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Drugs Jul 2023Tofersen (Qalsody) is an antisense oligonucleotide being developed by Biogen for the treatment of amyotrophic lateral sclerosis (ALS). On 25 April 2023, tofersen was... (Review)
Review
Tofersen (Qalsody) is an antisense oligonucleotide being developed by Biogen for the treatment of amyotrophic lateral sclerosis (ALS). On 25 April 2023, tofersen was approved in the USA for the treatment of ALS in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This article summarizes the milestones in the development of tofersen leading to this first approval for ALS.
Topics: Adult; Humans; Amyotrophic Lateral Sclerosis; Superoxide Dismutase; Oligonucleotides; Superoxide Dismutase-1; Mutation
PubMed: 37316681
DOI: 10.1007/s40265-023-01904-6 -
Cellular and Molecular Neurobiology Nov 2023Amyotrophic Lateral Sclerosis (ALS) is one of the commonest neurodegenerative diseases of adult-onset, which is characterized by the progressive death of motor neurons... (Review)
Review
Amyotrophic Lateral Sclerosis (ALS) is one of the commonest neurodegenerative diseases of adult-onset, which is characterized by the progressive death of motor neurons in the cerebral cortex, brain stem and spinal cord. The dysfunction and death of motor neurons lead to the progressive muscle weakness, atrophy, fasciculations, spasticity and ultimately the whole paralysis of body. Despite the identification of several genetic mutations associated with the pathogenesis of ALS, including mutations in chromosome 9 open reading frame 72 leading to the abnormal expansion of GGGGCC repeat sequence, TAR DNA-binding protein 43, fused in sarcoma/translocated in liposarcoma, copper/zinc superoxide dismutase 1 (SOD1) and TANK-binding kinase 1, the exact mechanisms underlying the specific degeneration of motor neurons that causes ALS remain incompletely understood. At present, since the transgenic model expressed SOD1 mutants was established, multiple in vitro models of ALS have been developed for studying the pathology, pathophysiology and pathogenesis of ALS as well as searching the effective neurotherapeutics. This review reviewed the details of present established in vitro models used in studying the pathology, pathophysiology and pathogenesis of ALS. Meanwhile, we also discussed the advantages, disadvantages, cost and availability of each models.
Topics: Animals; Humans; Mice; Amyotrophic Lateral Sclerosis; Superoxide Dismutase-1; Disease Models, Animal; Motor Neurons; Mutation; Superoxide Dismutase; Mice, Transgenic
PubMed: 37870685
DOI: 10.1007/s10571-023-01423-8 -
Biomolecules Dec 2023Recent years have seen an increased interest in the role of oxidative stress (OS) in pregnancy. Pregnancy inherently heightens susceptibility to OS, a condition fueled... (Review)
Review
Recent years have seen an increased interest in the role of oxidative stress (OS) in pregnancy. Pregnancy inherently heightens susceptibility to OS, a condition fueled by a systemic inflammatory response that culminates in an elevated presence of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the circulatory system. The amplified OS in pregnancy can trigger a series of detrimental outcomes such as underdevelopment, abnormal placental function, and a host of pregnancy complications, including pre-eclampsia, embryonic resorption, recurrent pregnancy loss, fetal developmental anomalies, intrauterine growth restriction, and, in extreme instances, fetal death. The body's response to mitigate the uncontrolled increase in RNS/ROS levels requires trace elements that take part in non-enzymatic and enzymatic defense processes, namely, copper (Cu), zinc (Zn), manganese (Mn), and selenium (Se). Determination of ROS concentrations poses a challenge due to their short half-lives, prompting the use of marker proteins, including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione (GSH). These markers, indicative of oxidative stress intensity, can offer indirect assessments of pregnancy complications. Given the limitations of conducting experimental studies on pregnant women, animal models serve as valuable substitutes for in-depth research. This review of such models delves into the mechanism of OS in pregnancy and underscores the pivotal role of OS markers in their evaluation.
Topics: Animals; Female; Humans; Pregnancy; Antioxidants; Reactive Oxygen Species; Placenta; Oxidative Stress; Superoxide Dismutase; Catalase; Glutathione; Glutathione Peroxidase; Pregnancy Complications
PubMed: 38136639
DOI: 10.3390/biom13121768 -
The Journal of Investigative Dermatology Oct 2023Atopic dermatitis (AD) is a complex disease characterized by chronic recurring eczema and pruritus. In addition, patients with AD display increased cutaneous and...
Atopic dermatitis (AD) is a complex disease characterized by chronic recurring eczema and pruritus. In addition, patients with AD display increased cutaneous and systemic levels of oxidative damage markers, whose source remains elusive. In this study, we investigated oxidative and mitochondrial stress in AD epidermis. The levels of superoxide dismutase 2 and hydrogen peroxide are augmented in the mitochondria of flaky tail (ft/ft) mouse keratinocytes, which is associated with the inhibition of the glutathione system and catalase. Furthermore, reduced levels of glutathione peroxidase 4 are associated with accumulation of malondialdehyde, 4-hydroxy-2-nonenal, and oxidized phosphatidylcholines in ft/ft epidermis. Cytochrome c is markedly increased in ft/ft epidermis, hence showing mitochondrial stress. Topical application of MitoQ, which is a mitochondrial-targeting antioxidant, to ft/ft mouse skin reduced damage to macromolecules and inflammation and restored epidermal homeostasis. Absence of alteration in the expression of superoxide dismutase 2, catalase, and glutathione peroxidase 4 and limited lipid peroxidation as well as oxidized phosphatidylcholines in the epidermis of Flg mice suggest that FLG deficiency marginally contributes to oxidative stress in ft/ft epidermis. Increased superoxide dismutase 2, lipid peroxidation, and cytochrome c in the epidermis of patients with AD, associated with reduced antioxidant response in primary AD keratinocytes, corroborate mitochondrial dysfunction and lack of cellular adjustment to oxidative stress in AD epidermis.
Topics: Humans; Mice; Animals; Dermatitis, Atopic; Catalase; Hydrogen Peroxide; Antioxidants; Cytochromes c; Phospholipid Hydroperoxide Glutathione Peroxidase; Eczema; Superoxide Dismutase; Oxidative Stress; Mitochondria
PubMed: 37085042
DOI: 10.1016/j.jid.2023.03.1680 -
Brain : a Journal of Neurology Nov 2023The current strategies to mitigate the toxicity of misfolded superoxide dismutase 1 (SOD1) in familial amyotrophic lateral sclerosis via blocking SOD1 expression in the...
The current strategies to mitigate the toxicity of misfolded superoxide dismutase 1 (SOD1) in familial amyotrophic lateral sclerosis via blocking SOD1 expression in the CNS are indiscriminative for misfolded and intact proteins, and as such, entail a risk of depriving CNS cells of their essential antioxidant potential. As an alternative approach to neutralize misfolded and spare unaffected SOD1 species, we developed scFv-SE21 antibody that blocks the β6/β7 loop epitope exposed exclusively in misfolded SOD1. The β6/β7 loop epitope has previously been proposed to initiate amyloid-like aggregation of misfolded SOD1 and mediate its prion-like activity. The adeno-associated virus-mediated expression of scFv-SE21 in the CNS of hSOD1G37R mice rescued spinal motor neurons, reduced the accumulation of misfolded SOD1, decreased gliosis and thus delayed disease onset and extended survival by 90 days. The results provide evidence for the role of the exposed β6/β7 loop epitope in the mechanism of neurotoxic gain-of-function of misfolded SOD1 and open avenues for the development of mechanism-based anti-SOD1 therapeutics, whose selective targeting of misfolded SOD1 species may entail a reduced risk of collateral oxidative damage to the CNS.
Topics: Mice; Animals; Superoxide Dismutase-1; Amyotrophic Lateral Sclerosis; Superoxide Dismutase; Epitopes; Phenotype; Protein Folding; Disease Models, Animal; Mice, Transgenic
PubMed: 37394908
DOI: 10.1093/brain/awad222 -
Biochimica Et Biophysica Acta.... Dec 2023Different SOD1 proteoforms are implicated## in both familial and sporadic cases of Amyotrophic Lateral Sclerosis (ALS), an aging-associated disease that affects motor...
Different SOD1 proteoforms are implicated## in both familial and sporadic cases of Amyotrophic Lateral Sclerosis (ALS), an aging-associated disease that affects motor neurons. SOD1 is crucial to neuronal metabolism and health, regulating the oxidative stress response and the shift between oxidative-fermentative metabolism, which is important for astrocyte-neuron metabolic cooperation. Neurons have a limited capacity to metabolize methylglyoxal (MGO), a potentially toxic side product of glycolysis. MGO is highly reactive and can readily posttranslationally modify proteins, in a reaction known as glycation, impacting their normal biology. Here, we aimed to investigate the effect of glycation on the aggregation and toxicity of human SOD1WT (hSOD1WT). Cells with deficiency in MGO metabolism showed increased levels of hSOD1WT inclusions, displaying also reduced hSOD1WT activity and viability. Strikingly, we also found that the presence of hSOD1WT in stress granules increased upon MGO treatment. The treatment of recombinant hSOD1WT with MGO resulted in the formation of SDS-stable oligomers, specially trimers, and thioflavin-T positive aggregates, which can promote cell toxicity and TDP-43 pathology. Together, our results suggest that glycation may play a still underappreciated role on hSOD1WT and TDP-43 pathologies in sporadic ALS, which could open novel perspectives for therapeutic intervention.
Topics: Humans; Superoxide Dismutase-1; Amyotrophic Lateral Sclerosis; Superoxide Dismutase; Maillard Reaction; Magnesium Oxide; Motor Neurons; DNA-Binding Proteins
PubMed: 37558009
DOI: 10.1016/j.bbadis.2023.166835 -
Journal of Cancer Research and... 2023Tobacco can alter the antioxidative capacity of saliva, and it is the first fluid that is exposed to tobacco. Superoxide dismutase (SOD) is the first line defense...
AIM AND OBJECTIVE
Tobacco can alter the antioxidative capacity of saliva, and it is the first fluid that is exposed to tobacco. Superoxide dismutase (SOD) is the first line defense antioxidant that plays an important protective role against peroxidation of lipids, converts superoxide radicals into hydrogen peroxide, and decreases the toxic effects of free radicals. The aim of this study was to estimate and compare the levels and activity of SOD in the saliva of smokeless tobacco (SLT) consumers and non-consumers.
METHOD AND METHODOLOGY
Total of 64 individuals were divided into two groups (study and control) with 32 patients each. The patients were divided into two groups-Group I: 32 healthy individuals who do not consume SLT (control group) and Group II: 32 individuals who consume SLT for a period more than 1 year (study group). Saliva samples were collected for analysis from both the groups.
RESULTS
The results of this study showed that antioxidant salivary SOD enzyme activity in tobacco chewers is higher in comparison to non-chewers.
CONCLUSION
The present study enlightens us to the possible relationship between SOD enzyme levels, oxidative stress, and tobacco habit. In initial or early stages, antioxidant levels increase, thereby showing an evidence of endogenous activity. But as the duration of the habit increases, there is decrease in the body's defense mechanism, and the level of SOD starts to fall resulting in oral lesions. This will help in establishing the reliability of SOD in saliva as a potential biomarker of oxidative stress in tobacco chewers. Further, it may also help in establishing the role of oxidative stress in the pathogenesis of premalignant lesions and oral cancer.
Topics: Humans; Tobacco, Smokeless; Antioxidants; Reproducibility of Results; Superoxide Dismutase; Saliva
PubMed: 37787309
DOI: 10.4103/jcrt.jcrt_1057_21 -
PeerJ 2023Oxidative stress refers to the imbalance between oxidants and antioxidants in organisms and often induces hepatic inflammation. Supplementing exogenous superoxide...
BACKGROUND
Oxidative stress refers to the imbalance between oxidants and antioxidants in organisms and often induces hepatic inflammation. Supplementing exogenous superoxide dismutase is an effective way to alleviate oxidative stress; however, the effects and mechanisms by which superoxide dismutase alleviates hepatic inflammation remain unclear.
METHODS
This study established a Kunming mouse model to verify and investigate the oxidative stress and hepatic inflammation-alleviating effects of the superoxide dismutase oral supplement that was prepared by our research group in a previous study.
RESULTS
The superoxide dismutase product significantly restored the body weight and liver alanine transaminase, aspartate aminotransferase, superoxide dismutase, catalase, glutathione, and glutathione peroxidase levels of oxidative stress induced mice. Moreover, exogenous superoxide dismutase significantly inhibited interleukin 1 and interleukin 6 mRNA expression in the livers of mice with hepatic inflammation. Transcriptomic analysis indicated that superoxide dismutase had a significant inhibitory effect on expression, alleviating oxidative stress damage, and mediating liver cell apoptosis by regulating the expression of , , and .
CONCLUSION
Our research verified the oxidative stress remediation effects of superoxide dismutase and its therapeutic role against hepatic inflammation. This study can lay a foundation for investigating the mechanism by which superoxide dismutase alleviates hepatic disease.
Topics: Mice; Animals; Transcriptome; Liver; Oxidative Stress; Superoxide Dismutase; Inflammation
PubMed: 37583908
DOI: 10.7717/peerj.15829 -
Environmental Science and Pollution... Oct 2023As an important raw material and intermediate product of the petrochemical industry, fluoranthene (Fla) can be emitted with industrial activities and has become a...
As an important raw material and intermediate product of the petrochemical industry, fluoranthene (Fla) can be emitted with industrial activities and has become a typical polycyclic aromatic hydrocarbon enriched in the Chinese topsoil layer, posing a significant threat to sensitive soil biota. Here, multispectral tools and molecular simulation techniques were integrated to elucidate the molecular mechanism of Fla interaction with key antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) at the molecular level. Meanwhile, we further revealed the cellular responses of SOD and CAT and the associated redox states in earthworm (Eisenia fetida) coelomocytes based on the molecular-level results. Our results showed that the exposure to Fla affected the backbone structure of SOD and CAT molecules and resulted in the formation of Fla-SOD polymers as well as an overall reduction in the size of the Fla-CAT binding system. Fla altered the microenvironment around Tyr residues in the SOD molecule and quenched the endogenous fluorescence of Tyr within the CAT molecule. In earthworm coelomocytes, Fla at 60 and 80 μM resulted in a significant elevation of CAT and SOD activities by 114% (p = 0.032) and 6.09% (p = 0.013), respectively. Molecular simulation results suggested that Fla-induced changes in the structure and conformation of SOD and CAT may be the key reason for their altered activities. The related redox homeostasis detection in earthworm coelomocytes indicated that high concentrations (80 μM) of Fla led to a significant accumulation of intracellular ROS (p = 0.018) and resulted in the development of lipid peroxidation. Our work contributes to an in-depth understanding of the biological effect of Fla to sensitive soil fauna, thus providing new ideas for Fla ecological risk prevention and control.
Topics: Animals; Catalase; Antioxidants; Superoxide Dismutase; Soil; Oligochaeta; Soil Pollutants; Oxidative Stress; Malondialdehyde
PubMed: 37698795
DOI: 10.1007/s11356-023-29703-2 -
Fish & Shellfish Immunology Jun 2024Copper/zinc superoxide dismutase (Cu/Zn-SOD) can effectively eliminate reactive oxygen species (ROS),avoid damage from O to the body, and maintain O balance. In this...
Copper/zinc superoxide dismutase (Cu/Zn-SOD) can effectively eliminate reactive oxygen species (ROS),avoid damage from O to the body, and maintain O balance. In this study, multi-step high-performance liquid chromatography (HPLC), combined with Mass Spectrometry (MS), was used to isolate and identify Cu/Zn-SOD from the serum of Pinctada fucata martensii (P. f. martensii) and was designated as PmECSOD. With a length of 1864 bp and an open reading frame (ORF) of 1422 bp, the cDNA encodes a 473 amino acid protein. The PmECSOD transcript was detected in multiple tissues by quantitative real-time PCR (qRT-PCR), with its highest expression level being in the gills. Additionally, the temporal expression of PmECSOD mRNA in the hemolymph was highest at 48 h after in vivo stimulation with Escherichia coli and Micrococcus luteus. The results from this study provide a valuable base for further exploration of molluscan innate immunity and immune response.
Topics: Animals; Pinctada; Superoxide Dismutase; Amino Acid Sequence; Immunity, Innate; Phylogeny; Gene Expression Profiling; Base Sequence; Sequence Alignment; Escherichia coli; DNA, Complementary; Micrococcus luteus; Gene Expression Regulation; RNA, Messenger
PubMed: 38701990
DOI: 10.1016/j.fsi.2024.109599