- Author: Kathy Keatley Garvey
The research, “Root-Knot Nematodes Produce Functional Mimics of Tyrosine-Sulfated Plant Peptides,” is published in the current edition of the Proceedings of the National Academy of Sciences (PNAS).
It's like hijacking plant development to facilitate parasitism, according to nematologist Shahid Siddique, an associate professor in the Davis Department of Entomology and Nematology and one of the corresponding authors of this study. “This finding showcases an amazing case of convergent evolution across three different types of organisms, revealing how diverse life forms can develop similar strategies for survival.”
The root-knot nematode, which threatens global food security, is a small worm-like organism that is a highly evolved obligate parasite, or an organism that cannot survive without its host. It is known to infest some 2000 crops worldwide. “These parasites have a remarkable ability to establish elaborate feeding sites in roots, which are their only source of nutrients throughout their life cycle,” the authors wrote.
“Root-knot nematodes are a major threat to various crops, including fruit trees and vegetables,” Siddique said. “In California, tomatoes, almonds, and walnuts are among the major hosts susceptible to root-knot nematode infection.”
Siddique and UC Davis distinguished professor Pamela Ronald, a plant pathologist and geneticist in the Department of Plant Pathology and the Genome Center, are the joint corresponding authors. Joint first-authors are Henok Zemene Yemer, formerly of the Siddique lab and now with Gingko Bioworks, Emeryville, and Dee Dee Lu of the Ronald lab.
The team also included emerita professor Valerie Williamson of the former Department of Nematology; Maria Florencia Ercoli, postdoctoral fellow in the Ronald lab; Alison Coomer Blundell, a doctoral candidate in the Siddique lab; and Paulo Vieira of the USDA's Mycology and Nematology Genetic Diversity and Biology Laboratory, Beltsville, Md.
“Plant peptides containing sulfated tyrosine (PSY)-family peptides are peptide hormones that promote root growth via cell expansion and proliferation,” the authors explained. “A PSY-like peptide produced by a bacterial pathogen has been shown to contribute to bacterial virulence. Here, we discovered that PSY-like peptides are encoded by a group of plant-parasitic nematodes known as root-knot nematodes. These nematode-encoded PSY mimics facilitate the establishment of parasitism in the host plant. Our findings are an example of a functional plant peptide mimic encoded by a phytopathogenic bacterium (prokaryote) and a plant-parasitic nematode (an animal).”
The research involved gene expression analysis and parasitism of tomato and rice plants.
The project drew financial support from a collaborative grant awarded to Siddique and Ronald from the National Science Foundation's Division of Integrative Organismal Systems.
Siddique, a member of the UC Davis faculty since 2019, focuses his research on basic as well as applied aspects of interaction between parasitic nematodes and their host plants. “The long-term object of our research is not only to enhance our understanding of molecular aspects of plant–nematode interaction but also to use this knowledge to provide new resources for reducing the impact of nematodes on crop plants in California.”
Ronald, noted for her innovative work in crop genetics, especially rice, is recognized for her research in infectious disease biology and environmental stress tolerance. Thomson Reuters named her one of the world's most influential scientific minds and Scientfic American recognized her as among the world's 100 most influential people in biotechnology. In 2022 Ronald received the Wolf Prize in Agriculture.
The next steps? “Currently, we are working to understand the mechanism by which these peptides contribute to the nematode infection,” Siddique said. “This entails the characterization of receptors involved and gaining insights into transcriptional changes.”
- Author: Kathy Keatley Garvey
Most studies of traumatic brain injuries (TBI) focus on the pathology of the injured brain, but newly published research indicates that the liver plays an important role in TBI, and a soluble epoxide hydrolase (sEH) inhibitor discovered by UC Davis distinguished professor Bruce Hammock could lead to therapeutic treatment.
The research, led by Professor Xinhong Zhu of the School of Biology and Biological Engineering, South China University of Technology, Guangzhou, and tested in the Zhu lab, appears in the Proceedings of the National Academy of Sciences (PNAS). Youngfeng Dai, PhD., is the first author.
“Using animal models, we found that the liver has a neuroprotective effect in the pathophysiology of TBI, although its role was very weak,” Zhu said. “Our data suggest that enhancement of this neuroprotective role of the liver could provide novel strategies for developing treatment of TBI.” Plans call for “moving toward a clinical study to detect whether hepatic sEH manipulation benefits patients with TBI.”
Their results highlight the neuroprotective role of the liver in TBI and suggest that targeting this neuroprotective role may represent a promising therapeutic strategy for TBI. Earlier clinical studies report that the overall mortality in patients with TBI and cirrhosis is nearly twice that in patients without cirrhosis.
In the paper, “Enhancement of the Liver's Neuroprotective Role Ameliorates Traumatic Brain Injury Pathology,” the authors describes TBI as a “pervasive problem worldwide, for which no effective treatment is currently available,” and “as a devastating injury that often results in long-term neurological deficits, including locomotor function and memory impairments.”
“Blood–brain barrier (BBB) disruption is a hallmark feature of TBI and is associated with brain edema and neuronal death,” the authors wrote. “Studies have shown that sEH inhibitors protect the BBB from brain injury. Therefore, we investigated whether deletion of hepatic Ephx2 protected the BBB following controlled cortical injury (CCI).”
“TBI leads to a breakdown of the blood brain barrier,” said co-author Hammock, a member of the National Academy of Sciences and the National Academy of Inventors and whose pioneering work on sEH inhibitors spans 50 years. “We see from cases like Muhammad Ali that repeated TBI can lead to chronic central nervous system injury, dementia and other issues.”
“In the study from the Zhu laboratory, one of the exciting basic discoveries is that mammals have a natural mechanism to partially address traumatic brain injury,” said Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “By a mechanism under investigation, the injured brain communicates to the liver to down-regulate the production of an enzyme called the soluble epoxide hydrolase (sEH) that degrades natural inflammation resolving mediators. Thus, the concentration of these injury-resolving mediators also produced in the liver go up reducing deleterious inflammation throughout the injured animal. This soluble epoxide hydrolase inhibitor used as a tool in these studies is building on this natural mechanism to minimize the harmful effects of TBI.”
"Importantly, the soluble epoxide hydrolase inhibitor that the authors used here is also currently in human clinical safety trials for treating pain and inflammation,” said psychiatrist and neuroscientist Dr. Andrew Pieper, the Rebecca A. Barchas Professor in Translational Psychiatry, Case Western Reserve University, Cleveland. “The results shown here indicate that this agent, or related materials altering this same pathway, might mitigate the acute and long-term complications of TBI, or of neuroinflammatory conditions of the brain in general. Pieper, who holds both a Ph.D. and a M.D.. is the Morley-Mather Chair in Neuropsychiatry, University Hospitals of Cleveland Medical Center; director of the Brain Health Medicines Center, Harrington Discovery Institute; and psychiatrist at Louis Stokes Cleveland VA Medical Center, Cleveland.
Neuroscience researcher Daniela Kaufer, associate dean of biological sciences at UC Berkeley and a professor with the Department of Integrative Biology and Helen Wills Neuroscience Institute, praised the research possibilities. “The brain has a barrier which helps protect it from harmful materials in the blood,” said Kaufer, who was not involved in the research. “TBI reduces this barrier and its reduction is associated with aging. Possibly the pathway described in this PNAS paper could be manipulated to protect the blood brain barrier and reduce the apparent aging of the brain caused by repeated TBI.”
“My understanding of how we classify milds at UC Davis right now is that these are patients that behaviorally are mild injuries, but that they have something on a CT or MRI scan that indicates that the injury is more than a concussion, said Gurkoff, who was not involved in the research. “These patients are more likely to have long-term effects than concussion alone, but a lot less likely than moderate-severe. They also don't usually end up in the ICU. Then there are the concussions. Head injuries but no evidence of a radiological finding.”
“Add on top of that, repeat mild or repeat concussion,” Gurkoff said. “While some investigators will suggest that we have a good handle on repeat TBI--I still think it is the Wild West. It is clear that in a subset of humans, repeat TBI, even concussive, is catastrophic. Others seem to be fine. We also haven't dissected whether repeat TBI on its own is causal --or because many of the patients are in high risk/high stress situations--and it is the combination of TBI/repeat TBI with something else.”
“What gets me excited about certain compounds--Bruce's would be an example--is that if you have a low-risk compound, is it feasible that you give it to patients who might not develop long-term consequences?” Gurkoff asked. “For example, let's say a patient comes in and based on his injury and history, we might estimate there is a 10 percent chance he has a problem. You aren't going to schedule these patients for surgery--on the extreme--because the risk is too high given they most likely will recover. Having a low-risk compound that can be given to soldiers, athletes, etc, with mild or repeat mild--or concussion/repeat concussion--would be fantastic!”
The research drew financial support from the National Natural Science Foundation of China, Scientific and Technological Innovation, and partial support from Hammock's grants from the National Institute of Environmental Health Sciences' RIVER Award (Revolutionizing Innovative, Visionary Environmental Health Research) and the National Institute of Neurological Disorders and Stroke.
“This pioneering study provides clear evidence of the importance of liver-derived epoxy fatty acids (EpFAs) and reactive astrocytes from the immune system in protecting the brain from significant damage and post-traumatic dysfunction following percussive injury,” said William Schmidt, EicOsis vice president of clinical development. “As of now, there are no proven drug therapies that provide protective effects to the brain following single or repeated blows to the head from falls, auto accidents, or sports injuries.”
“The data from this study,” Schmidt said, “provides a pathway for developing inhibitors of sEH that, in turn, will enhance the availability of EpFAs circulating in blood to protect and restore the blood-brain barrier following TBI. I am hopeful that further preclinical studies will confirm these data and lead to a new type of drug therapy based on inhibitors of the sEH enzyme.”
“Clinical studies for TBI may still be a year or so away,” Schmidt added, “but EicOsis has an sEH inhibitor in early clinical development that may be suitable in the future for evaluation in patients with TBI.”
Hammock and colleague Sarjeet Gill co-discovered sEH in 1969 when they were researching insect developmental biology and green insecticides in the UC Berkeley lab of John Casida (1929-2018).
The enzyme is a key regulatory enzyme involved in the metabolism of fatty acids. It regulates a new class of natural chemical mediators, which in turn regulates inflammation, blood pressure and pain. The epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, depression, pain, and inflammation, to name a few processes, Hammock said.
Resources:
PNAS paper: https://doi.org/10.1073/pnas.
Traumatic Brain Injury, National Institutes of Health
Traumatic Brain Injury, Mayo Clinic
Contacts:
Bruce Hammock, PhD: bdhammock@ucdavis.edu
Irene Cortés-Puch, M.D., EicOsis: icortespuch@eicosis.com
- Author: Kathy Keatley Garvey
Their work, “Insect Herbivory Within Modern Forests Is Greater than Fossil Localities,” appears in the Oct. 10th edition of the Proceedings of the National Academy of Sciences (PNAS). The first-of-its-kind study compares insect herbivore damage of modern-era plants with that of fossilized leaves dating as far back as 67 million years ago.
“Our work bridges the gap between those who use fossils to study plant-insect interactions over deep time and those who study such interactions in a modern context with fresh leaf material,” said lead researcher and ecologist Lauren Azevedo-Schmidt, formerly of the Department of Biology, University of Wyoming and now a postdoctoral research associate with the Climate Change Institute, University of Maine. “The difference in insect damage between the modern era and the fossilized record is striking.”
No stranger to UC Davis, Currano presented a UC Davis Department of Entomology and Nematology seminar, hosted by Meineke, on "Ancient Bug-Bitten Leaves Reveal the Impacts of Climate and Plant Nutrients on Insect Herbivores" on April 28, 2021.
“Plants and insects are the most diverse lineages on earth, but their interactions in the face of climate and other global changes are poorly understood…despite insect declines, insect damage to plants is elevated in the modern era compared with other time periods represented in the fossil record,” they wrote. “Plants today are experiencing unprecedented levels of insect herbivory, with unknown consequences for plant fitness and evolution.”
The scientists presented estimates for damage frequencies and diversities on fossil leaves from the Late Cretaceous (66.8 million years ago) through the Pleistocene (2.06 million years ago) and compared these estimates with recent (post-1955) leaves collected via paleobotanical methods from three modern ecosystems, including Harvest Forest, a 3000-acre ecological research area in managed by Harvard University and located in Petersham, Mass. The site, in operation since 1907, is one of North America's oldest managed forests.
Other ecosystems: the Smithsonian Environmental Research Center (SERC) of Chesapeake Bay, a 2,650-acre campus spanning forests, wetlands, marshes and 15 miles of protected shoreline, and the 3953-acre La Selva Research Station, Costa Rica, a private forest reserve.
The scientists advocate more research to determine the precise causes of increased insect damage to plants, but related that a “warming climate, urbanization and introduction of invasive species likely have had a major impact.”
“We hypothesize that humans have influenced (insect) damage frequencies and diversities within modern forests, with the most human impact occurring after the Industrial Revolution,” the researchers wrote. “Consistent with this hypothesis, herbarium specimens from the early 2000s were 23 percent more likely to have insect damage than specimens collected in the early 1900s, a pattern that has been linked to climate warming.”
“This research suggests that the strength of human influence on plant-insect interactions is not controlled by climate change alone but, rather, the way in which humans interact with the terrestrial landscape,” the researchers concluded.
Meineke, who joined the UC Davis faculty in 2020, served as a postdoctoral fellow at Harvard University Herbaria from 2016 to 2019, including a National Science Foundation-sponsored fellowship there in 2017. She holds a doctorate in entomology from North Carolina State University (2016), Raleigh, where she wrote her dissertation on “Understanding the Consequences of Urban Warming for Street Trees and Their Pests.”
Meineke helped spearhead the newly created Harvard Museum of Natural History's “In Search of Thoreau's Flowers: An Exploration of Change and Loss," hailed as an examination of the natural world and climate change at the intersections of science, art and history. The exhibit opened to the public May 14, 2022.
- Author: Kathy Keatley Garvey
The parallel, cluster-randomized, controlled trial revealed that a spatial repellent, currently under review by the World Health Organization (WHO), reduced human Aedes-borne virus infection by 34.1 percent.
“That is a significant statistical and public health reduction,” said Scott, an internationally recognized medical entomologist who retired from the UC Davis Department of Entomology and Nematology in 2015 but continues his scientific research on the ecology and epidemiology of dengue, a mosquito-borne viral infection transmitted mainly by A. aegypti. Dengue, one of the most rapidly increasing vector-borne infectious diseases, infects some 400 million people a year, with 4 billion people at risk annually.
The clinical study results mean that spatial repellents have “the potential to reduce a variety of vector-borne diseases, augment existing public health efforts, and can be an effective component in vector control intervention strategies,” Scott said.
The newly published research, “Efficacy of a Spatial Repellent for Control of Aedes-borne Virus Transmission: A Cluster-Randomized Trial in Iquitos, Peru,” appears in the Proceedings of the National Academy of Sciences (PNAS). The Bill and Melinda Gates Foundation funded the research in a grant to the University of Notre Dame (UND). Medical entomologist Nicole Achee, a research professor at UND, served as the project leader.
“To have shown a substantial public health impact at an endemic site, is rewarding,” said Scott, now a resident of Luck, Wis. “Our results provide valuable new data on mosquito control that will help to fill long-standing knowledge gaps and improve guidance for development of enhanced public health policy. Because literally billions of people around the globe are at risk of infection and disease from these viruses we are encouraged that results from our trial will contribute to improved health and well-being of so many people.”
Epidemiologist Amy Morrison, a 1996-2018 project scientist with the UC Davis Department of Entomology and Nematology and now with the UC Davis School of Veterinary Medicine's Department of Pathology, Microbiology and Immunology, served as the lead author of the PNAS paper. “This trial was the most logistically challenging field project I've ever participated in,” she said. “I led the field efforts in Iquitos, Peru where I have resided since 1998. Our research team continued to amaze me; they had to replace more than 20,000 products in more than 2,000 houses every 15 days and managed 80 percent coverage of participating houses. This type of vector control trial is very difficult to carry out so demonstrating protective efficacy is very gratifying.”
Achee said the Peru study outcomes “are a critical component to achieving our goals for supporting a WHO policy endorsement for spatial repellents. The reduction in Aedes-borne virus infection in at-risk participants seen in trial results have fundamentally contributed to the WHO encouraging further consideration for the use of this product class in public health worldwide. This is a historical milestone that was led by the UC Davis implementing team and I am thrilled to have been part of the collaborative effort."
Spatial repellents are “devices that contain volatile active ingredients that disperse in air,” the authors explained. “The active ingredients can repel mosquitoes from entering a treated space, inhibit attraction to human host cues, or disrupt mosquito biting and blood-feeding behavior and, thus, interfere with mosquito–human contact. Any of these outcomes reduce the probability of pathogen transmission.”
More than half of the world population is at risk for infection with viruses transmitted by Aedes mosquitoes, including include dengue, Zika, chikungunya, and yellow fever, the scientists wrote.
Vector interventions are needed for Aedes-borne viral (ABV) disease prevention “but their application is hindered by the lack of evidence proving they prevent infection or disease," they wrote. "Results from our ABV study will help guide public health authorities responsible for operational management and worldwide ABV disease control and incentivize new strategies for disease prevention.”
“The primary mosquito vector, Aedes aegypti, thrives in modern tropical urban environments. Despite decades of effort to control Ae. aegypti populations and prevent disease, the geographic range of illness and the viruses this mosquito transmits continue to expand,” they related. “Rigorously proven vector control interventions that measure protective efficacy against Aedes-borne viruses are limited to Wolbachia in a single trial in Indonesia and do not include any chemical interventions. Spatial repellents, a new option for efficient vector control, are designed to decrease human exposure to Aedes-borne viruses by releasing active ingredients into the air that disrupt mosquito–human contact and, thus, reduce the risk of human infection.”
The Iquitos trial is one of two trials recommended by WHO for assessing public health value and developing global health policy for the intervention class of spatial repellents. “Fully integrating vector control into Aedes-borne viral disease prevention programs requires quantitative guidance based on quantitative measures of the impact from each intervention component,” the authors wrote. “Ministries of Health, local to national governments, and nongovernmental organizations can use the Peru trial results as an evidence base for informed application of spatial repellents. Considering the growing public health threat from Aedes-borne viral disease, difficulties of developing vaccines against multiple viruses, and past poorly informed vector control failures, enhanced Aedes-borne viral disease prevention will benefit greatly from interventions, like the Peru trial, with proven public health value.
Thomas Scott. Scott, a member of three WHO committees and one of the world's Highly Cited Researchers for the third consecutive year, co-chairs a Lancet Commission that focuses on how prevention of viruses transmitted by Aedes mosquitoes. He served on the faculty of the Department of Entomology, University of Maryland, from 1983 to 1996 before joining the UC Davis entomology faculty as a professor of entomology and director of the Vector-Borne Disease Laboratory. Highly honored by his peers, Scott won the coveted Harry Hoogstraal Medal from the American Society of Tropical Medicine and Hygiene in 2018. He is a fellow of the American Society of Tropical Medicine and Hygiene, Entomological Society of America, and the American Association for the Advancement of Science. He holds bachelor and master's degrees from Bowling Green (Ohio) State University and a doctorate in ecology in 1981 from Pennsylvania State University.
Amy Morrison. Morrison, who holds a doctorate in public health from Yale University, with a concentration in epidemiology of infectious diseases, and a master's degree in public health from UCLA, has served as the principal investigator, co-principal investigator and a collaborator on a number of federally funded grants. She specializes in the epidemiology of tropical vector-borne diseases, with an emphasis on (1) arthropod vector ecology and dengue virus transmission dynamics and (2) spatial and temporal analyses using Geographic Information Systems.
As a project scientist, Morrison supervises multiple studies on A. aegypti and dengue virus transmission dynamics, including longitudinal cohort studies evaluating A. aegypti control interventions, and the role of human movement in dengue transmission dynamics in Iquitos, funded by National Institutes of Health, Military Infectious Disease Research Program and Bill and Melinda Gates Foundation. She is an active member of the American Mosquito Control Association, American Association for the Advancement of Science, Entomological Society of America, American Society of Tropical Medicine and Hygiene, and the Society of Vector Ecologists.
Nicole Achee. Achee is a research associate professor in the Department of Biological Sciences, UND, and holds a joint associate professor appointment in the Eck Institute for Global Health, UND. She worked as a medical entomologist in the international settings of Belize, Indonesia, Mexico, Nepal, Peru, South Korea, Suriname, Tanzania and Thailand. Her curriculum vitae includes principal investigator for large scale clinical trials in Peru and Indonesia. Both studies aimed “to generate evidence of the protective efficacy of spatial repellents for prevention of malaria and dengue human infections for use toward full World Health Organization public health policy recommendations,” she says on her website. Achee holds a doctorate in medical entomology from the Uniformed Services University of the Health Science, Bethesda, Md.
In addition to the Bill and Melinda Gates Foundation, the Iquitos project drew support from the Defense Threat Reduction Agency, Military Infectious Disease Research Program and the U.S. National Institute of Allergy and Infectious Diseases.
- 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
