scholarly journals Isolation of Peptide Transport System-6 from Brain Endothelial Cells: Therapeutic Effects with Antisense Inhibition in Alzheimer and Stroke Models

2008 ◽  
Vol 29 (2) ◽  
pp. 411-422 ◽  
Author(s):  
Dilek Dogrukol-Ak ◽  
Vijaya B Kumar ◽  
Jan S Ryerse ◽  
Susan A Farr ◽  
Sulekha Verma ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transport System ◽  
Efflux Pumps ◽  
Peptide Transport ◽  
Peptide Transporter ◽  
Therapeutic Effects ◽  
Brain Uptake ◽  
Model Of Alzheimer’S Disease ◽  
Stroke Models

By isolating for the first time ever a peptide transporter from the blood—brain barrier (BBB) and developing an antisense that selectively targets the brain-to-blood efflux component, we were able to deliver a therapeutic concentration of the neurotrophic peptide pituitary adenylate cyclase-activating polypeptide (PACAP) 27 to brain in animal models of Alzheimer's and stroke. Efflux pumps at the BBB are major causes of BBB impermeability to peptides. PACAP is neuroprotective in vitro in femtomole amounts, but brain uptake of PACAP27 is limited by an efflux component of peptide transport system-6 (PTS-6). Here, we characterized, isolated, and sequenced this component of PTS-6, identifying it as β-F1 ATPase, and colocalized it with PACAP27 on BBB endothelial cells. Antisenses targeting the BBB inhibited PACAP27 efflux, thus increasing brain uptake of PACAP27. Treatment with antisense +PACAP27 improved cognition in a mouse model of Alzheimer's disease and reduced infarct size after cerebral ischemia. This represents the first isolation from BBB tissue of a peptide transporter and shows that inhibition of peptide efflux pumps is a potential strategy for drug delivery to brain.

scholarly journals SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2209
Author(s):  
Nitin Kumar ◽  
Yu Zuo ◽  
Srilakshmi Yalavarthi ◽  
Kristina L. Hunker ◽  
Jason S. Knight ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Activation ◽  
Endothelial Injury ◽  
Spike Protein ◽  
Severe Illness ◽  
Therapeutic Effects ◽  
Vascular Effects ◽  
Adjunct Treatment ◽  
Tnf Α

Men are disproportionately affected by the coronavirus disease-2019 (COVID-19), and face higher odds of severe illness and death compared to women. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial injury are not defined. We determined the effects of SARS-CoV-2 spike protein-mediated endothelial injury under conditions of exposure to androgen dihydrotestosterone (DHT) and tumor necrosis factor-a (TNF-α) and tested potentially therapeutic effects of mineralocorticoid receptor antagonism by spironolactone. Circulating endothelial injury markers VCAM-1 and E-selectin were measured in men and women diagnosed with COVID-19. Exposure of endothelial cells (ECs) in vitro to DHT exacerbated spike protein S1-mediated endothelial injury transcripts for the cell adhesion molecules E-selectin, VCAM-1 and ICAM-1 and anti-fibrinolytic PAI-1 (p < 0.05), and increased THP-1 monocyte adhesion to ECs (p = 0.032). Spironolactone dramatically reduced DHT+S1-induced endothelial activation. TNF-α exacerbated S1-induced EC activation, which was abrogated by pretreatment with spironolactone. Analysis from patients hospitalized with COVID-19 showed concordant higher circulating VCAM-1 and E-Selectin levels in men, compared to women. A beneficial effect of the FDA-approved drug spironolactone was observed on endothelial cells in vitro, supporting a rationale for further evaluation of mineralocorticoid antagonism as an adjunct treatment in COVID-19.

scholarly journals Intracellular Delivery of Natural Antioxidants via Hyaluronan Nanohydrogels

Pharmaceutics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 532 ◽  
Author(s):  
Elita Montanari ◽  
Chiara Di Meo ◽  
Tommasina Coviello ◽  
Virginie Gueguen ◽  
Graciela Pavon-Djavid ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Water Solubility ◽  
Umbilical Vein ◽  
Aqueous Media ◽  
Intracellular Delivery ◽  
Natural Antioxidants ◽  
Bioactive Molecules ◽  
Therapeutic Effects ◽  
Antioxidant Agents

Natural antioxidants, such as astaxanthin (AX), resveratrol (RV) and curcumin (CU), are bioactive molecules that show a number of therapeutic effects. However, their applications are remarkably limited by their poor water solubility, physico-chemical instability and low bioavailability. In the present work, it is shown that self-assembled hyaluronan (HA)-based nanohydrogels (NHs) are taken up by endothelial cells (Human Umbilical Vein Endothelial Cells, HUVECs), preferentially accumulating in the perinuclear area of oxidatively stressed HUVECs, as evidenced by flow cytometry and confocal microscopy analyses. Furthermore, NHs are able to physically entrap and to significantly enhance the apparent water solubility of AX, RV and CU in aqueous media. AX/NHs, RV/NHs and CU/NHs systems showed good hydrodynamic diameters (287, 214 and 267 nm, respectively), suitable ζ-potential values (−45, −43 and −37 mV, respectively) and the capability to neutralise reactive oxygen species (ROS) in tube. AX/NHs system was also able to neutralise ROS in vitro and did not show any toxicity against HUVECs. This research suggests that HA-based NHs can represent a kind of nano-carrier suitable for the intracellular delivery of antioxidant agents, for the treatment of oxidative stress in endothelial cells.

scholarly journals Neurotrophin-3 Promotes the Neuronal Differentiation of BMSCs and Improves Cognitive Function in a Rat Model of Alzheimer's Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Zhongrui Yan ◽  
Xianjing Shi ◽  
Hui Wang ◽  
Cuiping Si ◽  
Qian Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Neuronal Differentiation ◽  
Molecular Mechanisms ◽  
Therapeutic Effects ◽  
Model Of Alzheimer’S Disease ◽  
Neurotrophin 3

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has the potential to be developed into an effective treatment for neurodegenerative diseases such as Alzheimer's disease (AD). However, the therapeutic effects of BMSCs are limited by their low neural differentiation rate. We transfected BMSCs with neurotrophin-3 (NT-3), a neurotrophic factor that promotes neuronal differentiation, and investigated the effects of NT-3 gene overexpression on the differentiation of BMSCs into neurons in vitro and in vivo. We further studied the possible molecular mechanisms. We found that overexpression of NT-3 promoted the differentiation of BMSCs into neurons in vitro and in vivo and improved cognitive function in rats with experimental AD. By contrast, silencing NT-3 inhibited the differentiation of BMSCs and decreased cognitive function in rats with AD. The Wnt/β-catenin signaling pathway was involved in the mechanism by which NT-3 gene modification influenced the neuronal differentiation of BMSCs in vitro and in vivo. Our findings support the prospect of using NT-3-transduced BMSCs for the development of novel therapies for AD.

scholarly journals Mechanically Stretched Mesenchymal Stem Cells Can Reduce the Effects of LPS-Induced Injury on the Pulmonary Microvascular Endothelium Barrier

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Jin-ze Li ◽  
Shan-shan Meng ◽  
Xiu-Ping Xu ◽  
Yong-bo Huang ◽  
Pu Mao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
Mechanical Stretch ◽  
Inflammatory Factors ◽  
Microvascular Endothelial Cell ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Microvascular Endothelium

Mesenchymal stem cells (MSCs) may improve the treatment of acute respiratory distress syndrome (ARDS). However, few studies have investigated the effects of mechanically stretched -MSCs (MS-MSCs) in in vitro models of ARDS. The aim of this study was to evaluate the potential therapeutic effects of MS-MSCs on pulmonary microvascular endothelium barrier injuries induced by LPS. We introduced a cocultured model of pulmonary microvascular endothelial cell (EC) and MSC medium obtained from MSCs with or without mechanical stretch. We found that Wright-Giemsa staining revealed that MSC morphology changed significantly and cell plasma shrank separately after mechanical stretch. Cell proliferation of the MS-MSC groups was much lower than the untreated MSC group; expression of cell surface markers did not change significantly. Compared to the medium from untreated MSCs, inflammatory factors elevated statistically in the medium from MS-MSCs. Moreover, the paracellular permeability of endothelial cells treated with LPS was restored with a medium from MS-MSCs, while LPS-induced EC apoptosis decreased. In addition, protective effects on the remodeling of intercellular junctions were observed when compared to LPS-treated endothelial cells. These data demonstrated that the MS-MSC groups had potential therapeutic effects on the LPS-treated ECs; these results might be useful in the treatment of ARDS.

scholarly journals Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells

2010 ◽  
Vol 103 (03) ◽  
pp. 441-451 ◽  
Author(s):  
Virginia Albiñana ◽  
Maria Bernabeu-Herrero ◽  
Roberto Zarrabeitia ◽  
Carmelo Bernabeu ◽  
Luisa Botella
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Estrogen Therapy ◽  
Clinical Manifestations ◽  
Transforming Growth Factor Β ◽  
Therapeutic Effects ◽  
Hereditary Haemorrhagic Telangiectasia ◽  
Cell Functions

SummaryHereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations. There are two predominant types of HHT caused by mutations in Endoglin (ENG) and activin receptor-like kinase 1 (ALK1) (ACVRL1) genes, HHT1 and HHT2, respectively. No cure for HHT has been found and there is a current need to find new effective drug treatments for the disease. Some patients show severe epistaxis which interferes with their quality of life. We report preliminary results obtained with Raloxifene to treat epistaxis in postmenopausal HHT women diagnosed with osteoporosis. We tried to unravel the molecular mechanisms involved in the therapeutic effects of raloxifene. ENG and ACVRL1 genes code for proteins involved in the transforming growth factor β pathway and it is widely accepted that haploinsufficiency is the origin for the pathogenicity of HHT. Therefore, identification of drugs able to increase the expression of those genes is essential to propose new therapies for HHT. In vitro results show that raloxifene increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells. Raloxifene also stimulates the promoter activity of these genes, suggesting a transcriptional regulation of ENG and ALK1. Furthermore, Raloxifene improved endothelial cell functions like tubulogenesis and migration in agreement with the reported functional roles of Endoglin and ALK1. Our pilot study provides a further hint that oral administration of raloxifene may be beneficial for epistaxis treatment in HHT menopausal women. The molecular mechanisms of raloxifene involve counteracting the haploin-sufficiency of ENG and ALK1.

scholarly journals Pinocembrin Protects Human Brain Microvascular Endothelial Cells against Fibrillar Amyloid-β1−40Injury by Suppressing the MAPK/NF-κB Inflammatory Pathways

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Rui Liu ◽  
Jin-ze Li ◽  
Jun-ke Song ◽  
Jia-lin Sun ◽  
Yong-jie Li ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Human Brain ◽  
Nuclear Translocation ◽  
Microvascular Endothelial Cells ◽  
Therapeutic Effects ◽  
Brain Microvascular Endothelial Cells ◽  
Nuclear Condensation ◽  
Microvascular Endothelial ◽  
Anti Inflammation

Cerebrovascular accumulation of amyloid-β(Aβ) peptides in Alzheimer’s disease (AD) may contribute to disease progression through Aβ-induced microvascular endothelial pathogenesis. Pinocembrin has been shown to have therapeutic effects in AD models. These effects correlate with preservation of microvascular function, but the effect on endothelial cells under Aβ-damaged conditions is unclear. The present study focuses on thein vitroprotective effect of pinocembrin on fibrillar Aβ1−40(fAβ1−40) injured human brain microvascular endothelial cells (hBMECs) and explores potential mechanisms. The results demonstrate that fAβ1−40-induced cytotoxicity in hBMECs can be rescued by pinocembrin treatment. Pinocembrin increases cell viability, reduces the release of LDH, and relieves nuclear condensation. The mechanisms of this reversal from Aβmay be associated with the inhibition of inflammatory response, involving inhibition of MAPK activation, downregulation of phosphor-IKK level, relief of IκBαdegradation, blockage of NF-κB p65 nuclear translocation, and reduction of the release of proinflammatory cytokines. Pinocembrin does not show obvious effects on regulating the redox imbalance after exposure to fAβ1−40. Together, the suppression of MAPK and the NF-κB signaling pathways play a significant role in the anti-inflammation of pinocembrin in hBMECs subjected to fAβ1−40. This may serve as a therapeutic agent for BMEC protection in Alzheimer’s-related deficits.

scholarly journals Interferon-γ Rapidly Increases Peptide Transporter (TAP) Subunit Expression and Peptide Transport Capacity in Endothelial Cells

1997 ◽  
Vol 272 (26) ◽  
pp. 16585-16590 ◽  
Author(s):  
Weilie Ma ◽  
Paul J. Lehner ◽  
Peter Cresswell ◽  
Jordan S. Pober ◽  
David R. Johnson
Keyword(s):  
Endothelial Cells ◽  
Interferon Γ ◽  
Peptide Transport ◽  
Peptide Transporter ◽  
Transport Capacity ◽  
Subunit Expression

The First Step into the Brain: Uptake of NIO-PBCA Nanoparticles by Endothelial Cells in vitro and in vivo, and Direct Evidence for their Blood-Brain Barrier Permeation

ChemMedChem ◽  
2008 ◽  
Vol 3 (9) ◽  
pp. 1395-1403 ◽  
Author(s):  
Clemens K. Weiss ◽  
Maria-Verena Kohnle ◽  
Katharina Landfester ◽  
Thomas Hauk ◽  
Dietmar Fischer ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Direct Evidence ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Blood Brain ◽  
The Brain
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