Blocking IL-11 signalling can help liver regenerate after injury from paracetamol toxicity
(Press-News.org) Singapore, 18 Jun 2021 - Scientists at Duke-NUS Medical School and National Heart Centre Singapore (NHCS), in collaboration with colleagues in Singapore and the UK, have shown that the human form of the signalling protein interleukin 11 (IL-11) has a damaging effect on human liver cells--overturning a prior hypothesis that it could help livers damaged by paracetamol poisoning. The finding, published last week in Science Translational Medicine, suggests that blocking IL-11 signalling could have a restorative effect.
Paracetamol, also called acetaminophen, is a widely available over-the-counter painkiller, and an overdose can lead to serious liver damage and even death. It is the most common pharmaceutical agent involved in toxic exposure in Singapore, while in the UK, 50,000 people a year show up at emergency departments with paracetamol poisoning. They can be treated with a drug called N-acetylcysteine if administered within eight hours of overdose. Any longer, however, and the only recourse may be a liver transplant.
To find treatments for the condition, scientists have been studying it in mice. Their investigations have shown that excessive doses of paracetamol deplete liver antioxidants. This leads to damage of mitochondrial proteins, triggering a cascade of events that lead to liver damage and liver cell death. Further studies showed that administration of anti-IL11 therapy in the form of an antibody drug not only reversed liver damage, but also supported liver regeneration and promoted survival in mice with liver injury. This led to the idea that anti-IL11 therapy could help treat humans with paracetamol poisoning.
"We recently found that IL-11 was actually detrimental for liver cell function in a fatty liver disease called non-alcoholic steatohepatitis (NASH)," said Assistant Professor Anissa Widjaja, from Duke-NUS' Cardiovascular and Metabolic Diseases (CVMD) Programme, the lead author of the study. "This made us want to look in more detail at what was happening in mouse models of paracetamol toxicity."
Employing an animal model conducted according to the National Advisory Committee for Laboratory Animal Research (NACLAR) guidelines, they found high serum levels of IL-11 in mice with paracetamol toxicity. Further investigations revealed that IL-11 was involved in activating pathways that led to liver cell death. Surprisingly, they found that mouse livers responded differently according to whether they were given human or mouse IL-11. The human form had a protective effect against liver damage while the mouse form caused liver cell death. When human IL-11 was administered in mice with paracetamol toxicity, it competed with the endogenous mouse IL-11, blocking its receptor. It was this blocking effect that protected against liver damage. Administering same-species IL-11 was damaging because it did not result in this competition and the resulting blocking effect.
"This means that IL-11 is actually a liver toxin," said Professor Stuart Cook, the senior author of the study, who is the Tanoto Foundation Professor of Cardiovascular Medicine at the SingHealth Duke-NUS Academic Medical Centre and Duke-NUS' CVMD Programme, and Senior Consultant at the Department of Cardiology at NHCS. "We found that blocking its cell receptors with an antibody can help the liver regenerate after it has been injured. This discovery could have implications for treating drug-induced liver failure, which can cause death if a liver transplant is not possible."
The study adds to the growing body of research on IL-11, led by Prof Cook, a leading expert who has dedicated years of study to this important signalling protein. In 2017, he co-founded Singapore-based Enleofen Bio as a spin-out from NHCS, SingHealth and Duke-NUS with the aim of developing first-in-class antibody therapeutics for the treatment of fibro-inflammatory human diseases. In 2019, Boehringer Ingelheim, a leading global pharmaceutical company in the treatment of fibrotic diseases and in therapeutic antibodies took an exclusive license to Enleofen's anti-IL11 platform.
Professor Patrick Casey, Senior Vice-Dean for Research at Duke-NUS, commented, "New insights from fundamental research enable scientists to not only test hypotheses, but also course-correct when the evidence overturns prior assumptions. Professor Cook and his team are among the leading experts on IL-11, and their latest findings yet again advance our understanding in this field of research."
The research team is now investigating whether IL-11 can stand in the way of the regeneration of other organs, like the kidneys, and whether it is involved in the loss of tissue function with advancing age.
[Attachments] See images for this press release:
ELSE PRESS RELEASES FROM THIS DATE:
Most of us have heard of Alzheimer's disease, a neurodegenerative disorder marked by brain cell death and the shrinking of the brain. It is the most common cause of dementia and cognitive impairment, which typically have a devastating effect on a person's quality of life. There is still no cure for Alzheimer's.
One way of tackling the progression of Alzheimer's disease (AD) is to prevent the underlying adverse changes in the brain. A team of researchers from the National Centre for Biological Sciences (NCBS) has recently published a study in the Journal of Medicinal Chemistry, dedicated to neuroprotection against these toxic changes. They used tiny free-living soil worms --called Caenorhabditis elegans--and the often-ornamental ...
Kanazawa, Japan - Interluekin-1α (IL-1α) is an important part of the immune response, but until now it has been unclear how this molecule is processed from its precursor, pro-IL-1α, and exits the cell during inflammasome activation. Now, researchers from Japan have found that gasdermin D, a protein that was already known to mediate pyroptosis, a form of regulated cell death, plays a crucial role in the maturation and release of IL-1α.
In a study published in March in Cell Reports, researchers from Kanazawa University report that, when the ...
COVID-19 has changed the world in unimaginable ways. Some have even been positive, with new vaccines developed in record time. Even the extraordinary lockdowns, which have had severe effects on movement and commerce, have had beneficial effects on the environment and therefore, ironically, on health. Studies from all around the world, including China, Europe and India, have found major drops in the level of air pollution. However, to fully understand the impact of anthropogenic causes, it is important to separate them from natural events in the atmosphere like wind flow.
To demonstrate this point, a new study by researchers at the Research Institute for Humanity and Nature, Japan, uses satellite data and mathematical modeling to explain just ...
Identifying the causes of human neurodegenerative diseases is a global research priority, warranting frequent reviews of the accumulating knowledge. In doing just that, biologists from the Plant Physiology Laboratory at the University of Guam and neuroscientists from the Experimental Medicine Program at The University of British Columbia have published an update on the reputed environmental toxins that have been suspected of being involved in mammal neurodegeneration. Their summary was published in April in the book Spectrums of Amyotrophic Lateral Sclerosis, which is available online ...
According to a recent Finnish study, higher levels of moderate and vigorous physical activity can curb arterial stiffening already in childhood. However, sedentary time or aerobic fitness were not linked to arterial health. The results, based on the ongoing Physical Activity and Nutrition in Children (PANIC) Study conducted at the University of Eastern Finland, were published in the Journal of Sports Sciences. The study was made in collaboration among researchers from the University of Jyväskylä, University of Eastern Finland, the Norwegian School of Sport sciences, and the University of Cambridge.
Arterial stiffening predisposes to heart diseases, ...
Tokyo, Japan - In Japan, thousands of homes and businesses and hundreds of lives have been lost to typhoons. But now, researchers have revealed that a new flood forecasting system could provide earlier flood warnings, giving people more time to prepare or evacuate, and potentially saving lives.
In a study published this month in Scientific Reports, researchers from The University of Tokyo Institute of Industrial Science have shown that a recently developed flood forecasting system provides much earlier advance warnings of extreme flooding events than current systems. ...
Germany is a hotspot for dragonflies and damselflies (Odonata) species in Europe, owing to the range of habitats and climates that it provides. While many recent and mostly small-scale studies suggest long-term declines of insect populations in different parts of Europe, studies of freshwater insects - including dragonflies and damselflies - suggest that some species have increased in occurrence. Researchers of iDiv, FSU and UFZ have now provided a nationwide analysis of the occurrence and distribution of dragonflies and damselflies in Germany between 1980 and 2016. For this, they analysed over 1 million occurrence records on 77 species from different regional ...
The population on Earth is increasingly growing and people are expected to live longer in the future. Thus, better and more reliable therapies to treat human diseases such as Alzheimer's and cardiovascular diseases are crucial. To cope with the challenge of ensuring healthy ageing, a group of international scientists investigated the potential of biosynthesising several polyamines and polyamines analogues with already known functionalities in treating and preventing age-related diseases.
One of the most interesting molecules to study was spermidine, which is a natural product already present in people's blood and an inducer of autophagy that is an essential cellular process for clearing damaged proteins, e.g., misfolded proteins ...
URBANA, Ill. - For the most accurate accounting of a product's environmental impact, scientists look at the product's entire life cycle, from cradle to grave. It's a grand calculation known as a life cycle assessment (LCA), and greenhouse gas emissions are a key component.
For corn ethanol, most greenhouse gas emissions can be mapped to the fuel's production, transportation, and combustion, but a large portion of the greenhouse gas calculation can be traced right back to the farm. Because of privacy concerns, however, scientists can't access individual farm management decisions such as fertilizer type and rate.
Nitrogen fertilizer data are an important piece of the calculation because a portion ...
A decade-long study of the most common forearm fracture in older adults revealed that personalized medicine catering to a patient's individual needs and environment, not age or X-rays, should guide treatment options.
Led by a Michigan Medicine physician, the research team examined treatment outcomes over two years for patients who fractured their distal radius, the larger of two bones in the forearm. They found no one-size-fits all method for treating the fracture, which more than 85,000 Medicare beneficiaries sustain annually.
"Traditionally, surgeons look at these broken bones on X-rays, and they have to assess various ways of fixing it based off fracture anatomy and patient age," said Kevin Chung, M.D., study lead and Charles B. G. De ...
LAST 30 PRESS RELEASES:
[Press-News.org] Blocking IL-11 signalling can help liver regenerate after injury from paracetamol toxicity