Glycyrrhizin Attenuates Proinflammatory Cytokines through a Peroxisome Proliferator-Activated Receptor-&amp;#947;-Dependent Mechanism and Experimental Vasospasm in a Rat Model

Chang, Chih-Zen; Wu, Shao-Chun; Kwan, Aij‐Lie

doi:10.1159/000381099

Cited by 17 publications

(9 citation statements)

References 46 publications

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“…Intrastriatal injections of 15d-PGJ 2 significantly increased PPARγ-DNA binding activity and the expression of catalase in the perihemorrhagic area 3h after ICH (Zhao et al ., 2006). However, in an experimental SAH model, PPARγ mRNA and protein levels were significantly reduced in the cortex compared to sham controls (Chang et al ., 2015a).…”

Section: Evidence Favoring a Beneficial Role Of Pparγ In The Injurmentioning

confidence: 99%

Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair

Cai

Yang

Liu

et al. 2018

Progress in Neurobiology

176

147

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Peroxisome proliferator-activated receptor γ (PPARγ) is a widely expressed ligand-modulated transcription factor that governs the expression of genes involved in inflammation, redox equilibrium, trophic factor production, insulin sensitivity, and the metabolism of lipids and glucose. Synthetic PPARγ agonists (e.g. thiazolidinediones) are used to treat Type II diabetes and have the potential to limit the risk of developing brain injuries such as stroke by mitigating the influence of comorbidities. If brain injury develops, PPARγ serves as a master gatekeeper of cytoprotective stress responses, improving the chances of cellular survival and recovery of homeostatic equilibrium. In the acute injury phase, PPARγ directly restricts tissue damage by inhibiting the NFκB pathway to mitigate inflammation and stimulating the Nrf2/ARE axis to neutralize oxidative stress. During the chronic phase of acute brain injuries, PPARγ activation in injured cells culminates in the repair of gray and white matter, preservation of the blood-brain barrier, reconstruction of the neurovascular unit, resolution of inflammation, and long-term functional recovery. Thus, PPARγ lies at the apex of cell fate decisions and exerts profound effects on the chronic progression of acute injury conditions. Here, we review the therapeutic potential of PPARγ in stroke and brain trauma and highlight the novel role of PPARγ in long-term tissue repair. We describe its structure and function and identify the genes that it targets. PPARγ regulation of inflammation, metabolism, cell fate (proliferation/differentiation/maturation/survival), and many other processes also has relevance to other neurological diseases. Therefore, PPARγ is an attractive target for therapies against a number of progressive neurological disorders.

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Section: Evidence Favoring a Beneficial Role Of Pparγ In The Injurmentioning

confidence: 99%

Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair

Cai

Yang

Liu

et al. 2018

Progress in Neurobiology

176

147

View full text Add to dashboard Cite

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“…Furthermore, glycyrrhizin attenuates pulmonary hypertension and pulmonary vascular remodeling in the monocrotaline-induced rat model of pulmonary arterial hypertension (Yang et al, 2014). Moreover, glycyrrhizin and its metabolites inhibit T helper (Th) type 2 immune response and the inflammatory vascular reaction in various animal models, such as asthma and subarachnoid hemorrhage (Chang et al, 2015; Ma et al, 2013; Sun et al, 2013; Wu et al, 2016). Given that tissue fibrosis, vasculopathy, and inflammation are the three primary pathological components of SSc, glycyrrhizin and its metabolites may have a beneficial disease-modifying effect.…”

Section: Introductionmentioning

confidence: 99%

Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis

Yamashita

Asano

Taniguchi

et al. 2017

Journal of Investigative Dermatology

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Systemic sclerosis (SSc) is a multisystem inflammatory and vascular disease resulting in extensive tissue fibrosis. Glycyrrhizin, clinically used for chronic hepatic diseases and itching dermatitis, modulates the pathological processes of inflammation, vasculopathy, and fibrosis in human diseases and their animal models. Therefore, we investigated a potential impact of glycyrrhizin on the key pathological manifestations of SSc, including inflammation, vasculopathy, and tissue fibrosis, with bleomycin-treated mice mimicking the fibrotic and inflammatory components of SSc and endothelial cell-specific Fli1-knockout mice recapitulating SSc vasculopathy. Glycyrrhizin significantly ameliorated dermal fibrosis in bleomycin-treated mice, which was partly attributable to blockade of transforming growth factor-β signaling in dermal fibroblasts through the downregulation of thrombospondin 1, a latent transforming growth factor-β receptor, and transcription factors Smad3 and Ets1. Furthermore, bleomycin-dependent induction of T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition were greatly suppressed in mice administered glycyrrhizin. Glycyrrhizin also improved vascular permeability of endothelial cell-specific Fli1-knockout mice by increasing the expression of molecules regulating vascular integrity. These results indicate that glycyrrhizin ameliorates bleomycin-induced dermal fibrosis through the inhibition of fibroblast activation, T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition and improves endothelial Fli1 deficiency-dependent vascular disintegrity, implying its potential as a disease-modifying drug for SSc.

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“…PKC regulates ET signaling [ 37 ]. PPAR alpha promotes formation and rupture of aneurysms in mice [ 38 ], but also decreases vasospasm-related cytokines [ 39 ] and hemoglobin-induced TLR4 expression in vascular myocytes [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

mRNA Expression Profiles from Whole Blood Associated with Vasospasm in Patients with Subarachnoid Hemorrhage

Stamova

Ander

et al. 2019

Neurocrit Care

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Background: Though there are many biomarker studies of plasma and serum in patients with aneurysmal subarachnoid hemorrhage (SAH), few have examined blood cells that might contribute to vasospasm. In this study, we evaluated inflammatory and prothrombotic pathways by examining mRNA expression in whole blood of SAH patients with and without vasospasm. Methods: Adult SAH patients with vasospasm (n = 29) and without vasospasm (n = 21) were matched for sex, race/ ethnicity, and aneurysm treatment method. Diagnosis of vasospasm was made by angiography. mRNA expression was measured by Affymetrix Human Exon 1.0 ST Arrays. SAH patients with vasospasm were compared to those without vasospasm by ANCOVA to identify differential gene, exon, and alternatively spliced transcript expression. Analyses were adjusted for age, batch, and time of blood draw after SAH. Results: At the gene level, there were 259 differentially expressed genes between SAH patients with vasospasm compared to patients without (false discovery rate < 0.05, |fold change| ≥ 1.2). At the exon level, 1210 exons representing 1093 genes were differentially regulated between the two groups (P < 0.005, ≥ 1.2 |fold change|). Principal components analysis segregated SAH patients with and without vasospasm. Signaling pathways for the 1093 vasospasm-related genes included adrenergic, P2Y, ET-1, NO, sildenafil, renin-angiotensin, thrombin, CCR3, CXCR4, MIF, fMLP, PKA, PKC, CRH, PPARα/RXRα, and calcium. Genes predicted to be alternatively spliced included IL23A, RSU1, PAQR6, and TRIP6. Conclusions: This is the first study to demonstrate that mRNA expression in whole blood distinguishes SAH patients with vasospasm from those without vasospasm and supports a role of coagulation and immune systems in vasospasm.

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Glycyrrhizin Attenuates Proinflammatory Cytokines through a Peroxisome Proliferator-Activated Receptor-γ-Dependent Mechanism and Experimental Vasospasm in a Rat Model

Cited by 17 publications

References 46 publications

Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair

Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair

Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis

mRNA Expression Profiles from Whole Blood Associated with Vasospasm in Patients with Subarachnoid Hemorrhage

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