scholarly journals Hydroxychloroquine Mitigates the Production of 8-Isoprostane and Improves Vascular Dysfunction: Implications for Treating Preeclampsia

2020 ◽  
Vol 21 (7) ◽  
pp. 2504
Author(s):  
Rahana Abd Rahman ◽  
Padma Murthi ◽  
Harmeet Singh ◽  
Seshini Gurungsinghe ◽  
Bryan Leaw ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Vascular Dysfunction ◽  
Umbilical Vein ◽  
In Vitro Study ◽  
Activin A ◽  
Hypoxic Injury ◽  
Tnf Α ◽  
Zona Occludens

In preeclampsia, widespread maternal endothelial dysfunction is often secondary to excessive generation of placental-derived anti-angiogenic factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), along with proinflammatory cytokines such as tumour necrosis factor-α (TNF-α) and activin A, understanding of which offers potential opportunities for the development of novel therapies. The antimalarial hydroxychloroquine is an anti-inflammatory drug improving endothelial homeostasis in lupus. It has not been explored as to whether it can improve placental and endothelial function in preeclampsia. In this in vitro study, term placental explants were used to assess the effects of hydroxychloroquine on placental production of sFlt-1, sEng, TNF-α, activin A, and 8-isoprostane after exposure to hypoxic injury or oxidative stress. Similarly, human umbilical vein endothelial cells (HUVECs) were used to assess the effects of hydroxychloroquine on in vitro markers of endothelial dysfunction. Hydroxychloroquine had no effect on the release of sFlt-1, sEng, TNF-α, activin A, or 8-isoprostane from placental explants exposed to hypoxic injury or oxidative stress. However, hydroxychloroquine mitigated TNF-α-induced HUVEC production of 8-isoprostane and Nicotinanamide adenine dinucleotide phosphate (NADPH) oxidase expression. Hydroxychloroquine also mitigated TNF-α and preeclamptic serum-induced HUVEC monolayer permeability and rescued the loss of zona occludens protein zona occludens 1 (ZO-1). Although hydroxychloroquine had no apparent effects on trophoblast function, it may be a useful endothelial protectant in women presenting with preeclampsia.

Tetrahydroxystilbene Glucoside Improves TNF-α-Induced Endothelial Dysfunction: Involvement of TGFβ/Smad Pathway and Inhibition of Vimentin Expression

2015 ◽  
Vol 43 (01) ◽  
pp. 183-198 ◽  
Author(s):  
Wenjuan Yao ◽  
Chengjing Gu ◽  
Haoran Shao ◽  
Guoliang Meng ◽  
Huiming Wang ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Nuclear Translocation ◽  
Cell Damage ◽  
Umbilical Vein ◽  
Polygonum Multiflorum ◽  
Vimentin Expression ◽  
Smad Signaling ◽  
Tnf Α ◽  
Umbilical Vein Endothelial Cells

Endothelial dysfunction plays an important role in the pathogenesis of atherogenesis. 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), an active component of the rhizome extract from Polygonum multiflorum (PM), exhibits significant anti-atherosclerotic activity. Here, we used human umbilical vein endothelial cells (HUVECs) induced by tumor necrosis factor-α (TNF-α) in vitro to investigate the cytoprotective effects of TSG on TNF-α-induced endothelial injury and the related mechanisms. Pretreatment with 50 and 100 μM TSG markedly attenuated TNF-α-induced loss of cell viability and release of lactate dehydrogenase (LDH) and inhibited TNF-α-induced cell apoptosis. The inhibition of vimentin expression was involved in the cytoprotection afforded by TSG. Using inhibitors for PI3K and TGFβ or siRNA for Akt and Smad2, we found that vimentin production in HUVECs is regulated by TGFβ/Smad signaling, but not by PI3K–Akt–mTOR signaling. Meanwhile, TSG inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by TNF-α. These results suggest that TSG protects HUVECs against TNF-α-induced cell damage by inhibiting vimentin expression via the interruption of the TGFβ/Smad signaling pathway.

scholarly journals Oxidative stress increases placental and endothelial cell activin A secretion

2007 ◽  
Vol 192 (3) ◽  
pp. 485-493 ◽  
Author(s):  
Stephen Mandang ◽  
Ursula Manuelpillai ◽  
Euan M Wallace
Keyword(s):  
Oxidative Stress ◽  
Umbilical Vein ◽  
Normal Pregnancy ◽  
Maternal Plasma ◽  
Activin A ◽  
Blood Monocytes ◽  
Wet Weight ◽  
Umbilical Vein Endothelial Cells ◽  
Circulating Levels

Circulating levels of activin A are significantly increased in women with preeclampsia when compared with those with a normal pregnancy. The mechanisms underlying these increased levels are unknown. We undertook these studies to explore whether oxidative stress might be the mechanism. We exposed trophoblast explants, human umbilical vein endothelial cells (HUVECs) and peripheral blood monocytes to oxidative stress in vitro using xanthine/xanthine oxidase (X/XO), measuring activin A and isoprostane in conditioned media and mRNA for activin βA in explants and HUVECs. We also measured isoprostane and activin A in serum from 21 women with preeclampsia and from 20 women with a normal pregnancy. Treatment with X/XO significantly increased 8-isoprostane production from placental explants, HUVECs and monocytes, indicative of oxidative stress, and significantly increased activin A output from placental explants (139.1 ± 27.4 per mg wet weight vs 322.9 ± 89.7 pg/ml per mg wet weight, P = 0.02) and from HUVECs (1.2 ± 0.2 vs 3.2 ± 1.8 ng/ml, P = 0.04). There was no effect on activin A output from monocytes. X/XO significantly increased βA mRNA in placental explants but not in HUVECs. Maternal plasma levels of 8-isoprostane and activin A were significantly higher in women with preeclampsia when compared with controls (333.8 ± 70 vs 176.3 ± 26.2 pg/ml, P = 0.04 and 49.5 ± 7 vs 13.1 ± 1.2 ng/ml, P < 0.001 respectively). In the women with preeclampsia, but not in those with a normal pregnancy, circulating levels of 8-isoprostane and activin A were significantly and positively correlated (r2 = 0.72; P < 0.001). These data suggest that oxidative stress may be one of the mechanisms underlying increased circulating activin A in preeclampsia.

scholarly journals Antioxidant Treatment Reverts Increased Arterial Basal Tone and Oxidative Stress in Nephrectomized (5/6) Hypertensive Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Rodrigo O. Marañón ◽  
Claudio Joo Turoni ◽  
Maria Sofia Karbiner ◽  
Nicolas Salas ◽  
Maria Peral de Bruno
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Dysfunction ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Basal Tone ◽  
No Bioavailability

Nonischemic 5/6 nephrectomized rat (NefR) is a model of chronic kidney disease. However, little is known about vascular dysfunction and its relation with hypertension in NefR.Aims. To evaluate possible alterations of endothelial function, NO-bioavailability, and basal tone in aorta from NefR and the role of oxidative stress. Sprague Dawley rats were divided into sham rats (SR), NefR, and NefR treated with tempol (NefR-T). Mean arterial pressure (MAP) and renal function were determined. In isolated aortic rings the following was measured: 1-endothelial function, 2-basal tone, 3-NO levels, 4-membrane potential (MP), and 5-oxidative stress. NefR increased MAP (SR: 119 ± 4 mmHg;n=7; NefR: 169 ± 6;n=8;P<0.001). Tempol did not modify MAP (NefR-T: 168 ± 10;n=6;P<0.001). NefR showed endothelial dysfunction, increased basal tone and decreased NO levels (SR: 32 ± 2 nA;n=7, NefR: 10 ± 2;n=8;P<0.001). In both in vitro and in vivo tempol improves basal tone, NO levels, and MP. Oxidative stress in NefR was reverted in NefR-T. We described, for the first time, that aorta from NefR presented increased basal tone related to endothelial dysfunction and decreased NO-bioavailability. The fact that tempol improves NO-contents and basal tone, without decrease MAP, indicates that oxidative stress could be implicated early and independently to hypertension, in the vascular alterations.

scholarly journals Linking In Vitro Models of Endothelial Dysfunction with Cell Senescence

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1323
Author(s):  
Francisco R. Jimenez Trinidad ◽  
Marta Arrieta Ruiz ◽  
Núria Solanes Batlló ◽  
Àngela Vea Badenes ◽  
Joaquim Bobi Gibert ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Umbilical Vein ◽  
In Vitro Models ◽  
Endothelial Cell Dysfunction ◽  
Gene Markers ◽  
Cell Dysfunction ◽  
Cellular Models

Endothelial cell dysfunction is the principal cause of several cardiovascular diseases that are increasing in prevalence, healthcare costs, and mortality. Developing a standardized, representative in vitro model of endothelial cell dysfunction is fundamental to a greater understanding of the pathophysiology, and to aiding the development of novel pharmacological therapies. We subjected human umbilical vein endothelial cells (HUVECs) to different periods of nutrient deprivation or increasing doses of H2O2 to represent starvation or elevated oxidative stress, respectively, to investigate changes in cellular function. Both in vitro cellular models of endothelial cell dysfunction-associated senescence developed in this study, starvation and oxidative stress, were validated by markers of cellular senescence (increase in β-galactosidase activity, and changes in senescence gene markers SIRT1 and P21) and endothelial dysfunction as denoted by reductions in angiogenic and migratory capabilities. HUVECs showed a significant H2O2 concentration-dependent reduction in cell viability (p < 0.0001), and a significant increase in oxidative stress (p < 0.0001). Furthermore, HUVECs subjected to 96 h of starvation, or exposed to concentrations of H2O2 of 400 to 1000 μM resulted in impaired angiogenic and migratory potentials. These models will enable improved physiological studies of endothelial cell dysfunction, and the rapid testing of cellular efficacy and toxicity of future novel therapeutic compounds.

scholarly journals TNF-α Receptor Inhibitor Alleviates Metabolic and Inflammatory Changes in a Rat Model of Ischemic Stroke

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 851
Author(s):  
Shih-Yi Lin ◽  
Ya-Yu Wang ◽  
Cheng-Yi Chang ◽  
Chih-Cheng Wu ◽  
Wen-Ying Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Rat Model ◽  
Brain Infarction ◽  
In Vitro Study ◽  
Neurological Deficits ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Receptor Inhibitor

Hyperglycemia and inflammation, with their augmented interplay, are involved in cases of stroke with poor outcomes. Interrupting this vicious cycle thus has the potential to prevent stroke disease progression. Tumor necrosis factor-α (TNF-α) is an emerging molecule, which has inflammatory and metabolic roles. Studies have shown that TNF-α receptor inhibitor R-7050 possesses neuroprotective, antihyperglycemic, and anti-inflammatory effects. Using a rat model of permanent cerebral ischemia, pretreatment with R-7050 offered protection against poststroke neurological deficits, brain infarction, edema, oxidative stress, and caspase 3 activation. In the injured cortical tissues, R-7050 reversed the activation of TNF receptor-I (TNFRI), NF-κB, and interleukin-6 (IL-6), as well as the reduction of zonula occludens-1 (ZO-1). In the in vitro study on bEnd.3 endothelial cells, R-7050 reduced the decline of ZO-1 levels after TNF-α-exposure. R-7050 also reduced the metabolic alterations occurring after ischemic stroke, such as hyperglycemia and increased plasma corticosterone, free fatty acids, C reactive protein, and fibroblast growth factor-15 concentrations. In the gastrocnemius muscles of rats with stroke, R-7050 improved activated TNFRI/NF-κB, oxidative stress, and IL-6 pathways, as well as impaired insulin signaling. Overall, our findings highlight a feasible way to combat stroke disease based on an anti-TNF therapy that involves anti-inflammatory and metabolic mechanisms.

scholarly journals Endothelial dysfunction in insulin-resistant rats is associated with oxidative stress and COX pathway dysregulation

2009 ◽  
pp. 499-509
Author(s):  
A Oudot ◽  
D Behr-Roussel ◽  
S Compagnie ◽  
S Caisey ◽  
O Le Coz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Vascular Dysfunction ◽  
Pressor Response ◽  
In Vitro Study ◽  
Cardiovascular Complications ◽  
Insulin Resistant ◽  
Pathway Dysregulation

Because insulin resistance is inevitably associated with cardiovascular complications, there is a need to further investigate the potential involvement of oxidative stress and the cyclo-oxygenase (COX) pathway in the vascular modifications associated to this pathological context. Endothelial function was evaluated in control and fructose-fed rats (FFR) by i) in vitro study of endothelium-dependent and -independent relaxations of aortic rings, and ii) in vivo telemetric evaluation of pressor response to norepinephrine. After 9 weeks of diet, FFR displayed hypertriglyceridemia, hyperinsulinemia and exaggerated response to glucose overload. Aortic rings from control rats and FFR exhibited comparable endothelium-dependent relaxations to Ach. In the presence of indomethacin, relaxations were significantly reduced. FFR showed exaggerated pressor responses to norepinephrine that were abolished with indomethacin. Urinary nitrites/nitrates, 8-isoprostanes and thromboxane B2 excretion levels were markedly enhanced in FFR, whereas the plasma levels of 6-keto prostaglandin F1α were unchanged. In conclusion, fructose overload in rats induced hypertriglyceridemia and insulin resistance associated with an enhanced oxidative stress. This was associated with COX pathway dysregulation which could be one of the contributors to subsequent vascular dysfunction. Consequently, reduction of oxidative stress and regulation of the COX pathway could represent new potential therapeutic strategies to limit vascular dysfunction and subsequent cardiovascular complications associated with insulin resistance.

scholarly journals Hyperglycemia Potentiates Prothrombotic Effect of Aldosterone in a Rat Arterial Thrombosis Model

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 471
Author(s):  
Anna Gromotowicz-Poplawska ◽  
Piotr Szoka ◽  
Agnieszka Zakrzeska ◽  
Patrycjusz Kolodziejczyk ◽  
Natalia Marcinczyk ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Arterial Thrombosis ◽  
Umbilical Vein ◽  
In Vitro Study ◽  
Plasminogen Activator Inhibitor ◽  
Diabetic Rats ◽  
Coagulation Cascade ◽  
Prothrombotic Effect

We investigated the role of aldosterone (ALDO) in the development of arterial thrombosis in streptozotocin-induced diabetic rats. To evaluate the effect of endogenous ALDO, the rats underwent adrenalectomy (ADX). ADX reduced the development of arterial thrombosis. A 1 h infusion of ALDO (30 μg/kg/h) enhanced thrombosis in adrenalectomized rats, while this effect was potentiated in diabetic rats. ALDO shortened bleeding time, increased plasma levels of tissue factor (TF) and plasminogen activator inhibitor, decreased plasma level of nitric oxide (NO) metabolites, and increased oxidative stress. Moreover, 2 h incubation of human umbilical vein endothelial cells (HUVECs) with ALDO (10−7 M) disrupted hemostatic balance in endothelial cells in normoglycemia (glucose 5.5 mM), and this effect was more pronounced in hyperglycemia (glucose 30 mM). We demonstrated that the acute ALDO infusion enhances arterial thrombosis in rats and hyperglycemia potentiates this prothrombotic effect. The mechanism of ALDO action was partially mediated by mineralocorticoid (MR) and glucocorticoid (GR) receptors and related to impact of the hormone on primary hemostasis, TF-dependent coagulation cascade, fibrinolysis, NO bioavailability, and oxidative stress balance. Our in vitro study confirmed that ALDO induces prothrombotic phenotype in the endothelium, particularly under hyperglycemic conditions.

Interactions Between Dental Composite Resins and Saliva A comparative biochemical in vitro study

2019 ◽  
Vol 56 (3) ◽  
pp. 529-533
Author(s):  
Mihaela Pantea ◽  
Diana Andreea Ighigeanu ◽  
Alexandra Totan ◽  
Maria Greabu ◽  
Daniela Miricescu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
In Vitro Study ◽  
Composite Resins ◽  
Vitro Study ◽  
Dental Composite ◽  
Gamma Glutamyl Transferase ◽  
Specific Protocol ◽  
Dental Composite Resins ◽  
Glutamyl Transferase

This in vitro study analyses the biochemical interaction between saliva and three types of dental composite resins (a direct resin, an indirect resin and a dual-cure resin used for cementation of indirect dental restorations). The resin samples were obtained following a specific protocol and in line with the producers� recommendations; the resin samples were incubated with saliva samples collected from 19 healthy volunteers. The obtained results showed that the tested composite resins did not produce significant changes in oxidative stress parameters that were analysed (albumin, uric acid, GGT / gamma glutamyl transferase, OXSR-1 / oxidative stress responsive kinase 1) and do not influence the inflammatory salivary status reflected by the levels of IL-6 - an inflammatory marker.

scholarly journals Generation of a Novel In Vitro Model to Study Endothelial Dysfunction from Atherothrombotic Specimens

2021 ◽  
Author(s):  
Susan Gallogly ◽  
Takeshi Fujisawa ◽  
John D. Hung ◽  
Mairi Brittan ◽  
Elizabeth M. Skinner ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
In Vitro Model ◽  
Umbilical Vein ◽  
Coronary Syndrome ◽  
Coronary Endothelial Cells ◽  
Vitro Model ◽  
Umbilical Vein Endothelial Cells

Abstract Purpose Endothelial dysfunction is central to the pathogenesis of acute coronary syndrome. The study of diseased endothelium is very challenging due to inherent difficulties in isolating endothelial cells from the coronary vascular bed. We sought to isolate and characterise coronary endothelial cells from patients undergoing thrombectomy for myocardial infarction to develop a patient-specific in vitro model of endothelial dysfunction. Methods In a prospective cohort study, 49 patients underwent percutaneous coronary intervention with thrombus aspiration. Specimens were cultured, and coronary endothelial outgrowth (CEO) cells were isolated. CEO cells, endothelial cells isolated from peripheral blood, explanted coronary arteries, and umbilical veins were phenotyped and assessed functionally in vitro and in vivo. Results CEO cells were obtained from 27/37 (73%) atherothrombotic specimens and gave rise to cells with cobblestone morphology expressing CD146 (94 ± 6%), CD31 (87 ± 14%), and von Willebrand factor (100 ± 1%). Proliferation of CEO cells was impaired compared to both coronary artery and umbilical vein endothelial cells (population doubling time, 2.5 ± 1.0 versus 1.6 ± 0.3 and 1.2 ± 0.3 days, respectively). Cell migration was also reduced compared to umbilical vein endothelial cells (29 ± 20% versus 85±19%). Importantly, unlike control endothelial cells, dysfunctional CEO cells did not incorporate into new vessels or promote angiogenesis in vivo. Conclusions CEO cells can be reliably isolated and cultured from thrombectomy specimens in patients with acute coronary syndrome. Compared to controls, patient-derived coronary endothelial cells had impaired capacity to proliferate, migrate, and contribute to angiogenesis. CEO cells could be used to identify novel therapeutic targets to enhance endothelial function and prevent acute coronary syndromes.

scholarly journals Alleviation of Oxidative Stress in Dental Pulp Cells Following 4-Hexylresorcinol Administration in a Rat Model

2021 ◽  
Vol 11 (8) ◽  
pp. 3637
Author(s):  
Jun-Ho Chang ◽  
Dae-Won Kim ◽  
Seong-Gon Kim ◽  
Tae-Woo Kim
Keyword(s):  
Oxidative Stress ◽  
Dental Pulp ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Mandibular Incisor ◽  
Tnf Α ◽  
Total Antioxidant ◽  
Pulp Cells ◽  
Pre Treatment

Damaged dental pulp undergoes oxidative stress and 4-hexylresorcinol (4HR) is a well-known antioxidant. In this study, we aimed to evaluate the therapeutic effects of a 4HR ointment on damaged dental pulp. Pulp cells from rat mandibular incisor were cultured and treated with 4HR or resveratrol (1–100 μM). These treatments (10–100 μM) exerted a protective effect during subsequent hydrogen peroxide treatments. The total antioxidant capacity and glutathione peroxidase activity were significantly increased following 4HR or resveratrol treatment (p < 0.05), while the expression levels of TNF-α and IL1β were decreased following the exposure to 4HR pre-treatment in an in vitro model. Additionally, the application of 4HR ointment in an exposed dental pulp model significantly reduced the expression of TNF-α and IL1β (p < 0.05). Conclusively, 4HR exerted protective effects against oxidative stress in dental pulp tissues through downregulating TNF-α and IL1β.

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