SERPINA3K Protects against Oxidative Stress via Modulating ROS Generation/Degradation and KEAP1-NRF2 Pathway in the Corneal Epithelium

Zhou, Tong; Zong, Rongrong; Zhang, Zhoujing; Zhu, Chunhui; Pan, Fangyu; Xiao, Xifeng; Liu, Zhen; He, Hui; Xing, Jian; Liu, Zuguo; Yan, Zhou

doi:10.1167/iovs.12-9729

Cited by 37 publications

(36 citation statements)

References 36 publications

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“…HCECs were seeded onto poly‐ l ‐lysine‐coated slips. After treatment with DI (0.25 m m ) or PBS for 2 h, HCECs were incubated with A. fumigatus at 37°C for 8 h. The immunocytochemistry protocol has been described in previous studies …”

Section: Methodsmentioning

confidence: 99%

“…After treatment with DI (0.25 mM) or PBS for 2 h, HCECs were incubated with A. fumigatus at 37°C for 8 h. The immunocytochemistry protocol has been described in previous studies. 33 The anti-Nrf2 antibody (Abcam, Cambridge, MA, USA) was used as the primary antibody. Fluorescein isothiocyanateconjugated donkey antirabbit antibody (1:100; Bioss, Beijing, China) was used as the secondary antibody.…”

Section: Immunofluorescence Stainingmentioning

confidence: 99%

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Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway

Lin

Wang

et al. 2020

Immunol Cell Biol

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Dimethyl itaconate (DI) is a membrane‐permeable itaconate derivative with anti‐inflammatory functions. However, the anti‐inflammatory effect of DI has never been studied in fungal keratitis. In this study, we tested the protective effect of DI against fungal keratitis and assessed the role of NF‐E2‐related factor‐2 (Nrf2)/heme oxygenase‐1 (HO‐1) signaling in this process. Eyes of C57BL/6 (B6) mice were treated with 2 mm DI after infection with Aspergillus fumigatus. Human corneal epithelial cells (HCECs) were pretreated with 0.25 mm DI and then incubated with A. fumigatus. Clinical scoring, slit‐lamp photography, myeloperoxidase determination, flow cytometry and immunostaining were used to assess the disease response and treatment efficacy. PCR, Western blot and ELISA were used to assess the expression of interleukin‐1β (IL‐1β), chemokine (C–X–C motif) ligand 1, IL‐6, IL‐8, Nrf2 and HO‐1. In addition, quantification of viable fungi, absorbance assays and fluorimetry were used to measure DI fungistatic activity. We observed that DI‐treated eyes showed decreased clinical scores, fungal loads, polymorphonuclear neutrophil (PMN) infiltration and cytokine expression, compared with phosphate‐buffered saline‐treated infected eyes. DI treatment decreased the cytokine levels in infected corneas and in HCECs stimulated with A. fumigatus. Moreover, DI treatment increased Nrf2 and HO‐1 expression in corneas and nuclear Nrf2 accumulation in HCECs. DI‐induced cytokine downregulation was inhibited by pretreatment with an Nrf2 or HO‐1 inhibitor. Finally, DI treatment reduced the A. fumigatus absorbance and fungal mass. These data indicate that DI protects against fungal keratitis by limiting inflammation via the Nrf2/HO‐1 signaling pathway and that DI inhibits the growth of A. fumigatus.

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Section: Methodsmentioning

confidence: 99%

Section: Immunofluorescence Stainingmentioning

confidence: 99%

Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway

Lin

Wang

et al. 2020

Immunol Cell Biol

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“…53 Kallistatin also decreased H 2 O 2 -mediated oxidative stress and down-regulated NAD(P)H oxidase expression in rat corneal epithelium and human hepatic stellate cells. 61,62 In cultured endothelial cells, kallistatin via its heparin-binding site antagonized TNF-α and TGF-β-induced NADPH oxidase activity and expression, and thus ROS formation, 22,36,38 whereas kallistatin's active site was crucial for stimulating the synthesis of the antioxidant proteins eNOS, SIRT1 and FoxO1. 22 Furthermore, kallistatin exhibited antioxidant activity in cultured pterygium epithelial cells by increasing expression of superoxide dismutase 2 (SOD2), 63 which is mediated by FoxO1.…”

Section: Kallistatin Acts As An Antioxidant To Protect Against Organ mentioning

confidence: 99%

Protective Role of Kallistatin in Vascular and Organ Injury

2016

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Kallistatin is an endogenous protein that exerts pleiotropic effects, including vasodilation and inhibition of angiogenesis, inflammation, oxidative stress, apoptosis, fibrosis, and tumor progression. Through its two functional domains – an active site and a heparin-binding site – kallistatin regulates differential signaling pathways and a wide spectrum of biological functions. Kallistatin's active site is key for inhibiting tissue kallikrein activity, and stimulating the expression of endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1) and suppressor of cytokine signaling 3 (SOCS3). Kallistatin via its heparin-binding site blocks signaling pathways mediated by growth factors and cytokines, such as vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), high mobility group box-1 (HMGB1), Wnt, transforming growth factor-β (TGF-β), and epidermal growth factor (EGF). Kallistatin gene or protein delivery protects against the pathogenesis of hypertension, heart and kidney damage, arthritis, sepsis, influenza virus infection, tumor growth and metastasis in animal models. Conversely, depletion of endogenous kallistatin by neutralizing antibody injection exacerbates cardiovascular and renal injury in hypertensive rats. Kallistatin levels are markedly reduced in rodents with hypertension, sepsis, streptozotocin-induced diabetes, and cardiac and renal injury. Kallistatin levels are also diminished in patients with liver disease, septic syndrome, diabetic retinopathy, severe pneumonia, inflammatory bowel disease, and obesity, prostate and colon cancer. Therefore, circulating kallistatin levels may serve as a new biomarker for human diseases. This review summarizes kallistatin's protective roles and mechanisms in vascular and organ injury, and highlights the therapeutic potential of kallistatin for multiple disease states.

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“…Generally, Nrf2 is negatively regulated by Keap‐1 in the cytosol and upon activation, and Nrf2 dissociates from the Keap‐1, translocates to the nucleus, and binds to the DNA promoter region of antioxidant‐response element (ARE). Then, Nrf2 initiates the activation of various cytoprotective enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione S‐transferase P (David, Rifkin, Rabbani, & Ceradini, ; Zhou et al, ), NAD (P)H:quinone oxidoreductase 1 (Dinkova‐Kostova & Talalay, ), heme oxygenase‐1 (HO‐1) (Roy, Praneetha, & Vendra, ), glutathione reductase (GR), and glutathione‐S‐transferase (GST), which detoxify ROS through glutathione (GSH) regulation (Miyamoto et al, ).…”

Section: Introductionmentioning

confidence: 99%

The protective effect of kaempferol on heart via the regulation of Nrf2, NF‐κβ, and PI3K/Akt/GSK‐3β signaling pathways in isoproterenol‐induced heart failure in diabetic rats

Zhang

Guo

Wang

et al. 2019

Drug Development Research

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This study was designed to delineate the effect of kaempferol (KF) on heart failure (HF) in diabetic rats. Streptozotocin‐induced male diabetic rats received KF orally at 10 and 20 mg/kg for 42 consecutive days. In last 2 days of the experimental period, isoproterenol was subcutaneously injected at 85 mg/kg to induce HF. The hearts were processed for hemodynamic, biochemical, molecular, and histological investigations. Systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure were elevated in KF‐treated HF‐induced diabetic rats. Moreover, KF treatment resulted in decreased fasting blood glucose and glycosylated hemoglobin levels with increased serum insulin levels. Besides, serum cardiac injury markers like troponin‐I, creatine kinase‐muscle/brain, lactate dehydrogenase, and brain natriuretic peptide levels were significantly reduced in KF treatment. KF treatment has shown decrease in cardiac heme oxygenase‐1, nuclear factor erythroid 2–related factor 2 (Nrf‐2), and γ‐glutamylcysteine synthetase with increased Keap1 mRNA levels. The cardioprotection of KF was improved by inhibition of apoptosis via blocking phosphorylation of Akt/glycogen synthase kinase (GSK)‐3β and p38 mitogen‐activated protein‐kinase/extracellular signal‐regulated kinases signaling pathways in HF‐induced diabetic rats. Moreover, reduced cardiac apoptosis in KF treatment was confirmed by decreased terminal deoxynucleotidyl transferase dUTP nick‐end labeling (TUNEL) positive cells, histopathological changes in HF‐induced diabetic rats. Therefore, the cardioprotective effect of KF is attributed to the regulation of Nrf2, nuclear factor kappa‐light‐chain‐enhancer of activated B cells, and Akt/GSK‐3β signaling pathways in HF‐induced diabetic rats.

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SERPINA3K Protects against Oxidative Stress via Modulating ROS Generation/Degradation and KEAP1-NRF2 Pathway in the Corneal Epithelium

Abstract: Collectively, SA3K protects against oxidative stress by targeting the ROS generation/degradation system and modulating the KEAP1-NRF2 signaling pathway.

Cited by 37 publications

References 36 publications

Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway

Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway

Protective Role of Kallistatin in Vascular and Organ Injury

The protective effect of kaempferol on heart via the regulation of Nrf2, NF‐κβ, and PI3K/Akt/GSK‐3β signaling pathways in isoproterenol‐induced heart failure in diabetic rats

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