Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukocyte infiltration in the CNS after trauma or inflammation is triggered in part by upregulation of the chemokine, monocyte chemoattractant protein-1 (MCP-1), in astrocytes. However the signals that induce the upregulation of MCP-1 in astrocytes are unknown. We have investigated the roles for ATP P2X7 receptor activation because ATP is an intercellular signaling transmitter that is released in both trauma and inflammation and P2X7 receptors are involved in immune system signaling. Astrocytes in primary cell culture and acutely isolated from the hippocampus were immunopositive for P2X7 receptors. In astrocyte cultures, application of the selective P2X7 agonist, benzoyl-benzoyl ATP (Bz-ATP), activated MAP kinases extracellular signal receptor-activated kinase 1 (ERK1), ERK2, and p38. Purinergic antagonists depressed this activation with a profile suggesting P2X7 receptors. Bz-ATP also increased MCP-1 expression in cultured astrocytes, and again P2X7 antagonists prevented this increase. Blocking either the ERK1/ERK2 or the p38 pathway (with PD98059 or SB203580, respectively) significantly inhibited Bz-ATP-induced MCP-1 expression. Coapplication of both antagonists caused a greater depression. We also tested the roles for ATP receptor activation in inducing MCP-1 upregulation in corticectomy, an in vivo model of trauma. This model of cortical trauma was previously shown to increase MCP-1 expression in vivo principally in astrocytes. Suramin, a wide-spectrum purinergic receptor antagonist, significantly depressed the rapid (3 hr) trauma-induced increase in MCP-1 mRNA. These data indicate that purinergic transmitter receptors in astrocytes are important in regulating chemokine synthesis. The regulation of MCP-1 in astrocytes by ATP may be important in mediating communication with hematopoietic inflammatory cells.
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PMID:P2X7-like receptor activation in astrocytes increases chemokine monocyte chemoattractant protein-1 expression via mitogen-activated protein kinase. 1154 24

In the present work, we studied the effects of the stimulation of the chemokine CXC receptor 4 (CXCR4) by the stromal-derived cell growth factor-1alpha (SDF-1alpha) on the evoked excitatory postsynaptic current. This was generated in Purkinje neurons (PN) from mouse cerebellar slices by the stimulation of parallel fibers. It was found that the amplitude of EPSC was reversibly reduced by SDF-1alpha application. This effect was dose-dependent (IC(50)=0.34 nM) and was abolished by the anti-CXCR4 monoclonal antibody (mAb) 12G5. This SDF-1alpha-induced synaptic depression was caused by a decrease of evoked glutamate release, rather than a decrease in the postsynaptic glutamate receptor (GluR) sensitivity, as the mean amplitude of the spontaneous EPSCs was not influenced by chemokine application. Moreover, NMDA receptors (NMDARs) are involved in EPSC depression being inhibited by the NMDAR blocker 2-amino-5-phosphonopentanoic acid (AP-5). The mechanisms by which SDF-1alpha modulates neurotransmission in the cerebellar cortex are discussed.
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PMID:Stimulation of chemokine CXC receptor 4 induces synaptic depression of evoked parallel fibers inputs onto Purkinje neurons in mouse cerebellum. 1204 72

We examined how acute diabetes mellitus and acute ethanol intoxication modulate factors that mediate immune responses as a basis for explaining the increased susceptibility to infection in these two conditions. Our working hypothesis is that ethanol intoxication in diabetes compromises host defense mechanisms to a greater extent than observed in each condition alone. Male and female rats were made diabetic with streptozotocin (65 mg/kg, i.p.). Forty-eight hours after administration of streptozotocin, rats either received no treatment (control group) or were treated with (1) ethanol (bolus injection of 1.75 g/kg, followed by a 3-h infusion at the rate of 300 mg/kg/h), (2) lipopolysaccharide [(LPS); 0.9 mg/kg], or (3) a combination of LPS+ethanol. At the end of 3 h, rats were killed, and the livers were digested by perfusion with collagenase-containing Hanks' balanced salt solution to isolate hepatocytes and Kupffer cells. To measure chemokine generation, hepatocytes (2.5x10(5) cells per well) and Kupffer cells (1x10(6) cells per well) were cultured for 20 h, and the supernatant was used to measure cytokine-induced neutrophil chemoattractant (CINC) and regulated on activation, normal T-cell expressed and secreted (RANTES) chemokines. Phagocytosis by Kupffer cells was measured by flow cytometry and expressed as mean channel fluorescence intensity (MCF). Induction of diabetes as well as treatment of nondiabetic rats with LPS, ethanol, or LPS+ethanol caused depression of MCF values of Kupffer cells. However, treatment of the diabetic male and female rats with LPS and LPS+ethanol increased the MCF values relative to those of Kupffer cells obtained from untreated diabetic rats, but administration of ethanol to diabetic rats did not have a similar effect. The induction of diabetes caused an increase in CINC generation by Kupffer cells obtained from male rats, but not from female rats. This diabetes-induced elevation of chemoattractant factor was decreased when diabetic animals were treated with LPS, ethanol, or LPS+ethanol, and the sex difference was obliterated. Thus, the induction of diabetes as well as treatment with LPS, ethanol, or LPS+ethanol in nondiabetic rats depressed the phagocytic capability of Kupffer cells, whereas the presence of endotoxemia (administration of the endotoxin LPS) or administration of LPS+ethanol reversed the diabetic effect, but ethanol intoxication did not. These findings seem to indicate a persistence of depression of host defense capacity in the ethanol-intoxicated diabetic condition. This is further reinforced by the depression of the diabetes-induced enhancement of chemotaxis when the diabetic rats became intoxicated.
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PMID:Immune response modulation in acutely ethanol-intoxicated, acutely diabetic male and female rats. 1469 62

Focal brain infarcts are surrounded by extended perilesional zones that comprise the partially ischemic penumbra but also completely non-ischemic cortex of the remote ipsilateral hemisphere. To delineate the impact of lesion-associated vs. remote processes on transcriptional programming after focal ischemia, we used cDNA array analysis, quantitative real-time polymerase chain reaction and immunohistochemistry in the photothrombosis model of circumscribed cortical ischemia in rats. At an early stage of 4 h after ischemia, gene induction occurred to a similar extent in the ischemic infarct and remote non-ischemic cortex of the ipsilateral hemisphere. Among the genes induced in non-ischemic cortex we found the NGF-inducible genes PC3, VGF and Arc, the transcriptional regulators I kappa B-alpha and Stat3, and the beta-chemokine MIP-1 alpha (CCL3). At 3 days, the spatial pattern of gene expression had changed dramatically with brain fatty acid-binding protein as the only gene significantly induced in non-ischemic ipsilateral cortex. In contrast, numerous genes were exclusively regulated at the lesion site, comprising genes involved in cell cycle regulation, proteolysis, apoptosis, lipid homeostasis and anti-inflammatory counter-regulation. Cortical spreading depression was identified as the main mechanism underlying gene induction in remote non-ischemic cortex. Our data demonstrate a dynamic spatiotemporal pattern of gene induction, which may contribute to delayed progression of damage or, alternatively, mediate neuroprotection, tissue remodeling and functional compensation.
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PMID:Transcriptional response to circumscribed cortical brain ischemia: spatiotemporal patterns in ischemic vs. remote non-ischemic cortex. 1507 45

Moderate-severe depression (MSD) is linked to overexpression of proinflammatory cytokines and chemokines. Fractalkine (FKN) and macrophage inflammatory protein-1 alpha (MIP-1alpha) are, respectively, members of CX3C and C-C chemokines, and both are involved in recruiting and activating mononuclear phagocytes in the central nervous system. We analysed the presence of FKN and MIP-1alpha in sera of untreated MSD patients and healthy donors. High FKN levels were observed in all MSD patients as compared with values only detectable in 26% of healthy donors. MIP-1alpha was measurable in 20% of patients, while no healthy donors showed detectable chemokine levels. In conclusion, we describe a previously unknown involvement of FKN in the pathogenesis of MSD, suggesting that FKN may represent a target for a specific immune therapy of this disease.
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PMID:Involvement of fractalkine and macrophage inflammatory protein-1 alpha in moderate-severe depression. 1522 13

Stromal cell-derived factor-1alpha (SDF-1alpha) is a chemokine whose receptor, CXCR4, is distributed in specific brain areas including hypothalamus. SDF-1alpha has recently been found to play important roles in neurons, although direct modulation of voltage-gated ionic channels has never been shown. In order to clarify this issue, we performed patch-clamp experiments in fetal mouse hypothalamic neurons in culture. SDF-1alpha (10 nm) decreased the peak and rising slope of the action potentials and spike discharge frequency in 22% of hypothalamic neurons tested. This effect was blocked by the CXCR4 antagonist AMD 3100 (1 microm) but not by the metabotropic glutamate receptor antagonist MCPG (500 microm), indicating a direct action of SDF-1alpha on its cognate receptor. This effect involved a depression of both inward and outward voltage-dependent currents of the action potential. We confirmed these effects in the human neuroblastoma cell line SH-SY5Y, which endogenously expresses CXCR4. Voltage-clamp experiments revealed that SDF-1alpha induced a 20% decrease in the peak of the tetrodotoxin-sensitive sodium current and tetraethylammonium-sensitive delayed rectifier potassium current, respectively. Both effects were concentration dependent, and blocked by AMD 3100 (200 nm). This dual effect was reduced or blocked by 0.4 mm GTPgammaS G-protein pre-activation or by pre-treatment with the G-protein inhibitor pertussis toxin (200 ng/mL), suggesting that it is mediated via activation of a G(i/o) protein. This study extends the functions of SDF-1alpha to a direct modulation of voltage-dependent membrane currents of neuronal cells.
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PMID:Stromal cell-derived factor-1alpha directly modulates voltage-dependent currents of the action potential in mammalian neuronal cells. 1585 99

Respiratory dysfunction during sepsis is common. However, although lung function can often be adequately supported, death frequently results from cardiovascular collapse. Despite intense investigation, the mechanism underlying the myocardial dysfunction of sepsis remains unclear. Macrophage migration inhibitory factor (MIF), an important cytokine released in sepsis and the acute respiratory distress syndrome, is a known cardiac depressant. We hypothesized that MIF released from the lung results in myocardial dysfunction during sepsis. In murine models of polymicrobial sepsis, we demonstrate a significant increase in the lungs of total and lavagable MIF between 20 and 30 h post induction of sepsis. At 30 h post sepsis, the lungs released MIF into the pulmonary circulation, increasing the plasma concentration by up to 51% in a single pass. Exogenous MIF, instilled into the lungs, increased alveolar keratinocyte-derived chemokine (KC), Macrophage inflammatory protein-2 (MIP2), and tumor necrosis factor alpha (TNFalpha) at 3 h, and plasma KC and MIP2 at 6 h postinstillation. This was associated with an increase in p38 mitogen-activated protein kinase and c-Jun N-terminal kinase phosphorylation. Because changes in mitogen-activated protein kinase activation can lead to myocardial depression, these data suggest that MIF released from the lungs may be responsible, at least in part, for the cardiac dysfunction seen in the late stages of sepsis.
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PMID:Macrophage migration inhibitory factor within the alveolar spaces induces changes in the heart during late experimental sepsis. 1631 87

This work reports the effect of chemokine fractalkine/CX3CL1, an endogenous small peptide highly expressed in the central nervous system, on evoked synaptic responses investigated in mouse CA1 stratum radiatum using an electrophysiological approach. We report that in acute mouse hippocampal slices, superfusion of CX3CL1 resulted in a reversible depression of the field excitatory postsynaptic potential (fEPSP) which developed within few seconds, increased for up to 10 min of application and disappeared within 30 min after the end of CX3CL1 treatment. We also show that CX3CL1-induced synaptic depression is (i) dose-dependent with IC50 and nH values of 0.7 nM and 1, respectively, (ii) not associated with a change in paired-pulse facilitation, (iii) mediated through CX3CL1 receptor (CX3CR1), being absent in CX3CR1-/- mice and inhibited in wild-type mice by a specific blocking antibody, and (iv) occluded by the induction of homosynaptic long-term depression (LTD). We conclude that CX3CL1 is a potent neuromodulator of the evoked excitatory synaptic transmission, sharing common mechanisms with LTD.
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PMID:Fractalkine/CX3CL1 depresses central synaptic transmission in mouse hippocampal slices. 1681 80

A growing literature suggests that psychosocial factors, such as chronic stress and depression, are associated with increased vulnerability to inflammatory disease; however, the mechanisms of this effect remain unclear. One possibility is that these psychosocial characteristics are associated with activation of innate inflammatory pathways. Here, we explore relationships between a range of psychosocial risk factors for inflammatory disease and a measure of inflammatory potential, lipopolysaccharide-induced production of the monocyte-derived proinflammatory cytokines/chemokines interleukin (IL)-1beta, IL-6, TNF-alpha, and IL-8 among a community sample of 183 healthy adults aged 30-54 years. After controlling for demographic factors, health behavior practices, blood pressure, and white blood cell count, hierarchical regression analyses revealed a positive relationship between production of IL-8 and symptoms of depression, trait negative affect, and perceived stress. In contrast, there was an inverse relationship between IL-8 production and perceived social support. Relationships between IL-8 and symptoms of depression and perceived stress were attributable primarily to dispositional differences in NA. The relationship between negative affect measures and IL-8 was independent of social support. Although there were significant univariate associations between higher IL-6 production and symptoms of depression and less social support, these relationships did not withstand adjustment for demographic controls. There were no significant associations between IL-1beta or TNF-alpha and any of the psychosocial parameters. Our findings suggest that individuals at greater psychosocial risk for the development of inflammatory diseases, including cardiovascular disease, also show greater stimulated production of the proinflammatory chemokine, IL-8. Further exploration of this potential psychophysiological pathway is warranted.
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PMID:Stimulated production of interleukin-8 covaries with psychosocial risk factors for inflammatory disease among middle-aged community volunteers. 1699 40

We examined the effects of the chemokine fractalkine (CX3CL1) on EPSCs evoked by electrical stimulation of Schaffer collaterals in patch-clamped CA1 pyramidal neurons from rat hippocampal slices. Acute application of CX3CL1 caused a sustained reduction of EPSC amplitude, with partial recovery after washout. CX3CL1-induced EPSC depression is postsynaptic in nature, because paired-pulse ratio was maintained, amplitude distribution of spontaneous excitatory postsynaptic currents shifted to lower values, and whole-cell current responses to AMPA were reversibly inhibited. EPSC depression by CX3CL1 is mediated by CX3CL1 receptor (CX3CR1), because CX3CL1 was unable to influence EPSC amplitude in CA1 pyramidal neurons from CX3CR1 knock-out mice. CX3CL1-induced depression of both EPSC and AMPA current was not observed in the absence of afferent fiber stimulation or AMPA receptor activation, respectively, indicating the requirement of sustained receptor activity for its development. Findings obtained from hippocampal slices, cultured hippocampal neurons, and transfected human embryonic kidney cells indicate that a Ca2+-, cAMP-, and phosphatase-dependent process is likely to modulate CX3CL1 effects because of the following: (1) CX3CL1-induced depression was antagonized by intracellular BAPTA, 8Br-cAMP, phosphatase inhibitors, and pertussis toxin (PTX); (2) CX3CL1 inhibited forskolin-induced cAMP formation sensitive to PTX; and (3) CX3CL1 inhibited forskolin-induced Ser845 GluR1 phosphorylation, which was sensitive to PTX and dependent on Ca2+ and phosphatase activity. Together, these findings indicate that CX3CL1 negatively modulates AMPA receptor function at active glutamatergic synapses through cell-signaling pathways by influencing the balance between kinase and phosphatase activity.
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PMID:Chemokine fractalkine/CX3CL1 negatively modulates active glutamatergic synapses in rat hippocampal neurons. 1703 33


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