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PubMed2003

Frequent overexpression of cyclin D1 in sporadic pancreatic endocrine tumours.

Pancreatic endocrine tumours (PETs) occur sporadically or are inherited as part of the multiple endocrine neoplasia type-1 syndrome. Little is known about the molecular events leading to these tumours. Cyclin D1, a key regulator of the G1/S transition of the cell cycle, is overexpressed in a variety of human cancers as well as certain endocrine tumours. We hypothesized that similar to other endocrine tumours, cyclin D1 is overexpressed in human sporadic PETs. Cyclin D1 protein overexpression was found in 20 of 31 PETs (65%) when compared with normal pancreatic tIssue. Furthermore, Northern blot analysis suggests that cyclin D1 up-regulation occurs at the post-transcriptional level in some PETs. Because the key cell growth signalling pathways p42/p44/ERK (extracellular signal-regulated kinase), p38/MAPK (mitogen-activated protein kinase), and Akt/PKB (protein kinase B) can regulate cyclin D1 protein expression in other cell types, pancreatic endocrine tumours were analysed with phospho-specific antibodies against the active forms of these proteins to elucidate a tIssue-specific regulatory mechanism of cyclin D1 in PETs. We found frequent activation of the p38/MAPK and Akt pathways, but down-regulation of the ERK pathway, in cyclin D1 overexpressing PETs. This study demonstrates that cyclin D1 overexpression is associated with human sporadic PET tumorigenesis, and suggests that this up-regulation may occur at the post-transcriptional level. These findings will direct future studies of PETs towards cell cycle dysregulation and the identification of key growth factor pathways involved in the formation of these tumours.

Adenoma, Islet Cell↗
PubMed2006

Glutathione-related enzymes and the eye.

Glutathione and the related enzymes belong to the defence system protecting the eye against chemical and oxidative stress. This review focuses on GSH and two key enzymes, glutathione reductase and glucose-6-phosphate dehydrogenase in lens, cornea, and retina. Lens contains a high concentration of reduced glutathione, which maintains the thiol groups in the reduced form. These contribute to lens complete transparency as well as to the transparent and refractive properties of the mammalian cornea, which are essential for proper image formation on the retina. In cornea, gluthatione also plays an important role in maintaining normal hydration level, and in protecting cellular membrane integrity. In retina, glutathione is distributed in the different types of retinal cells. Intracellular enzyme, glutathione reductase, involved in reducing the oxidized glutathione has been found at highest activity in human and primate lenses, as compared to other species. Besides the enzymes directly involved in maintaining the normal redox status of the cell, glucose-6-phosphate dehydrogenase which catalyzes the first reaction of the pentose phosphate pathway, plays a key role in protection of the eye against reactive oxygen species. Cornea has a high activity of the pentose phosphate pathway and glucose-6-phosphate dehydrogenase activity. Glycation, the non-enzymic reaction between a free amino group in proteins and a reducing sugar, slowly inactivates gluthathione-related and other enzymes. In addition, glutathione can be also glycated. The presence of glutathione, and of the related enzymes has been also reported in other parts of the eye, such as ciliary body and trabecular meshwork, suggesting that the same enzyme systems are present in all tissues of the eye to generate NADPH and to maintain gluthatione in the reduced form. Changes of glutathione and related enzymes activity in lens, cornea, retina and other eye tissues, occur with ageing, cataract, diabetes, irradiation and administration of some drugs.

Animals↗
PubMed2005

A hybrid approach for efficient and robust parameter estimation in biochemical pathways.

Developing suitable dynamic models of biochemical pathways is a key issue in Systems Biology. Predictive models for cells or whole organisms could ultimately lead to model-based predictive and/or preventive medicine. Parameter estimation (i.e. model calibration) in these dynamic models is therefore a critical problem. In a recent contribution [Moles, C.G., Mendes, P., Banga, J.R., 2003b. Parameter estimation in biochemical pathways: a comparison of global optimisation methods. Genome Res. 13, 2467-2474], the challenging nature of such inverse problems was highlighted considering a benchmark problem, and concluding that only a certain type of stochastic global optimisation method, Evolution Strategies (ES), was able to solve it successfully, although at a rather large computational cost. In this new contribution, we present a new integrated optimisation methodology with a number of very significant improvements: (i) computation time is reduced by one order of magnitude by means of a hybrid method which increases efficiency while guaranteeing robustness, (ii) measurement noise (errors) and partial observations are handled adequately, (iii) automatic testing of identifiability of the model (both local and practical) is included and (iv) the information content of the experiments is evaluated via the Fisher information matrix, with subsequent application to design of new optimal experiments through dynamic optimisation.

Algorithms↗
PubMed2004

Interleukin-8 production by THP-1 cells stimulated by Salmonella enterica serovar Typhimurium porins is mediated by AP-1, NF-kappaB and MAPK pathways.

Interleukin-8 (IL-8) is released in response to inflammatory stimuli, such as bacterial products. Either porins or lipopolysaccharide (LPS) stimulated THP-1 cells to release IL-8 after 24 h. We have previously reported that stimulation of monocytic cells with Salmonella enterica serovar Typhimurium porins led to the activation of mitogen-activated protein kinase cascades and of protein tyrosine kinases (PTKs). In this report, we demonstrate, using two potent and selective inhibitors of MEK activation by Raf-1 (PD-098059) and p38 (SB-203580), that both ERK1/2 and p38 pathways play a key role in the production of IL-8 by porins and LPS. Porin-stimulated expression of activating protein 1 (AP-1) and correlated IL-8 release is also inhibited by PD-098059 or SB-203580 indicating that the Raf-1/MEK1-MEK2/MAPK cascade is required for their activation. Also PTKs modulate the pathway that control IL-8 gene expression, in fact its expression is abolished by tyrphostin. By using N-acetyl-leucinyl-leucinyl-norleucinal-H (ALLN) an inhibitor of nuclear factor-kappaB (NF-kappaB) activity, we also observed IL-8 release modulation. Our results elucidate some of the molecular mechanisms by which AP-1 and NF-kappaB regulate IL-8 release and open new strategies for the design of specific molecules that will modulate IL-8 effects in various infectious diseases.

Cell Line↗
PubMed2024

cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.

Cytoplasmic mislocalization and aggregation of TDP-43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and are observed in the vast majority of both familial and sporadic cases. How these two interconnected processes are regulated on a molecular level, however, remains enigmatic. Genome-wide screens for modifiers of the ALS-associated genes TDP-43 and FUS have identified the phospholipase D (Pld) pathway as a key regulator of ALS-related phenotypes in the fruit fly Drosophila melanogaster [M. W. Kankel et al., Genetics 215, 747-766 (2020)]. Here, we report the results of our search for downstream targets of the enzymatic product of Pld, phosphatidic acid. We identify two conserved negative regulators of the cAMP/PKA signaling pathway, the phosphodiesterase dunce and the inhibitory subunit PKA-R2, as modifiers of pathogenic phenotypes resulting from overexpression of the Drosophila TDP-43 ortholog TBPH. We show that knockdown of either of these genes results in a mitigation of both TBPH aggregation and mislocalization in larval motor neuron cell bodies, as well as an amelioration of adult-onset motor defects and shortened lifespan induced by TBPH. We determine that PKA kinase activity is downstream of both TBPH and Pld and that overexpression of the PKA target CrebA can rescue TBPH mislocalization. These findings suggest a model whereby increasing cAMP/PKA signaling can ameliorate the molecular and functional effects of pathological TDP-43.

Animals↗
PubMedDate not supplied

Enzymatic basis of metal ion alterations of cellular heme and glutathione metabolism.

It is becoming increasingly apparent that the enzymes of heme and GSH metabolism pathways are extremely sensitive to metal ions. It follows that alterations in the activities of the enzymes of heme metabolism are often reflected in the heme dependent cellular functions, particularly those which depend on cytochrome P-450. Moreover, perturbations in cellular GSH levels may alter the biological inactivation of the intermediates of cytochrome P-450 activity normally inactivated by GSH-conjugation. The effects of transition and heavy metal ions on the heme metabolism pathway are perhaps of particular significance when exerted on the two key enzymes of the pathway: the delta-aminolevulinate synthetase, the initial and the rate-limiting enzyme of the heme biosynthetic pathway, and heme oxygenase, the rate-limiting enzyme of heme degradation pathway. The activities of other enzymes of the heme metabolism pathway are also effected by metal ions; the nature of the effect is generally that of inhibition. Similarly, the inhibition by heavy metal ions of the activities of GSSG-reductase, gamma-glutamylcysteine synthetase, and gamma-glutamyl transpeptidase, which are the key enzymes of GSH metabolism, have toxicological significance. However, it is important to recognize that the presently discussed effects of metal ions do not necessarily have negative biological implications. The rather intricate and interrelated effects of metal ions on heme and GSH metabolism pathway under certain circumstances may have positive ramifications.

5-Aminolevulinate Synthetase↗
PubMed2026

Multi-omics dynamic profiling reveals predictive biomarkers for first-line immunochemotherapy in extensive-stage small-cell lung cancer.

BACKGROUND: Extensive-stage small-cell lung cancer (ES-SCLC) is associated with a poor prognosis. Although first-line immunochemotherapy improves clinical outcomes, robust prognostic biomarkers for this treatment modality remain unavailable. The aim of this study was to identify non-invasive, easily accessible, and dynamically monitored biomarkers of ES-SCLC by machine learning integrating serum metabolomics, lipidomics, and proteomics at multiple time points. METHODS: A total of 816 serum samples were collected from ES-SCLC patients receiving first-line immunotherapy combined with chemotherapy or first-line chemotherapy for metabolomics, lipidomics, and proteomics analysis. The immunochemotherapy cohort was randomly divided into training and validation subsets at a 6:4 ratio. Biomarkers were identified using machine learning algorithms, and their prognostic significance was evaluated through receiver operating characteristic (ROC) analysis, Kaplan–Meier survival analysis, and multivariate Cox regression. Potential metabolic pathways and mechanisms were further explored via integrated multi-omic analysis. RESULTS: The immunochemotherapy exhibited a prolonged median progression-free survival (PFS) and higher objective response rate (ORR) compared to the chemotherapy group. A total of 5 serum metabolites (uric acid, L-aspartate-semialdehyde, dimethisterone, xanthine, L-cysteine), 6 lipids (Cer d18:1/26:0, Cer d18:2/25:0, SM d18:1/20:1, SM d17:1/25:1, DG O-18:1_16:0, PS 18:0_24:0), and 3 proteins (ACIN1, ACSL4, PHGDH) were identified and constructed into independent prognostic models. Among patients receiving immunochemotherapy, those categorized as low-risk based on the model demonstrated significantly longer PFS compared with those in the high-risk group. These prognostic signatures also retained predictive value in patients who underwent second-line treatment with anlotinib plus immunochemotherapy. Integrated analysis revealed that glycine, serine, and threonine metabolism was the commonly enriched pathway across all three omics layers. Notably, PHGDH (protein), L-aspartate-semialdehyde and L-cysteine (metabolites), and PS (18:0_24:0) (lipid), key elements in this pathway, were all incorporated in the predictive model. In addition, models of the composition of these substances after one cycle of treatment can still predict the prognosis of patients. CONCLUSION: In this study, we constructed and validated a set of non-invasive, dynamically monitorable prognostic models (containing 5 metabolites, 6 lipids, and 3 proteins) using machine learning by integrating multiple time point data from the serum metabolome, lipid panel, and proteome to accurately distinguish the prognostic risk of patients with ES-SCLC receiving immunochemotherapy. PFS was significantly prolonged in patients in the low-risk group, and this model remains predictive in the subsequent second-line treatment with anlotinib in combination with immunochemotherapy. Glycine-serine-threonine metabolic pathway may be the key mechanism, of which PHGDH, L-aspartate semialdehyde, L-cysteine and PS (18:0_24:0) are the core predictors. This study provides the first multi-omics dynamic prognostic tool for ES-SCLC immunochemotherapy and reveals potential therapeutic targets.

Humans↗
PubMed2006

Combined inhibition of the phosphatidylinositol 3-kinase/Akt and Ras/mitogen-activated protein kinase pathways results in synergistic effects in glioblastoma cells.

The present study uses cell-based screening assays to assess the anticancer effects of targeting phosphatidylinositol 3-kinase-regulated integrin-linked kinase (ILK) in combination with small-molecule inhibitors of Raf-1 or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK). The objective was to determine if synergistic interactions are achievable through the use of agents targeting two key cell signaling pathways involved in regulating glioblastoma cancer. The phosphatidylinositol 3-kinase/protein kinase B (PKB)/Akt and the Ras/MAPK pathway were targeted for their involvement in cell survival and cell proliferation, respectively. The glioblastoma cell lines U87MG, SF-188, and U251MG were transiently transfected with an antisense oligonucleotide targeting ILK (ILKAS) alone or in combination with the Raf-1 inhibitor GW5074 or with the MEK inhibitor U0126. Dose and combination effects were analyzed by the Chou and Talalay median-effect method and indicated that combinations targeting ILK with either Raf-1 or MEK resulted in a synergistic interaction. Glioblastoma cells transfected with ILKAS exhibited reduced levels of ILK and phosphorylated PKB/Akt on Ser473 but not PKB/Akt on Thr308 as shown by immunoblot analysis. These results were confirmed using glioblastoma cells transfected with ILK small interfering RNA, which also suggested enhanced gene silencing when used in combination with U0126. U87MG glioblastoma cells showed a 90% (P < 0.05) reduction in colony formation in soft agar with exposure to ILKAS in combination with GW5074 compared with control colonies. A substantial increase in Annexin V-positive cells as determined by using fluorescence-activated cell sorting methods were seen in combinations that included ILKAS. Combinations targeting ILK and components of the Ras/MAPK pathway result in synergy and could potentially be more effective against glioblastoma cancer than monotherapy.

Butadienes↗
PubMed2002

Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma.

Interleukin (IL)-5 and IL-13 are thought to play key roles in the pathogenesis of asthma. Although both cytokines use eotaxin to regulate eosinophilia, IL-13 is thought to operate a separate pathway to IL-5 to induce airways hyperreactivity (AHR) in the allergic lung. However, identification of the key pathway(s) used by IL-5 and IL-13 in the disease process is confounded by the failure of anti-IL-5 or anti-IL-13 treatments to completely inhibit the accumulation of eosinophils in lung tissue. By using mice deficient in both IL-5 and eotaxin (IL-5/eotaxin(-/-)) we have abolished tissue eosinophilia and the induction of AHR in the allergic lung. Notably, in mice deficient in IL-5/eotaxin the ability of CD4(+) T helper cell (Th)2 lymphocytes to produce IL-13, a critical regulator of airways smooth muscle constriction and obstruction, was significantly impaired. Moreover, the transfer of eosinophils to IL-5/eotaxin(-/-) mice overcame the intrinsic defect in T cell IL-13 production. Thus, factors produced by eosinophils may either directly or indirectly modulate the production of IL-13 during Th2 cell development. Our data show that IL-5 and eotaxin intrinsically modulate IL-13 production from Th2 cells and that these signaling systems are not necessarily independent effector pathways and may also be integrated to regulate aspects of allergic disease.

Adoptive Transfer↗
PubMed2004

Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis.

Although mutated forms of ras are not associated with the majority of breast cancers (<5%), there is considerable experimental evidence that hyperactive Ras can promote breast cancer growth and development. Therefore, we determined whether Ras and Ras-responsive signaling pathways were activated persistently in nine widely studied human breast cancer cell lines. Although only two of the lines harbor mutationally activated ras, we found that five of nine breast cancer cell lines showed elevated active Ras-GTP levels that may be due, in part, to HER2 activation. Unexpectedly, activation of two key Ras effector pathways, the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/AKT signaling pathways, was not always associated with Ras activation. Ras activation also did not correlate with invasion or the expression of proteins associated with tumor cell invasion (estrogen receptor alpha and cyclooxygenase 2). We then examined the role of Ras signaling in mediating resistance to matrix deprivation-induced apoptosis (anoikis). Surprisingly, we found that ERK and phosphatidylinositol 3'-kinase/AKT activation did not have significant roles in conferring anoikis resistance. Taken together, these observations show that Ras signaling exhibits significant cell context variations and that other effector pathways may be important for Ras-mediated oncogenesis, as well as for anoikis resistance, in breast cancer. Additionally, because ERK and AKT activation are not strictly associated with Ras activation, pharmacological inhibitors of these two signaling pathways may not be the best approach for inhibition of aberrant Ras function in breast cancer treatment.

Anoikis↗
PubMed2004

Wnt pathway curation using automated natural language processing: combining statistical methods with partial and full parse for knowledge extraction.

MOTIVATION: Wnt signaling is a very active area of research with highly relevant publications appearing at a rate of more than one per day. Building and maintaining databases describing signal transduction networks is a time-consuming and demanding task that requires careful literature analysis and extensive domain-specific knowledge. For instance, more than 50 factors involved in Wnt signal transduction have been identified as of late 2003. In this work we describe a natural language processing (NLP) system that is able to identify references to biological interaction networks in free text and automatically assembles a protein association and interaction map. RESULTS: A 'gold standard' set of names and assertions was derived by manual scanning of the Wnt genes website (http://www.stanford.edu/~rnusse/wntwindow.html) including 53 interactions involved in Wnt signaling. This system was used to analyze a corpus of peer-reviewed articles related to Wnt signaling including 3369 Pubmed and 1230 full text papers. Names for key Wnt-pathway associated proteins and biological entities are identified using a chi-squared analysis of noun phrases over-represented in the Wnt literature as compared to the general signal transduction literature. Interestingly, we identified several instances where generic terms were used on the website when more specific terms occur in the literature, and one typographic error on the Wnt canonical pathway. Using the named entity list and performing an exhaustive assertion extraction of the corpus, 34 of the 53 interactions in the 'gold standard' Wnt signaling set were successfully identified (64% recall). In addition, the automated extraction found several interactions involving key Wnt-related molecules which were missing or different from those in the canonical diagram, and these were confirmed by manual review of the text. These results suggest that a combination of NLP techniques for information extraction can form a useful first-pass tool for assisting human annotation and maintenance of signal pathway databases. AVAILABILITY: The pipeline software components are freely available on request to the authors. CONTACT: dstates@umich.edu SUPPLEMENTARY INFORMATION: http://stateslab.bioinformatics.med.umich.edu/software.html.

Animals↗
PubMed2002

[The mechanism of interferon-gamma increases growth hormone expression in rat pituitary GH(3) cells].

The method of luciferase reporter gene was used to investigate the effect of interferon-gamma (IFN-gamma) on the activity of human growth hormone (hGH) gene promoter in rat pituitary GH(3) cells, to elucidate the post-receptor signal transduction pathway and the key promoter sequence which mediated the action of IFN-gamma. The luciferase expression plasmid pGL(3)-484-Luc containing hGH gene promoter (-484-2 bp) and luciferase reporter gene were transfected alone or cotransfected with pituitary specific transcription factor Pit-1 expression plasmid (PcDNA-Pit-1-cDNA) or Pit-1 antisense oligonucleotide (Pit-1 OND) into rat GH(3) cells. The changes of luciferase expression in the GH(3) cells were determined, after treatment with IFN-gamma or IFN-gamma plus inhibitors of intracellular signaling pathways, to observe the effect of IFN-gamma and these inhibitors on the activity of hGH gene promoter. The various deletion constructs of Luc reporter: pGL(3)-380-Luc, pGL(3)-250-Luc, pGL(3)-132-Luc and pGL(3)-66-Luc, which contained the -380-2 bp, -250-2 bp, -132-2 bp and -66-2 bp sequences of hGH gene promoter, respectively, were transfected into GH(3) cells, then the changes of luciferase expression in the GH(3) cells were assayed, after treatment with IFN-gamma, to find out the key sequence which mediated the action of IFN-gamma. Our results showed that IFN-gamma (10(5) u/L, 10(6) u/L) could increase luciferase expression in GH(3)cells transfected with pGL(3)-484-Luc alone, the maximal action being 131% of the control (P<0.001). Among the inhibitors of intracellular signaling transduction pathways, only mitogen activated protein kinases (MAPK) inhibitor PD98059 (40 micromol/L) could completely blocked the stimulatory effect of IFN-gamma on hGH gene promoter activity. Pit-1 overexpression or inhibited Pit-1 expression, both had no effect on IFN-gamma-induced hGH gene promoter activity. When various deletion constructs of Luc reporter were transfected into GH(3) cells, only pGL(3)380-Luc and pGL(3)250-Luc still responded to IFN-gamma. In conclusion, IFN-gamma could increase the activity of hGH gene promoter in rat pituitary GH(3) cells. This stimulatory effect of IFN-gamma may be associated with the intracellular MAPK signaling pathway and with -252--132 bp sequence in hGH gene promoter, but had no relationship with pituitary specific transcription factor Pit-1.

Animals↗
PubMed2004

Principles of MAP kinase signaling specificity in Saccharomyces cerevisiae.

Cells respond to a plethora of signals using a limited set of intracellular signal transduction components. Surprisingly, pathways that transduce distinct signals can share protein components, yet avoid erroneous cross-talk. A highly tractable model system in which to study this paradox is the yeast Saccharomyces cerevisiae, which harbors three mitogen-activated protein kinase (MAPK) signal transduction cascades that share multiple signaling components. In this review we first describe potential mechanisms by which specificity could be achieved by signaling pathways that share components. Second, we summarize key features and components of the yeast MAPK pathways that control the mating pheromone response, filamentous growth, and the response to high osmolarity. Finally, we review biochemical analyses in yeast of mutations that cause cross-talk between these three MAPK pathways and their implications for the mechanistic bases for signaling specificity. Although much remains to be learned, current data indicate that scaffolding and cross pathway inhibition play key roles in the maintenance of fidelity.

Gene Expression Regulation, Fungal↗
PubMed2004

Regulators of nonsulfur purple phototrophic bacteria and the interactive control of CO2 assimilation, nitrogen fixation, hydrogen metabolism and energy generation.

For the metabolically diverse nonsulfur purple phototrophic bacteria, maintaining redox homeostasis requires balancing the activities of energy supplying and energy-utilizing pathways, often in the face of drastic changes in environmental conditions. These organisms, members of the class Alphaproteobacteria, primarily use CO2 as an electron sink to achieve redox homeostasis. After noting the consequences of inactivating the capacity for CO2 reduction through the Calvin-Benson-Bassham (CBB) pathway, it was shown that the molecular control of many additional important biological processes catalyzed by nonsulfur purple bacteria is linked to expression of the CBB genes. Several regulator proteins are involved, with the two component Reg/Prr regulatory system playing a major role in maintaining redox poise in these organisms. Reg/Prr was shown to be a global regulator involved in the coordinate control of a number of metabolic processes including CO2 assimilation, nitrogen fixation, hydrogen metabolism and energy-generation pathways. Accumulating evidence suggests that the Reg/Prr system senses the oxidation/reduction state of the cell by monitoring a signal associated with electron transport. The response regulator RegA/PrrA activates or represses gene expression through direct interaction with target gene promoters where it often works in concert with other regulators that can be either global or specific. For the key CO2 reduction pathway, which clearly triggers whether other redox balancing mechanisms are employed, the ability to activate or inactivate the specific regulator CbbR is of paramount importance. From these studies, it is apparent that a detailed understanding of how diverse regulatory elements integrate and control metabolism will eventually be achieved.

Alphaproteobacteria↗
PubMed2004

Protein kinase C and beyond.

Protein kinase C molecules regulate both positive and negative signal transduction pathways essential for the initiation and homeostasis of immune responses. There are multiple isoforms of protein kinase C that are activated differently by calcium and diacylglycerol, and these are activated mainly by antigen receptors in T cells, B cells and mast cells. Additionally, mammals express several other diacylglycerol binding proteins that are linked to a network of key signal transduction pathways that control lymphocyte biology. Diacylglycerol and protein kinase C regulate a broad range of gene transcription programs but also modulate integrins, chemokine responses and antigen receptors, thereby regulating lymphocyte adhesion, migration, differentiation and proliferation.

Animals↗
PubMed2006

Role of protein kinase C delta in curcumin-induced antioxidant response element-mediated gene expression in human monocytes.

The Nrf2/antioxidant response element (ARE) signaling pathway plays a key role in activating cellular antioxidants, including heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase-1 (NQO1), and glutathione. Protein kinase C (PKC) may also regulate these antioxidants, as PKC phosphorylates Nrf2 in vitro. This study examined the role of PKC in ARE-mediated gene regulation in human monocytes by curcumin, a potent inducer of the Nrf2/ARE pathway. Curcumin increased HO-1 and glutamyl cysteine ligase modulator (GCLM) expression and stimulated Nrf2 binding to the ARE. Curcumin also rapidly stimulated PKC phosphorylation and Ro-31-8220, a pan-PKC inhibitor, decreased curcumin-induced GCLM and HO-1 mRNA expression and ARE binding. Rottlerin (a PKC delta inhibitor) and PKC delta antisense oligonucleotides significantly inhibited curcumin-induced GCLM and HO-1 mRNA expression and ARE binding. Furthermore, a p38 MAP kinase inhibitor reduced GCLM and HO-1 expression and rottlerin inhibited curcumin-induced p38 phosphorylation. In summary, curcumin activates ARE-mediated gene expression in human monocytes via PKC delta, upstream of p38 and Nrf2.

Acetophenones↗
PubMed1997

Signal transduction pathways and their relevance in human astrocytomas.

Aberrations in a number of signal transduction pathways have been identified as playing a key role in the molecular pathogenesis of astrocytomas and their progression to high grade glioblastoma multiforme (GBM). GBMs are characterized by overexpression of the Platelet Derived Growth Factor Receptors (PDGFR) and their ligands (PDGF), as well as the Epidermal Growth Factor Receptor (EGF-R). These receptors activate the Ras pathway, a key cellular signal transduction pathway, culminating in the activation of a wide range of Ras-dependent cellular events. GBMs have also been found to either overexpression or lose expression of various Protein Kinase C (PKC) isoforms. Major strides are being made in developing pharmacological agents which specifically inhibit these growth factor receptors and intracellular signal transduction pathways. Elucidating the role of these pathways in GBMs is thus of major clinical importance, as these novel molecularly-targeted agents may prove of use in the clinical management of GBMs in the future.

Astrocytoma↗
PubMedDate not supplied

[The L-arginine/nitric oxide metabolic pathway. Its physiopathology and clinical implications].

The L-arginine/nitric oxide (NO) pathway plays a key role in a number of biological processes within most organs and systems. Increasing attention has been addressed to its involvement in the pathogenesis of various human diseases. In this review we examine the enzymology of different NO-synthase isoforms, the major NO detection techniques as well as the possible clinical and pharmacological implications of this new metabolic pathway.

Arginine↗