Scientific Program

Conference Series LLC Ltd invites all the participants across the globe to attend 13th World Congress on Pharmacology and Toxicology Melbourne, Australia.

Day 1 :

Keynote Forum

Jean-Marc Lemaitre

IRMB, France

Keynote: Developping strategies to fight tissue aging

Time : 10:00-10:45

Pharmacology Congress 2018 International Conference Keynote Speaker Jean-Marc Lemaitre photo
Biography:

He is currently working as deputy director for Institute of Regenerative Medicine and Biotherapy (IRMB) composed of a 150 persons. He is also a leader of a INSERM research team and director of a stem cell facility CHU (SAFE-iPSC) comprising more than 33 persons. He is mentoring 8 senior scientists (CR1, MCU, MCU/PH), 11 Ph.D. students and 3 Post-Docs, 9 technicians and engineers. Also he is an invited speaker in 48 national and international conferences and seminars in France and abroad in the last 5 years (3 plenary lectures).

Abstract:

TBS

Keynote Forum

Stefan Gluck

Celgene Corporation, USA

Keynote: State of the art and future of IO in solid tumors: Example is breast cancer

Time : 10:45-11:30

Pharmacology Congress 2018 International Conference Keynote Speaker Stefan Gluck photo
Biography:

Stefan Glück, MD, PhD is a medical oncologist with focus on solid tumors including brain cancer activities worldwide. Additionally, he is responsible for immuno-oncology programs in solid tumors and hematologic diseases and is in the area of early assets.  He completed his medical studies at the University of West Berlin, Germany in 1978 followed by a medical oncology & bone marrow transplant fellowship in Toronto, Canada.  Before becoming V.P. of Global Medical Affairs at Celgene Corp., he previously served as Sylvester Professor of Medicine at the Miller School of Medicine in Miami, Florida until 2014. From 2009-2010 he was assistant director of the Sylvester Comprehensive Cancer Center & associate chief for the Division of Hematology & Medical Oncology and from 2003-2008, he served as clinical director of the Braman Family Breast Cancer Institute in Miami, Florida. He has authored and co-authored over 260 articles and has written more than 350 papers at national and international meetings. 

Abstract:

The idea of using the immune system to fight cancer is over 100 years old. (Paul Ehrlich’s “Magic Bullet”) But immunotherapy in solid tumors (ST) has been disappointing over the last several decades. A new molecular approach led to a better understanding of the immune system. Check point regulation, understanding roles of Tregs, Th1 and Th2, development of CAR-T cells, as well as regulation of DC and Macrophages, has led to discovery of immune checkpoint inhibitors (ICI) and modulators that are currently used in studies of several STs. Positive studies have led to the US FDA approval of a few of these compounds. Moreover, MSI high (and dMMR) are the currently “best” predictive markers for IO therapy and recently, Pembrolizumab was approved in ST with this companion diagnostic marker. A number of large clinical trials in many ST and in all phases are underway (over 1000). We will discuss the mechanism of action, its impact on solid tumors, and some of the early results and next generations ICI. 

  • Sessions: Pharmacology; Toxicology; Drug Discovery & Drug Screening; Ethnopharmacology; Clinical Pharmacology & Receptor Therapy; Psychopharmacology & Neuropharmacology
Speaker
Biography:

Miyuki has her expertise in study of drug metabolizing enzymes as microsomal glutathione transferase 1 (MGST1) and cytochrome P450s (CYPs). In her CYP project, she has cloned plant cDNAs and addressed the substrate preference in
the fatty acid hydroxylation on active site modeling. In her MGST1 study, she has purified MGST1 protein and characterized its activation capacity and catalytic activity. Recently she designed and generated K mutants to understand the physiological function of MGST1 in addition to the traditional role of detoxifying xenobiotics on Phase II. She believes that MGST1 has critical cellular protective functions of scavenging the damaged cells in mitochondria and that the evidence will be shown in future. Currently she is focused on the study of brain infarction therapy using a MCAO (middle cerebral artery occlusion) model of mice using the basis of her experience of oxidative stress and prion studies.

Abstract:

Statement of Problem: Microsomal glutathione transferase 1 (MGST1) has been classified as a detoxifying enzyme of phase II traditionally and is involved in drug resistance [ref 4, 2]. It is distributed in mitochondria (mt) and in endoplasmic reticulum (ER) abundantly. The function as a drug-metabolizing enzyme in ER is well known, however the mitochondrial function is unclear in spite of the abundant expression.
Methodology & Theoretical Orientation: There is a unique lysine-25 that is conserved from fishes to humans in MAPEG family [ref 5]. We hypothesized
that the lysine-25 played an important role in the balanced mitochondria targeting of MGST1 protein.
To clarify it, we designed the K-mutants and then have expressed and characterized them in COS7 cells. Actually COS7 cells expressing I22K and F28KMGST1 as a K mutant indicated mt targeting, while COS7 cells overexpressing K25A-MGST1 with less charge were inserted to ER clearly in the confocal analyses [ref 1]. Interestingly COS7 cells expressing either I22K or F28K with each mitochondrial expression were concluded to be less viable than that of wild type MGST1. We made the structure graphics based on MGST1 (PDB ID: 2H8A) with PYMOL. It suggests that (i) F28 is located near K25-D78 salt bridge in the space of TM (Trans Membrane segment) 1 and TM2 in the same subunit and (ii) I22 interacts with the neighboring TM4 [ref1]. This might support the different mechanism of mitochondrial insult by K mutants although both K mutants targeted to mitochondria have capacity to induce cellular toxicity. In addition, the catalytic activity and the activation
capacity with N-ethylmaleimide could explain the different features of I22K and F28K-MGST1.
Conclusion & Significance: The key Lysine-25 has been conserved evolutionarily across species. The natural selection could be built as a cellular defense against the putative K-induced mitochondrial toxicity.

Speaker
Biography:

Michele Visentin is working in Department of Clinical Pharmacology and Toxicology at University Hospital Zurich, Switzerland

Abstract:

Background: Colistin is a member of the polymyxin family, a class of fatty acyl peptide antibiotics isolated from different species of Bacillus polymyxa seventy years ago. Colistin was gradually discontinued from clinical practice due to the high incidence of nephrotoxicity, however, the emergence of Multidrug-resistant (MDR) have made colistin the main option of the last decade for the treatment of MDR gram-negative bacterial infections. Colistin administration remains extremely challenging due to the high incidence of nephrotoxicity even when the target concentration would only be associated with bactericidal activity for organisms at the lower end of the susceptibility range. The mechanism behind colistin-induced nephrotoxicity is unknown. Mice exposed to colistin for a week showed sign of mitochondrial stress at the kidney cortex level.

Aim: This work aims to study the mechanism underlying colistin-induced mitochondrial dysfunction.

Results: Primary cultured proximal tubule cells exposed to colistin for 48h showed reduction of rhodamine123 accumulation in mitochondria, indicating mitochondrial membrane potential depolarization. Freshly isolated mitochondria from mouse kidney experienced a rapid, dose-dependent, depolarization, in presence of colistin, suggesting that mitochondrial damage was a primary effect of colistin. Isolated mitochondria were fully protected from colistin-induced membrane depolarization by co-incubation with ADP, and only partially protected by cyclosporine A, suggesting that colistin induced mitochondrial membrane depolarization by inducing the opening of the mitochondrial permeability transition pore (MPTP). Activated free fatty acids (e.g. palmitoyl-CoA) inhibit the adenosine nucleotide translocase (ANT) and induce the MPTP opening. As colistin contains a fatty acid chain (C7), the effect of colistin on the mitochondrial uptake of radiolabelled nucleotides was assessed (cis-inhibition assay). Colistin was able to reduce the [3H]ATP uptake in isolated mitochondria and an IC50 was computed to be 2.2 mM (95% CI 0.9 to 5.4).

Conclusions: Colistin induced mitochondrial membrane depolarization by inhibiting the adenosine nucleotide translocase (ANT) and, in turn, inducing the MPTP opening.

Speaker
Biography:

Nader G Abraham is working in Departments of Medicine and Pharmacology at New York Medical College, New York

Abstract:

We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on vascular function, in addition to its anti-apoptotic action; it increases insulin sensitivity and inhibits inflammation. To uncover the signaling mechanisms by which EET reduces cardiomyopathy, we hypothesized that EET infusion might ameliorate obesity-induced cardiomyopathy by improving HO-1, Wnt1, thermogenic gene levels and mitochondrial integrity in cardiac tissues and improved pericardial fat phenotype. EET reduced levels of fasting blood glucose, and pro-inflammatory adipokines including NOV signaling while increasing echocardiographic fractional shortening and O2 consumption. Of interest, we also noted a marked improvement in mitochondrial integrity, thermogenic genes, Wnt 1 and HO-1 signaling mechanisms.  Knockout of PGC1a in EET-treated mice resulted in a reversal of these beneficial effects including a decrease in myocardial Wnt1 and HO-1 expression and an increase in NOV. To further elucidate the effects of EET on pericardial adipose tissues, we observed EET treatment increases in adiponectin, PGC1α, pAMPK, insulin receptors phosphorylation and thermogenic genes resulting in a “Browning’ pericardial adipose phenotype under high fat diets. Collectively, these studies demonstrate that an EET-agonist increased Wnt1; HO-1 signaling whiles decreasing NOV pathways and the progression of cardiomyopathy. Furthermore, this report presents a portal into potential therapeutic approaches for the treatment of heart failure and metabolic syndrome.

New and Noteworthy

The mechanism by which EET acts on obesity-induced cardiomyopathy is unknown. We describe a previously unrecognized function of EET infusion that inhibits NOV levels and activates Wnt1, hence identifying NOV inhibition and enhanced Wnt1 expression as novel pharmacologic targets for the prevention and treatment of cardiomyopathy and heart failure.

 

Speaker
Biography:

Hiroshi Maruta is working at PAK Research Center, Melbourne, Australia.

Abstract:

Since our team at NIH found the very first member of PAK family kinases (called “myosin I heavy chain kinase”) in a soil amoeba in 1977, this family of RAC/CDC42-dependent Ser/Thr kinases kept expanding their territory during the last four decades. Among this unique family, however, PAK1 has been most extensively studied so far, mainly because it is essential for malignant transformation of mammalian cells, but non-essential for normal cell growth and shortens the heathy lifespan of small animals such as C. elegans and is involved even in PDGF/MSH-dependent melanogenesis. For this reason, a variety of PAK1-blockers/inhibitors have been developed or identified since the turn of this century, and some of them such as propolis and 15K could be potentially useful for therapy of solid tumors, promoting the longevity by suppressing a variety of other PAK1-dependent diseases/disorders such as AD (Alzheimer’s disease), hypertension and diabetes (type 2), and even for the cosmetic treatment of hyper-pigmentation (so-called “skin-whitening”). Thus,
the potential market value of these PAK1-blockers would be huge in both pharmaceutical and cosmetic industries. In this commentary, I shall briefly highlight the uniqueness of PAK1-blockers useful for signaling therapy causing no serious side effect, in contrast to conventional anti-cancer drugs such as DNA/ RNA/ microtubule poisons which clearly cause serious side effects such as hair-loss, suppression of immune system and loss of appetite. Rather
surprisingly, these PAK1-blockers such as propolis and 15K promote hair growth and boost even our immune system easing the damaging side effects caused by conventional anti-cancer drugs.

Speaker
Biography:

Our research goal is to understand the synaptic mechanisms involved in the pathophysiology of chronic pain and psychiatric disorders. We try to understand how brain circuit modulates neuronal transmission in midbrain periaqueductal gray, which is an critical region of midbrain for controlling of pain and emotion. We also try to understand how the analgesic compounds and antidepressants regulate pain and depression leads to therapeutic efficacy in the brain, especially in the periaqueductal gray.

 

Abstract:

Statement of the Problem: Major depressive disorder affecting more than 100 million people worldwide every year is a heterogeneous illness. To date, current pharmacotherapies require prolonged administration from several weeks to months for an appreciable response. This is particularly concerning given that suicide risk is elevated in subjects with depression.

Methodology & Theoretical Orientation: It is still unclear that whether ketamine metabolite (2R,6R-hydroxynorketamine; 2R,6R-HNK) rescues chronic stress-elicited depression-like behavior. Depression-like behavior in the rats were induced by learned helplessness (LH) procedure. Forced swim test (FST) and sucrose preference test (SPT) were used to study the depression-like behavior. Findings: Rats receiving learned helplessness procedure exhibited high failure rate in the escapable footshock test compared to control group. LH rats exhibited an increase in immobile time during the FST and a reduction in sucrose consumption. Intraperitoneal ketamine metabolite, 2R,6R-HNK, injection decreased immobile time during the FST and increased sucrose consumption in LH rats.

Conclusion & Significance: Ketamine metabolite 2R,6R-HNK rescues LH-induced depression-like behavior including despair behavior and anhedonia. These results may pave the foundation for a critical issue that ketamine metabolite, 2R,6R-HNK plays crucial roles in stress-induced depression-like behaviors and provides a new insight into depression management and development of antidepressants.

 

Speaker
Biography:

Katrin Mae M. Ortega, a bonifide graduate in Master of Science in pharmacy at the age of 25 years from of University Of Santo Tomas last June 2017 wherein she was awarded a dsitinction of Cum Laude. During her graduate study, Ms Ortega exhibited top performance during written examination as well as oral examinations. She got a Meritus honor on her thesis entitled “Antiangiogenic and AMP-Activated Protein Kinase Activities of Gracilaria coronopifolia J.G. Agardh Extracts”. This study as awarded gold medal in the Technical Poster Competition during 2nd International Science Graduate Scholars” Conference in the theme “From Disccoveries Today to Innovating Tommorow” held at the Philippine International Convention  Center Pasay City.

Abstract:

AMP-activated protein kinase (AMPK) is an intracellular energy sensor which is important in metabolic regulation, cell growth, and survival. Recently, dysfunction in AMPK is implicated to numerous angiogenesis-related diseases, however, the mechanism remains elusive. In this study, the antiangiogenic activity of the red alga, Gracilaria coronopifolia, was determined through cellular signaling pathway of AMPK. Chorioallantoic membrane (CAM) assay showed that all extracts of G. coronopifolia inhbited angiogenesis in a dose-dependent manner. Among them, dichloromethane extract exhibited the most potent antiangiogenic activity (IC50 =1.21 μg/mL, p=0.215) followed by hexane extract (IC50=3.08 μg/mL, p=0.479) and methanol extract (IC50=8.93 μg/mL, p= 0.042). Antiangiogenic activity was correlated to a low concentrations of Fe, Zn, and Cu of duck CAM determined using flame atomic absorption spectrometer (fAAS) and colorimetric assay. Likewise, In vitro AMPK signaling assay showed that all extracts activated AMPK, with dichloromethane extract having the lowest EC50 of 70.2 μg/mL. Thin layer chromatography (TLC) and gas chromatography-mass spectrometry (GC-MS) revealed the active component of each extracts. Notably, this is the first report on the AMPK activity of G. coronopifolia related to new blood vessel formation and a colorimetric-based correlation of angiogenesis based on Fe, Zn, and Cu concentration in the duck chorioallantoic membrane.

 

Speaker
Biography:

Poi Yee Cheong is currently pursuing her PhD degree at Monash University Malaysia. She has completed her Master degree in Medical Sciences at International Medical University, Malaysia. Her research interests focus on the characterization of the molecular mechanisms of benzyloxycarbonyl-phenylalanine-alanine-fluoromethylketone (z-FA-FMK) and benzyloxycarbonyl-phenylalanine-alanine-chloromethylketone (z-FA-CMK) induced toxicity in T cells. Both compounds are structurally similar; the former with fluorine in the methylketone group is immunosuppressive whereas the latter with chlorine induced cell death.

Abstract:

The cathepsin B inhibitor, benzyloxycarbonyl-phenylalanine-alanine-fluoromethyl ketone (z-FA-FMK) was found to readily inhibit Jurkat T cell proliferation at non-toxic concentrations. We showed that z-FA-FMK treatment leads to a decrease in intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) levels in Jurkat T cells. The inhibition of Jurkat T cell proliferation induced by z-FA-FMK were abolished by the presence of low molecular weight thiol-containing antioxidants such as GSH, N-acetylcysteine (NAC), L-cysteine but not with D-cysteine, which cannot be metabolized to GSH. These results suggest that the depletion of intracellular GSH is the underlying cause of z-FA-FMK-induced inhibition of cell proliferation in Jurkat T cells. Similarly, L-buthionine-sulfoximine (BSO) which blocks GSH biosynthesis also inhibits Jurkat T cell proliferation. In the presence of BSO, NAC has no effect on the inhibition of cell proliferation mediated by z-FA-FMK. Taken together, these results demonstrated that the inhibition of Jurkat T cell proliferation induced by z-FA-FMK is due to oxidative stress via the depletion of GSH.

 

Speaker
Biography:

Cao Donghua is a PhD candidate from Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences and  University of Chinese Academy of Sciences. Her Research Interest lies at the crossroads of chemistry and biology, and  endeavors to discover novel active natural products  from medicinal plant. She has published 3 papers in reputed journals .

Abstract:

 

Meliaceous limonoids, characteristic chemical markers of the Meliaceae family, are natural products with both fascinating structures and potential bioactivities that have attracted interest from both natural products chemists and synthetic chemists in the past half century. As part of a continuing search for structurally interesting and biologically important limonoids from the Meliaceae family, the leaves and twigs of Trichilia sinensis collected from Xishuangbanna, Yunnan province of China were investigated. Trichilia sinensis Bentv, a shrub, is native to the south of China and Vietnam, and it has traditional applications for the treatment of several diseases such as abdominal pain caused by Ascaris lumbricoides, chronic osteomyelitis, scabies, and eczema in folk medicine. The three novel rearranged mexicanolide-type limonoids (Trichiliasinenoids A-C) with an unprecedented C-29-C-7 connecting carbon skeleton formed by migration of C-7 from C-6 to C-29 of a mexicanolide-type limonoid precursor were isolated from the leaves and twigs of Trichilia sinensis. Their structures were assigned by spectroscopic analysis, and the absolute conīŦgurations were determined by X-ray crystallography and CD calculation. A possible biosynthetic pathway of Trichiliasinenoids A was also proposed. The three new limonoids were evaluated for their cytotoxic activity against human myeloid leukaemia (HL-60), hepatocellular carcinoma (SMMC-7721), lung cancer (A-549), breast cancer (MCF-7), and colon cancer (SW480) cell lines by MTS assay. Trichiliasinenoid B showed cytotoxicity against HL-60 cells, SMMC-7721 with an IC50 value of 5.2 mM and 30.6 mM, respectively, whereas other limonoids were inactive  and comparable to the cisplatin positive control (IC50: 1.1–17.3 m M).

 

Speaker
Biography:

Dr. Rishi Pal has completed Postgraduate degree in 2001 and Ph.D (Pharmacology) in 2007 from Faculty of Medicine, University of Delhi. He has awarded Postdoctoral training fellowship by University of Texas, MD Anderson Cancer Centre (UTMDACC), Houston, Texas, USA. He is Associate Professor, Department of Pharmacology & Therapeutics, King George’s Medical University, UP, Lucknow, India. He is supervising MD/PhD students for their thesis. He has published more than 25 research papers in journals of repute, one book, two book chapters and serving as reviewer of many scientific international journals.

Abstract:

Introduction: Phosphodiesterase (PDE) inhibitors are known to increase cAMP/cGMP in the cellular compartment and leads to signal transduction process in the various cell system. Here we focused on the anti-inflammatory & immunomodulatory protective role of some cAMP/cGMP-PDE inhibitors theophylline, pentoxifylline, sildinafil & rolipram and their interactions with nitric oxide (NO) modulators in complete Freund's adjuvant induced rheumatoid arthritis in rats.

Method: Wistar rats (200-300 gm, n=6/group) of either sex were used in the study. On day '0' rats were injected with 0.2 ml of complete Freund’s adjuvant (CFA) in sub-planter region of right hind paw along with 0.1 ml of squalene to develop RA while controls received only vehicle. PDE inhibitors drug treatment alone and in combination with NO modulators was given from day '14' to '28'. Arthritic parameters a) arthritis index, b) ankle diameter c) paw volume and their body weight were noted to evaluate progression of RA on day 0, 7, 14, 21 and 28. On day '28' rats were sacrificed and their blood and paws were collected for TNF-α and IL-10 cytokine estimation, pathological examination and NF-kB expression. Data obtained was analysed using two-way ANOVA followed by Newman-Keul’s posthoc test and p<0.05 was considered for significance.

Result: It was found that CFA significantly increased arthritis-index, paw volume, ankle diameter and serum TNF-α and NF-kB levels while body weight and serum IL-10 levels was significantly decreased (P<0.05). These CFA-induced changes were significantly reversed by theophylline (10 & 20 mg/kg), P<0.0001; pentoxifylline (5 & 10 mg/kg), P<0.002; rolipram (1 & 2 mg/kg), P<0.05; sildenafil (50 & 50 mg/kg) alone and in combination with L-arginine (100 mg/kg) and or L-NAME (10 mg/kg) in dose dependent manner (p<0.005) in all parameters (1). The maximum protective effects was observed in theophylline > pentoxifylline > rolipram > sildinafil with L-NAME 10 mg/kg combination treatment group (p<0.001). The data obtained was substantiated histopathological analysis (2).

Conclusion: Results of this study are suggestive of the involvement & interaction of NO with different PDE inhibitors. cAMP/cGMP mediated PDE inhibition may have protective role in pathogenesis of rheumatoid arthritis. Further studies are required to dissect out the role of PDE inhibitors and nitric oxide (NO) modulators at cellular level in RA.

Speaker
Biography:

Prakash Kinthada is a professor in chemistry at Sri Vidyanikethan Engineering college, JNTU University in Tirupathi, India.

 

Abstract:

Cancer is a dreadful disease and any practical solution in combating this disease is of paramount importance to public health. Cancer patients have burdened by drug induced toxic effects, and no turned to seek help from the complementary and alternative medicine hoping for a better cure. Research on Platinum based drugs and Non Platinum based drugs is a Multi-Million Dollar Industry in USA and there is every need to produce safe drugs for the cure of this monstrous disease. Flavonoids have a long history of use in traditional medicines in many cultures. The phytochemical, curcumin is one of the major dietary flavonoid, belonging to a group of flavonol, Curcumin is a natural polyphenol. It is highly potential molecule capable of preventing and treating various cancers.  Various dietary chemo preventive agents, turmeric powder or its extract are broadly used as therapeutic preparations in Indian System of medicine. We provide a summarized synthesis and structural determination of Curcumin Oxime, Curcumin Thiosemicarbazone derivative of Gold (III) complex. The use of these analogs for prevention of cancer tumor progression and treatments of human malignancies. A pharmacologic agent for treating and/or preventing cancer, among other diseases and conditions, and particularly breast, prostate, and pancreatic cancer, in humans and animals. The novel pharmacologic agent is an isoflavonoid or isoflavonoid mimetic covalently attached to a cytotoxic pharmacophore that, preferably has the ability to conjugate with a metal salt to form a more potent metal complex, particularly a Au (III) complex and other complexes of Platinum, Palladium, Ruthenium, Copper etc.

Speaker
Biography:

Anil Kumar is working in Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh, India

 

Abstract:

Therapeutic potential of berberine has been well documented in various neurological problems. However, neurological mechanism of berberine remains untapped in the light of its p-glycoprotein mediated gut efflux properties responsible for reduced bioavailability. The present study was designed to evaluate the neuroprotective mechanism of berberine and its effect on various behavioral alterations, oxidative stress, mitochondrial dysfunction, neuroinflammation and histopathological modifications in sporadic dementia of Alzheimer's type in rats. Berberine (25, 50 and 100 mg/kg) or verapamil (2.5 and 5 mg/kg) were used as a treatment drugs and memantine (5mg/kg) was used as a standard. In the present study, berberine and verapamil significantly attenuated behavioural, biochemical, cellular and histological alterations suggesting their neuroprotective potential. Further, treatment of berberine (25 and 50  mg/kg) with verapamil (2.5 and 5.0 mg/kg) combinations respectively significantly potentiated their neuroprotective effect which was significant as compared to their effect per se in ICV-STZ treated animals. The augmentative outcome of verapamil on the neuroprotective effect of berberine can be speculated due to the inhibition of P-gp efflux mechanism and the prevention of calcium homeostasis alteration. In addition, anti-inflammatory and antioxidant effects of both berberine and verapamil could also contribute in their protective effect.