Bleomycin upregulates gene expression of angiotensin-converting enzyme via mitogen-activated protein kinase and early growth response 1 transcription factor.

Pulmonary fibrosis is a progressive disorder characterized by the loss of alveolar architecture through epithelial and endothelial cell apoptosis and fibroblast proliferation. Recent studies showed that angiotensin-converting enzyme (ACE) activity is increased in fibrotic tissues, and ACE inhibitors administered in vivo ameliorate fibrosis, suggesting that ACE may play a critical role. However, the regulation of ACE expression is not well understood.

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors upregulate inducible NO synthase expression and activity in vascular smooth muscle cells.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase ameliorate atherosclerosis by both cholesterol-dependent and cholesterol-independent mechanisms. We examined whether HMG-CoA reductase inhibitors affect the expression and activity of inducible NO synthase (iNOS) in cultured rat aortic vascular smooth muscle (VSM) cells. Atorvastatin (34 to 68 micromol/L) markedly increased nitrite production, an increase that was essentially abrogated by the NO synthase inhibitor N(G)-monomethyl-L-arginine (500 micromol/L).

Randomized trial of filgrastim versus chemotherapy and filgrastim mobilization of hematopoietic progenitor cells for rescue in autologous transplantation.

Peripheral blood cell (PBC) rescue has become the mainstay for autologous transplantation in patients with lymphoma, multiple myeloma, and solid tumors. Different methods of hematopoietic progenitor cell (HPC) mobilization are in use without an established standard. Forty-seven patients with relapsed or refractory lymphoma received salvage chemotherapy and were randomized to have HPC mobilization using filgrastim [granulocyte-colony-stimulating factor (G-CSF)] alone for 4 days at 10 microg/kg per day (arm A) or cyclophosphamide (5 g/m(2)) and G-CSF at 10 microg/kg per day until hematologic recovery (arm B).

Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease.

Extracorporeal photochemotherapy (ECP) has been associated with clinical improvement in several patients with acute and chronic graft-versus-host disease (cGVHD) after allogeneic bone marrow transplantation, but the mechanism of action is unknown. This study tested the hypothesis that in patients with cGVHD, ECP modulates alloreactivity by affecting activated lymphocyte populations or by altering the interaction between effector lymphocytes and antigen-presenting cells (APCs). Ten patients who had refractory cGVHD were treated with ECP, and the clinical response to and immunologic effects of this therapy were assessed.

H(2)O(2) signals 5-HT-induced ERK MAP kinase activation and mitogenesis of smooth muscle cells.

Our previous studies have shown that 5-hydroxytryptamine (5-HT) induces cellular hyperplasia/hypertrophy through protein tyrosine phosphorylation, rapid formation of superoxide (O(2)(-)), and extracellular signal-regulated kinase (ERK)1/ERK2 mitogen-activated protein (MAP) kinase activation. Intracellularly released O(2)(-) is rapidly dismuted by superoxide dismutase (SOD) to H(2)O(2), another possible cellular growth mediator. In the present study, we assessed whether H(2)O(2) participates in 5-HT-induced mitogenic signaling.

A small molecule ligand of the glucagon-like peptide 1 receptor targets its amino-terminal hormone binding domain.

The glucagon-like peptide 1 receptor (GLP-1R) belongs to a distinct subgroup of G protein-coupled peptide hormone receptors (class B) that has been difficult to target by small molecule drugs. Here, we report that a non-peptide compound, T-0632, binds with micromolar affinity to the human GLP-1R and blocks GLP-1-induced cAMP production. Furthermore, the observation that T-0632 has almost 100-fold selectivity for the human versus the highly homologous rat GLP-1R provided an opportunity to map determinants of non-peptide binding.

Differences in synovial fluid levels of matrix metalloproteinases suggest separate mechanisms of pathogenesis in Lyme arthritis before and after antibiotic treatment.

The cause of persistent arthritis in patients with Lyme disease who have received standard antibiotic therapy remains an area of debate. In this study, synovial fluid levels of matrix metalloproteinases (MMPs) were compared in persons with untreated and antibiotic-resistant Lyme arthritis. Levels of MMP-1 and MMP-3, as determined by ELISA, were higher in untreated patients (P=.

Mechanisms of neutrophil apoptosis in uremia and relevance of the Fas (APO-1, CD95)/Fas ligand system.

The regulation of neutrophil apoptosis in chronic renal failure (CRF) has not been clearly defined. The Fas/FasL system is an important apoptotic regulatory pathway in a wide variety of cells. Fas is a widely expressed cell surface protein that transduces an apoptotic signal after interaction with its natural ligand FasL.

Neuropeptide Y has a central inhibitory action on the hypothalamic-pituitary-thyroid axis.

Recent evidence suggests that neuropeptide Y (NPY), originating in neurons in the hypothalamic arcuate nucleus, is an important mediator of the effects of leptin on the central nervous system. As these NPY neurons innervate hypophysiotropic neurons in the hypothalamic paraventricular nucleus (PVN) that produce the tripeptide, TRH, we raised the possibility that NPY may be responsible for resetting of the hypothalamic-pituitary-thyroid (HPT) axis during fasting. To test this hypothesis, the effects of intracerebroventricularly administered NPY on circulating thyroid hormone levels and proTRH messenger RNA in the PVN were studied by RIA and in situ hybridization histochemistry, respectively.

Functional testing of putative oligopeptide permease (Opp) proteins of Borrelia burgdorferi: a complementation model in opp(-) Escherichia coli.

Studies of the protein function of Borrelia burgdorferi have been limited by a lack of tools for manipulating borrelial DNA. We devised a system to study the function of a B. burgdorferi oligopeptide permease (Opp) orthologue by complementation with Escherichia coli Opp proteins.

Oxidative protein cross-linking reactions involving L-tyrosine in transforming growth factor-beta1-stimulated fibroblasts.

The mechanisms by which ligand-stimulated generation of reactive oxygen species in nonphagocytic cells mediate biologic effects are largely unknown. The profibrotic cytokine, transforming growth factor-beta1 (TGF-beta1), generates extracellular hydrogen peroxide (H2O2) in contrast to intracellular reactive oxygen species production by certain mitogenic growth factors in human lung fibroblasts. To determine whether tyrosine residues in fibroblast-derived extracellular matrix (ECM) proteins may be targets of H2O2-mediated dityrosine-dependent cross-linking reactions in response to TGF-beta1, we utilized fluorophore-labeled tyramide, a structurally related phenolic compound that forms dimers with tyrosine, as a probe to detect such reactions under dynamic cell culture conditions.

Phosphorylation of xanthine dehydrogenase/oxidase in hypoxia.

The enzyme xanthine oxidase (XO) has been implicated in the pathogenesis of several disease processes, such as ischemia-reperfusion injury, because of its ability to generate reactive oxygen species. The expression of XO and its precursor xanthine dehydrogenase (XDH) is regulated at pre- and posttranslational levels by agents such as lipopolysaccharide and hypoxia. Posttranslational modification of the protein, for example through thiol oxidation or proteolysis, has been shown to be important in converting XDH to XO.

Apoptosis of leukocytes: basic concepts and implications in uremia.

Circulating blood leukocytes have short life expectancies and end their lives by committing programmed cell death or apoptosis. Apoptosis is an active form of cell death that is initiated by a number of stimuli and is intricately regulated. Apoptosis in both excessive and reduced amounts has pathological implications.

Hypothalamic dorsomedial nucleus neurons innervate thyrotropin-releasing hormone-synthesizing neurons in the paraventricular nucleus.

To determine whether the hypothalamic dorsomedial nucleus (DMN) may serve as a relay center for the central actions of leptin on thyrotropin-releasing hormone (TRH)-synthesizing neurons in the paraventricular nucleus (PVN), axonal projections from the DMN to TRH-containing neurons in the PVN were studied using the anterogradely transported marker substance, Phaseolus vulgaris-leucoagglutinin (PHA-L). Stereotaxic injections of PHA-L were targeted to the mid-dorsal and mid-ventral portions of the DMN. After 10-14-day survival, the brains were prepared for immunohistochemistry and immunostained with an antibody directed against PHA-L.

Evaluation of study patients with Lyme disease, 10-20-year follow-up.

To determine the long-term impact of Lyme disease, we evaluated 84 randomly selected, original study patients from the Lyme, Connecticut, region who had erythema migrans, facial palsy, or Lyme arthritis 10-20 years ago and 30 uninfected control subjects. The patients in the 3 study groups and the control group did not differ significantly in current symptoms or neuropsychological test results. However, patients with facial palsy, who frequently had more widespread nervous system involvement, more often had residual facial or peripheral nerve deficits.

Endogenous antipyretics.

Fever is the hallmark of the stereotyped host response to microbial infection, although it is just one of a number of high-risk strategies employed by the infected host to clear itself of invading pathogens. The febrile response is accompanied by activation of multiple endogenous antipyretic systems that serve to suppress its magnitude or duration. These include neuroactive substances of neural and humoral origin, some of which (e.

Chronic graft-versus-host disease-related polymyositis as a cause of respiratory failure following allogeneic bone marrow transplant.

An unusual case of respiratory failure and dropped head syndrome as a complication of severe chronic graft-versus-host disease (GVHD)-related polymyositis is described. The patient required tracheostomy and mechanical ventilation but recovered following treatment with aggressive immunosuppression and intensive rehabilitation. The differential diagnoses of muscle weakness in the bone marrow transplant (BMT) patient and the dropped head syndrome are both discussed.

Reactive oxygen species in cell signaling.

Reactive oxygen species (ROS) are generated as by-products of cellular metabolism, primarily in the mitochondria. When cellular production of ROS overwhelms its antioxidant capacity, damage to cellular macromolecules such as lipids, protein, and DNA may ensue. Such a state of "oxidative stress" is thought to contribute to the pathogenesis of a number of human diseases including those of the lung.

Serum soluble Fas (CD95) and Fas ligand profiles in chronic kidney failure.

Apoptosis, or programmed cell death, is an active form of cell death that is initiated by a number of stimuli and is intricately regulated. Apoptosis in both excessive and reduced amounts has pathophysiologic implications. Accelerated programmed cell death has been observed in leukocytes among patients with chronic renal failure (CRF).

Estimating future hepatitis C morbidity, mortality, and costs in the United States.

Objectives: This study estimated future morbidity, mortality, and costs resulting from hepatitis C virus (HCV).

Methods: We used a computer cohort simulation of the natural history of HCV in the US population.

Results: From the year 2010 through 2019, our model projected 165,900 deaths from chronic liver disease, 27,200 deaths from hepatocellular carcinoma, and $10.

Regulation of STAT3 by direct binding to the Rac1 GTPase.

The signal transducers and activators of transcription (STAT) transcription factors become phosphorylated on tyrosine and translocate to the nucleus after stimulation of cells with growth factors or cytokines. We show that the Rac1 guanosine triphosphatase can bind to and regulate STAT3 activity. Dominant negative Rac1 inhibited STAT3 activation by growth factors, whereas activated Rac1 stimulated STAT3 phosphorylation on both tyrosine and serine residues.

Ras-dependent and -independent regulation of reactive oxygen species by mitogenic growth factors and TGF-beta1.

Mitogenic growth factors and transforming growth factor beta1 (TGF-beta1) induce the generation of reactive oxygen species (ROS) in nonphagocytic cells, but their enzymatic source(s) and regulatory mechanisms are largely unknown. We previously reported on the ability of TGF-beta1 to activate a cell surface-associated NADH:flavin:O(2) oxidoreductase (NADH oxidase) that generates extracellular H(2)O(2). In this study, we compared the ROS-generating enzymatic systems activated by mitogenic growth factors and TGF-beta1 with respect to the primary reactive species produced (O(2)(.

CCK receptor polymorphisms: an illustration of emerging themes in pharmacogenomics.

Polymorphisms in G-protein-coupled receptors can alter drug affinity and/or activity. In addition, genetic differences in amino acid sequences can induce ligand-independent signaling, which in turn can lead to disease. With growing efforts in the field of pharmacogenomics, it is anticipated that polymorphism-induced alterations in drug and/or receptor function will be a focus of increasing concern during the course of future drug-development efforts.

Mediation of Cryptosporidium parvum infection in vitro by mucin-like glycoproteins defined by a neutralizing monoclonal antibody.

The protozoan parasite Cryptosporidium parvum is a significant cause of diarrheal disease worldwide. Attachment to and invasion of host intestinal epithelial cells by C. parvum sporozoites are crucial steps in the pathogenesis of cryptosporidiosis.