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Research Highlights, Activities, and Publications

Vol. 14, Issue 1: July-Sept 2015

Senators Visit NCTR

Read about their visit.

U.S. Senator John Boozman, R-Ark.

U.S. Senator Jerry Moran, R-Kan.

Fructose Metabolism in Human Adiopcytes

Scientists from NCTR, Harbor-UCLA Medical Center, University of Ulm (Germany), and Nestle Institute of Health Sciences (Switzerland) have shown that fructose stimulates anabolic processes in adipocytes (fat cells) including: 1) increased glutamate and fatty acid synthesis and 2) increased fatty acid release from adipocytes. To study the metabolic responses to fructose, targeted stable isotope methods were used in cultured human fat cells that were exposed to a range of fructose concentrations equivalent to that reported in blood after consuming fructose. Additional in vivo studies are warranted as these results suggest that fatty acid accumulation is a key consequence of fructose metabolism in adipocytes. This study is available online atMetabolomics.

For additional information, contact Vijayalakshmi Varma, Biomarkers and Alternative Models Branch, Division of Systems Biology, or Richard Beger, Director, Biomarkers and Alternative Models Branch, Division of Systems Biology, FDA/NCTR.

miRNA Regulation as a Biomarker of Carcinogenicity

Scientists from FDA's NCTR, Dalian Medical University (China), and Universidad de Granada (Spain) utilized an integrated approach to assess the utility of miRNA regulation as a marker of carcinogenicity. Kidney samples from rats treated orally with a carcinogenic dose of aristolochic acid (an IARC Group I carcinogen and known rat-kidney carcinogen) were analyzed for miRNA and messenger RNA expression using deep sequencing and protein expression using proteomics. The analyses identified 63 miRNAs that were dysregulated in response to aristolochic acid. Half of the miRNAs were closely associated with cancer initiation and progression, as well as a cancer-related network associated with miRNA target regulation. This novel approach provides information on miRNA target regulation on a genome-wide scale and supports the application of miRNA expression as a biomarker of carcinogenicity. This study is now available online at BMC Genomics .

For additional information, please contact Tao Chen, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.

NCTR's Summer Student Research Program

During NCTR's 2015 Summer Student Research Program undergraduate and graduate students were paired with NCTR scientists and worked one-on-one with their mentors to gain hands-on research experience. This year's program hosted 23 students from colleges and universities representing 12 different states.

Sixteen undergraduates in the NCTR summer program also participated in the 4th Annual Central Arkansas Undergraduate Summer Research Symposium at the University of Arkansas for Medical Sciences. They presented a total of 15 poster presentations and one oral presentation of their 10-week summer research projects. NCTR’s participants received three of the seven awards for best poster presentations. Participation in this annual symposium allows NCTR to partner with other summer undergraduate research programs in central Arkansas to support training and professional development for the next generation of scientists.

For additional information, please contact Nysia George, Ph.D., Biostatistics Branch, Division of Bioinformatics and Biostatistics, FDA/NCTR or Laura Schnackenberg, Ph.D, Biomarkers and Alternative Models Branch, Division of Systems Biology, FDA/NCTR.

Dr. Orish Orisakwe,Visiting Scientist from Nigeria

NCTR welcomed Dr. Orish Ebere Orisakwe from Nigeria to conduct a three-month study stopover at FDA’s premier regulatory science research Center. His visit was coordinated through the Oak Ridge Institute for Science and Education (ORISE) Visiting Scholar program.

During his visit, he rotated through various research divisions and offices at NCTR, attended seminars, presentations, and workshops. Dr. Orisakwe shared his Nigerian research experience and reviewed divisional research on endocrine disruptors and epigenetics. He expressed interest in a possible collaboration with the Division of Biochemical Toxicology, citing NCTR’s state-of-the-art facilities and the tie-in to the mechanistic approach studies now being introduced at his University of Port Harcourt in Rivers State, Nigeria.

The bioinformatics research field is in the emerging stage in Nigeria regulatory science. Dr. Orisakwe expressed that certain aspects of research being conducted in NCTR’s Division of Bioinformatics and Biostatistics could help boost ongoing research and graduate toxicology studies for which he has responsibility. He believes that bioinformatics, and the models it utilizes, could prove a strong research tool for, “a lean nation like Nigeria in the development of predictive toxicology,” which would boost both preventive medicine and public health in the country.

Dr. Orisakwe concluded his visit saying, “I will be most delighted if my ORISE Visiting Scholar program [is] extended three months every year for the next three years (2016-2018) studying at NCTR. This will enable me to consolidate [activities] that will be of huge benefit in developing the toxicology program at my University and Nigeria at large.” Center Director Dr. William Slikker concurred, agreeing such an arrangement could prove beneficial to all.

Pediatric Anesthetic Effects on Lipid Metabolism in the Developing Brain

NCTR investigators, in collaboration with the University of Arkansas for Medical Sciences and the Sanford-Burnham Medical Research Institute at Lake Nona (Florida), have demonstrated significant changes in gene expression, cytokine levels, lipid content and composition, and enhanced neuronal damage in brains from infant nonhuman primates exposed to clinically relevant concentrations of sevoflurane (2.5%)—an anesthetic—for prolonged periods (9 hours). The use of lipidomics in this study is a novel approach to identify potential biomarkers and underlying mechanisms of anesthesia-induced neurotoxicity, and this study indicates that lipids could be sensitive indicators of brain status after anesthetic exposure. A manuscript describing this study is now available online at Toxicological Sciences.

For additional information, please contact Fang Liu, Ph.D, Division of Neurotoxicology or Merle Paule, Ph.D., Director, Division of Neurotoxicology, FDA/NCTR.

Bile Acids as Biomarkers of Drug-Induced Liver Injury

Scientists from NCTR, the University of Arkansas for Medical Sciences, Arkansas Children’s Hospital Research Institute, the Medical College of Wisconsin, and Children’s Mercy Hospital (Kansas City) explored the utility of metabolomics to discover blood biomarkers for evaluating the degree of liver injury in pediatric acetaminophen (APAP) overdose patients. The study showed an increase in five bile acids in APAP overdose patients compared to healthy controls. Additionally, three conjugated bile acids were found to have strong correlations to patients with high levels of APAP adducts. However, APAP protein adduct levels more accurately distinguished between patients with APAP overdose, low-dose exposure to APAP, and healthy controls. In overdose patients, bile acid elevations were associated with indicators of APAP metabolism and non-specific indicators of liver injury. This study illustrates the utility of metabolomics in biomarker discovery and suggests a potential role for bile acid profiles as biomarkers of drug-induced liver injury in drug development. A manuscript describing this study is available online at PLoS ONE.

For additional information, please contact Richard Beger, Ph.D., Director, Biomarkers and Alternative Models Branch, Division of Systems Biology, FDA/NCTR.

Flow Cytometric Method to DetectEscherichia coliO157:H7 in Spinach

Scientists from NCTR, FDA's Arkansas Regional Laboratory, and Vivione Biosciences, LLC. demonstrated that an NCTR-developed flow cytometry method reduced the total time to results to nine hours for low levels of inoculum in comparison to 51 hours for the standard BAM method, while retaining the same level of sensitivity in both methods. This analysis was part of an FDA level-2 external laboratory validation study designed to determine the method’s sensitivity and speed for analysis. Results of the study are available online at International Journal of Food Microbiology .

For additional information, please contact Dan Buzatu, Ph.D., or Jon Wilkes, Ph.D., Innovative Safety and Technologies Branch, Division of Systems Biology, FDA/NCTR.

Neuroprotective Effects of Acetyl-L-Carnitine

NCTR scientists have shown that acetyl-L-carnitine prevented dopamine transporter loss, dopaminergic neuronal-cell death and nerve conduction deficits in a rotenone-induced rat model of Parkinson’s disease. Rats with prolonged exposure to the pesticide rotenone demonstrated decreased motor conduction velocity and increased motor latency. Additionally, immunohistochemical analysis showed decreased tyrosine hydroxylase and dopamine transporter staining in brain tissue; whereas, co-treatment with acetyl-L-carnitine reduced these effects. These results are consistent with previous studies demonstrating neuroprotective properties of acetyl-L-carnitine and suggest a potential neuroprotective therapy for Parkinson’s disease. Results of the study are available online atNeuroscience Letters .

For additional information, please contact Zbigniew Binienda, DVM, Ph.D., or Sumit Sarkar, Ph.D., Division of Neurotoxicology, FDA/NCTR.

Mechanism of Cell Death in Macrophages Infected with FoodborneSalmonellaStrain

NCTR researchers have discovered that the cytolethal distending toxin B (CdtB) gene may play an important role in determining the toxicity of certain nontyphoidal strains of Salmonella. This study was featured on the cover of the journal DNA and Cell Biology and is currently available online .

CdtB is a conserved virulence factor inSalmonella entericaserovar Typhi, which has demonstrated great success as a human pathogen; it is the agent of typhoid fever. Current research results demonstrate that the CdtB gene can also be found in certain nontyphoidalSalmonella strains including SalmonellaJaviana, one of the five most commonly identified serotypes causing human illness in the United States. This result, combined with other study observation suggests the CdtB virulence factor can spread to other bacteria by horizontal transmission. Other study results suggest a mechanism by which the CdtB virulence factor would exert an influence on the infectivity of these non-typhoidal strains. CdtB in S. Javianawas demonstrated to interfere with the role of macrophages causing increased vacuolization and expression of the autophagosome marker LC3. Autophagy is known to both destroy internalized pathogens, and to destroy the infected cell.

For additional information, please contact Sangeeta Khare, Ph.D., Division of Microbiology, FDA/NCTR.