1,720,959 research outputs found
A new K+channel-independent mechanism is involved in the antioxidant effect of XE-991 in an in vitro model of glucose metabolism impairment: implications for Alzheimer’s disease
Full text linkAlzheimer's disease (AD) is a neurodegenerative disorder that represents the first cause of dementia. Although there has been significant progress in AD research, the actual mechanisms underlying this pathology remain largely unknown. There is increasing evidence that oxidative stress, metabolic alterations, and mitochondrial dysfunction are key players in the development and worsening of AD. As a result, in the past few years, remarkable attempts have been made to develop neuroprotective strategies against the impairment of mitochondrial dynamics and cell redox status. In the present study, we reveal a novel antioxidant K+ channel-independent effect of the M-current inhibitor XE-991 in SH-SY5Y cells differentiated with retinoic acid (RA) and primary rat cortical neurons exposed to the glycolysis inhibitor glyceraldehyde (GA). This experimental approach aimed to create a condition of hypometabolism accompanied by mitochondrial dysfunction and redox imbalance, as frequently observed in the beginning stage of the disease. We found that XE-991 exerted a neuroprotective action most likely through the resumption of superoxide dismutase (SOD) activity, which was significantly compromised during GA challenge. We also observed that the enhancement of SOD activity was accompanied by a sequence of positive effects; these included the reduction in basal Ca2+ levels within cytoplasmic and mitochondrial compartments, the decrease in mitochondrial reactive oxygen species (ROS) production, the modulation of AMPK/mTOR pathway, the recovery of ΔΨm collapse, the increase in the intracellular ATP content and the decrease in amyloid-β (Aβ) and hyperphosphorylated form of tau protein (pTau) levels. Collectively, our study reveals an off-target antioxidant effect of XE-991 and paves the way toward the further evaluation of new therapeutic uses of already existing molecules to accelerate the process of developing an effective therapy to counteract AD
Challenges and Opportunities from Targeting Inflammatory Responses to SARS-CoV-2 Infection: A Narrative Review
No full textThe novel coronavirus disease 2019 (COVID-19) is a global pandemic that continues to sweep across the world, posing an urgent need for effective therapies and prevention of the spread of the severe acute respiratory syndrome related to coronavirus-2 (SARS-CoV-2). A major hypothesis that is currently guiding research and clinical care posits that an excessive and uncontrolled surge of pro-inflammatory cytokines (the so-called "cytokine storm") drives morbidity and mortality in the most severe cases. In the overall efforts made to develop effective and safe therapies (including vaccines) for COVID-19, clinicians are thus repurposing ready-to-use drugs with direct or indirect anti-inflammatory and immunomodulatory activities. Speculatively, there are many opportunities and challenges in targeting immune/inflammatory processes in the evolving settings of COVID-19 disease because of the need to safely balance the fight against virus and aggressive inflammation versus the suppression of host immune defenses and the risk of additional harms in already compromised patients. To this end, many studies are globally underway to weigh the pros and cons of tailoring drugs used for inflammatory-driven conditions to COVID-19 patient care, and the next step will be to summarize the growing clinical trial experience into clean clinical practice. Based on the current evidence, anti-inflammatory drugs should be considered as complementary approaches to anti-viral drugs that need to be timely introduced in the management of COVID-19 according to disease severity. While drugs that target SARS-CoV-2 entry or replication are expected to confer the greatest benefits at the early stage of the infection, anti-inflammatory drugs would be more effective in limiting the inflammatory processes that drive the worsening of the disease
The Hidden Notes of Redox Balance in Neurodegenerative Diseases
Full text linkReactive oxygen species (ROS) are versatile molecules that, even if produced in the background of many biological processes and responses, possess pleiotropic roles categorized in two interactive yet opposite domains. In particular, ROS can either function as signaling molecules that shape physiological cell functions, or act as deleterious end products of unbalanced redox reactions. Indeed, cellular redox status needs to be tightly regulated to ensure proper cellular functioning, and either excessive ROS accumulation or the dysfunction of antioxidant systems can perturb the redox homeostasis, leading to supraphysiological concentrations of ROS and potentially harmful outcomes. Therefore, whether ROS would act as signaling molecules or as detrimental factors strictly relies on a dynamic equilibrium between free radical production and scavenging resources. Of notice, the mammalian brain is particularly vulnerable to ROS-mediated toxicity, because it possesses relatively poor antioxidant defenses to cope with the redox burden imposed by the elevated oxygen consumption rate and metabolic activity. Many features of neurodegenerative diseases can in fact be traced back to causes of oxidative stress, which may influence both the onset and progression of brain demise. This review focuses on the description of the dual roles of ROS as double-edge sword in both physiological and pathological settings, with reference to Alzheimer’s and Parkinson’s diseases
A strategic tool to improve the study of molecular determinants of Alzheimer’s disease: The role of glyceraldehyde
Full text linkAlzheimer's disease (AD) is the most prevalent form of dementia and is characterized by progressive neurodegeneration leading to severe cognitive, memory, and behavioral impairments. The onset of AD involves a complex interplay among various factors, including age, genetics, chronic inflammation, and impaired energy metabolism. Despite significant efforts, there are currently no effective therapies capable of modifying the course of AD, likely owing to an excessive focus on the amyloid hypothesis and a limited consideration of other intracellular pathways. In the present review, we emphasize the emerging concept of AD as a metabolic disease, where alterations in energy metabolism play a critical role in its development and progression. Notably, glucose metabolism impairment is associated with mitochondrial dysfunction, oxidative stress, Ca2+ dyshomeostasis, and protein misfolding, forming interconnected processes that perpetuate a detrimental self-feeding loop sustaining AD progression. Advanced glycation end products (AGEs), neurotoxic compounds that accumulate in AD, are considered an important consequence of glucose metabolism disruption, and glyceraldehyde (GA), a glycolytic intermediate, is a key contributor to AGEs formation in both neurons and astrocytes. Exploring the impact of GA-induced glucose metabolism impairment opens up exciting possibilities for creating an easy-to-handle in vitro model that recapitulates the early stage of the disease. This model holds great potential for advancing the development of novel therapeutics targeting various intracellular pathways implicated in AD pathogenesis. In conclusion, looking beyond the conventional amyloid hypothesis could lead researchers to discover promising targets for intervention, offering the possibility of addressing the existing medical gaps in AD treatment
Exploring the Role of NCX1 and NCX3 in an In Vitro Model of Metabolism Impairment: Potential Neuroprotective Targets for Alzheimer’s Disease
Full text linkSimple Summary Alzheimer's disease (AD) is a progressive neurodegenerative disorder and represents the most common cause of dementia among elderly people. It is characterized by the deterioration of brain cells and is linked to problems with energy production, cell metabolism, and harmful oxidative stress. Our study focused on two proteins called NCX1 and NCX3, which play a role in controlling calcium and sodium levels in cells. We wanted to understand whether these proteins may be involved in AD development when brain cells are exposed to metabolic impairment. To investigate this, we used a laboratory cell model and treated the cells with a substance called glyceraldehyde (GA) to mimic the metabolic dysfunction seen in AD. We used a technique called RNA interference to silence the expression of either NCX1 or NCX3 in the cells. We found that when NCX3 was silenced, the cells showed improved viability, increased energy production, and reduced damage from oxidative stress. Additionally, the levels of abnormal proteins associated with AD, such as A & beta; and pTau, were decreased. However, silencing NCX1 did not have the same positive effects, except for increased energy production. These findings suggest that targeting NCX3 may be a potential strategy to prevent the development of AD associated with metabolic dysfunction. Considering the paucity of pharmacological therapies, this knowledge could be valuable for identifying new potential treatments for AD. Alzheimer's disease (AD) is a widespread neurodegenerative disorder, affecting a large number of elderly individuals worldwide. Mitochondrial dysfunction, metabolic alterations, and oxidative stress are regarded as cooperating drivers of the progression of AD. In particular, metabolic impairment amplifies the production of reactive oxygen species (ROS), resulting in detrimental alterations to intracellular Ca2+ regulatory processes. The Na+/Ca2+ exchanger (NCX) proteins are key pathophysiological determinants of Ca2+ and Na+ homeostasis, operating at both the plasma membrane and mitochondria levels. Our study aimed to explore the role of NCX1 and NCX3 in retinoic acid (RA) differentiated SH-SY5Y cells treated with glyceraldehyde (GA), to induce impairment of the default glucose metabolism that typically precedes A & beta; deposition or Tau protein phosphorylation in AD. By using an RNA interference-mediated approach to silence either NCX1 or NCX3 expression, we found that, in GA-treated cells, the knocking-down of NCX3 ameliorated cell viability, increased the intracellular ATP production, and reduced the oxidative damage. Remarkably, NCX3 silencing also prevented the enhancement of A & beta; and pTau levels and normalized the GA-induced decrease in NCX reverse-mode activity. By contrast, the knocking-down of NCX1 was totally ineffective in preventing GA-induced cytotoxicity except for the increase in ATP synthesis. These findings indicate that NCX3 and NCX1 may differently influence the evolution of AD pathology fostered by glucose metabolic dysfunction, thus providing a potential target for preventing AD
Identification of glutamate-related disease-dependent alterations in subventricular NSCs of the 3xTg Alzheimer’s disease model, could they be involved in attempting damage repair?
No full textAlzheimer’s disease (AD) is an age-related neurodegenerative disorder characterised by several factors, such as impaired glutamate neurotransmission affecting crucial functions. Neural stem cells (NSCs) are present in the adult brains of all mammalian species and contribute to the continuous generation of neural cells throughout life. The disruption of glutamate levels during the development of AD could impact NSCs’ functionality, influencing their response to the microenvironment. In this work, we isolated adult neural stem cells from both triple transgenic (3xTg)-AD mice and age-matched wild type (WT) mice in order to gather information on any differences between them, particularly concerning the potential mechanisms involved in the internalisation of glutamate and its utilisation for energy production. The 3xTg model offers the ability to recapitulate human pathology with both plaque and tangle hallmarks that are involved in the process of glutamate release. In vitro culture 3xTg NSCs showed a slight morphological difference compared to WT cells and a massive reduction of proliferation and viability. Furthermore, 3xTg NSCs displayed an increase in the expression of glutamate transporters and glutamine synthetase, while glutamate dehydrogenase did not show any reduction, which is typical in AD brains. Data obtained from this basic research study suggest a possible involvement of glutamate in the cellular energy balance, indicating an attempted response of NSCs to the cytotoxic microenvironment in the early stage of AD pathology. This finding is of great interest, as it corroborates the hypothesis that targeting the glutamatergic system could be an extremely promising strategy for new therapeutics in AD
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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