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At least 1,621 records · Page 90Linked to original sources
PubMed1998

Understanding immunology in disease development and control.

Two functional aspects of the avian immune system, the humoral and the cell-mediated arms, provide the basis for the preventive and protective response against disease-causing microorganisms. On the other hand, certain avian diseases may induce a transient or permanent immunosuppressive state in one or both of these arms, leading to increased disease susceptibility. In addition to the classical immune response, manifested as antibody production or effector cell activation several cytokines and metabolites are also produced. The consequence of cytokine- and metabolite-mediated microenvironments may be either beneficial or result in a noninfectious immunopathology. Nevertheless, the integrity of the immune system and its functional modulation by factors such as genetics, nutrition, and prophylactic approaches continue to be an important focus of attention in current poultry research and production efforts.

Animals↗
PubMed2000

The role of B cells and autoantibodies in multiple sclerosis.

A variety of cellular and humoral immunological abnormalities have been observed in multiple sclerosis (MS). In the past few years, several lines of evidence converged to imply an important role of autoreactive antibodies and B cells in the pathogenesis of MS. Recent data suggest that autoantibodies may be harmful in lesion formation but also potentially beneficial in repair. This review surveys recent advances in the concepts of generation and nature of pathogenetic autoantibodies, their potential modes of action, mechanisms of their long-term persistence, and the role of the inflamed brain tissue as a B-cell-supporting microenvironment in MS. Based on the presence of specific autoantibodies, it seems possible to define distinct MS subgroups in the near future. The therapeutic relevance of these new findings is presented.

Animals↗
PubMed1998

Differential distribution of Fc gamma RIIIa in normal human tissues and co-localization with DAF and fibrillin-1: implications for immunological microenvironments.

Fc gamma RIIIa is a cytokine-inducible IgG Fc receptor implicated in the activation of macrophages by immune complexes. Differential expression of Fc gamma RIIIa by macrophages in different tissues may therefore modulate local immune responsiveness. Fc gamma RIIIa expression in normal human tissues was assessed semiquantitatively using microdensitometry. Synovial intimal, serosal, alveolar, salivary gland and placental macrophages, Kupffer cells, and macrophages in mechanically stressed dermis expressed high levels of Fc gamma RIIIa. Less consistent expression was seen in skeletal muscle and lymphoid organs. No significant expression was observed in brain, thyroid, spine, intestine, myocardium, prostate, uterus, flexor forearm dermis, uterus, or kidney. Staining for Fc gamma RIII was also observed on extracellular matrix, and co-localized with both complement decay-accelerating factor and fibrillin-1. It is proposed that differential levels of both cellular and extracellular Fc gamma RIIIa, by modulating the response to immune complexes, may contribute to relative tissue susceptibility to infection and autoimmune disease.

CD55 Antigens↗
PubMed1986

Dynamic variations of the brain cell microenvironment in relation to neuronal hyperactivity.

Neuronal hyperactivity has been shown to cause transient changes in ionic concentrations as well as in the volume of the extracellular space (ECS). During enhanced neuronal activity in the sensorimotor cortex of the cat, increases in the extracellular K+ concentration to a ceiling value of 10 mM have been observed concomitant with decreases in the Na+ concentration of similar magnitude. Simultaneously, the Cl- concentration rose steadily during the enhanced neuronal activity, and the extracellular space decreased by about 30%. A mathematical model allowed the interpretation of these concentration and volume changes as results of K+ release by active neurons in exchange for Na+, removal of K+ from the ECS by spatial glial buffering and movements of KCl into glial cells, as well as cell swelling due to metabolically induced transient increases in cellular osmolarity. Similar mechanisms have also been found to operate in gliotic scar tissue, where glial cells appeared to function the same way as in normal cortex, in rat hippocampal slices, and in preparations studied by other investigators.

Animals↗
PubMed2006

Tumor suppressive maspin and epithelial homeostasis.

Maspin is a 42-kDa novel serine protease inhibitor (serpin) with multifaceted tumor suppressive activities. To date, the consensus that maspin expression predicts a better prognosis still largely holds for breast, prostate, colon, and oral squamous cancers. Interestingly, however, more detailed analyses revealed a biphasic expression pattern of maspin in early steps of tumorigenicity and re-expression of maspin in dormant cancer metastatic revertants. These data suggest a sensitivity of maspin expression to changes of epithelial microenvironments, and a role of maspin in epithelial homeostasis. Experimental evidence consistently showed that maspin suppresses tumor growth, invasion and metastasis, induces tumor redifferentiation, and enhances tumor cell sensitivity to apoptosis. Maspin protein isolated from biological sources is a monomer, which is present as a secreted, a cytoplasmic, a nuclear, as well as a cell surface-associated protein. Nuclear maspin is associated with better prognoses of cancer. It is further noted that extracellular maspin is sufficient to block tumor induced extracellular matrix degradation, tumor cell motility and invasion, whereas intracellular maspin is responsible for the increased cellular sensitivity to apoptosis. Despite these exciting developments, the mechanistic studies of maspin have proven challenging primarily due to the lack of a prototype molecular model. Although the maspin sequence has overall homologies with other members in the serpin superfamily, it does not behave like a typical serpin, that is, non-inhibitory toward active serine proteases in solution. This novel feature is in line with the X-ray crystallographic evidence. Several recent studies dedicated to finding the maspin partners support a paradigm shift. The current review is intended to summarize these recent findings and discuss a new perspective of maspin in epithelial homeostasis.

Animals↗
PubMed2006

Photodynamic activity of a new sensitizer derived from porphyrin-C60 dyad and its biological consequences in a human carcinoma cell line.

The photokilling activity of a porphyrin-C(60) (P-C(60)) dyad was evaluated on a Hep-2 human larynx-carcinoma cell line. This study represents the first evaluation of a dyad, with high capacity to form a photoinduced charge-separated state, to act as agent to inactivate cells by photodynamic therapy (PDT). Cell treatment was carried out with 1 microM P-C(60) incorporated into liposomal vesicles. No dark cytotoxicity was observed using 1 microM P-C(60) concentration and during long incubation time (24h). The uptake of sensitizer into Hep-2 was studied at different times of incubation. Under these conditions, a value of 1.5 nmol/10(6)cells was found after 4h of incubation showing practically no change even after 24h. The cell survival after irradiation of the cells with visible light was dependent upon light exposure level. A high photocytotoxic effect was observed for P-C(60), which inactivated 80% of the cells after 54 J/cm(2) of irradiation. Moreover, the dyad kept a high photoactivity even under argon atmosphere. Thus, depending on the microenvironment where the sensitizer is localized, this compound could produce a biological photodamage through either a (1)O(2)-mediated photoreaction process or a free radical mechanism under low oxygen concentration. The mechanism of cell death was analyzed by Hoechst-33258, toluidine blue staining, TUNEL and DNA fragmentation. Cell cultures treated for 24h with P-C(60) and irradiated with a dose of 54 J/cm(2) showed a great amount of apoptotic cells (58%). Moreover, changes in cell morphology were analyzed using fluorescence microscopy with Hoechst-33258 under low oxygen concentration. Under this anaerobic condition, necrotic cellular death predominated on apoptotic pathway. There were more apoptotic cells under air irradiation condition than under argon irradiation condition. To determine the apoptotic pathway, caspase-3 activation was studied by caspase-3 activity detection kits. The last results showed that P-C(60) induced apoptosis by caspase-3-dependent pathway. These results indicated that molecular dyad, which can form a photoinduced charge-separated state, is a promising model for phototherapeutic agents and they have potential application in cell inactivation by PDT.

Caspase 3↗
PubMed2006

Cytokines in breast cancer.

In recent decades many advances have occurred in the understanding of the role of cytokines in breast cancer. New signalling pathways of interleukin (IL)-1 family, IL-6, IL-11, IL-18, interferons (IFNs) and interferon regulatory factors 1 (IRF-1) and 2 (IRF-2) have been found within tumour microenvironments and in metastatic sites. Some cytokines (IL-1, IL-6, IL-11, TGFbeta) stimulate while others (IL-12, IL-18, IFNs) inhibit breast cancer proliferation and/or invasion. Similarly, high circulating levels of some cytokines seem to be favourable (soluble IL-2R) while others are unfavourable (IL-1beta, IL-6, IL-8, IL-10, IL-18, gp130) prognostic indicators. So far IL-2, IFNalpha, IFNbeta and occasionally IFNgamma, IL-6, IL-12 have been the cytokines used for anti tumour treatment of advanced breast cancer either to induce or increase hormone sensitivity and/or to stimulate cellular immunity. Disappointing results occurred in most trials; however, two long-term pilot studies suggest that IL-2 and IFNbeta, when used appropriately can have a positive effect on clinical benefit and overall survival of patients with minimal residual disease after chemotherapy or with disseminated disease controlled by conventional endocrine therapy.

Animals↗
PubMed2003

Airway remodeling in asthma: new insights.

Asthma is increasing in prevalence worldwide as a result of factors associated with a Western lifestyle. The prevalence and chronic nature of the disease represent significant economic burdens. Despite advances in understanding the inflammatory and immunologic components of asthma, there is relatively little understanding of the cellular and molecular mechanisms underlying the structural changes seen in the asthmatic lung (airway remodeling). These changes include hypertrophy of bronchial smooth muscle, transformation of fibroblasts to myofibroblasts, and deposition of subepithelial collagen. Airway remodeling is linked to bronchial hyperresponsiveness to diverse triggers and a steeper trajectory of long-term decrease in lung function in asthmatic patients. Until recently, these remodeling changes have been considered to be secondary phenomena, developing late in the disease process as a consequence of persistent inflammation. We discuss an alternative view of asthma pathogenesis by emphasizing the importance of the airway microenvironment (the epithelial mesenchymal trophic unit) in the origins of the disease. Our proposals are supported by the recent identification of ADAM33 as an asthma susceptibility gene, the expression of which is abundant in airway fibroblasts and smooth muscle but absent from T lymphocytes or inflammatory cells that infiltrate the airway wall in patients with asthma.

Asthma↗
PubMed1991

The anion paradox in sodium taste reception: resolution by voltage-clamp studies.

Sodium salts are potent taste stimuli, but their effectiveness is markedly dependent on the anion, with chloride yielding the greatest response. The cellular mechanisms that mediate this phenomenon are not known. This "anion paradox" has been resolved by considering the field potential that is generated by restricted electrodiffusion of the anion through paracellular shunts between taste-bud cells. Neural responses to sodium chloride, sodium acetate, and sodium gluconate were studied while the field potential was voltage-clamped. Clamping at electronegative values eliminated the anion effect, whereas clamping at electropositive potentials exaggerated it. Thus, field potentials across the lingual epithelium modulate taste reception, indicating that the functional unit of taste reception includes the taste cell and its paracellular microenvironment.

Animals↗
PubMed2006

Myeloid suppressor cells regulate the adaptive immune response to cancer.

Inflammation resultant from tumor growth, infection with certain pathogens, or in some cases, trauma, can result in systemic release of cytokines, especially GM-CSF, that in turn stimulate the abundant production and activation of a population of immature myeloid cells, termed myeloid suppressor cells (MSCs), that have potent immunosuppressive functions. In this issue of the JCI, Gallina and colleagues have illuminated some complex issues concerning the development, activation, and function of MSCs (see the related article beginning on page 2777). They show that activation of MSCs is initiated in response to IFN-gamma, presumably produced in situ by antitumor T cells in the tumor microenvironment. After this triggering event, MSCs express 2 enzymes involved in l-arginine metabolism, Arginase I and iNOS, whose metabolic products include diffusible and highly reactive peroxynitrites, the ultimate biochemical mediators of T cell immune suppression. The multifaceted regulation of this complex suppressive effector system provides several potential therapeutic targets.

Animals↗
PubMed1994

Normal and abnormal development of the blood-brain barrier.

The blood-brain barrier is responsible for the maintenance of the neuronal microenvironment. This is accomplished by isolation of the brain from the blood by the tight junctions that join endothelial cells in cerebral microvessels, and by selective transport and metabolism of substances from blood or brain by the endothelial cells. This review describes the growth and maturation of the brain vasculature, and the development of the special properties of the endothelia at the blood-brain interface. Evidence suggests that the development of the unique properties of the brain microvasculature is a consequence of tissue-specific interactions between endothelial cells of extraneural origin and developing brain cells. The cellular and molecular mechanisms that control these processes are as yet unknown but this review will include experimental studies which have used in vivo and in vitro systems to investigate what factors may be involved, and some pathological conditions in which abnormal barrier development is thought to be an important aspect of the disease process.

Animals↗
PubMed1996

Quantitative examination of dynamic interneuronal coupling via single-spike extracellular potassium ion transients.

A computer simulation developed to examine activity-dependent, transient variations of local extracellular potassium ion concentration in the central nervous system is extended to a consideration of depolarizing interactions between an active (primary) neuronal membrane and adjacent quiescent neuronal membranes. A class of potassium-mediated depolarizing interactions is described and quantified in relation to the local histologic fine structure. With a relatively open and rapidly equilibrating extracellular environment, the interactions are in the millivolt range and thus are largely subthreshold. However, with a sufficiently restricted extracellular microenvironment and without additional dynamic mechanisms for enhanced potassium clearance, a single action potential is shown to be capable of producing secondary suprathreshold depolarization of the primary membrane. Such potassium-mediated self-excitation evolves to "autogenic" paroxysmal discharge, that is, a burst of activity terminating in sustained depolarization block. Similar suprathreshold ionic coupling between the primary membrane and its adjacent neuronal membranes can likewise yield "cooperative" paroxysmal discharge, wherein the burst of action potentials from the referential primary membrane interdigitates with homologous bursts in adjacent neuronal elements. The partitioning of the local extracellular space by fine cellular processes, fundamental to determining the magnitude of single-spike local extracellular potassium transients, is a basic determining factor for such putative potassium-mediated suprathreshold events. Of more general relevance is the existence of a class of robust but highly localized, subthreshold potassium-mediated ionic interactions that can support non-synaptic dynamic modulation of neuronal activity. Thus, in addition to providing a quantitative theory for the initiation and propagation of non-synaptic epileptiform events, the model suggests a mechanism for potassium-mediated and activity-dependent proximity modulation of neuronal network throughout that can be significant at normal levels of neuronal activity and normal histologic fine structure.

Action Potentials↗
PubMed2006

Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis.

Heparanase is an endoglycosidase which cleaves heparan sulfate (HS) and hence participates in degradation and remodeling of the extracellular matrix (ECM). Heparanase is preferentially expressed in human tumors and its over-expression in tumor cells confers an invasive phenotype in experimental animals. The enzyme also releases angiogenic factors from the ECM and thereby induces an angiogenic response in vivo. Heparanase upregulation correlates with increased tumor vascularity and poor post-operative survival of cancer patients. Heparanase is synthesized as a 65 kDa inactive precursor that undergoes proteolytic cleavage, yielding 8 and 50 kDa protein subunits that heterodimerize to form an active enzyme. Human heparanase is localized primarily within late endosomes and lysosomes and occasionally on the cell surface and within the cell nucleus. Transcriptional activity of the heparanase promoter is stimulated by demethylation, early growth response 1 (EGR1) transcription factor, estrogen, inflammatory cytokines and inactivation of p53. N-acetylated glycol-split species of heparin as well as siRNA heparanase gene silencing inhibit tumor metastasis and angiogenesis in experimental models. These observations and the unexpected identification of a single functional heparanase, suggest that the enzyme is a promising target for anti-cancer and anti-inflammatory drug development. Heparanase exhibits also non-enzymatic activities, independent of its involvement in ECM degradation and changes in the extracellular microenvironment. For example, cell surface expression of heparanase elicits a firm cell adhesion, reflecting an involvement in cell-ECM interaction. Heparanase enhances Akt signaling and stimulates PI3K- and p38-dependent endothelial cell migration and invasion. It also promotes VEGF expression via the Src pathway. The enzyme may thus activate endothelial cells and elicits angiogenic and survival responses. Studies with heparanase over-expressing transgenic mice revealed that the enzyme functions in normal processes involving cell mobilization, HS turnover, tissue vascularization and remodeling. In this review, we summarize the current status of heparanase research, emphasizing molecular and cellular aspects of the enzyme, including its mode of processing and activation, control of heparanase gene expression, enzymatic and non-enzymatic functions, and causal involvement in cancer metastasis and angiogenesis. We also discuss clinical aspects and strategies for the development of heparanase inhibitors.

Animals↗
PubMedDate not supplied

Immunonutrition: the pediatric experience.

The health benefits of specific nutrients in the diet are reviewed as they pertain to the pediatric population and its unique needs. Secretory immunoglobulins, lysozyme, interferon, and growth factors, among others, are known to confer immunological advantages to breast milk. Inhibition of bacterial pathogens, as well as permissive growth of a protective colonic ecoflora occur as a result of various cellular and biochemical mechanisms at play. The immunomodulatory properties of minerals such as iron, zinc, and selenium, are presented and the newly recognized protective role of vitamin A and its importance in developing countries and in conditions of compromised nutrition are discussed. The review also covers the role of arginine, glutamine, and nucleotides in adaptive responses of the developing gut and in pathologic states such as necrotizing enterocolitis, short bowel syndrome, and inflammatory bowel disease. Probiotics (specific microbial feeds with potential benefits to the host), and prebiotics (dietary components such as complex carbohydrates able to change the colonic microenvironment fostering colonization with non-enteropathogens) are areas of current interest because they offer alternatives for the management of the growing problem of multiple antibiotic resistance and overwhelming infections in the hospitalized patient.

Amino Acids↗
PubMed1998

Carrier-dependency of cellular differentiation induced by bone morphogenetic protein in ectopic sites.

Partially purified bone morphogenetic protein (BMP) was delivered into two different types of carriers, porous particles of hydroxyapatite (PPHAP) and particles of insoluble bone matrix (IBM), and the ossification process was examined after subcutaneous implantation of the BMP/PPHAP and BMP/IBM in rats. The ossification in the BMP/PPHAP system was predominantly direct through bone formation similar to intramembranous ossification, whereas in the BMP/IBM system it was predominantly endochondral. The differences observed between the BMP/PPHAP and the BMP/IBM indicate the importance of the structure and nature of the carrier in the process of bone induction. The findings suggest that bone and cartilage differentiation is controlled not only by the regulation factor (BMP), but also by its interaction with the carrier, and that the BMP-induced cell differentiation is dependent upon the microenvironment derived from the carrier.

Animals↗
PubMed2004

Immature dendritic cell transdifferentiation into osteoclasts: a novel pathway sustained by the rheumatoid arthritis microenvironment.

Dendritic cells (DCs), the mononuclear cells that initiate immune response, and osteoclasts, the multinucleated bone-resorbing cells, are derived from monocyte/macrophage precursor cells. Granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor (M-CSF) reciprocally regulate the differentiation of both lineages in mice. Using human monocyte-derived DCs generated in vitro, we show that immature DCs transdifferentiate into functional osteoclasts (OCs) in the presence of M-CSF and receptor activator of nuclear factor-kappaB ligand (RANKL). Transdifferentiation operates through fusion of intermediate adherent bipolar fusiform mononuclear cells expressing CD14, CD1a, and RANKL and able to induce RANKL(+) T-cell proliferation. Surprisingly, DC fusion in vitro is faster and more efficient than monocyte fusion to form multinucleated giant cells. The transdifferentiation process reported here supports the existence of a high cellular plasticity within differentiated myeloid phagocytes. Importantly, this process is greatly enhanced by rheumatoid arthritis synovial fluid and involves proinflammatory cytokines such as interleukin 1 or tumor necrosis factor alpha, as well as components of the extracellular matrix such as hyaluronic acid. Our data therefore suggest that DC-derived OCs may be directly involved in the osteolytic lesions observed in human inflammatory bone diseases such as rheumatoid arthritis or in particular forms of Langerhans cell histiocytosis, characterized by accumulation of immature skin DCs and chronic lytic bone lesions.

Adult↗
PubMed1992

Regulation of transient dopamine concentration gradients in the microenvironment surrounding nerve terminals in the rat striatum.

Synaptic overflow of dopamine in the striatum has been investigated during electrical stimulation of the medial forebrain bundle in anesthetized rats. Dopamine has been detected with Nafion-coated, carbon-fiber electrodes used with fast-scan voltammetry. In accordance with previous results, dopamine synaptic overflow is a function of the stimulation frequency and the anatomical position of the carbon-fiber electrode. In some positions the concentration of dopamine is found to respond instantaneously to the stimulus when the time-delay for diffusion through the Nafion film is accounted for. In these locations the measured rates of change of dopamine are sufficiently rapid such that extracellular diffusion is not apparent. The rate of dopamine overflow can be described by a model in which each stimulus pulse causes instantaneous release, and cellular uptake decreases the concentration between stimulus pulses. Uptake is found to be described by a constant set of Michaelis-Menten kinetics at each location for concentrations of dopamine from 100 nM to 15 microM. The concentration of dopamine released per stimulus pulse is found to be greatest at low frequency (< or = 10 Hz) with stimulus trains, and with single-pulse stimulations in nomifensine-treated animals. The frequency dependence of release is not an effect of dopamine receptor activation; haloperidol (2.5 mg/kg) causes a uniform increase in release at all frequencies. The absence of diffusional effects in the measurement locations means that the constants determined with the electrode are those operant inside intact striatal tissue during stimulated overflow. These values are then extrapolated to the case where a single neuron fires alone. The extrapolation shows that while the transient concentration of dopamine may be high (200 nM) at the interface of the synapse and the extrasynaptic region, it is normally very low (< 6 nM) in the bulk of extracellular fluid.

Animals↗
PubMed2005

Cellular abnormalities of blood vessels as targets in cancer.

Tumor blood vessels have multiple structural and functional abnormalities. They are unusually dynamic, and naturally undergo sprouting, proliferation, remodeling or regression. The vessels are irregularly shaped, tortuous, and lack the normal hierarchical arrangement of arterioles, capillaries and venules. Endothelial cells in tumors have abnormalities in gene expression, require growth factors for survival and have defective barrier function to plasma proteins. Pericytes on tumor vessels are also abnormal. Aberrant endothelial cells and pericytes generate defective basement membrane. Angiogenesis inhibitors can stop the growth of tumor vessels, prune existing vessels and normalize surviving vessels. Loss of endothelial cells is not necessarily accompanied by simultaneous loss of pericytes and surrounding basement membrane, which together can then provide a scaffold for regrowth of tumor vessels. Rapid vascular regrowth reflects the ongoing drive for angiogenesis and bizarre microenvironment in tumors that promote vascular abnormalities and thereby create therapeutic targets.

Angiogenesis Inhibitors↗