanied them with a camera and microphone. Each week both groups completed standardised questionnaires on physical activity, anxiety, mental well-being, quality of sleep, pain and sport motivation.
The training program was particularly effective in improving movement behavior in the participants: physical activity was initially as much as 65 per cent higher on average in the online group than in the comparison group, and still 20 to 25 per cent higher after four weeks. Thus, the course participants clearly surpassed the WHO recommendations of at least 150 minutes of moderate or 75 minutes of intensive exercise per week, while the control group only just attained these. At the same time the motivation to do sport, psychological well-being and sleep improved, and anxiety levels decreased. “While these improvements are minor, they are nevertheless potentially relevant," stresses study head Dr. Jan Wilke from the Institute of Sport Science at Goethe University Frankfurt. “Our participants were all healthy – the effects with patients could be significantly greater, in particular with people who have chronic disease." In addition, he said, four weeks is a very short period for such efficacy studies. Participants who took part in at least two courses per week stated their fitness was even better and they had a greater feeling of well-being, yet did not note any further improvement with sleep or fears.
Unfortunately, only just under half of the participants completed the study. The research group attributed this in particular to the considerable effort of completing the questionnaires each week. This frequent information retrieval was intended to ensure that the study would allow conclusions to be drawn even if the lockdown regulations were relaxed. The changes in local conditions in the same period could also have lowered the motivation of some participants, for example if local fitness studios had reopened. Moreover, the requirements were very strict: those who did not respond by completing the questionnaire were eliminated from the study.
“Train at home, but not alone" – it is best to train at home with others, this is how the working group summarised its findings on exercise offerings in the pandemic-induced lockdown. For: following the main section of the study – the live-streaming – when both groups had access to recorded contents, the differences that had been observed declined in part. According to Wilke, this is due to both the activation of the control group as well as to the change in the form of the physical activity intervention (live vs. recorded).
The study authors expressly underline the importance of exercise in our daily lives: in line with the latest data, physical inactivity causes eight to nine per cent of all premature deaths, increases the risk of cardiac disease, metabolic disorders and cancers, as well as proneness to the novel coronavirus. They believe that it is probably all the more important in lockdown to offer online training for people with chronic illnesses – for example diabetics – whose health could possibly suffer additionally under the restrictions imposed by a pandemic.
Publication: Jan Wilke, Lisa Mohr, Gustavo Yuki, Adelle Kemlall Bhundoo, David Jiménez-Pavón, Fernando Laiño, Niamh Murphy, Bernhard Novak, Stefano Nuccio, Sonia Ortega-Gómez, Julian David Pillay, Falk Richter, Lorenzo Rum, Celso Sanchez-Ramírez, David Url, Lutz Vogt, Luiz Hespanhol. Train at home, but not alone: a randomised controlled multicentre trial assessing the effects of live-streamed tele-exercise during COVID-19-related lockdowns. Br. J. Sports Med. (2022) https://doi.org/10.1136/bjsports-2021-104994
Caption: Sports offerings via live streaming promotes activity and well-being during pandemic lockdowns. Photo: Jan Wilke, Goethe-University Frankfurt
Dr. phil. Jan Wilke
Institute of Sports Sciences
Goethe University Frankfurt, Germany
Phone +49 (69) 798-24588,
Structure of key enzyme unravelled – possible starting point for antibacterial agents
A team from Research Unit 2251 of the German Research Foundation led by Goethe University has shed light on the structure of an enzyme important in the metabolism of the pathogenic bacterium Acinetobacter baumannii. The enzyme “MtlD" is critical for the bacterium's synthesis of the sugar alcohol mannitol, with which it protects itself against water loss and desiccation in dry or salty environments such as blood or urine. Structural analysis has revealed weak spots where it might be possible to inhibit the enzyme and thus attack the pathogen. (PNAS, DOI: 10.1073/pnas.2107994119)
FRANKFURT. Each year, over 670,000 people in Europe fall ill through pathogenic bacteria that are resistant to antibiotics, and 33,000 die of the diseases they cause. In 2017, the WHO named antibiotic resistance as one of the greatest threats to health worldwide. Especially feared are pathogens that are resistant to several antibiotics. Among them, Acinetobacter baumannii stands out, a bacterium with an extraordinarily pronounced ability to develop multiresistance and, as a “hospital superbug", dangerous above all for immunosuppressed patients. Acinetobacter baumannii is highly resilient because it can remain infectious for a long time even in a dry environment and thus endure on the keyboards of medical devices or on ward telephones and lamps. This property also helps the microbe to survive on dry human skin or in body fluids such as blood and urine, which contain relatively high concentrations of salts and other solutes.
The team from Research Unit 2251 of the German Research Foundation led by Goethe University has now shed light on a central mechanism via which Acinetobacter baumannii settles in such an adverse environment: like many bacteria as well as plants or fungi, Acinetobacter baumannii is able to synthesize the sugar alcohol mannitol, a substance excellent at binding water. In this way, Acinetobacter baumannii prevents desiccation.
Almost unique, however, is the way that Acinetobacter baumannii synthesizes mannitol: instead of two enzyme complexes as are common in most organisms, the two last steps in mannitol synthesis are catalysed by just one. A team of researchers led by Professor Beate Averhoff and Professor Volker Müller already discovered this “MtlD" enzyme with two catalytic activities back in 2018. The team headed by Professor Klaas Martinus Pos, who is also a member of the Research Unit, has now succeeded in shedding light on the enzyme's spatial structure.
He explains: “We've discovered that the enzyme is usually present in the form of free monomers. Although these have the necessary catalytic activities, they are inactive. Only a dry or salty environment triggers what is known as 'osmotic stress' in the bacterium, after which the monomers aggregate as dimers. Only then does the enzyme become active and synthesize mannitol." The researchers have also identified which parts in the structure are particularly important for the enzyme's catalytic functions and for dimer formation.
Professor Volker Müller, spokesperson for
Research Unit 2251, is convinced: “Our work constitutes an important new
approach for fighting this hospital pathogen since we've identified a
biochemically sensitive point in the pathogen's metabolism. In the future, this
could be the starting point for customized substances to inhibit the enzyme."
Publication: Heng-Keat Tam, Patricia König, Stephanie Himpich, Ngoc Dinh Ngu, Rupert Abele, Volker Müller, Klaas M. Pos: Unidirectional mannitol synthesis of Acinetobacter baumannii MtlD is facilitated by the helix-loop-helix-mediated dimer formation. Proc. Natl. Acad. Sci. U.S.A. (2022) https://www.pnas.org/doi/full/10.1073/pnas.2107994119
Caption: Resembles a butterfly: only in its dimer form does the mannitol-synthesizing enzyme of the hospital pathogen Acinetobacter baumannii protect the bacterium from water loss and desiccation. Picture: Klaas Martinus Pos, Goethe University Frankfurt
2) Acinetobacter baumannii
https://commons.wikimedia.org/wiki/File:Acinetobacter_baumannii.JPGCaption: Scanning electron micrograph (SEM) of a highly magnified cluster of Gram-negative, non-motile Acinetobacter baumannii bacteria. Photo: Janice Carr
Professor Volker Müller
Research Unit 2251 Spokesperson
Department of Molecular Microbiology & Bioenergetics
Institute for Molecular Biosciences
Goethe University Frankfurt, Germany
Tel.: +49 (0)69 798-29507
Professor Klaas Martinus Pos
Membrane Transport Machineries Group
Institute of Biochemistry
Goethe University Frankfurt, Germany
Tel.: +49 (0)69 798-29251