The genus Erica comprises five species (E. arborea, E. bocquetii, E. manipuliflora, E. sicula, E.... more The genus Erica comprises five species (E. arborea, E. bocquetii, E. manipuliflora, E. sicula, E. spiculifolia), in Turkey. In traditional Turkish medicine, the aerial parts of E. arborea and E. manipuliflora are used as diuretic and astringent and in the treatment of urinary infections. Additionally, the decoction of E. manipuliflora is used as weight-loss medicine, diuretic and in the treatment of diabetes, in Mugla (Turkey) and Western Mediterrenean Region in Turkey. This present study aimed to determine the cytotoxicity potentials of different extracts from this species and compare the cytotoxicity between its flowering and fruiting periods.
Several amphiphilic, chalcogen-based redox modulators have been synthesized which exhibit a wides... more Several amphiphilic, chalcogen-based redox modulators have been synthesized which exhibit a widespread, yet in some instances also selective, biological activity which is most likely based on their ability to modulate the intracellular redox balance and to interact with cellular membranes and specific proteins.
Various selenium-and tellurium-containing molecules are able to modulate the intracellular redox ... more Various selenium-and tellurium-containing molecules are able to modulate the intracellular redox state of cells, an effect which may be used for the (selective) targeting of cancer cells, which are naturally under oxidative stress (OS). As macrophages also generate an environment rich in Reactive Oxygen Species (ROS) and nitric oxide ( NO), they may represent an additional, prime target for such redoxmodulating agents. A range of selenium and tellurium-containing quinones have therefore been synthesized and subsequently tested in macrophage culture. The tellurium agents were generally cytotoxic at very low concentrations, and their mode of action seemed to involve the upregulation of intracellular ROS levels. This redox-modulating effect was confirmed by simple yeast-based chemogenetic analysis in conjunction with in vitro redox assays and electrochemistry. Together, these studies point towards an intracellular build-up of superoxide radicals as the most likely cause of toxicity. In contrast, some of the selenium derivatives were less toxic and exerted a pronounced inhibitory effect on the formation of lipopolysaccharide-induced NO production. Whilst the Te-analogues therefore may enable the resolute, effective and fairly selective targeting of macrophages, the selenium agents could act less severely, but equally effectively by interfering with inflammatory signalling molecules.
To assess the importance of the cysteine residues Cys347 and Cys351 in the carboxylic tail in the... more To assess the importance of the cysteine residues Cys347 and Cys351 in the carboxylic tail in the human D1 dopamine receptor, seven mutant receptors were constructed by PCR. The pharmacological and functional properties of the wild-type and mutant receptors were assessed following transient expression in COS-7 cells. Affinities for [3H]SCH 23390 of mutant S347 (Cys347-->Gly), T348 (Tyr348-->stop), S351 (Cys351-->Gly), T351 (Cys351-->stop), T352 (Pro352-->stop), and S347/S351 (Cys347-->Gly and Cys351-->Gly) were similar to that of wild-type receptor, whereas the expression levels were reduced up to 80%. The potency of dopaminergic antagonists for these mutant receptors was very similar to that of the wild-type receptor. However, mutant T347 (Cys347-->stop) showed a 15-25-fold reduced affinity for the antagonists SCH 23390, (+)-butaclamol, and cis-flupentixol, thus not allowing radioligand analysis. Wild-type and mutant receptors responded dose-dependently with similar potency to dopamine and SKF 38393 with an increased adenylyl cyclase activity. However, mutant receptors with the Cys347 residue changed or removed displayed a diminished ability to activate adenylyl cyclase. Dopamine preexposure desensitized wild-type and mutant S351 receptors. However, mutant receptors with Cys347 replaced or the distal part of the carboxyl tail removed were unable to desensitize. Thus, Cys347 in the cytoplasmic tail of the human D1 dopamine receptor is important for the receptor in maintaining the conformation for antagonist binding, to play a crucial role in activation of adenylyl cyclase, and to be essential for agonist-induced desensitization.
The atrial natriuretic peptide (ANP), a member of the natriuretic peptide family, is a cardiovasc... more The atrial natriuretic peptide (ANP), a member of the natriuretic peptide family, is a cardiovascular hormone which possesses well defined natriuretic, diuretic, and vasodilating properties. Most of the biological effects of ANP aremediated through its guanylyl cyclase coupled A receptor. Because ANP and its receptors have been shown to be expressed and differentially regulated in the immune system, it has been suggested that ANP has an immunomodulatory potency. Much investigation of the effects of ANP on the activation of macrophages has been carried out. ANP was shown to inhibit the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) in macrophages in an autocrine fashion. ANP in this context was shown to reduce significantly the activation of NF-kappaB and to destabilise iNOS mRNA. ANP, furthermore, can significantly reduce the LPS-induced secretion of tumour necrosis factor alpha (TNFalpha) in macrophages. The relevance of these findings on a re...
The atrial natriuretic peptide (ANP), a member of the natriuretic peptide family, is a cardiovasc... more The atrial natriuretic peptide (ANP), a member of the natriuretic peptide family, is a cardiovascular hormone which possesses well defined natriuretic, diuretic, and vasodilating properties. Most of the biological effects of ANP are mediated through its guanylyl cyclase coupled A receptor. Because ANP and its receptors have been shown to be expressed and differentially regulated in the immune system, it has been suggested that ANP has an immunomodulatory potency. Much investigation of the effects of ANP on the activation of macrophages has been carried out. ANP was shown to inhibit the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) in macrophages in an autocrine fashion. ANP in this context was shown to reduce significantly the activation of NF-κB and to destabilise iNOS mRNA. ANP, furthermore, can significantly reduce the LPS-induced secretion of tumour necrosis factor α (TNFα) in macrophages. The relevance of these findings on a regulatory role for ANP on TNFα in humans was shown by the fact that ANP significantly reduces the release of TNFα in whole human blood. It was furthermore shown to attenuate the release of interleukin 1β (IL1β). Interestingly, ANP did not affect the secretion of the anti-inflammatory cytokines IL10 and IL1 receptor antagonist (IL1ra). In summary, ANP was shown to reduce the secretion of inflammatory mediators in macrophages. Therefore, this cardiovascular hormone may possess anti-inflammatory potential.
The inducible nitric-oxide synthase (iNOS) synthesizes NO from L-arginine. Availability of L-argi... more The inducible nitric-oxide synthase (iNOS) synthesizes NO from L-arginine. Availability of L-arginine is maintained by a lipopolysaccharide (LPS)-induced induction of the CAT-2B amino acids transporter. Recently, we could show that the cardiovascular hormone atrial natriuretic peptide (ANP) inhibits the induction of iNOS in LPS-stimulated macrophages via its guanylate cyclase-coupled A-receptor. To investigate whether ANP exerts an effect on LPS-induced L-arginine uptake. Murine bone marrow derived macrophages were activated with LPS (1 microg/ml, 20 h) in the presence or absence of ANP or C-type natriuretic peptide (CNP). L-Arginine transport was determined by measuring the uptake of L-[(3)H]arginine. L-[(3)H]Arginine influx was also determined in LPS-activated cells in the presence of N(G)-monomethyl-L-arginine (L-NMMA), competitor amino acids, or ANP. Nitrite accumulation was determined in supernatants of LPS-activated cells cultured in the presence or absence of L-ornithine. ANP...
Journal of immunology (Baltimore, Md. : 1950), 2000
The atrial natriuretic peptide (ANP) is suggested to regulate inflammatory response by alteration... more The atrial natriuretic peptide (ANP) is suggested to regulate inflammatory response by alteration of macrophage functions. The aim of this study was to investigate whether ANP influences production of TNF-alpha. TNF-alpha production in murine bone marrow-derived macrophages was induced by LPS, and TNF-alpha secretion (+/-ANP) was determined by L929 bioassay. ANP dose dependently (10-8-10-6 M) inhibited TNF-alpha release by up to 95%. The effect was mediated via the guanylate cyclase-coupled A receptor, as was shown by employing dibutyryl-cGMP, the cGMP-inhibitory compound Ly-83583, and the A receptor antagonist HS-142-1. A specific ligand of the natriuretic peptide "clearance" receptor inhibited TNF-alpha production only at 10-7 and 10-8 M, but not at 10-6 M. The B receptor ligand C-type natriuretic peptide showed no TNF-alpha-inhibitory effect. To investigate the underlying mechanism of ANP-mediated TNF-alpha inhibition, Northern blot was performed. ANP-treated macrophage...
The Journal of pharmacology and experimental therapeutics, 1998
The seleno-organic drug ebselen (2-phenyl-1, 2-benzoisoselenazol-3(2H)-one) has glutathione perox... more The seleno-organic drug ebselen (2-phenyl-1, 2-benzoisoselenazol-3(2H)-one) has glutathione peroxidase-like activity, and inhibits lipoxygenases, oxidative burst of leukocytes, nitric oxide synthases, protein kinases and leukocyte migration. This study elaborates in vivo in mice hitherto unknown immunopharmacological properties of ebselen. The compound was comparatively investigated in two different T cell-dependent hepatic hyperinflammation models and in two alternative models of receptor-activated liver apoptosis. Mice orally pretreated with ebselen were dose-dependently protected from concanavalin A (ConA)-induced liver injury. In livers from ebselen-pretreated mice exposed to ConA, the nuclear antiapoptotic transcription factor NFkappaB was upregulated. The release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF) was downregulated, while the ciculating amount of the anti-inflammatory cytokine interleukin-10 (IL-10) was increased. Ebselen protected also from live...
The atrial natriuretic peptide (ANP) was described as a peptide hormone synthesized and secreted ... more The atrial natriuretic peptide (ANP) was described as a peptide hormone synthesized and secreted by heart atria. It plays an important role in the regulation of volume homeostasis; however, the functions of ANP are not restricted to cardiovascular effects. The biological profile of ANP is much broader than originally thought. This article focuses on the immunomodulatory and anti-inflammatory functions of ANP addressing; for example, the influence of ANP on macrophage functions. Another important aspect of ANP reviewed here is its cytoprotective potential. The beneficial effect of ANP in preventing cell damage caused by ischemia and reperfusion warrants special attention. The therapeutic potential of ANP in organ preservation could be important for transplantation medicine.
The adenovirus E1A12S gene product (WT12S) immortalizes epithelial cells and they retain their di... more The adenovirus E1A12S gene product (WT12S) immortalizes epithelial cells and they retain their dierentiated characteristics, but certain mutants cannot do the latter. Characterization of mutant immortalized epithelial cells indicated that they had undergone epithelial mesenchymal transition (EMT). Coexpression of V12ras with WT12S leads to benign tumors, but to malignant tumors with 12S mutants. Since EMT is critical for tumor progression, identi®cation of the molecular mechanisms involved should elucidate novel therapeutic targets. To this end, representational dierence analysis (RDA) was used to identify cDNAs upregulated in the mutant cell line. Thirty-®ve dierentially expressed mRNAs were identi®ed and classi®ed into several functional categories, including nine novel cDNAs. Among the 26 known cDNAs, extracellular matrix and related proteins made up the largest group of dierentially expressed genes, followed by growth factors and receptors and transcription factors. There was also an ion transporter, a cytoskeletal protein, glycosylation and amidinotransferase enzymes and proteins with unknown functions. Some of the known genes have previously been associated with EMT and/or tumor progression and thus served to validate the system to obtain the desired target genes, while other cDNAs are newly linked with dedierentiation/malignancy. Array analyses indicated that the cDNAs were speci®cally upregulated in invasive or metastatic tumors, especially of breast, uterus and lung, suggesting their involvement in the progression of these tumors. Oncogene (2001) 20, 6679 ± 6688.
Background and aims: Nanoparticles can pass the lung tissue, reach the circulation and in case of... more Background and aims: Nanoparticles can pass the lung tissue, reach the circulation and in case of transplacental transport may affect the unborn child. Aim of this work was to determine whether exposure to particulate matter containing nanoparticles in part resulting from diesel exhaust may influence cytokine levels in the cord blood of newborns. We hypothesized that proinflammatory markers are increased in children of highly exposed mothers compared to controls.
Toll-like receptors play an important role in endothelial inflammation; however, little is known ... more Toll-like receptors play an important role in endothelial inflammation; however, little is known on the mechanisms regulating their expression. Differential promoter DNA methylation is an increasingly recognized mechanism that determines a switch between gene silencing and gene transcription. We hypothesized that epigenetic mechanisms are involved in the regulation of endothelial TLR2 expression because of the localization of the TLR2 promoter on a CpG-island. Resting human umbilical vein endothelial cells (HUVECs) displayed rather low TLR2 mRNA expression, while a strong expression increase occurred under inflammatory conditions. We examined the TLR2 promoter methylation pattern in resting HUVECs and compared it to cells treated either with the inflammatory cytokine TNF-α or the DNA-demethylating agent 5-azacytidine. DNA bisulfite conversion was followed by either genomic sequencing or single nucleotide primer extension (SNuPE) HPLC. Results of both techniques showed a low- or non-methylated TLR2 promoter in resting HUVECs and no alteration of the methylation pattern under inflammatory conditions. Whereas 5-azacytidine significantly increased the mRNA expression of the epigenetically regulated gene H19, TLR2 expression was not affected. Taken together, employing different methodological approaches, our data show no implication of methylation pattern changes in inflammatory induction of TLR2 expression in human endothelial cells.
An article published recently in Cancer Research elegantly performed lipidomic and gene expressio... more An article published recently in Cancer Research elegantly performed lipidomic and gene expression analyses in a murine model of nonalcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) and compared the findings with serum samples from patients with fibrosis and HCC (1).
Glucocorticoids are well-established anti-inflammatory drugs thought to mainly act by inhibition ... more Glucocorticoids are well-established anti-inflammatory drugs thought to mainly act by inhibition of proinflammatory transcription factors like NF-B. In recent years, however, transcription factorindependent mechanisms of glucocorticoid action have been proposed, namely the influence on MAPK pathways. Here we identify MAPK phosphatase-1 (MKP-1) as a pivotal mediator of the anti-inflammatory action of glucocorticoids in the human endothelium.
The genus Erica comprises five species (E. arborea, E. bocquetii, E. manipuliflora, E. sicula, E.... more The genus Erica comprises five species (E. arborea, E. bocquetii, E. manipuliflora, E. sicula, E. spiculifolia), in Turkey. In traditional Turkish medicine, the aerial parts of E. arborea and E. manipuliflora are used as diuretic and astringent and in the treatment of urinary infections. Additionally, the decoction of E. manipuliflora is used as weight-loss medicine, diuretic and in the treatment of diabetes, in Mugla (Turkey) and Western Mediterrenean Region in Turkey. This present study aimed to determine the cytotoxicity potentials of different extracts from this species and compare the cytotoxicity between its flowering and fruiting periods.
Several amphiphilic, chalcogen-based redox modulators have been synthesized which exhibit a wides... more Several amphiphilic, chalcogen-based redox modulators have been synthesized which exhibit a widespread, yet in some instances also selective, biological activity which is most likely based on their ability to modulate the intracellular redox balance and to interact with cellular membranes and specific proteins.
Various selenium-and tellurium-containing molecules are able to modulate the intracellular redox ... more Various selenium-and tellurium-containing molecules are able to modulate the intracellular redox state of cells, an effect which may be used for the (selective) targeting of cancer cells, which are naturally under oxidative stress (OS). As macrophages also generate an environment rich in Reactive Oxygen Species (ROS) and nitric oxide ( NO), they may represent an additional, prime target for such redoxmodulating agents. A range of selenium and tellurium-containing quinones have therefore been synthesized and subsequently tested in macrophage culture. The tellurium agents were generally cytotoxic at very low concentrations, and their mode of action seemed to involve the upregulation of intracellular ROS levels. This redox-modulating effect was confirmed by simple yeast-based chemogenetic analysis in conjunction with in vitro redox assays and electrochemistry. Together, these studies point towards an intracellular build-up of superoxide radicals as the most likely cause of toxicity. In contrast, some of the selenium derivatives were less toxic and exerted a pronounced inhibitory effect on the formation of lipopolysaccharide-induced NO production. Whilst the Te-analogues therefore may enable the resolute, effective and fairly selective targeting of macrophages, the selenium agents could act less severely, but equally effectively by interfering with inflammatory signalling molecules.
To assess the importance of the cysteine residues Cys347 and Cys351 in the carboxylic tail in the... more To assess the importance of the cysteine residues Cys347 and Cys351 in the carboxylic tail in the human D1 dopamine receptor, seven mutant receptors were constructed by PCR. The pharmacological and functional properties of the wild-type and mutant receptors were assessed following transient expression in COS-7 cells. Affinities for [3H]SCH 23390 of mutant S347 (Cys347-->Gly), T348 (Tyr348-->stop), S351 (Cys351-->Gly), T351 (Cys351-->stop), T352 (Pro352-->stop), and S347/S351 (Cys347-->Gly and Cys351-->Gly) were similar to that of wild-type receptor, whereas the expression levels were reduced up to 80%. The potency of dopaminergic antagonists for these mutant receptors was very similar to that of the wild-type receptor. However, mutant T347 (Cys347-->stop) showed a 15-25-fold reduced affinity for the antagonists SCH 23390, (+)-butaclamol, and cis-flupentixol, thus not allowing radioligand analysis. Wild-type and mutant receptors responded dose-dependently with similar potency to dopamine and SKF 38393 with an increased adenylyl cyclase activity. However, mutant receptors with the Cys347 residue changed or removed displayed a diminished ability to activate adenylyl cyclase. Dopamine preexposure desensitized wild-type and mutant S351 receptors. However, mutant receptors with Cys347 replaced or the distal part of the carboxyl tail removed were unable to desensitize. Thus, Cys347 in the cytoplasmic tail of the human D1 dopamine receptor is important for the receptor in maintaining the conformation for antagonist binding, to play a crucial role in activation of adenylyl cyclase, and to be essential for agonist-induced desensitization.
The atrial natriuretic peptide (ANP), a member of the natriuretic peptide family, is a cardiovasc... more The atrial natriuretic peptide (ANP), a member of the natriuretic peptide family, is a cardiovascular hormone which possesses well defined natriuretic, diuretic, and vasodilating properties. Most of the biological effects of ANP aremediated through its guanylyl cyclase coupled A receptor. Because ANP and its receptors have been shown to be expressed and differentially regulated in the immune system, it has been suggested that ANP has an immunomodulatory potency. Much investigation of the effects of ANP on the activation of macrophages has been carried out. ANP was shown to inhibit the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) in macrophages in an autocrine fashion. ANP in this context was shown to reduce significantly the activation of NF-kappaB and to destabilise iNOS mRNA. ANP, furthermore, can significantly reduce the LPS-induced secretion of tumour necrosis factor alpha (TNFalpha) in macrophages. The relevance of these findings on a re...
The atrial natriuretic peptide (ANP), a member of the natriuretic peptide family, is a cardiovasc... more The atrial natriuretic peptide (ANP), a member of the natriuretic peptide family, is a cardiovascular hormone which possesses well defined natriuretic, diuretic, and vasodilating properties. Most of the biological effects of ANP are mediated through its guanylyl cyclase coupled A receptor. Because ANP and its receptors have been shown to be expressed and differentially regulated in the immune system, it has been suggested that ANP has an immunomodulatory potency. Much investigation of the effects of ANP on the activation of macrophages has been carried out. ANP was shown to inhibit the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) in macrophages in an autocrine fashion. ANP in this context was shown to reduce significantly the activation of NF-κB and to destabilise iNOS mRNA. ANP, furthermore, can significantly reduce the LPS-induced secretion of tumour necrosis factor α (TNFα) in macrophages. The relevance of these findings on a regulatory role for ANP on TNFα in humans was shown by the fact that ANP significantly reduces the release of TNFα in whole human blood. It was furthermore shown to attenuate the release of interleukin 1β (IL1β). Interestingly, ANP did not affect the secretion of the anti-inflammatory cytokines IL10 and IL1 receptor antagonist (IL1ra). In summary, ANP was shown to reduce the secretion of inflammatory mediators in macrophages. Therefore, this cardiovascular hormone may possess anti-inflammatory potential.
The inducible nitric-oxide synthase (iNOS) synthesizes NO from L-arginine. Availability of L-argi... more The inducible nitric-oxide synthase (iNOS) synthesizes NO from L-arginine. Availability of L-arginine is maintained by a lipopolysaccharide (LPS)-induced induction of the CAT-2B amino acids transporter. Recently, we could show that the cardiovascular hormone atrial natriuretic peptide (ANP) inhibits the induction of iNOS in LPS-stimulated macrophages via its guanylate cyclase-coupled A-receptor. To investigate whether ANP exerts an effect on LPS-induced L-arginine uptake. Murine bone marrow derived macrophages were activated with LPS (1 microg/ml, 20 h) in the presence or absence of ANP or C-type natriuretic peptide (CNP). L-Arginine transport was determined by measuring the uptake of L-[(3)H]arginine. L-[(3)H]Arginine influx was also determined in LPS-activated cells in the presence of N(G)-monomethyl-L-arginine (L-NMMA), competitor amino acids, or ANP. Nitrite accumulation was determined in supernatants of LPS-activated cells cultured in the presence or absence of L-ornithine. ANP...
Journal of immunology (Baltimore, Md. : 1950), 2000
The atrial natriuretic peptide (ANP) is suggested to regulate inflammatory response by alteration... more The atrial natriuretic peptide (ANP) is suggested to regulate inflammatory response by alteration of macrophage functions. The aim of this study was to investigate whether ANP influences production of TNF-alpha. TNF-alpha production in murine bone marrow-derived macrophages was induced by LPS, and TNF-alpha secretion (+/-ANP) was determined by L929 bioassay. ANP dose dependently (10-8-10-6 M) inhibited TNF-alpha release by up to 95%. The effect was mediated via the guanylate cyclase-coupled A receptor, as was shown by employing dibutyryl-cGMP, the cGMP-inhibitory compound Ly-83583, and the A receptor antagonist HS-142-1. A specific ligand of the natriuretic peptide "clearance" receptor inhibited TNF-alpha production only at 10-7 and 10-8 M, but not at 10-6 M. The B receptor ligand C-type natriuretic peptide showed no TNF-alpha-inhibitory effect. To investigate the underlying mechanism of ANP-mediated TNF-alpha inhibition, Northern blot was performed. ANP-treated macrophage...
The Journal of pharmacology and experimental therapeutics, 1998
The seleno-organic drug ebselen (2-phenyl-1, 2-benzoisoselenazol-3(2H)-one) has glutathione perox... more The seleno-organic drug ebselen (2-phenyl-1, 2-benzoisoselenazol-3(2H)-one) has glutathione peroxidase-like activity, and inhibits lipoxygenases, oxidative burst of leukocytes, nitric oxide synthases, protein kinases and leukocyte migration. This study elaborates in vivo in mice hitherto unknown immunopharmacological properties of ebselen. The compound was comparatively investigated in two different T cell-dependent hepatic hyperinflammation models and in two alternative models of receptor-activated liver apoptosis. Mice orally pretreated with ebselen were dose-dependently protected from concanavalin A (ConA)-induced liver injury. In livers from ebselen-pretreated mice exposed to ConA, the nuclear antiapoptotic transcription factor NFkappaB was upregulated. The release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF) was downregulated, while the ciculating amount of the anti-inflammatory cytokine interleukin-10 (IL-10) was increased. Ebselen protected also from live...
The atrial natriuretic peptide (ANP) was described as a peptide hormone synthesized and secreted ... more The atrial natriuretic peptide (ANP) was described as a peptide hormone synthesized and secreted by heart atria. It plays an important role in the regulation of volume homeostasis; however, the functions of ANP are not restricted to cardiovascular effects. The biological profile of ANP is much broader than originally thought. This article focuses on the immunomodulatory and anti-inflammatory functions of ANP addressing; for example, the influence of ANP on macrophage functions. Another important aspect of ANP reviewed here is its cytoprotective potential. The beneficial effect of ANP in preventing cell damage caused by ischemia and reperfusion warrants special attention. The therapeutic potential of ANP in organ preservation could be important for transplantation medicine.
The adenovirus E1A12S gene product (WT12S) immortalizes epithelial cells and they retain their di... more The adenovirus E1A12S gene product (WT12S) immortalizes epithelial cells and they retain their dierentiated characteristics, but certain mutants cannot do the latter. Characterization of mutant immortalized epithelial cells indicated that they had undergone epithelial mesenchymal transition (EMT). Coexpression of V12ras with WT12S leads to benign tumors, but to malignant tumors with 12S mutants. Since EMT is critical for tumor progression, identi®cation of the molecular mechanisms involved should elucidate novel therapeutic targets. To this end, representational dierence analysis (RDA) was used to identify cDNAs upregulated in the mutant cell line. Thirty-®ve dierentially expressed mRNAs were identi®ed and classi®ed into several functional categories, including nine novel cDNAs. Among the 26 known cDNAs, extracellular matrix and related proteins made up the largest group of dierentially expressed genes, followed by growth factors and receptors and transcription factors. There was also an ion transporter, a cytoskeletal protein, glycosylation and amidinotransferase enzymes and proteins with unknown functions. Some of the known genes have previously been associated with EMT and/or tumor progression and thus served to validate the system to obtain the desired target genes, while other cDNAs are newly linked with dedierentiation/malignancy. Array analyses indicated that the cDNAs were speci®cally upregulated in invasive or metastatic tumors, especially of breast, uterus and lung, suggesting their involvement in the progression of these tumors. Oncogene (2001) 20, 6679 ± 6688.
Background and aims: Nanoparticles can pass the lung tissue, reach the circulation and in case of... more Background and aims: Nanoparticles can pass the lung tissue, reach the circulation and in case of transplacental transport may affect the unborn child. Aim of this work was to determine whether exposure to particulate matter containing nanoparticles in part resulting from diesel exhaust may influence cytokine levels in the cord blood of newborns. We hypothesized that proinflammatory markers are increased in children of highly exposed mothers compared to controls.
Toll-like receptors play an important role in endothelial inflammation; however, little is known ... more Toll-like receptors play an important role in endothelial inflammation; however, little is known on the mechanisms regulating their expression. Differential promoter DNA methylation is an increasingly recognized mechanism that determines a switch between gene silencing and gene transcription. We hypothesized that epigenetic mechanisms are involved in the regulation of endothelial TLR2 expression because of the localization of the TLR2 promoter on a CpG-island. Resting human umbilical vein endothelial cells (HUVECs) displayed rather low TLR2 mRNA expression, while a strong expression increase occurred under inflammatory conditions. We examined the TLR2 promoter methylation pattern in resting HUVECs and compared it to cells treated either with the inflammatory cytokine TNF-α or the DNA-demethylating agent 5-azacytidine. DNA bisulfite conversion was followed by either genomic sequencing or single nucleotide primer extension (SNuPE) HPLC. Results of both techniques showed a low- or non-methylated TLR2 promoter in resting HUVECs and no alteration of the methylation pattern under inflammatory conditions. Whereas 5-azacytidine significantly increased the mRNA expression of the epigenetically regulated gene H19, TLR2 expression was not affected. Taken together, employing different methodological approaches, our data show no implication of methylation pattern changes in inflammatory induction of TLR2 expression in human endothelial cells.
An article published recently in Cancer Research elegantly performed lipidomic and gene expressio... more An article published recently in Cancer Research elegantly performed lipidomic and gene expression analyses in a murine model of nonalcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) and compared the findings with serum samples from patients with fibrosis and HCC (1).
Glucocorticoids are well-established anti-inflammatory drugs thought to mainly act by inhibition ... more Glucocorticoids are well-established anti-inflammatory drugs thought to mainly act by inhibition of proinflammatory transcription factors like NF-B. In recent years, however, transcription factorindependent mechanisms of glucocorticoid action have been proposed, namely the influence on MAPK pathways. Here we identify MAPK phosphatase-1 (MKP-1) as a pivotal mediator of the anti-inflammatory action of glucocorticoids in the human endothelium.
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