bluuebunny/crossref_metadata_2025_split huggingface dataset:
NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and organic solvents as the mechanism of chemical sensitivity in multiple chemical sensitivity
Authors: PALL MARTIN L. 
Published: August 2002

ABSTRACTMultiple chemical sensitivity (MCS) is a condition where previous exposure to hydrophobic organic solvents or pesticides appears to render people hypersensitive to a wide range of chemicals, including organic solvents. The hypersensitivity is often exquisite, with MCS individuals showing sensitivity that appears to be at least two orders of magnitude greater than that of normal individuals. This paper presents a plausible set of interacting mechanisms to explain such heightened sensitivity. It is based on two earlier theories of MCS: the elevated nitric oxide/peroxynitrite theory and the neural sensitization theory. It is also based on evidence implicating excessive NMDA activity in MCS. Four sensitization mechanisms are proposed to act synergistically, each based on known physiological mechanisms: Nitric oxide‐mediated stimulation of neurotransmitter (glutamate) release; peroxynitrite‐mediated ATP depletion and consequent hypersensitivity of NMDA receptors; peroxynitrite‐mediated increased permeability of the blood–brain barrier, producing increased accessibility of organic chemicals to the central nervous system; and nitric oxide inhibition of cytochrome P450 metabolism. Evidence for each of these mechanisms, which may also be involved in Parkinson's disease, is reviewed. These interacting mechanisms provide explanations for diverse aspects of MCS and a framework for hypothesis‐driven MCS research.—Pall, M. L. NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and organic solvents as the mechanism of chemical sensitivity in multiple chemical sensitivity. FASEB J. 16, 1407–1417 (2002)
In vivo gene transfer of soluble TNF‐α receptor 1 alleviates myocardial infarction
Authors: Sugano Masahiro , Koyanagi Masamichi , Tsuchida Keiko , Hata Tomoji , Makino Naoki 
Published: August 2002

ABSTRACTApoptosis is the major independent form of cardiomyocyte cell death in acute myocardial infarction (AMI). TNF‐α release early in the course of AMI contributes to myocardial injury, and TNF‐α induces apoptosis in cardiomyocytes. Soluble TNF‐alpha receptor 1 (sTNFR1) is an antagonist to TNF‐α. However, the effect of sTNFR1 on AMI remains unclear. Here we report that direct injection of an sTNFR1 expression plasmid DNA to the myocardium reduces infarct size in experimental rat AMI. Treatment with sTNFR1 expression plasmid DNA reduced the TNF‐α bioactivity in the myocardium and the apoptosis of cardiomyocytes. These findings suggest that the anti‐TNF‐α therapy by sTNFR1 can be a new strategy for treatment of AMI.
Extracellular signal‐regulated kinases phosphorylate 5lipoxygenase and stimulate 5‐lipoxygenase product formation in leukocytes
Authors: Werz Oliver , Bürkert Eva , Fischer Lutz , Szellas Dagmar , Dishart David , Samuelsson Bengt , Rådmark Olof , Steinhilber Dieter 
Published: August 2002

ABSTRACT5‐Lipoxygenase (5‐LO) is the key enzyme in the biosynthesis of proinflammatory leukotrienes. Here, we demonstrate that extracellular signal‐regulated kinases (ERKs) can phosphorylate 5‐LO in vitro. Efficient phosphorylation required the presence of unsaturated fatty acids and was abolished when Ser‐663 was mutated to alanine. In intact HeLa cells stimulated with arachidonic acid (AA), impaired 5‐LO product formation was evident in cells expressing the S663A‐5‐LO mutant compared with cells expressing wild‐type 5‐LO. For Mono Mac 6 cells, priming with phorbol myristate acetate (PMA) before stimulation with ionophore was required for ERK1/2 activation and efficient 5‐LO phosphorylation, in parallel with substantial AA release and 5‐LO product formation. Inhibition of PKC by GF109203x or MEK1/2 by U0126 (or PD98059) abolished the 5‐LO up‐regulation effects of PMA. In contrast, these inhibitors failed to suppress 5‐LO product formation induced by stimuli such as AA plus ionophore, which apparently do not involve the ERK1/2 pathway. Based on inhibitor studies, ERKs are also involved in AA‐stimulated 5‐LO product formation in PMNL, whereas a role for ERKs is not apparent in 5‐LO activation induced by ionophore or cell stress. Finally, the data suggest that ERKs and p38 MAPK‐regulated MAPKAPKs can act in conjunction to stimulate 5‐LO by phosphorylation.
Human TNF‐α in transgenic mice induces differential changes in redox status and glutathione‐regulating enzymes
Authors: Glosli Heidi , Tronstad Karl Johan , Wergedal Hege , Müller Fredrik , Svardal Asbjørn , Aukrust Pål , Berge Rolf Kristian , Prydz Hans 
Published: August 2002

ABSTRACTTumor necrosis factor α (TNF‐α) is a pleiotropic cytokine involved in several diseases. Various effects of TNF‐α are mediated by the induction of a cellular state consistent with oxidative stress. Glutathione (GSH) is a major redox‐buffer of eukaryotic cells and is important in the defense against oxidative stress. We hypothesized that persistent TNF‐α secretion could induce oxidative stress through modulation of GSH metabolism. This hypothesis was examined in a transgenic mouse model with low, persistent expression of human TNF‐α in the T cell compartment. Major findings were i) marked tissue‐specific changes in GSH redox status and GSH regulating enzymes, with the most pronounced changes in liver; ii) moderate changes in GSH metabolism and up‐regulation of GSH‐regulating enzymes were observed in lung and kidney from transgenic mice; and iii) liver, lung and kidney from transgenic mice had decreased levels of total glutathione, whereas splenic CD4+ and CD8+ T cells had a marked increase in oxidized glutathione as the major change.Oxidative stress induced by persistent low‐grade exposure to TNF‐α in transgenic mice appears to involve marked organ‐specific alterations in glutathione redox status and glutathioneregulating enzymes with the most pronounced changes in the liver. These mice constitute a useful model for immunodeficiency syndromes and chronic inflammatory diseases involving pathogenic interaction between TNF‐α and oxidative stress.
Androgen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motoneuronal processes
Authors: Piccioni Federica , Pinton Paolo , Simeoni Silvia , Pozzi Paola , Fascio Umberto , Vismara Guglielmo , Martini Luciano , Rizzuto Rosario , Poletti Angelo 
Published: August 2002

ABSTRACTThe CAG/polyglutamine (polyGln)‐related diseases include nine different members that together form the most common class of inherited neurodegenerative disorders; neurodegeneration is linked to the same type of mutation, found in unrelated genes, consisting of an abnormal expansion of a polyGln tract normally present in the wild‐type proteins. Nuclear, cytoplasmic, or neuropil aggregates are detectable in CAG/polyGln‐related diseases, but their role is still debated. Alteration of the androgen receptor (AR), one of these proteins, has been linked to spinal and bulbar muscular atrophy, an X‐linked recessive disease characterized by motoneuronal death. By using immortalized motoneuronal cells (the neuroblastoma‐spinal cord cell line NSC34), we analyzed neuropil aggregate formation and toxicity: green fluorescent protein‐tagged wild‐type or mutated ARs were cotransfected into NSC34 cells with a blue fluorescent protein tagged to mitochondria. Altered mitochondrial distribution was observed in neuronal processes containing aggregates; occasionally, neuropil aggregates and mitochondrial concentration corresponded to axonal swelling. Neuropil aggregates also impaired the distribution of the motor protein kinesin. These data suggest that neuropil aggregates may physically alter neurite transport and thus deprive neuronal processes of factors or components that are important for axonal and dendritic functions. The soma may then be affected, leading to neuronal dysfunctions and possibly to cell death.
Mechanical Stress‐induced DNA damage and rac‐p38MAPK Signal Pathways Mediate p53‐dependent Apoptosis in Vascular Smooth Muscle Cells
Authors: Mayr Manuel , Hu Yanhua , Hainaut Pierre , Xu Qingbo 
Published: August 2002

ABSTRACTRecently, we demonstrated that biomechanical stress induces apoptosis of vascular smooth muscle cells (SMCs) (Mayr et al., FASEB J. 2000; 15:261.270). In this article we investigated the molecular mechanisms of mechanical stress‐induced apoptosis. When SMCs were subjected to cyclic strain, tumor‐suppressor p53 was activated as evidenced by gel mobility shift assays and Western blot analyses. p53 activation was largely attenuated if SMCs were pretreated with SB202190, a specific p38MAPK inhibitor, or were stably transfected with dominant negative rac, an upstream signal transducer of p38MAPK pathways. Kinase assays provided direct evidence that p38MAPKs phosphorylated p53 within 30 min of cyclic strain. Additionally, mechanical stress resulted in oxidative DNA damage as detected by the presence of 8‐oxoguanine. Treatment with the antioxidant U‐74389G abrogated p53 activation. p53 activation was followed by expression and mitochondrial translocation of the proapoptotic protein Bax. Likewise, mechanical stress resulted in up‐regulation of anti‐apoptotic Bcl‐2 proteins, including Bcl‐2 and Bcl‐xL. However, a marked loss of mitochondrial membrane potential occurred in wild‐type, but not in p53−/−, SMCs. The latter lost their ability to express Bax and showed no apoptosis in response to cyclic strain. Taken together, our data provide the first evidence that SMC apoptosis induced by mechanical stress is p53‐dependent.
Glycosulfopeptides modeled on P‐selectin glycoprotein ligand‐1 inhibit P‐selectin‐dependent leukocyte rolling in vivo
Authors: Hicks Anne E.R. , Leppänen Anne , Cummings Richard D. , McEver Rodger P. , Hellewell Paul G. , Norman Keith E. 
Published: August 2002

ABSTRACTLeukocytic inflammation can be limited by inhibiting selectin‐dependent leukocyte rolling. In spite of intensive efforts to develop small molecule selectin inhibitors with defined structure‐activity profiles, inhibition of P‐selectin‐dependent leukocyte rolling in vivo by such a compound has yet to be described. We recently reported that glycosulfopeptides (GSP), modeled on the high affinity selectin ligand PSGL‐1, inhibit leukocyte binding to P‐selectin in vitro. Here, we have used intravital microscopy to investigate whether GSP can inhibit P‐selectin‐dependent leukocyte rolling in vivo. Surgical preparation of the mouse cremaster muscle for intravital microscopy induced P‐selectin‐dependent leukocyte rolling. Baseline rolling was recorded for 1 min followed by i.v. injection of GSP. 2‐GSP‐6 and 4‐GSP‐6 substantially reversed P‐selectindependent leukocyte rolling, whereas control GSP, which are not fully glycosylated, did not. Inhibition of leukocyte rolling by 2‐ and 4‐GSP‐6 lasted 2–4 min. Clearance studies with 125Ilabeled 4‐GSP‐6 demonstrated rapid reduction in its circulating levels concurrent with accumulation in urine. These data represent the first demonstration that a precisely defined structure based on a natural P‐selectin ligand can inhibit P‐selectin‐dependent leukocyte rolling in vivo.
Polycyclic aromatic hydrocarbons present in cigarette smoke cause endothelial cell apoptosis by a phospholipase A2dependent mechanism
Authors: Tithof Patricia K. , Elgayyar Mona , Cho Yeesook , Guan Wei , Fisher Aron B. , Peters‐Golden Marc 
Published: August 2002

ABSTRACTSmoking is a major risk factor for endothelial cell injury and subsequent coronary artery disease. Epidemiological studies implicate the phospholipase A2/arachidonic acid cascade in the mechanism by which smoking causes heart disease. However, specific components of cigarette smoke that activate this pathway have not been identified. The purpose of this study was to investigate the effects of polycyclic aromatic hydrocarbons contained in cigarette smoke on phospholipase A2 (PLA2) activity and apoptosis of human coronary artery endothelial cells. 1methylanthracene (1‐MA), phenanthrene (PA), and benzo(a)pyrene (B(a)P) caused significant release of 3H‐arachidonate from endothelial cells. 1‐MA and PA, but not B(a)P, also caused significant release of 3H‐linoleic acid. Release of fatty acids from membrane phospholipids preceded the onset of apoptosis. 3H‐arachidonate release and apoptosis induced by 1‐MA, B(a)P, and PA were inhibited by methylarachidonoyl‐fluorophosphonate, an inhibitor of Groups IV and VI PLA2s. Bromoenol lactone, an inhibitor of Group VI enzymes, inhibited both 3H‐arachidonate release and apoptosis induced by 1‐MA and PA, but not B(a)P. MJ33, an inhibitor of the acidic calcium‐independent PLA2, attenuated 3H‐arachidonate release and apoptosis by PA, but not 1MA or B(a)P. The presence of Groups IV and VI and the acidic iPLA2 in endothelial cells was demonstrated by reverse transcriptase‐polymerase chain reaction and Western analysis. These data suggest that 1‐MA, B(a)P and PA induce apoptosis of endothelial cells by a mechanism that involves activation of these three distinct isoforms of PLA2.
Innervation‐dependent phosphorylation and accumulation of αB–crystallin and Hsp27 as insoluble complexes in disused muscle
Authors: Kato Kanefusa , Ito Hidenori , Kamei Keiko , Iwamoto Ikuko , Inaguma Yutaka 
Published: August 2002

ABSTRACTLevels and phosphorylation states of the two small molecular chaperones, αB‐crystallin and Hsp27, in disused rat soleus muscles were determined by Western blot analysis of extracts with antibodies recognizing each of the two proteins and their phosphorylated serine residues. Increased phosphorylation and relocalization to insoluble fractions were found within a few days of hind‐limb suspension. High phosphorylation of αB‐crystallin at Ser‐59 (and to a certain extent, at Ser‐45) and of Hsp27 at Ser‐15 and Ser‐85, along with phosphorylated, active states of p38 and p44/42 mitogen‐activated protein kinases were maintained during hind‐limb suspension but promptly returned to control levels within a 5‐day recovery period. These results are similar to those observed with U373 MG glioma cells exposed to proteasome inhibitors (16). However, the responses of αB‐crystallin and Hsp27 in suspended soleus muscles did not appear with ipsilateral transection of the sciatic nerve trunk, indicating mediation by nerve activity. The fact that ubiquitinated proteins accumulated in the insoluble fractions of suspended soleus muscle further suggests participation of αB‐crystallin and Hsp27 in quality control of proteins in disused soleus muscle, with involvement of nerve activity‐dependent processes.
The human prostate cancer cell line LNCaP bears functional membrane testosterone receptors, which increase PSA secretion and modify actin cytoskeleton
Authors: Kampa M. , Papakonstanti E.A. , Hatzoglou A. , Stathopoulos E.N. , Stournaras C. , Castanas E. 
Published: August 2002

ABSTRACTRecent findings have shown that, in addition to the genomic action of steroids, through intracellular receptors, short‐time effects could be mediated through binding to membrane sites. In the present study of prostate cancer LNCaP cells, we report that dihydrotestosterone and the non‐internalizable analog testosterone‐BSA increase rapidly the release of prostate‐specific antigen (PSA) in the culture medium. Membrane testosterone binding sites were identified through ligand binding on membrane preparations, flow cytometry, and confocal laser microscopy of the non‐internalizable fluorescent analog testosterone‐BSA‐FITC, on whole cells. Binding on these sites is time‐ and concentration‐dependent and specific for testosterone, presenting a Kd of 10.9 nM and a number of 144 sites/mg protein (~13000 sites/cell). Membrane sites differ immunologically for intracellular androgen receptors. The secretion of PSA after membrane testosterone receptor stimulation was inhibited after pretreatment with the actin cytoskeleton disrupting agent cytochalasin B. In addition, membrane testosterone binding modifies the intracellular dynamic equilibrium of monomeric to filamentous actin and remodels profoundly the actin cytoskeleton organization. These results are discussed in the context of a possible involvement of these sites in cancer chemotherapy.
Interleukin‐1α (IL‐1α) promotes angiogenesis in vivo via VEGFR‐2 pathway by inducing inflammatory cell VEGF synthesis and secretion
Authors: Salven Petri , Hattori Koichi , Heissig Beate , Rafii Shahin 
Published: August 2002

ABSTRACTDuring inflammation, functional changes occur in the vasculature, including extensive endothelial cell mitotic activity and remodeling of capillaries. Interleukin‐1α. (IL‐1α) is a prototypical proinflammatory cytokine. Vascular endothelial growth factor (VEGF) is a strong endothelial cell‐specific mitogen that exerts a pivotal role in angiogenesis under physiological and pathological conditions. We show that IL‐1α stimulates VEGF secretion by human peripheral blood mononuclear cells (PBMNCs) in a dose‐dependent manner. This represents induction of de novo VEGF synthesis, as an induction of VEGF mRNA was observed. Also, the release of VEGF was blocked by cycloheximide. Reverse transcription‐polymerase chain reaction (RT‐PCR) detected four VEGF splice variants in unstimulated and in IL‐1α‐stimulated PBMNCs. in vivo in mice, subcutaneously administered IL‐1α caused a strong local angiogenic response, which was accompanied by an infiltrate of VEGF‐expressing inflammatory cells. The angiogenic effect of IL‐1α was blocked when the mice were treated with VEGF receptor 2 (VEGFR‐2) neutralizing antibodies. VEGFR‐1 blocking antibodies had a marginal inhibitory effect on IL‐1α‐induced angiogenesis. These observations indicate that IL‐1α induces angiogenesis by activating the VEGF‐VEGFR‐2 signaling pathway between inflammatory cells and blood vessel endothelial cells. This novel mechanism of IL‐1α‐action may enhance the shift to angiogenic phenotype in various conditions designated by excessive angiogenesis.
Delta opioid agonists and volatile anesthetics facilitate cardioprotection via potentiation of KATP channel opening
Authors: Patel Hemal H. , Ludwig Lynda M. , Fryer Ryan M. , Hsu Anna K. , Warltier David C. , Gross Garrett J. 
Published: August 2002

ABSTRACTOpioids and volatile anesthetics produce marked cardioprotective effects against myocardial infarction via the activation of ATP‐sensitive potassium (KATP) channels, however, the effect of combined treatment with both drugs is unknown. We examined the hypothesis that opioids and volatile anesthetics potentiate cardiac KATP channel opening, thereby enhancing cardioprotection. Rats were treated with the delta opioid agonists, TAN‐67 or BW373U86, or isoflurane, together or alone with and without diazoxide, a mitochondrial KATP channel opener. Glibenclamide, a non‐selective KATP channel blocker, was used to further characterize the signaling mechanism involved. Myocardial infarct size (IS) was determined by tetrazolium staining and was expressed as a percent of the area at risk (AAR). High doses of TAN‐67 (10 mg/kg), diazoxide (10 mg/kg), and isoflurane (1 MAC) produced a significant reduction in IS compared with the control group (30±3%, 36±5%, and 42±2 vs. 58±2%, respectively), whereas lower doses of the drugs had no effect except for the low dose of isoflurane (0.5 MAC). The combination of TAN‐67 and diazoxide or isoflurane and diazoxide resulted in a marked reduction in IS compared with controls in the presence of high (9±3% and 14±3%) and low (17±7% and 31±7%) dose combinations, respectively. The combination of TAN‐67 or BW373U86 and isoflurane also caused a striking reduction in IS/AAR (16±7% and 7±2%, respectively). To date, this is the first demonstration that opioids and volatile anesthetics work in conjunction to confer protection against myocardial infarction through potentiation of cardiac KATP channel opening.
Cleavage of hemoglobin by hookworm cathepsin D aspartic proteases and its potential contribution to host specificity
Authors: Williamson Angela L. , Brindley Paul J. , Abbenante Giovanni , Prociv Paul , Berry Colin , Girdwood Karen , Pritchard David I. , Fairlie David P. , Hotez Peter J. , Dalton John P. , Loukas Alex 
Published: August 2002

ABSTRACTHookworms routinely reach the gut of nonpermissive hosts but fail to successfully feed, develop, and reproduce. To investigate the effects of host‐parasite coevolution on the ability of hookworms to feed in nonpermissive hosts, we cloned and expressed aspartic proteases from canine and human hookworms. We show here that a cathepsin D‐like protease from the canine hookworm Ancylosotoma caninum (Ac‐APR‐1) and the orthologous protease from the human hookworm Necator americanus (Na‐APR‐1) are expressed in the gut and probably exert their proteolytic activity extracellularly. Both proteases were detected immunologically and enzymatically in somatic extracts of adult worms. The two proteases were expressed in baculovirus, and both cleaved human and dog hemoglobin (Hb) in vitro. Each protease digested Hb from its permissive host between twofold (whole molecule) and sixfold (synthetic peptides) more efficiently than Hb from the nonpermissive host, despite the two proteases' having identical residues lining their active site clefts. Furthermore, both proteases cleaved Hb at numerous distinct sites and showed different substrate preferences. The findings suggest that the paradigm of matching the molecular structure of the food source within a host to the molecular structure of the catabolic proteases of the parasite is an important contributing factor for host‐parasite compatibility and host species range.
Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: Implications for Parkinson's disease
Authors: Sriram Krishnan , Matheson Joanna M. , Benkovic Stanley A. , Miller Diane B. , Luster Michael I. , O'Callaghan James P. 
Published: August 2002

ABSTRACTThe pathogenic mechanisms underlying idiopathic Parkinson's disease (PD) remain enigmatic. Recent findings suggest that inflammatory processes are associated with several neurodegenerative disorders, including PD. Enhanced expression of the proinflammatory cytokine, tumor necrosis factor (TNF)‐α, has been found in association with glial cells in the substantia nigra of patients with PD. To determine the potential role for TNF‐α in PD, we examined the effects of the 1‐methyl‐4‐phenyl‐1,2,3,4‐tetrahydropyridine (MPTP), a dopaminergic neurotoxin that mimics some of the key features associated with PD, using transgenic mice lacking TNF receptors. Administration of MPTP to wild‐type (+/+) mice resulted in a time‐dependent expression of TNF‐α in striatum, which preceded the loss of dopaminergic markers and reactive gliosis. In contrast, transgenic mice carrying homozygous mutant alleles for both the TNF receptors (TNFR‐DKO), but not the individual receptors, were completely protected against the dopaminergic neurotoxicity of MPTP. The data indicate that the proinflammatory cytokine TNF‐α is an obligatory component of dopaminergic neurodegeneration. Moreover, because TNF‐α is synthesized predominantly by microglia and astrocytes, our findings implicate the participation of glial cells in MPTP‐induced neurotoxicity. Similar mechanisms may underlie the etiopathogenesis of PD.