Anti-Inflammatory Effects of Isopropyl 3-(3, 4-Dihydroxyphenyl)-2-Hydroxypropanoate, a Novel Metabolite from Danshen, on Activated Microglia

Wang, Shaoxia

doi:10.4077/cjp.2012.baa045

Cited by 14 publications

(6 citation statements)

References 17 publications

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“…p38 MAPK mediates the production of pro‐inflammatory cytokines, induced by β‐adrenoceptor activation (Yin et al ., ), and was also involved in apoptosis of cardiomyocytes induced by chronic isoprenaline stimulation (Jiao et al ., ). IDHP exerted anti‐inflammatory activity by abolishing TNF‐α and IL‐1β secretion from BV‐2 mouse microglial cells stimulated by LPS (Wang et al ., ). Therefore, the cardioprotective effects of IDHP would involve mechanisms other than the anti‐oxidative pathway (NOX2/ROS/p38) demonstrated here.…”

Section: Discussionmentioning

confidence: 97%

A metabolite of Danshen formulae attenuates cardiac fibrosis induced by isoprenaline, via a NOX2/ROS/p38 pathway

Yin

Bai

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSECardiac fibrosis is a common feature of advanced coronary heart disease and is characteristic of heart disease. However, currently available drugs against cardiac fibrosis are still very limited. Here, we have assessed the role of isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxylpropanoate (IDHP), a new metabolite of Danshen Dripping Pills, in cardiac fibrosis mediated by the β-adrenoceptor agonist, isoprenaline, and its underlying mechanisms. EXPERIMENTAL APPROACHIdentification of IDHP was identified by mass spectrometry, and proton and carbon nuclear magnetic resonance spectra. Myocardial collagen was quantitatively assessed with Picrosirius Red staining. Expression of mRNA for collagen was evaluated with real-time PCR. Phosphorylated and total p38 MAPK, NADPH oxidase (NOX) and superoxide dismutase (SOD) were analysed by Western blot. Generation of reactive oxygen species (ROS) generation was evaluated by dihydroethidium (DHE) fluorescent staining. NOX2 was knocked down using specific siRNA. KEY RESULTSIDHP attenuated β-adrenoceptor mediated cardiac fibrosis in vivo and inhibited isoprenaline-induced proliferation of neonatal rat cardiac fibroblasts (NRCFs) and collagen I synthesis in vitro. Phosphorylation of p38 MAPK, which is an important mediator in the pathogenesis of isoprenaline-induced cardiac fibrosis, was inhibited by IDHP. This inhibition of phospho-p38 by IDHP was dependent on decreased generation of ROS. These effects of IDHP were abolished in NRCFs treated with siRNA for NOX2. CONCLUSIONS AND IMPLICATIONSIDHP attenuated the cardiac fibrosis induced by isoprenaline through a NOX2/ROS/p38 pathway. These novel findings suggest that IDHP is a potential pharmacological candidate for the treatment of cardiac fibrosis, induced by β-adrenoceptor agonists.

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Section: Discussionmentioning

confidence: 97%

A metabolite of Danshen formulae attenuates cardiac fibrosis induced by isoprenaline, via a NOX2/ROS/p38 pathway

Yin

Bai

et al. 2015

British J Pharmacology

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“…A novel compound, isopropyl 3‐(3,4‐dihydroxyphenyl)‐2‐hydroxypropanoate (IDHP), was found to be a bioactive metabolite of Danshen during the research process of CDDP metabolism in vivo (Pei et al ., ; Wang et al ., 2011a; Zheng et al ., ). Our previous pharmacological study showed that IDHP possesses a variety of biological activities such as anti‐myocardial and anti‐cerebral ischemia (Cheng et al ., ; Tian et al ., ), anti‐hypoxia (Xiong et al ., ), anti‐arrhythmic (Wang et al ., ), anti‐myocardial fibrosis (Lu et al ., ; Yin et al ., ), anti‐oxidant (Cheng et al ., 2011), anti‐inflammation (Wang et al ., ) and vasodilative effects (Li et al ., ; Wang et al ., ). These remarkable activities give IDHP the potential to become a promising new drug for fighting diseases in the cardio‐cerebrovascular system.…”

Section: Introductionmentioning

confidence: 99%

Identification of metabolites of isopropyl 3‐(3,4‐dihydroxyphenyl)‐2‐hydroxypropanoate in rats by high‐performance liquid chromatography combined with electrospray ionization quadrupole time‐of‐flight tandem mass spectrometry

Yang

Jia

et al. 2015

Biomedical Chromatography

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Isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate (IDHP) is an investigational new drug having the capacity for treating ailments in cardiovascular and cerebrovascular system. In this work, a rapid and sensitive method using high performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (HPLC-ESI-Q-TOF-MS) was developed to reveal the metabolic profile of IDHP in rats after oral administration. The method involved pretreatment of the samples by formic acid-methanol solution (v:v, 5:95), chromatographic separation by an Agilent Eclipse XDB-C column (150 × 4.6 mm i.d., 5 µm) and online identification of the metabolites by Q-TOF-MS equipped with electrospray ionizer. A total of 16 metabolites from IDHP, including 4 phase I metabolites and 12 phase II metabolites, were detected and tentatively identified from rat plasma, urine and feces. Among these metabolites, Danshensu (DSS), a hydrolysis product of IDHP, could be further transformed to 11 metabolites. These results indicated that DSS was the main metabolite of IDHP in rats and the major metabolic pathways of IDHP in vivo were hydrolysis, O-methylation, sulfation, glucuronidation and reduction. The results also demonstrated that renal route was the main pathway of IDHP clearance in rat. The present study provided valuable information for better understanding the efficacy and safety of IDHP. This article is protected by copyright. All rights reserved.

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“…At present, it is well known that lipopolysaccharide (LPS) binding to the Toll‐like receptor 4 (TLR4) on the surface of microglia activates a series of complex intracellular inflammatory signaling pathways including nuclear factor‐κB (NF‐κB) signal [Yao et al, ]. NF‐κB plays a key role in inflammatory diseases because NF‐κB activation can induce inflammatory gene expression and further promote the production of inflammatory mediators from microglia, such as prostaglandin E 2 (PGE 2 ), tumor necrosis factor (TNF‐α), interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), and reactive oxygen species (ROS) [Wang et al, ; Park et al, ; Dilshara et al, ]. Moreover, NF‐κB transcriptional activity is required for TLR4‐mediated interaction of TRAF6 (TNF‐receptor‐associated factor 6) with TAK1 (TGFβ‐activated kinase 1) [Lucas and Maes, ].…”

mentioning

confidence: 99%

Anti‐Neuroinflammatory Effect of MC13, a Novel Coumarin Compound From Condiment Murraya, Through Inhibiting Lipopolysaccharide‐Induced TRAF6‐TAK1‐NF‐κB, P38/ERK MAPKS and Jak2‐Stat1/Stat3 Pathways

Zeng

Liao

et al. 2015

J of Cellular Biochemistry

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MC13 is a novel coumarin compound found in Murraya, an economic crop whose leaves are widely used as condiment (curry) in cuisine. The aims of the present study were to investigate the neuroprotective effects of MC13 on microglia-mediated inflammatory injury model as well as potential molecular mechanism. Cell viability and apoptosis assay demonstrated that MC13 was not toxic to neurons and significantly protected neurons from microglia-mediated inflammatory injury upon lipopolysaccharide (LPS) stimulation. Results showed that MC13 markedly inhibited LPS-induced production of various inflammatory mediators, including nitrite oxide (Griess method), TNF-α and IL-6 (ELISA assay) in a concentration-dependent manner. Mechanism study showed that MC13 could suppress the activation of NF-κB, which was the central regulator for inflammatory response, and also decreased the interaction of TGF-β-activated kinase 1 (TAK1)-binding protein (TAB2) with TAK1 and TNF receptor associated factor (TRAF6), leading to the decreased phosphorylation levels of NF-κB upstream regulators such as IκB and IκB kinase (IKK). MC13 also significantly down-regulated the phosphorylation levels of ERK and p38 MAPKs, which played key roles in microglia-mediated inflammatory response. Furthermore, MC13 inhibited Jak2-dependent Stat1/3 signaling pathway activation by blocking Jak2 phosphorylation, Stat1/3 phosphorylation, and nuclear translocation. Taken together, our results demonstrated that MC13 protected neurons from microglia-mediated neuroinflammatory injury by inhibiting TRAF6-TAK1-NF-κB, p38/ERK MAPKs, and Jak2-Stat1/3 pathways. Finally, MC13 might interact with LPS and interfere LPS-binding to cell membrane surface. These findings suggested that coumarin might act as a potential medicinal agent for treating neuroinflammation as well as inflammation-related neurodegenerative diseases.

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Anti-Inflammatory Effects of Isopropyl 3-(3, 4-Dihydroxyphenyl)-2-Hydroxypropanoate, a Novel Metabolite from Danshen, on Activated Microglia

Cited by 14 publications

References 17 publications

A metabolite of Danshen formulae attenuates cardiac fibrosis induced by isoprenaline, via a NOX2/ROS/p38 pathway

A metabolite of Danshen formulae attenuates cardiac fibrosis induced by isoprenaline, via a NOX2/ROS/p38 pathway

Identification of metabolites of isopropyl 3‐(3,4‐dihydroxyphenyl)‐2‐hydroxypropanoate in rats by high‐performance liquid chromatography combined with electrospray ionization quadrupole time‐of‐flight tandem mass spectrometry

Anti‐Neuroinflammatory Effect of MC13, a Novel Coumarin Compound From Condiment Murraya, Through Inhibiting Lipopolysaccharide‐Induced TRAF6‐TAK1‐NF‐κB, P38/ERK MAPKS and Jak2‐Stat1/Stat3 Pathways

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