Oxidative Stress in Mucopolysaccharidoses: Pharmacological Implications.
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ABSTRACT:
SUBMITTER: Pierzynowska K
PROVIDER: S-EPMC8468662 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. It this sense, it has been proposed that the use of small molecules, called pharmacological chaperones (PCs), can restore the folding, trafficking, and biological activity of mutated enzymes. PCs have the advantages of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity than enzyme replacement therapy. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.
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Project description:Myocardial ischemia or reperfusion increases the generation of reactive oxygen species (ROS) from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. ROS can be removed by eight endogenous antioxidant and redox systems, many components of which are expressed under the influence of the activated Nrf2 transcription factor. Transcriptomic profiling, sequencing of Nrf2-bound DNA, and Nrf2 gene knockout studies have revealed the power of Nrf2 beyond the antioxidant and detoxification response, from tissue recovery, repair, and remodeling, mitochondrial turnover, and metabolic reprogramming to the suppression of proinflammatory cytokines. Multifaceted regulatory mechanisms for Nrf2 protein levels or activity have been mapped to its functional domains, Nrf2-ECH homology (Neh)1-7. Oxidative stress activates Nrf2 via nuclear translocation, de novo protein translation, and increased protein stability due to removal of the Kelch-like ECH-associated protein 1 (Keap1) checkpoint, or the inactivation of β-transducin repeat-containing protein (β-TrCP), or Hmg-CoA reductase degradation protein 1 (Hrd1). The promise of small-molecule Nrf2 inducers from natural products or derivatives is discussed here. Experimental evidence is presented to support Nrf2 as a lead target for drug development to further improve the treatment outcome for myocardial infarction (MI).
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Project description: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, a wealth of evidence indicates that an excessive reactive oxygen species (ROS) production associated with an inefficient antioxidant defense represents an important pathological feature in ALS. Substantial evidence indicates that oxidative stress (OS) is implicated in the loss of MNs and in 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. Using specific queries for literature search on PubMed, we review here the role of OS-related mechanisms in ALS, including the involvement of altered mitochondrial function with repercussions in neurodegeneration. We also describe antioxidant compounds that have been mostly tested in preclinical and clinical trials of ALS, also describing their respective mechanisms of action. While the description of OS mechanism in the different mutations identified in ALS has as principal objective to clarify the contribution of OS in ALS, the description of positive and negative outcomes for each antioxidant is aimed at paving the way for novel opportunities for intervention. In conclusion, although antioxidant strategies represent a very promising approach to slow the progression of the disease, it is of utmost need to invest on the characterization of OS profiles representative of each subtype of patient, in order to develop personalized therapies, allowing to understand the characteristics of antioxidants that have beneficial effects on different subtypes of patients.
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Project description:Oxidative stress is induced once the balance of generation and neutralization of reactive oxygen species (ROS) is broken in the cell, and it plays crucial roles in a variety of natural and diseased processes. Infections of Flaviviridae viruses trigger oxidative stress, which affects both the cellular metabolism and the life cycle of the viruses. Oxidative stress associated with specific viral proteins, experimental culture systems, and patient infections, as well as its correlations with the viral pathogenesis attracts much research attention. In this review, we primarily focus on hepatitis C virus (HCV), dengue virus (DENV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and tick-borne encephalitis virus (TBEV) as representatives of Flaviviridae viruses and we summarize the mechanisms involved in the relevance of oxidative stress for virus-associated pathogenesis. We discuss the current understanding of the pathogenic mechanisms of oxidative stress induced by Flaviviridae viruses and highlight the relevance of autophagy and DNA damage in the life cycle of viruses. Understanding the crosstalk between viral infection and oxidative stress-induced molecular events may offer new avenues for antiviral therapeutics.
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Project description:IntroductionPathogenesis of Chagas disease (CD) caused by the protozoan parasite Trypanosoma cruzi (T. cruzi) involves chronic oxidative and inflammatory stress. In this review, we discuss the research efforts in therapeutic vaccine development to date and the potential challenges imposed by oxidative stress in achieving an efficient therapeutic vaccine against CD.Areas coveredThis review covers the immune and nonimmune mechanisms of reactive oxygen species production and immune response patterns during T. cruzi infection in CD. A discussion on immunotherapy development efforts, the efficacy of antigen-based immune therapies against T. cruzi, and the role of antioxidants as adjuvants is discussed to provide promising insights to developing future treatment strategies against CD.Expert opinionAdministration of therapeutic vaccines can be a good option to confront persistent parasitemia in CD by achieving a rapid, short-lived stimulation of type 1 cell-mediated immunity. At the same time, adjunct therapies could play a critical role in the preservation of mitochondrial metabolism and cardiac muscle contractility in CD. We propose combined therapy with antigen-based vaccine and small molecules to control the pathological oxidative insult would be effective in the conservation of cardiac structure and function in CD.
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Project description:Cardiovascular diseases (CVDs) are a group of disorders that affect the heart and blood vessels. Due to their multifactorial nature and wide variation, CVDs are the leading cause of death worldwide. Understanding the molecular alterations leading to the development of heart and vessel pathologies is crucial for successfully treating and preventing CVDs. One of the causative factors of CVD etiology and progression is acute oxidative stress, a toxic condition characterized by elevated intracellular levels of reactive oxygen species (ROS). Left unabated, ROS can damage virtually any cellular component and affect essential biological processes, including protein synthesis. Defective or insufficient protein translation results in production of faulty protein products and disturbances of protein homeostasis, thus promoting pathologies. The relationships between translational dysregulation, ROS, and cardiovascular disorders will be examined in this review.
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Project description:Zinc is an essential nutrient for human health and has anti-oxidative stress and anti-inflammatory functions. The association between zinc deficiency and the development of cardiovascular diseases (CVDs) has been supported by numerous studies. Supplementing zinc can reduce the risk of atherosclerosis and protect against myocardial infarction and ischemia/reperfusion injury. In this review we summarize the evidence in the literature, to consolidate the current knowledge on the dysregulation of zinc homeostasis in CVDs, and to explore the significant roles of the zinc homeostasis-regulatory proteins in cardiac physiology and pathophysiology. Moreover, this review also deliberates on the potential diagnostic and prognostic implications of zinc/zinc homeostasis-associated molecules (ZIP, ZnT, and MTs) in CVDs.
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Project description:The human thymus is a primary lymphoepithelial organ which supports the production of self-tolerant T cells with competent and regulatory functions. Paradoxically, despite the crucial role that it exerts in T cell-mediated immunity and prevention of systemic autoimmunity, the thymus is the first organ of the body that exhibits age-associated degeneration/regression, termed "thymic involution." A hallmark of this early phenomenon is a progressive decline of thymic mass as well as a decreased output of naïve T cells, thus resulting in impaired immune response. Importantly, thymic involution has been recently linked with cellular senescence which is a stress response induced by various stimuli. Accumulation of senescent cells in tissues has been implicated in aging and a plethora of age-related diseases. In addition, several lines of evidence indicate that oxidative stress, a well-established trigger of senescence, is also involved in thymic involution, thus highlighting a possible interplay between oxidative stress, senescence, and thymic involution.
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