Scientists pursue new compounds that can tackle inflammatory diseases

Investigators have known for some time that fasting, intense exercise or a low-carb diet can spur production of a compound called BHB, or β-hydroxybutyrate. Now, working with mouse models for inflammation, investigators at Yale say they have nailed down proof that BHB can directly inhibit the inflammatory protein NLRP3, which could have an impact in treating a range of diseases linked to inflammation, like diabetes, Alzheimer's, atherosclerosis and autoinflammatory conditions.

Almost simultaneously, investigators at Trinity College in Dublin say they identified a molecule that directly inhibits NLRP3, citing it as a prime candidate for heading off the full slate of diseases triggered by inflammation.

"It is a bit like a cog in a machine that drives these diseases," Luke O'Neill, a professor of biochemistry and director of Trinity Biomedical Sciences Institute, tells the Irish Examiner about MCC950. "I would not go as far as to say that what we have is a cure for all of them but, because they share an inflammatory component, this molecule can stop their progression."

At Yale, the focus has been on a metabolite that can naturally inhibit the protein.

Vishwa Deep Dixit

"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, a professor in the Section of Comparative Medicine at Yale School of Medicine.

NLRP3 is part of the inflammasome, the Yale scientists note. Introducing BHB into mouse models for inflammatory diseases linked to NLRP3 reduced inflammation, they say, adding that a ketogenic diet--high-fat, sufficient protein and low-carbohydrate--had the same effect. And they want to further their work to see if the approach may work on diseases associated with mutations of NLRP3.

"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. 

- here's the release on the Yale work
- read the story on the Irish team

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