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Archives of Biochemistry and Biophysics Jan 2021During cellular respiration, radicals, such as superoxide, are produced, and in a large concentration, they may cause cell damage. To combat this threat, the cell... (Review)
Review
During cellular respiration, radicals, such as superoxide, are produced, and in a large concentration, they may cause cell damage. To combat this threat, the cell employs the enzyme Cu/Zn Superoxide Dismutase (SOD1), which converts the radical superoxide into molecular oxygen and hydrogen peroxide, through redox reactions. Although this is its main function, recent studies have shown that the SOD1 has other functions that deviates from its original one including activation of nuclear gene transcription or as an RNA binding protein. This comprehensive review looks at the most important aspects of human SOD1 (hSOD1), including the structure, properties, and characteristics as well as transcriptional and post-translational modifications (PTM) that the enzyme can receive and their effects, and its many functions. We also discuss the strategies currently used to analyze it to better understand its participation in diseases linked to hSOD1 including Amyotrophic Lateral Sclerosis (ALS), cancer, and Parkinson.
Topics: Amino Acid Sequence; Animals; Antioxidants; Health; Humans; Superoxide Dismutase-1
PubMed: 33259795
DOI: 10.1016/j.abb.2020.108701 -
Cell Metabolism May 2021Poor maternal diet increases the risk of obesity and type 2 diabetes in offspring, adding to the ever-increasing prevalence of these diseases. In contrast, we find that...
Poor maternal diet increases the risk of obesity and type 2 diabetes in offspring, adding to the ever-increasing prevalence of these diseases. In contrast, we find that maternal exercise improves the metabolic health of offspring, and here, we demonstrate that this occurs through a vitamin D receptor-mediated increase in placental superoxide dismutase 3 (SOD3) expression and secretion. SOD3 activates an AMPK/TET signaling axis in fetal offspring liver, resulting in DNA demethylation at the promoters of glucose metabolic genes, enhancing liver function, and improving glucose tolerance. In humans, SOD3 is upregulated in serum and placenta from physically active pregnant women. The discovery of maternal exercise-induced cross talk between placenta-derived SOD3 and offspring liver provides a central mechanism for improved offspring metabolic health. These findings may lead to novel therapeutic approaches to limit the transmission of metabolic disease to the next generation.
Topics: AMP-Activated Protein Kinases; Animals; Cells, Cultured; DNA Demethylation; Diet, High-Fat; Exercise; Female; Hepatocytes; Humans; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mixed Function Oxygenases; Placenta; Pregnancy; Proto-Oncogene Proteins; Receptors, Calcitriol; Signal Transduction; Superoxide Dismutase
PubMed: 33770509
DOI: 10.1016/j.cmet.2021.03.004 -
Oxidative Medicine and Cellular... 2019The standard treatment for cancer is generally based on using cytotoxic drugs, radiotherapy, chemotherapy, and surgery. However, the use of traditional treatments has... (Review)
Review
The standard treatment for cancer is generally based on using cytotoxic drugs, radiotherapy, chemotherapy, and surgery. However, the use of traditional treatments has received attention in recent years. The aim of the present work was to provide an overview of medicinal plants effective on colon cancer with special emphasis on bioactive components and underlying mechanisms of action. Various literature databases, including Web of Science, PubMed, and Scopus, were used and English language articles were considered. Based on literature search, 172 experimental studies and 71 clinical cases on 190 plants were included. The results indicate that grape, soybean, green tea, garlic, olive, and pomegranate are the most effective plants against colon cancer. In these studies, fruits, seeds, leaves, and plant roots were used for and models. Various anticolon cancer mechanisms of these medicinal plants include induction of superoxide dismutase, reduction of DNA oxidation, induction of apoptosis by inducing a cell cycle arrest in S phase, reducing the expression of PI3K, P-Akt protein, and MMP as well; reduction of antiapoptotic Bcl-2 and Bcl-xL proteins, and decrease of proliferating cell nuclear antigen (PCNA), cyclin A, cyclin D1, cyclin B1 and cyclin E. Plant compounds also increase both the expression of the cell cycle inhibitors p53, p21, and p27, and the BAD, Bax, caspase 3, caspase 7, caspase 8, and caspase 9 proteins levels. In fact, purification of herbal compounds and demonstration of their efficacy in appropriate models, as well as clinical studies, may lead to alternative and effective ways of controlling and treating colon cancer.
Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Colonic Neoplasms; Humans; Oxidative Stress; Phytotherapy; Plants, Medicinal; Signal Transduction; Superoxide Dismutase
PubMed: 32377288
DOI: 10.1155/2019/2075614 -
Neurotherapeutics : the Journal of the... Jul 2022Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying... (Randomized Controlled Trial)
Randomized Controlled Trial
Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS.
Topics: Humans; Superoxide Dismutase-1; Amyotrophic Lateral Sclerosis; Superoxide Dismutase; Neurodegenerative Diseases; Oligonucleotides, Antisense; Biomarkers; RNA, Messenger; Mutation
PubMed: 35585374
DOI: 10.1007/s13311-022-01237-4 -
Cell Death and Differentiation Jun 2022Amyotrophic lateral sclerosis (ALS) is caused by selective degeneration of motor neurons in the brain and spinal cord; however, the primary cell death pathway(s)...
Amyotrophic lateral sclerosis (ALS) is caused by selective degeneration of motor neurons in the brain and spinal cord; however, the primary cell death pathway(s) mediating motor neuron demise remain elusive. We recently established that necroptosis, an inflammatory form of regulated cell death, was dispensable for motor neuron death in a mouse model of ALS, implicating other forms of cell death. Here, we confirm these findings in ALS patients, showing a lack of expression of key necroptotic effector proteins in spinal cords. Rather, we uncover evidence for ferroptosis, a recently discovered iron-dependent form of regulated cell death, in ALS. Depletion of glutathione peroxidase 4 (GPX4), an anti-oxidant enzyme and central repressor of ferroptosis, occurred in post-mortem spinal cords of both sporadic and familial ALS patients. GPX4 depletion was also an early and universal feature of spinal cords and brains of transgenic mutant superoxide dismutase 1 (SOD1), TDP-43 and C9orf72 mouse models of ALS. GPX4 depletion and ferroptosis were linked to impaired NRF2 signalling and dysregulation of glutathione synthesis and iron-binding proteins. Novel BAC transgenic mice overexpressing human GPX4 exhibited high GPX4 expression localised to spinal motor neurons. Human GPX4 overexpression in SOD1 mice significantly delayed disease onset, improved locomotor function and prolonged lifespan, which was attributed to attenuated lipid peroxidation and motor neuron preservation. Our study discovers a new role for ferroptosis in mediating motor neuron death in ALS, supporting the use of anti-ferroptotic therapeutic strategies, such as GPX4 pathway induction and upregulation, for ALS treatment.
Topics: Amyotrophic Lateral Sclerosis; Animals; Cell Death; Disease Models, Animal; Ferroptosis; Humans; Mice; Mice, Transgenic; Motor Neurons; Spinal Cord; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 34857917
DOI: 10.1038/s41418-021-00910-z -
Theranostics 2023Myocardial injury triggers intense oxidative stress, inflammatory response, and cytokine release, which are essential for myocardial repair and remodeling. Excess...
Myocardial injury triggers intense oxidative stress, inflammatory response, and cytokine release, which are essential for myocardial repair and remodeling. Excess reactive oxygen species (ROS) scavenging and inflammation elimination have long been considered to reverse myocardial injuries. However, the efficacy of traditional treatments (antioxidant, anti-inflammatory drugs and natural enzymes) is still poor due to their intrinsic defects such as unfavorable pharmacokinetics and bioavailability, low biological stability, and potential side effects. Nanozyme represents a candidate to effectively modulate redox homeostasis for the treatment of ROS related inflammation diseases. We develop an integrated bimetallic nanozyme derived from metal-organic framework (MOF) to eliminate ROS and alleviate inflammation. The bimetallic nanozyme (Cu-TCPP-Mn) is synthesized by embedding manganese and copper into the porphyrin followed by sonication, which could mimic the cascade activities of superoxide dismutase (SOD) and catalase (CAT) to transform oxygen radicals to hydrogen peroxide, followed by the catalysis of hydrogen peroxide into oxygen and water. Enzyme kinetic analysis and oxygen-production velocities analysis were performed to evaluate the enzymatic activities of Cu-TCPP-Mn. We also established myocardial infarction (MI) and myocardial ischemia-reperfusion (I/R) injury animal models to verify the ROS scavenging and anti-inflammation effect of Cu-TCPP-Mn. As demonstrated by kinetic analysis and oxygen-production velocities analysis, Cu-TCPP-Mn nanozyme possesses good performance in both SOD- and CAT-like activities to achieve synergistic ROS scavenging effect and provide protection for myocardial injury. In both MI and I/R injury animal models, this bimetallic nanozyme represents a promising and reliable technology to protect the heart tissue from oxidative stress and inflammation-induced injury, and enables the myocardial function to recover from otherwise severe damage. This research provides a facile and applicable method to develop a bimetallic MOF nanozyme, which represents a promising alternative to the treatment of myocardial injuries.
Topics: Animals; Reactive Oxygen Species; Metal-Organic Frameworks; Hydrogen Peroxide; Kinetics; Superoxide Dismutase; Oxygen; Myocardial Reperfusion Injury; Catalysis
PubMed: 37215581
DOI: 10.7150/thno.83543 -
Theranostics 2021Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by death of motor neurons in the brain and spinal cord. However, so far,...
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by death of motor neurons in the brain and spinal cord. However, so far, there is no effective treatment for ALS. In this study, R13, a prodrug of 7,8-dihydroxyflavone, selectively activating tyrosine kinase receptor B (TrkB) signaling pathway, was administered prophylactically to 40-day old SOD1 mice for 90 days. The motor performance was investigated by rotarod test, climbing-pole test, grip strength test and hanging endurance test. Afterwards, the spinal cord and medulla oblongata of 130-day old mice were harvested, and the proteomics revealed the effect of R13 on mouse protein expression profile. Astrocytes and microglial proliferation were assessed by immunohistochemical analysis. The number of motor neurons in the spinal cord is determined by Nissl staining. The effect of R13 on gastrocnemius morphology was assessed by HE staining. The effect of R13 on the survival rate was accomplished with worms stably expressing G93A SOD1. Behavioral tests showed that R13 significantly attenuated abnormal motor performance of SOD1 mice. R13 reduced the advance of spinal motor neuron pathology and gastrocnemius muscle atrophy. The proliferation of microglia and astrocytes was reduced by R13 treatment. Mitochondriomics analysis revealed that R13 modified the mitochondrial protein expression profiles in the medulla oblongata and spinal cord of SOD1 mice, particularly promoting the expression of proteins related to oxidative phosphorylation (OXPHOS). Further study found that R13 activated AMPK/PGC-1α/Nrf1/Tfam, promoted mitochondrial biogenesis and ameliorated mitochondrial dysfunction. Lastly, R13 prolonged the survival rate of worms stably expressing G93A SOD1. These findings suggest oral R13 treatment slowed the advance of motor system disease in a reliable animal model of ALS, supporting that R13 might be useful for treating ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Central Nervous System; Flavones; Humans; Mice; Mice, Transgenic; Mitochondria; Motor Activity; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 34158851
DOI: 10.7150/thno.56070 -
International Journal of Molecular... Dec 2022Redox equilibria and the modulation of redox signalling play crucial roles in physiological processes. Overproduction of reactive oxygen species (ROS) disrupts the... (Review)
Review
Redox equilibria and the modulation of redox signalling play crucial roles in physiological processes. Overproduction of reactive oxygen species (ROS) disrupts the body's antioxidant defence, compromising redox homeostasis and increasing oxidative stress, leading to the development of several diseases. Manganese superoxide dismutase (MnSOD) is a principal antioxidant enzyme that protects cells from oxidative damage by converting superoxide anion radicals to hydrogen peroxide and oxygen in mitochondria. Systematic studies have demonstrated that MnSOD plays an indispensable role in multiple diseases. This review focuses on preclinical evidence that describes the mechanisms of MnSOD in diseases accompanied with an imbalanced redox status, including fibrotic diseases, inflammation, diabetes, vascular diseases, neurodegenerative diseases, and cancer. The potential therapeutic effects of MnSOD activators and MnSOD mimetics are also discussed. Targeting this specific superoxide anion radical scavenger may be a clinically beneficial strategy, and understanding the therapeutic role of MnSOD may provide a positive insight into preventing and treating related diseases.
Topics: Humans; Superoxides; Antioxidants; Superoxide Dismutase; Reactive Oxygen Species; Oxidation-Reduction; Oxidative Stress
PubMed: 36555531
DOI: 10.3390/ijms232415893 -
Oxidative Medicine and Cellular... 2022Tardive dyskinesia (TD) is a prevalent movement disorder that significantly impacts patients with schizophrenia (SCZ) due to extended exposure to antipsychotics (AP).... (Review)
Review
Tardive dyskinesia (TD) is a prevalent movement disorder that significantly impacts patients with schizophrenia (SCZ) due to extended exposure to antipsychotics (AP). Several genetic polymorphisms, including superoxide dismutase (SOD) and DRD3 9ser, have been suggested as explanations why some patients suffer from TD. . A PubMed search was used to search relevant articles using the following keywords: "Tardive Dyskinesia and Superoxide Dismutase". Fifty-eight articles were retrieved. Among them, 16 were included in this review. . Overall, 58 studies were retrieved from PubMed. Most studies investigated the association between TD and the SOD-related polymorphisms. In addition, previous studies reported an association between TD occurrence and other genetic polymorphisms. . This study found that the risk of TD is associated with altered SOD levels and several genetic polymorphisms, including VAL 66 Met and DRD3 9ser.
Topics: Humans; Tardive Dyskinesia; Antipsychotic Agents; Polymorphism, Genetic; Schizophrenia; Superoxide Dismutase
PubMed: 36338339
DOI: 10.1155/2022/5748924 -
Open Biology Jun 2021Oxidative stress, the imbalance of the antioxidant system, results in an accumulation of neurotoxic proteins in Alzheimer's disease (AD). The antioxidant system is... (Review)
Review
Oxidative stress, the imbalance of the antioxidant system, results in an accumulation of neurotoxic proteins in Alzheimer's disease (AD). The antioxidant system is composed of exogenous and endogenous antioxidants to maintain homeostasis. Superoxide dismutase (SOD) is an endogenous enzymatic antioxidant that converts superoxide ions to hydrogen peroxide in cells. SOD supplementation in mice prevented cognitive decline in stress-induced cells by reducing lipid peroxidation and maintaining neurogenesis in the hippocampus. Furthermore, SOD decreased expression of BACE1 while reducing plaque burden in the brain. Additionally, Astaxanthin (AST), a potent exogenous carotenoid, scavenges superoxide anion radicals. Mice treated with AST showed slower memory decline and decreased depositions of amyloid-beta (A) and tau protein. Currently, the neuroprotective potential of these supplements has only been examined separately in studies. However, a single antioxidant cannot sufficiently resist oxidative damage to the brain, therefore, a combinatory approach is proposed as a relevant therapy for ameliorating pathological changes in AD.
Topics: Alzheimer Disease; Animals; Antioxidants; Biomarkers; Clinical Studies as Topic; Dietary Supplements; Disease Management; Disease Susceptibility; Drug Evaluation, Preclinical; Humans; Neurons; Oxidative Stress; Reactive Oxygen Species; Superoxide Dismutase; Treatment Outcome; Xanthophylls
PubMed: 34186009
DOI: 10.1098/rsob.210013