Dataset Information

Protective Effects of Sophoraflavanone G by Inhibiting TNF-α-Induced MMP-9-Mediated Events in Brain Microvascular Endothelial Cells.

ABSTRACT: The regulation of matrix metalloproteinases (MMPs), especially MMP-9, has a critical role in both physiological and pathological events in the central nervous system (CNS). MMP-9 is an indicator of inflammation that triggers several CNS disorders, including neurodegeneration. Tumor necrosis factor-α (TNF-α) has the ability to stimulate the production of different inflammatory factors, including MMP-9, in several conditions. Numerous phytochemicals are hypothesized to mitigate inflammation, including the CNS. Among them, a flavonoid compound, sophoraflavanone G (SG), found in Sophora flavescens has been found to possess several medicinal properties, including anti-bacterial and anti-inflammatory effects. In this study, mouse brain microvascular endothelial cells (bMECs) were used to explore TNF-α-induced MMP-9 signaling. The effects of SG on TNF-α-induced MMP-9 expression and its mechanisms were further evaluated. Our study revealed that the expression of MMP-9 in bMECs was stimulated by TNF-α through the activation of ERK1/2, p38 MAPK, and JNK1/2 via the TNF receptor (TNFR) with a connection to the NF-κB signaling pathway. Moreover, we found that SG can interact with the TNFR. The upregulation of MMP-9 by TNF-α may lead to the disruption of zonula occludens-1 (ZO-1), which can be mitigated by SG administration. These findings provide evidence that SG may possess neuroprotective properties by inhibiting the signaling pathways associated with TNFR-mediated MMP-9 expression and the subsequent disruption of tight junctions in brain microvascular endothelial cells.

SUBMITTER: Lee TH

PROVIDER: S-EPMC10779338 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Protective Effects of Sophoraflavanone G by Inhibiting TNF-α-Induced MMP-9-Mediated Events in Brain Microvascular Endothelial Cells.

Lee Tsong-Hai TH Chen Jiun-Liang JL Tsai Ming-Ming MM Wu Yi-Hsuan YH Tseng Hui-Ching HC Cheng Li-Ching LC Shanmugam Velayuthaprabhu V Hsieh Hsi-Lung HL

International journal of molecular sciences 20231224 1

The regulation of matrix metalloproteinases (MMPs), especially MMP-9, has a critical role in both physiological and pathological events in the central nervous system (CNS). MMP-9 is an indicator of inflammation that triggers several CNS disorders, including neurodegeneration. Tumor necrosis factor-α (TNF-α) has the ability to stimulate the production of different inflammatory factors, including MMP-9, in several conditions. Numerous phytochemicals are hypothesized to mitigate inflammation, inclu ...[more]

PMID: 38203454

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Project description:Endothelial cells (ECs) are an active component of the immune system and interact directly with inflammatory cytokines. While ECs are known to be polarized cells, the potential role of apicobasal polarity in response to inflammatory mediators has been scarcely studied. Acute inflammation is vital in maintaining healthy tissue in response to infection; however, chronic inflammation can lead to the production of systemic inflammatory cytokines and deregulated leukocyte trafficking, even in the absence of a local infection. Elevated levels of cytokines in circulation underlie the pathogenesis of sepsis, the leading cause of intensive care death. Because ECs constitute a key barrier between circulation (luminal interface) and tissue (abluminal interface), we hypothesize that ECs respond differentially to inflammatory challenge originating in the tissue versus circulation as in local and systemic inflammation, respectively. To begin this investigation, we stimulated ECs abluminally and luminally with the inflammatory cytokine tumor necrosis factor alpha (TNF-α) to mimic a key feature of local and systemic inflammation, respectively, in a microvascular mimetic (μSiM-MVM). Polarized IL-8 secretion and polymorphonuclear neutrophil (PMN) transmigration were quantified to characterize the EC response to luminal versus abluminal TNF-α. We observed that ECs uniformly secrete IL-8 in response to abluminal TNF-α and is followed by PMN transmigration. The response to abluminal treatment was coupled with the formation of ICAM-1-rich membrane ruffles on the apical surface of ECs. In contrast, luminally stimulated ECs secreted five times more IL-8 into the luminal compartment than the abluminal compartment and sequestered PMNs on the apical EC surface. Our results identify clear differences in the response of ECs to TNF-α originating from the abluminal versus luminal side of a monolayer for the first time and may provide novel insight into future inflammatory disease intervention strategies.

Project description:Endothelial cell dysfunction plays a crucial role in the early development of cerebral small vessel disease (CSVD). Arginase-1 (ARG1) is expressed in endothelial cells, and its deficiency may exacerbate cerebrovascular damage by increasing reactive oxygen species (ROS) production, thereby inducing endothelial cell apoptosis. Berbamine (BBM) has shown potential in neuroprotection and cardiovascular disease prevention. This study aimed to investigate the impact of ARG1 deficiency on human brain microvascular endothelial cells and the protective effects of BBM against ARG1 deficiency-induced damage. Human brain microvascular endothelial cells (HCMEC/D3) were cultured in vitro, and ARG1 knockdown or overexpression was achieved using plasmid transfection techniques. We examined the effects of ARG1 expression levels on HCMEC/D3 cell viability, migration, apoptosis, adhesion, and angiogenesis through cellular experiments. Additionally, we explored how ARG1 expression levels influenced arginine (Arg), nitric oxide (NO), and ROS levels in HCMEC/D3 cells. The results demonstrated that ARG1 deficiency inhibited HCMEC/D3 cell viability, migration, adhesion, and angiogenesis, while promoting apoptosis and elevating Arg, NO, and ROS levels in HCMEC/D3 cells. Next, the effect of different BBM concentrations on HCMEC/D3 cell viability was assessed using the CCK-8 assay, revealing that BBM at a concentration of 5 µM had no significant impact on cell viability. Subsequently, after successfully knocking down ARG1 in HCMEC/D3 cells, the cells were treated with BBM. The results showed that BBM effectively mitigated the negative effects of ARG1 deficiency on HCMEC/D3 cell viability, migration, apoptosis, adhesion, and angiogenesis, while also reducing Arg, NO, inducible nitric oxide synthase (iNOS), and ROS levels in HCMEC/D3 cells. In conclusion, this study suggests that ARG1 deficiency may damage HCMEC/D3 cells by increasing Arg levels, leading to elevated NO and ROS levels. BBM may provide protection to ARG1-deficient HCMEC/D3 cells by reducing Arg, NO, iNOS, and ROS levels. These findings deepen our understanding of the pathogenesis of CSVD and provide a theoretical basis for the clinical application of BBM.

Dataset Information

Protective Effects of Sophoraflavanone G by Inhibiting TNF-α-Induced MMP-9-Mediated Events in Brain Microvascular Endothelial Cells.

Publications

Protective Effects of Sophoraflavanone G by Inhibiting TNF-α-Induced MMP-9-Mediated Events in Brain Microvascular Endothelial Cells.

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