Day 1 :
The University of Western Ontario, Canada
Keynote: Connexin and Pannexin large-pore channels as potential therapeutic targets in drug discovery
Time : 10:00-10:40
Dale W. Laird is a Full Professor and Canada Research Chair in Gap Junctions and Disease. He has over 30 year of experience working with connexins, and more recently pannexins, and has published over 150 papers on their role in health and disease. He has received many awards for his research and is currently funded by the Canadian Institutes of Health Research
The connexin and pannexin families of large-pore forming channel proteins facilitate the passage of various ions, metabolites, and signaling molecules between cellular cytoplasms, either through extrusion into the extracellular milieu, or in the case of connexins, directly between cells. Connexins may functionally overlap with the activities of pannexin channels by participating in intercellular signaling by generating functional hemichannels at the cell surface, although this is not well documented in vivo. Connexin expression and regulation is tightly correlated with cancer onset and progression while mutations in half of the genes that encode the 21 member connexin gene family lead to over two dozen diseases ranging in severity from manageable developmental abnormalities to life-shortening organ failure. Our laboratory used tissue-relevant cells, primary cells, organotypic cultures, mouse models of human disease and induced pluripotent stem cells from connexin-linked disease patients to uncover ten distinct mechanisms by which connexin gene mutations cause disease. These mechanisms are subdivided into both gain- and loss- of function mutations. Once mechanistic information is known as to how mutant connexins cause disease, long-term goals include developing strategies to compensate for cellular defects triggered by these mutants. Complementary to these connexin studies, pannexin expression levels and regulation has been linked to over a dozen diseases that affect most of the major organs in the human anatomy. Since these channels function at the cell surface and pannexin polypeptide domains are exposed to the extracellular surface, they represent potentially druggable targets. This presentation will discuss pannexins and connexins as therapeutic targets in disease treatment. Funded by the Canadian Institutes of Health Research.
Figure 1: Schematic of connexins arranged into an intercellular gap junction channel (gap junctions denoted in green at points of cell -cell apposition) and hemichannels. Pannexins form a single membrane channel and appear dispersed throughout the plasma membrane when expressed in cells (red). Both connexin and pannexin channels allow for the passage of small molecules <1000 daltons.
D.W. Laird, C.C. Naus and P.D. Lampe (2017) “SnapShot: Connexins and disease”, Cell 170: 1260-1260e1.
E.R. Press, Q. Shao, J.J. Kelly, K. Chin, A. Alaga and D.W. Laird (2017) “Induction of cell death and gain-of-function properties of connexin26 mutants predict severity of skin disorders and hearing loss” Journal of Biological Chemistry 292: 9721-9732.
J.L. Esseltine, Q. Shao, C. Brooks, J. Sampson, D. Betts, C. Seguin and D.W. Laird (2017) “Connexin43 mutant patient-derived induced pluripotent stem cells exhibit altered differentiation potential” Journal of Bone and Mineral Research 32: 1368-1385. Selected for Journal Cover.
J. Esseltine and D.W. Laird (2016) “Next-generation connexin and pannexin biology” Trends in Cell Biology 26: 944-955.
T. Aasen, M. Mesnil, C.C. Naus, P.D. Lampe and D.W. Laird (2016) “Gap junctions and cancer: Communicating for
50 years” Nature Reviews Cancer 16: 775-788. Article selected for cover illustration.
The University of Jordan, Jordan
Time : 10:40-11:20
Professor Mubarak received his B.Sc. and M.Sc. degrees in chemistry from the University of Jordan in 1976 and 1978, respectively and obtained his Ph.D. degree from Indiana University, Bloomington, USA in 1982, under the supervision of Professor Dennis G. Peters. He served as the chairman of the department of chemistry at The University of Jordan and the Vice Dean of the Faculty of Science for several years. He is also an Adjunct professor of Chemistry at Indiana University, Bloomington (USA) since 2009. In addition to electrochemistry, Professor Mubarak’s research program is broadly based on synthetic organic chemistry, especially synthesis of compounds with expected biological activity, medicinal chemistry, and drug design and discovery. He is the author and coauthor of more than 180 research papers published in peer-reviewed journals in addition to chapters published in specialized books. He has also supervised 39 theses and dissertations.
Many natural products present in our diet, including flavonoids, can prevent the progression of cancer and other diseases. In addition, utilization of compounds extracted from medicinal plants to fight diseases and illnesses such as cancer, diabetes, cardiovascular disorders, and oxidative stress is gaining popularity due to their lesser side effects and cost. Advances in pharmacology, physiology, and immuno-nutrition have highlighted the importance of natural products as alternative medicines in the treatment of different diseases. In this respect, we will focus on the use of resveratrol, a natural polyphenol present in various fruits and vegetables such as grapes, and peanuts, which is potentially useful for anticancer therapy, whether alone or when combined with other chemotherapeutic drugs, and on its health-promoting potentials. Resveratrol has been found to act as a chemopreventive agent to cure multiple human diseases such as cancer, diabetes, obesity, as well as Huntington's, Alzheimer's, and Parkinson's diseases, along with asthma. It reduces incidence of arterial hypertension, heart failure and ischemic cardiac disease, and improves insulin sensitivity. Resveratrol also works as an antioxidant by promoting nitric oxide production, suppressing platelet aggregation, and enhancing high-density lipoprotein cholesterol. Therefore, the use of resveratrol as a health promoting dietary supplement is rapidly increasing in today's market. However, more investigations to assess the potential of this natural compound as a complementary or alternative medicine for preventing and treating diseases are needed. These may involve different pharmacokinetic parameters before this substance hits the market as a prescribed drug. In addition, development of standardized extract or dosage could also be pursued in clinical trials.
Recent Publications (minimum 5)
1. Rauf A, Imran M, Butt MS, Nadeem M, Peters DG,
Mubarak, MS (2016) Resveratrol as an Anticancer Agent: A Review. Critical Review in Food Science and Nutrition Published on line on Dec. 21, 2016. http://dx.doi.org/10.1080/10408398.2016.1263597.
2. Rauf A, Imran M, Suleria HA, Ahmad B, Peters DG, Mubarak MS (2017) A comprehensive review of health perspectives of resveratrol. Food and Fuction. DOI: 10.1039/C7FO01300K.
3. Al Khabbas MH, Ata SA, Abu-Dari KI, Tutunji MF, Mubarak MS (2017) Synthesis and characterization of new 1-hydroxy-2-pyridinethione derivatives: Their lead complexes and efficacy in the treatment of acute lead poisoning in rats. Journal Trace Elements in Medecine and Biology 44: 209-217.
4. Mabkhot, YN, Kaal NA, Alterary S, Al-Showiman SS, Farghaly, TA, Mubarak MS (2017) Antimicrobial activity of thiophene derivatives derived from ethyl (E)-5-(3- (dimethylamino)acryloyl)-4-methyl(phenylamino)thiophene-3-carboxylate. Chemistry Central Journal 11: 75.
5. Rauf A, Raza M, Patel S, Bawazeer S, Ben Hadda T, Jehan N, Mabkhot YN, Khan A, Mubarak MS (2017) Urease inhibition potential of di-nathodiospyrol from Diospyros lotus roots. Natural Product Research 31(10): 1214-1218.