Two Articles on treatments for inflammatory diseases & NLRP3 Scientists uncover marvel molecule that could lead to treatments for inflammatory diseases Date: February 16, 2015 Source: Trinity College Dublin Summary: Scientists have uncovered a marvel molecule that blocks a key driver of inflammatory diseases. The finding could meet a major unmet clinical need by inspiring new non-invasive treatments for arthritis, multiple sclerosis and Muckle-Wells syndrome, among a myriad of other inflammatory diseases. Scientists at Trinity College Dublin have uncovered a marvel molecule that blocks a key driver of inflammatory diseases. The finding could meet a major unmet clinical need by inspiring new non-invasive treatments for arthritis, multiple sclerosis and Muckle-Wells syndrome, among a myriad of other inflammatory diseases. In a study published this week in the world's leading preclinical medical journal Nature Medicine, the international research team led by Trinity and the University of Queensland Australia showed how the molecule MCC950 can suppress the 'NLRP3 inflammasome', which is an activator of the key process in inflammatory diseases. Inflammasomes have been identified as promising therapeutic targets by researchers over the last decade. And now the discovery of MCC950's abilities represents a hugely significant development in the effort to find treatments for inflammatory diseases, for which current therapies are either highly ineffective or have major limitations. Crucially, the finding also confirms that inflammatory diseases all share a common process, even though the part of the body becoming inflamed might differ. Professor of Biochemistry at Trinity, Luke O'Neill, is the joint senior scientist behind the discovery. He said: "Drugs like aspirin or steroids can work in several diseases, but can have side effects or be ineffective. What we have found is a potentially transformative medicine, which targets what appears to be the common disease-causing process in a myriad of inflammatory diseases." Dr Rebecca Coll, lead author on the paper, said: "MCC950 is blocking what was suspected to be a key process in inflammation. There is huge interest in NLRP3 both among medical researchers and pharmaceutical companies and we feel our work makes a significant contribution to the efforts to find new medicines to limit it." Professor Matt Cooper, chemist and co-senior author from the University of Queensland's Institute for Molecular Bioscience (IMB), added: "MCC950 is able to be given orally and will be cheaper to produce than current protein-based treatments, which are given daily, weekly, or monthly by injection. Importantly, it will also have a shorter duration in the body, allowing clinicians to stop the anti-inflammatory action of the drug if the patient ever needed to switch their immune response back to 100% in order to clear an infection." So far, the results have shown great promise for blocking multiple sclerosis in a model of that disease, as well as in sepsis, where in response to bacteria, potentially fatal blood poisoning occurs. However, the target for MCC950 is strongly implicated in diseases such as Alzheimer's disease, atherosclerosis, gout, Parkinson's disease and rheumatoid arthritis, which means it has the potential to treat all of these conditions. Another disease where the new drug might have significant benefits is Muckle-Wells syndrome, which is a rare and severe auto-inflammatory disorder. Using blood samples from patients, the authors showed that MCC950 can block the rogue gene responsible for repeated inflammatory activation in sufferers. Dr Dan Kastner of the National Institutes of Health USA, said: "MCC950 might well be a key addition to the options for treating Muckle-Wells syndrome and similar diseases." Professor O'Neill added: "We are really excited about MCC950. We believe this has real potential to benefit patients suffering from several highly debilitating diseases, where there is currently a dire need for new medicines." Story Source: The above story is based on materials provided by Trinity College Dublin. Note: Materials may be edited for content and length. Journal Reference: Rebecca C Coll, Avril A B Robertson, Jae Jin Chae, Sarah C Higgins, Raúl Muñoz-Planillo, Marco C Inserra, Irina Vetter, Lara S Dungan, Brian G Monks, Andrea Stutz, Daniel E Croker, Mark S Butler, Moritz Haneklaus, Caroline E Sutton, Gabriel Núñez, Eicke Latz, Daniel L Kastner, Kingston H G Mills, Seth L Masters, Kate Schroder, Matthew A Cooper, Luke A J O'Neill. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature Medicine, 2015; DOI: 10.1038/nm.3806 Trinity College Dublin. "Scientists uncover marvel molecule that could lead to treatments for inflammatory diseases." ScienceDaily. ScienceDaily, 16 February 2015. <www.sciencedaily.com/releases/2015/02/150216131119.htm>. Anti-inflammatory mechanism of dieting and fasting revealed Date: February 16, 2015 Source: Yale University Summary: Researchers have found that a compound produced by the body when dieting or fasting can block a part of the immune system involved in several inflammatory disorders such as type 2 diabetes, atherosclerosis, and Alzheimer's disease. Researchers at Yale School of Medicine have found that a compound produced by the body when dieting or fasting can block a part of the immune system involved in several inflammatory disorders such as type 2 diabetes, atherosclerosis, and Alzheimer's disease. In their study, published in the Feb. 16 online issue of Nature Medicine, the researchers described how the compound β-hydroxybutyrate (BHB) directly inhibits NLRP3, which is part of a complex set of proteins called the inflammasome. The inflammasome drives the inflammatory response in several disorders including autoimmune diseases, type 2 diabetes, Alzheimer's disease, atherosclerosis, and autoinflammatory disorders. "These findings are important because endogenous metabolites like BHB that block the NLRP3 inflammasome could be relevant against many inflammatory diseases, including those where there are mutations in the NLRP3 genes," said Vishwa Deep Dixit, professor in the Section of Comparative Medicine at Yale School of Medicine. BHB is a metabolite produced by the body in response to fasting, high-intensity exercise, caloric restriction, or consumption of the low-carbohydrate ketogenic diet. Dixit said it is well known that fasting and calorie restriction reduces inflammation in the body, but it was unclear how immune cells adapt to reduced availability of glucose and if they can respond to metabolites produced from fat oxidation. Working with mice and human immune cells, Dixit and colleagues focused on how macrophages -- specialized immune cells that produce inflammation -- respond when exposed to ketone bodies and whether that impacts the inflammasone complex. The team introduced BHB to mouse models of inflammatory diseases caused by NLP3. They found that this reduced inflammation, and that inflammation was also reduced when the mice were given a ketogenic diet, which elevates the levels of BHB in the bloodstream. "Our results suggest that the endogenous metabolites like BHB that are produced during low-carb dieting, fasting, or high-intensity exercise can lower the NLRP3 inflammasome," said Dixit. Story Source: The above story is based on materials provided by Yale University. The original article was written by Karen N. Peart. Note: Materials may be edited for content and length Journal Reference: Other authors on the study include Yun-Hee Youm, Kim Y. Nguyen, Ryan W Grant, Emily L. Goldberg, Monica Bodogai, Dongin Kim, Dominic D'Agostino, Noah Planavsky, Christopher Lupfer, Thirumala D Kanneganti, Seokwon Kang, Tamas L. Horvath, Tarek M. Fahmy, Peter A. Crawford, Arya Biragyn, and Emad Alnemri. The research was funded in part by National Institutes of Health grants AI105097, AGO43608, AG031797, and DK090556. Yale University. "Anti-inflammatory mechanism of dieting and fasting revealed." ScienceDaily. ScienceDaily, 16 February 2015. <www.sciencedaily.com/releases/2015/02/150216131146.htm>.