- 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
- Author: Kathy Keatley Garvey
They do UC Davis proud. Very proud.
They are UC Davis distinguished professor Bruce Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the Comprehensive Cancer Center; researcher Christophe Morisseau of the Hammock lab, and Seiya Kitamura, who studied with Hammock and Morisseau while working toward his doctorate as a member of the UC Davis Pharmacology/Toxicology Graduate Group. Kitamura is now a postdoctoral scholar at Scripps Research Institute in La Jolla.
The Royal Society of Chemistry (RSC) applauded the 47-member team of worldwide collaborators “for the development of multidimensional click chemistry, a next-generation click-technology that extends perfect bond creation into the three-dimensional world, opening doors to new frontiers in biomedicine, materials science, and beyond.”
K. Barry Sharpless of the Scripps Research Institute in La Jolla, who won the 2001 Nobel Prize for Sharpless epoxidation, led the team. “His magic is like the click-chemistry he invented,” Hammock said.
John Moses of the Cancer Center, Cold Spring Harbor Laboratory, New York, submitted the nomination on behalf of the team.
The team wrote in its award packet: “Click-chemistry and particularly the copper-catalyzed azide-alkyne-Huisgen cycloaddition (CuAAC), has had a profound impact on drug discovery (for which it was intended). It is now the 'go-to' technology in every corner of molecular science. The introduction of Sulfur(VI) fluoride exchange (SuFEx) in 2014 opened up a whole new world of possibilities for reliable bond-forming technology, particularly for chemical biology applications where the fugacity of sulfur-fluoride functional groups are primed for selective covalent bond formation with active protein sites.”
'Bench Warmer'
Morisseau described click chemistry “as such a ubiquitous tool in multiple aspects of science that kits are sold and the chemistry utilized without even recognizing where it comes from. Many of the beautiful and informative fluorescent pictures of cells on journal covers are based on click chemistry.”
Always humble, Morisseau quipped that his role on the team was minor, that of a “bench warmer.”
“Every good team has a few bench warmers,” Morisseau commented, looking through the list of team members, considered the “who's who of modern organic chemistry” at multiple stages of their careers.
UC Davis Distinguished Professor Bruce Hammock
Hammock said his involvement in click chemistry started when he was on sabbatical leave at UC San Diego. “Barry explained to me how one could use the SF bonds of SOF4 and related compounds to make additions one at a time and create a defined three-dimensional molecule with high precision. The potential of these reagents to design new pharmaceuticals and agricultural products was really exciting. Thus, our contribution was being there at the right time to show translation into the real world.”
Hammock is known for his expertise in chemistry, toxicology, biochemistry and entomology. Early in his career, he founded the field of environmental immunoassay, using antibodies and biosensors to monitor food and environmental safety, and human exposure to pesticides. His groundbreaking research in insect physiology, toxicology led to his development of the first recombinant virus for insect control
A member of the UC Davis faculty since 1980, Hammock has directed the UC Davis Superfund Research Program (funded by the National Institutes of Health's National Institute of Environmental Health Sciences) for nearly four decades, supporting scores of pre- and postdoctoral scholars in interdisciplinary research in 5 different colleges and graduate groups on campus. He is a fellow of the National Academy of Inventors, the National Academy of Sciences, and the Entomological Society of America. He is the recipient of scores of awards, including the first McGiff Memorial Awardee in Lipid Biochemistry; and the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. At UC Davis he received the Lifetime Achievement Award from the Chancellor, Distinguished Teaching Award and the Faculty Research Lectureship.
Hammock has authored or co-authored more than 1,200 peer-reviewed publications and holds more than 95 patents in agriculture, environmental science and medicinal chemistry.
As director of the UC Davis Superfund Research Program, he pioneered trans-disciplinary research across campus, engaging faculty in multiple colleges and schools “to transform the way we treat diseases in multiple species.”
RSC Horizon Prizes
The RSC Horizon Prizes “highlight the most exciting, contemporary chemical science at the cutting edge of research and innovation,” according to its website. “These prizes are for teams or collaborations who are opening up new directions and possibilities in their field, through ground-breaking scientific developments." The mission of the London-based RSC, founded in 1841, is to advance excellence in the chemical sciences.
Resources:
- Horizon Team Award
- Bruce Hammock: Lifetime Achievement Award from Chancellor
- Why Science Is Fun (feature on Bruce Hammock)
- Author: Kathy Keatley Garvey
The village of Villevieille recorded an historical high temperature of 113.2 degrees Fahrenheit on June 28.
The villagers probably wish they were at the University of California, Davis, where plans are underway for the 16th annual Bruce Hammock Lab Water Balloon Battle.
The balloon battle, known as "Bruce's Big Balloon Battle at Briggs" or "15 Minutes of Aim"--is set for 3 p.m., Friday, July 12 on the lawn at the northwest side of Briggs Hall, Kleiber Hall Drive, said coordinator Christopher Morisseau, a researcher in the Hammock lab. It's across from the UC Davis Fire Department.
Participants will fill 2000 balloons, starting at 1 p.m. on the grass by the loading dock. Morisseau said the policy is "no filling, no throwing" or "bring your own balloons." It is open to all who want to get wet, and children and spouses are always welcome.
Last year water balloons, water guns, super sprayers, and buckets prevailed in the international soakfest. International? Yes! Twenty-eight researchers in the Hammock lab from seven countries participated: the United Stares, China, France, Ukraine, Lebanon, Japan and Korea. They included postdoctoral scholars, researchers, graduate students, visiting scholars, visiting graduate students, visiting summer students, short-term visiting scholars and student interns.
Other professors and their labs traditionally join in the fun. Among them: Aldrin Gomes of the UC Davis Department of Neurobiology, Physiology and Behavior; Frank Zalom, UC Davis Department of Entomology and Nematology; Walter Leal of the UC Davis Department of Molecular and Cellular Biology; and the UC Davis Department of Mathematics.
Bruce Hammock, a UC Davis distinguished professor who holds a joint appointment with the UC Davis Department of Entomology and the UC Davis Comprehensive Cancer Center, hosts the annual event in mid-July when triple-digit temperatures strike the campus. It's an opportunity for the lab members--who work hard throughout the year and play hard for 15 minutes--to engage in a little fun and camaraderie. The thirsty lawn benefits, too.
Hammock, trained as a entomologist, chemist and toxicologist--and who now focuses his research on human health, is recognized for his work on using natural chemical mediators to control inflammation and intractable pain. An alumnus of UC Berkeley with a doctorate in entomology, Hammock joined the UC Davis faculty in 1980. He is the founding director (1987-present) of the UC Davis NIEHS (National Institute of Environmental Health Sciences) Superfund Research Program and is a founding member (1990-present) of the UC Davis Comprehensive Cancer Center. He has directed the UC Davis NIH/NIEHS Combined Analytical Laboratory for 25 years.
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 is the first McGiff Memorial Awardee in Lipid Biochemistry. The Eicosanoid Research Foundation honored him for work on oxidized lipids.
But when it's time for the annual water balloon battle, watch out! Like his research, Bruce Hammock is right on target.
- Author: Kathy Keatley Garvey
Water balloons, water guns, super sprayers, and buckets prevailed when dozens of scientists participated in the 15th annual Bruce Hammock Lab Water Balloon Battle on the Briggs Hall lawn at the University of California, Davis.
The July event, also known as "Bruce's Big Balloon Battle at Briggs," proved to be an international soakfest. That's because the 28 researchers in the Hammock lab hail from seven countries: the United Stares, China, France, Ukraine, Lebanon, Japan and Korea. They include postdoctoral scholars, researchers, graduate students, visiting scholars, visiting graduate students, visiting summer students, short-term visiting scholars and student interns.
The annual battle amounts to 15 minutes, or "15 Minutes of Aim." That's how long it takes for the some 40 water warriors to toss 2,000 water balloons. Joining in were scientists from the Aldrin Gomes lab, UC Davis Department of Neurobiology, Physiology and Behavior; Frank Zalom lab of the UC Davis Department of Entomology and Nematology; and the UC Davis Department of Mathematics, plus family and friends.
Hammock, a UC Davis distinguished professor who holds a joint appointment with the UC Davis Department of Entomology and the UC Davis Comprehensive Cancer Center, hosts the annual event in mid-July when triple-digit temperatures strike the campus. It's an opportunity for the lab members--who work hard throughout the year and play hard for 15 minutes--to engage in a little fun and camaraderie. The thirsty lawn benefits, too.
First the water warriors fill the balloons in an assemblyline procedure, and at exactly 3 p.m., the soakfest begins. As the H2O dwindles, they empty buckets at unsuspecting targets. The last part: picking up every single balloon remnant from the lawn.
Hammock, trained as a entomologist, chemist and toxicologist--and who now focuses his research on human health, is recognized for his work on using natural chemical mediators to control inflammation and intractable pain. He co-discovered the soluble epoxide hydrolase, and many of his more than 1100 publications and patents are on the P450 branch of the arachidonate cascade where the soluble epoxide hydrolase (sEH) degrades natural analgesic and anti-inflammatory compounds.
Hammock, an alumnus of UC Berkeley with a doctorate in entomology, joined the UC Davis faculty in 1980. He is the founding director (1987-present) of the UC Davis NIEHS (National Institute of Environmental Health Sciences) Superfund Research Program and is a founding member (1990-present) of the UC Davis Comprehensive Cancer Center. He has directed the UC Davis NIH/NIEHS Combined Analytical Laboratory for 25 years.
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 is the first McGiff Memorial Awardee in Lipid Biochemistry. The Eicosanoid Research Foundation recently honored him for work on oxidized lipids.
But on one day in July--for 15 minutes--noted academician Bruce Hammock leaves his Briggs Hall office and transforms into an elite water warrior. He's practiced for 15 years, 15 minutes at a time.
"Bruce has a good aim," said Christophe Morisseau, a Hammock lab researcher who coordinates the annual battles.
- Author: Kathy Keatley Garvey
What do you get?
An epic battle during the 15th annual Bruce Hammock Lab Water Balloon Battle on the Briggs Hall lawn at the University of California, Davis.
Who won? It was not distinguished professor Bruce Hammock, who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
It was undergraduate student Andrew Kisin of the lab of Aldrin Gomes, UC Davis Department of Neurobiology, Physiology and Behavior.
Hammock, clutching three water balloons, didn't stand a chance as Kisin raced toward him with a container full of water. The rest is history. Drenched history.
The annual battle amounts to 15 minutes, or "15 Minutes of Aim." That's how long it takes for the some 40 participants to toss 2,000 water balloons. Currently 28 researchers--from the United Staes, China, France, Ukraine, Lebanon, Japan and Korea--work in the Hammock lab. They include postdoctoral scholars, researchers, graduate students, visiting scholars, visiting graduate students, visiting summer students, short-term visiting scholars and student interns.
Trained as a entomologist, chemist and toxicologist--and who now focuses his research on human health, Bruce Hammock is known for his work on using natural chemical mediators to control inflammation and intractable pain. He co-discovered the soluble epoxide hydrolase, and many of his more than 1100 publications and patents are on the P450 branch of the arachidonate cascade where the soluble epoxide hydrolase (sEH) degrades natural analgesic and anti-inflammatory compounds.
Kisin, a second-year UC Davis student from San Jose, just enrolled at UC Davis a week ago. Majoring in biological sciences, he joined the Gomes lab to study "the effects of drugs such as ibuprofin on organs and may also study how proteasomes contribute to aging."
The annual event is open to all UC Davis personnel and their families. They fill the balloons, toss them and clean up the remnants--and then look forward to next year's battle.
Odds are that you won't find many water warriors like Bruce Hammock, whose credentials rival noted academicians worldwide. A native of Little Rock, Ark., who holds a doctorate from UC Berkeley, Bruce joined the UC Davis faculty in 1980. He is the founding director (1987-present) of the UC Davis NIEHS (National Institute of Environmental Health Sciences) Superfund Research Program and is a founding member (1990-present) of the UC Davis Comprehensive Cancer Center. He has directed the UC Davis NIH/NIEHS Combined Analytical Laboratory for 25 years.
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 is the first McGiff Memorial Awardee in Lipid Biochemistry. The Eicosanoid Research Foundation recently honored him for work on oxidized lipids.
But on one day in July--for 15 minutes--Bruce Hammock turns from academician to water warrior. And yes, he's excels at that, too! See what happened to his doctoral student Cindy McReynolds in one of the photos below.