A new side-effect of sufentanil: increased monocyte-endothelial adhesion

Abstract Background Opioids have been identified by the World Health Organization to be ‘indispensable for the relief of pain and suffering’. Side-effects, such as nausea, vomiting, postoperative delirium, and effects on breathing, of opioids have been well investigated; however, the influence of opioids on monocyte-endothelial adherence has never been reported. Therefore, we explored the effects of representative opioids, fentanyl, sufentanil, and remifentanil, on monocyte-endothelial adherence and the underlying mechanisms. Methods We built a cell adhesion model with U937 monocytes and human umbilical vein endothelial cells (HUVECs). Two kinds of connexin43 (Cx43) channel inhibitors, 18-α-GA and Gap 27, were used to alter Cx43 channel function in U937 monocytes and HUVECs, respectively, to determine the effects of Cx43 channels on U937-HUVEC adhesion. Subsequently, the effects of fentanyl, sufentanil and remifentanil on Cx43 channel function and U937-HUVEC adhesion were explored. Results When fentanyl, sufentanil and remifentanil acted on monocytes or endothelial cells, their effects on monocyte-endothelial adherence differed. When acting on U937 monocytes, sufentanil significantly increased U937-HUVEC adhesion which was associated with reduced release of ATP from Cx43 channels, while fentanyl and remifentanil did not have these influences. Although sufentanil could also inhibit Cx43 channel function in HUVECs, it had no effect on ATP release from HUVECs or U937-HUVECs adhesion. Conclusions We demonstrated that sufentanil application increases monocyte-endothelial adherence which was associated with reduced release of ATP from Cx43 channels in monocytes. This side-effect of sufentanil should be considered seriously by clinicians.

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A New Side-effect of Sufentanil: Increased Monocyte-endothelial Adhesion

10.21203/rs.3.rs-278451/v1 ◽

2021 ◽

Author(s):

Dongdong Yuan ◽

Zhaowei Zou ◽

Xianlong Li ◽

Nan Cheng ◽

Na Guo ◽

...

Keyword(s):

Endothelial Cells ◽

Side Effect ◽

Umbilical Vein ◽

Atp Release ◽

World Health ◽

Channel Function ◽

A Cell ◽

Underlying Mechanisms ◽

Health Organization ◽

Umbilical Vein Endothelial Cells

Abstract Background: Opioids have been identified by the World Health Organization to be ‘indispensable for the relief of pain and suffering’. Side-effects, such as nausea, vomiting, postoperative delirium, and effects on breathing, of opioids have been well investigated; however, the influence of opioids on monocyte-endothelial adherence has never been reported. Therefore, we explored the effects of representative opioids, fentanyl, sufentanil, and remifentanil, on monocyte-endothelial adherence and the underlying mechanisms. Methods: We built a cell adhesion model with U937 monocytes and human umbilical vein endothelial cells (HUVECs). Two kinds of connexin43 (Cx43) channel inhibitors, 18-α-GA and Gap 27, were used to alter Cx43 channel function in U937 monocytes and HUVECs, respectively, to determine the effects of Cx43 channels on U937-HUVEC adhesion. Subsequently, the effects of fentanyl, sufentanil and remifentanil on Cx43 channel function and U937-HUVEC adhesion were explored. Results: When fentanyl, sufentanil and remifentanil acted on monocytes or endothelial cells, their effects on monocyte-endothelial adherence differed. When acting on U937 monocytes, sufentanil significantly increased U937-HUVEC adhesion via the inhibition of Cx43 channels in U937 monocytes (the mechanism was related to Cx43 channels modulating ATP release), while fentanyl and remifentanil did not have these influences. Although sufentanil could also inhibit Cx43 channel function in HUVECs, it had no effect on ATP release from HUVECs or U937-HUVECs adhesion. Conclusions: We demonstrated that sufentanil application increases monocyte-endothelial adherence via the inhibition of ATP release mediated by Cx43 channels in monocytes. This side-effect of sufentanil should be considered seriously by clinicians.

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Homocysteine Induces Apoptosis of Human Umbilical Vein Endothelial Cells via Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/5736506 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 25

Author(s):

Zhimin Zhang ◽

Congying Wei ◽

Yanfen Zhou ◽

Tao Yan ◽

Zhengqiang Wang ◽

...

Keyword(s):

Endothelial Cells ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Umbilical Vein ◽

Dependent Manner ◽

Human Umbilical Vein ◽

Homologous Protein ◽

Intracellular Ros ◽

Underlying Mechanisms ◽

Umbilical Vein Endothelial Cells

Homocysteine- (Hcy-) induced endothelial cell apoptosis has been suggested as a cause of Hcy-dependent vascular injury, while the proposed molecular pathways underlying this process are unclear. In this study, we investigated the adverse effects of Hcy on human umbilical vein endothelial cells (HUVEC) and the underlying mechanisms. Our results demonstrated that moderate-dose Hcy treatment induced HUVEC apoptosis in a time-dependent manner. Furthermore, prolonged Hcy treatment increased the expression of NOX4 and the production of intracellular ROS but decreased the ratio of Bcl-2/Bax and mitochondrial membrane potential (MMP), resulting in the leakage of cytochrome c and activation of caspase-3. Prolonged Hcy treatment also upregulated glucose-regulated protein 78 (GRP78), activated protein kinase RNA-like ER kinase (PERK), and induced the expression of C/EBP homologous protein (CHOP) and the phosphorylation of NF-κb. The inhibition of NOX4 decreased the production of ROS and alleviated the Hcy-induced HUVEC apoptosis and ER stress. Blocking the PERK pathway partly alleviated Hcy-induced HUVEC apoptosis and the activation of NF-κb. Taken together, our results suggest that Hcy-induced mitochondrial dysfunction crucially modulated apoptosis and contributed to the activation of ER stress in HUVEC. The excessive activation of the PERK pathway partly contributed to Hcy-induced HUVEC apoptosis and the phosphorylation of NF-κb.

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H2O2 downregulate SIRT7`s protective role of endothelial premature dysfunction via microRNA-335-5p

Bioscience Reports ◽

10.1042/bsr20211775 ◽

2022 ◽

Author(s):

Yixin Liu ◽

Jinyu Yang ◽

Xi Yang ◽

Peng Lai ◽

Yi Mou ◽

...

Keyword(s):

Oxidative Stress ◽

Risk Factors ◽

Endothelial Cells ◽

Umbilical Vein ◽

Protective Role ◽

Atherosclerotic Cardiovascular Disease ◽

Contributing Factors ◽

Age Related ◽

Underlying Mechanisms ◽

Umbilical Vein Endothelial Cells

Endothelial senescence is believed to constitute the initial pathogenesis of the atherosclerotic cardiovascular disease (ASCVD). MicroRNA-335-5p (miR-335-5p) expression is significantly upregulated in oxidative stress-induced endothelial cells (ECs). Sirtuin7 (SIRT7) is considered to prevent EC senescence, yet data on its response to ASCVD risk factors are limited. This study analyzed the elevated levels of miR-335-5p and the decreased levels of SIRT7 in human umbilical vein endothelial cells (HUVECs) , and found that high glucose, tumour necrosis factor-α (TNF-α), and H2O2 are the three contributing factors that induced cellular senescence. The current study also assessed premature endothelial senescence and decreased proliferation, adhesion, migration, and nitric oxide secretion in HUVECs with these risk factors together with SIRT7-siRNA transfection. It found that the miR-335-5p inhibitor attenuated the downregulation of SIRT7 expression induced by oxidative stress in HUVECs, and SIRT7 overexpression exerts a rescue effect against miR-335-5p induced endothelial dysfunction. Furthermore, the direct binding of miR-335-5p to SIRT7 was observed in HEK-293T. Therefore, it can be inferred that miR-335-5p downregulates the expression of SIRT7 in human cells. Current findings may provide deeper insights into the underlying mechanisms of endothelial senescence and potential therapeutic targets of ASCVD as well as other age-related diseases.

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Simvastatin Attenuates H2O2-Induced Endothelial Cell Dysfunction by Reducing Endoplasmic Reticulum Stress

Molecules ◽

10.3390/molecules24091782 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1782 ◽

Cited By ~ 3

Author(s):

Zhiqiang He ◽

Xuanhong He ◽

Menghan Liu ◽

Lingyue Hua ◽

Tian Wang ◽

...

Keyword(s):

Signal Transduction ◽

Endothelial Cells ◽

Endoplasmic Reticulum ◽

Endothelial Dysfunction ◽

Er Stress ◽

Umbilical Vein ◽

Primary Role ◽

Intracellular Cholesterol ◽

Underlying Mechanisms ◽

Umbilical Vein Endothelial Cells

Atherosclerosis is the pathological basis of cardiovascular disease, whilst endothelial dysfunction (ED) plays a primary role in the occurrence and development of atherosclerosis. Simvastatin has been shown to possess significant anti-atherosclerosis activity. In this study, we evaluated the protective effect of simvastatin on endothelial cells under oxidative stress and elucidated its underlying mechanisms. Simvastatin was found to attenuate H2O2-induced human umbilical vein endothelial cells (HUVECs) dysfunction and inhibit the Wnt/β-catenin pathway; however, when this pathway was activated by lithium chloride, endothelial dysfunction was clearly enhanced. Further investigation revealed that simvastatin did not alter the expression or phosphorylation of LRP6, but reduced intracellular cholesterol deposition and inhibited endoplasmic reticulum (ER) stress. Inducing ER stress with tunicamycin activated the Wnt/β-catenin pathway, whereas reducing ER stress with 4-phenylbutyric acid inhibited it. We hypothesize that simvastatin does not affect transmembrane signal transduction in the Wnt/β-catenin pathway, but inhibits ER stress by reducing intracellular cholesterol accumulation, which blocks intracellular signal transduction in the Wnt/β-catenin pathway and ameliorates endothelial dysfunction.

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Melatonin inhibits high glucose-induced ox-LDL/LDL expression and apoptosis in human umbilical endothelial cells

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2020-0009 ◽

2020 ◽

Vol 0 (0) ◽

Cited By ~ 1

Author(s):

Yee Lian Tiong ◽

Khuen Yen Ng ◽

Rhun Yian Koh ◽

Gnanajothy Ponnudurai ◽

Soi Moi Chye

Keyword(s):

Endothelial Cells ◽

Umbilical Vein ◽

Annexin V ◽

Diabetic Patients ◽

Therapeutic Effects ◽

Pathway Activation ◽

Increased Risk ◽

Underlying Mechanisms ◽

Induced Apoptosis ◽

Umbilical Vein Endothelial Cells

AbstractBackgroundCardiovascular disease (CVD) is one of the major cause of mortality in diabetic patients. Evidence suggests that hyperglycemia in diabetic patients contributes to increased risk of CVD. This study is to investigate the therapeutic effects of melatonin on glucose-treated human umbilical vein endothelial cells (HUVEC) and provide insights on the underlying mechanisms.Materials and methodsCell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Reactive oxygen species (ROS) and membrane potential was detected using 2′,7′-dichlorofluorescein diacetate and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine iodide (JC-1) dye staining, respectively. While, cell apoptosis was determined by Annexin-V staining and protein expression was measured using Western blot.ResultsOur results suggested that melatonin inhibited glucose-induced ROS elevation, mitochondria dysfunction and apoptosis on HUVEC. Melatonin inhibited glucose-induced HUVEC apoptosis via PI3K/Akt signaling pathway. Activation of Akt further activated BcL-2 pathway through upregulation of Mcl-1 expression and downregulation Bax expression in order to inhibit glucose-induced HUVEC apoptosis. Besides that, melatonin promoted downregulation of oxLDL/LOX-1 in order to inhibit glucose-induced HUVEC apoptosis.ConclusionsIn conclusion, our results suggested that melatonin exerted vasculoprotective effects against glucose-induced apoptosis in HUVEC through PI3K/Akt, Bcl-2 and oxLDL/LOX-1 signaling pathways.

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Ninjurin 1 dodecamer peptide containing the N-terminal adhesion motif (N-NAM) exerts proangiogenic effects in HUVECs and in the postischemic brain

Scientific Reports ◽

10.1038/s41598-020-73340-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Seung-Woo Kim ◽

Hye-Kyung Lee ◽

Song-I. Seol ◽

Dashdulam Davaanyam ◽

Hahnbie Lee ◽

...

Keyword(s):

Endothelial Cells ◽

Signaling Pathways ◽

Umbilical Vein ◽

Artery Occlusion ◽

Tube Formation ◽

Neuroprotective Effects ◽

Angiogenic Effect ◽

A Cell ◽

Direct Binding ◽

Umbilical Vein Endothelial Cells

Abstract Nerve injury-induced protein 1 (Ninjurin 1, Ninj1) is a cell adhesion molecule responsible for cell-to-cell interactions between immune cells and endothelial cells. In our previous paper, we have shown that Ninj1 plays an important role in the infiltration of neutrophils in the postischemic brain and that the dodecamer peptide harboring the Ninj1 N-terminal adhesion motif (N-NAM, Pro26-Asn37) inhibits infiltration of neutrophils in the postischemic brain and confers robust neuroprotective and anti-inflammatory effects. In the present study, we examinedt the pro-angiogenic effect of N-NAM using human umbilical vein endothelial cells (HUVECs) and rat MCAO (middle cerebral artery occlusion) model of stroke. We found that N-NAM promotes proliferation, migration, and tube formation of HUVECs and demonstrate that the suppression of endogenous Ninj1 is responsible for the N-NAM-mediated pro-angiogenic effects. Importantly, a pull-down assay revealed a direct binding between exogenously delivered N-NAM and endogenous Ninj1 and it is N-terminal adhesion motif dependent. In addition, N-NAM activated the Ang1-Tie2 and AKT signaling pathways in HUVECs, and blocking those signaling pathways with specific inhibitors suppressed N-NAM-induced tube formation, indicating critical roles of those signaling pathways in N-NAM-induced angiogenesis. Moreover, in a rat MCAO model, intranasal administration of N-NAM beginning 4 days post-MCAO (1.5 µg daily for 3 days) augmented angiogenesis in the penumbra of the ipsilateral hemisphere of the brain and significantly enhanced total vessel lengths, vessel densities, and pro-angiogenic marker expression. These results demonstrate that the 12-amino acid Ninj1 peptide, which contains the N-terminal adhesion motif of Ninj1, confers pro-angiogenic effects and suggest that those effects might contribute to its neuroprotective effects in the postischemic brain.

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Ginsenoside Rb1 ameliorates lipopolysaccharide-induced albumin leakage from rat mesenteric venules by intervening in both trans- and paracellular pathway

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00168.2013 ◽

2014 ◽

Vol 306 (4) ◽

pp. G289-G300 ◽

Cited By ~ 21

Author(s):

Yu Zhang ◽

Kai Sun ◽

Yu-Ying Liu ◽

Yun-Pei Zhang ◽

Bai-He Hu ◽

...

Keyword(s):

Endothelial Cells ◽

Jugular Vein ◽

Umbilical Vein ◽

Nuclear Factor Κb ◽

Ginsenoside Rb1 ◽

Beneficial Effects ◽

Albumin Leakage ◽

Male Wistar Rats ◽

Underlying Mechanisms ◽

Umbilical Vein Endothelial Cells

Lipopolysaccharide (LPS) is one of the common pathogens that causes mesentery hyperpermeability- and intestinal edema-related diseases. This study evaluated whether ginsenoside Rb1 (Rb1), an ingredient of a Chinese medicine Panax ginseng, has beneficial effects on mesentery microvascular hyperpermeability induced by LPS and the underlying mechanisms. Male Wistar rats were continuously infused with LPS (5 mg·kg−1·h−1) via the left jugular vein for 90 min. In some rats, Rb1 (5 mg·kg−1·h−1) was administrated through the left jugular vein 30 min after LPS infusion. The dynamics of fluorescein isothiocynate-labeled albumin leakage from mesentery venules was assessed by intravital microscopy. Intestinal tissue edema was evaluated by hematoxylin and eosin staining. The number of caveolae in endothelial cells of microvessels was examined by electron microscopy. Confocal microscopy and Western blotting were applied to detect caveolin-1 (Cav-1) expression and phosphorylation, junction-related proteins, and concerning signaling proteins in intestinal tissues and human umbilical vein endothelial cells. LPS infusion evoked an increased albumin leakage from mesentery venules that was significantly ameliorated by Rb1 posttreatment. Mortality and intestinal edema around microvessels were also reduced by Rb1. Rb1 decreased caveolae number in endothelial cells of microvessels. Cav-1 expression and phosphorylation, VE-Cadherin phosphorylation, ZO-1 degradation, nuclear factor-κB (NF-κB) activation, and Src kinase phosphorylation were inhibited by Rb1. Rb1 ameliorated microvascular hyperpermeability after the onset of endotoxemia and improved intestinal edema through inhibiting caveolae formation and junction disruption, which was correlated to suppression of NF-κB and Src activation.

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Allicin Decreases Lipopolysaccharide-Induced Oxidative Stress and Inflammation in Human Umbilical Vein Endothelial Cells through Suppression of Mitochondrial Dysfunction and Activation of Nrf2

Cellular Physiology and Biochemistry ◽

10.1159/000475640 ◽

2017 ◽

Vol 41 (6) ◽

pp. 2255-2267 ◽

Cited By ~ 41

Author(s):

Min Zhang ◽

Huichao Pan ◽

Yinjie Xu ◽

Xueting Wang ◽

Zhaohui Qiu ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Inflammatory Response ◽

Vascular Injury ◽

Umbilical Vein ◽

Atp Release ◽

Antioxidant Enzyme Activities ◽

Protective Effects ◽

Endogenous Antioxidant ◽

Umbilical Vein Endothelial Cells

Background: Allicin, a major component of garlic, is regarded as a cardioprotective agent and is associated with increased endothelial function. Methods: The effects of allicin on lipopolysaccharide (LPS)-induced vascular oxidative stress and inflammation in cultured human umbilical vein endothelial cells (HUVECs) and the mechanisms underlying these effects were studied. The protective effects were measured using cell viability, a lactate dehydrogenase (LDH) assay and cell apoptosis as indicators, and the anti-oxidative activity was determined by measuring reactive oxygen species (ROS) generation, oxidative products and endogenous antioxidant enzyme activities. HUVEC mitochondrial function was assessed by determining mitochondrial membrane potential (MMP) collapse, cytochrome c production and mitochondrial ATP release. To investigate the potential underlying mechanisms, we also measured the expression of dynamic mitochondrial proteins using western blotting. Furthermore, we evaluated the Nrf2 antioxidant signaling pathway using an enzyme-linked immunosorbent assay (ELISA). Results: Our results demonstrated that allicin enhanced HUVEC proliferation, which was suppressed by LPS exposure, and LDH release. Allicin ameliorated LPS-induced apoptosis, suppressed ROS overproduction, reduced lipid peroxidation and decreased the endogenous antioxidant enzyme activities in HUVECs. These protective effects were associated with the inhibition of mitochondrial dysfunction as indicated by decreases in the MMP collapse, cytochrome c synthesis and mitochondrial ATP release. In addition, allicin attenuated the LPS-induced inflammatory responses, including endothelial cell adhesion and TNF-α and IL-8 production. Furthermore, allicin increased the expression of LXRα in a dose-dependent manner. Allicin-induced attenuation of inflammation was inhibited by LXRα siRNA treatment. Finally, allicin activated NF-E2-related factor 2 (Nrf2), which controls the defense against oxidative stress and inflammation. Conclusions: Taken together, the present data suggest that allicin attenuated the LPS-induced vascular injury process, which may be closely related to the oxidative stress and inflammatory response in HUVECs. Allicin modulated Nrf2 activation and protected the cells against LPS-induced vascular injury. Our findings suggest that allicin attenuated the LPS-induced inflammatory response in blood vessels.

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A Simplified Method for Quantifying Cell Migration/Wound Healing in 96-Well Plates

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057110361772 ◽

2010 ◽

Vol 15 (4) ◽

pp. 427-433 ◽

Cited By ~ 88

Author(s):

Patrick Y. K. Yue ◽

Emily P. Y. Leung ◽

N. K. Mak ◽

Ricky N. S. Wong

Keyword(s):

Cell Migration ◽

Umbilical Vein ◽

Cell Monolayer ◽

Migration Assay ◽

Migration Study ◽

A Cell ◽

Multiple Sample ◽

Underlying Mechanisms ◽

Umbilical Vein Endothelial Cells

Cell migration plays a key role in both normal physiological and pathological conditions. The study of cell migration and its underlying mechanisms is of great significance in various fields of research, including basic biology and pharmaceutical development. The cell migration or scratch wounding assay is an easy and economical in vitro method that allows researchers to assess a large number of testing compounds. Even though this simple assay has been used for decades, researchers are still trying to modify such experimental protocols and wounding devices. In this study, an 8-channel mechanical “wounder” was designed for performing a cell migration assay, particularly in a 96-well culture plate format. With special designs of a guiding bar and adjustable pins for use with disposable pipette tips, this wounder confined the scratch area within the center of each well to ensure a perfect contact between the pins and the well surface. As a result, this mechanical wounder produces a uniform denudation of a cell monolayer in a 96-well plate with a wound size of around 600 µm. Using this improved wounding device, the effects of epidermal growth factor and DL-α-difluoromethylornithine on the reepithelialization of rat intestinal epithelial cells (IEC-6) and serum on the wound recovery of human umbilical vein endothelial cells were demonstrated. This wounder facilitates cell migration study and can be applicable for multiple sample analysis.

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