scholarly journals Effects of Cadmium on ZO-1 Tight Junction Integrity of the Blood Brain Barrier

2019 ◽  
Vol 20 (23) ◽  
pp. 6010 ◽  
Author(s):  
Jacopo Junio Valerio Branca ◽  
Mario Maresca ◽  
Gabriele Morucci ◽  
Tommaso Mello ◽  
Matteo Becatti ◽  
...  
Keyword(s):  
Tight Junction ◽  
Er Stress ◽  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Caspase 3 ◽  
Specific Inhibitor ◽  
Brain Barrier ◽  
Oral Exposure ◽  
Blood Brain ◽  
Parkinson’S Diseases

Cadmium (Cd) is a highly toxic environmental pollutant released from the smelting and refining of metals and cigarette smoking. Oral exposure to cadmium may result in adverse effects on a number of tissues, including the central nervous system (CNS). In fact, its toxicity has been related to neurological disorders, as well as neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Under normal conditions, Cd barely reaches the brain in adults because of the presence of the blood–brain barrier (BBB); however, it has been demonstrated that Cd-dependent BBB alteration contributes to pathogenesis of neurodegeneration. However, the mechanism underlying Cd-dependent BBB alteration remain obscure. Here, we investigated the signaling pathway of Cd-induced tight junction (TJ), F-actin, and vimentin protein disassembly in a rat brain endothelial cell line (RBE4). RBE4 cells treated with 10 μM cadmium chloride (CdCl2) showed a dose- and time-dependent significant increase in reactive oxygen species (ROS) production. This phenomenon was coincident with the alteration of the TJ zonula occludens-1 (ZO-1), F-actin, and vimentin proteins. The Cd-dependent ROS increase elicited the upregulation of GRP78 expression levels, a chaperone involved in endoplasmic reticulum (ER) stress that induces caspase-3 activation. Further signal profiling by the pannexin-1 (PANX1) specific inhibitor 10Panx revealed a PANX1-independent increase in ATP spillage in Cd-treated endothelial cells. Our results point out that a ROS-dependent ER stress-mediated signaling pathway involving caspase-3 activation and ATP release is behind the BBB morphological alterations induced by Cd.

scholarly journals RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier Permeability

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2371 ◽  
Author(s):  
Shan Feng ◽  
Li Zou ◽  
Hongjin Wang ◽  
Ran He ◽  
Ke Liu ◽  
...  
Keyword(s):  
Tight Junction ◽  
Signaling Pathway ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Tight Junction Protein ◽  
Brain Barrier ◽  
Endothelin 1 ◽  
Blood Brain ◽  
Junction Protein ◽  
Bbb Permeability

Lipopolysaccaride (LPS) directly or indirectly injures brain microvascular endothelial cells (BMECs) and damages the intercellular tight junction that gives rise to altered blood-brain barrier (BBB) permeability. Catalpol plays a protective role in LPS-induced injury, but whether catalpol protects against LPS-caused damage of BBB permeability and the underlying mechanism remain to be delineated. Prophylactic protection with catalpol (5 mg/kg, i.v.) consecutively for three days reversed the LPS-induced damage of BBB by decreased Evans Blue (EB) leakage and restored tight junctions in C57 mice. Besides, catalpol co-administrated with LPS increased BMECs survival, decreased their endothelin-1, TNF-Α and IL-6 secretion, improved transmembrane electrical resistance in a time-dependent manner, and in addition increased the fluorescein sodium permeability coefficient of BMECs. Also, transmission electron microscopy showed catalpol protective effects on tight junctions. Fluorescence staining displayed that catalpol reversed the rearrangement of the cytoskeleton protein F-actin and upregulated the tight junction protein of claudin-5 and ZO-1, which have been further demonstrated by the mRNA and protein expression levels of ZO-1, ZO-2, ZO-3, claudin-5, and occludin. Moreover, catalpol concurrently downregulated the mRNA and protein levels of RhoA, and ROCK2, the critical proteins in the RhoA/ROCK2 signaling pathway. This study thus indicated that catalpol, via inhibition of the RhoA/ROCK2 signaling pathway, reverses the disaggregation of cytoskeleton actin in BMECs and prevents down-regulation of junctional proteins, such as claudin-5, occludin, and ZO-1, and decreases endothelin-1 and inflammatory cytokine secretion, eventually alleviating the increase in LPS-induced BBB permeability.

Combined Ischemic Preconditioning and Resveratrol Improved Bloodbrain Barrier Breakdown via Hippo/YAP/TAZ Signaling Pathway

2020 ◽  
Vol 18 (9) ◽  
pp. 713-722 ◽  
Author(s):  
Ganji Hong ◽  
Ying Yan ◽  
Yali Zhong ◽  
Jianer Chen ◽  
Fei Tong ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Ischemic Preconditioning ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Cerebral Infarct ◽  
Brain Barrier ◽  
Binding Motif ◽  
Blood Brain ◽  
Barrier Breakdown

Background: Transient Ischemia/Reperfusion (I/R) is the main reason for brain injury and results in disruption of the Blood-Brain Barrier (BBB). It had been reported that BBB injury is one of the main risk factors for early death in patients with cerebral ischemia. Numerous investigations focus on the study of BBB injury which have been carried out. Objective: The objective of this study was to investigate the treatment function of the activation of the Hippo/Yes-Associated Protein (YAP) signaling pathway by combined Ischemic Preconditioning (IPC) and resveratrol (RES) before brain Ischemia/Reperfusion (BI/R) improves Blood-Brain Barrier (BBB) disruption in rats. Methods: Sprague-Dawley (SD) rats were pretreated with 20 mg/kg RES and IPC and then subjected to 2 h of ischemia and 22 h of reperfusion. The cerebral tissues were collected; the cerebral infarct volume was determined; the Evans Blue (EB) level, the brain Water Content (BWC), and apoptosis were assessed; and the expressions of YAP and TAZ were investigated in cerebral tissues. Results: Both IPC and RES preconditioning reduced the cerebral infarct size, improved BBB permeability, lessened apoptosis, and upregulated expressions of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) compared to the Ischemia/Reperfusion (I/R) group, while combined IPC and RES significantly enhanced this action. Conclusion: combined ischemic preconditioning and resveratrol improved blood-brain barrier breakdown via Hippo/YAP/TAZ signaling pathway.

scholarly journals Lipid polymeric nanoparticles modified with tight junction-modulating peptides promote afatinib delivery across a blood–brain barrier model

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yu-Li Lo ◽  
Hua-Ching Lin ◽  
Shu-Ting Hong ◽  
Chih-Hsien Chang ◽  
Chen-Shen Wang ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Polymeric Nanoparticles ◽  
Growth Factor Receptor ◽  
Brain Barrier ◽  
Polymeric Nanoparticle ◽  
Blood Brain ◽  
Blood Brain Barrier Model ◽  
Delivery Platform

Abstract Background Brain metastases from non-small cell lung cancer (NSCLC) remain one of the most challenging malignancies. Afatinib (Afa) is an orally administered irreversible ErbB family blocker approved for epidermal growth factor receptor (EGFR)-mutated NSCLC. However, the incidence of brain metastases in patients with NSCLC and EGFR mutation is high. One of the major obstacles in the treatment of brain metastases is to transport drugs across the blood–brain barrier (BBB). A lipid polymeric nanoparticle (LPN) modified with a tight junction-modulating peptide is a potential formulation to deliver therapeutics across the BBB. FD7 and CCD are short peptides that perturb the tight junctions (TJs) of the BBB. In this study, the use of LPN modified with FD7 or CCD as a delivery platform was explored to enhance Afa delivery across the BBB model of mouse brain-derived endothelial bEnd.3 cells. Results Our findings revealed that Afa/LPN-FD7 and Afa/LPN-CCD exhibited a homogeneous shape, a uniform nano-scaled particle size, and a sustained-release profile. FD7, CCD, Afa/LPN-FD7, and Afa/LPN-CCD did not cause a significant cytotoxic effect on bEnd.3 cells. Afa/LPN-FD7 and Afa/LPN-CCD across the bEnd.3 cells enhanced the cytotoxicity of Afa on human lung adenocarcinoma PC9 cells. FD7 and CCD-modulated TJ proteins, such as claudin 5 and ZO-1, reduced transendothelial electrical resistance, and increased the permeability of paracellular markers across the bEnd.3 cells. Afa/LPN-FD7 and Afa/LPN-CCD were also partially transported through clathrin- and caveolae-mediated transcytosis, revealing the effective activation of paracellular and transcellular pathways to facilitate Afa delivery across the BBB and cytotoxicity of Afa on PC9 cells. Conclusion TJ-modulating peptide-modified LPN could be a prospective platform for the delivery of chemotherapeutics across the BBB to the brain for the potential treatment of the BM of NSCLC.

Abstract TP256: Mouse Model of Uremic Cerebral Microbleeds

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Wei Ling Lau ◽  
Mary Tarbiat-Boldaji ◽  
Hayley Smalls ◽  
Ane Nunes ◽  
Javad Savoj ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Cerebral Microbleeds ◽  
Brain Barrier ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Increased Risk ◽  
Junction Protein ◽  
Blood Brain Barrier Integrity

Introduction: Cerebral microbleeds are more common in chronic kidney disease (CKD) and dialysis patients compared to the general population. Diminished kidney function alone appears to be a risk factor for microbleeds, independent of age and hypertension. Microbleed burden in CKD patients is associated with increased risk of future hemorrhagic stroke and with cognitive dysfunction. The mechanisms that drive uremic microbleed formation are unclear. Hypothesis: We hypothesized that CKD mice are predisposed to develop cerebral microhemorrhages (the pathologic substrate of microbleeds), and that a standardized inflammatory stimulus (lipopolysaccharide, LPS) will amplify microhemorrhage burden in CKD mice compared to non-CKD controls (CTL). We also hypothesized that uremia induces depletion of tight junction proteins, altering blood-brain barrier integrity and representing a potential mechanism of microbleed formation. Methods: Animal groups included CTL (n=3), CKD (n=3), CTL+LPS (n=5) and CKD+LPS (n=5). CKD induction in male C57BL/6 mice was achieved via nephrotoxic adenine diet x18 days. Two weeks following CKD induction, CKD and control mice were treated with LPS 1 mg/kg i.p. dosed at 0, 6 and 24 hours. Brains were harvested one week after LPS injections and 40-micron sections were stained using Prussian blue to identify microhemorrhages. Immunohistochemistry was performed for the blood-brain barrier tight junction protein claudin-5. Results: CKD mice had significantly elevated blood urea nitrogen, and tubulointerstitial fibrosis was present on kidney histology. Total number of microhemorrhages per brain was 2.3±1.5 (mean ± standard error of the mean) for CTL mice, 8.3±1.5 for CKD mice, 23.2±4.2 for CTL+LPS mice, and 27.6±6.2 for CKD+LPS mice (p<0.05 for CKD+LPS vs. CTL). Immunostaining showed decreased claudin-5 expression in CKD mice compared to CTL. Conclusions: We have generated a mouse model that will facilitate future mechanistic studies in the field of uremic microbleeds. Our initial findings suggest that CKD alters blood-brain barrier integrity and that inflammation amplifies development of microbleeds in CKD.

Tight Junction Regulation by Morphine and HIV-1 Tat Modulates Blood–Brain Barrier Permeability

2008 ◽  
Vol 28 (5) ◽  
pp. 528-541 ◽  
Author(s):  
Supriya D. Mahajan ◽  
Ravikumar Aalinkeel ◽  
Donald E. Sykes ◽  
Jessica L. Reynolds ◽  
B. Bindukumar ◽  
...  
Keyword(s):  
Tight Junction ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Tight Junction Regulation ◽  
Hiv 1

scholarly journals Modulating the Blood-Brain Barrier by Light Stimulation of Molecular-Targeted Nanoparticles

2020 ◽  
Author(s):  
Xiaoqing Li ◽  
Vamsidhara Vemireddy ◽  
Qi Cai ◽  
Hejian Xiong ◽  
Peiyuan Kang ◽  
...  
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Therapeutic Interventions ◽  
Brain Barrier ◽  
Light Stimulation ◽  
Targeted Nanoparticles ◽  
Blood Brain ◽  
The Brain ◽  
Stimulation Of

AbstractThe blood-brain barrier (BBB) tightly regulates the entry of molecules into the brain by tight junctions that seals the paracellular space and receptor-mediated transcytosis. It remains elusive to selectively modulate these mechanisms and to overcome BBB without significant neurotoxicity. Here we report that light stimulation of tight junction-targeted plasmonic nanoparticles selectively opens up the paracellular route to allow diffusion through the compromised tight junction and into the brain parenchyma. The BBB modulation does not impair vascular dynamics and associated neurovascular coupling, or cause significant neural injury. It further allows antibody and adeno-associated virus delivery into local brain regions. This novel method offers the first evidence of selectively modulating BBB tight junctions and opens new avenues for therapeutic interventions in the central nervous system.One Sentence SummaryGentle stimulation of molecular-targeted nanoparticles selectively opens up the paracellular pathway and allows macromolecules and gene therapy vectors into the brain.

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