PubMed Health⌕ Search

Biomedical subjects

H Baumann

Publications and source records attributed to H Baumann.

At least 19 recordsLinked to original sources
PubMed1998

Neuropilin-1 is a placenta growth factor-2 receptor.

Placenta growth factor (PlGF) belongs to the family of vascular endothelial growth factors (VEGFs). It binds to the flt-1 VEGF receptor but not to the KDR/flk-1 receptor which is thought to mediate most of the angiogenic and proliferative effects of VEGF. Three PlGF isoforms are produced by alternative splicing. PlGF-1 and PlGF-3 differ from PlGF-2 since they lack the exon 6 encoded peptide which bestows upon PlGF-2 its heparin binding properties. Cross-linking experiments revealed that 125I-PlGF-2 binds to two endothelial cell surface receptors in a heparin dependent fashion. The binding of 125I-PlGF-2 to these receptors was inhibited by an excess of PlGF-2 and by the 165-amino acid form of VEGF (VEGF165), but not at all by VEGF121 and very marginally if at all by PlGF-1. The apparent molecular weight and the binding characteristics of these receptors correspond to those of the recently identified VEGF165 specific receptor neuropilin-1, and we therefore conclude that neuropilin-1 is a receptor for PlGF-2. The binding of 125I-PlGF-2 as well as the binding of 125I-VEGF165 to these receptors was inhibited by a synthetic peptide derived from exon 6 of PlGF. Furthermore, the binding of 125I-PlGF-2, but not that of 125I-VEGF165, was also inhibited by a synthetic peptide derived from exon 7 of PlGF. These observations indicate that the peptides encoded by these exons probably participate in the formation of the domain which mediates the binding of PlGF-2 to these receptors. We have also determined, using chemically modified heparin species, that the presence of sulfate moieties on the glucosamine-O-6 and on the iduronic acid-O-2 groups of heparin was required for the potentiation of 125I-PlGF-2 binding to these receptors. To determine if PlGF-2 is able to induce biological responses that are not induced by PlGF-1, we compared the effects of PlGF-1 and PlGF-2 on the migration and proliferation of endothelial cells. Both PlGF forms induced migration of endothelial cells. However, there was no quantitative difference between the response to PlGF-2 and the response to PlGF-1. Furthermore, neither PlGF-1 nor PlGF-2 had any effect upon the proliferation of the endothelial cells.

Animals↗
PubMed1998

Expression of signal transducers and activators of transcription proteins in acute myeloid leukemia blasts.

Hematopoietic cytokine receptor signaling pathways involve activation of signal transducers and activators of transcription (STAT) proteins, which are postulated to be involved in cellular differentiation. Aberrant STAT isoforms (beta forms rather than the normal alpha forms) have been described and have been found to block the normal signaling pathway from the receptor. Bcr/Abl proteins have been suggested to directly activate STATs, without exposure to growth factors. We asked whether STATs play a role in leukemogenesis. We analyzed constitutive and induced patterns of STAT activity in pretreatment blasts from 36 newly diagnosed acute myeloid leukemia (AML) patients and studied protein tyrosine kinases (PTKs) that may be involved in STAT activity, using in vitro and in-gel kinase assays. The beta forms were expressed in 21 of 27 samples (78%). Constitutive STAT3 and STAT5 activity was found in samples from 28 and 22% of patients, respectively. Response to exogenous cytokines identified two groups. STAT activity in one group was modulated by exogenous cytokines: constitutive STAT activity increased in some patients but decreased or disappeared in response to cytokines in others. The second group was cytokine insensitive. Additionally, we found constitutive PTK activity in two patients whose blasts demonstrated constitutive STAT activity, suggesting that PTKs use cytokine receptor signal pathways to activate STATs in AML blasts without exposure to exogenous cytokines. Our data suggest that (a) constitutive expression of aberrant STATs may be involved in blocking differentiation of AML blasts, (b) exogenous cytokines may activate STAT-inhibitory pathways, and (c) STATs may be activated by PTKs in some AML blasts.

Acute Disease↗
PubMed1998

IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses.

IL-6 is induced often together with the proinflammatory cytokines TNFalpha and IL-1 in many alarm conditions, and circulating IL-6 plays an important role in the induction of acute phase reactions. However, whether this endogenous IL-6 plays any additional pro- or antiinflammatory roles in local or systemic responses remains unclear. In this study, the role of IL-6 in acute inflammatory responses was investigated in animal models of endotoxic lung or endotoxemia by using IL-6+/+ and IL-6-/- mice. Aerosol exposure of endotoxin induced increased IL-6 and proinflammatory cytokines TNFalpha and MIP-2 and a neutrophilic response in the lung of IL-6+/+ mice. However, the levels of TNFalpha and MIP-2 and neutrophilia were significantly higher in the lung of IL-6-/- mice. The rate of neutrophil apoptosis in these mice was similar to that in IL-6+/+ mice. A low constitutive level of antiinflammatory cytokine IL-10 was not enhanced by endotoxin and remained similar in the lung in both IL-6+/+ and IL-6-/- mice. Systemically, intraperitoneal delivery of endotoxin resulted in much more pronounced circulating levels of TNFalpha, MIP-2, GM-CSF, and IFNgamma in IL-6-/- mice than in IL-6+/+ mice, and administration of recombinant IL-6 to IL-6-/- mice abolished these differences. In contrast, circulating IL-10 levels were induced to a similar degree in both IL-6+/+ and IL-6-/- mice. Thus, our studies reveal that endogenous IL-6 plays a crucial antiinflammatory role in both local and systemic acute inflammatory responses by controlling the level of proinflammatory, but not antiinflammatory, cytokines, and that these antiinflammatory activities by IL-6 cannot be compensated for by IL-10 or other IL-6 family members.

Acute-Phase Proteins↗
PubMed1998

Novel regio- and stereoselective O-6-desulfation of the glucosamine moiety of heparin with N-methylpyrrolidinone-water or N,N-dimethylformamide-water mixtures.

The degree of completeness and selectivity of the solvolytic O-6-desulfation reactions of the glucosamine moiety adjacent to the 2-O-sulfoiduronic acid group of heparin was systematically studied. Using solutions of various ammonium salts of heparin (salts of tributylamine, quinoline and pyridine) in mixtures of 9:1 aprotic solvents and water (solvents of medium polarity, in order of decreasing polarity: Me2SO > Me2NCHO > Me2NAc > N-methylpyrrolidinone), the influence of different reaction conditions were studied. The ammonium salt of heparin with a strong base (e.g., tributylamine) in Me2SO showed almost no desulfation, while in Me2NCHO a relatively low degree of completeness of O-6-desulfation (30%) with moderate selectivity (15% [I-2(OS)]-desulfation) was observed. Weak bases like quinoline or pyridine in Me2SO-water resulted in nearly complete [A-6(OS)]-desulfation (95 and 94%, respectively) with low selectivity [I-2(OS)]-desulfation (49 and 35%, respectively). The heparin pyridinium salt in Me2NCHO-water showed both a relatively high degree of completeness and high selectivity (72% [A-6(OS)]- and 8% [I-2(OS)]-desulfation). The highest regioselectivity (i.e., a high degree of completeness accompanied by high selectivity) was achieved using an N-methylpyrrolidinone-water mixture (88% [A-6(OS)]-desulfation and 10% [I-2(OS)]-desulfation). A nearly complete O-6-desulfation (95%), accompanied by a lower selectivity (18% [I-2(OS)]-desulfation), was achieved when the reaction was carried out twice. Lower temperature improved selectivity (5% [I-2(OS)]-desulfation) but reduced the completeness of [A-6(OS)]-desulfation (72%). In comparison with the variety of O-6-desulfations reported to date, the novel reactions presented in this article led to remarkable increase in completeness and regioselectivity of the reactions that were investigated.

Dimethylformamide↗
PubMed1998

Architecture of nonspecific protein-DNA interactions in the Sso7d-DNA complex.

Many biochemical processes, including DNA packing, maintenance and control, rely on non-sequence specific protein-DNA interactions. Nonspecific DNA-binding proteins have evolved to tolerate a wide range of DNA sequences, yet bind with a respectable affinity. The nonspecific binding requirement is in contrast to that imposed on, for example, transcription factors and implies a different structural basis for the biomolecular recognition process. To address this issue, and the mechanism for archaeal DNA packing, we determined the structure of the Sso7d protein from Sulfolobus solfataricus in complex with DNA. Sso7d binds DNA by placing a triple-stranded beta-sheet across the DNA minor groove. The protein is anchored in this position by the insertion of hydrogen bond-donating side chains into the groove and additionally stabilized by electrostatic and non-polar interactions with the DNA backbone. This structure explains how strong binding can be achieved independent of DNA sequence. Sso7d binding also distorts the DNA conformation and introduces significant unwinding of the helix. This effect suggests a mechanism for DNA packing in Sulfolobus based on negative DNA supercoiling.

Amino Acid Sequence↗
PubMed1998

Protein tyrosine phosphatase 2 (SHP-2) moderates signaling by gp130 but is not required for the induction of acute-phase plasma protein genes in hepatic cells.

Signals propagated via the gp130 subunit of the interleukin-6 (IL-6)-type cytokine receptors mediate, among various cellular responses, proliferation of hematopoietic cells and induction of acute-phase plasma protein (APP) genes in hepatic cells. Hematopoietic growth control by gp130 is critically dependent on activation of both STAT3 and protein tyrosine phosphatase 2 (SHP-2). To investigate whether induction of APP genes has a similar requirement for SHP-2, we constructed two chimeric receptors, G-gp130 and G-gp130(Y2F), consisting of the transmembrane and cytoplasmic domains of gp130 harboring either a wild-type or a mutated SHP-2 binding site, respectively, fused to the extracellular domain of the granulocyte colony-stimulating factor (G-CSF) receptor. Rat hepatoma H-35 cells stably expressing the chimeric receptors were generated by retroviral transduction. Both chimeric receptors transmitted a G-CSF-induced signal characteristic of that triggered by IL-6 through the endogenous gp130 receptor; i.e., both activated the appropriate JAK, induced DNA binding activity by STAT1 and STAT3, and up-regulated expression of the target APP genes, those for alpha-fibrinogen and haptoglobin. Notwithstanding these similarities in the patterns of signaling responses elicited, mutation of the SHP-2 interaction site in G-gp130(Y2F) abrogated ligand-activated receptor recruitment of SHP-2 as expected. Moreover, the tyrosine phosphorylation state of the chimeric receptor, the associated JAK activity, and the induced DNA binding activity of STAT1 and STAT3 were maintained at elevated levels and for an extended period of time in G-gp130(Y2F)-expressing cells following G-CSF treatment compared to that in cells displaying the G-gp130 receptor. H-35 cells ectopically expressing G-gp130(Y2F) were also found to display an enhanced sensitivity to G-CSF and a higher level of induction of APP genes. Overexpression of the enzymatically inactive SHP-2 enhanced the signaling by the wild-type but not by the Y2F mutant G-gp130 receptor. These results indicate that gp130 signaling for APP gene induction in hepatic cells differs qualitatively from that controlling the proliferative response in hematopoietic cells in not being strictly dependent on SHP-2. The data further suggest that SHP-2 functions normally to attenuate gp130-mediated signaling in hepatic (and, perhaps, other) cells by moderating JAK action.

Acute-Phase Proteins↗
PubMed1998

Expression and function of the megakaryocyte growth and development factor receptor in acute myeloid leukemia blasts.

The receptor for megakaryocyte growth and development factor (MGDF), also known as thrombopoietin, has recently been cloned. MGDF stimulates platelet production and maturation both in vitro and in vivo. MGDF may thus have a role in attenuating the thrombocytopenia associated with acute myeloid leukemia (AML) and its therapy. However, there is concern that MGDF might induce AML blast proliferation and thereby increase the risk of treatment failure. To address this concern, we studied the expression of c-mpl mRNA and c-Mpl protein by blasts from AML patients. In addition we examined the in vitro effect of MGDF as well as the combined effect of MGDF and granulocyte colony-stimulating factor (G-CSF) or stem cell factor (SCF) on leukemic blast proliferation, recruitment into S-phase, induction of programmed cell death and activation of signal transducers and activators of transcription (STAT) proteins. Our results demonstrate that blasts from a substantial proportion of cases of AML express the receptor at either the mRNA or protein level. Moreover, the function of the MGDF receptor was demonstrated by activation of STAT proteins following exposure to MGDF. Nevertheless, blast proliferation in response to MGDF was rare, and the proliferative effect of MGDF was less than that of G-CSF or SCF. Furthermore, MGDF did not prevent programmed cell death induced by cytarabine. Finally, there appeared to be no correlation between receptor expression by AML blasts and functional response to MGDF. Based on these data, it would appear that clinical trials of MGDF may be undertaken safely in patients with AML.

Acute Disease↗
PubMed1997

Transmembrane domain of gp130 contributes to intracellular signal transduction in hepatic cells.

Interleukin-6 (IL-6) induces the expression of acute phase plasma protein genes in hepatic cells through the action of gp130, the signal-transducing subunit of the IL-6 receptor. To identify whether the transmembrane domain of gp130 is required for signaling function, cytoplasmic forms of gp130 were constructed that consisted of the tetramerizing N-terminal domain of Bcr linked to the transmembrane and cytoplasmic domains of gp130 (Bcr/gp130) or just to the cytoplasmic domain of gp130 (Bcr/gp130DeltaTM). The expression and function of both constructs were determined in transiently transfected COS-1 and HepG2 cells. Bcr/gp130 is capable of interacting with JAK1, JAK2, and TYK2; is constitutively active; and induces gene expression through IL-6-responsive elements. In contrast, Bcr/gp130DeltaTM, while expressed at a higher level than Bcr/gp130 and still able to interact with JAK1, is ineffective in recruiting the endogenous signal transduction pathways for inducing gene expression. However, Bcr/gp130DeltaTM initiates partial signaling in the presence of overexpressed JAK1 and TYK2, but not JAK2. The data suggest that the transmembrane domain of gp130 is necessary for signal transduction and determines the interaction with members of the Janus kinase family.

Animals↗
PubMed1997

Constitutive and impaired signaling of leptin receptors containing the Gln --> Pro extracellular domain fatty mutation.

Leptin (OB), an adipocyte-secreted circulating hormone, and its receptor (OB-R) are key components of an endocrine loop that regulates mammalian body weight. In this report we have analyzed signal transduction activities of OB-R containing the fatty mutation [OB-R(fa)], a single amino acid substitution at position 269 (Gln --> Pro) in the OB-R extracellular domain that results in the obese phenotype of the fatty rat. We find that this mutant receptor exhibits both ligand-independent transcriptional activation via interleukin 6 and hematopoietin receptor response elements and ligand-independent activation of signal transducer and activator of transcription (STAT) proteins 1 and 3. However, OB-R(fa) is unable to constitutively activate STAT5B and is highly impaired for ligand induced activation of STAT5B compared with OB-R(wt). Introduction of the fatty mutation into a OB-R/G-CSF-R chimera generates a receptor with constitutive character that is similar but distinct from that of OB-R(fa). Constitutive mutant OB-R(fa) receptor signaling is repressed by coexpression of OB-R(wt). The implications of an extracellular domain amino acid substitution generating a cytokine receptor with a partially constitutive phenotype are discussed both in terms of the mechanism of OB-R triggering and the biology of the fatty rat.

Animals↗
PubMed1997

Leptin receptor action in hepatic cells.

Leptin, an adipocyte-secreted hormone, is one of the central regulators of body weight homeostasis. In humans and rodents, two major forms of leptin receptors (OB-R) are expressed. The short form (OB-RS), considered to lack signaling capability, is detected in many organs. In contrast, OB-R long form (OB-RL) predominates in the hypothalamus, but is also present at low levels in peripheral tissues. Transient transfection experiments have demonstrated that OB-RL transduces an intracellular signaling similar to interleukin (IL)-6 type-cytokine receptors. To define the specificity by which OB-R induces genes and cooperates with signal transduction pathways utilized by other hormones and cytokines, rat and human hepatoma cell lines were generated which stably express human OB-RL. Hepatoma cell lines selected for appreciable levels of OB-RL mRNA display enhanced leptin binding and responded to leptin with an IL-6 receptor-like signaling that includes the activation of STAT proteins, induction of acute-phase plasma proteins, and synergism with IL-1 and tumor necrosis factor-alpha. A leptin-mediated recruitment of phosphatidylinositol 3-kinase to insulin receptor substrate-2 was also detected. However, no significant tyrosine phosphorylation of insulin receptor substrate-2 and modulation of the immediate cell response to insulin were observed. The data suggest that OB-RL action in hepatic cells is equivalent to that of IL-6 receptor. However, leptin does not play a specific role in muting insulin action on hepatoma cells and therefore may not contribute to the diabetic symptoms associated with obesity.

Acute-Phase Proteins↗
PubMed1997

Influence of subunit combinations on signaling by receptors for oncostatin M, leukemia inhibitory factor, and interleukin-6.

Oncostatin M (OSM), leukemia inhibitory factor (LIF), and interleukin-6 (IL-6) induce expression of a similar set of acute phase plasma protein genes in hepatic cells. The redundant action of these cytokines has been ascribed to the involvement of the common signal-transducing receptor subunit, gp130, in combination with cytokine-specific, ligand-binding subunits. To define the specificity of the signal transduction by the LIF/OSM receptor (a heterodimer of gp130 and LIF receptor (LIFR)) and the OSM-specific receptor (a heterodimer of gp130 and OSM receptor (OSMR)), we reconstituted the receptor function by transfection into receptor-negative Hep3B hepatoma cells. Both receptors activate DNA binding activity of STAT1, -3, and -5B and induce gene transcription through IL-6-responsive elements. The signaling-competent cytoplasmic domain regions of OSMR and LIFR were defined by the analysis of progressive carboxyl-terminal deletion constructs. The 36 residue carboxyl-terminal region containing the distal box 3 sequence motif of OSMR is required for signal transduction by the OSM-specific receptor. In contrast, signaling by LIFR did not display the same requirement for receptor domains and was not strictly dependent on the box 3 elements. The signaling by endogenous LIF and OSM receptors differed from that by IL-6R by the prominent activation of STAT5 as shown in the mouse hepatoma cell line, Hepa-1. The data suggest that the signaling specificity of the receptors for the three cytokines is determined by the composition of the cytoplasmic domains associated in the signal-competent receptor complex and that the signaling is not identical among these cytokine receptors.

Animals↗
PubMed1997

The carboxyl-terminal region of STAT3 controls gene induction by the mouse haptoglobin promoter.

Haptoglobin (HP) is one of the major acute phase plasma proteins in the mouse, and its synthesis is additively induced by interleukin (IL)-6 and glucocorticoids. STAT3 serves as the mediator of the IL-6 receptor signal and appears to contribute to the transcriptional induction of acute phase protein genes. The carboxyl-terminal region of STAT3, consisting of an acidic domain and containing a serine phosphorylation site, has been proposed to contribute to the induction process. To assess the role of STAT3 in the transcriptional control of the HP promoter, we applied two mutant forms of STAT3: one with a deletion of the carboxyl-terminal 55 amino acid residues, STAT3Delta55C, and the other with a substitution of serine 727 to alanine, STAT3SA. Like the wild-type STAT3, both mutant STAT3 forms are activated by the signal-transducing subunit of the IL-6 receptor, gp130, or by co-transfected IL-3 receptor. Ectopic expression and activation of wild-type STAT3 or STAT3SA in HepG2 hepatoma cells similarly enhance transcription through the IL-6-response element of the HP promoter. This enhancement is specific for STAT3 and cannot be reproduced by STAT1 or STAT5. In contrast, STAT3Delta55C inhibits IL-6-induced transcriptional activation. Interestingly, whereas receptor-activated STAT3 also enhances stimulation of the haptoglobin promoter by dexamethasone through the glucocorticoid receptor, activated STAT3Delta55C reduces the regulation below the level achieved by the glucocorticoid receptor alone. This transdominant action by STAT3Delta55C is dependent on a functional IL-6-responsive element. The data suggest that the carboxyl-terminal domain, but not its serine phosphorylation site of STAT3, is required for transcription as part of the hematopoietin receptor signaling as well as for cooperation with other transcription factors such as the glucocorticoid receptor.

Alanine↗
PubMed1997

Characterization of interleukin-10 receptor expression on B-cell chronic lymphocytic leukemia cells.

B-cell chronic lymphocytic leukemia (B-CLL) cells accumulate in vivo in the G0/G1 phase of the cell cycle, suggesting that their malignant expansion is due, at least in part, to a delay in cell death. However, the cellular or molecular factors responsible for a delay in B-CLL cell death are unknown. B-CLL cells do express receptors for interferon-alpha (IFN-alpha) and IFN-gamma, and activation of both has been shown to promote B-CLL survival in vitro by preventing apoptosis. The interleukin-10 (IL-10) receptor is another member of the IFN receptor family, but its ligand, IL-10, has been reported to induce apoptosis in B-CLL cells. In the current study, we undertook a biochemical analysis of IL-10 receptor expression on freshly isolated B-CLL cells and characterized the functional responsiveness of IL-10 binding to its constitutively expressed receptor. We show that B-CLL cells bind IL-10 with significant specificity and express between 47 and 127 IL-10 receptor sites per cell, with a dissociation constant in the range of 168 to 426 x 10(-12) mol/L. Ligand binding and activation of the IL-10 receptor expressed on B-CLL cells results in the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 proteins. This pattern of STAT protein phosphorylation is identical to IL-10 receptor activation on normal cells and similar to IFN-alpha (STAT1 and STAT3) and IFN-gamma (STAT1) receptor activation in CLL. Further, in consecutive samples of fresh blood obtained from patients with B-CLL cells, the addition of IL-10 inhibited B-CLL proliferation, enhanced B-CLL differentiation, but did not induce apoptosis. Indeed, IL-10, like IFN-gamma, was able to significantly reduce the amount of B-CLL cell death caused by hydrocortisone-induced apoptosis. We conclude that cytokines, which signal through the interferon family of receptors, have comparable functional effects on B-CLL cells.

B-Lymphocytes↗
PubMed1997

A potential role for interleukin-15 in the regulation of human natural killer cell survival.

Resting lymphocyte survival is dependent upon the expression of Bcl-2, yet the factors responsible for maintaining lymphocyte Bcl-2 protein expression in vivo are largely unknown. Natural killer (NK) cells are bone marrow-derived lymphocytes that constitutively express the beta and common gamma(c) subunits of the IL-2 receptor (R) as a heterodimer with intermediate affinity for IL-2. IL-15 also binds to IL-2Rbeta gamma(c) and is much more abundant in normal tissues than IL-2. Mice that lack the IL-2 gene have NK cells, whereas mice and humans that lack IL-2R gamma(c) do not have NK cells. Further, treatment of mice with an antibody directed against IL-2Rbeta results in a loss of the NK cell compartment. These data suggest that a cytokine other than IL-2, which binds to IL-2Rbeta gamma(c), is important for NK cell development and survival in vivo. In the current report, we show that the recently described IL-15R(alpha) subunit cooperates with IL-2Rbeta gamma(c) to transduce an intracellular signal at picomolar concentrations of IL-15. We demonstrate that resting human NK cells express IL-15R(alpha) mRNA and further, that picomolar amounts of IL-15 can sustain NK cell survival for up to 8 d in the absence of serum. NK cell survival was not sustained by other monocyte-derived factors (i.e., TNF-alpha, IL-1beta, IL-10, IL-12) nor by cytokines known to use gamma(c) for signaling (i.e., IL-4, IL-7, IL-9, IL- 13). One mechanism by which IL-15 promotes NK cell survival may involve the maintenance of Bcl-2 protein expression. Considering these functional properties of IL-15 and the fact that it is produced by bone marrow stromal cells and activated monocytes, we propose that IL-15 may function as an NK cell survival factor in vivo.

Animals↗
PubMed1997

Leptin receptor (OB-R) signaling. Cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization.

The leptin receptor (OB-R) mediates the weight regulatory effects of the adipocyte secreted hormone leptin (OB). Previously we have shown that the long form of OB-R, expressed predominantly in the hypothalamus, can mediate ligand-induced activation of signal transducer and activator of transcription factors 1, 3, and 5 and stimulate transcription via interleukin-6 and hematopoietin receptor responsive gene elements. Here we report that deletion and tyrosine substitution mutagenesis of OB-R identifies two distinct regions of the intracellular domain important for signaling. In addition, granulocyte-colony stimulatory factor receptor/OB-R and OB-R/granulocyte-colony stimulatory factor receptor chimeras are signaling competent and provide evidence that aggregation of two OB-R intracellular domains is sufficient for ligand-induced receptor activation. However, signaling by full-length OB-R appears to be relatively resistant to dominant negative repression by signaling-incompetent OB-R, suggesting that mechanisms exist to permit signaling by the long form of OB-R even in the presence [corrected] of excess naturally occurring short form of OB-R.

Animals↗
PubMed1997

Vesnarinone inhibits immune-mediated but not Fas (CD95) agonist-mediated hepatic injury.

Previous studies have shown that the administration of concanavalin A (ConA) into mice induces immune-mediated liver injury, which can be largely abrogated by neutralizing tumor necrosis factor(TNF)alpha. Vesnarinone is an experimental drug which is known to inhibit TNF alpha release. Here we demonstrate that vesnarinone inhibits ConA-induced hepatic injury. In a dose-dependent manner, vesnarinone inhibits in several mouse strains the increase of serum aminotransferase concentrations. additional experiments show that vesnarinone inhibits ConA-mediated accumulation of DNA fragmentation in the liver. Furthermore, the drug significantly reduces the levels of circulating TNF alpha and interleukin-6 (IL-6). Vesnarinone does not modulate TNF alpha and IL-6 action on hepatic cells, as shown by its failure to reduce the cytokine specific-stimulation of acute phase plasma proteins in the rat hepatoma H-35 cell line. Neither vesnarinone nor anti-TNF alpha protect against direct liver injury induced by a sublethal dose of agonist anti-Fas (CD95) antibody. Taken together, these results suggest that vesnarinone blocks hepatic injury, in part by inhibiting the release of TNF alpha in vivo.

Acute-Phase Reaction↗
PubMed1997

Which glycosaminoglycans are suitable for antithrombogenic or athrombogenic coatings of biomaterials? Part I: Basic concepts of immobilized GAGs on partially cationized cellulose membrane.

Six different GAGs of different natural origin such as unfractionated heparin (HE), chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), endothelial cell surface heparan sulfate (ESHS), and hyaluronan (HA) have been ionically immobilized onto partially cationized cellulose membranes with a substitution degree of 0.06. The GAGs have been characterized in terms of total sulfate content and relative molecular weight. The amount of immobilized GAGs was 10(3) times higher than the theoretical amount for monomolecular side-to-side coordination on polymer surfaces. In a standardized perfusion system with shear rates of 1050 sec-1, 37 degrees C, and 5 minutes with citrated blood, the level of platelet adhesion was 100% for partially cationized membrane, 90% for HA, 75% for each HE, CS, DS, KS, 5% for unmodified cellulose membrane, and 5% for confluent bovine aorta endothelial cells, referred to subendothelial matrix as standard for 100% platelet adhesion. ESHS-coated membranes were completely inert to platelets. The amount of ionically released GAGs during perfusion was also estimated. The partial cationic membrane is a suitable polymer surface in combination with the perfusion system to estimate the hemocompatibility of ionically immobilized water-soluble polyanions in terms of platelet adhesion at defined shear rates. The results of platelet adhesion are discussed in terms of structure and analytical parameter of the immobilized GAGs.

Animals↗