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)

Serotonin 5-HT1 receptors are implicated in anxiety and depression. These receptors belong to the family A of G-protein-coupled receptors and couple to inhibitory G-proteins. Recent studies show that chronic activation of 5-HT1A receptors leads to proliferation of hippocampal neurons suggesting that neurogenesis contributes to the effects of antidepressants. However, the molecular mechanisms and pathways involved are not understood. We used Neuro 2A cells transfected with 5-HT1A receptors and SK-N-SH cells endogenously expressing the receptor to examine the effect of receptor activation on neuronal survival and neurite outgrowth. We find that receptor activation leads to increased neurite outgrowth that can be blocked by the receptor selective antagonist and by treatment with pertussis toxin or lactacystin implicating inhibitory G-proteins and proteasomal degradation in this process. Interestingly, the small G-protein Rap and the transcription factor STAT-3 are also involved since reducing the levels of Rap1 (using small interfering RNA) or STAT-3 (using dominant negative STAT3) significantly blocks 5-HT1A-receptor-mediated neurite outgrowth. The observed increase in the phosphorylation of Src and STAT-3, at sites leading to their activation, further supports a crucial role for these proteins in neurite outgrowth. We also find that prolonged activation of endogenous 5-HT1A receptors leads to increased cell survival even under starving conditions; this is completely blocked by co-treatment with the antagonist. Taken together, these findings indicate that activation of the 5-HT1A receptor leads to a number of neurotropic events by activating a series of signal transduction molecules leading to long-term changes required for neurogenesis.
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PMID:Serotonin receptor activation leads to neurite outgrowth and neuronal survival. 1592 28

Burkholderia pseudomallei, the causative agent of melioidosis, is a facultative intracellular gram-negative bacterium that is able to survive and multiply in macrophages. Previously, we reported that B. pseudomallei was able to escape macrophage killing by interfering with the expression of inducible nitric oxide synthase (iNOS). In the present study, we extended this finding and demonstrated that B. pseudomallei was able to activate the expression of suppressor of cytokine signaling 3 (SOCS3) and cytokine-inducible Src homology 2-containing protein (CIS) but not SOCS1 in a mouse macrophage cell line (RAW 264.7). The expression of SOCS3 and CIS in B. pseudomallei-infected macrophages directly correlated with a decreased gamma interferon (IFN-gamma) signaling response, as indicated by a reduction in Y701-STAT-1 phosphorylation (pY701-STAT-1). Moreover, a reduction in the expression of IFN-gamma-induced proteins, such as interferon regulatory factor 1 (IRF-1), was observed in B. pseudomallei-infected macrophages that were treated with IFN-gamma. Since pY701-STAT-1 and IRF-1 are essential transcription factors for regulating iNOS expression, the failure to activate these factors could also result in depression of iNOS expression and a loss of macrophage killing capacity. Taken together, the data indicate that the activation of SOCS3 and CIS expression in B. pseudomallei-infected macrophages interfered with IFN-gamma signaling, thus allowing the bacteria to escape killing by these phagocytic cells.
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PMID:Burkholderia pseudomallei-induced expression of suppressor of cytokine signaling 3 and cytokine-inducible src homology 2-containing protein in mouse macrophages: a possible mechanism for suppression of the response to gamma interferon stimulation. 1623 31

Cytokines are important mediators of cardiac disease. Accumulating evidence indicates that members of the interleukin-6 family of cytokines promote cardiac hypertrophy through the activation of the Janus kinase-signal transducer and activator of transcription (Jak/STAT) pathway. Aberrant Jak/STAT signaling may promote progression from hypertrophy to heart failure. Suppressor of cytokine signaling (SOCS) proteins are underexplored, negative regulators of Jak/STAT signaling. SOCS proteins may also interact with other inflammatory pathways known to affect cardiac function. A better understanding of the therapeutic potential of these proteins may lead to the controlled progression of heart failure and the limitation of myocardial depression. This review summarizes the cardiophysiological effect of the IL-6 cytokine family, outlines the mechanistic pathway of Jak/STAT signaling, explores the regulatory role of SOCS proteins in the heart, and discusses the potential of using SOCS proteins clinically.
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PMID:Jak/STAT/SOCS signaling circuits and associated cytokine-mediated inflammation and hypertrophy in the heart. 1691 47

The aim of the present study was to design an automated-gating hematology fluorescence flow cytometry methodology permitting the assessment of neutrophil and monocyte activation in EDTA-anticoagulated whole blood based on cell granularity, lipid membrane components, cell shape and volume, and total cell nucleic acid (NA) compounds. For particularly monitoring the proper functioning of patients' innate immune system as the first line defense against microbial invaders, the suitable test system should be rapid, simple, reliable by yielding reproducible results. It must be validated against established methods, and it must prove to work in selected clinical settings, e.g. in intensive care unit (ICU) environments. The adaptation of a routine hematology cell analyser utilizing fluorescence flow cytometry resulted in a potentially useful system for all requirements. It proved to detect in real-time and in a reliable and reproducible way the main cellular response reactions of neutrophils and monocytes during externally stimulated immune defense. Validation was successful when comparing it to established methods. The quantified activation effects were dose dependent from the applied activating agents. Cellular response kinetics could be measured and described and showed to be in line with the prevailing cell response models. Upon applying the test method to a healthy population of volunteers and a first cohort of ICU patients with and without evident immune depression, the test revealed excellent cellular responses to external activating cytotoxic stimuli (lipopolysaccharide; LPS) for the control group, slightly weaker response from ICU patients without immune depression and no response from patients with evident immune depression.We conclude that routine hematology fluorescence flow cytometry can accurately and reproducibly measure different activation steps of monocytes and polymorphonuclear neutrophilic granulocytes to defined external stimuli. This may potentially be applied as a STAT (Latin statim = immediately) and routine screening and surveillance method for inflammatory diseases.
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PMID:Automation and validation of a rapid method to assess neutrophil and monocyte activation by routine fluorescence flow cytometry in vitro. 1843 75

Interferon (IFN)-alpha is an innate immune cytokine that induces significant depressive symptoms in clinical populations. A number of mechanisms have been considered regarding the relationship between IFN-alpha and depression, including the effects of IFN-alpha on the hypothalamic-pituitary-adrenal (HPA) axis. Here, we examined the impact of mouse interferon (mIFN)-alpha and its signaling pathways on the functioning of the glucocorticoid receptor (GR), which plays a key role in HPA axis regulation. mIFN-alpha treatment (100-1000 IU/ml) of HT22 mouse hippocampal cells for 24h was found to significantly inhibit dexamethasone (DEX)-induced GR-mediated MMTV-luciferase activity and significantly decrease DEX-induced GR-binding to its DNA response element. Of note, mIFN-alpha treatment for 24h had no effect on DEX-induced GR translocation or GR protein expression. Inhibition of DEX-induced GR function by mIFN-alpha was significantly reversed by pharmacological inhibition of janus kinase/signal transducer and activator of transcription (Jak-STAT) signaling pathways, but not by inhibition of p38 mitogen-activated protein kinase. Moreover, pretreatment of cells with siRNA targeted to STAT5, but not STAT1 or STAT2, significantly attenuated IFN-alpha inhibition of DEX-induced MMTV-luciferase activity. Immunoprecipitation experiments revealed nuclear co-immunoprecipitation of activated STAT5 and GR following IFN-alpha plus DEX treatment. Taken together, these results indicate that negative regulation of GR function by IFN-alpha in hippocampal HT22 cells is mediated by activation of Jak/STAT signaling pathways leading to nuclear STAT5-GR protein-protein interactions. Given the role of GR in depressive disorders, IFN-alpha effects on GR function in cells of hippocampal origin may contribute to HPA axis alterations and depressive symptoms in IFN-alpha-treated patients.
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PMID:Interferon-alpha inhibits glucocorticoid receptor-mediated gene transcription via STAT5 activation in mouse HT22 cells. 1916 80

Insulin resistance and dyslipidemia are both considered to be risk factors for metabolic syndrome. Low levels of IGF1 are associated with insulin resistance. Elevation of low-density lipoprotein cholesterol (LDL-C) concomitant with depression of high-density lipoprotein cholesterol (HDL-C) increase the risk of obesity and type 2 diabetes mellitus (T2DM). Liver secretes IGF1 and catabolizes cholesterol regulated by the rate-limiting enzyme of bile acid synthesis from cholesterol 7alpha-hydroxylase (CYP7A1). NO-1886, a chemically synthesized lipoprotein lipase activator, suppresses diet-induced insulin resistance with the improvement of HDL-C. The goal of the present study is to evaluate whether NO-1886 upregulates IGF1 and CYP7A1 to benefit glucose and cholesterol metabolism. By using human hepatoma cell lines (HepG2 cells) as an in vitro model, we found that NO-1886 promoted IGF1 secretion and CYP7A1 expression through the activation of signal transducer and activator of transcription 5 (STAT5). Pretreatment of cells with AG 490, the inhibitor of STAT pathway, completely abolished NO-1886-induced IGF1 secretion and CYP7A1 expression. Studies performed in Chinese Bama minipigs pointed out an augmentation of plasma IGF1 elicited by a single dose administration of NO-1886. Long-term supplementation with NO-1886 recovered hyperinsulinemia and low plasma levels of IGF1 suppressed LDL-C and facilitated reverse cholesterol transport by decreasing hepatic cholesterol accumulation through increasing CYP7A1 expression in high-fat/high-sucrose/high-cholesterol diet minipigs. These findings indicate that NO-1886 upregulates IGF1 secretion and CYP7A1 expression to improve insulin resistance and hepatic cholesterol accumulation, which may represent an alternative therapeutic avenue of NO-1886 for T2DM and metabolic syndrome.
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PMID:NO-1886 suppresses diet-induced insulin resistance and cholesterol accumulation through STAT5-dependent upregulation of IGF1 and CYP7A1. 1981 88

Infection causes the production of proinflammatory cytokines, which act on the central nervous system (CNS) and can result in fever, sleep disorders, depression-like behavior, and even anorexia, although precisely how cytokines regulate the functions of the CNS remain unclear. In the present study, we investigated the regulatory-molecular mechanisms by which cytokines affect hypothalamic function in a state of infection. The intraperitoneal administration of lipopolysaccharide (LPS), a ligand of Toll-like receptor 4 (TLR4), time-dependently (2-24 h) increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in the hypothalamus and liver, which corresponded with anorexia observed within 24 h. Interestingly, the pattern of phosphorylation in response to LPS differed between the hypothalamus and liver. In the hypothalamus, LPS increased STAT3 phosphorylation from 2 h, with a peak at 4 h and a decline thereafter, whereas, in the liver, the peak activation of STAT3 persisted from 2 to 8 h. The time course of the LPS-induced expression of suppressor of cytokine signaling 3 (SOCS3), a STAT3-induced negative regulator of the Janus kinase-STAT pathway, was similar to that of STAT3 phosphorylation. Using mice deficient in myeloid differentiation primary-response protein 88 (MyD88), an adapter protein of TLR4, we found that LPS-induced STAT3 phosphorylation and SOCS3 expression in the hypothalamus and liver were predominantly mediated through MyD88. Moreover, we observed that MyD88-deficient mice were resistant to LPS-induced anorexia. Taken together, our findings reveal a novel mechanism, i.e., MyD88 plays a key role in mediating STAT3 phosphorylation and anorexia in the CNS in a state of infection and inflammation.
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PMID:MyD88 plays a key role in LPS-induced Stat3 activation in the hypothalamus. 1995 95

Hypericum perforatum extracts have been used to treat diseases, including mild-to-moderate depression and inflammatory conditions. It is particularly important to identify which constituents present in the H. perforatum extracts are responsible for its anti-inflammatory activity since consumers are taking H. perforatum preparations to treat inflammation. We used a combination of four putative bioactive constituents, called the 4-component-system that interacted synergistically to explain the light-activated anti-inflammatory activity of an H. perforatum fraction in RAW 264.7 mouse macrophages. We also combined the constituents at concentrations detected in the fraction to identify key molecular targets. LPS was used to model an inflammatory response, and the 4-component-system and H. perforatum fraction were used as treatments that inhibited LPS-induced prostaglandin E(2) (PGE(2)) production in RAW 264.7 mouse macrophages in the studies of gene expression profiles. We used Affymetrix genechips, statistical analysis, and quantitative real-time PCR to identify key gene targets of the 4-component-system and the sub-fraction from an H. perforatum ethanol extract. The H. perforatum sub-fraction, with or without LPS stimulation, affected far more genes than the 4-component-system with and without LPS. Genes involved in Janus kinase, as well as a signal transducer and activator of transcription (JAK-STAT) and eicosanoid pathways were identified that could account for the reduction in PGE(2) observed with both treatments in LPS-stimulated macrophages. Ten genes may be particularly important targets for activity of the 4-component-system and the fraction with LPS stimulation and these genes were involved in inflammatory signaling pathways, namely the JAK-STAT and eicosanoid pathways.
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PMID:Identification of JAK-STAT pathways as important for the anti-inflammatory activity of a Hypericum perforatum fraction and bioactive constituents in RAW 264.7 mouse macrophages. 2030 33

Leptin is an anorexigenic peptide which is synthesized in white adipose tissue. The actions of leptin are mediated by the leptin receptor which is abundantly localized in the hypothalamus and is involved in energy regulation and balance. Recently, there has been evidence suggesting that the leptin receptor is also present in the hippocampus and may be involved with hippocampal excitability and long-term depression. To investigate the physiological function of leptin signalling in the hippocampus, we studied the effects of leptin on methamphetamine-induced ambulatory hyperactivity by utilizing intra-hippocampal infusion (i.h.) in mice. Our results show that the infusion of leptin (5 ng each bilaterally i.h.) does not affect the basal ambulatory activity but significantly suppresses methamphetamine-induced ambulatory hyperactivity as compared to saline-infused controls. Interestingly, higher dose of leptin increases the suppression of the methamphetamine-induced ambulatory hyperactivity. The i.h. infusion of leptin did not activate the JAK-STAT pathway, which is the cellular signalling pathway through which leptin acts in the hypothalamus. The infusion of leptin also did not affect activation of p42/44 MAPK which is known to be another leptin-induced signalling pathway in the brain. These results demonstrate that leptin has a novel potential suppressive effect on methamphetamine-induced hyperlocomotion and also suggest that there must be an alternative pathway in the hippocampus through which leptin signalling is being mediated.
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PMID:Hippocampal leptin suppresses methamphetamine-induced hyperlocomotion. 2048 23

Human aging is associated with complex alterations that contribute to remodelling of physiological processes and ultimately manifests in loss of tissue/organ function. Peripheral blood T cells do not escape this phenomenon and undergo profound remodelling with aging. Thus, investigating the effects of aging on T cells transcriptomics and identifying the underlying regulatory mechanisms can be of extreme importance to understand the aging process in the Immune System (IS). To this aim, we performed an analysis of gene expression data of T cells collected from peripheral blood of 25 healthy human donors of different age from 25 to more than 95 years, in order to characterize changes that occur throughout the entire adult lifespan. By means of microarray analysis, we observed large groups of genes exhibiting non-monotonic expression patterns over time: such behaviour, that could not be observed in typical "two-group" experiments (e.g. young vs. old people) highlights similarities in gene expression profiles of young and "successfully aged" individuals. Genes whose expression profiles change during lifespan were grouped into three main patterns (eigenmodes) to which different biological functions were significantly associated. The analysis of KEGG pathways to which these genes belong indicated that the biological processes altered in T cell aging are not only those typically associated with immune cells (Jak-STAT signalling, T cell receptor signalling, cytokine-cytokine receptor interactions, etc.) but also some not specific of immune cells, such as long-term depression, PPAR and mTOR signalling, glucose and glutathione metabolism, suggesting that T cell aging may be representative of a more generalised aging phenomenon. Thus, the T cell may represent a useful cellular model to study organismal aging. We further searched for over-represented transcription factor binding sites (TFBSs) in the promoter regions of genes clustered by similarity of their age-related patterns to evidence possible co-regulation. A comparison between over-representation of TFBSs and the time course of the corresponding transcription factor (TF) expression levels revealed that a restricted group of TFs may play a central role in driving aging-specific changes in gene expression of T cells.
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PMID:Complex patterns of gene expression in human T cells during in vivo aging. 2068 23


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