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PubMed1988

Activation of factor VII bound to tissue factor: a key early step in the tissue factor pathway of blood coagulation.

Whether the factor VII/tissue factor complex that forms in tissue factor-dependent blood coagulation must be activated to factor VIIa/tissue factor before it can activate its substrates, factor X and factor IX, has been a difficult question to answer because the substrates, once activated, back-activate factor VII. Our earlier studies suggested that human factor VII/tissue factor cannot activate factor IX. Studies have now been extended to the activation of factor X. Reaction mixtures were made with purified factor VII, X, and tissue factor; in some experiments antithrombin III and heparin were added to prevent back-activation of factor VII. Factor X was activated at similar rates in reaction mixtures containing either factor VII or factor VIIa after an initial 30-sec lag with factor VII. In reaction mixtures with factor VII a linear activation of factor X was established several minutes before cleavage of 125I-labeled factor VII to the two-chain activated molecule was demonstrable on gel profiles. Adding antithrombin III and heparin blocked activation of factor X by factor VII/tissue factor but not by factor VIIa/tissue factor. When the antithrombin III and heparin were added 1 min after the other reagents, factor VII/tissue factor activation of factor X was not blocked. These data suggest that factor VII/tissue factor cannot activate measurable amounts of factor X over several minutes. Overall, our results support the hypothesis that a rapid preferential activation of factor VII bound to tissue factor by trace amounts of factor Xa is a key early step in tissue factor-dependent blood coagulation.

Antithrombin III↗
PubMed2006

Aberrant NF-kappaB activity in HaCaT cells alters their response to UVB signaling.

The immortalized keratinocyte cell line called HaCaT has been used in experiments as a convenient substitute for cultured normal human keratinocytes. However, some molecular differences have been identified that distinguish HaCaT cells from normal human keratinocytes, including differences in the NF-kappaB signaling pathway and in their response to UVB irradiation. NF-kappaB is a widely expressed transcription factor that is activated by a cacophony of stimuli, including inflammatory mediators such as TNFalpha and oxidative stressors such as UVB exposure. This report delineates and further elucidates the aberrant NF-kappaB signaling pathway and its effect in HaCaT cells exposed to UVB radiation or inflammatory mediators. We demonstrate that NF-kappaB DNA binding is activated by both UVB and TNFalpha, but discrepancies in the activation of key upstream signaling pathway components such as AKT phosphorylation and IkappaBalpha degradation exist. Disruption of the constitutive NF-kappaB activity in HaCaT cells resulted in alterations in NF-kappaB signaling that were more consistent with the NF-kappaB signaling pathway in normal human keratinocytes. These studies suggest that caution should be used in extrapolating the biological responses of HaCaT cells to those of normal human keratinocytes in the absence of confirmatory experiments.

Apoptosis↗
PubMed1995

Effect of adrenaline and phorbol myristate acetate or bacterial lipopolysaccharide on stimulation of pathways of macrophage glucose, glutamine and O2 metabolism. Evidence for cyclic AMP-dependent protein kinase mediated inhibition of glucose-6-phosphate dehydrogenase and activation of NADP+-dependent 'malic' enzyme.

Adrenaline has recently been shown to stimulate both glucose metabolism and H2O2 release by macrophages but the activity of the key pentose phosphate pathway enzyme, glucose-6-phosphate dehydrogenase (which generates the NADPH crucial for the reduction of molecular oxygen), was reduced under these conditions [Costa Rosa, Safi, Cury and Curi (1992) Biochem. Pharmacol. 44, 2235-2241]. We report here that adrenaline activates another NADPH-producing enzyme, NADP(+)-dependent 'malic' enzyme, while also inhibiting glucose-6-phosphate dehydrogenase, via cyclic AMP-dependent protein kinase (PKA) activation. Regulation of glucose-6-phosphate dehydrogenase activity by PKA has not been reported elsewhere. The sparing of some glucose from pentose phosphate pathway consumption may be important in the provision of glycerol 3-phosphate which in the macrophage may be required for new phospholipid synthesis. Glutamine oxidation was also stimulated by adrenaline thus providing increased substrate (malate) for NADP(+)-dependent 'malic' enzyme and therefore shifting some of the burden of NADPH production from glucose to glutamine metabolism. We also report a novel synergistic effect of adrenaline and some bacterial products and/or gamma-interferon in stimulating secretory and metabolic pathways in macrophages which may be a part of a larger network of signals that lead to enhanced macrophage activity.

Animals↗
PubMed2004

Nuclear receptor signaling and cardiac energetics.

The heart has a tremendous capacity for ATP generation, allowing it to function as an efficient pump throughout the life of the organism. The adult myocardium uses either fatty acid or glucose oxidation as its main energy source. Under normal conditions, the adult heart derives most of its energy through oxidation of fatty acids in mitochondria. However, the myocardium has a remarkable ability to switch between carbohydrate and fat fuel sources so that ATP production is maintained at a constant rate in diverse physiological and dietary conditions. This fuel selection flexibility is important for normal cardiac function. Although cardiac energy conversion capacity and metabolic flux is modulated at many levels, an important mechanism of regulation occurs at the level of gene expression. The expression of genes involved in multiple energy transduction pathways is dynamically regulated in response to developmental, physiological, and pathophysiological cues. This review is focused on gene transcription pathways involved in short- and long-term regulation of myocardial energy metabolism. Much of our knowledge about cardiac metabolic regulation comes from studies focused on mitochondrial fatty acid oxidation. The genes involved in this key energy metabolic pathway are transcriptionally regulated by members of the nuclear receptor superfamily, specifically the fatty acid-activated peroxisome proliferator-activated receptors (PPARs) and the nuclear receptor coactivator, PPARgamma coactivator-1alpha (PGC-1alpha). The dynamic regulation of the cardiac PPAR/PGC-1 complex in accordance with physiological and pathophysiological states will be described.

Adenosine Triphosphate↗
PubMed2003

Endocrine mechanisms of disease: Expression and degradation of androgen receptor: mechanism and clinical implication.

The androgen-androgen receptor (AR) signaling pathway plays a key role in proper development and function of male reproductive organs, such as prostate and epididymis, as well as nonreproductive organs, such as muscle, hair follicles, and brain. Abnormalities in the androgen-AR signaling pathway have been linked to diseases, such as male infertility, Kennedy's disease, and prostate cancer. Regulation of AR activity can be achieved in several different ways: modulation of AR gene expression, androgen binding to AR, AR nuclear translocation, AR protein stability, and AR trans-activation. This review covers mechanisms implicated in the control of AR protein expression and degradation, and their potential linkage to the androgen-related diseases. A better understanding of such mechanisms may help us to design more effective androgens and antiandrogens to battle androgen-related diseases.

Androgens↗
PubMed2003

Induction of apoptosis by caffeine is mediated by the p53, Bax, and caspase 3 pathways.

Caffeine is a key component of many popular drinks, especially tea and coffee. Previous reports have shown that caffeine may contribute to the chemopreventive effect of tea in animals. Here, we report that treatment with low concentrations of caffeine induced apoptosis in JB6 Cl41 cells. JB6 Cl41 cells were starved in 0.1% fetal bovine serum/MEM for 72 h and then treated with 50-450 microM caffeine for 24 h. Cells showed the typical DNA laddering pattern and other characteristics of apoptosis. The IC(50) of caffeine on JB6 Cl41 cells was 2.7 mM. Induction of apoptosis by caffeine appeared to be p53-dependent because cells lacking p53 (p53(-/-)) showed no signs of apoptosis after treatment with caffeine. Immunoprecipitation assays and Western blot analysis showed that caffeine induced phosphorylation of p53 at Ser(15) in JB6 Cl41 cells. The same low concentration of caffeine that was effective for inducing phosphorylation of p53 was also shown to increase p53 activation. Expression of Bax, another p53 target, distinctly increased in a time- and dose-dependent manner. Cleaved caspase 3 was also increased in a time- and dose-dependent manner. These data show that a low concentration of caffeine can induce p53-dependent apoptosis in JB6 cells through the Bax and caspase 3 pathways.

Animals↗
PubMed2006

Hedgehog signaling in small-cell lung cancer: frequent in vivo but a rare event in vitro.

The hedgehog (HH) signaling pathway plays multiple roles during embryonic development and increasing evidence suggests that this embryonic pathway is involved in development and progression of several human cancers including those of the brain, skin, lung and gastrointestinal tract. To investigate HH signaling activity in small-cell lung cancer (SCLC), we have performed gene expression analysis on members of the HH pathway on a panel of 20 SCLC cell lines. Sonic hedgehog (SHH) expression was detected in only DMS79 and GLC16 and only DMS114 expressed detectable protein levels of GLI1, one of the key transcription factors of the pathway. Involvement of HH signaling in SCLC proliferation was investigated in a subset of cell lines using the HH signaling inhibitor cyclopamine or small interfering RNA (siRNA) against GLI1. Cells expressing GLI1 responded only weakly to both cyclopamine and RNA interference, suggesting that HH signaling plays only a minor role in the growth of SCLC cell lines. To investigate HH pathway activity in vivo, GLI1 immunohistochemistry was performed on SCLC tumors. Interestingly, GLI1 was expressed in most SCLC tumors studied, indicating that HH signaling is important for in vivo growth of SCLC but establishment of cell lines from SCLC tumors may lead to loss of expression of key HH pathway members. Thus, the data support the idea that the HH pathway may be a therapeutic target in SCLC. However, the data also suggest that the SCLC cells can circumvent the apparent in vivo requirement of HH signaling.

Carcinoma, Small Cell↗
PubMed1996

Evolutionary conservation of a genetic pathway of programmed cell death.

Genetic analysis of programmed cell death in Caenorhabditis elegans has led to the identification of 13 genes that constitute a developmental pathway of programmed cell death. Two of the three key genes in this pathway, ced-9, a cell death suppressor, and ced-3, a cell death inducer, were found to encode proteins that share structural and functional similarities with the mammalian proto-oncogene product Bcl-2 and interleukin-1 beta converting enzyme, respectively. These results suggest that the genetic pathway of programmed cell death may be evolutionarily conserved from worms to mammals.

Animals↗
PubMed2006

Evaluation of regression models in metabolic physiology: predicting fluxes from isotopic data without knowledge of the pathway.

This study explores the ability of regression models, with no knowledge of the underlying physiology, to estimate physiological parameters relevant for metabolism and endocrinology. Four regression models were compared: multiple linear regression (MLR), principal component regression (PCR), partial least-squares regression (PLS) and regression using artificial neural networks (ANN). The pathway of mammalian gluconeogenesis was analyzed using [U-(13)C]glucose as tracer. A set of data was simulated by randomly selecting physiologically appropriate metabolic fluxes for the 9 steps of this pathway as independent variables. The isotope labeling patterns of key intermediates in the pathway were then calculated for each set of fluxes, yielding 29 dependent variables. Two thousand sets were created, allowing independent training and test data. Regression models were asked to predict the nine fluxes, given only the 29 isotopomers. For large training sets (>50) the artificial neural network model was superior, capturing 95% of the variability in the gluconeogenic flux, whereas the three linear models captured only 75%. This reflects the ability of neural networks to capture the inherent non-linearities of the metabolic system. The effect of error in the variables and the addition of random variables to the data set was considered. Model sensitivities were used to find the isotopomers that most influenced the predicted flux values. These studies provide the first test of multivariate regression models for the analysis of isotopomer flux data. They provide insight for metabolomics and the future of isotopic tracers in metabolic research where the underlying physiology is complex or unknown.

Journal Article↗
PubMed2005

Colorectal cancer: mutations in a signalling pathway.

Protein kinases are enzymes that are important for controlling cellular growth and invasion, and their malfunction is implicated in the development of some tumours. We analysed human colorectal cancers for genetic mutations in 340 serine/threonine kinases and found mutations in eight genes, including in three members of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway. The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for therapeutic intervention.

Colorectal Neoplasms↗
PubMed2001

Involvement of p38 mitogen-activated protein kinase signaling in transformed growth of a cholangiocarcinoma cell line.

Although mitogen-activated protein kinase (MAPK) pathways play a key role in cell growth, their role in mediating the altered growth phenotype of transformed cells remains unclear. The p44/p42 MAPK signaling cascades are activated by mitogenic stimulation of human cholangiocytes. In contrast, the p38 MAPK pathway is activated by mitogen stimulation of malignant, but not nonmalignant cholangiocytes. Thus, our aims were to determine the role of p38 MAPK signaling in mediating the growth phenotype of transformed cholangiocytes. KMCH-1 malignant human cholangiocytes required the presence of serum for proliferation, but were able to grow in reduced serum conditions. Inhibition of p38 MAPK decreased serum-dependent proliferation of KMCH-1 cells. Furthermore, inhibition of p38 MAPK, but not of p44/p42 MAPK, reduced anchorage-independent growth of KMCH-1 cells. Although both p38 and p44/p42 MAPK are activated in response to mitogens, they have divergent effects on anchorage-independent growth. Inhibition of p38 MAPK, but not of p44/p42 MAPK signaling, decreased cell cycle progression and increased expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIPl). However, expression of p27(KIP1) or p16(INK4A) was not altered by either pathway. Thus, mitogen activation of p38 MAPK decreases expression of p21(WAF1/CIP1) and mediates growth independent of anchorage signals, whereas mitogen activation of p44/p42 MAPK mediates an anchorage signal-dependent growth pathway. These data provide a link between aberrant stress-activated cell signaling and the altered growth phenotype of transformed cells that may be important for the development of therapies to limit transformed cell growth.

Bile Duct Neoplasms↗
PubMed2007

Helicobacter pylori-induced apoptosis in T cells is mediated by the mitochondrial pathway independent of death receptors.

BACKGROUND: Chronic infection with Helicobacter pylori is related to the pathogenesis of the noncardia carcinoma of the stomach. In this study we investigated the mechanisms of H. pylori-induced apoptosis in T lymphocytes, which could explain a mechanism of immune evasion facilitating chronic inflammation of the mucosa and gastric carcinogenesis. MATERIALS AND METHODS: The supernatant of H. pylori culture was used to study the mechanism of apoptosis induction in human leukaemia T cell lines Jurkat and CEM and in primary T cells. The cytotoxin associated gene A (CagA) and vacuolating cytotoxin A (Vac A) positive bacterial strain H. pylori 60190 (CagA(+), VacA(+)) and as a control the less toxic H. pylori strain Tx30a (CagA(-), VacA(-)) were used to produce the supernatant. Cell death was determined by DNA fragmentation and protein expression by Western blot. RESULTS: H. pylori 60190-induced apoptosis was neither blocked by inhibition of the death ligands TRAIL (TNF-related apoptosis-inducing ligand), CD95L/FasL and TNF-alpha (tumour necrosis factor-a) in wild type Jurkat cells nor in FADD(def) (Fas-associated death domain protein) and caspase-8(def) subclones of the Jurkat cell line. Yet, the pancaspase inhibitor zVAD-fmk could inhibit up to 90% of H. pylori-induced apoptosis. Stable transfection of Jurkat wild type cells with Bcl-x(L and) Bcl-2 resulted in marked reduction of H. pylori-induced apoptosis, showing that the mitochondrial pathway is the key regulator. This is supported by the finding that surviving primary human lymphocytes upregulate Bcl-2 when exposed to H. pylori supernatant. CONCLUSIONS: H. pylori-induced apoptosis of T cells is mediated by the mitochondrial pathway and could create a local environment that facilitates life-long infection by immune evasion.

Apoptosis↗
PubMed2006

Lethal mutations in the isoprenoid pathway of Salmonella enterica.

Essential isoprenoid compounds are synthesized using the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway in many gram-negative bacteria, some gram-positive bacteria, some apicomplexan parasites, and plant chloroplasts. The alternative mevalonate pathway is found in archaea and eukaryotes, including cytosolic biosynthesis in plants. The existence of orthogonal essential pathways in eukaryotes and bacteria makes the MEP pathway an attractive target for the development of antimicrobial agents. A system is described for identifying mutations in the MEP pathway of Salmonella enterica serovar Typhimurium. Using this system, point mutations induced by diethyl sulfate were found in the all genes of the essential MEP pathway and also in genes involved in uptake of methylerythritol. Curiously, none of the MEP pathway genes could be identified in the same parent strain by transposon mutagenesis, despite extensive searches. The results complement the biochemical and bioinformatic approaches to the elucidation of the genes involved in the MEP pathway and also identify key residues for activity in the enzymes of the pathway.

Erythritol↗
PubMed2003

Hypothalamic digoxin, hemispheric chemical dominance, and chronic bronchitis emphysema.

The isoprenoid pathway produces three key metabolites--endogenous digoxin (membrane sodium-potassium ATPase inhibitor, immunomodulator, and regulator of neurotransmitter/amino acid transport), dolichol (regulates N-glycosylation of proteins), and ubiquinone (free radical scavenger). This was assessed in patients with chronic bronchitis emphysema. The pathway was also assessed in patients with right hemispheric, left hemispheric, and bihemispheric dominance to find the role of hemispheric dominance in the pathogenesis of chronic bronchitis emphysema. All the 15 patients with chronic bronchitis emphysema were right-handed/left hemispheric dominant by the dichotic listening test. In patients with chronic bronchitis emphysema there was elevated digoxin synthesis, increased dolichol, and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate levels of RBC membrane in patients with chronic bronchitis emphysema. The same biochemical patterns were obtained in individuals with right hemispheric dominance. Endogenous digoxin by activating the calcineurin signal transduction pathway of T-cell can contribute to immune activation in chronic bronchitis emphysema. Increased free radical generation can also lead to immune activation. Endogenous synthesis of nicotine can contribute to the pathogenesis of the disease. Altered glycoconjugate metabolism and membranogenesis can lead to defective lysosomal stability contributing to the disease process by increased release of lysosomal proteases. The role of an endogenous digoxin and hemispheric dominance in the pathogenesis of chronic bronchitis emphysema and in the regulation of lung structure/function is discussed. The biochemical patterns obtained in chronic bronchitis emphysema is similar to those obtained in left-handed/right hemispheric chemically dominant individuals by the dichotic listening test. But all the patients with chronic bronchitis emphysema were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Chronic bronchitis emphysema occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function. Hemispheric chemical dominance can play a role in the regulation of lung function and structure.

Analysis of Variance↗
PubMed2003

Hypothalamic digoxin-mediated model for Parkinson's disease.

The isoprenoid pathway produces four key metabolites important in cellular function--digoxin (endogenous membrane Na(+)-K+ ATPase inhibitor), dolichol (important in N-glycosylation of proteins), ubiquinone (free-radical scavenger), and cholesterol (component of cellular membranes). This study assessed the changes in the isoprenoid pathway and the consequences of its dysfunction in Parkinson's disease (PD). There was an elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol levels, and a reduction in serum magnesium, RBC membrane Na(+)-K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine, and quinolinic acid were elevated, while tyrosine, morphine, dopamine, and noradrenaline were decreased. The total serum glycosaminoglycans (GAG) and glycosaminoglycan fractions (except chondroitin sulphates and hyaluronic acid), the activity of GAG degrading enzymes, carbohydrate residues of serum glycoproteins, the activity of glycohydrolase-beta galactosidase, and serum glycolipids were elevated. HDL cholesterol was reduced and free fatty acids increased. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins and cholesterol were reduced, while phospholipid was increased. The activity of all serum free-radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in PD, while the concentration of serum lipid peroxidation products and nitric oxide increased. A dysfunctional isoprenoid pathway and related cascade are important in the pathogenesis of Parkinson's disease. A hypothalamic digoxin mediated model for Parkinson's disease is also postulated.

Aged↗
PubMedDate not supplied

Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats.

The nitric oxide/guanylyl cyclase, cyclic guanosine monophosphate/phosphodiesterase 5 (NO/cGMP/PDE5) pathways play a key role in physiological and pathological situations, such as synaptic plasticity, learning and memory formation, diabetic gastropathy and neuropathy, long-term potentiation (LTP), epilepsy, cerebral ischemia, and neurodegenerative diseases. Several studies have demonstrated the alteration of NO-cGMP pathway in cognitive impairment. The present study was aimed to study the effect of sildenafil, a PDE5 inhibitor on diabetes and electroconvulsive shock (ECS)-induced cognitive dysfunction in rat using one-trial step-through type of passive avoidance and elevated plus-maze task. Diabetic and ECS-treated rats showed poor learning performance in step-through passive avoidance and plus-maze task. Acute administration of sildenafil significantly reversed the diabetes and ECS-induced retention deficits in both the test paradigms. Sildenafil also significantly improved the cognitive performance in young rats in both the paradigms. Furthermore, L-NAME, a non-selective NOS inhibitor and methylene blue, a guanylate cyclase inhibitor blocked the effect of sildenafil. The results thus suggest that cognitive impairment might be due to the modulatory effect of nNOS or PDE5 enzyme on cGMP levels. Moreover, sildenafil-induced reversal of cognitive impairment suggests the protective role of PDE5 inhibitors in neurodegenerative disorders.

Animals↗
PubMed2005

Pathway management in ambulatory wound care: defining local standards for quality improvement and interprofessional care.

Growing health care costs and changes in health care delivery, such as the adoption of the diagnosis-related groups, have tremendously affected treatment patterns all over the world. Pathway management is suitable to be responsive to the growing operating requirements and to manage effective and efficient medical care in hospitals. Pathways standardise clinical processes for patients with a similar diagnosis, procedure or symptom thereby optimising the quality of treatment and patient satisfaction. They are utilised by a multidisciplinary team with a primary focus on quality and coordination of care. Considering the key strategies of pathway management, an interprofessional team containing physicians and nurses developed and implemented a clinical pathway for ambulatory treatment of chronic wounds. A precise medical protocol was created to standardise routine procedures, to improve the treatment outcome and to provide an integrated documentation that enhances interprofessional collaboration. We designed a modular concept of four different sheets which provide pre-defined standards: (a) medical admission, (b) findings and history, (c) topic and systemic treatment and (d) evaluation of outcome criteria. Variances must be merely written down in detail. After 1 year in clinical practice, we state that the use of a clinical pathway for chronic wound management is an effective method of improving clinical processes and patient outcomes.

Ambulatory Care↗
PubMed2006

Runx2 phosphorylation induced by fibroblast growth factor-2/protein kinase C pathways.

Runx2 is a key transcription factor in osteoblast differentiation, and its activity is regulated by fibroblast growth factors (FGFs). Craniosynostosis, characterized by premature suture closure, results from mutations that generate constitutively active FGF receptors (FGFRs). We previously showed that FGF/FGFR-activated protein kinase C (PKC) is involved in the expression and activity of Runx2. Activated PKCdelta physically interacts with Runx2 in FGF2-stimulated MC3T3-E1 preosteoblastic cells. Immunopurified Runx2 protein reacted with PKCdelta kinase, and a phosphorylated 1460-Da peptide fragment (amino acids 241-252, 1380-Da) derived from Runx2 was also detected in MS analysis. Computer analysis predicted that Ser247 in this Runx2 can be a possible phosphorylation site by PKCdelta. We also showed that Runx2 activity after FGF stimulation correlates with the presence of the Runx2 Ser247 residue. The S247A (Ser --> Ala) mutation confers decreased transcriptional activity on a Runx2-responsive promoter after FGF treatment.

Animals↗