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At least 955 records · Page 53Linked to original sources
PubMedDate not supplied

Analysis of central regulatory pathways in p53-deficient primary cultures of malignant fibrous histiocytoma exposed to ifosfamide.

Soft tissue sarcomas frequently carry p53 mutations reducing chemotherapeutical response. Especially malignant fibrous histiocytoma (MFH) reveals a reduced ifosfamide (IF) chemosensitivity when compared to other sarcoma entities. This is the first study to analyze MFH cells for the effects of IF on the expression of the pathways P16-CDK4-Rb and P14ARF-MDM2-P73 regulating cell cycle. The aim was to identify candidate genes possibly involved in the anti-apoptotic response of p53-deficient MFH cells during chemotherapy. PCR, real-time RT-PCR and confocal laser scanning microscopy were applied on primary cultures of MFH cells containing defective p53 genes. The cultures were treated with different concentrations of IF. A non-treated MFH culture served as negative control. A threshold concentration of IF (100 microM) was determined sparing the majority of the cells (99%), whereas higher IF quantities caused complete apoptosis. Data collected over a period of 48 h showed that the MFH cells surviving 100 microM IF overexpressed the kinase gene CDK4 and oncogene MDM2 by a factor of 63. A similar strong increase was observed at the protein level for both proteins. In contrast, the other proteins analyzed were not detectable. Additionally, the MFH cells induced complex patterns of MDM2 mRNA splicing and an abnormal mRNA transcript carrying a novel MDM2 missense mutation. These effects were neither observed in the non-treated culture nor in cultures completely inducing spontaneous apoptosis. Therefore, we speculate that the induction of the gene CDK4, and especially of MDM2, is involved in anti-apoptotic mechanisms of p53-negative MFH cells tolerating IF in vitro. Further experiments are necessary to test whether the novel candidate genes favor development of chemoresistance and whether MDM2 mRNA splicing variants contribute to this process in vivo.

Actins↗
PubMedDate not supplied

[Analysis of inhibition in pathways of NADP.H2 and NAD.H2 oxidation in liver tissue microsomes].

Microsomal complexes of electron transfer were resistant to typical inhibitors of mitochondrial pathway of electron transport. In oxidation of NADP.H2 there were at least three point of molecular O2 reduction: NADP.H2-specific flavoprotein, Fe2+ participating in reactions of peroxidation of unsaturated fatty acids and cytochrome P-450. Efficiency of cytochrome P-450 inhibitors could not be evaluated by polarography as in the pathway several sites of molecular O2 activation were observed. In oxidation of NADP.H2 estimation of the rate of electron transfer reactions was carried out by monitoring of velocity of O2 absorption in presence of EDTA (inhibitor of the reaction of peroxidation) because about 50% of the total oxygen were utilized only in the process where NADP.H2 was oxidized. NAD.H2 oxidation, inhibited with EDTA, was activated by addition of Ca2+.

Animals↗
PubMed1988

Platelet-derived growth factor-induced c-myc RNA expression. Analysis of an inducible pathway independent of protein kinase C.

Platelet-derived growth factor (PDGF) is generally considered to stimulate phosphoinositide turnover resulting in activation of protein kinase C and increased cytoplasmic [Ca2+]. We have examined the role of these secondary effects in regulation of c-myc mRNA accumulation in the MG-63 human osteogenic sarcoma line. Treatment of quiescent cells with 12-O-tetradecanoyl phorbol-13-acetate (TPA) to down-regulate protein kinase C inhibited TPA-stimulated c-myc expression but did not affect the PDGF-modulated process. When cytoplasmic [Ca2+] was increased by addition of a Ca2+ ionophore (A23187 or ionomycin), no stimulation of c-myc RNA was seen; furthermore, these agents did not enhance the PDGF-modulated c-myc expression. Addition of EGTA to cultures treated with both PDGF and a Ca2+ ionophore did not inhibit c-myc induction but rather caused a superinduction of c-myc RNA accumulation. Superinduction occurred only if the [EGTA] was greater than [Ca2+] in the medium. This superinduction was distinct from the increased induction caused by inhibition of protein synthesis. Because PDGF-induced c-myc expression is independent of protein kinase C and increased cytoplasmic [Ca2+], the evidence suggests that PDGF modulates c-myc RNA accumulation in MG-63 cells via a novel pathway, seemingly uncoupled from the classic action of increased phosphoinositide metabolism.

Calcimycin↗
PubMed1987

[Analysis of the signalling pathway of TNF in normal cells and tumor cells].

The internalization process and intracellular distribution of 125I-labeled TNF, in L-M (murine tumorigenic fibroblasts, highly sensitive to TNF cytotoxicity) cells and in HEL (human embryonic lung cells, non-sensitive to TNF cytotoxicity) cells bearing TNF receptor, were elucidated by pulse-chasing and by Percoll density gradient centrifugation. Effect of TNF treatment on the RNA and protein synthesis of target cells was also studied using 3H-UDR and 35S-methionine incorporation. In both L-M and HEL cells, receptor-bound 125I-TNF was rapidly internalized and delivered to lysosomes within 15-30 min, followed by degradation and release into the culture medium. RNA synthesis and protein synthesis were not affected by TNF treatment in HEL cells, but marked stimulation (3.5 times and 4.2 times, respectively) was observed in L-M cells.

Animals↗
PubMed1980

[Clinical analysis of the pain pathways of labor (author's transl)].

Segmental epidural blocks by double catheters which were inserted in the thoracolumbar (Th12-L1) and lower lumbar region (L4-L5) were performed in eleven primiparas to investigate the correct pain pathways of labor and the sensory innervation of uterus. It is generally believed in Japan that the sensory nerves of the cervix of uterus enter the cord through the sacral segments (s2,3,4) and the uterine body through the thoracic segments (Th11, Th12). 5 ml dose of 0.5% bupivacaine (Marcaine) was used to the upper catheter (Th12-L1) during the first stage of labor. Segmental spread of analgesia was on average Th9.4-L1,6 and the duration was 1 hr 57 min +/- 34 min. Seven cases (64%) had no pain up to the full dilatation of cervix and four cases (36%) complained of the pain in the pudendal nerve region (S2,3,4) at the 8 cm dilatation of cervix due to the lower engagement of the fetal head. These findings suggest that not only the pain impulses during the first stage of labor which are resulted from the uterine contraction and the dilatation of the cervix enter the cord through Th10.Th11.Th12.L1 segments and no relation to sacral nerves.

Adult↗
PubMed1993

[An analysis of the central pathway of vestibulo-sympathetic responses].

In order to elucidate the relationship between several structures of CNS and the vestibulo-sympathetic response (VSR) in rat, the technique of spike triggering average (STA) was used. The spike of the neuron which responded to the pendular rotation (pendular positive unit, PPU) was used to trigger the onset of averaged activities of the splanchnic nerve (SN). Making use of the spike of PPU of nucleus vestibularis medialis (NVM) as an indicator, the SN-STA had a latency of 33.28 +/- 3.1 ms. SN-STA triggered by PPU of reticular formation (RF) of caudal brain stem, a positive response with a latency of 11.13 +/- 0.91 ms was observed. SN-STA triggered by PPU of vestibulocerebellum, a positive response with a latency of 21.86 +/- 1.73 ms was observed. Our results suggest that the nearest supraspinal relay may be the nuclei of medical RF in caudal brain stem and the descending flow of VSR was probably transmitted by the slow conducted fibers of reticulo-spinal tract. According to the latency of SN-STA by PPU of vestibulo-cerebellum, the vestibulcerebellum possibly executed a polysynaptic mission between the transmission of VSR outflow from NVM to RF nuclei of caudal brain stem.

Animals↗
PubMed1998

[The classification and analysis of the blood pathway in left ventricular cavity observed by left ventricular contrast echocardiography].

We can observe and analyse the blood pathway in left ventricular cavity by contrast echocardiography using sonicated albumin, because it can be through the pulmonary capillaries. I. The observational classification of the blood pathway in left ventricular cavity. Group I: The contrast medium comes to the apex directly from the mitral orifice. Group II: The contrast medium comes to the apex along the posterior wall forming the spiral flow and turns back to the outflow tract. Group III: The contrast medium is found like a fireworks only at the apex. II. The factors associated with the blood pathway in left ventricular cavity. 1. Abnormality of left ventricular wall motion, 2. The form of left ventricular cavity, 3. Early diastolic peak velocity of the transmitral flow, 4. A/E, 5. Left ventricular function.

Contrast Media↗
PubMed2005

Genome wide analysis of transcript levels after perturbation of the EGFR pathway in the Drosophila ovary.

Defects in the epidermal growth factor receptor (EGFR) pathway can lead to aggressive tumor formation. Activation of this pathway during normal development produces multiple outcomes at the cellular level, leading to cellular differentiation and cell cycle activation. To elucidate the downstream events induced by this pathway, we used genome-wide cDNA microarray technology to identify potential EGFR targets in Drosophila oogenesis. We focused on genes for which the transcriptional responses due to EGFR pathway activation and inactivation were in opposite directions, as this is expected for genes that are directly regulated by the pathway in this tissue type. We perturbed the EGFR pathway in epithelial follicle cells using seven different genetic backgrounds. To activate the pathway, we overexpressed an activated form of the EGFR (UAS-caEGFR), and an activated form of the signal transducer Raf (UAS-caRaf); we also over- or ectopically expressed the downstream homeobox transcription factor Mirror (UAS-mirr) and the ligand-activating serine protease Rhomboid (UAS-rho). To reduce pathway activity we used loss-of-function mutations in the ligand (gurken) and receptor (torpedo). From microarrays containing 6,255 genes, we found 454 genes that responded in an opposite manner in gain-of-function and loss-of-function conditions among which are many Wingless signaling pathway components. Further analysis of two such components, sugarless and pangolin, revealed a function for these genes in late follicle cell patterning. Of interest, components of other signaling pathways were also enriched in the EGFR target group, suggesting that one reason for the pleiotropic effects seen with EGFR activity in cancer progression and development may be its ability to regulate many other signaling pathways.

Animals↗
PubMed1995

Network analysis of PET-mapped visual pathways in Alzheimer type dementia.

Using path analysis to determine the systems-level neural networks mediating specific tasks from regional cerebral blood flow (rCBF) data obtained by positron emission tomography (PET), we recently found in young subjects strong functional linkages during a face matching task along a right hemisphere ventral network including occipital, temporal, and frontal regions. In this study, PET data obtained during a face matching task from mildly affected patients with dementia of the Alzheimer type (DAT) and healthy matched controls showed that (1) the neural model obtained in young subjects provides a good fit to data from old subjects; (2) although the DAT patients could perform this task with the same accuracy as controls, they did not use the same functional network.

Aged↗
PubMed2025

Circulating inflammatory proteins and osteomyelitis: A bidirectional Mendelian randomization and colocalization analysis.

Circulating inflammatory proteins (CIPs) have been implicated in the progression of osteomyelitis (OM); however, whether these proteins play a causal role or are merely a consequence remains unclear. This study aimed to assess the causal relationships between CIPs and OM using a bidirectional 2-sample Mendelian randomization (MR) approach. MR analyses were performed using genome-wide association study summary statistics for 91 inflammation-related proteins (n&#x2005;=&#x2005;14,824) and OM (1881 cases and 3,91,037 controls). The inverse variance weighted method was used as the primary analytical approach, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses were conducted to evaluate heterogeneity, horizontal pleiotropy, and robustness. Colocalization analysis was applied to identify shared causal variants, and pathway enrichment analysis was used to explore underlying biological mechanisms. Forward MR analysis revealed that elevated levels of tumor necrosis factor-beta (TNF-&#x3b2;) were significantly associated with increased OM risk (odds ratio [OR]&#x2005;=&#x2005;1.132; 95% confidence interval [CI]: 1.052-1.217; false discovery rate [FDR]&#x2005;=&#x2005;0.027). Conversely, decreased levels of osteoprotegerin (OR&#x2005;=&#x2005;0.772; 95% CI: 0.671-0.889; FDR&#x2005;=&#x2005;0.015) and adenosine deaminase (OR&#x2005;=&#x2005;0.811; 95% CI: 0.736-0.894; FDR&#x2005;<&#x2005;0.001) were associated with increased OM risk. Reverse MR analysis identified increased levels of interleukin-15 receptor alpha, C-X-C motif chemokine ligand 1, fms-related tyrosine kinase 3 ligand, interleukin-20, interleukin-10 (IL10), C-C motif chemokine ligand 19, and CXCL6 as being significantly associated with OM susceptibility (all FDR&#x2005;<&#x2005;0.05). Colocalization analysis provided strong evidence for a shared causal variant between TNF-&#x3b2; and OM (posterior probability for hypothesis 4&#x2005;=&#x2005;0.999). Enrichment analyses indicated involvement of implicated proteins in Toll-like receptor signaling and T-helper 17 cell differentiation pathways. This study identified several CIPs - including TNF-&#x3b2;, osteoprotegerin, and adenosine deaminase - as potentially causal in OM development. These findings highlight promising targets for future immunomodulatory therapies aimed at preventing or mitigating osteomyelitis.

Humans↗
PubMed1989

Isolation of constitutive mutations affecting the proline utilization pathway in Saccharomyces cerevisiae and molecular analysis of the PUT3 transcriptional activator.

The enzymes of the proline utilization pathway (the products of the PUT1 and PUT2 genes) in Saccharomyces cerevisiae are coordinately regulated by proline and the PUT3 transcriptional activator. To learn more about the control of this pathway, constitutive mutations in PUT3 as well as in other regulators were sought. A scheme using a gene fusion between PUT1 (S. cerevisiae proline oxidase) and galK (Escherichia coli galactokinase) was developed to select directly for constitutive mutations affecting the PUT1 promoter. These mutations were secondarily screened for their effects in trans on the promoter of the PUT2 (delta 1-pyrroline-5-carboxylate dehydrogenase) gene by using a PUT2-lacZ (E. coli beta-galactosidase) gene fusion. Three different classes of mutations were isolated. The major class consisted of semidominant constitutive PUT3 mutations that caused PUT2-lacZ expression to vary from 2 to 22 times the uninduced level. A single dominant mutation in a new locus called PUT5 resulted in low-level constitutive expression of PUT2-lacZ; this mutation was epistatic to the recessive, noninducible put3-75 allele. Recessive constitutive mutations were isolated that had pleiotropic growth defects; it is possible that these mutations are not specific to the proline utilization pathway but may be in genes that control several pathways. Since the PUT3 gene appears to have a major role in the regulation of this pathway, a molecular analysis was undertaken. This gene was cloned by functional complementation of the put3-75 mutation. Strains carrying a complete deletion of this gene are viable, proline nonutilizing, and indistinguishable in phenotype from the original put3-75 allele. The PUT3 gene encodes a 2.8-kilobase-pair transcript that is not regulated by proline at the level of RNA accumulation. The presence of the gene on a high-copy-number plasmid did not alter the regulation of one of its target genes, PUT2-lacZ, suggesting that the PUT3 gene product is not limiting and that a titratable repressor is not involved in the regulation of this pathway.

Cloning, Molecular↗
PubMed2003

Proteomic analysis of the benzoate degradation pathway in Acinetobacter sp. KS-1.

The purpose of this study was to perform proteome analysis of Acinetobacter sp. KS-1, a bacterium capable of degrading benzoate as a sole carbon source. In order to understand the benzoate degradation pathway used by strain KS-1, proteomes of benzoate-cultured and succinate-cultured KS-1 were comparatively analyzed by two dimensional gel electrophoresis (2-DE). Eighteen protein spots proteins were exclusively induced from the benzoate-cultured strain KS-1. Of these 18 spots, two benzoate-degrading enzymes (catechol 1,2-dioxygenase and beta-ketoadipate succinyl-CoA transferase) were identified by MS/MS analysis by MALDI-TOF/TOF mass spectrometry, which suggests that strain KS-1 degrades benzoate by the beta-ketoadipate pathway. DEAE-chromatography suggested that strain KS-1 induced only one type of catechol 1,2-dioxygenase during benzoate degradation. The catechol 1,2-dioxygenase was purified using three steps of ammonium sulfate precipitation, DEAE-sepharose, and Mono-Q chromatography. The purified catechol 1,2-dioxygenase of strain KS-1 had strong dioxygenase activity for 4-methylcatechol as well as catechol. Sequencing analysis using N-terminal and internal amino acid sequences showed that this catechol 1,2-dioxygenase is highly homologous with catechol 1,2-dioxygenase of Acinetobacter radioresistens. These results suggest that comparative proteomic analysis of biodegrading bacteria cultured under different conditions may be a useful initial step toward the elucidation of the aromatic compound degradation pathway.

Acinetobacter↗
PubMed2004

PathAligner: metabolic pathway retrieval and alignment.

MOTIVATION: Analysis of metabolic pathways is a central topic in understanding the relationship between genotype and phenotype. The rapid accumulation of biological data provides the possibility of studying metabolic pathways at both the genomic and the metabolic levels. Retrieving metabolic pathways from current biological data sources, reconstructing metabolic pathways from rudimentary pathway components, and aligning metabolic pathways with each other are major tasks. Our motivation was to develop a conceptual framework and computational system that allows the retrieval of metabolic pathway information and the processing of alignments to reveal the similarities between metabolic pathways. RESULTS: PathAligner extracts metabolic information from biological databases via the Internet and builds metabolic pathways with data sources of genes, sequences, enzymes, metabolites etc. It provides an easy-to-use interface to retrieve, display and manipulate metabolic information. PathAligner also provides an alignment method to compare the similarity between metabolic pathways. AVAILABILITY: PathAligner is available at http://bibiserv.techfak.uni-bielefeld.de/pathaligner.

Algorithms↗