WEBINAR SERIES:
Oxidative Stress: Biochemical and Pharmacological aspects
15:00-17:00 (CEST)
September 30, 2025,
15:00-17:00 (CEST)
Participation is free of charge but registration is compulsory at www.antiox.it
Aging is a multifaceted, inevitable natural process characterized by increased damage in all cellular macromolecules (DNA, RNA, proteins, lipids etc), thus resulting in downstream alterations in all metabolic pathways. In turn, these alterations enhance frailty and increase death probability. In parallel, aging represents a pivotal risk factor for the development of age-related diseases, including neurodegenerative diseases. More recently, the importance of controlling frailty via maintenance of well-being in all levels of life (cellular, tissular and organismal) for longer periods has been revealed and the notion of healthspan has emerged as the new target in anti-aging. Nrf2 has been shown to affect all the above-mentioned phenomena, namely healthspan, aging, longevity and age-related diseases. Moreover, we were the first to show that Nrf2 is down-regulated during cellular senescence, a fundamental hallmark of aging. Work in lower eukaryotes has revealed the link between Nrf2, aging and longevity while work in mammals has started revealing the importance of Nrf2 function in the aging progression. Nevertheless, little is known regarding the role of Nrf2 in human aging per se and additional research is required to fully understand its role. An overview of the effects of Nrf2 modulation on aging, healthspan and longevity will be presented.
Dr Chondrogianni is Research Director at the National Hellenic Research Foundation in Athens, Greece. She focuses on the genetic and environmental factors that govern healthspan, aging, longevity and age-related diseases with emphasis on proteasome regulation. She is seeking for compounds that may act as proteasome activators and thus may serve as anti-aging agents. She is equally interested in identifying compounds than can decelerate protein aggregation and thus the progression of proteinopathies with emphasis on Alzheimer’s disease using Caenorhabditis elegans as a model in combination with human cells of neuronal origin. She is an international patent holder that resulted in the development of novel anti-aging products (two relative product series in the (inter)national market). She is Associate Editor in Free Radical Biology & Medicine, Elsevier and elected Meeting Officer of the Society for Free Radical Research-Europe, responsible for the SFRR-E summer schools dedicated to early carrier researchers.
In recent years, the consumption of hypercaloric and ultra-processed foods has been associated with global growth in prevalence of chronic non-communicable diseases, all accounting for increased levels of oxidative stress (OS) and inflammation. Of greater concern, the sequelae of this nutritional stress may spread across generations through fetal programming. We have shown that high-fat diet feeding in pregnant mice increased neuroinflammation and reduced hippocampal Nrf2 antioxidant defenses in the adolescent offspring. These sex-dependent effects were associated with decreased brain plasticity and increased anxiety-like behavior. Moreover, in adulthood, mouse offspring showed derangements in glucose and fat metabolism accompanied by decreased hypothalamic glutathione levels. Prenatal administration of the antioxidant N-acetyl-cysteine exerted protective effects on brain development, behavior and metabolic functions at all ages. Besides synthetic antioxidants, nutraceutical compounds, such as polyphenols, are becoming ever more attractive due to their pleiotropic mechanisms of action dealing with resistance towards OS and immune challenges. In this regard, in a model of senescent mice exposed to Western diet we have provided evidence for rosmarinic acid to modulate hippocampal glutathione signaling pathway and to inhibit the onset of metabolic syndrome in males while preventing cognitive decline in both sexes. Moreover, we have shown that trehalose administration to senescent mice increased motor learning together with brain levels of NRF2 and autophagy, particularly in males. Our results provide evidence that unbalanced nutrition may finely modulate the Nrf2 pathway and redox balance in a sex-dependent manner affecting mental and metabolic health trajectories from early-life phases to senescence.
Dr. Berry is a researcher at the Center for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy. She holds a PhD in Neuroscience from Leiden University, The Netherlands. Research interests: to study the interaction between psychophysical and metabolic stressors as risk factors for mental health outcomes from prenatal life to senescence (both clinical and preclinical settings). Main emphasis is given to oxidative stress as a shared mechanism underlying mental health liability. Ongoing projects: improve the diagnosis of uni- and bipolar disorders through peripheral immunometabolic biosignatures of the diseases; assessing the anti-aging properties of curcumin in middle-aged subjects with metabolic syndrome. She is author of more than 60 papers in international Journals and serves as Associate Editor for the journals Neuroscience and Biobehavioral Reviews and Frontiers in Behavioral Neuroscience.
Mitochondrial dysfunction, oxidative stress, and proteolytic failure – leading to the accumulation of misfolded proteins and endoplasmic reticulum (ER) stress – are common contributing factors to the pathogenesis of Parkinson’s disease (PD). The PERK/eIF2α/ATF4 signalling branch of the unfolded protein response (UPR), plays a key role in cellular adaptation to ER stress and is also implicated in the regulation of NRF2, linking the UPR to antioxidant defences. We performed a global redox proteomic analysis of human PD brain samples revealing shifts in the redox state and abundance of several proteins when compared to controls. We have demonstrated that S-glutathionylation — a cysteine-specific post-translational modification mediated by Glutathione S-Transferase pi (GSTP) — can modulate the NRF2-Keap1 pathway. Evaluation of UPR markers revealed altered expression in human PD samples and in a murine model of PD. Wild-type and GSTP knockout C57BL/6 mice were exposed to the neurotoxin MPTP, and treated with tauroursodeoxycholic acid (TUDCA), a chemical chaperone known to enhance ER adaptive capacity. Our results indicate that MPTP-induced activation of the PERK pathway is altered in the absence of GSTP and that TUDCA treatment attenuates this activation, suggesting its potential in mitigating ER stress and restoring redox homeostasis. These findings provide new insights into the interplay between ER stress and antioxidant responses via the PERK/eIF2α/ATF4-NRF2 axis in PD and highlight potential therapeutic strategies targeting these pathways.
Andreia Neves Carvalho is an invited Assistant Professor at the Faculty of Pharmacy, Universidade de Lisboa. She holds a PhD in Pharmacy (specialization Biochemistry), by the University of Lisbon and was a post-doctoral fellow at the Vrije Universiteit Amsterdam, The Netherlands. Dr. Carvalho’s main research focus is on the characterization of the molecular mechanisms underlying mitochondrial dysfunction, oxidative and endoplasmic reticulum stress and associated neuro-axonal damage leading to neurodegeneration. She investigated the role of Nrf2 in the regulation of the antioxidant response in Parkinson’s disease (PD), focusing on the relevance of S-glutathionylation, a post-translational modification (PTM) relevant in redox signaling. Currently she is interested in the mechanisms regulating mitochondrial function, at the level of mitochondrial biogenesis and mitochondrial dynamics, namely through redox-mediated PTMs of key proteins involved in these processes, to identify new potential therapeutic targets for the treatment of neurodegenerative diseases.
Chronic activation of stress responses can drive harmful processes in the brain by linking protein misfolding, oxidative stress, and neurotoxicity. Findings from our laboratory highlight that disruption of the PERK arm of the unfolded protein response (UPR) is associated with the impairments of the Nrf2 antioxidant pathway, contributing to the development of Alzheimer-related signatures the brains of individuals with Down syndrome (DS). Additionally, we observed that metabolic dysfunction occurs alongside impaired protein homeostasis (proteostasis) and redox imbalance. Altogether these impairments promote behavioural deficits and cognitive decline. Our recent studies investigated, both in vitro and in vivo, the susceptibility of the DS phenotype to disturbances of proteostasis and of Nrf2 signalling under metabolic stress. In particular, we evaluated the effects of nutrients overload in dysregulating proteostasis and redox balance by altering the UPR and the Nrf2-mediated antioxidant response in primary cortical neurons and astrocytes from murine models of DS. Subsequently, by pharmacologically modulating the UPR we were able to improve stress responses and reduce oxidative stress. A similar scenario was observed in DS-derived peripheral cells. Overall, our findings suggest that metabolic dysfunction in DS plays a key role in impairing brain proteostasis by altering protein quality control systems and redox responses, thereby contributing to neurodegenerative processes and cognitive impairment. Targeting these molecular pathways may offer promising strategies for therapeutic intervention.
Fabio Di Domenico is a Full Professor of Biochemistry at Sapienza University of Rome. He trained under Prof. D. Allan Butterfield at the University of Kentucky, where he contributed to pioneering redox proteomics research aimed at uncovering the neurodegenerative mechanisms driven by oxidative damage in Alzheimer’s disease. His current research focuses on elucidating how redox imbalance and impaired proteostasis contribute to the pathogenesis of Alzheimer-like dementia. Findings from his laboratory suggest that the disrupted proteostasis observed in both Alzheimer’s disease and Down syndrome is closely linked to elevated oxidative stress, resulting from impaired antioxidant defenses and defective protein degradation pathways. More recently, his work has highlighted a critical role for chronic activation of the unfolded protein response and its dysregulated interplay with the Nrf2 signaling pathway in the onset and progression of dementia in these patient populations.
