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Min Dai - One of the best experts on this subject based on the ideXlab platform.
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Paeonol attenuated inflammatory response of endothelial cells via stimulating monocytes derived exosomal microrna 223
Frontiers in Pharmacology, 2018Co-Authors: Yarong Liu, Min Dai, Xianmei Xie, Ying SunAbstract:Introduction: Paeonol, an active compound isolated from the radix of Cortex Moutan, has been shown to have anti-atherosclerosis effects by regulating blood cells’ function and protecting vascular cells injury. Besides, emerging evidences has proven that exosomes might play a pivotal role in intercellular communication by transmiting proteins and microRNAs from cell to cell. However, the relationship between monocytes-derived exosomal microRNA-223 and vascular inflammation injury along with Paeonol’ effects are still not clear. Objective: Our study aimed to explain whether Paeonol’s protective effect on inflammatory response is related to the regulation of exosomal microRNA-223 in the VECs. Methods: ApoE−/− mice were fed with high fat diet to replicate the AS model. HE staining and immunohistochemistry was used to detect inflammatory response of aorta. The expression of IL-1β and IL-6 were detected by ELISA. Western blot was used to detect the expression of STAT3, pSTAT3, ICAM-1 and VCAM-1. qRT-PCR was used to detect miR-223 expression. Exosomes were extracted from THP-1 cells by differential centrifugation and observed by transmission electron microscope. Observation of exosomes uptake into HUVECs was realized by laser microscopy. miR-223 target gene was detected by double luciferase gene report test. Results: In vivo experiments confirmed that Paeonol restricted atherosclerosis development and increased miR-223 expression, inhibited STAT3 pathway in ApoE−/− mice. In vitro, miR-223 showed robust presence in THP-1 cells and undetectable in HUVECs. And we had observed that miR-223 could be internalized from THP-1 cells into HUVECs taking exosomes as a carrier. Paeonol obviously increased miR-223 expression in co-cultured HUVECs and exosomes in concentration dependent manner, compared to LPS group. In addition, Paeonol relieved inflammatory secretion, adhesion and STAT3 expression in HUVECs, which could be inverted after miR-223 inhibitor transfection into THP-1 cells. Conclusion: Paeonol could increase the expression of miR-223 in THP-1 derived exosomes and in HUVECs after uptake of exosomes, whereas decrease the expression of STAT3, p-STAT3 in HUVECs. Ultimately Paeonol decreased the expression of IL-1β, IL-6, ICAM-1, VCAM-1 in HUVECs and alleviated adhesion of THP-1 cells to HUVECs.
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Paeonol inhibits oxidized low density lipoprotein induced vascular endothelial cells autophagy by upregulating the expression of mirna 30a
Frontiers in Pharmacology, 2018Co-Authors: Li Yang, Min DaiAbstract:Paeonol from Cortex Moutan root is a potential therapeutic agent for atherosclerosis (AS). However, its mechanisms of action are still not fully understood. Vascular endothelial cells (VECs) autophagy plays a vital role in the initiation and progression of AS. In this study, we aim to investigate whether the protective effect of Paeonol on ox-LDL-induced VECs injury by regulating autophagy. To address this question, we used ox-LDL-induced rat VECs as a model system to elucidate the protective effect of Paeonol on VECs injury. This study displayed that ox-LDL (100 mg/L) treatment inhibited VEC growth in dose- and time-dependent manners, Paeonol (60 μM) shown potential in inhibiting ox-LDL-induced death. Furthermore, Paeonol significantly reduced ox-LDL-induced the formation of autophagy vacuoles and the expression of LC3II in VECs. Further double-luciferase reporter assay shown that miR-30a specifically binds to the 3'-UTR of Beclin-1 mRNA in VECs. Moreover, we found that ox-LDL decreased miR-30a and increased Beclin-1 expression, pretreatment with Paeonol could reverse the process of regulation in dose-dependent manners. In ox-LDL treated VECs, transfection with a miR-30a mimic significantly increased miR-30a expression and inhibited Beclin-1 and LC3II expression, thus enhanced the protective effects of Paeonol. Whereas transfection with a miR-30a inhibitor significantly decreased miR-30a expression and increased Beclin-1 and LC3II expression, thus attenuated the protective effects of Paeonol. In conclusion, this study has, for the ?rst time, highlighted that miR-30a might be a critical target of Paeonol against ox-LDL-induced VECs injury by inhibiting excessive autophagy. Paeonol may be one of promising candidate drug for treatment of AS.
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the anti atherosclerotic effect of Paeonol against vascular smooth muscle cell proliferation by up regulation of autophagy via the ampk mtor signaling pathway
Frontiers in Pharmacology, 2018Co-Authors: Aiwei Song, Min DaiAbstract:Introduction: Paeonol (2'-hydroxy-4'-methoxyacetophenone), isolated from moutan cortex, is an active component and has been shown to have anti-atherosclerotic and anti-proliferation effects on vascular smooth muscle cells (VSMCs). However, the possible role of Paeonol in protecting against VSMC proliferation as related to autophagy has yet to be elucidated. Materials and Methods: The athero-protective effects of Paeonol were evaluated in apoE-/- mice. The effects of Paeonol on VSMC proliferation and autophagy were examined by staining α-SMA and LC3II spots in the media layer of apoE-/- mice, respectively. CCK8 and BrdU assays were used to investigate the effects of Paeonol on cell proliferation in vitro. The autophagic levels in VSMCs were evaluated by detecting LC3II accumulation and p62 degradation by immunoblot analysis. To investigate if Paeonol could prevent VSMCs proliferation through autophagy induction, we tested the change in autophagy and cell proliferation by inhibition of autophagy. The levels of the AMPK/mTOR pathway in autophagy regulation were detected by immunoblot analysis. An AMPK inhibitor and si-AMPK transfection in VSMCs was used to confirm whether AMPK activity plays a key role in autophagy regulation of Paeonol. Results:In vivo experiments confirmed that Paeonol restricted atherosclerosis development and decreased the amount of VSMCs in the media layer of apoE-/- mice. Paeonol increased protein levels of LC3II and the presence of autophagosomes in the media layer of arteries, which implies that Paeonol may induce VSMCs autophagy in vivo. Paeonol showed potential in inhibiting ox-LDL-induced proliferation in vitro experiments. Paeonol dose-dependently enhanced the formation of acidic vesicular organelles and autophagosmomes, up-regulated the expression of LC3II and increased p62 degradation. The autophagy inhibitor CQ obviously attenuated Paeonol-induced autophagy and the anti-proliferation effect in VSMCs. In addition, Paeonol induced phosphorylation of AMPK and reduced phosphorylation of mTOR. An AMPK inhibitor reversed the Paeonol-induced p-mTOR/mTOR decrease. Paeonol induced LC3II conversion, increased p62 degradation and inhibited cell proliferation in VSMCs, the effects of which were abolished by si-AMPK. Conclusion: These results imply that Paeonol inhibits proliferation of VSMCs by up-regulating autophagy, and activating the AMPK/mTOR signaling pathway, providing new insights into the anti-atherosclerosis activity of Paeonol.
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Image_1_Paeonol Attenuated Inflammatory Response of Endothelial Cells via Stimulating Monocytes-Derived Exosomal MicroRNA-223.TIF
2018Co-Authors: Yarong Liu, Xianmei Xie, Ying Sun, Min DaiAbstract:Introduction: Paeonol, an active compound isolated from the radix of Cortex Moutan, has been shown to have anti-atherosclerosis effects by regulating blood cells’ function and protecting vascular cells injury. Besides, emerging evidences has proven that exosomes might play a pivotal role in intercellular communication by transmiting proteins and microRNAs from cell to cell. However, the relationship between monocytes-derived exosomal microRNA-223 and vascular inflammation injury along with Paeonol’ effects are still not clear.Objective: Our study aimed to explain whether Paeonol’s protective effect on inflammatory response is related to the regulation of exosomal microRNA-223 in the VECs.Methods: ApoE−/− mice were fed with high fat diet to replicate the AS model. HE staining and immunohistochemistry was used to detect inflammatory response of aorta. The expression of IL-1β and IL-6 were detected by ELISA. Western blot was used to detect the expression of STAT3, pSTAT3, ICAM-1 and VCAM-1. qRT-PCR was used to detect miR-223 expression. Exosomes were extracted from THP-1 cells by differential centrifugation and observed by transmission electron microscope. Observation of exosomes uptake into HUVECs was realized by laser microscopy. miR-223 target gene was detected by double luciferase gene report test.Results:In vivo experiments confirmed that Paeonol restricted atherosclerosis development and increased miR-223 expression, inhibited STAT3 pathway in ApoE−/− mice. In vitro, miR-223 showed robust presence in THP-1 cells and undetectable in HUVECs. And we had observed that miR-223 could be internalized from THP-1 cells into HUVECs taking exosomes as a carrier. Paeonol obviously increased miR-223 expression in co-cultured HUVECs and exosomes in concentration dependent manner, compared to LPS group. In addition, Paeonol relieved inflammatory secretion, adhesion and STAT3 expression in HUVECs, which could be inverted after miR-223 inhibitor transfection into THP-1 cells.Conclusion: Paeonol could increase the expression of miR-223 in THP-1 derived exosomes and in HUVECs after uptake of exosomes, whereas decrease the expression of STAT3, p-STAT3 in HUVECs. Ultimately Paeonol decreased the expression of IL-1β, IL-6, ICAM-1, VCAM-1 in HUVECs and alleviated adhesion of THP-1 cells to HUVECs.
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Table_1_Paeonol Attenuated Inflammatory Response of Endothelial Cells via Stimulating Monocytes-Derived Exosomal MicroRNA-223.DOC
2018Co-Authors: Yarong Liu, Xianmei Xie, Ying Sun, Min DaiAbstract:Introduction: Paeonol, an active compound isolated from the radix of Cortex Moutan, has been shown to have anti-atherosclerosis effects by regulating blood cells’ function and protecting vascular cells injury. Besides, emerging evidences has proven that exosomes might play a pivotal role in intercellular communication by transmiting proteins and microRNAs from cell to cell. However, the relationship between monocytes-derived exosomal microRNA-223 and vascular inflammation injury along with Paeonol’ effects are still not clear.Objective: Our study aimed to explain whether Paeonol’s protective effect on inflammatory response is related to the regulation of exosomal microRNA-223 in the VECs.Methods: ApoE−/− mice were fed with high fat diet to replicate the AS model. HE staining and immunohistochemistry was used to detect inflammatory response of aorta. The expression of IL-1β and IL-6 were detected by ELISA. Western blot was used to detect the expression of STAT3, pSTAT3, ICAM-1 and VCAM-1. qRT-PCR was used to detect miR-223 expression. Exosomes were extracted from THP-1 cells by differential centrifugation and observed by transmission electron microscope. Observation of exosomes uptake into HUVECs was realized by laser microscopy. miR-223 target gene was detected by double luciferase gene report test.Results:In vivo experiments confirmed that Paeonol restricted atherosclerosis development and increased miR-223 expression, inhibited STAT3 pathway in ApoE−/− mice. In vitro, miR-223 showed robust presence in THP-1 cells and undetectable in HUVECs. And we had observed that miR-223 could be internalized from THP-1 cells into HUVECs taking exosomes as a carrier. Paeonol obviously increased miR-223 expression in co-cultured HUVECs and exosomes in concentration dependent manner, compared to LPS group. In addition, Paeonol relieved inflammatory secretion, adhesion and STAT3 expression in HUVECs, which could be inverted after miR-223 inhibitor transfection into THP-1 cells.Conclusion: Paeonol could increase the expression of miR-223 in THP-1 derived exosomes and in HUVECs after uptake of exosomes, whereas decrease the expression of STAT3, p-STAT3 in HUVECs. Ultimately Paeonol decreased the expression of IL-1β, IL-6, ICAM-1, VCAM-1 in HUVECs and alleviated adhesion of THP-1 cells to HUVECs.
Mohd Rais Mustafa - One of the best experts on this subject based on the ideXlab platform.
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Paeonol attenuates lps induced endothelial dysfunction and apoptosis by inhibiting bmp4 and tlr4 signaling simultaneously but independently
Journal of Pharmacology and Experimental Therapeutics, 2018Co-Authors: Ker Woon Choy, Yeh Siang Lau, Dharmani Devi Murugan, Paul M Vanhoutte, Mohd Rais MustafaAbstract: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 protects against endoplasmic reticulum stress induced endothelial dysfunction via ampk pparδ signaling pathway
Biochemical Pharmacology, 2016Co-Authors: Ker Woon Choy, Mohd Rais Mustafa, Yeh Siang Lau, Jian Liu, Dharmani Devi Murugan, Chi Wai Lau, Li Wang, Lei Zhao, Yu HuangAbstract:Endoplasmic reticulum (ER) stress in endothelial cells often leads to endothelial dysfunction which underlies the pathogenesis of cardiovascular diseases. Paeonol, a major phenolic component extracted from Moutan Cortex, possesses various medicinal benefits which have been used extensively in traditional Chinese medicine. The present study investigated the protective mechanism of Paeonol against tunicamycin-induced ER stress in isolated mouse aortas and human umbilical vein endothelial cells (HUVECs). Vascular reactivity in aorta was measured using a wire myograph. The effects of Paeonol on protein expression of ER stress markers, reactive oxygen species (ROS) production, nitric oxide (NO) bioavailability and peroxisome proliferator-activated receptor δ (PPARδ) activity in the vascular wall were assessed by Western blot, dihydroethidium fluorescence (DHE) or lucigenin enhanced-chemiluminescence, 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM DA) and dual luciferase reporter assay, respectively. Ex vivo treatment with Paeonol (0.1μM) for 16h reversed the impaired endothelium-dependent relaxations in C57BJ/6J and PPARδ wild type (WT) mouse aortas following incubation with tunicamycin (0.5μg/mL). Elevated ER stress markers, oxidative stress and reduction of NO bioavailability induced by tunicamycin in HUVECs, C57BJ/6J and PPARδ WT mouse aortas were reversed by Paeonol treatment. These beneficial effects of Paeonol were diminished in PPARδ knockout (KO) mouse aortas. Paeonol increased the expression of 5' adenosine monophosphate-activated protein kinase (AMPK) and PPARδ expression and activity while restoring the decreased phosphorylation of eNOS. The present study delineates that Paeonol protects against tunicamycin-induced vascular endothelial dysfunction by inhibition of ER stress and oxidative stress, thus elevating NO bioavailability via the AMPK/PPARδ signaling pathway.
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Paeonol protects against premature senescence in endothelial cells by modulating sirtuin 1 pathway
Journal of Ethnopharmacology, 2014Co-Authors: Juliana Jamal, Mohd Rais Mustafa, Pooifong WongAbstract:Ethnopharmacological relevance: Paeonol is a phenolic compound isolated mainly from Moutan cortex, root bark of Chinese Peony tree. Moutan cortex holds a significant value in traditional Chinese medicine for alleviating various oxidative stress-related diseases mainly atherosclerosis and myocardial infarction. The present study seeks to identify the protective mechanisms of Paeonol in oxidative stress-induced premature senescence in endothelial cells. Materials and methods: HUVECs were pretreated with Paeonol or DMSO control at different doses for 24 h prior to an exposure of 200 μM of reactive oxygen species (ROS) inducer, hydrogen peroxide (H2O2). The protective effects of Paeonol against H2O2-induced senescence were evaluated and the activation of Sirtuin 1 pathway by Paeonol pretreatment was investigated in HUVECs. Results: Paeonol attenuated H2O2-induced cell growth arrest at G0/G1 phase, reduced the percentage of SA-β-Gal positive cells and increased BrdU incorporation. In addition, enzymatic Sirt1 activation assay indicated that Paeonol significantly increased lysyl deactylase activity of Sirt1 enzyme with a fold change of 2.470.195 (po0.05). Furthermore, pretreatment with Paeonol significantly decreased the levels of p53, acetyl H3K14 and H4K16 protein expression upregulated by H2O2 stimulation. The changes in the histone protein levels were accompanied with an increase in Sirt1 protein expression level. Conclusion: These findings suggest that Paeonol protects endothelial cells against oxidative stressinduced premature senescence by modulating the expressions of Sirt1 protein and its substrates.
Ker Woon Choy - One of the best experts on this subject based on the ideXlab platform.
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Paeonol attenuates lps induced endothelial dysfunction and apoptosis by inhibiting bmp4 and tlr4 signaling simultaneously but independently
Journal of Pharmacology and Experimental Therapeutics, 2018Co-Authors: Ker Woon Choy, Yeh Siang Lau, Dharmani Devi Murugan, Paul M Vanhoutte, Mohd Rais MustafaAbstract: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 protects against endoplasmic reticulum stress induced endothelial dysfunction via ampk pparδ signaling pathway
Biochemical Pharmacology, 2016Co-Authors: Ker Woon Choy, Mohd Rais Mustafa, Yeh Siang Lau, Jian Liu, Dharmani Devi Murugan, Chi Wai Lau, Li Wang, Lei Zhao, Yu HuangAbstract:Endoplasmic reticulum (ER) stress in endothelial cells often leads to endothelial dysfunction which underlies the pathogenesis of cardiovascular diseases. Paeonol, a major phenolic component extracted from Moutan Cortex, possesses various medicinal benefits which have been used extensively in traditional Chinese medicine. The present study investigated the protective mechanism of Paeonol against tunicamycin-induced ER stress in isolated mouse aortas and human umbilical vein endothelial cells (HUVECs). Vascular reactivity in aorta was measured using a wire myograph. The effects of Paeonol on protein expression of ER stress markers, reactive oxygen species (ROS) production, nitric oxide (NO) bioavailability and peroxisome proliferator-activated receptor δ (PPARδ) activity in the vascular wall were assessed by Western blot, dihydroethidium fluorescence (DHE) or lucigenin enhanced-chemiluminescence, 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM DA) and dual luciferase reporter assay, respectively. Ex vivo treatment with Paeonol (0.1μM) for 16h reversed the impaired endothelium-dependent relaxations in C57BJ/6J and PPARδ wild type (WT) mouse aortas following incubation with tunicamycin (0.5μg/mL). Elevated ER stress markers, oxidative stress and reduction of NO bioavailability induced by tunicamycin in HUVECs, C57BJ/6J and PPARδ WT mouse aortas were reversed by Paeonol treatment. These beneficial effects of Paeonol were diminished in PPARδ knockout (KO) mouse aortas. Paeonol increased the expression of 5' adenosine monophosphate-activated protein kinase (AMPK) and PPARδ expression and activity while restoring the decreased phosphorylation of eNOS. The present study delineates that Paeonol protects against tunicamycin-induced vascular endothelial dysfunction by inhibition of ER stress and oxidative stress, thus elevating NO bioavailability via the AMPK/PPARδ signaling pathway.
Yarong Liu - One of the best experts on this subject based on the ideXlab platform.
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Paeonol attenuated inflammatory response of endothelial cells via stimulating monocytes derived exosomal microrna 223
Frontiers in Pharmacology, 2018Co-Authors: Yarong Liu, Min Dai, Xianmei Xie, Ying SunAbstract:Introduction: Paeonol, an active compound isolated from the radix of Cortex Moutan, has been shown to have anti-atherosclerosis effects by regulating blood cells’ function and protecting vascular cells injury. Besides, emerging evidences has proven that exosomes might play a pivotal role in intercellular communication by transmiting proteins and microRNAs from cell to cell. However, the relationship between monocytes-derived exosomal microRNA-223 and vascular inflammation injury along with Paeonol’ effects are still not clear. Objective: Our study aimed to explain whether Paeonol’s protective effect on inflammatory response is related to the regulation of exosomal microRNA-223 in the VECs. Methods: ApoE−/− mice were fed with high fat diet to replicate the AS model. HE staining and immunohistochemistry was used to detect inflammatory response of aorta. The expression of IL-1β and IL-6 were detected by ELISA. Western blot was used to detect the expression of STAT3, pSTAT3, ICAM-1 and VCAM-1. qRT-PCR was used to detect miR-223 expression. Exosomes were extracted from THP-1 cells by differential centrifugation and observed by transmission electron microscope. Observation of exosomes uptake into HUVECs was realized by laser microscopy. miR-223 target gene was detected by double luciferase gene report test. Results: In vivo experiments confirmed that Paeonol restricted atherosclerosis development and increased miR-223 expression, inhibited STAT3 pathway in ApoE−/− mice. In vitro, miR-223 showed robust presence in THP-1 cells and undetectable in HUVECs. And we had observed that miR-223 could be internalized from THP-1 cells into HUVECs taking exosomes as a carrier. Paeonol obviously increased miR-223 expression in co-cultured HUVECs and exosomes in concentration dependent manner, compared to LPS group. In addition, Paeonol relieved inflammatory secretion, adhesion and STAT3 expression in HUVECs, which could be inverted after miR-223 inhibitor transfection into THP-1 cells. Conclusion: Paeonol could increase the expression of miR-223 in THP-1 derived exosomes and in HUVECs after uptake of exosomes, whereas decrease the expression of STAT3, p-STAT3 in HUVECs. Ultimately Paeonol decreased the expression of IL-1β, IL-6, ICAM-1, VCAM-1 in HUVECs and alleviated adhesion of THP-1 cells to HUVECs.
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Image_1_Paeonol Attenuated Inflammatory Response of Endothelial Cells via Stimulating Monocytes-Derived Exosomal MicroRNA-223.TIF
2018Co-Authors: Yarong Liu, Xianmei Xie, Ying Sun, Min DaiAbstract:Introduction: Paeonol, an active compound isolated from the radix of Cortex Moutan, has been shown to have anti-atherosclerosis effects by regulating blood cells’ function and protecting vascular cells injury. Besides, emerging evidences has proven that exosomes might play a pivotal role in intercellular communication by transmiting proteins and microRNAs from cell to cell. However, the relationship between monocytes-derived exosomal microRNA-223 and vascular inflammation injury along with Paeonol’ effects are still not clear.Objective: Our study aimed to explain whether Paeonol’s protective effect on inflammatory response is related to the regulation of exosomal microRNA-223 in the VECs.Methods: ApoE−/− mice were fed with high fat diet to replicate the AS model. HE staining and immunohistochemistry was used to detect inflammatory response of aorta. The expression of IL-1β and IL-6 were detected by ELISA. Western blot was used to detect the expression of STAT3, pSTAT3, ICAM-1 and VCAM-1. qRT-PCR was used to detect miR-223 expression. Exosomes were extracted from THP-1 cells by differential centrifugation and observed by transmission electron microscope. Observation of exosomes uptake into HUVECs was realized by laser microscopy. miR-223 target gene was detected by double luciferase gene report test.Results:In vivo experiments confirmed that Paeonol restricted atherosclerosis development and increased miR-223 expression, inhibited STAT3 pathway in ApoE−/− mice. In vitro, miR-223 showed robust presence in THP-1 cells and undetectable in HUVECs. And we had observed that miR-223 could be internalized from THP-1 cells into HUVECs taking exosomes as a carrier. Paeonol obviously increased miR-223 expression in co-cultured HUVECs and exosomes in concentration dependent manner, compared to LPS group. In addition, Paeonol relieved inflammatory secretion, adhesion and STAT3 expression in HUVECs, which could be inverted after miR-223 inhibitor transfection into THP-1 cells.Conclusion: Paeonol could increase the expression of miR-223 in THP-1 derived exosomes and in HUVECs after uptake of exosomes, whereas decrease the expression of STAT3, p-STAT3 in HUVECs. Ultimately Paeonol decreased the expression of IL-1β, IL-6, ICAM-1, VCAM-1 in HUVECs and alleviated adhesion of THP-1 cells to HUVECs.
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Table_1_Paeonol Attenuated Inflammatory Response of Endothelial Cells via Stimulating Monocytes-Derived Exosomal MicroRNA-223.DOC
2018Co-Authors: Yarong Liu, Xianmei Xie, Ying Sun, Min DaiAbstract:Introduction: Paeonol, an active compound isolated from the radix of Cortex Moutan, has been shown to have anti-atherosclerosis effects by regulating blood cells’ function and protecting vascular cells injury. Besides, emerging evidences has proven that exosomes might play a pivotal role in intercellular communication by transmiting proteins and microRNAs from cell to cell. However, the relationship between monocytes-derived exosomal microRNA-223 and vascular inflammation injury along with Paeonol’ effects are still not clear.Objective: Our study aimed to explain whether Paeonol’s protective effect on inflammatory response is related to the regulation of exosomal microRNA-223 in the VECs.Methods: ApoE−/− mice were fed with high fat diet to replicate the AS model. HE staining and immunohistochemistry was used to detect inflammatory response of aorta. The expression of IL-1β and IL-6 were detected by ELISA. Western blot was used to detect the expression of STAT3, pSTAT3, ICAM-1 and VCAM-1. qRT-PCR was used to detect miR-223 expression. Exosomes were extracted from THP-1 cells by differential centrifugation and observed by transmission electron microscope. Observation of exosomes uptake into HUVECs was realized by laser microscopy. miR-223 target gene was detected by double luciferase gene report test.Results:In vivo experiments confirmed that Paeonol restricted atherosclerosis development and increased miR-223 expression, inhibited STAT3 pathway in ApoE−/− mice. In vitro, miR-223 showed robust presence in THP-1 cells and undetectable in HUVECs. And we had observed that miR-223 could be internalized from THP-1 cells into HUVECs taking exosomes as a carrier. Paeonol obviously increased miR-223 expression in co-cultured HUVECs and exosomes in concentration dependent manner, compared to LPS group. In addition, Paeonol relieved inflammatory secretion, adhesion and STAT3 expression in HUVECs, which could be inverted after miR-223 inhibitor transfection into THP-1 cells.Conclusion: Paeonol could increase the expression of miR-223 in THP-1 derived exosomes and in HUVECs after uptake of exosomes, whereas decrease the expression of STAT3, p-STAT3 in HUVECs. Ultimately Paeonol decreased the expression of IL-1β, IL-6, ICAM-1, VCAM-1 in HUVECs and alleviated adhesion of THP-1 cells to HUVECs.
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Presentation_1_Paeonol Attenuated Inflammatory Response of Endothelial Cells via Stimulating Monocytes-Derived Exosomal MicroRNA-223.ZIP
2018Co-Authors: Yarong Liu, Xianmei Xie, Ying Sun, Min DaiAbstract:Introduction: Paeonol, an active compound isolated from the radix of Cortex Moutan, has been shown to have anti-atherosclerosis effects by regulating blood cells’ function and protecting vascular cells injury. Besides, emerging evidences has proven that exosomes might play a pivotal role in intercellular communication by transmiting proteins and microRNAs from cell to cell. However, the relationship between monocytes-derived exosomal microRNA-223 and vascular inflammation injury along with Paeonol’ effects are still not clear.Objective: Our study aimed to explain whether Paeonol’s protective effect on inflammatory response is related to the regulation of exosomal microRNA-223 in the VECs.Methods: ApoE−/− mice were fed with high fat diet to replicate the AS model. HE staining and immunohistochemistry was used to detect inflammatory response of aorta. The expression of IL-1β and IL-6 were detected by ELISA. Western blot was used to detect the expression of STAT3, pSTAT3, ICAM-1 and VCAM-1. qRT-PCR was used to detect miR-223 expression. Exosomes were extracted from THP-1 cells by differential centrifugation and observed by transmission electron microscope. Observation of exosomes uptake into HUVECs was realized by laser microscopy. miR-223 target gene was detected by double luciferase gene report test.Results:In vivo experiments confirmed that Paeonol restricted atherosclerosis development and increased miR-223 expression, inhibited STAT3 pathway in ApoE−/− mice. In vitro, miR-223 showed robust presence in THP-1 cells and undetectable in HUVECs. And we had observed that miR-223 could be internalized from THP-1 cells into HUVECs taking exosomes as a carrier. Paeonol obviously increased miR-223 expression in co-cultured HUVECs and exosomes in concentration dependent manner, compared to LPS group. In addition, Paeonol relieved inflammatory secretion, adhesion and STAT3 expression in HUVECs, which could be inverted after miR-223 inhibitor transfection into THP-1 cells.Conclusion: Paeonol could increase the expression of miR-223 in THP-1 derived exosomes and in HUVECs after uptake of exosomes, whereas decrease the expression of STAT3, p-STAT3 in HUVECs. Ultimately Paeonol decreased the expression of IL-1β, IL-6, ICAM-1, VCAM-1 in HUVECs and alleviated adhesion of THP-1 cells to HUVECs.
Dharmani Devi Murugan - One of the best experts on this subject based on the ideXlab platform.
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Paeonol attenuates lps induced endothelial dysfunction and apoptosis by inhibiting bmp4 and tlr4 signaling simultaneously but independently
Journal of Pharmacology and Experimental Therapeutics, 2018Co-Authors: Ker Woon Choy, Yeh Siang Lau, Dharmani Devi Murugan, Paul M Vanhoutte, Mohd Rais MustafaAbstract: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 protects against endoplasmic reticulum stress induced endothelial dysfunction via ampk pparδ signaling pathway
Biochemical Pharmacology, 2016Co-Authors: Ker Woon Choy, Mohd Rais Mustafa, Yeh Siang Lau, Jian Liu, Dharmani Devi Murugan, Chi Wai Lau, Li Wang, Lei Zhao, Yu HuangAbstract:Endoplasmic reticulum (ER) stress in endothelial cells often leads to endothelial dysfunction which underlies the pathogenesis of cardiovascular diseases. Paeonol, a major phenolic component extracted from Moutan Cortex, possesses various medicinal benefits which have been used extensively in traditional Chinese medicine. The present study investigated the protective mechanism of Paeonol against tunicamycin-induced ER stress in isolated mouse aortas and human umbilical vein endothelial cells (HUVECs). Vascular reactivity in aorta was measured using a wire myograph. The effects of Paeonol on protein expression of ER stress markers, reactive oxygen species (ROS) production, nitric oxide (NO) bioavailability and peroxisome proliferator-activated receptor δ (PPARδ) activity in the vascular wall were assessed by Western blot, dihydroethidium fluorescence (DHE) or lucigenin enhanced-chemiluminescence, 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM DA) and dual luciferase reporter assay, respectively. Ex vivo treatment with Paeonol (0.1μM) for 16h reversed the impaired endothelium-dependent relaxations in C57BJ/6J and PPARδ wild type (WT) mouse aortas following incubation with tunicamycin (0.5μg/mL). Elevated ER stress markers, oxidative stress and reduction of NO bioavailability induced by tunicamycin in HUVECs, C57BJ/6J and PPARδ WT mouse aortas were reversed by Paeonol treatment. These beneficial effects of Paeonol were diminished in PPARδ knockout (KO) mouse aortas. Paeonol increased the expression of 5' adenosine monophosphate-activated protein kinase (AMPK) and PPARδ expression and activity while restoring the decreased phosphorylation of eNOS. The present study delineates that Paeonol protects against tunicamycin-induced vascular endothelial dysfunction by inhibition of ER stress and oxidative stress, thus elevating NO bioavailability via the AMPK/PPARδ signaling pathway.
