Manganese Superoxide Dismutase Activity Research Articles

Polydatin Attenuates Intra-Uterine Growth Retardation-Induced Liver Injury and Mitochondrial Dysfunction in Weanling Piglets by Improving Energy Metabolism and Redox Balance.

The present study investigated the potential of polydatin to protect against liver injury and the mitochondrial dysfunction of weanling piglets suffering from intra-uterine growth retardation (IUGR). Thirty-six normal birth weight weanling piglets and an equal number of IUGR littermates were given a basal diet with or without polydatin (250 mg/kg) from 21 to 35 d of age. Plasma and liver samples were collected to measure biochemistry parameters at 35 d of age. IUGR caused hepatic apoptosis, mitochondrial dysfunction, and oxidative damage, along with a lower efficiency of energy metabolism and inferior antioxidant ability. Polydatin decreased apoptotic rate, improved the features of mitochondrial damage, inhibited mitochondrial swelling and superoxide anion formation, and preserved mitochondrial membrane potential in the liver. Concurrently, polydatin promoted mitochondrial biogenesis, increased sirtuin 1 activity, and upregulated the expression levels of several genes related to mitochondrial function and fitness. Polydatin also facilitated mitochondrial oxidative metabolism with a beneficial outcome of increased energy production. Furthermore, polydatin mitigated the IUGR-induced reduction in manganese superoxide dismutase activity and prevented the excessive accumulation of oxidative damaging products in the liver. These findings indicate that polydatin confers protection against hepatic injury and mitochondrial dysfunction in the IUGR piglets by improving energy metabolism and redox balance.

Impacts of Mn, Fe, and Oxidative Stressors on MnSOD Activation by AtMTM1 and AtMTM2 in Arabidopsis.

It has been reported that the mitochondrial carrier family proteins of AtMTM1 and AtMTM2 are necessary for manganese superoxide dismutase (MnSOD) activation in Arabidopsis, and are responsive to methyl viologen (MV)-induced oxidative stress. In this study, we showed that MnSOD activity was enhanced specifically by Mn treatments. By using AtMnSOD-overexpressing and AtMnSOD-knockdown mutant plants treated with the widely used oxidative stressors including MV, NaCl, H2O2, and tert-butyl hydroperoxide (t-BH), we revealed that Arabidopsis MnSOD was crucial for root-growth control and superoxide scavenging ability. In addition, it has been reported that E. coli MnSOD activity is inhibited by Fe and that MTM1-mutated yeast cells exhibit elevated Fe content and decreased MnSOD activity, which can be restored by the Fe2+-specific chelator, bathophenanthroline disulfonate (BPS). However, we showed that BPS inhibited MnSOD activity in AtMTM1 and AtMTM2 single- and double-mutant protoplasts, implying that altered Fe homeostasis affected MnSOD activation through AtMTM1 and AtMTM2. Notably, we used inductively coupled plasma-optical emission spectrometry (ICP-OES) analysis to reveal an abnormal Fe/Mn ratio in the roots and shoots of AtMTM1 and AtMTM2 mutants under MV stress, indicating the importance of AtMTM1 in roots and AtMTM2 in shoots for maintaining Fe/Mn balance.

MnSOD functions as a thermoreceptor activated by low temperature

A conservative characteristic of manganese superoxide dismutase is the rapid formation of product inhibition at high temperatures. At lower temperatures, the enzyme is less inhibited and undergoes more catalytic fast cycles before being product-inhibited. The temperature-dependent kinetics could be rationalized by the temperature-dependent coordination in the conserved center of manganese superoxide dismutase. As temperature decreases, a water molecule (WAT2) approaches or even coordinates Mn as the sixth ligand to interfere with O2•--Mn coordination and reduce product inhibition, so the dismutation should mainly proceed in the fast outer-sphere pathway at low temperatures. Cold-activation is an adaptive response to low temperature rather than a passive adaptation to excess superoxide levels since the cold-activated dismutase activity significantly exceeds the amount of superoxide in the cell or mitochondria. Physiologically speaking, cold activation of manganese superoxide dismutase mediates cold stress signaling and transduces temperature (physical signal) degree into H2O2 fluxes (chemical signal), which in turn may act as a second messenger to induce a series of physiological responses such as cold shock.

The relationship between cognitive impairment and superoxide dismutase activity in untreated first-episode patients with schizophrenia

Objectives : Cognitive decline is an essential characteristic of schizophrenia and may be due to the disturbance between reactive oxygen species generation and antioxidant capacity. The study aimed to explore the association between cognitive deficits and antioxidant defence parameters in untreated first-episode patients with schizophrenia. Methods : We determined important antioxidant enzymes, total superoxide dismutase (SOD) and manganese SOD (MnSOD), and their relationship with cognitive impairment in 168 untreated patients with first-episode schizophrenia and 168 age- and sex-matched healthy controls. The evaluation of psychopathological symptoms of all patients was based on the Positive and Negative Syndrome Scale (PANSS). We measured cognitive function by the Repeated Battery for the Assessment of Neuropsychological Status (RBANS) and activities of total SOD and MnSOD in all participants. Results : The results showed that untreated patients with first-episode schizophrenia had deficient cognitive functioning in four RBANS indices and total scores, except for the visuospatial/constructional index, as well as higher plasma total SOD activity compared with the control subjects. In addition, significant negative correlations were identified between MnSOD activity and attention index or RBANS total score in patients. Conclusions : Our results suggest that oxidative stress may be partly responsible for cognitive dysfunction in the early course of schizophrenia.

Effects of Manganese Hydroxychloride on Growth Performance, Antioxidant Capacity, Tibia Parameters and Manganese Deposition of Broilers.

Simple SummaryManganese is a vital trace element for the growth of broilers. In order to meet the requirement of manganese in broiler production, the additives of manganese sources are usually added into the diet for broilers. Manganese hydroxychloride is a category of hydroxy trace minerals. The present study investigated the effect of dietary supplemental manganese as manganese hydroxychloride for growth performance, antioxidant capacity, tibial quality, and manganese deposition of broilers and recommended that optimal supplementation with manganese as manganese hydroxychloride in diets for broilers was 50–90 mg/kg. This study provides a rational recommendation for the application of manganese hydroxychloride in broiler diets.This study was conducted to investigate the effects of dietary supplementation with manganese hydroxychloride (MHC) on production performance, antioxidant capacity, tibial quality, and manganese (Mn) deposition of broilers. A total of 756 one-day-old male Arbor Acres broilers were randomly allotted to 7 treatments of 6 replicates with 18 broilers per replicate. Broilers were fed corn-soybean meal basal diets supplemented of 100 mg/kg Mn as Mn sulfate (MnSO4), or 0, 20, 40, 60, 80, 100 mg/kg Mn as MHC for 42 days. The growth performance of broilers was not affected by dietary MnSO4 or MHC (p > 0.05), whereas the dressing percentage increased linearly (p < 0.05) with increasing of dietary MHC addition level. The activities of catalase (CAT) and manganese superoxide dismutase (MnSOD), and total antioxidant capability (T-AOC) in serum and liver on day 42 increased linearly (p < 0.05) with increasing of dietary MHC level, while malondialdehyde (MDA) concentration reduced linearly (p < 0.05). The length, strength, and density index of tibia increased linearly (p < 0.05) on day 21 as MHC supplementation level increased; there were no differences between MnSO4 group and 40–100 mg/kg Mn as MHC groups in tibial parameters of broilers (p > 0.05). As supplemental MHC levels increased, the Mn contents in heart, liver, kidney, and tibia increased linearly on day 42 (p < 0.05). In summary, dietary supplementation with MHC improved antioxidant capacity, bone quality, and Mn contents in broilers, but no effects on growth performance were detected. Based on the results of this study, dietary inclusion of 50–90 mg/kg Mn in the form of MHC to broilers is recommended.

Protective Effect of Manganese on Apoptosis and Mitochondrial Function of Heat-Stressed Primary Chick Embryonic Myocardial Cells.

Heat stress, as a kind of oxidative stress, induces cell apoptosis. Apoptosis is a form of programmed cell death, and mitochondria play an important role in apoptosis. Manganese (Mn) has an antioxidant capacity by enhancing the activity of manganese superoxide dismutase (MnSOD). To investigate the potential effect of Mn on heat stress-induced apoptosis and mitochondrial function, we examined crucial related factors in the context of heat stress using primary chick embryonic myocardial cells pretreated with Mn for 24h. The results showed that Mn restored the heat stress-induced decrease in cell viability and reduced the activities of caspase-3 (P < 0.05). The repression of the Δψm and intracellular ATP content caused by heat stress was reversed dramatically in the Mn pretreatment group (P < 0.05). Additionally, Mn inhibited heat stress-induced mitochondrial fission, as shown by decreased mitochondrial fission-related protein dynamin-related protein 1 (Drp1) expression and increased mitochondrial fusion-related protein optic atrophy 1 (Opa1) and mitofusin 1 (Mfn1) (P < 0.05) in primary chick embryonic myocardial cells. It was concluded that Mn attenuates the mitochondrial-mediated apoptosis pathway and sustains mitochondrial structure and function under heat stress in primary chick embryonic myocardial cells.

A role for Snail-MnSOD axis in regulating epithelial-to-mesenchymal transition markers expression in RPE cells

Age-related macular degeneration (AMD) is a common cause of vision loss. The epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells, accompanied by oxidative damage, plays a crucial role in AMD. It is well known that manganese superoxide dismutase (MnSOD) encoded by SOD2 is a critical molecule in fighting against oxidative stress, and Snail encoded by SNAI1 is the essential transcription factor for EMT. However, the effect of MnSOD on EMT and the underlying mechanism in RPE cells remains unknown. In this study, we found that MnSOD knockdown triggered the EMT by upregulating Snail, while MnSOD overexpression reversed EMT even with TGFβ treatment in RPE cells, and the anti-oxidative stress activity of MnSOD mediated this observation. In addition, Snail depletion increased both expression and activity of MnSOD while Snail overexpression decreased MnSOD expression and activity, and Dual-luciferase reporter and ChIP assays showed that Snail directly bound to E-box (CACCTG) in the SOD2 promoter. Moreover, MnSOD over-expression and Snail interference co-treatment strengthened the anti-oxidation and EMT reversing. Therefore, our findings demonstrate that MnSOD prevents EMT of RPE cells in AMD through inhibiting oxidative injury to RPE. Moreover, a critical EMT transcription factor, Snail, functions as a new negative transcriptional factor of SOD2. Herein, the Snail-MnSOD axis forms a mutual loop in the development of AMD, which may be a novel systemic treatment target for preventing AMD.

Mitochondrial Sirtuin TcSir2rp3 Affects TcSODA Activity and Oxidative Stress Response in Trypanosoma cruzi.

Trypanosoma cruzi faces a variety of environmental scenarios during its life cycle, which include changes in the redox environment that requires a fine regulation of a complex antioxidant arsenal of enzymes. Reversible posttranslational modifications, as lysine acetylation, are a fast and economical way for cells to react to environmental conditions. Recently, we found that the main antioxidant enzymes, including the mitochondrial superoxide dismutase A (TcSODA) are acetylated in T. cruzi, suggesting that protein acetylation could participate in the oxidative stress response in T. cruzi. Therefore, we investigated whether mitochondrial lysine deacetylase TcSir2rp3 was involved in the activity control of TcSODA. We observed an increased resistance to hydrogen peroxide and menadione in parasites overexpressing TcSir2rp3. Increased resistance was also found for benznidazole and nifurtimox, known to induce reactive oxidative and nitrosactive species in the parasite, associated to that a reduction in the ROS levels was observed. To better understand the way TcSir2rp3 could contributes to oxidative stress response, we analyzed the expression of TcSODA in the TcSir2rp3 overexpressing parasites and did not detect any increase in protein levels of this enzyme. However, we found that these parasites presented higher levels of superoxide dismutase activity, and also that TcSir2rp3 and TcSODA interacts in vivo. Knowing that TcSODA is acetylated at lysine residues K44 and K97, and that K97 is located at a similar region in the protein structure as K68 in human manganese superoxide dismutase (MnSOD), responsible for regulating MnSOD activity, we generated mutated versions of TcSODA at K44 and K97 and found that replacing K97 by glutamine, which mimics an acetylated lysine, negatively affects the enzyme activity in vitro. By using molecular dynamics approaches, we revealed that acetylation of K97 induces specific conformational changes in TcSODA with respect to hydrogen-bonding pattern to neighbor residues, suggesting a key participation of this residue to modulate the affinity to . Taken together, our results showed for the first time the involvement of lysine acetylation in the maintenance of homeostatic redox state in trypanosomatids, contributing to the understanding of mechanisms used by T. cruzi to progress during the infection.

Dietary manganese levels influence growth, manganese bioaccumulation and expression of genes involved in antioxidant response of swimming crab ( Portunus trituberculatus )

An 8-week feeding trial was conducted to investigate the effects of dietary manganese (Mn) levels on growth performance, Mn bioaccumulation in tissues and antioxidant capacity in juvenile swimming crab (Portunus trituberculatus). Six semipurified experimental diets were formulated to contain graded levels of Mn (manganese sulphate monohydrate as Mn source); the analysed Mn concentrations were 9.8, 20.2, 29.7, 38.2, 65.6 and 123.6 mg/kg. The percent weight gain (PWG) and specific growth rate (SGR) were significantly affected by dietary Mn levels; the highest PWG and SGR were found in crabs fed with the diet containing 38.2 mg/kg Mn. Crabs fed with the diet containing 123.6 mg/kg Mn had higher Mn concentration in muscle and carapace than those fed with the other diets. However, the highest Mn concentration in hepatopancreas was recorded in crabs fed with the diet containing 65.6 mg/kg Mn. Moreover, the lowest activities of manganese superoxide dismutase (Mn-SOD), catalase (CAT) and total antioxidant capacity (T-AOC) occurred at crabs fed with the dietary 9.8 mg/kg Mn. Crabs fed with the 9.8 mg/kg Mn diet exhibited lower relative expression of genes involved into antioxidant ability such as cytosolic manganese superoxide dismutase (cMnsod), glutathione peroxidase (gpx), peroxiredoxin (prx) and catalase (cat) in hepatopancreas than those fed with the other diets, and the highest expression were recorded in crabs fed with the diet containing 38.2 mg/kg Mn. Based on two slope broken-line and quadratic regression analysis of PWG against dietary Mn levels, the optimum dietary Mn requirement was estimated to be 48.02 and 53.30 mg/kg for juvenile Portunus trituberculatus. The present study provided further insight into the function of dietary Mn in crustacean.

Molecular characterization, immune responses, and functional activities of manganese superoxide dismutase in disk abalone (Haliotis discus discus)

Superoxide dismutases (SODs) are metalloenzymes that convert superoxide radicals to H2O2 and O2. Although SODs have been extensively studied in mammals and other species, comparative studies in invertebrates, such as abalones, are lacking. Here, we aimed to characterize manganese superoxide dismutase in disk abalone (Haliotis discus discus) (AbMnSOD) by assessing its transcriptional levels at different embryonic developmental stages. Additionally, the temporal expression of AbMnSOD in different abalone tissues in response to bacterial, viral, and pathogen-associated molecular pattern (PAMP) stimuli was investigated. SOD activity was measured at various recombinant protein concentrations via the xanthine oxidase/WST-1 system. Cell viability upon exposure to H2O2, wound healing ability, and subcellular localization were determined in AbMnSOD-transfected cells. AbMnSOD was 681 bp long and contained the SOD-A domain. AbMnSOD expression was higher at the trochophore stage than at the other stages. When challenged with immune stimulants, AbMnSOD showed the highest expression at 6 h post-injection (p.i.) for all stimulants except lipopolysaccharides. In the gills, the highest AbMnSOD expression was observed at 6 h p.i., except for the Vibrio parahaemolyticus challenge. Recombinant AbMnSOD showed concentration-dependent xanthine oxidase activity. Furthermore, AbMnSOD-transfected cells survived H2O2-induced apoptosis and exhibited significant wound gap closure. As expected, AbMnSOD was localized in the mitochondria of the cells. Our findings suggest that AbMnSOD is an essential antioxidant enzyme that participates in regulating developmental processes and defense mechanisms against oxidative stress in hosts.

LncDACH1 promotes mitochondrial oxidative stress of cardiomyocytes by interacting with sirtuin3 and aggravates diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a common complication in diabetic patients. The molecular mechanisms of DCM remain to be fully elucidated. The intronic long noncoding RNA of DACH1 (lncDACH1) has been demonstrated to be closely associated with heart failure and cardiac regeneration. In this study, we investigated the role of lncDACH1 in DCM and the underlying molecular mechanisms. The expression of lncDACH1 was increased in DCM hearts and in high glucose-treated cardiomyocytes. Knockout of lncDACH1 reduced mitochondrial oxidative stress, cell apoptosis, cardiac fibrosis and hypertrophy, and improved cardiac function in DCM mice. Overexpression of lncDACH1 exacerbated mitochondria-derived reactive oxygen species (ROS) level and apoptosis, decreased activity of manganese superoxide dismutase (Mn-SOD); while silencing of lncDACH1 attenuated ROS production, mitochondrial dysfunction, cell apoptosis, and increased the activity of Mn-SOD in cardiomyocytes treated with high glucose. LncDACH1 directly bound to sirtuin3 (SIRT3) and facilitated its degradation by ubiquitination, therefore promoting mitochondrial oxidative injury and cell apoptosis in mouse hearts. In addition, SIRT3 silencing abrogated the protective effects of lncDACH1 deficiency in cardiomyocytes. In summary, lncDACH1 aggravates DCM by promoting mitochondrial oxidative stress and cell apoptosis via increasing ubiquitination-mediated SIRT3 degradation in mouse hearts. Inhibition of lncDACH1 represents a novel therapeutic strategy for the intervention of diabetic cardiomyopathy.

281 The Effects of Whole Cottonseed Supplementation on Performance, Breeding Soundness Exams, and Manganese Superoxide Dismutase Concentrations in the Blood and Semen of Beef Bulls

Abstract The objective of this research was to determine the effects of whole cottonseed containing gossypol on post-pubertal beef bulls. In a two-year study, 46 Angus and Red Angus bulls (body weight 457.0 ± 85.2 kg; 16 to 20-months of age) were stratified by BW and randomly assigned to 1 of 3 levels of whole cottonseed supplementation while receiving ad libitum roughage. The treatments included: DD (n = 14, control; 3.18 kg/d of dried distillers grain, W/D (n = 16; 1.59 kg/d of whole cottonseed and 1.59 kg/d of dried distillers grain), or WW (n = 16 3.18 kg/d of whole cottonseed). Diets were formulated to be isocaloric and isonitrogenous. In both years, bulls were weighed, administered a breeding soundness exam, and morphological characteristics of spermatozoa were measured on d 0, 28, and 60. In year 1, blood and semen samples were collected on d 0, 28, and 60 to measure manganese superoxide dismutase activity. There was no treatment effect for blood or semen manganese superoxide dismutase concentration (P &amp;gt; 0.255). There was a treatment effect (P &amp;lt; 0.02) for average daily gain as bulls fed WW gained less compared to those fed WD and DD (0.96, 1.23, and 1.39 kg/d, respectively). No treatment effect was observed for scrotal circumference (P &amp;gt; 0.50). There were no treatment × time interactions, treatment, or time main effects for percentages of normal spermatozoa, spermatozoa with coiled or folded tails, or proximal droplets (P &amp;gt; 0.12). There was a treatment effect on the amount of swollen midpiece or abnormal head as bull in the DD treatment had a greater (P &amp;lt; 0.02) percentage of other abnormalities compared to WW, but WD was not different (P &amp;gt; 0.16). Inclusion of whole cottonseed may affect average daily gain, but does not affect reproductive parameters of beef bulls.

A potential role of Sirtuin3 and its target enzyme activities in patients with ovarian endometrioma

Objective Sirtuin3 (SIRT3) is a NAD+-dependent major mitochondrial deacetylase. In this study, we aimed to investigate SIRT3 levels and their target enzyme activities, including glutamate dehydrogenase (GDH), succinate dehydrogenase (SDH), and manganese superoxide dismutase (MnSOD), also to determine the antioxidant capacity and oxidative stress in tissue, mitochondria and serum samples in ovarian endometrioma patients. Methods We collected serum and endometrioma tissue samples from 30 patients. In the control group, we collected serum and eutopic endometrial tissue samples from 26 women without endometriosis. Results SIRT3 levels were significantly decreased in endometrioma tissue samples compared to the control group. There was no statistically significant difference in SIRT3 levels between patient and control serum samples. Furthermore, there was a decrease in GDH and SDH enzyme activities in both endometrioma tissue homogenate and mitochondria. MnSOD activity was decreased in tissue homogenate but increased in mitochondria and there was no difference in serum. While total SOD activity was decreased, CuZnSOD activity was increased in both tissue and serum samples. Besides these, total antioxidant capacity and advanced oxidation protein products (AOPP) levels were decreased in endometrioma tissue and mitochondria, but there was no difference in serum. Conclusions Our results suggested that decreased levels of SIRT3 in endometrioma may be an important factor in the weakening of mitochondrial energy metabolism and antioxidant defense in endometriosis. We think that SIRT3 deficiency may be an important factor underlying the pathogenesis of endometriosis. More detailed studies are needed to reveal the relationship between SIRT3 and metabolism and oxidative stress in ovarian endometrioma.

Protective effects of lycopene on mitochondrial oxidative injury and dysfunction in the liver of aflatoxin B1-exposed broilers

This study was conducted to investigate the effects of lycopene (LYC) on mitochondrial oxidative injury and dysfunction in the liver of aflatoxin B1 (AFB1)-exposed broilers. A total of 192 healthy 1-day-old male broilers were randomly divided into 3 groups with 8 replicates of 8 birds each. Birds in the 3 groups were fed basal diet (control), basal diet with 100 µg/kg AFB1, and basal diet with 100 µg/kg AFB1 and 200 mg/kg LYC, respectively. The experiment lasted 42 d. The results showed that AFB1 decreased average daily body weight gain (ADG), average daily feed intake, and gain to feed ratio (G :F) compared to the control group, the LYC supplementation increased ADG and G/F compared to AFB1 group (P < 0.05). Broilers in the AFB1 group had lower mitochondrial glutathione (mGSH) concentration and glutathione peroxidase (GSH-Px), manganese superoxide dismutase (MnSOD), and thioredoxin reductase activities, and higher hydrogen peroxide (H2O2) and reactive oxygen species (ROS) concentrations than the control group (P < 0.05). The LYC increased mGSH concentration and GSH-Px and MnSOD activities, and decreased H2O2 and ROS concentrations compared to AFB1 group (P < 0.05). Broilers fed the AFB1 diet showed increased mitochondrial swelling and decreased adenosine triphosphate concentration than the control group, and LYC had opposite effects (P < 0.05). The AFB1 decreased the activities of mitochondrial electron transfer chain (ETC) complexes I, II, III, and V, downregulated the mRNA expression levels of hepatic MnSOD, thioredoxin 2, thioredoxin reductase, peroxiredoxin-3, peroxisome proliferator-activated receptor γ coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor A compared with the control group (P < 0.05), and LYC increased activities of mitochondrial ETC complexes III and V, and upregulated mRNA expression levels of these genes in comparison to AFB1 group (P < 0.05). In conclusion, the LYC protected broilers from AFB1-induced liver mitochondrial oxidative injury and dysfunction by stimulating mitochondrial antioxidant capacity and maintaining mitochondrial biogenesis.

Manganese Mitigates Heat Stress–Induced Apoptosis by Alleviating Endoplasmic Reticulum Stress and Activating the NRF2/SOD2 Pathway in Primary Chick Embryonic Myocardial Cells

Heat stress leads to oxidative stress and induces apoptosis in various cells. Endoplasmic reticulum (ER) stress is an important apoptosis pathway. Manganese (Mn) has been shown to enhance the activity of manganese superoxide dismutase (MnSOD). To explore the potential effect of Mn on ER stress and apoptosis induced by heat stress, we examined crucial factors associated with heat stress, ER stress, and apoptosis in cultured primary chick embryonic myocardial cells that had been pretreated with 20μM Mn for 24h and then subjected to 4h of heat stress. The results showed that Mn decreased (P < 0.05) heat stress-induced reactive oxygen species (ROS) production and exerted antiapoptotic effects by increasing MnSOD enzymatic activity. The heat stress-induced accumulation of intracellular calcium was dramatically reduced (P < 0.05). Mn treatment significantly decreased (P < 0.05) the expression levels of the apoptosis-related gene Bax and ER stress markers glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP) in primary chick embryonic myocardial cells. Additionally, Mn reduced oxidative stress by activating the nuclear factor E2-related factor 2 (NRF2)/SOD2 signaling pathway. Taken together, our findings indicate that Mn attenuates heat stress-induced apoptosis by inhibiting ROS generation, intracellular calcium accumulation, and the ER stress pathway and activating the NRF2/SOD2 signaling pathway to protect myocardial cells from oxidative stress during chick embryonic development.

Gene Therapy for Systemic or Organ Specific Delivery of Manganese Superoxide Dismutase.

Manganese superoxide dismutase (MnSOD) is a dominant component of the antioxidant defense system in mammalian cells. Since ionizing irradiation induces profound oxidative stress, it was logical to test the effect of overexpression of MnSOD on radioresistance. This task was accomplished by introduction of a transgene for MnSOD into cells in vitro and into organs in vivo, and both paradigms showed clear radioresistance following overexpression. During the course of development and clinical application of using MnSOD as a radioprotector, several prominent observations were made by Larry Oberley, Joel Greenberger, and Michael Epperly which include (1) mitochondrial localization of either manganese superoxide dismutase or copper/zinc SOD was required to provide optimal radiation protection; (2) the time required for optimal expression was 12–18 h, and while acceptable for radiation protection, the time delay was impractical for radiation mitigation; (3) significant increases in intracellular elevation of MnSOD activity were required for effective radioprotection. Lessons learned during the development of MnSOD gene therapy have provided a strategy for delivery of small molecule SOD mimics, which are faster acting and have shown the potential for both radiation protection and mitigation. The purpose of this review is to summarize the current status of using MnSOD-PL and SOD mimetics as radioprotectors and radiomitigators.

Conjugated linoleic acid attenuates neuropathic pain induced by sciatic nerve in mice

Purpose: Conjugated linoleic acid (CLA) has been suggested to be necessary for human health, but there is limited research regarding its effect on neuropathic pain (NP). Here, we aim to investigate the potential effect of CLA administration on NP development and nerve recovery.&#x0D; Methods: Forty mice were divided into four equal groups randomly. The mice in control group underwent a sham operation to achieve a unilateral sciatic nerve cut. Other groups were subjected to partial sciatic nerve ligation (PSNL) surgery followed by 4 weeks of CLA treatment. Behavioral tests were performed shortly before mice were sacrificed. Blood, sciatic nerve and spinal cord tissues were collected after sacrifice. Electron microscopy was performed to determine myelin thickness and calculate myelin thickness/axon diameter ratio.&#x0D; Results: Mice that received daily oral CLA treatment for 4 weeks after PSNL surgery showed less mechanical and thermal allodynia than mice in PSNL surgery alone group. Behavioral tests showed that CLA treatment was associated with marked increases in both nerve conduction velocity (NCV) and force of gastrocnemius contraction. In addition, CLA reduced the levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), sciatic myeloperoxidase (MPO) activity, and activating transcription factor-3 (ATF-3) expression. CLA also restored mitochondrial manganese superoxide dismutase (MnSOD) activity which was decreased in the sciatic nerves and spinal cords of the PSNL surgery group. Regeneration of myelins and axons in nerve fibers in CLA group was faster and more complete than that in the vehicle group.&#x0D; Conclusion: The current study demonstrates that CLA effectively attenuates NP and significantly inhibits neuro-inflammation and oxidative stress. This treatment improves sciatic nerve form and function after injury, suggesting that it can attenuate NP.

Parecoxib alleviates the motor behavioral decline of aged rats by ameliorating mitochondrial dysfunction in the substantia nigra via COX-2/PGE2 pathway inhibition

Mitochondrial dysfunction manifests as an early event in the substantia nigra (SN) in aging and Parkinson disease. Cyclooxygenase 2 (COX-2), the rate-limiting enzyme in the prostaglandin E2 (PGE2) synthesis pathway, is implicated in aging and age-related neurodegenerative diseases; moreover, inhibition of COX-2 expression has been shown to be neuroprotective for nigrostriatal dopaminergic neurons. However, it is not known whether the neuroprotective effect of COX-2 inhibition is related to improved mitochondrial function during the aging process. To this end, we explored the effects of the selective COX-2 inhibitor parecoxib on mitochondrial function in the SN of aged rats. We found that parecoxib administration to aged rats for 10 weeks decreased COX-2/PGE2 expression, increased tyrosine hydroxylase and dopamine transporter expression in nigrostriatal dopaminergic neurons, and alleviated motor behavioral decline. Decreased malondialdehyde levels and an increased GSH/GSSG ratio as well as enhanced enzymatic activities of catalase and manganese superoxide dismutase in parecoxib-treated aged rats indicate that parecoxib administration elevated antioxidative ability in the SN during the aging process. Parecoxib treatment to aged rats promoted mitochondrial biogenesis by upregulating PGC-1α/NRF-1/TFAM, enhancing mitochondrial fusion by decreasing Drp1 levels and increasing Mfn1 and OPA1 levels, and activated mitophagy by increasing PINK1/Parkin levels while reducing p62/SQSTM1 levels, thereby coordinating mitochondrial homeostasis via inhibiting the COX-2/PGE2 pathway. Thus, our results strongly support the conclusion that parecoxib treatment is conducive to improving mitochondrial dysfunction in the SN upon aging in rats.

Melatonin postconditioning ameliorates anoxia/reoxygenation injury by regulating mitophagy and mitochondrial dynamics in a SIRT3-dependent manner

Ischaemia/reperfusion (I/R) injury is accompanied by excessive mitochondrial autophagy (mitophagy) and an imbalance in mitochondrial dynamics. Melatonin has been reported to alleviate I/R injury by regulating mitophagy and mitochondrial dynamics. However, the underlying mechanism associated with this activity is not fully understood. The goal of the present study was to investigate whether and how melatonin administration at the beginning of reoxygenation exerts protective effects by regulating mitophagy and mitochondrial dynamics. H9c2 cells were transfected with sirtuin 3 (SIRT3)-targeting siRNA and then subjected to anoxia/reoxygenation (A/R) injury, with melatonin (150 μM) administered at the onset of reoxygenation. Biomarkers related to cellular apoptosis, oxidative stress, mitochondrial function, mitophagy and mitochondrial dynamics were assessed, and the expression and activity of SIRT3 was also measured. Mitochondrial fission and mitophagy were activated after A/R injury and were accompanied by cellular apoptosis, oxidative stress, and mitochondrial dysfunction. However, melatonin postconditioning inhibited excessive mitochondrial fission and mitophagy, promoted mitochondrial fusion, restored mitochondrial function and reduced cellular apoptosis, and the mitophagy inhibitor 3-methyladenine (3-MA) also attenuated A/R-induced apoptosis. Moreover, the A/R-induced decreases in SIRT3 and manganese superoxide dismutase (SOD2) activities were ameliorated by melatonin. However, SIRT3 silencing abolished the beneficial effects of melatonin, eliminated the inhibitory effects of melatonin on mitochondrial fission and mitophagy, and reversed the melatonin-induced increase in SOD2 activity. These results indicate that melatonin postconditioning protects H9c2 cells from A/R injury by inhibiting excessive mitophagy and maintaining the balance of mitochondrial fission and fusion in a SIRT3-dependent manner.

58 The Effect of Altering Dietary Manganese and Selenium Levels on the Growth Performance and Blood Manganese-superoxide Dismutase Activity in Nursery Pigs

Abstract The objective of this study was to determine the effect of altering dietary levels of manganese and selenium on growth performance and MnSOD specific activity. Weaned piglets were blocked by weight (n = 216; 5.21 ± 1.17 kg; 21 ± 3 d) and sex (2 barrows and 2 gilts/pen). Pens within a block were randomly assigned to dietary treatments in a factorial design with main effects of Se (0.1 and 0.3 ppm) and Mn (0, 12, and 24 ppm). Diets (n = 9 pens/treatment) were fed in three phases (P1 = d 1–7, P2 = d 7–21, P3 = d 21–35). Pigs and orts were weighed weekly and pigs were bled on d 0, 7, 21, and 35 for analysis of specific activity of red blood cell MnSOD. Data were analyzed as 2x3 factorial design via SAS PROC GLM. There were no Se effects or Mn x Se interactions observed. There was a linear increase (P &amp;lt; 0.05) in overall ADG (397, 424, and 438 g day-1pig-1 for 0, 12, 24 ppm Mn, respectively). There was a linear trend (P &amp;lt; 0.1) in overall ADFI (557, 560, 592 g day-1pig-1 for 0, 12, 24 ppm Mn, respectively). Feed efficiency (d 0–35) across increasing Mn levels were 0.71, 0.76, 0.74 (P &amp;gt; 0.1). MnSOD activity in RBC increased from d 0–7, peaked on d 7 and decreased to d 35. On d 7, diets with 12 and 0 ppm Mn had significantly increased (P &amp;lt; 0.05) MnSOD activity (0.91 and 0.87 IU mg-1 protein, respectively) compared to diets with 24 ppm Mn (0.67 IU mg-1 protein). The dietary treatment that best maintained MnSOD activity was 0.3 ppm Se and 12 ppm Mn supplemented, while ADG was maximized in the diet with 0.3 ppm Se and 24 ppm Mn supplementation.