BTI Professor Daniel Klessig and lab members Research Associate Hyong Woo Choi and Postdoctoral scientist Murli Manohar.
Aspirin’s active form, salicylic acid, blocks a protein called HMGB1, which triggers inflammation in damaged tissues. The new findings may explain the disease-preventing effects of a low-dose aspirin regimen and offer hope that more effective aspirin-like drugs may be developed for a wide variety of diseases.
“We’ve identified what we believe is a key target of aspirin’s active form in the body, salicylic acid, which is responsible for some of the many therapeutic effects that aspirin has. This protein, HMGB1, is associated with many prevalent, devastating diseases in humans, including rheumatoid arthritis, heart disease, sepsis and inflammation-associated cancers, such as colorectal cancer and mesothelioma,” said senior author Daniel Klessig, a professor at BTI and Cornell University.
Aspirin’s pain relieving effects have long been attributed to its ability to block the enzymes cyclooxygenase 1 and 2, which produce prostaglandins- hormone-like compounds that cause inflammation and pain -a discovery that netted its discoverer, John Vane, a Nobel prize. However, the body rapidly converts aspirin to salicylic acid, which is a much less effective inhibitor of cyclooxygenase 1 and 2 than aspirin. Nonetheless, it has similar pharmacological effects as aspirin, suggesting that salicylic acid may interact with additional proteins.
“Some scientists have suggested that salicylic acid should be called ‘vitamin S’, due to its tremendous beneficial effects on human health, and I concur,” said lead author Hyong Woo Choi, a research associate at BTI.
In the current study, researchers discovered the interaction between salicylic acid and HMGB1 by screening extracts prepared from human tissue culture cells to find proteins that could bind to salicylic acid. They identified one of these proteins as HMGB1. These screens have also identified a key suspect in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases + ~2 dozen additional candidates that have yet to be characterized.
In the body, HMGB1 is normally found inside the nucleus, but can enter the blood stream when released from injured tissues or secreted by certain immune or cancer cells. The protein in the blood stream triggers inflammation by recruiting immune cells involved in preventing infections and repairing damaged tissues. HMGB1 also activates these recruited immune cells to express genes that code for cytokines. Using assays that measured the effects of salicylic acid on the recruitment and activation of immune cells, they showed that salicylic acid could block both of these functions at concentrations similar to those found in people on low-dose aspirin.
Klessig and Gaetano Montelione not only confirm that salicylic acid can bind to HMGB1, but also to identify the salicylic acid binding sites. The Klessig group identified 2 derivatives of salicylic acid, which are far more effective than salicylic acid in blocking HMBG1’s pro-inflammatory activities. They synthesized one compound in the lab, while a second was isolated from a licorice plant used as a Chinese medicinal herb.
“We’ve identified both synthetic and natural derivatives of salicylic acid which are 50 to 1000 times more than salicylic acid or aspirin in suppressing the pro-inflammatory activity of extracellular HMGB1,” said Klessig, “thereby providing proof of concept that more effective salicylic acid-based drugs are attainable.” http://bti.cornell.edu/news/new-study-provides-key-insights-into-aspirins-disease-fighting-abilities/
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