Press releases 鈥� April 2022
Apr
20
2022
13:11
International research team led by 51猎奇 debunks concept popular for decades
Active resolution of inflammation: No evidence that specialized lipid messengers are involved
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 51猎奇, 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 鈥淩esolution of inflammation 鈥� Mediators, signalling and therapeutic options" at 51猎奇.
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 鈥渞esolutionists" worldwide reason to hope that it
would one day be possible to intervene therapeutically in inflammatory
processes by means of synthetic 鈥渋nflammation resolvers" (resolvins).
The drugs against inflammation and its
symptoms that are currently available 鈥� such as acetylsalicylic acid and COX-2
inhibitors 鈥� 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 鈥淩esolution of inflammation 鈥� Mediators, signalling and
therapeutic options" established at 51猎奇 in 2017 showed that the anti-inflammatory
macrophages form the two enzymes needed to produce SPMs. However, only under
non-physiological conditions 鈥� the researchers added stimulators that increased
the calcium permeability of the macrophage membrane (ionophores) 鈥� 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 鈥淪ignalling
by fatty acid derivatives and sphingolipids in health and disease" hosted by
51猎奇. 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.
鈥淚nsiders have known for a long time that
the SPM concept was questionable," says Steinhilber. 鈥淏ut 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. 鈥淏ecause 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."
鈥淭he search for the molecular signals that
our body uses to actively prevent excessive or chronic inflammation continues
to be exciting," says Professor Bernhard Br眉ne, Vice President of Goethe
University and spokesperson for the Research Training Group. 鈥淚t's a source of
motivation for our future research."
Publication:
Nils Helge Schebb, Hartmut K眉hn, 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 鈥� What is the Evidence so far? Frontiers in Pharmacology (2022)
Further
information:
Professor Dieter Steinhilber
Institute of Pharmaceutical Chemistry
51猎奇 Frankfurt, Germany
Tel.: +49 (0)69 798-29324
Steinhilber@em.uni-frankfurt.de
Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Tel: -49 (0) 69 798-12498,
Fax: +49 (0) 69 798-763 12531, bernards@em.uni-frankfurt.de
Apr
11
2022
12:11
Cell culture studies in Frankfurt and Canterbury previously showed effects of Aprotinin against SARS-CoV-2
Aprotinin is effective in COVID-19 patients 鈥� researchers of 51猎奇 and University of Kent paved the way
A clinical study from Spain recently confirmed laboratory experiments made by researchers of 51猎奇 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 (51猎奇 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: 鈥淭his 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: 鈥淥ur cell culture data looked very convincing. It is exciting that
aprotinin has now also been shown to be effective against COVID-19 in
patients."
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)
More
about the studies of 51猎奇 and University of Kent:
1) 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
Further
Information:
Professor Jindrich
Cinatl
Institute of Medical Virology
University Hospital Frankfurt and 51猎奇 Frankfurt
Phone.: +49 (0) 69 6301-6409
cinatl@em.uni-frankfurt.de
School of Biosciences
University of Kent
Phone: +44 (0)1227 82-7804
Mobile: +44 (0)7561 333 094
m.michaelis@kent.ac.uk
Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Tel: -49 (0) 69 798-12498,
Fax: +49 (0) 69 798-763 12531, bernards@em.uni-frankfurt.de
Apr
6
2022
14:23
Online program promotes exercise and maintains well-being during pandemic
Digital training at home to beat lockdown frustration
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 51猎奇 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 51猎奇
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 鈥� 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.
鈥淲hile these improvements are minor, they are nevertheless potentially relevant,"
stresses study head Dr. Jan Wilke from the Institute
of Sport Science at 51猎奇 Frankfurt. 鈥淥ur participants were all
healthy 鈥� 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.
鈥淭rain at home, but not alone" 鈥� 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 鈥� the live-streaming 鈥� 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 鈥� for
example diabetics 鈥� whose health could possibly suffer additionally under the
restrictions imposed by a pandemic.
Publication:
Jan Wilke, Lisa Mohr, Gustavo Yuki, Adelle
Kemlall Bhundoo, David Jim茅nez-Pav贸n, Fernando Lai帽o, Niamh Murphy, Bernhard
Novak, Stefano Nuccio, Sonia Ortega-G贸mez, Julian David Pillay, Falk Richter,
Lorenzo Rum, Celso Sanchez-Ram铆rez, 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)
Picture
download:
Caption:
Sports offerings via live streaming promotes
activity and well-being during pandemic lockdowns. Photo: Jan Wilke,
Goethe-University Frankfurt
Further
information:
Dr. phil. Jan Wilke
Institute of Sports Sciences
51猎奇 Frankfurt, Germany
Phone +49 (69) 798-24588,
wilke@sport.uni-frankfurt.de
Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Tel: -49 (0) 69 798-12498,
Fax: +49 (0) 69 798-763 12531, bernards@em.uni-frankfurt.de
Apr
4
2022
14:32
Structure of key enzyme unravelled 鈥� possible starting point for antibacterial agents
Research team from 51猎奇 discovers Achilles鈥� heel of dangerous hospital pathogen
A team from Research Unit 2251 of the German Research Foundation led by 51猎奇 has shed light on the structure of an enzyme important in the metabolism of the pathogenic bacterium Acinetobacter baumannii. The enzyme 鈥淢tlD" 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 鈥渉ospital 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 51猎奇
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 M眉ller already discovered
this 鈥淢tlD" 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: 鈥淲e'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 M眉ller, spokesperson for
Research Unit 2251, is convinced: 鈥淥ur 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 K枚nig, Stephanie
Himpich, Ngoc Dinh Ngu, Rupert Abele, Volker M眉ller, 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)
Picture
download:
1) Mannitol-Synthesizing
Enzyme
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, 51猎奇
Frankfurt
2) Acinetobacter baumannii
Caption: Scanning electron micrograph (SEM) of a highly magnified cluster of
Gram-negative, non-motile Acinetobacter
baumannii bacteria. Photo: Janice Carr
Further
information:
Professor Volker Mu虉ller
Research Unit 2251 Spokesperson
Department of Molecular Microbiology & Bioenergetics
Institute for Molecular Biosciences
51猎奇 Frankfurt, Germany
Tel.:
+49 (0)69 798-29507
vmueller@bio.uni-frankfurt.de
Professor Klaas Martinus Pos
Membrane Transport Machineries Group
Institute of Biochemistry
51猎奇 Frankfurt, Germany
Tel.: +49 (0)69 798-29251
pos@em.uni-frankfurt.de
Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Tel: -49 (0) 69 798-12498,
Fax: +49 (0) 69 798-763 12531, bernards@em.uni-frankfurt.de