An enzyme inhibitor developed in the UC Davis laboratory of Bruce Hammock and tested in mice by a team of international researchers shows promise that it could lead to a drug to prevent or reduce the disabilities associated with the neurodevelopmental disorders of autism and schizophrenia.
“We discovered that soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Inhibiting that enzyme stops the inflammation and the development of autism-like and schizophrenia-like symptoms in animal models,” said collaborator Kenji Hashimoto, a professor with the Chiba University Center for Forensic Mental Health, Japan. The scientists found higher levels of sEH in a key region of the brain—the prefrontal cortex of juvenile offspring-- after maternal immune activation (MIA).
“Mothers who have MIA, which results from severe stress in that region of the brain, have an increased occurrence of neurodevelopment disorders in their offspring,” Hashimoto explained. “In our study, the sEH enzyme increased dramatically in a key brain region of mice pups from mothers with MIA.”
The research, published today (March 18) in the Proceedings of the National Academy of Sciences (PNAS), is the work of 14 researchers from Chiba University Center for Forensic Mental Health; the Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, in Wako, Saitama, Japan; and the Hammock laboratory.
Research in Mice Pups
By inhibiting sEH, the researchers reversed cognitive and social interaction deficiencies in the mice pups. They hypothesize that this is due to increasing natural chemicals, which prevent brain inflammation. In people, this could reduce the disabilities associated with autism, such as anxiety, gastrointestinal disturbances and epilepsy.
“The same chemical and biochemical markers behaved as predicted in human stem cells,” said Hammock, a distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
Earlier studies have indicated a genetic disposition to the disorders. The team also studied postmortem brain samples from autism patients that confirmed the alterations.
“In the case of both autism and schizophrenia, the epidemiology suggests that both genetics and environment are contributing factors,” said neuroscientist and associate professor Amy Ramsey of the Department of Pharmacology and Toxicology, University of Toronto, who was not involved in the study. “In both cases, maternal infection is a risk factor that might tip the scales for a fetus with a genetic vulnerability. This study is important because it shows that their drug can effectively prevent some of the negative outcomes that occur with prenatal infections. While there are many studies that must be done to ensure its safe use in pregnant women, it could mitigate the neurological impacts of infection during pregnancy.”
Neuroscientist Lawrence David, professor and chair of the School of Public Health, University of Albany, N.Y., who was not involved in the research, said that the study might lead to “an important therapeutic intervention for neurodevelopment disorders.”
Might Be Important Therapeutic Invervention
“There is increasing evidence that maternal immune activation activities (MIA) during fetal development can lead to aberrant neurobehaviors, including autistic-like activities,” said Lawrence, who studies neuroimmunology and immunotoxicology. The study “suggests that enzymatic control of fatty acid metabolism is implicated in neuroinflammation associated with schizophrenia and autism spectrum disorders. The expression of Ephx2 giving rise to soluble epoxide hydrolase (sEH) influences production of fatty acid metabolites, which elevate inflammation in the experimental model of mice after MIA; the sEH inhibitor TPPU (N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl)-urea) was postnatally used to improved behaviors. Analysis of cadaver brains from individuals with ASD also expressed increased sEH. Fatty acid metabolites have been known to affect fetal development, especially that of the brain; therefore, TPPU might be an important therapeutic intervention for neurodevelopmental disorders.”
Molecular bioscientist Isaac Pessah of the UC Davis School of Veterinary Medicine, distinguished professor and associate dean of research and graduate education in the Department of Molecular Biosciences, described the findings as “significant” and called for more detailed and expanded studies.
“There is mounting evidence that inappropriate maternal immune responses during pregnancy to infection contributes elevated risk to autism spectrum disorder, at least in a fraction of cases,” Pessah said. “The most significant findings reported here is that a commonly used mouse model of immune-triggered behavioral deficits mimicking some of the core symptoms in autistic children can be suppressed by inhibiting a novel biochemical target, soluble epoxide hydrolase; a target not previously explored as a target for therapeutic intervention to treat ASDs. These findings provide a rational basis for more detailed and expanded studies in mice carrying mutations implicated in ASDs to determine whether the therapeutic benefits of soluble epoxide hydrolase inhibitor(s) observed in this study are more generalizable.”
Autism in the United States
The Center for Disease Control and Prevention (CDC) estimates that 1 in 68 children in the United States have autism, commonly diagnosed around age 3. It is four times more common in boys than girls. CDC defines autism spectrum disorder as a “developmental disability that can cause significant social, communication and behavioral challenges.” The disorder impairs the ability to communicate and interact.
Approximately 3.5 million people or 1.2 percent of the population in the United States are diagnosed with schizophrenia, one of the leading causes of disability, according to the Schizophrenia and Related Disorders Alliance of America (SARDAA). Scores more go unreported. Approximately three-quarters of persons with schizophrenia develop the illness between 16 and 25 years of age. Statistics also show that between one-third and one half of all homeless adults have schizophrenia, and 50 percent of people diagnosed have received no treatment. Among the symptoms: delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, and obsessive-compulsive disorders, such as hoarding, according to SARDAA.
Promising Prophylactic or Theraputic Target
In their research paper, titled “Key Role of Soluble Epoxide Hydrolase in the Neurodevelopmental Disorders of Offspring After Maternal Immune Activation,” the scientists described sEH as “a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.”
First author Min Ma and second Qian Ren of the Hashimoto lab conducted the animal and biochemical work, while chemists Jun Yang and Sung Hee Hwang of the Hammock lab performed the chemistry and analytical chemistry. Takeo Yoshikawa, a team leader with the RIKEN's Molecular Psychiatry Laboratory, performed measurements of gene expression in the neurospheres from iPSC (induced pluripotent stem cells) from schizophrenia patients and postmortem brain samples from autism patients.
Hashimoto described the international collaboration as “exciting and productive.” This is their third PNAS paper in a series leading to endoplasmic reticulum stress. “We report discovery of a biochemical axis that leads to multiple neurological disorders, including depression, Parkinson's disease, schizophrenia, autism spectrum disorders and similar diseases,” he said.
First Human Trials
William Schmidt, vice president of clinical development at EicOsis, a Davis-based company developing inhibitors to sEH to treat unmet medical needs in humans and companion animals, said the company is developing a first-in-class therapy for neuropathic and inflammatory pain. “EicOsis is in the process of finalizing our first human trials on the inhibitors of the soluble epoxide hydrolase, originally reported from UC Davis,” Schmidt said. “We are targeting the compounds as opioid replacements to treat peripheral neuropathic pain. It is exciting that the same compound series may be used to prevent or treat diseases of the central nervous system.”
Several grants from the National Institutes of Health, awarded to Hammock, supported the research. Hammock praised the many collaborators and students he has worked with on the project. “This work illustrates the value of research universities in bringing together the diverse talent needed to address complex problems,” Hammock said. “It also illustrates the value of fundamental science. This autism research can be traced directly to the fundamental question of how caterpillars turn into butterflies.”
Now working solely on research to benefit humankind, Hammock began his career in insect science at UC Berkeley where he investigated how epoxide hydrolase degrades a caterpillar's juvenile hormone. The process leads to metamorphosis from the larval stage to the adult insect. Hammock then wondered "Does the enzyme occur in plants? Does it occur in mammals?"
It does, and particularly as a soluble epoxide hydrolase in mammals.
"Science is full of surprises," said Hammock, who founded EicOsis to help human patients conquer pain without opioids. "We need to remember that the concept, the clinical target, and even the chemical structure, came from asking how caterpillars turn into butterflies."
ABSTRACT, PNAS Paper, "Key Role of Soluble Epoxide Hydrolase in the Neurodevelopmental Disorders of Offspring After Maternal Immune Activation"
“Maternal infection during pregnancy increases the risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy-fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, the expression of sEH (or EPHX2) mRNA in iPSC-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in the postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment of TPPU (a potent sEH inhibitor) into juvenile offspring from P28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV)-immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV-immunoreactivity in the mPFC of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH would represent a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.”
Related Research Published in PNAS
- Soluble Epoxide Hydrolase Plays a Key Role in the Pathogenesis of Parkinson's Disease
- Gene Deficiency and Pharmacological Inhibition of Soluble Epoxide Hydrolase Confers Resilience to Repeated Social Defeat Stress
Should auld acquaintance be forgot,
and never brought to mind?
No, they won't—at least not for Bruce Hammock, a distinguished professor at the University of California, Davis, and the hundreds of scientists he's trained over an academic career spanning more than four decades at UC Davis and UC Riverside.
Looking back over 2018, Hammock remembers fondly the weekend that 100 of his former laboratory alumni from 10 countries traveled to Davis to honor his work, reunite, collaborate, and reminiscence.
Billed as “Biochemistry and Society: Celebrating the Career of Professor Bruce Hammock,” the three-day event drew Hammock lab alumni from throughout the United States, as well as Egypt, Spain, China, Australia, New Zealand, Germany, Sweden, Canada and the Czech Republic.
“It was really special and I will treasure that weekend always,” said Hammock, who trained scientists at UC Riverside for five years before joining the UC Davis faculty in 1980. He currently holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. He has directed the UC Davis Superfund Program, funded by the National Institutes of Health's National Institute of Environmental Health (NIH/NIEHS), for 31 years.
The distinguished professor, known for his expertise in chemistry, toxicology, biochemistry and entomology, meshes all four sciences in his 50-year research on acute and neuropathic pain in humans and companion animals. It all began with his basic research on how caterpillars become butterflies, research that led to key discoveries about chronic pain.
Since then, his lab has generated more than 80 patents, 300 postdoctoral fellows, and more than 65 graduates, who now hold positions of distinction in academia, industry and government.
Hammock's colleagues, and former postdoctoral fellows, graduate and undergraduate students and visiting scholars arrived at the lab reunion with their spouses--as well as their scientific posters for display and discussion. The posters covered everything from ground-breaking research in prestigious journals to a humorous look at his annual water balloon battles in front of Briggs Hall.
The scientists dined at the UC Davis Conference Center, the Buehler Alumni Center and the Stonegate Country Club; shared months, years and decades of memories; and toasted, roasted and gifted their mentor. Hammock, in turn, toasted, roasted and gifted them.
“We had a blast,” recalled organizer Shirley Gee, a former research toxicologist and manager of the Hammock lab for 31 years. She retired in June 2016 after 40 years of service with the university.
“I have had a vision of this event to honor Bruce for many years now, and it was such a thrill to see it come together,” she said. “Reconnecting in person with all the alumni and their families was more rewarding than I could have imagined, but even more importantly was the thrill of watching alumni reconnect with each other! There were a lot of tears in the house. Many people I think were surprised by how the years melted away when they began reacquainting. I think that speaks to the environment that Bruce created that led to many strong personal and professional bonds.”
Gee credited her seven-member committee—former Hammock students Keith Wing, Jim Ottea, Tom Sparks, Babak Borhan, Qing Li; postdoctoral fellow and “academic grandson” Kin Sing Stephen Lee, a former student of Babak Borhan; and colleague Sarjeet Gill, now a distinguished professor at UC Riverside, with greatly contributing to the success of the one-of-a-kind celebration.
As graduate students, and Hammock and Gill worked together in the John Casida lab at UC Berkeley and later in Larry Gilbert's lab where they co-discovered the enzyme, soluble epoxide hydrolase. Hammock remembers researching juvenile hormones and what's involved in "how caterpillars became butterflies."
Hammock has studied the enzyme system and its inhibitors ever since. He recently formed a Davis-based company, EicOsis, to develop an orally active non-addictive drug for inflammatory and neuropathic pain for human beings and companion animals. Human clinical trials are scheduled to begin in 2019. Several seed-fund grants and a NIH/NINDS (National Institute of Neurological Disorders and Stroke) Blueprint Development Grant support EicOsis.
Hammock, described at the lab reunion as a “genius,” collaborates with scientists worldwide in what's been described as “unprecedented research with a multidisciplinary, integrated approach to research focused on insect biology, mammalian enzymology, and analytical chemistry.” He has authored more than 1000 publications on a wide range of topics in entomology, biochemistry, analytical and environmental chemistry in high quality journals, and has been cited more than 54,000 times. In the epoxide hydrolase field, the Hammock laboratory has published almost 900 peer-reviewed papers.
Tom Sparks, who was Hammock's first graduate student at UC Riverside, chronicled Hammock's career and recalled humorous anecdotes from his early professorship at UC Riverside. A former professor at Louisiana State University, and now a research fellow in Discovery Research at Dow AgroSciences (now Corteva Agriscience, Indianapolis, Sparks praised Hammock's intellect and curiosity. “For Bruce, it was all about the journey, looking around and operative at the interface between entomology, biochemistry and chemistry.”
Gill, along with University of Utah emeritus professor Glenn Prestwich and UC Davis research scientist Karen Wagner also delivered presentations, fondly recalling their shared time and science with Hammock.
Keith Wing, who was Hammock's second graduate student at UC Riverside/Davis, served as emcee at the lab reunion. A former senior research associate at DuPont and Rohm and Haas and current consultant, Wing said “Bruce has inspired many hundreds of developing scientists. For myself and many others, he was able to see what we could become as scientists and social contributors before we could see it ourselves."
Qing Li, a professor in the University of Hawaii's Department of Molecular Biosciences and Bioengineering College of Tropical Agriculture and Human Resources who received his doctorate from UC Davis, studying with major professors Bruce Hammock and James Seiber, said that "Bruce is an eminent scientist and a great mentor. Many of us have benefited from his effective mentorship. Back in 1990, after he signed my dissertation, he shook my hand, and then he asked me to tape-record it and give him the recordings -- a great 'homework' assignment and good practices for me."
Others commented that they learned this from Hammock: “We explore the unexpected and get to do things that don't work” and “Design things to fail; when they don't fail follow along.”
Hammock, the crowd agreed, seems to follow baseball legend Yogi Berra's sage advice: “If you come to a fork in the road, take it.”
Gill praised Hammock's “impact on human health, environmental health” as well as his love of the outdoors—from kayaking to mountain climbing.
Numerous alumni lauded Hammock's sense of humor. One scientist quoted Albert Einstein as saying “Creativity is intelligence having fun” and added “Bruce is always having fun.”
Among the other comments:
- “I never heard him speak a cross word.”
- "He treats everyone with respect.”
- "Bruce loves science and he loves people.”
- "He never heard a crazy idea.”
- "What Bruce does—he delivers the future.”
- "Bruce has a lot of determination and can approach difficult problems from multiple angles.”
- "Bruce values strong relationships with friends he has made over the years”
A native of Little Rock, Ark., Hammock received his bachelor of science degree, magna cum laude, in 1969 from Louisiana State University, Baton Rouge, where he majored in entomology and minored in zoology and chemistry. Then it was off to UC Berkeley, for his doctorate in entomology/toxicology in 1973, and postdoctoral fellowship.
It was at UC Berkeley where he met and married his wife, Lassie, who had just entered the doctoral program in plant physiology. They married in 1972 and then “the Army called me up,” Hammock remembers.
Hammock served as a public health medical officer/first lieutenant with the U.S. Army Academy of Health Science in San Antonio, Texas; and then did more postdoctoral research at the Rockefeller Foundation, Department of Biology, Northwestern University, Evanston. Ill.
Hammock then joined the faculty of the Division of Toxicology and Physiology, UC Riverside Department of Entomology in 1975 before heading for UC Davis in 1980 to accept a joint-faculty appointment in toxicology and entomology.
Bruce and Lassie reared three children: Tom, Bruce and Frances. “Frances and her husband, Adrian, teach math at UC San Diego; Bruce is on the UC Davis School of Veterinary Medicine faculty; and Tom, a graduate of the American Film Institute Conservatory, makes movies,” Hammock said, adding that he and Lassie appeared in one of the movies that Tom directed: "The Last Survivors."
Highly honored by his peers, Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of scores of awards, including the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics; and the first McGiff Memorial Awardee in Lipid Biochemistry.
Hammock told the crowd at the reunion that he began his career studying insect science but switched to human research after encountering “all the suffering involved in acute and neuropathic pain.”
His insect science research centered around how a key enzyme, epoxide hydrolase, degrades a caterpillar's juvenile hormone, leading to metamorphosis from the larval stage to the adult insect. He then wondered "Does the enzyme occur in plants? Does it occur in mammals?" It does, and particularly as a soluble epoxide hydrolase in mammals.
“It is always important to realize that the most significant translational science we do in the university is fundamental science,” said Hammock. “The extreme and poorly treated pain that I observed as a medical officer in a burn clinic in the Army, is a major driver for me to translate this knowledge to help patients with severe pain.”
And it all began with him asking how caterpillars turn into butterflies.
"Science is full of surprises," the distinguished UC Davis professor said. "We need to remember that the concept, the clinical target, and even the chemical structure came from asking how caterpillars turn into butterflies."
A newly published study by a team of scientists at Chiba University, Japan and at the University of California, Davis shows that inhibiting an enzyme, the soluble epoxide hydrolase (sEH), plays a key role in curbing the inflammation associated with the development and progression of Parkinson's disease, an age-related brain disorder that affects a million Americans, mostly 60 and over.
The research, published today in the Proceedings of the National Academy of Sciences, is primarily the work of scientists in the labs of Kenji Hashimoto, a professor with the Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan, and Bruce Hammock, UC Davis distinguished professor of entomology with a joint appointment in the UC Davis Comprehensive Cancer Center.
“Our research suggests that the sEH inhibitor may prevent the progression of Parkinson's disease (PD) as well as treat patients with dementia of Lewy bodies (DLB) if the sEH inhibitor is used in early phases of patients with these disorders,” said Hashimoto, whose career spans 30 years in the development of blood biomarkers and novel therapeutic drugs and includes more than 550 publications on the topic. “Both PD and DLB are chronic and progressive movement disorders. However, the precise causes of these diseases are largely unknown.”
Statistics indicate physicians diagnose 60,000 new cases of Parkinson's disease every year in the United States. The average age of onset is 60, and is more predominant among men.
Hammock said that the work by lead author Qian Ren and his colleagues in the Hashimoto lab “shows that markers and symptoms of Parkinson's disease in whole mice and in human cells with a mutation associated with Parkinson's disease can be treated with a small druglike molecule. By establishing this causal chain of events leading to Lewy body disorders we can better predict environmental chemicals that could predispose people to Parkinson's disease and possibly even treat the disease.”
The paper, titled “Soluble Epoxide Hydrolase Plays a Key Role in the Pathogenesis of Parkinson's Disease,” is co-authored by 14 scientists, including Professor Hammock and Jun Yang and Sung Hee Hwang, all part of the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
“Although there are many medications available to treat symptoms in PD, these do not prevent the progression of the disease, and, to date, no agent with a disease-modifying or neuroprotective indication for PD has been approved,” said Hashimoto. “Therefore, the development of new drugs possessing disease-modifying and /or neuroprotective properties is critical.”
In research studies involving mice, the scientists found “that sEH plays a key role in the inflammation associated with PD pathogenesis and the mechanisms that lead to the disease,” Hashimoto said. “The sEH inhibitor or deletion of the sEH gene protected against MPTP-induced neurotoxicity in mouse brain.” MPTP is an acronym for methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine, a relative of cyperquat and paraquat herbicides. “Our findings indicate that sEH inhibitors or epoxy fatty acids mimics may be promising prophylactic or therapeutic drugs for alpha-synuclein-related neurodegenerative disorders.”
Robert Higgins, emeritus professor of neuropathology at the UC Davis School of Veterinary Medicine, said: "I find it exciting that Ren and colleagues illustrate a promising path to a drug to prevent the progression of Parkinson's disease. It is impressive how far this work has come since we collaborated with Shirley Gee and the Hammock laboratory on developing a sheep model of Parkinson's disease in the early 1980s."
Neurosurgeon Cesar Borlongan of Morsani College of Medicine, University of South Florida, who was not involved in the study, praised the findings as advancing “our understanding of how Parkinson's disease evolves.” Describing Parkinson's disease as “a devastating brain disorder that mostly affects the aging population,” he said: “There is no cure, only relief from symptoms which include tremors, muscle rigidity, slurred speech, and freezing of gait.”
“While we know that a certain group of brain cells that produce dopamine are selectively destroyed in Parkinson's patients, what triggers this brain cell death remains poorly understood,” said Borlongan, a distinguished professor and vice chair for Research, Department of Neurosurgery and Brain Repair. “In their paper, the authors observed that a protein called soluble epoxide hydrolase (sEH) may be key to the demise of the brain dopamine cells. In small and large animal models of Parkinson's disease, and further confirmed in a group of PD patients, this protein is highly elevated in specific regions of the brain implicated in dopamine cell death.”
Borlongan pointed out that “Equally compelling evidence demonstrated that using a drug that inhibits sEH can reduce brain inflammation and levels of sEH and effectively lessen PD-associated toxicity in the animal models of the disease. Clinical trials of sEH inhibitors in heart and lung disease have been ongoing over the last decade, and may facilitate the entry of these drugs for PD. These results advance our understanding of how PD may evolve, but also point to its novel treatment.”
Qing Li, a professor in the Department of Molecular Biosciences and Bioengineering, College of Tropical Agriculture and Human Resources, University of Hawaii at Mānoa, who also was not involved in the study, called Parkinson's disease “a devastating neurodegenerative disorder that affects patients and caregivers alike with a significant economic burden in the United States and worldwide.”
This basic research drew support from several grants from Japan, including the Strategic Research Program for Brain Sciences, and at UC Davis, grants funded by the National Institute of Health's Institute of Environmental Health Sciences (NIH/NIEHS), and the NIEHS Superfund Program.
Hammock, a member of the National Academy of Sciences and the National Academy of Inventors, has directed the NIH/NIEH Superfund Program for more than 30 years.
Hammock said the soluble epoxide hydrolase inhibitors that inhibit the soluble epoxide hydrolase will soon enter human clinical trials supported by the NIH-NINDS Blueprint Program (NIH's Health's National Institute of Neurological Disorders and Stroke). “These drugs could provide relief for patients with a wide variety of inflammatory diseases,” he said.
The Hammock laboratory has published nearly 900 peer-reviewed papers on the sEH enzyme, discovered while Hammock and Sarjeet Gill (now of UC Riverside) were researching insect developmental biology and green insecticides at UC Berkeley. The work, begun in 1969, led to the discovery that many regulatory molecules are controlled as much by degradation as by biosynthesis, Hammock said. These epoxy fatty acid chemical mediators control blood pressure, fibrosis, immunity, tissue growth, and pain and inflammation.
To date, journals have published more than 17,000 peer-reviewed papers on the sEH enzyme and its inhibitors. Hammock credits the NIEHS for supporting his research in this area since the 1970s.
A Davis-based company, EicOsis, is developing inhibitors to sEH
to treat unmet medical needs in humans and animals. The company recently received a multi-million dollar grant from the NIH/NINDS Blueprint Program to move sEH inhibitors through phase I human clinical trials. “We are developing a non-opiate analgesic to treat the chronic pain often associated with diabetes,” said William Schmidt, vice president of clinical development at EicOsis. “Once we have investigational new drug status from the Food and Drug Administration and have finished our phase I trial, physicians will be able initiate their own trials with the EicOsis compound on Parkinson's disease and other Lewy body disorders.”
(Embargo lifts at noon, Pacific Time, April 30)
The research, published April 30 in the Proceedings of the National Academy of Sciences, indicates that inhibiting an enzyme, soluble epoxide hydrolase--discovered in the Bruce Hammock lab at UC Davis--may reduce the risk of obesity-related inflammation of the colon.
Co-first authors Weicang Wang and Jianan Zhang of the Guodong Zhang lab, Department of Food Science, University of Massachusetts (UMass) and Jun Yang of the Hammock lab and the UC Davis Comprehensive Cancer Center, noted that 30 percent of Americans are obese, and these individuals have a 30 to 60 percent higher risk of developing colon cancer. It is the third most common cancer and the second leading cause of cancer-related deaths in the United States. Colon inflammation is an early symptom of cancer.
“But to date, the mechanisms by which obesity increases cancer risks are not well understood, and there are few effective strategies to prevent obesity-enhanced colon cancer, said co-author Guodong Zhang, a former postdoctoral researcher in the Hammock lab and now an assistant professor of food science at UMass where he focuses his research on prevention of colonic inflammation (inflammatory bowel disease) and colon cancer.
“Our study showed that soluble epoxide hydrolase and its metabolites are over-expressed in colon of obese mice,” Zhang said. “In addition, we found that pharmacological inhibition or genetic deletion of soluble epoxide hydrolase (sEH) abolishes obesity-induced inflammation and activation of pro-tumorigenic pathways in colon. These results showed that sEH is an essential enzyme involved in obesity-enhanced colonic inflammation and potentially colon cancer, and pharmacological inhibitors of sEH could be novel agents for prevention of these diseases.”
In the study, the 18-member team, including five UC Davis researchers, investigated the roles of sEH in obesity-induced colonic inflammation, which included using two different sEH inhibitors and a knockout mouse genetically modified not to produce sEH. Results proved similar in all cases.
They further conducted another study in both lean and obese mice with experimentally induced colon inflammation and used molecular analyses to follow a pathway called Wnt. About 90 percent of sporadic colorectal cancers have activating mutations within the Wnt pathway. The team found that obesity increases activation of Wnt signaling in the colon, but it can be abolished by the two different inhibitors and the knockout.
“The sEH inhibitor blocked obesity-induced colon inflammation,” said co-author Bruce Hammock, distinguished professor of entomology who holds a joint appointment with the UC Davis Comprehensive Cancer Center. “This worked even for mice on high fat diets.”
“Colon inflammation is highly associated with a variety of diseases and the inflammation often progresses to colon cancer,” Hammock said. “Weicang Wang, Guodong Zhang and co-workers have done a meticulous job investigating the biologically active fats including fatty acid diols that are associated with the inflammation. By blocking the production of these diols they were able to block the inflammation.”
Co-authors Jun Yang, Debin Wan, Jia Sun of the Hammock lab, as well as Jun-Yan Liu of China, a former postdoctoral researcher in the Hammock lab, did the analytical chemistry, and co-author Sung Hee Hwang of the Hammock lab did the organic chemistry, making the compounds that were used.Jun-Yan Liu is already collecting human samples to test the hypothesis in man, Hammock revealed.
The soluble epoxide hydrolase inhibitors that block production of these diols will soon enter human clinical trials supported by the NIH-NINDS Blueprint Program (National Institutes of Health's National Institute of Neurological Disorders and Stroke). “These drugs could provide relief for patients with a wide variety of inflammatory bowel diseases and possibly reduce obesity driven colon cancer,” Hammock said.
The team hailed this as a promising treatment in humans, but acknowledged that “mice and humans are very different.” However, Jun-Yan Liu is already collecting human samples to extend the study, and Hammock pointed out that they hope that the soluble epoxide hydrolase inhibitor will be in human clinical trials this year.
“The study was an exciting discovery from lipidomics technique,” said co-lead author Jun Yang. “The consistent results from pharmacologic inhibition and genetic knockout (KO) as well as the signaling pathway mechanistic studies all support sEH as a potential treatment for obesity- induced colon inflammation. “
Noted pathologist Guang-Yu Yang, M.D., Ph.D. of the Feinberg School of Medicine, Northwestern University, Chicago, who was not involved in the study, observed that the Zhang and Hammock labs “have now sequentially demonstrated that 1) there is an increased expression of sEH and its eicosanoid metabolites in the colons of high fat diet-induced obese mice; and 2) the knockout or inhibition of sEH ablates obesity-induced colonic inflammation and decreases obesity-induced activation of Wnt signaling. This study raises interest in further investigating whether the ablation of obesity-induced colonic inflammation by sEH knockout or inhibition may lead to inhibition of obesity-promoted colorectal carcinogenesis.”
“Thus far, non-steroidal anti-inflammatory drugs (NSAIDs) and Cyclooxygenase 2 (COX-2) inhibitor (coxibs) have been the most promising agents for the prevention of colorectal cancer,” Yang said. “However, the side effect profile and risk of adverse events including gastrointestinal (GI) bleeding and cardiovascular events frequently prohibit their widespread clinical use.”
The pathologist said that “co-targeting sEH and COX-2 to manipulate eicosanoid metabolites has the high potential to synergistically enhance the inhibition of obesity-promoted inflammation and carcinogenesis while also reducing the adverse effects of coxibs and NSAIDs.”
The five UC Davis researchers—Bruce Hammock, Jun Yang, Jia Sun, and Sung Hee Hwang and Debin Wan—are all with the Hammock lab and the UC Davis Comprehensive Cancer Center.
Other UMass researchers were Yuxin Wang, Wiepeng Qi, Haixia Yang, and Professor Yeonhwa Park, Department of Food Science, Katherine. Sanidad, Food Science and Molecular and Cellular Biology Graduate Program, and Professor Daeyoung Kim ofthe Department of Mathematics and Statistics.
The abstract: “Obesity is associated with enhanced colonic inflammation, whichis a major risk factor for colorectal cancer. Considering the obesityepidemic in Western countries, it is important to identify noveltherapeutic targets for obesity-induced colonic inflammation, todevelop targeted strategies for prevention. Eicosanoids are endogenouslipid signaling molecules involved in regulating inflammationand immune responses. Using an LC-MS/MS–based lipidomics approach,we find that obesity-induced colonic inflammation is associatedwith increased expression of soluble epoxide hydrolase (sEH)and its eicosanoid metabolites, termed fatty acid diols, in colon tissue.Furthermore,we find that pharmacological inhibition or genetic ablation of sEH reduces colonic concentrations of fatty acid diols,attenuates obesity-induced colonic inflammation, and decreasesobesity-induced activation ofWnt signaling in mice. Together, theseresults support that sEH could be a novel therapeutic target forobesity-induced colonic inflammation and associated diseases.”
This work, titled “Lipidomic Profiling Reveals Soluble Epoxide Hydrolase as a Therapeutic Target of Obesity-Induced Colonic Inflammation,” drew grant support from the USDA's National Institute for Food and Agriculture; National Institutes of Health's National Institute of Environmental HealthSciences (NIH/NIEHS); NIEHS Superfund Research Program, and the National Natural Science Foundation of China.
Hammock, a member of the National Academy of Sciences and the National Academy of Inventors, directs two major UC Davis programs; the Superfund Program financed by the National Institute of Environmental Health's National Institute of Environmental Health Sciences (NIH-NIEHS); and the NIH Biotechnology Training Program.
The Hammock laboratory has published almost 900 peer-reviewed papers on the sEH enzyme, discovered while Hammock and Sarjeet Gill (now of UC Riverside) were researching insect developmental biology and green insecticides at UC Berkeley. The work, begun in 1969, led to the discovery that many regulatory molecules are controlled as much by degradation as by biosynthesis, Hammock said. These epoxy fatty acid chemical mediators control blood pressure, fibrosis, immunity, tissue growth, and pain and inflammation.
For many years Gill and Hammock were alone in studying this enzyme but today its importance is well recognized in mammalian biology, with more than 17,000 peer-reviewed papers in the area. Hammock credits the NIEHS for supporting research in this area since the 1970s.
A Davis-based company, EicOsis, has received a large grant from the U.S. National Institutes of Health to move inhibitors to the clinic to treat diabetic neuropathic pain. “We are developing a non opiate analgesic to treat the chronic pain often associated with diabetes and hope to be in human trials over the next 12 months,” said William Schmidt, vice president of clinical development at EicOsis.
Newly published research by an international team of scientists, headed by the Jun-Yan Liu lab of Tongji University, Shanghai, China, and the Bruce Hammock lab at the University of California, Davis, may provide promising therapeutic strategies for those suffering from acute kidney injury (AKI), formerly called acute renal failure.
AKI, common in hospitalized patients—especially among older adults in intensive care--occurs when the kidneys suddenly fail to filter waste products from the blood. Many of these patients do not recover or require dialysis or transplantation, or partly recover and are thus at risk for worsening kidney disease.
The paper, published in the current edition of the Proceedings of the National Academy of Sciences, found that a small molecule inhibitor of soluble epoxide hydrolase developed in the Hammock lab at UC Davis, helped alleviate AKI in mice and prolonged their lives.
“The soluble epoxide hydrolase or sEH degrades chemically stable fatty acid epoxides,” explained Hammock, a UC Davis distinguished professor who holds a joint appointment in the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “But sometimes it can be useful to block the function of sEH, so that beneficial fatty acid epoxides, like those from omega-3 and omega-6 fatty acids, are not degraded. These fatty acid epoxides have been found to protect the kidney, reduce inflammation, inflammatory pain, and even chronic or neuropathic pain.”
In general, the epoxides of docosahexaenoic acid (DHA) from fish oil make the soluble epoxide hydrolase inhibitors even more effective, the Hammock lab has found. “However, in this case, the fish oil seemed to be deleterious rather than beneficial when combined with the sEH inhibitors with kidney injury,” Hammock said. This was unexpected and the investigators caution that fish oil may not always have beneficial effects.
Professor Jun-Yan Liu, a former postgraduate researcher and assistant project scientist in the Hammock lab, related that the lipid mediators that preserve the kidney in AKI are termed EETs. “Their levels can be changed by altering their degradation or biosynthesis with selective inhibitors. This increase in EET resulted in anticipated decreases in the plasma level of creatinine and urea nitrogen—both biomarkers for kidney injury.” He added that they are looking forward to the epoxide hydrolase inhibitors finishing phase I clinical trials in humans so they can be evaluated for preventing or treating AKI.
Specifically, the researchers discovered that a 14(15)-EET mitigated kidney injury and prolonged life, while another epoxide, 19(20)-EDP from fish oil, exacerbated the kidney injury and shortened life. “We found that epoxides of docosahexaenoic acid (DHA) and DHA-enriched fish oil worsened kidney injury prophylactically and therapeutically in multiple animal models of AKI,” wrote Liu, pointing out that fish oil has proven beneficial in a number of other investigations.
Statistics show that “the incidence of AKI in hospitalized patients increased dramatically from 4.9 percent in 1983 to 20 percent in 2012,” the researchers wrote in their paper. “The mortality from AKI is greater than 50 percent; worldwide, approximately 2 million people die of AKI every year. Therefore, novel, safe and effective approaches are urgently needed to prevent and treat AKI.”
“Because AKI has no specific effective therapy and treatment is merely supportive frequently requiring hemodialysis any new treatment or therapeutic paradigm would be welcome in the nephrology community and has the potential to improve the lives of many patients with AKI,” said kidney expert Dr. Robert Weiss, a professor of medicine in the UC Davis Division of Nephrology, who was not involved in the research.
Kidney injury expert Alan Parrish of the University of Missouri's School of Medicine, Columbia, also not involved in the research, called the findings “significant.”
“The collaborative studies between Dr. Liu's and Hammock's group are an elegant, and timely, contribution to our understanding of acute kidney injury (AKI),” said Parrish, vice chair for education and director of Graduate Studies for Medical Pharmacology at the medical school. “AKI has potentially devastating short-term consequences - high mortality - as well as the detrimental long-term impact on renal function. Importantly, specific interventions to treat AKI in patients have not yet been identified. These results are significant in that they provide a unique mechanistic insight into pathways targeted by soluble epoxide hydrolase inhibitors that attenuate AKI, providing a powerful rationale for future clinical trials in AKI patients.”
The paper is the work of scientists led by Jun-Yan Liu from the Center for the Nephrology and Metabolomics and Division of Nephrology and Rheumatology, Tongji University School of Medicine, Shanghai, China: Bing-Qing Deng, Ying Luo, Xin Kang, Chang-Bin Li, Jian Huang, Da-Yong Hu, Ming-Yu Wu, and Ai Peng; and Hammock and his lab researchers Jun Yang, Christophe Morrisseau, Kin Sing Stephen Lee at UC Davis.