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Journal of Biomolecular Structure &... Sep 2022Superoxide dismutases (SODs) are regarded as important antioxidants for protecting cells against damage arising from oxidative stress. Much research is focused on...
Superoxide dismutases (SODs) are regarded as important antioxidants for protecting cells against damage arising from oxidative stress. Much research is focused on finding new chemicals with an ability to boost human SOD activity. In the research described herein a structure-based approach was used to identify new human Cu-Zn superoxide dismutase (SOD1) modulators based on previously reported plasmodium falciparum iron SOD inhibitors using induced fit docking and molecular dynamic (MD) protocols. The compound with the highest docking binding energy was selected for further structure simplification followed by structural similarity and MD in order to find a new activator/inhibitor scaffold of the SOD1 enzyme. According to the docking survey of the mentioned series, 1,4-bis(3-(1,4,8-trichloro-10Hphenothiazin-10-yl) propyl) piperazine (DS88) was the top scoring compound interacting with the SOD1 active site channel. Following structure simplification and similarity search, the most promising scaffold which is closely related to the phenothiazine antipsychotic class, was identified. Compared with the normal blood SOD1 activity, the percent of O production increased with trifluoperazine, while it decreased with the chlorpromazine. The molecular dynamic investigation shows that trifluoperazine exerts its SOD1 activating effect by stabilizing electrostatic loop while chlorpromazine employs SOD1 inhibition activity through repositioning of the electrostatic loop and increasing its distance from the catalytic metal site which diminished substrate specificity and catalytic activity of the SOD1 enzyme. The results identified the preferred region, orientation, and types of interaction for each activator or inhibitor compound.
Topics: Catalytic Domain; Chlorpromazine; Humans; Superoxide Dismutase; Superoxide Dismutase-1; Trifluoperazine
PubMed: 33663349
DOI: 10.1080/07391102.2021.1893819 -
Proceedings of the National Academy of... Aug 2023Amyotrophic lateral sclerosis (ALS) is a fatal disease affecting upper and lower motor neurons. Microglia directly interact with motor neurons and participate in the...
Amyotrophic lateral sclerosis (ALS) is a fatal disease affecting upper and lower motor neurons. Microglia directly interact with motor neurons and participate in the progression of ALS. Single-cell mass cytometry (CyTOF) analysis revealed prominent expression of α5 integrin in microglia and macrophages in a superoxide dismutase-1 G93A mouse model of ALS (SOD1). In postmortem tissues from ALS patients with various clinical ALS phenotypes and disease duration, α5 integrin is prominent in motor pathways of the central and peripheral nervous system and in perivascular zones associated with the blood-brain barrier. In SOD1 mice, administration of a monoclonal antibody against α5 integrin increased survival compared to an isotype control and improved motor function on behavioral testing. Together, these findings in mice and in humans suggest that α5 integrin is a potential therapeutic target in ALS.
Topics: Mice; Humans; Animals; Amyotrophic Lateral Sclerosis; Superoxide Dismutase-1; Integrin alpha5; Motor Cortex; Mice, Transgenic; Superoxide Dismutase; Macrophages; Disease Models, Animal
PubMed: 37523555
DOI: 10.1073/pnas.2306731120 -
Molecules (Basel, Switzerland) Jan 2022CD44, a cell-adhesion molecule has a dual role in tumor growth and progression; it acts as a tumor suppressor as well as a tumor promoter. In our previous work, we... (Review)
Review
CD44, a cell-adhesion molecule has a dual role in tumor growth and progression; it acts as a tumor suppressor as well as a tumor promoter. In our previous work, we developed a tetracycline-off regulated expression of CD44's gene in the breast cancer (BC) cell line MCF-7 (B5 clone). Using cDNA oligo gene expression microarray, we identified (superoxide dismutase 2) as a potential CD44-downstream transcriptional target involved in BC metastasis. gene belongs to the family of iron/manganese superoxide dismutase family and encodes a mitochondrial protein. plays a role in cell proliferation and cell invasion via activation of different signaling pathways regulating angiogenic abilities of breast tumor cells. This review will focus on the findings supporting the underlying mechanisms associated with the oncogenic potential of in the onset and progression of cancer, especially in BC and the potential clinical relevance of its various inhibitors.
Topics: Animals; Breast Neoplasms; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors; Neoplasm Invasiveness; Superoxide Dismutase; Transcriptional Activation
PubMed: 35164076
DOI: 10.3390/molecules27030811 -
Journal of Molecular Medicine (Berlin,... Jan 2020Free radicals and other oxidants are critical determinants of the cellular signaling pathways involved in the pathogenesis of several human diseases including... (Review)
Review
Free radicals and other oxidants are critical determinants of the cellular signaling pathways involved in the pathogenesis of several human diseases including inflammatory diseases. Numerous studies have demonstrated the protective effects of antioxidant enzymes during inflammation by elimination of free radicals. The superoxide dismutase (SOD), an antioxidant enzyme, plays an essential pathogenic role in the inflammatory diseases by not only catalyzing the conversion of the superoxide to hydrogen peroxide and oxygen but also affecting immune responses. There are three distinct isoforms of SOD, which distribute in different cellular compartments such as cytosolic SOD1, mitochondrial SOD2, and extracellular SOD3. Many studies have investigated the anti-oxidative effects of SOD3 in the inflammatory diseases. Herein, in this review, we focus on the current understanding of SOD3 as a therapeutic protein in inflammatory diseases such as skin, autoimmune, lung, and cardiovascular inflammatory diseases. Moreover, the mechanism(s) by which SOD3 modulates immune responses and signal initiation in the pathogenesis of the diseases will be further discussed.
Topics: Animals; Antioxidants; Arthritis; Diabetes Complications; Humans; Inflammation; Isoenzymes; Lung Diseases; Oxidative Stress; Phylogeny; Reactive Oxygen Species; Skin Diseases; Superoxide Dismutase
PubMed: 31724066
DOI: 10.1007/s00109-019-01845-2 -
Protein and Peptide Letters 2023Designing effective diagnostics, biotherapeutics, and biocatalysts are a few interesting potential outcomes of protein engineering. Despite being just a few decades old,... (Review)
Review
Designing effective diagnostics, biotherapeutics, and biocatalysts are a few interesting potential outcomes of protein engineering. Despite being just a few decades old, the discipline of de novo protein designing has provided a foundation for remarkable outcomes in the pharmaceuticals and enzyme industries. The technologies that will have the biggest impact on current protein therapeutics include engineered natural protein variants, Fc fusion protein, and antibody engineering. Furthermore, designing protein scaffolds can be used in developing next-generation antibodies and in transplanting active sites in the enzyme. The article highlights the important tools and techniques used in protein engineering and their application in the engineering of enzymes and therapeutic proteins. This review further sheds light on the engineering of superoxide dismutase, an enzyme responsible for catalyzing the conversion of superoxide radicals to oxygen and hydrogen peroxide by catalyzing a redox reaction at the metal center while concurrently oxidizing and reducing superoxide free radicals.
Topics: Proteins; Protein Engineering; Superoxide Dismutase; Antibodies; Oxidation-Reduction
PubMed: 37211849
DOI: 10.2174/0929866530666230519122612 -
Analytical Chemistry Aug 20221,4-Dithiothreitol (DTT), a highly water-soluble and well-known reducing agent for preservation and regeneration of sulfhydryl groups in biomedical applications, has...
1,4-Dithiothreitol (DTT), a highly water-soluble and well-known reducing agent for preservation and regeneration of sulfhydryl groups in biomedical applications, has been developed as an efficient and stable coreactant of lucigenin for the first time. DTT efficiently reacts with lucigenin to generate intense chemiluminescence (CL), eliminating the need for external catalysts to facilitate the lucigenin CL. The DTT-lucigenin CL is approximately 15-fold more intense when compared with the lucigenin-HO classical system. Superoxide dismutase (SOD) remarkably quenches the DTT-lucigenin CL. Based on this phenomenon, a newly developed CL approach for the determination of SOD was proposed with a linear range of 0.01-1.5 μg/mL and a limit of detection of 2.2 ng/mL. Various factors affecting the CL emission of the DTT-lucigenin probe were studied and optimized. Plausible mechanistic pathways for the CL coreaction of lucigenin with DTT were proposed and fully discussed. Our proposed method not only has the merit of being selective toward the target analytes but also eliminates the need for the complex synthesis of luminescent probes and facilitates the sensitive detection of SOD in human serum and cosmetics SOD raw material with satisfactory recoveries.
Topics: Acridines; Dithiothreitol; Humans; Hydrogen Peroxide; Luminescent Agents; Luminescent Measurements; Superoxide Dismutase
PubMed: 35878317
DOI: 10.1021/acs.analchem.2c01690 -
Molecular Metabolism Sep 2022Mutations in the copper-zinc superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), a progressive fatal neuromuscular disease characterized...
OBJECTIVE
Mutations in the copper-zinc superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), a progressive fatal neuromuscular disease characterized by motor neurons death and severe skeletal muscle degeneration. However, there is no effective treatment for this debilitating disease, since the underlying cause for the pathogenesis remains poorly understood. Here, we investigated a role of acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1), an acyltransferase that promotes mitochondrial dysfunction in age-related diseases by catalyzing pathological remodeling of cardiolipin, in promoting the development of ALS in the SOD1 transgenic mice.
METHODS
Using SOD1 transgenic mice with targeted deletion of the ALCAT1 gene and treated with Dafaglitapin (Dafa), a very potent and highly selective ALCAT1 inhibitor, we determined whether ablation or pharmaceutical inhibition of ALCAT1 by Dafa would mitigate ALS and the underlying pathogenesis by preventing pathological remodeling of cardiolipin, oxidative stress, and mitochondrial dysfunction by multiple approaches, including lifespan analysis, behavioral tests, morphological and functional analysis of skeletal muscle, electron microscopic and Seahorse analysis of mitochondrial morphology and respiration, western blot analysis of the SOD1 protein aggregation, and lipidomic analysis of cardiolipin content and acyl composition in mice spinal cord.
RESULTS
ALCAT1 protein expression is potently upregulated in the skeletal muscle of the SOD1 mice. Consequently, ablation or pharmacological inhibition of ALCAT1 by Dafa attenuates motor neuron dysfunction, neuronal inflammation, and skeletal muscle atrophy in SOD1 mice by preventing SOD1 protein aggregation, mitochondrial dysfunction, and pathological CL remodeling, leading to moderate extension of lifespan in the SOD1 transgenic mice.
CONCLUSIONS
ALCAT1 promotes the development of ALS by linking SOD1 protein aggregation to mitochondrial dysfunction, implicating Dafa as a potential treatment for this debilitating disorder.
Topics: Acyltransferases; Amyotrophic Lateral Sclerosis; Animals; Cardiolipins; Disease Models, Animal; Mice; Mice, Transgenic; Protein Aggregates; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 35772643
DOI: 10.1016/j.molmet.2022.101536 -
Journal of Neural Transmission (Vienna,... Jun 2022Autism spectrum disorder is a pervasive neurodevelopmental disorder with a substantial contribution to the global disease burden. Despite intensive research efforts, the...
Autism spectrum disorder is a pervasive neurodevelopmental disorder with a substantial contribution to the global disease burden. Despite intensive research efforts, the aetiopathogenesis remains unclear. The Janus-faced antioxidant enzymes superoxide dismutase 1-3 have been implicated in initiating oxidative stress and as such may constitute a potential therapeutic target. However, no measurement has been taken in human autistic brain samples. The aim of this study is to measure superoxide dismutase 1-3 in autistic cerebral organoids as an in vitro model of human foetal neurodevelopment. Whole brain organoids were created from induced pluripotent stem cells from healthy individuals (n = 5) and individuals suffering from autism (n = 4). Using Pierce bicinchoninic acid and enzyme-linked immunosorbent assays, the protein and superoxide dismutase 1, 2, and 3 concentrations were quantified in the cerebral organoids at days 22, 32, and 42. Measurements were normalized to the protein concentration. Results represented using medians and interquartile ranges. Using Wilcoxon matched-pairs signed-rank test, an abrupt rise in the superoxide dismutase concentration was observed at day 32 and onwards. Using Wilcoxon rank-sum test, no differences were observed between healthy (SOD1: 35.56 ng/mL ± 3.46; SOD2: 2435.80 ng/mL ± 1327.00; SOD3: 1854.88 ng/mL ± 867.94) and autistic (SOD1: 32.85 ng/mL ± 5.26; SOD2: 2717.80 ng/mL ± 1889.10; SOD3: 1690.18 ng/mL ± 615.49) organoids. Cerebral organoids recapitulate many aspects of human neurodevelopment, but the diffusion restriction may render efforts in modelling differences in oxidative stress futile due to the intrinsic hypoxia and central necrosis.
Topics: Autism Spectrum Disorder; Humans; Isoenzymes; Organoids; Oxidative Stress; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 35266053
DOI: 10.1007/s00702-022-02472-x -
Journal of Materials Chemistry. B Sep 2021Superoxide dismutases (SODs) are a group of metalloenzymes that catalyze the dismutation of superoxide radicals (O˙) into hydrogen peroxide (HO) and oxygen (O). As the... (Review)
Review
Superoxide dismutases (SODs) are a group of metalloenzymes that catalyze the dismutation of superoxide radicals (O˙) into hydrogen peroxide (HO) and oxygen (O). As the first line of defense against reactive oxygen species (ROS)-mediated damage, SODs are expected to play an important role in the treatment of oxidative stress-related diseases. However, the clinical applications of SODs have been severely limited by their structural instability and high cost. Compared with natural enzymes, nanozymes, nanomaterials with enzyme-like activity, are more stable, and economical, can be easily modified and their activities can be adjusted. Due to their excellent characteristics, nanozymes have attracted widespread attention in recent years and are expected to become effective substitutes for natural enzymes in many application fields. Importantly, some nanozymes with SOD-like activity have been developed and proved to have a mitigating effect on diseases caused by oxidative stress. These studies on SOD-like nanozymes provide a feasible strategy for breaking through the dilemma of SOD clinical applications. However, at present, the specific catalytic mechanism of SOD-like nanozymes is still unclear, and many important issues need to be resolved. Although there are many comprehensive reviews to introduce the overall situation of the nanozyme field, the research on SOD-like nanozymes still lacks a systematic review. From the structure and mechanism of natural SOD enzymes to the structure and regulation of SOD-like nanozymes, and then to the measurement and application of nanozymes, this review systematically summarizes the recent progress in SOD-like nanozymes. The existing shortcomings and possible future research hotspots in the development of SOD-like nanozymes are summarized and prospected. We hope that this review would provide ideas and inspirations for further research on the catalytic mechanism and rational design of SOD-like nanozymes.
Topics: Animals; Antioxidants; Biocompatible Materials; Humans; Materials Testing; Superoxide Dismutase
PubMed: 34161407
DOI: 10.1039/d1tb00720c -
Nature Neuroscience Dec 2021Amyotrophic lateral sclerosis (ALS) is a devastating disorder in which motor neurons degenerate, the causes of which remain unclear. In particular, the basis for...
Amyotrophic lateral sclerosis (ALS) is a devastating disorder in which motor neurons degenerate, the causes of which remain unclear. In particular, the basis for selective vulnerability of spinal motor neurons (sMNs) and resistance of ocular motor neurons to degeneration in ALS has yet to be elucidated. Here, we applied comparative multi-omics analysis of human induced pluripotent stem cell-derived sMNs and ocular motor neurons to identify shared metabolic perturbations in inherited and sporadic ALS sMNs, revealing dysregulation in lipid metabolism and its related genes. Targeted metabolomics studies confirmed such findings in sMNs of 17 ALS (SOD1, C9ORF72, TDP43 (TARDBP) and sporadic) human induced pluripotent stem cell lines, identifying elevated levels of arachidonic acid. Pharmacological reduction of arachidonic acid levels was sufficient to reverse ALS-related phenotypes in both human sMNs and in vivo in Drosophila and SOD1 mouse models. Collectively, these findings pinpoint a catalytic step of lipid metabolism as a potential therapeutic target for ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Humans; Induced Pluripotent Stem Cells; Lipid Metabolism; Mice; Mice, Transgenic; Motor Neurons; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 34782793
DOI: 10.1038/s41593-021-00944-z