- Author: Kathy Keatley Garvey
A blood plasma biomarker discovered in hospitalized COVID-19 patients may not only predict the severity of adult respiratory distress syndrome (ARDS) but further research may lead to inhibiting the progression, a team of eight University of California researchers announced today.
The UC researchers, primarily from the laboratory of UC Davis distinguished professor Bruce Hammock, found that four compounds in the blood of COVID-19 patients are highly associated with the disease. Their paper, “Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections,” is published as open access in the current edition of Frontiers in Physiology.
ARDS, characterized by fluid build-up in the lungs, is the second leading cause of death in COVID-19 patients, next to viral pneumonia, according to the National Center for Biotechnology Information.
“Different outcomes from COVID-19 infections are both terrifying from a human health perspective and fascinating from a research perspective,” said UC Davis lead author and doctoral candidate Cindy McReynolds of the Hammock lab. “Our data provide an important clue to help determine what impacts the severity of COVID-19 outcomes. Initially, we focused on the immune response and cytokine profile as important drivers in severity, but considering what we now know from our study and others in the field, lipid mediators may be the missing link to answering questions such as why some people are asymptomatic while others die, or why some disease resolves quickly while others suffer from long-haul COVID.”
The compounds, known as leukotoxins and leukotoxin diols, originate from linoleic acid, the body's most abundant dietary fat, said Hammock, who holds a joint appointment in the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center and directs the National Institute of Environmental Health Sciences (NEIHS) Superfund Research Program at UC Davis. “The leukotoxins (also called EpOMEs) are converted to the leukotoxin diols (also called DiHOMES) by the soluble epoxide hydrolase we work on.”
“So the leukotoxins and leukotoxin diols,” Hammock said, “are indicators of respiratory problems in COVID-19 patients as plasma biomarkers. They also present a pathway for reducing ARDS in COVID-19 if we could inhibit the soluble epoxide hydrolase, a key regulatory enzyme involved in the metabolism of immune resolving fatty acids.”
Professor John Imig, director and eminent scholar of the Medical College of Wisconsin's Drug Discovery Center, who was not involved in the study, said: “The COVID-19 pandemic has demonstrated that coronaviruses can have deadly consequences. Lung distress is a major reason for death in COVID-19 patients infected with the coronavirus (SARS-CoV-2). The findings of McReynolds et al. identified lipids called leukotoxin diols in the blood of COVID-19 patients that could act as a biomarker for lung distress. In addition, leukotoxin diols could be responsible for lung distress in COVID-19 patients. Excitingly, this suggest that therapies to lower leukotoxin diols could treat lung distress and prevent death in COVID-19 patients.”
“The findings presented in this paper bring important attention to a role for oxylipin metabolites in COVID-19 infections,” said Professor A. Daniel Jones of Michigan State University's Department of Biochemistry and Molecular Biology and director of the university's Research Technology Facility's Mass Spectrometry and Metabolomics Core. “Most notably, metabolites known as DiHOMEs which have been previously implicated in lung inflammation show promise for their potential to predict outcomes in COVID patients and guide therapeutic, and perhaps dietary interventions beneficial to human populations.” Jones, who was not involved in the study, serves as secretary of the Metabolomics Association of North America.
The UC Davis scientists used clinical data collected from six patients with laboratory-confirmed SARS-CoV-2 infection and admitted to the UC Davis Medical Center, Sacramento, and 44 healthy samples carefully chosen from the healthy control arm of a recently completed clinical study.
The Hammock lab's 50-year research on soluble epoxide hydrolase (sEH) and its inhibitors led the professor to found and direct EicOsis Human Health, a Davis-based company that is developing a potent soluble epoxide hydrolase inhibitor for pain relief. Epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, depression, pain, inflammation and other processes.
But more recently, the Hammock lab has turned its attention to using sEH as a means to resolve inflammation associated with COVID-19 and the fibrosis that can follow.
Lipid metabolism researcher Ameer Taha of the UC Davis Department of Food Science and Technology pointed out that linoleic acid is an essential fatty acid present in only small amounts in our evolutionary diets. “In addition to nutritional and structural roles of linoleate, minor linoleate metabolites including the leukotoxin diols (also known as DiHOMEs) regulate a number functions including body temperature, cardiac health and vascular permeability. This study cautions that now with dietary linoleate levels at an all-time high, in periods of high stress as with COVID-19, these regulatory functions may become detrimental.”
The paper is the work of Hammock, McReynolds and Jun Yang of the Department of Entomology and Nematology and EicOsis Human Health; Irene Cortes-Puch of the Department of Entomology and Nematology, EicOsis Human Health, and the Department of Internal Medicine's Division of Pulmonary Critical Care and Sleep Medicine; Resmi Ravindran and Imran Khan of the Department of Pathology and Laboratory Medicine; Bruce G. Hammock of UC Davis Department of Veterinary Medicine, Aquatic Health; and Pei-an Betty Shih of the UC San Diego Department of Psychiatry.
“This study resulted from an exciting collaboration with Imran Khan and Angela Haczku of the UC Davis School of Medicine to identify potential biomarkers for differentiating the severity of COVID-19 diseases,” said Yang, the corresponding author.
The research drew financial support from several National Institutes of Health agencies: National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program and R35 grant, National Institute of General Medical Sciences (NIGMS),and the National Institute of Mental Health (NIMH).
Resources:
- EicOsis: Developing a New Approach to Treat Pain
- Bruce Hammock: Lifetime Achievement Award from the Chancellor
- Cindy McReynolds Receives Major NIH Training Grant
- Cancer Team's Research Paper Named Journal of Clinical Investigation's Editor's Pick (Includes Bruce Hammock and Jun Yang)
Contacts:
- Bruce Hammock at bdhammock@ucdavis.edu
- Cindy McReynolds at cbmcreynolds@eicosis.com or cbmcreynolds@ucdavis.edu
- Jun Yang at junyang@ucdavis.edu
- Author: Kathy Keatley Garvey
The paper, which indicates that a brain enzyme could play a key role in curbing or preventing the progression of Parkinson's disease, is one of four singled out as exemplary on the NIEHS website.
“This could be a “revolutionary paper that could cure Parkinson's disease,” commented co-author Bruce Hammock, a UC Davis distinguished professor of entomology with a joint appointment with the UC Davis Comprehensive Cancer Center. He is the 30-year director of the UC Davis NIEHS Superfund Program, which helped fund the research. "A related compound to the drug used in the paper will enter human safety trials sponsored by NIH in early 2019."
The team of 14 scientists demonstrated that inhibiting the enzyme soluble epoxide hydrolase (sEH) compound in mice helped curb the inflammation associated with the development and progression of Parkinson's disease (PD), an age-related brain disorder that affects a million Americans, mostly 60 and over.
The researchers exposed mice to methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine (MPTP), a neurotoxicant that leads to symptoms of PD in animals. They found two approaches that protected against MPTP-induced neurotoxicity in the mouse brain--adding a potent sEH inhibitor, and genetically modifying mice to not produce sEH.
“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.” Lead author was Qian Ren of the Hashimoto lab.
Hammock and a colleague Sarjeet Gill (now of UC Riverside) discovered the sEH enzyme in a UC Berkeley lab while they were researching insect developmental biology and green insecticides. 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.
The Hammock laboratory has published nearly 900 peer-reviewed papers on the sEH enzyme. To date, journals have published more than 17,000 peer-reviewed papers on the sEH enzyme and its inhibitors. Hammock credits the NIEHS with 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.”
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,” said Hammock, who is a member of the National Academy of Sciences and the National Academy of Inventors.
Resources:
- See initial news story on UC Davis Department of Entomology and Nematology website
- See PNAS paper
- Author: Kathy Keatley Garvey
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.”
- Author: Kathy Keatley Garvey
(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.
- Author: Kathy Keatley Garvey
Researchers at the Huazhong University of Science and Technology, Wuhan China, used the drug developed at UC Davis to show that the neurofibrillary pathology of an Alzheimer's disease-related protein could be dramatically reduced. Their work was published in December in the Journal of Huazhong University of Science and Technology.
“They further demonstrated the mechanism of action of the UC Davis drug in blocking the oxidative stress-driven phosphorylation events associated with Alzheimer's disease,” Hammock said. The UC Davis drug stabilizes natural anti-inflammatory mediators by inhibiting an enzyme called soluble epoxide hydrolase (sEH) discovered at UC Davis and recently spotlighted in the Proceedings of the National Academy of Sciences and the National Institutes of Health's PubMed.
“I was thrilled to see this paper on tau phosphorylation from Huazhong University shows that our drug could block a key event and a key enzyme called GSK-3 beta thought critical in the development of Alzheimer's disease,” said Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
“We were planning to do this study, but having another laboratory do it with our compound was even better,” he said. “Since our publication last year in PNAS that showed UC Davis soluble epoxide hydrolase inhibitors both prevented and reversed depression, we have been excited about trying to block the development of Alzheimer's disease.”
The PNAS paper, “Gene Deficiency and Pharmacological Inhibition of Soluble Epoxide Hydrolase Confers Resilience to Repeated Social Defeat Stress,” was co-authored by a 13-member research team led by Hammock and Kenji Hashimoto of Chiba University Center's Division of Clinical Neuroscience, Japan. They found that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression and several other disorders of the central nervous system. Co-authors of the paper included Hammock lab researchers Christophe Morisseau, Jun Yang and Karen Wagner.
Hammock credited several UC Davis colleagues for their work leading to the publications. Research from the labs of Liang Zhang and Qing Li at the University of Hawaii--Qing is a former UC Davis doctoral student--pointed out some of the mechanisms involved in cognitive decline which associate professor Aldrin Gomes of the UC Davis Department of Neurobiology, Physiology and Behavior and Fawaz Haj of the UC Davis Department of Nutrition “have shown to be blocked by the natural metabolites stabilized by the UC Davis drugs,” Hammock said.
One of the Hammock lab drugs is moving toward human clinical trials for neuropathic pain through a Davis-based company, EicOsis, LLC, and the financial support of the Blueprint Program through NIH's National Institute of Neurological Disorders and Stroke. Hammock founded the company to develop inhibitors to the soluble epoxide hydrolase, a key regulatory enzyme involved in the metabolism of fatty acids, to treat unmet medical needs in human and animals.
“The clinical back-up candidate at EicOsis penetrates the blood brain barrier and should be a perfect compound to test if this class of chemistry can prevent cognitive decline and Alzheimer's disease,” Hammock said.
The National Institute of Environmental Health Sciences, National Institutes of Health, funded the research.
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 the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. He directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.