Luteolin exerts an anticancer effect on gastric cancer cells through multiple signaling pathways and regulating miRNAs
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Accumulating studies confirmed that luteolin, a common dietary flavonoid which is widely distributed in plants and has diverse beneficial biological function, including anti-oxidant, anti-inflammation and anticancer properties.However, the detail mechanisms of luteolin on GC are poorly understood.Here, we investigated the anticancer effect of luteolin in GC cells in vitro and in vivo.Luteolin reduced the cell viability in a time and dose-dependent manner.Luteolin significantly inhibited cell cycle progress, colony formation, proliferation, migration, invasion and promoted apoptosis in vitro and in vivo.Luteolin also regulated these biological effects associated regulators.Mechanically, luteolin treatment regulated Notch1, PI3K, AKT, mTOR, ERK, STAT3 and P38 signaling pathways and modulated a series of miRNAs expression.These findings provide novel insight into the molecular function of luteolin which suggest its potential as a therapeutic agent for human GC.The inhibitory effect of four structurally related flavonoids, apigenin, baicalein, luteolin and quercetin on the matrix metalloproteinase (MMP)-9 and -13 expressions in osteoblasts was investigated. Treatment with IL-1β induced both MMP-9 and -13 mRNA expressions as measured by quantitative real-time PCR. Luteolin and apigenin decreased IL-1β-induced MMP-9 and -13 mRNA expressions, whereas baicalein and quercetin showed little effects. Related to signalling, treatment with IL-1β induced ERK phosphorylation as measured by Western blotting. Further studies showed that transfection with a constitutively active form of the Ras protein (Ras(V12)) induced stronger ERK phosphorylation and upregulated MMP-9 and -13 mRNA expressions. However, transfection with a dominant-negative form of the Ras protein (Ras(N17)) inhibited the ERK activation and MMP-9 and -13 mRNA expressions induced by IL-1β, which supported the involvement of ERK signalling in IL-1β-induced MMP-9 and -13 expressions. Treatment with luteolin effectively inhibited the IL-1β-induced ERK activation in dose-dependent manner. Taken together, luteolin might inhibit IL-1β-induced MMP-9 and -13 expressions, in part, via inhibition of ERK signalling.
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Abstract As the intestinal epithelium is vulnerable to oxidative stress because of frequent enterocyte renewal and continuous exposure to exogenous agents, it is meaningful to figure out how the epithelial cells exert antioxidant function. We previously synthesized a novel biogenic nanoselenium (BNS) particles and proved that BNS could effectively improve intestinal antioxidative function through activating Nrf2‐ARE pathway. The objective of the present study was to investigate the mechanism by which BNS activate Nrf2‐ARE pathway on the physiological function of intestinal epithelial cells. In the present study, we demonstrated that treatment of IPEC‐J2 cells with BNS particles not only elevated the levels of downstream proteins of nuclear factor (erythroid‐derived‐2)‐like 2 (Nrf2) such as heme oxygenase‐1 and NQO‐1 in a time‐dependent manner which started to weaken at 12 hr after treatment but also significantly activated Nrf2, mitogen‐activated protein kinase (MAPK), and protein kinase B (AKT) pathway in a time‐dependent manner within 24 hr. BNS particles significantly increased the content of phosphorylated‐Nrf2, without evident influence on the level of Kelch‐like ECH‐associated protein 1 (Keap1). Moreover, BNS also induced the activation of p38, extracellular signal‐regulated kinase 1/2 (ERK1/2), c‐Jun N‐terminal kinase, and AKT while phosphorylating Nrf2. Using specific protein kinase inhibitors, we found that the Nrf2‐phosphorylating and antioxidative effects of BNS particles were abolished when p38, ERK1/2, and AKT were significantly inhibited. Overall, our data demonstrated that BNS particles activated Nrf2‐ARE pathway through p38, ERK1/2, and AKT mediated‐phosphorylation of Nrf2 to improve the antioxidant function of intestinal epithelial cells
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A flavonoid, luteolin, was isolated from the leaves of Syzygium myrtifolium. The compound was purified using vacuum liquid chromatography with the help of a specific guidance for the flavonoid isolation. The chemical structure of this compound was determined based on measurements of UV, IR and NMR spectroscopic data. The occurrence of luteolin in S. myrtifolium is firstly reported from this study.
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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant, exposure to it eliciting a broad spectrum of deleterious pathophysiological effects. Since mitogen-activated protein kinase (MAPK) pathways appear to play an important role in both cell survival and the apoptotic process, we assessed the effects of TCDD on the activation of extracellular signal-regulated kinase (ERK), Jun-N-terminal kinase (JNK), p38 MAPKs and caspase-3 in RAW 264.7 cells. TCDD treatment induced a transient upshift in ERK activity, followed by a decline, but a concomitant dramatic activation of p38. However, TCDD did not cause any apparent change in the activity of JNK, though it induced an up-regulation in caspase-3 activity. These results demonstrate that the equilibrium between the ERK and p38 pathways is critical to the fate of the cells, and that the activation of p38, upstream of caspase, plays an important role in the apoptotic process. The data obtained in this study also suggests that TCDD activates the MAPK pathway via an arylhydrocarbon receptor (AhR)-independent mechanism in RAW 264.7 murine macrophages.
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A method to determine luteolin inthe extracts from peanut shell by HPLC is reported. Flavonoids were extracted with different solvents, and determined by spectrophotometric method of NaNO_ 2Al(NO_ 3)_ 3NaOH system. Results showed that the contents of flavonoid and luteolin in the product extracted by 60% acetone were high.
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BACKGROUND: The effects of aging on the cardiovascular system contribute to substantial alterations in cellular morphology and function. The variables regulating these changes are unknown; however, one set of signaling molecules which may be of particular importance in mediating numerous cellular responses including control of cell growth, differentiation and adaptation are the proteins associated with the mitogen activated protein kinase (MAPK) signaling systems. Further MAPKs have emerged as critical components for regulating numerous mechanotrasductive cellular responses. Previous reports have suggested that agng impairs biaxial-loading induced MAPK phosphorylation. How agigng may affect uniaxial mechanotrasductive processes is not clear. PURPOSE: Here we investigate the ability of a uniaxial stretch activate MAPK pathways in adult (6 mo old), aged (30 mo old) and very aged (36 mo old) Fischer 344 x Brown Norway rats. METHODS: Aortea of adult (6 month), aged (30 month), and very aged (36 month) Fischer 344/NNiaHSD X Brown Norway / BiNia rats were subjected to acute bout of a 20% uniaxial stretch. MAPK protein expression, basal phosphorylation and the uniaxial stretch induced changes in phosphorylation were evaluated by immunoblotting. RESULTS: Western blotting of the MAPK family proteins extracellular signal-regulated kinase (ERK) 1/2, p38-, and c-Jun NH2-terminal kinase (JNK)-MAPKs showed differential expression and basal activation between these proteins with age, with notably higher phosphorylation in ERK1/2 and JNK compared to the 6 month aniumals. However, an acute bout of a 20% uniaxial stretch using an ex vivo aortic preparation demonstrated similar regulation of ERK 1/2 MAPK, p38-, and JNK MAPK. CONCLUSIONS: These observations confirm previous data demonstrating MAPK proteins are mechanically regulated, and in addition, suggest that MAPK signaling following uniaxial stretch is not altered with aging. Taken together, these data may help explain the age related changes in vascular morphology, function and response to injury. (Supported by funds from NSF Grant #0314742)
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AIM:To investigate the apoptotic effect of cepharanthine(CEP)on neonatal rat cardiomyocytes (NRCMs)and the underlying mechanisms.METHODS:MTT assay was used to detect the viability of the cells.CEP-induced apoptosis in NRCMs was evaluated by Hoechst 33342 staining and the expression of activated caspase-3.The phosphorylation levels of mitogen-activated protein kinases(MAPKs),such as extracellular signal-regulated kinase (ERK),c-jun N-terminal kinase(JNK)and p38 MAPK,were examined by Western blotting.The specific inhibitors of ERK and p38 MAPK were applied for identifying the roles of the corresponding signal pathways in CEP-induced apoptosis of cardiomyocytes.RESULTS:CEP inhibited the viability of NRCMs in a dose-and time-dependent manners.Positive nuclear fragmentation and activated caspase-3 were found in CEP-treated NRCMs.The phosphorylation levels of ERK and p38 MAPK were significantly elevated in CEP-treated NRCMs,but the change of JNK was not obvious.SB203580, an inhibitor of p38 MAPK,significantly alleviated the apoptotic effect induced by CEP.However,PD98059,an inhibitor of ERK1/2,did not significantly reduce the apoptotic effect.CONCLUSION:p38 MAPK is involved in CEP-induced apoptosis in NRCMs.
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Luteolin is a naturally occurring flavone that reportedly has anti-inflammatory effects. Because most luteolin is conjugated following intestinal absorption, free luteolin is likely present at low levels in the body. Therefore, luteolin metabolites are presumably responsible for luteolin bioactivity. Here we confirmed that luteolin glucuronides, especially luteolin-3'-O-glucuronide, are the major metabolites found in plasma after oral administration of luteolin (aglycone) or luteolin glucoside (luteolin-7-O-glucoside) to rats. Luteolin-4'-O-glucuronide and luteolin-7-O-glucuronide were also detectable together with luteolin-3'-O-glucuronide in the liver, kidney, and small intestine. Next, we prepared these luteolin glucuronides and compared the anti-inflammatory effects of luteolin and luteolin glucuronides on gene expression in lipopolysaccharide-treated RAW264.7 cells. Luteolin glucuronides, especially luteolin-7-O-glucuronide, reduced expression of inflammatory genes in the cells, although their effects were weaker than those of luteolin. These results indicate that the active compound responsible for the anti-inflammatory effect of luteolin in vivo would be luteolin glucuronide and/or residual luteolin.
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