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ABSTRACT: The lymph has long been considered as the plasma filtrate and the proteomes of the lymph have received scanty attention. Currently, mesenteric lymph is reported to play an important role in the pathogenesis of multiple organ dysfunction syndrome in some critical illnesses. A better understanding of the composition and proteomes of mesenteric lymph becomes imperative to disclose the mechanistic role of mesenteric lymph. Seven male Sprague-Dawley rats were fasted overnight, and anesthetized to collect plasma and mesenteric lymph. The specimens were subjected to proteomic analysis using twodimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). An average of 434 and 412 protein spots were found in the gels of the plasma and mesenteric lymph respectively. Peptide mass fingerprint analysis identified 77 proteins for 212 protein spots. The 2-DE proteomic pattern of mesenteric lymph was largely similar to that of the plasma. As in the plasma, large protein spots of albumin dominated the protein pattern in mesenteric lymph. Other major proteins identified in 2-DE gels included immunoglobulin heavy and light chains, fibrinogen α-, β- and γ-chains, serotransferrin, protease inhibitors, kininogens, macroglobulins, haptoglobin, and apolipoproteins. Meanwhile, mesenteric lymph contained an array of proteins that differentiated it from the plasma. The most differentially expressed proteins in mesenteric lymph were γ-fibrinogen, protease inhibitors, and proteins related to lipid transport/metabolism. The study presents a detailed description of mesenteric lymph proteomes of a common experimental animal in physiological status using a common proteomic approach. These results provide the basis for future research.
The Chinese journal of physiology 06/2013; 56(3). · 0.56 Impact Factor
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Shao-Jung Lo,
Li-Ching Fan,
Yow-Fu Tsai,
Kuo-Yang Lin,
Hsiao-Ling Huang,
Tong-Hong Wang,
Hsuan Liu,
Tse-Chin Chen,
Shiu-Fen Huang,
Chee-Jen Chang,
Yu-Jr Lin,
Benjamin Yat-Ming Yung, Sen-Yung Hsieh
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ABSTRACT: Death evasion is crucial for both carcinogenesis and resistance to anticancer therapies. Recently we identified nucleophosmin (NPM) as a key factor counteracting death stimuli in human hepatocellular carcinoma (HCC) cells. Here we report the identification of a novel NPM-BCL2-associated X protein (BAX) pathway orchestrating death evasion in human HCC cells. Silencing of NPM expression significantly sensitized HCC cells, particularly those bearing inactivated p53 (Huh7, Hep3B, and Mahlavu), to UV irradiation, mitomycin C, doxorubicin, cisplatin, sorafenib, and lapatinib. This sensitizing effect was not further changed as p53 expression had been simultaneously silenced. Following cell stress, NPM and BAX were induced and exported out of nucleoli and nucleus, respectively. BAX was translocated to cytoplasm in cells with relatively high NPM level, or accumulated in the mitochondria in cells with relatively low NPM level and undergoing apoptosis. Subcellular fractionation revealed that silencing of NPM expression greatly enhanced mitochondrial translocation and oligomerization of BAX in Huh7 and Mahlavu cells. In situ proximity ligation assays and reciprocal co-immunoprecipitation evidenced direct interaction between NPM and BAX in the cytoplasm. Silencing of BAX expression abolished the sensitization effect exerted by silencing of NPM in HCC cells. Clinically, upregulation of NPM was significantly associated with advanced tumor stage and poor prognosis. Conclusion: Via directly blockading BAX mitochondrial translocation and activation, NPM helps human HCC cells evade death induction independently of p53-mediated cell death. Silencing of NPM significantly sensitized HCC cells to anticancer therapies. NPM is a potential co-target in combination with other therapies for HCC particularly harboring inactivated p53. Our findings are of clinical significance, since NPM upregulation and p53 mutations are usually found in advanced human cancers, including HCC. (HEPATOLOGY 2012.).
Hepatology 12/2012; · 11.66 Impact Factor
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ABSTRACT: Unusual hypervascularity is a hallmark of human hepatocellular carcinoma (HCC). Although microRNA-214 (miR-214) is upregulated in other human cancers, it is downregulated in HCC. We elucidated the biological and clinical significance of miR-214 downregulation in HCC.
MicroRNAs deregulated in HCC were identified using array-based microRNA profiling. A luciferase reporter assay confirmed target association between miR-214 and the hepatoma-derived growth factor (HDGF). Tube formation and in vivo angiogenesis assays validated the roles of miR-214/HDGF in angiogenesis.
miR-214 downregulation was associated with higher tumor recurrence and worse clinical outcomes. Ectopic expression of miR-214 suppressed xenograft tumor growth and microvascularity of the tumors and their surrounding tissues. The genes downregulated by ectopic expression of miR-214 were involved in the regulation of apoptosis, cell cycle, and angiogenesis. Integrated analysis disclosed HDGF as a downstream target of miR-214. Conditioned medium of HCC cells contained bioactivity to stimulate tube formation of human umbilical vein endothelial cells, which was abolished by pretreatment of the conditioned media with HDGF antibodies, suppression of HDGF expression or ectopic expression of miR-214 in the donor HCC cells. The angiogenic activity of the conditioned media, lost by ectopic expression of miR-214 in the donor cells, was restored by supplementation with recombinant HDGF. In vivo tumor angiogenesis assays showed significant suppression of tumor vascularity by ectopic expression of miR-214.
A novel role of microRNA in tumorigenesis is identified. Downregulation of miR-214 contributes to the unusual hypervascularity of HCC via activation of the HDGF paracrine pathway for tumor angiogenesis.
Journal of Hepatology 05/2012; 57(3):584-91. · 9.26 Impact Factor
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ABSTRACT: Most hepatocellular carcinoma (HCC) is generated from chronic hepatitis and cirrhosis. To discover new markers for early HCC in patients with chronic hepatitis and cirrhosis, we initiated our search in the interstitial fluid of tumor (TIF) via differential gel electrophoresis and antibody arrays and identified secreted ERBB3 isoforms (sERBB3). The performance of serum sERBB3 in diagnosis of HCC was analyzed using receiver operating characteristic curves (ROC). The serum sERBB3 level was significantly higher in HCC than in cirrhosis (p < 0.001) and chronic hepatitis (p < 0.001). The accuracy of serum sERBB3 in detection of HCC was further validated in two independent sets of patients. In discrimination of early HCC from chronic hepatitis or cirrhosis, serum sERBB3 had a better performance than alpha-fetoprotein (AFP) (areas under ROC [AUC]: sERBB3 vs AFP = 93.1 vs 81.0% from chronic hepatitis and 70.9 vs 62.7% from cirrhosis). Combination of sERBB3 and AFP further improved the accuracy in detection of early HCC from chronic hepatitis (AUC = 97.1%) or cirrhosis (AUC = 77.5%). Higher serum sERBB3 levels were associated with portal-vein invasion and extrahepatic metastasis of HCC (p = 0.017). Therefore, sERBB3 are serum markers for early HCC in patients with chronic hepatitis and cirrhosis.
Journal of Proteome Research 08/2011; 10(10):4715-24. · 5.11 Impact Factor
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Sen-Yung Hsieh,
Jung-Ru He,
Chih-Yun Hsu,
Wan-Ju Chen,
Rabindranath Bera,
Kuo-Yang Lin,
Tsung-Chieh Shih,
Ming-Chin Yu,
Yu-Jr Lin,
Chee-Jen Chang,
Wen-Hui Weng,
Shiu-Fen Huang
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ABSTRACT: Intrahepatic metastasis is the primary cause of the high recurrence and poor prognosis of human hepatocellular carcinoma (HCC). However, neither its molecular mechanisms nor markers for its prediction before hepatectomy have been identified. We recently revealed up-regulation of erythroblastic leukemia viral oncogene homolog 3 (ERBB3) in human HCC. Here we examined the clinical and biological significance of ERBB3 in HCC. Up-regulation of ERBB3 in HCC was strongly associated with male gender (P < 0.001), chronic hepatitis B (P = 0.002), microscopic vascular invasion (P = 0.034), early recurrence (P = 0.003), and worse prognosis (P = 0.004). Phosphorylated ERBB3 and its ligands [neuregulins (NRGs)] were detected in both HCC tissues and cells. Phosphorylation of ERBB3 could be induced by conditioned media of HCC cells and abolished by the pretreatment of conditioned media with anti-NRG antibodies or by the silencing of the endogenous NRG expression of the donor HCC cells. Human epidermal growth factor receptor 2 was required for ERBB3 phosphorylation. The downstream phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene homolog pathways were primarily elicited by NRG1/ERBB3 signaling, whereas the mitogen-activated protein kinase/extracellular signal-regulated kinase pathways were elicited by both epidermal growth factor/epidermal growth factor receptor and NRG1/ERBB3 signaling. The activation and silencing of ERBB3-dependent signaling had potent effects on both the migration and invasion of HCC cells, but neither had significant effects on the proliferation of HCC cells, tumor formation, or tumor growth in vitro and in vivo. CONCLUSION: The constitutive activation of ERBB3-dependent signaling via the NRG1/ERBB3 autocrine loop plays a crucial role in the regulation of cell motility and invasion, which contribute to intrahepatic metastasis and early recurrence of HCC. ERBB3 is a marker for the prediction of intrahepatic metastasis and early recurrence. ERBB3-dependent signaling is a candidate target for the treatment of microscopic vascular invasion and for the prevention of HCC recurrence.
Hepatology 02/2011; 53(2):504-16. · 11.66 Impact Factor
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ABSTRACT: Huntington's disease (HD) is a progressive neurodegenerative disease caused by an unstable CAG trinucleotide repeat expansion. The need for biomarkers of onset and progression in HD is imperative, since currently reliable outcome measures are lacking. We used two-dimensional electrophoresis and mass spectrometry to analyze the proteome profiles in cerebrospinal fluid (CSF) of 6 pairs of HD patients and controls. Prothrombin, apolipoprotein A-IV (Apo A-IV) and haptoglobin were elevated in CSF of the HD patients in comparison with the controls. We used western blot as a semi-quantified measurement for prothrombin and Apo A-IV, as well as enzyme linked immunosorbent assay (ELISA) for measurement of haptoglobin, in 9 HD patients and 9 controls. The albumin quotient (Qalb), a marker of blood-brain barrier (BBB) function, was not different between the HD patients and the controls. The ratios of CSF prothrombin/albumin (prothrombin/Alb) and Apo A-IV/albumin (Apo A-IV/Alb), and haptoglobin level were significantly elevated in HD. The ratio of CSF prothrombin/Alb significantly correlated with the disease severity assessed by Unified Huntington's Disease Rating Scale (UHDRS). The results implicate that increased CSF prothrombin, Apo A-IV, and haptoglobin may be involved in pathogenesis of HD and may serve as potential biomarkers for HD.
PLoS ONE 01/2011; 6(1):e15809. · 4.09 Impact Factor
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ABSTRACT: Frequent intrahepatic metastasis causes early tumor recurrence and dismaying prognosis of human hepatocellular carcinoma (HCC). We recently identified overexpression of stathmin1 (STMN1) in human HCC. This study was designed to elucidate the clinical and biological significance of overexpression of STMN1 in HCC. Expression of STMN1 was conducted by quantitative reverse transcription-polymerase chain reaction and immunoblotting assays on 58 pairs of HCC and para-tumor liver tissues from patients with HCC along with normal liver tissues as the controls. Association of STMN1 overexpression with tumor recurrence and prognosis was investigated by Kaplan-Meier cumulative survival and Cox Regression analyses. Roles of STMN1 in cell cycle, cell motility, and invasion were determined by in vitro assays. STMN1 overexpression in hepatoma was strongly associated with local invasion (P = 0.031), early recurrence (P = 0.002), and poor prognosis (P = 0.005), and was an independent indicator for tumor recurrence (P = 0.0045). STMN1 overexpression further identified subgroups of HCC patients with higher tumor recurrence and worse prognosis among HCC patients with early tumor stage (T1) or intermediate histological grades (G2 and G3), both of whom represent the majority of HCC patients receiving primary curative hepatectomy. Silencing STMN1 expression via RNA interference suppressed invasion activity, while ectopic expression of STMN1 enhanced cell invasion and caused polyploidy of cells. In conclusion, STMN1 overexpression could predict early tumor recurrence and poor prognosis, particularly at early stage of hepatoma. Overexpression of STMN1 promoted polyploidy formation, tumor-cell invasion, and intrahepatic metastasis, suggesting that STMN1 can be a target for anti-cancer therapy of human hepatoma.
Molecular Carcinogenesis 03/2010; 49(5):476-87. · 3.16 Impact Factor
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ABSTRACT: Recent studies have documented the association of mesenteric lymphatic route with adult respiratory distress syndrome and multiple organ failure after hemorrhagic shock. However, the mediators and mechanisms of the toxic effects of mesenteric lymph remain unclear. This study aimed to identify mediators or biomarkers in the mesenteric lymph through comparative proteomic analysis. Fourteen mature male Sprague-Dawley rats were randomly divided and subjected to trauma (laparotomy) plus hemorrhagic shock or trauma plus sham shock. Mesenteric lymph samples were collected before shock and at 3 h after resuscitation from hemorrhagic shock (or sham shock). To investigate changes in proteome profiles between preshock and 3-h postshock (or 3-h post-sham shock) mesenteric lymph samples, two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were performed. We found a more than 2-fold change in abundance of 31 protein spots in the lymph samples. Mass spectrometry analyses identified 12 distinct proteins. Four proteins were consistently upregulated in the 3-h postshock lymph samples, including serum albumin precursor, two isoforms of cytoplasmic actin, complement C3 precursor, and major urinary protein precursor. Two proteins, including haptoglobin and one unidentified protein, were consistently downregulated. The deregulation of these proteins was confirmed by Western blots. Most of these altered proteins are functionally implicated in tissue inflammation. The findings of this study provide a starting point for investigating the functions of these proteins in hemorrhagic shock-induced lung injury and hold great promise for the development of potential therapeutic interventions.
Shock (Augusta, Ga.) 12/2009; 34(3):291-8. · 2.87 Impact Factor
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ABSTRACT: Investigating aberrant DNA methylation in the cancer genome may identify genes that play an important role in tumor progression. In this study, we combined differential methylation hybridization and a CpG microarray platform to characterize methylation profiles and identify novel candidate genes associated with hepatocellular carcinoma (HCC). The genomic DNA of 21 paired adjacent normal and HCC samples was used, and results were analyzed by hierarchical clustering. Twenty-seven hypermethylated candidates and 38 hypomethylated candidates were obtained. Six candidate genes from the hypermethylated group were validated by combined bisulfite restriction analysis; two genes, human kallikrein 10 gene (KLK10) and oxoglutarate (alpha-ketoglutarate) receptor 1 gene (OXGR1), were further analyzed by bisulfite sequencing. The DNA hypermethylation status of KLK10 and OXGR1 were subsequently examined in HCC cell lines and clinical samples using methylation-specific PCR. In 49 HCC samples, 46 (94%) showed that at least one of these two genes was highly methylated. Moreover, KLK10 and OXGR1 mRNA levels were inversely correlated (r = -0.435 and -0.497, P < 0.05) with DNA methylation as examined in paired adjacent normal and tumor samples. Statistical analyses further indicated that KLK10 hypermethylation was significantly associated with cirrhosis (P = 0.042) and HCV infection (P = 0.017) as well as inversely associated with HBV infection (P = 0.023). Furthermore, restoration of KLK10 and OXGR1 expression reduced the ability of anchorage-independent growth, and sensitized HCC cells to doxorubicin- or 5-fluorouracil-induced cytotoxicity. Our results suggest that the hypermethylated KLK10 and OXGR1 are frequent in HCC and may be useful as markers for clinical application.
Genes Chromosomes and Cancer 09/2009; 48(12):1057-68. · 3.31 Impact Factor
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ABSTRACT: Evading apoptosis is pivotal in both of carcinogenesis and resistance to anticancer therapy. We investigated the molecules and pathways of apoptosis evasion in human hepatoma cells by irradiating hepatoma cells with optimized UV (so-called "hormetic responses"). Proteins and pathways related to hormetic responses were identified via proteomic approaches followed by reconstruction of function-networks. Of the 2326 defined protein spots, 42 distinct proteins significantly changed their expression. Eleven hormetic response proteins (HINT1, PHB, CTSD, ANXA1, LGASL1, TPT1, NPM, PRDX2, UCHL1, CERK, and C1QBP) were involved in 5 death-regulatory pathways, including the p53-dependent apoptotic pathway, protein ubiquinization, cellular redox, calcium-mediated signaling pathway, and sphingomyelin-metabolism pathway. Knockdown of HINT1 expression via RNA interference increased tumor cell resistance to apoptosis induction, while silencing NPM, UCHL1, or CERK greatly sensitized tumor cells to apoptosis induction. In conclusion, NPM, UCHL1, and CERK act as apoptosis-evasion proteins that may serve as therapeutic targets for hepatoma. Silencing their expression would increase therapeutic efficacy, thereby reducing the corresponding doses and side-effects of anticancer therapy. This model of induction of cellular hormetic responses to identify apoptosis-evasion molecules/pathways via proteomic approaches can be applied to other modalities of anticancer therapy.
Journal of Proteome Research 07/2009; 8(8):3977-86. · 5.11 Impact Factor
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ABSTRACT: Streptococcus pneumoniae is the primary pathogen causing community acquired pneumonia in children. Despite medical progress, the prevalence of complicated pneumococcal pneumonia became increased without apparent explanations. Two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) were used to compare the plasma protein profiles from children with different severities of pneumococcal pneumonia. Plasma samples from 14 cases, 7 with complicated and the other 7 with uncomplicated pneumonia, were analyzed. Complicated pneumonia was defined by the presence of pleural fluid parameters consistent with empyema, and/or a computed tomography compatible with necrotizing pneumonitis. The normal control group included 7 age-matched volunteers. By comparing the plasma proteins of patients with different severities, 4 proteins with significant differences were identified. The up-regulated proteins were haptoglobin and immunoglobulin kappa chain. The down-regulated were apolipoprotein A-I (Apo-AI) and transthyretin. All these proteins are known to take part in the inflammation reaction, which implicates the active innate immune responses in severe infections of S. pneumoniae. In addition, the up-regulated haptoglobin, which protects lung tissues against oxidative damage by the clearance of hemoglobin, can also act as an inflammatory inhibitor. Thus, our data seem to indicate that inflammation balance may take place in the occurrence of complicated pneumococcal pneumonia.
Scandinavian Journal of Infectious Diseases 05/2009; 41(6-7):416-24. · 1.72 Impact Factor
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Li-Ching Lee,
Chiung-Mei Chen,
Fen-Lin Chen,
Pei-Ying Lin,
Ya-Chin Hsiao,
Pin-Rong Wang,
Ming-Tsan Su,
Hsiu-Mei Hsieh-Li,
Ji-Chuu Hwang,
Chung-Hsin Wu,
Guan-Chiun Lee,
Sher Singh,
Yenshou Lin, Sen-Yung Hsieh,
Guey-Jen Lee-Chen,
Jung-Yaw Lin
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ABSTRACT: Expansion of the CAG repeat of the TATA-box binding protein (TBP) gene has been identified as the causative mutations in spinocerebellar ataxia 17 (SCA17). TBP is ubiquitously expressed in both central nervous system and peripheral tissues. The underlying molecular changes of SCA17 are rarely explored.
To study the molecular mechanisms underlying SCA17, we generated stably induced isogenic 293 cells expressing normal TBP-Q(36) and expanded TBP-Q(61) and analyzed the expressed proteins using two-dimensional difference in gel electrophoresis (2D-DIGE), followed by mass spectrometry and immunoblotting.
Upon induction with doxycycline, the expanded TBP-Q(61) formed aggregates with significant increase in the cell population at subG1 phase and cleaved caspase-3. Proteomics study identified a total of 16 proteins with expression changes greater than 1.5 fold. Among the 16 proteins, PARK7, GLRX3, HNRNPA1, GINS1, ENO1, HNRPK and NPM1 are increased, and SERPINA5, HSPA5, VCL, KHSRP, HSPA8, HNRPH1, IMMT, VCP and HNRNPL are decreased in cells expressing TBP-Q(61) compared with those expressing TBP-Q(36). The altered expression of HSPA5, HSPA8 and PARK7 were further validated by 2D and Western immunoblot analyses.
The results illustrate the utility of proteomics to identify alterations of proteins which underlie pathogenesis of SCA17, and may serve as potential therapeutic targets.
Clinica chimica acta; international journal of clinical chemistry 11/2008; 400(1-2):56-62. · 2.54 Impact Factor
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ABSTRACT: In children, pleural empyema is a recognized complication of severe pneumonia and is characterized by loculated effusions with fibrin septations. The aim of this study was to evaluate the relationship between proinflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6], intrapleural fibrinolytic system enzymes [tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1)], and common biochemical indices during pleural infection.
Children with pneumonia complicated by para-pneumonic effusions were enrolled into our study and underwent real-time chest sonography. The patients were divided into 3 groups by ultrasound using a recognized staging system of pleural effusions. Staging of progressive pleural infection was used to correlate with the characteristics of pleural effusions. The correlation of various pleural variables with the formation of complicated para-pneumonic effusions (CPE) was performed and pleural variables for predicting subsequent intervention procedures were also analyzed.
A total of 57 patients were enrolled in the present study. Univariate analysis revealed that the amounts of biochemical indices (pH, glucose, lactate dehydrogenase), proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), and fibrinolytic system enzymes (tPA, PAI-1) were significantly different with the progressive stages of para-pneumonic effusions (Ptrend < 0.05). For all proinflammatory cytokines, a positive correlation was found with lactate dehydrogenase and PAI-1, whereas a negative correlation was found with pH, glucose, and tPA. Moreover, these cytokines were also significantly correlated with PAI-1 in both non-CPE and CPE. The pleural fluid findings of IL-1beta (> or =50 pg/mL), PAI-1 (> or =1252 ng/mL), and pH (< or =7.30) were the most significant predictive factors for subsequent intervention procedures (P < 0.001).
The increased release of proinflammatory cytokines in pleural fluid caused by bacteria may result in an imbalance of the fibrinolytic system, which can subsequently lead to fibrin deposition and intervention procedures.
The Pediatric Infectious Disease Journal 09/2008; 27(8):699-703. · 3.58 Impact Factor
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ABSTRACT: Deregulation of cell cycle leads to cell transformation and cancer development. Here we present profiling the proteome dynamics using 2-DE and constructing the associated functional networks during the cell cycle of human hepatoma cells, Mahlavu. The protein dynamics was validated by hierarchical clustering analysis on the proteome, and by Northern blot assays on the selected 14-3-3 proteins. Of the 2665 protein spots, 201 with variation coefficient of expression dynamics >20% throughout the cell cycle were subjected to analysis. Degree of the global protein dynamics was phase dependent with the greatest in transitional phases of S/G2, G2/M, and G1/S. Concurrence of pathways coordinating cell-cycle progression versus arrest, and/or pathways regulating apoptosis versus antiapoptosis was always identified during the cell cycle, suggesting the existence of counteracting mechanisms for intracellular homeostasis. Data mining of the results suggested that the key transcription factors in G0/G1, G1/S, S, and G2/M were p53 and SP1, c-Myc, c-Myc and p53, and YY1 and c-Jun, respectively. Our findings for the first time provide insights into the regulation of mammalian cell-cycle progression at the proteome level, and grant a model to study disease mechanisms and to discover therapeutic targets for anticancer therapy.
Proteomics 07/2008; 8(14):2872-84. · 4.43 Impact Factor
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ABSTRACT: Gallbladder (GB) polyps are tumor or tumor-like projections arising from GB mucosa. Although most polyps are benign, some early GB carcinomas present as polypoid lesions. The diagnosis of GB polyps is relatively easy by ultrasonography. Although numerous studies have investigated GB polyps, few studies have addressed the prevalence of and factors associated with GB polyps for specific ethnic populations. This study analyzes the prevalence and factors associated with GB polyps in a Chinese population who can afford a paid general checkup.
The prevalence of and risk factors for GB polyps diagnosed by ultrasonography were retrospectively investigated in 34 669 Chinese patients who underwent a general checkup at Chang Gung Memorial Hospital (Taipei, Taiwan) between 2000 and 2003. Demographic, hemogram, serum biochemistry, hepatitis B surface antigen, hepatitis C antibody, and ultrasonography study data was available for all the patients. The correlations between the prevalence of GB polyps and age, sex, body height, body weight, body mass index, hemogram, serum biochemistry, and viral markers were examined for all the patients.
Excluding the patients who underwent cholecystectomy, the overall prevalence of GB polyps was 9.5% and highest for middle-aged males. The analyzed risk factors with increased odds ratios (OR) for the development of GB polyps were male sex (OR 0.646, P < 0.0005) and hepatitis B virus surface antigen positivity (OR 1.113, P < 0.0005). Other demographic characteristics and biochemical parameters, including body height, body weight, body mass index, lipid profile, chronic hepatitis C virus infection, and liver function did not correlate with the presence of GB polyps.
The prevalence of GB polyps among the Chinese in this study is higher than that reported for other populations. Chinese males and other patients with chronic hepatitis B viral infections have a high risk for developing GB polyps.
Journal of Gastroenterology and Hepatology 06/2008; 23(6):965-9. · 2.87 Impact Factor
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ABSTRACT: To investigate the role of nuclear factor of activated T cell 2 (NFAT2), the major NFAT protein in peripheral T cells, in sustained T cell activation and intractable inflammation in human ulcerative colitis (UC).
We used two-dimensional gel-electrophoresis, immunohistochemistry, double immunohistochemical staining, and confocal microscopy to inspect the expression of NFAT2 in 107, 15, 48 and 5 cases of UC, Crohn's disease (CD), non-specific colitis, and 5 healthy individuals, respectively.
Up-regulation with profound nucleo-translocation/activation of NFAT2 of lamina propria mononuclear cells (LPMC) of colonic mucosa was found specifically in the affected colonic mucosa from patients with UC, as compared to CD or NC (P < 0.001, Kruskal-Wallis test). Nucleo-translocation/activation of NFAT2 primarily occurred in CD8+T, but was less prominent in CD4+ T cells or CD20+B cells. It was strongly associated with the disease activity, including endoscopic stage (tau = 0.2145, P = 0.0281) and histologic grade (tau = 0.4167, P < 0.001).
We disclose for the first time the nucleo-translocation/activation of NFAT2 in lamina propria mononuclear cells in ulcerative colitis. Activation of NFAT2 was specific for ulcerative colitis and highly associated with disease activity. Since activation of NFAT2 is implicated in an auto-regulatory positive feedback loop of sustained T-cell activation and NFAT proteins play key roles in the calcium/calcineurin signaling pathways, our results not only provide new insights into the mechanism for sustained intractable inflammation, but also suggest the calcium-calcineurin/NFAT pathway as a new therapeutic target for ulcerative colitis.
World Journal of Gastroenterology 03/2008; 14(11):1759-67. · 2.47 Impact Factor
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ABSTRACT: Accurate and rapid identification of pathogenic microorganisms is of critical importance in disease treatment and public health. Conventional work flows are time-consuming, and procedures are multifaceted. MS can be an alternative but is limited by low efficiency for amino acid sequencing as well as low reproducibility for spectrum fingerprinting. We systematically analyzed the feasibility of applying MS for rapid and accurate bacterial identification. Directly applying bacterial colonies without further protein extraction to MALDI-TOF MS analysis revealed rich peak contents and high reproducibility. The MS spectra derived from 57 isolates comprising six human pathogenic bacterial species were analyzed using both unsupervised hierarchical clustering and supervised model construction via the Genetic Algorithm. Hierarchical clustering analysis categorized the spectra into six groups precisely corresponding to the six bacterial species. Precise classification was also maintained in an independently prepared set of bacteria even when the numbers of m/z values were reduced to six. In parallel, classification models were constructed via Genetic Algorithm analysis. A model containing 18 m/z values accurately classified independently prepared bacteria and identified those species originally not used for model construction. Moreover bacteria fewer than 10(4) cells and different species in bacterial mixtures were identified using the classification model approach. In conclusion, the application of MALDI-TOF MS in combination with a suitable model construction provides a highly accurate method for bacterial classification and identification. The approach can identify bacteria with low abundance even in mixed flora, suggesting that a rapid and accurate bacterial identification using MS techniques even before culture can be attained in the near future.
Molecular & Cellular Proteomics 03/2008; 7(2):448-56. · 7.40 Impact Factor
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Kuo-Hsuan Chang,
Rong-Kuo Lyu,
Mu-Yun Tseng,
Long-Sun Ro,
Yih-Ru Wu,
Hong-Shiu Chang,
Wen-Chuin Hsu,
Hung-Chou Kuo,
Chin-Chang Huang,
Chun-Che Chu, Sen-Yung Hsieh,
Chiung-Mei Chen
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ABSTRACT: Guillain-Barré Syndrome (GBS) is a rare autoimmune inflammatory polyneuropathy with a high risk of respiratory failure and unclear pathogenesis. Currently, there are no valid biomarkers for diagnosis of GBS. We used 2-DE and MS to analyze the protein profiles of five pairs of cerebrospinal fluid (CSF) samples of the GBS patients and the patient controls. Three proteins (orosomucoid, haptoglobin and apolipoprotein A-IV) were up-regulated, and two proteins (prostaglandin D2 synthase and transthyretin) were down-regulated in the CSF of the GBS patients. The CSF haptoglobin level, quantified by enzyme-linked immunosorbent assay, was significantly higher in the GBS patients (12.44 ± 2.70 μg/mL) compared to the chronic inflammatory demyelinating polyradiculoneuropathy (2.82 ± 0.83 μg/mL), viral meningitis (3.57 ± 0.97 μg/mL) and control patients (1.44 ± 0.35 μg/mL, p<0.05). This study indicated that protein profile analysis using a combination of 2-DE and MS provides an effective strategy for elucidating the pathogenesis and identifying potential CSF biomarkers for GBS. The raised intrathecal synthesis of haptoglobin specifically only in GBS patients, but not in patients with other neurological diseases examined, provides evidence of central nervous system involvement in GBS, and may be used as a potential diagnostic marker for GBS.
Proteomics. Clinical applications 05/2007; 1(5):467-75. · 1.97 Impact Factor
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ABSTRACT: Ulcerative colitis (UC) is a chronic inflammatory disorder primarily affecting the colon mucosa. Its etiology and pathogenesis remain unclear. We used 2-DE and MS to identify differentially expressed proteins among the UC active, UC inactive, nonspecific colitis, and normal colon mucosa. Thirteen down-regulated and six up-regulated proteins were identified. Of the down-expressed proteins, eight (heat-shock protein 90 (HSPA9B), heat-shock protein 60 (HSPD1), H+-transporting two-sector ATPase (ATP5B), prohibitin (PHB), mitochondrial malate dehydrogenase (MDH2), voltage-dependent anion-selective channel protein 1 (VDAC1), thioredoxin peroxidase (PRDX1), and thiol-specific antioxidant (PRDX2)) were mitochondrial proteins, three (ATP5B, MDH2, triosephosphate isomerase) were involved in energy generation, three (PRDX1, PRDX2, SELENBP1) were cellular antioxidants, and six (HSPD1, HSPA9B, PRDX1, PRDX2, PHB, VDAC1) were stress-response proteins. Transmission electron microscopy revealed pathological alterations of mitochondrial ultrastructures even before the global colonocyte changes in the UC colon mucosa. PHB, an essential mitochondrial component protein, was down-expressed in the disease active as well as inactive colon mucosa from the patients of UC, indicative of an early event of mitochondrial changes during UC development. In contrast, aberrant activation of NFAT and ectopic expression of potential immunogenic proteins (tumor rejection antigen 1 and poliovirus receptor related protein 1) were found in the UC-diseased colon mucosa. Our findings suggest the implications of colonocyte mitochondrial dysfunction and perturbed mucosa immune regulation in the pathogenesis of UC and provide potential targets for the development of a new therapy.
PROTEOMICS 11/2006; 6(19):5322-31. · 4.51 Impact Factor
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ABSTRACT: Blood is an ideal source for biomarker discovery. However, little has been done to address the effects of sampling, handling and storage procedures on serum/plasma proteomes. We used magnetic bead-based MALDI-TOF MS to systematically evaluate the influence of each procedure on low-molecular-weight serum/plasma proteome profiling on the basis of the whole spectra. We found that sampling procedures, including the selection of blood collection tubes and anticoagulants, variations in clotting time or time lag before centrifugation, and hemolysis, displayed significant effects on the proteomes. Moreover, serum and plasma were mutually incompatible for proteome comparison. By contrast, overnight fasting, handling procedures, including centrifugation speeds (1500 x g vs. 3000 x g) or time (15 min vs. 30 min), and storage conditions, such as at 4 degrees C or 25 degrees C for up to 24 h or at -80 degrees C for up to 3 months, and repeated freeze/thaw of up to ten cycles, had relatively minor effects on the proteomes based upon our analysis of about 100 peaks. We concluded that low-molecular-weight serum/plasma proteomes were diversely affected by sampling, handling and storage with most change from variations of sampling procedures. We therefore suggest the necessity of standardizing sampling procedure for proteome comparison and biomarker discovery.
PROTEOMICS 06/2006; 6(10):3189-98. · 4.51 Impact Factor
