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  • 2010-2014
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  • Human  (776)
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  • 1
    Electronic Resource
    Electronic Resource
    Postoperative colonic motility and tone in patients after colorectal surgery (2000)
    Springer
    Diseases of the colon & rectum 43 (2000), S. 932-939 
    Details
    ISSN: 1530-0358
    Keywords: Barostat ; Colon ; Human ; Ileus ; Manometry ; Motility ; Postoperative ; Rectum ; Surgery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: Colonic motility is crucial for the resolution of postoperative ileus. However, few data are available on postoperative colonic motility and no data on postoperative colonic tone. We aimed to characterize postoperative colonic tone and motility in patients. METHODS: Nineteen patients were investigated with combined barostat and manometry recordings after left colonic surgery. During surgery a combined recording catheter was placed in the colon with two barostat bags and four manometry channels cephalad to the anastomosis. Recordings were performed twice daily from Day 1 to Day 3 after surgery. RESULTS: Manometry showed an increasing colonic motility index, which was a mean (± standard error of the mean) of 37±5 mmHg/minute on Day 1, 87±19 mmHg/minute on Day 2, and 102±13 mmHg/minute on Day 3 (P〈0.05 for Day 1vs. Day 2 and Day 2vs. Day 3). Low barostat bag volumes indicating a high colonic tone were observed on Day 1 after surgery and increased subsequently (barostat bag I was 19±4, 32±6, and 32±6 ml; barostat bag II was 13±1, 19±3, and 22±5 ml on Days 1, 2, and 3, respectively; for both barostat bagsP〈0.05 for Day 1vs. Day 2 but not Day 2vs. Day 3). CONCLUSIONS: Colonic motility increased during the postoperative course. The low barostat bag volumes indicated a high colonic tone postoperatively which would correspond to a contracted rather than to a distended colon. High colonic tone postoperatively may be relevant for pharmacologic treatment of postoperative ileus.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02237353
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  • 2
    Electronic Resource
    Electronic Resource
    Precancerous conditions for pancreatic cancer (2000)
    Springer
    Journal of hepato-biliary-pancreatic surgery 7 (2000), S. 575-579 
    Details
    ISSN: 1436-0691
    Keywords: Key words Precancerous conditions ; Pancreatic duct adenocarcinoma ; Hamster ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Precancerous conditions for ductal adenocarcinoma of the pancreas in hamsters and human beings are discussed. In hamsters, ductal adenocarcinomas induced by nitrosamines are of nonmucin-hypersecreting tubular or papillary tumor types, and genetic alterations resembling these types are found in their human counterparts. Ductal lesions develop step-by-step from hyperplasias to carcinomas, and atypical ductal cell hyperplasias may be precancerous. In humans, ductal lesions, hyperplasias, or dysplasias, with or without mucin hypersecretion, are possible preneoplastic conditions. Genetic or phenotypic markers to determine their likelihood of progressing to pancreatic duct adenocarcinomas are a high priority for future research.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005340070006
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  • 3
    Electronic Resource
    Electronic Resource
    Centriacinar region inflammatory disease in young individuals: a comparative study of Miami and Los Angeles residents (2000)
    Springer
    Virchows Archiv 437 (2000), S. 422-428 
    Details
    ISSN: 1432-2307
    Keywords: Keywords Lung ; Ozone ; Centriacinar ; Human ; Autopsy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Semiquantitative measurements of chronic inflammation of the centriacinar region (proximal acinus of lung) were compared between 20 Miami and 18 Los Angeles residents (ages 11–30 years) for whom smoking histories were available. Mean extent and severity scores of four lung sites were higher for Los Angeles than Miami residents, with effect of city statistically significant for extent (P=0.02). Also, maximum scores for extent and severity by city were significantly greater for Los Angeles residents (P=0.02, each), but not by smoking history. Smokers did have higher scores for mean extent and severity (by lung site and smoking history), but neither this nor inclusion of smoking and city in the model reached significance. With respect to maximum extent and maximum severity scores, a stratified comparison of cities by smoking history showed a trend (not significant) toward higher scores for Los Angeles residents. Mean extent and severity scores for the lower lobe were higher for basilar sections than for apical sections (each P〈0.001). Cumulative data indicate that expanded pathologic studies are essential for efforts to complete a convergence of epidemiological and experimental data implicating exceedences of the Federal ozone standard as a contributor to human lung injury.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004280000262
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  • 4
    Electronic Resource
    Electronic Resource
    Ciliogenesis and ciliary abnormalities (2000)
    Springer
    Medical electron microscopy 33 (2000), S. 109-114 
    Details
    ISSN: 1437-773X
    Keywords: Key words Ciliogenesis ; Ciliated cell ; Abnormal cilia ; Basal body ; Ultrastructure ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cilia are motile processes extending from the basal bodies, playing important roles in the mucociliary clearance in the respiratory tract and the transport of the ovum from the ovary to the uterus in mammals. Ciliogenesis is divided into four stages: (1) duplication of centrioles; (2) migration of centrioles to the apical cell surface to become basal bodies; (3) elongation of cilia containing the axoneme; and (4) formation of accessory structures of basal bodies. The orderly course of ciliogenesis appears to be disturbed by various internal and external factors and, as a result, various unusual forms of the ciliary apparatus develop in the cell. Inhibition of basal body migration results in development of intracytoplasmic axonemes, cilia within periciliary sheaths, and intracellular ciliated cysts. Swollen cilia and the bulging type of compound cilia are formed during ciliary budding and elongation. This review also discusses the origin, composition, and function of the centriolar precursor structures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s007950000009
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  • 5
    Electronic Resource
    Electronic Resource
    Differential expressions of protein kinase C isozymes during proliferation and differentiation of human skeletal muscle cells in vitro (2000)
    Springer
    Acta neuropathologica 99 (2000), S. 96-104 
    Details
    ISSN: 1432-0533
    Keywords: Key words Skeletal muscle ; Human ; Differentiation ; Protein kinase C ; Isozymes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The mechanism of skeletal muscle regeneration in vivo can be well modeled in vitro by culturing skeletal muscle cells. In these cultures mononuclear satellite cells fuse to form polynuclear myotubes by proliferation and differentiation. The aim of this study was to determine how the different protein kinase C (PKC) isozymes were expressed during differentiation of human skeletal muscle in vitro. The expressions of desmin, used as a muscle-specific intermediate filament protein marker of differentiation, and of different PKC isozymes were detected by single and double immunohistochemical labeling, and by Western blot analysis. In skeletal muscle cells we could identify five PKC isozymes (PKCα, -γ, -η, -θ and -ζ). The expressions of PKCα and -ζ did not change significantly during differentiation; their levels of expression were high in the early immature cells and remained unchanged in later phases. In contrast, the expression levels of PKCγ and -η increased with differentiation. Furthermore, the cellular localization of PKCγ markedly altered during differentiation, with a perinuclear-nuclear to cytoplasmic translocation. The change in the level of expression of PKCθ during differentiation showed different pattern; its expression was high during the early phases, but a decreased immunostaining was detected in the matured, well-differentiated myotubes. We conclude, therefore, that cultured human skeletal muscle cells possess a characteristic PKC isozyme pattern, and that the different phases of differentiation are accompanied by different expression patterns of the various isozymes. These data suggest the possible functional and differential roles of PKC isozymes in human skeletal muscle differentiation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00007429
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  • 6
    Electronic Resource
    Electronic Resource
    The transient disappearance of cytokeratin in human fetal and adult ovaries (2000)
    Springer
    Anatomy and embryology 201 (2000), S. 207-215 
    Details
    ISSN: 1432-0568
    Keywords: Keywords Granulosa cells ; Ontogeny ; Ovary ; Rete ovarii ; Cytokeratin ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Cells from the inner and outer granulosa cell layers of the ovarian follicles differ in function, probably because of their different origins from the surface epithelium and from the rete. This suggestion has not so far been thoroughly investigated in the human ovary. We examined fetal ovaries from the early, middle and late gestational periods, ovaries from fertile women, and preovulatory follicular cells obtained from patients under in vitro fertilization therapy (IVF). Indirect immunohistology and immunocytology were used to detect the presence of cytokeratin (CK)-positive epithelial cells. In fetal ovaries from the early gestational period, prominent rete tubules (sometimes with oocytes) appeared to be fused with the sex cords and primordial follicles. Both showed CK-positively, detected with the pan-CK antibody Lu-5. Cytokeratin 19 was clearly expressed in the fusion area. In the fetal and adult ovaries, CK-positive follicular or granulosa cells were noted in the primordial and primary follicles as well as the preovulatory follicles. Cytokeratin was not detected in the granulosa cells of growing follicles, CK-positive and -negative luteal cells were identified in the developing corpus luteum. We conclude for the human ovary: (1) the heterogeneous morphology of granulosa cells may be explained by their twofold origin from the surface epithelium and the rete, (2) the rete tubules appear to be involved in folliculogenesis, (3) the transient absence of CK expression in growing follicles compared to resting and mature follicles or to the developing corpus luteum indicates a particular role of CK-positive cells at the periovulatory period.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004290050019
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  • 7
    Electronic Resource
    Electronic Resource
    Preliminary functional analysis of human epidermal T cells (2000)
    Springer
    Archives of dermatological research 292 (2000), S. 9-15 
    Details
    ISSN: 1432-069X
    Keywords: Key words Epidermal T cells ; Function ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The function of human epidermal T cells (ETC) is unknown. In the present study, dermal T cells (DTC), ETC and keratinocytes were cultured from normal human skin. DTC and ETC lines were expanded in medium containing interleukin 2. The autologous keratinocytes were transfected with a human papillomavirus 16 E6 and E7 plasmid to produce an immortal keratinocyte line “HEK001”. Lymphocyte migration and adhesion to HEK001 was assessed in calcein fluorimetric assays. ETC migrated towards HEK001 three to four times more than DTC. ETC adhered to HEK001 two to four times more than DTC. The proportion of ETC expressing the cutaneous lymphocyte-associated antigen was greater than that of DTC (26% and 1%, respectively). The keratinocyte line HEK001 expressed ICAM-1 following stimulation with TNF-α or IFN-γ and following coculture with autologous cutaneous T cells. A blocking anti-ICAM-1 antibody reduced DTC and ETC adhesion to HEK001 by 30% and 50%, respectively. Therefore, cutaneous T cells may upregulate keratinocyte ICAM-1 expression which mediates adhesion to autologous keratinocytes. These results are consistent with the hypothesis that the ETC and DTC populations are distinct. Both directed migration (epidermotropism) and selective retention may be involved in the development and maintenance of the ETC population in normal human skin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00007461
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  • 8
    Electronic Resource
    Electronic Resource
    Intraoperative endogenous erythropoietin levels and changes in intravascular blood volume in healthy humans (2000)
    Springer
    Annals of hematology 79 (2000), S. 183-186 
    Details
    ISSN: 1432-0584
    Keywords: Key words Erythropoietin ; Endogenous ; Blood volume ; Human ; Intraoperative
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  There is accumulating evidence of a relationship between changes in intravascular blood volume and endogenous erythropoietin (EPO) levels. In this study, eight healthy adult American Society of Anesthesiologists class-I patients due for prolonged elective surgery were randomised either to preoperative hypervolaemic haemodilution using hydroxyethyl starch, followed by intraoperative crystalloid infusion, or to standard intraoperative normovolaemic fluid balance management using crystalloids (control group). Electrolytes, creatinine, urea, osmolality, urine output and blood gases were monitored pre- and intraoperatively for 6 h, Comparable cardiopulmonary and renal homeostasis were maintained in both groups. We found that central venous pressure increased and EPO levels decreased, both significantly, in the hypervolaemic haemodilution group relative to controls. There were no significant intergroup changes in any other parameters. By controlling for other known determinants of EPO levels, our data indicate a relationship between EPO levels and changes in intravascular blood volume in humans, supporting the notion of EPO as a volume-regulated, and possibly volume-regulating, hormone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002770050577
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  • 9
    Electronic Resource
    Electronic Resource
    Differential regulation of the monocytic calcium-binding peptides macrophage-inhibiting factor related protein-8 (MRP8/S100A8) and allograft inflammatory factor-1 (AIF-1) following human traumatic brain injury (2000)
    Springer
    Acta neuropathologica 100 (2000), S. 627-634 
    Details
    ISSN: 1432-0533
    Keywords: Key words Allograft-inflammatory factor-1 ; Microglia response factor-1 ; Macrophage-inhibiting factor ; related-protein-8/S100A8 ; Traumatic brain injury ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Intracellular calcium (Ca2+) has been shown to function as second messenger and to be associated with activation of different cell types including microglia. Previously, in human focal cerebral infarctions an early expression of macrophage-related protein-8 (MRP8/ S100A8), a member of the Ca2+-binding S100-protein family, in microglia has been reported. On the other hand, a delayed activation of microglia was observed following traumatic brain injury (TBI). We therefore examined immunohistochemically microglial expression of MRP8 and allograft inflammatory factor-1 (AIF-1), identical to microglial response factor-1 (mrf-1) and ionized calcium binding adaptor molecule-1 (iba1) in human brains after TBI and in control brains. Both, MRP8 and AIF-1 are Ca2+-binding peptides which have been associated with microglial activation in experimental models and in human cerebral infarctions. Detection of AIF-1 in controls confirmed constitutive expression of this peptide in a subset of microglial cells. After TBI, the density of AIF-1+ microglia did not increase significantly. Lesional expression of AIF-1 did not significantly differ from other brain regions. Furthermore, following TBI, we found no significant differences in the density of AIF-1+ microglia as compared to controls. Microglial MRP8 expression was not detectable in controls and within the first 3 days post TBI, but increased rapidly after 3 days post TBI, suggesting a subpopulation of microglial cells to be AIF-1–/MRP8+. We conclude that the delayed expression of MRP8 and the lack of AIF-1 up-regulation in microglia after TBI is in contrast to ischemic brain lesions and might reflect different activation cascades of microglia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004010000232
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  • 10
    Electronic Resource
    Electronic Resource
    Melanomas with concordant loss of multiple melanocytic differentiation proteins: immune escape that may be overcome by targeting unique or undefined antigens (2000)
    Springer
    Cancer immunology immunotherapy 48 (2000), S. 661-672 
    Details
    ISSN: 1432-0851
    Keywords: Keywords Melanoma ; Antigens ; Cytotoxic ; T lymphocytes ; Human ; Immunotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Melanoma-reactive HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) lines generated in vitro lyse autologous and HLA-matched allogeneic melanoma cells and recognize multiple shared peptide antigens from tyrosinase, MART-1, and Pmel17/gp100. However, a subset of melanomas fail to be lysed by these T cells. In the present report, four different HLA-A*0201+ melanoma cell lines not lysed by melanoma-reactive allogeneic CTL have been evaluated in detail. All four are deficient in expression of the melanocytic differentiation proteins (MDP) tyrosinase, Pmel17/gp100, gp75/trp-1, and MART-1/Melan-A. This concordant loss of multiple MDP explains their resistance to lysis by melanoma-reactive allogeneic CTL and confirms that a subset of melanomas may be resistant to tumor vaccines directed against multiple MDP-derived epitopes. All four melanoma lines expressed normal levels of HLA-A*0201, and all were susceptible to lysis by xenoreactive-peptide-dependent HLA-A*0201-specific CTL clones, indicating that none had identifiable defects in antigen-processing pathways. Despite the lack of shared MDP-derived antigens, one of these MDP-negative melanomas, DM331, stimulated an effective autologous CTL response in vitro, which was restricted to autologous tumor reactivity. MHC-associated peptides isolated by immunoaffinity chromatography from HLA-A1 and HLA-A2 molecules of DM331 tumor cells included at least three peptide epitopes recognized by DM331 CTL and restricted by HLA-A1 or by HLA-A*0201. Recognition of these CTL epitopes cannot be explained by defined, shared melanoma antigens; instead, unique or undefined antigens must be responsible for the autologous-cell-specific anti-melanoma response. These findings suggest that immunotherapy directed against shared melanoma antigens should be supplemented with immunotherapy directed against unique antigens or other undefined antigens, especially in patients whose tumors do not express MDP.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002620050015
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  • 11
    Electronic Resource
    Electronic Resource
    G7c, a novel gene in the mouse and human major histocompatibility complex class III region, possibly controlling lung tumor susceptibility (2000)
    Springer
    Immunogenetics 51 (2000), S. 383-386 
    Details
    ISSN: 1432-1211
    Keywords: Key words MHC class III region ; Mouse ; Human ; G7c ; Lung tumor susceptibility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002510050634
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  • 12
    Electronic Resource
    Electronic Resource
    New alleles of human immunoglobulin κ J segments IGKJ2 and IGKJ4 (2000)
    Springer
    Immunogenetics 51 (2000), S. 487-488 
    Details
    ISSN: 1432-1211
    Keywords: Key words Immunoglobulin ; J segments ; IGKJ genes ; Alleles ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002510050647
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  • 13
    Electronic Resource
    Electronic Resource
    Toxicokinetic modelling of methyl formate exposure and implications for biological monitoring (2000)
    Springer
    International archives of occupational and environmental health 73 (2000), S. 479-487 
    Details
    ISSN: 1432-1246
    Keywords: Key words Biological monitoring ; Formate ; Formic acid ; Human ; Methanol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A toxicokinetic (TK) model was developed to describe the inhalation exposure in humans to methyl formate (MF), a catalyst used in foundries, and to discuss biological monitoring. The TK model consisted of four compartments: MF, the metabolites – methanol (MeOH) and formic acid (FA) – and, in addition, a urinary compartment describing the saturable reabsorption of FA. Levels of MeOH and FA in urine, from an experimental study (100 ppm MF, 8 h at rest), validated the present model. The TK model describes well the general behaviour of MeOH and FA in urine after MF exposure. A nonlinear and a linear relationship respectively, was predicted between MF exposure and FA or MeOH excretion in urine, and this has previously been seen after occupational MF exposure. The present model has been modified to simulate MeOH exposure as well. Generally low exposures (concentration or exercise) produce only marginal increases in FA urinary excretions, but when exposure is elevated, urinary FA excretion increases because of saturation in the mechanism of reabsorption. Using FA urinary excretion as the critical indicator, because of its link to health effects, an occupational exposure limit value for MF of no greater than 50 ppm should be selected (based on predictions with the TK model). MeOH in urine can be considered as a biomarker for MF at low exposure, because of lower background values and of a linear relationship with exposure. At higher exposures, however, FA could be used as a biomarker as it becomes progressively more sensitive. But the use of biological monitoring for MF is difficult because of individual variations in background values. Under the present state of knowledge both FA and MeOH should be used to estimate only group exposures, rather than individual exposures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004200000170
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  • 14
    Electronic Resource
    Electronic Resource
    Abuse liability assessment of sibutramine, a novel weight control agent (2000)
    Springer
    Psychopharmacology 147 (2000), S. 339-346 
    Details
    ISSN: 1432-2072
    Keywords: Key words Sibutramine ; d-Amphetamine ; Abuse potential ; Subjective effect ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Sibutramine (Meridia) is a serotonin and norepinephrine reuptake inhibitor marketed for weight control. Previous studies demonstrated low abuse potential for 20 and 30 mg sibutramine (doses near the therapeutic range); however, no data existed on supratherapeutic doses. This study, therefore, examined 25 and 75 mg sibutramine in humans compared to d-amphetamine (20 mg) as a positive control and placebo as a negative control. Objectives: The study examined the acute subjective, reinforcing, and physiological effects of sibutramine to assess its abuse liability. Methods: Twelve polydrug abusers with no history of drug dependence participated in this double-blind, inpatient/outpatient study. Volunteers participated in four drug sessions, in which they completed subjective effects scales including the Profile of Mood States (POMS), Visual Analog Scales (VAS), and the Addiction Research Center Inventory (ARCI). The Multiple Choice Procedure (MCP) was used to evaluate reinforcing efficacy. Results: Sibutramine 25 mg produced subjective effects that were indistinguishable from placebo. Sibutramine 75 mg produced significant unpleasant effects, such as Anxiety, Confusion, and decreased Vigor. On the MCP, volunteers chose to give up an average of $4.04 from their study pay rather than receive the higher dose of sibutramine again. In contrast, d-amphetamine 20 mg produced positive mood changes and was well liked. Conclusions: These data indicate sibutramine lacks amphetamine-type abuse liability when administered acutely.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050001
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  • 15
    Electronic Resource
    Electronic Resource
    Predicting haloperidol occupancy of central dopamine D2 receptors from plasma levels (2000)
    Springer
    Psychopharmacology 149 (2000), S. 1-5 
    Details
    ISSN: 1432-2072
    Keywords: Key words Haloperidol ; Dopamine ; Receptor occupancy ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Positron emission tomography (PET) is increasingly being used to study dopamine receptor occupancy and the clinical effects of antipsychotic medication. Dopamine D2 receptor occupancy has been shown to predict several clinical effects of antipsychotic medication including therapeutic response, motor and endocrine side-effects. Plasma levels may be used as a surrogate marker for central occupancy if the relationship between these two measures may be accurately described. This study was designed to test the capacity of a previously derived relationship equation (%D2 occupancy=plasma level/ED50+plasma level, where ED50= 0.40 ng/ml) to predict striatal D2 occupancy from plasma level. Twenty-one patients receiving treatment with low dose haloperidol underwent a 11C-raclopride PET scan to measure D2 occupancy. The D2 occupancy levels were accurately predicted by use of the previously generated equation with only a small degree of error (3.89% CI 0.45–7.33). Predicted and measured D2 occupancy values correlated closely (Pearson’s r=0.864, P=0.003). The study indicates that reliable prediction of D2 occupancy from plasma levels is possible. This provides a potentially useful surrogate measure of D2 occupancy for research and possibly clinical practice, as the routine use of PET to measure occupancy levels is not feasible.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002139900333
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  • 16
    Electronic Resource
    Electronic Resource
    Conditioned effects of environmental stimuli paired with smoked cocaine in humans (2000)
    Springer
    Psychopharmacology 149 (2000), S. 24-33 
    Details
    ISSN: 1432-2072
    Keywords: Key words Cocaine ; Conditioning ; Cardiovascular effect ; Subjective effect ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Clinical data suggest that stimuli paired with cocaine use acquire emergent stimulus effects, such as the ability to elicit cocaine craving. Objectives: The purpose of this study was to determine the conditioned effects of neutral stimuli paired with cocaine smoking. Methods: Eight experienced adult cocaine smokers participated in 22 experimental sessions while residing on a Clinical Research Center. One set of cues (CS–) was paired with placebo smoked cocaine and one set of cues (CS+) was paired with 25 mg smoked cocaine. Results: After 18 training trials, the effects of cocaine on heart rate and ratings of ”anxious” were greater, and skin temperature and ratings of ”tired” were smaller when compared to the effects of cocaine after the first training trial. When instructed to select a cue to experience after training, seven of eight participants selected the CS+, while only three of the participants selected the CS+ prior to training, i.e., the CS+ functioned as a conditioned reinforcer. Presentation of the CS+ alone without cocaine during extinction trials increased HR, SP, and ratings of ”anxious””tired”, and ”I want cocaine” and decreased skin temperature. These changes elicited by presentation of the CS+ decreased over the course of the extinction sessions. Conclusions: The present results indicate that classical conditioning is one mechanism by which stimuli paired with cocaine acquire emergent stimulus effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002139900340
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  • 17
    Electronic Resource
    Electronic Resource
    Striate cortex in humans demonstrates the relationship between activation and variations in visual form (2000)
    Springer
    Experimental brain research 130 (2000), S. 221-226 
    Details
    ISSN: 1432-1106
    Keywords: Key words Visual perception ; Object recognition ; Functional magnetic resonance imaging ; Neuroimaging ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Electrophysiologic and functional imaging studies have shown that the visual cortex produces differential responses to the presence or absence of structure within visual textures. To further define and characterize regions involved in the analysis of form, functional magnetic resonance imaging (fMRI) was used to detect changes in activation during the viewing of four levels of isodipole textures. The texture levels systematically differed in the density of visual features such as extended contours and blocks of solid color present within the images. A linear relationship between activation level and density of structure was observed in the striate cortex of human subjects. This finding suggests that a special subpopulation of striate cortical neurons participates in the ability to extract and process structural continuity within visual stimuli.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002210050024
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  • 18
    Electronic Resource
    Electronic Resource
    Species differences in response to diethylhexylphthalate: suppression of apoptosis, induction of DNA synthesis and peroxisome proliferator activated receptor alpha-mediated gene expression (2000)
    Springer
    Archives of toxicology 74 (2000), S. 85-91 
    Details
    ISSN: 1432-0738
    Keywords: Key words Diethylhexylphthalate ; Peroxisome proliferation ; Hepatocarcinogenesis ; Species differences ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Diethylhexylphthalate (DEHP) is a phthalate plasticizer that belongs to the peroxisome proliferator (PP) class of rodent nongenotoxic hepatocarcinogens. Previously, we have shown that MEHP (a principal metabolite of DEHP and the proximal PP) induced DNA synthesis and suppressed apoptosis in rat but not in human hepatocytes in vitro. Here, we present further studies of species differences in response to DEHP. In rats, 4 days of exposure to DEHP (950 mg/kg per day by gavage) induced peroxisomal β-oxidation, DNA synthesis and suppressed apoptosis. In contrast, there was no response of guinea pig liver to DEHP. In rat hepatocytes in vitro, MEHP (250, 500 and 750 μM) induced peroxisomal β-oxidation, DNA synthesis and suppressed apoptosis. In contrast to the pleiotropic response noted in rat hepatocytes, there was no response of human hepatocytes to 250, 500 or 750 μM MEHP. PPs activate the peroxisome proliferator activated receptor alpha (PPARα) that binds to DNA at peroxisome proliferator response elements (PPREs) within the promoters of PP-responsive genes such as rat acyl CoA oxidase (ACO). However, the human ACO gene promoter differs at three bases within the PPRE from the rat ACO promoter and appears refractory to PPs. To address species differences in response to DEHP at the molecular level, we used promoter-reporter gene assays to compare the ability of MEHP to induce gene expression from the rat or the human ACO promoter. MEHP gave a concentration-dependent increase in reporter gene expression from the rat ACO gene promoter with either mouse or human PPARα. In contrast, the human ACO promoter was unable to drive MEHP-induced gene transcription irrespective of the species origin of PPARα. These data provide further weight of evidence at the cellular and molecular levels for a lack of risk to human health from the phthalate DEHP.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050657
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  • 19
    Electronic Resource
    Electronic Resource
    Effect of human plasma on the reactivation of sarin-inhibited human erythrocyte acetylcholinesterase (2000)
    Springer
    Archives of toxicology 74 (2000), S. 21-26 
    Details
    ISSN: 1432-0738
    Keywords: Key words Organophosphate ; Acetylcholinesterase ; Oximes ; Human ; Reactivation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The reactivation of organophosphate-inhibited acetylcholinesterase (AChE) by oximes inevitably results in the formation of highly reactive phosphoryloximes (POX), which are able to re-inhibit the enzyme. In this study, the dependence of POX formation on AChE concentration was investigated with sarin-inhibited human erythrocyte AChE (EryAChE). A marked dependence was found with obidoxime but not with the experimental oxime HI 6, suggesting great differences in the decomposition rates of the respective POXs. At a physiological erythrocyte content the reactivation of EryAChE was markedly affected by POX with obidoxime and pralidoxime (2-PAM) but not with the newer oximes HI 6 and HLö 7. Addition of extensively dialysed, sarin-treated human plasma reduced the reactivation by obidoxime and 2-PAM even more. Obidoxime and 2-PAM were superior to HI 6 and HLö 7 in reactivating butyrylcholinesterase (BChE). This effect was pronounced in diluted plasma, but was obscured in concentrated plasma, probably because of re-inhibition by the generated POX. Addition of native erythrocytes to sarin-treated plasma resulted in marked inhibition of EryAChE in the presence of obidoxime, suggesting a higher affinity of the POX for EryAChE. The results indicate that obidoxime and 2-PAM may reactivate sarin-inhibited AChE insufficiently due to re-inhibition by the POX formed. In addition, the re-inhibition of EryAChE may be aggravated by the POX that is produced during BChE reactivation. These reactions must be regarded as therapeutically detrimental and disqualify those oximes which are capable of forming stable POX by reactivation of BChE.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050647
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  • 20
    Electronic Resource
    Electronic Resource
    Motor neurones in culture as a model to study ALS (2000)
    Springer
    Journal of neurology 247 (2000), S. I28 
    Details
    ISSN: 1432-1459
    Keywords: Key words Motor neurone ; Astrocyte ; Human ; Tissue culture ; ALS ; Glutamate ; Calcium ; SOD-1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Defining the basis of the selective cell vulnerability of motor neurones (MN) represents the key issue in amyotrophic lateral sclerosis (ALS), and tissue culture models are the ideal system for the identification of the MN specific features at the single cell level. Neurone-astrocyte metabolic interactions, which have a critical role in MN through glutamatergic toxicity, have been mostly defined in vitro. Ca++ metabolism, which appears to play a critical role in inducing MN loss in ALS, has been successfully studied using in vitro cell models. Furthermore, primary cultures demonstrated that apoptotic or necrotic death of neurones after injury depends upon the cell energetic status. Superoxide dismutase-1 (SOD-1) mutations were successfully expressed in cultured rodent MNs, providing a critical assay to sequence the molecular processes responsible for MN degeneration due to the identified genetic defect. The recent identification of genes that separate humans from apes further increases the value of the human in vitro models to better understand specific human cellular properties. Purified human MNs and astrocytes can today be obtained from the human embryonic spinal cord anterior horns. Interactions at the single cell level can be dissected using the cDNA amplification techniques. The effects of molecules affecting MN survival, neurite extension, and metabolism can easily be defined in vitro, gaining a critical mass of information of immediate clinical application in the treatment of patients affected by ALS. Understanding the properties of human MNs in vitro represents today a significant and critical tool that can easily be reached after extension of the available knowledge from non-primate to human research. Human MN culture studies can greatly contribute to identifying the primitive critical cellular events responsible for the MN degeneration observed in ALS and to gaining crucial information ¶on new therapeutical agents.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004150050554
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  • 21
    Electronic Resource
    Electronic Resource
    Rejection and tacrolimus conversion therapy in paediatric liver transplantation (2000)
    Springer
    Transplant international 13 (2000), S. S341 
    Details
    ISSN: 1432-2277
    Keywords: Key words Liver transplantation ; Rejection ; Tacrolimus ; Human ; Child
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rejection and efficacy of rescue therapy with tacrolimus were evaluated in 50 children who underwent primary, ABO-compatible, liver transplantation. Six patients who died within the first week and one child who underwent retransplantation from an ABO-incompatible donor were excluded from the study. No patient or graft were lost due to rejection. We observed 48 episodes of rejection in 33 patients. Fourteen patients required conversion to tacrolimus for steroid-resistant rejection with resolution of rejection. One of these children developed PTLD. Other indications for conversion were neurotoxicity and hirsutism. One patient developed blindness of unknown origin after the conversion. Other side effects of tacrolimus were minor and resolved by lowering the dose. Five patients developed rejection after conversion; all achieved resolution with either steroid therapy or increase of tacrolimus dose. In conclusion, our study confirms that tacrolimus is an effective rescue therapy for paediatric liver transplantation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001470050357
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  • 22
    Electronic Resource
    Electronic Resource
    Transdifferentiation of somatotrophs to thyrotrophs in the pituitary of patients with protracted primary hypothyroidism (2000)
    Springer
    Virchows Archiv 436 (2000), S. 43-51 
    Details
    ISSN: 1432-2307
    Keywords: Key words Pituitary ; Human ; Somatotroph ; Thyrotroph hyperplasia ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In patients with protracted primary hypothyroidism, the pituitary is enlarged due to the lack of feedback inhibition by thyroid hormone. In the present work, adenohypophysial biopsies from three women with protracted primary hypothyroidism were investigated by routine histology, immunocytochemistry, double immunostaining, immunoelectron microscopy, and combined immunocytochemistry – in situ hybridization. These methods confirmed the presence of massive thyrotroph hyperplasia and the formation of ”thyroidectomy” or ”thyroid deficiency” cells. A number of thyroidectomy cells were found to be immunoreactive for growth hormone (GH). Double immunostaining and immunoelectron microscopy revealed the presence of bihormonal cells containing both GH and thyroid stimulating hormone (TSH). Immunostaining combined with in situ hybridization revealed GH immunoreactive cells expressing TSH mRNA as well as TSH immunopositive cells expressing GH mRNA. Our findings provide conclusive evidence that somatotrophs may transform to thyrotrophs. Thus, in addition to multiplication of thyrotrophs, transdifferentiation of GH cells to thyrotrophs contributes to the increase of TSH-producing cells. The presence of such bihormonal cells best termed ”thyrosomatotrophs” supports the concept that adenohypophysial cells are not irreversibly committed to the production of one single hormone and that their phenotype can change in response to functional demand.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00008197
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  • 23
    Electronic Resource
    Electronic Resource
    Magnetic resonance spectroscopy of brain in epilepsy (2000)
    Springer
    Child's nervous system 16 (2000), S. 235-241 
    Details
    ISSN: 1433-0350
    Keywords: Key words Magnetic resonance spectroscopy ; Epilepsy ; Brain metabolism ; GABA ; N-Acetyl aspartate ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The current applications of magnetic resonance spectroscopy (MRS) in the clinical management of epileptic patients are reviewed. A major contribution of MRS to epilepsy is its ability to determine lateralisation before surgical resection of the diseased brain region. Phosphorus-31 and proton single-voxel MRS identify abnormalities in high-energy metabolism, neuronal function and neurotransmitter levels, but information can only be obtained from restricted regions of the brain. Spectroscopic imaging techniques (also known as chemical shift imaging) provide a metabolic mapping of the whole brain. They expand the range of applications of MRS to other types of epilepsy (neocortical, frontal) than temporal lobe epilepsy, which is the most often studied. Also, spectral editing techniques in proton MRS make it possible to detect and monitor drug-induced variations of GABA in the human brain, opening new insights into patient response to drug therapy of epilepsy. MRS is playing an increasing role in the noninvasive characterisation and management of epileptic patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003810050504
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  • 24
    Electronic Resource
    Electronic Resource
    The reliability of balance tests performed on the kinesthetic ability trainer (KAT 2000) (2000)
    Springer
    Knee surgery, sports traumatology, arthroscopy 8 (2000), S. 180-185 
    Details
    ISSN: 1433-7347
    Keywords: Keywords Proprioception ; Equilibrium ; Posture ; Reproducibility of results ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Sports Science
    Notes: Abstract The Kinesthetic Ability Trainer (KAT 2000) is a balance platform designed for training and functional testing of the neuromuscular control system. Forty healthy and sports-active persons were tested and 1 month later retested to investigate the reliability of the KAT 2000 testing “one-leg static balance” and “two-leg dynamic balance”. A significant improvement at retesting on the same day was seen in both tests; furthermore the dynamic test result improved significantly with retesting 1 month later. The data obtained made it possible to calculate the 95% confidence limits for an unchanged test result for a single person and a group of persons. The results show a clear learning effect when the persons are retested, especially in the dynamic test. The KAT 2000 can be used as a tool for testing groups of persons both in short- and long-term studies, but it cannot be used for testing single persons due to the great variance in the test results. Further investigations involving injured persons are needed to determine the range of improvement after intervention.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001670050211
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  • 25
    Electronic Resource
    Electronic Resource
    Vitamin C induced apoptosis in human articular chondrocytes (2000)
    Springer
    Pflügers Archiv 440 (2000), S. r046 
    Details
    ISSN: 1432-2013
    Keywords: Key words vitamin C (L-ascorbic acid) ; apoptosis ; human articular chondrocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Chondrocytes present in articular cartilage survive as a resident cell population throughout the lifespan of the individual organism. However, articular chondrocytes as other cells also undergo apoptosis and there is an ever increasing list of diverse stimuli that can induce this phenomenon in vitro. Our main interest was to investigate potential cytotoxic effects of vitamin C (L-ascorbic acid) on human articular chondrocytes. The present study suggests that vitamin C can induce apoptosis in a cell culture of chondrocytes after 18 h of cultivation. Apoptosis-inducing activity of L-ascorbic acid is dose dependent and significantly affected by the presence of serum. The increased number of vitamin C induced apoptotic cells was associated with DNA fragmentation and morphological changes of the cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004240000001
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  • 26
    Electronic Resource
    Electronic Resource
    Identification and molecular cloning of cathepsin P, a novel human putative cysteine protease of the papain family (2000)
    Springer
    Pflügers Archiv 439 (2000), S. r116 
    Details
    ISSN: 1432-2013
    Keywords: Key words cDNA ; Human ; Cathepsin P ; Propeptide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A cDNA encoding a novel human putative member of the papain family of cysteine peptidases has been cloned. The protease, named cathepsin P, is synthesized as a preproprotein. The presumed propeptide of 38 amino acids is followed by a 242-residue mature protein. The mature protease region is 30% identical to human papain-like cathepsins, with all the residues important for catalysis conserved. No similarity was observed in the propeptide region. On the contrary, the proenzyme shares 51-87% residues with some precursors of cysteine proteases from other species that have not yet been characterized. They all show a nearly completely conserved “CYTRED motif” in the propeptide region, not present in other members of the family, and could therefore constitute a distinct subfamily.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004240000112
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  • 27
    Electronic Resource
    Electronic Resource
    Downstream molecular determinants of response to 5-fluorouracil and antifolate thymidylate synthase inhibitors (2000)
    Springer
    Annals of oncology 11 (2000), S. 385-391 
    Details
    ISSN: 1569-8041
    Keywords: 5-fluorouracil ; antifolates ; apoptosis ; DNA repair ; p53 ; thymidylate synthase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Thymidylate synthase (TS) is an essential enzyme for the de novo synthesis of thymidylate and subsequently DNA synthesis. TS has been usedas a target for cancer chemotherapy in the development of fluoropyrimidinessuch as 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine and of novelfolate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), ZD9331,LY231514 (ALIMTA, Pemetrexed), AG337 (Thymitaq, Nolatrexed) and AG331.Although TS has been considered as a target for chemotherapy, the precisemechanism by which TS inhibition leads to cell death is still not completelyresolved. TS inhibition results in depletion of dTTP, an essential precursorfor DNA, and an increase in dUTP. This results in the so-called thymine-lessdeath due to misincorporation of dUTP into DNA; its excision, catalysed byuracil-DNA glycosylase, results in DNA damage. Both this imbalance indTTP/dUTP and DNA damage can result in induction of downstream events, leadingto apoptosis. On the other hand a specific interaction exists betweenoncogenes and TS, by binding of TS protein to the p53and c-mycRNA, while wt p53can also inhibit TS promotor activity. TSinhibition by either 5-FU or antifolates can also result in a depression ofTS protein mediated inhibition of TS mRNA translation leading to induction ofmore TS protein synthesis, and p53protein may further deregulatethis process. These complex indirect and direct interactions between oncogenesand TS may have as yet unclear clinical implications, since most data arebased on in vitroor in vivo studies and some results arecontradictive. In some preliminary clinical studies evidence was postulatedfor a combined prognostic role for TS and p53.This knowledge shouldbe used to design clinical studies with the aim to deliver effective treatmentto potentially sensitive patients both in the adjuvant setting and in advancedstage disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008351221345
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  • 28
    Electronic Resource
    Electronic Resource
    Evidence for the induction of apoptosis by endosulfan in a human T-cell leukemic line (2000)
    Springer
    Molecular and cellular biochemistry 205 (2000), S. 53-66 
    Details
    ISSN: 1573-4919
    Keywords: endosulfan ; cytotoxicity ; mitochondria ; apoptosis ; Jurkat cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Several organochlorinated pesticides including DDT, PCBs and dieldrin have been reported to cause immune suppression and increase susceptibility to infection in animals. Often this manifestation is accompanied by atrophy of major lymphoid organs. It has been suggested that increased apoptotic cell death leading to altered T-B cell ratios, and loss of regulatory cells in critical numbers leads to perturbations in immune function. The major objective of our study was to define the mechanism by which endosulfan, an organochlorinated pesticide, induces human T-cell death using Jurkat, a human T-cell leukemic cell line, as an in vitro model. We exposed Jurkat cells to varying concentrations of endosulfan for 0-48 h and analyzed biochemical and molecular features characteristic of T-cell apoptosis. Endosulfan lowered cell viability and inhibited cell growth in a dose- and time-dependent manner. DAPI staining was used to enumerate apoptotic cells and we observed that endosulfan at 10-200 μM induced a significant percentage of cells to undergo apoptotic cell death. At 48 h, more than 90% cells were apoptotic with 50 μM of endosulfan. We confirmed these observations using both DNA fragmentation and annexin-V binding assays. It is now widely being accepted that mitochondria undergo major changes early during the apoptotic process. We examined mitochondrial transmembrane potential (ΔΨm) in endosulfan treated cells to understand the role of the mitochondria in T-cell apoptosis. Within 30 min of chemical exposure, a significant percentage of cells exhibited a decreased incorporation of DiOC6(3), a cationic lipophilic dye into mitochondria indicating the disruption of ΔΨm. This drop in ΔΨm was both dose- and time-dependent and correlated well with other parameters of apoptosis. We also examined whether this occurred by the down regulation of bcl-2 protein expression that is likely to increase the susceptibility of Jurkat cells to endosulfan toxicity. Paradoxically, the intracellular expression of bcl-2 protein was elevated in a dose dependent manner suggesting endosulfan-induced apoptosis occurred by a non-bcl-2 pathway. Based on these data, as well as those reported elsewhere, we propose the following sequence of events to account for T-cell apoptosis induced by endosulfan: uncoupling of oxidative phosphorylation → excess ROS production → GSH depletion → oxidative stress → disruption of ΔΨm → release of cytochrome C and other apoptosis related proteins to cytosol → apoptosis. This study reports for the first time that endosulfan can induce apoptosis in a human T-cell leukemic cell line which may have direct relevance to loss of T cells and thymocytes in vivo. Furthermore, our data strongly support a role of mitochondrial dysfunction and oxidative stress in endosulfan toxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007080910396
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  • 29
    Electronic Resource
    Electronic Resource
    Effect of regulated expression of the fragile histidine traid gene on cell cycle and proliferation (2000)
    Springer
    Molecular and cellular biochemistry 204 (2000), S. 83-88 
    Details
    ISSN: 1573-4919
    Keywords: FHIT ; cell cycle ; ecdysone ; tumor suppressor ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The mechanism of tumor suppressor action of the fragile histidine triad (FHIT) gene is unknown. Disruption of cell cycle regulation leads to the tumor formation and many tumor suppressor genes suppress tumorigenesis through their effect on cell cycle regulation. We examined the expression of FHIT during the cell cycle, and determined whether overexpression of FHIT affects cell cycle kinetics and apoptosis. The FHIT cDNA was cloned into the ecdysone-inducible expression vector in both the sense and antisense orientations. Overexpression of the sense or antisense construct did not affect cell proliferation, cell cycle distribution or apoptosis in human 293T cells. Analysis of the FHIT expression in 293T cells collected at various cell cycle phases showed that the expression of FHIT is not under cell cycle regulation. These results indicate that the tumor suppressor activity of the FHIT gene may be independent of an effect on the cell cycle and apoptosis mechanisms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007068823848
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  • 30
    Electronic Resource
    Electronic Resource
    Regulation of tumor growth and metastasis of human melanoma by the CREB transcription factor family (2000)
    Springer
    Molecular and cellular biochemistry 212 (2000), S. 19-28 
    Details
    ISSN: 1573-4919
    Keywords: melanoma ; transcription factors ; CREB ; invasion ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The purpose of this study was to determine the role of CREB and its associated proteins in melanoma progression. We used MeWo human melanoma cells transfected with a dominant negative construct of CREB, KCREB. KCREB has a mutation in its DNA-binding domain and can not bind the CRE element. Expression of KCREB yields proper heterodimerization with CREB and its associated proteins, but the proteins associated with KCREB do not confer the same degree of transcriptional activity as they would in the case of wild-type CREB. Here, we demonstrate that expression of KCREB in MeWo melanoma cells leads to a decrease in their tumorigenicity and metastatic potential in nude mice. We identified two mechanisms that explain at least partially this effect of KCREB. The first, is one in which CREB and its associated proteins play an essential role in invasion. We showed that the invasive properties of KCREB-transfected MeWo cells were reduced due to the downregulation of the CRE-dependent expression of the type IV collagenase MMP-2 and the adhesion molecule MCAM/MUC18. In the second mechanism, CREB and its associated proteins act as survival factors for human melanoma cells. Here we demonstrated that expression of KCREB in MeWo cells rendered them susceptible to apoptosis induced by thapsigargin, which in turn increased the intracellular level of Ca2+. Thapsigargin induced CREB and ATF-1 phosphorylation and activated CRE-dependent transcription in MeWo cells. Collectively, our data demonstrate that CREB and its associated proteins play an important role in tumor growth and metastasis of human melanoma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007128101751
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  • 31
    Electronic Resource
    Electronic Resource
    Increased T-type Ca2+ channel activity as a determinant of cellular toxicity in neuronal cell lines expressing polyglutamine-expanded human androgen receptors (2000)
    Springer
    Molecular and cellular biochemistry 203 (2000), S. 23-31 
    Details
    ISSN: 1573-4919
    Keywords: T-type Ca2+ channel ; polyglutamine-expanded androgen receptor ; CAG trinucleotide repeats ; spinobulbar muscular atrophy ; apoptosis ; motorneuron ; cell lines ; neuroblastoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract We have analyzed Ca2+ currents in two neuroblastoma-motor neuron hybrid cell lines that expressed normal or glutamine-expanded human androgen receptors (polyGln-expanded AR) either transiently or stably. The cell lines express a unique, low-threshold, transient type of Ca2+ current that is not affected by L-type Ca2+ channel blocker (PN 200-110), N-type Ca2+ channel blocker (ω-conotoxin GVIA) or P-type Ca2+ channel blocker (Agatoxin IVA) but is blocked by either Cd2+ or Ni2+. This pharmacological profile most closely resembles that of T-type Ca2+ channels [1-3]. Exposure to androgen had no effect on control cell lines or cells transfected with normal AR but significantly changed the steady-state activation in cells transfected with expanded AR. The observed negative shift in steady-state activation results in a large increase in the T-type Ca2+ channel window current. We suggest that Ca2+ overload due to abnormal voltage-dependence of transient Ca2+ channel activation may contribute to motor neuron toxicity in spinobulbar muscular atrophy (SBMA). This hypothesis is supported by the additional finding that, at concentrations that selectively block T-type Ca2+ channel currents, Ni2+ significantly reduced cell death in cell lines transfected with polyGln-expanded AR.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007010020228
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  • 32
    Electronic Resource
    Electronic Resource
    Synergistic effects of 8-Cl-cAMP and retinoic acids in the inhibition of growth and induction of apoptosis in ovarian cancer cells: Induction of retinoic acid receptor β (2000)
    Springer
    Molecular and cellular biochemistry 204 (2000), S. 1-9 
    Details
    ISSN: 1573-4919
    Keywords: retinoic acid ; RARβ ; protein kinase A ; apoptosis ; caspase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Both cAMP and retinoids play a role in cell differentiation and the control of cell growth. A site-selective cAMP analog, 8-Cl-cAMP and retinoic acid synergistically inhibit growth and induce apoptosis in certain cancer cells. In advanced or recurrent malignant diseases, retinoic acid (RA) is not effective even at doses that are toxic to the host. The objective of our present study was to examine the mechanism(s) of synergistic effects of retinoic acid (9-cis, 13-cis or all-trans RA) and 8-Cl-cAMP on apoptosis in human ovarian cancer NIH: OVCAR-3 and OVCAR-8 cells. RA induced growth inhibition and apoptosis in OVCAR-3 and OVCAR-8 cells. 8-Cl-cAMP acted synergistically with RA in inducing and activating retinoic acid receptor β (RARβ) which correlates with growth inhibition and apoptosis in both cell types. In addition, induction of apoptosis by RA plus 8-Cl-cAMP requires caspase-3 activation followed by cleavage of anti-poly(ADP-ribose) polymerase. Furthermore, mutations in CRE-related motif within the RARβ promoter resulted in loss of both transcriptional activation of RARβ and synergy between RA and 8-Cl-cAMP. RARβ expression appears to be associated with induction of apoptosis. Introduction of the RARβ gene into OVCAR-3 cells resulted in gain of RA sensitivity. Loss of RARβ expression, therefore, may contribute to the tumorigenicity of human ovarian cancer cells. Thus, combined treatment with RA and 8-Cl-cAMP may provide an effective means for inducing RARβ expression leading to apoptosis in ovarian cancer cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007074814676
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  • 33
    Electronic Resource
    Electronic Resource
    Transcriptional activation of p21WAF1by PTEN/MMAC1 tumr suppressor (2000)
    Springer
    Molecular and cellular biochemistry 203 (2000), S. 59-71 
    Details
    ISSN: 1573-4919
    Keywords: PTEN tumor suppressor ; cyclin-dependent kinase inhibitors ; apoptosis ; chemosensitivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The recently discovered tumor suppressor gene PTEN has been found mutated in many types of advanced tumors. When introduced into tumor cells that lack the wild-type allele of the gene, PTEN was able to suppress the growth of these cells. Here, we have analyzed how PTEN might alter cell cycle-regulatory controls to achieve this growth-inhibitory effect. We found that overexpression of PTEN stimulates the synthesis of three inhibitors of cyclin-dependent kinases, p21WAF1, p27KIP1, and p57,KIP2. This effect is very specific, as the expression of other components of the cell cycle engine, various cyclins and cyclin-dependent kinases, is not affected. For p21WAF1 we show that this induction is due to the p53-independent transcriptional activation of its promoter. In addition, increased expression of PTEN rendered the cells more sensitive to apoptotic cell death. Therefore, our data suggest a two-fold mechanism of growth inhibition by PTEN: one that acts via the increased expression of CKIs such as p21WAF1, and another that augments the cellular propensity for apoptotic cell death.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007024624967
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  • 34
    Electronic Resource
    Electronic Resource
    Unmodified calcium concentrations in tumour necrosis factor receptor subtype-mediated apoptotic cell death (2000)
    Springer
    Molecular and cellular biochemistry 211 (2000), S. 19-26 
    Details
    ISSN: 1573-4919
    Keywords: tumour necrosis factor ; receptors ; subtypes ; calcium ; apoptosis ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Tumour necrosis factor-α (TNF) receptors mediate a variety of effects dependent on cell type. A role for Ca2+ in TNF-induced death remains uncertain. Here we investigated restricting intracellular/extracellular Ca2+ in HeLa epithelial carcinoma cells expressing low and high levels of p75TNFR receptor subtype and KYM-1 rhabdomyosarcoma cells, models of rapid TNF-induced apoptosis. Ca2+-chelators EGTA and BAPTA-AM as well as microsomal Ca2+-ATPase inhibitor thapsigargin, did not alter TNF-induced death. TNF was also unable to alter resting [Ca2+]i levels which remained 〈 200 nM even during times when these cells were undergoing apoptotic cell death. These findings indicate no role for modulated Ca2+ concentrations in TNF-induced apoptotic cell death.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007189911897
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    Molecular Steps of Cell Suicide: An Insight into Immune Senescence (2000)
    Springer
    Journal of clinical immunology 20 (2000), S. 229-239 
    Details
    ISSN: 1573-2592
    Keywords: Aging ; apoptosis ; TNF receptor ; Fas ; Fas ligand ; mitochondria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The cellular and molecular basis of immune senescence is unclear. A number of mechanisms have been proposed. In this issue of the Journal of Clinical Immunology, some of the mechanisms for various immunologic abnormalities in aging are presented. In this article, various molecular steps of both death receptor and mitochondrial pathways of apoptosis in general are reviewed. In particular, the role of apoptosis in T-cell immune senescence is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006653917314
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  • 36
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    Differential responses to Bcl-2 family genes to etoposide in chronic myeloid leukemia K562 cells (2000)
    Springer
    Molecular and cellular biochemistry 206 (2000), S. 43-50 
    Details
    ISSN: 1573-4919
    Keywords: etoposide ; Bcl-XL ; Bax ; apoptosis ; K562 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Etoposide is a potent anticancer agent that is used to treat various tumors. We have investigated the dose-dependent effect of etoposide on apoptosis using chronic myeloid leukemia K562 cells treated with low (5 μM) or high (100 μM) concentrations of the drug. At a low concentration, etoposide induced little apoptosis at 24 h, while about 20% of the cells showed apoptosis morphologically at a high concentration. Processing of caspase-3 was slightly detected from 12 h and became obvious at 24 h with 100 μM etoposide. Caspase-3-like protease activity was detected at 24 h with a high concentration. Moreover, these changes were accompanied by cleavage of poly ADP ribose polymerase (PARP). Changes of the mRNA levels of most apoptosis-regulating genes were not prominent at both concentrations, except for the rapid induction of c-IAP-2/HIAP-1 and the down-regulation of Bcl-XL by 100 μM etoposide. The downregulation of Bcl-XL protein occurred from 6 h, while Bax protein conversely showed a slight increase from 6 h. Taken together, the present findings show that the dose-dependent apoptotic effect of etoposide is based on a change in the balance between Bcl-XL and Bax, which precedes the activation of caspase-3.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007056727876
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  • 37
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    Electronic Resource
    Glycochenodeoxycholic acid (GCDC) induced hepatocyte apoptosis is associated with early modulation of intracellular PKC activity (2000)
    Springer
    Molecular and cellular biochemistry 207 (2000), S. 19-27 
    Details
    ISSN: 1573-4919
    Keywords: PKC ; apoptosis ; bile acid ; hepatocyte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The effect of GCDC-induced apoptosis on PKC activity and PKC's role in GCDC-induced hepatocyte apoptosis is unclear. The specific aims of this study were to determine if GCDC-induced apoptosis changed intracellular PKC activity and if modulation of PKC activity affected GCDC-induced hepatocyte apoptosis. Apoptosis was induced in isolated hepatocytes using GCDC. PKC activity was measured and specific PKC and calpain inhibitors were used to study the effects of PKC and calpain modulation on GCDC-induced apoptosis. After 4 h exposure, 50 μM GCDC induced apoptosis in 42% of hepatocytes. Intracellular PKC activity decreased to 44% of controls 2 h after exposure of hepatocytes to GCDC (p 〈 0.001). Pre-incubation of hepatocytes with the calpain protease inhibitor restored PKC activity in GCDC exposed hepatocytes to 91± 5% of control cells. Pre-incubation of hepatocytes with a calpain inhibitor decreased GCDC-induced apoptosis as did pre-incubation with the PKC activating phorbol ester, PMA. The combination of calpain inhibition and PMA further reduced GCDC-induced apoptosis but caused low level hepatic apoptosis. Inhibition of PKC with chelerythrine also substantially reduced GCDC-induced hepatocyte apoptosis. GCDC-induced apoptosis is associated with decreases in total cellular PKC activity, which appear to be dependent on intracellular calpain-like protease activity. The combination of protease inhibition and phorbol ester pretreatment preserved total cellular PKC activity and decreased GCDC-induced apoptosis but induced low level apoptosis in the absence of GCDC exposure. PKC inhibition also decreased GCDC-induced hepatocyte apoptosis highlighting the complex interactions of PKC and proteases during GCDC-induced apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007021710825
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  • 38
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    Dexamethasone increases the incorporation of [3H] serine into phosphatidylserine and the activity of serine base exchange enzyme in mouse thymocytes: A possible relation between serine base exchange enzyme and apoptosis (2000)
    Springer
    Molecular and cellular biochemistry 211 (2000), S. 61-67 
    Details
    ISSN: 1573-4919
    Keywords: phosphatidylserine ; base exchange ; apoptosis ; thymocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The exposure of phosphatidylserine toward the external surface of the membrane is a well-established event of programmed cell death. The possibility that an apoptotic stimulus influences the metabolism of this phospholipid could be relevant not only in relation to the previously mentioned event but also in relation to the capability of membrane phosphatidylserine to influence PKC activity. The present investigation demonstrates that treatment of mouse thymocytes with the apoptotic stimulus dexamethasone, enhances the incorporation of [3H]serine into phosphatidylserine. Cell treatment with dexamethasone also enhanced the activity of serine base exchange enzyme, assayed in thymocyte lysate. Both the effects were observed at periods of treatment preceding DNA fragmentation. The addition of unlabelled ethanolamine, together with [3H]serine to the medium containing dexamethasone-treated thymocytes lowered the radioactivity into phosphatidylserine. Serine base exchange enzyme activity was influenced by the procedure used to prepare thymocyte lysate and was lowered by the addition of fluoroaluminate, that is widely used as a G-protein activator. The increase of serine base exchange enzyme activity induced by dexamethasone treatment was observed independently by the procedure used to prepare cell lysate and by the presence or absence of fluoroaluminate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007102531404
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  • 39
    Electronic Resource
    Electronic Resource
    Attenuation of macrophage apoptosis by the cAMP-signalling system (2000)
    Springer
    Molecular and cellular biochemistry 212 (2000), S. 35-43 
    Details
    ISSN: 1573-4919
    Keywords: cAMP ; CRE ; Cox-2 ; NO ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Previous studies revealed that expression and activation of cyclooxygenase-2 (Cox-2) conveyed a protective principle in murine macrophages, thus attenuating pro-apoptotic actions of chemotherapeutic agents or programmed cell death as a result of massive nitric oxide (NO) generation. Expression of Cox-2 was achieved by treatment of cells with lipopolysaccharide/interferon-γ or nontoxic doses of NO releasing agents. We reasoned E-type prostanoid formation, and in turn an intracellular cAMP increase as the underlying protective mechanism. To prove our hypothesis, we analyzed the effects of lipophilic cAMP-analogs on NO, cisplatin, or etoposide induced apoptosis in RAW 264.7 macrophages. Selected apoptotic parameters comprised DNA fragmentation (diphenylamine assay), annexin V staining of phosphatidylserine, caspase activity (quantitated by the cleavage of a fluorogenic caspase-3-like substrate Ac-DEVD-AMC), and mitochondrial membrane depolarisation (ΔΨ). Western blots detected accumulation of the tumor suppressor protein p53, relocation of cytochrome c to the cytosol, and expression of the anti-apoptotic protein Bcl-xL. Prestimulation with lipophilic cAMP-analogs attenuated apoptosis with the notion that cell death parameters were basically absent. To verify gene induction by cAMP in association with protection we established activation of cAMP response element binding protein (CREB) by gel-shift analysis and moreover, treated macrophages with oligonucleotides containing a cAMP-responsive element (CRE) in order to scavenge CREB. Decoy oligonucleotides, but not control oligonucleotides, attenuated cAMP-evoked protection and reestablished pro-apoptotic parameters. We conclude that gene induction by cAMP protects macrophages towards apoptosis that occurs as a result of excessive NO formation or addition of chemotherapeutica. Attenuating programmed cell death by the cAMP-signaling system may be found in association with Cox-2 expression and tumor formation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007124203607
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  • 40
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    Electronic Resource
    Hydrogen peroxide-induced apoptosis in human hepatoma cells is mediated by CD95(APO-1/Fas) receptor/ligand system and may involve activation of wild-type p53 (2000)
    Springer
    Molecular biology reports 27 (2000), S. 1-11 
    Details
    ISSN: 1573-4978
    Keywords: apoptosis ; CD95 ; human hepatoma cell ; hydrogen peroxide ; p53
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Reactive oxygen species (ROS) play an important role in cell death induced by many different stimuli. Direct exposure of human hepatoma cell line SMMC-7221 to hydrogen peroxide (H2O2) can induce apoptosis characterized by morphological evidence and fragmentation of DNA assayed by terminal deoxynucleotidyl transferase assay (TUNEL assay). Analysis of flow cytometry indicated that H2O2 can decrease the level of CD95(APO-1/Fas), and it is confirmed that H2O2 can also activate the differential expression of some specific gene such as p53 by means of RT-PCR technique. The results indicated that CD95 signal transduction system may be involved in the H2O2-induced apoptosis, and can regulate some specific genes associated with apoptosis in transcription and translation levels such as p53.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007003229171
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  • 41
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    Caffeine withdrawal increases cerebral blood flow velocity and alters quantitative electroencephalography (EEG) activity (2000)
    Springer
    Psychopharmacology 147 (2000), S. 371-377 
    Details
    ISSN: 1432-2072
    Keywords: Key words Cerebral blood flow velocity ; EEG ; Caffeine ; Withdrawal ; Physical dependence ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Cessation of daily caffeine consumption produces a withdrawal syndrome comprised of subjective symptoms and functional impairment. Few controlled studies have examined the physiological effects of caffeine withdrawal. Objective: The present study examined the effect of caffeine withdrawal on cerebral blood flow velocity and quantitative EEG. Methods: Ten volunteers reporting moderate caffeine intake (mean 333 mg/day) participated in this double-blind study. Subjects completed several tests when maintaining their normal diet (baseline period) and during two 1-day periods during which they consumed caffeine-free diets and received capsules containing placebo (placebo test session) or caffeine (caffeine test session) in amounts equal to their baseline daily caffeine consumption. Blood flow velocity was determined for four arteries: right and left middle (MCA), and right and left anterior (ACA) cerebral arteries using pulsed transcranial Doppler sonography. EEG was recorded for 3 min from eight scalp sites while subjects sat, with eyes closed, in a sound-attenuated electronically shielded chamber. Subjective effects were assessed with questionnaires. Results: Results showed an effect of the placebo (21-h withdrawal) condition compared to the caffeine condition. Placebo significantly increased the mean velocity, systolic velocity and diastolic velocity (cm/s) in all four cerebral arteries. In the MCA, the pulsatility index was significantly decreased following placebo. Placebo significantly increased EEG theta power. Placebo also produces subjective effect changes, including increases in heavy feelings in arms and legs and decreases in ability to concentrate. The caffeine and baseline conditions produced similar results on both the physiological and subjective measures. Conclusion: Cessation of daily caffeine consumption produced changes in cerebral blood flow velocity and quantitative EEG. These changes may be related to classic caffeine withdrawal symptoms of headache, drowsiness and decreased alertness.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050005
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  • 42
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    Electronic Resource
    Reinforcing and subjective effects of morphine in human opioid abusers: effect of dose and alternative reinforcer (2000)
    Springer
    Psychopharmacology 148 (2000), S. 272-280 
    Details
    ISSN: 1432-2072
    Keywords: Key words Opioids ; Self-administration ; Progressive ratio ; Drug abuse ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Although most opioid self-administration research has been conducted with laboratory animals, such research with humans is necessary to answer questions unique to human drug-taking behavior. Objective: We investigated the influence of morphine dose and an alternative non-drug reinforcer on choice between morphine versus money and examined the relationship between drug-reinforced behavior and subjective euphoria. Methods: Five male opioid users participated in the 7-week study. During the first 5 weeks, a single dose of morphine (0, 4, 8, 16, or 32 mg/70 kg) was available each week. On Monday, subjects received an IM injection of the dose tested that week. On Tuesday, Thursday, and Friday, subjects could work for morphine or money under a second-order, progressive ratio schedule. For each primary ratio completed on the drug lever, subjects earned one-ninth of the available drug dose, and for each ratio completed on the money lever, subjects earned $1. Total amount of drug earned was administered in a single IM injection at the end of the session; money earned was credited to the subject’s account. Results: As morphine dose increased, responding for drug increased in an orderly manner and responding for money decreased. During the final phase of the study, the lowest and highest doses that maintained drug responding for each subject were repeated, and the value of the alternative reinforcer was increased to $2 per ratio. This manipulation was associated with decreased drug-maintained responding at the lowest, but not the highest, reinforcing dose of morphine. Conclusion: The progressive ratio, concurrent access procedure may be useful in predicting the outcome of drug abuse treatment interventions that use alternate reinforcement strategies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050051
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  • 43
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    Electronic Resource
    Antisense Downregulation of the Apoptosis-related Bcl-2 and Bcl-xL Proteins: A New Approach to Cancer Therapy (2000)
    Springer
    Molecular biology 34 (2000), S. 875-887 
    Details
    ISSN: 1608-3245
    Keywords: antisense oligonucleotides ; oncogenesis ; therapy of cancer ; apoptosis ; bcl family
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Members of the bcl-2 family genes are thought to be central regulators of apoptosis. Overexpression of antiapoptotic proteins, such as Bcl-2 and Bcl-xL, contributes not only to the development of cancer but also to its resistance against a wide variety of anticancer agents. Thus, downregulation of Bcl-2 and Bcl-xL can potentially be used to improve therapeutic approaches to advanced cancer. The use of antisense biotechnology to downregulate antiapoptotic bcl family members in diverse cancers in vitro and in vivo is reviewed. The effects and potential limitations of antisense strategies are also discussed in the context of a critical view of recent research in the field.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026679826610
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  • 44
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    Electronic Resource
    Induction of apoptosis in cultured cells by extracts from shiitake (Lentinula edodes) mycelial culture broth (2000)
    Springer
    Mycoscience 41 (2000), S. 623-631 
    Details
    ISSN: 1618-2545
    Keywords: apoptosis ; caspase-3 ; E2F factor ; Lentinula edodes ; mycelial culture broth
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Extracts fromshiitake (Lentinula edodes) mycelial culture broth, by an organic solvent ethyl acetate, inhibited the proliferation of cultured cells. At lower concentrations (1.25–15 μg/ml), this inhibition, measured by the MTT assay, was dose- and cell line-dependent. Inhibition of tumor cells, such as Caski, SiHa, HeLa, HP-1 and A375, byL. edodes-436 extracts was stronger than inhibition of normal cells (3T3). At 20 μg/ml, the extracts induced changes in cell shape, DNA-fragmentation and the activation of caspase-3. The extracts also inhibited the binding of E2F protein to its promoter. The results suggest that extracts ofL. edodes culture broth contain substances that have the ability to induce apoptosis in the cultured cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02460929
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  • 45
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    Electronic Resource
    Effect of dietary control on plasma nitrate level and estimation of basal systemic nitric oxide production rate in humans (2000)
    Springer
    Heart and vessels 15 (2000), S. 274-279 
    Details
    ISSN: 1615-2573
    Keywords: Key words Basal systemic nitric oxide production rate ; Fasting ; Human ; Plasma nitrate ; Single-compartment model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract It is of great interest and value to evaluate the systemic nitric oxide (NO) production rate in humans under various conditions. However, the currently available estimation methods are troublesome and time-consuming. We thus aimed at developing a simple method to estimate the basal systemic NO production rate in humans based on a steady-state analysis, i.e., a balance between the systemic NO production rate and the total nitrate elimination rate. Plasma nitrate concentrations of young healthy volunteers (n = 7 in group 1; n = 9 in group 2) were measured for 2 days. In group 1, all subjects had the same meals for 7 days prior to the plasma nitrate measurement. In group 2, all subjects were allowed free diets. The plasma nitrate concentrations were highly influenced by dietary nitrite/nitrate intake in both groups and reached the steady-state levels after 14-h fasting. Accordingly, the basal systemic NO production rates were estimated from the plasma nitrate concentrations after 14-h fasting (group 1, 630 ± 37 nmol min−1 = 0.78 ± 0.03 μmol kg−1 h−1; group 2, 597 ± 45 nmol min−1 = 0.66 ± 0.05 μmol kg−1 h−1, P = not significant vs group 1). These estimated values were comparable to the values obtained by other methods. In conclusion, the present estimation method with 14-h fasting using a single-compartment analysis was found to be a simple approach to quantitative evaluation and intra- and interindividual comparisons of the basal systemic NO production rates in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003800070005
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  • 46
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    Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease (2000)
    Springer
    Heart and vessels 15 (2000), S. 18-22 
    Details
    ISSN: 1615-2573
    Keywords: Key words Heat shock protein ; Antibody ; Vascular disease ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Heat shock proteins (Hsp) are families of phylogenetically conserved molecules that have a range of cytoprotective and intracellular functional roles. Reactivity to heat shock proteins has been implicated in the development of autoimmune disease and tissue expression of heat shock proteins and increased levels of anti-Hsp antibodies have also been reported in vascular disease. This study compared circulating levels of Hsp60 and Hsp70 and antihuman Hsp60, antihuman Hsp70, and antimycobacterial Hsp65 antibodies in peripheral (PVD) and renal (RVD) vascular disease with those in age- and sex-matched controls. Levels of Hsp70 were higher in both PVD (median 580 vs 40; P 〈 0.01) and RVD (median 160 vs 0; P 〈 0.03), whereas there were no differences in Hsp60 levels. Anti-Hsp60 antibody levels were elevated in PVD (146 vs 81 arbitrary units/ml; P 〈 0.04), but not RVD. This is the first study to demonstrate increased levels of circulating Hsp70 in pathological disease states; however, its physiological role remains to be determined.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003800070043
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  • 47
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    Facilitation of the withdrawal reflex by repeated transcutaneous electrical stimulation: an experimental study on central integration in humans (2000)
    Springer
    European journal of applied physiology 81 (2000), S. 165-173 
    Details
    ISSN: 1439-6327
    Keywords: Key words Temporal summation ; Repeated electrical stimulation ; Experimental pain ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the present human study, we aimed to investigate the facilitation of both the subjective pain responses, and the withdrawal reflex to consecutive transcutaneous electrical stimuli as measures of temporal summation. The frequency (0.5–20 Hz) and intensity (0.4–0.8 times the reflex threshold,  ×RT) of the electrical stimuli were systematically varied. When using repeated stimulation, the stimulus intensity that evoked pain was lower than that required by a single stimulus (temporal summation). Temporal summation leading to pain was found to depend significantly upon both frequency and intensity (e.g. stimulation at 1 Hz caused summation at 0.8 × RT, whereas stimulation at 20 Hz caused summation at 0.6 × RT). The strongest reflex facilitation, and hence the strongest pain intensity was obtained for stimulation at 10–20 Hz at an intensity of 0.8 × RT. In conclusion, the results of the present human study demonstrate clearly that a stimulus that is perceived as a localised, repetitive tactile tap can be integrated and cause severe pain. This suggests that pathologically generated sparse nociceptive afferent activity causes strong pain by central integration. This might be one mechanism to explain why clinical conditions can become excruciatingly painful despite the fact that the pathophysiological changes seem to be marginal (e.g. minor nerve trauma).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004210050026
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  • 48
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    Electronic Resource
    Changes in muscle afferents, motoneurons and motor drive during muscle fatigue (2000)
    Springer
    European journal of applied physiology 83 (2000), S. 106-115 
    Details
    ISSN: 1439-6327
    Keywords: Key words Central fatigue ; Muscle fatigue ; Human ; Motor cortex ; Motoneuron
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Fatigue is a reduction of maximal muscle force or power that occurs with exercise. It is accompanied by changes at multiple levels in the motor pathway and also by changes in the discharge patterns of muscle afferents. Changes in afferent firing can lead to altered perceptions and can also act on the efferent pathway. Changes in the motor pathway include slowing of motor unit firing rates during sustained maximal voluntary contractions (MVCs). Muscle responses to stimulation at different levels of the motor pathway also change. Transcranial magnetic stimulation of the motor cortex and stimulation of descending tracts in the spinal cord in human subjects show an increase in the response of the cortex and a decrease in response of the motoneuron pool during sustained MVCs. In addition, the silent period following magnetic stimulation is prolonged. During relaxation after fatiguing exercise, muscle responses to stimulation of the motor cortex are initially facilitated and are then depressed for many minutes, whereas responses to descending tract stimulation are initially depressed but recover over about 2 min. Although some of the loss of force of fatigue does occur through inadequate drive to the muscle, it is not clear which, if any, of the changes described in the cortex or the motoneurons are responsible for loss of maximal voluntary force and thus contribute to fatigue. Changes may be associated with muscle fatigue without causing it.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004210000269
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  • 49
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    Electronic Resource
    Position sense acuity is diminished following repetitive low-intensity work to fatigue in a simulated occupational setting (2000)
    Springer
    European journal of applied physiology 81 (2000), S. 361-367 
    Details
    ISSN: 1439-6327
    Keywords: Key words Fatigue ; Glenohumeral joint ; Human ; Occupational musculoskeletal problems ; Proprioception
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Repetitive work to fatigue is soundly associated with work-related musculoskeletal disorders (WMSD), although the underlying mechanisms are poorly understood. In the present study, we tested the hypothesis that fatiguing work leads to proprioceptive deficits, which can be an initiating factor for the occurrence of WMSD. Thus, the position sense of the shoulder was determined for 13 males and 13 females before and after performing repetitive low-intensity arm work to fatigue in a simulated occupational setting. From a starting position of 45° to the sagittal plane, position sense tests consisted of subjects attempting to actively reproduce target positions of horizontal movements to 15° and 30° (shoulder adduction) and to 60° and 75° (shoulder abduction). An analysis of variance revealed that the absolute error was significantly increased following fatigue for the subjects as a group (P 〈 0.001). Furthermore, females had an overall higher error than males (P 〈 0.01). No difference in error was detected for the shorter movements versus the longer movements. However, the overall absolute error for adduction was significantly higher than for abduction (P 〈 0.001). The results of the present study support the hypothesis of diminished proprioceptive acuity following low-intensity work to fatigue. A reduction in position sense acuity could lead to impairment in motor control, which would further impact on position sense. Thus, a vicious cycle may be activated that might result in WMSD. The poorer position sense acuity observed for females may contribute to the explanation of why females demonstrate a higher incidence of WMSD than males.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004210050055
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  • 50
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    Electronic Resource
    Changes in cross-sectional area in human exercising and non-exercising skeletal muscles (2000)
    Springer
    European journal of applied physiology 81 (2000), S. 210-213 
    Details
    ISSN: 1439-6327
    Keywords: Key words Cross-sectional area ; Exercise ; Human ; Reflex sympathetic activity ; Skeletal muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This research was performed to study how the cross-sectional area (CSA) changes in the skeletal muscles of exercising (E-leg) and contralateral non-exercising (N-leg) legs and to evaluate to what extent changes in CSA mirror changes in blood flow or extravascular water displacement. Seven healthy volunteers performed plantar flexion exercise at three different exercise intensities for 10 min each. Six plantar flexions followed by a 2-s rest in between allowed repeated measurement of the blood flow to the lower limbs by duplex ultrasonography in the popliteal artery and CSA by magnetic resonance imaging. The CSA was measured using manual planimetry at rest and after 3 and 9 min of the exercise periods. The CSA increased in the E-leg by 4.5% and decreased in the N-leg by −2.4%, from rest to highest exercise intensity. Post-exercise imaging of the E-leg showed a bi-phasic recovery of CSA with a rapid phase followed by a slower phase while the blood flow very rapidly returned almost to basal. The time course of the post-exercise decrease indicated that about 50% of the increase in CSA at the highest exercise intensity might have been a result of extravascular water displacement and 50% of an increase in the vasculature volume related to the flow increase. The CSA reduction in N-leg seems to have been related to vasoconstriction, probably mainly of the capacitance vessels since blood flow was not reduced.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004210050032
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  • 51
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    Electronic Resource
    Sympathetic stimulation induced by hand cooling alters cold-induced vasodilatation in humans (2000)
    Springer
    European journal of applied physiology 81 (2000), S. 303-309 
    Details
    ISSN: 1439-6327
    Keywords: Key words Local cold ; Extremities ; Cold induced vasodilatation ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Hand cooling is a cold pressor test, which induces general sympathetic stimulation. This cooling procedure is often performed to investigate cold induced vasodilatation (CIVD) in one finger. To investigate the effects of this sympathetic stimulation on local CIVD, 12 subjects immersed either the right index finger (T1), right hand (T2) or left hand and right index finger (T3) for 30 min in water at 5°C followed by 15-min recovery. Skin temperature and skin blood flow (Q˙ sk) measured by laser Doppler flowmetry on the right index finger, as well as heart rate (f c) and mean arterial blood pressure ( ), were continuously monitored during the three tests. Cutaneous vascular conductance was calculated as Q˙ sk/ . Concentrations of plasma noradrenaline (NA) and adrenaline (AD) were measured at different times during the tests. The results showed no cardiovascular change in T1, whereas f c and increased significantly at the beginning of both T2 and T3. Similarly, sympathetic stimulation was reflected in the NA concentrations, which increased significantly (P 〈 0.01) during T2 and T3 after 5 min of immersion, and remained elevated until the recovery period. The AD concentration did not change during the three tests. During T2, the CIVD appeared later and slower in comparison with T1 [CIVD onset: 12.81 (SEM 2.30) min in T2 and 5.62 (SEM 0.33) min in T1] . During T3, the CIVD onset was not delayed compared to T1 [6.38 (SEM 0.67) min], but the rewarming was lower [+5.40 (SEM 0.86)°C in T3 and +9.10 (SEM 1.31)°C in T1]. These results showed that CIVD could be altered by sympathetic stimulation but it also appeared that the onset of CIVD could be influenced by local cooling, independently of the general sympathetic stimulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004210050047
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    Electronic Resource
    Muscle and tendon stiffness in patients with upper motor neuron lesion following a stroke (2000)
    Springer
    European journal of applied physiology 82 (2000), S. 275-279 
    Details
    ISSN: 1439-6327
    Keywords: Key words Eccentric-concentric actions ; Electromyography ; Gastrocnemius muscle ; Soleus muscle ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The objective of this study was to investigate muscle and tendon stiffness in the triceps surae muscles in patients who had previously had a stroke. The participants were 12 men showing slight to moderate degrees of muscle tonus in the affected leg. All patients showed minimal or no overt clinical motor symptoms, and all walked without mechanical aid. Muscle strengths in isometric and isokinetic activities were measured, as was passive resistance during plantarflexion in each leg. Walking speed was also measured. Evaluations of physical performance and muscle tone were made. Muscle and tendon stiffness was calculated from measurements whilst passively stretching during electrical stimulation, separately for each leg. Muscle strength was significantly higher in the non-affected than in the affected leg. Muscle stiffness was significantly higher in the affected leg than in the non-affected leg. Tendon stiffness was significantly higher in the non-affected than in the affected leg. The higher muscle stiffness in the affected leg might enhance the possibility for storing elastic energy during preactivation. Lower tendon stiffness in the affected leg might reduce the development of fatigue in movements at low velocities.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004210000216
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  • 53
    Electronic Resource
    Electronic Resource
    Leg-press resistance training during 20 days of 6° head-down-tilt bed rest prevents muscle deconditioning (2000)
    Springer
    European journal of applied physiology 82 (2000), S. 30-38 
    Details
    ISSN: 1439-6327
    Keywords: Key words Bed rest ; Resistance training ; Skeletal muscle ; Physiological cross-sectional area ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The purpose of this study was to investigate the effects of resistance training on the morphological and functional properties of human lower limb muscles during 20 days of 6° head-down-tilt bed rest. Nine men were randomly assigned to the resistance training group (BR-Tr, n=5) or the non-training, control group (BR-Cont, n=4). Isometric leg-press exercises were performed: 3 s × 30 repetitions (30 s rest between repetitions) daily for 20 days during the bed-rest period. Serial axial magnetic resonance images were taken from the right thigh and leg muscles, and muscle volume, muscle length, and fibre length were estimated. The physiological cross-sectional areas (PCSAs) of the knee extensor, knee flexor, ankle plantarflexor, and ankle dorsiflexor (tibialis anterior) muscle groups were determined as muscle volume multiplied by the cosine of the angle of fibre pennation divided by fibre length. Maximum voluntary contraction (MVC) during knee extension was measured. No significant changes were observed in the PCSA of the knee extensor muscles in BR-Tr group, whereas the PCSA in the BR-Cont group decreased by 7.8%. The PCSA of the knee flexor and plantarflexor muscles in the BR-Tr group and BR-Cont group significantly decreased after bed rest (knee flexors, 10.2% and 11.5%; plantarflexors, 13.0% and 12.8%, respectively). However, in both groups bed rest had no effect on the muscle volume and PCSA of the tibialis anterior. MVC was maintained by resistance training in the BR-Tr group (decreased by 1%). In contrast, a decline of strength was observed in the BR-Cont group (−16%), but this result was not statistically significant. These results suggest that isometric leg-press training prevents the deconditioning (i.e. atrophy and decline of strength) of the knee extensor muscle group.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004210050648
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  • 54
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    Electronic Resource
    Prolongation of murine hybridoma cell survival in stationary batch culture by Bcl-xL expression (2000)
    Springer
    Cytotechnology 34 (2000), S. 131-139 
    Details
    ISSN: 1573-0778
    Keywords: apoptosis ; bcl-xL ; cell growth ; cell viability ; hybridoma ; myeloma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract While the ectopic expression of the anti-apoptoticprotein Bcl-2 has been shown to significantly increaseboth cell viability and antibody production in batchculture, some cell lines are refractory to thesemanipulations. For example, the NS/O and theP3x63Ag8.653 murine myelomas, which express highendogenous levels of the Bcl-2 homologue Bcl-xL, areboth resistant to the anti-apoptotic effect of Bcl-2.This indicates that, in these cells, Bcl-2 and Bcl-xLmay be functionally redundant. In order to define therole which Bcl-xL plays in hybridoma cultures, we usedthe Sp2/0-Ag14 cell line. This murine hybridomaexpresses low levels of Bcl-xL and is highly sensitiveto apoptosis induction by cycloheximide (CHX) and byamino acid depletion. Bcl-xL-transfected Sp2/0-Ag14cells were more resistant than the wild type and theplasmid-containing cells to apoptosis induced by CHXand by glutamine depletion. Moreover, when compared tothe vector-transfected control, Bcl-xL-Sp2/0 cellsexhibited a substantial increase in viability instationary batch culture. Interestingly, Sp2/0-Ag14cells overexpressing Bcl-xL showed a growth behaviourthat was similar to the parent myeloma cell lineP3x63Ag8.653. Our results suggest that Bcl-xLexpression levels are sufficient to account for therelative robustness of some hybridoma cell lines instationary batch cultures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008186302600
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    Electronic Resource
    Establishment of an apoptosis-suppressible,cell-cycle arrestable cell line and its applicationfor enhancing protein production of serum-free or-supplemented culture (2000)
    Springer
    Cytotechnology 32 (2000), S. 125-134 
    Details
    ISSN: 1573-0778
    Keywords: antisense ; apoptosis ; cell cycle ; c-jun ; protein production
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract Expression of c-jun gene induces apoptosis ofcells cultured in serum-free medium. It also promotescell-cycling in serum-containing medium, leading cellsto die by overgrowth. Previously, we established anapoptosis-suppressible, cell-cycle arrestable cellline, c-jun AS, by transfecting Friend murineerythroleukemia (F-MEL) cells with adexamethasone-inducible antisense c-jun gene.Induction of the antisense c-jun transcriptionwith dexamethasone suppressed c-jun expression.As a result, c-jun AS cells survived inserum-free medium containing dexamethasone for a longtime, while F-MEL cells died quickly in the presenceor absence of dexamethasone. In serum-containingmedium, the growth of c-jun AS cells was viablyblocked by inducing antisense c-juntranscription, and the cells survived at thenon-growth state avoiding overgrowth. In the presentstudy, protein productivity of c-jun AS cellswas examined in comparison with that of wild typeF-MEL cells. C-jun AS and F-MEL cells werefurther transfected with a vector for expressingalkaline phosphatase as a protein to be produced, andnamed c-jun AS-SEAP and F-MEL-SEAP cells,respectively. In the serum-free medium withdexamethasone, c-jun AS-SEAP cells produced theprotein for up to 6 days, while F-MEL-SEAP cellsstopped production on day 3 due to cell death causedby serum deprivation. In the serum-containing mediumwith dexamethasone, c-jun AS-SEAP cells wereviably arrested in the cell cycle, and cell death dueto overgrowth was avoided. As the result, they couldproduce the protein for up to 18 days, whileF-MEL-SEAP cells stopped production within 7 days dueto cell death caused by overgrowth.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008149218360
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    Electronic Resource
    Decrease in cell surface sialic acid in etoposide-treated Jurkat cells and the role of cell surface sialidase (2000)
    Springer
    Glycoconjugate journal 17 (2000), S. 301-306 
    Details
    ISSN: 1573-4986
    Keywords: sialidase ; sialyltransferase ; apoptosis ; Jurkat cells ; etoposide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The present study investigated the mechanism underlying alterations of cell surface sugar chains of Jurkat cells by inducing apoptosis with etoposide, an inhibitor of topoisomerase II. Within 3[emsp4 ]h of etoposide treatment, flowcytometric analysis revealed a decrease in Maackia amurensis agglutinin recognized α2,3-linked sialic acid moieties and an increase in Ricinus communis agglutinin recognized galactose. The results suggested that asialo-sugar chains on glycoconjugates were rapidly induced on the etoposide-treated cell surface. To clarify the desialylation mechanism, we studied α2,3-sialyltransferase mRNA expression and the activity of sialidase on the cell surface during etoposide-induced apoptosis. The expression of hST3Gal III and hST3Gal IV mRNAs were down-regulated and sialidase activity on the cell surface increased threefold within 2[emsp4 ]h of etoposide treatment. Moreover, the decrease in α2,3-linked sialic acid levels was significantly suppressed in the presence of 2,3-dehydro-2-deoxy-N-acetylneuraminic acid, an inhibitor of sialidase. These results suggested that activation or exposure of sialidase on the cell surface was induced by etoposide treatment and was the main cause of the decrease in sialic acids.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007165403771
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  • 57
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    Electronic Resource
    Quercetin inhibits the invasion and mobility of murine melanoma B16-BL6 cells through inducing apoptosis via decreasing Bcl-2 expression (2000)
    Springer
    Clinical & experimental metastasis 18 (2000), S. 415-421 
    Details
    ISSN: 1573-7276
    Keywords: apoptosis ; Bcl-2 ; cell cycle ; invasion ; metastasis ; mobility ; melanoma B16-BL6 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Quercetin has been known to have anti-tumor and anti-oxidation activities. In the present study, we have investigated its in vitro anti-metastatic activity. Quercetin inhibited the invasion and mobility of murine melanoma B16-BL6 cells in a dose-dependent manner but did not affect their adhesion to either laminin, fibronectin, or type VI collagen. Moreover, quercetin significantly inhibited the proliferation of B16-BL6 cells only in the case of time incubation longer than 48 h. Quercetin dose-dependently decreased the cell rates in S and G2–M phases of cell cycle. The effect of quercetin to cause a remarkable apoptosis of B16-BL6 cells was also demonstrated by flow cytometric assay as well as DNA fragmentation with a typical 180-bp ladder band in agarose electrophoresis and a quantitative analysis. Furthermore, quercetin markedly inhibited the expression of anti-apoptotic protein Bcl-2 but hardly influenced Bcl-XL. These results suggest that the inhibition of quercetin on invasiveness and migration of B16-BL6 cells are closely associated with the arrest of cell cycle as well as the induction of apoptosis by decreasing the Bcl-2 expression.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1010960615370
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  • 58
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    Electronic Resource
    In vitro effects of cholesteryl butyrate solid lipid nanospheres as a butyric acid pro-drug on melanoma cells: Evaluation of antiproliferative activity and apoptosis induction (2000)
    Springer
    Clinical & experimental metastasis 18 (2000), S. 663-673 
    Details
    ISSN: 1573-7276
    Keywords: apoptosis ; butyrate ; cell cycle ; cholesteryl butyrate ; drug delivery ; melanoma ; solid lipid nanospheres
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Literature data show that butyric acid derivatives bear a dose-dependent differentiative anti-proliferative activity on cancer cell lines and that apoptosis induction may play a major role. Although it was recently shown that solid lipid nanospheres (SLNs) are a suitable tool for several in vivo drug administration routes, there is little available information on melanoma cell lines. This study was aimed at evaluating the anti-proliferative and apoptotic in vitro effects of cholesteryl butyrate (chol-but) SLNs on melanoma cells. Increasing concentrations of chol-but SLNs were used to test two melanoma cell lines. Both cell lines were treated with Na-butyrate (Na-but) and chol-but SLNs for viability. Those tested with chol-but SLNs were more effective than Na-butirate (3 to 72 h). The apoptotic effects of chol-but SLNs were evaluated between 3 and 72 h by annexin-V (ANX-V)/propidium iodide (PI) staining and the antiproliferative effect by PI staining. Apoptosis anti-proliferative-regulatory proteins as bcl-2, Fas/APO1 (CD95) and PCNA (PC10) were also investigated. Flow cytometric analyses evidenced a G0/1-S transition block and a `sub-G0/1' apoptotic peak from 0.5 to 1.0 mM butyric acid. In ANX-V/PI flow cytometric staining, a dose- and time-dependent increase in the apoptotic cell percentage (ANX-V+) coupled with a down-regulation of PC10 and bcl-2 and a parallel up-regulation of Fas/APO1 (CD95) were found in both lines started after 3 to 24 h of chol-but SLNs treatment. Results show that chol-but SLNs exerts a dose/time-dependent effect in melanoma cell apoptosis induction between 3 and 24 h and a dose but not time-dependent effect after 24 h of treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1013186331662
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  • 59
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    Electronic Resource
    Drug-induced Apoptosis by Anti-microtubule Agent, Estramustine Phosphate on Human Malignant Glioma Cell Line, U87MG; in vitro Study (2000)
    Springer
    Journal of neuro-oncology 47 (2000), S. 133-140 
    Details
    ISSN: 1573-7373
    Keywords: apoptosis ; DNA ; glioma ; estramustine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The drug effect of estramustine phosphate (EMP), an anti-microtubule agent on human glioma cells has been studied with the focus being mainly its cytotoxity or its targeting of organelles. However, the pharmacological knowledge of estramustine with respect to its cytotoxity and mechanism is limited. To acquire such knowledge, the present study investigates the ability of EMP to induce apoptosis in a human malignant glioma cell line. Transmission electron microscope (TEM) images were examined to monitor periodic changes. Agarose gel electrophoresis was also examined. Cellular DNA fragmentation ELISA was performed to investigate the DNA fragmentation rates and an MTT assay was studied to evaluate the ID50. A TEM study revealed condensing and fragmentation of the chromatin. Laddering of the bands was observed in all EMP exposure groups in agarose gel electrophoresis. DNA fragmentation in all EMP groups began at 0.5 h following an exposure with EMP and increased in a dose- and time-dependent manner as revealed by DNA ELISA fragmentation. ID50 at 24 h was 5.0 µM according to the MTT assay, a value close to 4.8 µM of ID50 was revealed by the DNA fragmentation assay. None of the above mentioned changes was observed in the control group. These results indicated that EMP caused a drug-induced apoptosis in the human malignant glioma cell line, U87MG.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006393705560
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  • 60
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    Electronic Resource
    Selenium Causes Growth Inhibition and Apoptosis in Human Brain Tumor Cell Lines (2000)
    Springer
    Journal of neuro-oncology 46 (2000), S. 125-133 
    Details
    ISSN: 1573-7373
    Keywords: selenium ; human glioma cells ; mitochondria ; apoptosis ; fibroblasts ; ultrastructure ; MTT
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We examined the effect of the trace element selenium on human glioma cell lines: T98G, U373MG, and U87MG, in addition to dermal fibroblast cells. Cultures were incubated with sodium selenite, and the following parameters were studied: cell growth, mitochondrial function, and ultrastructure. Cell growth was assayed by counting the number of viable cells after treatment with selenium. Mitochondrial function was analyzed using the MTT (tetrazolium salt reduction) assay. Apoptosis was determined by evaluating nuclear chromatin condensation by electron microscopy. The results indicated that selenium had a significant inhibitory effect on the growth of the tumor cells but had little effect upon dermal fibroblasts which had been passaged numerous times. Selenium also induced mitochondrial damage as shown by MTT assay in two brain tumor cell lines and in minimally passaged fibroblasts, but it had little effect upon the high-passage fibroblasts. Ultrastructurally, mitochondria had electron-dense inclusions resulting from selenium treatment. High rates of apoptosis were induced by selenium in the tumor cell lines and in the minimally passaged fibroblasts, whereas the fibroblasts with a high number of passages had some resistance to selenium treatment. This study correlates the adverse effects of selenium on mitochondrial function, inhibition of cell growth, and apoptosis and shows that selenium similarly affects three different brain tumor cell lines and minimally passaged fibroblasts. Further, the results with fibroblasts show that some types of cells after repeated passages can develop resistance to selenium damage.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006436326003
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  • 61
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    Electronic Resource
    Cytotoxic Effect through Fas/APO-1 Expression due to Vitamin K in Human Glioma Cells (2000)
    Springer
    Journal of neuro-oncology 47 (2000), S. 31-38 
    Details
    ISSN: 1573-7373
    Keywords: glioma ; apoptosis ; vitamin K ; reactive oxygen intermediates ; Fas/APO-1 ; flow cytometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Congeners of vitamin K have been found to inhibit growth in various rodent and human tumor cells, but the mechanisms of the inhibitory action are still not well understood. To investigate the modes of actions of vitamin K, we used several vitamin K analogs and examined their cytotoxic effect for human glioma cell lines RBR17T and U251. The analogs included vitamin K1 (VK1), vitamin K2 (VK2), vitamin K3 (VK3), and geranylgeraniol (GGO) which form an unsaturated side chain of VK2. Cell viability was estimated by MTT assay. DNA fragmentation was demonstrated by gel electrophoresis and flow cytometry. In order to study the mechanism of apoptosis, we measured the changes of intracellular reactive oxygen intermediates (ROI) and Fas/APO-1 expression by flow cytometry. The results showed: (1) VK2, VK3, and GGO inhibited cell growth; (2) VK3 had a more potent cytotoxic effect than VK2, and VK3 enhanced the cytotoxic effect of antitumor agents (ACNU and IFN-beta) in RBR17T cells; (3) VK2, VK3, and GGO induce apoptosis; (4) VK3 increased the expression of Fas/APO-1 although VK2 and GGO did not increase its expression in glioma cells; (5) VK3 increased the production of intracellular ROI. Catalase and reduced glutathione (GSH) inhibited production of intracellular ROI and antagonized inhibition of cell-growth induced by VK2, but failed to antagonize that of VK2 and GGO. We hypothesize that VK3 induces apoptosis by promoting the generation of intracellular ROI and Fas/APO-1 expression. On the other hand, VK2 and GGO induce apoptosis but most likely by some other unknown pathway.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006443422488
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  • 62
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    Electronic Resource
    Meningiomas in Singapore: Demographic and Biological Characteristics (2000)
    Springer
    Journal of neuro-oncology 47 (2000), S. 153-160 
    Details
    ISSN: 1573-7373
    Keywords: tumour ; apoptosis ; incidence ; p53 ; bax ; immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We sought to determine the relative incidence of meningiomas compared to other central nervous system tumours in an Asian surgical series, as well as the demographic and biological characteristics of these meningiomas. A review of 655 consecutive cases of central nervous system tumours from 583 patients representing the last five years admissions to one hospital in Singapore was undertaken. A total of 33 malignant/atypical tumours from 19 patients and 196 benign meningiomas from 187 patients were identified. Twenty malignant/atypical and 20 benign tumours were selected at random and subjected to histochemical and immunohistochemical analysis using antibodies directed against p53, bax and 3′-DNA hydroxy groups (TUNEL). Meningiomas comprised some 35.2% of all central nervous system tumours with malignant/atypical meningiomas representing 9.2% of meningiomas. Histochemically, necrosis was the predominant finding. However, peri-necrotic areas displayed p53 positivity in 10% of cases and bax positivity in 25% of cases. Apoptotic cells were detected in the peri-necrotic areas in 90% of benign and 75% of malignant/atypical meningiomas. Meningiomas represent the predominant form of central nervous system tumour in the Singaporean population, and aberration of p53 expression is not associated with tumour formation or progression. There was a slight but non-significant reduction in apoptosis in the progression from benign to malignant meningioma, suggesting that in contrast to many other tumour types disruption of cellular apoptosis is not a predominant driving force in Asian meningioma tumourigenesis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006484829159
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    Electronic Resource
    Human Malignant Glioma Therapy Using Anti-αVβ3 Integrin Agents (2000)
    Springer
    Journal of neuro-oncology 46 (2000), S. 135-144 
    Details
    ISSN: 1573-7373
    Keywords: apoptosis ; cRGDfV ; human gliomas ; integrin αVβ3 ; mouse glioma model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults and is invariably fatal. We have investigated the effect of cyclo-(Arg-Gly-Asp-D-Phe-Val) (cRGDfV) peptide on survival of human malignant glioma cells in vitro and in vivo. Immunofluorescent analyses revealed the presence of αVβ3 integrin on U-87MG and U-373MG cells, but minimal expression on U-251MG cells. Treatment of U-87MG and U-373MG cells in vitro with cRGDfV (20 µg/ml), but not the linear peptide, resulted in the appearance of rounded and loosely attached cells with subsequent cell death. By comparison, neither this cyclic peptide nor its linear homolog had any significant effect on growth and morphology of U-251MG cells. The death of cRGDfV-treated (20 µg/ml) glioma cells was blocked by pretreatment (10 µM) of cells with DEVD-FMK and LEHD-FMK, inhibitors of caspase-3 and caspase-9, respectively. Moreover, when glioma cells grown as spheroids were treated with cRGDfV (50 µg/ml), spheroid formation was markedly reduced. Further, treatment of intracranial U-87MG tumors in scid mice with cyclic peptide significantly (p〈0.001) prolonged their survival. These results indicated (i) that cRGDfV induced apoptosis of human glioma cells by binding αVβ3 integrin expressed on their cell surfaces and (ii) that cRGDfV may be an effective and non-toxic direct anti-tumor therapy for αVβ3-expressing GBMs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006444300504
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    Electronic Resource
    Distinct Radiochemotherapy Protocols Differentially Influence Cellular Proliferation and Expression of p53 and Bcl-2 in Glioblastoma Multiforme Relapses In Vivo (2000)
    Springer
    Journal of neuro-oncology 48 (2000), S. 121-129 
    Details
    ISSN: 1573-7373
    Keywords: apoptosis ; proliferation ; p53 ; Bcl-2 ; transglutaminase ; immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Several protocols for the adjuvant treatment of glioblastoma multiforme (GBM) are currently being evaluated. In this context, little is known about the influence of radiochemotherapy on apoptosis and the expression of apoptosis-related proteins in vivo. We have analyzed the incidence of apoptosis using in situ nick translation (ISNT) and expression of Ki-67 (MIB-1), p53 (DO-1 and DO-7), Bcl-2 and transglutaminase II (TGase II) by immunohistochemistry in 41 patients with GBM and their matched relapses. Sixteen patients received radiochemotherapy, 18 irradiation and 7 no treatment. Radiochemotherapy resulted in an increase in Bcl-2+ cells (p=0.013). Irradiation caused the reduction of MIB-1+ (p=0.0015), DO-7+ (p=0.0043) and the increase of Bcl-2+ cells (p=0.016). We calculated a positive correlation between high TGase II scores in patients preceding radiochemotherapy (p=0.0186) and no treatment (p=0.0158), low ISNT scores (p=0.0018) and high DO-1 scores (p=0.0233) in patients preceding irradiation and short time to progression. These data show that distinct postsurgical radiochemotherapy protocols differentially alter cellular proliferation and expression of p53 and Bcl-2 in GBM relapses. Furthermore, we show that ISNT, DO-1 and TGase II labeling scores are therapy-specific predictors of time to progression in GBM patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006462618800
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  • 65
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    Electronic Resource
    Altered Nuclear Localization of Bax Protein in BCNU-resistant Glioma Cells (2000)
    Springer
    Journal of neuro-oncology 49 (2000), S. 117-129 
    Details
    ISSN: 1573-7373
    Keywords: apoptosis ; chemotherapy resistance ; bcl-2 ; bax ; glioma ; nucleolus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To investigate the role of apoptosis suppression in glioma chemotherapy resistance, protein levels and subcellular localization of bcl-2 family members were investigated in 2 pairs of sensitive cell lines and their in vitro generated resistant derivatives. The alkylating agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), induced apoptosis in both sensitive cell strains and apoptosis was suppressed in both resistant derivatives. Both resistant cell lines contained altered regulation of a bcl-2 related protein consistent with the suppression of apoptosis. Independent of which bcl-2 family member was dysregulated, resistance was associated with altered regulation in the subcellular localization of bax protein. Following BCNU treatment, bax accumulated in nucleoli and a nuclei containing fraction of sensitive cells but not their resistant derivatives. Nuclear accumulation was an early event in apotosis induction. These data indicates altered subcellular localization of bax may play a role in resistance. In addition, the association between an early, nucleolar localization of bax and the induction of apoptosis suggests that localization of bax to nucleoli may play a role in apoptosis-induction of glioma cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026574123273
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  • 66
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    Ultrastructural Observations and DNA Degradation Analysis of Pepper Leaves Undergoing a Hypersensitive Reaction to Xanthomonas campestris pv. Vesicatoria (2000)
    Springer
    European journal of plant pathology 106 (2000), S. 423-431 
    Details
    ISSN: 1573-8469
    Keywords: apoptosis ; bacteria ; chromatin condensation ; DNA degradation analysis ; plant ; programmed cell death
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Ultrastructural details of the hypersensitive reaction induced by infiltration with avirulent race 2 Xanthomonas campestris pv. vesicatoria in pepper ‘Early Calwonder-10R’ leaves (incompatible interaction) are reported. Affected cells displayed plasmalemma undulations and disruption, lysis of the chloroplast membrane, degeneration of other organelles, general cytoplasm disorganisation and, often, protoplast shrinkage. The nuclei contained large masses of electron-dense material, apparently formed by chromatin aggregation. In many cases a single chromatin-like layer was deposited on the inner side of the nuclear envelope leaving a finely granular matrix in the centre of the nucleus; the nucleolus usually disappeared. The nuclear envelope was sometimes ruptured and the internal matrix leaked into the cytoplasm. The content of many affected cells eventually coagulated and became very electron-dense. The walls often collapsed. All these alterations were especially visible in spongy mesophyll cells at sites where bacteria occurred in the intercellular spaces. Although some of the nuclear and cytoplasmic alterations recall certain aspects of apoptotic cell death, molecular determinations did not reveal any DNA degradation in hypersensitively reacting tissues. The first cell alterations in leaves infected with the virulent bacterial race 1 (compatible interaction) were observed only 27 h after inoculation, when the cytoplasm of some cells showed limited internal disorganisation and plasmolysis at sites where bacterial colonies developed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008773321809
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    Angiostatin and Angiostatin-related Proteins (2000)
    Springer
    Cancer and metastasis reviews 19 (2000), S. 97-107 
    Details
    ISSN: 1573-7233
    Keywords: angiogenesis ; angiostatin ; cancer biology ; cancer therapy ; proteolysis ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The study of angiogenesis, and the promise of angiogenesis inhibition as a means of cancer therapy, has dramatically accelerated in the last several years. The discovery and publication of angiostatin by O'Reilly and colleagues in Judah Folkman's lab in 1994 has greatly contributed to this progress. Angiostatin is a kringle-containing fragment of plasminogen, which is a potent inhibitor of angiogenesis in-vivo, and selectively inhibits endothelial cell proliferation and migration in-vitro. There have been a number of proposed proteolytic mechanisms by which plasminogen is cleaved to form angiostatin, and the resulting cleavage products contain different NH2 and COOH termini of the angiostatin. Therefore, it is possible that there are more than one angiostatin isoforms (or angiostatin-related proteins) which occur in one or more normal or pathophysiological situations. It is also possible that some of the proteolytic processes which can convert plasminogen to angiostatin-like proteins are simply laboratory artifacts. Angiostatin-related proteins exert potent endothelial cell inhibitory activity, including the induction of apoptosis, and inhibition of migration, and the intact kringle structures are believed to be necessary for the antiangiogenic activity. Efforts are now underway to translate the understanding of the biology of angiostatin to clinical practice, which includes phase 1 clinical trials with recombinant angiostatin K1–3 (kringles 1–3) as well as phase 1 trials of an Angiostatin Cocktail, which induces the direct in vivo conversion of plasminogen to angiostatin 4.5 (kringles 1–4, plus most of kringle 5). The translation of the basic science of angiostatin and angiostatin-related proteins to clinical trial promises to provide an important new tool in the treatment of cancer by inhibition of angiogenesis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026525121027
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    Biological Features of Premalignant Disease in the Human Breast (2000)
    Springer
    Journal of mammary gland biology and neoplasia 5 (2000), S. 351-364 
    Details
    ISSN: 1573-7039
    Keywords: Human ; breast cancer ; premalignant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Most human invasive breast cancers (IBCs)4 arise from preexisting benign lesions. There are many types of benign lesions in the human breast and only a few appear to have significant premalignant potential (atypical hyperplasias and in situ carcinomas). These lesions are relatively common and only a small proportion progress to IBC. They are currently defined by their histological features and their prognosis is imprecisely estimated from indirect evidence based on epidemiological studies. Although lesions within specific categories look alike, they must possess morphologically silent biological differences motivating some to remain stable and others to progress. Understanding the biological changes responsible for the development and progression of premalignant disease is a very active area of medical research. Progress in this area may provide new opportunities for breast cancer prevention by providing strategies to treat premalignant lesions before they develop or become cancerous. A large number of biological features have been evaluated in this setting during the past decade. This review discusses a few features that appear to be particularly important and have been studied in a relatively comprehensive manner.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009573710675
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    Minireview: Apoptosis as seen through a lens (2000)
    Springer
    Apoptosis 5 (2000), S. 203-209 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; lens development ; organelle loss ; denucleation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The lens represents an ideal model system for studying many of the cellular and molecular events of differentiation. It is composed of two ectodermally-derived cell types: the lens epithelial cells and the lens fibre cells, which are derived from the lens epithelial cells by differentiation. Programmed removal of nuclei and other organelles from the lens fibre cells ensures that an optically clear structure is created, while the morphology of the degenerating nuclei is similar to that observed during apoptosis and is accompanied by DNA fragmentation. These observations suggest the existence of biochemical parallels between the process of lens fibre cell organelle loss and classical apoptosis. For example, proteins encoded by the bcl-2 and caspase gene families are expressed in developing lenses and nuclear degeneration in lens fibre cells can be inhibited in vivo by overexpression of bcl-2 and in vitro by incubation of differentiating lens epithelial cell cultures with caspase inhibitors. Thus, the developing lens may represent a particularly useful model system for researchers interested in apoptosis. In this review, the recent literature pertaining to lens fibre cell organelle loss and its relationship to apoptosis is reviewed and possible future research directions are suggested.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009653326511
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    The Daxx enigma (2000)
    Springer
    Apoptosis 5 (2000), S. 217-220 
    Details
    ISSN: 1573-675X
    Keywords: Daxx ; apoptosis ; Fas ; PML ; ND10
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Several reports describing Daxx and its putative role have emerged without a unifying theme. While Daxx has been implicated in apoptosis, it remains unclear whether Daxx is pro- or anti-apoptotic, and whether its role in apoptosis is direct or indirect. Moreover, whether Daxx plays alternative or additional roles in regulating transcription, centromere binding or any number of other activities within the cell, is uncertain. The ability of Daxx to interact with a wide variety of molecules in yeast-interaction trap systems (Table 1) has allowed for this range of speculation. The fact that Daxx contains no significant homology to other known proteins has rendered its study all the more challenging.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009696227420
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    Activation of MAD 2 checkprotein and persistence of cyclin B1/CDC 2 activity associate with paclitaxel-induced apoptosis in human nasopharyngeal carcinoma cells (2000)
    Springer
    Apoptosis 5 (2000), S. 235-241 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; cyclin B1/CDC 2 ; G2/M arrest ; MAD 2 ; paclitaxel
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Paclitaxel (Taxol™) is a microtubule-interfering agent that induced persistent and transient G2/M arrest before apoptosis in human nasopharyngeal carcinoma (NPC) cells at high and low concentrations, respectively. In this study, we intended to explore the underlying molecular events and found that cellular cyclin B1/CDC 2 kinase activity was increased and persisted for 〉6 h upon paclitaxel treatment both at high and low concentrations. Furthermore, activation of MAD 2 checkprotein could account for the loss of cyclin B1 ubiquitination and the persistence of cyclin B1/CDC 2 activation in the cases. To investigate the involvement of cyclin B1 and MAD 2 activation in paclitaxel-induced apoptosis, we introduced affinity-purified anti-cyclin B1 and MAD 2 antibodies into NPC cells by electroporation before the further paclitaxel treatment. The antibodies against cyclin B1 and MAD 2 indeed attenuated paclitaxel-induced cytotoxicity and DNA fragmentation. Our study suggests that activation of cyclin B1/CDC 2 and MAD 2 were the M-phase events required for paclitaxel-induced apoptosis in NPC cells. The dys-regulated cyclin B1/CDC 2 activation could enhance the prometaphase progression, but activation of MAD 2 rendered cells inable to exit from the metaphase. Under this circumstance, cells were probably going to “mitotic catastrophe” and ultimately, destined to apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009652412399
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    Induction of apoptosis by adenovirus E4orf4 protein (2000)
    Springer
    Apoptosis 5 (2000), S. 211-215 
    Details
    ISSN: 1573-675X
    Keywords: adenovirus ; E4orf4 ; apoptosis ; protein phosphatase 2A (PP2A) ; caspases ; cancer ; gene therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Adenovirus E4orf4 protein is a multifunctional viral regulator that induces p53-independent apoptosis in transformed cells, but not in normal cells. E4orf4-induced apoptosis can occur without activation of known caspases, although E4orf4 induces caspase activity in some cell lines. The interaction of E4orf4 with a specific subpopulation of protein phosphatase 2A (PP2A) molecules that contain B subunits, but not with those that contain B′ subunits, is required for induction of apoptosis. This review suggests the potential use of E4orf4 in cancer therapy, and discusses whether E4orf4-induced apoptosis plays a role in the viral life cycle. Future research directions are also highlighted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009644210581
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    Apoptosis and the cell cycle in Xenopus: PMA and MPMA exposure of splenocytes (2000)
    Springer
    Apoptosis 5 (2000), S. 225-233 
    Details
    ISSN: 1573-675X
    Keywords: Amphibia ; apoptosis ; cancer ; cell cycle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Spontaneous and induced cancers are rare in non-isogeneic or inbred amphibians. Neoplastic cells become immortalized through loss of a normal capacity to die by apoptosis. Mature lymphocytes of mammals require activation and entry into the cell cycle in order to become susceptible to apoptosis. Whether Xenopus lymphocytes differ from mammalian lymphocytes in this regard is examined. In vitro exposure of PMA, or its analogue, MPMA, to adult splenocytes of Xenopus laevis was used to affect apoptosis. Flow cytometric analysis of FITC-Annexin V/propidium iodide (PI) fluorescence (apoptosis) and BrdU uptake (DNA synthesis) were assayed concurrently in the same lymphocyte population over time. Significant increases in apoptotic levels were induced throughout a 72 hour period in PMA-treated cells only. Lymphocytes were also separated by size for analysis. Several sub-populations of lymphocytes were identified, the most interesting of which was small and apoptotic within 4 hours, after PMA exposure. PMA-induced DNA synthesis did not become elevated until after 24 hours. “Direct” apoptosis, i.e. without cell cycle entry, was found only in these small, mature lymphocytes. Since small lymphocytes make up the vast majority of those being analyzed, “direct” apoptosis may be a determining mechanism in the resistance to neoplasia observed in Amphibia. Cells that die more readily are less likely to transform into neoplastic cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009600428328
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    Caspase-3 activates endo-exonuclease: Further evidence for a role of the nuclease in apoptosis (2000)
    Springer
    Apoptosis 5 (2000), S. 243-254 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; caspase-3 ; nuclease ; endo-exonuclease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Single-strand DNase and poly rAase, activities characteristic of endo-exonuclease, were co-activated in nuclear fractions of HL-60 cells by caspase-3. Activation was accompanied by cleavages of large soluble polypeptides (130–185 kDa) and a 65 kDa inactive chromatin-associated polypeptide related to the endo-exonuclease of Neurospora crassa as detected on immunoblots. The major products seen in vitro were a 77 kDa soluble polypeptide and an active chromatin-associated 34 kDa polypeptide. When HL-60 cells were induced to undergo apoptosis by treating with 50 μM etoposide (VP-16) for 4 hours, 77 kDa and 40 kDa polypeptides accumulated in nuclear fractions. Chromatin DNA fragmentation activity was also activated in cytosol and nuclear extract either by pre-treating the cells in vivo with VP-16 or by treating the cytosol in vitro with caspase-3 or dATP and cytochrome c. Endo-exonuclease activated by caspase-3 in cytosol-derived fractions augmented chromatin DNA fragmentation activity in vitro. Endo-exonuclease is proposed to act in vivo in conjunction with the caspase-activated DNase (CAD) to degrade chromatin DNA during apoptosis of HL-60 cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009604529237
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    Apoptosis, cross-presentation, and the fate of the antigen specific immune response (2000)
    Springer
    Apoptosis 5 (2000), S. 307-314 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; cancer ; cross-priming ; cross-tolerance ; dendritic cells ; T lymphocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Induction of cell death by apoptosis, also called programmed cell death, and clearance of apoptotic bodies by scavenger cells has long thought to be an efficient means to dispose of unwanted cells without causing inflammatory responses able to mediate specific reactions. However, a number of evidences have been accumulated suggesting that apoptotic cell death is implicated in the pathogenesis of systemic and organ specific autoimmune diseases. In addition, recognition and engulfement of apoptotic cells by professional antigen presenting cells, such as dendritic cells, and their interaction with effector immune cells have been recently described to result in apoptotic cell-derived antigen specific tolerance. This review will summarise the most recent findings on the immunogenic potential of cells undergoing programmed death.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009671105696
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    Endothelial cell survival and apoptosis in the tumor vasculature (2000)
    Springer
    Apoptosis 5 (2000), S. 323-328 
    Details
    ISSN: 1573-675X
    Keywords: Angiogenesis ; angiopoietins ; apoptosis ; integrins ; vascular endothelial growth factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Angiogenesis is essential for the growth and metastasis of solid tumors. The balance of endothelial cell (EC) proliferation and apoptosis is a major determinant in tumor angiogenesis. Recently, several studies demonstrated that numerous angiogenic factors not only induce angiogenesis but also function as EC survival factors. Vascular endothelial growth factor (VEGF), a potent angiogenic factor, is also an EC survival factor in embryonic vasculogenesis and tumor angiogenesis. VEGF activates specific intracellular survival pathways in ECs including Bcl-2, A1, IAP, Akt, and Erk. Integrins may function as EC survival factors by preventing anoikis by enhancing binding to the extracellular matrix. In addition, integrins may function in concert with VEGF to promote EC survival. Angiopoietin-1 (Ang-1) has recently been shown to stabilize EC networks by binding to the EC-specific tyrosine kinase receptor Tie-2. Pericytes also function as EC survival factors, by cell-cell contact, secretion of survival factors, or both. Targeting any of the above mechanisms for EC survival may provide novel antineoplastic strategies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009679307513
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    Induction of apoptosis in human cancer cells by TZT-1027, an antimicrotubule agent (2000)
    Springer
    Apoptosis 5 (2000), S. 345-353 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; antimicrotubule agent ; cell cycle ; dolastatin 10 ; TZT-1027
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract TZT-1027, a newly synthesized dolastatin 10 derivative, is a potent antitumor agent which inhibits microtubule polymerization and perturbs microtubule dynamics. In this report, we investigated whether TZT-1027 inhibited the growth of various human cancer cells, and the cell death caused by TZT-1027 was due to apoptosis. In addition, we elucidated the apoptosis machinery induced by treatment with TZT-1027. The 50% growth-inhibitory concentrations (IC50 values) of TZT-1027 on cancer cells derived from various sources were not more than 5.9 ng/ml. TZT-1027 showed superior cytotoxicity than any other antitumor agents. Next, we evaluated morphological nuclear change, namely, chromatin condensation and DNA fragmentation. We used three cancer cell lines derived from different types in view of having apoptosis related protein, human leukemia HL-60 (in the presence of both Caspase-3 and Bcl-2), human breast cancer MCF-7 (in the absence of Caspase-3), and human prostate cancer DU145 (in the absence of Bcl-2). TZT-1027 induced DNA fragmentation in the presence but not absence of Caspase-3. Nevertheless, apoptic chromatin condensation was observed in all cancer cells even if there was no Caspase-3. Furthermore, we examined whether TZT-1027, microtubule-disrupting agent, influenced cell cycle progression. Flow cytometric analysis revealed the cells treated with TZT-1027, and with the other antimicrotubule agents, to be arrested at the G2/M phase and subsequently to show fragmented DNA smaller than that of G1 phase cells. Moreover, we tested TZT-1027 for its ability to induce Bcl-2 phosphorylation in human cancer cell lines. TZT-1027 and other agents which interacted with microtubules induced Bcl-2 phosphorylation, whereas DNA-damaging agents did not. The present results suggested an association of the growth-inhibitory effect of TZT-1027 with the induction of apoptosis and indicated that the apoptosis induced by TZT-1027 was followed by G2/M arrest even if there was no Caspase-3 or Bcl-2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009687609330
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    Increased apoptosis and increased clonogenic survival of 12V-H-ras transformed rat fibroblasts in response to cisplatin (2000)
    Springer
    Apoptosis 5 (2000), S. 355-367 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; chemotherapy resistance ; clonogenicity ; ras
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Mutationally activated Ras is involved in tumor progression and likely also in drug resistance. Using survival, viability and apoptosis assays, we have here compared the cisplatin sensitivities of FR3T3 rat fibroblasts and a 12V-H-ras transformed subline (Ras2:3). Around 24 h after cisplatin treatment Ras2:3 cells showed higher apoptosis levels and lower viability than FR3T3. This increased sensitivity correlated with weaker cisplatin-induced activation of Jun N-terminal kinase (JNK). In contrast to apoptosis assays, colony formation assays showed that Ras2:3 were more resistant to cisplatin than were FR3T3. This was partly due to the increased cisplatin sensitivity of FR3T3 seeded at low densities, as required in colony formation assays. In addition, Ras2:3 cisplatin survivors had a higher relative proliferative capacity. Cell cycle analyses showed that FR3T3 cells initially responded with a dose-dependent G2 arrest, while Ras2:3 accumulated in S-phase. Experiments with an anti-apoptotic mutant of MEKK1 suggested that the apoptotic response of Ras2:3 cells is not specific to the S-phase fraction. In summary, the cisplatin response of ras-transformed fibroblasts is distinct from that of parental cells, in that they show increased apoptosis, a different cell cycle response and increased post-treatment proliferative capacity. The results illustrate the need to carefully consider methods and protocols for in vitro studies on chemotherapy sensitivity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009639726168
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    Role of reactive oxygen species (ROS) in apoptosis induction (2000)
    Springer
    Apoptosis 5 (2000), S. 415-418 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; death receptors ; inflammation ; reactive oxygen species (ROS)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Reactive oxygen species (ROS) and mitochondria play an important role in apoptosis induction under both physiologic and pathologic conditions. Interestingly, mitochondria are both source and target of ROS. Cytochrome c release from mitochondria, that triggers caspase activation, appears to be largely mediated by direct or indirect ROS action. On the other hand, ROS have also anti-apoptotic effects. This review focuses on the role of ROS in the regulation of apoptosis, especially in inflammatory cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009616228304
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    CD95/CD95L interactions and their role in autoimmunity (2000)
    Springer
    Apoptosis 5 (2000), S. 419-424 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; diabetes ; Fas ; organ-specific auto-immunity ; thyroiditis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract CD95 (Fas/Apo-1) is a broadly expressed death receptor involved in a variety of physiological and pathological apoptotic processes. Since its discovery, defects in CD95/CD95L system have been proposed as major pathogenic factors responsible for impaired immunological tolerance to self antigens and autoimmunity. Later, analysis of altered sensitivity to CD95-induced apoptosis in cells targeted by the immune response has revealed an unexpected role for CD95 and CD95L in organ-specific autoimmunity. CD95 has been shown to be expressed and functional in virtually all cell types that are target of the organ-specific autoimmune response. Here we review some of the major findings concerning the role of CD95 in autoimmunity, in dysfunctions due to increased or decreased CD95-induced apoptosis.
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    URL: http://dx.doi.org/10.1023/A:1009668212375
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    Role of apoptosis in autoimmunity (2000)
    Springer
    Apoptosis 5 (2000), S. 443-449 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; autoimmunity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Apoptosis is a physiological form of cell death required to ensure that the rate of cell division is balanced by the rate of cell death in multicellular organisms. Dysregulation of apoptosis is associated with the pathogenesis of a wide array of diseases: cancer, neurodegeneration, autoimmunity, heart disease and others. In this review we collect arguments supporting a hypothesis of a dysregulated apoptosis leading to development of autoimmunity like systemic lupus erythematosus (SLE). This notion is supported by occurence of known autoantigens in apoptotic blebs, in vitro findings of an increased rate of apoptotic lymphoblasts despite optimal cytokine stimulation combined with a defective in vitro clearance of apoptotic bodies by SLE phagocytes. Moreover, we and others could generate histone-specific lymphocytic cell lines from cells after activation with autologous apoptotic material. These lymphocytes could stimulate autologous B-lymphocytes to produce of anti-dsDNA antibodies, a diagnostic hallmark for SLE. Finally, antibodies against phospholipids like phosphatidylserine are often associated with systemic autoimmunopathies like SLE and others. Phosphatidylserine is exposed on apoptotic cells as early sign of programmed cell death and serves as phagocyte recognition molecule for apoptotic cells. Formation of immune complexes and deposition in tissues might lead to organ damage and disease. This scenario will be discussed in this review in detail.
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    URL: http://dx.doi.org/10.1023/A:1009692902805
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    Apoptosis in Alzheimer's disease—an update (2000)
    Springer
    Apoptosis 5 (2000), S. 9-16 
    Details
    ISSN: 1573-675X
    Keywords: Aging ; Alzheimer's disease ; amyloid precursor protein ; apoptosis ; Bcl-2 ; caspase ; presenilin ; transcription factor ; β amyloid.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Alzheimer's disease (AD) is the most common human neurodegenerative disorder characterized by the progressive deterioration of cognition and memory in association with the presence of senile plaques, neurofibrillary tangles, and massive loss of neurons. Most cases of AD are late-onset and sporadic, but in some cases the disease is inherited as an autosomal dominant trait. Four different genes, the amyloid precursor protein, apolipoprotein E, and presenilins 1 and 2 have been implicated in the etiology of familial AD. It is now generally accepted that massive neuronal death due to apoptosis is a commmon characteristic in the brains of patients suffering from neurodegenerative diseases, and apoptotic cell death has been found in neurons and glial cells in AD. This review summarizes the current findings regarding the evidence for apoptosis in AD and discusses the possible involvement of apoptosis-regulating factors in the pathology of AD. Modification of the apoptotic cascade could be considered as a primary therapeutic strategy for the disease.
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    URL: http://dx.doi.org/10.1023/A:1009625323388
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    Caspase-dependent and -independent death pathways in cancer therapy (2000)
    Springer
    Apoptosis 5 (2000), S. 17-20 
    Details
    ISSN: 1573-675X
    Keywords: Anti-tumor drugs ; apoptosis ; cancer ; caspases ; necrosis.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The majority of current anticancer therapies induce tumor cell death through the induction of apoptosis. Alterations in the apoptotic pathways may determine tumor resistance to these therapies. Activation of the proteolytic cascade involving caspase family members is a critical component of the execution of cell death in apoptotic cells. However, recent studies suggest that cell death can proceed in the absence of caspases. In this review we describe the role of caspase-dependent and -independent pathways as targets for anticancer treatment; better understanding of diverse modes of tumor cell death will help to avoid ineffective treatment and provide a molecular basis for the new strategies targeting caspase-independent death pathways in apoptosis-resistant forms of cancer.
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    URL: http://dx.doi.org/10.1023/A:1009677307458
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    A short peptide derived from the antisense homology box of Fas ligand induces apoptosis in anti-Fas antibody-insensitive human ovarian cancer cells (2000)
    Springer
    Apoptosis 5 (2000), S. 37-41 
    Details
    ISSN: 1573-675X
    Keywords: Anti-Fas antibody ; antisense homology box-derived peptide ; apoptosis ; Fas ligand ; ovarian cancer.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract We found that a short synthetic peptide corresponding to the “antisense homology box” of Fas ligand induced apoptotic cell death of Fas-expressing human ovarian cancer cell lines. The peptide was deduced from residues 256–265 of human Fas ligand, based on the hypothesis that it should contain a specific binding site to the corresponding Fas. Interestingly, the ovarian cancer cell line NOS4, which was sensitive to anti-Fas antibody induced apoptosis, was not affected by the peptide, whereas another cell line, SKOV-3, which was insensitive to anti-Fas antibody, was killed by the peptide. Thus, this short peptide was shown to have a unique activity to induce apoptosis in human ovarian cancer cells in a manner different from anti-Fas antibody.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009633525205
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    Early transitory rise in intracellular pH leads to Bax conformation change during ceramide-induced apoptosis (2000)
    Springer
    Apoptosis 5 (2000), S. 551-560 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; Bax ; ceramide ; mitochondria ; pH
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Ceramide can induce apoptosis through a caspase independent pathway. Bax has been described as able to kill cells in the absence of caspase activity, therefore we measured Bax in situ during ceramide-induced apoptosis using anti-Bax antibodies and flow cytometry analysis. An early (〈30 min) increase in Bax labeling was observed after the addition of several ceramide species to several hemopoietic-related cell types. On U937, this increase was not due to antigens synthesis or processing, but rather an increased accessibility or reactivity of Bax antigens for antibodies. This increased immuno-reactivity of Bax was not inhibited by Z-VAD-fmk nor leupeptin, and preceded nuclear fragmentation by several hours. Such an increase in immuno-reactivity was also observed after Fas ligation, but it occurred later (〉2 h) accompanying nuclear apoptosis, and was inhibited by Z-VAD-fmk. Bax immuno-reactivity was found to be related to intracellular pH (pHi), and C2-Ceramide (C2-Cer) induced a very early (〈10 min) transitory increase in pHi. Both Bax immuno-reactivity and pHi increases were dependent on the mitochondrial permeability transition pore (PTP) status. It was concluded from these results that C2-Cer induced a transitory increase in pHi in relation to the PTP. This rise in pHi led to conformational changes in Bax which could be responsible for further apoptosis in the C2-Cer pathway while it was a consequence of caspase activation in the Fas pathway.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009693630664
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  • 86
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    Experimental Chagas disease: Phagocytosis of apoptotic lymphocytes deactivates macrophages and fuels parasite growth (2000)
    Springer
    Apoptosis 5 (2000), S. 221-224 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; macrophages ; Chagas disease ; Trypanosoma cruzi ; T lymphocytes ; vitronectin receptor ; transforming growth factor-beta ; prostaglandins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009648311490
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  • 87
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    Electronic Resource
    Ethanol-induced apoptotic neurodegeneration in the developing brain (2000)
    Springer
    Apoptosis 5 (2000), S. 515-521 
    Details
    ISSN: 1573-675X
    Keywords: anesthetics ; apoptosis ; barbiturates ; benzodiazepines ; ethanol ; GABAA receptors ; ketamine ; NMDA receptors ; phencyclidine ; synaptogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract It has been known for three decades that ethanol, the most widely abused drug in the world, has deleterious effects on the developing human brain, but progress has been slow in developing animal models for studying this problem, and the underlying mechanisms have remained elusive. Recently, we have shown that during the synaptogenesis period, also known as the brain growth spurt period, ethanol has the potential to trigger massive neuronal suicide in the in vivo mammalian brain. The brain growth spurt period in humans spans the last trimester of pregnancy and first several years after birth. The NMDA antagonist and GABAmimetic properties of ethanol may be responsible for its apoptogenic action, in that other drugs with either NMDA antagonist or GABAmimetic actions also trigger apoptotic neurodegeneration in the developing brain. Our findings provide a likely explanation for the reduced brain mass and neurobehavioral disturbances associated with the human fetal alcohol syndrome. Furthermore, since NMDA antagonist and GABAmimetic drugs are sometimes abused by pregnant women and also are used as anticonvulsants, sedatives or anesthetics in pediatric medicine, our findings raise several complex drug safety issues. In addition, the observation that ethanol and several other drugs trigger massive neuronal apoptosis in the developing brain provides an unprecedented opportunity to study both neuropathological aspects and molecular mechanisms of apoptotic neurodegeneration in the in vivo mammalian brain.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009685428847
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  • 88
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    Electronic Resource
    Suicidal differential housekeeping gene activity in apoptosis induced by DCNP (2000)
    Springer
    Apoptosis 5 (2000), S. 379-388 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; ATP depletion ; cell acidification and shrinkage ; CpG-specific megabase fragmentations ; DCNP (2,6-dichloro-4-nitrophenol) ; housekeeping genes ; microarray (genechip) ; zVAD-fmk
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Previous suggestions of CpG-specific apoptotic commitment implied critical epigenetic modulation of house-keeping genes which have canonical CpG islands at 5′ promoter regions. Differential housekeeping gene activity however has not been shown. Using a focussed microarray (genechip) of 22 housekeeping genes we show this in apoptosis induced in human Chang liver cells by DCNP (2,6-dichloro-4-nitrophenol), a non-genotoxic inhibitor of sulfate detoxification. 3–7 folds downregulation of 9 genes in glycolysis, tricarboxylic acid cycle and the respiratory electron transport chain suggested gene-directed energy depletion which was correlated with observed ATP depletion. 4 folds downregulation of the pyruvate dehydrogenease gene suggested gene-directed metabolic acidosis which was correlated with observed cell acidification. Other differential housekeeping gene activity, including 4 folds upregulation of microtubular alpha-tubulin gene, and 2 folds upregulation of ubiquitin, also had a bearing on apoptosis. Broadspectrum zVAD-fmk caspase inhibition abolished 200 bp DNA ladder fragmentations but not the CpG-specific megabase fragmentations and other hallmarks of cell destruction, suggesting a caspase-independent cell death. Death appeared committed at gene-level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009695811147
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  • 89
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    Concanavalin A induced apoptosis in murine macrophage PU5-1.8 cells through clustering of mitochondria and release of cytochrome c (2000)
    Springer
    Apoptosis 5 (2000), S. 369-377 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; concanavalin A ; cytochrome c release ; mitochondria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Concanavalin A (ConA), normally a mitogen of T-lymphocytes, was found to be a cell cycle-independent apoptosis-inducing agent in cultured murine macrophage PU5-1.8 cells. This assertion is based on the following observations: (1) ConA increased the number of cells with hypo-diploid DNA in a dose dependent manner as revealed by flow cytometry; (2) ConA elicited DNA fragmentation and the cytotoxicity of ConA was suppressed by α-D-methylmannoside which blocks the lectin site of ConA; (3) ConA was able to release cytochrome c (cyto c) into the cytosol of PU5-1.8 cells. When isolated mitochondria were incubated with ConA, release of cyto c was observed too. Interestingly, clustering of mitochondria was found in the cytosol under a confocal microscope after ConA treatment. When cells were incubated with ConA-FITC and subsequently with mitotracker red (a probe for mitochondria), co-localization of fluorescence signals was observed. These results suggest that ConA was delivered to the mitochondria, induced mitochondrial clustering and released cyto c. Our results also show that introduction of exogenous cyto c electroporationally into ConA-untreated cells elicited DNA fragmentation. On the other hand, introduction of specific antibody against cyto c into PU5-1.8 cells suppressed the ConA-mediated cell death. Taken together, our results indicate that ConA induced apoptosis in PU5-1.8 cells through mitochondrial clustering and release of cyto c and the release of cyto c was sufficient to elicit apoptosis in PU5-1.8 cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009691727077
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  • 90
    Electronic Resource
    Electronic Resource
    Regulation of apoptosis in mast cells (2000)
    Springer
    Apoptosis 5 (2000), S. 435-441 
    Details
    ISSN: 1573-675X
    Keywords: activation ; apoptosis ; death receptors ; glucocorticosteroids ; mast cells ; survival factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Apoptosis is a physiological process of cell death that occurs in all multicellular organisms. Its dysregulation has been postulated as one of the main causes in the development of diseases such as cancer, AIDS, autoimmune diseases and allergy. Apoptosis has been mainly studied in the inflammatory cells that participate in the late and chronic stages of allergy (eosinophils, neutrophils, lymphocytes and macrophages) as a new way to elucidate the pathogenesis of this disease. Nevertheless, much less it is known about the regulation of apoptosis in the “initiators” of the allergic process: The Mast Cells. In normal conditions, mast cells are described as long-living cells that keep a constant number of cells in tissues. However, increased numbers of mast cells are observed in the late phase of asthma and in both the inflammatory and in the repair/remodeling stage of various inflammatory/fibrotic disorders. In this report, we discuss the possible mechanisms that regulate the apoptotic process in normal conditions and disease, such as survival factors and death receptors. A link between mast cell activation, during the early stages of the allergic process, and triggering of anti-apoptotic signaling pathways is also suggested as an important contributor to the extended life of mast cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009680500988
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  • 91
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    Apoptosis and airway inflammation in asthma (2000)
    Springer
    Apoptosis 5 (2000), S. 473-485 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; asthma ; inflammation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Asthma is a disease characterized by a chronic inflammation of the airways and by structural alterations of bron-chial tissues, often referred to as airway remodelling. The development of chronic airway inflammation in asthma depends upon the continuous recruitment of inflammatory cells from the bloodstream towards the bronchial mucosa and by their subsequent activation. It is however increasingly accepted that mechanisms involved in the regulation of the survival and apoptosis of inflammatory cells may play a central role in the persistent inflammatory process characterizing this disease. Increased cellular recruitment and activation, enhanced cell survival and cell:cell interactions are therefore the key steps in the development of chronic airway inflammation in asthma, and represent the major causes for tissue damge, repair and remodelling.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009661406440
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  • 92
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    Electronic Resource
    The molecular control of DNA damage-induced cell death (2000)
    Springer
    Apoptosis 5 (2000), S. 491-507 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; Bcl-2 ; caspases ; death receptors ; DNA damage ; p53
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Because of the singular importance of DNA for genetic inheritance, all organisms have evolved mechanisms to recognize and respond to DNA damage. In metazoans, cells can respond to DNA damage either by undergoing cell cycle arrest, to facilitate DNA repair, or by undergoing cell suicide. Cell death can either occur by activation of the apoptotic machinery or simply be a consequence of irreparable damage that prevents further cell division. In germ cells, mechanisms for limiting alterations to the genome are required for faithful propagation of the species whereas in somatic cells, responses to DNA damage prevent the accumulation of mutations that might lead to aberrant cell proliferation or behavior. Several of the genes that regulate cellular responses to DNA damage function as tumor suppressors. The clinical use of DNA damaging agents in the treatment of cancer can activate these tumor suppressors and exploits the cellular suicide and growth arrest mechanisms that they regulate. It appears that in some but not all types of tumors the propensity to undergo apoptosis is a critical determinant of their sensitivity to anti-cancer therapy. This review describes current understanding of the molecular control of DNA damage-induced apoptosis with particular attention to its role in tumor suppression and cancer therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009617727938
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  • 93
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    Electronic Resource
    Protection of apoptotic cell death by protein A (2000)
    Springer
    Apoptosis 5 (2000), S. 509-514 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; protection ; protein A ; pro- and anti-apoptotic factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The word “Apoptosis” or pragrammed cell death is described as the ultimate end of multiple cellular events converging from numerous initiating events to the ultimate death of a cell or organism. Several processes, such as initiation of death signals at the plasma membrane, expression of pro-apoptotic oncoproteins, activation of death proteases, endonucleases etc., that ultimately coalesce to a common irreversible execution phase, lead to cell demise. Counteracting the death signals are cell survival factors. A balance between the cell death and cell survival factors plays a major role in the decision making process as to whether a cell should die or must live. It is, therefore, hypothesized that if the balance can be shifted in favor of cell survival, one might be able to arrest the aging process, save the injured cells or else if the balance is shifted toward cell-kill it might help destroy tumors and other undesirable cells. Protein A (PA) of Staphylococcus aureus has been found to have multifarious biological response modifying properties. It has been shown to possess anti-tumor, anti-toxic, anti-parasitic and antifungal activities. It also acts as a potent immunostimulator. PA can protect bone marrow progenitor cells from zidovudin(AZT)-induced apoptosis and can stimulate immunocyte proliferation, thereby helping to replenish/restore the depleted hematopoietic cell pool. Such ability to replenish hematopoietic cells is a common property of PA observed against a number of toxic drugs/chemicals, such as cyclophosphamide, benzene, aflatoxin, salmonella endotoxin, etc. Interestingly, it was further demonstrated in our laboratory that PA can selectively kill tumor cells without affecting normal cells of the host. A search for the mechanisms of PA action revealed that this bacterial protein could shift the balance between pro- and anti-apoptotic proteins in favor of survival in normal cells, but in favor of cell death in tumor cells at a particular dose level. This unique property of PA suggests that controlled use of such type of Biological Response Modifier might help in controlling both cell growth and death phenomena.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009633412009
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  • 94
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    Electronic Resource
    ATM dependent apoptosis in the nervous system (2000)
    Springer
    Apoptosis 5 (2000), S. 523-529 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; ATM ; DNA damage ; ionizing radiation ; p53
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Ataxia-telangiectasia is a human syndrome resulting from mutations of the ATM protein kinase that is characterized by radiation sensitivity and neurodegeneration. Although neuroprotective, the molecular details of ATM function in the nervous system are uncertain. However, in the mouse, Atm is essential for ionizing radiation-induced apoptosis in select postmitotic populations of the developing nervous system. Atm-dependent apoptosis in the nervous system also requires p53, consistent with the well-established link of p53 as a major substrate of ATM. Furthermore, the proapoptotic effector Bax is also required for most, but not all, Atm-dependent apoptosis. Therefore, after DNA damage in the developing nervous system, Atm initiates a p53-dependent apoptotic cascade in differentiating neural cells. Together, these data suggest ATM-dependent apoptosis may be important for elimination of neural cells that have accumulated genomic damage during development, thus preventing dysfunction of these cells later in life.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009637512917
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  • 95
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    Electronic Resource
    Caspase-dependent and independent cell death in rat hepatoma 5123tc cells (2000)
    Springer
    Apoptosis 5 (2000), S. 265-275 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; DNA fragmentation ; necrosis ; phosphorylation ; protease inhibitors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The objective of this study was to establish whether apoptosis in 5123tc rat hepatoma cells required the caspase-3 dependent pathway. Apoptosis was induced by either growth factor deprivation or treatment with a topoisomerase II inhibitor, VM26, in the absence or presence of caspase inhibitors (DEVD-fmk, z-VAD-fmk and BAF). The results indicated that, although these inhibitors at 10 μM concentration completely blocked caspase-3 activity, they had no effect on either the rate of cell death or on any other apoptotic features, e.g., chromatin condensation, DNA fragmentation, protein cleavage, suggesting that caspase-3 was not required to mediate nuclear destruction in these hepatoma cells. At higher concentrations, up to 100 μM, z-VAD-fmk and BAF, but not DEVD-fmk, did block apoptosis, however, they also caused cell swelling and membrane permeabilization, which are the hallmarks of necrotic cell death. Clearly, high concentrations of these inhibitors must have interfered non-specifically with other metabolic pathways, e.g., z-VAD-fmk at a high concentration blocked protein phosphorylation, and caused cell death by a different mechanism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009608630145
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  • 96
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    Homocysteine-thiolactone induces caspase-independent vascular endothelial cell death with apoptotic features (2000)
    Springer
    Apoptosis 5 (2000), S. 403-411 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; atherosclerosis ; cell culture ; endothelial function ; mitochondria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Objective. Cell death is generally classified into two large categories: apoptosis, which represents active, physiological programmed cell death, and necrosis, which represents passive cell death without underlying regulatory mechanisms. Apoptosis plays an important role in tissue homeostasis and its role in endothelium integrity can be influenced by the functional status of endothelial cells. Homocysteine, a sulfated amino-acid product of methionine demethylation, is an independent risk factor for vascular disease (arterial and venous thombosis). Our goal was to investigate the thiol-derivatives effect on the endothelial cell apoptosis. Methods. Three parameters were measured: mitochondrial membrane potential using DiOC6(3) as the probe, DEVDase activation, and phosphatidylserine exposure on the cell surface with fluorosceinated annexin V labeling which allows apoptosis to be distinguished from necrosis. Results. Homocysteine-thiolactone induced endothelial cell apoptosis in a concentration-dependent manner (range: 50–200 μ M), independently of the caspase pathway. Only homocysteine-thiolactone, among the thiol derivatives tested, induced apoptosis. Apoptosis was not influenced by the serum concentration in culture medium, suggesting that the observed apoptotic process could occur in vivo. None of the inhibitors used (e.g., leupeptin, fumosinin Bl, catalase, or z-VAD-fmk) was able to prevent homocysteine-induced apoptosis of vascular endothelial cells. Conclusion. The apoptosis of vascular endothelial cells induced by high concentration of homocysteine-thiolactone might be one step atherosclerotic cardiovascular disease, and contribute to its complication.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009652011466
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  • 97
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    Regulation of neutrophil apoptosis: A role for protein kinase C and phosphatidylinositol-3-kinase (2000)
    Springer
    Apoptosis 5 (2000), S. 451-458 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; inflammation ; neutrophil ; PI-3-kinase ; PKC ; T-cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Neutrophils play a central role in host defense and are recruited in vast numbers to sites of infection where they phagocytose and kill invading bacterial pathogens. Neutrophils have a short half-life that is extended at the inflamed site by pro-inflammatory cytokines and contact with bacterial cell walls. Normal resolution of inflammation involves the removal of neutrophils and other inflammatory cells by the induction of apoptosis. Spontaneous neutrophil apoptosis does not require Fas ligation, but is mediated by caspases 3, 8 and possibly caspase 9 and also involves activation of protein kinase C-δ. With chronic inflammatory disease, neutrophil apoptosis is delayed by pro-inflammatory cytokines, leading to persistence of neutrophils at the inflamed site and non-specific tissue damage. Here we discuss the evidence for inhibition of neutrophil apoptosis via signaling though PI-3-kinase and downstream pathways, including PDK-1 and PKB. Therapeutic strategies to resolve chronic inflammation could therefore usefully target neutrophil apoptosis and the PI-3-kinase or PKC-δ signaling pathways.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009601220552
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  • 98
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    GnRH-Bik/Bax/Bak chimeric proteins target and kill adenocarcinoma cells; the general use of pro-apoptotic proteins of the Bcl-2 family as novel killing components of targeting chimeric proteins (2000)
    Springer
    Apoptosis 5 (2000), S. 531-542 
    Details
    ISSN: 1573-675X
    Keywords: adenocarcinoma cells ; apoptosis ; Bcl-2 family proteins ; chimeric proteins ; GnRH-binding site ; targeting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract In recent years chimeric proteins carrying bacterial toxins as their killing moiety, have been developed to selectively recognize and kill cell populations expressing speciific receptors. The involvement of Gonadotropin releasing hormone (GnRH) has been demonstrated in several adenocarcinomas and a GnRH-bacterial toxin chimeric protein (GnRH-PE66) was thus developed and found to specifically target and kill adenocarcinoma cells both in vitro and in vivo. Because of the immunogenicity and the non-specific toxicity of the bacterial toxins, we have developed new chimeric proteins, introducing apoptosis inducing proteins of the Bcl-2 family as novel killing components. Sequences encoding the human Bik, Bak or Bax proteins were fused to the GnRH coding sequence at the DNA level and were expressed in E. coli. GnRH-Bik, GnRH-Bak and GnRH-Bax new chimeric proteins efficiently and specifically inhibited the cell growth of adenocarcinoma cell lines and eventually led to cell death. All three Bcl2-proteins-based chimeric proteins seem to induce apoptosis within the target cells, without any additional cell death stimulus. Apoptosis-inducing-proteins of the Bcl-2 family targeted by the GnRH are novel potential therapeutic reagents for adenocarcinoma treatment in humans. This novel approach could be widely applied, using any molecule that binds a specific cell type, fused to an apoptosis-inducing protein.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009689529756
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  • 99
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    CDK inhibitors suppress apoptosis induced by chemicals and by excessive expression of a cell death gene, reaper, in Drosophila cells (2000)
    Springer
    Apoptosis 5 (2000), S. 543-550 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; CDK ; cell cycle ; cell death gene ; drosophila ; reaper
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The present study was aimed to investigate whether or not cyclin-dependent kinases (CDKs) participate in different cascades leading to apoptosis. We examined the effects of two CDK inhibitors, olomoucine (OLM) and buty-rolactone-I (BL-I), on apoptosis induced in two kinds of Drosophila cell lines. Increases of caspase activity induced by actinomycin D, cycloheximide, H-7 or A23187 in a Drosophila neuronal cell line, ML-DmBG2-c2, and induced by excessive expression of a Drosophila cell death gene, reaper, in Drosophila S2 cells were suppressed by 24-h pretreatment of each CDK inhibitor. Concomitant with the suppression of the caspase activity, fragmentations of cells and DNA, representatives of apoptosis, were also inhibited. These results suggest that CDK(s) participates in progression of apoptosis. However, these effects of the CDK inhibitors were also observed even at lower doses which did not affect cell proliferation. Therefore, it was shown that apoptosis is not always related to cell cycle in Drosophila cells. It was also suggested that the target(s) of the CDK inhibitors locates upstream of caspase in the cascade(s) of apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009641613826
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  • 100
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    Induction of Apoptosis in WEHI 231 Cells by Cationic Liposomes (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 515-520 
    Details
    ISSN: 1573-904X
    Keywords: apoptosis ; cationic liposome ; B cell ; WEHI 231 ; reactive oxygen species
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Liposomes are of considerable interest as drug carriers andimmunoadjuvants. However, few investigators have studied thechanges exerted by liposomes in the cells with which they interact.The purpose of this study was to investigate whether liposomes induceapoptosis in B cells. Methods. The mouse immature B cell line WEHI 231 cells and mousesplenic B cells were treated with liposomes, and the induction ofapoptosis was evaluated by monitoring changes in DNA content, DNAfragmentation and chromatin condensation by flow cytometry, agarosegel electrophoresis and by morphological investigation. Results. Cationic liposomes induced apoptosis in WEHI 231 cells, butneutral and anionic liposomes did not. A contact time of 30 minbetween WEHI 231 cells and cationic liposomes was sufficient toinduce apoptosis, and 80% of the cells showed hypodiploid DNAcontent. Apoptosis induced by cationic liposomes composed ofstearylamine was inhibited by addition of the oxidant scavenger,N-acetyl-cysteine. Conclusions. Cationic liposomes induced apoptosis in WEHI 231 cells,and the production of reactive oxygen species is important in theregulation of apoptosis induced by cationic liposomes. It is well knownthat cationic liposomes show cytotoxicity, and apoptosis may be oneof the causes of this toxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007552529280
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