Biography:

Nukhet Aykin-Burns has received her PhD degree from the University of Missouri-Rolla focusing on antioxidant-based therapies in lead poisoning and completed her Post-doctoral training in the Free Radical and Radiation Biology Program at the University of Iowa. She is an Assistant Professor of Pharmaceutical Sciences at University of Arkansas for Medical Sciences, Member of the College of Pharmacy Division of Radiation Health. Her research focuses on reactive oxygen species (ROS), radiation induced (IR and UV) normal tissue damage and wound healing as well as polychlorinated biphenyl (PCB) induced oxidative stress.

Abstract:

Sirtuin3 (SIRT3) is the major deacetylase in mitochondria. It has been determined that SIRT3 null mice have deficiencies in ATP production and demonstrate a susceptibility to develop metabolic syndrome. Polychlorinated biphenyls (PCBs) are organic pollutants that accumulate in adipose tissue and have been shown to disrupt metabolism. They have been proposed to contribute to metabolic diseases including diabetes and obesity. Our goal is to examine the effects of 4-hydroxy-3,3’-dichlorobiphenyl (4OH-PCB11), a major PCB 11 metabolite, on fatty acid and glucose metabolism using embryonic fibroblasts (MEF) isolated from SIRT3 wild type and SIRT3 null mice. RT² Profiler™ PCR array for fatty acid metabolism demonstrated a dose dependent up-regulation of ACOT12, ACSBG2, ACSM2, FABP1, OXCT2A, GK2, HMGS2, LPI, SLC27A5 and ACSL1 genes in SIRT3^–/– MEFs compared to Sirt3^+/+ MEFs following 24 hours treatment with 0.1, 1 and 3 μM 4OH-PCB11. PCR array for glucose metabolism also demonstrated up-regulation of G6PC, PDK4 and PRPS1L1 in both SIRT3^–/– and SIRT3^+/+ MEFs upon 3 μM 4OH-PCB11 exposure, however fold increases in the expression of these genes were more pronounced in the knockout background. On the other hand, the expression of PYGL gene was down-regulated in both SIRT3^–/– and SIRT3^+/+ MEFs at comparable levels. Our future studies will investigate the enzymatic activities of proteins encoded by these genes as well as utilize proteomics and metabolomics approaches to determine if they are specific SIRT3 targets during PCB induced cellular stress.

Biography:

Xiu-Ti Hu has his expertise in drug addiction and neuro-HIV research, which focuses on elucidating mechanisms that underlie neuronal dysfunction in the mesocorticolimbic dopamine system. He has published 58 peer-reviewed scientific articles and 10 invited book chapters.

Abstract:

Cocaine is a highly-addictive psychostimulant that affects cognition. Despite combination antiretroviral therapy (cART), mild forms of HIV-Associated Neurocognitive Disorders (HAND) are still prevalent and are expected to increase with the aging HIV⁺ population. HIV-infected cocaine abusers display more severe progression of HAND than non-abusing HIV/AIDS patients. The medial prefrontal cortex (mPFC) is a regulator of addiction and neurocognition and is altered profoundly by chronic cocaine/HIV exposure in vivo. Mechanisms underlying mPFC neuronal dysregulation by cocaine/HAND are not fully understood, especially during aging but dysregulated neuronal Ca²⁺ homeostasis may play a critical role. Our studies focus on the effects of chronic cocaine, HIV and aging on voltage-gated Ca²⁺ channel (VGCC) function in mPFC pyramidal neurons, using cocaine-exposure and/or the HIV-1 transgenic (Tg) rat model. We perform electrophysiology (whole-cell patch-clamping) in brain slices to assess neuronal excitability and Ca²⁺ influx via VGCCs (represented by Ca²⁺ spikes) as well as biochemical studies (Western blotting) to evaluate changes in VGCC protein levels. We found that (1) Firing of mPFC pyramidal neurons is abnormally-increased and associated with excessive Ca²⁺ influx (which is toxic) via VGCCs in adolescent (~7 weeks-old) cocaine-exposed rats or HIV-1 Tg rats; (2) Similar neuronal/VGCC dysregulation occurs in young adult cocaine-exposed and/or HIV-1 Tg rats (6 month-old; 6mo), but some dysfunctions are significantly greater following combined exposure and (3) mPFC hyper-excitability remains in older (12 mo) HIV-1 Tg rats but with different mechanisms (unaltered voltage-sensitive Ca²⁺ influx associated with reduced L-channel protein levels). These findings reveal that mPFC excitability is altered by chronic cocaine, HIV and aging through different mechanisms. Besides Ca²⁺ dysregulation, our parallel studies also suggest that dysfunctional K⁺ channels also play a role in cocaine/HIV-induced mPFC hyperactivity. Together, our studies demonstrate that chronic exposure to cocaine/HIV in vivo significantly alters Ca²⁺ homeostasis in mPFC neurons, which could be exacerbated during aging.

Biography:

You Yang Zhao is the William G Swartchild’s Jr. Distinguished Research Professor and Program Director for Lung and Vascular Biology at the Ann & Robert H Lurie Children’s Hospital of Chicago, and Department of Pediatrics at Northwestern University Feinberg School of Medicine. He received his training in cardiopulmonary vascular biology at Harvard University and UCSD. Prior to his tenure at LCH, he was a Professor at the Department of Pharmacology at the University of Illinois at Chicago and Senior Research Scientist in Cardiovascular Drug Discovery in Pharmacia/Pfizer Inc. His research is focused on lung and vascular biology to delineate the molecular mechanisms of endothelial regeneration and resolution of inflammatory injury, as well as pulmonary vascular remodeling in the pathogenesis of pulmonary arterial hypertension (PAH), and thereby to provide novel druggable targets and therapeutic strategies for treatment of acute respiratory distress syndrome and PAH. He has published many papers in top-tier journals such as Nat Med, PNAS, J Clin Invest, J Exp Med and Circulation. His lab is well-funded with multiple R01 grants and PPG grant from NIH.

Abstract:

Statement of the Problem: Evidence from human and animal studies has shown the key role of microvascular leakage in determining the outcome of sepsis and acute respiratory distress syndrome (ARDS). However, little is known about the signaling pathways regulating endothelial regeneration and vascular repair following sepsis challenge, and hence no crucial druggable targets identified yet for development of effective drug(s) and the mortality rate remains as high as 40%.

Methodology & Theoretical Orientation: Employing genetic lineage tracing mice to define the cell origin of endothelial regeneration responsible for vascular repair. Various genetically modified mouse models as well as pharmacological approach were used to identify the transcriptional factors and underlying signaling pathways mediating endothelial regeneration.

Findings: Employing a genetic lineage tracing approach, here we show that resident endothelial cell is the origin of endothelial regeneration in mouse lungs after lipopolysaccharide-induced inflammatory injury. Mice with Tie2Cre-mediated disruption of FoxM1 in endothelial cells exhibited impaired endothelial regeneration and vascular repair and thus the forkhead transcriptional factor FoxM1 is the critical TF for endothelial regeneration. Employing pharmacological inhibitors, we demonstrate that endothelial regeneration selectively requires activation of p110γPI3K signaling, which thereby mediates the expression of the endothelial reparative transcription factor FoxM1. We further identified SDF-1a as the critical agonist to activate the GPCR-dependent p110gPI3K in EC through CXCR4 and thereby induced FoxM1-dependent endothelial regeneration. We also observed diminished expression of p110g in pulmonary vascular ECs of ARDS patients associated with severe sepsis, suggesting that impaired p110g-FoxM1 endothelial regeneration and vascular repair signaling pathway is a critical factor in persistent leaky lung microvessels and edema formation in the disease. In aged mice, we observed defective endothelial regeneration and vascular repair which was caused by impaired p110g-FoxM1 signaling. We will discuss the pharmacological approach to activate this intrinsic regenerative pathway in aged lungs to restore vascular integrity and promote survival following sepsis challenge.

Conclusion & Significance: We identify endothelial p110g-FoxM1 signaling axis as the critical mediator of endothelial regeneration and vascular repair following sepsis challenge. Activation of this intrinsic regenerative pathway may represent a novel strategy for the treatment of severe sepsis and ARDS.

Biography:

Lingyun Li has her expertise in biotechnology and pharmaceutical preclinical development (focusing on pharmacology and toxicology) in the areas of Oncology, Cardiovascular, and Renal Diseases. As a Pharmacologist, she has previously worked at J&J and Sanofi in Drug Discovery and Development. She is currently the Director of Biology and Pharmacology at Relypsa, Inc. She has experience supporting all stages of drug development (preclinical, IND to phase 3, and NDA). She has experience working with small molecules, biologics, and polymer drugs, and has extensive regulatory experience interacting with FDA and EMA.

Abstract:

Statement of the Problem: Hyperkalemia is a potentially life-threatening condition, and patients with chronic kidney disease, diabetes, or who are taking renin–angiotensin–aldosterone system inhibitors are at increased risk of this disorder. Colonic potassium secretion can increase to compensate when urinary potassium excretion is impaired, but this adaptation is insufficient and hyperkalemia still results. Patiromer is a novel, spherical, nonabsorbed polymer designed to bind and remove potassium, primarily in the colon. Patiromer has been found to decrease serum potassium in patients with hyperkalemia having chronic kidney disease who were on renin–angiotensin–aldosterone system inhibitors. Patiromer was approved in the United States in late 2015 as Veltassa® for the treatment of hyperkalemia. It is the first new therapy available for hyperkalemia management in over 50 years.

Methodology & Theoretical Orientation: Results of nonclinical studies and an early phase clinical study are reported here.

Findings: Studies with radiolabeled drug were conducted in rats and in dogs. This work confirmed that patiromer was not absorbed into the systemic circulation. Results of an in vitro study showed that patiromer was able to bind 8.5 to 8.8 mEq of potassium per gram of polymer at a pH similar to that found in the colon and had a much higher potassium-binding capacity compared with other resins, including polystyrene sulfonate. In hyperkalemic rats a decrease in serum potassium was observed associated with an increase in fecal potassium excretion. In a clinical study in healthy adult volunteers, a significant increase in fecal potassium excretion and a significant decrease in urinary potassium excretion were observed.

Conclusion & Significance: Overall, patiromer is a high-capacity potassium binder, and the chemical and physical characteristics of patiromer may lead to good clinical efficacy, tolerability, and patient acceptance.

Biography:

Uma Sankar investigates the precise role of Ca²⁺/calmodulin-dependent protein kinase (CaMK) signaling in bone remodeling and maintenance, with a key emphasis on translational studies involving CaMK kinase 2 (CaMKK2) pharmacological inhibition as a bone anabolic therapeutic strategy in the prevention and reversal of post-menopausal, age-as well as treatment-induced osteoporosis, fracture healing and osteoarthritis.

Abstract:

Fractures associated with osteoporosis and acute trauma result in significant medical costs, loss of productivity and patient quality of life. Currently, there are no effective pharmacological treatments that promote efficient healing of bone fractures. Ca²⁺/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) has roles in the anabolic and catabolic pathways of bone remodeling. Its pharmacological inhibition with STO-609 protects from post-menopausal osteoporosis and reverses age-associated bone loss. In this study, we hypothesized that targeting CaMKK2 will accelerate fracture healing. To this end, unilateral femoral fractures were generated in 10 week old male C57BL6 mice. Tri-weekly intraperitoneal injections of saline (n=30) or STO-609 (n=30; 10 µmol/kg body weight) were administered for 4 weeks post-fracture. Fractured calluses were analyzed at days 3, 7, 14 and 28 days by micro-computed tomography (micro-CT), immunohistochemistry and qPCR to assess healing. During normal fracture healing in mice, hypertrophic chondrocytes appear at the callus around day 14, produce vascular endothelial growth factor (VEGF) which elicits migration of mesenchymal stem cells (MSCs). Treatment with STO-609 results in a marked elevation in hypertrophic chondrocytes and VEGF as well as a dramatic influx of MSCs in the callus by day 7. By day 14, these calluses possess significantly higher levels of osteocalcin and calcified matrix compared to controls. Micro-CT analyses reveal that STO-609-treated calluses possess significantly more bony-callus area by 2 weeks and mature bone by 4 weeks post-fracture. Thus, STO-609-treated mice possess more mature and stronger secondary bone in their calluses indicating faster repair of the fracture. Toxicology analyses indicate no alteration in blood or hepatic biochemistry following STO-609 treatment. Altogether, our observations reveal that CaMKK2 inhibition using its selective pharmacological inhibitor STO-609 results in the acceleration of key early cellular and molecular mechanisms involved in fracture healing such that healing is accelerated by a whole week.

Biography:

Laszlo Forro holds the Chair of Nanostructures and Novel Electronic Materials at Ecole Polytechnique Fédérale de Lausanne, Switzerland. He is leading an interdisciplinary research activity, ranging from novel electronic materials, through functional nanostructures to biomaterials. He puts strong emphases on the study of health hazards of nanostructures like carbon nanotubes, graphene, boron nitride nanowires and lately of photovoltaic perovskites. He is a Member of the Hungarian Academy of Sciences, Member of the Croatian Academy of Sciences, Member of the Serbian Academy of Sciences and Arts and Doctor Honoris Causa of the University of Szeged, Hungary.

Abstract:

The CH₃NH₃PbI₃ perovskite is currently the most promising compound in photovoltaic (PV) technologies for making highly efficient solar cells because of their simple fabrication procedure, low price and high efficiency. Several companies are already building perovskite-based PV devices for commercialization in the near future. Nevertheless, the perovskite contains Pb and safety concerns during PV fabrication and transportation have not yet been addressed. But not only direct human exposure is an issue, but its release into the environment, soil and waterways, after failure of large area solar cells also represents major health risks. Here is an extensive toxicity study of the most promising photovoltaic perovskites CH₃NH₃PbI₃ and CH₃NH₃SnI₃ are presented. On cell cultures, the zoom-in in vitro (modification of the genes upon perovskite exposure, biochemical changes, various assays) and on living organisms (C. elegans and Drosophila) the zoom-out in vivo studies both show a high level of toxicity. The results are conclusive and encouraging the scientific community to conduct further tests on more complex organisms, but also to search for new materials which do not represent risk to the environment.

Biography:

Jane C Quinn is the Founder of a multidisciplinary research team at Charles Sturt University which investigates the etiology, activity and mode of actions of chemicals, both naturally-occurring products and synthetic compounds, which cause toxic outbreaks in domestic and native animals. Her research focuses on neuroactive and photocytotoxic compounds and disease outbreaks caused by ingestion of toxic plants in domestic livestock. With an extensive background in neuroscience research she also advises veterans and government agencies on the effects of neurotoxic chemicals in veterans, with a special interest in members of the quinolone family of anti-malarials. She is currently based at Charles Sturt University in rural New South Wales, Australia.

Abstract:

Biserrula pelecinus L. is an annual legume native to the southern Mediterranean. It was first introduced to Australia in 1991 as a potentially valuable rotational pasture species for livestock production. It produces large quantities of biomass, exhibits drought tolerance and is effective for weed suppression in pasture rotations. However, despite proving to be a valuable addition to the pasture toolbox, producers in NSW and WA have reported a limiting factor to uptake: Incidence of severe photosensitization when grazing sheep on Biserrula pastures. Biserrula photosensitivity, anecdotally, appears to be associated with non-senescent foliage and shows an increased severity of clinical signs in young animals grazing green tissues; however, the pathogenesis of this photosensitization and the metabolites responsible are, as yet, unknown. Studies reported in this project have identified that both commercially available cultivars of Biserrula, ‘Casbah’ and ‘Mauro’ can cause outbreaks of primary photosensitization. This work identified that fresh foliar extracts were photosensitizing and that this activity diminished greatly with drying. Both cultivars were found to be equally bioactive and photocytotoxic activity was associated with extracts from field-grown Biserrula at all stages of plant growth until senescence. Biochemical analysis using fractionated extracts, bioactivity-guided metabolic profiling using liquid chromatography mass spectroscopy and quadripole time-of-flight (UPLC/MS-QToF) analysis has resulted in identification of multiple novel molecular features with high statistically significant likelihood of causal compounds present in both the complex crude extract and the purified bioactive fractions. The process undertaken to define the etiology of Biserrula photosensitization and identification of bioactive phototoxic secondary metabolites, will be presented.

Biography:

Rebeca Lopez-Marure is the Student of Biology and obtained her Doctorate in Biomedical Sciences from Autonomous National University of Mexico. Her topic of investigation is the signal transduction involved in the antiproliferative effect induced by Dehydroepiandrosterone (DHEA) in cancer and its protective effect on cardiovascular diseases. She has published 40 papers in international journals. She works as Researcher in Medical Sciences in the National Institute of Cardiology “Ignacio Chavez” in Mexico City.

Abstract:

Titanium dioxide nanoparticles (TiO₂ NPs), a nanotechnology product, are used in the industry in the production of cosmetics, sunscreens, household products, surface coatings and plastics, among others. Due to their small size, they can translocate from lungs to blood and have direct contact with cardiac cells; therefore, in this work the toxic effect of TiO₂ NPs on cardiomyoblasts of rat H9c2 was evaluated. Cell proliferation and viability were determined by the MTT reduction assay and crystal violet staining, respectively; oxidative stress by DCF oxidation and changes in the mitochondrial potential with Rh123. Cell death was evaluated by annexin-V, staining with iodide propidium and formation of autophagic vacuoles was measured by flow cytometry. Phases of the cell cycle were also evaluated determining the DNA quantity. TiO₂ NPs decreased cell proliferation and metabolic activity from 20 µg/ml at 48 hours of treatment, induced oxidative stress increasing DCF oxidation and produced changes in the mitochondrial potential and disruption of the cell plasma membrane. These effects were not related with changes in cell cycle phases; however, they were associated with an increase of events in the sub-G1 region which was linked with necrotic death and autophagy. In conclusion, TiO₂ NPs induced a toxic effect on cardiomyoblasts indicating that human exposure to these nanoparticles could be dangerous to health and could be associated with the development of cardiovascular diseases, where oxidative stress and cell death are involved.

Biography:

Rohini Padma has completed her BS in the year 1996 and MS in 1998 from Kakatiya University, Warangal, India. She is working as an Assistant Professor in Government Degree and PG College in India. She has been teaching Undergraduate and Post-graduate students for the past 16 years. She is pursuing her Doctoral degree (PhD) from Kakatiya University, India. She has keen interest in the areas of environmental toxicology, biodiversity, restoration of natural ecosystems especially fresh water lakes. Presently, she is involved in research related to environmental toxicology of fresh water organisms exposed to different toxicants particularly with reference to pharmaceutical contamination.

Abstract:

The occurrence of pharmaceuticals in aquatic environment is of a serious concern all over the world in recent times. Diclofenac is a widely prescribed non-steroidal anti-inflammatory drug. It has been frequently detected in surface waters in the range of ng/l to μg/l. There are evidences of its negative impact in aquatic organisms like phytoplankton, zooplankton and fish. The present study aims to investigate the biochemical alterations in fresh water fish, Channa punctatus on exposure to Diclofenac. The fish were exposed for 96 hours to three different concentrations 5 ppm, 25 ppm and 50 ppm of Diclofenac. The effect was observed in vital tissues like brain, gill, muscle, liver and kidney with respect to control fish. Proteins were estimated by Lowry et al. method, carbohydrates by Anthrone method and phospholipids by Zilversmidth and Davis method. Succinate dehydrogenase enzyme activity was quantitated by Nachlas et al. method. There was reduction in the level of proteins, carbohydrates and phospholipids and SDH enzyme activity in all tissues at all the set concentrations of Diclofenac. There was maximum depletion of proteins in the liver (73.9%) at 50 ppm and minimum in brain (6.87%) at 5 ppm when compared to control. The maximum depletion of carbohydrates occurred in liver (64.55%) at 50 ppm and minimum in kidney (7.42%) at 5 ppm. The high decline of phospholipids was in liver (64.55%) at 50 ppm and minimum in gill (3.42%) at 5 ppm. The maximal SDH enzyme inhibition was in liver (72.72%) at 50 ppm and minimum in muscle (18.18%) at 5 ppm against control. The alterations in all biochemical parameters were significant and dose dependent. The reduction in all parameters may be due to toxic stress created by Diclofenac. This analysis suggests that proteins, carbohydrates, phospholipids and SDH enzyme can be employed as efficient biomarkers in toxic studies. It also signifies that pharmaceutical residues alter the biochemical composition of non-target organisms like fish.