Gabriele Werner-Felmayer - Academia.edu (original) (raw)

Papers by Gabriele Werner-Felmayer

Chemistry and Biology of Pteridines and Folates, 2002

Nitric oxide synthases catalyze a complex reaction converting L-arginine to citrulline and nitric... more Nitric oxide synthases catalyze a complex reaction converting L-arginine to citrulline and nitric oxide. In addition to heme, FAD, FMN and NADPH, nitric oxide synthases require tetrahydrobiopterin as cofactor. Tetrahydrobiopterin is known to stabilize the active, dimeric conformation of the enzyme (1), which has a high-spin heme iron (2) and an increased affinity for the substrate L-arginine (3). In addition to these allosteric roles, an electronic contribution of the tetrahydrobiopterin cofactor to the nitric oxide synthase reaction has been intensely searched for. The most convincing evidence for such an electronic contribution provided the detection of tetrahydrobiopterin-derived radicals being formed in dependence of the nitric oxide synthase reaction (4, 5, 6).

Journal of Clinical Epidemiology, 1989

Cambridge quarterly of healthcare ethics : CQ : the international journal of healthcare ethics committees, 2016

Assisted reproductive technologies (ARTs) and reproductive genetic technologies (RGTs) are intert... more Assisted reproductive technologies (ARTs) and reproductive genetic technologies (RGTs) are intertwined and coevolving. These technologies are increasingly used to fulfill socially and culturally framed requests, for example, "family balancing," or to enable postmenopausal women or homosexual couples to have genetically linked children. The areas of ART and RGT are replete with ethical issues, because different social practices and legal regulations, as well as economic inequalities within and among countries, create vulnerable groups and, therefore, the potential for exploitation. This article provides an overview of the ART and RGT landscape in Pakistan and analyzes the available online content addressing Pakistani citizens and international clients. We explored the topic in view of socioeconomic challenges in Pakistan, particularly deeply rooted poverty, lack of education, gender discrimination, and absence of regulation. As online information given by ART and RGT provid...

Clinical ethics consultation is a relatively young field of expertise that supports ethically ref... more Clinical ethics consultation is a relatively young field of expertise that supports ethically reflected decision-making. This process shakes up the existing hierarchy in two ways; first, by involving further perspectives in a structured and transparent way, and, second, by shifting the focus to a more comprehensive, interdisciplinary view. A major challenge for those providing clinical ethics consultation is building trust, which involves being considerate towards the needs of patients, relatives and healthcare professionals as well as towards customs and organizational culture. As this service emphasizes the relational aspect of medical care, it is difficult to realize within existing institutional frameworks. This paper explores how clinical ethics consultation developed and changed over the past few decades alongside an evolving understanding of respect for patient autonomy within an ethics of care approach. One of the most influential images related to clinical ethics consultati...

Cellular and Molecular Life Sciences

Plasmalogens are an abundant class of glycerophospholipids in the mammalian body, with special oc... more Plasmalogens are an abundant class of glycerophospholipids in the mammalian body, with special occurrence in the brain and in immune cell membranes. Plasmanylethanolamine desaturase (PEDS1) is the final enzyme of plasmalogen biosynthesis, which introduces the characteristic 1-O-alk-1′-enyl double bond. The recent sequence identification of PEDS1 as transmembrane protein 189 showed that its protein sequence is related to a special class of plant desaturases (FAD4), with whom it shares a motif of 8 conserved histidines, which are essential for the enzymatic activity. In the present work, we wanted to gain more insight into the sequence–function relationship of this enzyme and mutated to alanine additional 28 amino acid residues of murine plasmanylethanolamine desaturase including those 20 residues, which are also totally conserved—in addition to the eight-histidine-motif—among the animal PEDS1 and plant FAD4 plant desaturases. We measured the enzymatic activity by transient transfecti...

Clinical ethics consultation is a relatively young field of expertise that supports ethically ref... more Clinical ethics consultation is a relatively young field of expertise that supports ethically reflected decision-making. This process shakes up the existing hierarchy in two ways; first, by involving further perspectives in a structured and transparent way, and, second, by shifting the focus to a more comprehensive, interdisciplinary view. A major challenge for those providing clinical ethics consultation is building trust, which involves being considerate towards the needs of patients, relatives and healthcare professionals as well as towards customs and organizational culture. As this service emphasizes the relational aspect of medical care, it is difficult to realize within existing institutional frameworks. This paper explores how clinical ethics consultation developed and changed over the past few decades alongside an evolving understanding of respect for patient autonomy within an ethics of care approach. One of the most influential images related to clinical ethics consultati...

Papers may be copied, distributed, displayed, performed and modified according to the Creative Co... more Papers may be copied, distributed, displayed, performed and modified according to the Creative Commons Attribution ShareAlike 4.0 (CC BY-SA 4.0). Papers published through begutachtet.at have undergone a double blind peer-review process. More information can be found at <www.begutachtet.at>

Die Beitrage des Bandes beschaftigen sich mit Begutachtungspraktiken verschiedener Epochen und ze... more Die Beitrage des Bandes beschaftigen sich mit Begutachtungspraktiken verschiedener Epochen und zeigen die Entwicklung des Gutachtens als einen Prozess auf, der zunehmend der Diskussion, Ausverhandlung und dem Einfluss von Wissen und Gegenwissen um soziokulturelle Normen unterliegt. Ausgehend von der Annahme, dass der Medizin in der Klassifikation, Bewertung und Einschatzung bzw. in der Subjektivierung von Einzelnen und Gruppen eine besondere Bedeutung zukommt, ruckt insbesondere jenes Verhaltnis in den Fokus, das durch die Tatigkeit des Gutachtens zwischen und fur Menschen hergestellt wird.

Trends in Biotechnology, 2020

Brocher Foundation in Geneva but were involved with the planning and preparation of the meeting a... more Brocher Foundation in Geneva but were involved with the planning and preparation of the meeting and manuscript.

Israel journal of health policy research, Jan 18, 2012

Since the successful introduction of in vitro fertilization in 1978, medically assisted reproduct... more Since the successful introduction of in vitro fertilization in 1978, medically assisted reproduction (MAR) has proliferated in multiple clinical innovations. Consequently, egg cells have become an object of demand for both infertility treatment and stem cell research, and this raises complex legal, ethical, social and economic issues.In this paper we compare how the procurement and use of human egg cells is regulated in two countries: Israel and Austria. Israel is known for its scientific leadership, generous public funding, high utilization and liberal regulation of assisted reproductive technology (ART). Austria lies at the other extreme of the regulatory spectrum in terms of restrictions on reproductive interventions.In both countries, however, there is a constant increase in the use of the technology, and recent legal developments make egg cells more accessible. Also, in both countries the scarcity of egg cells in concert with the rising demand for donations has led to the emerg...

Medicine and law, 2010

Biomedicine is a fast moving and often challenging research field. To this extent, it seems that ... more Biomedicine is a fast moving and often challenging research field. To this extent, it seems that preserving one's integrity is becoming more and more complex and occasionally stressful for individual researchers. Highly competitive funding and publication, the commercialization of biomedicine in general, the media hype about some scientific fields, the politicization of research and higher education, and, last but not least, the increasing specialization necessary to deal with increasingly sophisticated experimental systems and technologies are aspects of this complexity. While guidelines and overseeing control boards are important regulatory instruments, which also serve to enhance awareness of scientific integrity and to increase transparency, are not sufficient to maintain and further develop a positive academic climate that motivates the community to adhere to high and consistent professional ethics. Here, scientific misconduct and misbehaviour will be illustrated by referri...

Transplantation Journal, 2004

Klinische Wochenschrift, 1990

Journal of Biological Chemistry, 2002

GTP cyclohydrolase I feedback regulatory protein (GFRP) is a 9.7-kDa protein regulating GTP cyclo... more GTP cyclohydrolase I feedback regulatory protein (GFRP) is a 9.7-kDa protein regulating GTP cyclohydrolase I activity in dependence of tetrahydrobiopterin and phenylalanine concentrations, thus enabling stimulation of tetrahydrobiopterin biosynthesis by phenylalanine to ensure its efficient metabolism by phenylalanine hydroxylase. Here, we were interested in regulation of GFRP expression by proinflammatory cytokines and stimuli, which are known to induce GTP cyclohydrolase I expression. Recombinant human GFRP stimulated recombinant human GTP cyclohydrolase I in the presence of phenylalanine and mediated feedback inhibition by tetrahydrobiopterin. Levels of GFRP mRNA in human myelomonocytoma (THP-1) cells remained unaltered by treatment of cells with interferon-␥ or interleukin-1␤, but were significantly down-regulated by bacterial lipopolysaccharide (LPS, 1 g/ml), without or with cotreatment by interferon-␥, which strongly up-regulated GTP cyclohydrolase I expression and activity. GFRP expression was also suppressed in human umbilical vein endothelial cells treated with 1 g/ml LPS, as well as in rat tissues 7 h post intraperitoneal injection of 10 mg/kg LPS. THP-1 cells stimulated with interferon-␥ alone showed increased pteridine synthesis by addition of phenylalanine to the culture medium. Cells stimulated with interferon-␥ plus LPS, in contrast, showed phenylalanine-independent pteridine synthesis. These results demonstrate that LPS down-regulates expression of GFRP, thus rendering pteridine synthesis independent of metabolic control by phenylalanine.

Immunogenetics, 2001

The CXC chemokine or small inducible cytokine B (SCYB) subfamily includes the T-cell chemoattract... more The CXC chemokine or small inducible cytokine B (SCYB) subfamily includes the T-cell chemoattractants MIG (CXCL9, SCYB9), IP-10 (CXCL10, SCYB10), and I-TAC (CXCL11, SCYB11). These three highly homologous chemokines lack the glutamic acidleucine-arginine (ELR) motif and signal via the CXCR3 receptor. Previous work showed that the genes encoding these chemokines are localized in an individual minicluster on human Chromosome (Chr) 4 at position 4q21.2. Recently, we identified mouse Scyb11 and mapped this gene by fluorescence in situ hybridization (FISH) to mouse Chr 5E3, the orthologous locus to human 4q21 where the other two homologous mouse genes, Scyb9 and Scyb10, have also been localized. Since SCYB10 and SCYB11 are not represented in the recently published draft sequence of the human genome, we wanted to clarify exactly the order and distances of the three chemokine genes using two-color FISH on stretched DNA fiber preparations. Here, we report the simultaneous localization of all three genes and provide high-resolution visual maps of this chemokine cluster from both mouse and human. The three chemokine genes were found within a range of 32 kb on mouse and 29 kb on human DNA fiber targets. The precise physical distances were defined, and an almost identical arrangement of the human and mouse homologues was identified, indicating that this CXC chemokine mini-cluster has been completely conserved evolutionarily since the divergence of mouse and human. Our results refine previous maps of the three genes, support the hypothesis that they resulted from gene duplication that took place in a common ancestor of mouse and human, and provide complementary information on a region of the draft sequence of human Chr 4 that is not yet covered. Keywords CXC chemokine • Human chromosome 4 • Mouse chromosome 5 • Gene evolution • Fiber-FISH M.E. and M.T. contributed equally to this study and therefore share first authorship.

FEBS Letters, 1995

Tumor necrosis factor-a and the formation of reactive oxygen intermediates are central mediators ... more Tumor necrosis factor-a and the formation of reactive oxygen intermediates are central mediators of apoptosis. Recent data indicated a role of neopterin and 7,8-dihydroneopterin in oxygen radical mediated processes. We have therefore investigated the effect of neopterin-derivatives on TNFa induced apoptosis of the monocyte-like cell line U937. At an elevated concentration 7,8-dihydroneopterin was found to superinduce TNFa mediated programmed cell death due to the formation of reactive oxygen intermediates. Our results imply that in combination with TNFa high concentrations of 7,8-dihydroneopterin enhances apoptosis due to oxidative stress on cells.

FEBS Letters, 1994

We have previously shown that neopterin, 6-o-erythro-trihydroxypropyl-pteridine, synthesized by h... more We have previously shown that neopterin, 6-o-erythro-trihydroxypropyl-pteridine, synthesized by human monocytes/macrophages upon stimulatlon by interferon-y, enhances toxicity of reactive oxygen at neutral or slightly alkaline pH (7.5), but not at acidic pH (below 6.5). In the present study, we explored in more detail the necessary requirements for neopterin to modulate the effects of hydrogen peroxide in a luminol-dependent chemiluminescence assay. We demonstrate that neopterin enhances hydrogen peroxide effects only in the presence of iron chelator complexes like iron-(III)-or iron-(II)-EDTA or iron-(III)-DTPA. Thus, iron chelator complexes together with neopterin may play an important role in macrophagemediated effector mechanisms.

FEBS Letters, 1994

We have previously shown that neopterin enhances hydrogen peroxide and chloramine T activity in a... more We have previously shown that neopterin enhances hydrogen peroxide and chloramine T activity in a luminol-dependent chemiluminescence assay and strengthens toxicity of these agents against bacteria at slightly alkaline pH @H 7.5), while 7,8-dihydroneopterin was shown to be a scavenger independent of the pH value. Besides various oxidants, phenolic antioxidants were shown to specifically induce expression of the c-fos and c-&n mRNAs. Using an inducible cfosCAT reporter transactivation system we studied the function of the pteridine derivatives on c-fos transactivation. For the first time, we demonstrate that neopterin and 7,8_dihydroneopterin, particularly together with cyclic guanosine monophosphate, induce c-fos gene expression. In humans, interferon-y induces the release of neopterin and 7,8-dihydroneopterin and also the synthesis of nitric oxide radical which in turn stimulate the formation of cGMP. Thus, in certain situations all three substances, namely neopterin, 7,8-dihydroneopterin and cGMP, may be present locally and even in the circulation at the same time. Based on our findings this constellation would significantly enhance the risk of c-fos gene expression and therefore promote tumour growth and development.

European Journal of Haematology, 2009

Chronic inflammatory disorders are associated with an increased risk of patients developing anaem... more Chronic inflammatory disorders are associated with an increased risk of patients developing anaemia. There is some evidence that cytokines released during cell-mediated immune responses are capable of inhibiting bone marrow haematopoiesis. In vitro, interferon gamma and tumour-necrosis factor alpha inhibit growth of erythroid precursor cells. The mode of action of these cytokines is probably associated with their antiproliferative capacity. Decrease of serum iron and increase of storage iron in patients appears to be a consequence of the defense strategy of macrophages during long-lasting inflammatory disorders. Decreased serum iron correlates to decreased haemoglobin concentrations. In view of this, the development of anaemia seems likely to result from the altered iron metabolism induced by stimulated macrophages. Low haemoglobin levels and associated hypoxia up-regulate the release of erythropoietin, which can explain why increased circulating erythropoietin is usually found in patients with anaemia.

Chemistry and Biology of Pteridines and Folates, 2002

Nitric oxide synthases catalyze a complex reaction converting L-arginine to citrulline and nitric... more Nitric oxide synthases catalyze a complex reaction converting L-arginine to citrulline and nitric oxide. In addition to heme, FAD, FMN and NADPH, nitric oxide synthases require tetrahydrobiopterin as cofactor. Tetrahydrobiopterin is known to stabilize the active, dimeric conformation of the enzyme (1), which has a high-spin heme iron (2) and an increased affinity for the substrate L-arginine (3). In addition to these allosteric roles, an electronic contribution of the tetrahydrobiopterin cofactor to the nitric oxide synthase reaction has been intensely searched for. The most convincing evidence for such an electronic contribution provided the detection of tetrahydrobiopterin-derived radicals being formed in dependence of the nitric oxide synthase reaction (4, 5, 6).

Journal of Clinical Epidemiology, 1989

Cambridge quarterly of healthcare ethics : CQ : the international journal of healthcare ethics committees, 2016

Assisted reproductive technologies (ARTs) and reproductive genetic technologies (RGTs) are intert... more Assisted reproductive technologies (ARTs) and reproductive genetic technologies (RGTs) are intertwined and coevolving. These technologies are increasingly used to fulfill socially and culturally framed requests, for example, "family balancing," or to enable postmenopausal women or homosexual couples to have genetically linked children. The areas of ART and RGT are replete with ethical issues, because different social practices and legal regulations, as well as economic inequalities within and among countries, create vulnerable groups and, therefore, the potential for exploitation. This article provides an overview of the ART and RGT landscape in Pakistan and analyzes the available online content addressing Pakistani citizens and international clients. We explored the topic in view of socioeconomic challenges in Pakistan, particularly deeply rooted poverty, lack of education, gender discrimination, and absence of regulation. As online information given by ART and RGT provid...

Clinical ethics consultation is a relatively young field of expertise that supports ethically ref... more Clinical ethics consultation is a relatively young field of expertise that supports ethically reflected decision-making. This process shakes up the existing hierarchy in two ways; first, by involving further perspectives in a structured and transparent way, and, second, by shifting the focus to a more comprehensive, interdisciplinary view. A major challenge for those providing clinical ethics consultation is building trust, which involves being considerate towards the needs of patients, relatives and healthcare professionals as well as towards customs and organizational culture. As this service emphasizes the relational aspect of medical care, it is difficult to realize within existing institutional frameworks. This paper explores how clinical ethics consultation developed and changed over the past few decades alongside an evolving understanding of respect for patient autonomy within an ethics of care approach. One of the most influential images related to clinical ethics consultati...

Cellular and Molecular Life Sciences

Plasmalogens are an abundant class of glycerophospholipids in the mammalian body, with special oc... more Plasmalogens are an abundant class of glycerophospholipids in the mammalian body, with special occurrence in the brain and in immune cell membranes. Plasmanylethanolamine desaturase (PEDS1) is the final enzyme of plasmalogen biosynthesis, which introduces the characteristic 1-O-alk-1′-enyl double bond. The recent sequence identification of PEDS1 as transmembrane protein 189 showed that its protein sequence is related to a special class of plant desaturases (FAD4), with whom it shares a motif of 8 conserved histidines, which are essential for the enzymatic activity. In the present work, we wanted to gain more insight into the sequence–function relationship of this enzyme and mutated to alanine additional 28 amino acid residues of murine plasmanylethanolamine desaturase including those 20 residues, which are also totally conserved—in addition to the eight-histidine-motif—among the animal PEDS1 and plant FAD4 plant desaturases. We measured the enzymatic activity by transient transfecti...

Clinical ethics consultation is a relatively young field of expertise that supports ethically ref... more Clinical ethics consultation is a relatively young field of expertise that supports ethically reflected decision-making. This process shakes up the existing hierarchy in two ways; first, by involving further perspectives in a structured and transparent way, and, second, by shifting the focus to a more comprehensive, interdisciplinary view. A major challenge for those providing clinical ethics consultation is building trust, which involves being considerate towards the needs of patients, relatives and healthcare professionals as well as towards customs and organizational culture. As this service emphasizes the relational aspect of medical care, it is difficult to realize within existing institutional frameworks. This paper explores how clinical ethics consultation developed and changed over the past few decades alongside an evolving understanding of respect for patient autonomy within an ethics of care approach. One of the most influential images related to clinical ethics consultati...

Papers may be copied, distributed, displayed, performed and modified according to the Creative Co... more Papers may be copied, distributed, displayed, performed and modified according to the Creative Commons Attribution ShareAlike 4.0 (CC BY-SA 4.0). Papers published through begutachtet.at have undergone a double blind peer-review process. More information can be found at <www.begutachtet.at>

Die Beitrage des Bandes beschaftigen sich mit Begutachtungspraktiken verschiedener Epochen und ze... more Die Beitrage des Bandes beschaftigen sich mit Begutachtungspraktiken verschiedener Epochen und zeigen die Entwicklung des Gutachtens als einen Prozess auf, der zunehmend der Diskussion, Ausverhandlung und dem Einfluss von Wissen und Gegenwissen um soziokulturelle Normen unterliegt. Ausgehend von der Annahme, dass der Medizin in der Klassifikation, Bewertung und Einschatzung bzw. in der Subjektivierung von Einzelnen und Gruppen eine besondere Bedeutung zukommt, ruckt insbesondere jenes Verhaltnis in den Fokus, das durch die Tatigkeit des Gutachtens zwischen und fur Menschen hergestellt wird.

Trends in Biotechnology, 2020

Brocher Foundation in Geneva but were involved with the planning and preparation of the meeting a... more Brocher Foundation in Geneva but were involved with the planning and preparation of the meeting and manuscript.

Israel journal of health policy research, Jan 18, 2012

Since the successful introduction of in vitro fertilization in 1978, medically assisted reproduct... more Since the successful introduction of in vitro fertilization in 1978, medically assisted reproduction (MAR) has proliferated in multiple clinical innovations. Consequently, egg cells have become an object of demand for both infertility treatment and stem cell research, and this raises complex legal, ethical, social and economic issues.In this paper we compare how the procurement and use of human egg cells is regulated in two countries: Israel and Austria. Israel is known for its scientific leadership, generous public funding, high utilization and liberal regulation of assisted reproductive technology (ART). Austria lies at the other extreme of the regulatory spectrum in terms of restrictions on reproductive interventions.In both countries, however, there is a constant increase in the use of the technology, and recent legal developments make egg cells more accessible. Also, in both countries the scarcity of egg cells in concert with the rising demand for donations has led to the emerg...

Medicine and law, 2010

Biomedicine is a fast moving and often challenging research field. To this extent, it seems that ... more Biomedicine is a fast moving and often challenging research field. To this extent, it seems that preserving one's integrity is becoming more and more complex and occasionally stressful for individual researchers. Highly competitive funding and publication, the commercialization of biomedicine in general, the media hype about some scientific fields, the politicization of research and higher education, and, last but not least, the increasing specialization necessary to deal with increasingly sophisticated experimental systems and technologies are aspects of this complexity. While guidelines and overseeing control boards are important regulatory instruments, which also serve to enhance awareness of scientific integrity and to increase transparency, are not sufficient to maintain and further develop a positive academic climate that motivates the community to adhere to high and consistent professional ethics. Here, scientific misconduct and misbehaviour will be illustrated by referri...

Transplantation Journal, 2004

Klinische Wochenschrift, 1990

Journal of Biological Chemistry, 2002

GTP cyclohydrolase I feedback regulatory protein (GFRP) is a 9.7-kDa protein regulating GTP cyclo... more GTP cyclohydrolase I feedback regulatory protein (GFRP) is a 9.7-kDa protein regulating GTP cyclohydrolase I activity in dependence of tetrahydrobiopterin and phenylalanine concentrations, thus enabling stimulation of tetrahydrobiopterin biosynthesis by phenylalanine to ensure its efficient metabolism by phenylalanine hydroxylase. Here, we were interested in regulation of GFRP expression by proinflammatory cytokines and stimuli, which are known to induce GTP cyclohydrolase I expression. Recombinant human GFRP stimulated recombinant human GTP cyclohydrolase I in the presence of phenylalanine and mediated feedback inhibition by tetrahydrobiopterin. Levels of GFRP mRNA in human myelomonocytoma (THP-1) cells remained unaltered by treatment of cells with interferon-␥ or interleukin-1␤, but were significantly down-regulated by bacterial lipopolysaccharide (LPS, 1 g/ml), without or with cotreatment by interferon-␥, which strongly up-regulated GTP cyclohydrolase I expression and activity. GFRP expression was also suppressed in human umbilical vein endothelial cells treated with 1 g/ml LPS, as well as in rat tissues 7 h post intraperitoneal injection of 10 mg/kg LPS. THP-1 cells stimulated with interferon-␥ alone showed increased pteridine synthesis by addition of phenylalanine to the culture medium. Cells stimulated with interferon-␥ plus LPS, in contrast, showed phenylalanine-independent pteridine synthesis. These results demonstrate that LPS down-regulates expression of GFRP, thus rendering pteridine synthesis independent of metabolic control by phenylalanine.

Immunogenetics, 2001

The CXC chemokine or small inducible cytokine B (SCYB) subfamily includes the T-cell chemoattract... more The CXC chemokine or small inducible cytokine B (SCYB) subfamily includes the T-cell chemoattractants MIG (CXCL9, SCYB9), IP-10 (CXCL10, SCYB10), and I-TAC (CXCL11, SCYB11). These three highly homologous chemokines lack the glutamic acidleucine-arginine (ELR) motif and signal via the CXCR3 receptor. Previous work showed that the genes encoding these chemokines are localized in an individual minicluster on human Chromosome (Chr) 4 at position 4q21.2. Recently, we identified mouse Scyb11 and mapped this gene by fluorescence in situ hybridization (FISH) to mouse Chr 5E3, the orthologous locus to human 4q21 where the other two homologous mouse genes, Scyb9 and Scyb10, have also been localized. Since SCYB10 and SCYB11 are not represented in the recently published draft sequence of the human genome, we wanted to clarify exactly the order and distances of the three chemokine genes using two-color FISH on stretched DNA fiber preparations. Here, we report the simultaneous localization of all three genes and provide high-resolution visual maps of this chemokine cluster from both mouse and human. The three chemokine genes were found within a range of 32 kb on mouse and 29 kb on human DNA fiber targets. The precise physical distances were defined, and an almost identical arrangement of the human and mouse homologues was identified, indicating that this CXC chemokine mini-cluster has been completely conserved evolutionarily since the divergence of mouse and human. Our results refine previous maps of the three genes, support the hypothesis that they resulted from gene duplication that took place in a common ancestor of mouse and human, and provide complementary information on a region of the draft sequence of human Chr 4 that is not yet covered. Keywords CXC chemokine • Human chromosome 4 • Mouse chromosome 5 • Gene evolution • Fiber-FISH M.E. and M.T. contributed equally to this study and therefore share first authorship.

FEBS Letters, 1995

Tumor necrosis factor-a and the formation of reactive oxygen intermediates are central mediators ... more Tumor necrosis factor-a and the formation of reactive oxygen intermediates are central mediators of apoptosis. Recent data indicated a role of neopterin and 7,8-dihydroneopterin in oxygen radical mediated processes. We have therefore investigated the effect of neopterin-derivatives on TNFa induced apoptosis of the monocyte-like cell line U937. At an elevated concentration 7,8-dihydroneopterin was found to superinduce TNFa mediated programmed cell death due to the formation of reactive oxygen intermediates. Our results imply that in combination with TNFa high concentrations of 7,8-dihydroneopterin enhances apoptosis due to oxidative stress on cells.

FEBS Letters, 1994

We have previously shown that neopterin, 6-o-erythro-trihydroxypropyl-pteridine, synthesized by h... more We have previously shown that neopterin, 6-o-erythro-trihydroxypropyl-pteridine, synthesized by human monocytes/macrophages upon stimulatlon by interferon-y, enhances toxicity of reactive oxygen at neutral or slightly alkaline pH (7.5), but not at acidic pH (below 6.5). In the present study, we explored in more detail the necessary requirements for neopterin to modulate the effects of hydrogen peroxide in a luminol-dependent chemiluminescence assay. We demonstrate that neopterin enhances hydrogen peroxide effects only in the presence of iron chelator complexes like iron-(III)-or iron-(II)-EDTA or iron-(III)-DTPA. Thus, iron chelator complexes together with neopterin may play an important role in macrophagemediated effector mechanisms.

FEBS Letters, 1994

We have previously shown that neopterin enhances hydrogen peroxide and chloramine T activity in a... more We have previously shown that neopterin enhances hydrogen peroxide and chloramine T activity in a luminol-dependent chemiluminescence assay and strengthens toxicity of these agents against bacteria at slightly alkaline pH @H 7.5), while 7,8-dihydroneopterin was shown to be a scavenger independent of the pH value. Besides various oxidants, phenolic antioxidants were shown to specifically induce expression of the c-fos and c-&n mRNAs. Using an inducible cfosCAT reporter transactivation system we studied the function of the pteridine derivatives on c-fos transactivation. For the first time, we demonstrate that neopterin and 7,8_dihydroneopterin, particularly together with cyclic guanosine monophosphate, induce c-fos gene expression. In humans, interferon-y induces the release of neopterin and 7,8-dihydroneopterin and also the synthesis of nitric oxide radical which in turn stimulate the formation of cGMP. Thus, in certain situations all three substances, namely neopterin, 7,8-dihydroneopterin and cGMP, may be present locally and even in the circulation at the same time. Based on our findings this constellation would significantly enhance the risk of c-fos gene expression and therefore promote tumour growth and development.

European Journal of Haematology, 2009

Chronic inflammatory disorders are associated with an increased risk of patients developing anaem... more Chronic inflammatory disorders are associated with an increased risk of patients developing anaemia. There is some evidence that cytokines released during cell-mediated immune responses are capable of inhibiting bone marrow haematopoiesis. In vitro, interferon gamma and tumour-necrosis factor alpha inhibit growth of erythroid precursor cells. The mode of action of these cytokines is probably associated with their antiproliferative capacity. Decrease of serum iron and increase of storage iron in patients appears to be a consequence of the defense strategy of macrophages during long-lasting inflammatory disorders. Decreased serum iron correlates to decreased haemoglobin concentrations. In view of this, the development of anaemia seems likely to result from the altered iron metabolism induced by stimulated macrophages. Low haemoglobin levels and associated hypoxia up-regulate the release of erythropoietin, which can explain why increased circulating erythropoietin is usually found in patients with anaemia.