- Author: Kathy Keatley Garvey
Professor Denison, who retired in 2018, joined the department in 1992 and advanced to professor in 1997. He served as a researcher in the UC Davis SRP, funded by National Institute of Environmental Health Sciences (NIEHS), for more than 25 years.
Over a 44-year period, Denison focused his research on understanding the molecular mechanisms by which a protein known as the Ah receptor mediates the biological/toxicological actions of dioxins and related chemicals. He was widely acclaimed for his development of the Chemical Activated LUciferase gene eXpression (CALUX) assay, a cell-based bioassay used to detect specific environmental contaminants, including, but not limited, to dioxin-like chemicals and environmental hormones (endocrine disruptors).
The test, approved by the intergovernmental Organization of Economic Cooperation and the U.S. Department of Environmental Protection Agency, is the international standard for detecting environmental contaminants in the protection of human health. Denison also made other seminal contributions to the Ah receptor field and was a leader in advancing the study of Ah receptor biology, said UC Davis distinguished professor Bruce Hammock, the founding director of UC Davis SRP and a close friend and colleague of Denison's.
“He is best possibly known for his fundamental work on the mechanism of action of TCDD and the translation of this knowledge into a quantitative, rapid and inexpensive assays for tetrachlorodioxin like chemicals and other chemicals that bound to the aryl hydrocarbon hydroxylase receptor," Hammock said. "He went on to use the CALUX format to measure a number of other small molecule receptor interactions. Mike was also funded for much of his career by competitive grants from NIEHS, including his MS and PhD work.”
Robert Rice, professor and chair of the Department of Environmental Toxicology, said that "Mike's absence leaves quite a void in our department. Even in retirement, he continued to be a source of wisdom and amusement, and he was still an inspiration to students."
Rice added that he first met Denison in 1992 when he joined the faculty, "and I ended up being department chair in recent years after he declined the position."
Denison, trained in biology, marine biology, animal physiology and environmental toxicology, received his associate of arts degree in biology from the County College of Morris, N.J. in 1975, and his bachelor's degree in marine biology from St. Francis College, Biddeford, Maine, in 1977. He obtained his master's degree in animal physiology from Mississippi State University, Starkville, in 1980, and went on to receive his doctorate in environmental toxicology from Cornell University, Ithaca, N.Y., in 1983. Denison did postdoctoral research at the Department of Clinical Pharmacology, Hospital for Sick Children, Toronto, Canada, from 1983 to 1985, and with Stanford University's Department of Pharmacology, 1985-1988.
Denison began his academic career as an assistant professor in the Department of Biochemistry at Michigan State University, East Lansing, from 1988 to 1992, and then relocated to the UC Davis Department of Environmental Toxicology.
Michael and his twin brother, Steven, were born on Dec. 8, 1954, in Shirley, Mass., the sons of Alan (deceased) and Alma Denison. While the father served in the U.S. Army, the family lived in numerous places around the world and settled in Wharton, N.J. when boys were 11.
“Michael was a happy and optimistic person,” said his widow Grace Bedoian, who retired in 2014 as a UC Davis SRP administrator and a member of the Hammock lab. “The only thing he took seriously was science, which he loved."
“His typical day was spent at work, conducting his research and mentoring students, returning home and making a wonderful dinner at the end of the day, and then retreating to his home office to work until the wee hours of the following morning," she said. "He maintained curiosity and wonder of the world around him. He loved to solve problems and figure out how things worked. He was generous with his friends and colleagues alike and always quick to offer his services to those in need."
Denison is survived by his widow, Grace; his mother, Alma; two brothers (Steven and Daniel) and their wives (Gloria and Angela); two nieces, two nephews, and several grandnephews.
The family thanks the staff at Yolo Cares of Davis for “their exceptional expertise, kindness and compassion in providing in-home hospice care for Michael. All of the staff members at Yolo Cares are truly angels on this earth.” In lieu of flowers, donations may be made to Yolo Cares by contacting (530) 758-5566 or http://www.yolocares.org.
Donations also may be made to the Michael S. Denison, Ph.D. '83 Environmental Toxicology Research Fund, an endowment created at Cornell University by a colleague. Checks payable to Cornell University may be mailed to Cornell University, Box 37334, Boone, IA 50037-0334. In the memo field or in the correspondence, donors are asked to add: Michael S. Denison, Ph.D. '83 Environmental Toxicology Research Fund #0018594. Online gifts can be made at https://giving.cornell.edu/, notating Michael S. Denison, Ph.D. '83 Environmental Toxicology Research Fund #0018594 on the online giving form. ChristyAgnese, director of development in the College of Agriculture and Life Sciences, Cornell University, may be contacted at (607) 279-6884 for further assistance.
- Author: Kathy Keatley Garvey
Every year some 10,000 burn victims in the United States undergo an acute inflammatory reaction and die of burn-related infections, according to the Centers for Disease Control and Prevention.
Now a newly published study by a research team from the laboratory of distinguished professor Bruce Hammock, University of California, Davis, and the Department of Surgery, University of Cincinnati College of Medicine (UC CoM), has identified a key regulatory mechanism in inflammation that may lead to new targets for resolving that inflammation—and the inflammation of patients with sepsis, cancer and COVID.
In research published in the current edition of Proceedings of the Natural Academy of Sciences, the scientists announced that they have discovered a pathway that regulates the immune response after infection or injury, such as burns. Dysregulation of this pathway could differentiate those who are at risk of fatal sepsis or help identify targets to resolve this unregulated inflammation.
“We are very excited about the findings in this paper and the far-reaching impacts it could have on understanding a key regulatory step in the immune response,” said co-lead author and researcher Cindy McReynolds of the Hammock lab and director of research at EicOsis, a Davis-based company founded by Hammock. Hammock, the corresponding author of the publication, has been involved in enzyme research for more than 50 years.
“Our previous work identified that these same lipid mediators were up-regulated in severe COVID infections, and we are now finding that these compounds play a role in modulating the immune response so that the body is unable to fight infection or respond properly to trauma without leading to a potentially fatal overreaction,” said McReynolds, who holds a doctorate in pharmacology and toxicology from UC Davis.
“The immunological disbalance we see in many cases of severe burn injury, trauma and sepsis pose a huge clinical challenge as we lack the understanding of how to diagnose and treat it,” said co-lead author Dr. Christian Bergmann, formerly with UC CoM's Department of Surgery and now headquartered in Germany with the University of Ulm's Department of Trauma Surgery, Hand, Plastic and Reconstructive Surgery. “With this work, we reveal an important mechanism how immune cells are functionally disabled by sEH-derived metabolites of linoleic acid.”
“The natural compounds we are studying in this paper are metabolites of linoleic acid (LA), an essential fatty acid the body needs in very small amounts to survive and is only available through the diet,” McReynolds explained. “At lower concentrations, these metabolites are necessary for regulating thermogenesis and heart health but promote inflammation at higher concentrations. LA is more stable and much cheaper than longer chain polyunsaturated fatty acids, so heavily processed foods have higher LA content to increase shelf-life. Additionally, agricultural practices, such as feeding animals corn-based diets, have increased LA in meats and dairy products.”
The research, titled "sEH-Derived Metabolites of Linoleic Acid Drive Pathologic Inflammation while Impairing Key Innate Immune Cell Function in Burn Injury,” is co-authored by Debin Wan, formerly of the Hammock lab and now a scientist at Escape Bio, San Francisco; Nalin Singh of the Hammock lab; and three UC CoM researchers: Charles Caldwell, professor and director, Division of Research, Department of Surgery; Dorothy Supp, adjunct professor in the Department of Surgery and a scientific staff member at Shriners Children's Ohio; and Holly Goetzman, principal research assistant in the Caldwell lab.
“Chronic pain is an enormous emotional and economic burden for more than 100 million people in the United States alone,” said co-author Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. "The extreme and poorly treated pain that I observed as a medical officer working in a burn clinic in the Army, is a major driver for me to translate laboratory research to help patients with severe pain and at risk from sepsis." Another major influence: his mother served 15 years as a nurse in a children's hospital burn center, caring for hundreds of patients.
Hammock founded EicOsis in December 2011 to advance novel, safe and effective oral treatments for patients suffering from pain and inflammation. The LLC is developing a new class of oral non-narcotic analgesics based on inhibition of the soluble epoxide hydrolase enzyme. Human clinical trials are underway to test the drug candidate, EC5026, a first-in-class, small molecule that potently inhibits sEH. The sEH inhibitors have already shown to be effective for inflammatory and neuropathic pain in animals, with no apparent adverse or addictive reactions.
Several grants supported the research: Dr. Bergmann received a grant from Deutsche Forschungsgemeinschaft (German Research Foundation) and a National Institutes of Health (NIH) grant from the National Institute of General Medical Sciences (NIGMS); Supp, a grant from the Shriners Hospitals for Children; and Hammock, a RIVER (Revolutionizing Innovative Visionary, Environmental Health) grant from the NIH's National Institute of Environmental Health (NIEHS), and an NIH/NIEHS Superfund Program grant. Hammock has directed the UC Davis Superfund Program for nearly four decades.
Resources:
- PNAS paper
- UC Davis distinguished professor Bruce Hammock, bdhammock@ucdavis.edu
- Author: Kathy Keatley Garvey
“We show that both activities of soluble epoxide hydrolase enzyme (sEH), the center of 50 years work in the Hammock laboratory, and a second integrated phosphatase activity, discovered by us 20 years ago in the same protein, have complementary biological action in vivo, with implications in cardiac biology,” said biochemist and co-author Christophe Morisseau of the Hammock lab who researches the biology and pharmaceutical applications of epoxide hydrolase inhibition in diabetes, pulmonary and cardiovascular diseases.
The research paper, titled “CRISPR/Cas9-mediated Inactivation of the Phosphatase Activity of Soluble Epoxide 1 Hydrolase Prevents Obesity and Cardiac Ischemic Injury,” involved recombinant animal models.
The abstract reads: “Although the physiological role of the C-terminal hydrolase domain of the soluble epoxide hydrolase (sEH-H) is well investigated, the function of its N-terminal phosphatase activity (sEH-P) remains unknown. This study aimed to assess in vivo the physiological role of sEH-P.”
“Such di catalytic activities of separate enzymes jointed during the evolutionary process have been said a Rosetta stone for understanding cell biology,” said co-author Hammock, a UC Davis distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. For the past 50 years, the Hammock lab has been studying sEH inhibitors, leading to drugs that target such diseases as diabetes, hypertension (heart disease), Alzheimer's disease, and cancer. Co-discovered by Hammock and Sarjeet Gill, now a UC Davis distinguished professor at UC Riverside, sEH is a key regulatory enzyme involved in the metabolism of fatty acids.
The work of the UC Davis-French team collaboration may have implications in major diseases of the circulatory system, including atherosclerosis, coronary artery disease, stroke, and hypertension. Research shows that patients with diabetes, obesity, dyslipidemia, cancer, fibrosis, and sepsis have a significant increase in the risk and incidence of cardiovascular disease.
Bellien, a professor in the Department of Pharmacology who holds a doctorate in pharmacology from the Rouen University School of Pharmacy, heads a research group on endothelial protection within INSERM U1096. The endothelium is a thin membrane that lines the inside of the heart and blood vessels. Bellien and his team study the role of endothelial lipid mediators in the pathophysiology of cardiovascular diseases, and notably to study new approaches to treat vascular and valvular calcification. They have been collaborating with the UC Davis team since 2014.
- Author: Kathy Keatley Garvey
The Academic Senate, acknowledging that the University of California “has a long tradition of service to the state and the people of California” and that “faculty members use their expertise in teaching, research, and professional competence to make unpaid contributions to local, statewide, national, or international public arenas,” annually singles out an exceptional faculty member who “continues the tradition and demonstrate the commitment of UC Davis to public service.”
“Distinguished Professor Walter Leal helped to address the critical need for accurate and accessible COVID-19 information,” according to the Academic Senate notice. “He conceptualized, organized, and moderated four COVID-19 symposia for the public. Through meticulous research, he brought together physicians, former patients, and public health experts to provide the most up-to-date information early in the pandemic, including highlighting equity gaps in treatment.”
“Professor Leal dedicated much of his sabbatical time to developing valuable public resources, thus providing high-quality information during a time of rampant misinformation,” the Academic Senate related. “He also champions global learning, putting long-term efforts into global collaborations to enhance education.”
Gov. Gavin Newsom's issued a stay-at-home order on March 19, 2020, and the following day, UC Davis Chancellor Gary May told the campus community: “Most of our employees should already be at home where the governor wants you to be, and where we want you to be, for the sake of your own health and to help limit the spread of the coronavirus.”
“On March 22 came the first reported death from COVID in Yolo County,” wrote Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “On April 23, Distinguished Professor Walter Leal, as a timely service to the UC Davis community and the general public, organized and moderated the first of his COVID-19 symposiums. What Dr. Leal did, and did so well in the throes of the raging pandemic, was to help the UC Davis community and the general public understand a disease that would go on to claim the lives of nearly 800,000 Americans. Two weeks prior to each symposium, he worked daily from 5 a.m. to 11 p.m., reading the scientific literature, interviewing experts, lining up the speakers; gathering relevant questions from the public, and generally, taking care of all the logistics."
You Are My Heroes. The webinars drew scores of comments. “You are my heroes,” wrote one viewer. “This [the symposium] gave me a sense of hope and calmed my anxiety like nothing else. Part of what has been so hard is all the disinformation and complete lies and contradictions that are happening daily. To hear people, real doctors and scientists who are knowledgeable talk about what is going on and why is so appreciated! I learned so much; wish you were the ones leading [our] government through this! Having a family zoom tonight to relay the info! I (offer) much gratitude to UC Davis! My husband says ditto.”
Professor Leal's plans for a single webinar quickly grew to three more to meet the growing demand of information and translation.
“Few are aware that Dr. Leal interrupted his sabbatical leave to complete his mission,” Hammock pointed out. “Personally, this was not unusual. Having known Dr. Leal for more than two decades, I am fully aware of how altruistic and dedicated he is. He firmly believes that a primary mission of a land-grant university is to serve the public.”
A native of Brazil and fluent in three languages, Leal was educated in Brazil, Japan and the United States, pursuing the scientific fields of chemical engineering, agricultural chemistry, applied biochemistry, entomology and chemical ecology. After serving in a leadership capacity in Japan's Ministry of Agriculture, Forestry, and Fisheries for five years, he joined the Department of Entomology faculty in 2000. Leal chaired the department from 2002 to 2013 before accepting an appointment as a professor of biochemistry with the Department of Molecular and Cellular Biology.
Widely known for his research, teaching and mentorships, Leal is an elected Fellow of the National Academy of Inventors, American Association for the Advancement of Science, California Academy of Sciences, Royal Entomological Society and the Entomological Society of America (ESA). The UC Davis Academic Senate named him the recipient of its 2020 Distinguished Teaching Award for Undergraduate Teaching, and the Pacific Branch of ESA presented him with its 2020 Award of Excellent in Teaching.
A Treasured Note. Leal treasures a handwritten note from a 12-year-old boy, who (according to his mother) was struggling with autism. “Dear Scientist, I hope you can make the vaccine for the coronavirus and to make us live forever,” the boy wrote. “And you can do it. We believe in you. Love XX.”
His mother updated the UC Davis professor in the fall of 2021: “ (XX) wanted me to tell you that he feels so much safer now that he has the vaccine! He is so thankful for all the scientists working so hard to find a solution to make the world safer and continue researching to prevent additional variant outbreaks. He is back in school full time now and is enjoying being able to be with his teachers and classmates.”
- Author: Kathy Keatley Garvey
A natural product from the dried root of a pea-family plant, potentially combined with an enzyme inhibitor discovered in the Bruce Hammock laboratory at the University of California, Davis, may provide hope in alleviating neuroinflammation in Parkinson's disease, an eight-member team of researchers from Dalian Medical University, China, and UC Davis announced today.
Their novel research, published in the current edition of the Proceedings of the National Academy of Sciences (PNAS), shows that a soluble epoxide hydrolase (sEH) inhibitor and kurarinone, a compound from the dried root of Sophora flavescens, reduced neuroinflammation in an animal model with Parkinson's disease (PD). The dried root, also known as kushen in Chinese, has been used for hundreds of years in traditional Chinese medicines.
“Traditional Chinese medicines play an immeasurable role in the treatment of all kinds of diseases,” said thelead researcher Cheng-Peng Sun, a Dalian Medical University associate professor who is partnering with the Hammock lab on the PD research. For the past 35 years, Hammock, a distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, has researched enzyme inhibitors that dramatically reduce inflammation, inflammatory pain and neuropathic pain.
“We investigated the neuroprotective effects of S. flavescens in Parkinson's disease based on the neuroinflammation,” Sun explained. “Our extensive studies indicated that kurarinone possesses several pharmacological effects, including anti-inflammatory and antioxidative activities.”
The research, titled “Kurarinone Alleviated Parkinson's Disease via Stabilization of Epoxyeicosatrienoic Acids in Animal Model (Mice),” may lead to an effective therapy for PD, a progressive neurogenerative or brain disorder which affects more than 10 million people worldwide, including a million in the United States, according to the Mayo Clinic. Most PD patients are 65 or over and most are men. There is no cure.
“Basically, kurarinone targets the soluble epoxide hydrolase (sEH), which is a key regulatory enzyme involved in the metabolism of fatty acids, and inhibitors of the sEH enzyme resolve neuroinflammation,” said Professor Hammock, corresponding author. “The enzyme regulates a newly studied class of natural chemical mediators, which in turn regulates inflammation, blood pressure and pain.”
“We have known for a number of years that the soluble epoxide hydrolase inhibitors, now in human safety trials, are active in reducing the development of Parkinson's disease in several rodent models,” Hammock said. “The evidence for this is quite strong, particular based on work of our longterm collaborator Kenji Hashimoto at Chiba University in Japan. Certainly, Parkinson's disease is one of our targets for the sEH inhibitors, but the regulatory path is slow and expensive. This path becomes much faster for a natural product, so the discovery of this natural product from Cheng-Peng's laboratory potentially offers relief to patients far faster than a classical pharmaceutical.”
“In addition to its use as a natural product for treating Parkinson's disease, kurarinone provides a new model for the design of still more active compounds to block the neuroinflammation associated with multiple neurodegenerative diseases where sEH inhibitors have shown efficacy in rodent models including Alzheimer's, autism, and other disorders,” Hammock said. “The fact that kurarinone binds in the sEH enzyme in an adjacent but non-identical site opens the door to new synthetic drugs for these diseases.”
Co-author Christophe Morisseau, a biochemist in the Hammock lab, performed the enzyme kinetics, demonstrating the potency of the compound and how it interacts with the enzyme. “This research is important in two ways,” he said. “In lay terms, it demonstrates the use of a natural compound to treat Parkinson's disease. Right now, there is no effective treatment for this disease, so this is pretty cool. And we show that the compound used has a novel mechanism of inhibiting sEH compared to the previous inhibitors published.”
UC Davis Health System neurologist and School of Medicine Professor Lin Zhang, who is known for his PD expertise (he was not involved in the study), praised the research as novel and “Although we now have multiple medications to manage the debilitating symptoms of Parkinson's disease, we still don't have a way to stop the progression of the disease, not to mention having a cure,” said Zhang, who treats PD patients. “The conventional wisdom believes the reason for that is that we have been only treating the symptoms, not the cause of the disease. One of the contributing causes, as evidenced recently, has been neuroinflammation.”
A common Parkinson model comes from mice treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Tragically this deadly drug was discovered as an impurity in a recreational “This paper shows that when parkinsonian mice were treated with the natural product kurarinone, their Parkinson-like behaviors were significantly alleviated by attenuation of neurotoxicity,” Zhang said. “The same natural product was able to suppress sEH activities selectively so much so that neuroinflammation was markedly ameliorated. Furthermore, when the same models had their sEH gene knocked out, kurarinone did not provide additional protection against Parkinsonism.”
“This paper shows that kurarinone, a natural product, is able to alleviate Parkinson symptoms,” Zhang pointed out. “The mechanism for that has something to do with the fact that kurarinone targets soluble epoxide hydrolase (sEH) which mediates neuroinflammation. Products capable of inhibiting sEH like kurarinone can provide a novel, yet promising, mechanism to reduce neuroinflammation, subsequently treating neurodegenerative disorders including PD at its core.”
Added Zhang: “These findings presented in this paper help to solidify the candidacy of sEH as a key player of PD pathogenesis via neuroinflammation, underscoring the role of sEH inhibitors as a new class of anti-neuroinflammatory pharmaceuticals treating neurodegenerative disorders including PD.”
What's the next step?
“We hope that the natural herbal medicine will offer some relief from Parkinson's disease,” said Sun.
Added Morisseau: “We also hope to increase kurarinone levels in the plant and ensure that the extracts are nontoxic and effective. Possibly we can even find a food plant that is effective.”
Hammock lab researcher Sung Hee Hwang, an organic chemist, has been making small molecule inhibitors for Parkinson's disease, “and the crystal structure of sEH bound to kurarinone will be a great help to him,” Hammock said. “He has been working with Jogen Atone who is just finishing his doctorate in the UC Davis Pharmacology Toxicology program working on basic aspects of Parkinson's disease and environmental chemicals that may cause it.”
Sophora (the Arabic name for a pea-flowered tree) is a genus of about 45 species of evergreen trees and shrubs in the pea family, Fabaceae. The species are native to southern Asia, Australasia, various Pacific islands, western South America, the western United States, Florida and Puerto Rico. About fifteen of these species have a long history of use in traditional Chinese
“Now that we have a lead structure, we hope to screen related species for related compounds and efficacy,” Morisseau said.
“Parkinson's disease occurs when nerve cells in the basal ganglia, an area of the brain that controls movement, become impaired and/or die,” according to the National Institute on Aging (NIA). “Normally, these nerve cells, or neurons, produce an important brain chemical known as dopamine. When the neurons die or become impaired, they produce less dopamine, which causes the movement problems of Parkinson's. Scientists still do not know what causes cells that produce dopamine to die.”
“One clear risk factor for Parkinson's disease is age,” NIA says. “Although most people with Parkinson's first develop the disease at about age 60, about 5 to 10 percent of people with Parkinson's have ‘early-onset' disease, which begins before the age of 50. Early-onset forms of Parkinson's are often, but not always, inherited, and some forms have been linked to specific gene mutations.”
Hammock expressed hope that a variety of research pathways, such as the one resulting in kurarinone, “can lead to therapies, preventions and cures of Parkinson's disease and other neuroinflammatory problems associated with aging.”
Contact:
Bruce Hammock, bdhammock@ucdavis.edu