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Objective To investigate the changes of serum 8-hydroxy-2′-deoxyguanosine ( 8-OHdG), NTproBNP and manganese superoxide dismutase (MnSOD) in patients with heart failure (HF), and their correlation with cognitive function. Methods Ninety-six patients with HF were prospectively selected as reserach objects (HF group), meanwhile, another 96 healthy physical examinees were also enrolled as the control group. The cognitive function of the HF patients was assessed by the Montreal cognitive assessment (MoCA) score. The serum levels of 8-OHdG, NT-proBNP and MnSOD were compared between the two groups, and patients with different cognitive status at admission. The correlation between the levels of the above three serum markers and MoCA score was also analyzed. The diagnostic value of the above three serum indicators for cognitive dysfunction at admission was analyzed. Results The levels of serum 8-OHdG and NT-proBNP in patients with HF at admission were significantly higher than those in the control group, while the level of serum MnSOD was significantly lower (all P<0. 01). The levels of serum 8-OHdG and NT-proBNP in HF patients with cognitive dysfunction were significantly higher than those in HF patients with normal cognition funtion, while the level of serum MnSOD was significantly lower (all P< 0. 01). For the HF patients at admission, the levels of serum 8-OHdG and NT-proBNP were both positively correlated with the MoCA score, while the level of serum MnSOD was negatively correlated with the MoCA score (all P<0. 05). In the diagnosis of cognitive dysfunction among HF patients, the area under the curve, sensitivity, and specificity of the combination of serum 8-OHdG, NT-proBNP, and MnSOD levels at admission were all significantly higher than those by using any single of the three indicators. Conclusion The serum levels of 8-OHdG, NT-proBNP and MnSOD are closely related to complicated cognitive dysfunction in patients with HF. The joint detection of the three markers significantly increases the diagnostic value of cognitive dysfunction in HF patients, which could provide references for clinical treatment. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose: To investigate the neuroprotective effects of the SOD2 gene in cerebral ischemia reperfusion injury function and the underlying mechanisms in a mice model of middle cerebral artery ischemia reperfusion. Methods: SOD2 transgenic mice were engineered using transcription activator-like effector nucleases, and the genotype was identified using PCR after every three generations. Transgenic and C57BL/6J wild type mice were simultaneously subjected to the middle cerebral artery occlusion model. Results: SOD2 expression in the brain, heart, kidney, and skeletal muscle of transgenic mice was significantly higher than that in the wild type. Following ischemia reperfusion, the infarct volume of wild type mice decreased after treatment with fenofibrate compared to the CMC group. Infarction volume in SOD2 transgenic mice after CMC and fenofibrate treatment was significantly reduced. The recovery of cerebral blood flow in wild type mice treated with fenofibrate was significantly enhanced compared with that in the CMC group. Conclusions: The expression of SOD2 in transgenic mice was significantly higher than that in wild type mice, the neuroprotective role of fenofibrate depends on an increase in SOD2 expression.

Biomaterials encounter considerable challenges in extensive bone defect regeneration. The amelioration of outcomes may be attainable through the orchestrated modulation of both innate and adaptive immunity. Silicon‐hydroxyapatite, for instance, which solely focuses on regulating innate immunity, is inadequate for long‐term bone regeneration. Herein, extra manganese (Mn)‐doping is utilized for enhancing the osteogenic ability by mediating adaptive immunity. Intriguingly, Mn‐doping engenders heightened recruitment of CD4+ T cells to the bone defect site, concurrently manifesting escalated T helper (Th) 2 polarization and an abatement in Th1 cell polarization. This consequential immune milieu yields a collaborative elevation of interleukin 4, secreted by Th2 cells, coupled with attenuated interferon gamma, secreted by Th1 cells. This orchestrated interplay distinctly fosters the osteogenesis of bone marrow stromal cells and effectuates consequential regeneration of the mandibular bone defect. The modulatory mechanism of Th1/Th2 balance lies primarily in the indispensable role of manganese superoxide dismutase (MnSOD) and the phosphorylation of adenosine 5′‐monophosphate‐activated protein kinase (AMPK). In conclusion, this study highlights the transformative potential of Mn‐doping in amplifying the osteogenic efficacy of silicon‐hydroxyapatite nanowires by regulating T cell‐mediated adaptive immunity via the MnSOD/AMPK pathway, thereby creating an anti‐inflammatory milieu favorable for bone regeneration. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of the fusion of leader peptide on the structure of human manganese superoxide dismutase (SOD2) and anti-cisplatin (DDP)-induced renal injury. Methods The effect of mitochondrion targeting sequence (MTS) on the structure and activity of SOD2 was analyzed by structure prediction and superoxide dismutase (SOD) specific-activity determination. The DDP injury model of Kunming (KM) mice was established, and amifostine (AMFT) was set as a positive control. Indicators such as kidney index, renal function, kidney antioxidant capacity, and appearance and pathology changes of mice kidney were used to evaluate the effect of MTS-SOD2 against DDP-induced kidney injury. Results The MTS leader peptide seemed to change the secondary and tertiary structures of SOD2 to some extent, but it also increased the specific activity of the MTS-SOD2 protein. Pre-administration of a medium dose of MTS-SOD2 (0.84 mg/kg) before the use of DDP significantly reduced the level of renal malondialdehyde and increased the SOD activity and total antioxidant capacity (T-AOC) in the kidney, thereby reducing the renal pathological damage and consequently maintaining renal function. The overall protective effect of MTS-SOD2 was comparable to or even better than that of 200 mg/kg AMFT. Conclusion The MTS leader peptide enhances the activity of SOD2 and confers it with an excellent anti-DDP-induced renal-injury effect because of its transmembrane function.

Abstract Biomaterials encounter considerable challenges in extensive bone defect regeneration. The amelioration of outcomes may be attainable through the orchestrated modulation of both innate and adaptive immunity. Silicon‐hydroxyapatite, for instance, which solely focuses on regulating innate immunity, is inadequate for long‐term bone regeneration. Herein, extra manganese (Mn)‐doping is utilized for enhancing the osteogenic ability by mediating adaptive immunity. Intriguingly, Mn‐doping engenders heightened recruitment of CD4+ T cells to the bone defect site, concurrently manifesting escalated T helper (Th) 2 polarization and an abatement in Th1 cell polarization. This consequential immune milieu yields a collaborative elevation of interleukin 4, secreted by Th2 cells, coupled with attenuated interferon gamma, secreted by Th1 cells. This orchestrated interplay distinctly fosters the osteogenesis of bone marrow stromal cells and effectuates consequential regeneration of the mandibular bone defect. The modulatory mechanism of Th1/Th2 balance lies primarily in the indispensable role of manganese superoxide dismutase (MnSOD) and the phosphorylation of adenosine 5′‐monophosphate‐activated protein kinase (AMPK). In conclusion, this study highlights the transformative potential of Mn‐doping in amplifying the osteogenic efficacy of silicon‐hydroxyapatite nanowires by regulating T cell‐mediated adaptive immunity via the MnSOD/AMPK pathway, thereby creating an anti‐inflammatory milieu favorable for bone regeneration.

Aim: To investigate the mechanism of p53-mediated suppression of heat stress-induced oxidative stress damage by manganese superoxide dismutase (MnSOD) in endothelial cells (ECs). Methods: Primary ECs isolated from mouse aortas were used to examine the effects of heat stress on vascular ECs viability and apoptosis. We measured MnSOD expression, reactive oxygen species (ROS) production, p53 expression, viability, and apoptosis of heat stress-induced ECs. We also tested the protective effects of MitoQ10, a mitochondrial-targeted antioxidant, and Pifithrin-α, a p53 inhibitor, in ECs from a mouse model of heat stroke. Results: Heat stress increased cellular apoptosis, ROS production, and p53 expression, while reducing cellular viability and MnSOD expression in ECs. We also showed that the suppression of MnSOD expression by heat stress in ECs was mediated by interactions between p53 and Sp1. Furthermore, MitoQ10 and Pifithrin-α alleviated heat stress-induced oxidative stress and apoptosis in ECs. Conclusion: Our results revealed that p53-mediated MnSOD downregulation is a key mechanism for heat stress-induced oxidative stress damage in ECs and indicated that MitoQ10 and Pifithrin-α could be potential therapeutic agents for heat stroke.

Manganese superoxide dismutase (MnSOD) and catalase (CAT) could eliminate reactive oxygen species (ROS) and maintain the reduction-oxidation balance in cells. This study aimed to investigate their functions in turbot (Scophthalmus maximus) response to the Vibro anguillarum challenge. SmMnSOD, the full-length liver cDNA of MnSOD from S. maximus, was cloned by fast amplification of cDNA ends (RACE). Sequencing of nucleotides indicated that the SmMnSOD cDNA was 1267 base pairs with a 684-base-pair open reading frame, encoding a 228 amino acid protein with 28 amino acid residues. The SmMnSOD sequence contains MnSOD signatures (DVWEHAYY) and probable N-glycosylation sites (NVT, NHT, and NLS). The deduced sequence of SmMnSOD revealed sequence homology between 85.3% and 92.9% with those of other species. A phylogenetic study found that SmMnSOD clustered with other fish MnSOD, indicating that SmMnSOD was a member of the MnSOD family. The SmMnSOD transcript was discovered by qRT-PCR in the gill, stomach, head-kidney, muscle, liver, intestine, and heart of S. maximus, with the highest expression in the liver. Upon intervention by V. anguillarum, the liver and head kidney transcript levels of SmMnSOD were up-regulated at 12 and 48 h, whereas the temporal expression profiles of the CAT transcript increased at 6 and 24 h. As the pathogenic bacterial stress processing was prolonged to 72 h, the liver and head kidney transcript levels of SmMnSOD and CAT decreased gradually. Thus, SmMnSOD was triggered and may be related to S. maximus' immunological responses against V. anguillarum. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of the fusion of leader peptide on the structure of human manganese superoxide dismutase (SOD2) and anti-cisplatin (DDP)-induced renal injury. Methods The effect of mitochondrion targeting sequence (MTS) on the structure and activity of SOD2 was analyzed by structure prediction and superoxide dismutase (SOD) specific-activity determination. The DDP injury model of Kunming (KM) mice was established, and amifostine (AMFT) was set as a positive control. Indicators such as kidney index, renal function, kidney antioxidant capacity, and appearance and pathology changes of mice kidney were used to evaluate the effect of MTS-SOD2 against DDP-induced kidney injury. Results The MTS leader peptide seemed to change the secondary and tertiary structures of SOD2 to some extent, but it also increased the specific activity of the MTS-SOD2 protein. Pre-administration of a medium dose of MTS-SOD2 (0.84 mg/kg) before the use of DDP significantly reduced the level of renal malondialdehyde and increased the SOD activity and total antioxidant capacity (T-AOC) in the kidney, thereby reducing the renal pathological damage and consequently maintaining renal function. The overall protective effect of MTS-SOD2 was comparable to or even better than that of 200 mg/kg AMFT. Conclusion The MTS leader peptide enhances the activity of SOD2 and confers it with an excellent anti-DDP-induced renal-injury effect because of its transmembrane function. [ABSTRACT FROM AUTHOR]

1,2-Dimethylhydrazine (DMH) is a plant toxicant that enters the food web through the diet. It is biotransformed into azoxymethane, a colon carcinogen, during the first hepatic passage. In mice, this study assessed the role of glutamate dehydrogenase (GDH), a key glutaminolysis enzyme in DMH-induced colorectal cancer (CRC). Colon samples were taken from mice given 6 or 15 weekly doses of 20 mg/kg DMH and serially sacrificed. Repeated DMH doses induced early aberrant crypt foci that evolved into irreversible adenocarcinomas over 24 weeks, along with an increase in GDH and lactate dehydrogenase activities (+ 122%, + 238%, P < 0.001), indicating a switch to aerobic glycolysis and glutaminolysis. Transcriptional downregulation of the endogenous GDH inhibitor, sirtuin4, and two redox regulators, mitochondrial sestrin2 and nuclear factor (erythroid derivative 2)-like 2 (− 26% and − 22%, P < 0, 05; and − 30%, P < 0.01), exacerbated mitochondrial stress by boosting mitochondrial superoxide dismutase activity (+ 240% (P < 0.001) while depressing catalase activity and GSH levels (− 57% and − 60%, P < 0.001). In vitro, allosteric GDH inhibition by 50 µM epigallocatechin gallate decreased human carcinoma (HCT-116) cells' viability, clonogenicity, and migration (− 43% and − 57%, P < 0.001, 41%, P < 0.05), while stimulating ROS release (+ 57%, P < 0.001). Dimethylfumarate (DMF), a linear electrophile and mitochondrial fumarate analog, rebalanced ROS levels (− 34%, P < 0.05) and improved GDH activity, cell viability, and tumorogenic capacity (+ 20%, 20%, P < 0.001; and 33%, P < 0.05). Thus, the pathological remodeling of colon mucosa is supported by metabolic reprogramming bypassing uncoupled mitochondria. DMF highlights the critical role of electrophile response elements in modulating redox mithormesis and redox homeostasis during CRC. [ABSTRACT FROM AUTHOR]

Considerable amounts of oxidants are produced in cerebral ischemia, where oxidative stress plays a key role in neuronal damage after ischemia. Klotho, an anti-aging protein, alleviates oxidative stress by activating the transcription of an important antioxidant enzyme, manganese superoxide dismutase (MnSOD), in the nervous system. Thus, increased Klotho expression level could lead to a reduction in neuronal damages after brain ischemia via lowering oxidative stress. It is known that physical activity increases Klotho expressions. In this study, we assessed neuroprotective effects of preconditioning exercise in rats (treadmill running at a speed of 20 m/min,30 min/day, six days/week, for3 weeks) on hippocampal Klotho and MnSOD expression in the brain using an animal model of stroke, middle cerebral artery occlusion (MCAO). Our study revealed a reduction in hippocampal Klotho and MnSOD expression as well as CA1 neuronal activity in MCAO compared to the sham group. Exercise prevented the ischemia-induced decline in Klotho and MnSOD expression levels as well as CA1 neuronal activity in Exercise + MCAO compared to the MCAO group. Also, exercise significantly improved the neurological scores and reduced brain infarction area in Exercise + MCAO in comparison to MCAO group. There was a post-ischemia deficit in the working memory, as measured by spontaneous alternation percentage using Y-maze test, in MCAO compared to the sham group. The latter effect was not observed in the Exercise + MCAO group, which could be related to an increase in the antioxidant capacity as exhibited by Klotho and MnSOD up-regulation. The results were confirmed with a positive correlation between Klotho expression and MnSOD expression which allows proposing Klotho as a potential neuroprotective protein in ischemic stroke with respect to antioxidant defense. In general, the present study suggested that preconditioning exercise induced upregulation of Klotho and MnSOD, as well as attenuated the post-ischemic injuries. The upregulation of Klotho might be an underlying mechanism by which preconditioning exercise plays as a neuroprotective factor against post-ischemic neural injuries in ischemic rats.

Abstract Background Superoxide dismutases (SODs, EC 1.15.1.1) are defense proteins that can be used as sweepers to clear reactive oxygen species (ROS). They have been widely studied in the plant. Intensive research demonstrates that SOD plays an essential role in plants. However, in Pleurotus ostreatus, the function and regulatory pathway of SOD in the growth and development and the abiotic stress response have not been clear. Results In this study, three MnSOD-encoding genes of the P. ostreatus CCMSSC00389 strain were cloned and identified. Mnsod1, Mnsod2, and Mnsod3 were interrupted by 3, 7, and 2 introns, and encoded proteins of 204, 220, and 344 amino acids, respectively. By comparing the relative expression of three MnSOD-encoding genes in mycelia, the results showed that the gene with the highest primary expression was Mnsod1. Subsequently, the function of P. ostreatus Mnsod1 was explored by overexpression (OE) and RNA interference (RNAi). The results showed that during the growth and development of P. ostreatus, MnSOD1 protein increased gradually from mycelia to the fruiting body, but decreased in spores. The change of Mnsod1 transcription level was not consistent with the changing trend of MnSOD1 protein. Further studies showed that during primordia formation, the expression of Mnsod1 gradually increased, reaching a peak at 48 h, and the transcription level was 2.05-folds compared to control. H2O2 content progressively accumulated during the formation of primordia, and its change trend was similar to that of Mnsod1 transcription. OE-Mnsod1-1 and OE-Mnsod1-21 strains accelerated the formation of primordia. The results suggested that Mnsod1 may participate in the formation rate of P. ostreatus primordium by regulating the signal molecule H2O2. In addition, OE-Mnsod1-1 and OE-Mnsod1-21 strains shortened the mycelial recovery time after heat stress and improved the tolerance of the strains to 2.5 mM and 5 mM H2O2, which showed that Mnsod1 was involved in the response of P. ostreatus mycelium to heat stress. Conclusions This study indicates that Mnsod1 plays an active role in the formation of P. ostreatus primordia and the response to abiotic stress.

Lipoteichoic acid isolated from Staphylococcus aureus (aLTA) is known to regulate the production of pro-inflammatory cytokines through TLR2-mediated signaling pathways. In our previous study, we found that aLTA significantly increased manganese superoxide dismutase (MnSOD) in the THP-1 human monocyte-like cell line, but the role of MnSOD in the regulation of cytokine production was not elucidated. In the current study, we found that MnSOD was involved in aLTA-mediated cytokine production. The signaling pathways associated with aLTA-mediated MnSOD induction in THP-1 cells included TLR2-MyD88-IRAK2, JNK (c-Jun N-terminal kinases)1/2 and nuclear factor- κB (NF-κB). We also found MnSOD was involved in the regulation of IL-1β and TNF-α, which were induced by early signaling pathways, including JNK1/2, p38, and NF-κB p65. In addition, MnSOD was also involved in the production of IL-6 and CCL2 in aLTA-stimulated THP-1 cells through activation of late signaling pathways such as JAK2-STAT3. Taken together, our data suggest that aLTA-mediated MnSOD production involved in the regulation of cytokine production and it may be the cause of one of the excessive inflammatory reactions caused by S. aureus.

Manganese Superoxide Dismutase (MnSOD) represents a mitochondrial protein that scavenges reactive oxygen species (ROS) responsible for oxidative stress. A known single nucleotide polymorphism (SNP) rs4880 on the SOD2 gene, causing a mutation from alanine to valine (Ala16Val) in the primary structure of immature MnSOD, has been associated with several types of cancer and other autoimmune diseases. However, no conclusive correlation has been established yet. This study aims to determine the effect of the alanine to valine mutation on the secondary structure of the MnSOD mitochondrial targeting sequence (MTS). A model for each variant of the MTS was prepared and extensively simulated with molecular dynamics simulations using the CHARMM36m force field. The results indicate that the alanine variant of the MTS preserves a uniform α-helical secondary structure favorable for the protein transport into mitochondria, whereas the valine variant quickly breaks down its α-helix. Thus, the alanine MTS represents the more active MnSOD variant, the benefits of which have yet to be determined experimentally. [ABSTRACT FROM AUTHOR]

Considerable amounts of oxidants are produced in cerebral ischemia, where oxidative stress plays a key role in neuronal damage after ischemia. Klotho, an anti-aging protein, alleviates oxidative stress by activating the transcription of an important antioxidant enzyme, manganese superoxide dismutase (MnSOD), in the nervous system. Thus, increased Klotho expression level could lead to a reduction in neuronal damages after brain ischemia via lowering oxidative stress. It is known that physical activity increases Klotho expressions. In this study, we assessed neuroprotective effects of preconditioning exercise in rats (treadmill running at a speed of 20 m/min,30 min/day, six days/week, for3 weeks) on hippocampal Klotho and MnSOD expression in the brain using an animal model of stroke, middle cerebral artery occlusion (MCAO). Our study revealed a reduction in hippocampal Klotho and MnSOD expression as well as CA1 neuronal activity in MCAO compared to the sham group. Exercise prevented the ischemia-induced decline in Klotho and MnSOD expression levels as well as CA1 neuronal activity in Exercise + MCAO compared to the MCAO group. Also, exercise significantly improved the neurological scores and reduced brain infarction area in Exercise + MCAO in comparison to MCAO group. There was a post-ischemia deficit in the working memory, as measured by spontaneous alternation percentage using Y-maze test, in MCAO compared to the sham group. The latter effect was not observed in the Exercise + MCAO group, which could be related to an increase in the antioxidant capacity as exhibited by Klotho and MnSOD up-regulation. The results were confirmed with a positive correlation between Klotho expression and MnSOD expression which allows proposing Klotho as a potential neuroprotective protein in ischemic stroke with respect to antioxidant defense. In general, the present study suggested that preconditioning exercise induced upregulation of Klotho and MnSOD, as well as attenuated the post-ischemic injuries. The upregulation of Klotho might be an underlying mechanism by which preconditioning exercise plays as a neuroprotective factor against post-ischemic neural injuries in ischemic rats. • Preconditioning exercise attenuates the stroke-associated neurological deficits. • Preconditioning exercise augments the firing rate of CA1 neurons in ischemic brain. • Preconditioning exercise increases the post-ischemic expressions of Klotho and MnSOD. • The expression of Klotho negatively correlates with stroke-related deficits. [ABSTRACT FROM AUTHOR]

Background: There is accumulating evidence indicating that inflammation and oxidative stress are involved in the pathogenesis of atrial fibrillation (AF). The role of manganese superoxide dismutase (MnSOD) in the initiation and maintenance of AF has not yet been well characterized. The aim of our study is to investigate whether or not plasma MnSOD levels are associated with AF. Methods: We enrolled a total of 130 consecutive patients with AF as the case group (paroxysmal AF: 87, persistent AF: 43) and 58 patients without a history of AF as the control group after screening. Baseline clinical characteristics, laboratory and echocardiographic parameters were collected. Plasma levels of nicotinamide-adenine dinucleotide phosphate oxidase 4 (NOX4) and MnSOD were measured by an enzyme-linked immunosorbent assay (ELISA) method. These data were compared between the different groups. The relationship between MnSOD and other parameters was assessed using Spearman correlation. Multivariable logistic regression analysis was performed to identify independent predictors of AF. The area under the curve (AUC) from receiver operating characteristics (ROC) analysis was constructed to explore the value of MnSOD in predicting the occurrence of AF. Results: The levels of MnSOD were the highest in the paroxysmal AF group, followed by the persistent AF group, and the lowest in the controls. Meanwhile, the levels in the paroxysmal AF group were significantly higher than those in the controls [322.84 (165.46, 547.61) vs. 201.83 (129.53, 301.93), p = 0.002], but no significant difference was found between the paroxysmal AF group and persistent AF group, as well as the persistent AF group and the controls. Spearman correlation analysis indicated that there was a significantly negative correlation between MnSOD levels and LAD (r = −0.232, p = 0.008) and a positive correlation between MnSOD levels and RDW-CV (r = 0.214, p = 0.014) in the case group. Multivariate logistic regression analysis indicated that MnSOD levels [odds ratio (OR): 1.003, 95% confidence interval (CI): 1.001–1.005, p = 0.002] were an independent risk factor for paroxysmal AF, and the best cut-off value of MnSOD in predicting paroxysmal AF gained by ROC curve analysis was 311.49 ug/mL (sensitivity of 52.9%, specificity of 77.6%, AUC = 0.668). Conclusion: Oxidative stress underlies the pathogenesis of AF and may play a stronger role in paroxysmal AF than persistent AF. Our study showed an independent association between increased circulating plasma MnSOD levels and the occurrence of paroxysmal AF. [ABSTRACT FROM AUTHOR]

Background: Superoxide dismutases (SODs, EC 1.15.1.1) are defense proteins that can be used as sweepers to clear reactive oxygen species (ROS). They have been widely studied in the plant. Intensive research demonstrates that SOD plays an essential role in plants. However, in Pleurotus ostreatus, the function and regulatory pathway of SOD in the growth and development and the abiotic stress response have not been clear. Results: In this study, three MnSOD-encoding genes of the P. ostreatus CCMSSC00389 strain were cloned and identified. Mnsod1, Mnsod2, and Mnsod3 were interrupted by 3, 7, and 2 introns, and encoded proteins of 204, 220, and 344 amino acids, respectively. By comparing the relative expression of three MnSOD-encoding genes in mycelia, the results showed that the gene with the highest primary expression was Mnsod1. Subsequently, the function of P. ostreatus Mnsod1 was explored by overexpression (OE) and RNA interference (RNAi). The results showed that during the growth and development of P. ostreatus, MnSOD1 protein increased gradually from mycelia to the fruiting body, but decreased in spores. The change of Mnsod1 transcription level was not consistent with the changing trend of MnSOD1 protein. Further studies showed that during primordia formation, the expression of Mnsod1 gradually increased, reaching a peak at 48 h, and the transcription level was 2.05-folds compared to control. H2O2 content progressively accumulated during the formation of primordia, and its change trend was similar to that of Mnsod1 transcription. OE-Mnsod1-1 and OE-Mnsod1-21 strains accelerated the formation of primordia. The results suggested that Mnsod1 may participate in the formation rate of P. ostreatus primordium by regulating the signal molecule H2O2. In addition, OE-Mnsod1-1 and OE-Mnsod1-21 strains shortened the mycelial recovery time after heat stress and improved the tolerance of the strains to 2.5 mM and 5 mM H2O2, which showed that Mnsod1 was involved in the response of P. ostreatus mycelium to heat stress. Conclusions: This study indicates that Mnsod1 plays an active role in the formation of P. ostreatus primordia and the response to abiotic stress. [ABSTRACT FROM AUTHOR]

Background: NKT-like cells are T lymphocytes coexpressing several NK cell-associated receptors. They are effector lymphocytes of innate and adaptive immunity, and their number increases with age. The study aimed to analyze the expression of cellular protective proteins, i.e. sirtuin 1 (SIRT1), heat shock protein 70 (HSP70) and manganese superoxide dismutase (SOD2) in NKT-like and T cells of the young ('young', 31 subjects, age range 19–24 years), seniors aged under 85 ('old'; 30 subjects, age range 65–84 years) and seniors aged over 85 ('oldest', 24 subjects, age range 85–94 years). Both NKT-like and T cells were cultured for 48 h and stimulated with IL-2, LPS and PMA with ionomycin and compared with unstimulated control cells. Results: The oldest seniors varied from the other age groups by significantly increased expression of SIRT1 and HSP70 in both NKT-like and T cells observed in both stimulated and nonstimulated cells. The analyzed lymphocyte populations of the oldest revealed not only the highest expression of these proteins but also insensitivity to all types of applied stimulation. When NKT-like cells were compared to T cells, higher expression of the studied protective proteins was observed in both stimulated and unstimulated NKT-like cells. Neither CD3 + CD56+ nor CD3+ cells revealed elevated expression of SOD2, and these cells responded to stimulation until very advanced age. T cells revealed higher sensitivity to stimulation with IL-2 regarding SIRT1 and HSP70 expression. NKT-like cells were more sensitive to stimulation with PMA and ionomycin concerning the expression of these proteins. IL-2 did not induce a significant increase in SOD2 expression in the studied age groups. Conclusions: The oldest seniors developed an adaptive stress response in both T and NKT-like cells regarding the expression of SIRT1 and HSP70, which was increased and insensitive to further stimulation in contrast to SOD2, which showed a more inducible pattern of expression. CD3 + CD56+ cells exhibited higher expression of cellular protective proteins than CD3+ cells in both stimulated and control, nonstimulated cells. NKT-like and T cells showed a distinct sensitivity to the applied stimulatory factors in the respective age groups. [ABSTRACT FROM AUTHOR]

Asbestos is a mineral known as human carcinogenic material. Exposure to asbestos both in an occupational and environmental way causes asbestosis and mesothelioma. ROS contributes to the development of pulmonary-toxicity induced asbestos.We aimed to determine the levels of important mitochondrial substances such as manganese superoxide dismutase (MnSOD) and Thioredoxin (Trx2) in asbestosis and mesothelioma patients. The study was performed with the patients admitted to outpatient clinics of Chest Diseases and Thoracic Surgery, at Medicine Faculty, Bozok University. Group 1 (healthy control group, n=27): Consisting of healthy individuals (54.18±9.89 years old), Group 2 (patients group, n=34): Evaluation of clinical, pathological and radiological analysis, patients who defined as mesothelioma and/or pleural plaques and asbestosis (60.24±15.24 years old). Patients, who were not biopsied or not available for biopsy due to comorbid diseases, were not included in the study.Biochemical analysis was done in Selcuk University Medicine Faculty Research Laboratories.Serum Trx2 and MnSOD levels were determined by the Elisa method. The results of Trx2 were calculated as pg/µg protein. MnSOD samples were determined as ng/µg protein. MnSOD and Trx2 levels in the patients group were statistically lower than the levels of the healthy group (p=0.000, p=0.048), respectively.Trx2 levels were 1.74±0.33 pg/µg protein in a healthy group whereas were 0.89±0.10 pg/µg protein in asbestosis and mesothelioma group. Serum MnSOD levels were 1.38±0.24 and 0.29±0.11 ng/µg protein in healthy and patients groups, respectively.These significant changes in malignant mesothelioma patients reflect the impairment of the oxidant-antioxidant balance system. The study presents basic findings for the clinical meaning of mentioned biochemical parameters in mesothelioma patients. [Med-Science 2020; 9(4.000): 912-6]

Manganese Superoxide Dismutase (MnSOD) represents a mitochondrial protein that scavenges reactive oxygen species (ROS) responsible for oxidative stress. A known single nucleotide polymorphism (SNP) rs4880 on the SOD2 gene, causing a mutation from alanine to valine (Ala16Val) in the primary structure of immature MnSOD, has been associated with several types of cancer and other autoimmune diseases. However, no conclusive correlation has been established yet. This study aims to determine the effect of the alanine to valine mutation on the secondary structure of the MnSOD mitochondrial targeting sequence (MTS). A model for each variant of the MTS was prepared and extensively simulated with molecular dynamics simulations using the CHARMM36m force field. The results indicate that the alanine variant of the MTS preserves a uniform α-helical secondary structure favorable for the protein transport into mitochondria, whereas the valine variant quickly breaks down its α-helix. Thus, the alanine MTS represents the more active MnSOD variant, the benefits of which have yet to be determined experimentally.

AIM: To investigate the role of reactive oxygen species (ROS) and antioxidant mechanism underlying the metabolic memory of bovine retinal pericytes (BRPs) induced by high glucose. METHODS: Effects of high glucose levels and culture time on BRPs viability were evaluated by CCK-8. BRPs were grown in high-glucose media (30 mmol/L) for 4d followed by culture in normal glucose condition (5.6 mmol/L) for 4d in an experimental group. In contrast, in negative and positive control groups, BRPs were grown in either normal-glucose media or high-glucose media for 8d, respectively. The ROS levels, apoptosis, the expression and activity of manganese superoxide dismutase (MnSOD) in BRPs, as well as the protective effect of adeno-associated viral (AAV)-mediated over expression of MnSOD were determined separately by DCHFA, ELISA and Western blot. RESULTS: Comparing the result of cells apoptosis, activity and protein expression of MnSOD and caspase-3, the cell culture system that exposed in sequence in 30 mmol/L and normal glucose for 4d was demonstrated as a suitable model of metabolic memory. Furthermore, delivery of antioxidant gene MnSOD can decrease BRPs apoptosis, reduce activated caspase-3, and reverse hyperglycemic memory by reducing the ROS of mitochondria. CONCLUSION: Increased ROS levels and decreased MnSOD levels may play important roles in pericyte loss of diabetic retinopathy. BRPs cultured in high glucose for 4d followed by normal glucose for 4d could be an appropriate model of metabolic memory. rAAV-MnSOD gene therapy provides a promising strategy to inhibit this blinding disease.

Aims: Hypoglycemia is associated with increased reactive oxygen species (ROS) production and vascular events. We have previously reported that low-glucose (LG) conditions induce mitochondrial ROS (mtROS) production in aortic endothelial cells (ECs). However, the mechanism by which hypoglycemia promotes diabetic retinopathy (DR) is unclear. Blood-retinal barrier (BRB) disruption occurs in the early stages of DR. We hypothesized that the mechanisms underlying hypoglycemia-induced DR are associated with BRB breakdown due to mtROS generation during hypoglycemia. Here, we aimed to determine whether hypoglycemia exacerbated mtROS production and induced BRB disruption. Results: We observed that hypoglycemia induced mtROS production by increasing fatty acid oxidation (FAO), which was suppressed by overexpression of mitochondrial-specific manganese superoxide dismutase (MnSOD) in retinal ECs. Furthermore, FAO blockade decreased the hypoglycemia-induced mtROS production. Recurrent hypoglycemia increased albumin leak in diabetic mice retina, which was suppressed in diabetic vascular endothelial cell-specific MnSOD transgenic (eMnSOD-Tg) mice. Pharmacological FAO blockade also reduced mtROS production, reduced vascular endothelial growth factor (VEGF) production during hypoglycemia, and prevented retinal vascular permeability in diabetic mice. MnSOD overexpression or carnitine palmitoyltransferase I (CPT1) blockade suppressed vascular endothelial-cadherin phosphorylation under LG in retinal ECs. Innovation and Conclusion: Reduction of mtROS and VEGF production via pharmacological FAO and/or CPT1 blockade may prevent hypoglycemia-induced worsening of DR. [ABSTRACT FROM AUTHOR]

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Electrophilic aldehyde (4-hydroxynonenal; 4-HNE), formed after lipid peroxidation, is a mediator of mitochondrial dysfunction and implicated in both the pathogenesis and the progression of cardiovascular disease. Manganese superoxide dismutase (MnSOD), a nuclear-encoded antioxidant enzyme, catalyzes the dismutation of superoxide radicals (O2•-) in mitochondria. To study the role of MnSOD in the myocardium, we generated a cardiomyocyte-specific SOD2 (SOD2Δ) deficient mouse strain. Unlike global SOD2 knockout mice, SOD2Δ mice reached adolescence; however, they die at ~4 months of age due to heart failure. Ultrastructural analysis of SOD2Δ hearts revealed altered mitochondrial architecture, with prominent disruption of the cristae and vacuole formation. Noninvasive echocardiographic measurements in SOD2Δ mice showed dilated cardiomyopathic features such as decreased ejection fraction and fractional shortening along with increased left ventricular internal diameter. An increased incidence of ventricular tachycardia was observed during electrophysiological studies of the heart in SOD2Δ mice. Oxidative phosphorylation (OXPHOS) measurement using a Seahorse XF analyzer in SOD2Δ neonatal cardiomyocytes and adult cardiac mitochondria displayed reduced O2 consumption, particularly during basal conditions and after the addition of FCCP (H+ ionophore/uncoupler), compared to that in SOD2fl hearts. Measurement of extracellular acidification (ECAR) to examine glycolysis in these cells showed a pattern precisely opposite that of the oxygen consumption rate (OCR) among SOD2Δ mice compared to their SOD2fl littermates. Analysis of the activity of the electron transport chain complex identified a reduction in Complex I and Complex V activity in SOD2Δ compared to SOD2fl mice. We demonstrated that a deficiency of SOD2 increases reactive oxygen species (ROS), leading to subsequent overproduction of 4-HNE inside mitochondria. Mechanistically, proteins in the mitochondrial respiratory chain complex and TCA cycle (NDUFS2, SDHA, ATP5B, and DLD) were the target of 4-HNE adduction in SOD2Δ hearts. Our findings suggest that the SOD2 mediated 4-HNE signaling nexus may play an important role in cardiomyopathy.

AimAccumulated evidence indicates that neurotrophin deregulations, oxidative stress injury, and mitochondrial dysfunction have been involved in bipolar disorder (BD); however, their real roles in BD are unclear. Investing the possible interaction between three systems is worthwhile understanding this complex process.MethodsWe measured plasma brain-derived neurotrophic factor (BDNF) level, leukocytes mitochondrial DNA copy number (mtDNAcn), and activities of antioxidant enzymes in BD patients (n = 97) and healthy controls (n = 31). Analysis of variance and linear regression analyses were performed to explore the interaction between mtDNAcn, antioxidant enzymes, and BDNF.ResultsCompared with healthy controls, there were significant decreases of glutathione peroxidase activity, BDNF levels, and mtDNA content, significant increases of manganese superoxide dismutase (MnSOD) activity among BD patients (all p < 0.05). Regression analysis showed MnSOD activity had a moderate effect on BDNF (beta = 0.23, t = 8.5, p = 0.001). Copper zinc SOD and total SOD activity were significantly correlated with Hamilton Depression Scale scores in depressive patients (r = −0.38, p = 0.013; r = −0.35, p = 0.022). Unexpectedly, we observed no significant correlation between mtDNA content and BDNF in BD patients (p > 0.05).ConclusionThe findings coincide with our hypothesis that abnormal antioxidant enzymes, mtDNAcn, and peripheral BDNF may be involved in the course of BD. There were significant correlations between peripheral BDNF, antioxidant enzyme activities and mtDNAcn, suggesting that oxidative stress, mitochondrial function, and BDNF may influence each other in BD.

The mitochondria are a major source of reactive oxygen species (ROS). Superoxide anion (O2•–) is produced by the process of oxidative phosphorylation associated with glucose, amino acid, and fatty acid metabolism, resulting in the production of adenosine triphosphate (ATP) in the mitochondria. Excess production of reactive oxidants in the mitochondria, including O2•–, and its by-product, peroxynitrite (ONOO–), which is generated by a reaction between O2•– with nitric oxide (NO•), alters cellular function via oxidative modification of proteins, lipids, and nucleic acids. Mitochondria maintain an antioxidant enzyme system that eliminates excess ROS; manganese superoxide dismutase (Mn-SOD) is one of the major components of this system, as it catalyzes the first step involved in scavenging ROS. Reduced expression and/or the activity of Mn-SOD results in diminished mitochondrial antioxidant capacity; this can impair the overall health of the cell by altering mitochondrial function and may lead to the development and progression of kidney disease. Targeted therapeutic agents may protect mitochondrial proteins, including Mn-SOD against oxidative stress-induced dysfunction, and this may consequently lead to the protection of renal function. Here, we describe the biological function and regulation of Mn-SOD and review the significance of mitochondrial oxidative stress concerning the pathogenesis of kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), with a focus on Mn-SOD dysfunction.

Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the “Two Hit Theory” to the “Multiple Hit Theory”. However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS). The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first “Achilles’ heel” of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor). Recently, a new isoform of human manganese superoxide dismutase (MnSOD) was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel recombinant protein (rMnSOD) potentially represents a new and highly efficient adjuvant therapy to counteract the progression from NASH to HCC.

The wood frog, Rana sylvatica, is the primary model animal used for studying vertebrate freeze tolerance. Freeze tolerance adaptations by wood frogs are mediated by a set of well-tuned regulatory controls at the molecular level, starting from cell signal transduction and gene expression events that are ultimately reflected in protective responses by multiple cell systems. Previous studies provided excellent presumptive evidence for the involvement of the NF-κB transcription factor in freeze tolerance. The present study of the NF-κB pathway focussed on freezing time points, 4 h frozen and 24 h frozen for liver and skeletal muscle in wood frog. The total protein levels of the major NF-κB subunits p50 and p65, its inhibitor, p-IκB, and downstream targets, ferritin heavy chain (FHC) and manganese superoxide dismutase (MnSOD) were quantified using western blots. Results showed a significant increase in the levels of NF-κB subunits and its downstream targets during freezing. Nuclear distributions of NF-κB subunits and transcript levels of FHC were analysed to delve deeper into the pathway. Results obtained from nuclear distribution analysis were consistent with the total protein levels showing increased levels of p50 and p65 during 24 h freezing conditions compared to controls but no change in phospho-p65 levels. Further, FHC transcript levels increased in 24 h frozen liver but did not change in frozen muscles. These findings suggest the activation of NF-κB antioxidant defenses in wood frogs during freezing in potential anticipation of high oxidative stress during reperfusion during thawing. [ABSTRACT FROM AUTHOR]

Aim of research was assessment of the levels of antioxidant biomarkers associated with mitochondrial function in young patients with gastroesophageal reflux disease (GERD) and autoimmune thyroiditis (AIT). This study included 165 patients of them 120 patients with GERD and AIT - the main group, 45 patients with isolated GERD - the comparison group. The examined contingent was presented by students aged 18 to 25 years. The control group consisted of 20 healthy individuals of corresponding gender, age and social status (students). Total antioxidant activity (TAS-TAC) was determined in blood serum of study persons with enzyme immunoassays (ELISA, Elabscience, USA), levels of manganese superoxide dismutase (MnSOD) – with enzyme immunoassays (ELISA, Elabscience, USA) and Klotho protein - with enzyme immunoassays (ELISA, Elabscience, USA). Statistical data processing by the Statistica Basic Academic 13 for Windows En local was made. In examined patients with esophageal and thyroid pathologies the decline of total antioxidant activity has been revealed. The MnSOD level in patients with comorbidity of GERD and AIT and isolated GERD was significantly higher as compare to control group. Significant increasing of Klotho protein in serum of young patients was observed. We assessed imbalance between decline of extracellular antioxidants and activation of mitochondrial antioxidants which is more pronounced in combination of diseases. The increase of biomarkers of mitohondrial antioxidant defense system with non-specific citoprotection mechanism in patients with GERD provides the basis to consider MnSOD and Klotho protein as prognostic indicator of clinical outcome of disease in young age. Under combination of GERD and AIT the tendency to overexpression of MnSOD and depression of total antioxidant activity has been revealed, this may cause the deterioration of mitochondrial function. [ABSTRACT FROM AUTHOR]

Aim: Accumulated evidence indicates that neurotrophin deregulations, oxidative stress injury, and mitochondrial dysfunction have been involved in bipolar disorder (BD); however, their real roles in BD are unclear. Investing the possible interaction between three systems is worthwhile understanding this complex process. Methods: We measured plasma brain-derived neurotrophic factor (BDNF) level, leukocytes mitochondrial DNA copy number (mtDNAcn), and activities of antioxidant enzymes in BD patients (n = 97) and healthy controls (n = 31). Analysis of variance and linear regression analyses were performed to explore the interaction between mtDNAcn, antioxidant enzymes, and BDNF. Results: Compared with healthy controls, there were significant decreases of glutathione peroxidase activity, BDNF levels, and mtDNA content, significant increases of manganese superoxide dismutase (MnSOD) activity among BD patients (all p < 0.05). Regression analysis showed MnSOD activity had a moderate effect on BDNF (beta = 0.23, t = 8.5, p = 0.001). Copper zinc SOD and total SOD activity were significantly correlated with Hamilton Depression Scale scores in depressive patients (r = −0.38, p = 0.013; r = −0.35, p = 0.022). Unexpectedly, we observed no significant correlation between mtDNA content and BDNF in BD patients (p > 0.05). Conclusion: The findings coincide with our hypothesis that abnormal antioxidant enzymes, mtDNAcn, and peripheral BDNF may be involved in the course of BD. There were significant correlations between peripheral BDNF, antioxidant enzyme activities and mtDNAcn, suggesting that oxidative stress, mitochondrial function, and BDNF may influence each other in BD. [ABSTRACT FROM AUTHOR]

The mitochondria are a major source of reactive oxygen species (ROS). Superoxide anion (O2•–) is produced by the process of oxidative phosphorylation associated with glucose, amino acid, and fatty acid metabolism, resulting in the production of adenosine triphosphate (ATP) in the mitochondria. Excess production of reactive oxidants in the mitochondria, including O2•–, and its by-product, peroxynitrite (ONOO–), which is generated by a reaction between O2•– with nitric oxide (NO•), alters cellular function via oxidative modification of proteins, lipids, and nucleic acids. Mitochondria maintain an antioxidant enzyme system that eliminates excess ROS; manganese superoxide dismutase (Mn-SOD) is one of the major components of this system, as it catalyzes the first step involved in scavenging ROS. Reduced expression and/or the activity of Mn-SOD results in diminished mitochondrial antioxidant capacity; this can impair the overall health of the cell by altering mitochondrial function and may lead to the development and progression of kidney disease. Targeted therapeutic agents may protect mitochondrial proteins, including Mn-SOD against oxidative stress-induced dysfunction, and this may consequently lead to the protection of renal function. Here, we describe the biological function and regulation of Mn-SOD and review the significance of mitochondrial oxidative stress concerning the pathogenesis of kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), with a focus on Mn-SOD dysfunction. [ABSTRACT FROM AUTHOR]

Environmental melamine exposure increases the risks of oxidative stress and early kidney injury. Manganese superoxide dismutase (MnSOD), glutathione peroxidase, and catalase can protect the kidneys against oxidative stress and maintain normal function. We evaluated whether their single-nucleotide polymorphisms (SNPs) could modify melamine’s effects. A total of 302 patients diagnosed with calcium urolithiasis were enrolled. All patients provided one-spot overnight urine samples to measure their melamine levels, urinary biomarkers of oxidative stress and renal tubular injury. Median values were used to dichotomize levels into high and low. Subjects carrying the T allele of rs4880 and high melamine levels had 3.60 times greater risk of high malondialdehyde levels than those carrying the C allele of rs4880 and low melamine levels after adjustment. Subjects carrying the G allele of rs5746136 and high melamine levels had 1.73 times greater risk of high N-Acetyl-β-d-glucosaminidase levels than those carrying the A allele of rs5746136 and low melamine levels. In conclusion, the SNPs of MnSOD, rs4880 and rs5746136, influence the risk of oxidative stress and renal tubular injury, respectively, in calcium urolithiasis patients. In the context of high urinary melamine levels, their effects on oxidative stress and renal tubular injury were further increased.

This study examined the effects of chronic restraint stress (CRS: 2 hours × 14 days) on gene expression of three antioxidant enzymes, copper, zinc superoxide dismutase (SOD 1), manganese superoxide dismutase (SOD 2) and catalase (CAT) in the rat hippocampus. Also, we examined changes in the activities of SOD 1, SOD 2 and CAT in the hippocampus of chronically stressed rats. Investigated parameters were quantifi ed by using real-time RT-PCR, Western blot analysis and assay of enzymatic activity. We found that CRS did not change mRNA and protein levels of SOD 1 and CAT, but increased mRNA and protein levels of SOD 2. However, CRS treatment increased the enzyme activities of SOD 1, SOD 2 and CAT. Our fi ndings indicate that the increased activity of antioxidant enzymes (SOD 1, SOD 2 and CAT) in the hippocampus may be an important adaptive phenomenon of the antioxidant defense system in chronically stressed rats.

Background: Oxidative stress has been implicated in various diseases including atherosclerosis; the most common pathologic process underlying acute myocardial infarction (AMI). The manganese superoxide dismutase (MnSOD) antioxidant enzyme affords the major defense against reactive oxygen species (ROS) within the mitochondria. MnSOD Alanine16Valine (A16V) single nucleotide polymorphism (SNP) has been shown to decrease MnSOD detoxification activity. Aim: A case-control study was conducted to investigate the association between MnSOD A16V polymorphism and the incidence of AMI in the Egyptians, investigate the contribution of oxidative stress represented by hexanoyl lysine adduct (HEL), an oxidative stress biomarker, in the pathogenesis of AMI and finally correlate the MnSOD genotypes with HEL serum levels. Methods: A total of 200 Egyptian subjects were recruited for the study; 100 AMI patients and 100 control subjects. Genotypes of the MnSOD A16V polymorphism were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum HEL was measured by ELISA. Results: A significant difference in the distribution of the MnSOD A16V genotypes was observed; VV genotype was significantly higher in AMI than controls (p ≤ 0.0001). Also, studying the allele frequencies revealed that Val allele was significantly higher in AMI than controls (p ≤ 0.0001). Serum analysis showed higher levels of HEL in AMI patients (p = 0.0142). Furthermore, HEL levels were found to be significantly higher in VV genotype in AMI (p = 0.0273). Conclusions: Our study suggests that MnSOD A16V polymorphism is associated with increased risk of developing AMI in the Egyptians. Moreover, the VV genotype is associated with higher HEL levels.

Background/Aims: Microglial activation is an important pathological feature in the brains of patients with Alzheimer’s disease (AD), and amyloid-β (Aβ) peptides play a crucial role in microglial activation. In addition, edaravone (EDA) was recently shown to suppress oxidative stress and proinflammatory cytokine production in APPswePS1dE9 (APP/PS1) mice. However, the mechanism by which EDA inhibits the Aβ-induced proinflammatory response in microglia is poorly understood. Methods: The mitochondrial membrane potential (∆ψm) was evaluated using JC-1 staining. Intracellular reactive oxygen species (ROS) and mitochondrial ROS levels were detected using CM-H2DCFDA and MitoSOXTM Red, respectively. The levels of CD11b, NLRP3, pro-caspase-1 and manganese superoxide dismutase (SOD-2) were observed by western blotting, and the levels of interleukin-1beta (IL-1β) in culture supernatants were quantified using an ELISA kit. Results: Aβ induced microglia activation and mitochondrial dysfunction. In addition, mitochondrial dysfunction was associated with ROS accumulation and activation of the NLRP3 inflammasome. Importantly, Aβ induced activation of the NLRP3 inflammasome, leading to caspase-1 activation and IL-1β release in microglia. Moreover, EDA obviously attenuated the depolarization of ∆ψm, reduced mitochondria-derived ROS production and increased SOD-2 activity, resulting in the suppression of NLRP3 inflammasome-mediated IL-1β secretion in Aβ-treated microglia. Conclusion: EDA is a mitochondria-targeted antioxidant and exhibits anti-inflammatory effects on Aβ-treated microglia.

BACKGROUND: Excessive exercises cause a large accumulation of oxidative active substances in the body to damage skeletal muscle cells. Mitochondria play a key role in energy metabolism during exercise. Studies have shown that Rhodiola can reduce the level of lipid peroxidation in muscle tissue and protect damaged endothelial cells. OBJECTIVE: To explore the mechanism underlying Rhodiola improving skeletal muscle function of mice with high intensity exercise by regulating mitochondrial function. METHODS: The study protocol was approved by the Ethics Committee of Xi’an Shiyou University in China. Forty BALB/c mice were divided into blank control group, exercise group, Rhodiola control group and Rhodiola intervention group. Mice in the blank control had no exercise and intervention. Mice in exercise group were given intragastric administration of normal saline followed by high intensity exercise. Mice in Rhodiola intervention group and Rhodiola control group were given intragastric administration of the mixture of Rhodiola and normal saline, followed by exercise or not. The interventions were performed once a day for 28 consecutive days. Body mass, forearm grip strength and exhaustion time were observed. Western blot assay was used to detect expression of manganese superoxide dismutase protein, p53 protein, mitochondrial origin and autophagy-associated protein in the skeletal muscle. RT-qPCR was used to detect skeletal muscle Mfn-1, Mfn-2, Opa-1, Drp-1, and fis-1 mRNA expression. RESULTS AND CONCLUSION: (1) From the 2nd week, the grip strength of forelimbs in the exercise group was significantly lower than that in the other three groups (P < 0.05), but there was no significant difference among blank control group, Rhodiola control group, and Rhodiola intervention group (P > 0.05). (2) At the 3rd and 4th weeks, the exhaustion time of weight-bearing swimming training was significantly shorter in the exercise group than the Rhodiola intervention group (P < 0.05). (3) The levels of manganese superoxide dismutase protein and p53 protein in skeletal muscle cells of mice in the exercise group were significantly higher than those in the other groups (P < 0.05). The levels of manganese superoxide dismutase protein and p53 protein in skeletal muscle cells of mice in the Rhodiola intervention group were significantly higher than those in the Rhodiola control group (P < 0.05). (4) Compared with the blank control group, the levels of PGC-1a and LC3-II/LC3-I in skeletal muscle cells of mice in the exercise group increased significantly, while the levels of Atg7 and P62 decreased significantly (P < 0.05). Compared with the Rhodiola control group, the levels of PGC-1a and LC3-II/LC3-I in skeletal muscle cells of mice in the Rhodiola intervention group increased significantly, while the levels of Atg7 and P62 decreased significantly (P < 0.05). (5) Compared with the blank control group, the expression of fusion gene and Drp-1 gene in the exercise group decreased and increased, respectively, but there was no significant difference between the two groups (P > 0.05). Compared with the blank control group, the Rhodiola exercise intervention group also showed a downward trend in the expression of fusion gene and an upward trend in the expression of Drp-1 mRNA, but there was no significant difference between the two groups (P > 0.05). To conclude, Rhodiola can significantly improve the exercise endurance of mice with high intensity exercise, which may be related to the improvement of skeletal muscle mitochondrial autophagy, origin and fusion-division. [ABSTRACT FROM AUTHOR]

Introduction: Aldehyde dehydrogenase 1-positive (ALDH1+) breast cancer stem cells (BCSCs) are a small population of tumor cells with high capacity of tumorigenicity and oxidative stress. Manganese superoxide dismutase (MnSOD) is specifically expressed in mitochondria as the primary defense against superoxides, which are one of the causes of oxidative stress in cells. The aim of this study was to determine the impact of suppressing MnSOD expression using small interfering RNA (siRNA) on the stemness, tumorigenicity, and viability of BCSCs. Materials and Methods: In vitro transfection of ALDH1+ BCSCs was performed using 33 and 66 µM specific MnSOD siRNA under standard culture conditions. Total RNA and protein were extracted from the transfected cells using TriPure® Isolation Reagent and RIPA® lysis buffer. Cell viability was measured using a trypan blue exclusion assay. The relative expression of MnSOD and OCT4 mRNAs was analyzed using one-step quantitative reverse transcription polymerase chain reaction. MnSOD activity was determined by xanthine oxidase inhibition assay (RanSOD® kit). Cellular superoxides were measured using a dihydroethidium assay, and tumorigenicity was observed with mammosphere-forming unit. Results: After siRNA incubation for 48 h, MnSOD was suppressed by 0.176-fold (P < 0.01), MnSOD enzyme-specific activity was reduced 70.4%, cellular superoxide levels increased by 1.13-fold, OCT4 expression was suppressed by 1.98-fold (P < 0.05), and mammosphere-forming unit decreased by 36.5% (P < 0.05) compared with the corresponding negative controls. The viability of the ALDH1+ BCSCs was reduced 75% (P < 0.05). Conclusion: Our results suggest that suppression of MnSOD expression may be a promising target to reduce stemness and tumorigenicity of ALDH1+ BCSCs. [ABSTRACT FROM AUTHOR]

Bladder dysfunction in diabetes progresses gradually over time. However, the mechanisms of the development are not clear. We tested the hypothesis that oxidative stress plays a key role in the development of diabetic bladder dysfunction using an inducible smooth muscle (SM)-specific superoxide dismutase 2 (Sod2) gene knockout (SM-Sod2 KO) mouse model. Eight-week-old male Sod2lox/lox, SM-CreERT2(ki)Cre/+ mice and wildtype mice were assigned to diabetic or control groups. 4-Hydroxytamoxifen was injected into Sod2lox/lox, SM-CreERT2(ki)Cre/+ mice to activate CreERT2-mediated deletion of Sod2. Diabetes was induced by injection of streptozotocin, whereas control mice were injected with vehicle. Nine weeks later, bladder function was evaluated, and bladders were harvested for immunoblot analysis. Wild-type diabetic mice presented compensated bladder function along with increased nitrotyrosine and MnSOD in detrusor muscle. Induction of diabetes in SM-Sod2 KO mice caused deteriorated bladder function and even greater increases in nitrotyrosine compared with wild-type diabetic mice. Expression levels of apoptosis regulator Bax and cleaved caspase-3 were increased, but apoptosis regulator Bcl-2 expression was decreased in detrusor muscle of both diabetic groups, with more pronounced effects in SM-Sod2 KO diabetic mice. Our findings demonstrate that exaggerated oxidative stress can accelerate the development of bladder dysfunction in diabetic mice and the enhanced activation of apoptotic pathways in the bladder may be involved in the process. [ABSTRACT FROM AUTHOR]

It is now accepted that nutrient abundance in the blood, especially glucose, leads to the generation of reactive oxygen species (ROS), ultimately leading to increased oxidative stress in a variety of tissues. In the absence of an appropriate compensatory response from antioxidant mechanisms, the cell, or indeed the tissue, becomes overwhelmed by oxidative stress, leading to the activation of intracellular stress-associated pathways. Activation of the same or similar pathways also appears to play a role in mediating insulin resistance, impaired insulin secretion, and late diabetic complications. The ability of antioxidants to protect against the oxidative stress induced by hyperglycemia and elevated free fatty acid (FFA) levels in vitro suggests a causative role of oxidative stress in mediating the latter clinical conditions. In this review, we describe common biochemical processes associated with oxidative stress driven by hyperglycemia and/or elevated FFA and the resulting clinical outcomes: β-cell dysfunction and peripheral tissue insulin resistance. [ABSTRACT FROM AUTHOR]

In pathological conditions such as status epilepticus (SE), neuronal cell death can occur due to oxidative stress that is caused by an excessive production and accumulation of reactive oxygen species (ROS). Sirtuin3 (Sirt3) plays an important role in maintaining appropriate ROS levels by regulating manganese superoxide dismutase (MnSOD), which scavenges ROS in mitochondria. Using a SE model, we demonstrated that Sirt3 directly regulated MnSOD activity by deacetylation, which protects hippocampal cells against damage from ROS. Furthermore, we showed that after formation in the nucleus, Sirt3 is primarily located in the mitochondria, where it is activated and exerts its major function. Sirt3 then completed its pathway and moved back into the nucleus. Our data indicate that Sirt3 has an important function in regulating MnSOD, which results in decreased ROS in hippocampal cells. Sirt3 may have potential as an effective therapeutic target in SE conditions that would delay the progression of epileptogenesis. [ABSTRACT FROM AUTHOR]

Abstract In order to improve manganese-SOD stability, three mutations were constructed via site-directed mutagenesis, and the root mean square fluctuation (RMSF) and root mean square deviation (RMSD) were used as stability assessment indexes. The amino acids of V140, E155 and E215 from wild-type mouse Mn-SOD was replaced to L140, W155 and W215, and a recombinant plasmid containing DNA segment coding wild-type and mutant Mn-SOD protein was transformed into Escherichia coli BL21 for expression. The highest enzyme activity of the mutations-MnSOD was 2050 U/mg. In addition, the recombinant protein, TM-MnSODV140L, E155W, E215W exhibited higher working temperature and improved stability compared with the wild-type Mn-SOD. Furthermore, CD spectrum analysis of the improved mutants and wild-type enzyme showed that there was no significant change in their secondary structures. This study not only expands the scope of the application of enzymes, but also helps us understand the relationship between protein structure and function. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the possible association between the genetic polymorphism of the enzyme superoxide dismutase 2 (SOD2, also known as manganese-dependent SOD), Ala16Val (rs4880), and primary brain tumor risk in the Turkish population. Frequency of the SOD2 gene rs4880 polymorphism was identified in 225 Turkish individuals (120 controls and 105 patients with primary brain tumor) by polymerase chain reaction-restriction fragment length polymorphism. Subject demographics and clinical characteristics were also recorded. The findings were evaluated using logistic regression and χ2 tests. Logistic regression analysis indicated that smoking did not increase the risk for primary brain tumor [odds ratio (OR)=0.77, 95% confidence interval (CI)= 0.44-1.33, χ2=0.352, P=0.860]. Similarly, there was no statistically significant difference in the family history of cancer incidence between the control subjects and the primary brain tumor patients (OR=0.81, 95% CI=0.39-1.71, χ2=0.340, P=0.560). There was no significant association of the histopathological type, genotype/allele frequencies and inheritance models of tumor with the gene variants among the patients with primary brain tumor. In summary, the results of the present study indicated that the Ala16Val polymorphism of the SOD2 gene was not associated with primary brain tumor risk in the Turkish population studied. [ABSTRACT FROM AUTHOR]

In acidic soils with manganese (Mn) toxicity, arbuscular mycorrhizal fungi (AMF) can improve plant host growth by enhancing nutrition and protecting against environmental stress. The intact extraradical mycelium (ERM) of AMF is able to survive Mediterranean summer conditions and provide an earlier colonization of winter crops. This study evaluated if summer season conditions hindered the beneficial effects of wheat colonization by the intact ERM associated with a native plant, in acidic soil. Wheat was grown in soil with intact or disrupted ERM associated with Ornithopus compressus (ORN), developed for 7 or 24 weeks, to simulate ERM summer survival. The activity of antioxidant enzymes was determined, and the quantitative analysis of Mn and macronutrients was performed by inductively coupled plasma mass spectrometry (ICP-MS), in wheat shoots and respective subcellular fractions. Wheat colonization by intact ERM decreased shoot Mn concentration but increased the proportion of Mn in the apoplast. Overall, antioxidant enzymatic activity decreased but the proportion of Mn-superoxide dismutase activity over the remaining isoforms increased, suggesting its important role in the AMF-mediated mitigation of Mn toxicity. Summer conditions did not substantially reduce the benefits provided by ORN ERM. A no-till strategy allied to the development of native microbiota can contribute to the sustainable optimization of acidic soil use.

The crystal structure of 13R-manganese lipoxygenase (MnLOX) of Gaeumannomyces graminis (Gg) in complex with zonadhesin of Pichia pastoris was solved by molecular replacement. Zonadhesin contains β-strands in two subdomains. A comparison of Gg-MnLOX with the 9S-MnLOX of Magnaporthe oryzae (Mo) shows that the protein fold and the geometry of the metal ligands are conserved. The U-shaped active sites differ mainly due to hydrophobic residues of the substrate channel. The volumes and two hydrophobic side pockets near the catalytic base may sanction oxygenation at C-13 and C-9, respectively. Gly-332 of Gg-MnLOX is positioned in the substrate channel between the entrance and the metal center. Replacements with larger residues could restrict oxygen and substrate to reach the active site. C18 fatty acids are likely positioned with C-11 between Mn2+OH2 and Leu-336 for hydrogen abstraction and with one side of the 12Z double bond shielded by Phe-337 to prevent antarafacial oxygenation at C-13 and C-11. Phe-347 is positioned at the end of the substrate channel and replacement with smaller residues can position C18 fatty acids for oxygenation at C-9. Gg-MnLOX does not catalyze the sequential lipoxygenation of n-3 fatty acids in contrast to Mo-MnLOX, which illustrates the different configurations of their substrate channels.

Surgical intervention utilizing various approaches is a cornerstone in the management of breast cancer. The surgical approaches include lumpectomy, mastectomy, axillary lymph node dissection, and primary or delayed reconstruction. Post-mastectomy radiotherapy is frequently recommended in cases of advanced tumors and extensive lymph node involvement. However, there are several adverse effects of radiotherapy. In this article, we critically reviewed the various complications. Additionally, we discussed the biological basis of radiation-induced tissue damage, the impact of implant-based and autologous tissue reconstruction, and the functional and aesthetic results of the reconstruction. Indeed, several radioprotective agents can attenuate the adverse effects of post-mastectomy radiotherapy while sustaining oncologic efficacy. Radioprotective agents, including free radical scavengers and antioxidants, offer promising strategies to protect tissues from the oxidative stress and inflammation induced by radiotherapy. The role of several radioprotective agents, including amifostine, N-acetylcysteine, tempol, manganese superoxide dismutase (MnSOD) plasmid liposomes, vitamin E, and beta-carotene has been analyzed with a focus on their logistical applications in breast reconstruction. Despite several challenges, the integration of radioprotective agents into post-mastectomy radiotherapy protocols offers significant potential to improve reconstructive outcomes. Development of novel radioprotective agents with improved selectivity and fewer side effects and large-scale clinical trials in diverse group of patients are warranted to determine long-term safety and efficacy., Competing Interests: Competing interests All authors have read the manuscript and declare no conflict of interest. No writing assistance was utilized in the production of this manuscript.

Aim: To investigate the mechanism of p53-mediated suppression of heat stress-induced oxidative stress damage by manganese superoxide dismutase (MnSOD) in endothelial cells (ECs)., Methods: Primary ECs isolated from mouse aortas were used to examine the effects of heat stress on vascular ECs viability and apoptosis. We measured MnSOD expression, reactive oxygen species (ROS) production, p53 expression, viability, and apoptosis of heat stress-induced ECs. We also tested the protective effects of MitoQ10, a mitochondrial-targeted antioxidant, and Pifithrin-α, a p53 inhibitor, in ECs from a mouse model of heat stroke., Results: Heat stress increased cellular apoptosis, ROS production, and p53 expression, while reducing cellular viability and MnSOD expression in ECs. We also showed that the suppression of MnSOD expression by heat stress in ECs was mediated by interactions between p53 and Sp1. Furthermore, MitoQ10 and Pifithrin-α alleviated heat stress-induced oxidative stress and apoptosis in ECs., Conclusion: Our results revealed that p53-mediated MnSOD downregulation is a key mechanism for heat stress-induced oxidative stress damage in ECs and indicated that MitoQ10 and Pifithrin-α could be potential therapeutic agents for heat stroke., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jian Gong reports financial support was provided by Shenzhen City 10.13039/501100012245Science and Technology Planning Project of Guangdong Province (JCYJ20180228162214347). Jian Gong reports financial support was provided by Special fund for economic and technological development of Longgang District, Shenzhen city Medical and health science and technology program projects (LGWJ2021148). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)