Role of EGFR/ErbB2 and PI3K/AKT/e-NOS in Lycium barbarum polysaccharides Ameliorating Endothelial Dysfunction Induced by Oxidative Stress

2019 ◽  
Vol 47 (07) ◽  
pp. 1523-1539 ◽  
Author(s):  
Wenjuan Zhang ◽  
Huifang Yang ◽  
Lingqin Zhu ◽  
Yan Luo ◽  
Lihong Nie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Cell Viability ◽  
Therapeutic Option ◽  
Critical Role ◽  
Ang Ii ◽  
Lycium Barbarum ◽  
Underlying Mechanisms ◽  
Lycium Barbarum Polysaccharides

Lycium barbarum polysaccharides (LBP) are the major ingredients of wolfberry. In this study, we investigated the role of LBP in endothelial dysfunction induced by oxidative stress and the underlying mechanisms using thoracic aortic endothelial cells of rat (RAECs) as a model. We found that Ang II inhibits cell viability of RAECs with 10[Formula: see text][Formula: see text]mol/L of Ang II treatment for 24[Formula: see text]h most potential ([Formula: see text]), the level of reactive oxygen species (ROS) is increased by Ang II treatment ([Formula: see text]), and the expression of Occludin and Zonula occludens-1 (ZO-1) is decreased by Ang II treatment ([Formula: see text]). However, preincubation of cells with LBP could inhibit the changes caused by Ang II, LBP increased cell viability ([Formula: see text]), decreased the level of ROS ([Formula: see text]), and up-regulated the expression of Occludin ([Formula: see text]) and ZO-1. In addition, Ang II treatment increased the expression of EGFR and p-EGFR (Try1172) and which can be inhibited by LBP. On the contrary, expression of ErbB2, p-ErbB2 (Try1248), PI3K, p-e-NOS (Ser1177) ([Formula: see text]), and p-AKT (Ser473) ([Formula: see text]) was inhibited by Ang II treatment and which can be increased by LBP. Treatment of the cells with inhibitors showed that the regulation of p-e-NOS and p-AKT expression by Ang II and LBP can be blocked by PI3K inhibitor wortmannin but not EGFR and ErbB2 inhibitor AC480. Taken together, our results suggested that LBP plays a critical role in maintaining the integrality of blood vessel endothelium through reduced production of ROS via regulating the activity of EGFR, ErbB2, PI3K/AKT/e-NOS, and which may offer a novel therapeutic option in the management of endothelial dysfunction.

scholarly journals The role of diabetes in the onset and development of endothelial dysfunction

2020 ◽  
Vol 66 (1) ◽  
pp. 47-55
Author(s):  
Era B. Popyhova ◽  
Tatiana V. Stepanova ◽  
Dar’ya D. Lagutina ◽  
Tatiana S. Kiriiazi ◽  
Alexey N. Ivanov
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Critical Role ◽  
Vascular Complications ◽  
Glycation End Products ◽  
Smooth Muscle Cell Migration ◽  
Basic Functions ◽  
Cell Migration And Proliferation ◽  
Radical Processes

The vascular endothelium performs many functions. It is a key regulator of vascular homeostasis, maintains a balance between vasodilation and vasoconstriction, inhibition and stimulation of smooth muscle cell migration and proliferation, fibrinolysis and thrombosis, and is involved to regulation of platelet adhesion and aggregation. Endothelial dysfunction (ED) plays the critical role in pathogenesis of diabetes mellitus (DM) vascular complications. The purpose of this review was to consider the mechanisms leading to the occurrence of ED in DM. The paper discusses current literature data concerning the role of hyperglycemia, oxidative stress, advanced glycation end products in endothelial alteration. A separate section is devoted to the particularities of the functioning of the antioxidant system and their significance in the development of ED in DM. The analysis of the literature allows to conclude that pathological activation of glucose utilization pathways causes damage of endothelial cells, which is accompanied by disorders of all their basic functions. Metabolic disorders in DM cause a pronounced imbalance of free radical processes and antioxidant defense, accompanied by oxidative stress of endotheliocytes, which contributes to the progression of ED and the development of vascular complications. Many aspects of multicomponent regulatory reactions in the pathogenesis of the development of ED in DM have not been sufficiently studied.

scholarly journals Critical role of caveolin-1 in aflatoxin B1-induced hepatotoxicity via the regulation of oxidation and autophagy

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Qingqiang Xu ◽  
Wenwen Shi ◽  
Pan Lv ◽  
Wenqi Meng ◽  
Guanchao Mao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Aflatoxin B1 ◽  
Cell Apoptosis ◽  
Critical Role ◽  
Hepatic Cell ◽  
Hepatocellular Injury ◽  
Caveolin 1 ◽  
Induced Apoptosis

AbstractAflatoxin B1 (AFB1) is a potent hepatocarcinogen in humans and exposure to AFB1 is known to cause both acute and chronic hepatocellular injury. As the liver is known to be the main target organ of aflatoxin, it is important to identify the key molecules that participate in AFB1-induced hepatotoxicity and to investigate their underlying mechanisms. In this study, the critical role of caveolin-1 in AFB1-induced hepatic cell apoptosis was examined. We found a decrease in cell viability and an increase in oxidation and apoptosis in human hepatocyte L02 cells after AFB1 exposure. In addition, the intracellular expression of caveolin-1 was increased in response to AFB1 treatment. Downregulation of caveolin-1 significantly alleviated AFB1-induced apoptosis and decreased cell viability, whereas overexpression of caveolin-1 reversed these effects. Further functional analysis showed that caveolin-1 participates in AFB1-induced oxidative stress through its interaction with Nrf2, leading to the downregulation of cellular antioxidant enzymes and the promotion of oxidative stress-induced apoptosis. In addition, caveolin-1 was found to regulate AFB1-induced autophagy. This finding was supported by the effect that caveolin-1 deficiency promoted autophagy after AFB1 treatment, leading to the inhibition of apoptosis, whereas overexpression of caveolin-1 inhibited autophagy and accelerated apoptosis. Interestingly, further investigation showed that caveolin-1 participates in AFB1-induced autophagy by regulating the EGFR/PI3K-AKT/mTOR signaling pathway. Taken together, our data reveal that caveolin-1 plays a crucial role in AFB1-induced hepatic cell apoptosis via the regulation of oxidation and autophagy, which provides a potential target for the development of novel treatments to combat AFB1 hepatotoxicity.

scholarly journals Endothelial Dysfunction, Inflammation, and Oxidative Stress in COVID-19—Mechanisms and Therapeutic Targets

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Adriana Fodor ◽  
Brandusa Tiperciuc ◽  
Cezar Login ◽  
Olga H. Orasan ◽  
Andrada L. Lazar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Respiratory Failure ◽  
Endothelial Dysfunction ◽  
Clinical Manifestations ◽  
Therapeutic Targets ◽  
Lung Damage ◽  
Wide Range ◽  
Underlying Mechanisms ◽  
And Oxidative Stress

The outbreak of the COVID-19 pandemic represents an ongoing healthcare emergency responsible for more than 3.4 million deaths worldwide. COVID-19 is the disease caused by SARS-CoV-2, a virus that targets not only the lungs but also the cardiovascular system. COVID-19 can manifest with a wide range of clinical manifestations, from mild symptoms to severe forms of the disease, characterized by respiratory failure due to severe alveolar damage. Several studies investigated the underlying mechanisms of the severe lung damage associated with SARS-CoV-2 infection and revealed that the respiratory failure associated with COVID-19 is the consequence not only of acute respiratory distress syndrome but also of macro- and microvascular involvement. New observations show that COVID-19 is an endothelial disease, and the consequent endotheliopathy is responsible for inflammation, cytokine storm, oxidative stress, and coagulopathy. In this review, we show the central role of endothelial dysfunction, inflammation, and oxidative stress in the COVID-19 pathogenesis and present the therapeutic targets deriving from this endotheliopathy.

scholarly journals Lycium Barbarum Polysaccharides Alleviates Oxidative Damage Induced by H2O2 Through Down-Regulating MicroRNA-194 in PC-12 and SH-SY5Y Cells

2018 ◽  
Vol 50 (2) ◽  
pp. 460-472 ◽  
Author(s):  
Tong Niu ◽  
Liuzhong Jin ◽  
Shizhen Niu ◽  
Cunqi Gong ◽  
Hui Wang
Keyword(s):  
Oxidative Stress ◽  
Flow Cytometry ◽  
Western Blot ◽  
Cell Viability ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Akt Pathway ◽  
Lycium Barbarum ◽  
Cord Injury ◽  
Lycium Barbarum Polysaccharides

Background/Aims: Currently, scientists attempt to improve outcome of spinal cord injury (SCI) via reducing secondary injury during SCI. Oxidative stress is critical for pathophysiology of secondary damage, thus we mainly focused on the anti-oxidant effects of Lycium barbarum polysaccharides (LBPs) on PC-12 and SH-SY5Y cells as well as the underlying mechanisms. Methods: Oxidative stress was induced by H2O2 stimulation. Effects of LBPs on cell viability, apoptosis, and expression of proteins associated with apoptosis and autophagy in H2O2-induced cells were assessed by CCK-8 assay, flow cytometry assay and Western blot analysis, respectively. Then, expression of miR-194 was determined by qRT-PCR. Expression of miR-194 was dysregulated, and whether LBPs affected H2O2-treated cells through modulating miR-194 was verified. The expression of key kinases in the PI3K/AKT pathway and the intracellular levels of ROS and NO were testified by Western blot analysis and flow cytometry with fluorescent probes. Results: H2O2-induced decrease of cell viability and increases of apoptosis and autophagy in PC-12 cells were mitigated by LBPs treatment. Next, we found that miR-194 expression was both down-regulated by LBPs treatment in PC-12 and SH-SY5Y cells. More experiments consolidated that influence of LBPs on H2O2-treated cells was reversed by miR-194 overexpression while was augmented by miR-194 inhibition. LBPs elevated the phosphorylated levels of PI3K and AKT and reduced levels of ROS and NO through miR-194. Conclusion: LBPs alleviated H2O2-induced decrease of cell viability, and increase of apoptosis and autophagy through down-regulating miR-194. Moreover, LBPs activated the PI3K/AKT pathway and reduced oxidative stress through miR-194.

Abstract P618: Inactivation of Mitochondrial Deacetylase Sirt3 Promotes Vascular Oxidative Stress, Increases Endothelial Dysfunction and Exacerbates Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Anna E Dikalova ◽  
Roman Uzhachenko ◽  
Hana A Itani ◽  
David G Harrison ◽  
Sergey Dikalov
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Endothelial Dysfunction ◽  
Ex Vivo ◽  
Fold Increase ◽  
Organ Damage ◽  
Ang Ii ◽  
Wild Type ◽  
Vascular Oxidative Stress

Endothelial dysfunction is associated with aging, diabetes, hyperlipidemia, obesity and these risk factors affect the expression and activity of the mitochondrial deacetylase Sirt3. Sirt3 activates major antioxidant SOD2 by deacetylation of specific lysine residues and Sirt3 depletion increases oxidative stress. We hypothesized that loss of vascular Sirt3 increases endothelial dysfunction, promotes hypertension and end organ damage. The role of vascular Sirt3 was studied in wild-type C57Bl/6J mice and tamoxifen-inducible smooth muscle specific Sirt3 knockout mice (Smc Sirt3 KO ) using angiotensin II model of hypertension (Ang II, 0.7 mg/kg/day). Western blot showed 30% reduction of vascular Sirt3 and 2-fold increase in SOD2 acetylation in Ang II-infused WT mice. We have tested if ex vivo treatment of aorta with Sirt3 activator resveratrol improves endothelial function. Indeed, ex vivo incubation with resveratrol (10 μM) significantly reduced SOD2 acetylation, diminished mitochondrial O 2 and increased endothelial NO to normal level while Sirt3-inactive analog dihydroresveratrol had no effect. Specific role of vascular Sirt3 was studied in Smc Sirt3 KO mice by crossing floxed Sirt3 mice with mice carrying gene for inducible cre in the vascular smooth muscle. Sirt3 deletion exacerbates hypertension (165 mm Hg vs 155 mm Hg in wild-type) and significantly increases mortality in Ang II-infused Smc Sirt3 KO mice (60% vs 10% in wild-type) associated with severe edema and aortic aneurysm (100% vs 20% in wild-type). Decrease of NO is a hallmark of endothelial dysfunction in hypertension due to vascular oxidative stress. Indeed, Ang II infusion increased vascular O 2 by 2-fold and reduced endothelial NO by 2-fold. Interestingly, Ang II infusion in Smc Sirt3 KO mice caused severe vascular oxidative stress (3-fold increase in O 2 ) and exacerbated endothelial dysfunction (4-fold decrease in NO). These data indicate that reduced vascular Sirt3 activity occurs in hypertension and this promotes vascular oxidative stress, increases endothelial dysfunction, exacerbates hypertension, increases end-organ-damage and mortality. It is conceivable that Sirt3 agonists and SOD2 mimetics may have therapeutic potential in cardiovascular disease.

scholarly journals Role of Nox isoforms in angiotensin II-induced oxidative stress and endothelial dysfunction in brain

2012 ◽  
Vol 113 (2) ◽  
pp. 184-191 ◽  
Author(s):  
Sophocles Chrissobolis ◽  
Botond Banfi ◽  
Christopher G. Sobey ◽  
Frank M. Faraci
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Minor Role ◽  
Oxygen Species ◽  
Ang Ii ◽  
Wild Type ◽  
Vascular Beds ◽  
A Minor

Angiotensin II (Ang II) promotes vascular disease through several mechanisms including by producing oxidative stress and endothelial dysfunction. Although multiple potential sources of reactive oxygen species exist, the relative importance of each is unclear, particularly in individual vascular beds. In these experiments, we examined the role of NADPH oxidase (Nox1 and Nox2) in Ang II-induced endothelial dysfunction in the cerebral circulation. Treatment with Ang II (1.4 mg·kg−1·day−1 for 7 days), but not vehicle, increased blood pressure in all groups. In wild-type (WT; C57Bl/6) mice, Ang II reduced dilation of the basilar artery to the endothelium-dependent agonist acetylcholine compared with vehicle but had no effect on responses in Nox2-deficient (Nox2−/y) mice. Ang II impaired responses to acetylcholine in Nox1 WT (Nox1+/y) and caused a small reduction in responses to acetylcholine in Nox1-deficient (Nox1−/y) mice. Ang II did not impair responses to the endothelium-independent agonists nitroprusside or papaverine in either group. In WT mice, Ang II increased basal and phorbol-dibutyrate-stimulated superoxide production in the cerebrovasculature, and these increases were abolished in Nox2−/y mice. Overall, these data suggest that Nox2 plays a relatively prominent role in mediating Ang II-induced oxidative stress and cerebral endothelial dysfunction, with a minor role for Nox1.

Autophagy Modulators and Neuroinflammation

2020 ◽  
Vol 27 (6) ◽  
pp. 955-982 ◽  
Author(s):  
Kyoung Sang Cho ◽  
Jang Ho Lee ◽  
Jeiwon Cho ◽  
Guang-Ho Cha ◽  
Gyun Jee Song
Keyword(s):  
Neurodegenerative Disorders ◽  
Neurological Disorders ◽  
Mammalian Cells ◽  
Critical Role ◽  
Therapeutic Agents ◽  
Mechanisms Of Action ◽  
Scientific Interest ◽  
Therapeutic Tools ◽  
Underlying Mechanisms

Background: Neuroinflammation plays a critical role in the development and progression of various neurological disorders. Therefore, various studies have focused on the development of neuroinflammation inhibitors as potential therapeutic tools. Recently, the involvement of autophagy in the regulation of neuroinflammation has drawn substantial scientific interest, and a growing number of studies support the role of impaired autophagy in the pathogenesis of common neurodegenerative disorders. Objective: The purpose of this article is to review recent research on the role of autophagy in controlling neuroinflammation. We focus on studies employing both mammalian cells and animal models to evaluate the ability of different autophagic modulators to regulate neuroinflammation. Methods: We have mostly reviewed recent studies reporting anti-neuroinflammatory properties of autophagy. We also briefly discussed a few studies showing that autophagy modulators activate neuroinflammation in certain conditions. Results: Recent studies report neuroprotective as well as anti-neuroinflammatory effects of autophagic modulators. We discuss the possible underlying mechanisms of action of these drugs and their potential limitations as therapeutic agents against neurological disorders. Conclusion: Autophagy activators are promising compounds for the treatment of neurological disorders involving neuroinflammation.

LncRNA SNHG12 Improves Cerebral Ischemic-reperfusion Injury by Activating SIRT1/FOXO3a Pathway through I nhibition of Autophagy and Oxidative Stress

2020 ◽  
Vol 17 (4) ◽  
pp. 394-401
Author(s):  
Yuanhua Wu ◽  
Yuan Huang ◽  
Jing Cai ◽  
Donglan Zhang ◽  
Shixi Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Cell Activity ◽  
Ht22 Cells ◽  
Cerebral Ischemic ◽  
Cerebral Ischemic Reperfusion ◽  
And Oxidative Stress

Background: Ischemia/reperfusion (I/R) injury involves complex biological processes and molecular mechanisms such as autophagy. Oxidative stress plays a critical role in the pathogenesis of I/R injury. LncRNAs are the regulatory factor of cerebral I/R injury. Methods: This study constructs cerebral I/R model to investigate role of autophagy and oxidative stress in cerebral I/R injury and the underline regulatory mechanism of SIRT1/ FOXO3a pathway. In this study, lncRNA SNHG12 and FOXO3a expression was up-regulated and SIRT1 expression was down-regulated in HT22 cells of I/R model. Results: Overexpression of lncRNA SNHG12 significantly increased the cell viability and inhibited cerebral ischemicreperfusion injury induced by I/Rthrough inhibition of autophagy. In addition, the transfected p-SIRT1 significantly suppressed the release of LDH and SOD compared with cells co-transfected with SIRT1 and FOXO3a group and cells induced by I/R and transfected with p-SNHG12 group and overexpression of cells co-transfected with SIRT1 and FOXO3 further decreased the I/R induced release of ROS and MDA. Conclusion: In conclusion, lncRNA SNHG12 increased cell activity and inhibited oxidative stress through inhibition of SIRT1/FOXO3a signaling-mediated autophagy in HT22 cells of I/R model. This study might provide new potential therapeutic targets for further investigating the mechanisms in cerebral I/R injury and provide.

MiR-485-5p Promotes Neuron Survival through Mediating Rac1/Notch2 Signaling Pathway after Cerebral Ischemia/Reperfusion

2020 ◽  
Vol 17 (3) ◽  
pp. 259-266 ◽  
Author(s):  
Xuan Chen ◽  
Sumei Zhang ◽  
Peipei Shi ◽  
Yangli Su ◽  
Dong Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Therapeutic Option ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Small Gtpase ◽  
Luciferase Reporter ◽  
Pathological Feature ◽  
In Cells

Objective: Ischemia-reperfusion (I/R) injury is a pathological feature of ischemic stroke. This study investigated the regulatory role of miR-485-5p in I/R injury. Methods: SH-SY5Y cells were induced with oxygen and glucose deprivation/reoxygenation (OGD/R) to mimic I/R injury in vitro. Cells were transfected with designated constructs (miR-485- 5p mimics, miR-485-5p inhibitor, lentiviral vectors overexpressing Rac1 or their corresponding controls). Cell viability was evaluated using the MTT assay. The concentrations of lactate dehydrogenase, malondialdehyde, and reactive oxygen species were detected to indicate the degree of oxidative stress. Flow cytometry and caspase-3 activity assay were used for apoptosis assessment. Dual-luciferase reporter assay was performed to confirm that Rac family small GTPase 1 (Rac1) was a downstream gene of miR-485-5p. Results: OGD/R resulted in decreased cell viability, elevated oxidative stress, increased apoptosis, and downregulated miR-485-5p expression in SH-SY5Y cells. MiR-485-5p upregulation alleviated I/R injury, evidenced by improved cell viability, decreased oxidative markers, and reduced apoptotic rate. OGD/R increased the levels of Rac1 and neurogenic locus notch homolog protein 2 (Notch2) signaling-related proteins in cells with normal miR-485-5p expression, whereas miR- 485-5p overexpression successfully suppressed OGD/R-induced upregulation of these proteins. Furthermore, the delivery of vectors overexpressing Rac1 in miR-485-5p mimics-transfected cells reversed the protective effect of miR-485-5p in cells with OGD/R-induced injury. Conclusion: This study showed that miR-485-5p protected cells following I/R injury via targeting Rac1/Notch2 signaling suggest that targeted upregulation of miR-485-5p might be a promising therapeutic option for the protection against I/R injury.

scholarly journals Role of Vascular Endothelial Growth Factor (VEGF) in Human Embryo Implantation: Clinical Implications

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 253
Author(s):  
Xi Guo ◽  
Hong Yi ◽  
Tin Chiu Li ◽  
Yu Wang ◽  
Huilin Wang ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Recurrent Miscarriage ◽  
Embryo Implantation ◽  
Critical Role ◽  
Angiogenic Factor ◽  
Vascular Endothelial ◽  
Underlying Mechanisms ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is a well-known angiogenic factor that plays a critical role in various physiological and pathological processes. VEGF also contributes to the process of embryo implantation by enhancing embryo development, improving endometrial receptivity, and facilitating the interactions between the developing embryo and the endometrium. There is a correlation between the alteration of VEGF expression and reproductive failure, including recurrent implantation failure (RIF) and recurrent miscarriage (RM). In order to clarify the role of VEGF in embryo implantation, we reviewed recent literature concerning the expression and function of VEGF in the reproductive system around the time of embryo implantation and we provide a summary of the findings reported so far. We also explored the effects and the possible underlying mechanisms of action of VEGF in embryo implantation.

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