demethylasterriquinone b1
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2018 ◽  
Vol 40 (2) ◽  
pp. 374-391 ◽  
Author(s):  
Richard S Beard ◽  
Brian A Hoettels ◽  
Jamie E Meegan ◽  
Travis S Wertz ◽  
Byeong J Cha ◽  
...  

Inflammation-induced blood–brain barrier (BBB) dysfunction and microvascular leakage are associated with a host of neurological disorders. The tight junction protein claudin-5 (CLDN5) is a crucial protein necessary for BBB integrity and maintenance. CLDN5 is negatively regulated by the transcriptional repressor FOXO1, whose activity increases during impaired insulin/AKT signaling. Owing to an incomplete understanding of the mechanisms that regulate CLDN5 expression in BBB maintenance and dysfunction, therapeutic interventions remain underdeveloped. Here, we show a novel isoform-specific function for AKT2 in maintenance of BBB integrity. We identified that AKT2 during homeostasis specifically regulates CLDN5-dependent barrier integrity in brain microvascular endothelial cells (BMVECs) and that intervention with a selective insulin-receptor (IR) agonist, demethylasterriquinone B1 (DMAQ-B1), rescued IL-1β-induced AKT2 inactivation, FOXO1 nuclear accumulation, and loss of CLDN5-dependent barrier integrity. Moreover, DMAQ-B1 attenuated preclinical CLDN5-dependent BBB dysfunction in mice subjected to experimental autoimmune encephalomyelitis. Taken together, the data suggest a regulatory role for IR/AKT2/FOXO1-signaling in CLDN5 expression and BBB integrity during neuroinflammation.


Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Richard S Beard ◽  
Ricci J Haines ◽  
Jonathan W Overstreet ◽  
Jamie E Meegan ◽  
Mack H Wu ◽  
...  

Blood-brain barrier (BBB) dysfunction is a hallmark of neuroinflammation brought on by pathologies such as stroke and amyloid angiopathy. Inflammatory cytokines that act directly on cerebral endothelium can impair tight junction (TJ) stability. We previously identified a mechanism for IL-1β-mediated dysfunction involving inactivation of the PI3K/Akt pathway, activation of the transcription factor FoxO1, and FoxO1-dependent transcriptional repression of the TJ gene claudin-5 (Cldn5). Here we used an insulin mimetic, Demethylasterriquinone B1 (DMAQ-B1), to test the hypotheses that targeted activation of the PI3K/Akt pathway: 1) enhances cerebral endothelial barrier function, 2) reverses IL-1β-mediated dysfunction and 3) attenuates neuroinflammation-induced BBB dysfunction. In Vitro: Primary cerebral microvascular endothelial cells (CMVECs) were grown in collagen-coated dishes, transwell inserts (0.4 μm pores), or ECIS Arrays (Applied Biophysics). Culture media was conditioned with vehicle control, IL-1β (100 ng/mL), and/or DMAQ-B1 (2.5-10 μM). DMAQ-B1 dose-dependently activated Akt (increased pT308), inactivated FoxO1 (decreased nuclear localization), increased Cldn5 expression (WB, ICC), increased transendothelial electrical resistance (TER), and decreased CMVEC monolayer permeability (Ps). Akt silencing (siRNA), PI3K inhibition (LY294002), or IL-1β treatment downregulated Cldn5 and induced CMVEC barrier dysfunction. DMAQ-B1 (5 μM) reversed IL-1β-mediated Akt inactivation, FoxO1 activation, Cldn5 downregulation and CMVEC barrier dysfunction. In Vivo: We used a murine model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE). Cerebral microvascular enriched fractions from EAE-induced mice had less pT308 Akt, increased FoxO1 nuclear accumulation, and decreased Cldn5 expression compared to control. Decreased Cldn5 expression and increased BBB hyperpermeability (sodium fluorescein extravasation) observed in EAE-induced mice was attenuated by 24 hour DMAQ-B1 (5 mg/kg; oral gavage) treatment. These results indicate that promoting PI3K/Akt pathway activation with DMAQ-B1 during neuroinflammatory pathologies may provide a novel therapeutic approach to attenuate BBB dysfunction.


ChemInform ◽  
2010 ◽  
Vol 32 (28) ◽  
pp. no-no
Author(s):  
Kuniaki Tatsuta ◽  
Hiroshi Mukai ◽  
Kazuki Mitsumoto

2007 ◽  
Vol 50 (15) ◽  
pp. 3423-3426 ◽  
Author(s):  
Hyunsoo Kim ◽  
Liu Deng ◽  
Xin Xiong ◽  
William D. Hunter ◽  
Melissa C. Long ◽  
...  

2005 ◽  
Vol 127 (13) ◽  
pp. 4609-4624 ◽  
Author(s):  
Michael C. Pirrung ◽  
Yufa Liu ◽  
Liu Deng ◽  
Diana K. Halstead ◽  
Zhitao Li ◽  
...  

ChemInform ◽  
2003 ◽  
Vol 34 (36) ◽  
Author(s):  
Nicholas J. G. Webster ◽  
Kaapjoo Park ◽  
Michael C. Pirrung

ChemBioChem ◽  
2003 ◽  
Vol 4 (5) ◽  
pp. 379-385 ◽  
Author(s):  
Nicholas J. G. Webster ◽  
Kaapjoo Park ◽  
Michael C. Pirrung

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