Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction

Haorah, James; Knipe, Bryan; Leibhart, Jessica; Ghorpade, Anuja; Persidsky, Yuri

doi:10.1189/jlb.0605340

Cited by 242 publications

(231 citation statements)

References 70 publications

(77 reference statements)

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“…However, for the cases of alcohol and suffering from a psychiatric condition, the present study may not represent accurate interactions of these factors with the expression of cytokines. This limitation is relevant considering the reported effects of alcohol on inflammatory processes in the brain (49,50) and the association between cytokines and psychiatric diseases (40,41). Future studies matching controls and suicides for these factors, expanding the analysis to other brain regions, and including additional cytokines will be necessary to strengthen the evidence on the involvement of cytokines in suicide.…”

Section: Discussionmentioning

confidence: 99%

Elevated cytokine expression in the orbitofrontal cortex of victims of suicide

Tonelli

Stiller

Rujescu

et al. 2007

Acta Psychiatr Scand

217

145

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Objective-Based on the reported association between cytokines with depression and suicide, and evidence of increased markers of inflammation in the brain of suicide victims, the present study examined the expression of cytokines in the orbitofrontal cortex of suicide victims.Method-In a postmortem sample obtained from the Brodman area 11 of suicides (n = 34) and controls (n = 17), real-time RT-PCR was used to compare the expression of mRNA species for tumor necrosis factor-a (TNF-α), interleukin (IL)-1β, 4, 5, 6, and 13.Results-Increased expression of IL-4 was found in women suicide victims and IL-13 in men suicide victims. Elevated but not significant cytokine expression was also observed for TNF-α in women suicide victims. • Limited information on psychiatric diagnoses and blood toxicology in the suicide group. Conclusion-To NIH Public Access

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Section: Discussionmentioning

confidence: 99%

Elevated cytokine expression in the orbitofrontal cortex of victims of suicide

Tonelli

Stiller

Rujescu

et al. 2007

Acta Psychiatr Scand

217

145

View full text Add to dashboard Cite

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“…Following exposure to ROS generated by phagocyte respiratory burst, direct oxidation of actin results in rapid assembly of filaments (81). Additional cytoskeleton rearrangement is induced through redox activation of signaling pathways affecting Src and Rho (82), and induction of myosin light chain phosphorylation leads to increased contractility and monocytic migration (83). Prolonged exposure to oxidants induces NQO1, which might stabilize RILaltCterm thereby assisting in gradual recovery of the changes in actin cytoskeleton and in cell motility.…”

Section: Discussionmentioning

confidence: 99%

Actin Cytoskeleton Remodeling by the Alternatively Spliced Isoform of PDLIM4/RIL Protein

Guryanova

Drazba

Frolova

et al. 2011

Journal of Biological Chemistry

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RIL (product of PDLIM4 gene) is an actin-associated protein that has previously been shown to stimulate actin bundling by interacting with actin-cross-linking protein ␣-actinin-1 and increasing its affinity to filamentous actin. Here, we report that the alternatively spliced isoform of RIL, denoted here as RILaltCterm, functions as a dominant-negative modulator of RIL-mediated actin reorganization. RILaltCterm is regulated at the level of protein stability, and this protein isoform accumulates particularly in response to oxidative stress. We show that the alternative C-terminal segment of RILaltCterm has a disordered structure that directs the protein to rapid degradation in the core 20 S proteasomes. Such degradation is ubiquitin-independent and can be blocked by binding to NAD(P)H quinone oxidoreductase NQO1, a detoxifying enzyme induced by prolonged exposure to oxidative stress. We show that either overexpression of RILaltCterm or its stabilization by stresses counteracts the effects produced by full-length RIL on organization of actin cytoskeleton and cell motility. Taken together, the data suggest a mechanism for fine-tuning actin cytoskeleton rearrangement in response to stresses. RIL (reversion-induced LIM domain protein) (also known as PDLIM4) is a member of ALP/Enigma family of PDZ and LIM domain-containing adapter proteins found in association with actin cytoskeleton (1, 2). ALP/Enigma genes/proteins are highly conserved throughout evolution with a single member in Caenorhabditis elegans (alp-1/eat-1) and Drosophila melanogaster (tungus) and seven different genes in mammals (3-6). Most of the family members, including the C. elegans prototype, associate with actin cytoskeleton via ␣-actinins (ALP/ PDLIM3 (7-9), CLP-36/PDLIM1 (10 -12), Mystique/PDLIM2 (13), RIL/PDLIM4 (12, 14), Enigma Homolog/ENH/PDLIM5 (15), and ZASP/Cypher/PDLIM6) (16 -18), or Filamin A (PDLIM2) (13) or ␤-tropomyosin (Enigma/PDLIM7) (19). The EHN/PDLIM5 has also been reported to affect actin structure by binding the Spine-associated RapGAP (SPAR) (20). Proteins of the PDLIM family mostly function to maintain the structure of Z-discs and are responsible for the integrity of muscle fibers by stabilizing the actin filaments (4, 21, 22). Thus, ablation of Alp or Cypher/ZASP genes leads to cardiomyopathies and/or skeletal myopathies in various animal models from fly to zebrafish to mouse (23-26), whereas mutations in hCypher have been shown to cause similar pathologies in humans (22,(27)(28)(29). In nonmuscle cells, PDLIM proteins fulfill similar role in stabilizing actin stress fibers. Specifically, binding to RIL increases the affinity of ␣-actinin-1 to filamentous actin (F-actin), leading to dramatic rearrangement of the actin cytoskeleton (1). Alternative splicing adds yet another level of complexity and flexibility to fine-tuning the function of ALP/Enigma proteins. With the exception of the CLP-36, the PDLIM genes were reported to express up to six alternatively spliced mRNA species that often include LIM-less isoforms. These splice ...

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“…[12][13][14] In fact, an in vitro study has demonstrated that the oxidative stress resulting from alcohol metabolism in brain microvascular endothelial cells can lead to BBB breakdown in alcohol abuse, serving as an aggravating factor in neuroinflammatory disorders. 15 We did not measure the serum level of ethanol, but the patient had recently consumed about 100 g of alcohol.…”

Section: Discussionmentioning

confidence: 99%

Acute Pancreatitis and Posterior Reversible Encephalopathy Syndrome: A Case Report

et al. 2016

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RESUMOA síndrome de enfalopatia posterior reversível é uma síndrome neurológica caracterizada por cefaleias, confusão, alterações visuais e convulsões associada a áreas de edema cerebral identificável em exames de neuroimagem. Os autores relatam o caso de um homem, 33 anos, leucodérmico, com história de alcoolismo e tabagismo crónico, que recorre ao serviço de urgência por epigastralgia em cinturão e vómitos com cerca de seis horas de evolução e cefaleia holocraneana intensa há duas horas. Ao exame objectivo, apresentava tensão arterial de 190/100 mmHg e empastamento no epigastro. Analiticamente, amilase 193 U/L e lipase 934 U/L. Durante a observação no serviço de urgência, apresentou uma crise tónico-clónica generalizada. A ecografia abdominal realizada foi sugestiva de pancreatite, sem sinais de litíase biliar. A tomografia computorizada crânio-encefálica demonstrou hemorragia subaracnoideia e pequena hemorragia cortical frontal direita. A ressonância magnética nuclear crânio-encefálica realizada uma semana após a admissão revelou áreas de hipersinal T2/FLAIR bilaterais e simétricas na substância branca subcortical das regiões parietais e frontais superiores, sugerindo o diagnóstico de síndrome de enfalopatia posterior reversível. Na tomografia computorizada abdominal (10 dias após a admissão) visualizou-se pâncreas espessado, em relação com processo inflamatório e dois pequenos focos hipodensos na parte anterior do corpo, traduzindo pequenos focos de necrose. A investigação de defeitos trombofílicos revelou uma mutação do gene G20210A da protrombina em heterozigotia. O doente teve alta sem sequelas neurológicas, e assintomático. A ressonância magnética nuclear crânio-encefálica de controlo confirmou a reversão das lesões, confirmando o diagnóstico. Palavras-chave: Alcoolismo/complicações; Edema Cerebral; Pancreatite Alcoólica; Síndrome de Enfalopatia Posterior Reversível. ABSTRACTThe posterior reversible encephalopathy syndrome is a neurological syndrome characterized by headache, confusion, visual disturbances and seizures associated with identifiable areas of cerebral edema on imaging studies. The authors report the case of a man, 33 years-old, leukodermic with a history of chronic alcohol and tobacco consumption, who is admitted to the emergency department for epigastric pain radiating to the back and vomiting with about six hours of evolution and an intense holocranial headache for two hours. His physical examination was remarkable for a blood pressure of 190/100 mmHg and tenderness in epigastrium. His analytical results revealed emphasis on amylase 193 U/L and lipase 934 U/L. During the observation in the emergency department, he presented a generalized tonic-clonic seizure. Abdominal ultrasonography was performed and suggestive of pancreatitis without gallstones signals. Head computed tomography showed subarachnoid haemorrhage and a small right frontal cortical haemorrhage. The brain magnetic resonance imaging done one week after admission showed areas of a bilateral and symmetrical T2 / FLAIR hyperinte...

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Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction

Cited by 242 publications

References 70 publications

Elevated cytokine expression in the orbitofrontal cortex of victims of suicide

Elevated cytokine expression in the orbitofrontal cortex of victims of suicide

Actin Cytoskeleton Remodeling by the Alternatively Spliced Isoform of PDLIM4/RIL Protein

Acute Pancreatitis and Posterior Reversible Encephalopathy Syndrome: A Case Report

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