REDOX WEBINAR SERIES

Oxidative Stress: Biochemical and Pharmacological Aspects

Programme

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  • Seminar #1 - 11 February

    Ferroptosis: from metabolism to disease treatment

    15:00-15:10

    Welcome and Introduction
    Mauro Maccarrone
    (University of L'Aquila, Italy)

    15:10-15:40

    Ferroptosis and Metabolism

    Fulvio Ursini

    Fulvio Ursini
    (University of Padua, Italy)

    15:40-16:10

    Targeting Ferroptosis for the Treatment of as-yet-Incurable Diseases

    Marcus Conrad

    Marcus Conrad
    (Helmholtz Zentrum München, Germany)

    16:10-17:00

    Questions and Answers

    Mauro Maccarrone

    Mauro Maccarrone, Dr. Enzymology and Bio-Organic Chemistry, is Professor and Chair of Biochemistry at the Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila (Italy). He is also Head of the Lipid Neurochemistry Unit at the European Center for Brain Research – IRCCS Santa Lucia Foundation, Rome. For his research activity he has received the “4th Royan International Research Award for Reproductive Biomedicine” (2003), the “2007 IACM Award for Basic Research”, the “2016 Mechoulam Award”, and the “2020 Tu Youyou Award”. Chair of the 2015 Gordon Research Conference on “Cannabinoid Function in the CNS”. Visiting Professor at Leiden University (Leiden Institute of Chemistry, The Netherlands) in 2017. Faculty member of The Lambert Center for the Study of Medicinal Cannabis and Hemp at Thomas Jefferson University in Philadelphia, since 2019. Visiting Professor at Cambridge University (Department of Psychology, U.K.) in 2019. Published more than 510 full papers, of which 60 with I.F. ≥ 9 (total I.F. > 2600; citations >18000, h-index = 70 according to Scopus). Listed among the Top Italian Scientists.

    Ferroptosis & Metabolism

    Fulvio Ursini
    Dept of Molecular Medicine, University of Padua, Italy

    Ferroptosis is a form of cell death operated by lipid peroxidation (LPO) under control of GPx4 activity. Since LPO is initiated from traces of LOOH, the question emerges about their formation. The most reasonable candidate is the protonated form of superoxide. While we do not have evidence for a role of respiratory chain, we showed we observed, instead, that it is the pyruvate dehydrogenase complex (PDC) that both produces superoxide and supports ferroptosis when GSH is low. The source of superoxide is the autoxidation of dihydrolipoamide. Further, GSH depletion inhibits the kinase that inhibits PDC. In a perspective of tissue homeostasis, it is the energetic metabolism, associated to a decreased nucleophilic tone, that both supports energy demanding proliferation and sensitizes cells to a regulated form of death.

    Fulvio Ursini

    Fulvio Ursini, born 1951, serves as professor of biochemistry, School of Medicine, University of Padova. The leitmotif of its studies has been the mechanism of antioxidant effect. These studies led to the discovery of the selenoenzyme GPx4, the functional inactivation of which activates lipid peroxidation and a regulated form of cell death named ferroptosis. He described the chemistry of the functional interaction between enzymatic antioxidant systems-reducing hydroperoxides and chain breaking antioxidants reducing lipid hydroperoxyl radicals. This interplay between a nucleophilic displacement reaction and free radical scavenging contributed to bridging the gap between chemistry and cell biology of free radical oxidations in biology. In the frame of studies on antioxidant mechanisms, he unraveled the role of GPx4 in protein oxidation required for spermatogenesis. This clarified the role of selenium catalysis in male fertility. He first described the post-prandial oxidative stress and the protective role of foods containing nucleophiles (such as wine or beer). The pathophysiological outcome of these studies led to the description of an innovative modification of LDL, where a misfolding of a specific loop of ApoB, where the shift from alpha to beta structure leads to the formation toxic amyloid like aggregates compatible with an atherogenic effect.

    Targeting ferroptosis for the treatment of as-yet-incurable diseases

    Marcus Conrad
    Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Munich, Germany

    Ferroptosis is a quite recently described metabolic form of non-apoptotic cell death characterized by the iron-dependent oxidative destruction of cellular membranes. Emerging evidence established that ferroptosis is the underlying cause of a number of diseases such as neurodegeneration, tissue ischemia/reperfusion injury and certain cancers. While glutathione peroxidase 4 remains the guardian of ferroptosis, genome-wide CRISPR/Cas and genetic suppressors screens have uncovered additional molecular players that impact on the cells’ susceptibility toward ferroptosis. As such, the ever-growing list of distinct molecular players of the ferroptotic cell death process will aid in the development of target-based novel therapies to alleviate ferroptosis-based diseases.

    Marcus Conrad

  • Seminar #2 - 11 March

    Redox therapies for neurodegenerative diseases: lights and shadows

    15:00-15:10

    Welcome and Introduction
    Luciano Saso
    (Faculty of Pharmacy and Medicine, Sapienza University of Rome)

    15:10-15:30

    The NRF2-KEAP1 Signaling Pathway as a Pharmacological Target in Neurodegenerative diseases

    Antonio Cuadrado

    Antonio Cuadrado
    (Dept of Biochemistry, Medical School, Autonomous University of Madrid, Spain)

    15:30-15:50

    Breaking the vicious cycle of oxidative stress – inflammation – cell death by reversible cysteine modifications of Keap1

    Albena DinkovaKostova

    Albena T. Dinkova-Kostova
    (Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, UK)

    15:50-16:10

    Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention

    Paulo Oliveira

    Paulo J. Oliveira
    (CNC-Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building, Biocant Park, Cantanhede, Portugal)

    16:10-17:00

    Questions and Answers

    The NRF2-KEAP1 Signaling Pathway as a Pharmacological Target in Neurodegenerative diseases

    Antonio Cuadrado
    Dept of Biochemistry, Medical School,
    Autonomous University of Madrid, Spain
    Email: antonio.cuadrado@uam.es

    The etiology of Alzheimer’s disease (AD) remains largely unknown and the therapeutic approaches to stop disease progression have consistently failed. This fact indicates that, in addition to the largely studied amyloid and Tau pathophenotypes, other crucial factors must be considered. Our view is that the loss of homeostatic responses in the elderly is a very relevant factor for AD onset and progression. In recent years, a master regulator of homeostatic responses has been found in the transcription factor NRF2 (Nuclear factor E2-Related Factor 2). NRF2 regulates the expression of over 250 homeostatic genes that play crucial roles in protection against oxidative, inflammatory, metabolic, and proteotoxic forms of cellular stress, all of which are well established pathomechanisms of AD and its co-morbidities. In postmortem brain samples of AD patients, neurons expressing aggregates of TAU or APP exhibit increased levels of the NRF2 targets NQO1 and SQSTM1 and in protein lysates we found upregulation of NRF2 in parallel to increased markers of microgliosis, astrogliosis and inflammation. These results suggest that the increase in NRF2 activity found in the patients is a partially unsuccessful attempt of the diseased brain to compensate the pathologic events. Consistent with this hypothesis, reinforcement of the NRF2 signature in mouse models of AD by daily treatment with an NRF2 activator reduced glial and inflammatory markers and improved cognition and motor complications.

    Antonio Cuadrado

    Antonio Cuadrado is full professor of Biochemistry and Molecular Biology at the Department of Biochemistry, Medical School, Autonomous University of Madrid. He obtained his PhD degree in 1985 and enjoyed several postdoctoral stays in the National Cancer Institute-NIH with the help of Fulbright and Fogarty fellowships. He established his independent laboratory as Professor of Biochemistry in 1997 with a main interest on the study of molecular mechanisms involved in initiation and progression of neurodegenerative diseases. For the past years his main lane of research has been the validation of transcription factor NRF2, master regulator of cellular homeostasis, with four main lines of activity: i) The transcription factor NRF2 as a new therapeutic target in Parkinson's and Alzheimer’s diseases. ii) Role of oxidative stress in neuronal death and neuroinflammation in neurodegenerative diseases. iii) Pharmacological regulation of autophagy in the brain as a novel therapeutic strategy for neurodegenerative proteinopathies. iv) Development of new NRF2-modulating drugs. Dr. Cuadrado has been awarded several research projects funded by private, local, and governmental agencies to study the molecular basis of Parkinson’s and Alzheimer’s disease. He has published over 150 primary and review articles, of which more than 80 are related to neuroprotection in preclinical models of Parkinson’s and Alzheimer’s disease, that have been cited over 12500 times. He is grant and fellowship evaluation consultant for Spanish governmental and autonomic agencies. As a professor, Dr. Cuadrado has participated in multiple teaching activities for the Bachelor degrees of Biochemistry and Medicine, with special focus on research training. Prof. Cuadrado received a Testimonial of Recognition by the Tohoku Medical Society. Sendai, Japan, in 2014. He is Honorary Scientist at "Victor Babes National Institute of Pahtology" Bucharest, Romania since 2017. In 2019, he was invested Doctor Honoris Causa by Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.

    Breaking the vicious cycle of oxidative stress – inflammation – cell death by reversible cysteine modifications of Keap1

    Albena T. Dinkova-Kostova
    Jacqui Wood Cancer Centre, Division of Cellular Medicine, University of Dundee School of Medicine, Dundee, DD1 9SY, Scotland, United Kingdom
    E-mail: a.dinkovakostova@dundee.ac.uk

    Disrupted redox and protein homeostasis and chronic inflammation engage in a vicious cycle that leads to cell death, and are characteristic features of all neurodegenerative diseases. Transcription factor Nrf2 and its partner Kelch-like ECH-associated protein 1 (Keap1), regulate the expression of large networks of genes encoding proteins that provide powerful and long-lasting protection against damage by oxidants and pro-inflammatory agents. Most pharmacological activators of Nrf2 (termed inducers) are electrophiles that reversibly bind to highly reactive sensor cysteines within Keap1, impairing its repressor function, and allowing for Nrf2 accumulation and enhanced transcription of its target genes. The Keap1/Nrf2 regulatory network includes drug metabolizing, antioxidant, anti-inflammatory, metabolic enzymes, as well as autophagy-related proteins and thus Nrf2 has a critical role in the maintenance of the cellular redox and protein homeostasis, and in the resolution of inflammation. Nrf2 inducers that bind reversibly to Keap1 are protective in cell culture and animal models of neurodegeneration and have documented beneficial effects in humans.

    Albena T. Dinkova-Kostova

    Albena Dinkova-Kostova graduated in Biochemistry and Microbiology from Sofia University (Bulgaria), and obtained her PhD degree in Biochemistry and Biophysics from Washington State University (USA). She subsequently trained in Pharmacology at Johns Hopkins University School of Medicine (USA), where she continues to hold an Adjunct Professor position. She joined the University of Dundee in 2007 as a Research Councils UK Academic Fellow, and is now Professor of Chemical Biology. Her group collaborates with basic scientists and clinicians and with the pharmaceutical industry. In her research, at the interface of Chemical Biology and Medicine, she is committed to understanding how cells and organisms respond to oxidative, inflammatory, and metabolic stress, and is working towards development of strategies for protection against chronic disease. She is named among the top influential academics in Clarivate’s Highly Cited Researchers 2019 & 2020 lists.

    Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention

    Paulo J. Oliveira
    CNC-Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building, Biocant Park, Cantanhede, Portugal
    Email: pauloliv@cnc.uc.pt

    Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease or Charcot disease, is a fatal neurodegenerative disease that affects motor neurons (MNs) and leads to death within 2-5 years of diagnosis, without any effective therapy available. Although the pathological mechanisms leading to ALS are still unknown, an excessive reactive oxygen species (ROS) production associated with a weak antioxidant defense may represent an essential pathological feature in ALS. Substantial evidence indicates that oxidative stress (OS) is implicated in the loss of MNs and mitochondrial dysfunction, contributing decisively to neurodegeneration in ALS. Although the modulation of OS represents a promising approach to protect MNs from degeneration, the fact that several antioxidants with beneficial effects in animal models failed to show any therapeutic benefit in patients raises several questions that should be analyzed. We will describe antioxidant compounds tested in ALS preclinical and clinical trials, also describing their respective mechanisms of action. We will describe novel data with mitochondria-targeted dietary polyphenols. While the description of OS mechanism in the different mutations identified in ALS has as principal objective to clarify OS's contribution in ALS, the description of positive and negative outcomes for each antioxidant paves the way for novel opportunities for intervention. Funding: Work in the author's laboratory is funded by the European Regional Development Fund (ERDF), through the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT–Fundação para a Ciência e a Tecnologia, under projects PTDC/MED-FAR/29391/2017, POCI-01-0145-FEDER-029391 (Mito4ALS), PTDC/BTM-SAL/29297/2017, POCI-01-0145-FEDER-029297 (MitoScreening), and UIDB/04539/2020.

    Paulo J. Oliveira

    Paulo J. Oliveira is currently Principal Investigator at the CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Portugal. He is the current leader of the “Mitochondria, Metabolism and Disease” group (shorturl.at/rsLRZ) and of the MitoXT: Mitochondrial Toxicology and Experimental Therapeutics laboratory. He received his Bachelor of Science in Biochemistry from the University de Coimbra in 1999. In 2003, he completed his PhD in Cellular Biology from the same University. After completing his doctorate, Paulo Oliveira spent more than three years working at the Medical School of the University of Minnesota, Duluth, USA, where he collaborated with several researchers and contributed to the publication of several peer-reviewed manuscripts. Paulo Oliveira current research interests focus on mitochondrial biology, investigating the alteration of cardiac mitochondrial function by physical activity and diet, cardiac mitochondrial dysfunction and cell death caused by anti-neoplastic agents, mitochondrial alterations during cancer stem cell differentiation and carcinogenesis or rational designing of mitochondria-directed antioxidants. Paulo has about 230 peer-reviewed publications and a large number of collaborations in Europe, Africa and in the USA. He has also received several prizes from the Portuguese Cardiology Society for his work on cardiac mitochondrial research. Besides research, Paulo Oliveira is often involved in teaching at the Department of Life Sciences, University of Coimbra, as well as in other Universities in Portugal and elsewhere, besides in numerous science communication activities. Of importance, he has maintained a consistent primary role in the organization of national and international scientific meetings, including the International Courses in Toxicology (2005-2010 in Coimbra), Annual Meeting of the European Society for Clinical Investigation (2013, Albufeira, Portugal and 2019, Coimbra, Portugal), the 2014 Meeting of the Portuguese Biochemical Society, and FEBS Advanced Lecture Courses in Oncometabolism (2017, Figueira da Foz, Portugal and 2019 Luso, Portugal). Since May 2019, Paulo Oliveira is also President of the European Society for Clinical Investigation, after being its Vice-President for 2 years. Paulo Oliveira has also been reviewer for more than 40 different scientific journals and over 10 different funding agencies, including the European Commission (Research Executive Agency) and the Portuguese Foundation for Science and Technology. His research group is supported by competitive national and international funding agencies, including the Portuguese Foundation for Science and Technology, the European Commission, and private foundations. Paulo is also co-founder of the start-up MitoTAG and is co-inventor in two patents. Since 2020, Paulo is Vice-President of the CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.

    Luciano Saso

    Prof. Luciano Saso (luciano.saso@uniroma1.it) is a Member of the Faculty of Pharmacy and Medicine, Sapienza University of Rome, Italy (https://www.uniroma1.it/en/). He is author of more than 250 original scientific articles published in peer reviewed international journals with impact factor (H-index Google Scholar = 49, H-index SCOPUS = 39, Total Impact Factor > 800) working mainly in the field of pharmacological modulation of oxidative stress. He coordinated several international research projects and has been referee for many national and international funding agencies and international scientific journals in the last 25 years. He has been Editor and Guest Editor of Special Issues of different international journals including ANTIOXIDANTS, JOURNAL OF PHARMACY AND PHARMACOLOGY, FRONTIERS IN PHARMACOLOGY, FRONTIERS IN CELLULAR NEUROSCIENCE, MOLECULES, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. More information is available at https://www.researchgate.net/profile/Luciano-Saso.

  • Seminar #3 - 26 April

    Crosstalk between oxidative stress and metabolic defects: implications for Alzheimer's disease

    15:00-15:10

    Welcome and Introduction
    Luciano Saso
    (Faculty of Pharmacy and Medicine, Sapienza University of Rome)

    15:10-15:40

    Amyloid β-peptide and brain oxidative damage: focus on the intersection of the lipid peroxidation product HNE covalently bound to brain proteins, glucose dysmetabolism, and Alzheimer disease

    D Allan Butterfield

    D. Allan Butterfield
    (Dept of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA)

    15:40-16:00

    Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease

    Paula I. Moreira

    Paula I. Moreira
    (Institute of Physiology, Faculty of Medicine, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal)

    16:00-16:20

    Down Syndrome is a metabolic disease: altered insulin signaling mediates brain dysfunctions

    Marzia Perluigi

    Marzia Perluigi
    (Dept of Biochemical Sciences, Sapienza University of Rome, Italy)

    16:20-17:00

    Questions and Answers

    Amyloid β-peptide and brain oxidative damage: focus on the intersection of the lipid peroxidation product HNE covalently bound to brain proteins, glucose dysmetabolism, and Alzheimer disease

    D. Allan Butterfield
    Dept of Chemistry and Sanders-Brown Center on Aging
    University of Kentucky, Lexington, KY, USA

    Alzheimer disease (AD), an age-related neurodegenerative disorder, is characterized pathologically by the presence of senile plaques (rich in amyloid beta-peptide (1-42) [Aβ(1-42)], neurofibrillary tangles (hyperphosphorylated tau), and neurite and synapse loss, and clinically by progressive diminution of memory and loss of higher executive cognitive functions, resulting in dementia. Knowledge of the underlying etiology and pathogenesis of AD is needed to effectively use agents to retard or prevent this ongoing and worsening public health crisis. Oligomeric Aβ(1-42) is neurotoxic and associated with oxidative damage in vitro and in vivo. Protein oxidation is indexed by elevated protein carbonyls and 3-nitrotyrosine, while lipid peroxidation is indexed in our laboratory by elevation of protein-bound 4-hydroxynonenal (HNE). Redox proteomics, pioneered in the Butterfield laboratory, identified oxidatively dysfunctional brain proteins in oligomeric Aβ(1-42) preclinical models and human studies, including amnestic mild cognitive impairment (MCI), and familial-, preclinical-, early-, and late-AD, Down syndrome (DS), and DS with AD (the DS studies in collaboration with Prof. Marzia Perluigi, Sapienza University of Rome). Among the major pathways affected by Aβ(1-42)-associated lipid peroxidation and consequent HNE bound to proteins are those involved in glucose metabolism, known to decreased in AD and MCI brains. That is, Ab42-mediated lipid peroxidation, leading to HNE and protein oxidative modification and dysfunction, occurs early in AD pathogenesis, resulting in decreased glucose metabolism, including diminished glycolysis, TCA cycle efficiency, and mitochondrial function with consequent loss of ATP production. This, in turn, leads to excitotoxicity, loss of neurotransmission, synaptic plasticity and cell structure, elevated neuroinflammation, impaired protein folding and degradation, and altered signal transduction. We propose oligomeric Aβ(1-42)-associated oxidative modification of brain glycolytic and TCA enzymes and ATP synthase in AD and MCI brains leads to glucose dysmetabolism, resulting in decreased ATP production with consequent loss of neuronal cell potentials and large influx of neurotoxic Ca2+. In turn, prolonged elevated Ca2+ causes necrotic and apoptotic neuronal death indexed by decreased thickness of hippocampus (memory loss) and frontal cortex (higher executive function loss). Recent neuroimaging studies on three continents involving thousands of pre-symptomatic persons carrying genes that cause familial AD for over 22 years prior to onset of symptoms and three years thereafter precisely confirmed the above order of events in AD brains proposed by our laboratory. Consistent with our hypothesis, we demonstrated that synaptic membranes, isolated from brains of targeted-replacement mice in which human apolipoprotein E2, E3, or E4 replaced mice ApoE, when treated with Aβ(1-42) led to elevated oxidative damage in the order apoE4 > apoE3 > apoE2. This is the same order of elevated risk of developing AD as a function of ApoE allele. We hypothesize that apoE4, which lacks key Cys residues and therefore does not bind HNE, in marked contrast to efficient binding of HNE by one Cys residue in apoE3 and two Cys residues in apoE2, does not prevent binding of neurotoxic HNE to key glucose metabolic proteins. Thereby, apoE4 contributes to the elevated risk of developing AD by those who inherit the ApoE4 allele. Our studies identified potential therapeutic targets, which if protected by pharmacology, lifestyle interventions or treatments to reduce Aβ production or limit HNE-mediated damage caused by lipid peroxidation induced by this neurotoxic peptide, could be beneficial in preventing or delaying the progression of this devastating dementing disorder. Support: NIH grants to Professor Butterfield.

    D. Allan Butterfield

    Professor Butterfield earned his Ph.D. in Physical Chemistry from Duke University (Durham, North Carolina), followed by a National Institutes of Health (NIH) Postdoctoral Fellowship in Neurosciences at the Duke University School of Medicine. In 1975, he joined the Faculty of the Department of Chemistry at the University of Kentucky and quickly rose through the ranks to Full Professor. He is currently the University of Kentucky Alumni Association Endowed Professor of Biological Chemistry, Associate Vice President for Research, Director of the Redox Metabolism Core of the National Cancer Institute-designated UK Markey Cancer Center, and among the Faculty of the world-renowned Sanders-Brown Center on Aging. Professor Butterfield’s research centers on oxidative damage, redox proteomics, and alterations in glucose metabolism and autophagy (and other aspects of the proteostasis network) in brains of persons with Alzheimer disease and Down syndrome, as well as brain alterations in cancer survivors who demonstrate cognitive loss following chemotherapy. Prof. Butterfield has trained 67 Ph.D. and M.S. students and 30 postdoctoral scholars (5 of whom are from the Sapienza University of Rome), which has led to his more than 670 scientific publications [h-index = 112]. His research has been continuously funded for 46 years by NIH or other federal and private funding agencies. Professor Butterfield was recognized recently as the 10th most important scientist in the world in the field of Alzheimer disease research (of approximately 150,000 AD researchers) for the period 2010-2020 based on data mining of the PubMed website. He received the Presidential Award for Excellence in Science Mentoring from President Clinton in the White House, and Prof. Butterfield was elected a Fellow of the Society for Redox Biology and Medicine, an international scientific society from whom he also was presented the 2013 Discovery Award for his seminal and paradigm-shifting research on the role of oxidative stress in the etiology and pathogenesis of Alzheimer disease associated with amyloid beta-peptide.

    Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease

    Paula I. Moreira
    CNC – Center for Neuroscience and Cell Biology
    University of Coimbra & Faculty of Medicine
    University of Coimbra, Coimbra, Portugal

    Mitochondria fulfill a number of essential cellular functions, and it is recognized that the strict regulation of the structure, function, turnover and transport of these organelles is a control node for the maintenance of cellular homeostasis. Although the precise culprit in the pathogenesis of Alzheimer’s disease (AD) is still obscure, mitochondria and redox imbalance have been proposed to be early events. Studies from our laboratory demonstrate that mitochondria from AD preclinical models are characterized by a defective respiratory chain and an impaired phosphorylation system culminating in an energy crisis. An increased production of mitochondrial reactive oxygen species, reduced antioxidant defenses and defective turnover were also observed. Interestingly, our studies also demonstrate that AD shares several common features with type 2 diabetes including a similar profile of mitochondrial abnormalities and oxidative stress. Our findings suggest that strategies aimed at ameliorating mitochondria and redox status could represent effective preventive and/or therapeutic strategies.

    Paula I. Moreira

    Paula I. Moreira received her PhD in Biomedical Sciences from University of Coimbra, Portugal. She is Assistant Professor at Faculty of Medicine, University of Coimbra and Principal Investigator at the Center for Neuroscience and Cell Biology, University of Coimbra, Portugal. Moreira’s research team is interested in elucidating the role of mitochondria, metabolic hormones and sex dimorphism in brain changes occurring in diabetes and age-related neurodegenerative diseases, particularly Alzheimer’s disease. Pharmacological and non-pharmacological strategies capable of ameliorating mitochondria homeostasis are also being investigated as possible treatments. Moreira is author of > 200 peer-reviewed publications (H-index = 62; > 19500 citations; Scopus) and serves on the editorial board of several international peer-reviewed journals including Antioxidants & Redox Signaling, Biochimica et Biophysica Acta – Molecular Basis of Disease and Journal of Alzheimer’s Disease. She was a member of the Committee on Novo Nordisk Foundation Challenge Programme 2020 – Biomedicine and Health Sciences and is an ad hoc reviewer for Marie Sklodowska-Curie Individual Fellowships, European Science Foundation and Alzheimer’s Association, among others. Moreira won the Stimulus to Research prize, in 2003, supported by the Calouste Gulbenkian Foundation and, in 2008, the L’Oréal for Women in Science Award supported by L'Oreal Portugal/UNESCO/FCT.

    Down Syndrome is a metabolic disease: altered insulin signaling mediates brain dysfunctions

    Marzia Perluigi
    Dept of Biochemical Sciences
    Sapienza University of Rome, Italy

    Down Syndrome (DS) is the most frequent chromosomal abnormality that causes intellectual disability, resulting from the presence of an extra complete or segment of chromosome 21 (HSA21). In addition, trisomy of HSA21 contributes to altered energy metabolism that appears to be a strong determinant in the development of pathological phenotypes associated with DS. Alterations include, among others, mitochondrial defects, increased oxidative stress levels, impaired glucose, and lipid metabolism, finally resulting in reduced energy production and cellular dysfunctions. These molecular defects seem to account for a high incidence of metabolic disorders, i.e., diabetes and/or obesity, as well as a higher risk of developing Alzheimer's disease (AD) in DS. A dysregulation of the insulin signaling with reduced downstream pathways represents a common pathophysiological aspect in the development of both peripheral and central alterations leading to diabetes/obesity and AD. Considering that DS subjects are at high risk to develop early onset Alzheimer disease, they can offer a unique opportunity to decipher the link between trisomy of HSA21 and defects of insulin and insulin-related pathways in both aging and neurodegeneration. Drawing the molecular signature underlying these processes in DS is a key challenge to identify novel drug targets and set up new prevention strategies aimed to reduce the impact of AD in DS.

    Marzia Perluigi

    Marzia Perluigi’s laboratory focused the attention on the analysis of oxidative modifications of proteins and how dysfunction of selected proteins translate into pathological features of a disease state. By following this approach we contributed to shed light on critical molecular determinants underlying aging and cognitive dysfunction. Particularly, my team focuses on redox mechanisms of neurodegeneration in Down Syndrome (DS) and Alzheimer Disease (AD). Results obtained by the analysis of human specimens and studies from mouse and cellular models of the disease reveal a molecular link between protein oxidation/aggregation, the integrity of the protein quality control system (proteasome, UPS and autophagy), dysfunction of energy metabolism and neurodegeneration. Many common pathological hallmarks exist between DS and AD, including deposition of amyloid plaques, NFTs, increased oxidative damage and impaired mitochondrial function, among others. Intriguingly, we propose that all of these processes seem to be joined by a ‘leitmotif’ – oxidative stress – since they are all the cause and/or the consequence of increased free-radical burden. In addition, other than proteostasis and glucose metabolism, redox proteomics studies allowed the identification of oxidized proteins belonging to several dysfunctional pathways among which, detoxification systems, excitotoxicity or synapse function that highly correlates with DS and AD pathological features supporting the role of protein oxidative damage in neurodegeneration and cognitive decline. Further, we recently demonstrated the disturbance of PI3K/Akt/mTOR axis in DS brain, prior and after development of AD. Aberrant mTOR signalling in the brain affects multiple pathways including glucose metabolism, energy production, mitochondrial function and autophagy. All these events are key players in age-related cognitive decline and contribute to the development of Alzheimer-like dementia in DS. Restoration of mTOR signaling may be a powerful strategy to prevent/delay the onset of dementia in DS as well as in the general population. She is currently the Chair of European Chapter of the T21Research Society.

    Luciano Saso

    Prof. Luciano Saso (luciano.saso@uniroma1.it) is a Member of the Faculty of Pharmacy and Medicine, Sapienza University of Rome, Italy (https://www.uniroma1.it/en/). He is author of more than 250 original scientific articles published in peer reviewed international journals with impact factor (H-index Google Scholar = 49, H-index SCOPUS = 39, Total Impact Factor > 800) working mainly in the field of pharmacological modulation of oxidative stress. He coordinated several international research projects and has been referee for many national and international funding agencies and international scientific journals in the last 25 years. He has been Editor and Guest Editor of Special Issues of different international journals including ANTIOXIDANTS, JOURNAL OF PHARMACY AND PHARMACOLOGY, FRONTIERS IN PHARMACOLOGY, FRONTIERS IN CELLULAR NEUROSCIENCE, MOLECULES, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. More information is available at https://www.researchgate.net/profile/Luciano-Saso.

  • Seminar #4 - 13 May

    Radioprotectors and radiosensitizers in cancer therapy

    15:00-15:10

    Welcome and Introduction
    Luciano Saso
    (Faculty of Pharmacy and Medicine, Sapienza University of Rome)

    15:10-15:30

    Targeting redox metabolism for cancer therapy: from the bench to the bedside

    Douglas R. Spitz

    Douglas R. Spitz
    (Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA)

    15:30-15:50

    SOD mimics act as a radiosensitizer by enhancing hydrogen peroxide levels and altering metabolism in prostate cancer cells

    Paula I. Moreira

    Rebecca Oberley-Deegan
    (Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA)

    15:50-16:10

    Advancing redox principles and chemistry for diagnosis and treatment of radiation resistant cancer

    Cristina M. Furdui

    Cristina M. Furdui
    (Department of Internal Medicine, and Co-Director of the Center for Redox Biology and Medicine at Wake Forest School of Medicine, Winston-Salem, NC, USA)

    16:10-17:00

    Questions and Answers

    Targeting Redox Metabolism for Cancer Therapy:
    From the Bench to the Bedside

    Douglas R. Spitz, PhD
    Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, IA, USA

    Relative to normal cells, cancer cells have been shown to demonstrate fundamental alterations in oxidative metabolism leading to increased steady-state levels of superoxide, hydrogen peroxide, and labile iron pools. Alterations in cancer cell oxidative metabolism in turn lead to disruptions in many redox sensitive signaling and gene expression pathways that impact cell growth, differentiation, genomic instability, and cancer progression. Cancer cells adapt to this altered metabolic state by activating many signaling and gene expression pathways that allow them to survive and continue to progress to malignancy. The current talk will discuss how pharmacological ascorbate and superoxide dismutase mimics can be used to target the oxidative metabolic frailties of cancer versus normal cells to enhance therapeutic outcomes to radio-chemo-therapies both in pre-clinical and clinical trials. The long-term goal is to utilize a detailed mechanistic understanding of alterations in cancer versus normal cell oxidative metabolism and redox biology to develop rapidly implementable new strategies that can enhance tumor responses while protecting normal tissues during standard radio-chemo-therapy protocols. (supported by P01 CA217797, P01 CA244091, P50 CA174521, P30 CA086862, R01 CA182804, R50 CA243693, T32 CA078586)

    Douglas R. Spitz

    Douglas R. Spitz, PhD is a Professor of Radiation Oncology, Director of the Free Radical and Radiation Biology PhD Program, and Director of the Free Radical Metabolism and Imaging Program in the Holden Comprehensive Cancer Center at the University of Iowa. Dr. Spitz received his B.A. in 1978 from Grinnell College and his Ph.D. in 1984 from The University of Iowa working with Dr. Larry Oberley. He did his post-doctoral work at the University of California San Francisco with Drs. Gloria Li and William Dewey and has held faculty positions at the University of Virginia, Washington University in St. Louis, and the University of Iowa. His research is supported by the NIH/NCI to participate in both basic science and translational cancer research projects designed to target oxidative metabolism for improving responses to cancer therapy.

    SOD mimics act as a radiosensitizer by enhancing hydrogen peroxide levels and altering metabolism in prostate cancer cells

    Rebecca Oberley-Deegan
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, NE, USA

    Prostate cancer patients are often treated with radiotherapy. MnTE-2-PyP, is a superoxide dismutase (SOD) mimic and a known radioprotector of normal tissues. Our recent work demonstrates that MnTE-2-PyP also inhibits prostate cancer progression with radiotherapy; however, the mechanisms remain unclear. We have identified that MnTE-2-PyP-induced intracellular H2O2 levels are critical in inhibiting growth of prostate cancer cells. High H2O2 levels by MnTE-2-PyP treatment induced nuclear fragmentation in PC3 cells, which could be synergistically enhanced with radiotherapy both in vitro and in vivo. In LNCaP cells, disturbing H2O2 balance may contribute to the bi-nucleation phenomenon. We found that MnTE-2-PyP induced protein oxidations in PC3 cells and one major group of oxidized protein targets were involved in energy metabolism. The oxidative phosphorylation rates were significantly enhanced in both PC3 and LNCaP cells with MnTE-2-PyP treatment, but mitochondrial membrane potential was unaffected. In addition, MnTE-2-PyP significantly increased NAD(P)+/NAD(P)H ratios in PC3 and LNCaP cells in a dose-dependent manner, which was mainly due to a reduction of cellular NAD(P)H pool. Correspondingly, we observed a significant decrease of activity in glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD), which are major cellular NADPH producing enzymes in pentose phosphate pathway. A decrease of GSH/GSSG ratios were confirmed in MnTE-2-PyP-treated prostate cancer cells, which may result from the decreased glutathione reductase (GR) activity due to NADPH depletion. We conclude that the increased H2O2 levels, protein oxidative modifications, mitotic catastrophe, cellular energy metabolism alterations, and NAD(P)H depletion caused by MnTE-2-PyP are all likely factors contributing to prostate cancer cell growth inhibition.

    Rebecca Oberley-Deegan

    Dr. Rebecca Oberley-Deegan received her Ph.D. University of Iowa, Iowa City Iowa and did her postdoctoral training at National Jewish Health, Denver, Colorado. She joined the University of Nebraska Medical Center (UNMC) in Omaha, Nebraska in 2014 as an assistant professor and is currently an associate professor at UNMC. Dr. Oberley-Deegan’s laboratory has previously shown that a catalytically active antioxidant can protect normal prostate tissues during radiation but not prostate tumor tissues. The focus of her research is determining the mechanisms by which antioxidants can protect normal tissues from radiation while simultaneously making the tumor vulnerable to radiation damage. Dr. Oberley-Deegan’s is focusing specifically on the role of free radical signaling to transform fibroblasts and inflammatory cells in normal tissues, which results in damage to these tissues. In the context of prostate cancer, her group is focusing on inhibiting the signaling events controlled by radiation-induced free radicals involved in tumor survival and metastasis.

    Advancing Redox Principles and Chemistry for Diagnosis and Treatment of Radiation Resistant Cancer

    Cristina M. Furdui
    Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, NC, USA

    Redox metabolism is a driving regulator of cancer progression, response to therapies and long-term patient’s quality of life. Well-established cancer therapies, including radiotherapy, either directly impact redox metabolism or have redox-dependent mechanisms of action defining their clinical efficacy. This seminar will present an overview of principles, reagents and methods for tracking redox processes in biological systems focusing on protein sulfenylation, and how these are applied in conjunction with computational modeling to gain knowledge of the mechanisms underlying the resistance to radiotherapy in Head and Neck Cancer (HNC). Furthermore, the seminar will present new applications of protein sulfenylation reagents as chemotherapeutics and PET imaging diagnostics for radiation resistant HNC.

    Cristina M. Furdui

    Dr. Cristina Furdui is Professor in the Department of Internal Medicine, Section on Molecular Medicine with joint appointments in the Departments of Biochemistry and Cancer Biology at Wake Forest School of Medicine, and affiliate faculty in the Department of Chemistry, Wake Forest University. She serves as Co-Director of the Center for Redox Biology and Medicine and the NIH T32 training program in Redox Biology and Medicine, and Director of the Proteomics and Metabolomics Shared Resource supported by the Wake Forest Comprehensive Cancer Center. She chaired the Gordon Research Conference on Thiol-Based Redox Regulation & Signaling in 2016 and serves on the Editorial Board for J Biol Chem, Antioxidants, and Chem Res Toxicol. Her research combines chemical and systems biology approaches to interrogate redox mechanisms of disease. Current projects focus on: 1) development of chemical probes and methods for analysis of protein oxidation; 2) functional studies of redox-regulated proteins; 3) cancer prevention, treatment and quality of life with emphasis on lung and head and neck cancer; 4) mechanisms and new therapies targeting inflammation and sepsis; and, 5) biospecimen preservation to advance analysis of clinical biomarkers and precision medicine. Dr. Furdui is also the co-founder of Xoder Technologies, LLC, a company dedicated to the advancement of redox knowledge.

    Luciano Saso

    Prof. Luciano Saso (luciano.saso@uniroma1.it) is a Member of the Faculty of Pharmacy and Medicine, Sapienza University of Rome, Italy (https://www.uniroma1.it/en/). He is author of more than 250 original scientific articles published in peer reviewed international journals with impact factor (H-index Google Scholar = 49, H-index SCOPUS = 39, Total Impact Factor > 800) working mainly in the field of pharmacological modulation of oxidative stress. He coordinated several international research projects and has been referee for many national and international funding agencies and international scientific journals in the last 25 years. He has been Editor and Guest Editor of Special Issues of different international journals including ANTIOXIDANTS, JOURNAL OF PHARMACY AND PHARMACOLOGY, FRONTIERS IN PHARMACOLOGY, FRONTIERS IN CELLULAR NEUROSCIENCE, MOLECULES, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. More information is available at https://www.researchgate.net/profile/Luciano-Saso.

  • Seminar #5 - 24 June

    Oxidative Stress: Biochemical and Pharmacological Aspects

    15:00-15:10

    Welcome and Introduction
    Mauro Maccarrone
    (University of L'Aquila, Italy)

    15:10-15:40

    Oxidative stress and antioxidant-based therapies in male infertility

    Barbara Tavazzi

    Barbara Tavazzi
    (Catholic University of Rome, Italy)

    15:40-16:10

    A glance on antioxidants: the role of sulfur amino acids in retinal disorders

    Marcello Allegretti

    Marcello Allegretti
    (Dompè, L’Aquila, Italy)

    16:10-17:00

    Questions and Answers

    Mauro Maccarrone

    Mauro Maccarrone, Dr. Enzymology and Bio-Organic Chemistry, is Professor and Chair of Biochemistry at the Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila (Italy). He is also Head of the Lipid Neurochemistry Unit at the European Center for Brain Research – IRCCS Santa Lucia Foundation, Rome. For his research activity he has received the “4th Royan International Research Award for Reproductive Biomedicine” (2003), the “2007 IACM Award for Basic Research”, the “2016 Mechoulam Award”, and the “2020 Tu Youyou Award”. Chair of the 2015 Gordon Research Conference on “Cannabinoid Function in the CNS”. Visiting Professor at Leiden University (Leiden Institute of Chemistry, The Netherlands) in 2017. Faculty member of The Lambert Center for the Study of Medicinal Cannabis and Hemp at Thomas Jefferson University in Philadelphia, since 2019. Visiting Professor at Cambridge University (Department of Psychology, U.K.) in 2019. Published more than 510 full papers, of which 60 with I.F. ≥ 9 (total I.F. > 2600; citations >18000, h-index = 70 according to Scopus). Listed among the Top Italian Scientists.

    Oxidative stress and antioxidant-based therapies in male infertility

    Barbara Tavazzi
    Catholic University of Rome, Italy

    Under physiological conditions, reactive oxygen species (ROS) play pivotal roles in various processes of human spermatozoa. Indeed, semen requires the intervention of ROS to accomplish different stages of its maturation. Overproduction of ROS is potentially harmful, and may concomitantly occur to excess generation of reactive nitrogen species (RNS), leading to oxidative/nitrosative stress. Spermatozoa are provided with a set of scavenger enzymes and human seminal plasma has a specific pattern of water- and fat-soluble low-molecular weight antioxidants aimed to decrease risks associated with oxidative/nitrosative stress. Various studies clearly demonstrated that male infertility is characterized by various signs of molecular damages caused by increased ROS and RNS production. Therefore, clinical studies have been conducted using the administration of antioxidant-based therapies as potentially valid tool to treat male infertility.

    Barbara Tavazzi

    Prof. Barbara Tavazzi received her Ph.D. University of Rome La Sapienza, and did her postdoctoral training at University of Rome "Tor Vergata", Rome, Italy where she remain as researcher until to 2003. Starting from that year at present, she joined the Catholic University of Rome as Associate Professor in Biochemistry and has assistantship at the Diagnostic Area and Infectious Diseases, Clinical Chemistry, Fondazione Policlinico Universitario A. Gemelli IRCCS of Rome. In the October 2021, she will start her activity as Full Professor of Biochemistry at the Faculty of Medicine and Surgery of the Saint Camillus International University of Health and Medical Sciences (UniCamillus) in Rome.
    The focus of her research is oriented mainly towards research areas related to biochemistry, clinical biochemistry and translational medicine, in particular the field of metabolomics, targeted proteomics and regulation and gene expression. The main lines of research can be summarized as follows:
    biochemical assessment (energy metabolism, mitochondrial function, oxidative/nitrosative stress, enzymatic activities); biochemical (energy metabolism, mitochondrial function, oxidative stress/nitrosis, enzyme activities) and molecular (gene expression) assessment of brain damage in experimental head trauma (weight drop model with diffuse axonal damage); analysis of low molecular weight metabolites in biological fluids (CSF, blood, urine) for the assessment of oxidative/nitrosative stress damage and alterations of energy metabolism in human head trauma; research of circulating and urinary biomarkers (metabolic, protein and molecular) with prognostic value in chronic neurodegenerative diseases (multiple sclerosis, amyotrophic lateral sclerosis); research on circulating and urinary biomarkers (metabolic, protein and molecular) in the pathology of male and female infertility, with particular attention to metabolomic parameters and oxidative and nitrosative stress.

    A glance on antioxidants: the role of sulfur amino acids in retinal disorders

    Marcello Allegretti, PhD
    Chief Scientific Officer Dompé farmaceutici S.p.A., Italy

    Oxidative stress plays a major role in the neurodegenerative process. Retinal cell survival involves a balance between reactive oxygen species (ROS) and antioxidant scavengers to counteract oxidative stress (OS) injury. The retina is susceptible to OS due to its elevated oxygen consumption and exposure to visible light, which results in cellular damage caused by ROS. Elevated OS levels determine dramatic changes that lead to visual impairment. Age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma are ocular disorders that can lead to visual loss, and for which the involvement of ROS has been evoked. The retina is endowed with an efficient innate immune system that activates three essential pathways: migration of microglia, stimulation of the complement system, and inflammasome assembly in the retinal pigment epithelium (RPE). For this response, retinal cells are endowed with a variety of immune receptors and mediators in charge to help the cells to eliminate the insult. Under OS, the activation of this immune pathway aims to repair tissue homeostasis. Still, under continual stress, the inflammatory system's chronic hyperactivation can determine dramatic tissue changes and damage, resulting in irreversible retinal pathologies, including AMD or DR.
    Sulfur amino acids (SAAs), such as methionine and taurine are necessary for the synthesis of proteins and serve as precursors of important cofactors and metabolites, thus playing a critical role in health maintenance. Methionine and taurine are present in ocular tissues, such as cornea, iris, lens, ciliary bodies, vitreous, and retina. Although their role in the retina is unclear, numerous events have been attributed to them, involving osmoregulation, antioxidant defence, stress responses, and protein stabilization.
    The role of sulfur amino acids as regulators of retinal cell functions will be discussed.

    Marcello Allegretti

    Since 2009:

    • Chief Scientific Officer at Dompé farmaceutici managing Dompé’s Research and Development activities and pre-clinical and clinical drug development programs - from active ingredient identification to market authorization - including relationships with international regulatory authorities.
    • Number of university teaching positions.
    • Published work in over 40 scientific journals.
    • Over 30 international patents.

    Prior 2009:

    • Degree in Medical Chemistry from The Sapienza University of Rome.
    • Member of the American Chemical Society.
    • Member of the Italian Chemistry Society.
  • Seminar #6 - 6 July

  • Seminar #7 - 7 September

  • Seminar #8 - 4 October

  • Seminar #9 - 14 October

  • Seminar #10 - 18 November

  • Seminar #11 - 2 December

  • Seminar #12 - 16 December