Prof. D. Allan Butterfield is the University of Kentucky Alumni Association Endowed Professor of Biological Chemistry, Associate Vice President for Research, Faculty of the Sanders-Brown Center on Aging, and a Fellow of the Society for Redox Biology and Medicine (SfRBM) at the University of Kentucky. He is the recipient of the Discovery Award from the SfRBM in 2013. Prof. Butterfield’s career is marked by his seminal research on the oxidative damage in the brains of persons with Alzheimer disease (AD) and its earlier stage, mild cognitive impairment (MCI). He also pioneered the methods of Redox Proteomics to identify oxidatively modified brain proteins in persons with AD and MCI. Prof. Butterfield showed that amyloid beta-peptide oligomers lead to lipid peroxidation, which leads to the neurotoxic product, 4-hydroxy-2-nonenal (HNE). Prof. Butterfield demonstrated that this highly reactive molecule binds to and causes dysfunction of brain proteins, among which are those associated with glucose metabolism, proteostasis, insulin signaling, and the mTORC1 pathway, all of which are dysfunctional in AD and MCI. His research has resulted in more than 630 publications with a h-index of 123 and has been supported by grants from the National Institutes of Health. He has graduated 68 PhD and MS students and trained more than 30 postdoctoral scholars and visiting scientists.
Speaker
Institution
Tentative Topic (subject to change)
Time in Singapore (S), Rome, Italy (R), and Lexington, Kentucky USA (L)
S
R
L
Professor D. Allan Butterfield
University of Kentucky
Focus and Format of the Symposium and Introduction of the Symposium Speakers
2100-2110 hours
1500-1510 hours
9:00-9:10 am
Professor Barry Halliwell
National University of Singapore
Ergothionine: Novel Neuroprotectant Based on Redox Mechanisms
2110 hours
1510 hours
9:10-9:45 am
Associate Professor Eugenio Barone
Sapienza University of Roma
Insulin Signaling in Alzheimer Disease Brain and Models Thereof
2145-2220 hours
1545-1620 hours
9:45-10:20 am
Professor Daret K. St. Clair
University of Kentucky
Redox Biology of Cancer and Cancer Chemotherapy
2220-2255 hours
1620-1655 hours
10:20-10:55 am
Professor D. Allan Butterfield
University of Kentucky
Closing Remarks
2255-2300 hours
1655-1700
10:55-11:00 am
Ergothionine: Novel Neuroprotectant Based on Redox Mechanisms
The human diet contains multiple compounds with antioxidant properties in vitro, including vitamins E and C, carotenoids and polyphenols such as the flavonoids. These may all perform important roles in the human body but the evidence that polyphenols, carotenoids and even vitamin C exert major antioxidant activities in vivo is generally unconvincing. Much attention is being given to a unique diet-derived thiol/thione with antioxidant properties, namely ergothioneine (ET). Low blood levels of ET appear to be a risk factor for the development of neurodegenerative and cardiovascular diseases, frailty, eye disease and age-related diseases generally. Based on studies in a range of in vitro and in vivo (animal) models, ET has exhibited the ability to modulate inflammation, scavenge free radicals, protect against acute respiratory distress syndrome, prevent endothelial dysfunction, protect against ischemia-reperfusion injury, slow neurodegeneration, counteract iron dysregulation, hinder lung and liver fibrosis, and mitigate damage to the lungs, kidneys, liver, gastrointestinal tract, and testis. There is evidence that ET is specifically accumulated at sites of tissue injury, so we have called it an “adaptive antioxidant” that may not interfere with the normal physiological roles of ROS. We have identified “risk levels” of low blood ET concentrations in human subjects. But does low ET predispose to age-related diseases or is it a spurious correlation? Animal studies suggest the former, but only double-blind placebo-controlled human clinical trials will provide the final answer.
by Professor Barry Halliwell, National University of Singapore
D. Phil. (Oxford), D. Sc. (London) Chairman, BMRC Advisory Council (BMAC), Agency for Science, Technology & Research (A*STAR) Distinguished Professor, Department of Biochemistry , National University of Singapore (NUS) Senior Advisor, Academic Appointments and Research Excellence, Office of the Senior Deputy President and Provost, NUS Programme Leader, Neurobiology Research Programme, Life Sciences Institute E-mail: bchbh@nus.edu.sg Website: https://medicine.nus.edu.sg/bch/faculty/barry-halliwell/ https://www.lsi.nus.edu.sg/corp/neurobiology/programme-leader/
Professor Halliwell graduated from Oxford University with BA (first class honours) and D.Phil degrees. He holds a Doctor of Science degree from the University of London. He was a faculty member with King’s College London (1974-2000) and held a prestigious Lister Institute Research fellowship. He was a Visiting Research Professor of Internal Medicine and Biochemistry at the University of California Davis (1995-1999). He now holds several key positions in Singapore, as indicated above.
Professor Halliwell is recognized for his seminal work on the role of free radicals and antioxidants in biological systems, being one of the world’s most highly-cited researchers with a Hirsch-Index of 167. His Oxford University Press book with John Gutteridge Free Radicals in Biology and Medicine, now in its fifth edition (2015) is regarded worldwide as an authoritative text. He was honoured as a Citation Laureate (2021) for pioneering research in free-radical chemistry including the role of free radicals and antioxidants in human disease. The distinction is awarded by Clarivate to researchers whose work is deemed to be of “Nobel Class” as they are among the most influential, even transformative, in their fields. He was one of 16 scientists (only three in Chemistry) listed in the 2021 Hall of Citation Laureates.
Insulin Signaling in Alzheimer Disease Brain and Models Thereof
Brain insulin signalling acts as a key regulator for gene expression and cellular metabolism, both events sustaining neuronal activity and synaptic plasticity mechanisms. Alterations of this pathway, known as brain insulin resistance, are associated with a higher risk to develop age-related cognitive decline and neurodegeneration. Studies from our group uncovered the role of the enzyme biliverdin reductase A (BVR-A) that, beyond its activity in the degradation pathway of heme, is a novel regulator of the insulin signalling. BVR-A is a direct target of the insulin receptor (IR), similar to the insulin receptor substrate-1 (IRS1). IR phosphorylates BVR-A on specific Tyr residues and activates BVR-A to function as Ser/Thr/Tyr kinase. In addition, downstream from IRS1, BVR-A works as a scaffold protein favoring: the translocation of GLUT4-containing vesicles to the plasma membrane (to increase glucose uptake in response to insulin), the AKT-mediated inhibition of GSK3β (that promotes cell survival) and the AMPK-mediated inhibition of MTOR (that is involved in autophagy). Ground-breaking findings from our group revealed that oxidative stress-induced impairment of BVR-A is a key event driving brain insulin resistance development in AD. Conversely, rescuing BVR-A activity reduces oxidative stress levels and ameliorate brain insulin signalling activation, both events contributing to improved cognitive functions in animal models of neurodegeneration. Overall, our data suggest that BVR-A represents a molecular bridge between oxidative stress and insulin signalling and studies to deep investigate its role during the development of neurodegenerative disorders are ongoing in our lab.
by Associate Professor Eugenio Barone, Sapienza University of Roma
Eugenio Barone, Pharm.D., Ph.D., Sapienza University of Rome
Eugenio Barone, is Associate Professor of Biochemistry at Sapienza University of Rome (IT). He graduated in Pharmaceutical Chemistry and Technology in 2006 and got a PhD in Neuroscience in 2011. The overarching goal of his laboratory is to clarify the link beteween defects of neurotrophic signaling (insulin and GLP1) and increased cell damage during ageing and neurodegeneration. During the last years he focused on Down syndrome and his lab demonstrated for the fisrt time that brain insulin resistance develops very early in DS, independenlty of peripheral alterations [Neurobiol Dis (2020); Free Rad Biol Med (2021); Alzheimer’s and Dementia (2021)]. Dr. Barone authored 90 publications, most of wich dealing with the role of oxidative stress in neurodegenerative disorders, i.e., Alzheimer disease and DS.
Cancer is a disease that accounts for nearly one in six deaths worldwide. Unfortunately, the goal of safely curing cancer is unrealized because cancer treatments cause toxicities to non-cancer tissues. Decades of research have extended our understanding of redox biology in cancer. While our knowledge once was limited to knowing the importance of reactive oxygen-derived species (ROS) in cell killing and of antioxidants in protecting cells from ROS-mediated toxicity, the body of knowledge now includes recognizing the dual roles of antioxidants in both killing cancer cells and protecting normal cells from ROS generating chemotherapy. These antioxidant/prooxidant (redox-active) properties are best represented by the enzyme Manganese containing superoxide dismutase (MnSOD), which cycles active site manganese through varying oxidation states. MnSOD plays a critical role in physiological and pathological conditions. The expression of MnSOD is tightly regulated at multiple levels, especially at the onset of, and during, cancer progression. These findings have contributed to the current recognition that cancer cells are usually under higher oxidative stress conditions than normal cells are and because the elevated redox state of a cancer cell could be pushed over a threshold, death occurs as a result of treatment with redox-active antioxidants. The properties represented by MnSOD have led to the development of "redox-active" drugs capable of acting as weak prooxidants or mimicking endogenous enzyme activity. This presentation will briefly summarize the history of our investigations into the properties of MnSOD and the MnSOD mimetics that have advanced to early phase clinical trials with highly encouraging outcomes.
by Professor Daret K. St. Clair, University of Kentucky
Dr. Daret St. Clair is the James Graham Brown Foundation Endowed Chair in Neuroscience, Assocaite Director for Basic Research, Director of the Center for Cancer and Metabolisms, and Professor of Toxicology and Cancer Biology at the University of Kentucky. She is the recipient of the 2018 Lifetime Achievement Award from the Society of Redox Biolgy. Her career is marked by the seminal work on the role of manganese superoxide dismutase (MnSOD) in cancer development and therapy. Her research team has resolved long-debated questions about MnSOD expression in cancer and has demonstrated that the presence of MnSOD inversely regulates the induction and progression of cancer. Dr. St. Clair's investigations of the mechanisms mediating the unique role of MnSOD are fundamental contributions to the recognition that cancer cells are under higher oxidative stress than their normal cell counterparts. Her studies have elevated the redox biology field to its stature as an important component of cancer research.
