Role of matrix metalloproteinase-2/9 (MMP2/9) in lead-induced changes in an <i>in vitro</i> blood-brain barrier model

Liu, Xinqin; Su, Peng; Meng, Shanshan; Aschner, Michael; Cao, Yupeng; Luo, Wenjing; Zheng, Gang; Liu, Mingchao

doi:10.7150/ijbs.20670

Cited by 40 publications

(21 citation statements)

References 25 publications

(30 reference statements)

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“…In recent decades, MMP-2 and MMP-9 have been widely studied. The expression of MMP-2 and MMP-9 were involved in BBB disruption and neuroinflammation [27,28]. One study found that TNF-α led to an increased expression of MMP-2 and MMP-9 in human umbilical vein endothelial cells [29].…”

Section: Discussionmentioning

confidence: 99%

Propofol attenuates TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells by inhibiting Ca2+/CAMK II/ERK/NF-κB signaling pathway

et al. 2019

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Metalloproteinase 9 (MMP-9) is able to degrade collagen IV, an important component of blood-brain barrier (BBB). Expression of MMPs, especially MMP-9, correlates with BBB disruption during central nervous system inflammation. Propofol has been reported to have anti-inflammation effects. In this study, we investigated the effects of propofol on TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells (hCMEC/D3 cells) and explored the underlying mechanisms. The hCMEC/D3 cells were treated with propofol (25 μM), followed by TNF-α (25 ng/mL). We showed that TNF-α treatment markedly increased MMP-9 expression and decreased collagen IV expression in hCMEC/D3 cells, which was blocked by pretreatment with propofol. TNF-αinduced downregulation of collagen IV was also reversed by MMP-9 knockdown with siRNA. We revealed that TNF-α upregulated MMP-9 expression in hCMEC/D3 cells through activation of Ca 2+ /CAMK II/ERK/NF-κB signaling pathway; co-treatment with inhibitors of CaMK II (KN93), ERK (LY3214996), NF-κB (PDTC) or Ca 2+ chelator (BAPTA-AM) abrogated the effect of TNF-α on MMP-9 expression. We further established an in vitro BBB model by co-culturing of hCMEC/D3 cells and human astrocytes for 6 days and measuring trans-endothelial electrical resistance (TEER) to reflect the BBB permeability. TNF-α treatment markedly decreased TEER value, which was attenuated by pretreatment with propofol (25 μM) or MMP-9 knockdown with siRNA. In conclusion, propofol inhibits TNF-α-induced MMP-9 expression in hCMEC/D3 cells via repressing the Ca 2+ /CAMKII/ERK/NF-κB signaling pathway. TNF-αimpaired BBB integrity could be reversed by propofol, and propofol attenuates the inhibitory effect of TNF-α on collagen IV.

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Section: Discussionmentioning

confidence: 99%

Propofol attenuates TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells by inhibiting Ca2+/CAMK II/ERK/NF-κB signaling pathway

et al. 2019

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“…The presently observed enrichment of the Ca 2+ signaling pathway suggests that Ca 2+ signaling may be involved in the development of cerebral hernia. Furthermore, the enrichment of genes related to the blood–brain barrier, including CD99 , MMP2 , and MMP9 [ 51 , 52 , 53 ] indicates the potential damage of the blood–brain barrier during the development of cerebral hernia.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the Forebrain Disorder in a Chicken Model of Cerebral Hernia

Tao

Zhou

Zheng

et al. 2020

Genes

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Cerebral hernia in crested chicken has been characterized as the protrusion of cerebral hemispheres into the unsealed skull for hundreds of years, since Charles Darwin. The development of deformed forebrain (telencephalon) of cerebral hernia remains largely unknown. Here, the unsealed frontal skull combined with misplaced sphenoid bone was observed and potentially associated with brain protuberance. The shifted pallidum, elongated hippocampus, expanded mesopallium and nidopallium, and reduced hyperpallium were observed in seven regions of the malformed telencephalon. The neurons were detected with nuclear pyknosis and decreased density. Astrocytes showed uneven distribution and disordered protuberances in hyperpallium and hippocampus. Transcriptome analyses of chicken telencephalon (cerebral hernia vs. control) revealed 547 differentially expressed genes (DEGs), mainly related to nervous system development, and immune system processes, including astrocyte marker gene GFAP, and neuron and astrocyte developmental gene S100A6. The upregulation of GFAP and S100A6 genes in abnormal telencephalon was correlated with reduced DNA methylation levels in the promoter regions. The morphological, cellular, and molecular variations in the shape, regional specification, and cellular states of malformed telencephalon potentially participate in brain plasticity and previously reported behavior changes. Chickens with cerebral hernia might be an interesting and valuable disease model to further explore the recognition, diagnosis, and therapy of cerebral hernia development of crested chickens and other species.

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“…Our study found that serum occludin level correlated well with the grade of brain edema, suggesting that damage to occludin in the BBB may be a common molecular mechanism underlying the development of brain edema in patients with brain tumors. Some studies of glioma have shown that MMP expression or activation is related to the down-regulation of occludin in the BBB, which leads to destruction of the BBB 27,28 . It is possible that MMP activation may be a major mechanism by which degradation of occludin and damage to the BBB occurs in patients with brain tumors.…”

Section: Discussionmentioning

confidence: 99%

Peripheral blood occludin level as a biomarker for preoperative cerebral edema in patients with brain tumors

Shi

Cheng

Zhang

et al. 2020

Preprint

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ObjectiveCerebral edema is a common complication of brain tumors in the perioperative period. However, there is currently no reliable and convenient method to evaluate the extent of brain edema. The objective of this study is to explore the ability of serum occludin level to predict the extent of perioperative brain edema and outcome in patients with brain tumors.MethodsThis prospective study enrolled 55 patients with brain tumors and 24 healthy controls from Sanbo Brain Hospital from June 2019 through November 2019. Serum occludin level was measured preoperatively and on postoperative day 1. Peritumoral edema was assessed preoperatively using magnetic resonance imaging. Pericavity brain edema on postoperative day 1 was evaluated using computed tomography.ResultsCompared with healthy controls, serum occludin level was higher in patients with brain tumors both preoperatively and postoperatively (P < 0.001). Serum occludin level was significantly positively correlated with the extent of brain edema preoperatively (r = 0.78, P < 0.001) and postoperatively (r = 0.59, P < 0.001). At an optimal cutoff of 3.015 ng/mL, preoperative serum occludin level discriminated between mild and severe preoperative brain edema with a sensitivity of 90.48% and a specificity of 84.62%. At an optimal cutoff value of 3.033 ng/mL, postoperative serum occludin level distinguished between mild and severe postoperative brain edema with a sensitivity of 97.30% and a specificity of 55.56%. ConclusionsSerum occludin level is associated with cerebral edema and could potentially be used as a biomarker for perioperative cerebral edema.

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Role of matrix metalloproteinase-2/9 (MMP2/9) in lead-induced changes in an in vitro blood-brain barrier model

Cited by 40 publications

References 25 publications

Propofol attenuates TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells by inhibiting Ca2+/CAMK II/ERK/NF-κB signaling pathway

Propofol attenuates TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells by inhibiting Ca2+/CAMK II/ERK/NF-κB signaling pathway

Deciphering the Forebrain Disorder in a Chicken Model of Cerebral Hernia

Peripheral blood occludin level as a biomarker for preoperative cerebral edema in patients with brain tumors

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