Paeonol protects endotoxin-induced acute kidney injury: potential mechanism of inhibiting TLR4-NF-κB signal pathway

Fan, Hui; Dong, Qi; Chen, Yu; Zhao, Feng; Liu, Tao; Zhang, Zuo-Kai; Yang, Mingyan; Zhang, Leiming; Chen, Daquan; Du, Yuan

doi:10.18632/oncotarget.8347

Cited by 50 publications

(30 citation statements)

References 43 publications

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“…Toll-like receptor 4 (TLR4) was considered as one of the candidates after analysis. Previous studies showed that TLR4 mediates microbial infection of immune and inflammatory responses and is involved in the pathogenesis of ALI [29]. Furthermore, it has been reported that miR-27a attenuated the inflammatory response during microglial activation by targeting TLR4 [26].…”

Section: Tlr4 Was a Direct Target Of Mir-27amentioning

confidence: 98%

MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inﬂammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway

et al. 2018

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Acute lung injury (ALI) is a critical clinical condition with a high mortality rate, characterized with excessive uncontrolled inflammation and apoptosis. Recently, microRNAs (miRNAs) have been found to play crucial roles in the amelioration of various inflammation-induced diseases, including ALI. However, it remains unknown the biological function and regulatory mechanisms of miRNAs in the regulation of inﬂammation and apoptosis in ALI. The aim of this study is to identify and evaluate the potential role of miRNAs in ALI and reveal the underlying molecular mechanisms of their effects. Here, we analyzed microRNA expression profiles in lung tissues from LPS-challenged mice using miRNA microarray. Because microRNA-27a (miR-27a) was one of the miRNAs being most significantly downregulated, which has an important role in regulation of inflammation, we investigated its function. Overexpression of miR-27a by agomir-27a improved lung injury, as evidenced by the reduced histopathological changes, lung wet/dry (W/D) ratio, lung microvascular permeability and apoptosis in the lung tissues, as well as ameliorative survival of ALI mice. This was accompanied by the alleviating of inflammation, such as the reduced total BALF cell and neutrophil counts, decreased levels of tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-6) interleukin-1β (IL-1β) and myeloperoxidase (MPO) activity in BAL fluid. Toll-like receptor 4 (TLR4), an important regulator of the nuclear factor kappa-B (NF-κB) signaling pathway, was identified as a novel target of miR-27a in RAW264.7 cells. Furthermore, our results showed that LPS stimulation increased the expression of MyD88 and NF-κB p65 (p-p65), but inhibited the expression of inhibitor of nuclear factor-κB-α (IκB-α), suggesting the activation of NF-κB signaling pathway. Further investigations revealed that agomir-miR-27a reversed the promoting effect of LPS on NF-κB signaling pathway. The results here suggested that miR-27a alleviates LPS-induced ALI in mice via reducing inﬂammation and apoptosis through blocking TLR4/MyD88/NF-κB activation.

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Section: Tlr4 Was a Direct Target Of Mir-27amentioning

confidence: 98%

MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inﬂammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway

et al. 2018

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“…The phytoactive compound prevents lung inflammation and fibrosis induced by bleomycin in mice and rats (Liu et al, 2014) and lipopolysaccharide (LPS) . In vitro and in vivo, paeonol also decreases inflammation and injury induced by LPSs in N9 microglia cells and in murine kidneys by inhibiting the Toll-like receptor 4 (TLR4) and nuclear factor-kB (NF-kB) signaling pathways (Tseng et al, 2012;Fan et al, 2016). Additionally, paeonol suppresses cigarette smoke-induced release of interleukin-8 by virtue of its antioxidant properties and by inhibiting both reactive oxygen species (ROS)-sensitive 59 AMP kinase/mitogen-activated protein kinase (MAPK) signaling and the downstream NF-kB, thus reducing pulmonary inflammation (Liu et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Paeonol Attenuates LPS-Induced Endothelial Dysfunction and Apoptosis by Inhibiting BMP4 and TLR4 Signaling Simultaneously but Independently

Choy

Lau

Murugan

et al. 2017

J Pharmacol Exp Ther

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Inflammatory injury of the endothelium leads to apoptosis and endothelial dysfunction. The current study explored the effect and mechanisms of paeonol in inflammation-induced apoptosis and endothelial dysfunction induced by lipopolysaccharides (LPSs). The effects of paeonol on LPS-induced inflammatory injury were assessed by Western blotting, flow cytometry and reactive oxygen species (ROS) measurement in human umbilical vein endothelial cells (HUVECs) and C57BL/6J mice. Vascular reactivity of isolated mouse aortae was examined using wire myographs. The exposure of HUVECs to LPS increased the protein presence of Toll-like receptor 4 (TLR4), bone morphogenic protein 4 (BMP4), BMP receptor type 1A, nicotinamide adenine dinucleotide phosphate oxidase subunit 2, mitogen-activated protein kinase (MAPK), inducible nitric oxide synthase (iNOS), and cleaved caspase 3, as well as decreased it in phosphorylated endothelial nitric oxide synthase; these effects were prevented by treatment with paeonol. Similarly, cotreatment with paeonol reversed BMP4-induced apoptosis in HUVECs. Relaxation in response to the endothelium-dependent vasodilator acetylcholine were impaired in mouse aortae after exposure to LPSs; this endothelial dysfunction was reversed by cotreatment with paeonol, noggin (a BMP4 inhibitor), TAK242 (TLR4 antagonist), apocynin (an ROS scavenger), MAPK inhibitors, and AG (an iNOS inhibitor). BMP4 small interfering RNAs (siRNAs) abolished LPS-induced upregulation of BMP4 and cleaved caspase 3 protein, but not in cells treated with TLR4 siRNA and vice versa. The silencing of TLR4 and BMP4 abolished the inhibitory effects of paeonol on LPS-induced activation of cleaved caspase 3. The present results demonstrate that paeonol reduces LPS-induced endothelial dysfunction and apoptosis by inhibiting TLR4 and BMP4 signaling independently.

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“…Paeonol prevents IκBα degradation and NF‐κB transcription activity in LPS/D‐galactosamine‐induced acute liver failure in mice (Gong et al, ) or in LPS‐induced RAW264.7 cells (Himaya et al, ). Paeonol has protective effects on endotoxin‐induced kidney injury through inhibiting the expressions of phosphorylated NF‐κB p65, IκBα, and IKKβ and restraining NF‐κB p65 DNA‐binding activity (Fan et al, ). Paeonol suppresses intercellular adhesion molecule‐1 expression in TNF‐α‐stimulated human umbilical vein endothelial cells by inhibiting IκBα phosphorylation and NF‐κB p65 translocation into the nucleus (Nizamutdinova et al, ).…”

Section: Discussionmentioning

confidence: 99%

Paeonol ameliorates monosodium urate‐induced arthritis in rats through inhibiting nuclear factor‐κB‐mediated proinflammatory cytokine production

Chen

Jia

Yin

et al. 2019

Phytotherapy Research

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Moutan Cortex has been widely used to treat various types of arthritis in traditional Chinese medicine. Paeonol is isolated as an active ingredient from Moutan Cortex. However, the effect and potential mechanism of paeonol on gouty arthritis have not been evaluated. In this study, rats were treated intragastrically with paeonol for consecutive 7 days. On Day 5, rats were intra‐articularly injected with monosodium urate (MSU) crystals in the ankle joints to induce MSU‐induced arthritis (MIA). Paw volume was detected at various time points. Gait score was measured at 24 hr after MSU crystal injection. Ankle joints were collected for evaluation of histological score and expression of proinflammatory cytokines using hematoxylin and eosin staining and immunohistochemistry staining, respectively. Nuclear level of nuclear factor (NF)‐κBp65 in synovial tissues was analyzed by western blot assay. NF‐κB DNA‐binding activity was measured by enzyme linked immunosorbent assay. Paeonol markedly lowered the paw volume, gait score, and histological score in MIA rats. Mechanistically, paeonol markedly reduced the expression of TNF‐α, IL‐1β, and IL‐6 in synovial tissues of MIA rats. In addition, the elevated level of p65 in nucleus and NF‐κB DNA‐binding activity in synovial tissues of MIA rats were reduced significantly by paeonol treatment. These findings suggest that paeonol exerts anti‐inflammatory effect in MIA rats through inhibiting expression of proinflammatory cytokines and NF‐κB activation.

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Paeonol protects endotoxin-induced acute kidney injury: potential mechanism of inhibiting TLR4-NF-κB signal pathway

Cited by 50 publications

References 43 publications

MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inﬂammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway

MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inﬂammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway

Paeonol Attenuates LPS-Induced Endothelial Dysfunction and Apoptosis by Inhibiting BMP4 and TLR4 Signaling Simultaneously but Independently

Paeonol ameliorates monosodium urate‐induced arthritis in rats through inhibiting nuclear factor‐κB‐mediated proinflammatory cytokine production

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