Abstract 123: Age-Related Endothelial Senescence is Driven by Thrombospondin-1-Activated NADPH Oxidase Nox1

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Daniel N Meijles ◽  
Imad Al Ghouleh ◽  
Sanghamitra Sahoo ◽  
Jefferson H Amaral ◽  
Heather Knupp ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Vascular Diseases ◽  
Dependent Manner ◽  
Wild Type ◽  
Molecular Control ◽  
Redox Biology ◽  
Age Related ◽  
P53 Activation

Organismal aging represents an independent risk factor underlying many vascular diseases, including systemic and pulmonary hypertension, and atherosclerosis. While the mechanisms driving aging are largely elusive, a steady persistent increase in tissue oxidative stress has been associated with senescence. Previously we showed TSP1 elicits NADPH oxidase (Nox)-dependent vascular smooth muscle cell oxidative stress. However mechanisms by which TSP1 affects endothelial redox biology are unknown. Here, we tested the hypothesis that TSP1 induces endothelial oxidative stress-linked senescence in aging. Using rapid autopsy disease-free human pulmonary (PA) artery, we identified a significant positive correlation between age, protein levels of TSP1, Nox1 and the cell-cycle repressor p21cip (p<0.05). Age also positively associated with increased Amplex Red-detected PA hydrogen peroxide levels (p<0.05). Moreover, treatment of human PA endothelial cells (HPAEC) with TSP1 (2.2nM; 24h) increased expression (~1.9 fold; p<0.05) and activation of Nox1 (~1.7 fold; p<0.05) compared to control, as assessed by Western blot and SOD-inhibitable cytochrome c reduction. Western blotting and immunofluorescence showed a TSP1-mediated increase in p53 activation, indicative of the DNA damage response. Moreover, TSP1 significantly increased HPAEC senescence in a p53/p21cip/Rb-dependent manner, as assessed by immunofluorescent detection of subcellular localization and senescence-associated β-galactosidase staining. To explore this pathway in vivo, middle-aged (8-10 month) wild-type and TSP1-null mice were utilized. In the TSP1-null, reduced lung senescence, oxidative stress, Nox1 levels and p21cip expression were observed compared to wild-type supporting findings in human samples and cell experiments. Finally, prophylactic treatment with specific Nox1 inhibitor NoxA1ds (10μM) attenuated TSP1-induced HPAEC ROS, p53 activation, p21cip expression and senescence. Taken together, our results provide molecular insight into the functional interplay between TSP1 and Nox1 in the regulation of endothelial senescence, with implications for molecular control of the aging process.

Abstract 200: CD40 Signaling Mediates Postischemic Inflammation, Oxidative Stress, And Tissue Injury Following Focal Cerebral Ischemia

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Rong Jin ◽  
Zifang Song ◽  
Shiyong Yu ◽  
Daniel J Daunis ◽  
Brittany S Hopkins ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Nadph Oxidase ◽  
Tissue Damage ◽  
Tissue Injury ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Wild Type ◽  
Cox 2

Rationale: Although CD40/CD40 ligand (CD40L) signaling has been implicated in clinical and experimental ischemic strokes, the underlying mechanisms are largely unclear. Objective: We investigated how CD40 participates in the cellular and molecular events underlying the postischemic inflammation and oxidative stress that may contribute to the tissue damage during cerebral ischemia. Methods and Results: Wild-type (WT, n=164) and CD40 knockout mice (n=132) were subjected to middle cerebral artery occlusion (MCAO, 60 minutes) followed by reperfusion. We found that ischemia/reperfusion induced CD40 expression in the brain in a time-dependent manner, primarily localized to the microvascular endothelial cells in the early phase (6h) and then to the activated microglia in the later time (24h). The adhesion and infiltration of neutrophils as well as the activation and expansion of microglia induced by ischemia/reperfusion were inhibited in CD40-/- mice, which were time-dependently correlated with suppressing nuclear factor-kB activation and proinflammatory cytokines (IL-1β, TNFα) and adhesion molecules (E- and P-selectin, ICAM-1,MCP-1). Infarct volumes and mortality were reduced in CD40-/- mice at 72h after ischemia/reperfusion. Treatment with an inhibitor of either NADPH oxidase or COX-2, the known enzymes that contributes to the tissue damage, reduced ischemic brain injury in wild-type mice, but not in CD40-/- mice. In contrast, treatment with an inhibitor of inducible nitric oxide synthase (iNOS) further reduced tissue injury in CD40-/- mice. Consistently, ischemia/reperfusion-induced upregulation of NADPH oxidase (Nox2, and Nox4) and COX-2, but not iNOS, were attenuated in CD40-/- mice. Conclusions: The findings unveil an essential role for CD40 in the regulation of early molecular and cellular events leading to postischemic inflammation. Inhibition of CD40 signaling may be a valuable therapeutic approach to counteract the deleterious effects of postischemic inflammation.

scholarly journals The Protective Effects of α-Mangostin Attenuate Sodium Iodate-Induced Cytotoxicity and Oxidative Injury via Mediating SIRT-3 Inactivation via the PI3K/AKT/PGC-1α Pathway

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1870
Author(s):  
Chen-Ju Chuang ◽  
Meilin Wang ◽  
Jui-Hsuan Yeh ◽  
Tzu-Chun Chen ◽  
Shang-Chun Tsou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Caspase 3 ◽  
Cell Damage ◽  
Outer Nuclear Layer ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Dependent Manner ◽  
Protective Effects ◽  
Age Related

It is well known that age-related macular degeneration (AMD) is an irreversible neurodegenerative disease that can cause blindness in the elderly. Oxidative stress-induced retinal pigment epithelial (RPE) cell damage is a part of the pathogenesis of AMD. In this study, we evaluated the protective effect and mechanisms of alpha-mangostin (α-mangostin, α-MG) against NaIO3-induced reactive oxygen species (ROS)-dependent toxicity, which activates apoptosis in vivo and in vitro. MTT assay and flow cytometry demonstrated that the pretreatment of ARPE-19 cells with α-MG (0, 3.75, 7.5, and 15 μM) significantly increased cell viability and reduced apoptosis from NaIO3-induced oxidative stress in a concentration-dependent manner, which was achieved by the inhibition of Bax, cleaved PARP-1, cleaved caspase-3 protein expression, and enhancement of Bcl-2 protein. Furthermore, pre-incubation of ARPE-19 cells with α-MG markedly inhibited the intracellular ROS and extracellular H2O2 generation via blocking of the abnormal enzyme activities of superoxide dismutase (SOD), the downregulated levels of catalase (CAT), and the endogenous antioxidant, glutathione (GSH), which were regulated by decreasing PI3K-AKT-PGC-1α-STRT-3 signaling in ARPE-19 cells. In addition, our in vivo results indicated that α-MG improved retinal deformation and increased the thickness of both the outer nuclear layer and inner nuclear layer by inhibiting the expression of cleaved caspase-3 protein. Taken together, our results suggest that α-MG effectively protects human ARPE-19 cells from NaIO3-induced oxidative damage via antiapoptotic and antioxidant effects.

scholarly journals Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis

2019 ◽  
Author(s):  
Simon Couly ◽  
Bilal Khalil ◽  
Véronique Viguier ◽  
Julien Roussel ◽  
Tangui Maurice ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
High Energy ◽  
Dependent Manner ◽  
Wild Type ◽  
Sigma 1 Receptor ◽  
Atp Levels ◽  
Sigma 1 ◽  
Lateral Sclerosis

Abstract Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that regulates mitochondrial respiration but also controls cellular defense against ER and oxidative stress. This makes S1R a potential therapeutic target in amyotrophic lateral sclerosis (ALS). Especially, as a missense mutation E102Q in S1R has been reported in few familial ALS cases. However, the pathogenicity of S1RE102Q and the beneficial impact of S1R in the ALS context remain to be demonstrated in vivo. To address this, we generated transgenic Drosophila that express human wild-type S1R or S1RE102Q. Expression of mutant S1R in fly neurons induces abnormal eye morphology and locomotor defects in a dose-dependent manner. This was accompanied by abnormal mitochondrial fragmentation, reduced ATP levels and a higher fatigability at the neuromuscular junction during high energy demand. Overexpressing IP3 receptor or glucose transporter mitigates the S1RE102Q-induced eye phenotype, further highlighting the role of calcium and energy metabolism in its toxicity. More importantly, we showed that wild-type S1R rescues locomotor activity and ATP levels of flies expressing the key ALS protein, TDP43. Moreover, overexpressing wild-type S1R enhances resistance of flies to oxidative stress. Therefore, our data provide the first genetic evidence that mutant S1R recapitulates ALS pathology in vivo while increasing S1R confers neuroprotection against TDP43 toxicity.

Hexagonal boron nitride nanoparticles trigger oxidative stress by modulating thiol/disulfide homeostasis

2021 ◽  
pp. 096032712110028
Author(s):  
F Kar ◽  
İ Söğüt ◽  
C Hacıoğlu ◽  
Y Göncü ◽  
H Şenturk ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Boron Nitride ◽  
Hexagonal Boron Nitride ◽  
Chemical Properties ◽  
Heart Tissue ◽  
Albino Rats ◽  
Dependent Manner ◽  
Tissue Samples ◽  
Boron Nitride Nanoparticles

Background: Hexagonal boron nitride nanoparticles (hBN NPs) are encouraging nanomaterials with unique chemical properties in medicine and biomedical fields. Until now, the optimal hBN NP’s dosage and biochemical mechanism that can be used for in vivo systems has not been fully revealed. The main aim of this article is to reveal characteristics, serum and tissue interactions and any acute cytotoxic effect of different dose of hBN NPs for the first time. Methods: hBN NPs at concentrations varying between 50–3200 µg/kg was administered by intravenous injection to Wistar albino rats (n = 80) divided into seven dosage and control groups. Blood and tissue samples were taken after 24 hours. Results: Our findings suggested that higher doses hBN NPs caused oxidative stress on the serum of rats dose-dependently. However, hBN NPs did not affect thiol/disulfide homeostasis on kidney, liver, spleen, pancreas and heart tissue of rats. Furthermore, hBN NPs increased serum disulfide formation by disrupting the thiol/disulfide balance in rats. Also, LOOH and MPO levels increased at high doses, while CAT levels decreased statistically. Conclusion: The results revealed that hBN NPs induce oxidative stress in a dose-dependent manner by modulating thiol/disulfide homeostasis in rats at higher concentrations

scholarly journals Impact of Polyphenolic-Food on Longevity: An Elixir of Life. An Overview

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 507
Author(s):  
Rosaria Meccariello ◽  
Stefania D’Angelo
Keyword(s):  
Oxidative Stress ◽  
Food Sources ◽  
Preventive Action ◽  
Nutritional Interventions ◽  
Beneficial Effects ◽  
Age Related ◽  
Macromolecular Damage ◽  
And Oxidative Stress

Aging and, particularly, the onset of age-related diseases are associated with tissue dysfunction and macromolecular damage, some of which can be attributed to accumulation of oxidative damage. Recently, growing interest has emerged on the beneficial effects of plant-based diets for the prevention of chronic diseases including obesity, diabetes, and cardiovascular disease. Several studies collectively suggests that the intake of polyphenols and their major food sources may exert beneficial effects on improving insulin resistance and related diabetes risk factors, such as inflammation and oxidative stress. They are the most abundant antioxidants in the diet, and their intake has been associated with a reduced aging in humans. Polyphenolic intake has been shown to be effective at ameliorating several age-related phenotypes, including oxidative stress, inflammation, impaired proteostasis, and cellular senescence, both in vitro and in vivo. In this paper, effects of these phytochemicals (either pure forms or polyphenolic-food) are reviewed and summarized according to affected cellular signaling pathways. Finally, the effectiveness of the anti-aging preventive action of nutritional interventions based on diets rich in polyphenolic food, such as the diets of the Blue zones, are discussed.

scholarly journals Estrogen Up-Regulates Hepatic Expression of Suppressors of Cytokine Signaling-2 and -3 in Vivo and in Vitro

Endocrinology ◽  
2004 ◽  
Vol 145 (12) ◽  
pp. 5525-5531 ◽  
Author(s):  
Gary M. Leong ◽  
Sofia Moverare ◽  
Jesena Brce ◽  
Nathan Doyle ◽  
Klara Sjögren ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Hepatoma Cells ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Wild Type ◽  
Hepatic Expression ◽  
Suppressors Of Cytokine Signaling

Abstract Suppressors of cytokine signaling (SOCS) are important negative regulators of cytokine action. We recently reported that estrogen stimulates SOCS-2 expression and inhibits GH signaling in kidney cells. The effects of estrogen on SOCS expression in other tissues are unclear. The aim of this study was to investigate in vivo and in vitro whether estrogen affected SOCS expression in the liver, a major target organ of GH. The in vivo hepatic effects of estrogen on ovariectomized mice lacking estrogen receptor (ER)-α, ERβ, or both and their wild-type littermates were examined by DNA microarray analysis. In vitro, the effects of estrogen on SOCS expression in human hepatoma cells were examined by reverse transcription quantitative PCR. Long-term (3 wk) estrogen treatment induced a 2- to 3-fold increase in hepatic expression of SOCS-2 and -3 in wild-type and ERβ knockout mice but not in those lacking ERα or both ER subtypes. Short-term treatment (at 24 h) increased the mRNA level of SOCS-3 but not SOCS-2. In cultured hepatoma cells, estrogen increased SOCS-2 and -3 mRNA levels by 2-fold in a time- and dose-dependent manner (P &lt; 0.05). Estrogen induced murine SOCS-3 promoter activity by 2-fold (P &lt; 0.05) in constructs containing a region between nucleotides −1862 and −855. Moreover, estrogen and GH had additive effects on the SOCS-3 promoter activity. In summary, estrogen, via ERα, up-regulated hepatic expression of SOCS-2 and -3, probably through transcriptional activation. This indicates a novel mechanism of estrogen regulation of cytokine action.

scholarly journals Pathological Relationship between Intracellular Superoxide Metabolism and p53 Signaling in Mice

2021 ◽  
Vol 22 (7) ◽  
pp. 3548
Author(s):  
Kenji Watanabe ◽  
Shuichi Shibuya ◽  
Yusuke Ozawa ◽  
Toshihiko Toda ◽  
Takahiko Shimizu
Keyword(s):  
Apoptotic Cell ◽  
Oxygen Species ◽  
Double Knockout ◽  
In Vivo Experiments ◽  
P53 Signaling ◽  
Tissue Degeneration ◽  
Age Related ◽  
Tissue Changes ◽  
P53 Activation

Intracellular superoxide dismutases (SODs) maintain tissue homeostasis via superoxide metabolism. We previously reported that intracellular reactive oxygen species (ROS), including superoxide accumulation caused by cytoplasmic SOD (SOD1) or mitochondrial SOD (SOD2) insufficiency, induced p53 activation in cells. SOD1 loss also induced several age-related pathological changes associated with increased oxidative molecules in mice. To evaluate the contribution of p53 activation for SOD1 knockout (KO) (Sod1−/−) mice, we generated SOD1 and p53 KO (double-knockout (DKO)) mice. DKO fibroblasts showed increased cell viability with decreased apoptosis compared with Sod1−/− fibroblasts. In vivo experiments revealed that p53 insufficiency was not a great contributor to aging-like tissue changes but accelerated tumorigenesis in Sod1−/− mice. Furthermore, p53 loss failed to improve dilated cardiomyopathy or the survival in heart-specific SOD2 conditional KO mice. These data indicated that p53 regulated ROS-mediated apoptotic cell death and tumorigenesis but not ROS-mediated tissue degeneration in SOD-deficient models.

In vivo acute testicular testosterone response to injection of luteinizing hormone in the rat fetus

1993 ◽  
Vol 128 (3) ◽  
pp. 268-273 ◽  
Author(s):  
René Habert
Keyword(s):  
Plasma Concentration ◽  
Luteinizing Hormone ◽  
Leydig Cells ◽  
Time Dependent ◽  
Fetal Life ◽  
Dependent Manner ◽  
Adult Rats ◽  
Rat Fetus ◽  
Age Related

The acute in vivo testosterone response to LH stimulation and its change during late fetal life were determined in the rat. In 18.5-day-old fetuses, testicular testosterone content was increased in a dose-and time-dependent manner after fetal subcutaneous LH injection. The maximum response was small: the testicular content and plasma concentration were increased by 200% and 2 50% over basal values respectively, while they were increased 1100% and 1200% in adult rats. Similarly, comparable low responses were obtained after subcutaneously injecting the fetuses with human chorionic gonadotropin (hCG) and after injecting LH into the vitelline vein. Between days 18.5 and 21.5 of fetal life, the testosterone levels in the testis and plasma of uninjected or PBS-injected fetuses decreased and were comparable in both groups. In maximally LH-stimulated fetuses, the testicular content did not change with age, and plasma concentration was lower on day 21.5 than on day 18.5. Since the number of Leydig cells increases 1.5 to 2-fold between days 18.5 and 21.5, these results show an age-related decrease in basal and maximally LH-stimulated in vivo testosterone secretions per Leydig cell during late fetal life.

Sign in / Sign up

Export Citation Format

Share Document