New research from the Keck School of Medicine of the University of Southern California (USC) may help prevent damage to the liver caused by drugs like acetaminophen and other stressors.
Acetaminophen, more commonly known as Tylenol, helps relieve pain and reduce fever. The over-the-counter drug is a major ingredient in many cold and flu remedies as well as prescription painkillers like Percocet and Vicodin.
However, metabolized by the liver, acetaminophen is the most common cause of drug-induced liver disease and acute liver failure in the United States and United Kingdom. Tylenol's maker announced in July that it was lowering the maximum recommended daily dosage to 3,000 milligrams to help prevent accidental overdoses.
Doctors at the Keck School of Medicine of USC have identified a protein on the mitochondria of liver cells in mice that, when silenced, protects against liver toxicity usually associated with excess doses of acetaminophen.
They found that the protein Sab, or SH3-domain binding protein 5, binds with the enzyme JNK (c-Jun N-terminal kinase). JNK regulates cellular metabolism and survival in response to stress, protecting cells when activated for brief intervals. However, JNK also kills cells when activated for prolonged periods of time.
"Because the short-term activation of JNK is associated with cell survival, Sab is potentially a better target than inhibiting JNK, which could have adverse effects," said Neil Kaplowitz, M.D., the study's lead investigator and professor of medicine at the Keck School.
Researchers have long believed that acetaminophen was converted into toxic metabolites that, in excess, overwhelm liver cells, causing them to die. In a 2008 study, Kaplowitz, who holds the Keck School's Thomas H. Brem Chair in Medicine and Veronica P. Budnick Chair in Liver Disease, and other USC colleagues turned that theory around — they found that it was not the metabolite, but rather the sustained activation of JNK that harmed the organ. By inhibiting JNK activation in mice, injury to the liver caused by large doses of acetaminophen was avoided.
In the current study, published online by the Journal of Biological Chemistry in August, the scientists silenced Sab in mice, which did not affect the metabolism of acetaminophen but successfully prevented liver injury. They also tested the effect on liver injury caused by apoptosis, or programmed cell death in response to inflammatory proteins that are implicated in many diseases and tissues — silencing Sab protected the liver in that case, too.
"We proved that the sustained activation of JNK targets Sab and is a requirement for the subsequent death of liver cells," Kaplowitz said. "We then showed that it is a universal effect. Developing a drug to protect against cell death, one could argue to target JNK — but that's a double-edged sword. This provides a whole new target: Create a drug that inhibits the interaction between JNK and Sab."
Co-authors include Sanda Win, Tin Aung Than, Derick Han and Lydia M. Petrovic. Their research was funded by the National Institutes of Health.
Alison Trinidad | EurekAlert!
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences