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At least 559 records · Page 31Linked to original sources
PubMed2002

A metal chelator, diphenylthiocarbazone, induces apoptosis in acute promyelocytic leukemia (APL) cells mediated by a caspase-dependent pathway without a modulation of retinoic acid signaling pathways.

A metal chelator, diphenylthiocarbazone (dithizone), has been reported to induce differentiation and apoptosis of the human myeloid leukemia cell line HL-60, however, very little is known about the mechanism of dithizone-induced apoptosis. Here, we report for the first time that dithizone can induce inhibition of cellular growth of retinoic acid (RA)-sensitive NB4 and RA-resistant UF-1 APL cells via induction of apoptosis but not differentiation. Treatment of NB4 cells with dithizone markedly-induced apoptosis, which was associated with the loss of mitochondrial transmembrane potentials (Delta Psi(m)) and activation of caspase-3 and -9. Further investigation of the RA-resistant UF-1 APL cells showed that dithizone-induced apoptosis to a lesser extent. However, neither dithizone alone nor in combination with all-trans RA induced the expression of myeloid differentiation antigen CD11b. Concomitantly, the degradation of PML/RARalpha fusion protein was not observed after treatment with dithizone alone, and the degradation was not enhanced by the combination of dithizone and all-trans RA. We conclude that dithizone, a metal chelator, induced apoptosis without differentiation in APL cells in association with Delta Psi(m) collapse and caspase-3 and -9 activation.

Amino Acid Chloromethyl Ketones↗
PubMed2003

The pathway study: results of a pilot feasibility study in patients suspected of having lung carcinoma investigated in a conventional chest clinic setting compared to a centralised two-stop pathway.

UNLABELLED: The best chance of cure in non-small cell lung cancer (NSCLC) is surgical resection, but UK rates of 8% compare poorly to 25% in the USA and Europe. Delays in diagnosis in the current UK system may be one reason for such discrepancy. To address this problem we set up a rapid diagnostic system and compared it to the conventional method of investigations in a pilot randomised trial. METHODS: Eighty-eight patients were prospectively enrolled from three District General Hospitals and randomised to either investigation locally or to the rapid system at The Royal Marsden Hospital. The pilot end-points were feasibility and audit of radical treatment rates to enable estimates for patient numbers for the full study. RESULTS: Forty-five and 43 patients were in the central and conventional arms, respectively (65% male, median age 69 years). There was a 4-week improvement in time to first treatment in those in the central arm (P=0.0025) with 13/30 (43%) and 9/27 (33%) patients having radical treatment in the central and conventional arms, respectively. Patients in the conventional arm felt the diagnostic process was too slow (P=0.02) while those in the central arm seemed to have a better care experience (P=0.01). There were significantly less visits to the general practitioner (GP) in the central arm (P=0.02). CONCLUSIONS: This pilot study demonstrates that the full study is feasible but would require the commitment and involvement of a large number of patients and physicians. The results show several advantages to investigations and diagnosis in the central arm, particularly in time to treatment initiation, patient satisfaction and rate of radical treatments. The improved rate of radical treatment could lead to an improved survival rate.

Aged↗
PubMed2000

C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway.

Caenorhabditis elegans modulates its locomotory rate in response to its food, bacteria, in two ways. First, well-fed wild-type animals move more slowly in the presence of bacteria than in the absence of bacteria. This basal slowing response is mediated by a dopamine-containing neural circuit that senses a mechanical attribute of bacteria and may be an adaptive mechanism that increases the amount of time animals spend in the presence of food. Second, food-deprived wild-type animals, when transferred to bacteria, display a dramatically enhanced slowing response that ensures that the animals do not leave their newly encountered source of food. This experience-dependent response is mediated by serotonergic neurotransmission and is potentiated by fluoxetine (Prozac). The basal and enhanced slowing responses are distinct and separable neuromodulatory components of a genetically tractable paradigm of behavioral plasticity.

Animals↗
PubMed2005

Clinical potential of inhibitors of survival pathways and activators of apoptotic pathways in treatment of cervical cancer: changing the apoptotic balance.

Cervical cancer is the most common gynaecological malignant disorder worldwide. The best possible treatment of locally advanced cervical cancer is a combination of radiation and cisplatin-based chemotherapy. However, 5-year overall survival is still only 52%. To improve treatment results, research should focus on the discovery of innovative drug strategies. Drugs directed at inducing tumour-cell apoptosis are regarded as important treatment modalities. Here, we present an overview of the molecular options that can change the apoptotic balance in cervical cancer, through increasing death-receptor-mediated apoptosis, the use of proteasome inhibitors, short interfering RNAs, or non-steroidal anti-inflammatory drugs (NSAIDs). Furthermore, the potential of attacking prosurvival signalling through the epidermal-growth-factor receptor and insulin-like-growth-factor receptor to support the apoptotic process is discussed. Additional research is needed to elucidate the clinical potential of these compounds in the treatment of cervical cancer.

Antineoplastic Agents↗
PubMed1994

Chemical pathways of peptide degradation. VI. Effect of the primary sequence on the pathways of degradation of aspartyl residues in model hexapeptides.

The influence of the primary sequence on the degradation of Asp4 residues (e.g., formation of the cyclic imide and Asp-X and/or X-Asp amide bond hydrolysis) was investigated using Val-Tyr-Y-Asp-X-Ala hexapeptides. These reactions were proposed to involve cyclization, which would duly be sensitive to steric hindrance. The effects on the rates of individual degradation routes and product distribution under both acidic and alkaline conditions were assessed upon substitutions made on the C-terminal side (X) and on the N-terminal side (Y) of the Asp residue. As expected, the rate of intramolecular formation of cyclic imide and, thus, the product yield were most affected by the size of the amino acid on the C-terminal side of the Asp residue. However, such structural changes had little or no impact on the rate of Asp-X and Y-Asp amide bond hydrolysis. In the former case, the substituted site was one atom removed from the reaction site, accounting for the diminished steric effect observed. As for the latter, the site of substitution was not a participant in the reaction itself, and hence, the rate was unperturbed by this modification. Placing Ser and Val C terminally to the Asp residue prompted racemization and peptide bond hydrolysis to occur under alkaline conditions. N-Terminal substitution of Pro with Gly had no effect on the rate of isomerization via cyclic imide formation but greatly enhanced the rate of Y-Asp amide bond hydrolysis.

Amino Acid Sequence↗
PubMed1991

Comparison of benzyl alcohol dehydrogenases and benzaldehyde dehydrogenases from the benzyl alcohol and mandelate pathways in Acinetobacter calcoaceticus and from the TOL-plasmid-encoded toluene pathway in Pseudomonas putida. N-terminal amino acid sequences, amino acid compositions and immunological cross-reactions.

1. N-Terminal sequences were determined for benzyl alcohol dehydrogenase, benzaldehyde dehydrogenase I and benzaldehyde dehydrogenase II from Acinetobacter calcoaceticus N.C.I.B. 8250, benzyl alcohol dehydrogenase and benzaldehyde dehydrogenase encoded by the TOL plasmid pWW53 in Pseudomonas putida MT53 and yeast K(+)-activated aldehyde dehydrogenase. Comprehensive details of the sequence determinations have been deposited as Supplementary Publication SUP 50161 (5 pages) at the British Library Document Supply Centre, Boston Spa. Wetherby. West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1991) 273. 5. The extent of sequence similarity suggests that the benzyl alcohol dehydrogenases are related to each other and also to established members of the family of long-chain Zn2(+)-dependent alcohol dehydrogenases. Benzaldehyde dehydrogenase II from Acinetobacter appears to be related to the Pseudomonas TOL-plasmid-encoded benzaldehyde dehydrogenase. The yeast K(+)-activated aldehyde dehydrogenase has similarity of sequence with the mammalian liver cytoplasmic class of aldehyde dehydrogenases but not with any of the Acinetobacter or Pseudomonas enzymes. 2. Antisera were raised in rabbits against the three Acinetobacter enzymes and both of the Pseudomonas enzymes, and the extents of the cross-reactions were determined by immunoprecipitation assays with native antigens and by immunoblotting with SDS-denatured antigens. Cross-reactions were detected between the alcohol dehydrogenases and also among the aldehyde dehydrogenases. This confirms the interpretation of the N-terminal sequence comparisons and also indicates that benzaldehyde dehydrogenase I from Acinetobacter may be related to the other two benzaldehyde dehydrogenases. 3. The amino acid compositions of the Acinetobacter and the Pseudomonas enzymes were determined and the numbers of amino acid residues per subunit were calculated to be: benzyl alcohol dehydrogenase and TOL-plasmid-encoded benzyl alcohol dehydrogenase, 381; benzaldehyde dehydrogenase I and benzaldehyde dehydrogenase II, 525; TOL-plasmid-encoded benzaldehyde dehydrogenase, 538.

Acinetobacter↗
PubMed2000

A scaffold protein in the c-Jun NH2-terminal kinase signaling pathways suppresses the extracellular signal-regulated kinase signaling pathways.

We previously reported that c-Jun NH(2)-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1) functions as a putative scaffold factor in the JNK mitogen-activated protein kinase (MAPK) cascades. In that study we also found MEK1 and Raf-1, which are involved in the extracellular signal-regulated kinase (ERK) MAPK cascades, bind to JSAP1. Here we have defined the regions of JSAP1 responsible for the interactions with MEK1 and Raf-1. Both of the binding regions were mapped to the COOH-terminal region (residues 1054-1305) of JSAP1. We next examined the effect of overexpressing JSAP1 on the activation of ERK by phorbol 12-myristate 13-acetate in transfected COS-7 cells and found that JSAP1 inhibits ERK's activation and that the COOH-terminal region of JSAP1 was required for the inhibition. Finally, we investigated the molecular mechanism of JSAP1's inhibitory function and showed that JSAP1 prevents MEK1 phosphorylation and activation by Raf-1, resulting in the suppression of the activation of ERK. Taken together, these results suggest that JSAP1 is involved both in the JNK cascades, as a scaffolding factor, and the ERK cascades, as a suppressor.

Animals↗
PubMed2004

The chloride permeation pathway of a glutamate transporter and its proximity to the glutamate translocation pathway.

Excitatory amino acid transporters (EAATs) regulate glutamate concentrations in the brain to maintain normal excitatory synaptic transmission. A widely accepted view of transporters is that they consist of a pore with alternating access to the intracellular and extracellular solutions, which serves to couple ion movement to the movement of substrate. However, recent observations that EAATs, and also a number of other neurotransmitter transporters, can also function as ligand-gated chloride channels have blurred the distinctions between transporters and ion channels. Here we show that mutations in the second transmembrane domain (TM2) of EAAT1 alter anion permeation properties without affecting glutamate transport and that a number of TM2 residues are accessible to the external aqueous solution. Furthermore, we demonstrate that the extracellular edge of TM2 is in close proximity to a membrane-associated domain that influences glutamate transport. This study will provide the foundation for beginning to understand how transporters can function as both transporters and ion channels.

Amino Acid Sequence↗
PubMed1989

The mitogenic signaling pathway but not the plasminogen activator-inducing pathway of basic fibroblast growth factor is mediated through protein kinase C in fetal bovine aortic endothelial cells.

Basic fibroblast growth factor (bFGF) induces cell proliferation and plasminogen activator (PA) activity in transformed fetal bovine aortic endothelial (FBAE) GM 7373 cells. A similar response is observed after treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). In these cells, bFGF and TPA cause activation of protein kinase C (PKC), as demonstrated by the induction of the phosphorylation of an 87-kD PKC substrate in intact cells and by the increase in membrane-associated PKC activity. Activation of PKC by bFGF or TPA is inhibited in cells made PKC-deficient by pretreatment with high concentrations of TPA. The mitogenic activity of bFGF or of TPA is completely inhibited in PKC-deficient cells or in naive cells treated with the PKC inhibitor H-7. However, these cells proliferate in response to serum, epidermal growth factor, and dibutyryl cyclic AMP. Similar results are obtained in normal FBAE AG 7680 cells. These data indicate that activation of PKC is responsible for the mitogenic activity of bFGF in FBAE cells. On the contrary, the PA-inducing activity of bFGF is unaffected by down-regulation of PKC or by treatment with the PKC inhibitor H-7 in both transformed GM 7373 and normal AG 7680 cells. bFGF induces a rapid 45Ca influx in naive and in PKC-deprived GM 7373 cells. In these cells, addition of EGTA to the incubation medium prevents both the 45Ca influx and the increase in PA activity induced by bFGF, without affecting its mitogenic activity. Even though the involvement of PKC in the increase of cell-associated PA activity induced by bFGF can not be completely dismissed, the present results suggest a role of calcium entry in the modulation of the PA-inducing activity of bFGF.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

An apical-type trafficking pathway is present in cultured oligodendrocytes but the sphingolipid-enriched myelin membrane is the target of a basolateral-type pathway.

Myelin sheets originate from distinct areas at the oligodendrocyte (OLG) plasma membrane and, as opposed to the latter, myelin membranes are relatively enriched in glycosphingolipids and cholesterol. The OLG plasma membrane can therefore be considered to consist of different membrane domains, as in polarized cells; the myelin sheet is reminiscent of an apical membrane domain and the OLG plasma membrane resembles the basolateral membrane. To reveal the potentially polarized membrane nature of OLG, the trafficking and sorting of two typical markers for apical and basolateral membranes, the viral proteins influenza virus-hemagglutinin (HA) and vesicular stomatitis virus-G protein (VSVG), respectively, were examined. We demonstrate that in OLG, HA and VSVG are differently sorted, which presumably occurs upon their trafficking through the Golgi. HA can be recovered in a Triton X-100-insoluble fraction, indicating an apical raft type of trafficking, whereas VSVG was only present in a Triton X-100-soluble fraction, consistent with its basolateral sorting. Hence, both an apical and a basolateral sorting mechanism appear to operate in OLG. Surprisingly, however, VSVG was found within the myelin sheets surrounding the cells, whereas HA was excluded from this domain. Therefore, despite its raft-like transport, HA does not reach a membrane that shows features typical of an apical membrane. This finding indicates either the uniqueness of the myelin membrane or the requirement of additional regulatory factors, absent in OLG, for apical delivery. These remarkable results emphasize that polarity and regulation of membrane transport in cultured OLG display features that are quite different from those in polarized cells.

Animals↗
PubMed2000

MAP kinase pathways activated by stress: the p38 MAPK pathway.

A stress-activated serine/threonine protein kinase, p38 mitogen-activated protein kinase (p38 MAPK), belongs to the MAP kinase superfamily. Diverse extracellular stimuli, including ultraviolet light, irradiation, heat shock, high osmotic stress, proinflammatory cytokines and certain mitogens, trigger a stress-regulated protein kinase cascade culminating in activation of p38 MAPK through phosphorylation on a TGY motif within the kinase activation loop. p38 MAPK appears to play a major role in apoptosis, cytokine production, transcriptional regulation, and cytoskeletal reorganization, and has been causally implicated in sepsis, ischemic heart disease, arthritis, human immunodeficiency virus infection, and Alzheimer's disease. The availability of specific inhibitors helps to clarify the role that p38 MAPK plays in these processes, and may ultimately offer therapeutic benefit for certain critically ill patients.

Apoptosis↗
PubMed2006

Local activation of the tissue factor-factor VIIa pathway in patients with pneumonia and the effect of inhibition of this pathway in murine pneumococcal pneumonia.

OBJECTIVE: The tissue factor (TF)-factor VIIa (FVIIa) complex not only is essential for activation of blood coagulation but also affect the inflammatory response during sepsis. The objective of this study was to determine the role of TF-FVIIa in pneumonia caused by Streptococcus pneumoniae, the most important causative organism in community-acquired pneumonia and a major cause of sepsis. DESIGN: A controlled, in vivo laboratory study. SETTING: Research laboratory of a health sciences university. PATIENTS AND SUBJECTS: Patients with unilateral community-acquired pneumonia and female BALB/c mice. INTERVENTIONS: Bilateral bronchoalveolar lavage was performed in patients with community-acquired pneumonia. In mice, pneumonia was induced by intranasal inoculation with S. pneumoniae with or without concurrent inhibition of TF-FVIIa by subcutaneous injections of recombinant nematode anticoagulant protein (rNAPc2). MEASUREMENTS AND MAIN RESULTS: Patients with unilateral community-acquired pneumonia demonstrated elevated concentrations of FVIIa, soluble TF, and thrombin-antithrombin complexes in bronchoalveolar lavage fluid obtained from the infected site compared with the uninfected site. Mice with S. pneumoniae pneumonia displayed increased TF expression and fibrin deposits in lungs together with elevated thrombin-antithrombin complex levels in bronchoalveolar lavage fluid; inhibition of TF-FVIIa by rNAPc2 attenuated the procoagulant response in the lung but did not affect host defense, as reflected by an unaltered outgrowth of pneumococci and an unchanged survival. CONCLUSIONS: These data suggest that TF-FVIIa activity contributes to activation of coagulation in the lung during pneumococcal pneumonia but does not play an important role in the antibacterial host defense in this murine model.

Adult↗