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Increased Apoptosis (increased + apoptosi)
Selected AbstractsDevelopmental toxicity of indium: Embryotoxicity and teratogenicity in experimental animalsCONGENITAL ANOMALIES, Issue 4 2008Mikio Nakajima ABSTRACT Indium, a precious metal classified in group 13 (IIIB) in the periodic table, has been used increasingly in the semiconductor industry. Because indium is a rare metal, technology for indium recycling from transparent conducting films for liquid crystal displays is desired, and its safety evaluation is becoming increasingly necessary. The developmental toxicity of indium in experimental animals was summarized. The intravenous or oral administration of indium to pregnant animals causes growth inhibition and the death of embryos in hamsters, rats, and mice. The intravenous administration of indium to pregnant animals causes embryonic or fetal malformation, mainly involving digit and tail deformities, in hamsters and rats. The oral administration of indium also induces fetal malformation in rats and rabbits, but requires higher doses. No teratogenicity has been observed in mice. Caudal hypoplasia, probably due to excessive cell loss by increased apoptosis in the tailbud, in the early postimplantation stage was considered to account for indium-induced tail malformation as a possible pathogenetic mechanism. Findings from in vitro experiments indicated that the embryotoxicity of indium could have direct effects on the conceptuses. Toxicokinetic studies showed that the embryonic exposure concentration was more critical than the exposure time regarding the embryotoxicity of indium. It is considered from these findings that the risk of the developmental toxicity of indium in humans is low, unless an accidentally high level of exposure or unknown toxic interaction occurs because of possible human exposure routes and levels (i.e. oral, very low-level exposure). [source] Treadmill exercise in mice increases intestinal lymphocyte loss via apoptosisACTA PHYSIOLOGICA, Issue 3 2003L. Hoffman-Goetz Abstract Strenuous exercise is associated with a transient decline in circulating lymphocytes, possibly through increased apoptosis. Intestinal lymphocytes are important effector cells of intestinal immune function but have not been studied in relation to exercise. Aim:, The purpose of the present study was to examine the effect of exercise on intestinal lymphocyte phenotypes and apoptosis. Methods:, Female C57BL/6 mice (n = 112) were randomized to: (1) treadmill running (90 min, 32 m min,1, 8° grade) and killed immediately after exercise, (2) treadmill running and killed 2 h after exercise, (3) treadmill running and killed 24 h after exercise or (4) a non-exercised control condition with exposure to treadmill noise and vibration without running. Results:, Flow cytometry indicated that the total intestinal CD3+T (P < 0.01), CD4+T (P < 0.005), CD8+T (P < 0.05), pan-NK (P < 0.005) and CD19+B (P < 0.05) lymphocytes were significantly lower 24 h after exercise compared with non-exercised controls. Significantly more CD3+T (P < 0.05) and CD8+T (P < 0.05) intestinal lymphocytes stained positive for annexin V, a marker of apoptosis, at 24 h after exercise compared with intestinal lymphocytes from non-exercised controls. Plasma corticosterone and 8-isoprostane concentrations were also significantly higher immediately after exercise compared with other exercise conditions. Conclusion:, Acute strenuous exercise increases intestinal T (CD3+ and CD8+) lymphocyte loss and apoptosis. The extent to which the exercise-induced apoptosis in intestinal lymphocytes is mediated by increased glucocorticoid concentrations in the gastrointestinal tract will require further studies. [source] Targeted deletion of Dicer disrupts lens morphogenesis, corneal epithelium stratification, and whole eye developmentDEVELOPMENTAL DYNAMICS, Issue 9 2009Yan Li Abstract Dicer, a ribonuclease essential for miRNA processing, is expressed abundantly in developing mouse cornea and lens. We studied the roles of Dicer and miRNAs in eye development by conditionally deleting the Dicer gene in the mouse lens and corneal epithelium. Adult Dicer conditional null (DicerCN) mice had severe microphthalmia with no discernible lens and a poorly stratified corneal epithelium. Targeted deletion of Dicer effectively inhibited miRNA processing in the developing lens at 12.5 day of embryogenesis (E12.5). Lens development initiated normally but underwent progressive dystrophy between E14.5 and E18.5. Microarray analysis revealed activation of P53 signaling in DicerCN lenses at E13.5, consistent with increased apoptosis and reduced cell proliferation between E12.5 and E14.5. Expression of Pax6 and other lens developmental transcription factors were not greatly affected between E12.5 and E14.5 but decreased as the lens degenerated. Our data indicated an indispensible role for Dicer and miRNAs in lens and corneal development. Developmental Dynamics 238:2388,2400, 2009. © 2009 Wiley-Liss, Inc. [source] Progressive CD127 down-regulation correlates with increased apoptosis of CD8 T cells during chronic HIV-1 infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2009Shu-Ye Zhang Abstract Chronic HIV-1 infection can induce a significant decrease in CD127 expression on CD8 T cells, but the underlying mechanisms and immunological consequences are unclear. In this study, we investigated CD127 expression on CD8 T cells from a total of 51 HIV-1-infected subjects and 16 healthy individuals and analyzed the association between CD127 expression and CD8 T-cell apoptosis in these HIV-1-infected subjects. We found that CD127 expression on total CD8 T cells was significantly down-regulated, which was correlated with the increased CD8 T-cell apoptosis and disease progression of chronic HIV-1 infection. The in vitro addition of IL-7 efficiently rescued the spontaneous apoptosis of CD8 T cells from HIV-1-infected individuals. IL-7 stimulation also transiently down-regulated CD127 expression, whereas some of the CD127, CD8 T cells regained CD127 expression soon after IL-7 was retracted from the incubation medium. Thus, IL-7 stimulation reduced apoptosis of both CD127+ and CD127,CD8 T cells to some degree. These data indicate that CD127 loss might impair IL-7 signaling and increase CD8 T-cell apoptosis during HIV-1 infection. This study, therefore, will extend the notion that IL-7 could be a good candidate for immunotherapy in HIV-1-infected patients. [source] Attenuated apoptosis response to Fas-ligand in active ulcerative colitisINFLAMMATORY BOWEL DISEASES, Issue 12 2008Jakob B. Seidelin MD Abstract Background: From mainly carcinoma cell line studies, apoptosis has been thought to play a major role in the pathogenesis of ulcerative colitis (UC). Apoptosis has been suggested to be due to a Fas ligand / Fas receptor interaction, but has never been studied in cells from patients with active UC. The aim was to investigate both the spontaneous and the cell death receptor ligand-induced apoptosis in UC. Methods: Twenty patients with UC and 16 control subjects who underwent routine colonoscopy either for the control or surveillance of their disease or where the diagnosis of irritable bowel syndrome was subsequently reached were included. Cultures of isolated colonic crypts were obtained from biopsies and cultured for 4 to 16 hours with Fas ligand or Fas ligand and costimulation with interferon-, (IFN-,). Control experiments were performed on HT29 cells. Apoptosis was assessed by independent methods. Results: Isolated colonocytes from healthy subjects or patients with remission in UC had a dose-dependent response to Fas ligand. This response was abolished in patients with active UC (P < 0.002), and costimulation with IFN-, did not alter this response. Patients with active UC had an increased apoptosis rate of 9.5% compared with controls (P < 0.05). Conclusions: The current study indicates that colonocytes do not respond to cytokine exposure and inflammation by an increased vulnerability, as previously thought. Colonocytes seem to activate cytoprotective programs in response to inflammation. Apart from supporting the regeneration process during inflammation, this response could additionally cause an increased susceptibility to neoplastic transformation. (Inflamm Bowel Dis 2008) [source] Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF-,B and induction of apoptosisINTERNATIONAL JOURNAL OF CANCER, Issue 3 2009Paolo Onori Abstract Caffeic acid phenethyl ester (CAPE) inhibits the growth of tumor cells and is a known inhibitor of nuclear factor kappa beta (NF-,B), which is constitutively active in cholangiocarcinoma (CCH) cells. We evaluated the effects of CAPE on CCH growth both in vitro and in vivo. Inhibition of NF-,B DNA-binding activity was confirmed in nuclear extracts treated with CAPE at 50, 40 and 20 ,M. CAPE decreases the expression of NF-,B1 (p50) and RelA (p65). CAPE decreased the growth of a number of CCH cells but not normal cholangiocytes. Cell cycle decrease was seen by a decrease in PCNA protein expression and the number of BrdU-positive cells treated with CAPE at 20 ,M compared to vehicle. Inhibition of growth and increased cell cycle arrest of Mz-ChA-1 cells by CAPE were coupled with increased apoptosis. Bax expression was increased, whereas Bcl-2 was decreased in cells treated with CAPE compared to vehicle. In vivo studies were performed in BALB/c nude (nu/nu) mice implanted subcutaneously with Mz-ChA-1 cells and treated with daily IP injections of DMSO or CAPE (10 mg/kg body weight in DMSO) for 77 days. Tumor growth was decreased and tumor latency was increased 2-fold in CAPE compared to vehicle-treated nude mice. In tumor samples, decreased CCH growth by CAPE was coupled with increased apoptosis. CAPE both in vivo and in vitro decreases the growth of CCH cells by increasing apoptosis. These results demonstrate that CAPE might be an important therapeutic tool in the treatment of CCH. © 2009 UICC [source] The p75NTR neurotrophin receptor is a tumor suppressor in human and murine retinoblastoma developmentINTERNATIONAL JOURNAL OF CANCER, Issue 9 2008Helen Dimaras Abstract The transition from the benign retinal tumor retinoma to its malignant counterpart retinoblastoma is accompanied by the loss of expression of the p75NTR neurotrophin receptor. This change in expression is mimicked in the TAg-RB murine model of retinoblastoma, where early tumors retain expression of p75NTR and advanced tumors lack it. We sought to determine the functional effect on tumor development of absence of p75NTR from the onset of TAg-RB tumor initiation. TAg-RB mice were crossed with either p75NTR exon 3 (E3KO) or exon 4 knockout (E4KO) mice to produce TAg-RB offspring that lacked one or both normal p75NTR alleles. The average tumor area per eye as a percentage of retinal area was measured. TAg-RB/E3KO (TAg-RBE3KO) and heterozygous mice showed no significant difference in tumor area compared to the TAg-RB control mice at any time point studied. However, TAg-RB/E4KO (TAg-RBE4KO) and heterozygous mice displayed a significantly larger tumor area than the TAg-RB control mice. Furthermore, adenoviral-mediated expression of p75NTR in a p75NTR -deficient human retinoblastoma cell line resulted in increased apoptosis. Our results confirm that p75NTR suppresses progression of both human and TAg-RB murine retinoblastoma, and holds promise as a target for future therapy of the disease. © 2008 Wiley-Liss, Inc. [source] Rapamycin together with herceptin significantly increased anti-tumor efficacy compared to either alone in ErbB2 over expressing breast cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2007Lu-Hai Wang Abstract The objective of this study was to assess the anti-tumor efficacy of rapamycin alone or in combination with herceptin in breast cancer. A total of 20 human breast cancer lines were examined for expression of various receptor tyrosine kinases and activation of their down stream signaling molecules, as well as for their invasion and colony forming ability. The ErbB2 and PI3 kinase pathway inhibitors were tested for the inhibition on breast cancer cell growth and tumor development. Seven of the 20 lines displayed an elevated level of ErbB2, others had varying level of EGF, IGF-1 or insulin receptor. Over 30% of the lines also had constitutive activation of Akt and MAP kinase. The lines displayed a wide range of colony forming and invasion ability. The PI3 kinase pathway inhibitors LY294002 and rapamycin inhibited the colony forming ability of all of the lines with the ErbB2 overexpressing lines having a higher sensitivity. A similar trend was observed for inhibition of invasion by LY294002. Rapamycin alone and additively together with herceptin inhibited the breast cancer cell growth especially in ErbB2 overexpressing cells. Rapamycin and herceptin synergistically inhibited tumor growth and endpoint tumor load in a xenograft model using a MCF-7 subline and in a MMTV-ErbB2 transgenic model. Rapamycin and herceptin significantly reduced the level of cyclin D1 and D3 and increased the cleavage of caspase 3 suggesting an increased apoptosis. Our results suggest that rapamycin together with herceptin has an enhanced anti-cancer effect and could be developed as an improved therapeutic regimen for breast cancer. © 2007 Wiley-Liss, Inc. [source] Fas ligand expressed in colon cancer is not associated with increased apoptosis of tumor cells in vivoINTERNATIONAL JOURNAL OF CANCER, Issue 2 2003Aileen Houston Abstract Expression of Fas ligand (FasL/CD95L) may help to maintain colon cancers in a state of immune privilege by inducing apoptosis of antitumor immune effector cells. Colon tumor-derived cell lines appear to be relatively insensitive to apoptosis mediated by their own or exogenous FasL in vitro, despite expression of cell surface Fas. In our present study, we sought to investigate if FasL upregulated in human colon cancers leads to any increase in apoptosis of the tumor cells in vivo. FasL and Fas receptor (APO-1/CD95) expression by tumor cells were detected immunohistochemically. Apoptotic tumor cell death was detected by immunohistochemistry for caspase-cleaved cytokeratin-18. FasL expression did not correlate with the extent of apoptosis of tumor cells. There was no significant local difference in the frequency of apoptosis of tumor cells between tumor nests that expressed FasL (mean = 2.4%) relative to those that did not (mean = 2.6%) (p = 0.625, n = 10; Wilcoxon signed rank). FasL expressed by the tumor cells appeared to be functional, since FasL expression in tumor nests correlated with diminished infiltration of tumor-infiltrating lymphocytes (TILs). TILs were detected using immunohistochemistry for CD45. Expression of FasL by tumor nests was associated with a mean 4-fold fewer TILs relative to FasL-negative nests (range 2.4,33-fold, n = 10, p < 0.003). Together, our results indicate that colon tumors are insensitive to FasL-mediated apoptosis in vivo. © 2003 Wiley-Liss, Inc. [source] Apoptosis in hepatitis CJOURNAL OF VIRAL HEPATITIS, Issue 5 2003J. Kountouras Summary. The apoptotic process appears to be a host defence mechanism against viral infections and tumourigenesis. However, many viral genomes encode proteins, which repress apoptosis so as to escape from immune attack by the host. Therefore, virus,host interactions may determine viral persistence, extent and severity of liver inflammation and possibly viral hepatocarcinogenesis. Apoptosis of liver cells may play a significant role in the pathogenesis of hepatitis C. Pathomorphologic features of increased apoptosis include shrinkage and fragmentation of nuclei/cytoplasm in piecemeal necrosis areas, acidophilic bodies, and focal cell dropout in the liver lobule. The hepatitis C virus (HCV) core protein exhibits both proapoptotic or antiapoptotic actions. Modulation of apoptosis may involve binding of HCV core protein to the intracellular signal transducing portion of death receptors and displacement of signalling molecules. Apoptosis may occur in the absence of significant transaminase elevation, thereby explaining the lack of correlation between biochemical activity and liver cell histological injury. Monitoring caspase activation might provide a reliable tool to estimate the efficacy of HCV therapy, and might open challenging therapeutic strategies in HCV infection. The antiviral effect of interferon may be mediated through induction of apoptosis. Lastly, administration of the antiapoptotic ursodeoxycholic acid in HCV infection is compatible with the notion that apoptosis may represent a mechanism for viral shedding rather than for viral elimination, thereby raising the concept that inhibition of apoptosis could ameliorate hepatitis C. [source] G2/M checkpoint gene expression in developing germ cellsMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 5 2007Suzanne Hasthorpe Abstract Cell cycle progression is prevented by signal transduction pathways known as checkpoints which are activated in response to replication interference and DNA damage. We cloned a G2/M cell cycle phase-related checkpoint gene from a neonatal mouse testis cDNA library which was identified as mouse claspin, a proposed adaptor protein for Chk1. As part of a study on germ cell differentiation we examined the expression of the checkpoint gene, Chk1, and claspin at 12.5 and 14.5 days post coitum (dpc) and in the post-natal phase. Chk1 mRNA expression increased from 12.5 to 14.5 dpc in female gonads and was strong in males at both time points. Claspin however, was not detected until 14.5 dpc. This suggests there may be some dissociation of claspin expression from Chk1 in fetal germ cell development. Chk1 and claspin expression was also studied in testis over the first 3 days following birth, when apoptosis regulates germ stem cell number. We modulated checkpoint-related gene expression in testis using the anti-metabolite, 5-fluorouracil, resulting in increased apoptosis and upregulation of Chk1 (P,<,0.0001) and Cdc2 (P,<,0.02) mRNA. Although we do not fully understand the role checkpoint gene expression has during mammalian germ cell development this report is the first to show the expression of checkpoint-related genes in early mammalian germ cells. Mol. Reprod. Dev. 74: 531,538, 2007. © 2007 Wiley-Liss, Inc. [source] Enhanced monocyte binding to human cytomegalovirus-infected syncytiotrophoblast results in increased apoptosis via the release of tumour necrosis factor alphaTHE JOURNAL OF PATHOLOGY, Issue 4 2005Gary Chan Abstract We have shown that monocytes bound to intercellular adhesion molecules (ICAM-1) on syncytialized placental trophoblasts (ST) induce trophoblast apoptosis, and that ST infection by human cytomegalovirus (HCMV) up-regulates ICAM-1. We hypothesize that the focal loss of trophoblast seen in HCMV-infected placenta is mediated by increased adherence of monocytes at sites of infection. We find that ST cultures (differentiated from primary cytotrophoblasts) increase monocyte binding when infected with HCMV. Monocyte adhesion was inhibited by antibodies to ICAM-1 and its ligand leukocyte function-associated molecule (LFA-1) on monocytes. When co-cultured with adhering monocytes, infected ST cultures had higher levels of apoptosis than infected cultures alone. Although trophoblast apoptosis clustered around adhering monocytes, it occurred only in non-infected cells. Blocking monocyte binding with ICAM-1 and LFA-1 antibodies reduced the rate of apoptosis to that of the infected culture. Co-cultures incubated with TNF, antibody and EGF inhibited both monocyte- and HCMV-induced apoptosis but did not block binding. We conclude that HCMV stimulates ST culture expression of ICAM-1, which binds to LFA-1 on monocytes that release TNF,, thereby inducing apoptosis of neighbouring uninfected trophoblasts. The above data indicates that trophoblast loss associated with HCMV infection can be caused by increased monocyte adhesion to ST. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Evidence for a pathogenetic role of interleukin-18 in cutaneous lupus erythematosusARTHRITIS & RHEUMATISM, Issue 10 2008Dong Wang Objective Cutaneous manifestations are the most common clinical features of lupus erythematosus (LE). The aim of this study was to analyze differences in the inflammatory response of keratinocytes from patients with cutaneous LE (CLE) compared with healthy controls. Methods Keratinocytes from LE patients and controls were cultured from epidermal stem cells of the hair follicle of anagen head hairs. Functional responses of keratinocytes to cytokine stimulation were determined by flow cytometry and enzyme-linked immunosorbent assay. Biopsy samples of lesional skin were analyzed by immunohistochemistry. Results Keratinocytes from CLE patients expressed higher levels of IL-18 receptor on their cell surface in response to tumor necrosis factor , (TNF,) or interferon-, stimulation. In response to IL-18 stimulation, these cells produced large amounts of TNF,. Of note, in the presence of IL-18, CLE keratinocytes failed to express IL-12. IL-12 has previously been shown to protect keratinocytes from ultraviolet irradiation,induced apoptosis. Keratinocytes from LE patients were more prone to die upon exposure to IL-18, and this increased apoptosis was abrogated by blockade of endogenously produced TNF, as well as by the addition of exogenous IL-12. IL-18 was highly expressed in biopsy samples of lesional skin from CLE patients. Conclusion Our results demonstrate an intrinsic difference in the inflammatory response of keratinocytes and indicate an autocrine feedback loop involving TNF,, IL-18, and IL-12 family members. Our results suggest that IL-18 may occupy an important position in the cytokine hierarchy in CLE, indicating the potential benefit of a local agent that blocks IL-18 activity in the treatment of the manifestations of CLE. [source] Disturbed morphogenesis of cardiac outflow tract and increased rate of aortic arch anomalies in the offspring of diabetic ratsBIRTH DEFECTS RESEARCH, Issue 12 2004Daniël G.M. Molin Abstract BACKGROUND Maternal diabetes (MD) is a risk factor for offspring to develop cardiovascular anomalies; this is of growing clinical concern since the number of women in childbearing age with compromised glucose homeostasis is increasing. Hyperglycemia abrogates cardiovascular development in vitro; however, a link to cardiovascular defects in diabetic offspring remains to be investigated. METHODS We have studied cardiovascular development in offspring of MD rats by examining serial histological sections of GD 12.0,18.0 offspring. Development of pharyngeal arch artery malformations was analyzed and related to intracardiac anomalies. RESULTS Pharyngeal arch artery and intracardiac defects were present in 27 of 37 MD GD 13.0,18.0 offspring. Early sixth arch arteries showed abrogated arteriogenesis, whereas fourth arch artery defects developed as a result of abnormal remodeling. Morphometrical analysis showed increased apoptosis in regressing artery segments and reduced apoptosis in persisting artery segments. Double outlet right ventricle with infundibular stenosis (tetralogy of Fallot) was predominantly found in combination with sixth artery defects and pulmonary atresia. As confirmed by morphometric analysis and three-dimensional (3D)-reconstructions, outflow tract defects coincided with endocardial cushion hypoplasia. Cases with teratology of Fallot additionally showed a shorter outflow tract. No relation with apoptosis or disturbed neural crest cell migration was found. CONCLUSIONS Our data uniquely demonstrate mechanistic differences involved in the development of sixth and fourth artery anomalies. Whereas increased apoptosis induces fourth artery anomalies, pulmonary outflow obstruction abrogates sixth artery differentiation independent of apoptosis. The model presented allows analysis of diabetic conditions on cardiovascular development in vivo, essential for elucidating this teratology. Birth Defects Research (Part A), 2004. © 2004 Wiley-Liss, Inc. [source] | |||||||||||||