A novel compound derived from danshensu inhibits apoptosis via upregulation of heme oxygenase-1 expression in SH-SY5Y cells

Pan, Li-Long; Liu, Xinhua; Jia, Yijun; Wu, Dan; Xiong, Qinghui; Gong, Qihai; Wang, Yang; Zhu, Yi‐Zhun

doi:10.1016/j.bbagen.2013.01.008

Cited by 34 publications

(40 citation statements)

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“…On the contrary, LY294002 significantly reduced LPS-induced iNOS expression and NO generation, which was consistent with the previous studies that activation of PI3K/Akt pathway participated in LPS-induced inflammatory mediators [43,44]. Meanwhile, many chemopreventive phytochemicals exhibited simultaneous induction of Nrf2-regulated cytoprotective protein expression and inhibition of NF-κB-regulated inflammatory response via activation of PI3K/Akt signaling pathway [12,40]. This contradictory results were likely that phosphorylation of Akt was involved in ZY-1A4 induction of gene expression which was important to defend against LPS-induced deleterious effect through the PI3K/Akt pathway.…”

Section: Discussionsupporting

confidence: 79%

“…We previously reported that a derivative of danshensu, another active compound of danshen, was able to induce the expression of HO-1 [12]. To determine the effect of ZY-1A4 on HO-1 expression, cells were incubated with various concentrations of ZY-1A4 for the indicated periods.…”

Section: Resultsmentioning

confidence: 99%

“…Cumulative evidences suggest heme oxygenase-1 (HO-1) functions as a cytoprotective enzyme against inflammatory responses through production of its metabolites such as carbon monoxide (CO), bilirubin, and free iron [11,12,13,14]. HO-1 also negatively regulates NF-κB activation and subsequent iNOS expression [15,16,17].…”

Section: Introductionmentioning

confidence: 99%

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Induction of Heme Oxygenase-1 by Sodium 9-Hydroxyltanshinone IIA Sulfonate Derivative Contributes to Inhibit LPS-Mediated Inflammatory Response in Macrophages

Liu

Wang

Xiao

et al. 2015

Cell Physiol Biochem

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Background/Aim: Sodium 9-acetoxyltanshinone IIA sulfonate (ZY-1A4), a novel compound derived from sodium 9-hydroxyltanshinone IIA sulfonate, was synthesized with potential biological activities. This study aimed to explore the effects of ZY-1A4 on lipopolysaccharide (LPS)-triggered inflammatory response and the underlying mechanisms. Methods: Activation of RAW264.7 macrophages was induced by LPS. The effects of ZY-1A4 on inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) generation, nuclear factor-κB (NF-κB) activation, heme oxygenase-1 (HO-1) expression, and nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway were evaluated to elucidate its underlying mechanisms on inflammatory responses. Results: ZY-1A4 concentration-dependently reduced iNOS expression and NO production, and inhibited c-Jun-N-terminal kinase 1/2 (JNK1/2) phosphorylation and NF-κB activation in LPS-stimulated macrophages. In addition, ZY-1A4 concentration- and time-dependently induced HO-1 expression associated with degradation of Kelch-like ECH-associated protein 1 (Keap1) and nuclear translocation of Nrf2, while the effect of ZY-1A4 was abolished by a phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Intriguingly, pharmacological inactivation of HO-1 with zinc protoporphyrin IX reversed anti-inflammatory effect of ZY-1A4, but the anti-inflammatory effect of ZY-1A4 was largely mimicked by HO-1 by-products carbon monoxide and bilirubin. Furthermore, the inhibitory effect of ZY-1A4 on LPS-induced iNOS expression and NO release was abolished by HO-1 siRNA or LY294002. Conclusion: Our results demonstrated that ZY-1A4 suppressed LPS-induced iNOS expression and NO generation via modulation of NF-κB activation and HO-1 expression. This new finding might shed light to the prevention and therapy of cardiovascular diseases.

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Section: Discussionsupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

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Induction of Heme Oxygenase-1 by Sodium 9-Hydroxyltanshinone IIA Sulfonate Derivative Contributes to Inhibit LPS-Mediated Inflammatory Response in Macrophages

Liu

Wang

Xiao

et al. 2015

Cell Physiol Biochem

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“…Previous studies have confirmed that DSS has biological activities in that it improves microcirculation and exerts cardiovascular protective effects. For example, DSS has been shown to restore endothelium-dependent vasorelaxation via the prostacyclin pathway by increasing cyclooxygenase (COX)-2 gene expression and prostacyclin production (25), and thus it suppresses the formation of reactive oxygen species (ROS) and protects the myocardium against ischemia (26), protecting endothelial cells against injury induced by inflammation and inhibiting apoptosis (27,28), as well as inhibiting cardiac fibrosis through the negative regulation of ROS-/p38 MAPK signaling (29).…”

Section: Introductionmentioning

confidence: 99%

Danshensu protects against ischemia/reperfusion injury and inhibits the apoptosis of H9c2 cells by reducing the calcium overload through the p-JNK-NF-κB-TRPC6 pathway

Meng

Shi

et al. 2015

International Journal of Molecular Medicine

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Abstract. Ischemia-reperfusion (I/R) plays an important role in myocardial injury. In the present study, we aimed to examine the protective effects of Danshensu (DSS) against I/R injury and to elucidate the underlying mechanisms. For this purpose, H9c2 cells were cultured in hypoxic solution in a hypoxic incubator for 2 h, and then cultured in a high oxygen incubator for various periods of time and pre-treated with or without DSS, ammonium pyrrolidine dithiocarbamate (PDTC) or SP600125 [a c-Jun N-terminal kinase (JNK) inhibitor]. Cell apoptosis and cytosolic free Ca 2+ ([Ca 2+ ] i ) levels were analyzed by flow cytometry. The protein expression levels of JNK, phosphorylated (p-)JNK, nuclear factor-κB (NF-κB) and transient receptor potential cation channel, subfamily C, member 6 (TRPC6) were measured by western blot analysis. The mRNA expression levels of JNK were measured by RT-qPCR. The results revealed that TRPC6 protein expression, the cell apoptotic rate and the [Ca 2+ ] i levels increased in a timedependent manner in the H9c2 cells following the induction of I/R injury. The apoptotic rate and TRPC6 protein expression decreased when the cells were treated with DSS prior to the induction of I/R injury. The knockdown of JNK expression by siRNA decreased the p-JNK and TRPC6 protein expression levels in the H9c2 cells subjected to I/R injury. The protein expression levels of p-JNK and NF-κB in the nucleus increased significantly when the H9c2 cells were subjected to I/R injury, whereas NF-κB expression in the cytoplasm decreased in a time-dependent manner. However, p-JNK, NF-κB and TRPC6 protein expression, the [Ca 2+ ] i level and cell apoptosis decreased when the H9c2 cells were pre-treated with DSS or SP600125. Therefore, our data suggest that DSS prevents myocardial I/R injury by inhibiting p-JNK activation and NF-κB translocation, which potentially upregulate TRPC6 expression, increase the [Ca 2+ ] i level, and result in the apoptosis of H9c2 cells.

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“…DSS has biological activities in improving microcirculation, suppressing the formation of ROS, protecting the myocardium against ischemia, 14) protecting endothelial cells against injury induced by inflammation, and enhancing anti-apoptosis. 15,16) However, the role of DSS in cardiac fibroblasts (CFs) remains unclear.…”

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confidence: 99%

Danshensu Inhibits β-Adrenergic Receptors-Mediated Cardiac Fibrosis by ROS/p38 MAPK Axis

Tian

et al. 2014

Biological & Pharmaceutical Bulletin

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Danshensu, the effective ingredient of the plant Salvia miltiorrhiza (Danshen), has been widely used for treatment of cardiovascular diseases. Cardiac fibrosis is an important process in pathological cardiac remodeling and leads to heart failure. We investigated the effect of Danshensu on β-adrenergic receptor (β-AR)-mediated cardiac fibrosis and the involved signaling transduction. Danshensu inhibited cardiofibroblast proliferation and collagen I synthesis induced by isoproterenol (ISO), a selective β-AR agonist. Phosphorylation of p38 mitogen-activated protein kinase (MAPK), which mediates ISO-induced cardiac fibrosis, was negatively regulated in this process. The negative regulation depended on the ISO inhibition of reactive oxygen species (ROS) production. Taken together, Danshensu may inhibit β-AR-mediated cardiac fibrosis by negative regulation of ROS-p38 MAPK signaling.Key words Danshensu; β-adrenergic receptor; cardiac fibrosis; p38 MAPK; reactive oxygen specy Cardiac fibrosis is a pivotal phenomenon in pathological cardiac remodeling and is a hallmark of heart diseases. It is characterized by excessive extracellular matrix accumulation and fibroblast deposition and eventually destroys the organ architecture and abolishes normal function.1-3) Myocardial fibrosis is a major biological determinant of fatal events in cardiac remodeling, including heart failure, severe arrhythmias and sudden cardiac death.4,5) Cardiac fibrosis can be caused by various factors, such as the chronic activation of the sympathetic nervous system, myocardial hypoxia, ischemia, senescence, inflammation and hormones. β-Adrenergic receptors (β-ARs) and their associated guanine nucleotide regulatory protein (G protein)/adenylyl cyclase signal transduction pathways, are central to the regulation of cardiac function. Continuous activation of β-ARs plays an important role in cardiac dysfunction.6-8) Cardiac function was altered in β 1 -AR transgenic mice with cardiac hypertrophy, which could be inhibited by β-AR blockers.8) Consecutive administration with isoproterenol (ISO), a β-AR agonist, caused cardiac fibrosis in rats. 9,10) p38 mitogen-activated protein kinase (p38 MAPK) and reactive oxygen species (ROS) play a critical role in cardiac * To whom correspondence should be addressed. e-mail: lizijian@bjmu.edu.cn;zhengxh@nwu.edu.cnThe authors declare no conflict of interest. # These authors contributed equally to this work.

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A novel compound derived from danshensu inhibits apoptosis via upregulation of heme oxygenase-1 expression in SH-SY5Y cells

Cited by 34 publications

References 35 publications

Induction of Heme Oxygenase-1 by Sodium 9-Hydroxyltanshinone IIA Sulfonate Derivative Contributes to Inhibit LPS-Mediated Inflammatory Response in Macrophages

Induction of Heme Oxygenase-1 by Sodium 9-Hydroxyltanshinone IIA Sulfonate Derivative Contributes to Inhibit LPS-Mediated Inflammatory Response in Macrophages

Danshensu protects against ischemia/reperfusion injury and inhibits the apoptosis of H9c2 cells by reducing the calcium overload through the p-JNK-NF-κB-TRPC6 pathway

Danshensu Inhibits β-Adrenergic Receptors-Mediated Cardiac Fibrosis by ROS/p38 MAPK Axis

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