scholarly journals Formononetin inhibits lipopolysaccharide-induced release of high mobility group box 1 by upregulating SIRT1 in a PPARδ-dependent manner

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4208 ◽  
Author(s):  
Jung Seok Hwang ◽  
Eun Sil Kang ◽  
Sung Gu Han ◽  
Dae-Seog Lim ◽  
Kyung Shin Paek ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Specific Inhibitor ◽  
High Mobility ◽  
Inhibitory Effect ◽  
Sirtuin 1 ◽  
High Mobility Group ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Sirt1 Expression

Background The release of high mobility group box 1 (HMGB1) induced by inflammatory signals acts as a cellular alarmin to trigger a chain of inflammatory responses. Although the inflammatory actions of HMGB1 are well studied, less is known about the therapeutic agents that can impede its release. This study investigated whether the isoflavonoid formononetin can modulate HMGB1 release in cellular inflammatory responses. Methods RAW264.7 murine macrophages were exposed to lipopolysaccharide (LPS) in the presence or absence of formononetin. The levels of HMGB1 release, sirtuin 1 (SIRT1) expression, and HMGB1 acetylation were analyzed by immunoblotting and real-time polymerase chain reaction. The effects of resveratrol and sirtinol, an activator and inhibitor of SIRT1, respectively, on LPS-induced HMGB1 release were also evaluated. Results Formononetin modulated cellular inflammatory responses by suppressing the release of HMGB1 by macrophages exposed to LPS. In RAW264.7 cells, formononetin significantly attenuated LPS-induced release of HMGB1 into the extracellular environment, which was accompanied by a reduction in its translocation from the nucleus to the cytoplasm. In addition, formononetin significantly induced mRNA and protein expression of SIRT1 in a peroxisome proliferator-activated receptor δ (PPARδ)-dependent manner. These effects of formononetin were dramatically attenuated in cells treated with small interfering RNA (siRNA) against PPARδ or with GSK0660, a specific inhibitor of PPARδ, indicating that PPARδ is involved in formononetin-mediated SIRT1 expression. In line with these effects, formononetin-mediated inhibition of HMGB1 release in LPS-treated cells was reversed by treatment with SIRT1-targeting siRNA or sirtinol, a SIRT1 inhibitor. By contrast, resveratrol, a SIRT1 activator, further potentiated the inhibitory effect of formononetin on LPS-induced HMGB1 release, revealing a possible mechanism by which formononetin regulates HMGB1 release through SIRT1. Furthermore, modulation of SIRT1 expression by transfection of SIRT1- or PPARδ-targeting siRNA significantly counteracted the inhibitory effects of formononetin on LPS-induced HMGB1 acetylation, which was responsible for HMGB1 release. Discussion This study shows for the first time that formononetin inhibits HMGB1 release by decreasing HMGB1 acetylation via upregulating SIRT1 in a PPARδ-dependent manner. Formononetin consequently exhibits anti-inflammatory activity. Identification of agents, such as formononetin, which can block HMGB1 release, may help to treat inflammation-related disorders.

scholarly journals BST204 Protects Dexamethasone-Induced Myotube Atrophy through the Upregulation of Myotube Formation and Mitochondrial Function

2021 ◽  
Vol 18 (5) ◽  
pp. 2367
Author(s):  
Ryuni Kim ◽  
Hyebeen Kim ◽  
Minju Im ◽  
Sun Kyu Park ◽  
Hae Jung Han ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Inflammatory Responses ◽  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dry Extract ◽  
Myotube Formation ◽  
Species Production

BST204 is a purified ginseng dry extract that has an inhibitory effect on lipopolysaccharide-induced inflammatory responses, but its effect on muscle atrophy is yet to be investigated. In this study, C2C12 myoblasts were induced to differentiate for three days followed by the treatment of dexamethasone (DEX), a corticosteroid drug, with vehicle or BST204 for one day and subjected to immunoblotting, immunocytochemistry, qRT-PCR and biochemical analysis for mitochondrial function. BST204 alleviates the myotube atrophic effect mediated by DEX via the activation of protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling. Through this pathway, BST204 suppresses the expression of muscle-specific E3 ubiquitin ligases contributing to the enhanced myotube formation and enlarged myotube diameter in DEX-treated myotubes. In addition, BST204 treatment significantly decreases the mitochondrial reactive oxygen species production in DEX-treated myotubes. Furthermore, BST204 improves mitochondrial function by upregulating the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) in DEX-induced myotube atrophy. This study provides a mechanistic insight into the effect of BST204 on DEX-induced myotube atrophy, suggesting that BST204 has protective effects against the toxicity of a corticosteroid drug in muscle and promising potential as a nutraceutical remedy for the treatment of muscle weakness and atrophy.

scholarly journals Rosiglitazone Inhibits Adrenocortical Cancer Cell Proliferation by Interfering with the IGF-IR Intracellular Signaling

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-11 ◽  
Author(s):  
Giulia Cantini ◽  
Adriana Lombardi ◽  
Elisabetta Piscitelli ◽  
Giada Poli ◽  
Elisabetta Ceni ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Phosphatidyl Inositol ◽  
Inhibitory Effect ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Adrenocortical Cancer ◽  
Peroxisome Proliferator Activated Receptor ◽  
Igf I

Rosiglitazone (RGZ), a thiazolidinedione ligand of the peroxisome proliferator-activated receptor (PPAR)-γ, has been recently described as possessing antitumoral properties. We investigated RGZ effect on cell proliferation in two cell line models (SW13 and H295R) of human adrenocortical carcinoma (ACC) and its interaction with the signaling pathways of the activated IGF-I receptor (IGF-IR). We demonstrate a high expression of IGF-IR in the two cell lines and in ACC. Cell proliferation is stimulated by IGF-I in a dose- and time-dependent manner and is inhibited by RGZ. The analysis of the main intracellular signaling pathways downstream of the activated IGF-IR, phosphatidyl inositol 3-kinase (PI3K)-Akt, and extracellular signal-regulated kinase (ERK1/2) cascades reveals that RGZ rapidly interferes with the Akt and ERK1/2 phosphorylation/activation which mediates IGF-I stimulated proliferation. In conclusion, our results suggest that RGZ exerts an inhibitory effect on human ACC cell proliferation by interfering with the PI3K/Akt and ERK1/2 signaling pathways downstream of the activated IGF-IR.

scholarly journals Activation of Peroxisome Proliferator-Activated Receptorγby Rosiglitazone Inhibits Lipopolysaccharide-Induced Release of High Mobility Group Box 1

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Jung Seok Hwang ◽  
Eun Sil Kang ◽  
Sun Ah Ham ◽  
Taesik Yoo ◽  
Hanna Lee ◽  
...  
Keyword(s):  
Cellular Response ◽  
Survival Rates ◽  
High Mobility ◽  
Inhibitory Effect ◽  
High Mobility Group ◽  
Raw 264.7 Cells ◽  
Signal Molecules ◽  
Peroxisome Proliferator ◽  
Treatment And Prevention ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are shown to modulate the pathological status of sepsis by regulating the release of high mobility group box 1 (HMGB1), a well-known late proinflammatory mediator of sepsis. Ligand-activated PPARs markedly inhibited lipopolysaccharide- (LPS) induced release of HMGB1 in RAW 264.7 cells. Among the ligands of PPAR, the effect of rosiglitazone, a specific ligand for PPARγ, was superior in the inhibition of HMGB1 release induced by LPS. This effect was observed in cells that received rosiglitazone before LPS or after LPS treatment, indicating that rosiglitazone is effective in both treatment and prevention. Ablation of PPARγwith small interfering RNA or GW9662-mediated inhibition of PPARγabolished the effect of rosiglitazone on HMGB1 release. Furthermore, the overexpression of PPARγmarkedly potentiated the inhibitory effect of rosiglitazone on HMGB1 release. In addition, rosiglitazone inhibited LPS-induced expression of Toll-like receptor 4 signal molecules, suggesting a possible mechanism by which rosiglitazone modulates HMGB1 release. Notably, the administration of rosiglitazone to mice improved survival rates in an LPS-induced animal model of endotoxemia, where reduced levels of circulating HMGB1 were demonstrated. Taken together, these results suggest that PPARs play an important role in the cellular response to inflammation by inhibiting HMGB1 release.

scholarly journals HMGB1 Is Involved in the Protective Effect of the PPARαAgonist Fenofibrate against Cardiac Hypertrophy

PPAR Research ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Zhankui Jia ◽  
Rui Xue ◽  
Gangqiong Liu ◽  
Ling Li ◽  
Jinjian Yang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Nuclear Dna ◽  
Inflammatory Responses ◽  
High Mobility ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Inhibitory Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hmgb1 Expression ◽  
Potential Strategy

High mobility group box 1 (HMGB1) is a ubiquitous nuclear DNA-binding protein whose function is dependent on its cellular location. Extracellular HMGB1 is regarded as a delayed mediator of proinflammatory cytokines for initiating and amplifying inflammatory responses, whereas nuclear HMGB1 has been found to prevent cardiac hypertrophy and heart failure. Because fenofibrate, a peroxisome proliferator-activated receptorα(PPARα) agonist, has shown both protective effects against cardiac hypertrophy and inhibitory effects against inflammation, the potential modulation of HMGB1 expression and secretion by fenofibrate is of great interest. We herein provide evidence that fenofibrate modulates basal and LPS-stimulated HMGB1 expression and localization in addition to secretion of HMGB1 in cardiomyocytes. In addition, administration of fenofibrate to mice prevented the development of cardiac hypertrophy induced by thoracic transverse aortic constriction (TAC) while increasing levels of nuclear HMGB1. Altogether, these data suggest that fenofibrate may inhibit the development of cardiac hypertrophy by regulating HMGB1 expression, which provides a new potential strategy to treat cardiac hypertrophy.

Abstract 3608: High Mobility Group A1 Protein - A New Regulator for Peroxisome Proliferator-Activated Receptor Gamma Transcriptional Repression in Human Aortic Smooth Muscle Cells

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Mandy Bloch ◽  
Anna Foryst-Ludwig ◽  
Thomas Unger ◽  
Ulrich Kintscher
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Gene Transcription ◽  
Promoter Activity ◽  
High Mobility ◽  
Muscle Cells ◽  
High Mobility Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Aortic Smooth Muscle

The study aimed to identify new nuclear cofactors for PPARgamma (peroxisome proliferator-activated receptor gamma)-dependent gene transcription in human aortic smooth muscle cells (HASMC) in order to develop new PPARgamma-ligands with improved clinical safety in the absence of deleterious cardiovascular side effects. Using an Oligo GEArray® Human Nuclear Receptors and Coregulators Microarray for gene expression profiling, we identified the transcriptional regulator and chromatin modifying High Mobility Group (HMG) A1 protein highly expressed in unstimulated HASMC. PPARgamma-dependent gene regulation was studied by analysis of PMA-induced MMP-9 (matrix metalloproteinase 9) expression ± pioglitazone (pio 10μM). PMA (50ng/ml) stimulated MMP-9 mRNA expression by 46.3±22.3-fold (p<0.05 vs. vehicle) which was markedly blocked by pio (10μM: 17.4±4.8-fold vs. PMA alone p<0.05). Pio also blocked PMA-induced MMP-9 promoter activity by 45% in transactivation assays in HEK293 using a pGL3-MMP-9 2.2 kb construct. To evaluate the role of HMGA1, gene silencing experiments with siRNA for HMGA1 were performed (91 % in HASMC and 80.2% in HEK293 reduction of HMGA1 protein expression). HMGA1 siRNA completely abolished PPARgamma-mediated MMP9-mRNA repression (control siRNA: pio-mediated MMP-9 regulation vs. PMA alone: −66.8 % in HASMC and −59.3% in HEK293 p<0.01; HMGA1 siRNA: pio-mediated MMP-9 regulation vs. PMA alone: +10.7 % in HASMC and +14.7% in HEK293 vs. PMA alone; p=n.s.). Knockdown of HMGA1 expression reverse trans-repression of MMP9 by PPARgamma in HASMCs. By using ChIP assay we could demonstrate that pio-induced PPARgamma activation leads to a potent recruitment of PPARgamma (3.0 fold vs.1.15 fold PMA alone) and HMGA1 complexes (1.24 fold vs. 0.0 fold PMA alone) to the MMP9 promoter in HASMC. In consonance with reduced promoter activity, RNA-Polymerase II was removed from the MMP9 promoter by pio (0.08 fold vs 1.04 fold PMA alone). In conclusion, HMGA1 is required for PPARgamma-mediated repression of MMP-9 gene transcription. Ligand-induced HMGA1-PPARgamma interactions might be an important determinant for ligand-specific anti-atherosclerotic actions.

Lipopolysaccharide inhibits the expression of resistin in adipocytes

2013 ◽  
Vol 51 (3) ◽  
pp. 287-299 ◽  
Author(s):  
Xinxin Xiang ◽  
Wenjiao An ◽  
Changtao Jiang ◽  
Jing Zhao ◽  
Xian Wang ◽  
...  
Keyword(s):  
Lipid A ◽  
Ex Vivo ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Pharmacological Intervention ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Resistin Mrna

Resistin is an adipocytokine leading to insulin resistance. Endotoxin/lipopolysaccharide (LPS) has been reported to decrease the expression of resistin mRNA and protein in both lean and db/db obese mice, although the underlying mechanism remains unclear. Several models such as ex vivo culture of adipose tissues, primary rat adipocytes and 3T3-L1 adipocytes were used to further characterize the effect of LPS on the expression of resistin. LPS attenuated both the resistin mRNA and protein in a time- and dose-dependent manner. In the presence of actinomycin D, LPS failed to reduce the half-life of resistin mRNA, suggesting a transcriptional mechanism. The lipid A fraction is crucial for the inhibition of resistin expression induced by LPS. Pharmacological intervention of c-Jun N-terminal kinase (JNK) reversed the inhibitory effect of LPS. LPS down-regulated CCAAT/enhancer-binding protein α (C/EBP-α; CEBPA) and peroxisome proliferator-activated receptor γ (PPAR-γ; PPARG), while activation of C/EBP-α or PPAR-γ by either over-expressing these transcriptional factors or by rosiglitazone, an agonist of PPAR-γ, blocked the inhibitory effect of LPS on resistin. C/EBP homologous protein (CHOP-10; DDIT3) was up-regulated by LPS, while a CHOP-10 antisense oligonucleotide reversed the decrement of resistin protein induced by LPS. Taken together, these results suggest that LPS inhibits resistin expression through a unique signaling pathway involving toll-like receptor 4, JNK, CHOP-10 and C/EBP-α/PPAR-γ.

scholarly journals Elucidation of cGMP-dependent induction of mitochondrial biogenesis through PKG and p38 MAPK in the kidney

2020 ◽  
Vol 318 (2) ◽  
pp. F322-F328 ◽  
Author(s):  
Pallavi Bhargava ◽  
Jaroslav Janda ◽  
Rick G. Schnellmann
Keyword(s):  
Mitochondrial Biogenesis ◽  
Specific Inhibitor ◽  
Soluble Guanylyl Cyclase ◽  
Peroxisome Proliferator ◽  
Nuclear Fraction ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pharmacological Agents ◽  
Downstream Target

Previous studies have shown that cGMP increases mitochondrial biogenesis (MB). Our laboratory has determined that formoterol and LY344864, agonists of the β2-adrenergic receptor and 5-HT1F receptor, respectively, signal MB in a soluble guanylyl cyclase (sGC)-dependent manner. However, the pathway between cGMP and MB produced by these pharmacological agents in renal proximal tubule cells (RPTCs) and the kidney has not been determined. In the present study, we showed that treatment of RPTCs with formoterol, LY344864, or riociguat, a sGC stimulator, induces MB through protein kinase G (PKG), a target of cGMP, and p38, an associated downstream target of PKG and a regulator of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression in RPTCs. We also examined if p38 plays a role in PGC-1α phosphorylation in vivo. Administration of l-skepinone, a potent and specific inhibitor of p38α and p38β, to naïve mice inhibited phosphorylated PGC-1α localization in the nuclear fraction of the renal cortex. Taken together, we demonstrated a pathway, sGC/cGMP/PKG/p38/PGC-1α, for pharmacological induction of MB and the importance of p38 in this pathway.

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