Background LOX-1, a lectin-like receptor on endothelial cells, facilitates the uptake of oxidized low-density lipoprotein (oxLDL). Expression of LOX-1 is involved in the pathobiological effects of ...oxLDL in endothelial cells, including reactive oxygen species (ROS) generation, suppression of endothelial nitric oxide synthase (eNOS) activity, and leukocytic adhesion. Moderate consumption of phenolic-enriched food may have a protective effect against the development of atherosclerosis via the antioxidant capacity of phenolic compounds at the endothelial level. In this study, we determined whether ellagic acid, a polyphenolic compound widely distributed in fruits and nuts, protects against oxLDL-induced endothelial dysfunction by modulating the LOX-1-mediated signaling pathway. Methods Human umbilical vein endothelial cells (HUVECs) were pretreated with ellagic acid at doses of 5, 10, 15, and 20 μM for 2 hours and then incubated with oxLDL (150 μg/mL) for an additional 24 hours. Results LOX-1 protein expression was markedly lower after exposure to oxLDL in HUVECs pretreated with ellagic acid or diphenyleneiodonium, a well-known inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, than in HUVECs exposed to oxLDL alone, suggesting that ellagic acid deactivates NADPH oxidase. We also found that oxLDL activated the membrane assembly of p47phox , Rac1, gp91 and p22phox , and the subsequent induction of ROS generation; however, ROS generation was markedly suppressed in cells pretreated with ellagic acid or anti-LOX-1 monoclonal antibody. In addition, oxLDL down-regulated eNOS and up-regulated inducible NO synthase (iNOS), thereby augmenting the formation of NO and protein nitrosylation. Furthermore, oxLDL induced the phosphorylation of p38 mitogen-activated protein kinase, activated the NF-κB-mediated inflammatory signaling molecules interleukin-(IL) 6 and IL-8 and the adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin, and stimulated the adherence of THP-1 (a human acute monocytic leukemia cell line) to HUVECs. Pretreatment with ellagic acid, however, exerted significant cytoprotective effects in all events. Conclusion Findings from this study may provide insight into a possible molecular mechanism by which ellagic acid inhibits LOX-1-induced endothelial dysfunction. Our data indicate that ellagic acid exerts its protective effects by inhibiting NADPH oxidase-induced overproduction of superoxide, suppressing the release of NO by down-regulating iNOS, enhancing cellular antioxidant defenses, and attenuating oxLDL-induced LOX-1 up-regulation and eNOS down-regulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
RAGE (receptor for advanced glycation end-product) is thought to be associated with metastasis and poor prognosis of various types of cancer. However, RAGE is constitutively expressed in the normal ...lung and down-regulated in cancerous lung, while the opposite evidence shows that RAGE-mediated signaling contributes to the tumorigenesis of lung cancer. Therefore, the role of RAGE in lung cancer progression is still unclear to be further investigated. In this study, RAGE-overexpressed stable clones of human lung cancer A549 cells and two local lung adenocarcinoma cell lines CL1-0 and CL1-5 were utilized to verify the effect of RAGE on lung cancer cells while the in vivo xenograft animal model was further performed to evaluate the role of RAGE in the progression of lung cancer. The growth of A549 cells was inhibited by RAGE overexpression. p53-dependent p21
expression contributed to RAGE-induced growth inhibition by suppressing CDK2 kinase activity and retinoblastoma protein (RB) phosphorylation in vitro. On the other hand, RAGE overexpression promoted migration, invasion, and mesenchymal features of lung adenocarcinoma cells through ERK signaling. Furthermore, an in vivo xenograft experiment indicated that RAGE promoted the metastasis of lung cancer cells with p21
up-regulation, ERK activation, and the changes of EMT markers. Regarding to the involvement of tumor-associated macrophage (TAM) in the microenvironment, we monitored the expressions of TAM markers including CD68 and CD163 as well as angiogenesis marker CD31 in xenograft slice. The data showed that RAGE might induce the accumulation of TAM in lung cancer cells and further accelerate the in vivo tumor growth. In summary, our study provides evidence indicating the distinct in vitro and in vivo effects of RAGE and related mechanisms on tumor growth and metastasis, which shed light on the oncogenic role of RAGE in lung cancer.
Essential oils extracted from aromatic plants exhibit important biological activities and have become increasingly important for the development of aromatherapy for complementary and alternative ...medicine. The essential oil extracted from Cinnamomum cassia Presl (CC-EO) has various functional properties; however, little information is available regarding its anti-tyrosinase and anti-melanogenic activities. In this study, 16 compounds in the CC-EO have been identified; the major components of this oil are cis-2-methoxycinnamic acid (43.06%) and cinnamaldehyde (42.37%). CC-EO and cinnamaldehyde exhibited anti-tyrosinase activities; however, cis-2-methoxycinnamic acid did not demonstrate tyrosinase inhibitory activity. In murine B16 melanoma cells stimulated with α-melanocyte-stimulating hormone (α-MSH), CC-EO and cinnamaldehyde not only reduced the melanin content and tyrosinase activity of the cells but also down-regulated tyrosinase expression without exhibiting cytotoxicity. Moreover, CC-EO and cinnamaldehyde decreased thiobarbituric acid-reactive substance (TBARS) levels and restored glutathione (GSH) and catalase activity in the α-MSH-stimulated B16 cells. These results demonstrate that CC-EO and its major component, cinnamaldehyde, possess potent anti-tyrosinase and anti-melanogenic activities that are coupled with antioxidant properties. Therefore, CC-EO may be a good source of skin-whitening agents and may have potential as an antioxidant in the future development of complementary and alternative medicine-based aromatherapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The development of microarrays permits us to monitor transcriptomes on a genome-wide scale. To validate microarray measurements, quantitative-real time-reverse transcription PCR (Q-RT-PCR) is one of ...the most robust and commonly used approaches. The new challenge in gene quantification analysis is how to explicitly incorporate statistical estimation in such studies. In the realm of statistical analysis, the various available methods of the probe level normalization for microarray analysis may result in distinctly different target selections and variation in the scores for the correlation between microarray and Q-RT-PCR. Moreover, it remains a major challenge to identify a proper internal control for Q-RT-PCR when confirming microarray measurements.
Sixty-six Affymetrix microarray slides using lung adenocarcinoma tissue RNAs were analyzed by a statistical re-sampling method in order to detect genes with minimal variation in gene expression. By this approach, we identified DDX5 as a novel internal control for Q-RT-PCR. Twenty-three genes, which were differentially expressed between adjacent normal and tumor samples, were selected and analyzed using 24 paired lung adenocarcinoma samples by Q-RT-PCR using two internal controls, DDX5 and GAPDH. The percentage correlation between Q-RT-PCR and microarray were 70% and 48% by using DDX5 and GAPDH as internal controls, respectively.
Together, these quantification strategies for Q-RT-PCR data processing procedure, which focused on minimal variation, ought to significantly facilitate internal control evaluation and selection for Q-RT-PCR when corroborating microarray data.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Luteolin, a plant flavonoid, has potent anti-inflammatory properties both in vitro and in vivo. However, the molecular mechanism of luteolin-mediated immune modulation has not been fully understood. ...In this study, we examined the effects of luteolin on the production of nitric oxide (NO) and prostaglandin E
2 (PGE
2), as well as the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) in mouse alveolar macrophage MH-S and peripheral macrophage RAW 264.7 cells. Luteolin dose-dependently inhibited the expression and production of these inflammatory genes and mediators in macrophages stimulated with lipopolysaccharide (LPS). Semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay further confirmed the suppression of LPS-induced TNF- α, IL-6, iNOS and COX-2 gene expression by luteolin at a transcriptional level. Luteolin also reduced the DNA binding activity of nuclear factor-kappa B (NF-κB) in LPS-activated macrophages. Moreover, luteolin blocked the degradation of IκB-α and nuclear translocation of NF-κB p65 subunit. In addition, luteolin significantly inhibited the LPS-induced DNA binding activity of activating protein-1 (AP-1). We also found that luteolin attenuated the LPS-mediated protein kinase B (Akt) and IKK phosphorylation, as well as reactive oxygen species (ROS) production. In sum, these data suggest that, by blocking NF-κB and AP-1 activation, luteolin acts to suppress the LPS-elicited inflammatory events in mouse alveolar macrophages, and this effect was mediated, at least in part, by inhibiting the generation of reactive oxygen species. Our observations suggest a possible therapeutic application of this agent for treating inflammatory disorders in lung.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objectives
This study explored resistance functions and their interactions in de novo AML treated with the “7 + 3” induction regimen.
Methods
We analyzed RNA‐sequencing profiles of whole bone marrow ...samples from 52 de novo AML patients who completed the “7 + 3” regimen and stratified patients into CR (n = 35) and non‐CR (n = 17) groups.
Results
A systematic gene set analysis revealed significant associations between chemoresistance and mTOR (P < .001), myc (P < .001), mitochondrial oxidative phosphorylation (P < .001), and stemness (P = .002). These functions were independent with regard to gene contents and activity scores. An integration of these four functions showed a prediction of chemoresistance (area under the receiver operating characteristic curve = 0.815) superior to that of each function alone. Moreover, our proposed seven‐gene scoring system significantly correlated with the four‐function model (r = .97; P < .001) to predict chemoresistance to the “7 + 3” regimen. On multivariate analysis, a seven‐gene score of ≥−0.027 (hazard ratio: 11.18; 95% confidence interval: 2.06‐60.65; P = .005) was an independent risk factor for induction failure.
Conclusions
Myc, OXPHOS, mTOR, and stemness were responsive for chemoresistance in AML. Treatments other than the “7 + 3” regimen need to be considered for de novo AML patients predicted to be refractory to the “7 + 3” regimen.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The microRNA, miR-141, is a promising biomarker for prostate cancer. We implement here a two-step sensing platform for the sensitive detection of miR-141. The first step involves the use of ...semiconductor CdSe/ZnS quantum dots (QDs) modified by FRET quencher-functionalized nucleic acids, that include the recognition sequence for miR-141 and a telomerase primer sequence for the second step of the analytical platform. Subjecting the probe-modified QDs to miR-141, in the presence of duplex specific nuclease, DSN, leads to the formation of a miR-141/probe duplex and to its DSN-mediated cleavage, while regenerating the miR-141. The DSN-induced cleavage of the quencher units leads to the activation of the fluorescence of the QDs, thus allowing the optical detection of miR-141 with a sensitivity corresponding to 1.0 × 10
M. The nucleic acid residues associated with the QDs after cleavage of the probe nucleic acids by DSN act as primers for telomerase. The subsequent telomerase/dNTPs-stimulated elongation of the primer units forms G-quadruplex telomer chains. Incorporation of hemin in the resulting G-quadruplex telomer chains yields horseradish peroxidase-mimicking DNAzyme units, that catalyze the generation of chemiluminescence in the presence of luminol/H
O
. The resulting chemiluminescence intensities provide a readout signal for miR-141, DL = 2.8 × 10
M. The first step of the sensing platform is non-selective toward miR-141 and the resulting fluorescence may be considered only as an indicator for the existence of miR-141. The second step in the sensing protocol, involving telomerase, provides a selective chemiluminescence signal for the existence of miR-141. The two-step sensing platform is implemented for the analysis of miR-141 in serum samples from healthy individuals and prostate cancer carriers. Impressive discrimination between healthy individuals and prostate cancer carriers is demonstrated.
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IJS, KILJ, NUK, UL, UM, UPUK
Highlights • Cytotoxic concentration of antrocin induced both intrinsic and extrinsic apoptosis in human bladder cancer cells. • Antrocin increases Fas, DR5, Bax expression and caspase-3, -8 and -9 ...activation. • Non-cytotoxic concentrations of antrocin inhibit cellular mobility. • Antrocin inhibits mobility via inactivating FAK-paxillin and ERK-c-Fos-MMP2 pathways.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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