Content uploaded by Inmaculada Tasset
Author content
All content in this area was uploaded by Inmaculada Tasset on Apr 09, 2015
Content may be subject to copyright.
Oxidative stress and inflammation biomarkers in the blood of patients with Huntington's disease
Abstract
Huntington's disease (HD) is a neurodegenerative disorder for which there is no effective treatment. Oxidative stress and inflammation are known to be involved in HD, but the precise relationship between the two remains unclear. The aim of this study was to analyze oxidative stress and inflammation biomarkers in blood of patients with HD with a view to identifying potential links between them.
Blood samples were collected from 13 patients with HD and from 10 age- and sex-matched controls, and the following were measured: C-reactive proteins, myeloperoxidase (MPO)/white blood cell (WBC) ratio, interleukin-6 (IL-6), thioredoxin reductase-1 (TrRd-1), thioredoxin-1 (Trx-1), total nitrites (NOx), nitric oxide synthase (NOS) and nitrotyrosine.
Results showed that HD is associated to a reduction of TrRd-1 and Trx-1 levels in plasma and erythrocytes, and with an increase in the MPO/WBC ratio. A positive correlation was observed between global oxidative stress (GOS) and MPO/WBC. No changes were found in NOS and Nox levels with respect to controls.
Oxidative damage may be linked to the inflammatory response in HD, via a peripheral immune response.
... Based on the inclusion and exclusion criteria, 13 studies (Björkqvist et al., 2008b;Chang et al., 2015a;Corey-Bloom et al., 2020;Dalrymple et al., 2007a;Du et al., 2021;Gruber et al., 2013;Leblhuber et al., 1998a;Sánchez-López et al., 2012a;Silajdžić et al., 2013;Szafran et al., 2018;Battaglia et al., 2011;Plinta et al., 2021;Bouwens et al., 2014) were considered for this study, of which 10 studies had sufficient quantitative data and were included in the meta-analysis and reported in this study (Björkqvist et al., 2008b;Chang et al., 2015a;Corey-Bloom et al., 2020;Dalrymple et al., 2007a;Du et al., 2021;Leblhuber et al., 1998a;Sánchez-López et al., 2012a;Silajdžić et al., 2013;Szafran et al., 2018;Bouwens et al., 2014). ...
... Based on the inclusion and exclusion criteria, 13 studies (Björkqvist et al., 2008b;Chang et al., 2015a;Corey-Bloom et al., 2020;Dalrymple et al., 2007a;Du et al., 2021;Gruber et al., 2013;Leblhuber et al., 1998a;Sánchez-López et al., 2012a;Silajdžić et al., 2013;Szafran et al., 2018;Battaglia et al., 2011;Plinta et al., 2021;Bouwens et al., 2014) were considered for this study, of which 10 studies had sufficient quantitative data and were included in the meta-analysis and reported in this study (Björkqvist et al., 2008b;Chang et al., 2015a;Corey-Bloom et al., 2020;Dalrymple et al., 2007a;Du et al., 2021;Leblhuber et al., 1998a;Sánchez-López et al., 2012a;Silajdžić et al., 2013;Szafran et al., 2018;Bouwens et al., 2014). ...
... In this study, we considered papers published until March 2023 totaling 10 studies (Björkqvist et al., 2008b;Chang et al., 2015a;Corey-Bloom et al., 2020;Dalrymple et al., 2007a;Du et al., 2021;Leblhuber et al., 1998a;Sánchez-López et al., 2012a;Silajdžić et al., 2013;Szafran et al., 2018). Nine inflammatory markers were included in the metaanalyses, namely IL-1β (Björkqvist et al., 2008b;Du et al., 2021), IL-2 (Björkqvist et al., 2008b;Du et al., 2021), IL-6 (Björkqvist et al., 2008b;Chang et al., 2015a;Corey-Bloom et al., 2020;Dalrymple et al., 2007a;Du et al., 2021;Sánchez-López et al., 2012a;Szafran et al., 2018), IL-8 (Björkqvist et al., 2008b;Du et al., 2021), IL-10 (Björkqvist et al., 2008b;Du et al., 2021), TNF-α (Björkqvist et al., 2008b;Du et al., 2021), interferon-γ (IFN-γ) (Björkqvist et al., 2008b;Du et al., 2021), Complement 3 (C3) (Leblhuber et al., 1998a;Silajdžić et al., 2013), and CRP (Corey-Bloom et al., 2020;Sánchez-López et al., 2012a;Silajdžić et al., 2013;Bouwens et al., 2014). ...
... Neutrophil degranulation results in the liberation of a variety of enzymes, including myeloperoxidase (MPO), neutrophil elastase (NE), and matrix metalloproteinases (MMPs) (40). Previous studies have confirmed a significant increase in the MPO/WBC ratio in HD patients compared to HCs, suggesting an increase in WBC activity (41). Our study found a trend toward an increased absolute neutrophil count in HD patients. ...
Objectives
This study aims to elucidate the role of peripheral inflammation in Huntington’s disease (HD) by examining the correlation of peripheral inflammatory markers with clinical manifestations and disease prognosis.
Methods
This investigation involved 92 HD patients and 92 matched healthy controls (HCs). We quantified various peripheral inflammatory markers and calculated their derived metrics including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII). Clinical assessments spanning cognitive, motor, and disease severity were administered. Comparative analysis of inflammatory markers and clinical correlations between HD and controls was performed. Kaplan–Meier survival analysis and Cox regression model were used to assess the effect of inflammatory markers on survival.
Results
The study revealed that HD patients had significantly reduced lymphocyte counts, and LMR. Conversely, NLR, PLR, and SII were elevated compared to HCs. Lymphocyte levels inversely correlated with the age of onset and monocyte levels inversely correlated with the UHDRS-total functional capacity (TFC) scores. After adjusting for age, sex, and CAG repeat length, lymphocyte count, NLR, PLR, and SII were significantly correlated with the progression rate of TFC scores. Elevated levels of white blood cells and monocytes were associated with an increased risk of disability and mortality in the HD cohort.
Conclusion
Our findings indicate that HD patients display a distinct peripheral inflammatory profile with increased NLR, PLR, and SII levels compared to HCs. The peripheral inflammation appears to be linked with accelerated disease progression and decreased survival in HD.
... Neuronal death can activate inflammatory mechanisms, which in turn cause neurodegeneration leading to a vicious cycle [98]. Elevated levels of cytokines have been found in fluids of both animal models and HD patients [99][100][101][102][103]. Unfortunately, until now, anti-inflammatory and antioxidant agents have rarely achieved effectiveness in HD treatment [103]. ...
Oxidative stress (OS) and inflammation are two important and well-studied pathological hallmarks of neurodegenerative diseases (NDDs). Due to elevated oxygen consumption, the high presence of easily oxidizable polyunsaturated fatty acids and the weak antioxidant defenses, the brain is particularly vulnerable to oxidative injury. Uncertainty exists over whether these deficits contribute to the development of NDDs or are solely a consequence of neuronal degeneration. Furthermore, these two pathological hallmarks are linked, and it is known that OS can affect the inflammatory response. In this review, we will overview the last findings about these two pathways in the principal NDDs. Moreover, we will focus more in depth on amyotrophic lateral sclerosis (ALS) to understand how anti-inflammatory and antioxidants drugs have been used for the treatment of this still incurable motor neuron (MN) disease. Finally, we will analyze the principal past and actual clinical trials and the future perspectives in the study of these two pathological mechanisms.
... 17 However, other factors are also likely to affect cognitive functioning in HD, given that the onset and progression of cognitive decline in HD are highly variable, and because cognitive deficits do not appear to map onto brain changes in premanifest HD. [17][18][19] In non-HD populations, depression and cognitive impairment are strongly linked to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and inflammation in the central nervous system (CNS) and periphery. [20][21][22][23][24][25][26][27] Notably, both the HPA axis and the immune system are known to be dysregulated in HD, as indicated by altered salivary and plasma cortisol levels, [28][29][30][31] higher levels of inflammatory cytokines within brain tissue, cerebrospinal fluid, and blood plasma, [32][33][34][35][36] and increased microglial activation within the striatum and cortex. [37][38][39][40] However, current evidence for the relationships of HPA axis functioning with depression and cognition in HD is inconsistent. ...
Objective
Huntington's disease (HD) is an inherited neurodegenerative disease involving progressive motor abnormalities, cognitive decline, and psychiatric disturbances. Depression and cognitive difficulties are among the most impactful symptoms of HD, yet the pathogenesis of these symptoms is not fully understood. HD involves low‐level chronic inflammation and dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, which are linked to depression and cognitive impairment in non‐HD populations. However, previous research on the relationships of these pathologies with depression and cognition in HD is limited and inconsistent.
Methods
Fifty‐three adults with the HD gene expansion (30 premanifest and 23 manifest) completed measures of depression and cognitive functioning. Forty‐eight out of 53 participants provided hair samples for quantification of cortisol, and 34 participants provided blood samples for quantification of peripheral inflammatory cytokines. We examined the associations of four cytokines (interleukin [IL]‐6, IL‐10, IL‐1β, and tumor necrosis factor [TNF]‐α) and cortisol levels with depression and cognitive scores.
Results
In unadjusted models, higher levels of plasma IL‐6, IL‐10, and TNF‐α correlated with higher depression scores, and higher levels of IL‐10 and TNF‐α correlated with poorer cognitive performance. After controlling for age, sex, and body mass index, only the correlations of IL‐10 with depression and cognitive performance remained significant. No correlations were evident with hair cortisol.
Interpretations
Peripheral inflammation is associated with depression symptoms and cognitive impairment in HD. Our findings suggest that interactions between the immune and nervous systems are important in HD, and highlight the potential of chronic inflammation as a therapeutic target in early stages of HD.
Trinucleotide repeat expansion disorders, a diverse group of neurodegenerative diseases, are caused by abnormal expansions within specific genes. These expansions trigger a cascade of cellular damage, including protein aggregation and abnormal RNA binding. A key contributor to this damage is oxidative stress, an imbalance of reactive oxygen species that harms cellular components. This review explores the interplay between oxidative stress and the NRF2 pathway in these disorders. NRF2 acts as the master regulator of the cellular antioxidant response, orchestrating the expression of enzymes that combat oxidative stress. Trinucleotide repeat expansion disorders often exhibit impaired NRF2 signaling, resulting in inadequate responses to excessive ROS production. NRF2 activation has been shown to upregulate antioxidative gene expression, effectively alleviating oxidative stress damage. NRF2 activators, such as omaveloxolone, vatiquinone, curcumin, sulforaphane, dimethyl fumarate, and resveratrol, demonstrate neuroprotective effects by reducing oxidative stress in experimental cell and animal models of these diseases. However, translating these findings into successful clinical applications requires further research. In this article, we review the literature supporting the role of NRF2 in the pathogenesis of these diseases and the potential therapeutics of NRF2 activators.
Introduction:
Huntington's Disease (HD) is a genetic neurodegenerative disease for which there is currently no disease-modifying treatment. One of several underlying mechanisms proposed to be involved in HD pathogenesis is inflammation; there is now accumulating evidence that the immune system may play an integral role in disease pathology and progression. As such, modulation of the immune system could be a potential therapeutic target for HD.
Areas covered:
To date, the number of trials targeting immune aspects of HD has been limited. However, targeting it, may have great advantages over other therapeutic areas, given that many drugs already exist that have actions in this system coupled to the fact that inflammation can be measured both peripherally and, to some extent, centrally using CSF and PET imaging. In this review, we look at evidence that the immune system and the newly emerging area of the microbiome are altered in HD patients, and then present and discuss clinical trials that have targeted different parts of the immune system.
Expert opinion:
We then conclude by discussing how this field might develop going forward, focusing on the role of imaging and other biomarkers to monitor central immune activation and response to novel treatments in HD.
The most common neurodegenerative diseases (NDDs), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are the seventh leading cause of mortality and morbidity in developed countries. Clinical observations of NDD patients are characterized by a progressive loss of neurons in the brain along with memory decline. The common pathological hallmarks of NDDs include oxidative stress, the dysregulation of calcium, protein aggregation, a defective protein clearance system, mitochondrial dysfunction, neuroinflammation, neuronal apoptosis, and damage to cholinergic neurons. Therefore, managing this pathology requires screening drugs with different pathological targets, and suitable drugs for slowing the progression or prevention of NDDs remain to be discovered. Among the pharmacological strategies used to manage NDDs, natural drugs represent a promising therapeutic strategy. This review discusses the neuroprotective potential of seaweed and its bioactive compounds, and safety issues, which may provide several beneficial insights that warrant further investigation.
This book on medical biotechnology offers a wide array of topics and cutting-edge research in the field featuring contributions from multiple authors, each specializing in their respective areas, making it highly valuable to science students and enthusiasts. The book provides a comprehensive coverage on a diverse range of topics, including sequence analysis, network pharmacology, drug discovery, CRISPR-Cas technology, precision medicine, neuroimaging biomarkers, therapeutics for neurodegenerative diseases, molecular pathogenesis of various diseases, plant-derived antioxidants, genetic approaches for disease diagnosis, cancer progression, immunotherapy, cancer biomarker identification, RNA Interference (RNAi), and nanotechnology in drug discovery and delivery, thus giving a holistic understanding of medical biotechnology.
Each chapter delves into the latest research and developments in its respective field, offering readers insights into cutting-edge advancements in medical biotechnology. This up-to-date information will be invaluable to science students and enthusiasts who want to stay at the forefront of the field.
The book adopts an interdisciplinary approach by incorporating elements of biology, genetics, computational techniques, nanotechnology, and more, thus, enables readers to see the interconnectedness of different scientific disciplines and how they contribute to medical biotechnology.
The book emphasizes practical applications, such as drug discovery, disease treatment, gene editing, and targeted drug delivery. This focus on real-world applications would be useful to readers interested in applying biotechnological techniques in the medical field. The book also acknowledges the serious challenges faced in the field of medical biotechnology and offers potential solutions to overcome these challenges to foster innovative thinking.
As a reader, you will gain a comprehensive understanding of various aspects of medical biotechnology, equipping you with knowledge that can contribute to technological breakthroughs, advancements in medicine, and the betterment of human life.
Background
Animal data and postmortem studies suggest a role of oxidative stress in the Huntington's disease (HD), but in vivo human studies have been scarce.
Aim
To assess the presence of oxidative stress in HD patients and its occurrence relative to clinical symptoms.
Methods
Oxidative stress markers were determined in plasma of HD patients (n = 19), asymptomatic HD gene carriers (with > 38 CAG repeats) (n = 11) and their respective sex and agematched healthy controls (n = 47 and n = 22) in a cross-sectional study.
Results
With adjustment for age and sex, HD patients had higher plasma lipid peroxidation (LP) levels (ratio 1.20, 95% CI 1.09 to 1.32, p < 0.001) and lower reduced glutathione (GSH) levels (ratio 0.72, CI 0.55 to 0.94, p = 0.011) than their age and sex-matched controls. Although considerably younger, HD gene carriers did not differ from HD patients regarding LP and GSH levels, and had higher plasma LP (ratio 1.16, CI 1.02 to 1.32, p = 0.016) and lower GSH than their matched controls (ratio 0.73, CI 0.5 to 1.05). They had higher LP (ratio 1.18, CI 1.02 to 1.34, p = 0.019) and lower GSH (ratio 0.75, CI 0.51 to 1.11) than the healthy subjects matched to HD patients.
Conclusions
Oxidative stress is more pronounced in HD patients and asymptomatic HD gene carriers than in healthy subjects. Differences in plasma LP and GSH are in line with the brain findings in animal models of HD. Data suggest that oxidative stress occurs before the onset of the HD symptoms.
Alzheimer's disease (AD) is the most common neurodegenerative disorder that affects the elderly. The increase of life-expectancy is transforming AD into a major health-care problem. AD is characterized by a progressive impairment of memory and other cognitive skills leading to dementia. The major pathogenic factor associated to AD seems to be amyloid-beta peptide (Aβ) oligomers that tend to accumulate extracellularly as amyloid deposits and are associated with reactive microglia and astrocytes as well as with degeneration of neuronal processes. The involvement of microglia and astrocytes in the onset and progress of neurodegenerative process in AD is becoming increasingly recognized, albeit it is commonly accepted that neuroinflammation and oxidative stress can have both detrimental and beneficial influences on the neural tissue. However, little is known about the interplay of microglia, astrocytes and neurons in response to Aβ, especially in the early phases of AD. This review discusses current knowledge about the involvement of neuroinflammation in AD pathogenesis, focusing on phenotypic and functional responses of microglia, astrocytes and neurons in this process. The abnormal production by glia cells of pro-inflammatory cytokines, chemokines and the complement system, as well as reactive oxygen and nitrogen species, can disrupt nerve terminals activity causing dysfunction and loss of synapses, which correlates with memory decline; these are phenomena preceding the neuronal death associated with late stages of AD. Thus, therapeutic strategies directed at controlling the activation of microglia and astrocytes and the excessive production of pro-inflammatory and pro-oxidant factors may be valuable to control neurodegeneration in dementia.
Oxidative damage and inflammation are important features of the brain pathology of Alzheimer's disease (AD). Oxidative damage can be found in membranes (lipid peroxidation), proteins (nitrosylation and other post-translational changes) and nucleic acids. Inflammatory changes include activation of microglia and astrocytes, with increased levels of proinflammatory cytokines. Not all of these changes are specific to AD, and occur in other neurodegenerative disorders. Both oxidative stress and inflammation are potential therapeutic targets in AD, and biomarkers could help to identify and monitor key pathways in patients with AD. This article summarizes progress in developing cerebrospinal fluid biomarkers related to oxidative stress and inflammation, problems and pitfalls related to systemic (blood- or urine-based) biomarkers in this area, and future research directions and applications.
The Unified Huntington's Disease Rating Scale (UHDRS) was developed as a clinical rating scale to assess four domains of clinical performance and capacity in HD: motor function, cognitive function, behavioral abnormalities, and functional capacity. We assessed the internal consistency and the intercorrelations for the four domains and examined changes in ratings over time. We also performed an interrater reliability study of the motor assessment. We found there was a high degree of internal consistency within each of the domains of the UHDRS and that there were significant intercorrelations between the domains of the UHDRS, with the exception of the total behavioral score. There was an excellent degree of interrater reliability for the motor scores. Our limited longitudinal database indicates that the UHDRS may be useful for tracking changes in the clinical features of HD over time. The UHDRS assesses relevant clinical features of HD and appears to be appropriate for repeated administration during clinical studies.
The redox-sensitive transcription factor NF-κB mediates the expression of genes involved in inflammation and cell survival. Thioredoxin reductase-1 (TR1) and its substrate thioredoxin-1 act together to reduce oxidized cysteine residues within the DNA-binding domain of NF-κB and promote maximal DNA-binding activity in vitro. It is not clear, however, if NF-κB is regulated via this mechanism within living cells. The purpose of this study was to determine the mechanism of NF-κB modulation by TR1 in cells stimulated with the inflammatory cytokine tumor necrosis factor-α (TNF). In both control cells and cells depleted of TR1 activity through chemical inhibition or siRNA knockdown, TNF stimulation resulted in degradation of the cytoplasmic NF-κB inhibitor IκB-α and translocation of NF-κB to the nucleus. Similarly, the DNA-binding activity and redox state of NF-κB were unaffected by TR1 depletion. In contrast, NF-κB-mediated gene expression was markedly inhibited in cells lacking TR1 activity, suggesting that the transactivation potential of NF-κB is sensitive to changes in TR1 activity. Consistent with this concept, phosphorylation of the transactivation domain of NF-κB was inhibited in the presence of curcumin. Surprisingly, another TR1 inhibitor, 1-chloro-2,4-dinitrobenzene, had no effect, and siRNA knockdown of TR1 actually increased phosphorylation at this site. These results demonstrate that TR1 activity controls the transactivation potential of NF-κB and that more than one mechanism may mediate this effect.
This study examined global oxidative stress (GOS) and antioxidant system and their correlation with disease stage in 19 patients with HD. The results revealed an increase in oxidative stress biomarkers and a reduction in antioxidant systems in HD patients. The effects were more intense in HD1 than in HD2 patients. Additionally, carbonylated proteins and GOS were correlated with disease stage. These findings suggest that oxidative stress plays an important role in the pathogenesis of HD.
The two major neuropathologic hallmarks of AD are extracellular Amyloid beta plaques and intracellular neurofibrillary tangles. A number of additional pathogenic mechanisms have been described, including inflammation and oxidative damage. Regarding inflammation, several cytokines and chemokines have been detected both immunohistochemically and in Cerebrospinal Fluid from patients. Some of them, including Tumor Necrosis Factor-alpha, Interferon-gamma-inducible Protein-10, Monocyte Chemotactic Protein-1 and Interleukin-8, are increased in AD and in Mild Cognitive Impairment, considered the prodromal stage of AD, suggesting that these modifications occur very early during the development of the disease, possibly explaining the failure of trials with anti-inflammatory agents in patients with severe AD. Further evidence suggests that cytokines and chemokines could play a role in other neurodegenerative disorders. These disorders are considered multifactorial diseases, and genetic factors influence pathological events and contribute to change the disease phenotype from patient to patient. Gene polymorphisms in crucial molecules, including cytokines, chemokines and molecules related to oxidative stress, may act as susceptibility factors, or may operate as regulatory factors, modulating the severity of pathogenic processes.
Alzheimer's disease (AD) is the most common form of dementia. It is characterized by extracellular deposition of a specific protein, beta-amyloid peptide fibrils, and is accompanied by extensive loss of neurons in the brains of affected individuals. Although the pathophysiologic mechanism is not fully established, inflammation appears to be involved. Neuroinflammation has been known to play a critical role in the pathogenesis of chronic neurodegenerative disease in general, and in AD in particular. Numerous studies show the presence of a number of markers of inflammation in the AD brain: elevated inflammatory cytokines and chemokines, and accumulation of activated microglia in the damaged regions. Epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs suppresses the progression of AD and delays its onset, suggesting that there is a close correlation between neuroinflammation and AD pathogenesis. The aim of this review is (1) to assess the association between neuroinflammation and AD through discussion of a variety of experimental and clinical studies on AD and (2) to review treatment strategies designed to treat or prevent AD.
Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by expended CAG repeats in the Huntingtin (Htt) gene. The resultant mutant Htt (mHtt) forms aggregates in neurons and causes neuronal dysfunctions. The major characteristic of HD is the selective loss of neurons in the striatum and cortex, which leads to movement disorders, dementia, and eventual death. Expression of mHtt was also found in non-neuronal cells in the brain, suggesting non-cell-autonomous neurotoxicity in HD. As was documented in many different neurodegenerative disorders, elevated inflammatory responses are also reported in HD. To date, effective treatments for this devastating disease remain to be developed. This review focuses on the importance of glial cells and inflammation in HD pathogenesis. Potential anti-inflammatory interventions for HD are also discussed.