Increased Incidence of Colorectal Malignancies in Renal Transplant Recipients: A Case Control Study : Colorectal Neoplasia in Renal Transplant Recipients

Park, J. M.,Choi, M.-G.,Kim, S. W.,Chung, I.-S.,Yang, C. W.,Kim, Y. S.,Jung, C. K.,Lee, K. Y.,Kang, J.-H. Wiley (Blackwell Publishing) 2010 American journal of transplantation Vol.10 No.9

<P>This study was to evaluate the frequency of colorectal neoplasia in renal transplant recipients and to investigate the association with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection. We compared the frequency of colorectal neoplasia among renal transplant recipients with that of the healthy subjects. Specimens of colorectal neoplasia were examined for EBV and CMV using in situ hybridization and immunohistochemistry, respectively. Of 796 renal transplantation cohorts, 315 were enrolled. The frequency of colorectal neoplasia among the patients was 22.9%. Compared with the healthy subjects, the odds ratio (OR) for advanced adenoma was 3.32 (95% CI, 1.81-6.10). The frequency of cancer among the patients was 1.9% (OR, 12.0; 95% CI, 1.45-99.7). A long interval between transplantation and colonoscopy was a significant factor in the development of advanced colorectal neoplasia. EBV positivity was detected in 30.6% of colorectal neoplasia specimens from renal transplant recipients, which was higher than that for the controls (p = 0.002). CMV was not detected in any lesions of patients or controls. In conclusion, renal transplant recipients have a significantly increased risk of advanced colorectal neoplasia. EBV was more frequently found in specimens of advanced colorectal neoplasm obtained from the renal transplant recipients.</P>

Protective Effect of Lycopene on Oxidative Stress-Induced Cell Death of Pancreatic Acinar Cells

Seo, Jeong Yeon,Masamune, Atsushi,Shimosegawa, Tooru,Kim, Hyeyoung Wiley (Blackwell Publishing) 2009 Annals of the New York Academy of Sciences Vol.1171 No.1

<P>Previously we showed that the underlying mechanism of oxidative stress-induced apoptosis is nuclear loss of DNA repair protein Ku70 and Ku80, which are involved in the DNA repair process of double-strand breaks. Lycopene acts as an antioxidant and a singlet oxygen quencher. In the present study, we aim to investigate whether lycopene protects oxidative stress-induced cell death of pancreatic acinar AR42J cells by preventing the loss of Ku70 in the nucleus. The cells received oxidative stress caused by glucose oxidase acting on beta-D-glucose (glucose/glucose oxidase) and were cultured in the absence or presence of various concentrations of lycopene. Viable cell numbers, the levels of H(2)O(2) in the medium, level of Ku70 protein, and Ku-DNA-binding activity were determined. As a result, glucose/glucose oxidase induced the decrease in cell viability, increase in H(2)O(2) production, decrease in Ku70 levels in whole-cell extracts and nuclear extracts, and decrease in Ku-DNA-binding activity of AR42J cells. Lycopene inhibited glucose/glucose oxidase-induced cell death by preventing nuclear loss of Ku70 and a decrease in Ku-DNA-binding activity of AR42J cells. In conclusion, lycopene may be beneficial for the treatment of oxidative stress-induced cell death by preventing loss of DNA repair protein Ku70.</P>

Inhibitory Mechanism of Omega-3 Fatty Acids in Pancreatic Inflammation and Apoptosis

Park, Kyung Suk,Lim, Joo Weon,Kim, Hyeyoung Wiley (Blackwell Publishing) 2009 Annals of the New York Academy of Sciences Vol.1171 No.1

<P>Oxidative stress is regarded as a major pathogenic factor in acute pancreatitis. Inflammation and apoptosis linked to oxidative stress has been implicated in cerulein-induced pancreatitis as an experimental model of acute pancreatitis. Recently, we found that reactive oxygen species mediate inflammatory cytokine expression and apoptosis of pancreatic acinar cells stimulated with cerulein. Omega-3 fatty acids show antioxidant action in various cells and tissues. In the present study, we investigated whether omega-3 fatty acids inhibit cytokine expression in cerulein-stimulated pancreatic acinar cells and whether omega-3 fatty acids suppress apoptotic cell death in pancreatic acinar cells exposed to hydrogen peroxide. We found that omega-3 fatty acids, such as docosahexaenoic acid (DHA) and alpha-linolenic acid (ALA), suppressed the expression of inflammatory cytokines (IL-1beta, IL-6) and inhibited the activation of transcription factor activator protein-1 in cerulein-stimulated pancreatic acinar cells. DHA and ALA inhibited DNA fragmentation, inhibited the decrease in cell viability, and inhibited the expression of apoptotic genes (p53, Bax, apoptosis-inducing factor) induced by hydrogen peroxide in pancreatic acinar cells. In conclusion, omega-3 fatty acids may be beneficial for preventing oxidative stress-induced pancreatic inflammation and apoptosis by inhibiting inflammatory cytokine and apoptotic gene expression of pancreatic acinar cells.</P>

Organization, Integration, and Assembly of Genetic and Epigenetic Regulatory Machinery in Nuclear Microenvironments : Implications for Biological Control in Cancer

Stein, Gary S.,Zaidi, Sayyed K.,Stein, Janet L.,Lian, Jane B.,Van Wijnen, Andre J.,Montecino, Martin,Young, Daniel W.,Javed, Amjad,Pratap, Jitesh,Choi, Je-Yong,Ali, Syed A.,Pande, Sandhya,Hassan, Moha Wiley (Blackwell Publishing) 2009 Annals of the New York Academy of Sciences Vol.1155 No.1

<P>There is growing awareness that the fidelity of gene expression necessitates coordination of transcription factor metabolism and organization of genes and regulatory proteins within the three-dimensional context of nuclear architecture. The regulatory machinery that governs genetic and epigenetic control of gene expression is compartmentalized in nuclear microenvironments. Temporal and spatial parameters of regulatory complex organization and assembly are functionally linked to biological control and are compromised with the onset and progression of tumorigenesis. High throughput imaging of cells, tissues, and tumors, including live cell analysis, is expanding research's capabilities toward translating components of nuclear organization into novel strategies for cancer diagnosis and therapy.</P>

Effects of Omega-3 Fatty Acids on Apoptosis of Human Gastric Epithelial Cells Exposed to Silica-Immobilized Glucose Oxidase

Yu, Ji Hoon,Kang, Sin-Gun,Jung, Un-Young,Jun, Chul-Ho,Kim, Hyeyoung Wiley (Blackwell Publishing) 2009 Annals of the New York Academy of Sciences Vol.1171 No.1

<P>Oxidative stress plays a critical role in apoptosis of gastric epithelial cells. Omega-3 fatty acids show anti-inflammatory and/or anticancer effects and regulate apoptosis in various cells. In this study, we aimed to investigate whether omega-3 fatty acids inhibit oxidative stress-induced apoptosis of gastric epithelial cells. The cells received oxidative stress caused by silica-immobilized glucose oxidase acting on beta-D-glucose and cultured in the absence or presence of alpha-linolenic acid or docosahexanoic acid. Viable cell numbers, levels of H(2)O(2) in the medium, DNA fragmentation, and protein levels of p53 and Bax were determined. As a result, silica-immobilized glucose oxidase acting on beta-D-glucose consistently and reproducibly produced H(2)O(2), which decreased cell viability and increased DNA fragmentation of the cells. Omega-3 fatty acids inhibited oxidative stress-induced cell death, DNA fragmentation, and induction of p53 and Bax of the cells. The silica-immobilized glucose oxidase could be a useful tool for studies on oxidative stress-induced cellular events because it is reusable and forms a stable enzyme system acting on glucose. Omega-3 fatty acids may be beneficial for preventing oxidative stress-induced apoptosis by inhibiting apoptotic gene expression and DNA fragmentation of gastric epithelial cells.</P>

15-Deoxy-Δ12,14-prostaglandin J2 Induces Upregulation of Multidrug Resistance-Associated Protein 1 via Nrf2 Activation in Human Breast Cancer Cells

Song, Na-Young,Kim, Do-Hee,Kim, Eun-Hee,Na, Hye-Kyung,Surh, Young-Joon Wiley (Blackwell Publishing) 2009 Annals of the New York Academy of Sciences Vol.1171 No.1

<P>15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a representative J-series cyclopentenone prostaglandin, exerts cytoprotective effects that are mainly mediated by Nrf2. Nrf2 is a major transcription factor involved in the transactivation of genes encoding many phase 2 detoxifying and antioxidant enzymes via interaction with the antioxidant response element (ARE). Recently it has been reported that expression of phase 3 efflux transporters, such as multidrug resistance-associated proteins (MRPs), is also regulated by Nrf2. It is well known that cancer cells overexpressing MRPs are more resistant to anticancer drugs. In the present study we have found that 15d-PGJ(2) induces the expression of MRP1, one of the phase 3 efflux transporters, in human breast cancer cells (MCF-7). In addition, treatment of MCF-7 cells with 15d-PGJ(2) resulted in nuclear translocation and DNA binding of Nrf2. In contrast to 15d-PGJ(2), 9,10-dihydro-15d-PGJ(2), an analogue of 15d-PGJ(2) that lacks an electrophilic cyclopentenone ring moiety, failed to induce not only Nrf2 activation but also MRP1 upregulation in MCF-7 cells. 15d-PGJ(2)-induced MRP1 overexpression was abrogated by Nrf2 gene knockdown, using RNA interference. These results, taken together, suggest that 15d-PGJ(2) induces MRP1 upregulation via Nrf2-ARE signaling.</P>

Head-Shaking Nystagmus in Central Vestibulopathies

Choi, Kwang-Dong,Kim, Ji Soo Wiley (Blackwell Publishing) 2009 Annals of the New York Academy of Sciences Vol.1164 No.1

<P>Mechanisms of head-shaking nystagmus (HSN) require further exploration in central vestibular disorders. To determine whether impaired uvulonodular inhibition over the velocity storage of the vestibulo-ocular reflex (VOR) is the mechanism of ipsilesional HSN in lateral medullary infarction (LMI), 17 patients with ipsilesional HSN and LMI underwent measurements of the VOR gains during low-frequency sinusoidal harmonic accelerations, and the time constants (TC) of the VOR and tilt suppression of the post-otatory nystagmus during step-velocity rotation. Compared with normal controls, the patients showed increased VOR gains without difference between ipsi- and contralesional rotations, while the VOR TCs were decreased without directional asymmetry during step-velocity rotation. In contrast, the patients showed impaired tilt suppression of the postrotatory nystagmus, and the impairment of tilt suppression was more severe after contralesional than ipsilesional rotation. The asymmetric tilt suppression may generate ipsilesional HSN by increasing contralesional velocity storage during head shaking, and may be ascribed to disruption of ipsilesional nodulo-uvular inhibition of the velocity storage mechanism.</P>

Profiling Cancer Stem Cells in Androgen-Responsive and Refractory Human Prostate Tumor Cell Lines

Cocciadiferro, Letizia,Miceli, Vitale,Kang, Kyung-Sun,Polito, Lucia M.,Trosko, James E.,Carruba, Giuseppe Wiley (Blackwell Publishing) 2009 Annals of the New York Academy of Sciences Vol.1155 No.1

<P>In this study, we investigated androgen metabolism in two different human prostate cancer cell lines, the androgen-responsive LNCaP cells and the nonresponsive PC3 cells. Following 24-h and 72-h incubation with either testosterone (T) or androstenedione (Ad) used as precursor, divergent patterns and rates of androgen metabolism were observed. Given the recent interest in the multiple uses of embryonic and adult stem cells for basic and applied research, we compared the expression of three presumptive stem cell markers (Oct-4, SUZ-12, and Cripto-1), along with connexin 43 (Cx43), Cx32, and androgen receptor (AR), used as cell differentiation gene markers. In anchorage-independent cell growth conditions, the expression levels of candidate markers of cancer stem cells initially increased (days 2-4) but drastically fell thereafter (day 6) in both cell lines. Results of immunocytochemical assay (ICA) largely confirmed those obtained by RT-PCR. Interestingly, both symmetrical and asymmetrical cell divisions were revealed in PC3 cells using Oct-4 immunostaining. Our data suggest that both androgen-responsive and androgen-nonresponsive prostate tumor cell lines contain a presumptive cancer stem cell population that can be identified using a panel of selected gene markers, including Oct-4, SUZ-12, and Cripto-1.</P>

Gallic Acid Induces Neuronal Cell Death through Activation of c-Jun N-Terminal Kinase and Downregulation of Bcl-2

Kang, Min Kyung,Kang, Nam Joo,Jang, Young Jin,Lee, Ki Won,Lee, Hyong Joo Wiley (Blackwell Publishing) 2009 Annals of the New York Academy of Sciences Vol.1171 No.1

<P>Oxidative stress induced by reactive oxygen species (ROS) is strongly associated with the pathogenesis of various neurodegenerative disorders, including Alzheimer's disease. We investigated the possible combined effects of gallic acid and resveratrol, which are major antioxidants present in fruit, including grapes, on PC12 rat pheochromocytoma (PC12) cell death. Gallic acid did not protect against H(2)O(2)-induced PC12 cell death; it reduced the viability of PC12 cells in a dose-dependent manner. Gallic acid also induced cleavage of poly (ADP-ribose) polymerase, which is strongly related to apoptosis in neurons. Gallic acid induced the phosphorylation of c-Jun N-terminal protein kinase (JNK) and the downregulation of Bcl-2 in PC12 cells. Treatment of PC12 cells with resveratrol increased their viability in a dose-dependent manner by blocking the activation of JNK and the downregulation of Bcl-2. Furthermore, gallic acid led to a progressive reduction in the viability of vector-transfected PC12 cells, which was delayed in PC12 cells that overexpressed Bcl-2. The JNK inhibitor SP600125 protected against gallic acid-induced PC12 cell death. Collectively, these findings suggest that the combined effects of dietary phenolic phytochemicals on oxidative neuronal cell death and antioxidants differ in ROS-mediated neuronal cell death.</P>

Green Tea Catechin Controls Apoptosis in Colon Cancer Cells by Attenuation of H2O2-Stimulated COX-2 Expression via the AMPK Signaling Pathway at Low-Dose H2O2

Park, In-Ja,Lee, Yun-Kyoung,Hwang, Jin-Taek,Kwon, Dae-Young,Ha, Joohun,Park, Ock Jin Wiley (Blackwell Publishing) 2009 Annals of the New York Academy of Sciences Vol.1171 No.1

<P>This study investigated the apoptotic regulation by green tea catechin epigallcatechin-3-gallate (EGCG) on colon cancer cells in the presence of low-dose H(2)O(2) known to exert the activation of signal pathways leading to cell proliferation. In the presence of low-dose H(2)O(2), EGCG induced apoptosis and abolished the cell-proliferative effect exhibited by low-dose H(2)O(2). This reduction of growth was accompanied by an activation of AMP-activated kinase (AMPK), a decrease in cyclooxygenase-2 (COX-2) expression and prostaglandin E(2) (PGE(2)) levels, and the induction of apoptotic markers such as p53 and poly(ADP-ribose) polymerase (PARP) cleavage. The low-dose H(2)O(2) stimulated COX-2 expression, and treating cells with synthetic AMPK activator AICAR (5-aminoimiazole-4-carboxamide-1-beta-d-ribofuranoside) resulted in greater suppression of COX-2 expression and PGE(2). By treating cells with high concentrations of the reactive oxygen species (ROS) scavenger NAC (N-acetyl-1-cysteine), the apoptotic effect of EGCG was abolished and led to suppression of AMPK and COX-2, indicating that the liberation of excessive ROS might be the upstream signal of the AMPK-COX-2 signaling pathway even in the presence of low-dose H(2)O(2).</P>