1,721,068 research outputs found
Fluid redox biomarkers in neurological disease
No full textModulation of Oxidative Stress: Biochemical, Physiological and Pharmacological Aspects explores the field using an interdisciplinary approach, including chemical, biological, physiological, pharmaceutical, pharmacological and physicochemical perspectives. The book is comprised of three main parts, with the first discussing the biochemical aspects of oxidative stress modulation. Other sections cover physiological and pathophysiological aspects on relevant conditions, including aging, neurological diseases, cerebral cavernous malformation, maternal and early-life malnutrition, Alzheimer’s disease, liver transplant, and cancer. Final content is dedicated to pharmacological aspects and includes chapters on phytotherapy and flavonoids.
This book is a strong reference for pharma researchers in academia and industry considering leveraging modulation of oxidative stress as a strategy for the development of new drugs. Biochemists and Nutritionists may also benefit of the foundational understanding of cellular redox processes laid out.Redox imbalance is a common physiopathological feature in neurological disease, especially those with a relevant neurodegenerative component. The consequent damage to biomolecules leads to the generation of various relatively stable by-products, which can serve as biomarkers of oxidative stress. A wealth of epidemiological and clinical evidence has found an association between alteration of these fluid biomarkers and the occurrence of neurological diseases, in particular Alzheimer's disease (AD), vascular dementia (VD), and Parkinson's disease (PD). However, also conflicting results are reported. Herein, we systematically review the published data on this topic highlighting the methodological issues that hinder the definitive appreciation of the use of redox biomarkers in the diagnosis and prediction of the above-mentioned disorders
Redox Regulation of Nucleotide-Binding and Oligomerization Domain-Like Receptors Inflammasome
No full textSignificance: Inflammasomes are multimeric complexes that, as part of the innate immune response, sense a wide range of pathogenic and sterile stimuli. They consist of three components, namely a sensor protein, an adaptor, and procaspase-1, which once activated result in secretion of proinflammatory interleukin (IL)-1b and IL-18 and, eventually, in a gasdermin D–dependent lytic cell death called pyroptosis. Recent Advances: Since their discovery 20 years ago, the molecular mechanisms underlying the regulation of inflammasomes have been extensively studied. Oxidative stress appears as a major contributor to modulate inflammasomes, especially NLRP3 as well as NLRP1, NLRP6, and NLRC4. Growing evidence supports the idea that the positive feedback between redox imbalance and inflammasome-driven inflammation fuels an OxInflammatory state in a variety of human pathologies. Critical Issues: The current knowledge about the redox signaling pathways involved in inflammasomes activation and functions are here highlighted. In addition, we discuss the role of this complex molecular network interaction in the onset and progression of pathological conditions including neurological and metabolic diseases as well as skin disorders, also with an insight on COVID-19–related pathology. Finally, the therapeutic strategies able to mitigate the redox-mediated inflammasome activation with synthetic and natural compounds as well as by acting on inflammasome-related post-translational modifications and microRNAs are also addressed. Future Directions: Further investigations leading to a deeper understanding of the reciprocal interaction between inflammasomes and reactive oxygen species will help identify other molecular targets for modulating their hyperactivated state, and to design novel therapeutics for chronic OxInflammatory conditions
Keratinocytes oxidative damage mechanisms related to airbone particle matter exposure
Full text linkEpidemiological evidences have correlated airbone particulate matter (PM) to adverse health effects, mainly linking to pulmonary and cardiovascular disease. Nevertheless, only recently, some studies reported detrimental effects of PM on other organs such as skin. In a recent work, we have reported increased oxidative and inflammatory responses in Reconstituted Human Epidermis (RHE) exposed to ambient particles (CAPs) and we also demonstrated the ability of CAPs to penetrate the skin tissue.The present study was aimed to better understand the cellular mechanisms beyond the oxidative changes induced by CAPs (5-10-25. μg/mL) in human immortalized keratinocytes (HaCaT).After 24. h of treatment, CAPs were able to enter the cells leading to a decrease in viability, increased levels of 4-hydroxinonenal products (4-HNE) and IL-1α release. Overall these data, suggest lipid and protein oxidative damage, as well as an increase of inflammatory response after being challenged with CAPs. In addition, 3. h after CAPs exposure we found a significant increase in NF-kB and Nrf2 translocation into the nucleus. In contrast, no differences in gene expression and enzymatic activity of Nrf2 target genes were detected. This last finding could be explained by the ability of CAPs to possibly alter the binding of Nrf2 to the ARE DNA sequence.Fil: Romani, Arianna. Università di Ferrara; ItaliaFil: Cervellati, Carlo. Università di Ferrara; ItaliaFil: Muresan, Ximena M.. Università di Ferrara; ItaliaFil: Belmonte, Giuseppe. Università di Ferrara; ItaliaFil: Pecorelli, Alessandra. North Carolina State University; Estados UnidosFil: Cervellati, Franco. Università di Ferrara; ItaliaFil: Benedusi, Mascia. Università di Ferrara; ItaliaFil: Evelson, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular. Departamento de Patología; ArgentinaFil: Valacchi, Giuseppe. Università di Ferrara; Italia. North Carolina State University; Estados Unido
Omega-3 nutritional intervention as therapeutic co-adjuvant approach to improve Rett syndrome clinical and biochemical features
No full text4-hydroxynonenal protein adducts: Key mediator in Rett syndrome oxinflammation
No full textIn the last 15 years a strong correlation between oxidative stress (OxS) and Rett syndrome (RTT), a rare neurodevelopmental disorder known to be caused in 95% of the cases, by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, has been well documented. Here, we revised, summarized and discussed the current knowledge on the role of lipid peroxidation byproducts, with special emphasis on 4-hydroxynonenal (4HNE), in RTT pathophysiology. The posttranslational modifications of proteins via 4HNE, known as 4HNE protein adducts (4NHE-PAs), causing detrimental effects on protein functions, appear to contribute to the clinical severity of the syndrome, since their levels increase significantly during the subsequent 4 clinical stages, reaching the maximum degree at stage 4, represented by a late motor deterioration. In addition, 4HNE-PA are only partially removed due to the compromised functionality of the proteasome activity, contributing therefore to the cellular damage in RTT. All this will lead to a characteristic subclinical inflammation, defined “OxInflammation”, derived by a positive feedback loop between OxS byproducts and inflammatory mediators that in a long run further aggravates the clinical features of RTT patients. Therefore, in a pathology completely orphan of any therapy, aiming 4HNE as a therapeutic target could represent a coadjuvant treatment with some beneficial impact in these patients.
Exploring the possible link between MeCP2 and oxidative stress in Rett syndrome
No full textRett syndrome (RTT, MIM 312750) is a rare and orphan progressive neurodevelopmental disorder affecting girls almost exclusively, with a frequency of 1/15,000 live births of girls. The disease is characterized by a period of 6 to 18 months of apparently normal neurodevelopment, followed by early neurological regression, with a progressive loss of acquired cognitive, social, and motor skills. RTT is known to be caused in 95% of the cases by sporadic de novo loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene encoding methyl-CpG binding protein 2 (MeCP2), a nuclear protein able to regulate gene expression. Despite almost two decades of research into the functions and role of MeCP2, little is known about the mechanisms leading from MECP2 mutation to the disease. Oxidative stress (OS) is involved in the pathogenic mechanisms of several neurodevelopmental and neurodegenerative disorders, although in many cases it is not clear whether OS is a cause or a consequence of the pathology. Fairly recently, the presence of a systemic OS has been demonstrated in RTT patients with a strong correlation with the patients' clinical status. The link between MECP2 mutation and the redox imbalance found in RTT is not clear. Animal studies have suggested a possible direct correlation between Mecp2 mutation and increased OS levels. In addition, the restoration of Mecp2 function in astrocytes significantly improves the developmental outcome of Mecp2-null mice and reexpression of Mecp2 gene in the brain of null mice restored oxidative damage, suggesting that Mecp2 loss of function can be involved in oxidative brain damage. Starting from the evidence that oxidative damage in the brain of Mecp2-null mice precedes the onset of symptoms, we evaluated whether, based on the current literature, the dysfunctions described in RTT could be a consequence or, in contrast, could be caused by OS. We also analyzed whether therapies that at least partially treated some RTT symptoms can play a role in defense against OS. At this stage we can propose that OS could be one of the main causes of the dysfunctions observed in RTT. In addition, the major part of the therapies recommended to alleviate RTT symptoms have been shown to interfere with oxidative homeostasis, suggesting that MeCP2 could somehow be involved in the protection of the brain from OS
Compromised immune/inflammatory responses in Rett syndrome
No full textMutations in X-linked gene methyl-CpG-binding protein 2 (MECP2), a key transcriptional regulator, account for most cases of Rett syndrome (RTT), a devastating neurodevelopmental disorder with no known cure. Despite extensive research to elucidate MeCP2 functions, the mechanisms underlying RTT pathophysiology are still unclear. In addition to a variety of neurological symptoms, RTT also includes a plethora of additional phenotypical features including altered lipid metabolism, redox imbalance, immune dysfunction and mitochondrial abnormalities that explain its multisystemic nature. Here, we provide an overview of the current knowledge on the potential role of dysregulated inflammatory and immune responses in RTT. The findings show that abnormalities of humoral and cell-mediated immunity together with chronic low-grade inflammation in multiple organs represent not only clinical manifestations of RTT but rather can contribute to its development and deteriorating course. A future research challenge could be to target therapeutically immune dysfunction as a novel means for RTT management
OxInflammation in Rett syndrome
No full textRett syndrome (RTT) is an orphan progressive neurodevelopmental disease affecting almost exclusively females (frequency 1:10,000). RTT clinical expression is typically characterized by loss of purposeful hand movements, severe mental retardation and motor impairment, breathing disorders, ataxia and increased risk of sudden death. Although the main genetic cause, i.e. mutation in the methyl-CpG binding protein 2 gene (MECP2), has been already identified, the molecular and pathogenic mechanisms by which MECP2 deficiency drives pathology in RTT remains not fully understood. A wealth of evidence from our and other laboratories suggests a potential causal relationship between MECP2 dysfunction and systemic redox imbalance, a condition that has been widely found in association with RTT. In turn, a "short-circuit" of redox pathways may contribute to the systemic immune dysfunction expressed as cytokines/chemokines dysregulation, a feature clearly emerged from two recent studies on RTT patients. In this light, the purpose of this review is to describe and to stimulate a new discussion on the idea that systemic subclinical inflammation and oxidative stress are crucial players of a detrimental vicious circle, driving the pathogenesis and clinical course of RTT
Tropospheric ozone effect on olfactory perception and olfactory bulb dopaminergic interneuron excitability
No full textOzone (O3) forms in the Earth's atmosphere, both naturally and by reactions of man-made air pollutants. Deleterious effects of O3 have been found in the respiratory system. Here, we examine whether O3 alters olfactory behavior and cellular properties in the olfactory system. For this purpose, mice were exposed to O3 at a concentration found in highly polluted city air [0.8 ppm], and the behavior elicited by social and non-social odors in abituation/dishabituation tests was assessed. In addition, the electrical responses of dopaminergic olfactory bulb (OB) neurons were also evaluated. O3 differentially compromises olfactory perception to odors: it reduces responses to social and non-social odors in Swiss Webster mice, while this effect was observed in C57BL/6 J mice only for some non-social odors. Additionally, O3 reduced the rate of spontaneous spike firing in periglomerular dopaminergic cells (PG-DA) of the OB. Because this effect could reflect changes in excitability and/or synaptic inputs, the ability of O3 to alter PG-DA spontaneous activity was also tested together with cell membrane resistance, membrane potential, rheobase and chronaxie. Taken together, our data suggest the ability of O3 to affect olfactory perception
The complexity of Rett syndrome models: Primary fibroblasts as a disease-in-a-dish reliable approach
No full textRett syndrome (RTT) is a progressive neurodevelopmental disease, which affects almost exclusively the female gender (prevalence of about 1:10,000). RTT symptoms are usually characterized by loss of purposeful hand skills, mental retardation and motor impairment, resulting in a plethora of other systemic co-morbidities. Mutations in the methyl-CpG binding protein 2 gene (MECP2) are the main genetic cause of the disorder, however molecular mechanisms leading from MeCP2 defects to this complicated pathology still need to be clarified. To investigate this and other aspects of RTT, several experimental models have been generated that include animal models, and in vitro approaches. In this article we briefly summarized the main models used for RTT investigations, and special focus is given to the use of primary fibroblasts isolated from RTT patients, since they represent a reliable disease-in-a-dish model, which can help researcher to elucidate cellular and molecular mechanisms of this disease
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