- Author: Kathy Keatley Garvey
Reporter Juliette Smith of KTXL Fox40 News (she holds a master's degree in broadcast reporting and production, University of Southern California) just did an excellent piece on Hammock and his work. It aired Monday, Nov. 25. (Watch news story)
The gist: Newly published research shows that a key regulatory enzyme inhibitor that Hammock discovered can alleviate inflammation linked to health issues caused by a high-sugar diet.
Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, puts it succinctly: "PNAS paper: UC Davis drug candidate in rodents improves gut health from over consumption of sucrose."
He's the co-author of “Metabolomics Reveals Soluble Epoxide Hydrolase as a Therapeutic Target for High-Sucrose Diet-Mediated Gut Barrier Dysfunction,” published in the current edition of Proceedings of the National Academy of Sciences. It's the work of a 14-member international team. (See news story on Department of Entomology and Nematology website)
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.
“We know that a high-sugar diet can lead to multiple serious health problems, and can be a silent killer,” Hammock told us. “We also know that underlying mechanisms and therapeutic strategies to alleviate the results of a high-sucrose diet remain largely unknown. Our research shows that this inhibitor alleviates inflammation and is not acting as an anti-inflammatory compound.”
Indeed, obesity is a major issue. More than 70 percent of Americans are overweight, and 40 percent are obese, according to the Centers for Disease Control and Prevention. The average American consumes 100 pounds of sugar a year, says USDA's Agricultural Research Service. That's a lot of sugar!
“Human translation of this research could be rapid because thesEH inhibitors are currently being evaluated in human clinical trials for other disorders,” said nutrition researcher Guodong Zhang, a member of the UC Davis Department of Nutrition faculty, and a former postdoctoral fellow in the Hammock lab. He was 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.
Exciting? Yes. "The important work identified in this paper indicates potential future therapeutic targets for sEH inhibitors," said EicOsis CEO Cindy McReynolds, a UC Davis doctoral alumna.
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 more than 50 years in research leading to drugs that target such diseases as diabetes, hypertension (heart disease), Alzheimer's disease, and cancer. He traces his interest back to his graduate student days in the John Casida lab at UC Berkeley. He and fellow graduate student Sarjeet Gill, now a distinguished professor emeritus at UC Riverside, were researching insect developmental biology and green insecticides when they co-discovered the target enzyme in mammals that regulates epoxy fatty acids.
“We were researching juvenile hormones, and how a caterpillar turns into a butterfly,” Hammock said.
"Science," as Hammock is fond of saying, "is full of surprises."
Indeed. We're looking forward to more science and more surprises...
- 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/
- Author: Kathy Keatley Garvey
Bruce Hammock a distinguished entomology professor at the University of California, Davis, began his career trying to figure out how to control pests. Now he's making news with his potent enzyme inhibitor that dramatically reduces inflammation, inflammatory pain and neuropathic pain.
He couldn't have been more pleased or proud when a colleague in Spain published ground-breaking research on diabetes using the Hammock-discovered soluble epoxide hydrolase (sEH) inhibitor.
Researchers in the Joan Clària laboratory at the University of Barcelona, Spain, discovered that diabetes can be prevented and reversed, at least in genetically obese mice.
The study, published in the Proceedings of the National Academy of Sciences, revealed that when the sEH inhibitor was used in mice with a high level of omega-3 fats, the treatment both prevented the onset of diabetes and reversed the effects of diabetes in obese mice. Clària is an associate professor at the Barcelona University School of Medicine and a senior consultant at the Biochemistry and Molecular Genetics Service of the Hospital Clínic of Barcelona.
“Our previous studies show the drug we are working on will reduce the symptoms of diabetes in mice by itself,” Hammock said, “but the excitement about Joan Clària's work is that if the mice have a genetically increased level of omega-3 fatty acids--the drug offers prevention or cure in mice.”
This is breaking news that we hope will lead to targeting diabetes in humans. Worldwide, some 347 million people have diabetes, according to the World Health Organization. The Center for Disease Control and Prevention (CDC) estimates that 29.1 million Americans or 9.3 percent of the population have diabetes, either diagnosed or undiagnosed.
Hammock explained that the epoxide metabolites of the omega-3 fatty acid DHA are stabilized by inhibiting sEH, "and these metabolites contribute a great deal to the beneficial effects of an omega-3 diet." Previous UC Davis research in the laboratories of Bruce Hammock, Nipavan Chiamvimonvat, Robert Weiss, Anne Knowlton and Fawaz Haj showed that the enzyme reduces or reverses such diabetes-linked medical issues as renal failure, hypertension, diabetic pain, hardening of the arteries, and heart failure.
In the paper, titled “Inhibition of Soluble Epoxide Hydrolase Modulates Inflammation and Autophagy in Obese Adipose Tissue and Liver: Role for Omega-3 Epoxides,” Clària described the administration of the sEH inhibitor as “a promising strategy to prevent obesity-related co-morbidities.” Technically, the study “demonstrates that stabilization of cytochrome P-450 epoxides derived from omega-3 polyunsaturated fatty acids through inhibition of the inactivating enzyme soluble epoxide hydrolase (sEH) exerts beneficial actions in counteracting metabolic disorders associated with obesity, including insulin resistance and fatty liver disease,” Clària said.
Clària said the study also “sheds more light on the role of sEH in cellular homeostasis by providing evidence that omega-3 epoxides and sEH inhibition regulate autophagy and endoplasmic reticulum stress in insulin-sensitive tissues, especially the liver.”
Cristina López-Vicario was the first-author of the research paper. In addition to Clària and Hammock, other co-authors were José Alcaraz-Quiles, Verónica García-Alonso, Bibiana Rius, Aritz Lopategi, Ester Titos and Vicente Arroyo, all of the Clària lab or associates; and Sung Hee Hwang of the Hammock Lab, UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center
Hammock has worked on the mechanism of hydrolytic enzymes and their effect on human health for more than 35 years. He is developing both enzyme inhibitors and natural products as drugs for use in the United States and developing countries. His work has helped identify new targets for the action of drugs and other compounds to improve health and predict risk from various environmental chemicals.
Hammock is the founder and CEO of EicOsis, and through EicOsis, the compounds are in clinical trials for companion animals and the Pre-Investigational New Drug Application (Pre-IND) Consultation Program for neuropathic pain in human diabetics.
Hammock was recently selected a fellow of the National Academy of Inventors (NAI), which honors academic invention and encourages translations of inventions to benefit society and a member of the National Academy of Sciences. He directs the campuswide Superfund Research Program and National Institutes of Health Biotechnology Training Program.
