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‣ Pathogen Strategies to Evade Innate Immune Response: A Signaling Point of View

Neves, Bruno Miguel; Lopes, Maria Celeste; Cruz, Maria Teresa
Fonte: InTech Publicador: InTech
Tipo: Parte de Livro
Português
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An effective host defense against pathogens requires appropriate recognition of the invading microorganism by immune cells, conducing to an inflammatory process that involves recruitment of leukocytes to the site of infection, activation of antimicrobial effector mechanisms and induction of an adaptive immune response that ultimately will promote the clearance of infection. All these events require the coordination of multiple signaling pathways, initially triggered by the contact of the pathogen with innate immune cells. The “signal alarm” is normally triggered by ligation of microorganism, or microorganism’s components, to pattern-recognition receptors, causing their phosphorylation and recruitment of adapter molecules, which in turn will activate second messengers within the cytosol of the cells, allowing the transduction of the signal. The second messengers are often protein kinases that in a cascade process ultimately activate the transcription factors responsible for the expression of effector molecules like, cytokines, chemokines and reactive oxygen species, crucial elements to mount an adequate immune response. The activity of such critical intracellular signaling pathways is a process extremely well controlled by a balance of positive and negative regulation...

‣ Glutamate regulation of DARPP-32 phosphorylation in neostriatal neurons involves activation of multiple signaling cascades

Nishi, Akinori; Watanabe, Yasuo; Higashi, Hideho; Tanaka, Masatoshi; Nairn, Angus C.; Greengard, Paul
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
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488.17094%
Dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) plays a central role in medium spiny neurons in the neostriatum in the integration of various neurotransmitter signaling pathways. In its Thr-34-phosphorylated form, it acts as a potent protein phosphatase-1 inhibitor, and, in its Thr-75-phosphorylated form, it acts as a cAMP-dependent kinase inhibitor. Here, we investigated glutamate-dependent signaling cascades in mouse neostriatal slices by analyzing the phosphorylation of DARPP-32 at Thr-34 and Thr-75. Treatment with glutamate (5 mM) caused a complex change in DARPP-32 Thr-34 phosphorylation. An initial rapid increase in Thr-34 phosphorylation was NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/metabotropic glutamate-5 receptor-dependent and was mediated through activation of a neuronal nitric oxide synthase/nitric oxide/cGMP/cGMP-dependent kinase signaling cascade. A subsequent decrease in phosphorylation was attributable to activation of an NMDA/AMPA receptor/Ca2+/protein phosphatase-2B signaling cascade. This decrease was followed by rephosphorylation via a pathway involving metabotropic glutamate-5 receptor/phospholipase C and extracellular receptor kinase signaling cascade. Treatment with glutamate initially decreased Thr-75 phosphorylation through activation of NMDA/AMPA receptor/Ca2+/protein phosphatase-2A signaling. Thereafter...

‣ Activation of Interleukin-1 Signaling Cascades in Normal and Osteoarthritic Articular Cartilage

Fan, Zhiyong; Söder, Stephan; Oehler, Stephan; Fundel, Katrin; Aigner, Thomas
Fonte: American Society for Investigative Pathology Publicador: American Society for Investigative Pathology
Tipo: Artigo de Revista Científica
Publicado em /09/2007 Português
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Interleukin (IL)-1 is one of the most important catabolic cytokines in rheumatoid arthritis. In this study, we were interested in whether we could identify IL-1 expression and activity within normal and osteoarthritic cartilage. mRNA expression of IL-1β and of one of its major target genes, IL-6, was observed at very low levels in normal cartilage, whereas only a minor up-regulation of these cytokines was noted in osteoarthritic cartilage, suggesting that IL-1 signaling is not a major event in osteoarthritis. However, immunolocalization of central mediators involved in IL-1 signaling pathways [38-kd protein kinases, phospho (P)-38-kd protein kinases, extracellular signal-regulated kinase 1/2, P-extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase 1/2, P-c-Jun NH2-terminal kinase 1/2, and nuclear factor κB] showed that the four IL-1 signaling cascades are functional in normal and osteoarthritic articular chondrocytes. In vivo, we found that IL-1 expression and signaling mechanisms were detectible in the upper zones of normal cartilage, whereas these observations were more pronounced in the upper portions of osteoarthritic cartilage. Given these expression and distribution patterns, our data support two roles for IL-1 in the pathophysiology of articular cartilage. First...

‣ A Hidden Feedback in Signaling Cascades Is Revealed

Ventura, Alejandra C.; Sepulchre, Jacques-A.; Merajver, Sofía D.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Cycles involving covalent modification of proteins are key components of the intracellular signaling machinery. Each cycle is comprised of two interconvertable forms of a particular protein. A classic signaling pathway is structured by a chain or cascade of basic cycle units in such a way that the activated protein in one cycle promotes the activation of the next protein in the chain, and so on. Starting from a mechanistic kinetic description and using a careful perturbation analysis, we have derived, to our knowledge for the first time, a consistent approximation of the chain with one variable per cycle. The model we derive is distinct from the one that has been in use in the literature for several years, which is a phenomenological extension of the Goldbeter-Koshland biochemical switch. Even though much has been done regarding the mathematical modeling of these systems, our contribution fills a gap between existing models and, in doing so, we have unveiled critical new properties of this type of signaling cascades. A key feature of our new model is that a negative feedback emerges naturally, exerted between each cycle and its predecessor. Due to this negative feedback, the system displays damped temporal oscillations under constant stimulation and...

‣ Primary Platelet Signaling Cascades and Integrin-mediated Signaling Control ADP-ribosylation Factor (Arf) 6-GTP Levels during Platelet Activation and Aggregation*

Karim, Zubair A.; Choi, Wangsun; Whiteheart, Sidney W.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 02/05/2008 Português
Relevância na Pesquisa
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Previous studies showed that ADP-ribosylation factor 6 (Arf6) is important for platelet function; however, little is known about which signaling events regulate this small GTP-binding protein. Arf6-GTP was monitored in platelets stimulated with a number of agonists (TRAP, thrombin, convulxin, collagen, PMA, thapsigargin, or A23187) and all led to a time-dependent decrease in Arf6-GTP. ADP and U46619 were without effect. Using inhibitors, it was shown that the decrease of Arf6-GTP is a direct consequence of known signaling cascades. Upon stimulation via PAR receptors, Arf6-GTP loss could be blocked by treatment with U-73122, BAPTA/AM, Ro-31-8220, or Gö6976, indicating requirements for phospholipase C, calcium, and protein kinase C (PKC) α/β, respectively. The Arf6-GTP decrease in convulxin-stimulated platelets showed similar requirements and was also sensitive to piceatannol, wortmannin, and LY294002, indicating additional requirements for Syk and phosphatidylinositol 3-kinase. The convulxin-induced decrease was sensitive to both PKCα/β and δ inhibitors. Outside-in signaling, potentially via integrin engagement, caused a second wave of signaling that affected Arf6. Inclusion of RGDS peptides or EGTA, during activation...

‣ Positional Information Generated by Spatially Distributed Signaling Cascades

Muñoz-García, Javier; Neufeld, Zoltan; Kholodenko, Boris N.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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489.9279%
The temporal and stationary behavior of protein modification cascades has been extensively studied, yet little is known about the spatial aspects of signal propagation. We have previously shown that the spatial separation of opposing enzymes, such as a kinase and a phosphatase, creates signaling activity gradients. Here we show under what conditions signals stall in the space or robustly propagate through spatially distributed signaling cascades. Robust signal propagation results in activity gradients with long plateaus, which abruptly decay at successive spatial locations. We derive an approximate analytical solution that relates the maximal amplitude and propagation length of each activation profile with the cascade level, protein diffusivity, and the ratio of the opposing enzyme activities. The control of the spatial signal propagation appears to be very different from the control of transient temporal responses for spatially homogenous cascades. For spatially distributed cascades where activating and deactivating enzymes operate far from saturation, the ratio of the opposing enzyme activities is shown to be a key parameter controlling signal propagation. The signaling gradients characteristic for robust signal propagation exemplify a pattern formation mechanism that generates precise spatial guidance for multiple cellular processes and conveys information about the cell size to the nucleus.

‣ Identification of intracellular signaling cascades mediating the PACAP-induced increase in guinea pig cardiac neuron excitability

Tompkins, John D.; Parsons, Rodney L.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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PACAP increases excitability of guinea pig cardiac neurons, an effect mediated through activation of PAC1 receptors. The signaling cascades that couple activation of the PAC1 receptor to alterations in membrane ionic conductances responsible for the PACAP effect are unknown. Intracellular recordings were made from neurons in kinase inhibitor-treated cardiac ganglia preparations to determine which of the intracellular cascades activated by PAC1 receptor stimulation mediate the PACAP effect. In control cells, long depolarizing current steps elicited 1–3 action potentials. In contrast, during application of 10 nM PACAP, depolarizing current pulses elicited multiple action potential firing (≥5 action potentials) in 79% of the neurons. Pretreatment with an adenylyl cyclase inhibitor, SQ 22536 (100 μM), suppressed the PACAP-induced increase in excitability whereas the presence of U-73122 (10 μM), a potent phospholipase C (PLC) inhibitor, had no effect. Thus, activation of adenylyl cyclase, but not PLC, was a critical step mediating the PACAP effect. Pretreatment with H-89 (1 μM), a protein kinase A inhibitor and PD 98059 (50 μM), a MEK kinase inhibitor, also significantly blunted the PACAP-induced increase in excitability. Furthermore...

‣ Coupling of Ionic Events to Protein Kinase Signaling Cascades upon Activation of α7 Nicotinic Receptor: COOPERATIVE REGULATION OF α2-INTEGRIN EXPRESSION AND Rho KINASE ACTIVITY*

Chernyavsky, Alexander I.; Arredondo, Juan; Qian, Jing; Galitovskiy, Valentin; Grando, Sergei A.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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480.60805%
Defining the signaling mechanisms and effector proteins mediating phenotypic and mechanical plasticity of keratinocytes (KCs) during wound epithelialization is one of the major goals in epithelial cell biology. The acetylcholine (ACh)-gated ion channels, or nicotinic ACh receptors (nAChRs), mediate the nicotinergic signaling that controls crawling locomotion of KCs. To elucidate relative contributions of the ionic and protein kinase-mediated events elicited due to activation of α7 nAChRs, we quantitated expression of α2-integrin gene at the mRNA and protein levels and also measured Rho kinase activity in KCs stimulated with the α7 agonist AR-R17779 while blocking the Na+ or Ca2+ entry and/or inhibiting signaling kinases. The results demonstrated the existence of the two-component signaling systems coupling the ionic events and protein kinase signaling cascades downstream of α7 nAChR to simultaneous up-regulation of α2-integrin expression and activation of Rho kinase. The Raf/MEK1/ERK1/2 cascade up-regulating α2-integrin was activated due to both Ca2+-dependent recruitment of Ca2+/calmodulin-dependent protein kinase II and protein kinase C and Ca2+-independent activation of Ras. Likewise the phosphatidylinositol 3-kinase-mediated activation of Rho kinase was elicited due to both Ca2+ entry-dependent involvement of Ca2+/calmodulin-dependent protein kinase II and Ca2+-independent activation of Jak2. Thus...

‣ Overnutrition and maternal obesity in sheep pregnancy alter the JNK-IRS-1 signaling cascades and cardiac function in the fetal heart

Wang, Jingying; Ma, Heng; Tong, Chao; Zhang, Hanying; Lawlis, Gavin B.; Li, Yuanda; Zang, Mengwei; Ren, Jun; Nijland, Mark J.; Ford, Stephen P.; Nathanielsz, Peter W.; Li, Ji
Fonte: The Federation of American Societies for Experimental Biology Publicador: The Federation of American Societies for Experimental Biology
Tipo: Artigo de Revista Científica
Publicado em /06/2010 Português
Relevância na Pesquisa
479.7466%
Maternal obesity in pregnancy predisposes offspring to insulin resistance and associated cardiovascular disease. Here, we used a well-established sheep model to investigate the effects of maternal obesity on cardiac functions. Multiparous ewes were assigned to a control (CON) diet [100% of National Research Council (NRC) recommendations] or an obesogenic (OB) diet (150% of NRC recommendations) from 60 d before conception to necropsy on d 135 of pregnancy. Fetal blood glucose and insulin were increased (P<0.01, n=8) in OB (35.09±2.03 mg/dl and 3.40±1.43 μU/ml, respectively) vs. CON ewes (23.80±1.38 mg/dl and 0.769±0.256 μU/ml). Phosphorylation of AMP-activated protein kinase (AMPK), a cardioprotective signaling pathway, was reduced (P<0.05), while the stress signaling pathway, p38 MAPK, was up-regulated (P<0.05) in OB maternal and fetal hearts. Phosphorylation of c-Jun N-terminal kinase (JNK) and insulin receptor substrate-1 (IRS-1) at Ser-307 were increased (P<0.05) in OB fetal heart associated with lower downstream PI3K-Akt activity (P<0.05), indicating impaired cardiac insulin signaling. Although OB fetal hearts exhibited a normal contractile function vs. CON fetal hearts during basal perfusion, they developed an impaired heart-rate-left-ventricular-developed pressure product in response to high workload stress. Taken together...

‣ Neutral Antibodies to the TSH Receptor Are Present in Graves’ Disease and Regulate Selective Signaling Cascades

Morshed, Syed A.; Ando, Takao; Latif, Rauf; Davies, Terry F.
Fonte: The Endocrine Society Publicador: The Endocrine Society
Tipo: Artigo de Revista Científica
Português
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TSH receptor (TSHR) antibodies (Abs) may be stimulating, blocking, or neutral in their functional influences and are found in patients with autoimmune thyroid disease, especially Graves’ disease (GD). Stimulators are known to activate the thyroid epithelial cells via both Gs- and Gq-coupled signaling pathways, whereas blockers inhibit the action of TSH and may act as weak agonists. However, TSHR neutral Abs do not block TSH binding and are unable to induce cAMP via Gsα. The importance of such neutral Abs in GD remains unclear because their functional consequence has been assumed to be zero. We hypothesized that: 1) neutral TSHR Abs are more common to GD than generally recognized; 2) they may induce distinct signaling imprints at the TSHR not seen with TSH itself; and 3) these signaling events may alter cellular function. To evaluate these hypotheses, we first confirmed the presence of neutral TSHR Abs in sera from patients with GD and then, using mouse and hamster neutral TSHR monoclonal Abs (N-mAbs) performed detailed signaling studies, including a proteomic Ab array, with rat thyrocytes (FRTL-5) as targets. This allowed us to examine a battery of signaling cascades and their downstream effectors. Neutral TSHR Abs were indeed frequently present in sera from patients with GD. Sixteen of 27 patients (59%) had detectable neutral TSHR Abs by competition assay with N-mAbs. On examining signaling cascades...

‣ The Role of Specific Mitogen-Activated Protein Kinase Signaling Cascades in the Regulation of Steroidogenesis

Manna, Pulak R.; Stocco, Douglas M.
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
Português
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Mitogen-activated protein kinases (MAPKs) comprise a family of serine/threonine kinases that are activated by a large variety of extracellular stimuli and play integral roles in controlling many cellular processes, from the cell surface to the nucleus. The MAPK family includes four distinct MAPK cascades, that is, extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, c-Jun N-terminal kinase or stress-activated protein kinase, and ERK5. These MAPKs are essentially operated through three-tiered consecutive phosphorylation events catalyzed by a MAPK kinase kinase, a MAPK kinase, and a MAPK. MAPKs lie in protein kinase cascades. The MAPK signaling pathways have been demonstrated to be associated with events regulating the expression of the steroidogenic acute regulatory protein (StAR) and steroidogenesis in steroidogenic tissues. However, it has become clear that the regulation of MAPK-dependent StAR expression and steroid synthesis is a complex process and is context dependent. This paper summarizes the current level of understanding concerning the roles of the MAPK signaling cascades in the regulation of StAR expression and steroidogenesis in different steroidogenic cell models.

‣ β-Adrenergic Receptor-PI3K Signaling Crosstalk in Mouse Heart: Elucidation of Immediate Downstream Signaling Cascades

Zhang, Weizhi; Yano, Naohiro; Deng, Minzi; Mao, Quanfu; Shaw, Sunil K.; Tseng, Yi-Tang
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 19/10/2011 Português
Relevância na Pesquisa
488.17094%
Sustained β-adrenergic receptors (βAR) activation leads to cardiac hypertrophy and prevents left ventricular (LV) atrophy during LV unloading. The immediate signaling pathways downstream from βAR stimulation, however, have not been well investigated. The current study was to examine the early cardiac signaling mechanism(s) following βAR stimulation. In adult C57BL/6 mice, acute βAR stimulation induced significant increases in PI3K activity and activation of Akt and ERK1/2 in the heart, but not in lungs or livers. In contrast, the same treatment did not elicit these changes in β1/β2AR double knockout mice. We further showed the specificity of β2AR in this crosstalk as treatment with formoterol, a β2AR-selective agonist, but not dobutamine, a predominantly β1AR agonist, activated cardiac Akt and ERK1/2. Acute βAR stimulation also significantly increased the phosphorylation of mTOR (the mammalian target of rapamycin), P70S6K, ribosomal protein S6, GSK-3α/β (glycogen synthase kinase-3α/β), and FOXO1/3a (the forkhead box family of transcription factors 1 and 3a). Moreover, acute βAR stimulation time-dependently decreased the mRNA levels of the muscle-specific E3 ligases atrogin-1 and muscle ring finger protein-1 (MuRF1) in mouse heart. Our results indicate that acute βAR stimulation in vivo affects multiple cardiac signaling cascades...

‣ Downscaling the Analysis of Complex Transmembrane Signaling Cascades to Closed Attoliter Volumes

Grasso, Luigino; Wyss, Romain; Piguet, Joachim; Werner, Michael; Hassaïne, Ghérici; Hovius, Ruud; Vogel, Horst
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 05/08/2013 Português
Relevância na Pesquisa
480.60805%
Cellular signaling is classically investigated by measuring optical or electrical properties of single or populations of living cells. Here we show that ligand binding to cell surface receptors and subsequent activation of signaling cascades can be monitored in single, (sub-)micrometer sized native vesicles with single-molecule sensitivity. The vesicles are derived from live mammalian cells using chemicals or optical tweezers. They comprise parts of a cell’s plasma membrane and cytosol and represent the smallest autonomous containers performing cellular signaling reactions thus functioning like minimized cells. Using fluorescence microscopies, we measured in individual vesicles the different steps of G-protein-coupled receptor mediated signaling like ligand binding to receptors, subsequent G-protein activation and finally arrestin translocation indicating receptor deactivation. Observing cellular signaling reactions in individual vesicles opens the door for downscaling bioanalysis of cellular functions to the attoliter range, multiplexing single cell analysis, and investigating receptor mediated signaling in multiarray format.

‣ Is There a Role for Treating Inflammation in Moyamoya Disease?: A Review of Histopathology, Genetics, and Signaling Cascades

Young, Adam M. H.; Karri, Surya K.; Ogilvy, Christopher S.; Zhao, Ninghui
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 14/08/2013 Português
Relevância na Pesquisa
481.04766%
Moyamoya disease is a slowly progressing steno-occlusive condition affecting the cerebrovasculature. Affecting the terminal internal carotid arteries (ICA) and there branches, bilaterally, a resulting in a fine vascular network in the base of the brain to allow for compensation of the stenosed vessels. While there is obvious evidence of the involvement of inflammatory proteins in the condition, this has historically not been acknowledged as a causal factor. Here we describe the fundamental histopathology, genetics, and signaling cascades involved in moyamoya and debate whether these factors can be linked as causal factor for the condition or whether they are simply a secondary result of the ischemia described in the condition. A particular focus has been placed on the multitude of signaling cascades linked to the condition as these are viewed as having the greatest therapeutic potential. As such we hope to draw some novel insight into potential diagnostic and therapeutic inflammatory targets in the condition.

‣ Estrogen action and cytoplasmic signaling cascades. Part I: membrane-associated signaling complexes

Segars, James H.; Driggers, Paul H.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/2002 Português
Relevância na Pesquisa
486.95477%
Remarkable progress in recent years has suggested that estrogen action in vivo is complex and often involves activation of cytoplasmic signaling cascades in addition to genomic actions mediated directly through estrogen receptors α and β. Rather than a linear response mediated solely through estrogen-responsive DNA elements, in vivo estrogen might simultaneously activate distinct signaling cascades that function as networks to coordinate tissue responses to estrogen. This complex signaling system provides for exquisite control and plasticity of response to estrogen at the tissue level, and undoubtedly contributes to the remarkable tissue-specific responses to estrogens. In part I of this series, we summarize cytoplasmic signaling modules involving estrogen or estrogen receptors, with particular focus on recently described membrane-associated signaling complexes.

‣ Therapeutic CK2 inhibition attenuates diverse prosurvival signaling cascades and decreases cell viability in human breast cancer cells

Gray, G. Kenneth; McFarland, Braden C.; Rowse, Amber L.; Gibson, Sara A.; Benveniste, Etty N.
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 23/07/2014 Português
Relevância na Pesquisa
481.04766%
Breast cancer is the most common malignancy in women worldwide and remains a major cause of mortality, thus necessitating further therapeutic advancements. In breast cancer, numerous cell signaling pathways are aberrantly activated to produce the myriad phenotypes associated with malignancy; such pathways include the PI3K/Akt/mTOR, NF-κB and JAK/STAT cascades. These pathways are highly interconnected, but one prominent lateral enhancer of each is the remarkably promiscuous kinase CK2. CK2 expression has been shown to be elevated in cancer, thus implicating it in tumorigenesis through its effects on oncogenic signaling cascades. In this study, we identify aberrant expression of CK2 subunits in human breast samples from The Cancer Genome Atlas dataset. Additionally, two specific small molecule inhibitors of CK2, CX-4945 and TBB, were used to examine the role of CK2 in two human breast cancer cell lines, MDA-MB-231 and MCF-7 cells. We show that CK2 inhibition attenuates constitutive PI3K/Akt/mTOR, NF-κB and STAT3 activation and inducible NF-κB and JAK/STAT activation and downstream transcriptional activity. CX-4945 treatment caused a range of phenotypic changes in these cell lines, including decreased viability, cell cycle arrest, apoptosis and loss of migratory capacity. Overall...

‣ Tumor necrosis factor-alpha mediates activation of NF-κB and JNK signaling cascades in retinal ganglion cells and astrocytes in opposite ways

Dvoriantchikova, Galina; Ivanov, Dmitry
Fonte: BlackWell Publishing Ltd Publicador: BlackWell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
488.85965%
Tumor necrosis factor-alpha (TNF) is an important mediator of the innate immune response in the retina. TNF can activate various signaling cascades, including NF-κB, nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways. The harmful role of these pathways, as well as of TNF, has previously been shown in several retinal neurodegenerative conditions including glaucoma and retinal ischemia. However, TNF and TNF-regulated signaling cascades are capable not only of mediating neurotoxicity, but of being protective. We performed this study to delineate the beneficial and detrimental effects of TNF signaling in the retina. To this end, we used TNF-treated primary retinal ganglion cell (RGC) and astrocyte cultures. Levels of expression of NF-κB subunits in RGCs and astrocytes were evaluated by quantitative RT-PCR (qRT-PCR) and Western blot (WB) analysis. NF-κB and JNK activity in TNF-treated cells was determined in a time-dependent manner using ELISA and WB. Gene expression in TNF-treated astrocytes was measured by qRT-PCR. We found that NF-κB family members were present in RGCs and astrocytes at the mRNA and protein levels. RGCs failed to activate NF-κB in the presence of TNF, a phenomenon that was associated with sustained JNK activation and RGC death. However...

‣ Is There a Role for Treating Inflammation in Moyamoya Disease?: A Review of Histopathology, Genetics, and Signaling Cascades

Young, Adam M. H.; Karri, Surya K.; Ogilvy, Christopher S.; Zhao, Ninghui
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
481.04766%
Moyamoya disease is a slowly progressing steno-occlusive condition affecting the cerebrovasculature. Affecting the terminal internal carotid arteries (ICA) and there branches, bilaterally, a resulting in a fine vascular network in the base of the brain to allow for compensation of the stenosed vessels. While there is obvious evidence of the involvement of inflammatory proteins in the condition, this has historically not been acknowledged as a causal factor. Here we describe the fundamental histopathology, genetics, and signaling cascades involved in moyamoya and debate whether these factors can be linked as causal factor for the condition or whether they are simply a secondary result of the ischemia described in the condition. A particular focus has been placed on the multitude of signaling cascades linked to the condition as these are viewed as having the greatest therapeutic potential. As such we hope to draw some novel insight into potential diagnostic and therapeutic inflammatory targets in the condition.

‣ A formulation of the channel capacity of biochemical signaling cascades

Tsuruyama, Tatsuaki
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
481.04766%
Living organisms are non-equilibrium, fluctuating, dynamic systems containing multi-step biological signaling cascades (BSC) with the ability to transduce changes in the concentration of extracellular molecules such as cytokines into changes in gene expression. Here, we derived basic equations that describe the channel capacity and information density of BSC in terms of the average entropy production rate deduced using the fluctuation theorem.; Comment: Another article arXiv:1205.0382 [q-bio.MN] "The channel capacity and information density of biochemical signaling cascades " is the revised version of this article

‣ Regulation of CaMKKβ Dependent Signaling Pathways

Green, Michelle Frances
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2011 Português
Relevância na Pesquisa
482.64164%

Ca2+/Calmodulin-dependent protein kinase kinase β(CaMKKβ) is a serine/threonine directed kinase which is activated following increases in intracellular Ca2+. CaMKKβ activates Ca2+/Calmodulin-dependent protein kinase I (CaMKI), Ca2+/Calmodulin-dependent protein kinase IV (CaMKIV), and the AMP-dependent protein kinase (AMPK) in a number of physiological pathways including learning and memory formation, neuronal differentiation, and regulation of energy balance. The purpose of the work presented in this dissertation is to better understand the regulation of CaMKKβ activity and specificity in CaMKKβ-dependent signaling cascades. First, the CaMKKβ-AMPK signaling complex is examined using biochemical assays. In both brain and cell lysates CaMKKβ and AMPK form a stable complex which can be examined by co-immunoprecipitation. This complex lacks the AMPKγ subunit and is not allosterically activated by adenosine 5'-monophohphate (AMP) binding. Using a series of CaMKKβ and AMPK mutants it was determined that the kinase domains of CaMKKβ and AMPK are necessary for their interaction and CaMKKβ must be active and bound to adenosine 5'-triphosphate (ATP) to form a complex with AMPK. However...