scholarly journals Exosome-based delivery of super-repressor IκBα relieves sepsis-associated organ damage and mortality

2020 ◽  
Vol 6 (15) ◽  
pp. eaaz6980 ◽  
Author(s):  
Hojun Choi ◽  
Youngeun Kim ◽  
Amin Mirzaaghasi ◽  
Jaenyoung Heo ◽  
Yu Na Kim ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Umbilical Vein ◽  
Active Form ◽  
Active Role ◽  
Nuclear Factor Κb ◽  
Organ Damage ◽  
Therapeutic Drug ◽  
Delivery Vehicle ◽  
Septic Mouse ◽  
Umbilical Vein Endothelial Cells

As extracellular vesicles that play an active role in intercellular communication by transferring cellular materials to recipient cells, exosomes offer great potential as a natural therapeutic drug delivery vehicle. The inflammatory responses in various disease models can be attenuated through introduction of super-repressor IκB (srIκB), which is the dominant active form of IκBα and can inhibit translocation of nuclear factor κB into the nucleus. An optogenetically engineered exosome system (EXPLOR) that we previously developed was implemented for loading a large amount of srIκB into exosomes. We showed that intraperitoneal injection of purified srIκB-loaded exosomes (Exo-srIκBs) attenuates mortality and systemic inflammation in septic mouse models. In a biodistribution study, Exo-srIκBs were observed mainly in the neutrophils, and in monocytes to a lesser extent, in the spleens and livers of mice. Moreover, we found that Exo-srIκB alleviates inflammatory responses in monocytic THP-1 cells and human umbilical vein endothelial cells.

scholarly journals Atorvastatin Inhibits Endothelial PAI-1-Mediated Monocyte Migration and Alleviates Radiation-Induced Enteropathy

2021 ◽  
Vol 22 (4) ◽  
pp. 1828
Author(s):  
Seo Young Kwak ◽  
Sunhoo Park ◽  
Hyewon Kim ◽  
Sun-Joo Lee ◽  
Won-Suk Jang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Responses ◽  
Umbilical Vein ◽  
Plasminogen Activator Inhibitor ◽  
Endothelial Damage ◽  
Plasminogen Activator Inhibitor 1 ◽  
Monocyte Migration ◽  
Radiation Induced ◽  
Umbilical Vein Endothelial Cells ◽  
Pai 1

Intestinal injury is observed in cancer patients after radiotherapy and in individuals exposed to radiation after a nuclear accident. Radiation disrupts normal vascular homeostasis in the gastrointestinal system by inducing endothelial damage and senescence. Despite advances in medical technology, the toxicity of radiation to healthy tissue remains an issue. To address this issue, we investigated the effect of atorvastatin, a commonly prescribed hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor of cholesterol synthesis, on radiation-induced enteropathy and inflammatory responses. We selected atorvastatin based on its pleiotropic anti-fibrotic and anti-inflammatory effects. We found that atorvastatin mitigated radiation-induced endothelial damage by regulating plasminogen activator inhibitor-1 (PAI-1) using human umbilical vein endothelial cells (HUVECs) and mouse model. PAI-1 secreted by HUVECs contributed to endothelial dysfunction and trans-endothelial monocyte migration after radiation exposure. We observed that PAI-1 production and secretion was inhibited by atorvastatin in irradiated HUVECs and radiation-induced enteropathy mouse model. More specifically, atorvastatin inhibited PAI-1 production following radiation through the JNK/c-Jun signaling pathway. Together, our findings suggest that atorvastatin alleviates radiation-induced enteropathy and supports the investigation of atorvastatin as a radio-mitigator in patients receiving radiotherapy.

scholarly journals Regulatory T Cells Protect Fine Particulate Matter-Induced Inflammatory Responses in Human Umbilical Vein Endothelial Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Wen-cai Zhang ◽  
Yan-ge Wang ◽  
Zheng-feng Zhu ◽  
Fang-qin Wu ◽  
Yu-dong Peng ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Particulate Matter ◽  
Inflammatory Cytokines ◽  
Fine Particles ◽  
Inflammatory Responses ◽  
Umbilical Vein ◽  
Fine Particulate Matter ◽  
Fine Particulate ◽  
Umbilical Vein Endothelial Cells

Objective. To investigate the role of CD4+CD25+T cells (Tregs) in protecting fine particulate matter (PM-) induced inflammatory responses, and its potential mechanisms.Methods. Human umbilical vein endothelial cells (HUVECs) were treated with graded concentrations (2, 5, 10, 20, and 40 µg/cm2) of suspension of fine particles for 24h. For coculture experiment, HUVECs were incubated alone, with CD4+CD25−T cells (Teff), or with Tregs in the presence of anti-CD3 monoclonal antibodies for 48 hours, and then were stimulated with or without suspension of fine particles for 24 hours. The expression of adhesion molecules and inflammatory cytokines was examined.Results. Adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), and inflammatory cytokines, such as interleukin (IL-) 6 and IL-8, were increased in a concentration-dependent manner. Moreover, the adhesion of human acute monocytic leukemia cells (THP-1) to endothelial cells was increased and NF-κB activity was upregulated in HUVECs after treatment with fine particles. However, after Tregs treatment, fine particles-induced inflammatory responses and NF-κB activation were significantly alleviated. Transwell experiments showed that Treg-mediated suppression of HUVECs inflammatory responses impaired by fine particles required cell contact and soluble factors.Conclusions. Tregs could attenuate fine particles-induced inflammatory responses and NF-κB activation in HUVECs.

Mechanotransduction by integrin is essential for IL-6 secretion from endothelial cells in response to uniaxial continuous stretch

2005 ◽  
Vol 288 (5) ◽  
pp. C1012-C1022 ◽  
Author(s):  
Akitoshi Sasamoto ◽  
Masato Nagino ◽  
Satoshi Kobayashi ◽  
Keiji Naruse ◽  
Yuji Nimura ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Kinase Inhibitor ◽  
Umbilical Vein ◽  
Nuclear Factor Κb ◽  
Inhibitory Peptide ◽  
Signaling Mechanism ◽  
Iκb Kinase ◽  
Intracellular Ca ◽  
Protein Kinase C Inhibitor ◽  
Umbilical Vein Endothelial Cells

We previously reported that uniaxial continuous stretch in human umbilical vein endothelial cells (HUVECs) induced interleukin-6 (IL-6) secretion via IκB kinase (IKK)/nuclear factor-κB (NF-κB) activation. The aim of the present study was to clarify the upstream signaling mechanism responsible for this phenomenon. Stretch-induced IKK activation and IL-6 secretion were inhibited by application of α5β1 integrin-inhibitory peptide (GRGDNP), phosphatidylinositol 3-kinase inhibitor (LY-294002), phospholipase C-γ inhibitor (U-73122), or protein kinase C inhibitor (H7). Although depletion of intra- or extracellular Ca2 + pool using thapsigargin (TG) or EGTA, respectively, showed little effect, a TG-EGTA mixture significantly inhibited stretch-induced IKK activation and IL-6 secretion. An increase in the intracellular Ca2 + concentration ([Ca2 +]i) upon continuous stretch was observed even in the presence of TG, EGTA, or GRGDNP, but not in a solution containing the TG-EGTA mixture, indicating that both integrin activation and [Ca2 +]i rise are crucial factors for stretch-induced IKK activation and after IL-6 secretion in HUVECs. Furthermore, while PKC activity was inhibited by the TG-EGTA mixture, GRGDNP, LY-294002, or U-73122, PLC-γ activity was retarded by GRGDNP or LY-294002. These results indicate that continuous stretch-induced IL-6 secretion in HUVECs depends on outside-in signaling via integrins followed by a PI3-K-PLC-γ-PKC-IKK-NF-κB signaling cascade. Another crucial factor, [Ca2 +]i increase, may at least be required to activate PKC needed for NF-κB activation.

Generation and role of angiostatin in human platelets

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3217-3223 ◽  
Author(s):  
Paul Jurasz ◽  
David Alonso ◽  
Susana Castro-Blanco ◽  
Ferid Murad ◽  
Marek W. Radomski
Keyword(s):  
Umbilical Vein ◽  
Blood Clot ◽  
Active Form ◽  
Angiogenesis Inhibitor ◽  
Human Platelets ◽  
Healthy Human ◽  
Vessel Growth ◽  
Umbilical Vein Endothelial Cells

AbstractPlatelets regulate new blood vessel growth, because they contain a number of angiogenesis promoters and inhibitors. Additionally, platelets contain matrix metalloproteinases (MMPs), which when released mediate platelet adhesion and aggregation, and plasminogen, a fibrinolytic system enzyme that serves to limit blood clot formation. Enzymatic cleavage of plasminogen by MMPs generates angiostatin, an angiogenesis inhibitor. Therefore, we examined whether platelets generate angiostatin during aggregation in vitro. Platelets were isolated from healthy human donors and then aggregated with collagen, thrombin, or HT-1080 fibrosarcoma cells. Angiostatin was detected by Western blot analysis in the platelet releasates of all blood donors irrespective of the aggregating agent used. Platelet pellet homogenates showed the presence of angiostatin in all donors, which was released upon aggregation. Furthermore, platelet-derived angiostatin was isolated and purified by lysine-Sepharose affinity chromatography from collagen-aggregated platelet releasates. Bioassay of platelet-derived angiostatin showed that it inhibited the formation of capillary structures by human umbilical vein endothelial cells (HUV-EC-Cs) in an in vitro angiogenesis model. Inhibition of angiostatin in platelet releasates promoted the formation of capillary structures by HUV-EC-Cs. We conclude that healthy human platelets contain angiostatin, which is released in active form during platelet aggregation, and platelet-derived angiostatin has the capacity to inhibit angiogenesis.

scholarly journals CTRP3 Protects against High Glucose-Induced Cell Injury in Human Umbilical Vein Endothelial Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Fang Wang ◽  
Linlin Zhao ◽  
Yingguang Shan ◽  
Ran Li ◽  
Guijun Qin
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
High Glucose ◽  
Cell Injury ◽  
Umbilical Vein ◽  
Cell Loss ◽  
Inflammatory Factors ◽  
Therapeutic Drug ◽  
Human Umbilical Vein ◽  
Umbilical Vein Endothelial Cells

Aims. Inflammation was closely associated with diabetes-related endothelial dysfunction. C1q/tumor necrosis factor-related protein 3 (CTRP3) is a member of the CTRP family and can provide cardioprotection in many cardiovascular diseases via suppressing the production of inflammatory factors. However, the role of CTRP3 in high glucose- (HG-) related endothelial dysfunction remains unclear. This study evaluates the effects of CTRP3 on HG-induced cell inflammation and apoptosis. Materials and Methods. To prevent high glucose-induced cell injury, human umbilical vein endothelial cells (HUVECs) were pretreated with recombinant CTRP3 for 1 hour followed by normal glucose (5.5 mmol/l) or high glucose (33 mmol/l) treatment. After that, cell apoptosis and inflammatory factors were determined. Results. Our results demonstrated that CTRP3 mRNA and protein expression were significantly decreased after HG exposure in HUVECs. Recombinant human CTRP3 inhibited HG-induced accumulation of inflammatory factors and cell loss in HUVECs. CTRP3 treatment also increased the phosphorylation levels of protein kinase B (AKT/PKB) and the mammalian target of rapamycin (mTOR) in HUVECs. CTRP3 lost its inhibitory effects on HG-induced cell inflammation and apoptosis after AKT inhibition. Knockdown of endogenous CTRP3 in HUVECs resulted in increased inflammation and decreased cell viability in vitro. Conclusions. Taken together, these findings indicated that CTRP3 treatment blocked the accumulation of inflammatory factors and cell loss in HUVECs after HG exposure through the activation of AKT-mTOR signaling pathway. Thus, CTRP3 may be a potential therapeutic drug for the prevention of diabetes-related endothelial dysfunction.

scholarly journals Curcumin Protects Human Umbilical Vein Endothelial Cells against H2O2-Induced Cell Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Jipeng Ouyang ◽  
Rong Li ◽  
Haiqin Shi ◽  
Jianping Zhong
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Cell Death ◽  
Cell Injury ◽  
Umbilical Vein ◽  
Therapeutic Drug ◽  
Human Umbilical Vein ◽  
Antioxidative Enzyme Activities ◽  
Apoptosis Related Protein ◽  
Umbilical Vein Endothelial Cells

Migraine is a prevalent neurological disorder which causes a huge economic burden on society. It is thought to be a neurovascular disease with oxidative stress might be involved. Curcumin, one of the major ingredients of turmeric, has potent antioxidative and anti-inflammatory properties, but whether it could be used as a potential treatment for migraine remains to be explored. In the present study, human umbilical vein endothelial cells (HUVECs) were pretreated with various concentrations of curcumin (0 μM, 10 μM, 20 μM, 30 μM, 40 μM, and 50 μM) for 12 h, thereby exposed to H2O2 (100 μM) for another 12 h. The viability of HUVECs was tested by the CCK-8 assay, and the activities of antioxidant enzymes including superoxide dismutase (SOD) and glutathione (GSH) were also examined. Intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) were assayed to determine H2O2-induced oxidative stress. In addition, several cell death-related genes (p53, p21, Bax, and Bcl-2) were detected by PCR, and an apoptosis-related protein (caspase3) was evaluated by western blotting. Our results showed that curcumin improved the H2O2-induced decrease of cell viability and antioxidative enzyme activities and decreased the level of oxidative stress. As a conclusion, curcumin could mitigate H2O2-induced oxidative stress and cell death in HUVECs and may be a potential therapeutic drug for migraine.

Factor Xa inhibits HMGB1-induced septic responses in human umbilical vein endothelial cells and in mice

2014 ◽  
Vol 112 (10) ◽  
pp. 757-769 ◽  
Author(s):  
Wonhwa Lee ◽  
Sae-Kwang Ku ◽  
Jong-Sup Bae
Keyword(s):  
Endothelial Cells ◽  
Nuclear Dna ◽  
Inflammatory Responses ◽  
Umbilical Vein ◽  
Cecal Ligation ◽  
Post Treatment ◽  
Coagulation Cascade ◽  
Factor X ◽  
Human Umbilical Vein ◽  
Umbilical Vein Endothelial Cells

SummaryNuclear DNA-binding protein high mobility group box 1 (HMGB1) acts as a late mediator of severe vascular inflammatory conditions, such as sepsis. Activated factor X (FXa) is an important player in the coagulation cascade responsible for thrombin generation, and it influences cell signalling in various cell types by activating protease-activated receptors (PARs). However, the effect of FXa on HMGB1-induced inflammatory response has not been studied. First, we addressed this issue by monitoring the effects of post-treatment with FXa on lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated regulation of pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Post-treatment with FXa was found to suppress LPS-mediated release of HMGB1 and HMGB1-mediated cytoskeletal rearrangements. FXa also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice. In addition, FXa inhibited the production of tumour necrosis factor-α and interleukin (IL)-1β. FXa also facilitated the downregulation of CLP-induced release of HMGB1, production of IL-6, and mortality. Collectively, these results suggest that FXa may be regarded as a candidate therapeutic agent for treating vascular inflammatory diseases by inhibiting the HMGB1 signalling pathway.

scholarly journals Sodium tanshinone IIA sulfonate prevents lipopolysaccharide-induced inflammation via suppressing nuclear factor-κB signaling pathway in human umbilical vein endothelial cells

2018 ◽  
Vol 96 (1) ◽  
pp. 26-31 ◽  
Author(s):  
Jun Cheng ◽  
Tangting Chen ◽  
Pengyun Li ◽  
Jing Wen ◽  
Ningbo Pang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Umbilical Vein ◽  
Nuclear Factor Κb ◽  
Tanshinone Iia ◽  
Nuclear Factor ◽  
Human Umbilical Vein ◽  
Tnf Α ◽  
Sodium Tanshinone Iia Sulfonate ◽  
Umbilical Vein Endothelial Cells

Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, has been demonstrated to have potent anti-inflammatory properties. However, the protective effects of STS on lipopolysaccharide (LPS)-induced inflammation in endothelial cells remain to be elucidated. In the present study, human umbilical vein endothelial cells (HUVECs) were used to explore the effects of STS on LPS-induced inflammation and the molecular mechanism involved. HUVECs were pretreated with STS for 2 h, followed by stimulation with LPS. Then expression and secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and the activation of nuclear factor-κB (NF-κB) were assessed. The results demonstrated that STS significantly decreased LPS-induced TNF-α and IL-1β protein expression in HUVECs. Similarly, the increased levels of TNF-α and IL-1β in cell supernatants stimulated by LPS were also significantly inhibited by STS. Furthermore, STS inhibited LPS-induced NF-κB p65 phosphorylation and nuclear translocation. All the results suggest that STS prevents LPS-induced inflammation through suppressing NF-κB signaling pathway in endothelial cells, indicating the potential utility of STS for the treatment of inflammatory diseases.

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