Metformin Preserves VE–Cadherin in Choroid Plexus and Attenuates Hydrocephalus via VEGF/VEGFR2/p-Src in an Intraventricular Hemorrhage Rat Model

Shen, Dan; Ye, Xianghua; Li, Jiawen; Hao, Xiaodi; Jin, Luhang; Jin, Yujia; Tong, Lifang; Gao, Feng

doi:10.3390/ijms23158552

Cited by 8 publications

(2 citation statements)

References 65 publications

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“…In a mouse model of IVH, VE-cadherin levels are decreased in the choroid plexus, contributing to the development of hydrocephalus. Metformin has been identified as a potential protective agent because it maintains VE-cadherin expression in the choroid plexus, which is dependent on the suppression of the VEGF/ VEGFR2/p-Src pathway[20]. In addition, the interaction of VE-cadherin with other proteins such as p120-catenin and β-catenin is critical for maintaining vascular integrity.…”

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confidence: 99%

“…In addition, the interaction of VE-cadherin with other proteins such as p120-catenin and β-catenin is critical for maintaining vascular integrity. Loss of VE-cadherin function can disrupt junctional complexes and alter the localization of other junctional proteins, leading to increased vascular permeability and impaired BBB function[20]. These findings suggest that VE-cadherin is a key player in the pathophysiology of ICH and associated complications, making it a promising target for developing therapies aimed at protecting the BBB and improving patient outcomes after intracranial hemorrhage incidents.…”

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Correlation of P352L, R538G Col4A1 Gene, RS951733 Col4A2 Gene Locus Polymorphisms, IFN-, IL-17, and VE-Cadherin Levels with the Event of Non-Lobar Spontaneous Intracerebral Hemorrhage in Hypertension Patients: Research Protocol (Preprint)

Tjili,

Syafrita,

Darwin

et al. 2024

Preprint

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BACKGROUND Background: Stroke is an acute and focal neurological deficit syndrome. By definition, it can be interpreted as a clinical syndrome resulting from vascular injury (infarction, bleeding) in the central nervous system. Hypertension is the main risk factor of non-lobar intracerebral hemorrhage (ICH), in which around 85% of ICH patients are hypertensive. Hypertension is often found to damage the basement membrane of blood vessel walls. It can also induce tissue injury by increasing the inflammatory cytokines IL 17 and IFN-γ and reducing the expression of VE-Cadherin. Genetically, mutation of the genes Col4A1 and Col4A2 has been correlated with the incidence of non-lobar intracerebral hemorrhage. OBJECTIVE Objective: The aim is to investigate the correlation between the P352L, R538G Col4A1 gene, RS9521733 Col4A2 gene locus polymorphisms, levels of IFN-γ, IL-17, and VE-Cadherin with the event of non-lobar spontaneous intracerebral hemorrhage in hypertensive patients. METHODS Method: This is a research protocol. This research will be an observational study with a comparative cross-sectional approach where the dependent and independent variables will be examined at the same time. This research was designed to investigate the correlation between the P352L, R538G Col4A1 gene, RS9521733 Col4A2 gene locus polymorphisms, level of IFN-γ, IL-17, and VE-Cadherin with the incident of spontaneous non-lobar intracerebral hemorrhage in hypertensive patients. Blood samples will be collected from hypertensive patients with non-lobar intracerebral hemorrhage stroke patients with hypertension and hypertensive patients without intracerebral hemorrhage. The samples will be analyzed using ELISA and transcription polymerase chain reaction (PCR). Data analysis will involve statistical tests with descriptive analysis, univariate analysis, and bivariate analysis. RESULTS Results: This research is at the protocol development stage. A pilot study regarding its feasibility has been completed in January 2023. The results of the study are expected to be available by the end of 2024. CONCLUSIONS Conclusion: A study of the relationship between Col4A1, Col4A2 gene polymorphisms, levels of IFN-γ, IL-17, and VE-Cadherin on the incidence of non-lobar intracerebral hemorrhage in hypertension patients is expected to increase understanding and expand knowledge of the pathophysiology of the risk of non-lobar intracerebral hemorrhage in hypertension patients.

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Correlation of P352L, R538G Col4A1 Gene, RS951733 Col4A2 Gene Locus Polymorphisms, IFN-, IL-17, and VE-Cadherin Levels with the Event of Non-Lobar Spontaneous Intracerebral Hemorrhage in Hypertension Patients: Research Protocol (Preprint)

Tjili,

Syafrita,

Darwin

et al. 2024

Preprint

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Identification of CSPG4 as a Biomarker and Therapeutic Target for Infantile Post‐Hemorrhagic Hydrocephalus via Multi‐Omics Analysis

Chen,

Wang,

Peng

et al. 2024

Advanced Science

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Intraventricular hemorrhage in preterm neonates has become a major global health problem and is associated with a high risk of post‐hemorrhagic hydrocephalus (PHH). Identifying diagnostic markers and therapeutic targets is a focal challenge in the PHH prevention and control. Here, this study applies multi‐omics analyses to characterize the biochemical, proteomic, and metabolomic profiles of the cerebrospinal fluid (CSF) in clinical human cohorts to investigate disease development and recovery processes occurring due to PHH. Integrative multiomics analysis suggests that the over‐representation of ferroptosis, calcium, calcium ion binding, and cell adhesion signaling pathways is associated with PHH. Bioinformatic analysis indicates that chondroitin sulfate proteoglycan 4 (CSPG4) is discovered as a CSF biomarker and positively correlated with the ventricular size and the rate of periventricular leukomalacia. Next, it is further demonstrated that these signaling pathways are dysregulated in the choroid plexus (ChP) in PHH by using in vitro cellular experiments and rat models of PHH, whereas CSPG4 silencing can suppress ferroptosis, cell adhesion function, and the intracellular flow of Ca2+. These findings broaden the understanding of the pathophysiological mechanisms of PHH and suggest that CSPG4 may be an effective therapeutic target for PHH.

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Simulated microgravity‐induced dysregulation of cerebrospinal fluid immune homeostasis by disrupting the blood–cerebrospinal fluid barrier

Yang,

Cui,

Zhao

et al. 2024

Brain and Behavior

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BackgroundThe blood–cerebrospinal fluid barrier (BCSFB) comprises the choroid plexus epithelia. It is important for brain development, maintenance, function, and especially for maintaining immune homeostasis in the cerebrospinal fluid (CSF). Although previous studies have shown that the peripheral immune function of the body is impaired upon exposure to microgravity, no studies have reported changes in immune cells and cytokines in the CSF that reflect neuroimmune status. The purpose of this study is to investigate the alterations in cerebrospinal fluid (CSF) immune homeostasis induced by microgravity and its mechanisms. This research is expected to provide basic data for brain protection of astronauts during spaceflight.MethodsThe proportions of immune cells in the CSF and peripheral blood (PB) of SMG rats were analyzed using flow cytometry. Immune function was evaluated by measuring cytokine concentrations using the Luminex method. The histomorphology and ultrastructure of the choroid plexus epithelia were determined. The concentrations of intercellular junction proteins in choroid plexus epithelial cells, including vascular endothelial‐cadherin (VE‐cadherin), zonula occludens 1 (ZO‐1), Claudin‐1 and occludin, were detected using western blotting and immunofluorescence staining to characterize BCSFB injury.ResultsWe found that SMG caused significant changes in the proportion of CD4 and CD8 T cells in the CSF and a significant increase in the levels of cytokines (GRO/KC, IL‐18, MCP‐1, and RANTES). In the PB, there was a significant decrease in the proportion of T cells and NKT cells and a significant increase in cytokine levels (GRO/KC, IL‐18, MCP‐1, and TNF‐α). Additionally, we observed that the trends in immune markers in the PB and CSF were synchronized within specific SMG durations, suggesting that longer SMG periods (≥21 days) have a more pronounced impact on immune markers. Furthermore, 21d‐SMG resulted in ultrastructural disruption and downregulated expression of intercellular junction proteins in rat choroid plexus epithelial cells.ConclusionsWe found that SMG disrupts the BCSFB and affects the CSF immune homeostasis. This study provides new insights into the health protection of astronauts during spaceflight.

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Metformin Preserves VE–Cadherin in Choroid Plexus and Attenuates Hydrocephalus via VEGF/VEGFR2/p-Src in an Intraventricular Hemorrhage Rat Model

Cited by 8 publications

References 65 publications

Correlation of P352L, R538G Col4A1 Gene, RS951733 Col4A2 Gene Locus Polymorphisms, IFN-, IL-17, and VE-Cadherin Levels with the Event of Non-Lobar Spontaneous Intracerebral Hemorrhage in Hypertension Patients: Research Protocol (Preprint)

Correlation of P352L, R538G Col4A1 Gene, RS951733 Col4A2 Gene Locus Polymorphisms, IFN-, IL-17, and VE-Cadherin Levels with the Event of Non-Lobar Spontaneous Intracerebral Hemorrhage in Hypertension Patients: Research Protocol (Preprint)

Identification of CSPG4 as a Biomarker and Therapeutic Target for Infantile Post‐Hemorrhagic Hydrocephalus via Multi‐Omics Analysis

Simulated microgravity‐induced dysregulation of cerebrospinal fluid immune homeostasis by disrupting the blood–cerebrospinal fluid barrier

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