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Caterpillar Fungus Yields Clues to Anti-Inflammatory Strategies

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By Sharon Kingman
Staff Writer

LONDON – A compound isolated from a traditional Chinese medicine has specific anti-inflammatory properties and could offer a way to develop a new class of anti-inflammatory drugs.

The compound, called cordycepin, is present in the Cordyceps fungus, which parasitizes the hibernating caterpillars of a type of moth found in Tibet.

Researchers in the UK now have established that cordycepin reduces the accumulation of inflammatory gene products in airway smooth muscle cells – one of the types of cells that are affected by asthma.

Cornelia de Moor, lecturer in RNA biology in the School of Pharmacy at the University of Nottingham, told BioWorld International: "We have found that cordycepin can inhibit the inflammatory response. Even if cordycepin itself turns out to be too toxic or too unstable to use as a drug, this work has given us better insights into how inflammatory genes are turned on very quickly, and this knowledge could allow us in the future to identify other molecules that would form a new class of anti-inflammatory drugs, alongside corticosteroids such as prednisone and nonsteroidal anti-inflammatories such as ibuprofen."

De Moor and her colleagues reported their findings in the Nov. 18, 2012, issue of RNA, in a paper, titled "Inhibition of polyadenylation reduces inflammatory gene induction."

As an RNA biologist, De Moor was interested in studying the cellular process called polyadenylation. That is the means by which the cell adds a series of adenosine bases to the ends of growing messenger RNA (mRNA) molecules. Those "polyA" tails signal to the cell that the mRNA molecule is ready for use. During translation of the message, the cell removes bits of the polyA tails and, once they have gone completely, the mRNA becomes the substrate for RNA-eating enzymes and is degraded.

Cordycepin has been known for a long time as a reagent that inhibits polyadenylation. In addition, previous work by De Moor's group and others had suggested that cordycepin had many different biological effects on rapidly dividing cells, such as a reduction in their protein synthesis and cell adhesion. For that reason, many researchers regarded it as a potential cancer drug. "People gave lots of different explanations for how it worked but because our work suggested that cordycepin inhibited polyadenylation, we started to wonder if all the biological effects people had seen were due to inhibition of polyadenylation," De Moor said.

From their previous paper, the researchers had some indications cordycepin repressed particular genes, and that might correlate with how quickly the mRNA ages. "Our results made us suspect that how quickly a mRNA is degraded is related to whether it is sensitive to cordycepin or not, which made us think that a rapid transcriptional response would be more sensitive to cordycepin," De Moor said.

Despite having used cordycepin in polyadenylation research for 15 years, De Moor only discovered the history of that reagent during the previous project, when she started researching the literature on the biological effects of cordycepin. The compound is found in a fungus that infects the caterpillars of the moth, Hepilus fabricius. The caterpillars of that moth hibernate in the ground over winter; if infected by spores of the Cordyceps fungus, they die, producing a fungal fruiting body in the spring.

Used in traditional Chinese medicine for an estimated 1,000 years, caterpillar fungus is highly prized and even a small amount can cost hundreds of dollars. By custom, the caterpillars, complete with the projecting fruiting body of the fungus, which looks like a worm emerging from the caterpillar's body, are used to stuff a duck, which is then boiled. The resulting broth, which is said to taste pleasant, is then drunk, often as a remedy for a cough.

"When I started researching its use in Chinese medicine, it occurred to me that if it had such a miraculous effect on the people taking it, then it was probably an anti-inflammatory effect because that is what tends to make people feel better quickly," De Moore noted.

Collaborating with researchers in the Division of Respiratory Medicine at the University of Nottingham, De Moor and her colleagues then set out to show that the anti-inflammatory effects of cordycepin were indeed due to its inhibition of polyadenylation. "Its effects on the induction of inflammatory genes were amazing right from the beginning," she said. "And the surprising thing was that it affected only the induction of inflammatory RNAs and not RNAs from housekeeping genes. We think, therefore, that there must be a fundamental difference in how polyadenylation occurs in inflammatory genes, which are highly regulated, compared to housekeeping genes, which are continuously turned on."

De Moor's group now has a new grant from the Biotechnology and Biological Sciences Research Council to investigate the reasons for that difference between the two types of genes in more depth.

"We also want to obtain funds to allow us to study the effects of cordycepin in animal models of inflammatory diseases," De Moor said. "We don't think cordycepin will be as toxic as has been previously thought, because it does not affect all mRNAs. In fact, a recent publication in the Journal for Experimental Biology indicates that cordycepin reduces the effects of aging, indicating that in low doses it is beneficial rather than toxic, even in the long term.

"But even if it does turn out to be too toxic in higher doses, our work shows us that inhibition of polyadenylation is a good anti-inflammatory strategy," she added. "We have some ideas about how to find other drugs that will work in the same way, using the knowledge that we have gathered."