- Author: Kathy Keatley Garvey
Well, you never know where research will take you.
UC Davis distinguished professor Bruce Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, remembers how it all started.
He and fellow graduate student Sarjeet Gill, now a distinguished professor emeritus at UC Riverside, were researching insect development lab in John Casida's lab at UC Berkeley when they co-discovered the target enzyme in mammals that regulates epoxy fatty acids.
Or as Hammock said: “We were researching juvenile hormones, and how a caterpillar turns into a butterfly."
Fast forward to today.
Newly published research shows that a key regulatory enzyme inhibitor discovered in the Hammock lab can alleviate inflammation linked to health issues that are caused by a high-sugar diet.
The research paper, “Metabolomics Reveals Soluble Epoxide Hydrolase as a Therapeutic Target for High-Sucrose Diet-Mediated Gut Barrier Dysfunction,” appears in today's edition of Proceedings of the National Academy of Sciences (PNAS). A 14-member international research team, including Hammock, authored the paper.
Lead author Jun-Yan Liu, a professor at Chongqing Medical University, China, and a former research scientist (7.5 years) in the Hammock lab, said a soluble epoxide hydrolase (sEH) inhibitor alleviated a gut barrier dysfunction caused by high-sucrose diet in a murine (mouse) model and shows promise in humans.
“Our research showed that a 16-week high sucrose diet in a murine model showed colon inflammation and a tight junction impairment,” said Liu, who specializes in metabolomics, bio-analytical chemistry, molecular pharmacology, and natural medicinal chemistry. “When we treated the mice with a chemical inhibitor of sEH, that reduced the colon inflammation and improved the tight junction impairment. That was further supported by the conditional knockout of sEH in intestinal epithelia.”
“Such gut barrier dysfunctions allow microorganisms and deleterious inflammatory materials to cross the gut wall, leading to the increased risk of a variety of diseases and particularly those associated with intestinal disease," Hammock said.
Hammock praised Liu for his work. “When Dr. Jun-Yan Liu was a postgraduate in my laboratory, he made many of the fundamental discoveries on how metabolites of polyunsaturated fatty acids regulate biology and how the soluble epoxide hydrolase inhibitors developed here can reduce inflammation and pain by altering this pathway. His studies bring up that excessive amounts of the common dietary sugar sucrose can in fact increase deleterious inflammation in rodent models and that inflammation can be at least partly resolved by an inhibitor of the soluble epoxide hydrolase now in human clinical trials. These data suggest that a lifestyle change or pharmaceutical could reduce this chronic inflammation problem associated with high sucrose consumption but also may provide a mechanism leading to its cause."
Nutrition researcher Guodong Zhang, a member of the UC Davis Department of Nutrition faculty, and a former postdoctoral fellow in the Hammock lab with Liu, commented that the study “suggests that soluble epoxide hydrolase (sEH) plays an important role in regulating intestinal barrier functions. However, the molecular mechanisms leading to intestinal barrier dysfunction remain poorly understood, and there are few available therapeutic approaches to target barrier functions.”
“I am so pleased that this pair of scientists (Zhang and Liu) are following how diet controls both the initiation and resolution of inflammation to improve human health,” Hammock commented.
“Human translation of this research could be rapid because the sEH inhibitors are currently being evaluated in human clinical trials for other disorders,” said Zhang, referring to EicOsis, a Davis-based clinical startup that Hammock co-founded in 2011 to alleviate chronic pain without the use of opioids. Its drug candidate, EC5026, has successfully completed Phase 1 human clinical trials, with no side effects.
Said Cindy McReynolds, CEO and co-founder of EicOsis: “The important work identified in this paper indicates potential future therapeutic targets for sEH inhibitors.”
Other co-authors of the PNAS paper include UC Davis organic chemist Sung Hee Hwang of the Hammock lab; and Liu's colleagues, Zhi Lin, Xian Fu, Qing Jiang, Xue Zhou, Hou-Hua Yin, Kai-I Ni, Qing-Jin Pan, Xin He, Ling-Tong Zhang, Yi-Weng Meng and Ya-Nan Lia. The team thanked biochemist Christophe Morisseau, a research scientist in the Hammock lab for reviewing the research paper.
Scientists agree that obesity is a worldwide challenge, and it continues to be a complex and costly chronic disease. Research nutritionist Susan Raatz, with the USDA's Agricultural Research Service at the Grand Forks Human Nutrition Research Center, expresses alarm about Americans' sugar intake and the health risks. “The average American eats (or drinks) 34 teaspoons of sugars a day, which is equal to 500-plus calories,” she recently wrote in a USDA publication. “This averages more than 100 pounds of sugars per person each year. Sugar intake has drastically increased over the last century. In 1822, the average American ate in 5 days the amount of sugar found in one of today's 12-ounce sodas. Now, we eat that much every 7 hours!” (See https://tinyurl.com/4cmyamez)
Hammock, a member of the UC Davis faculty since 1980, and a fellow of the National Academy of Inventors and the U.S. National Academy of Sciences, has studied sEH inhibitors for 50 years in research leading to drugs that target such diseases as diabetes, hypertension (heart disease), Alzheimer's disease, and cancer.
I keep telling Professor Hammock he'll win the Nobel Prize some day...
(Read the full news story at https://tinyurl.com/dw6k9cbh and the PNAS paper at https://tinyurl.com/49hk77dy/
