- 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
UC Davis received three awards:
- Medical entomologist-geneticist Geoffrey Attardo received the Medical, Urban, and Veterinary Entomology Award. (See news story)
- Doctoral student Erin Taylor Kelly of the Attardo lab won the Student Leadership Award (See news story)
- Undergraduate entomology student Gwen Erdosh of the Louie Yang lab and a member of the Research Scholars Program in Insect Biology, won the inaugural Dr. Stephen Garczynski Undergraduate Research Scholarship (See news story)
The branch encompasses 11 Western states, parts of Canada and Mexico and several U.S. territories.
In the United States: Alaska, Arizona, California, Hawai'i, Idaho, Montana, Nevada, Oregon, Utah, Washington, Wyoming
U.S. Territories: American Samoa, the Federated States of Micronesia, Guam, Johnston Atoll, Commonwealth of the Northern Mariana Islands, Midway Islands, Wake Island
In Canada: Alberta, British Columbia, Northwest Territories, Saskatchewan, Yukon
In Mexico: Baja California, Baja California Sur, Sinaloa, Sonora
Congratulations to all the winners!
- Author: Kathy Keatley Garvey
The display will include:
- What's in the jar?
- Celery infected with root-knot nematodes
- Tree swallow infected with Diplotriaena
- White-tailed deer eye infected with a Thelazia species
- Peach root infected with root-knot nematodes
- Mormon crickets infected with Gordius robustus
- Lettuce infected with root-knot nematodes
- Garlic damaged by Ditylenchus dipsaci
- Horse stomach infected with three parasites: Parascaris (roundworms), tapeworms, and botfly larvae.
- Grape roots infected with root-knot nematodes
- Sweet potato infected with root-knot nematodes
- Sugar beet infected with cyst nematodes
- Peach root infected with cyst nematodes
- Sugar beet infected with root-knot nematodes
- Ascaris lumbricoides (roundworm)
- Minke whale infected infected with ascaridoid nematodes
- Heartworm of dog
The event is set for 11 a.m. to 3 p.m. in the UC Davis Conference Center, 555 Alumni Lane. Admission and parking are free, but visitors must adhere to the COVID-19 Campus Ready guidelines. Masks will be required in accordance with campus policies, organizers said. Visitors can also sign up at the Conference Center for limited tours. Several museums or collections will be offering tours. (See news story)
"Plant-parasitic nematodes are destructive pests causing losses of billions of dollars annually," Siddique says on his website. "Economic, health, and environmental considerations make natural host plant resistance a preferred strategy for nematode control, but there are limitations to this approach. In many cases, the resistance conferred by resistance genes is partial, and some of the nematodes are able to survive. Similarly, nematode resistance genes are often effective against only one or a few species, whereas plants are exposed to several pathogens in the field. Another concern is the emergence of pathotypes that can overcome resistance. In view of all these limitations, it is important to identify additional mechanisms and tools that can be used to develop novel and sustainable approaches to the management of nematodes."
"Research in the Siddique lab focuses on basic as well as applied aspects of interaction between parasitic nematodes and their host plants," Siddique points out on his website. "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."
Coomer, a second-year doctorate student, recently won a worldwide competition competition sponsored by the International Federation of Nematology Societies (IFNS) for her three-minute thesis on root-knot nematodes. She delivered her video presentation virtually on “Trade-Offs Between Virulence and Breaking Resistance in Root-Knot Nematodes.” She will be awarded a busary and plaque at the 7th International Congress of Nematology (ICN), set May 1-6 in Antibes, France.
Coomer earlier was selected one of the nine finalists in the 22-participant competition, vying against eight other graduate students from the University of Idaho, Moscow; and universities in England, Australia, Brazil, Ireland, Kenya, Belgium and South Africa.
The UC Davis Biodiversity Museum Day is traditionally held on the Saturday of Presidents' Day weekend. However, last year's event was virtual, and this year's event is centrally located in an exposition. For more information, access the UC Davis Biodiversity Museum Day website and/or connect with Instagram,Twitter, and Facebook.
- 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.”
