6^th Global Summit on Toxicology and Applied Pharmacology October 17-19, 2016 (10 Plenary Forums - 1 Event)
Houston, Texas, USA

Biography:

Ping Song has completed his PhD in 1994 from Texa Tech University. He is a global regulatory team leader for seeds/traits in Dow Agro Sciences LLC, a R&D driven agricultural company. He has published two book chapters and more than 25 papers in peer-reviewed journals.

Abstract:

When evaluating the potential cross reactivity of a novel protein with known allergens, amino acid sequences are often compared using bioinformatic approaches. A high quality curated database containing allergen sequences is a fundamental requirement for executing sequence comparisons. Existing sequence comparisons have been based on sequence similarity, identical short-mer amino acid matches, motif identification, machine-learning models, and 3-D structure prediction. Tools based on these approaches are publically available and have been investigated for their sensitivity and selectivity. Although fraught with poor specificity and other technical issues, the FAO/WHO/Codex Alimentarius method is the standard for regulatory submissions to government agencies. This approach involves searching for >35% identity over 80 amino acids or more by local alignment algorithms such as FASTA or BLAST. However, the literature has clearly demonstrated that use of amino acid similarity in combination with a statistical measure of power, like E-values, can be equally sensitive but with greater specificity (fewer false-positives). A one-to-one FASA comparison with a biologically relevant E-value as a criterion is such an approach, and this method additionally avoids some of the technical shortfalls of an amino acid identity-based algorithm. In the future, modern genome sequencing techniques offer the promise of increasingly powerful bioinformatic analysis of food proteins for allergenic risk.

Biography:

Amr Amin has completed his PhD at University of Illinois at Chicago and received a Post-doctoral training in the field of molecular genetics at University of Pennsylvania School of Medicine. He started his academic career at UAE University where he currently serves as a Full Professor of Cell Biology. His research focuses on ways to control cancer, particularly liver cancer. He has published many research articles and reviews and serves as reviewer and as an editorial member of many specialized peer-reviewed journals. He is also a member of many specialized societies and the sole recipient of multiple national and international scientific awards.

Abstract:

Liver cancer is the second most common cause of cancer-related death worldwide. The prognosis of patients with liver cancer is usually poor; hence, a novel approach against liver cancer is essential for a better therapeutic outcome. Saffron and its active constituents were reported to have antioxidant, anti-inflammatory and anti-tumor properties. The aim of this study was to investigate chemopreventive action of crocin, one of the promising active constituents of saffron, against diethylnitrosamine (DEN)-induced liver cancer in rats, and the possible mechanisms by which crocin exerts its anti-tumor effects. Findings reported herein demonstrated the anti-proliferative and pro-apoptotic properties of crocin when administrated in DEN-treated rats. Additionally, crocin exhibited anti-inflammatory properties that inhibited NF-kB, among other inflammatory markers. According to our network analysis, NF-kB was identified as a regulatory hub and therefore, a candidate therapeutic drug target. Together, these findings nominate crocin as a candidate chemopreventive and therapeutic agent against HCC.

Biography:

Dr. Sakhila Banu obtained her Bachelors and Master’s degrees from the Madurai Kamaraj University, India. She completed her MPhil and PhD degrees in Endocrinology from the University of Madras, India and pursued her post-doctoral fellowships at the Laval University and University of Montreal. She is currently an Assistant Professor in the Department of Veterinary Integrative Biosciences (VIBS), College of Veterinary Medicine & Biomedical Sciences, Texas A&M University. She started an effective interdisciplinary research program in the field of female reproductive toxicology. Her major goal is to understand the adverse effects of chromium VI, a heavy metal endocrine disruptor in the environment, on female fertility and fetal development. Her research has been funded by the National Institute of Environmental Health Sciences (NIEHS) and the Department of Defense, and other private foundations. She received several awards such as USDA-NRI Merit Award, and Outstanding Scientific Achievement Award, College of Veterinary Medicine & Biomedical Sciences. Her specific research goal is to develop a strong basic research program in Reproductive Toxicology that can be translated to identify new intervention strategies for mitigating adverse effects of heavy metal endocrine disrupting chemicals (EDCs). Her long-term goals are two-fold: 1) to understand the molecular mechanism of heavy metal-induced adverse effects on ovarian and uterine function, pregnancy outcome, and placental and fetal development; 2) to understand the protective effects of various natural and synthetic antioxidants (such as edaravone, glutathione, vitamin C and resveratrol) against the deleterious effects of heavy-metal EDCs.  Current research in her lab is focused on the study of reproductive and developmental toxicity of hexavalent chromium (CrVI). Drinking water contamination with CrVI in the United States is a growing problem due to increased usage of CrVI and improper disposal of Cr waste into the environment. Significant contamination with CrVI has been found in the drinking water sources of all the states in the U.S. Effects of Cr on reproductive health in women and development in children have received less attention. Epidemiological data document that women exposed to Cr in environmental or occupational settings suffer from infertility, gynecological problems, congenital malformation of fetuses, neonatal mortality, and premature abortions with increased levels of Cr in their blood, urine and placenta. Cr can bind directly to DNA and nuclear proteins, cause DNA strand breaks and mutations, alter the balance between reactive oxygen species (ROS) and antioxidants, and activate several cell signaling pathways. Therefore, her current research objective is to determine molecular pathways and identify target genes/proteins by which Cr alters prenatal development and organogenesis of female reproductive system in the offspring.

Abstract:

Environmental exposure to endocrine disruptors (EDCs) is linked to several ovarian diseases such as premature ovarian failure, polycystic ovary syndrome, early menopause and infertility in women. Hexavalent chromium (CrVI) is a heavy metal EDC, widely used in more than 50 industries including chrome plating, welding, wood processing and tanneries. Recent data from USEPA indicate increased levels of Cr in drinking water from several cities in the US, which predisposes Americans to various health problems. Our previous findings demonstrated that prenatal and early postnatal exposure to CrVI caused ovarian failures in F1 offspring. Two main goals of our laboratory are to identify the molecular mechanism behind CrVI-induced reproductive failure, and to identify intervention strategies to mitigate CrVI-induced female reproductive failures. Pregnant rats were treated with potassium dichromate (CrVI) during prenatal period (gestational days) 9.5-14.5, or postnatal period from postnatal day (PND)-1 - 21, through drinking water, and the fetuses or pups were exposed to CrVI through transplacental transfer and mother’s milk, respectively. Ovaries were removed from the fetuses and postnatal rats, and various analyses were performed. Results showed that gestational exposure to CrVI: (i) increased germ cell/oocyte apoptosis and advanced germ cell nest (GCN) breakdown; (ii) increased POF markers spatio-temporally during GCN breakdown; and (iii) decreased POF markers during postnatal follicle development. Resveratrol (RVT), a polyphenolic component in grapes and red wine, has been known for its cytoprotective actions against several diseases. However, beneficial effects of RVT against early exposure to endocrine disrupting chemicals (EDCs) has not been understood. Lactating mother rats that were exposed to CrVI received resveratrol (RVT) supplementation (10 mg/kg body wt., through oral gavage daily). Lactational exposure to CrVI increased atresia of follicles by interfering with steroidogenic pathway and oxidative stress pathways. RVT mitigated the effects of CrVI and protected against CrVI-toxicity of the ovary.

Biography:

Bethany R Baumgart completed her Bachelor of Science degree in Biology in 2009 and Master of Science degree in Biology and Biotechnology in 2011, both from Ball State University. She is a Research Scientist I in Toxicology at Bristol-Myers Squibb Company with roles as a member of the Molecular and In Vitro Toxicology Laboratory as well as nonclinical study director.

Abstract:

Pharmaceutical formulations (vehicles) used to administer test articles to animals often contain excipients to enhance delivery of the test compound. The common excipient d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) increases solubility and maximizes systemic exposure of lipophilic test articles. Given the well established antioxidant properties of d-α-tocopheryl succinate (TS), a component of TPGS, and d-α-tocopherol (TOC), hydrolyzed TS, we examined the potential protective effects of vehicles containing TPGS. Such effects could mask potential toxicities of test articles, including processes involved in carcinogenesis, and impact nonclinical safety assessments. Male and female Sprague-Dawley rats were administered vehicles containing 5% or 40% TPGS (70 or 550 mg/kg/day TS, respectively) orally for 1 week. A control group was administered polyethylene glycol-400 (PEG-400; no vitamin E) orally and positive control animals received a single 100 mg/kg intraperitoneal (IP) injection of TS. Additionally, whole blood from untreated animals was incubated with 5 or 50mM H₂O₂ ex vivo with or without TS (0.5, 5, 50, or 500μM) or ascorbate (1mM), as a positive control, for 1 hour. Plasma, liver, and adrenal gland concentrations of TS and TOC as well as oxidative status of plasma were evaluated following oral administration of TPGS-containing vehicles, IP injection of TS, or treatment of whole blood with H₂O₂ ex vivo. Oral TPGS administration did not affect TOC concentrations in plasma or adrenal glands and caused only transient increases in liver. Concentrations of TS in plasma, liver, and adrenal glands were undetectable in control animals, but increased with administration of vehicles containing 5 and 40% TPGS. Oral administration of TPGS did not reduce plasma lipid peroxidation in vivo. Substantially greater TS concentrations (100× greater than in vivo) added to H₂O₂-treated whole blood ex vivo were also unable to reduce lipid peroxidation. These results provide evidence that administration of oral TPGS vehicles is unlikely to impact nonclinical carcinogenicity safety assessments of pharmaceuticals.

Biography:

Grace-Anne Bent has received PhD from University of the West Indies. She is a lecturer of analytical chemistry in the Department of Chemistry at The University of the West Indies, St. Augustine Campus, Trinidad and Tobago. Her research interests include food safety and security, investigating the chemistry of food and food related toxins in an effort to minimize human exposure by understanding their mechanisms of interaction (in vivo and in vitro). She has published a book and 7 journal articles. She is also the recipient of several research awards.

Abstract:

Exposure to acrylamide (AA) or its metabolite glycidamide (GA), in foodstuffs, is a major concern today. This paper communicates recent developments concerning the role that AA and its metabolite GA, potentially toxic food contaminants, produced on frying, steaming (heat treatments above 100^oC) carbohydrate-based foodstuff via Maillard reaction involving asparagine and reducing sugars. It has been proposed that detoxification of AA and GA occurs primarily via conjugation with thiols via the Michael-addition reaction. Recent investigations to study the reactivity of thiols towards AA and GA included the use of: glutathione (GSH), L-cysteine (CySH) and captopril (CapSH). GSH and CySH are naturally occurring in the body while CapSH is synthetic and usually administered in the form of a drug used for the treatment of congestive heart failure. The kinetic rates of conjugation reactions follow: CySH>GSH>CapSH as opposed to CySH>CapSH>GSH expected based on molecular sizes. Preliminary comparative DFT (density functional theory) calculations on AA and thiols provide information that close hydrogen interactions between GSH and AA; which is absent in CySH and CapSH explains the observed rate trend. Furthermore, preliminary DFT calculations show that there is an open question of H-transfer via intra-molecular GSH or H-transfer via solvent water molecules.

Biography:

Margarita C. Curras-Collazo completed her Ph.D in Medical Physiology from The Ohio State University and postdoctoral studies in neuropharmacology at the University of North Carolina, Chapel Hill and at Emory University. She is an Associate Professor of Neuroscience in the Department of Cell Biology & Neuroscience at the University of California, Riverside. Research in the Curras-Collazo lab focuses on transcellular and biochemical mechanisms underlying neurosecretion in the neuroendocrine hypothalamus as well as the neurotoxicological and endocrine disruptive effects of environmental pollutants such as brominated flame retardants. She has published more than 35 papers in reputed journals and has served as an ad hoc reviewer for the National Science Foundation, American Heart Association, and Department of Defense as well as international agencies.

Abstract:

Organohalogen pollutants such as polychlorinated biphenyls (PCBs ) and polybrominated diphenyl ethers (PBDEs) act as endocrine disrupting chemicals. We have also shown that these toxicants alter vasopressin neurosecretion from magnocellular neuroendocrine cells of the supraoptic nucleus of the rat hypothalamus (SON) and osmoregulatory capacity mediated by vasopressin.  Because VP responses to hyperosmotic stimulation are regulated by nitric oxide (NO) signaling, we studied NO synthase (NOS) activity in the SON as potential target of PCB-induced disruption of neuroendocrine processes. To examine PCB-induced changes in NOS activity under normosmotic and hyperosmotic conditions, male Sprague-Dawley rats were exposed to the industrial PCB mixture, Aroclor 1254 (30 mg/kg/day) during gestation.  NADPH-diaphorase (NADPH-d) activity assessed in SON sections at 3 ages: postnatal day 10, early adult (3-5 months) or late adult (14-16 months). Hyperosmotic treatment increased mean NADPH-d staining density of oil hyperosmotic controls by 19.9% in early adults and 58% in late adulthood vs normosmotic controls. In utero exposure to PCBs occluded hyperosmotic-induced upregulation of NADPH-d activity to control levels in early adults. In contrast, rats that received PCB exposure as early adults orally for 14 days displayed normal NOS responses to hyperosmotic stimulation. Therefore, our findings show that developmental but not adult exposure to PCBs significantly reduces NOS responses to hyperosmolality in neuroendocrine cells. Late adulthood hyperosmotic rats still displayed 28% reduced NOS activity and reduced osmoregulatory capacity during osmotically activated conditions produced by in utero exposure. Plasma osmolality values were 375.0 ± 9 vs 348.6 ± 8 mOsm/L for hyperosmotic late adult rats treated with A1254 vs oil controls, respectively. These findings suggest that developmental PCBs permanently compromise NOS signaling necessary for activated neuroendocrine responses with potential osmoregulatory consequences.

Biography:

Alexei Basnakian received his PhD and DSc degrees from the Russian Academy of Medical Science, both in the field of DNA endonucleases. He had postdoctoral trainings in molecular biology at the Harvard Medical School and in toxicology/cancer research at the National Center for Toxicological Research. Dr. Basnakian is Professor in the Department of Pharmacology and Toxicology, and Director of the DNA Damage and Toxicology Core Center at the University of Arkansas for Medical Sciences, and Research Career Scientist at the Veteran’s Hospital in Little Rock, Arkansas, USA. He is an author of more than 85 peer-reviewed papers and 12 reviews or book chapters. Dr. Basnakian is an Editorial Board member of several biomedical journals, and a member of NIH and VA grant study sections. His research interests are in DNA endonucleases and DNA damage associated with toxicity, anti-cancer therapy, cell injury and cell death.

Abstract:

Apoptotic endonucleases are the enzymes that universally induce irreversible cell death by fragmenting DNA in response to cell injury. While most of the DNase/endonuclease activity is used after cell death, the latest studies showed that genetic inactivation of some endonucleases provide protection of cells and tissues against DNA breaks induced by cytotoxic stimuli. These data suggest that DNases act before the “point of no return” in cell death, and display a possibility for new therapeutics aimed to inhibit endonucleases for tissue protection. However, inhibitors of apoptotic endonucleases are not available. We have developed several high throughput screening assays based on a proprietary fluorescent probe. This assays applied in solution allowed the identification of several new inhibitors of two apoptotic DNases, deoxyribonuclease I (DNase I) and endonucleases G (EndoG). The DNase inhibitors were able to partially protect kidney cells and mice from cisplatin toxicity. These or similar assays have a great promise as tools for new drug discovery.

Biography:

Dr. Renee S Arias in 1988-1992 was Quality control of inoculants based on symbiotic nitrogen fixing bacteria (Rhizobium spp. and Bradyrhizobium japonicum), and effect of fungicides on pre-inoculated leguminous seeds for Rhizobacter Argentina Co., Argentina. He was Teaching Assistant Plant Microbial Interactions, two semesters, Department of Plant Pathology, University of Hawaii, Spring 1995 and Spring 1997. From 2000 – 2002 he was Research Associate, HARC (Hawaiian Agriculture Research Center).  2011 to present Dr. Renee S Arias is a Research Pathologist, at the USDA-ARS-SAA, Peanut diseases with focus on Aflatoxin.

Abstract:

Approximately 4.5 billion people are chronically exposed to aflatoxins, these are powerful carcinogens produced by Aspergillus flavus and A. parasiticus.  High levels of aflatoxins in crops result in approximately 100 million metric tons of cereals, nuts, root crops and other agricultural products being destroyed or diverted to non-human consumption each year.  We have targeted silencing of 5-genes in the aflatoxin biosynthesis pathway of Aspergillus by RNA interference (RNAi) from the plant host to reduce/eliminate aflatoxin accumulation in peanut and maize seeds.  Given that no method existed to analyze the effectiveness of RNAi against aflatoxins, and that testing of hundreds of plants in the field under aflatoxin-conducive conditions is not an option in this case, we developed a method of challenging with aflatoxigenic Aspergillus the RNAi treated seeds, and then analyze those seeds by ultra-performance liquid chromatography (UPLC). In parallel, we developed a workflow to obtain information of those isolates at the DNA sequencing level. This workflow includes fungal isolation, 25 InDel fingerprinting followed by cluster analysis, and whole genome sequencing of clade representatives. This method also allows analysis of small seed pieces for gene expression by real-time PCR (RT-PCR) and small RNA sequencing.  Solving the aflatoxin problem in crops would be equivalent to increasing food production by millions of tons that could be safely consumed instead of being discarded or diverted to other uses.

Biography:

Lawrence C Sowers received his PhD in Physical Biochemistry from Duke University. Following Post-doctoral positions at Harvard and the University of Southern California, he began his independent career at the City of Hope National Medical Center. He then moved on to Loma Linda Medical School and then to the University of Texas Medical Branch where he is currently Professor and Chair of the Department of Pharmacology and Toxicology. He is currently a member of the Cancer Etiology study section and a Member of the Editorial Board of the Journal of Biological Chemistry.

Abstract:

The DNA of all organisms undergoes persistent DNA damage and repair. Additionally, DNA bases undergo enzymatically-mediated modifications involved in both stem cell differentiation and increased immune diversity. Many of these modified bases are removed from DNA by glycosylases of the base excision repair system. Therefore, the released free bases represent the end product of DNA metabolism in most organisms. While a substantial number of investigations have focused on the identification and measurement of modified bases in DNA, few have examined the free bases products released either spontaneously or enzymatically. We have developed a method for examining free bases in extracts of animal tissues which involves HPLC separation followed by GC/MC/MS analysis using stable isotope analogs. The challenges and advantages of this method, which has been applied to the normal rodent brain, will be discussed.

Biography:

Abstract:

The replication-dependent histone genes are the only metazoan genes whose messenger RNA (mRNA) does not terminate with a poly(A) tail at the 3’ end. Instead, the histone mRNAs display a stem-loop structure at their 3’ end. Stem-loop binding protein (SLBP) binds the stem-loop and regulates canonical histone mRNA metabolism.   We report that exposure to arsenic, a carcinogenic metal, decreases cellular levels of SLBP by inducing its proteasomal degradation and inhibiting SLBP transcription via epigenetic mechanisms. Notably, arsenic exposure dramatically increases polyadenylation of canonical histone H3.1 mRNA possibly through downregulation of SLBP expression. The polyadenylated H3.1 mRNA induced by arsenic is not susceptible to normal degradation that occurs at the end of S phase, resulting in continued presence into mitosis, increased total H3.1 mRNA, and increased H3 protein levels.  Excess expression of canonical histones has been shown to increase sensitivity to DNA damage, as well as increase the frequency of missing chromosomes and induce genomic instability. Our hypothesis is that H3.1 genes are initially transcribed with a normal stem-loop construct at the 3’ end of the mRNA. Arsenic depletes nuclear levels of SLBP resulting in H3.1 transcripts unbound to SLBP. These unbound transcripts lose their stem-loop structure at the 3’ end and acquire a poly(A) tail, which increases the half-life and facilitates translation of the mRNA, two factors that provide for increased H3.1 protein levels.  The poly(A) H3.1 mRNA is not susceptible to normal degradation that occurs at the end of S phase allowing for its presence in other phases of the cell cycle. Over-expression of SLBP suppressed the effect of As on H3.1 polyadenylation.   Knockdown of SLBP by siRNA induced anchorage independent growth of BEAS2B cells.  Transfection of Polyadenlated H3.1 but not H3.3 also induced anchorage independent growth in BEAS2B cells. Anchorage independent growth was also induced in human Urothelial cells by transfection of polyadenylated H3.1 but not H3.3.

Biography:

Amira Amin Wahdan has completed her Doctorate degree from Tanta University. She is a lecturer in Forensic Medicine and Clinical Toxicology department, Faculty of Medicine, Tanta University. She is a reviewer in reputed journal.

Abstract:

Metal phosphides are highly effective insecticides and rodenticide. They are used as a cheap rodenticide in developing countries. The aim of this study was to detect the incidence of methemoglobinemia and intravascular hemolysis in some cases of acute phosphide poisoning. This is a cross sectional study which was conducted on 50 cases suffering from acute metal phosphide poisoning admitted to Tanta toxicology unit, from October 2014 till March 2015. For each case, the following were done: history taking, physical examination and laboratory investigations (including measurement of methemoglobin (Met-Hb) level, arterial blood gas analysis, routine investigations, lactate dehydrogenase enzyme and complete blood picture with reticulocytic count). Eight cases (16%) had combined methemoglobinemia and hemolysis. Aluminum phosphide was the toxic agent in seven of them and zinc phosphide in only one. Three cases (6%) had methemoglobinemia alone; one of them was poisoned by aluminum phosphide and the other two by zinc phospide. Another three cases had hemolysis alone; one of them was due to aluminum phosphide and the other two were due to zinc phospide. So the present study included a total of eleven cases (22%) of methemoglobinemia. The mean Met-Hb level was 14.45±9.32% and1.63±0.45% in cases with high and normal Met-Hb level respectively, with a significant statistical difference between both. Furthermore, the mean oxygen saturation showed a significant statistical difference between both. A total of eleven cases (22%) of hemolysis were also included. It was concluded that methemoglobinemia and hemolysis can complicate the course of acute phosphide poisoning.

Biography:

Natasa Petronijevic, MD, PhD has finished her PhD thesis in 2001 at the School of Medicine, University of Belgrade, Serbia. She is a specialist of Clinical Biochemistry and Laboratory Medicine. She is a project leader of scientific projects financed by Serbian Government Ministry of Science and a reviewer in several respectable international journals. She is a course Director of Medical Biochemistry and Director of PhD studies of Neuroscience at the School of Medicine, University of Belgrade. She is a President of Section for Clinical biochemistry, Serbian Medical Society. She has published more than 35 papers in reputed journals.

Abstract:

Association of aluminum (Al) and some neurodegenerative disorders, including Alzheimer’s disease (AD), is implicated in 1965 when Al was recognized as neurotoxin. Since then, the role of Al as a pathogenetic factor in AD was suggested by many epidemiological studies. The exact mechanism responsible for changes induced by Al is not known. We have analyzed the effects of ingested Al on the acetylcholinesterase (AChE), NADPH oxidase (NOX2), respiratory chain enzymes and oxidative stress parameters in Mongolian gerbils brain. Also, the protective effects of intrahippocampal application of green tea leaf extract and glucose-6-phosphate dehydrogenase on aluminium-induced brain toxicity were studied. Adult gerbils were acutely (LD₂₅), or subacutely (LD₁₀) exposed to aluminum chloride by gavage and sacrificed 2, 6 or 24 hours after acute and 21 days after sub-acute treatment. Intrahipocampally solutions were injected into the CA1 region using a stereotaxic frame for small animals. The expressions of amyloid and tau protein, as well as, membrane-bound (gp91phox, p22phox) and cytosolic (p40phox, p47phox, p67phox) NOX2 subunits, the activity of AChE and oxidative stress parameters were determined in specific brain structures. Changes of AChE and COX activities, as well as, oxidative stress parameters were seen as the earliest effects of Al treatment. The changes of the expression of NOX subunits were seen six hour after acute poisoning. After subacute Al ingestion the oxidative stress was pronounced. Decreased gp91phox and increased p67phox expressions were seen in cortex while in the hippocampus the decrease of p67phox was noticed. Green tea leaf extract and glucose-6-phosphate dehydrogenase have shown protective effects.

Biography:

Swati Omanwar completed her PhD in 2008 in Medical Physiology from Faculty of Medical Sciences, University of Delhi. She is presently as Scientist at School of Sciences, Indira Gandhi National Open University, New Delhi. She has published more than 17 papers in reputed journals and has been serving as reviewer for many.

Abstract:

Mercury, a heavy metal belonging to the transition element series of the periodic table, is widespread and persistent in the environment as an industrial pollutant. Any pollutant affecting human is transported to various organs by the cardiovascular system. Epidemiological and animal studies have suggested a strong association between the environmental and occupational exposure to mercury and risk of cardiovascular diseases (CVD). Toxicity from mercury is associated with in vivo oxidative stress. Mercury exposure induce the generation of reactive oxygen species (ROS) with subsequent oxidative damage in several organs and systems, as well as alter the antioxidant defence system in cells (6-10).Vascular endothelium, is very sensitive to oxidative stress and plays a vital role in the organization and function of the blood vessel and maintains homeostasis of the circulatory system and normal arterial function. Functional disruption of the endothelium is recognized as the beginning event that triggers the development of consequent cardiovascular disease (CVD) including atherosclerosis and coronary heart disease. Oxidative stress which results in endothelial dysfunction and loss of endothelium dependent vasorelaxation is one of the most commonly observed cardiovascular effects of mercury exposure. The endothelium can evoke relaxations and contractions of the underlying smooth muscle, by releasing vasoactive agents. Nitric oxide (NO), formed by endothelial NO synthase (eNOS), is the best characterized endothelium derived relaxing factor (EDRF). The release of NO is down regulated/upregulated by factors like oxidative stress, estrogen and diseases like diabetes and hypercholelestrolemia etc. The inhibition/activation of eNOS by mercury, affecting the NO release is majorly regulated by superoxide anions and minorly may be by insulin, estrogen, omega 3 unsaturated fatty acid and hypercholesterolemia and is one of the proposed mechanisms for mercury-induced vascular diseases. In addition, during exposure to mercury, overproduction of reactive oxygen species (ROS) can occur, resulting in oxidative stress, which is another major risk factor for endothelial dysfunction.

Conclusion: NO signaling mechanism and oxidative stress play a vital function in the mercury –induced cardiovascular diseases in the populations exposed to mercury.

Biography:

Mercy Ekwere has over 20 years of teaching experience in Biochemistry. She is rounding up her PhD under Associate professor F E Uboh and assisting in the supervision of Dr Uboh’s students. She has several publications to her credit.

Abstract:

Crude oil composition varies slightly by its source but contains many chemicals with toxic properties that are fairly in animals and human. Male and female albino rats weighing between 120kg and 200kg were grouped separately into test groups and control groups. Each group had five rats and was administered 60mg/kg body weight of crude oil orally for 28 days except for the control groups. The total body weights were taken at 7days interval for 28 days. Results showed a progressive decrease in total body weight of rats and a significant (p<0.05) decrease in average body weight of both male and female albino rats compared with respective control groups. Additionally, all test animals exhibited adverse reactions like itching watery eyes, sleepiness, shortening of breath and release of mucous. Also, there was a marked sign of dehydration and impaired digestion in week four of administration.

Biography:

Dr. Noreen, Toxicologist & Wellness Media Expert, also known as "The Tox Doc", is a toxicologist that specializes in environmental, space, food and nutritional toxicology. Her personal mission is to translate the language of science for non-scientists in order to educate and inform the public of critical issues that affect their health and quality of life. Dr. Noreen has completed her Doctor of Philosophy (Ph.D.), Environmental Toxicology in 2003 at the Texas Southern University. Dr. Noreen is serving as an editorial member of the Journal of Clinical Toxicology and The International Journal of Disaster Advances. Dr. Noreen has been with NASA* since 2004 & worked as the first female Space Toxicologist. She has authored a number of research articles in Space Toxicology & planetary dust toxicity.

Abstract:

Nicotine has long been regarded as one of the most toxic chemicals/drugs to human health. However, for centuries, it has also been used therapeutically.  Recently, investigations into its use for treating diseases such as ADHD, depression, Alzheimer & Parkinson diseases, digestive disorders, pain management and cognitive enhancement, have been eliciting more attention due to the development of non-prescription therapeutic products.   Given that the toxicity of over the counter (OTC) nicotine products for use in cessation of smoking is generally accepted as low-to-none, when used as directed, product developers assume that these same levels are toxicologically safe for non-smoking cessation products.  This may be the case, since the bulk of safety assessments for these products (such as electronic cigarettes) only point to risks from mishandling by non-target populations (children, pets, abusers) – not the levels of nicotine. Given the multiple routes of exposure (inhalation, ingestion and dermal absorption) that are already approved for nicotine replacement therapy (NRC) we explore and debate the best way for Toxicologists to assess non-NRC replacement therapeutic products.

Biography:

Dr. Gunnar Boysen has completed MS Biology in 1996 at the University of Kaiserslautern, The German Cancer Research Center, Heidelberg, Germany. Dr. Gunnar completed his PhD (Chemistry), Department of Chemistry University of Kaiserslautern Germany, and University of Minnesota cancer Center, Minneapolis, MN in 2002. Then in 2005 he completed Postdoctoral in the Department of Environmental Sciences and Engineering at The University of North Carolina at Chapel Hill. Dr. Gunnar Boysen is currently Associate Professor in the Department of Environmental and Occupational Health at University of Arkansas for Medical Science, USA

Abstract:

Increased glutamine uptake is known to drive cancer cell proliferation, making tumor cells glutamine-dependent. Studying lymph node aspirates containing malignant lung tumor cells showed a strong correlation between glutamine consumption and glutathione excretion. Subsequent validation in A549 and H460 lung tumor cell lines show that glutamine drives synthesis and excretion of μ molar amounts of glutathione. Glutathione is the most abundant and most widely studied endogenous antioxidant. Glutathione concentrations in normal tissues are in the µmolar range, which is 10,000 fold higher than the concentration of reactive oxygen species. This stoichiometric disconnect has been poorly understood. To understand the molecular function of μ molar concentrations of glutathione in lung tumor model we studied glutathione metabolism. Glutathione is degraded by γ-glutamyl transpeptidase (GGT) by transferring the glutamyl group to amino acids to facilitate the amino acid uptake. Inhibition of glutaminase or GGT essentially abolished glutathione synthesis and formation of γ-glutamyl amino acids. Both enzymes were found to be essential for cell proliferation. Quantitative evaluation of glutathione’s many functions led us to believe that glutathione’s main function is to store building blocks for biosynthesis and trigger cell proliferation or apoptosis, depending on nutrition availability. Consequently, cell viability is mainly controlled by a stable metabolite, glutathione, instead of the common belief that these processes are controlled by unstable radical chemistry.

Biography:

Bangyan Stiles joined the faculty of the Department of Pharmaceutical Sciences to form the Department of Pharmacology and Pharmaceutical Sciences, at the USC School of Pharmacy in December 2005. She was promoted to Associate Professor with tenure in 2012. Over the past ten years, she has built a successful program that allows her team to explore the complicated pathogenesis of chronic disease and apply therapies to test the translational value of our discoveries. Her group is the leader in understanding the contribution of lipid metabolism to liver cancer targeting the phosphatidylinositol-3 kinase (PI3K) and related signaling pathway.

Abstract:

Liver kinase B 1 (LKB1 or STK11) and PTEN (phosphatase and tensin homologue deleted on chromosome 10) are two tumor suppressors that both regulate the mTOR signaling pathway. Deletion studies show that loss of either Stk11 or Pten leads to liver injury. In this study, we investigated the molecular mechanisms underlying such toxicity. We show here that the hepatocyte transporter for bilirubin, multidrug resistant protein (MRP2) is significantly affected by LKB1 loss, correlating with the increases in plasma bilirubin levels. Both the levels and localization of MRP2 are altered by LKB1 loss. MRP2 levels are significantly reduced as a result of LKB1 loss in the liver of Stk11 (LKO) or Stk11/Pten (LPKO) double deleted mice vs. the controls. MRP2 is a multi-drug resistant transporter localized to the canalicular membrane of hepatocytes in the control. MRP2 functions to transport various molecules across the apical membrane including bilirubin. In the LKO and LPKO livers, the canalicular localization of MRP2 is lost and became diffusely localized to both nucleus and the cytoplasm. This observed regulation of MRP2 by LKB1 likely contributed to the lack of cellular polarity and the early lethality phenotype associated with LKO mice.

Biography:

Luis A Lopez-Fernandez is currently the Head of the Laboratory of Pharmacogenetics and Pharmacogenomics at Hospital General Universitario Gregorio Marañón in Madrid, Spain. He has completed his PhD from the University of Alcalá de Henares and Post-doctoral studies from Spanish Research Council and Centre de Biochimie (Nice, France). He is a Member of the Board of the Spanish Society of Pharmacogenetics and Pharmacogenomics. He was granted a Miguel Servet II position for young researchers. He has published more than fifty articles in international journals in the fields of oncology, genomics and pharmacogenetics.

Abstract:

Adverse reactions (ADRs) to chemotherapy agents, which can lead to treatment discontinuations and to the loss of treatment lines, are one of the major issues in the treatment of colorectal cancer. Individual genetic variants affect susceptibility to these adverse reactions. Several polymorphisms have been identified although they still need validation due to controversial results. Furthermore, new genetic variants need to be identified to increase the prediction power of existing tests. The aim of our work is to validate previously identified polymorphisms and to identify new variants. Three different approaches were followed: an association study of previously identified SNPs with adverse reactions to capecitabine-based treatments in a cohort of colorectal cancer patients, an association study of tag-SNPs with adverse reactions to capecitabine-based treatments in the same cohort, and a whole exome study in eight colorectal cancer patients suffering from high toxicity to capecitabine-based treatments. Results validate several SNPs associated with ADR to capecitabine in CRC. A test can identify patients at high risk of severe overall toxicity more precisely than regular tests. Tag-SNPs allow identifying new SNPs related to ADR in fluoropyrimidine-treated patients. Finally, exome sequencing allows us to obtain a complete profile of genetic variants in exons, splice sites and 5’ and 3’ untranslated regions in all genes participating in fluoropyrimidine pathway. In summary, this global approach is an excellent way to increase the knowledge of fluoropyrimidine-related adverse reaction pharmacogenetics and to increase the predictive power of pharmacogenetic tests in this field.

Biography:

G. Jean Harry, Ph.D., is head of the Neurotoxicology Group. She obtained an M.S. in neuropharmacology from Virginia Commonwealth University with a research focus in drugs of abuse. Her Ph.D. was obtained from VCU in 1981, and bridged the fields of neuropharmacology and neurotoxicology with her research conducted at NIH. Postdoctoral work was conducted in an NIH Training Program in Neuropathology followed by an NIH independent fellowship award in the Biochemistry Department, University of North Carolina. Following a position within the Developmental Disorders Center at UNC, she joined NIEHS as head of Neurotoxicology Group in 1990.

Abstract:

Neuroinflammation is associated with a variety of states within the brain including injury, disease, neurological disorders, and aging.  These states have often been associated with a morphological shift in the brain monocyte, the microglia, suggesting an anatomical approach to determining the neuro-inflammatory responses. Of concern is the heterogeneity of the microglia response and the beneficial versus detrimental nature of the response and how this relates to morphological changes in microglia is not clearly characterized. As the primary cellular source for inflammatory factors, microglia serve surveillance, maintenance and repair functions and display varied phenotypes, some beneficial while others require active regulatory control. Dissecting the distinct phenotypes of microglia subsets as associated with various functions (e.g., clearance of debris, synaptic remodeling and neuronal protection) is a critical step in characterizing unique responses contributing to functional differences. Using the trimethyltin mouse model of inflammatory-related hippocampal injury, resident microglia morphological heterogeneity was examined across hippocampal sub-regions and found to be associated with a spatial and temporal elevation of pro and anti-inflammatory cytokines, iNos, and complement expression. These patterns were differentially associated with neuronal death and synaptic loss but were also related to the repair mechanisms initiated.  Upon further examination by protein micro-characterization, unique profiles were demonstrated in the distinct hippocampal regions suggestive of phenotypic classifications of microglial and their environmental niches. Further examination of microglia heterogeneity of morphology and associated molecular/biochemical factors will significantly contribute to our understanding of the functional impact of a microglia/neuroinflammatory response following chemical exposure.

Biography:

Chunxu Hai is Professor from Fourth Military Medical University. He is the Director of Shaanxi Key Lab of Free Radical Biology and Medicine, Fourth Military Medical University. As corresponding author, he has published more than 40 SCI-indexed papers in reputed journals and has been serving as an Editorial Board Member of repute.

Abstract:

The present study was designed to investigate the effect of diosgenin (DSG) on metabolic dysfunction and to elucidate the possible molecular mechanisms. High fat (HF) diet-fed mice and 3T3-L1 preadipocytes was used to evaluate the effect of DSG. We showed that DSG attenuated metabolic dysfunction in HF diet-fed mice, as evidenced by reduction of blood glucose level and improvement of glucose and insulin intolerance. DSG ameliorated oxidative stress, reduced body weight, fat pads, and systematic lipid profiles and attenuated lipid accumulation. DSG inhibited 3T3-L1 adipocyte differentiation and reduced adipocyte size through regulating key factors. DSG inhibited PPARγ and its target gene expression both in differentiated 3T3-L1 adipocytes and fat tissues in HF diet-fed mice. Overexpression of PPARγ suppressed DSG-inhibited adipocyte differentiation. DSG significantly increased nuclear expression of ERβ. Inhibition of ERβ significantly suppressed DSG-exerted suppression of adipocyte differentiation and PPARγ expression. In response to DSG stimulation, ERβ bound with RXRα and dissociated RXRα from PPARγ, leading to the reduction of transcriptional activity of PPARγ. These data provide new insight into the mechanisms underlying the inhibitory effect of DSG on adipocyte differentiation and demonstrate that ERβ-exerted regulation of PPARγ expression and activity is critical for DSG-inhibited adipocyte differentiation.

Biography:

Carlos Horacio Laino received his PhD degree in Pharmacology from University of Buenos Aires, Argentina and completed his Post-graduate studies in the laboratory of the Research Department of Neuroscience, Center for Addiction and Mental Health, Research Foundation of Toronto, Canada. Then, he joined the National University of La Rioja (Argentina) in 2005 and is currently an Associate Professor of Pharmacology and Toxicology. He further received an award for Innovative Research Work from the National Innovation Submit & Showcase Tech Connect World in 2013 and 2014. His research focuses on drug discovery in several therapeutic areas, especially pain.

Abstract:

The treatment of acute and chronic severe pain remains a major daily challenge for health professionals in clinical practice. Chronic pain impairs the quality of life, especially of the elderly. With the increase in life expectancy, the development of chronic pain secondary to degenerative diseases or various types of cancer has also increased. Morphine is a potent analgesic mostly used to control pain. However, long term treatment develops several problems, such as loss of analgesic efficacy (tolerance), increased sensitivity to pain (hyperalgesia) and adverse effects like constipation, nausea, vomiting, sedation, drowsiness, pruritus and weight loss. These effects, together with tolerance and hyperalgesia, may require the use of increasingly higher doses to get the same analgesic effect or discontinue its use, which constitutes a failure of the treatment against pain. Also, because morphine has a short analgesic effect, doses should be administered every 4 hours, causing difficulties for the patient. This project describes a technological development with an innovative character, both in its pharmaceutical composition (morphine and omega-3 fatty acids) and in the pharmacological treatment associated with its use. The main advantage of the new pharmaceutical composition and pharmacological treatment lies in the control of pain with a sub-therapeutic dose of morphine which would eliminate or potentially decrease its adverse effects. Other important clinical benefits of using it in terminally ill patients, (such as cancer sufferers) or patients with other types of chronic diseases are the decrease in tolerance to analgesic effect and the reduction in body weight loss and constipation.

Biography:

Xue Zhou received her BS degree in Environmental Sciences from Wuhan University in 2003 and obtained her PhD degree in Environmental Health Sciences from New York University in 2010. She is currently Associate Professor at School of Public Health, Huazhong University of Science and Technology. She has more than 20 publications in reputed journals.

Abstract:

Organically modified rectorite (OREC) micro/nanoparticles can be synthesized by organic modification from calcium rectorite (Ca²⁺-REC or REC), a common form of rectorite in nature. Although REC and OREC have potential applications in food packing and drug delivery, their cytotoxicity is not clear. In the present study, we investigated and compared the cytotoxicity of REC and OREC micro/nanoparticles in Chang liver and HepG2 cells. The interlayer spacing of OREC was enlarged after organic modification. REC and OREC could be taken up by Chang liver cells after treatment. REC and OREC induced cytotoxicity in Chang liver and HepG2 cells at almost all doses (1, 2.5, 5, 7.5, and 10μg/mL) after 6, 24, and 48 h of treatment (P<0.05 or P<0.01). OREC was more cytotoxic than REC. However, there was no difference in the cytotoxicity of REC and OREC between the two cell lines. After treatment with REC or OREC at 7.5 and 10μg/mL for 24 h, the apoptotic and necrotic percentages of Chang liver cells were increased (P<0.05 or P<0.01). The levels of apoptosis-related proteins Bax, Bcl-2, and pro-caspase-3 were all decreased in Chang liver cells after 24h of exposure to REC or OREC at 5, 7.5 and 10μg/mL. There was no change in Bax/Bcl-2 ratio after treatment, indicating that REC or OREC-induced apoptosis was not associated with Bax-related mitochondria-mediated apoptotic pathway. Our results suggested that OREC was more cytotoxic than REC, but the underlying mechanisms need further investigation.

Biography:

Xin Wang has completed his PhD from Fourth Military Medical University. He is the Vice Director of Department of Toxicology, Fourth Military Medical University. As first author or corresponding author, he has published 20 SCI-indexed papers in reputed journals and has been serving as an Editorial Board Member of several journals.

Abstract:

In view of the critical role of redox system in numerous physiological and pathophysiological processes, it is important to clearly understand the constitution and regulatory mechanism of redox system. In this work, we will systematically review the current data detailing the reactive oxygen species (ROS), enzymatic and non-enzymatic antioxidants and redox sensitive transcription factors and we give a brief description of redox-exerted epigenetic and post-translational regulation. We propose that the redox system functions as a “Redox Chain”, consisting of “ROS-generating Enzyme Chain”, “Combined Antioxidant Chain” and “Transcription Factor Chain”. We suggest that redoxomic techniques should be extensively applied to understand the biological effects of redox alterations in a more integrated way. A stable and standardized “redox index” is urgently needed for the evaluation of the general redox status. We suggest that for the redox intervention of an individual, an individualized assessment of the redox status in the body should be conducted. The strategy of intervention is to maintain general redox balance rather than to conduct simple pro-oxidant or anti-oxidative interventions. These findings provide valuable new insights into redox system and open up new paths for the control of redox-related disorders.

Biography:

Arunava Ghosh completed his Bachelor of Science degree in Zoology and Master of Science degree in Environmental Science from Calcutta University. He has completed his PhD from Calcutta University in Biotechnology in 2013. In his Doctoral research, he investigated the effects of smoke exposure on protein modification and emphysematous lung damage. At present he is carrying out Post-doctoral studies in Dr. Robert Tarran’s lab at Marsico Lung Institute/UNC CF Center, University of North Carolina at Chapel Hill as Postdoctoral Research Associate (TCORS School of Medicine). His present research endeavors are focused on the effects of New and Emerging Tobacco Products on lung.

Abstract:

Cigarette smoking has been identified as the most important source of morbidity and mortality worldwide. Generally the life expectancy of smokers is nearly 14 years less than nonsmokers Apart from causing the various life-threatening diseases, cigarette smoke (CS) is also known to produce hypoxia.  Chronic hypoxia may be a cause of early aging, morbidity and premature death. Also, smoking during pregnancy causes reduced availability of oxygenated blood to the fetus resulting in intrauterine hypoxia and various risks for the unborn child.  Earlier we had shown that p-benzoquinone (p-BQ), derived from p-benzosemiquinone of CS in the smoker’s lungs, gets into the blood stream and forms covalent adducts with serum albumin resulting in alteration of its structure and ligand binding capacity. Here we show by mass spectrometric analyses that in smoker’s blood p-BQ forms covalent adducts with cysteine 93 residues in both the β chains of hemoglobin (Hb) producing Hb-p-BQ adducts. UV-Vis spectra and CD spectra analyses show that upon complexation with p-BQ, the structure of Hb is altered.  Compared to nonsmoker’s Hb, the content of α-helix decreased significantly in smoker’s Hb (p=0.0224). p-BQ also induces aggregation of smoker’s Hb as demonstrated by SDS-PAGE, dynamic light scattering and atomic force microscopy. Alteration of Hb structure in smoker’s blood is accompanied by loss of oxygen binding capacity. Our results provide the first proof that p-BQ is a cause of hypoxia in smokers.

Biography:

Danila Cuomo is a PhD student in Science for Environment and Health at University of Sannio in Italy. She is performing her research activity in the Prof. Ambrosino Systems Toxicology Laboratory at Biogem in Ariano Irpino. In spring 2015, she was a research scholar at Health Science Center of Texas A&M University in College Station, TX. Her work aims to investigate the impact of environmental issues on endocrine system. Recently, she is focusing on reproductive health. Using OMICS approaches, she aspires to identify novel biomarkers detectable in human fluids, useful to predict reproductive diseases, such as premature ovarian aging.

Abstract:

Toxicogenomics accomplished to standard toxicology are considered a powerful method for low-dose endocrine disruptor compounds (EDCs) testing. In recent years, it has been developed a strong demand for reducing the use of small mammals in chemical testing. To meet this need, it is necessary to estimate the possibility of validly replacing them with cellular and no-mammal models. We explored this aspect investigating the activity of BPA as EDC in immortalized rat follicular cell line (FRTL-5), in primary pancreatic islets and hepatocytes, models for endodermal cells. In FRTL-5 environmental doses of BPA induce the transcription of thyroid specific genes and their transcriptional regulators. Furthermore, we highlighted the activation of NF-kB pathway in thyrocytes after BPA exposure. Basic on our data, we developed a reporter cell line able to sense BPA at very low concentrations. By gene expression analysis, we revealed that thyrocyte transcriptome reacts dynamically to low-dose BPA exposure. Particularly, we uncovered its capability to weaken cellular response to a further stress factor. Environmental exposure to BPA does not impact hepatocyte transcriptome. On the other side, the expression of few genes is altered in ex-vivo cultured pancreatic islets, leading to impairment of mitochondrial activity and apoptosis. Also in this case, the experimental activity highlighted that BPA exposure can alter cells ability to respond to damages. Overall, we propose new mechanisms for BPA toxicity that are exerted, exclusively, in presence of further stressors. This observation suggests revisions in the development of experimental plans including multiple exposure conditions.

Biography:

Ahmad Sharanek has obtained a Master’s degree in Cancerology from the Lebanese University in Beirut. He traveled to France to prepare a PhD on mechanisms of drug-induced liver injuries under the supervision of Professor André Guillouzo. He obtained his PhD in June 2015 from Rennes 1 University and is currently pursuing Post-doctoral studies at Rennes 1 University. He has published 6 papers in reputed journals.

Abstract:

Intra-hepatic cholestasis is a frequent manifestation of drug-induced liver injury in humans and its prediction represents a major challenge. We aimed to investigate mechanisms involved in drug-induced cholestasis using human HepaRG cells. We found that bile canaliculi (BC) of untreated HepaRG hepatocytes underwent spontaneous contractions, which are essential for bile acid (BA) efflux and require alternations in myosin light chain phosphorylation/dephosphorylation. Short-term treatment with prototypical cholestatic compounds was found to result in alterations of BC dynamics typified by either constriction or dilation of BC. These morphological alterations were associated with disruption of the ROCK/MLCK/myosin pathway either directly or by targeting different levels of the ROCK/MLCK axis and its associated MAP-kinases. HepaRG cells produced normal conjugated BAs. Cholestatic drugs showed variable potency to cause BAs accumulation: different total BAs content and BAs profiles in either supernatants or cell layers were evidenced. Repeated treatments as well as co-treatments with pro-inflammatory cytokines, IL1 and IL6, aggravate cholestatic features induced by certain cholestatic drugs. Together, these results provide the first demonstration that cholestatic drugs alter BC structures by targeting the ROCK/MLCK pathway and cause BAs accumulation concomitantly to occurrence of various other cholestatic features, in an in vitro human liver cell model, thereby mimicking drug-induced in vivo liver cholestasis. These studies highlight new insights into mechanisms underlying bile flow failure and can be used to identify new predictive biomarkers and therapeutics of drug-induced cholestasis

Biography:

Alicja Urbaniak received her MSc degree in Chemistry at the Adam Mickiewicz University in Poznan, Poland, where she continued her chemistry education as a PhD student. Since June 2016, she has worked as a graduate student at University of Arkansas for Medical Sciences in Prof. Anna Radominska-Pandya’s group. She was awarded the best Master’s Thesis in quantum chemistry when she defended in Poland in 2012. She is an author of four scientific papers and presented her research results at 32 scientific conferences. Her scientific interests are related to the organic chemistry of natural compounds and their metabolism.

Abstract:

Resveratrol (3, 5, 4`-trihydroxy-trans-stilbene, tRV) is a polyphenol found in numerous plant species, e. g. grapes, berries, peanuts, that exhibits many beneficial properties namely antioxidant, anti-inflammatory and cytostatic. However, its wide application is limited due to its rapid metabolism and low solubility. Our laboratory synthesized 16 derivatives of tRV by conjugation with other bioactive compounds such as hydroxycinnamic acids. Rigorous structure identification was carried out, and the crystal structure of selected compounds was determined. In this work, tRV esters were tested for biological activity. Specifically, radical scavenging effect, elastase, collagenase and the inhibitory activity of tyrosynase and cholinesterases were investigated in vitro studies. Interestingly, resveratryl tri-p- and tri-m-coumatare were the best inhibitors of both cholinesterases. We have also checked the ability of resveratrol esters to bind to and activate CB1 and CB2 cannabinoid receptors. Preliminary data indicates that several of tRV esters also bind to CB1 and CB2 with low affinity (µmol range) but comparable to tRV. Based on these observations, we hypothesiezed that CB1 and CB2 receptors may play an important role in the molecular mechanism of action for tRV esters. Minor modifications to the basic tRV structure resulted in marked alterations in the affinity of various analogs for CBRs; this indicates that tRV could be used as a scaffold for the design of highly selective and efficacious CB1R and CB2R ligands. It is expected that the conjugation of tRV with other bioactive compounds may lead to synergistic biological effects and, consequently, higher activity as compared to the unbound, individual components.

Biography:

Abstract:

Aflatoxin B₁ (AFB₁) is a class 1 carcinogen and a common food contaminant worldwide. It is also a major cause of the development of hepatocellular carcinoma (HCC), making dietary exposure to this toxin very concerning. Existing strategies to reduce AFB₁ exposure are limited and as a result, many people are exposed to this toxin worldwide. Issues with current detoxification strategies include harmful byproduct formation, incomplete removal, or the requirement of sophisticated infrastructures. Our study aims to develop a new chemical treatment process to modify AFB₁ into a non-carcinogenic form using benign reagents found in human diets. Our strategy targets the mutagenic site of the AFB₁ molecule, the 8,9-double bond, by adducting it to selected amino acids in dietary proteins. Identification and quantification of aflatoxins was performed using high performance liquid chromatography-electrospray ionization-time of flight mass spectrometry (HPLC-ESI-TOFMS). Optimization of AFB₁ hydration was carried out by incubating in various organic acids as well as increasing temperature. Newly formed AFB_2a was introduced to alkaline solutions containing amino acids, peptides, and other biological molecules. Products were identified based on changes in retention times and accurate mass values. Mutagenicity of the resulting adduct was determined using an Ames’ test with and without the presence of hepatic microsomes. This study provides a basis for developing a safe and effective detoxification method for contaminated foods, reducing exposure to AFB₁ worldwide.

Biography:

Thomas Weber completed his PhD at Texas A&M University followed by a NIEHS Post-doctoral fellowship at The University of Texas at Austin. He is currently a staff scientist at the Pacific Northwest National Laboratory. He has published 43 papers in reputed journals, 3 book chapters on cell signaling and protein phosphorylation in toxicology and a Reference Module in Biomedical Sciences (Elsevier publications). He is recipient of a US Patent, Federal Laboratory Consortium Award and R&D 100 award for development of technologies for cellular biomonitoring at the Pacific Northwest National Laboratory. Current projects in addition to studies on oscillatory behavior encompass molecular profiling of radiation resistance for consideration in clinical radiotherapy and medical countermeasures, development of lung organotypic platforms as toxicological screens and non-invasive biomonitoring using saliva as matrix.

Abstract:

Oscillatory behavior occurs in pathways central to toxicological responses, including ERK, NF-κB, p53-MDM2 and Ca²⁺, however, the specific biological information encoded by oscillations is incompletely understood. We are the first to demonstrate that ERK oscillations regulate unique gene expression patterns in multiple experimental model systems, indicating that transcriptional regulation is one output for oscillatory behavior. We will discuss our most advanced experimental human model system that highlights a linkage between ERK oscillations and a transcriptional co-activator (MED1) whose half-life and activity is directly regulated by ERK-dependent phosphorylation as a feasible mechanism. Several toxicants (oxygen free radicals, ionizing radiation, bromate) inhibit ERK oscillations, and exploit well established stress-responsive signaling pathways (e.g. p38) to inhibit ERK signaling. However, the ERK feedback control processes specifically regulated by the stress response are undefined. We will also discuss experimental evidence that the inappropriate regulation of negative feedback loops in the ERK pathway can result in aberrant activation of ERK signaling, a response that has received little attention in a toxicological context. Finally, we have observed negative selection of ERK oscillations in vitro which may be important in view of the increased emphasis placed on in vitro screening assays in toxicology. Transcriptional misregulation is a mechanism frequently associated with toxic outcomes, therefore, the aberrant regulation of ERK oscillations by toxicants warrants further consideration in view of the unique gene expression profiles associated with this dynamic signaling behavior.

Biography:

Chunyuan Jin has completed his PhD from Tokyo University and Postdoctoral studies with Dr. Gary Felsenfeld at NIH. He is an Assistant Professor of Environmental Medicine at NYU School of Medicine. He has published more than 25 papers in reputed journals such as Nature Genetics and Genes & Development.

Abstract:

Acrolein is a α,β-unsaturated aldehyde, which is abundant in cigarette smoke and coking fumes. It is a potential major carcinogen of smoking-related lung cancer, yet the underlying mechanisms are not fully understood. We find that acrolein form adducts with histones and acrolein-modified histones are resistant to acetylation. Cellular fractionation analyses further reveal that exposure of cells to acrolein specifically inhibits acetylations of N-terminal tails of cytosolic histones H3 and H4, modifications that are important for nuclear import and chromatin assembly. Accordingly, the association of H3/H4 with histone chaperone ASF1B and translocator protein importin 4 is disrupted and the nuclear import of H3 is inhibited in cells following acrolein exposure. Moreover, ChIP (chromatin immunoprecipitation) assays exhibit that the levels of histone H3 are drastically decreased at the majority of genomic loci tested and H3 amount in chromatin fragments is depleted by acrolein exposure. These data indicate that acrolein exposure leads to compromise of the chromatin assembly. Interestingly, in vitro plasmid supercoiling assays reveal that treatment of either histones or ASF1B with acrolein has no effect on formation of plasmid supercoiling, while exposure of histones to acrolein prior to histone acetylation leads to the inhibition of RSF (Remodeling and Spacing Factor) chromatin assembly, which requires acetylated histones for efficient assembly. The results suggest that acrolein-protein adduct formation itself does not directly interfere with nucleosome assembly. We propose that acrolein compromises chromatin assembly via reacting with histone lysine residues at the sites critical for chromatin assembly and prevents these sites from physiological modifications.

Biography:

Mahsa Karbaschi has completed her PhD in Cancer Studies and Molecular Medicine at the University of Leicester in the UK and Post-doctoral studies from Florida International University in Florida, US. Her research interest is in formation and repair of oxidatively damaged DNA and also in development of new methodologies for the evaluation of DNA damage.  
 

Abstract:

Classically, the nucleotide excision repair (NER) of cyclobutane pyrimidine dimers (CPD) is a lengthy process (t_1/2 > 48 h). Using the T4 endonuclease V-modified comet assay, we uniquely found a far more rapid repair of UVA-induced CPD (t_1/2 = 4.5 h) in human skin keratinocytes. The repair of UVB-induced CPD began to slow within 1 h of irradiation, causing damage to persist for over 36 h. A similar trend was noted for the repair of oxidatively-modified purine nucleobases. Supportive of this differential repair, we noted an up-regulation of key genes associated with NER in UVA-irradiated cells, whereas the same genes were down regulated in UVB-irradiated cells. There were no significant differences in cell viability between the two treatments over the first 6 h post-irradiation, but after 24 h apoptosis had increased significantly in the UVB-irradiated cells. The role of apoptosis was confirmed using a pan-caspase inhibitor, which increased CPD repair, similar to that seen with UVA. These data indicate that the cellular ‘decision’ for apoptosis/DNA repair occurs far earlier than previously understood, and that the induction of apoptosis leads to lesion persistence, and not vice versa. This also highlights a new, potential increased carcinogenic risk from UVA-induced DNA damage as, rather than undergoing apoptosis, high levels of damage are tolerated and repaired, with the attendant risk of mutation.

Biography:

Carlos Horacio Laino received his PhD degree in Pharmacology from University of Buenos Aires, Argentina and completed his Post-graduate studies in the laboratory of the Research Department of Neuroscience, Center for Addiction and Mental Health, Research Foundation of Toronto, Canada. Then, he joined the National University of La Rioja (Argentina) in 2005 and is currently an Associate Professor of Pharmacology and Toxicology. He further received an award for Innovative Research Work from the National Innovation Submit & Showcase – Tech Connect World in 2013 and 2014. His research focuses on drug discovery in several therapeutic areas, especially pain.

Abstract:

Combination therapy is often used to increase the clinical utility of analgesic agents. The co-administration of two compounds may achieve analgesia at doses lower than those required for either compound alone, leading to enhanced pain relief and a reduction in adverse effects. A tricyclic antidepressant, such as amitriptyline, is often used to treat many types of persistent pain, with their efficacy in this regard being well established. These conditions include diabetic neuropathy, postherpetic neuralgia, headache, arthritis, and chronic back pain. The disadvantages of using amitriptyline include side effects such as cardiovascular problems (e.g., hypertension, postural hypotension and arrhythmias), drowsiness, dry mouth, nausea, changes in body weight and constipation. The aim of this study was to examine in rats the antinociceptive effect of omega-3 fatty acids alone as well as in combined chronic treatments with amitriptyline (AMI) in the hot plate test. We found that compared to control, omega-3 fatty acids dose-dependently increased the latency time, indicative of an antinociceptive effect, with the co-administration of AMI (20 mg/kg/day) and omega-3 fatty acids (0.72 g/kg/day) revealing a higher antinociceptive efficacy than the individual treatments. The combination of omega-3 fatty acids with amitriptyline might produce better analgesia, thereby increasing the efficacy of pain management and reducing side effects through the use of a smaller dose of antidepressant.

Biography:

Dr. Xue Zhou got her B.S. degree in Environemtal Sciences from Wuhan University in 2003, and got her Ph.D. degree in Environmental Health Sciences from New York University in 2010. She is currently Associate Professor at School of Public Health, Huazhong University of Science and Technology. She has more than 20 publications in reputed journals.

Abstract:

Sirtuin6 (SIRT6), a member of NAD⁺-dependent deacetylases that plays a key role in aging, cancer, and metabolism, has been shown to have anti-fibrosis function in heart and liver, but whether SIRT6 plays a role in idiopathic pulmonary fibrosis (IPF) has been poorly explored. Epithelial to mesenchymal cell transition (EMT), a process by which fully differentiated epithelial cells convert to a mesenchymal phenotype, has been involved in the pathogenesis of IPF. In the present study, SIRT6 expression was upregulated in both TGF-β1-induced EMT in A549 cells and bleomycin (BLM)-induced EMT in mice. Forced expression of SIRT6 by adenovirus transfection of A549 cells significantly abrogated TGF-β1-induced EMT-like phenotype and EMT-associated cell behavior. In A549 cells, TGF-β1-induced activation of TGF-β1/smad3 signaling and increase of smad3-snail1 interaction was ameliorated by overexpression of SIRT6. Upregulation of EMT related transcription factors by TGF-β1 treatment was also restored by overexpression of SIRT6. Further in vivo studies showed that lung targeted delivery of SIRT6 using adeno-associated virus transfection blunted BLM-induced pulmonary EMT and fibrosis as evidenced by a reduction of epithelium undergoing EMT and collagen deposition. Our findings unravel a novel role of SIRT6 as a key modulator in the phenotypic conversion of epithelial to mesenchymal cells and suggest it as an attractive potential therapeutic target for IPF.

Biography:

Grace-Anne Bent has received PhD from University of the West Indies. She is a lecturer of analytical chemistry in the Department of Chemistry at The University of the West Indies, St. Augustine Campus, Trinidad and Tobago. Her research interests include food safety and security, investigating the chemistry of food and food related toxins in an effort to minimize human exposure by understanding their mechanisms of interaction (in vivo and in vitro). She has published a book and 7 journal articles. She is also the recipient of several research awards.

Abstract:

Pesticides are a group of plant protection chemicals aimed at eradicating pests to improve crop yields. However, pesticides are toxic and can result in carcinogenic and neurologic effects on humans and animals who come in contact with them. Humans can come in contact with pesticides by direct or indirect application in the field or by consuming foods that have pesticide residues remaining after application. Pesticide residue analysis has been given high priority globally since the world’s population became much more conscious about the health hazards caused by exposure to pesticide residues. In Trinidad and Tobago, there is still yet to be defined the maximum allowable limit of pesticide residues on produce. Thus, the need for the analysis of pesticide residue levels in foods which form part of a typical “Trinbago” diet. Traditionally, pesticide residue analysis is a laborious process that involves the use of many toxic and expensive chemicals, thus making the routine analysis of food crops for pesticides a deterrent for the average farmer. As such, the quick, easy, cheap, effective, rugged and safe (QuEChERS) method was developed which reduces the sample preparation time and the use of toxic chemicals tremendously. However, the analysis can still be quite expensive. This research aims at developing a cheaper variation to the traditional QuEChERS method. This method has been tested on select organochlorine (OC) and organophosphate (OP) pesticides in selected food matrices. Recoveries ranged from 60-125 % with a relative standard deviation < 20 %.  The method was successfully tested on samples from the Chaguanas District, Central Trinidad.