10^th Global Summit on Toxicology and Applied Pharmacology July 20-22, 2017 Chicago, Illinois, USA

Biography:

Mufeed J Ewadh has expertise in many fields of biochemistry research in his institute dealing with health problem, herbal extraction and alternative medicine. He did his Post-doctorate course at Marburg University, Germany and participated in electrophoresis workshop in Japan for two weeks as well as in biochemical workshop in Leipzig, Germany. He is the Chief Editor of Medical Journal of Babylon, Iraq.

Abstract:

Introduction: Medicinal plants are considered as important source of medicines and drugs manufacturer because they contain active compounds that had medical biological activity, so it has adopted in the preparation and the preparation of a lot of drugs because of their speed in the therapeutic effect and the lack appearance of negative side effects which caused by medications which chemically manufactured, where underwent a lot of scientific studies and extensive research to uncover some important plants, which have had a significant positive impact on public health and the impact in many diseases, including cancer.

Aim: The present study aimed to use raw Catharanthus roseus as herbal medicinal plant for the purpose of its use in the medical and pharmaceutical fields and alternative medicine, or the so-called herbs medicine, for the purpose of reducing or eliminating the leukemia and complications of this disease.

Methodology: The present study included 60 Albino male mice divided into four groups with count 15 mice for each. Group-A was the control group, Group-B was mice with oral feeding of C. roseus plant, Group-C was induced leukemia mice by subcutaneous injection of (300 mg/kg B.W benzene), while Group-D was induced leukemia mice treated by oral feeding C. roseus plant. "SHIMADZU" HPLC was used for Vincristine estimation in plant and vitamin D in mice serum. ELISA technique was used for serum ferritin determination. UV-VIS spectrophotometer has been used for estimation of GSH-Px and GST activities using special kits, while AAS technique was used for essential trace elements determination. There were Hb and WBC examinations and histopathology study for liver, kidney, spleen and bone marrow were done.

Results: Analysis showed that C. roseus contain Vincristine drug up to148 µg/gm. The following table shows the statistically significant effect of vincristine, antioxidants and other active ingredients on vital parameters of treated mice:

Conclusion: This study concluded that C. roseus had direct impact on biological system included alkaloid VCR, which significantly improve the efficiency of treatment for AL and extend survival in mice and have antioxidant activity in biological system.

Biography:

Prasanth Puthanveetil has done his PhD in Pharmacology especially in the area of cardiovascular diseases from the University of British Columbia. Following his Post-doctoral training at NIEHS/NIH, University of Western Ontario and University of Michigan, he was selected for a full time tenure track faculty position at Roosevelt University School of Pharmacy. He has published more than 22 peer-reviewed articles, in top tier journals. He is an active member of many professional associations including American Heart Association and AACP. He also serves as Editorial Board Member of several peer-reviewed journals. At RUCOP, he has set up his own research program on metabolic signaling in cardiovascular and renal tissue. His special interests include endocrine disorders like diabetes and Cushing’s syndrome and its impact on cardiovascular health.

Abstract:

Statement of the Problem: The widely used potent anti-inflammatory agent, glucocorticoids, shows a behavioral paradox. Even though used extensively for treating severe pain and inflammation, in excess could results in metabolic and endocrine complications resulting in Cushing’s syndrome like symptoms. Even though they produce major side effects following chronic treatment, the primary focus has been on direct genomic effects and very less emphasize has been put on their nongenomic effects. Non genomic mechanisms of glucocorticoids are mostly mediated by various stress kinases. When there is an over activation of this non genomic arm of glucocorticoids could result in metabolic complications that potentiate glucolipotoxic events in cardiovascular tissue.

Theoretical Orientation: In this commentary, I would like to shed light on this non genomic effect of glucocorticoids as shown by my own and other’s work.

Findings: Using in vivo and in vitro model systems, we have shown that glucocorticoids in excess under normal physiological conditions could activate this non genomic pathway mediated by stress kinase pathways leading to glucolipotoxicity in the cardiovascular tissue.

Conclusion & Significance: Making use of this knowledge, we tried to interfere or inhibit the mediators in this non genomic signaling axis and was able to normalize the glucolipotoxicity and associated complications in the cardiovascular tissue. This information will really help to provide more awareness to the population who are on long term glucocorticoid treatment and also in long term stress situations.

Biography:

Hanan H Hagar, B Pharm, MS, PhD, is a Professor of Pharmacology in Medical College, King Saud University. She received her BPharm degree (Excellent with honors) from Zagazig University, Egypt. She completed her MPharm degree from Zagazig University, Egypt and PhD from Zagazig University in collaboration with University of Arkansas for Medical Sciences, USA. She usually has excellent evaluation and Deanship of Quality. She is a member of many societies and a Member of Advisory Board for many international journals liek Saudi Pharmaceutical Journal, Dataset Papers of Pharmacology, Hindawi Publishing Corporation, SciTz Medical and Clinical Toxicology, Journal of Nutrition & Food Sciences, JSM Renal Medicine and SRL Nephrology & Therapeutics. She served also as invited reviewer for many national and international journals worldwide as Urological Research (UK); Clinica Chimica Acta (Netherlands); Cell & Tissue Transplantation & Therapy (New-zeland); Digestive Diseases and Sciences (Netherlands) and Acta Pharmacologica Sinica (China). She had actively participated in many local and international conferences as poster or oral presentation. She was invited as a speaker in many conferences. She has published over 30 research articles in peer reviewed ISI international journals. She has been awarded for many projects by many financial sources. These projects were funded by different organizations as King Abdul Aziz City for Science and Technology (KACST), Saudi Arabia; Research Center at Women Students-Medical Studies & Sciences Sections, King Saud University; Research Center at College of Medicine, King Saud University and Saudi Arabia Basic Industries Corporation (SABIC). Due to her scientific record, she was included in the 2009-2010 Edition of "Who's Who in Medicine and Healthcare", the American biographical works “Great Minds of  the 21st Century”, 2010 England and “Woman of the year in Medicine and Health care”, 2010.

Abstract:

Implication of oxidative stress and inflammatory mechanisms in adriamycin nephropathy has been suggested. Reactive oxygen species may activate latent matrix metalloproteinases (MMP) that ultimately may induce glomerulosclerosis and fibrosis. Little is known about the effect of MMP inhibitors on focal segmental glomerulosclerosis. This study examined the role of MMP in adriamycin nephropathy as an animal model of glomerulosclerosis using MMP inhibitors, SB-3CT and doxycycline. Forty (40) male Wistar rats were used and allocated into four groups as follows: Normal control rats (n=10), adriamycin treated rats (n=10) and SB-3CT+adriamycin-treated rats (n=10), doxycycline+adriamycin-treated rats (n=10). Adriamycin nephropathy was induced by a single injection of adriamycin (7.5 mg/kg) intraperitoneally. SB-3CT was given at a dose of (1 mg/kg/day, i.p.) while doxycycline was given at a dose of (30 mg/kg/day, i.p.). Therapy was initiated at once after induction of adriamycin nephropathy and continued for 4 weeks. Adriamycin nephropathy resulted in deterioration in lipid profile (elevated serum triglycerides and cholesterol levels) and in kidney function (elevated serum creatinine, BUN) and reduction in serum albumin and total protein levels while their levels were increased in urine. Lipid profile was also changed. Adriamycin-treated rats showed increased tumor necrosis factor-α (TNF-α); intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-b1 and tissue inhibitor of metalloproteinase-1 and 2 (TIMP-1 and TIMP-2) in the kidney as assessed by ELISA technique. MMP activities (MMP-2 and MMP-9) were also induced using zymography technique and western blot analysis. Histological changes were also noted on kidney using hematoxylin and eosin. Immunohistochemical studies revealed increased staining of collagen IV in the renal cortex. MMP inhibitors, doxycycline and SB-3CT significantly reduced serum BUN, creatinine and renal cytokines. Lipid abnormalities were also corrected back to normal. This was parallel to reduction in collagen IV immunostaining and improvement in histological changes. These results suggested that MMP inhibitors may have promise as anti-inflammatory, anti-proliferative and endothelial cell protective. MMP inhibitors may be potential future candidates to provide more effective therapy to halt the development of glomerulosclerosis.

Biography:

K Bischoff is the Director of the Analytical Toxicology Unit of the New York State Animal Health Diagnostic Center (AHDC) at Cornell University for 13 years. She teaches clinical toxicology to veterinary students at Cornell University and has lectured as an invited speaker on topics related to veterinary toxicology around the United States and Asia and started working towards Master’s degree in Public Health in 2017.

Abstract:

Seven goats and one ram presented with clinical signs including regurgitation, obtundation, anorexia, apparent pain and bloat. The animals had escaped from their barn and it was discovered that they had ingested leaves of Pieris japonica, Japanese pieris, a grayanotoxin-containing plant. Animals were treated with antibiotics, calcium borogluconate, B vitamins and activated charcoal within the first 24-hours post exposure, which was followed by the recovery of the ram and two goats and the death of two goats. Approximately 36 hours after Japanese pieris ingestion, one of the three remaining anorectic goats was dosed with intravenous lipid emulsion (ILE). This goat recovered within a few hours. The remaining two goats were given ILE the next day and appeared to recover, but one died a week later of aspiration pneumonia.

Biography:

Peter Osei Boamah is a Senior Lecturer at the School of Applied Sciences and Arts, Department of Ecological Agriculture, Bolgatanga Polytechnic, Ghana. He has expertise in synthesis and application of low molecular weight chitosan and has published many articles. He is also a Reviewer of number of journals.

Abstract:

Chitosan and its derivatives possess valuable properties for its use as a sorbent for the removal of heavy metals from aqueous solution. In the present study, the thermodynamics of Cu²⁺, Pb²⁺ and Cd²⁺ sorption onto low molecular weight chitosan (CS₈) using isothermal titration calorimetry (ITC) were investigated. Based on the ITC data, the stoichiometry data were 0.36±0.023, 0.813±0.015 and 0.029±0.006 for Cu²⁺, Pb²⁺ and Cd²⁺, respectively. The binding association constant (Ka) varied from (1.74±0.333)×10⁴M^-1 to (17.3±18.9)×10⁴M^-1. Also, all binding reactions to low molecular weight chitosan (CS₈) were enthalpically favored and the interaction between the sorbent and the metal ions were enthalpically not driven at 25 °C. Furthermore, free energy of reaction values were all determined to be negative indicating spontaneous reactions. In conclusion, the ITC instrument was successfully used to measure directly the stoichiometry (N), binding association constant (Ka), the enthalpy change (ΔH) and the entropy change (ΔS).

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:

Yalavarthy Prameela Devi has obtained her MSc in Zoology with Environmental Biology specialization and PhD in Environmental Biology from S V University, India in 1984. She is presently working as the Dean, Faculty of Sciences at Kakatiya University, India. She has 33 years of teaching and 37 years of research experience and has good knowledge in Environmental Biotechnology and Environmental Bioanalytical Techniques. She is an Endeavour Fellow of Australia 2010. She has published nearly 110 scientific research papers and presented over 100 talks at various national and international seminars, workshops, training programs and conferences. She has received UGC Research Award, India in 2006. Her research interests include the development of low cost field kits for environmental monitoring of toxic chemicals using biological principles, environmental toxicology, ecological restoration and environmental management and global climate change. She is an Honorary Adviser to many environmental consultancy service companies in India.

Abstract:

Personal care products refer to a wide variety of items that are found in the health and beauty sections of drug and departmental stores. Some of these products are cosmetics which includes skin moisturizers, perfumes, lipsticks, fingernail polishes, eye and facial makeup preparations, shampoos, hair colors, toothpastes and deodorants and also covers some drugs like skin protectants (lip balms and diaper ointments), mouthwashes marketed with therapeutic claims, antiperspirants and treatments for dandruff or acne. Most personal care products on the market contain toxic chemicals like triclosan, parabens, phthalates, synthetic colors, fragrance, sodium lauryl sulfate (SLS), formaldehyde and toluene. These chemicals linked to hormonal imbalance, reproductive health problems and even cancer. Many of these chemicals in personal care products have never been tested for safety and may also accumulate and interact in potentially harmful ways. The load adds up quickly day after day as we swallow, breathe in and lather up and these toxins enter into our bodies and may have lasting impact. Many people may not realize that ingredients in cosmetics and personal care products can enter into the environment and harm the environment and may have adverse effects on plants animals and humans. Sorption and photolytic degradation mitigate the availability of these chemicals to aquatic biota and the byproducts of such chemicals may be more resistant to degradation and have higher toxicity than the parent compound. We have studied the toxic effects of Triclosan, a high production volume ingredient used as a bactericide in personal care products such as toothpaste and deodorant, on bacteria, zooplankton and an aquatic fish, Channa punctatus, which is a very common edible fish in south India. We have selected these organisms as these are important in the ecosystem function and any possible damage to these organisms will have an adverse effect in maintaining the balance of the ecosystem. Acute toxicity evaluation of fish on LC₅₀, behavioral changes, biochemical and molecular alterations, histopathological changes were studied. Effects of triclosan on bacterial activity and on zooplankton were also evaluated. The result indicate that triclosan exerts a marked influence on the parameters tested which indicate that if triclosan is discharged into the environment at high levels, the possible destruction of the balance of the ecosystem is expected.

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:

Andrea Randi has her expertise in evaluation of pesticides mechanisms of action that act as endocrine disruptors, specifically those ligand compounds of the aryl hydrocarbon receptors (AhR). In her laboratory, she is developing two main lines of work, one related to the induced effects by these compounds in the mammary gland and another in the uterus. In mammary gland, her interest is to investigate the different processes of breast cancer progression, such as proliferation, angiogenesis, migration, invasion and metastasis, analyzing the signaling pathways related with growth factor receptors, AhR and estrogen receptors. On the other hand, in the uterus, she is engaged in analyzing the effects on the development of endometriosis, evaluating the growth of endometriotic lesions, proliferation, migration, invasion and angiogenesis.

Abstract:

Given the number of women affected by breast cancer, considerable interest has been raised in understanding the relationships between environmental chemicals and disease development. Hexachlorobenzene (HCB) is a widespread organochlorine pesticide detected in mother’s milk and lipid foods. HCB is a dioxin-like compound that weakly binds to the aryl hydrocarbon receptor (AhR), a transcription factor that regulates gene expression associated with proliferation, angiogenesis, migration and invasion. We previously demonstrated that HCB acts as an endocrine disruptor in rat mammary gland and an inducer of cell proliferation. Our studies using negative estrogen receptor alpha (-ERα) MDA-MB-231 human breast cancer cells showed that HCB increases cell migration and invasion and enhances tumor growth stimulating lung and liver metastasis in mice breast cancer models. Increasing evidence indicates that transforming growth factor-β1 (TGF-β1) can contribute to tumor maintenance and progression. In a recent investigation, we found that HCB increases TGF-β1 protein levels and activation, as well as Smad3, JNK and p38 phosphorylation in MDA-MB-231. Real time-qPCR results indicated that HCB reduces AhR mRNA expression through TGF-β1 signaling but enhances TGF-β1 mRNA levels involving AhR. HCB enhances cell migration and invasion through the Smad, JNK and p38 pathways. These results demonstrate that HCB modulates the crosstalk between AhR and TGF-β1 and consequently exacerbates a pro-migratory phenotype in this cell line. Finally, HCB induces the angiogenic switch and increases vascular endothelial growth factor (VEGF) expression in a xenograft model with MDA-MB-231. Human microvascular endothelial cells exposed to HCB showed an increase in cyclooxygenase-2 (COX-2), VEGF and AhR expression. HCB induces cell migration and neovasculogenesis in an AhR, COX-2 and VEGF receptor 2-dependent manner. Altogether, the results showed that HCB is able to modulate several breast cancer-related processes in vitro and in vivo and suggest that HCB may be a risk factor for human breast cancer progression.

Biography:

Chun-Yu Chuang focuses her research on biological effects of environmental factors on gene expression relevant to diseases.

Abstract:

Our study established a research scheme of integrative transcriptomic analysis for investigating the neurodegenerative toxicity of silver nanoparticles (AgNPs) and applying to explore drug repurposing of spinal muscular atrophy (SMA). The transcriptomic analysis of mouse brain neural cells after AgNPs exposure found that the gene expressions of C-X-C motif chemokine 13 (CXCL13), macrophage receptor with collagenous structure (MARCO) and glutathione synthetase (GSS) were induced for inflammatory response and oxidative stress, and additionally amyloid precursor protein (APP) was induced and neprilysin (NEP) and low-density lipoprotein receptor (LDLR) were reduced for Aβ plaque production and aggregation. It suggested AgNPs could alter gene expressions of Aβ deposition potentially to cause neurodegenerative disorder (Alzheimer's disease) progression underlying Aβ deposition. On the other hand, the 39 human microarray datasets across different types of SMA tissues were used for the integrative transcriptomic analysis, which identified TNFα-BMP4-SERPINE1-GATA6 pathway associated with disease severity. Down-regulation of bone morphogenetic protein 4 (BMP4) may be one of the key points in SMA pathogenesis. BMP4 expression can be induced by cholesterol lowering drug Atorvastatin. SMA mice receiving Atorvastatin treatment prolonged the lifespan, increased body weight, improved motor coordination and exhibited reduced motor neuron degeneration and muscle and cardiac atrophy. In conclusion, the integrative transcriptomic analysis is a useful tool for toxicological effect evaluation and drug repurposing.

Biography:

K Prasuna has completed her BSc and MS from Kakatiya University, India. Presently, she is pursuing her PhD at the same university. She has worked as an Associate Pathologist in Clinical Laboratory at Saudi Arabia for about 15 years. Her research interests include environmental toxicology, study of medicinal plants and isolation of bio active compounds for drug development. Currently, she is working on extraction of medicinal plants for isolation and characterization of bioactive compounds to test for anti-venom properties especially for testing the inhibitory activity of toxic proteins.

Abstract:

Statement of the Problem: The need for higher production of food makes us to use pesticides for disease control in both plants and animals. Pesticides usage will harm to the non-target organisms also in the ecosystem. Fish species are very sensitive to various chemicals and will have deleterious effects on the growth and reproduction. The present study was conducted to investigate the effect of acute toxicity of Butachlor, an herbicide, on biochemical alterations and enzymatic inhibition of Indian major carp, Labeo rohita.

Methodology & Theoretical Orientation: The median lethal concentration (LC₅₀) value of the toxicant was estimated by using Finney’s Probit Analysis. The biochemical and enzymatic parameters were estimated spectrophotometrically using standard methods. The LC₅₀ of Butachlor was found to be 0.85 mg/l for 96 hours. Fish were exposed to sublethal doses for 1 day and 10 days to evaluate the biochemical alterations and enzymatic inhibition.

Findings: During sublethal exposures, a significant decrease in glycogen, protein, lipid, carbohydrate and free amino acid (FAA) content was observed. An increase in the level of lactate dehydrogenase (LDH) activity was noticed and a significant decrease in levels of succinate dehydrogenase (SDH) and malate dehydrogenase (MDH) activity were observed in pesticide exposed tissues of gill, liver, kidney, muscle, intestine and brain when compared with the control tissues. The biochemical alterations might be due to the disruption of internal organs. Increase in enzyme activity may be due to the damage caused to the lysosomal membrane, thus permitting the leakage of lysosomal enzyme into cytosol.

Conclusion & Significance: Decrease in enzyme activity infers to energy metabolism of the nervous system, arrest the transmission of nerve impulses and thereby causing behavioral changes. Thus the above parameters could be effectively used as potential biomarkers of the pesticide toxicity to the fishes.

Biography:

Kirti Satheesh Pawar is a Critical Care and Pain Consultant and has expertise in the management of organophosphorus poisoning since 20 years. She has been invited for many national and international clinical meetings to discuss her research and experience in the field of Organophosphorus Poisoning. She is keen to understand controversies in the treatment of organophosphorus poisoning by re-analyzing clinical evidence in this field. She is honored with many awards for her outstanding contribution in the medical field. She believes in ethical medical practice and updating medical knowledge with clinical relevance.

Abstract:

Statement of the Problem: Treatment of Organophosphorus Poisoning (OPP) is a Global challenge. 20% death rate in OPP cases is tragic. Standard treatment for OPP is to give intravenous atropine and pralidoxime. Role of oximes needs more clinical evidence and is need of time. We studied causes of success and failure of oxime therapy in OPP cases and tried to revisit an antidote, atropine, for its extrapolated role in OPP cases since decades.

Methodology & Theoretical Orientation: Atropine is a muscarinic antidote to treat the muscarinic crisis. Oximes reactivate inhibited acetylcholinesterase by organophosphates and checks uninhibited action of acetylcholine at neuromuscular junction. We studied major clinical trials and studies of oximes till date to understand factors affecting success or failure of oxime therapy as well as revisited atropine therapy to understand its effect on outcome.

Findings: WHO recommended minimum dose of pralidoxime as a baseline while treating patients of moderately severe OP poisoning. Unfortunately in last 20 years only two randomized controlled trials (RCT’s) followed this regimen. Use of suboptimal dosage of oximes is a major cause of its ineffectiveness. Inadequacy of respiratory support system could be a major drawback. Failure to maintain optimum oxime concentration as long as active organophosphates are inhibiting acetylcholinesterase is an additional reason for ineffectiveness of oximes. Expenses of pralidoxime is also limiting factor for its liberal use.

Conclusion & Significance: World needs evidence for use of oxime in OPP cases. RCTs to be conducted in future should strictly follow WHO recommended minimum dose of oximes and to be conducted in intensive care unit where cardiorespiratory support system is adequate. An affordable pralidoxime preparation should be a part of public health response. We researchers strongly believe the drug pralidoxime will save many lives and can substantially reduce mortality in OPP cases.

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.

Biography:

Blake R Rushing is a PhD Candidate in the Department of Pharmacology and Toxicology at the Brody School of Medicine at East Carolina University, USA.

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 themutagenic 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 effectivedetoxification method for contaminated foods, reducing exposure to AFB₁ worldwide.

Biography:

Mayel Gharanei has completed his PhD on the investigation of the cardiotoxicity of Doxorubicin and strategies for adjunctive cardioprotection. During his PhD, he worked on the optimization of the cardiac work loop technique for safety assessment of pharmaceutical compounds. During his Post-doctoral research, he undertook dedicated studies on the development and validation of the cardiac rat papillary muscle and human trabeculae muscle work loop technique. He is working as the Lead Research Scientist at InoCardia where he supervises research staff and projects associated with testing pharmaceutical compounds on rat papillary and human trabeculae muscle mechanics. As a Research Fellow at Coventry University, he is supervising PhD and Masters by Research students in the field of cardiotoxicity, myocardial ischemia reperfusion injury, cardioprotection, obesity, aging and development and validation of novel clinically relevant cardiovascular non-clinical assays.

Abstract:

Adverse drug response is a significant risk to human health and is costly to the pharmaceutical industry when compounds are withdrawn from market. In vitro cardiac safety testing is generally conducted using predominantly animal tissue or cells or stem cell derived cardiac myocytes. Although side effects of drugs can be caused by many things, one area of great concern is the effects of drugs on the force that heart muscle can produce during its role in pumping blood around the body. Development of a human heart contractility assay would greatly improve the understanding of the human relevance of non-clinical findings; a chemical might cause a change in cardiac contractility in animals but not humans and vice versa. The pharmaceutical, biotechnology, cosmetic, agrochemical, food industries and regulators require an improved assessment of cardiovascular liability associated with drug/chemical-induced changes in cardiac contractility that is more predictive than existing assays. We have demonstrated that the work loop cardiac contractility assay is 93% predictive of human findings than existing assays when using animal tissue. We have expanded this investigation to determine whether the human cardiac work loop assay had the potential to provide a more predictive model of heart muscle dynamics to assess inotropic effects. To validate this assay, a range of positive and negative inotropic agents were tested and effective concentrations compared with those tested in the clinic. The human cardiac muscle work loop assay predicted inotropic effects at clinically relevant concentrations. The human cardiac work loop assay is a new approach to the detection of drug effects on cardiac contractility, providing a superior predictivity of inotropy assessment and importantly identifying inotropy risk at clinically relevant concentrations. The use of human tissue has the potential to replace the use of animals and provide greater concordance with man.

Biography:

Amanpreet Singh is a Post-doctoral Fellow at Mycology Lab, Wadsworth Center, New York State Department of Health, USA. He has obtained his PhD from Department of Biochemistry and Molecular Biology from Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA. His research interests comprise understanding the molecular mechanism of DNA replication checkpoint pathway and fungal pathogenesis.

Abstract:

Mutations in the hem13-1 (heme synthesis) and erg11-1 (ergosterol biosynthesis) pathways genes significantly sensitize the fission yeast Schizosaccharomyces pombe to the ribonucleotide reductase inhibitor hydroxyurea (HU). Our results have also shown that treatment with small molecule inhibitors of the enzyme Erg11 and heme biosynthesis phenocopies the erg11-1 and hem13-1 mutants in sensitizing wild type cells to HU. HU interacts synergistically with several Erg11 inhibitors and the heme biosynthesis inhibitor sampangine in suppressing cell growth or inducing cell death in S. pombe. Importantly, the synergistic drug interactions are likely conserved in eukaryotes because similar synergism has been seen observed in phylogenetically divergent yeast Saccharomyces cerevisiae and the opportunistic fungal pathogen Candida albicans. Based on our genetic data in S. pombe, combinations of sampangine with Erg11 inhibitors are found to be remarkably synergistic in inducing the cell death in C. albicans. Together, these results strongly suggest that HU, sampangine and the Erg11 inhibitors can be further developed in drug combinations for the treatment of fungal infections or other diseases such as cancer. Our results suggests that the combination therapy has the potential to tackle various issues associated with single drug therapy such as toxicity to the hosts, less therapeutic effect, narrower spectrum of activity and more importantly, the development of drug resistance.

Biography:

Abstract:

Adipogenesis refers to the differentiation of pre-adipocytes into mature fat cells, i.e., the development of adipose tissue, which varies according to sex and age. Adipocytes differentiate from stellate or fusiform precursor cells of mesenchymal origin. Adiponectin has been postulated to act an important role in the modulation of glucose and lipid metabolism in insulin-sensitive tissue in both humans and animals. The transition from pre to post menopause is associated with the emergency of many features of metabolic state. The intraabdominal body fat increases, low density lipoprotein and triglyceride levels increase while high density lipoprotein decreases. In our study, we aimed to study the changes in adiponectin and anthropometric parameters after menopause. For this purpose the ELISA methods was used in the study to evaluate the values of adiponectin. A total of 70 female in menopause and 90 control subjects were included in this study. The results showed that adiponectin, BMI and blood pressure increased with menopause and in order to investigate the effect of menopause on these parameters, further work must be carried out in the near future.