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    Superoxide dismutase 3 prevents early stage diabetic retinopathy in streptozotocin-induced diabetic rat model. Lee Ji-Yeon,Kim Mirinae,Oh Su Bin,Kim Hae-Young,Kim Chongtae,Kim Tae-Yoon,Park Young-Hoon PloS one PURPOSE:To identify the effects of superoxide dismutase (SOD)3 on diabetes mellitus (DM)-induced retinal changes in a diabetic rat model. METHODS:Diabetic models were established by a single intraperitoneal injection of streptozotocin (STZ) in Sprague-Dawley rats. After purification of the recombinant SOD3, intravitreal injection of SOD3 was performed at the time of STZ injection, and 1 and 2 weeks following STZ injection. Scotopic and photopic electroretinography (ERG) were recorded. Immunofluorescence staining with ɑ-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), pigment epithelium-derived factor (PEDF), Flt1, recoverin, parvalbumin, extracellular superoxide dismutase (SOD3), 8-Hydroxy-2'deoxyguanosine (8-OHdG) and tumor necrosis factor-ɑ (TNF-ɑ) were evaluated. RESULTS:In the scotopic ERG, the diabetic group showed reduced a- and b-wave amplitudes compared with the control group. In the photopic ERG, b-wave amplitude showed significant (p < 0.0005) reduction at 8 weeks following DM induction. However, the trend of a- and b-wave reduction was not evident in the SOD3 treated group. GFAP, Flt1, 8-OHdG and TNF-ɑ immunoreactivity were increased, and ɑ-SMA, PEDF and SOD3 immunoreactivity were decreased in the diabetic retina. The immunoreactivity of these markers was partially recovered in the SOD3 treated group. Parvalbumin expression was not decreased in the SOD3 treated group. In the diabetic retinas, the immunoreactivity of recoverin was weakly detected in both of the inner nuclear layer and inner plexiform layer compared to the control group but not in the SOD3 treated group. CONCLUSIONS:SOD3 treatment attenuated the loss of a/b-wave amplitudes in the diabetic rats, which was consistent with the immunohistochemical evaluation. We also suggest that in rod-dominant rodents, the use of blue on green photopic negative response (PhNR) is effective in measuring the inner retinal function in animal models of diabetic retinopathy. SOD3 treatment ameliorated the retinal Müller cell activation in diabetic rats and pericyte dysfunction. These results suggested that SOD3 exerted protective effects on the development of diabetic retinopathy. 10.1371/journal.pone.0262396
    SOD3 decreases ischemic injury derived apoptosis through phosphorylation of Erk1/2, Akt, and FoxO3a. Laatikainen Lilja E,Incoronato Mariarosaria,Castellone Maria Domenica,Laurila Juha P,Santoro Massimo,Laukkanen Mikko O PloS one BACKGROUND:Extracellular superoxide dismutase (SOD3), which dismutates superoxide anion to hydrogen peroxide, has been shown to reduce the free radical stress derived apoptosis in tissue injuries. Since both superoxide anion and hydrogen peroxide have a marked impact on signal transduction pathways and could potentially explain a number of apoptosis and survival -related phenomena in different pathological conditions, we clarified the impact of SOD3 on Akt and Erk1/2 cell survival pathways in rat hind limb injury model. METHODOLOGY AND PRINCIPAL FINDINGS:Based on our data, the hind limb ischemic rats treated with virally delivered sod3 have milder injury and less apoptosis than control animals that could be due to parallel activation of pro-proliferative and anti-apoptotic Erk1/2 and Akt pathways. The common downstream factor of both signaling pathways, the apoptosis related forkhead box protein O3a (FoxO3a), was phosphorylated and translocated to the cytoplasm in sod3 treated tissues and cell line. Additionally, we obtained increased mRNA production of elk-1, ets-1, and microRNA 21 (miR-21), whereas synthesis of bim mRNA was decreased in sod3 overexpressing tissues. We further showed that overexpression of sod3 modulated redox related gene expression by downregulating nox2 and inos when compared to injured control animals. CONCLUSIONS AND SIGNIFICANCE:The study shows the complexity of SOD3-derived effects on tissue injury recovery that are not limited to the reduction of superoxide anion caused cellular stress but highlights the impact of SOD3 related signal transduction on tissue functions and suggests an important role for SOD3 in attenuating cell stress effects in different pathological conditions. 10.1371/journal.pone.0024456
    Changes in expression of the antioxidant enzyme SOD3 occur upon differentiation of human bone marrow-derived mesenchymal stem cells in vitro. Nightingale Helen,Kemp Kevin,Gray Elizabeth,Hares Kelly,Mallam Elizabeth,Scolding Neil,Wilkins Alastair Stem cells and development The discovery that mesenchymal stem cells (MSCs) secrete SOD3 may help explain studies in which MSCs have direct antioxidant activities both in vivo and in vitro. SOD3 is an antioxidant enzyme that dismutes toxic free radicals produced during inflammatory processes. Therefore, MSC production and secretion of active and therapeutically significant levels of SOD3 would further support the use of MSCs as a cellular based antioxidant therapy. The aim of this study was therefore to investigate in vitro if MSC differentiation down the adipogenic, chondrogenic, and osteogenic lineages influences the expression of the antioxidant molecule SOD3. Human bone marrow MSCs and their differentiated progeny were cultured under standard conditions and both the SOD3 gene and protein expression examined. Following adipogenesis, cultures demonstrated that both SOD3 protein and gene expression are significantly increased, and conversely, following chondrogenesis SOD3 protein and gene expression is significantly decreased. Following osteogenesis there were no significant changes in SOD3 protein or gene expression. This in vitro study describes the initial characterization of SOD3 expression and secretion by differentiated MSCs. This should help guide further in vivo work establishing the therapeutic and antioxidative potential of MSC and their differentiated progeny. 10.1089/scd.2011.0516
    SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2α. Mira Emilia,Carmona-Rodríguez Lorena,Pérez-Villamil Beatriz,Casas Josefina,Fernández-Aceñero María Jesús,Martínez-Rey Diego,Martín-González Paula,Heras-Murillo Ignacio,Paz-Cabezas Mateo,Tardáguila Manuel,Oury Tim D,Martín-Puig Silvia,Lacalle Rosa Ana,Fabriás Gemma,Díaz-Rubio Eduardo,Mañes Santos Nature communications One drawback of chemotherapy is poor drug delivery to tumor cells, due in part to hyperpermeability of the tumor vasculature. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme usually repressed in the tumor milieu. Here we show that specific SOD3 re-expression in tumor-associated endothelial cells (ECs) increases doxorubicin (Doxo) delivery into and chemotherapeutic effect on tumors. Enhanced SOD3 activity fostered perivascular nitric oxide accumulation and reduced vessel leakage by inducing vascular endothelial cadherin (VEC) transcription. SOD3 reduced HIF prolyl hydroxylase domain protein activity, which increased hypoxia-inducible factor-2α (HIF-2α) stability and enhanced its binding to a specific VEC promoter region. EC-specific HIF-2α ablation prevented both the SOD3-mediated increase in VEC transcription and the enhanced Doxo effect. SOD3, VEC, and HIF-2α levels correlated positively in primary colorectal cancers, which suggests a similar interconnection of these proteins in human malignancy. 10.1038/s41467-018-03079-1
    Extracellular Vesicles from SOD3-Transduced Stem Cells Exhibit Improved Immunomodulatory Abilities in the Murine Dermatitis Model. Yang Ji Won,Seo Yoojin,Shin Tae-Hoon,Ahn Ji-Su,Oh Su-Jeong,Shin Ye Young,Kang Min-Jung,Lee Byung-Chul,Lee Seunghee,Kang Kyung-Sun,Hur Jin,Kim Yeon-Soo,Kim Tae-Yoon,Kim Hyung-Sik Antioxidants (Basel, Switzerland) The immunoregulatory abilities of mesenchymal stem cells (MSCs) have been investigated in various autoimmune and allergic diseases. However, the therapeutic benefits observed in preclinical settings have not been reproducible in clinical trials. This discrepancy is due to insufficient efficacy of MSCs in harsh microenvironments, as well as batch-dependent variability in potency. Therefore, to achieve more beneficial and uniform outcomes, novel strategies are required to potentiate the therapeutic effect of MSCs. One of simple strategies to augment cellular function is genetic manipulation. Several studies showed that transduction of antioxidant enzyme into cells can increase anti-inflammatory effects. Therefore, we evaluated the immunoregulatory abilities of MSCs introduced with extracellular superoxide dismutase 3 (SOD3) in the present study. SOD3-overexpressed MSCs (SOD3-MSCs) reduced the symptoms of murine model of atopic dermatitis (AD)-like inflammation, as well as the differentiation and activation of various immune cells involved in AD progression. Interestingly, extracellular vesicles (EVs) isolated from SOD3-MSCs delivered SOD3 protein. EVs carrying SOD3 also exerted improved therapeutic efficacy, as observed in their parent cells. These results suggest that MSCs transduced with SOD3, an antioxidant enzyme, as well as EVs isolated from modified cells, might be developed as a promising cell-based therapeutics for inflammatory disorders. 10.3390/antiox9111165
    Vascular endothelial growth factor C promotes breast cancer progression via a novel antioxidant mechanism that involves regulation of superoxide dismutase 3. Wang Chu-An,Harrell J Chuck,Iwanaga Ritsuko,Jedlicka Paul,Ford Heide L Breast cancer research : BCR INTRODUCTION:Triple-negative breast cancers, particularly the claudin-low subtype, are highly aggressive and exhibit increased tumor-initiating cell (TIC) characteristics. In this study, we demonstrate that vascular endothelial growth factor C (VEGF-C) is highly expressed in the claudin-low breast cancer subtype and also that it mediates tumor progression, not only through its role in lymphangiogenesis but also through regulating TIC characteristics and the response to reactive oxygen species (ROS). METHODS:VEGF C expression was examined in breast cancer subtypes, and a VEGF C expression signature was derived. VEGF C expression and/or its associated signature was correlated with TIC and chemoresistance signatures. In vitro and in vivo assays were performed to determine whether VEGF-C expression alters TIC characteristics and the response of breast cancer cells to chemotherapy and oxidative stress. Array analysis was used to identify a downstream effector of VEGF-C, superoxide dismutase 3 (Sod3), which was tested for its involvement in VEGF-C-mediated resistance to oxidative stress and enhancement of in vivo metastasis. The VEGF-C-associated receptor neuropilin 2 (Nrp2) was knocked down to determine whether it is required for the observed effects of VEGF-C. Expression of VEGF C and Sod3 was assessed in human breast cancers. RESULTS:VEGF C is highly expressed in claudin-low breast cancers, and VEGF C and the VEGF C signature are associated with TIC-related gene signatures. VEGF-C-knockdown in mammary carcinoma cells decreases TIC properties in vitro and in vivo, sensitizing cells to oxidative stress and chemotherapy. We identified Sod3 as a target of VEGF-C in breast cancer cells by demonstrating that it is required for VEGF-C-mediated cell survival in response to oxidative stress and for VEGF-C-mediated metastasis. We demonstrate that Nrp2 is the VEGF-C-associated receptor that mediates alterations in Sod3 expression and the response of tumor cells to oxidative stress. We show that VEGF C and Sod3 are positively associated in human breast cancer. CONCLUSIONS:We describe a novel mechanism by which VEGF-C contributes to metastasis via its ability to enhance TIC-associated characteristics, particularly the response to ROS. We identified Sod3 as a critical mediator of VEGF-C-induced metastasis, and we provide evidence that the VEGF-C-Sod3 axis plays a role in human breast cancers. 10.1186/s13058-014-0462-2
    Neonatal Extracellular Superoxide Dismutase Knockout Mice Increase Total Superoxide Dismutase Activity and VEGF Expression after Chronic Hyperoxia. Antioxidants (Basel, Switzerland) Bronchopulmonary dysplasia (BPD) is a common lung disease affecting premature infants that develops after exposure to supplemental oxygen and reactive oxygen intermediates. Extracellular superoxide dismutase (SOD3) is an enzyme that processes superoxide radicals and has been shown to facilitate vascular endothelial growth factor (VEGF) and nitric oxide (NO) signaling in vascular endothelium. We utilized a mouse model of neonatal hyperoxic lung injury and SOD3 knockout (KO) mice to evaluate its function during chronic hyperoxia exposure. Wild-type age-matched neonatal C57Bl/6 (WT) and SOD3 (KO) mice were placed in normoxia (21% FiO, RA) or chronic hyperoxia (75% FiO, O) within 24 h of birth for 14 days continuously and then euthanized. Lungs were harvested for histologic evaluation, as well as comparison of antioxidant enzyme expression, SOD activity, VEGF expression, and portions of the NO signaling pathway. Surprisingly, KO-O mice survived without additional alveolar simplification, microvascular remodeling, or nuclear oxidation when compared to WT-O mice. KO-O mice had increased total SOD activity and increased VEGF expression when compared to WT-O mice. No genotype differences were noted in intracellular antioxidant enzyme expression or the NO signaling pathway. These results demonstrate that SOD3 KO mice can survive prolonged hyperoxia without exacerbation of alveolar or vascular phenotype. 10.3390/antiox10081236
    Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages. Petersen Steen Vang,Poulsen Nanna Bach,Linneberg Matthiesen Cecilie,Vilhardt Frederik Antioxidants (Basel, Switzerland) Macrophages and related tissue macrophage populations use the classical NADPH oxidase (NOX2) for the regulated production of superoxide and derived oxidants for pathogen combat and redox signaling. With an emphasis on macrophages, we discuss how sorting into secretory storage vesicles, agonist-responsive membrane trafficking, and segregation into sphingolipid and cholesterol-enriched microdomains (lipid rafts) determine the subcellular distribution and spatial organization of NOX2 and superoxide dismutase-3 (SOD3). We discuss how inflammatory activation of macrophages, in part through small GTPase Rab27A/B regulation of the secretory compartments, mediates the coalescence of these two proteins on the cell surface to deliver a focalized hydrogen peroxide output. In interplay with membrane-embedded oxidant transporters and redox sensitive target proteins, this arrangement allows for the autocrine and paracrine signaling, which govern macrophage activation states and transcriptional programs. By discussing examples of autocrine and paracrine redox signaling, we highlight why formation of spatiotemporal microenvironments where produced superoxide is rapidly converted to hydrogen peroxide and conveyed immediately to reach redox targets in proximal vicinity is required for efficient redox signaling. Finally, we discuss the recent discovery of macrophage-derived exosomes as vehicles of NOX2 holoenzyme export to other cells. 10.3390/antiox10020172
    The dynamic uptake and release of SOD3 from intracellular stores in macrophages modulates the inflammatory response. Hu Lili,Zachariae Elias D,Larsen Ulrike G,Vilhardt Frederik,Petersen Steen V Redox biology Superoxide dismutase 3 (SOD3) is an extracellular enzyme with the capacity to modulate extracellular redox conditions by catalyzing the dismutation of superoxide to hydrogen peroxide. In addition to synthesis and release of this extracellular protein via the secretory pathway, several studies have shown that the protein also localizes to intracellular compartments in neutrophils and macrophages. Here we show that human macrophages release SOD3 from an intracellular compartment within 30 min following LPS stimulation. This release acutely increases the level of SOD3 on the cell surface as well as in the extracellular environment. Generation of the intracellular compartment in macrophages is supported by endocytosis of extracellular SOD3 via the LDL receptor-related protein 1 (LRP1). Using bone marrow-derived macrophages established from wild-type and SOD3 mice, we further show that the pro-inflammatory profile established in LPS-stimulated cells is altered in the absence of SOD3, suggesting that the active release of this protein affects the inflammatory response. The internalization and acute release from stimulated macrophages indicates that SOD3 not only functions as a passive antioxidant in the extracellular environment, but also plays an active role in modulating redox signaling to support biological responses. 10.1016/j.redox.2019.101268