Institute for Integrative Toxicology
News Article | May 8, 2017
EAST LANSING, Mich. -- When it comes to research warning us about the latest health risks or touting the latest cure, a new Michigan State University study indicates that many people won't trust the findings when an industry partner, even with a good reputation, is involved. The study, now published in PLOS ONE, could present scientists with the additional dilemma of finding alternative funding sources, especially during a time when federal funding may be scarce, that won't jeopardize the perceived integrity of their research. "People have a hard time seeing research related to health risks as legitimate if done with a corporate partner," said John Besley, lead author and an associate professor who studies the public's perception of science. "This initial study was meant to understand the scope of the problem. Our long-term goal though is to develop a set of principles so that quality research that's tied to a company will be better perceived by the public." Using research about genetically modified foods and trans fats, study participants were randomly assigned to evaluate one of 15 different partnership scenarios that included varying combinations of scientists from a university, a government agency, a non-governmental organization and a large food company. The results clearly showed that the public's skepticism increased substantially when a food company was in the mix. In fact, in one portion of the study, 77 percent of participants who were asked to describe their views about this type of partnership scenario had something negative to say about it and questioned whether it could produce good results. When the partnership didn't include a corporate partner, only 28 percent of participants said something negative. The research also indicated that this unfavorable perception didn't change much, even if other entities, such as the Centers for Disease Control and Prevention, were included as additional partners. "This tells us that you can't just add organizations from various sectors and hope people will expect these partners to balance each other out," Besley said. According to Besley, scientists often spend a good portion of their time trying to find the resources to pay for things like equipment, data collection and staff for their research projects. And as federal and state funding continues to hang in the balance, along with ever-increasing competition for grant dollars, this makes looking for alternative funding sources a priority. "Ultimately, the hope is to find some way to ensure quality research isn't rejected just because of who is involved," Besley said. "But for now, it looks like it may take a lot of work by scientists who want to use corporate resources for their studies to convince others that such ties aren't affecting the quality of their research." Additional MSU contributors include Nagwan Zahry, in the College of Communication Arts and Sciences; Aaron McCright and Kevin Elliott, Lyman Briggs College; Norbert Kaminski, Institute for Integrative Toxicology; as well as Joseph Martin, University of Leeds, United Kingdom. MSU's Science and Society at State, or S3, funded the study. Michigan State University has been working to advance the common good in uncommon ways for more than 150 years. One of the top research universities in the world, MSU focuses its vast resources on creating solutions to some of the world's most pressing challenges, while providing life-changing opportunities to a diverse and inclusive academic community through more than 200 programs of study in 17 degree-granting colleges.
News Article | May 9, 2017
Marijuana isn’t exactly synonymous with mental sharpness, but surprising new research has found that it might help protect the brain from the effects of aging. A German study on mice published in the journal Nature Medicine found that low, regular doses of tetrahydrocannabinol (THC), the psychoactive ingredient found in marijuana, may help to keep our brains from slowing down as we get older. For the study, researchers from the University of Bonn and Hebrew University spent a month giving daily THC to mice that were two months, one year, and 18 months old, and studied the effects on each. Scientists first tested the mice on their ability to recognize familiar objects and navigate a water maze without the influence of THC and found that, while younger mice did well, older mice struggled. Once they were given THC, the younger mice had a drop in performance, but older mice showed improvement that lasted for weeks afterward — and even did as well as younger mice that had no THC. Researchers say that THC in older mice might stimulate the brain’s endocannabinoid system, a group of brain and nervous system receptors that become less active as we age. Of course, the study was conducted on mice, not humans, and it’s too soon to recommend that adults start taking daily doses of THC based on this. But The Guardian reports that the scientists are planning to start a clinical trial to test this on humans later this year. “If we can rejuvenate the brain so that everybody gets five to 10 more years without needing extra care, then that is more than we could have imagined,” study co-author Andras Bilkei-Gorzo told The Guardian. Norbert E. Kaminski, PhD, director of the Institute for Integrative Toxicology at Michigan State University, tells Yahoo Beauty that while it’s too soon to draw any conclusions from the research, there may be something to it. “If low doses of THC decrease decline in cognitive function in senior citizens, this could be beneficial,” he says. Kaminski also notes that many diseases that cause a decline of cognitive function, such as Alzheimer’s disease and Parkinson’s disease, are thought to be due, in part, to chronic inflammation in the brain. Cannabinoids like THC have anti-inflammatory properties, he says, which may be beneficial for some older patients suffering from certain neurodegenerative diseases. Gary Wenk, PhD, a professor in the departments of Psychology & Neuroscience & Molecular Virology, Immunology, and Medical Genetics at the Ohio State University and Medical Center who is a member of the Governor’s Marijuana Advisory Committee, agrees. He tells Yahoo Beauty that the research “presents clear evidence for the cognitive and neurological benefits of low-dose marijuana use in the aging brain.” Wenk, who also has studied the impact of low-dose cannabinoids, says THC acts by reducing brain inflammation and its consequences upon normal brain function as people age. “It’s a very positive effect that is seen at quite low doses,” he says. Seth Ammerman, MD, a clinical professor at Stanford University’s department of pediatrics in the division of adolescent medicine, tells Yahoo Beauty that THC affects younger brains differently because it can disrupt normal pathways of brain development. But once a person’s brain has fully developed, Ammerman says, it’s “possible” that THC can help stabilize elements in the endocannabinoid system so that the effects of aging on the brain are tempered in a way. Of course, THC is responsible for the high that people feel from marijuana, so dosing is important. Women’s health expert Jennifer Wider, MD, tells Yahoo Beauty she has some concerns. “It has been well-established that THC comes along with side effects — even in older people,” she says, listing anxiety, paranoid thinking patterns, drowsiness, slowed sense of time, and dizziness as examples. “More research will be needed before this could become an accepted therapeutic modality.” Ammerman agrees, noting that “there are still a lot of unanswered questions.” Follow us on Instagram, Facebook, and Pinterest for nonstop inspiration delivered fresh to your feed, every day. For Twitter updates, follow @YahooStyle and @YahooBeauty.
Kopec A.K.,Institute for Integrative Toxicology |
Joshi N.,Institute for Integrative Toxicology |
Joshi N.,Michigan State University |
Lash L.H.,Wayne State University |
And 4 more authors.
Toxicological Sciences | Year: 2017
Trichloroethylene (TCE) is a persistent environmental contaminant proposed to contribute to autoimmune disease. Experimental studies in lupus-prone MRL+/+mice have suggested that TCE exposure can trigger autoimmune hepatitis. The vast majority of studies examining the connection between TCE and autoimmunity utilize this model, and the impact of TCE exposure in other established models of autoimmune liver disease is not known. We tested the hypothesis that TCE exposure exacerbates experimental hepatic autoimmunity in dominant negative transforming growth factor beta receptor type II (dnTGFBRII) mice, which develop serological and histological features resembling human primary biliary cholangitis. Female 8-week-old wild-type and dnTGFBRII mice were exposed to TCE (0.5 mg/ml) or vehicle (1% ethoxylated castor oil) in the drinking water for 12 or 22 weeks. Liver histopathology in 20- and 30-week-old wild-type mice was unremarkable irrespective of treatment. Mild portal inflammation was observed in vehicle-exposed 20-week-old dnTGFBRII mice and was not exacerbated by TCE exposure. Vehicle-exposed 30-week-old dnTGFBRII mice developed anti-mitochondrial antibodies, marked hepatic inflammation with necrosis, and hepatic accumulation of both B and T lymphocytes. To our surprise, TCE exposure dramatically reduced hepatic parenchymal inflammation and injury in 30-week-old dnTGFBRII mice, reflected by changes in hepatic proinflammatory gene expression, serum chemistry, and histopathology. Interestingly, TCE did not affect hepatic B cell accumulation or induction of the anti-inflammatory cytokine IL10. These data indicate that TCE exposure reduces autoimmune liver injury in female dnTGFBRII mice and suggests that the precise effect of environmental chemicals in autoimmunity depends on the experimental model. © The Author 2017.
Maiuri A.R.,Institute for Integrative Toxicology |
Hession S.L.,Center for Statistical Training and Consulting |
Hession S.L.,Michigan State University
Journal of Pharmacology and Experimental Therapeutics | Year: 2017
Idiosyncratic drug-induced liver injury (IDILI) typically occurs in a small fraction of patients and has resulted in removal of otherwise efficacious drugs from the market. Current preclinical testing methods are ineffective in predicting which drug candidates have IDILI liability. Recent results suggest that immune mediators such as tumor necrosis factor-A (TNF) and interferon-g (IFN) interact with drugs that cause IDILI to kill hepatocytes. This proof-of-concept study was designed to test the hypothesis that drugs can be classified according to their ability to cause IDILI in humans using classification modeling with covariates derived from concentration-response relationships that describe cytotoxic interaction with cytokines. Human hepatoma (HepG2) cells were treated with drugs associated with IDILI or with drugs lacking IDILI liability and cotreated with TNF and/or IFN. Detailed concentration-response relationships were determined for calculation of parameters such as the maximal cytotoxic effect, slope, and EC50 for use as covariates for classification modeling using logistic regression. These parameters were incorporated into multiple classification models to identify combinations of covariates that most accurately classified the drugs according to their association with human IDILI. Of 14 drugs associated with IDILI, almost all synergized with TNF to kill HepG2 cells and were successfully classified by statistical modeling. IFN enhanced the toxicity mediated by some IDILI-Associated drugs in the presence of TNF. In contrast, of 10 drugs with little or no IDILI liability, none synergized with inflammatory cytokines to kill HepG2 cells and were classified accordingly. The resulting optimal model classified the drugs with extraordinary selectivity and specificity. © 2017.
Henriquez J.E.,Michigan State University |
Henriquez J.E.,Institute for Integrative Toxicology |
Rizzo M.D.,Michigan State University |
Rizzo M.D.,Institute for Integrative Toxicology |
And 6 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2017
Plasmacytoid dendritic cells (pDCs) play a crucial role in host antiviral immune response through secretion of type I interferon. Interferon alpha (IFNα), a type I IFN, is critical for mounting the initial response to viral pathogens. A consequence of Human Immunodeficiency Virus-1 (HIV) infection is a decrease in both pDC number and function, but prolonged pDC activity has been linked with progression from HIV infection to the development of AIDS. Patients with HIV in the United States routinely use cannabinoid-based therapies to combat the side effects of HIV infection and antiretroviral therapy. However, cannabinoids, including Δ9-tetrahydrocannabinol (THC), are well-characterized immunosuppressants. Here, we report that THC suppressed secretion of IFNα by pDC from both healthy and HIV+ donors through a mechanism involving impaired phosphorylation of interferon regulatory factor 7. These results suggest that THC can suppress pDC function during the early host antiviral response by dampening pDC activation. © Copyright 2017 Wolters Kluwer Health, Inc. All rights reserved.
PubMed | Institute for Integrative Toxicology, University of Oslo, Michigan State University, Biochemistry & Molecular Biology; and 2 more.
Type: Journal Article | Journal: Toxicological sciences : an official journal of the Society of Toxicology | Year: 2016
We have previously shown that in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited NAFLD progression, central carbon, glutaminolysis, and serine/folate metabolism are reprogrammed to support NADPH production and ROS defenses. To further investigate underlying dose-dependent responses associated with TCDD-induced fibrosis, female C57BL/6 mice were gavaged with TCDD every 4 days (d) for 28 d or 92 d. RNA-Seq, ChIP-Seq (2h), and 28 d metabolomic (urine, serum, and hepatic extract) analyses were conducted with complementary serum marker assessments at 92 d. Additional vehicle and 30 g/kg treatment groups were allowed to recover for 36 d following the 92-d treatment regimen to examine recovery from TCDD-elicited fibrosis. Histopathology revealed dose-dependent increases in hepatic fat accumulation, inflammation, and periportal collagen deposition at 92 days, with increased fibrotic severity in the recovery group. Serum proinflammatory and profibrotic interleukins-1, -2, -4, -6, and -10, as well as TNF- and IFN-, exhibited dose-dependent induction. An increase in glucose tolerance was observed with a concomitant 3.0-fold decrease in hepatic glycogen linked to increased ascorbic acid biosynthesis and proline metabolism, consistent with increased fibrosis. RNA-Seq identified differential expression of numerous matrisome genes including an 8.8-fold increase in Tgfb2 indicating myofibroblast activation. Further analysis suggests reprogramming of glycogen, ascorbic acid, and amino acid metabolism in support of collagen deposition and the use of proline as a substrate for ATP production via the proline cycle. In summary, we demonstrate that glycogen, ascorbic acid, and amino acid metabolism are also reorganized to support remodeling of the extracellular matrix, progressing to hepatic fibrosis in response to chronic injury from TCDD.