New Hope in a Traditional Chinese Therapy

New Hope in a Traditional Chinese Therapy

By Eugene Curtin

Could a chemical compound found in this flowering plant, known commonly as Monnier’s snowparsley or She Chuang Zi in Chinese, help asthmatics breathe easier?

Two Creighton professors are forging a new front in the war on an inflammatory disease so old it was remarked upon in ancient Egypt, and so persistent that the World Health Organization estimates that 339 million people worldwide suffer from it today.

Asthma, a chronic inflammatory disease of the airways to the lungs, has drawn the attention of Yaping Tu, PhD, and Peter Abel, PhD, both professors in the Creighton School of Medicine’s Department of Pharmacology and Neuroscience.

Tu and Abel are among a team of participants drawn from multiple national and international research groups charged with investigating the possibility that a new method of relieving asthmatic attacks might be obtained by using osthole, a derivative of the traditional Chinese medicine She Chuang Zi.

The result of that investigation was featured in Science Signaling, a peer-reviewed scientific journal published weekly by the 172-year-old American Association for the Advancement of Science (AAAS), and referenced in Science, also published by the AAAS.

The question posed was simple enough: Could a chemical compound found in a plant used in traditional Chinese healing, with claims to address everything from low libido to cancer, actually relieve airway constriction in asthmatic patients?

The answer, the study found, was yes.

Titled “Airway Relaxation Mechanisms and Structural Basis of Osthole to Improve Lung Function in Asthma,” the study found that osthole “fully relaxed” airways that proved resistant to the standard inhalers — or bronchodilators — that for decades have been the primary response to asthmatic attacks. It was the search for such alternative treatments, in the face of evidence that airways can develop resistance to traditional therapies, that spurred the National Institutes of Health and the state of Nebraska, through its LB595 research program, to fund the study.

Resistance to traditional bronchodilators has drawn the attention of other research projects, such as a 2016 study by the Cleveland Clinic, that stated traditional therapies are “ineffective for as many as 40% of people with asthma.”

Even if that number were a smaller fraction, Tu says, alternatives should be sought.

“It’s a way to rescue these patients who are potentially in a situation where resistance means they have to be hospitalized, or who, because of severe bronchoconstriction, might face death,” he says.

“It’s variable, of course. There are people who respond and people who don’t respond. What is happening is that the more people take these bronchodilators, and in higher dosages, the more resistance develops. So, it’s an issue.”

Abel and Tu’s participation in the study emerged about five years ago when co-researchers in an earlier study of smoking-related diseases described a pressing need for therapies to treat asthmatics for whom common bronchodilators proved ineffective.

Happily, this coincided with discussions Tu was having with Zhengyu Cao, PhD, who is now a professor with the Department of Pharmacology in the School of Traditional Chinese Medicine at China Pharmaceutical University in Nanjing, China, but who was then an assistant professor at Creighton.

Cao had amassed a library of compounds derived from Chinese herbal medicines, several of which were identified, after using mouse lungs as models, as effective asthma treatments.

Tu and Cao had discussed the potential of Chinese herbal medicines to provide new treatment options, and, Abel says, that collaboration began the process.

“They got together and said, ‘OK, let us look at some of these herbal products and see whether there is anything that might lead us to say that this one or that one could be useful in helping us address these problems,’” he says. “That’s kind of how this whole thing started.”

It helped, as the international osthole research team was assembled, that Tu was already researching how cellular signaling impacts asthma, and that Abel is an expert in integrative and organ systems pharmacology with many years of experience in drug development.

It also helped that Taotao Wei, PhD, a professor at the Institute of Biophysics, Chinese Academy of Sciences in Beijing, and his research group, stood ready to help. That collaboration used crystallography to demonstrate that osthole could bind with the enzyme PDE4D and disrupt its activity in order to promote airway relaxation.

Now that the effectiveness of the osthole molecule has been demonstrated, what’s next?

“We will now take osthole as our foundation and engineer it to be a better agent, to be the kind of thing that might interest a pharmaceutical company,” Abel says. “We have a medicinal chemist in our department, so the engineering is something that we can do here. Once we have that better molecule, we can start talking to a pharmaceutical company or a biotech company.

“That is the pathway for us.”