- Author: Kathy Keatley Garvey
DAVIS--Newly published research in the Proceedings of the National Academy of Sciences (PNAS) indicates that a drug discovered and developed in the laboratory of Bruce Hammock,UC Davis Department of Entomology and Nematology, may have a major role in preventing and treating llnesses associated with obesity.
More than 43 percent of adults in the United States are obese, according to the Center for Disease Control and Prevention (CDC). Obesity increases the risk of coronary artery disease, stroke, type 2 diabetes, and certain kinds of cancer.
The drug, a soluble epoxide hydrolase (sEH) inhibitor, appears to regulate “obesity-induced intestinal barrier dysfunction and bacterial translocation,” the 12-member team of researchers from UC Davis, University of Massachusetts and University of Michigan discovered. The same non-opioid drug is being investigated in human clinical safety trials in Texas to see if it blocks chronic pain associated with diseases such as spinal cord injury, diabetes and inflammatory bowel disease.
The research, funded by multiple federal grants, is titled “Soluble Epoxide Hydrolase Is an Endogenous Regulator of Obesity-Induced Intestinal Barrier Dysfunction and Bacterial Translocation.”
“Obesity usually causes the loss of tight junctions and leaky gut,” said first author Yuxin Wang, a postdoctoral researcher who joined the Hammock lab in 2019 from the Department of Food Sciences, University of Massachusetts, Amherst. “In normal conditions, the gut mucosal barrier is like a defender to protect us from the ‘dirty things' in the lumen, such as bacteria and endotoxin. For obese individuals, the defender loses some function and leads to more ‘bad things' going into the circulation system, causing systemic or other organ disorders.”
Although intestinal dysfunction and other problems enhancing bacterial translocation underlies many human diseases, “the mechanisms remain largely unknown,” said Wang, who holds a doctorate in biochemistry and molecular biology from the Chinese Academy of Sciences. “What we found is sEH inhibition can repair the defender function (barrier function), decrease the ‘bad things' going into the blood (bacteria translocation), and reduce inflammation of fat.”
“Our research shows that sEH is a novel endogenous regulator of obesity-induced intestinal barrier dysfunction and bacterial translocation,” said corresponding author Guodong Zhang, a former researcher in the Hammock lab and now with the Food Science Department and Molecular and Cellular Biology Graduate Program at the University of Massachusetts. “To date, the underlying mechanisms for obesity-induced intestinal barrier dysfunction remain poorly understood. Therefore, our finding provides a novel conceptual approach to target barrier dysfunction and its resulting disorders with clinical/transitional importance.”
Corresponding author Hammock, a distinguished UC Davis professor who holds a joint appointment with the Department of Entomology and Nematology and the Comprehensive Cancer Center, praised Zhang's “amazing record while he was a postgraduate at UC Davis, and now in Food Science Department at the University of Massachusetts, where he recently received tenure.”
Zhang mentored two co-authors of the paper: Yuxin and Weicang Wang, both formerly of the Department of Food Science, University of Massachusetts and now with the Hammock lab.
“I feel so lucky that Yuxin and Weicang have joined my laboratory,” Hammock said. “The drugs studied in this PNAS paper are now in human clinical trials and on a path to replace opioid analgesics for pain treatment. I hope the continuing work of Guodong, Weicang and Yuxin will evaluate them as treatments for a variety of inflammatory bowel diseases.”
Andreas Baumler, professor and vice chair of research in the UC Davis Department of Medical Microbiology and Immunology, who was not affiliated with the study, said: “Obesity-induced gut leakage and bacterial translocation can be ameliorated by targeting microbes with antibiotics, suggesting that the microbiota contributes to disease. However, the work by Zhang and co-workers suggest that rather than targeting the microbes themselves, obesity-induced gut leakage and bacterial translocation can be normalized by silencing a host enzyme, which identifies host metabolism as an alternative therapeutic target.”
In addition to Hammock, Zhang, Yuxin and her husband Weicang, the other eight co-authors on the team are:
- Jun Yang, Sung Hee Hwang, and Debin Wan of the Hammock lab, UC Davis Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center
- Kin Sing Stephen Lee, formerly of the Hammock lab, and Maris Cinelli, both of the Department of Pharmacology and Toxicology, Michigan State University, Lansing
- Katherine Sanidad and Hang Xiao, Department of Food Science and the Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst
- Daeyoung Kim, Department of Mathematics and Statistics, University of Massachusetts, Amherst
The abstract: “Intestinal barrier dysfunction, which leads to translocation of bacteria or toxic bacterial products from the gut into bloodstream and results in systemic inflammation, is a key pathogenic factor in many human diseases. However, the molecular mechanisms leading to intestinal barrier defects are not well understood, and there are currently no available therapeutic approaches to target intestinal barrier function. Here we show that soluble epoxide hydrolase (sEH) is an endogenous regulator of obesity-induced intestinal barrier dysfunction. We find that sEH is overexpressed in the colons of obese mice. In addition, pharmacologic inhibition or genetic ablation of sEH abolishes obesity-induced gut leakage, translocation of endotoxin lipopolysaccharide or bacteria, and bacterial invasion-induced adipose inflammation. Furthermore, systematic treatment with sEH-produced lipid metabolites, dihydroxyeicosatrienoic acids, induces bacterial translocation and colonic inflammation in mice. The actions of sEH are mediated by gut bacteria-dependent mechanisms, since inhibition or genetic ablation of sEH fails to attenuate obesity-induced gut leakage and adipose inflammation in mice lacking gut bacteria. Overall, these results support that sEH is a potential therapeutic target for obesity-induced intestinal barrier dysfunction, and that sEH inhibitors, which have been evaluated in human clinical trials targeting other human disorders, could be promising agents for prevention and/or treatment.”
The research was funded by grants from the National Institute of Food and Agriculture, U.S. Department of Food and Agriculture (USDA); National Cancer Institute; USDA Hatch Grant; National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program; and a National Science Foundation.
According to the CDC, many of obesity-related conditions that lead to diseases are preventable. In 2008, the estimated annual medical cost of obesity in the United States tallied $147 billion. The medical cost for obese individuals averaged $1,429 higher than those of normal weight.
Contact: Bruce Hammock, bdhammock@ucdavis.edu
- Author: Kathy Keatley Garvey
The scenario begins when aggregations of beetle larvae of Meloe franciscanus emit chemical signals that mimic the sex pheromones of female bees luring male digger bees to make contact. The Meloe larvae then attach to males bees on contact, Habropoda pallida, from California's Mojave Desert and H. miserabilis from the coastal dunes of Oregon.
During subsequent copulations, the larvae transfer from males to females, hitching a ride on female bees to their nests, where the larvae feed on the provisions and the bee egg, and emerge as adults the following winter, said Saul-Gershenz. The research paper, “Deceptive Signals and Behaviors of a Cleptoparasitic Beetle Show Local Adaptation to Different Host bee Species,” appears in the current edition of Proceedings of the National Academy of Sciences (PNAS).
In solving the puzzle, the scientists tested whether geographically isolated populations of M. franciscanus larvae--from Oregon's coast and California's Mojave Desert--use local adaptations to exploit their respective hosts, H. miserabilis and H. pallida.
“Interestingly, male H. miserabilis were attracted to conspecific females and to aggregations of local Meloe larvae, but not to male bees,” Saul-Gershenz said. “Importantly, male bees of both bee species were more attracted to local parasite larvae than larvae from the distant locale because the larvae tailored their pheromone-mimicking blends to the pheromones of their local hosts. Additionally, the larval aggregation adapted their perching height at each location to the patrolling height of local male bees.”
In their abstract, the scientists wrote: "Chemosensory signals play a key role in species recognition and mate location in both invertebrate and vertebrate species. Closely related species often produce similar but distinct signals by varying the ratios or components in pheromone blends to avoid interference in their communication channels and minimize cross- attraction among congeners. However, exploitation of reproductive signals by predators and parasites also may provide strong selective pressure on signal phenotypes. For example, bolas spiders mimic the pheromones of several moth species to attract their prey, and parasitic blister beetle larvae, known as triungulins, cooperatively produce an olfactory signal that mimics the sex pheromone of their female host bees to attract male bees, as the first step in being transported by their hosts to their nests.”
“In both cases, there is strong selection pressure on the host to discriminate real mates from aggressive mimics and, conversely, on the predator, parasite, or parasitoid to track and locally adapt to the evolving signals of its hosts,” the co-authors pointed out. “Here we show local adaptation of a beetle, Meloe franciscanus (Coleoptera: Meloidae), to the pheromone chemistry and mate location behavior of its hosts, two species of solitary bees in the genus Habropoda. We report that M. franciscanus' deceptive signal is locally host-adapted in its chemical composition and ratio of components, with host bees from each allopatric population preferring the deceptive signals of their sympatric parasite population. Furthermore, in different locales, the triungulin aggregations have adapted their perching height to the height at which local male bees typically patrol for females. "
Saul-Gershenz said that the study “provides strong evidence for two different but complementary types of local adaptation in geographically isolated populations of a parasitic insect.” Specifically, the beetles locally adapt their deceptive chemical signals to the differing pheromone blends of their local host species and “the local nest parasites are significantly more attractive to male bees than nonlocal parasites, using transplant experiments.” The scientists identified the attractant blends for the two host species and the compounds that the beetle larvae produce to attract their hosts. They also showed that the two parasite populations have evolved divergent host-matching behaviors.
“The blister beetle Meloe franciscanus has turned out to be an engaging research subject, commented Saul-Gershenz, who received her doctorate in entomology from UC Davis, studying with Neal Williams and Steve Nadler, professor and chair of the UC Davis Department of Entomology and Nematology. She is now an associate director of research, Wild Energy Initiative, John Muir Institute of the Environment, UC Davis. “The larvae cooperate with their siblings for a brief period; they mimic the pheromone of their hosts; they are locally adapted to different hosts both chemically and behaviorally; and their emergence times are plastic across their geographic range. It has been fantastic to unravel this species' puzzle.”
She credited the counsel of the “true native bee icons in my field"--Robbin Thorp, UC Davis distinguished emeritus professor of entomology; research entomologist Jim Cane, Agricultural Research Service of U.S. Department of Agriculture; research entomologist Tom Zavortink, Bohart Museum of Entomology and former professor and chair of the University of Francisco Department of Biology; blister beetle (Meloidae) expert John Pinto, UC Riverside emeritus professor; and emeritus entomologist Rick Westcott, Oregon Department of Agriculture.
Future plans? Saul-Gershenz and Millar will continue exploring chemical communication signals as reproductive isolating mechanisms and the effect of eavesdropping parasites, parasitoids and predators on these signals. “I also plan to continue collaborating with Dr. Rebecca Hernandez and her lab members (UC Davis Department of Land, Air and Water Resources, and the Wild Energy Initiative of the John Muir Institute of the Environment) on the intersection of utility-scale solar energy development and our wildlife resources,” Saul-Gershenz said. In addition, she will continue her research on the impact on native bee diversity and pollination services from utility-scale solar development in the western deserts.
The research drew funding from Sean and Anne Duffey and Hugh and Geraldine Dingle Research Fellowship, the Community Foundation's Desert Legacy Fund, California Desert Research, Disney Wildlife Conservation Fund, and UC Davis Department of Entomology and Nematology fellowships.
- Author: Kathy Keatley Garvey
(Embargo lifts at noon, Pacific Time, April 30)
The research, published April 30 in the Proceedings of the National Academy of Sciences, indicates that inhibiting an enzyme, soluble epoxide hydrolase--discovered in the Bruce Hammock lab at UC Davis--may reduce the risk of obesity-related inflammation of the colon.
Co-first authors Weicang Wang and Jianan Zhang of the Guodong Zhang lab, Department of Food Science, University of Massachusetts (UMass) and Jun Yang of the Hammock lab and the UC Davis Comprehensive Cancer Center, noted that 30 percent of Americans are obese, and these individuals have a 30 to 60 percent higher risk of developing colon cancer. It is the third most common cancer and the second leading cause of cancer-related deaths in the United States. Colon inflammation is an early symptom of cancer.
“But to date, the mechanisms by which obesity increases cancer risks are not well understood, and there are few effective strategies to prevent obesity-enhanced colon cancer, said co-author Guodong Zhang, a former postdoctoral researcher in the Hammock lab and now an assistant professor of food science at UMass where he focuses his research on prevention of colonic inflammation (inflammatory bowel disease) and colon cancer.
“Our study showed that soluble epoxide hydrolase and its metabolites are over-expressed in colon of obese mice,” Zhang said. “In addition, we found that pharmacological inhibition or genetic deletion of soluble epoxide hydrolase (sEH) abolishes obesity-induced inflammation and activation of pro-tumorigenic pathways in colon. These results showed that sEH is an essential enzyme involved in obesity-enhanced colonic inflammation and potentially colon cancer, and pharmacological inhibitors of sEH could be novel agents for prevention of these diseases.”
In the study, the 18-member team, including five UC Davis researchers, investigated the roles of sEH in obesity-induced colonic inflammation, which included using two different sEH inhibitors and a knockout mouse genetically modified not to produce sEH. Results proved similar in all cases.
They further conducted another study in both lean and obese mice with experimentally induced colon inflammation and used molecular analyses to follow a pathway called Wnt. About 90 percent of sporadic colorectal cancers have activating mutations within the Wnt pathway. The team found that obesity increases activation of Wnt signaling in the colon, but it can be abolished by the two different inhibitors and the knockout.
“The sEH inhibitor blocked obesity-induced colon inflammation,” said co-author Bruce Hammock, distinguished professor of entomology who holds a joint appointment with the UC Davis Comprehensive Cancer Center. “This worked even for mice on high fat diets.”
“Colon inflammation is highly associated with a variety of diseases and the inflammation often progresses to colon cancer,” Hammock said. “Weicang Wang, Guodong Zhang and co-workers have done a meticulous job investigating the biologically active fats including fatty acid diols that are associated with the inflammation. By blocking the production of these diols they were able to block the inflammation.”
Co-authors Jun Yang, Debin Wan, Jia Sun of the Hammock lab, as well as Jun-Yan Liu of China, a former postdoctoral researcher in the Hammock lab, did the analytical chemistry, and co-author Sung Hee Hwang of the Hammock lab did the organic chemistry, making the compounds that were used.Jun-Yan Liu is already collecting human samples to test the hypothesis in man, Hammock revealed.
The soluble epoxide hydrolase inhibitors that block production of these diols will soon enter human clinical trials supported by the NIH-NINDS Blueprint Program (National Institutes of Health's National Institute of Neurological Disorders and Stroke). “These drugs could provide relief for patients with a wide variety of inflammatory bowel diseases and possibly reduce obesity driven colon cancer,” Hammock said.
The team hailed this as a promising treatment in humans, but acknowledged that “mice and humans are very different.” However, Jun-Yan Liu is already collecting human samples to extend the study, and Hammock pointed out that they hope that the soluble epoxide hydrolase inhibitor will be in human clinical trials this year.
“The study was an exciting discovery from lipidomics technique,” said co-lead author Jun Yang. “The consistent results from pharmacologic inhibition and genetic knockout (KO) as well as the signaling pathway mechanistic studies all support sEH as a potential treatment for obesity- induced colon inflammation. “
Noted pathologist Guang-Yu Yang, M.D., Ph.D. of the Feinberg School of Medicine, Northwestern University, Chicago, who was not involved in the study, observed that the Zhang and Hammock labs “have now sequentially demonstrated that 1) there is an increased expression of sEH and its eicosanoid metabolites in the colons of high fat diet-induced obese mice; and 2) the knockout or inhibition of sEH ablates obesity-induced colonic inflammation and decreases obesity-induced activation of Wnt signaling. This study raises interest in further investigating whether the ablation of obesity-induced colonic inflammation by sEH knockout or inhibition may lead to inhibition of obesity-promoted colorectal carcinogenesis.”
“Thus far, non-steroidal anti-inflammatory drugs (NSAIDs) and Cyclooxygenase 2 (COX-2) inhibitor (coxibs) have been the most promising agents for the prevention of colorectal cancer,” Yang said. “However, the side effect profile and risk of adverse events including gastrointestinal (GI) bleeding and cardiovascular events frequently prohibit their widespread clinical use.”
The pathologist said that “co-targeting sEH and COX-2 to manipulate eicosanoid metabolites has the high potential to synergistically enhance the inhibition of obesity-promoted inflammation and carcinogenesis while also reducing the adverse effects of coxibs and NSAIDs.”
The five UC Davis researchers—Bruce Hammock, Jun Yang, Jia Sun, and Sung Hee Hwang and Debin Wan—are all with the Hammock lab and the UC Davis Comprehensive Cancer Center.
Other UMass researchers were Yuxin Wang, Wiepeng Qi, Haixia Yang, and Professor Yeonhwa Park, Department of Food Science, Katherine. Sanidad, Food Science and Molecular and Cellular Biology Graduate Program, and Professor Daeyoung Kim ofthe Department of Mathematics and Statistics.
The abstract: “Obesity is associated with enhanced colonic inflammation, whichis a major risk factor for colorectal cancer. Considering the obesityepidemic in Western countries, it is important to identify noveltherapeutic targets for obesity-induced colonic inflammation, todevelop targeted strategies for prevention. Eicosanoids are endogenouslipid signaling molecules involved in regulating inflammationand immune responses. Using an LC-MS/MS–based lipidomics approach,we find that obesity-induced colonic inflammation is associatedwith increased expression of soluble epoxide hydrolase (sEH)and its eicosanoid metabolites, termed fatty acid diols, in colon tissue.Furthermore,we find that pharmacological inhibition or genetic ablation of sEH reduces colonic concentrations of fatty acid diols,attenuates obesity-induced colonic inflammation, and decreasesobesity-induced activation ofWnt signaling in mice. Together, theseresults support that sEH could be a novel therapeutic target forobesity-induced colonic inflammation and associated diseases.”
This work, titled “Lipidomic Profiling Reveals Soluble Epoxide Hydrolase as a Therapeutic Target of Obesity-Induced Colonic Inflammation,” drew grant support from the USDA's National Institute for Food and Agriculture; National Institutes of Health's National Institute of Environmental HealthSciences (NIH/NIEHS); NIEHS Superfund Research Program, and the National Natural Science Foundation of China.
Hammock, a member of the National Academy of Sciences and the National Academy of Inventors, directs two major UC Davis programs; the Superfund Program financed by the National Institute of Environmental Health's National Institute of Environmental Health Sciences (NIH-NIEHS); and the NIH Biotechnology Training Program.
The Hammock laboratory has published almost 900 peer-reviewed papers on the sEH enzyme, discovered while Hammock and Sarjeet Gill (now of UC Riverside) were researching insect developmental biology and green insecticides at UC Berkeley. The work, begun in 1969, led to the discovery that many regulatory molecules are controlled as much by degradation as by biosynthesis, Hammock said. These epoxy fatty acid chemical mediators control blood pressure, fibrosis, immunity, tissue growth, and pain and inflammation.
For many years Gill and Hammock were alone in studying this enzyme but today its importance is well recognized in mammalian biology, with more than 17,000 peer-reviewed papers in the area. Hammock credits the NIEHS for supporting research in this area since the 1970s.
A Davis-based company, EicOsis, has received a large grant from the U.S. National Institutes of Health to move inhibitors to the clinic to treat diabetic neuropathic pain. “We are developing a non opiate analgesic to treat the chronic pain often associated with diabetes and hope to be in human trials over the next 12 months,” said William Schmidt, vice president of clinical development at EicOsis.
- Author: Kathy Keatley Garvey
“We think that this research will lead to a very positive outcome to improve the lives of cystic fibrosis patients,” said co-author Bruce Hammock, distinguished professor in the UC Davis Department of Entomology and Nematology who holds a joint appointment with the UC Davis Comprehensive Cancer Center.
The research, published in the current edition of the Proceedings of the National Academy of Sciences, links a newly discovered class of bacterial enzymes to battling cystic fibrosis, a progressive, genetic disease characterized by persistent lung infections and inability to breathe normally.
Senior author Jennifer Bomberger of the Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine explained that the opportunistic bacterium, Pseudomonas aeruginosa, outcompetes other microorganisms in a cystic fibrosis patient's lungs and establishes a stronghold.
The scientific discovery could lead to new therapies that would interrupt or correct the bacterial sabotage, Hammock and Bomberger said.
“This paper is the outcome of an exciting and interdisciplinary project,” said Hammock, who directs the UC Davis Superfund Program financed by the National Institutes of Health's National Institute of Environmental Health Sciences (NIH-NIEHS).
“It started several years ago with the NIEHS Superfund Program funding both a group at Dartmouth and at UC Davis. A very productive and exciting collaboration resulted in looking at how to mitigate the effects of environmental chemicals on human health. Our collaborative work led to this joint publication which yields exciting hope for cystic fibrosis patients.”
Bomberger continues to work on the biology of the system while the Dartmouth and Davis groups have developed inhibitors of the action of CIF to stabilize pro-resolving mediators, reduce inflammation, and control periodic flare ups of bacterial infections.
"It will be key to devise a way to remove P. aeruginosa's ability to capitalize on the body's natural inflammatory response, without eliminating that response," said Bomberger. "Inflammation is happening for a reason—to clear infection. We just need it to temper the response when it is not effectively doing its job or is no longer needed."
Other co-authors of the paper include Hammock lab members Christophe Morisseau and Jun Yang, both from the UC Davis Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center. .Institutions involved in the study also included the Harvard School of Medicine.
- Author: Kathy Keatley Garvey
(News embargo lifts at noon Monday, May 19, 2014, Pacific Time)
Listen to Video, Robert Reiner (YouTube, Created by Professor James Carey)
DAVIS--Newly published research involving a 12-year study of dengue infections in Iquitos, Peru—an international team project led by researchers at the University of California, Davis—helps explain why interventions are frequently unsuccessful in efforts to prevent the mosquito-borne disease.
The research, headed by Professor Thomas Scott of the UC Davis Department of Entomology and Nematology, is published May 19 in Proceedings of the National Academy of Sciences (PNAS).
"Defining variation in the risk of dengue transmission has been a roadblock to understanding disease dynamics and designing more realistic and effective disease prevention programs,” said Scott, noted dengue researcher and a senior author of the paper, “Time-Varying, Serotype-Specific Force of Infection of Dengue Virus.”
“This study is an important step toward overcoming that obstacle,” Scott said. “We hope our results will help reduce the burden of this increasingly devastating disease."
“Typically, most infections go unnoticed and as such, measuring and modeling transmission intensity is problematic,” Reiner said.
Dengue virus is transmitted by Aedes aegypti, a mosquito that bites during the daytime as people move about in their daily routines.
“Our work suggests that certain serotypes can infect up to 33 percent of the susceptible population in a single year and that 79 percent of the population of Iquitos would need to be protected from any further infection to eliminate transmission. Further, our estimates form a detailed description of virus transmission dynamics that provides a basis for understanding the long-term persistence of dengue and for improving disease prevention programs.”
Reiner, who holds a doctorate in statistics from the University of Michigan, joined the Scott lab in September 2011. He has just accepted a position as assistant professor in the Department of Epidemiology and Biostatistics, Indiana University, Bloomington.
“The marked variation in transmission intensity that we detected indicates that intervention targets based on one-time estimates of the force of infection (FoI) could underestimate the level of effort needed to prevent disease,” the authors wrote in their abstract. “Our description of dengue virus transmission dynamics is unprecedented in detail, providing a basis for understanding the persistence of this rapidly emerging pathogen and improving disease prevention programs.”
“There is no vaccine nor drug that is effective against this virus,” said Scott, who has studied dengue more than 25 years and is recognized as the leading expert in the ecology and epidemiology of the disease.
While vaccines are under development, it is not clear how they can be best applied when they are available, including in combination with other interventions like mosquito control, Scott said. “New disease prevention tools, in addition to vaccines, and an improved understanding of virus transmission dynamics, which will enhance surveillance and epidemic response, are needed to reduce the global burden of dengue.”
The work was supported by the RAPPID program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health; Innovative Vector Control Consortium; U.S. Department of Defense Global Emerging Infections Systems Research Program Work Unit; Military Infectious Disease Research Program Work Units; Deployed Warfighter Protection Program, Department of Defense; and a Wellcome Trust.