3^rd World Congress on Pharmacology August 08-10, 2016 Birmingham, UK

Ai-Lin Liu completed her PhD in 2009 from the University of Macau. She has engaged in anti-AD drug discovery and mechanism researh, anti-influenza drug discovery and mechanism research, drug informatics and computational pharmacology for more than 10 years. She has published more than 50 papers in the international reputed journals, applied more than 10 patents and obtained 4 prizes for her outstanding scientific research.

Alzheimer’s disease (AD) treatment is a worldwide difficult problem, since the therapeutic effect of the present anti-AD drugs are not very ideal, and the development of new drugs is still facing various dificulties. DL0410, which is a candidate drug targeting multi-target, is undergoing a systematic preclinical studies, incluing pilot-scale synthesis, crystal polymorphism and bioavailability evaluation, preparation formulation, quality control, stability studies, pharmadynamics, action mechanisms, pharmacokinetics and safety evaluation. Compared with the clinical first-line anti-AD drugs, such as Donepezil and Rivastigmine, its advantages lie in the following aspects. Firstly, DL0410 displays stronger efficacy, and possesses polypharmacology features. It can regulate not only the balance of cholinesterases, improve the function of cholinergic system, but also acetylcholine mediated ion channel receptor α7nAChR. Meanwhile, it can not only block a lot of neuropathies caused by various pathogenic factors including Aβ aggregation, oxidation stress and inflammatory factors, but also increase the long term potential to improve the ability of memory and learning. The studies to explain these bioactivities and reveal their relationship will be performed in the future. Secongdly, DL0410 is very safe. The acute toxic effect of oral administration in mice showed its LD50 as 977 mg/kg, while its optimal effective dose is around 3~10 mg/kg, so its therapy index is more than 97.7. Thirdly, DL0410 without choral atom is easily synthesized and cheap. It can be widely used in clinic after the approval for AD treatment. In conclusion, DL0410 is a promising candidate for the future AD treatment.

Minyoung Lee has completed his PhD at the age of 34 years from college of medicine, Kyunghee University. Shee is the senior researcher of Korea institue of Radiological and medical sciences. She has published more than 25 papers in reputed journals until 2000.

Treatments of cancer try to destroy the entire tumor, but this tends to require lethal compounds and high doses of radiation. Recently, considerable attention has focused on therapy-induced senescence (TIS), which can be induced in tumor cells by low doses of therapeutic drugs or radiation, and provides a barrier to cancer development. However, the molecular mechanisms governing TIS remain unclear. Special attention has been paid to the potential anti-cancer effect of aspirin against human colorectal cancer (CRC). In this study, we investigated the effects of aspirin on TIS of CRC cells, and show that it occurs via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), two key regulators of cellular energy metabolism. Aspirin increased the senescence of CRC cells, increased the protein levels of SIRT1, phospho-AMPK (T172), and phospho-acetyl CoA carboxylase (S79), and reduced the cellular level of ATP. SiRNA-mediated down-regulation or pharmacological inhibition of SIRT1 or AMPK considerably reduced the aspirin-induced cellular senescence in CRC cells. In contrast, treatment with a SIRT1 agonist or an AMP analog (AICAR) induced cellular senescence. Remarkably, knockdown of SIRT1 abolished the aspirin-induced activation of AMPK, and vice versa. During the progress of aspirin-induced cellular senescence in CRC cells, SIRT1 showed increased deacetylase activity at an early time point, but was characterized by decreased activity with increased cytoplasmic localization at a later time point. Taken together, these results suggest that aspirin could provide anti-cancer effects by inducing senescence in CRC cells through the reciprocal regulation of SIRT1-AMPK signaling pathways.

Yang Li has completed his PhD and postdoctoral studies from Tongji Medical College of HUST. He is expert of National Natural Science Foundation of China, committee member of China Medicinal Biotechnology Association, and the standing board or special reviewers of 10 journals. He has published more than 26 papers as first or Corresponding author.

Brugada syndrome (BrS), which causes arrhythmias that lead to sudden cardiac death, is linked to loss-of- function mutations that affect sodium channels. Here, we investigate the rescue effect of alpha- allocryptopine (All) from Chinese herbal medicine in a T353I mutation of SCN5A, which combines trafficking abnormalities with Brugada syndrome. SCN5A-T353I expressed in HEK293 cells showed a small peak current (Ipeak) of only 59.6% of WT and an observably sustained current (Isus). We found that after treatment with All by direct perfusion for 5 min, neither WT nor T353I currents markedly changed. However, after incubating with All for 24 h, Ipeak of the T353I in HEK293 cells was strongly enhanced. Furthermore, the enhanced plasma membrane (PM) expression of Nav1.5 was detected, indicating the rescued defective trafficking. Interestingly, the Isus of T353I was significantly inhibited by All, which reduces the occurrence of LQT syndrome 3 (LQT3). We provide evidence that All can rescue the trafficking deficiencies and restore the cellular electrophysiological characteristics of SCN5A-T353I. This feature of All may benefit patients with the BrS-associated Nav1.5 channel and might have other potential therapeutic effects.

Kecheng Lei is studying for a Doctor's degree in Jianwen Liu’s Lab. She has published a paper in Tumor Biology in 2015.

Photodynamic therapy (PDT) has been recognized as an innovated therapeutic modality for the treatment of various cancers. In this study, we evaluated the anticancer effect of a new photosensitizer 3B in breast cancer, which was considered one of the most common cancers in women worldwide. Here, we determined the effect of 3B not only on the cell growth, apoptosis, and Warburg effect in vitro but also on the anti-cancer effect in nude mice in vivo. Our results showed that 3B was primarily accumulated in mitochondria, increased the level of ROS, induced apoptotic cells death via Bcl-2 family, and its activity could be blocked by the caspase inhibitor (Z-VAD-FMK). Furthermore, we found that 3B had the ability to repress glucose consumption and lactate generation in breast cancer cells. Meanwhile, 3B inhibited the expression of IL-6 that affected the glycolysis pathway. As we hypothesized, the present study also showed that 3B could repress JAK-STAT3 pathway as well as revealed the significant inhibitory effect on the expression of miRNA-155-5p, which took a prominent role in inflammation. Over-expressed miRNA-155-5p could increase the Warburg effect, though it might be reversed by 3B. In vivo study, 3B made a significant opening inhibition of tumor growth and showed drug toxicity hardly. These data supported that 3B might develop as potential therapeutic drug for the treatment of breast cancer.

Thabiso Tlaila has recently completed his Masters in Pharmacology at the University of KwaZulu-Natal (UKZN). The School of Health Sciences at UKZN and the prestigious Innovation Masters Scholarship from the National Research Foundation (NRF) funded his Masters research project. Thabiso has won several awards, in the most recent; he took 1st prize for a Masters Poster Presentation at the UKZN Annual Health Science Symposium.

Diabetic patients are two to three times more likely to develop active tuberculosis infections compared to non-diabetics. Co-morbidity of diabetes and TB infection is rising and contributes to an increased disease and pill burden. Citrus fruit flavonoid naringenin has been reported to have antimicrobial and antidiabetic activities. The aim of the study was to develop synthetic analogues of the naringenin moiety that can be used as potential agents with dual activity against type 2 diabetes and TB infections. A novel series of 4-[(cyclopropylcarbonyl) amino] chalcones were synthesized. An intermediate compound, N-(4-acetylphenyl) cyclopropanecarboxamide was synthesized and thereafter reacted with commercially available aldehydes to yield the final amino-chalcone series. In vitroantimycobacterial activity was determined against M. tuberculosis (M.tb) strain H37Rv grown under aerobic conditions using dual optical or fluorescence read out methods. In silicostudies were carried out to determine binding affinities of these compounds on adenosine monophosphate activated protein kinase (AMPK) and also on malate synthase: an enzyme that has been implicated in the latency and adhesion of M.tb. A series of 11 novel compounds were successfully synthesized, characterized and tested against M.tb; 7 compounds were found to be active against the TB strain and 3 showed promising activity with MICs (μM) of 32, 48 and 49. These compounds showed good binding affinity to malate synthase and AMPK with binding scores reaching -8.2 and -9.2 Kcal/mol respectively. Naringenin analogues can be targeted as potential compounds for co-morbid TB and type 2 diabetes treatment. In vitro and in vivoantidiabetic and antimycobacterial studies should be done to further elucidate the molecular mechanisms of these compounds.

Anne-Laure Pittet completed her PhD in Life Sciences from the University of Lausanne (Switzerland). She completed a Master of Advanced Studies (MAS) in Business Management at the University of Geneva (Switzerland). She is currently an Associate Researcher at the University Institute of the History of Medicine and Public Health (IUHMSP), Lausanne, Switzerland. Her main topic of interest is the interactions between the physicians, the pharmaceutical industry and the health authorities.

Opinion leaders (OLs) are a tool for promoting new medicines that the pharmaceutical industry has adopted relatively recently. The literature related to OLs is increasing worldwide, but at the same time this is revealing major confusion about the very concept of OLs. For this reason, we decided to clarify this concept using the primary sociological definition of OLs and clarifying the different roles that the OLs can play. This typology will be discussed (local/ expert and peer/ formal and informal/ key roles). We tested the typology in the context of French-speaking Switzerland using a qualitative study. Of the different roles, the “key” OL role was mainly used by the pharmaceutical industry to promote new medicines. While OLs and physicians are resistant to “key” OLs interventions, the pharmaceutical industry is subtly shifting its strategy towards OLs having a “local” role, as these OLs are well perceived by the medical community.

Jing Ai has completed her PhD at the age of 36 years from Department of Phamacology, Harbin Medical University and postdoctoral studies from College of Bioinformatics Science and Technology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University. She has published more than 40 papers in reputed journals and has been serving as an editorial board member of PloS One.

Large cohort studies have revealed a close relationship between cognitive impairment and cardiovascular diseases, although the mechanism underlying this relationship remains incompletely understood. In this study, using a transgenic (Tg) mouse model of cardiac-specific over-expression of microRNA-1-2 (miR-1-2), we observed that microRNA-1 (miR-1) levels were increased not only in the heart but also in the hippocampus and blood, whereas its levels did not change in the skeletal muscle of Tg mice compared with age-matched wild type (WT) mice. Six-month-old Tg mice showed cognitive impairment compared with age-matched WT mice, as assessed using the Morris Water Maze test. The brain-derived neurotrophic factor (BDNF) level and cyclic AMP-responsive element-binding protein (CREB) phosphorylation were also significantly reduced in the hippocampi of the Tg mice, as evaluated by western blot. Further examination showed that BDNF proteins expression was down- or up-regulated by miR-1 over-expression or inhibition, respectively, and was unchanged by binding site mutations or miRNA-masks for the 3’UTR of Bdnf, indicating that this gene is a potential target of miR-1. Knockdown of miR-1 by hippocampal stereotaxic injection of an anti-miR-1 oligonucleotide fragment carried by a lentivirus vector (lenti-pre-AMO-miR-1) led to up-regulation of BDNF expression and prevented the reduction in cognitive performance in the Tg mice without affecting cardiac function. Our findings demonstrate that cardiac over-expression of miR-1 also induces behavioral abnormalities that may be associated, at least in part, with the down-regulation of BDNF expression in the hippocampus. This study definitely contributes to the understanding of the relationship between cardiovascular disease and cognitive impairment.

Xi Chen has completed her master degree study from PLA General Hospital, and is majoring in her doctoral study from PLA General Hospital. Her major research covers electrophysiological study related to arrhythmia and mitochondrial genetic study related to hyperetension. She has published 3 papers as first author during her studies.

Brugada syndrome (BrS), a cardiac disorder predisposing to a high risk of sudden cardiac death, is associated with loss-of-function in sodium current (INa). Exposure of tricyclic antidepressants (TCAs) has been reported to induce BrS phenotype. However, the michanisms by which TCAs induce BrS remains unclear. Therefore, we investigate the effect of TCAs on Nav1.5. Four widely used TCAs (amitriptyline, nortriptyline clomipramine and desipramine) were tested for their pharmacological effect. Neonatal rat ventricular myocytes were used for patch clamp and immunofluorescence experiments. Nortriptyline, clomipramine and desipramine showed similar effect on Ipeak of Nav1.5 by way of either acute administration or chronic incubation for 24h. While amitriptyline exhibit more impressive effect through chronic incubation than through acute administration. Ipeak of Nav1.5 decreased for 43.4% after co-incubation with amitriptyline for 24h. No significant difference in steady-state activation and steady-state inactivation processes was observed between cells before and after co-incubation with amitriptyline. Confocal imaging showed decreased expression of Nav1.5 on plasma membrane and increased expression of Nav1.5 around nuclear in cells co-incubation with amitriptyline for 24 h, which indicated trafficking abnormalities of Nav1.5 induced by amitriptyline. We provide evidence that amitriptyline can induce the trafficking abnormalities of Nav1.5. The chronic effect of amitriptyline may lay foundation for researches on potential treatment of Nav1.5-associated BrS.

Mariam Yousif completed her PhD at School of Pharmacy & Pharmacology in University of Bath, UK in 1996. She works as a professor of Pharmacology in Faculty of Medicine at Kuwait University. She published more than 50 papers in peer reviewed journals and served as a reviewer for different journals in the field of pharmacology. Her research interest is in studying signal transduction pathways involved in mediating cardiovascular dysfunction in tpe 1 diabetes.

Angiotensin-(1-7) may have beneficial effects in erectile dysfunction (ED) associated with diabetes mellitus. The objective of this study was to investigate the effects of chronic administration of Ang-(1-7) on phosphodiesterase (PDE) levels in the rat CC. Male Wister rats weighing 300 g were used according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Diabetes was induced by ip injection (55 mg/kg) of streptozotocin (STZ). After 3 weeks of diabetes induction, Ang-(1-7) was administered ip (576 μg/kg/day) for another 3 weeks and animals were sacrificed at the end of 6 weeks. Animal groups were: Group 1: Control, Group 2: Control+Ang-(1-7), Group 3: STZ; Group 4: STZ+Ang-(1-7). Rats were sacrificed at the end of the study. Longitudinal strips of CC from control and diabetic rats were suspended in organ-baths. The reactivity of the tissues to the vasodilator agonists Ang-(1-7) and carbachol was determined by measurement of changes in isometric tension. The isolated penile tissues from different animal groups were homogenized and PDE activity was measured using a luminescence-based kit. The relaxant responses to Ang-(1-7) and carbachol were significantly impaired in diabetic CC. Pre-incubation of the CC from diabetic animals with Ang-(1-7) resulted in significant enhancement in carbachol-induced relaxation. Diabetes caused a significant increase in the activity of PDE in penile tissue. Chronic treatment with Ang-(1-7) significantly reduced STZ-induced activation of PDE activity. Ang-(1-7) induced an attenuation in the increased penile PDE activity of diabetic rats which may provide a new therapeutic tool to correct ED.

George J Amabeoku has a qualification in Pharmacology. He has lectured at Universities in Nigeria, Zimbabwe and now in South Africa. His research interest and expertise are in the field of neuro-psychopharmacology which he now applies to traditional medicine where he focuses on the evaluation of the neuro-psychopharmacological activities of medicinal plants used in South Africa with a view to validating their efficacy.

Purpose: The use of medicinal plants in South Africa is an old age practice. Ballota africana is a commonly used medicinal plant in the country by traditional medicine practitioners to treat headaches and insomnia amongst other ailments. However, there is no information in literature to verify the effectiveness of B. africana in the treatment of headaches and insomnia. The study, therefore, investigated the anti-nociceptive and central nervous system depressant activities of the leaf methanol extract of this plant species in mice. Materials & Method: Fresh leaves of Ballota africana were collected from Kirstenbosch Botanical Gardens, South Africa, verified by the curator of the Gardens and a taxonomist in the Department of Biodiversity and Conservation Biology, University of the Western Cape, South Africa and a voucher specimen (UWC 102 Amabeoku) deposited in the University Herbarium. Leaf methanol extract of the plant species was prepared using standard extraction methods. The acetic acid writhing and the hot plate tests were used to determine the anti-nociceptive effects while pentobarbitone induced sleep and locomotor activity tests were used to evaluate the sedative-hypnotic effect of the plant species. Phytochemical qualitative analysis, acute toxicity and HPLC studies of the plant species were also carried out using standard methods. Results: The phytochemical qualitative analysis carried out on the dried powdered leaves of Ballota Africana showed the presence of triterpene steroids, saponins, tannins, flavonoids and reducing sugars. Leaf methanol extract of B. africana (25-400 mg/kg,i.p.), paracetamol (500 mg/kg, i.p.) or indomethacin (20 mg/kg, p.o.) significantly reduced 3% acetic acid (0.25 ml, i.p.)-induced writhes. Combined therapy of the lowest and sub effective doses of leaf methanol extract of B. africana (12.5 mg/kg, i.p.) and indomethacin (10 mg/kg, p.o.) which are in themselves ineffective against 3% acetic acid (0.25 ml, i.p.)-induced writhes, significantly reduced 3% acetic acid (0.25 ml, i.p.)-induced writhes. Leaf methanol extract of B. africana (25-400 mg/kg, i.p.) and morphine significantly delayed the reaction time of mice to thermal stimulation 15, 30, 45, and 60 min after treatment. Dimethylsulfoxide (0.25 ml, i.p.) did not significantly affect 3% acetic acid (0.25 ml, i.p.)-induced writhes or thermal stimulation. Leaf methanol extract of B. africana (25-400 mg/kg,i.p.) significantly and dose dependently prolonged pentobarbitone (40 mg/kg, i.p.)-induced sleep in mice. Diazepam (0.5 mg/kg, i.p.) significantly prolonged pentobarbitone (40 mg/kg, i.p.)-induced sleep in mice. Leaf methanol extract of B. africana (25-400 mg/kg,i.p.) significantly and dose dependently reduced the locomotor activity of mice. Diazepam (0.5 mg/kg, i.p.) significantly reduced the locomotor activity of mice. Dimethylsulfoxide (0.25 ml, i.p.) did not significantly affect pentobarbitone (40 mg/kg, i.p.)-induced sleep in mice or locomotor activity of mice. The LD50 value obtained for the leaf methanol extract of B. africana following oral administration was probably over 4000 mg/kg. The HPLC finger-print of the methanol extract showed characteristic peaks at the following retention times: 3.556, 9.127, 10.062, 13.499, 26.613, 29.519 and 30.166 min. In conclusion, the data obtained show that leaf methanol extract of B. Africana has both anti-nociceptive and sedative-hypnotics effects.

Zeting Yuan received her Master’s degree in Pharmacy from East China University of Science and Technology in 2012. In May 2013, she became a Research Associate of Putuo Hospital and Cancer Institute, Shanghai University of Traditional Chinese Medicine, studying on Pharmacology of Traditional Chinese Medicine and the mechanism of overcoming multidrug resistance in the colorectal cancer

Cinobufagin（CI）is a major bioactive component of Venenum Bufonis, which is a traditional Chinese medicine obtained from the skin and parotid venom glands of toads, and has been found to induce cell apoptosis in various types of cancer cells. The objective of this study was to investigate the reversal effect of CI on P-gp-mediated MDR. Effects of CI on cytotoxicity of anticancer drugs and intracellular accumulation of P-gp substrate Rhodamine 123 were examined in P-gp -overexpression cells. Its molecular mechanism and effect on regulating P-gp expression were further investigated by ATPase assay and Western blot. Our results showed that CI significantly enhanced the sensitivity of P-gp-overexpressing cells to anticancer drugs in HCT116/L and Cao-2/ADR cells without affecting their corresponding parental cells. It also remarkably increased intracellular accumulation of Rhodamine 123 in those cells. Further mechanistic studies demonstrated that the circumvention of P-gp-mediated MDR by CI was result from uncompetitive inhibition of P-gp ATPase activity but not to alter the P-gp expression. Our findings demonstrated that CI could be used as a promising lead compound for further development into selective and efficient MDR reversing agents for combination use with P-gp substrate drugs in cancer chemotherapy.

Jae Young Choi has completed his PhD from Yonsei University and Post-doctoral studies from Stanford University. He has published more than 50 papers in reputed journals

Objective: Pendrin, encoded by SLC26A4 is expressed in distal collecting tubule of kidney. Recent data support that pendrin also play an important role in Cl absorption in kidney. We found new pendrin inhibitors by high throughput chemical screening. We evaluated the effect of pendrin inhibitors in urine output, and urinary Na+/Cl- excretion in mice. Methods: After set up the screening system for pendrin inhibitors using pH sensitive dye and pendrin transfected cell line, we screened 65,000 small molecule. The effect of lead compounds on urine out-put and Na+/Cl- excretion was checked in C57B6 mice in metabolic cage. Results: Two novel compounds (PI-YS 01 and PI-YS-02) have inhibitory effect on Cl-/HCO3- exchange activity in pendrin infected cell line. These compounds also increase urine out-put in mice. In high Na diet mice, PI-YS-01 and PI-YS-02 increased urinary Na+/Cl- excretion. Conclusion: Pendrin inhibitors increased urine output and urinary Na+/Cl- excretion. Our data suggest that pendrin can be a new target for anti-hypertensive drug

Sabrina Kraft is a Biologist and has completed her PhD in 2015 at the University Hospital in Heidelberg. Currently, she is working as a Group Leader in the Pharmacology Department of Preclinical Research at Dr. Willmar Schwabe Pharmaceuticals in Karlsruhe (Germany).

WS® 5570 is a stabilized drymethanolicextract (80% V/V;drug-extract ration 3-7:1) from Hypericum perforatum L. (St. John's wort) with defined contents of hyperforin, hypericin, and flavonoids. It is an approved medication for the treatment of mild or moderate depression in Germany and many other countries worldwide. Circadian rhythms have been shown to be fundamentally disturbed in patients with depression, which also suffer frequently frominsomnia. H. perforatum contains melatonin, known as the "sleeping hormone" and hypericin, a potent photodynamic agent. Melatonin and analog compounds have been observed to exert beneficial effects not only on sleep and circadian abnormalities but also mood disorders, learning and memory. Hence, the present work investigated the effect of WS® 5570 on the melatonergic system known to be involved in the genesis of depression. Receptor binding studies demonstrated that WS® 5570 and isolated ingredients hypericin, hyperforin and flavonoid 13’, II8-biapigenin inhibit binding of [125I]-2-iodomelatonin to human melatonin MT1 and MT2 receptors at concentrations between 3 and 30 µg/ml. In male rats, oral treatment with 100-900 mg/kg WS® 5570 for 4 consecutive days dose-dependently increased and prolonged peak melatonin plasma levels during the dark phase of a fixed 12 h diurnal light cycle. The present results indicate that WS® 5570 in a dual manner interferes with the melatonergic system and by these means may at least partly exert its positive therapeutic effects on mood and disturbed sleep in depression. However, further studies are required to elaborate the mode of action in more detail.