bluuebunny/crossref_metadata_2025_split huggingface dataset:
Are chemokines the third major system in the brain?
Authors: Adler Martin W , Rogers Thomas J 
Published: October 2005

AbstractChemokines are a family of small proteins involved in cellular migration and intercellular communication. Although the chemokines and their receptors are located throughout the brain, they are not distributed uniformly. Among the chemokines and their receptors that are arrayed disproportionately in glia and neurons are monocyte chemotactic protein-1/CC chemokine ligand 2 (CCL2), stromal cell-derived factor-1/CXC chemokine ligand 12 (CXCL12), fractalkine/CX3C chemokine ligand 1, interferon-γ-inducible-protein-10/CXCL10, macrophage inflammatory protein-1α/CCL3, and regulated on activation, normal T cell expressed and secreted/CCL5. In the brain, they are found in the hypothalamus, nucleus accumbens, limbic system, hippocampus, thalamus, cortex, and cerebellum. The uneven distribution suggests that there may be functional roles for the chemokine “system,” comprised of chemokine ligands and their receptors. In addition to anatomical, immunohistochemical, and in vitro studies establishing the expression of the chemokine ligands and receptors, there is an increasing body of research that suggests that the chemokine system plays a crucial role in brain development and function. Our data indicate that the chemokine system can alter the actions of neuronally active pharmacological agents including the opioids and cannabinoids. Combined with evidence that the chemokine system in the brain interacts with neurotransmitter systems, we propose the following hypothesis: The endogenous chemokine system in the brain acts in concert with the neurotransmitter and neuropeptide systems to govern brain function. The chemokine system can thus be thought of as the third major transmitter system in the brain.
Leukocytes in the regulation of pain and analgesia
Authors: Rittner H L , Machelska H , Stein C 
Published: October 2005

AbstractWhen tissue is destroyed or invaded by leukocytes in inflammation, numerous mediators are delivered by the circulation and/or liberated from resident and immigrated cells at the site. Proalgesic mediators include proinflammatory cytokines, chemokines, protons, nerve growth factor, and prostaglandins, which are produced by invading leukocytes or by resident cells. Less well known is that analgesic mediators, which counteract pain, are also produced in inflamed tissues. These include anti-inflammatory cytokines and opioid peptides. Interactions between leukocyte-derived opioid peptides and opioid receptors can lead to potent, clinically relevant inhibition of pain (analgesia). Opioid receptors are present on peripheral endings of sensory neurons. Opioid peptides are synthesized in circulating leukocytes, which migrate to inflamed tissues directed by chemokines and adhesion molecules. Under stressful conditions or in response to releasing agents (e.g., corticotropin-releasing factor, cytokines, noradrenaline), leukocytes can secrete opioids. They activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuropeptides. This review presents discoveries that led to the concepts of pain generation by mediators secreted from leukocytes and of analgesia by immune-derived opioids.
Aberrant expression of neutrophil and macrophage-related genes in a murine model for human neutrophil-specific granule deficiency
Authors: Gombart Adrian F , Krug Utz , O'Kelly James , An Eun , Vegesna Vijaya , Koeffler H Phillip 
Published: October 2005

AbstractNeutrophil-specific granule deficiency involves inheritance of germline mutations in the CCAAT/enhancer-binding protein ε (C/EBPE) gene. Humans and mice lacking active C/EBPε suffer frequent bacterial infections as a result of functionally defective neutrophils and macrophages. We hypothesized that these defects reflected dysregulation of important immune response genes. To test this, gene expression differences of peritoneally derived neutrophils and macrophages from C/EBPε−/− and wild-type mice were determined with DNA microarrays. Of 283 genes, 146 known genes and 21 expressed sequence tags (ESTs) were down-regulated, and 85 known genes and 31 ESTs were up-regulated in the C/EBP−/− mice. These included genes involved in cell adhesion/chemotaxis, cytoskeletal organization, signal transduction, and immune/inflammatory responses. The cytokines CC chemokine ligand 4, CXC chemokine ligand 2, and interleukin (IL)-6, as well as cytokine receptors IL-8RB and granulocyte-colony stimulating factor, were down-regulated. Chromatin immunoprecipitation analysis identified binding of C/EBPε to their promoter regions. Increased expression for lipid metabolism genes apolipoprotein E (APOE), scavenger receptor class B-1, sorting protein-related receptor containing low-density lipoprotein receptor class A repeat 1, and APOC2 in the C/EBPε−/− mice correlated with reduced total cholesterol levels in these mice before and after maintenance on a high-fat diet. Also, C/EBPε-deficient macrophages showed a reduced capacity to accumulate lipids. In summary, dysregulation of numerous, novel C/EBPε target genes impairs innate immune response and possibly other important biological processes mediated by neutrophils and macrophages.
Distribution and leukocyte contacts of γδ T cells in the lung
Authors: Wands J M , Roark Christina L , Aydintug M Kemal , Jin Niyun , Hahn Youn-Soo , Cook Laura , Yin Xiang , Dal Porto Joseph , Lahn Michael , Hyde Dallas M , Gelfand Erwin W , Mason Robert J , O'Brien Rebecca L , Born Willi K 
Published: October 2005

AbstractPulmonary γδ T cells protect the lung and its functions, but little is known about their distribution in this organ and their relationship to other pulmonary cells. We now show that γδ and αβ T cells are distributed differently in the normal mouse lung. The γδ T cells have a bias for nonalveolar locations, with the exception of the airway mucosa. Subsets of γδ T cells exhibit further variation in their tissue localization. γδ and αβ T cells frequently contact other leukocytes, but they favor different cell-types. The γδ T cells show an intrinsic preference for F4/80+ and major histocompatibility complex class II+ leukocytes. Leukocytes expressing these markers include macrophages and dendritic cells, known to function as sentinels of airways and lung tissues. The continuous interaction of γδ T cells with these sentinels likely is related to their protective role.
Spontaneous neutrophil apoptosis and regulation of cell survival by granulocyte macrophage-colony stimulating factor
Authors: Kobayashi Scott D , Voyich Jovanka M , Whitney Adeline R , DeLeo Frank R 
Published: October 2005

AbstractPolymorphonuclear leukocytes (PMNs or neutrophils) are the most prominent cellular component of the innate immune system in humans and produce an array of potent cytotoxic molecules. It is important that neutrophils undergo constitutive (spontaneous) apoptosis as a mechanism to facilitate normal cell turnover and immune system homeostasis. Conversely, several proinflammatory cytokines, including granulocyte macrophage-colony stimulating factor (GM-CSF), prolong neutrophil survival. The molecular mechanisms that regulate PMN apoptosis or survival remain incompletely defined. To that end, we compared global gene expression in human neutrophils during spontaneous apoptosis with that in cells cultured with human GM-CSF. Genes encoding proteins that inhibit apoptosis, such as myeloid cell leukemia sequence 1, caspase 8 and Fas-associated via death domain-like apoptosis regulator (CFLAR), B cell chronic lymphocytic leukemia/lymphoma 2 (BCL2)/adenovirus E1B 19 kDa-interacting protein 2 (BNIP2), and serum/glucocorticoid-regulated kinase (SGK), were down-regulated coincident with neutrophil apoptosis. In contrast, those encoding apoptosis inhibitor 5, BCL2-like 1, BNIP2, CFLAR, SGK, and tumor necrosis factor α-induced protein 8 were up-regulated in PMNs cultured with GM-CSF. Correspondingly, GM-CSF delayed PMN apoptosis (P&lt;0.03), increased cell viability (P&lt;0.03), and prolonged neutrophil phagocytic capacity (P&lt;0.05). Prolonged functional capacity was paralleled by striking up-regulation of proinflammatory genes and proteins, including CD14, CD24, CD66, and human leukocyte antigen-DR. In addition, expression of SGK protein diminished during PMN apoptosis but was restored by culture with GM-CSF, suggesting SGK is involved in leukocyte survival. These studies provide a global view of the molecular events that regulate neutrophil survival and apoptosis.
Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo
Authors: Delgado Mario , Chorny Alejo , Gonzalez-Rey Elena , Ganea Doina 
Published: October 2005

AbstractCD4+CD25+ regulatory T (Treg) cells control the immune response to a variety of antigens, including self-antigens, and several models support the idea of the peripheral expansion of CD4+CD25+ Treg cells. Although hormones such as estrogen and α-melanocyte-stimulating hormone have been recently reported to expand the CD4+CD25+ Foxp3-expressing Treg cell compartment, little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4+CD25+ Treg cells. In this study, we report on the capacity of the vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, to induce functional Treg cells in vivo. The administration of VIP together with specific antigen to T cell receptor (TCR)-transgenic (Tg) mice results in the expansion of the CD4+CD25+, Foxp-3/neuropilin 1-expressing T cells, which inhibit responder T cell proliferation through direct cellular contact. In addition to the increase in the number of CD4+CD25+ Treg cells, VIP induces more efficient suppressors on a per-cell basis. The VIP-generated CD4+CD25+ Treg cells transfer suppression, inhibit delayed-type hypersensitivity in TCR-Tg hosts, and prevent graft-versus-host disease in irradiated hosts reconstituted with allogeneic bone marrow.
Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction
Authors: Haorah J , Knipe B , Leibhart J , Ghorpade A , Persidsky Y 
Published: October 2005

AbstractBrain microvascular endothelial cells (BMVEC) connected by tight junctions (TJ) form a tight monolayer at the blood-brain barrier (BBB). We investigated the idea that BBB dysfunction seen in alcohol abuse is associated with oxidative stress stemming from ethanol (EtOH) metabolism in BMVEC. Exposure to EtOH induced catalytic activity/expression of EtOH-metabolizing enzymes, which paralleled enhanced generation of reactive oxygen species (ROS). EtOH-mediated oxidative stress led to activation of myosin light chain (MLC) kinase, phosphorylation of MLC and TJ proteins, decreased BBB integrity, and enhanced monocyte migration across BBB. Acetaldehyde or ROS donors mimicked changes induced by EtOH in BMVEC. Thus, oxidative stress resulting from alcohol metabolism in BMVEC can lead to BBB breakdown in alcohol abuse, serving as an aggravating factor in neuroinflammatory disorders.
Viral strategies for evading antiviral cellular immune responses of the host
Authors: Iannello Alexandre , Debbeche Olfa , Martin Elodie , Attalah Lynda Habiba , Samarani Suzanne , Ahmad Ali 
Published: October 2005

Abstract
The host invariably responds to infecting viruses by activating its innate immune system and mounting virus-specific humoral and cellular immune responses. These responses are aimed at conrolling viral replication and eliminating the infecting virus from the host. However, viruses have evolved numerous strategies to counter and evade host's antiviral responses. Providing specific examples from the published literature, we discuss in this review article various strategies that viruses have developed to evade antiviral cellular responses of the host. Unraveling these viral strategies allows a better understanding of the host-pathogen interactions and their coevolution. This knowledge is important for identifying novel molecular targets for developing antiviral reagents. Finally, it may also help devise new knowledge-based strategies for developing antiviral vaccines.
Structural organization of the neutrophil NADPH oxidase: phosphorylation and translocation during priming and activation
Authors: Sheppard Forest R , Kelher Marguerite R , Moore Ernest E , McLaughlin Nathan J D , Banerjee Anirban , Silliman Christopher C 
Published: October 2005

AbstractThe reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is part of the microbicidal arsenal used by human polymorphonuclear neutrophils (PMNs) to eradicate invading pathogens. The production of a superoxide anion (O2–) into the phagolysosome is the precursor for the generation of more potent products, such as hydrogen peroxide and hypochlorite. However, this production of O2– is dependent on translocation of the oxidase subunits, including gp91phox, p22phox, p47phox, p67phox, p40phox, and Rac2 from the cytosol or specific granules to the plasma membrane. In response to an external stimuli, PMNs change from a resting, nonadhesive state to a primed, adherent phenotype, which allows for margination from the vasculature into the tissue and chemotaxis to the site of infection upon activation. Depending on the stimuli, primed PMNs display altered structural organization of the NADPH oxidase, in that there is phosphorylation of the oxidase subunits and/or translocation from the cytosol to the plasma or granular membrane, but there is not the complete assembly required for O2– generation. Activation of PMNs is the complete assembly of the membrane-linked and cytosolic NADPH oxidase components on a PMN membrane, the plasma or granular membrane. This review will discuss the individual components associated with the NADPH oxidase complex and the function of each of these units in each physiologic stage of the PMN: rested, primed, and activated.
Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury byPropioni- bacterium acnes
Authors: Romics Laszlo , Dolganiuc Angela , Velayudham Arumugam , Kodys Karen , Mandrekar Pranoti , Golenbock Douglas , Kurt-Jones Evelyn , Szabo Gyongyi 
Published: October 2005

AbstractRecognition of Gram-positive bacteria by Toll-like receptor 2 (TLR2) induces activation of proinflammatory pathways. In mice, sensitization with the Gram-positive Propionibacterium acnes followed by a challenge with the TLR4 ligand, lipopolysaccharide (LPS), results in fulminant hepatic failure. Here, we investigated the role of TLR2 in liver sensitization to LPS-induced injury. Stimulation of Chinese hamster ovary cells and peritoneal macrophages with heat-killed P. acnes required expression of TLR2 but not of TLR4, suggesting that P. acnes was a TLR2 ligand. Cell activation by P. acnes was myeloid differentiation primary-response protein 88 (MyD88)-dependent, and it was augmented by coexpression of CD14 in mouse peritoneal macrophages. In vitro, P. acnes behaved as a TLR2 ligand and induced TLR4 hetero- and TLR2 homotolerance in peritoneal macrophages. In vivo priming of wild-type mice with P. acnes, but not with the selective TLR2 ligands peptidoglycan and lipotheicoic acid, resulted in hepatocyte necrosis, hyperelevated serum levels of tumor necrosis factor α (TNF-α), interleukin (IL)-6, interferon-γ (IFN-γ), and IL-12 (p40/p70), and increased RNA expression of proinflammatory cytokines (IL-12p40, IL-1α, IL-6, IL-1β, IL-18, IFN-γ) in the liver after a LPS challenge. Furthermore, P. acnes priming sensitized TLR2-deficient (TLR2−/−) but not MyD88−/− mice to LPS-induced injury, evidenced by hepatocyte necrosis, increased levels of serum TNF-α, IFN-γ, IL-6, and liver proinflammatory cytokine mRNA expression. IFN-γ, a cytokine sensitizing to endotoxin, was induced by P. acnes in splenocytes of TLR2−/− and TLR9−/− but not MyD88−/− mice. These results suggest that although P. acnes triggers TLR2-mediated cell activation, TLR2-independent but MyD88-dependent mechanisms mediate in vivo sensitization by P. acnes for LPS-induced liver injury.
Different signaling pathways inhibit DNA methylation activity and up-regulate IFN-γ in human lymphocytes
Authors: Bonilla-Henao Victoria , Martínez Raquel , Sobrino Francisco , Pintado Elizabeth 
Published: October 2005

AbstractDNA methylation is recognized increasingly for its prominent role in controlling diverse immune processes. In this study, we show that in Jurkat T cells and fresh peripheral lymphocytes, short-time incubation with protein kinase C activators or phosphatase inhibitors down-regulate DNA methylation activity in a dose-dependent manner. This inhibition correlates with the induction of the interferon-γ (IFN-γ) gene, which contains several CG sequences in its promoter. The expression of mRNA and protein of the different DNA methyltransferases did not decrease after the treatment. In addition, sulfydryl reagents have a strong inhibitory effect on DNA methylation activity and also induce IFN-γ gene expression, thus suggesting a link between both effects.
Effects of Short-Term Experimental Insulin Resistance and Family History of Diabetes on Pancreatic β-Cell Function in Nondiabetic Individuals
Authors: Rasouli Neda , Hale Terri , Kahn Steven E. , Spencer Horace J. , Elbein Steven C. 
Published: October 2005

Context: Normal glucose homeostasis is maintained despite reductions in insulin sensitivity by increasing insulin secretion. This ability to compensate for reduced insulin sensitivity is highly heritable, but the mechanisms for this compensation or its failure in type 2 diabetes (T2DM) are unknown.
Objective: The objective of this study was to test whether individuals with a family history of T2DM have a fixed decrease in β-cell mass or function that would be revealed as an impaired insulin secretory response to short-term insulin resistance.
Design: Glucose tolerance, insulin sensitivity (SI), and insulin response to iv glucose (AIRG) were compared in nondiabetic individuals with and without a family history of diabetes before and after nicotinic acid (NA) treatment.
Setting: This study was performed at the Ambulatory General Clinical Research Center.
Subjects: Healthy, nonobese, nondiabetic individuals with or without a family history of T2DM were studied.
Interventions: Oral NA was given, with a final dose of 2 g/d, for at least 7 d.
Main Outcome Measure: The main outcome measure was the disposition index (insulin sensitivity × insulin response) in response to NA.
Results: Postchallenge plasma glucose levels rose during NA therapy regardless of family history. Neither group adequately increased their AIRG to maintain the disposition index. Family members did not differ from controls at baseline or after NA treatment for any outcome measure, but only 28 of 52 subjects experienced a 25% or greater fall in SI with NA treatment.
Conclusions: Short-term β-cell compensation to NA-induced insulin resistance was incomplete and did not differ by genetic predisposition. A genetic defect controlling β-cell growth in response to chronic insulin resistance better explains differences in the ability to compensate for insulin resistance than an inherited, fixed defect in β-cell mass.
Hypothalamus-Pituitary-Adrenal Hyperactivity in Human Aging Is Partially Refractory to Stimulation by Mineralocorticoid Receptor Blockade
Authors: Giordano Roberta , Bo Mario , Pellegrino Micaela , Vezzari Marco , Baldi Matteo , Picu Andreea , Balbo Marcella , Bonelli Lorenza , Migliaretti Giuseppe , Ghigo Ezio , Arvat Emanuela 
Published: October 2005

Context: The hypothalamus-pituitary-adrenal (HPA) axis is mainly regulated by CRH, arginine vasopressin, and glucocorticoid feedback. Hippocampal mineralocorticoid receptors mediate proactive glucocorticoid feedback and mineralocorticoid antagonists, accordingly, stimulate HPA axis. Age-related HPA hyperactivity reflects impaired glucocorticoid feedback at the suprapituitary level.
Design: ACTH, cortisol, and dehydroepiandrosterone (DHEA) secretion were studied in eight healthy elderly (75.1 ± 3.2 yr) and eight young (25.0 ± 4.6 yr) subjects during placebo or canrenoate (CAN) administration (200 mg iv bolus followed by 200 mg infused over 4 h).
Results: During placebo administration, ACTH and cortisol areas under the curve (AUCs) in elderly subjects were higher than in young subjects (P ≤ 0.01); conversely, DHEA AUCs in elderly subjects were lower than in young subjects (P = 0.002). CAN increased ACTH, cortisol, and DHEA levels in both groups. In young subjects, ACTH, cortisol, and DHEA levels at the end of CAN infusion were higher (P ≤ 0.05) than after placebo. In elderly subjects, at the end of CAN infusion, ACTH, cortisol, and DHEA levels were higher (P = 0.01) than after placebo. Under CAN, ACTH and cortisol AUCs were persistently higher (P ≤ 0.01) and DHEA AUCs lower (P = 0.006) in elderly than in young subjects. Cortisol AUCs after CAN in young subjects did not become significantly different from those in elderly subjects after placebo.
Conclusions: 1) Evening-time ACTH and cortisol secretion in elderly subjects is higher than in young subjects; 2) ACTH and cortisol secretion in elderly subjects is enhanced by CAN but less than that in young subjects; and 3) DHEA hyposecretion in elderly subjects is partially restored by mineralocorticoid antagonism. Age-related variations of HPA activity may be determined by some derangement in mineralocorticoid receptors function at the hippocampal level.
Prognostic Factors for Persistent or Recurrent Disease of Papillary Thyroid Carcinoma with Neck Lymph Node Metastases and/or Tumor Extension beyond the Thyroid Capsule at Initial Diagnosis
Authors: Leboulleux Sophie , Rubino Carole , Baudin Eric , Caillou Bernard , Hartl Dana M. , Bidart Jean-Michel , Travagli Jean-Paul , Schlumberger Martin 
Published: October 2005

Context: Reliable prognostic factors are needed in papillary thyroid cancer patients to adapt initial therapy and follow-up schemes to the risks of persistent and recurrent disease.
Objective and Settings: To evaluate the respective prognostic impact of the extent of lymph node (LN) involvement and tumor extension beyond the thyroid capsule, we studied a group of 148 consecutive papillary thyroid cancer patients with LN metastases and/or extrathyroidal tumor extension. Initial treatment, performed at the Institut Gustave Roussy between 1987 and 1997, included in all patients a total thyroidectomy with central and ipsilateral en bloc neck dissection followed by radioactive iodine ablation.
Results: Uptake outside the thyroid bed, demonstrating persistent disease, was found on the postablation total body scan (TBS) in 22% of the patients. With a mean follow-up of 8 yr, eight patients (7%) with a normal postablation TBS experienced a recurrence. Ten-year disease-specific survival rate was 99% (confidence interval, 97–100%). Significant risk factors for persistent disease included the numbers of LN metastases (&gt;10) and LN metastases with extracapsular extension (ECE-LN &gt;3), tumor size (&gt;4 cm), and LN metastases location (central). Significant risk factors for recurrent disease included the numbers of LN metastases (&gt;10), ECE-LN (&gt;3), and thyroglobulin level measured 6–12 months after initial treatment after T4 withdrawal.
Conclusion: We highlight an excellent survival rate and suggest risk classifications of persistent and recurrent disease based on the numbers of LN metastases and ECE-LN, LN metastases location, tumor size, and thyroglobulin level.