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Journal of Nanobiotechnology May 2024Various clinical symptoms of digestive system, such as infectious, inflammatory, and malignant disorders, have a profound impact on the quality of life and overall... (Review)
Review
Various clinical symptoms of digestive system, such as infectious, inflammatory, and malignant disorders, have a profound impact on the quality of life and overall health of patients. Therefore, the chase for more potent medicines is both highly significant and urgent. Nanozymes, a novel class of nanomaterials, amalgamate the biological properties of nanomaterials with the catalytic activity of enzymes, and have been engineered for various biomedical applications, including complex gastrointestinal diseases (GI). Particularly, because of their distinctive metal coordination structure and ability to maximize atom use efficiency, single-atom nanozymes (SAzymes) with atomically scattered metal centers are becoming a more viable substitute for natural enzymes. Traditional nanozyme design strategies are no longer able to meet the current requirements for efficient and diverse SAzymes design due to the diversification and complexity of preparation processes. As a result, this review emphasizes the design concept and the synthesis strategy of SAzymes, and corresponding bioenzyme-like activities, such as superoxide dismutase (SOD), peroxidase (POD), oxidase (OXD), catalase (CAT), and glutathione peroxidase (GPx). Then the various application of SAzymes in GI illnesses are summarized, which should encourage further research into nanozymes to achieve better application characteristics.
Topics: Humans; Gastrointestinal Diseases; Nanostructures; Animals; Enzymes; Superoxide Dismutase; Catalase; Catalysis; Glutathione Peroxidase
PubMed: 38796465
DOI: 10.1186/s12951-024-02569-3 -
Methods in Molecular Biology (Clifton,... 2022Localizing metal binding to specific sites in proteins remains a challenging analytical problem in vitro and in vivo. Although metal binding can be maintained by...
Localizing metal binding to specific sites in proteins remains a challenging analytical problem in vitro and in vivo. Although metal binding can be maintained by "native" electrospray ionization with intact proteins for quantitation by mass spectrometry, subsequent fragmentation of proteins with slow-heating methods like collision-induced dissociation (CID) can scramble and detach metals. In contrast, electron capture dissociation (ECD) fragmentation produces highly localized bond cleavage that is well known to preserve posttranslational modifications. We show how a newly available ECD tool that can be retrofitted on standard QTOF mass spectrometers allows the sites of copper and zinc binding to be localized in the antioxidant enzyme Cu, Zn superoxide dismutase (SOD1). The loss of zinc from Cu, Zn SOD1 has been shown to induce motor neuron death and could have a causal role in the fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The methods described enable copper loss to be distinguished from zinc using distinct ECD fragments of SOD1 and are broadly applicable to other metalloproteins.
Topics: Amyotrophic Lateral Sclerosis; Copper; Electrons; Humans; Mutation; Neurodegenerative Diseases; Superoxide Dismutase; Superoxide Dismutase-1; Zinc
PubMed: 35657595
DOI: 10.1007/978-1-0716-2325-1_14 -
Zoological Science Nov 2014In the present study, an extracellular copper-zinc superoxide dismutase (ecCuZnSOD) gene and a mitochondrial manganese superoxide dismutase (mtMnSOD) gene were cloned...
In the present study, an extracellular copper-zinc superoxide dismutase (ecCuZnSOD) gene and a mitochondrial manganese superoxide dismutase (mtMnSOD) gene were cloned from hemocytes of red claw crayfish, Cherax quadricarinatus. The open reading frame (ORF) of ecCuZnSOD is 498 bp and encodes a 166 amino acids (aa) protein, whereas the ORF of mtMnSOD is 654 bp and encodes a 218 aa protein. The amino acid sequences of C. quadricarinatus ecCuZnSOD and mtMnSOD showed high similarities with those of ecCuZnSODs and mtMnSODs of other crustaceans, respectively. Both ecCuZnSOD and mtMnSOD of C. quadricarinatus were highly expressed in hepatopancreas, hemocytes, intestine, and gill; low transcript levels were seen in other tissues (heart, muscle, and nerve). The immune responses of ecCuZnSOD and mtMnSOD were studied following inoculation with Spiroplasma eriocheiris and Aeromonas hydrophila. After S. eriocheiris or A. hydrophila challenge, mRNA transcription of ecCuZnSOD and mtMnSOD in hemocytes and gill was upregulated. mRNA transcription of ecCuZnSOD in the hepatopancreas was also upregulated after S. eriocheiris or A. hydrophila inoculation. mtMnSOD in hepatopancreas was upregulated after A. hydrophila inoculation, whereas this was down-regulated after S. eriocheiris challenge. After S. eriocheiris and A. hydrophila challenge, total SOD activity and CuZnSOD activity both increased compared to control group. The results showed that these SODs from C. quadricarinatus likely play an important role in protecting some tissues from reactive oxygen intermediates produced during challenge from S. eriocheiris and A. hydrophila.
Topics: Amino Acid Sequence; Animals; Astacoidea; Base Sequence; Cloning, Molecular; DNA, Complementary; Gene Expression Regulation, Enzymologic; Male; Molecular Sequence Data; Phylogeny; Superoxide Dismutase
PubMed: 25366155
DOI: 10.2108/zs140007 -
Biochemical and Biophysical Research... Oct 2019Metal ion coordination is an essential step for the maturation of metalloenzymes. Generally, the metal coordination sites are thought to be fully occupied to achieve the...
Metal ion coordination is an essential step for the maturation of metalloenzymes. Generally, the metal coordination sites are thought to be fully occupied to achieve the maximum activity and stability. In this research, we compared the structural features, activity and stability of the apo-, semiholo- and holo-forms of a hyperthermostable tetrameric Fe-superoxide dismutase (SOD). Strikingly, the three forms of enzymes had similar compact tetrameric structures. Removal of iron ions destabilized subunit-subunit interactions during guanidine hydrochloride-induced unfolding. The partially metalized semiholoenzyme possessed most of the activity and identical hyperthermostability of the holoenzyme, but weaker propensity to aggregate. Furthermore, both of the iron content and activity of the semiholoenzyme were unaffected by a 200-fold excess iron ions in solutions, suggesting that conformation of the apo-subunits were forced to the close state by the iron-containing subunits. These observations suggest that fully metalized enzyme is probably nonessential for multimeric metalloenzymes and the semiholoenzyme may be a better choice. The unique properties of semiholoenzyme also provide the organisms a compromised solution to survival under metal deficiency conditions.
Topics: Enzyme Stability; Humans; Models, Molecular; Mutagenesis, Site-Directed; Superoxide Dismutase; Temperature
PubMed: 31477266
DOI: 10.1016/j.bbrc.2019.08.135 -
European Review For Medical and... Apr 2021While both first-line antioxidant enzymes and oxidation products have been considered as markers of periodontal disease, their assessment in the diagnosis of periodontal...
OBJECTIVE
While both first-line antioxidant enzymes and oxidation products have been considered as markers of periodontal disease, their assessment in the diagnosis of periodontal disease is more complicated. Some, such as superoxide dismutase (SOD, glutathione peroxidase (GPx) and reduced glutathione (GSH), have indicated significant differences between patients with chronic and aggressive periodontitis.
PATIENTS AND METHODS
Participants (101) were divided into a control group of healthy individuals and, following diagnosis, patients with gingivitis, chronic periodontitis, and aggressive periodontitis. Compounds reflecting tissue destruction, inflammatory processes or antioxidant responses, such as sirtuins (SIRT-1, SIRT-2), metalloproteinases (MMP), SOD, GPx, GSH, and glutathione reductase (GR) were measured in saliva.
RESULTS
SIRT-2 levels were significantly increased in all patients. In patients with gingivitis, MMP (p<0.05) and GPx (p<0.01) were significantly increased. In patients with chronic and aggressive periodontitis, SOD activities were increased (p<0.001) while GPx and GR were decreased (p<0.001). Relative activities of MMP were higher in patients with aggressive periodontitis.
CONCLUSIONS
Measurements of SIRT-2 and SOD clearly showed increased levels of oxidative stress in cases of periodontitis with a subsequent inhibition of other antioxidant enzymes. Levels of GSH suggest reversibility of the conditions with appropriate intervention. With the assessment of the trends of these selected antioxidant markers, it is possible to determine the prognosis of the disease.
Topics: Biomarkers; Humans; Periodontitis; Prognosis; Saliva; Sirtuin 2; Superoxide Dismutase
PubMed: 33928601
DOI: 10.26355/eurrev_202104_25724 -
Journal of Cellular Biochemistry Mar 2019Oxidative stress is a major factor in aging processes. Superoxide dismutase 3 (SOD3) plays a key role in the protection of extracellular oxidative stress. Missense...
Oxidative stress is a major factor in aging processes. Superoxide dismutase 3 (SOD3) plays a key role in the protection of extracellular oxidative stress. Missense mutations in SOD3 have been described to be associated with the occurrence of pulmonary, cardiovascular, and neoplastic diseases. This study aims to analyze the effects of missense mutations on the SOD3 structure and function by modeling a complete SOD3 structure as well as analyzing the differences between the wild-types and mutants using computational simulations. Here, ten algorithms were used to predict the structural and functional effects of missense mutations. A complete model of SOD3 protein was made by ab initio and comparative modeling using the Rosetta algorithm and validated by PROCHECK, Verify 3D, QMEAN, and ProSa. Molecular dynamics (MD) simulations were performed and analyzed using the GROMACS package. The deleterious potential of the A58T and R231G mutants was not predicted by the majority of the used algorithms. The analyzed mutations were predicted as destabilizing by at least one algorithm. The MD analyses indicated that protein flexibility may be increased by all of the analyzed mutations, while the protein-ligand stability may be decreased. They also suggested that the variants A91T and R231G increase the overall dimensions of SOD3 and decrease its accessible surface area. Our findings, therefore, indicated that the analyzed mutations could affect the protein structure and its ability to interact with other molecules, which may be related to the functional impairment of SOD3 upon A58T and R231G mutations, as well as their involvement in pathologies.
Topics: Algorithms; Amino Acid Substitution; Computer Simulation; Humans; Molecular Dynamics Simulation; Mutation, Missense; Superoxide Dismutase
PubMed: 30206983
DOI: 10.1002/jcb.27636 -
Metallomics : Integrated Biometal... May 2018Human MnSOD is a homotetramer and represents an essential mitochondrial antioxidant enzyme, which catalyzes the dismutation of superoxide radicals (O2˙-) at near... (Review)
Review
Human MnSOD is a homotetramer and represents an essential mitochondrial antioxidant enzyme, which catalyzes the dismutation of superoxide radicals (O2˙-) at near diffusion-controlled rates. Under a variety of disease conditions and in the process of aging, nitric oxide (˙NO) can outcompete MnSOD and react with O2˙- to yield the potent oxidant peroxynitrite (ONOO-). Then, peroxynitrite can promote the regio-specific nitration of MnSOD at active site tyrosine 34, which turns the enzyme inactive. In this review we assess the kinetic aspects of the formation of peroxynitrite in the presence of MnSOD and the biochemical mechanisms of peroxynitrite-mediated MnSOD nitration. In particular, the central role of the Mn atom in the reaction of the enzyme with peroxynitrite (k = 1.0 × 105 M-1 s-1 per tetramer at pH = 7.4 and T = 37 °C) and the catalysis of nitration at the active site are disclosed. Then, we analyze at the atomic level of detail how a single oxidative post-translational modification in the enzyme, namely the nitration of tyrosine 34, results in enzyme inactivation. Herein, kinetic, molecular, structural biology and computational studies are integrated to rationalize the specificity and impact of peroxynitrite-dependent MnSOD tyrosine nitration in vitro and in vivo from both functional and structural perspectives.
Topics: Catalysis; Humans; Metals; Models, Molecular; Nitric Oxide; Peroxynitrous Acid; Superoxide Dismutase; Tyrosine
PubMed: 29737331
DOI: 10.1039/c7mt00348j -
Brain, Behavior, and Immunity Oct 2022Neuroinflammation is one of the main hallmarks of amyotrophic lateral sclerosis (ALS). Recently, peripheral immune cells were discovered as pivotal players that promptly...
Neuroinflammation is one of the main hallmarks of amyotrophic lateral sclerosis (ALS). Recently, peripheral immune cells were discovered as pivotal players that promptly participate in this process, speeding up neurodegeneration during progression of the disease. In particular, infiltrating T cells and natural killer cells release inflammatory cytokines that switch glial cells toward a pro-inflammatory/detrimental phenotype, and directly attack motor neurons with specific ligand-receptor signals. Here, we assessed the presence of lymphocytes in the spinal cord of sporadic ALS patients. Furthermore, we demonstrate that blocking the extravasation of immune cells in the central nervous system using Natalizumab (NAT), an antibody for the α4 integrin, reduces the level of interferon-γ in the spinal cord of ALS mouse models, such as the hSOD1 and TDP43 mice, modifying microglia and astrocytes phenotype, increasing motor neuron number and prolonging the survival time. Taken together, our results establish a central role for the immune cells as drivers of inflammation in ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Mice; Mice, Transgenic; Motor Neurons; Neuroinflammatory Diseases; Spinal Cord; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 35688338
DOI: 10.1016/j.bbi.2022.06.004 -
Neuroscience and Biobehavioral Reviews Jan 2016Amyotrophic lateral sclerosis (ALS) is now recognized as a multisystem disorder, in which the primary pathology is the degeneration of motor neurons, with cognitive... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is now recognized as a multisystem disorder, in which the primary pathology is the degeneration of motor neurons, with cognitive and/or behavioral dysfunctions that constitutes the non-motor manifestations of ALS. The combination of clinical, neuroimaging, and neuropathological data, and detailed genetic studies suggest that ALS and frontotemporal dementia (FTD) might form part of a disease continuum, with pure ALS and pure FTD at the two extremes. Mutations in the superoxide dismutase 1 (SOD1) gene were the first genetic mutations linked to the insurgence of ALS. Since that discovery numerous animal models carrying SOD1 mutations have been created. Despite their limitations these animal models, particularly the mice, have broaden our knowledge on the system alterations occurring in the ALS spectrum of disorders. The present review aims at providing an overview of the data obtained with the SOD1 animal models first and foremost on the cortical and subcortical regions, the cortico-striatal and hippocampal synaptic plasticity, dendritic branching and glutamate receptors function.
Topics: Amyotrophic Lateral Sclerosis; Animals; Cognition Disorders; Disease Models, Animal; Humans; Mice, Transgenic; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 26602023
DOI: 10.1016/j.neubiorev.2015.11.006 -
Endogenous Copper for Nanocatalytic Oxidative Damage and Self-Protection Pathway Breakage of Cancer.ACS Nano Oct 2021Nanocatalytic medicine is one of the most recent advances in the development of nanomedicine, which catalyzes intratumoral chemical reactions to produce toxins such as...
Nanocatalytic medicine is one of the most recent advances in the development of nanomedicine, which catalyzes intratumoral chemical reactions to produce toxins such as reactive oxygen species for cancer specific treatment by using exogenous-delivered catalysts such as Fenton agents. However, the overexpression of reductive glutathione and Cu-Zn superoxide dismutase in cancer cells will significantly counteract the therapeutic efficacy by reactive oxygen species-mediated oxidative damages. Additionally, the direct delivery of iron-based Fenton agents may arouse undesired detrimental effects such as anaphylactic reactions. In this study, instead of exogenously delivering Fenton agents, the endogenous copper ions from intracellular Cu-Zn superoxide dismutase have been employed as the source of Fenton-like agents by chelating the Cu ions from the superoxide dismutase using a common metal ion chelator, ,,',-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN), followed by the TPEN-Cu(II) chelate reduction to TPEN-Cu(I) by reductive glutathione. Briefly, TPEN was loaded in a disulfide bond-containing link poly(acrylic acid) shell-coated hybrid mesoporous silica/organosilicate (MSN@MON) nanocomposite as a reductive glutathione-responsive nanoplatform, which features inter-related triple functions: intratumoral reductive glutathione-responsive link poly(acrylic acid) disruption and TPEN release; the accompanying reductive glutathione consumption and Cu-Zn superoxide dismutase deactivation by TPEN chelating Cu ions from this superoxide dismutase; and the Fenton reaction catalyzed by TPEN-Cu(I) chelate as a Fenton-like agent generated from TPEN-Cu(II) reduction by the remaining reductive glutathione in cancer cells, thereby cutting off the self-protection pathway of cancer cells under severe oxidation stress and ensuring cancer cell apoptosis by reactive oxygen species produced by the catalytic Fenton-like reactions. Such a nanocatalyst demonstrates excellent biosafety and augmented therapeutic efficacy by simultaneous nanocatalytic oxidative damage and intrinsic protection pathway breakage of cancer cells.
Topics: Chelating Agents; Copper; Humans; Neoplasms; Oxidative Stress; Superoxide Dismutase
PubMed: 34652919
DOI: 10.1021/acsnano.1c05451