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Neurobiology of Disease Aug 2023The progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS) is caused by a decline in motor neuron function, resulting in worsened motor impairments,...
The progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS) is caused by a decline in motor neuron function, resulting in worsened motor impairments, malnutrition, respiratory failure and mortality, and there is a lack of effective clinical treatments. The exact mechanism of motor neuronal degeneration remains unclear. Previously, we reported that ferroptosis, which is characterized by the accumulation of lipid peroxide and glutathione depletion in an iron-dependent manner, contributed to motor neuronal death in ALS cell models with the hSOD1 (human Cu/Zn-superoxide dismutase) gene mutation. In this study, we further explored the role of ferroptosis in motor neurons and its regulation in mutant hSOD1 cell and mouse models. Our results showed that ferroptosis was activated in hSOD1 NSC-34 cells and mouse models, which was accompanied by decreased nuclear retention of nuclear factor erythroid 2-related factor 2 (NRF2) and downregulation of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) levels. Moreover, RTA-408, an NRF2 activator, inhibited ferroptosis in hSOD1 NSC-34 cells by upregulating the protein expression of SLC7A11 and GPX4. Moreover, hSOD1 mice treated with RTA-408 showed obvious improvements in body weight and motor function. Our study demonstrated that ferroptosis contributed to the toxicity of motor neurons and that activating NRF2 could alleviate neuronal degeneration in ALS with the hSOD1 mutation.
Topics: Animals; Humans; Mice; Amyotrophic Lateral Sclerosis; Disease Models, Animal; Ferroptosis; Mice, Transgenic; Motor Neurons; Mutation; Neurodegenerative Diseases; Neuroprotection; NF-E2-Related Factor 2; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 37352984
DOI: 10.1016/j.nbd.2023.106210 -
Nature Communications Oct 2023Cold stress affects rice growth and productivity. Defects in the plastid-localized pseudouridine synthase OsPUS1 affect chloroplast ribosome biogenesis, leading to...
Cold stress affects rice growth and productivity. Defects in the plastid-localized pseudouridine synthase OsPUS1 affect chloroplast ribosome biogenesis, leading to low-temperature albino seedlings and accumulation of reactive oxygen species (ROS). Here, we report an ospus1-1 suppressor, sop10. SOP10 encodes a mitochondria-localized pentatricopeptide repeat protein. Mutations in SOP10 impair intron splicing of the nad4 and nad5 transcripts and decrease RNA editing efficiency of the nad2, nad6, and rps4 transcripts, resulting in deficiencies in mitochondrial complex I, thus decrease ROS generation and rescuing the albino phenotype. Overexpression of different compartment-localized superoxide dismutases (SOD) genes in ospus1-1 reverses the ROS over-accumulation and albino phenotypes to various degrees, with Mn-SOD reversing the best. Mutation of SOP10 in indica rice varieties enhances cold tolerance with lower ROS levels. We find that the mitochondrial superoxide plays a key role in rice cold responses, and identify a mitochondrial superoxide modulating factor, informing efforts to improve rice cold tolerance.
Topics: Plant Proteins; Superoxides; Oryza; Reactive Oxygen Species; Mitochondrial Proteins; Mitochondria; Gene Expression Regulation, Plant
PubMed: 37880207
DOI: 10.1038/s41467-023-42269-4 -
Investigative Ophthalmology & Visual... Sep 2023We hypothesized that antioxidative enzymes supplementation could be a treatment option for dry eye. We investigated the efficacy of oral administration of...
PURPOSE
We hypothesized that antioxidative enzymes supplementation could be a treatment option for dry eye. We investigated the efficacy of oral administration of Bacillus-derived superoxide dismutase (Bd-SOD) in a murine experimental dry eye (EDE).
METHODS
In part I, mice were randomly assigned to normal control, EDE, and mice groups that were treated with oral Bd-SOD after induction of EDE (EDE + Bd-SOD group; four mice in each group). Expression of SOD2, a major antioxidant enzyme with manganese as a cofactor, was assessed by immunofluorescence staining. In part II, mice were divided into seven groups (six mice in each group): normal control, EDE, vehicle-treated, topical 0.05% cyclosporin A (CsA)-treated, and oral Bd-SOD-treated (2.5, 5.0, and 10.0 mg/kg Bd-SOD) groups. Tear volume, tear-film break-up time (TBUT), and corneal fluorescein-staining scores (CFS) were measured at zero, five, and 10 days after treatment. Ten days after treatment, 2',7'-dichlorodihydrofluorescein diacetate for reactive oxygen species (ROS), enzyme-linked immunosorbent for malondialdehyde, and TUNEL assays for corneal apoptosis, flow cytometry inflammatory T cells, and histological assessment were performed.
RESULTS
Compared to the normal control group in part I, the EDE group showed significantly decreased SOD2 expression by immunofluorescence staining. However, the EDE + Bd-SOD group recovered similar to the normal control group. In part II, ROS, malondialdehyde, and corneal apoptosis were decreased in CsA and all Bd-SOD-treated groups. Corneal and conjunctival inflammatory T cells decreased, and conjunctival goblet cell density increased in CsA-treated and Bd-SOD-treated groups. Compared to the CsA-treated group, the 2.5 mg/kg Bd-SOD-treated group showed increased TBUT and decreased inflammatory T cells, and the 5.0 mg/kg Bd-SOD-treated group showed decreased CFS and increased conjunctival goblet cells.
CONCLUSIONS
Oral Bd-SOD administration might increase autogenous SOD2 expression in ocular surface tissue in EDE and could be developed as a complementary treatment for DE in the future.
Topics: Animals; Mice; Reactive Oxygen Species; Superoxide Dismutase; Oxidative Stress; Antioxidants; Dry Eye Syndromes; Apoptosis; Bacillus; Cyclosporine
PubMed: 37721740
DOI: 10.1167/iovs.64.12.30 -
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 -
Scientific Reports Jul 2023Lambda-cyhalothrin (LCT) is one of the most frequently utilized pyrethroids. This study aimed to explore the toxic effects of subacute exposure to LCT on the pancreas...
Lambda-cyhalothrin (LCT) is one of the most frequently utilized pyrethroids. This study aimed to explore the toxic effects of subacute exposure to LCT on the pancreas and the hepatic glucose metabolism in adult male albino rats. 20 rats were equally grouped into; Control group and LCT group. The latter received LCT (61.2 mg/kg b.wt.), orally on a daily basis for 28 days. At the end of experiment, blood samples were collected for the determination of serum glucose and insulin levels. Pancreases were harvested and levels of malondialdehyde (MDA); catalase (CAT); superoxide dismutase (SOD); reduced glutathione (GSH); tumor necrosis factor-α (TNF-α); interleukin-6 (IL-6); nuclear factor erythroid 2-related factor 2 (Nrf2); heme oxygenase 1 (HO-1); and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were assessed. Also, liver samples were analyzed for the activity of glucose metabolism enzymes, glycogen content, and pyruvate and lactate concentrations. Histopathological and immunohistochemical examinations of pancreatic tissues were undertaken as well. Results revealed hyperglycemia, hypoinsulinemia, increased MDA, TNF-α, IL-6, and NF-κB levels, in association with reduced CAT, SOD, GSH, Nrf2, and HO-1 levels in LCT group. Liver analyses demonstrated a clear disturbance in the hepatic enzymes of glucose metabolism, diminished glycogen content, decreased pyruvate, and increased lactate concentrations. Besides, pancreatic islets displayed degenerative changes and β-cells loss. Immunohistochemistry revealed diminished area percentage (%) of insulin and Nrf2 and increased TNF-α immunoreaction. In conclusion, subacute exposure to LCT induces pancreatic toxicity, mostly via oxidative and inflammatory mechanisms, and dysregulates hepatic glucose metabolism in albino rats.
Topics: Rats; Male; Animals; NF-kappa B; NF-E2-Related Factor 2; Interleukin-6; Tumor Necrosis Factor-alpha; Pyrethrins; Superoxide Dismutase; Pancreas; Glucose; Insulins; Oxidative Stress
PubMed: 37463968
DOI: 10.1038/s41598-023-38661-1 -
Scientific Reports Nov 2023In cardiovascular disease, pathological and protective roles are reported for the Th2 cytokines IL-4 and IL-13, respectively. We hypothesised that differential effects...
In cardiovascular disease, pathological and protective roles are reported for the Th2 cytokines IL-4 and IL-13, respectively. We hypothesised that differential effects on macrophage function are responsible. Type I and II receptor subunit (IL-2Rγ, IL-4Rα and IL-13Rα1) and M2 marker (MRC-1, CCL18, CCL22) expression was assessed via RT-qPCR in IL-4- and IL-13-treated human primary macrophages. Downstream signalling was evaluated via STAT1, STAT3 and STAT6 inhibitors, and IL-4- and IL-13-induced reactive oxygen species (ROS) generation assessed. IL-4 and IL-13 exhibited equivalent potency and efficacy for M2 marker induction, which was attenuated by STAT3 inhibition. Both cytokines enhanced PDBu-stimulated superoxide generation however this effect was 17% greater with IL-4 treatment. Type I IL-4 receptor expression was increased on M1-like macrophages but did not lead to a differing ability of these cytokines to modulate M1-like macrophage superoxide production. Overall, this study did not identify major differences in the ability of IL-4 and IL-13 to modulate macrophage function, suggesting that the opposing roles of these cytokines in cardiovascular disease are likely to be via actions on other cell types. Future studies should directly compare IL-4 and IL-13 in vivo to more thoroughly investigate the therapeutic validity of selective targeting of these cytokines.
Topics: Humans; Cardiovascular Diseases; Cytokines; Interleukin-13; Interleukin-4; Macrophages; Reactive Oxygen Species; Superoxides
PubMed: 37949903
DOI: 10.1038/s41598-023-46237-2 -
Neural Regeneration Research Aug 2023We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations... (Review)
Review
We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson's disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.
PubMed: 36751779
DOI: 10.4103/1673-5374.363185 -
PloS One 2024Superoxide dismutase (SOD) is an antioxidant enzyme that protects the body from free radicals. It has both antioxidant and immunomodulatory properties, inducing...
Superoxide dismutase (SOD) is an antioxidant enzyme that protects the body from free radicals. It has both antioxidant and immunomodulatory properties, inducing macrophage polarization from M1 to M2. Macrophages, key mediators of the innate immune response, are divided into the M1 (pro-inflammatory) and M2 (anti-inflammatory) subtypes. In this study, we aimed to assess the antioxidant and neuroprotective effects of SOD on nerve cells and its immunomodulatory effects on macrophages. We observed that SOD inhibited the accumulation of reactive oxygen species and enhanced the viability of H2O2-treated nerve cells. Furthermore, SOD reduced the degree of necrosis in nerve cells treated with the conditioned medium from macrophages, which induced inflammation. In addition, SOD promoted the M1 to M2 transition of macrophages. Our findings suggest that SOD protects nerve cells and regulates immune responses.
Topics: Animals; Superoxide Dismutase; Mice; Macrophages; Humans; Neuroprotective Agents; RAW 264.7 Cells; Reactive Oxygen Species; Neuroblastoma; Cell Line, Tumor; Hydrogen Peroxide; Cell Survival; Antioxidants
PubMed: 38743689
DOI: 10.1371/journal.pone.0303136 -
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 -
Computational and Structural... Dec 2024Flavin-binding cryptochromes are blue-light sensitive photoreceptors that have been implicated with magnetoreception in some species. The photocycle involves an...
Flavin-binding cryptochromes are blue-light sensitive photoreceptors that have been implicated with magnetoreception in some species. The photocycle involves an intra-protein photo-reduction of the flavin cofactor, generating a magnetosensitive radical pair, and its subsequent re-oxidation. Superoxide (O) is generated in the re-oxidation with molecular oxygen. The resulting O-containing radical pairs have also been hypothesised to underpin various magnetosensitive traits, but due to fast spin relaxation when tumbling in solution would require immobilisation. We here describe our insights in the binding of superoxide to cryptochrome 4 from based on extensive all-atom molecular dynamics studies and density-functional theory calculations. The positively charged "crypt" region that leads to the flavin binding pocket transiently binds O at 5 flexible binding sites centred on arginine residues. Typical binding times amounted to tens of nanoseconds, but exceptional binding events extended to several hundreds of nanoseconds and slowed the rotational diffusion, thereby realising rotational correlation times as large as 1 ns. The binding sites are particularly efficient in scavenging superoxide escaping from a putative generation site close to the flavin-cofactor, possibly implying a functional relevance. We discuss our findings in view of a potential magnetosensitivity of biological flavin semiquinone/superoxide radical pairs.
PubMed: 38204818
DOI: 10.1016/j.csbj.2023.12.009