Glycyrrhizin, a High-Mobility Group Box 1 Inhibitor, Improves Lipid Metabolism and Suppresses Vascular Inflammation in Apolipoprotein E Knockout Mice

Ding, Jiawang; Luo, Chan; Wang, Xinan; Zhou, Tian; Zheng, Xia-Xia; Zhang, Zaiqiang; Yu, Bin; Zhang, Jing; Tong, Xiaohong

doi:10.1159/000495310

Cited by 10 publications

(7 citation statements)

References 39 publications

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“…SREBP-1c coordinates the synthesis of FA and cholesterol, and FAS is its downstream transcription factor (32). A previous study has reported that GA can improve lipid metabolism in AS and inhibit vascular inflammation in Apoe -/mice (19). The results from the present study demonstrated that GA could inhibit the expression of the lipid-related proteins FAS and SREBP-1c in DM-AS rats.…”

Section: Discussionsupporting

confidence: 66%

“…These findings suggested that GA may have some therapeutic effects on DM-AS. GA is a small inhibitor of HMGB1 that has a protective effect on blood vessels in AS (19,30) and can decrease renal complications caused by DM (21). In the present study, GA was found to inhibit the expression of HMGB1 in DM-AS rats.…”

Section: Discussionsupporting

confidence: 56%

“…Glycyrrhizic acid (GA), an inhibitor of HMGB1, may have a protective effect in AS. Ding et al (19) reported that GA decreases high-fat diet-induced AS in Apoe -/mice by significantly decreasing serum HMGB1 and lipid levels, and by increasing the regulatory T-cell/T helper T-cell ratio. In addition, it has been demonstrated that GA can prevent diabetic nephropathy by activating the AMP-activated protein kinase/sirtuin 1/peroxisome proliferator-activated receptor γ co-activator 1 signaling pathway in db/db mice (20).…”

Section: Introductionmentioning

confidence: 99%

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Gycyrrhizic acid alleviates atherosclerotic lesions in rats with diabetes mellitus

Zhao

Zhang

2021

Mol Med Rep

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Gycyrrhizic acid (GA), an inhibitor of high mobility group box 1 (HMGB1), inhibits inflammatory responses and is involved in the occurrence and development of several inflammation-related diseases. However, the role of GA in the atherosclerotic lesions caused by diabetes mellitus (DM) remains unknown. In the present study, Sprague Dawley rats were selected to desi=gn a diabetic atherosclerosis (AS) model. Rats from the DM-AS group were subsequently divided into DM-AS, DM-AS + GA (50 mg/kg) and DM-AS + GA (150 mg/kg) groups. Biochemical analyzers were used to measure levels of blood glucose, fasting insulin, total cholesterol, total triglyceride, low-density lipoprotein and high-density lipoprotein. The number of plaques was recorded after collection of thoracic aortas from the rats. The intimal thickness of arterial tissue was detected by hematoxylin and eosin staining. The expression levels of CD68 and α-smooth muscle actin (α-SMA) were detected by immunohistochemistry. The expression of tumor necrosis factor-α, interleukin (IL)-6 and IL-1β in the serum of the rats was detected by ELISA. The expression of fatty acid synthetase, sterol regulatory element binding protein 1C, HMGB1 and receptor for advanced glycation end products (RAGE) was detected by western blotting. Reverse transcription quantitative PCR was used to detect the mRNA expression of HMGB1 and RAGE. The results demonstrated that GA treatment could decrease the body weight, blood glucose level and biochemical parameters of AS DM rats in a dose-dependent manner. In addition, GA decreased the intimal thickness of carotid artery and the formation of plaque in rats with diabetic AS. Furthermore, GA inhibited macrophage activation and decreased α-SMA expression in vascular smooth muscle cells, and decreased the expression of proteins (FAS and SREBP-1c) and inflammatory factors. Taken together, the findings from the present study demonstrated that GA may have a therapeutic effect on DM-associated AS. This study provides a theoretical basis for the treatment of diabetic AS.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

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Gycyrrhizic acid alleviates atherosclerotic lesions in rats with diabetes mellitus

Zhao

Zhang

2021

Mol Med Rep

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“…[ 26 ] In vitro studies have found out that inhibiting HMGB1 improves lipids metabolism, decreases AS plaque area, and restores Treg/Th17 cell ratio. [ 27 ] miRNAs bind to the 3′‐untranslated region (3′‐UTR) of mRNA to cause translational inhibition or mRNA degradation, which is one of the important ways for miRNAs to exert their biological functions. A recent study reports that miR‐24 can repress the abnormal proliferation and migration of VSMCs via suppressing HMGB1.…”

Section: Discussionmentioning

confidence: 99%

miR‐141‐5p suppresses vascular smooth muscle cell inflammation, proliferation, and migration via inhibiting the HMGB1/NF‐κB pathway

Chen

et al. 2021

J Biochem & Molecular Tox

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MicroRNAs (miRNAs) have been identified as significant modulators in the pathogenesis of atherosclerosis (AS). Additionally, the dysregulation of vascular smooth muscle cells (VSMCs) is a crucial biological event during AS. Our study aimed to explore the functional roles and molecular mechanisms of miR‐141‐5p in VSMCs dysfunction. C57BL/6 mice were used to establish AS animal model. Human VSMCs were treated by oxidized low‐density lipoprotein (ox‐LDL) to establish AS cell model. Quantitative real‐time polymerase chain reaction (qRT‐PCR) was employed to probe miR‐141‐5p and high‐mobility group box 1 (HMGB1) mRNA expressions in VSMCs or plasma samples of the mice. Inflammatory cytokines were detected by enzyme‐linked immunosorbent assay kits. Cell counting kit‐8 and bromodeoxyuridine assays were performed to evaluate cell proliferation. Cell migration and apoptosis were detected with Transwell assay and flow cytometry analysis, respectively. The target gene of miR‐141‐5p was predicted with the TargetScan database, and the interaction between miR‐141‐5p and HMGB1/nuclear factor‐κB (NF‐κB) was further validated by dual‐luciferase reporter assay, qRT‐PCR, and Western blot analysis. miR‐141‐5p was found to be decreased in the plasma of patients and mice model with AS. Its expression was also downregulated in VSMCs treated by ox‐LDL. miR‐141‐5p overexpression inhibited the inflammation, proliferation, migration of VSMCs, and promoted the apoptosis of VSMCs. HMGB1 was identified as a direct target of miR‐141‐5p, and miR‐141‐5p could repress the activity of HMGB1/NF‐κB signaling. HMGB1 restoration reversed the effects of miR‐141‐5p, and NF‐κB inhibitor JSH‐23 showed similar effects with miR‐141‐5p mimics. miR‐141‐5p inhibits VSMCs’ dysfunction by targeting the HMGB1/NF‐κB pathway, which probably functions as a protective factor during the development of AS.

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“…В экспериментальных исследованиях было показано, что HMGB1 посредством связывания с TLR4 на макрофагах способствовал развитию и прогрессированию атеросклероза у ApoE -/мышей [14]. С другой стороны, нейтрализация HMGB1 приводила к уменьшению тяжести развивающегося атеросклеротического поражения, что позволяет рассматривать его как возможную терапевтическую мишень [11,17,31].…”

Section: Introductionunclassified

Relationships between serum HMGB1 concentration and subpopulation composition of circulating monocytes in patients with subclinical atherosclerosis

et al. 2022

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Chronic non-infectious inflammation of low intensity is the most important mechanism of development and progression in atherosclerosis. Under the conditions of persistent non-resolving inflammation observed in the vascular wall and atherosclerotic plaque (ASB), permanent tissue damage occurs, thus leading to increased formation of endogenous danger-associated molecular patterns (DAMPs). The non-histone chromosomal protein HMGB1 may be regarded as a prototypical DAMPs. HMGB1 acts as a DAMP if entering the extracellular space, causing inflammation by its binding to pattern-recognizing receptors (TLR2, TLR4, RAGE, CD36, etc.). A number of clinical studies have revealed higher HMGB1 levels in the blood of patients with coronary heart disease and atherosclerotic disease of the lower limb arteries, as well as its interrelations with the burden of coronary artery atherosclerosis. Currently, the mechanisms of HMGB1-mediated atherosclerosis progression are studied only fragmentary. The aim of our study was to investigate relationships between the serum HMGB1 level and subsets of circulating monocyte subpopulations in patients with subclinical atherosclerosis.The study enrolled patients aged 40-64 years with subclinical atherosclerosis of peripheral arteries. Serum HMGB1 concentration was determined using enzyme immunoassay kits (Human HMGB1/HMG-1 ELISA Kit, NBP2-62766, Novus Biologicals, USA). The serum HMGB1 threshold was 18.75 pg/ml, whereas the measurement range was 31.25 to 2000 pg/ml. Phenotyping of the blood monocyte subpopulations was performed by flow cytometry using Navios 6/2 device (Beckman Coulter, USA).An increase in serum HMGB1 concentration was associated with decreased number of classical M2 monocytes, and an increase in intermediate and M1 monocytes. Moreover, an increase in HMGB1 concentration was associated with higher numbers of classical, intermediate, and non-classical monocytes expressing CD36 and TLR2. Increased HMGB1 concentration (from Q1 to Q4) correlated with higher numbers of classical (p = 0.001) and intermediate monocytes (p = 0.006) but not with non-classical phenotypes (p = 0.147). Upon increase of HMGB1 concentration (Q1 to Q4), we have found an increase in the number of classical (p < 0.0001), intermediate (p < 0.0001), and non-classical (p < 0.0001), CD36-expressing monocytes. An increased number of intermediate (p = 0.022; p1, 4 = 0.034) and non-classical, TLR2-expressing monocytes was also revealed (p = 0.002; p1, 4 = 0.035). By mean of correlation analysis, IL-1β concentrations showed direct correlation with the number of M1 monocytes (r = 0.268; p = 0.035) and inverse relation with the number of M2 monocytes (r = -0.376; p = 0.003).Increased serum HMGB1 concentration in patients with subclinical atherosclerosis was associated with decreased numbers of classical and M2 monocytes, as well as higher numbers of intermediate and M1 monocytes, like as with increased contents of intermediate and non-classical monocytes expressing CD36 and TLR2. IL-1β levels directly correlated with HMGB1 concentration and the number of Mi-monocytes.

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Glycyrrhizin, a High-Mobility Group Box 1 Inhibitor, Improves Lipid Metabolism and Suppresses Vascular Inflammation in Apolipoprotein E Knockout Mice

Cited by 10 publications

References 39 publications

Gycyrrhizic acid alleviates atherosclerotic lesions in rats with diabetes mellitus

Gycyrrhizic acid alleviates atherosclerotic lesions in rats with diabetes mellitus

miR‐141‐5p suppresses vascular smooth muscle cell inflammation, proliferation, and migration via inhibiting the HMGB1/NF‐κB pathway

Relationships between serum HMGB1 concentration and subpopulation composition of circulating monocytes in patients with subclinical atherosclerosis

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