Modulation of SOD3 Levels Is Detrimental to Retinal Homeostasis

Retinal oxidative stress is a common secondary feature of many retinal diseases. Though it may not be the initial insult, it is a major contributor to the pathogenesis of highly prevalent retinal dystrophic diseases like macular degeneration, diabetic retinopathy, and retinitis pigmentosa. We explored the role of superoxide dismutase 3 (SOD3) in retinal homeostasis since SOD3 protects the extracellular matrix (ECM) from oxidative injury. We show that SOD3 is mainly extracellularly localized and is upregulated as a result of environmental and pathogenic stress. Ablation of SOD3 resulted in reduced functional electroretinographic responses and number of photoreceptors, which is exacerbated with age. By contrast, overexpression showed increased electroretinographic responses and increased number of photoreceptors at young ages, but appears deleterious as the animal ages, as determined from the associated functional decline. Our exploration shows that SOD3 is vital to retinal homeostasis but its levels are tightly regulated. This suggests that SOD3 augmentation to combat oxidative stress during retinal degenerative changes may only be effective in the short-term.

Superoxide Dismutase 3-Transduced Mesenchymal Stem Cells Preserve Epithelial Tight Junction Barrier in Murine Colitis and Attenuate Inflammatory Damage in Epithelial Organoids

Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory bowel disease (IBD) have not been uncovered. Therefore, in the present study, we investigated whether SOD3 can protect intestinal cells or organoids from inflammation-mediated epithelial damage. Cells or mice were treated with SOD3 protein or SOD3-transduced mesenchymal stem cells (MSCs). Caco-2 cells or intestinal organoids stimulated with pro-inflammatory cytokines were used to evaluate the protective effect of SOD3 on epithelial junctional integrity. Dextran sulfate sodium (DSS)-induced colitis mice received SOD3 or SOD3-transduced MSCs (SOD3-MSCs), and were assessed for severity of disease and junctional protein expression. The activation of the mitogen-activated protein kinase (MAPK) pathway and elevated expression of cytokine-encoding genes decreased in TNF-α-treated Caco-2 cells or DSS-induced colitis mice when treated with SOD3 or SOD3-MSCs. Moreover, the SOD3 supply preserved the expression of tight junction (ZO-1, occludin) or adherence junction (E-cadherin) proteins when inflammation was induced. SOD3 also exerted a protective effect against cytokine- or ROS-mediated damage to intestinal organoids. These results indicate that SOD3 can effectively alleviate enteritis symptoms by maintaining the integrity of epithelial junctions and regulating inflammatory- and oxidative stress.

Tempeh extract reduces cellular ROS levels and upregulates the expression of antioxidant enzymes

Tempeh is an Indonesian traditional food produced from soybeans through a mould fermentation involving Rhizopus oligosporus. It is rich in bioactive phytochemicals, including isoflavones that are known to exhibit antioxidant activities. This study aimed to investigate the ability of tempeh ethanol extract to reduce cellular reactive oxygen species (ROS) levels in HepG2 cells in vitro. Tempeh extract exhibited greater total phenolics, total flavonoids and free radical inhibition capacity than soybean extract. Both tempeh extract and soybean extract reduced the basal levels of cellular ROS in the cells, but tempeh extract induced higher expression of antioxidant enzymes [catalase, superoxide dismutase-2 (SOD2) and superoxide dismutase-3 (SOD3)] compared to soybean extract. This study provides novel evidence suggesting the ability of tempeh to tackle cellular oxidative stress by upregulating the expression of antioxidant enzymes. These findings would give an insight into the potential of tempeh to be developed as a functional food beneficial for human health.

Association among extracellular superoxide dismutase genotype, plasma concentration, and comorbidity in the very old and centenarians

Superoxide dismutase 3 (SOD3), an antioxidant enzyme, is known as extracellular SOD (EC-SOD) because it is the predominant form in extracellular fluids. The diversity of plasma EC-SOD concentration is associated with the SOD3 p.R231G missense variant genotype. To clarify the association among SOD3 genotype, plasma EC-SOD concentration, and comorbidity in Oldest Old, we analyzed genome-wide associations with plasma EC-SOD concentration and associations between EC-SOD concentration and medical history classified by the SOD3 genotype in the Very Old (85–99 years old, n = 505) and Centenarians (over 100 years old, n = 595). The results revealed that SOD3 p.R231G was the most significant variant associated with plasma EC-SOD concentration. Although no significant difference was observed in medical histories between the SOD3 p.R231G variant non-carriers and carriers, higher EC-SOD concentration in plasma of SOD3 p.R231G variant non-carriers was associated with a high odds ratio for chronic kidney disease (OR = 2.70, 95% CI = 1.98–3.72) and low odds ratio for diabetes mellitus (DM) (OR = 0.61, 95% CI = 0.39–0.95). Comparison with 11 plasma biomarkers for age-related disease showed that plasma EC-SOD concentration correlated with adiponectin and estimated glomerular filtration rate with creatinine correction; therefore, we deduced that EC-SOD co-operates with adiponectin and possesses beneficial functions for DM in the Oldest Old.

Superoxide Dismutase 3 Controls the Activation and Differentiation of CD4+T Cells

Superoxide dismutase 3 (SOD3), a well-known antioxidant has been shown to possess immunomodulatory properties through inhibition of T cell differentiation. However, the underlying inhibitory mechanism of SOD3 on T cell differentiation is not well understood. In this study, we investigated the effect of SOD3 on anti-CD3/CD28- or phorbol myristate acetate (PMA) and ionomycin (ION)-mediated activation of mouse naive CD4+ T cells. Our data showed that SOD3 suppressed the expression of activation-induced surface receptor proteins such as CD25, and CD69, and cytokines production. Similarly, SOD3 was found to reduce CD4+T cells proliferation and suppress the activation of downstream pathways such as ERK, p38, and NF-κB. Moreover, naïve CD4+T cells isolated from global SOD3 knock-out mice showed higher expression of CD25, CD69, and CD71, IL-2 production, proliferation, and downstream signals compared to wild-type CD4+T cells. Whereas, the use of DETCA, a known inhibitor of SOD3 activity, found to nullify the inhibitory effect of SOD3 on CD4+T cell activation of both SOD3 KO and wild-type mice. Furthermore, the expression of surface receptor proteins, IL-2 production, and downstream signals were also reduced in Th2 and Th17 differentiated cells upon SOD3 treatment. Overall, our data showed that SOD3 can attenuate CD4+T cell activation through modulation of the downstream signalings and restrict CD4+T cell differentiation. Therefore, SOD3 can be a promising therapeutic for T cell-mediated disorders.