Pei-Jung Lu

National Cheng Kung University, 臺南市, Taiwan, Taiwan

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Publications (99)431.48 Total impact

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    ABSTRACT: Rationale: Non-small cell lung cancer (NSCLC) carries a poor survival rate mainly due to metastasis. However, the molecular mechanisms that govern NSCLC metastasis are undescribed. Huntingtin interacting protein-1 (HIP1) is known to play a role in tumorigenesis, we tested the involvement of HIP1 in NSCLC progression and metastasis. Objectives: HIP1 expression was measured in human NSCLC tumors and correlation with survival outcome was evaluated. Furthermore, we investigated the ability of HIP1 to suppress a metastasis. The molecular mechanism by which HIP1 contributes to suppress metastasis was investigated. Methods: We used tissue arrays containing samples from 121 NSCLC patients to analyze HIP1 expression by immunohistochemistry (IHC). In order to investigate the role of HIP1 expression on metastasis, we evaluated cellular mobility, migration and invasion using lung adenocarcinoma (AdCA) cells with modified HIP1 expression levels. The human disease mouse models with the same cells were applied to evaluate the HIP1 suppressing metastasis and its mechanism in vivo. Measurements and main results: HIP1 expression in AdCA progression was found to be an early-stage prognostic biomarker, with low expression correlated to poor prognosis. We also found HIP1 to be a metastatic suppressor in AdCA. HIP1 significantly repressed the mobility of lung cancer cells both in vitro and in vivo, and regulated the epithelial-mesenchymal transition (EMT) by repressing AKT/GSK3β/β-catenin signaling. Conclusions: HIP1 serves as an early-stage prognostic biomarker and a metastatic suppressor. Reduced expression during AdCA progression can relieve HIP1 suppression of Akt-mediated EMT and thereby lead to development of late metastases and poor prognosis.
    No preview · Article · Nov 2015 · American Journal of Respiratory and Critical Care Medicine
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    ABSTRACT: G-protein-coupled receptor kinase interacting protein 1 (GIT1) is participated in cell movement activation, which is a fundamental process during tissue development and cancer progression. GIT1/PIX forming a functional protein complex that contributes to Rac1/Cdc42 activation, resulting in increasing cell mobility. Although the importance of Rac1/Cdc42 activation is well documented in cancer aggressiveness, the clinical importance of GIT1 remains largely unknown. Here, we investigated the clinical significance of GIT1 expression in non-small-cell lung cancer (NSCLC) and also verified the importance of GIT1-Rac1/Cdc42 axis in stimulating NSCLC cell mobility. The result indicated higher GIT1 expression patients had significantly poorer prognoses in disease-free survival (DFS) and overall survival (OS) compared with lower GIT1 expression patients. Higher GIT1 expression was an independent prognostic factor by multivariate analysis and associated with migration/invasion of NSCLC cells in transwell assay. In vivo studies indicated that GIT1 promotes metastasis of NSCLC cells. Finally, GIT1 was found to stimulate migration/invasion by altering the activity of Rac1/Cdc42 in NSCLC cells. Together, the GIT1 expression is associated with poor prognosis in patients with NSCLC. GIT1 is critical for the invasiveness of NSCLC cells through stimulating the activity of Rac1/Cdc42.
    Preview · Article · Oct 2015 · Oncotarget
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    ABSTRACT: Background: In lung cancer, uPA, its receptor (uPAR), and the inhibitors PAI-1 and PAI-2 of the plasminogen activator family interact with MMP-2 and MMP-9 of the MMP family to promote cancer progression. However, it remains undetermined which of these markers plays the most important role and may be the most useful indicator to stratify the patients by risk. Methods: We determined the individual prognostic value of these 6 markers by analyzing a derivation cohort with 98 non-small cell lung cancer patients by immunohistochemical staining. The correlation between the IHC expression levels of these markers and disease prognosis was investigated, and an immunohistochemical panel for prognostic prediction was subsequently generated through prognostic model analysis. The value of the immunohistochemical panel was then verified by a validation cohort with 91 lung cancer patients. Results: In derivation cohort, PAI-2 is the most powerful prognostic factor (HR = 2.30; P = 0.001), followed by MMP-9 (HR = 2.09; P = 0.019) according to multivariate analysis. When combining PAI-2 and MMP-9, the most unfavorable prognostic group (low PAI-2 and high MMP-9 IHC expression levels) showed a 6.40-fold increased risk of a poor prognosis compared to the most favorable prognostic group (high PAI-2 and low MMP-9 IHC expression levels). PAI-2 and MMP-9 IHC panel could more precisely identify high risk patients in both derivation and validation cohort. Conclusions: We revealed PAI-2 as the most powerful prognostic marker among PA and MMP protease family even after considering their close relationships with each other. By utilizing a combination of PAI-2 and MMP-9, more precise prognostic information than merely using pathological stage alone can be obtained for lung cancer patients.
    Full-text · Article · Aug 2015 · PLoS ONE
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    ABSTRACT: Heme oxygenase (HO)-1 confers transient resistance against oxidative damage, including renal ischemia-reperfusion injury (IRI). We investigated the potential protective effect of HO-1 induction in a mouse model of renal IRI induced by bilateral clamping of the kidney arteries. The mice were randomly assigned to five groups to receive an intraperitoneal injection of PBS, hemin (an HO-1 inducer, 100 μmol/kg), hemin + ZnPP (an HO-1 inhibitor, 5 mg/kg), hemin + PD98059 (a MEK-ERK inhibitor, 10 mg/kg) or a sham operation. All of the groups except for the sham-operated group underwent 25 minutes of ischemia and 24 to 72 hours of reperfusion. Renal function and tubular damage were assessed in the mice that received hemin or the vehicle treatment prior to IRI. The renal injury score and HO-1 protein levels were evaluated via H&E and immunohistochemistry staining. Hemin-preconditioned mice exhibited preserved renal cell function (BUN: 40 ± 2 mg/dl, creatinine: 0.53 ± 0.06 mg/dl), and the tubular injury score at 72 hours (1.65 ± 0.12) indicated that tubular damage was prevented. Induction of HO-1 induced the phosphorylation of extracellular signal-regulated kinases (ERK) 1/2. However, these effects were abolished with ZnPP treatment. Kidney function (BUN: 176 ± 49 mg/dl, creatinine: 1.54 ± 0.39 mg/dl) increased, and the tubular injury score (3.73 ± 0.09) indicated that tubular damage also increased with ZnPP treatment. HO-1-induced tubular epithelial proliferation was attenuated by PD98059. Our findings suggest that HO-1 preconditioning promotes ERK1/2 phosphorylation and enhances tubular recovery, which subsequently prevents further renal injury. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jul 2015 · Biochimica et Biophysica Acta
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    ABSTRACT: Aberrant Wnt signaling appears to play an important role in the onset of diabetes. Moreover, the insulin signaling pathway is defective in the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHRs) and fructose-fed rats. Nevertheless, the relationships between Wnt signaling and the insulin pathway and the related modulation of blood pressure (BP) in the central nervous system have yet to be established. The aim of this study was to investigate the potential signaling pathways involved in Wnt-mediated blood pressure regulation in the NTS. Pretreatment with the low density lipoprotein receptor-related protein (LRP) antagonist Dickkopf-1 (DKK1) significantly attenuated the Wnt3a-induced depressor effect and nitric oxide production. Additionally, inhibition of LRP6 activity using DKK-1 significantly abolished Wnt3a-induced glycogen synthase kinase 3β (GSK-3β)(S9), extracellular signal-regulated kinases 1/2(T202/Y204), ribosomal protein S6 kinase(T359/S363) and Akt(S473) phosphorylation and increased IRS1(S332) phosphorylation. GSK-3β was also found to directly bind to IRS1 and induce the phosphorylation of IRS1 at Ser332 in the NTS. By contrast, administration of the GSK-3β inhibitor TWS119 into the brain decreased the BP of hypertensive rats by enhancing IRS1 activity. Taken together, these results suggest that the GSK-3β-IRS1 pathway may play a significant role in Wnt-mediated central BP regulation. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    No preview · Article · Apr 2015 · Diabetes
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    ABSTRACT: Pancreatic beta-cells are particularly susceptible to fatty-acid-induced endoplasmic reticulum (ER) stress and apoptosis. To understand how beta-cells sense fatty acid stimuli and translate into a long-term adaptive response, we investigated whether palmitic acid (PA) regulates early growth response-1 (Egr-1), an immediate-early transcription factor, which is induced by many environmental stimuli and implicated in cell proliferation, differentiation, and apoptosis. We found that Egr-1 was rapidly and transiently induced by PA in MIN6 insulinoma cells, which was accompanied by calcium influx and ERK1/2 phosphorylation. Calcium chelation and MEK1/2 inhibition blocked PA-induced Egr-1 upregulation, suggesting that PA induces Egr-1 expression through a calcium influx-MEK1/2-ERK1/2 cascade. Knockdown of Egr-1 increased PA-induced caspase-3 activation and ER stress markers and decreased PA-induced Akt phosphorylation and insulin secretion and signaling. Akt replenishment and insulin supplementation rescued PA-induced apoptosis in Egr-1 knockdown cells. These results suggest that the absence of Egr-1 loses its ability to couple the short-term insulin/Akt pathway to long-term survival adaptation. Finally, Egr-1-deficient mouse islets are more susceptible to ex vivo stimuli of apoptosis. In human pancreatic tissues, EGR1 expression correlated with expression of ER stress markers and anti-apoptotic gene. In conclusion, Egr-1 is induced by PA and further attempts to rescue beta-cells from ER stress and apoptosis through improving insulin/Akt signaling. Our study underscores Egr-1 as a critical early sensor in pancreatic beta-cells to translate fatty acid stimuli into a cellular adaptation mechanism.
    No preview · Article · Mar 2015 · Journal of Molecular Medicine
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    ABSTRACT: WW domain-containing oxidoreductase (WWOX) has been reported to be a tumor suppressor in multiple cancers, including prostate cancer. WWOX can induce apoptotic responses to inhibit tumor progression, and the other mechanisms of WWOX in tumor suppression have also been reported recently. In this study, we found significant down-regulation of WWOX in prostate cancer specimens and prostate cancer cell lines compared with the normal controls. In addition, an ectopically increased WWOX expression repressed tumor progression both in vitro and in vivo. Interestingly, overexpression of WWOX in 22Rv1 cells led to cell cycle arrest in the G1 phase but did not affect sub-G1 in flow cytometry. GFP-WWOX overexpressed 22Rv1 cells were shown to inhibit cell cycle progression into mitosis under nocodazole treatment in flow cytometry, immunoblotting and GFP fluorescence. Further, cyclin D1 but not apoptosis correlated genes were down-regulated by WWOX both in vitro and in vivo. Restoration of cyclin D1 in the WWOX-overexpressed 22Rv1 cells could abolish the WWOX-mediated tumor repression. In addition, WWOX impair c-Jun-mediated cyclin D1 promoter activity. These results suggest that WWOX inhibits prostate cancer progression through negatively regulating cyclin D1 in cell cycle lead to G1 arrest. In summary, our data reveal a novel mechanism of WWOX in tumor suppression.
    Full-text · Article · Feb 2015 · Cell cycle (Georgetown, Tex.)
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    ABSTRACT: Background Pin1 promotes oncogenesis by regulating multiple oncogenic signaling. In this study, we investigated the involvement of Pin1 in tumor progression and in the prognosis of human esophageal squamous cell carcinoma (ESCC).ResultsWe observed that proliferation, clonogenicity and tumorigenesis of CE81T cells were inhibited by Pin1 knockdown. We next analyzed Pin1 expression in clinical ESCC specimens. When compared to the corresponding non-tumor part, Pin1 protein and mRNA levels in tumor part were higher in 84% and 62% patients, respectively. By immunohistochemistry, we identified that high Pin1 expression was associated with higher primary tumor stage (p = 0.035), higher overall cancer stage (p = 0.047) and poor overall survival (p < 0.001). Furthermore, the association between expression of Pin1 and levels of ß-catenin and cyclin D in cell line and clinical specimens was evaluated. ß-catenin and cyclin D1 were decreased in CE81T cells with Pin1 knockdown. Cyclin D1 level correlated with Pin1 expression in clinical ESCC specimens.Conclusions Pin1 upregulation was associated with advanced stage and poor prognosis of ESCC. Pin1 knockdown inhibited aggressiveness of ESCC cells. ß-catenin and cyclin D1 were positively regulated by Pin1. These results indicated that targeting Pin1 pathway could represent a potential modality for treating ESCC.
    Full-text · Article · Aug 2014 · Journal of Biomedical Science
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    ABSTRACT: Rationale: Metabolic alterations contribute to cancer development and progression. However, the molecular mechanisms relating metabolism to cancer metastasis remain largely unknown. Objectives: To identify a key metabolic enzyme that is aberrantly overexpressed in invasive lung cancer cells and to investigate its functional role and prognostic value in lung cancer. Methods: The differential expression of metabolic enzymes in non-invasive CL1-0 cells and invasive CL1-5 cells was analyzed by a gene expression microarray. The expression of target genes in clinical specimens from lung cancer patients was examined by immunohistochemistry. Pharmacological and gene knockdown/overexpression approaches were used to investigate the function of the target gene during invasion and metastasis in vitro and in vivo. The association between the target gene expression and clinicopathological parameters was further analyzed. Bioinformatic analyses were used to discover the signaling pathways involved in target gene-regulated invasion/migration. Measurements and Main Results: Squalene synthase (SQS) was up-regulated in CL1-5 cells and in the tumor regions of the lung cancer specimens. Loss of function or knockdown of SQS significantly inhibited invasion/migration and metastasis in cell and animal models and vice versa. High expression of SQS was significantly associated with poor prognosis among lung cancer patients. Mechanistically, SQS contributed to a lipid-raft-localized enrichment of tumor necrosis factor-α receptor 1 (TNFR1) in a cholesterol-dependent manner, which resulted in the enhancement of NF-κB activation leading to MMP1 up-regulation. Conclusions: Up-regulation of SQS promotes metastasis of lung cancer by enhancing TNFR1 and NF-κB activation and MMP1 expression. Targeting SQS may have considerable potential as a novel therapeutic strategy to treat metastatic lung cancer.
    Full-text · Article · Aug 2014 · American Journal of Respiratory and Critical Care Medicine
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    ABSTRACT: The transcriptional network of the SRY (sex determining region Y)-box 17 (SOX17) and the prognostic impact of SOX17 protein expression in human cancers remain largely unclear. In this study, we evaluated the prognostic effect of low SOX17 protein expression and its dysregulation of transcriptional network in esophageal squamous cell carcinoma (ESCC). Low SOX17 protein expression was found in 47.4% (73 of 154) of ESCC patients with predicted poor prognosis. Re-expression of SOX17 in ESCC cells caused reduced foci formation, cell motility, decreased ESCC xenograft growth and metastasis in animals. Knockdown of SOX17 increased foci formation in ESCC and normal esophageal cells. Notably, 489 significantly differential genes involved in cell growth and motility controls were identified by expression array upon SOX17 overexpression and 47 genes contained putative SRY element in their promoters. Using quantitative chromatin immunoprecipitation-PCR and promoter activity assays, we confirmed that MACC1, MALAT1, NBN, NFAT5, CSNK1A1, FN1 and SERBP1 genes were suppressed by SOX17 via the SRY binding-mediated transcriptional regulation. Overexpression of FN1 and MACC1 abolished SOX17-mediated migration and invasion suppression. The inverse correlation between SOX17 and FN1 protein expression in ESCC clinical samples further strengthened our conclusion that FN1 is a transcriptional repression target gene of SOX17. This study provides compelling clinical evidence that low SOX17 protein expression is a prognostic biomarker and novel cell and animal data of SOX17-mediated suppression of ESCC metastasis. We establish the first transcriptional network and identify new suppressive downstream genes of SOX17 which can be potential therapeutic targets for ESCC.
    Full-text · Article · Aug 2014 · International Journal of Cancer
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    ABSTRACT: We have synthesized certain indeno[1,2-c]quinolin-11-one derivatives for antiproliferative evaluation. Among them, 9-methoxy-6-{4-[(oxiran-2-yl)methyl]piperazin-1-yl}-11H-indeno[1,2-c]quinolin-11-one O-(oxiran-2-yl)methyl oxime (12) exhibited strong antiproliferative activities against the growth of Hela, SKHep, MDA-MB-231, and H1299 cells with IC50 values of 0.54, 0.99, 0.79, and 1.18 μM respectively. Compound 12 was also found to be a potent DNA intercalating agent. Mechanism studies indicated that DNA damage was strongly induced by 12-treated cells even at a low concentration of 5.0 μM. Our results demonstrated that 12 significantly increased Bax expression, activation of caspase-3 and -7, enhanced the cleavage of PARP, and decreased Bcl-2 expression in H1299 cells. Compound 12 also significantly decreased the HDAC6, SIRT1, FOXO3a, p-Akt, and PTEN expression in H1299 cells.
    No preview · Article · Jul 2014 · Medicinal Chemistry Communication
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    ABSTRACT: Background Osteopontin (OPN) is a secreted phosphoprotein expressed by neoplastic cells involved in the malignant potential and aggressive phenotypes of human malignancies, including gastrointestinal stromal tumors (GISTs). Our previous study showed that OPN can promote tumor cell proliferation in GISTs. In this series, we further aim to investigate the effect of OPN on apoptosis in GISTs. Methods The expression of apoptotic and anti-apoptotic proteins in response to OPN was evaluated. In vitro effects of OPN against apoptosis in GIST were also assessed. GIST specimens were also used for analyzing protein expression of specific apoptosis-related molecules and their clinicopathologic significance. Results Up-regulation of β-catenin and anti-apoptotic proteins Mcl-1 with concomitant suppression of apoptotic proteins in response to OPN was noted. A significant anti-apoptotic effect of OPN on imatinib-induced apoptosis was identified. Furthermore, Mcl-1 overexpression was significantly associated with OPN and β-catenin expression in tumor tissues, as well as worse survival clinically. Conclusions Our study identifies anti-apoptotic effects of OPN that, through β-catenin-mediated Mcl-1 up-regulation, significantly antagonized imatinib-induced apoptosis in GISTs. These results provide a potential rationale for therapeutic strategies targeting both OPN and Mcl-1 of the same anti-apoptotic signaling pathway, which may account for resistance to imatinib in GISTs.
    Full-text · Article · Jun 2014 · World Journal of Surgical Oncology
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    ABSTRACT: Upregulation of Pin1 was shown to advance the functioning of several oncogenic pathways. It was recently shown that Pin1 is potentially an excellent prognostic marker and can also serve as a novel therapeutic target for prostate cancer. However, the molecular mechanism of Pin1 overexpression in prostate cancer is still unclear. In the present study, we showed that mRNA expression levels of Pin1 were not correlated with Pin1 protein levels in prostate cell lines which indicated that Pin1 may be regulated at the post-transcriptional level. A key player in post-transcriptional regulation is represented by microRNAs (miRNAs) that negatively regulate expressions of protein-coding genes at the post-transcriptional level. A bioinformatics analysis revealed that miR-296-5p has a conserved binding site in the Pin1 3'-untranslated region (UTR). A luciferase reporter assay demonstrated that the seed region of miR-296-5p directly interacts with the 3'-UTR of Pin1 mRNA. Moreover, miR-296-5p expression was found to be inversely correlated with Pin1 expression in prostate cancer cell lines and prostate cancer tissues. Furthermore, restoration of miR-296-5p or the knockdown of Pin1 had the same effect in inhibition the ability of cell proliferation and anchorage-independent growth of prostate cancer cell lines. Our results support miR-296-5p playing a tumor-suppressive role by targeting Pin1 and implicate potential effects of miR-296-5p in the prognosis of and clinical application to prostate cancer therapy.
    Full-text · Article · Jun 2014 · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
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    ABSTRACT: Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients. Methods: Illumina's GoldenGate methylation array, supervised principal components, Kaplan-Meier survival analyses and Cox regression model were conducted on dissected tumor tissues from a training cohort of 40 ESCC patients to identify potential CpG methylation biomarkers. Pyrosequencing quantitative methylation assay were performed to validate prognostic CpG methylation biomarkers in 61 ESCC patients. The correlation between DNA methylation and RNA expression of a validated marker, SOX17, was examined in a validation cohort of 61 ESCC patients. Results: We identified a panel of nine CpG methylation probes located at promoter or exon1 region of eight genes including DDIT3, FES, FLT3, NTRK3, SEPT5, SEPT9, SOX1, and SOX17, for prognosis prediction in ESCC patients. Risk score calculated using the eight-gene panel statistically predicted poor outcome for patients with high risk score. These eight-gene also showed a significantly higher methylation level in tumor tissues than their corresponding normal samples in all patients analyzed. In addition, we also detected an inverse correlation between CpG hypermethylation and the mRNA expression level of SOX17 gene in ESCC patients, indicating that DNA hypermethylation was responsible for decreased expression of SOX17. Conclusions: This study established a proof-of-concept CpG methylation biomarker panel for ESCC prognosis that can be further validated by multiple cohort studies. Functional characterization of the eight prognostic methylation genes in our biomarker panel could help to dissect the mechanism of ESCC tumorigenesis.
    Full-text · Article · May 2014 · International journal of medical sciences
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    ABSTRACT: Bilateral lesions of nucleus tractus solitarii in rat result in acute hypertension, pulmonary edema, and death within hours. The hypertension results from excessive catecholamine release. Catecholamine can activate connexin43 to regulate cell death. There is no study investigating the cardiopulmonary impacts of different adrenergic blockers and apoptosis mechanism in rat model. The authors microinjected 6-hydroxydopamine into nucleus tractus solitarii of the rat (n = 8 per group) and evaluated the cardiopulmonary changes after treatment with different concentrations of α1-blockers, α2-blockers, β-blockers, and α-agonists. In the rat model, the authors found that prazosin (0.15 mg/kg) treatment could preserve cardiac output and reverse neutrophil infiltrations in lungs and lead to prevent pulmonary hemorrhagic edema. The time-dependent increases in connexin43 and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells induced by 6-hydroxydopamine lesions were decreased after prazosin treatment (terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells at 6 h: 64.01 ± 2.41% vs. 24.47 ± 3.10%; mean ± SD, P < 0.001, in heart, and 80.83 ± 2.52% vs. 2.60 ± 1.03%, P < 0.001, in lung). However, propranolol caused further compromise of the already impaired cardiac output with consequence of rapid death. Phenylephrine enhanced the phenotype in the link between connexin43 expressions and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells but not yohimbine. Connexin43 expressions and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were more decreased with prazosin (0.15 and 0.3 mg/kg) than that with prazosin (0.05 mg/kg) treatment. α1-Receptors are the keystones of the phenotype. In some brainstem encephalitis and brain injury with nucleus tractus solitarii involvement, early α1-receptor blockade treatment may prevent acute death from tissue apoptosis. α-Blockers can also decrease cerebral perfusion pressure, and further studies are needed in translation to brain injury with increased intracranial pressure.
    No preview · Article · Mar 2014 · Anesthesiology
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    ABSTRACT: Oxidative stress is an important pathogenic factor in the development of hypertension. Resveratrol, an important antioxidant in red wine, improves NO bioavailability to prevent cardiovascular disease. The aim of this study was to examine whether resveratrol decreased ROS generation, thereby reducing blood pressure in rats with fructose-induced hypertension. The fructose (fed with 10% fructose) or resveratrol (10 mg/kg/day) treatment for 1 week, then the systolic blood pressure (SBP) of the rats was measured by tail-cuff method. Endogenous in vivo O2 (-) production in the NTS was determined with dihydroethidium (DHE). Real-time PCR and immunoblotting analyses were used to quantify RNA and protein expression levels. ROS levels in the NTS was higher, by contrast, the NO level was significantly decreased in fructose-fed rats. The RNA and protein levels of NADPH oxidase subunits (p67, p22-phox) were elevated and that SOD2 was reduced in fructose-fed rats. In addition, AMPK T172 phosphorylation levels in the NTS were lower in fructose-fed rats, while treatment with an AMPK activator (resveratrol) had the opposite effect in the fructose-fed rats. Interestingly, BP was significantly reduced in fructose-fed rats both by the administration of resveratrol beginning at week 0 and by treatment with resveratrol beginning at week 2; the NO level in the NTS was significantly increased. Collectively, resveratrol decreased BP through the phosphorylation of AMPK, AKT, and nNOS in fructose-fed rats. These novel findings suggest that the resveratrol may be a potential pharmacological candidate for the treatment of hypertension.
    Full-text · Article · Feb 2014 · British Journal of Pharmacology
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    ABSTRACT: Recent clinical studies found that fructose intake leads to insulin resistance and hypertension. Fructose consumption promotes protein fructosylation and formation of superoxide. In a previous study, we revealed that inhibition of superoxide production in the nucleus tractus solitarii (NTS) reduces blood pressure. Caffeine displays significant antioxidant ability in protecting membranes against oxidative damage and can lower the risk of insulin resistance. However, the mechanism through which caffeine improves fructose-induced insulin resistance is unclear. The aim of this study was to investigate whether caffeine consumption can abolish superoxide generation to enhance insulin signaling in the NTS, thereby reducing blood pressure in rats with fructose-induced hypertension. Treatment with caffeine for 4 weeks decreased blood pressure, serum fasting glucose, insulin, homeostatic model assessment-insulin resistance, and triglyceride levels and increased the serum direct high-density lipoprotein level in fructose-fed rats but not in control rats. Caffeine treatment resulted in the recovery of fructose-induced decrease in nitric oxide production in the NTS. Immunoblotting and immunofluorescence analyses further showed that caffeine reduced the fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1(S307)) and reversed Akt(S473) and neuronal nitric oxide synthase phosphorylation. Similarly, caffeine was able to improve insulin sensitivity and decrease insulin levels in the NTS evoked by fructose. Caffeine intake also reduced the production of superoxide and expression of receptor of advanced glycation end product in the NTS. These results suggest that caffeine may enhance insulin receptor substrate 1-phosphatidylinositol 3-kinase-Akt-neuronal nitric oxide synthase signaling to decrease blood pressure by abolishing superoxide production in the NTS.
    Full-text · Article · Dec 2013 · Hypertension
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    ABSTRACT: Heat shock proteins (HSPs), which are members of the chaperone family of proteins, are essential factors for cellular responses to environmental stressors, such as hyperthermia, and are antiapoptotic. The transcription of HSPs is mainly controlled by heat shock transcription factor 1 (HSF1). In response to environmental stress, HSF1 forms a trimer, undergoes hyperphosphorylation, and is translocated to the nucleus. In this study, we show that upon heat shock treatment of cells, a WW domain-containing propyl-isomerase, PIN1, is able to colocalize to and associate with phospho-HSF1 at Ser326 in the nucleus via its WW domain. This interaction is required for the DNA-binding activity of HSF1 and is consistent with the lower induction of HSPs in PIN1-deficient cells. This function of PIN1 is further demonstrated by in vivo refolding and survival assays, which have shown that PIN1-deficient cells are temperature sensitive and develop apoptosis upon exposure to an environmental challenge. Moreover, the reduced levels of HSPs in PIN1-deficient cells resulted in less efficient refolding of denatured proteins. Based on our results, we propose a novel role for PIN1 whereby it acts as a stress sensor regulating HSF1 activity in response to stress on multiple levels through the transcriptional activation of stress response elements in embryonic fibroblast cells, tumor cells, and neurons.
    Preview · Article · Oct 2013 · Molecular and Cellular Biology
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    ABSTRACT: Background and Purpose Clinical studies indicate that statins have a BP-lowering effect in hypercholesterolemic individuals with hypertension. Specifically, statins modulate BP through the up-regulation of endothelial NOS (eNOS) activation in the brain. However, the signalling mechanisms through which statins enhance eNOS activation remain unclear. Therefore, we examined the possible signalling pathways involved in statin-mediated BP regulation in the nucleus tractus solitarii (NTS). Experimental Approach To investigate the involvement of Ras and other signalling pathways in simvastatin-induced effects on BP, BP and renal sympathetic nerve activity (RSNA) were determined in spontaneously hypertensive rats (SHRs) before and after i.c.v. administration of simvastatin in the absence and presence of a Ras-specific inhibitor (farnesyl thiosalicylic acid, FTS), a geranylgeranyltransferase inhibitor (GGTI-2133), a PI3K inhibitor (LY294002) or a MAPK-ERK kinase (MEK) inhibitor (PD98059). Key Results FTS significantly attenuated the decrease in BP and increased NO evoked by simvastatin and reversed the decrease in basal RSNA induced by simvastatin. Immunoblotting and pharmacological studies showed that inhibition of Ras activity by FTS significantly abolished simvastatin-induced phosphorylation of ERK1/2, ribosomal protein S6 kinase (RSK), Akt and decreased eNOS phosphorylation. Likewise, administration of Akt and ERK1/2 signalling inhibitors, LY294002 and PD98059, attenuated the reduction in BP evoked by simvastatin. Furthermore, i.c.v. simvastatin decreased Rac1 activation and the number of ROS-positive cells in the NTS. Conclusions and Implications Simvastatin modulates central BP control in the NTS of SHRs by increasing Ras-mediated activation of the PI3K-Akt and ERK1/2-RSK signalling pathways, which then up-regulates eNOS activation.
    Full-text · Article · Oct 2013 · British Journal of Pharmacology
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    ABSTRACT: [Formula: see text]-6-Hydroxy-9-methoxy-6-(piperazin-1-yl)-11[Formula: see text]-indeno[1,2-[Formula: see text]]quinolin-11-one [Formula: see text]-2-(pyrrolidin-1-yl)ethyl oxime (2c) was identified as a potential dual topo I/II inhibitor in our previous paper. In continuation for the search of more potent compounds, we describe herein the preparation of certain indeno[1,2-[Formula: see text]]quinoline derivatives and evaluation of their antiproliferation, DNA binding affinity, and topoisomerases (topo I and topo II) inhibitory activities. Among them, [Formula: see text]-9-[3-(dimethylamino)propoxy]-11[Formula: see text]-indeno[1,2-[Formula: see text]]quinolin-11-one [Formula: see text]-3-(dimethylamino)propyl oxime (11b) and its analog 11c exhibited approximately equal activity to the lead compound 2c against the growth of HeLa and A549 cancer cells. Both compounds 11b and 11c were more active than 2c in the inhibition of topo I and topo II. However, none of them exhibited significant DNA binding affinity while 2c was a very strong DNA binding agent. Compound 11b exhibited a high oral bioavailability of 39.8 % while the oral bioavailability of 2c and 11c was only 10.9 and 8.6 %, respectively. The in vivo anti-tumor evaluation of 11b in nude mice bearing subcutaneous breast cancer tumors revealed that treatment with low (10 mg/kg) or high (30 mg/kg) doses of 11b dramatically diminished tumor growth. Therefore, compound 11b is identified as a potential non-DNA intercalating dual topo I/II inhibitor.
    No preview · Article · Sep 2013 · Molecular Diversity

Publication Stats

1k Citations
431.48 Total Impact Points

Institutions

  • 2008-2015
    • National Cheng Kung University
      • Institute of Clinical Medicine
      臺南市, Taiwan, Taiwan
    • Sun Yat-Sen University
      Shengcheng, Guangdong, China
    • National Yang Ming University
      • School of Medicine
      T’ai-pei, Taipei, Taiwan
  • 2011
    • National Cheng Kung University Hospital
      • Department of Pediatrics
      臺南市, Taiwan, Taiwan
  • 2009
    • Tamkang University
      • Department of Chemistry
      T’ai-pei, Taipei, Taiwan
  • 2006-2008
    • National Sun Yat-sen University
      • Department of Biological Science
      Kao-hsiung-shih, Kaohsiung, Taiwan
  • 2004-2008
    • VGHKS Kaohsiung Veterans General Hospital
      • • Department of Nephrology
      • • Department of Internal Medicine
      Kao-hsiung-shih, Kaohsiung, Taiwan