scholarly journals LysoPC and PAF Trigger Arachidonic Acid Release by Divergent Signaling Mechanisms in Monocytes

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Janne Oestvang ◽  
Marit W. Anthonsen ◽  
Berit Johansen
Keyword(s):  
Intracellular Signaling ◽  
Platelet Activating Factor ◽  
Low Density Lipoproteins ◽  
Intracellular Signaling Pathway ◽  
Signaling Mechanisms ◽  
Paf Receptor ◽  
Sequential Activation ◽  
Acid Release ◽  
Atherosclerosis Prevention ◽  
Macrophage Accumulation

Oxidized low-density lipoproteins (LDLs) play an important role during the development of atherosclerosis characterized by intimal inflammation and macrophage accumulation. A key component of LDL is lysophosphatidylcholine (lysoPC). LysoPC is a strong proinflammatory mediator, and its mechanism is uncertain, but it has been suggested to be mediated via the platelet activating factor (PAF) receptor. Here, we report that PAF triggers a pertussis toxin- (PTX-) sensitive intracellular signaling pathway leading to sequential activation of sPLA2, PLD, cPLA2, and AA release in human-derived monocytes. In contrast, lysoPC initiates two signaling pathways, one sequentially activating PLD and cPLA2, and a second parallel PTX-sensitive pathway activating cPLA2with concomitant activation of sPLA2, all leading to AA release. In conclusion, lysoPC and PAF stimulate AA release by divergent pathways suggesting involvement of independent receptors. Elucidation of monocyte lysoPC-specific signaling mechanisms will aid in the development of novel strategies for atherosclerosis prevention, diagnosis, and therapy.

scholarly journals Paf receptor expression in the marsupial embryo and endometrium during embryonic diapause

Reproduction ◽  
2014 ◽  
Vol 147 (1) ◽  
pp. 21-31 ◽  
Author(s):  
Jane C Fenelon ◽  
Geoff Shaw ◽  
Chris O'Neill ◽  
Stephen Frankenberg ◽  
Marilyn B Renfree
Keyword(s):  
Platelet Activating Factor ◽  
Tammar Wallaby ◽  
Receptor Expression ◽  
Limiting Factor ◽  
Embryonic Diapause ◽  
Paf Receptor ◽  
Sequential Activation ◽  
Uterine Environment ◽  
Low Levels

The control of reactivation from embryonic diapause in the tammar wallaby (Macropus eugenii) involves sequential activation of the corpus luteum, secretion of progesterone that stimulates endometrial secretion and subsequent changes in the uterine environment that activate the embryo. However, the precise signals between the endometrium and the blastocyst are currently unknown. In eutherians, both the phospholipid Paf and its receptor, platelet-activating factor receptor (PTAFR), are present in the embryo and the endometrium. In the tammar, endometrial Paf releasein vitroincreases around the time of the early progesterone pulse that occurs around the time of reactivation, but whether Paf can reactivate the blastocyst is unknown. We cloned and characterised the expression of PTAFR in the tammar embryo and endometrium at entry into embryonic diapause, during its maintenance and after reactivation. Tammar PTAFR sequence and protein were highly conserved with mammalian orthologues. In the endometrium, PTAFR was expressed at a constant level in the glandular epithelium across all stages and in the luminal epithelium during both diapause and reactivation. Thus, the presence of the receptor appears not to be a limiting factor for Paf actions in the endometrium. However, the low levels of PTAFR in the embryo during diapause, together with its up-regulation and subsequent internalisation at reactivation, supports earlier results suggesting that endometrial Paf could be involved in reactivation of the tammar blastocyst from embryonic diapause.

Oxygen-dependent PAF receptor binding and intracellular signaling in ovine fetal pulmonary vascular smooth muscle

2005 ◽  
Vol 288 (5) ◽  
pp. L879-L886 ◽  
Author(s):  
Basil O. Ibe ◽  
Ada M. Portugal ◽  
Shiva Chaturvedi ◽  
J. Usha Raj
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Cell Signaling ◽  
Oxygen Tension ◽  
Intracellular Signaling ◽  
Platelet Activating Factor ◽  
Calcium Flux ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Paf Receptor

Circulating levels of platelet-activating factor (PAF) are high in the fetus, and PAF is active in maintaining high PVR in fetal hypoxia (Ibe BO, Hibler S, Raj J. J Appl Physiol 85: 1079–1085, 1998). PAF synthesis by fetal pulmonary vascular smooth muscle cells (PVSMC) is high in hypoxia, but how oxygen tension affects PAF receptor (PAF-r) binding in PVSMC is not known. We studied the effect of oxygen tension on PAF-r binding and signaling in fetal PVSMC. PAF binding was saturable. PAF-r density (Bmax: fmol/106 cells; means ± SE, n = 6), 25.2 ± 0.77 during hypoxia (Po2 <40 Torr), was higher than 13.9 ± 0.44 during normoxia (Po2 ∼100 Torr). Kd was twofold lower in hypoxia than normoxia. PAF-r protein expression, 35–40% greater in hypoxia, was inhibited by cycloheximide, a protein synthesis inhibitor, suggesting translational regulation. IP3 release, an index of PAF-r-mediated cell signaling, was greater in hypoxia (EC50: hypoxia, 2.94 ± 0.61; normoxia, 5.85 ± 0.51 nM). Exogenous PAF induced 50–90% greater intracellular calcium flux in cells during hypoxia, indicating hypoxia augments PAF-r-mediated cell signaling. PAF-r phosphorylation, with or without 5 nM PAF, was 40% greater in hypoxia. These data show 1) hypoxia upregulates PAF-r binding, PAF-r phosphorylation, and PAF-r-mediated intracellular signaling, evidenced by augmented IP3 production and intracellular Ca2+ flux; and 2) hypoxia-induced PAF-r phosphorylation results in activation of PAF-r-mediated signal transduction. The data suggest the fetal hypoxic environment facilitates PAF-r binding and signaling, thereby promoting PAF-mediated pulmonary vasoconstriction and maintenance of high PVR in utero.

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

2012 ◽  
Vol 92 (4) ◽  
pp. 1699-1775 ◽  
Author(s):  
Gábor Pethő ◽  
Peter W. Reeh
Keyword(s):  
Nitric Oxide ◽  
Sensory Neurons ◽  
Intracellular Signaling ◽  
Platelet Activating Factor ◽  
Nerve Endings ◽  
Behavioral Models ◽  
Cellular Models ◽  
Signaling Mechanisms ◽  
The Central Nervous System

Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation or excitation by these substances of nociceptive nerve endings or fibers implicates generation of action potentials which then travel to the central nervous system and may induce pain sensation. Sensitization of nociceptors refers to their increased responsiveness to either thermal, mechanical, or chemical stimuli that may be translated to corresponding hyperalgesias. This review aims to give an account of the excitatory and sensitizing actions of inflammatory mediators including bradykinin, prostaglandins, thromboxanes, leukotrienes, platelet-activating factor, and nitric oxide on nociceptive primary afferent neurons. Manifestations, receptor molecules, and intracellular signaling mechanisms of the effects of these mediators are discussed in detail. With regard to signaling, most data reported have been obtained from transfected nonneuronal cells and somata of cultured sensory neurons as these structures are more accessible to direct study of sensory and signal transduction. The peripheral processes of sensory neurons, where painful stimuli actually affect the nociceptors in vivo, show marked differences with respect to biophysics, ultrastructure, and equipment with receptors and ion channels compared with cellular models. Therefore, an effort was made to highlight signaling mechanisms for which supporting data from molecular, cellular, and behavioral models are consistent with findings that reflect properties of peripheral nociceptive nerve endings. Identified molecular elements of these signaling pathways may serve as validated targets for development of novel types of analgesic drugs.

THE ROLE OF PHOSPHATIDYLINOSITOL-3-KINASE IN CARCINOGENESIS

2017 ◽  
Vol 63 (4) ◽  
pp. 545-556
Author(s):  
Natalya Oskina ◽  
Aleksandr Shcherbakov ◽  
Maksim Filipenko ◽  
Nikolay Kushlinskiy ◽  
L. Ovchinnikova
Keyword(s):  
Genetic Disease ◽  
Intracellular Signaling ◽  
Somatic Mutations ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Phosphatidylinositol 3 Kinase ◽  
Intracellular Signaling Pathway ◽  
Metabolic Activities ◽  
Carcinogenic Process

Currently it is established that cancer is a genetic disease and that somatic mutations are the initiators of the carcinogenic process. The PI3K/AKT/mTOR pathway is an important intracellular signaling pathway regulating the cell growth and metabolic activities. Aberrant activation of the PI3K pathway is commonly observed in many different cancers. In this review we analyze the genetic alterations of PI3K pathway in a variety of human malignancies and discuss their possible implications for diagnosis and therapy.

scholarly journals PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

2021 ◽  
Vol 22 (7) ◽  
pp. 3464
Author(s):  
Rosalin Mishra ◽  
Hima Patel ◽  
Samar Alanazi ◽  
Mary Kate Kilroy ◽  
Joan T. Garrett
Keyword(s):  
Clinical Trials ◽  
Intracellular Signaling ◽  
Pi3k Pathway ◽  
Combination Therapies ◽  
Intracellular Signaling Pathway ◽  
Pi3k Inhibitors ◽  
Promising Therapeutic Target ◽  
Cancer Cell Survival ◽  
Current Therapies ◽  
Cancer Types

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.

The Pleiotropic Intricacies of Hedgehog Signaling: From Craniofacial Patterning to Carcinogenesis

FACE ◽  
2021 ◽  
pp. 273250162110243
Author(s):  
Mikhail Pakvasa ◽  
Andrew B. Tucker ◽  
Timothy Shen ◽  
Tong-Chuan He ◽  
Russell R. Reid
Keyword(s):  
Intracellular Signaling ◽  
Limb Development ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Craniofacial Development ◽  
Signaling Cascade ◽  
Signaling Mechanisms ◽  
Intracellular Signaling Cascade ◽  
And Function

Hedgehog signaling was discovered more than 40 years ago in experiments demonstrating that it is a fundamental mediator of limb development. Since that time, it has been shown to be important in development, homeostasis, and disease. The hedgehog pathway proceeds through a pathway highly conserved throughout animals beginning with the extracellular diffusion of hedgehog ligands, proceeding through an intracellular signaling cascade, and ending with the activation of specific target genes. A vast amount of research has been done elucidating hedgehog signaling mechanisms and regulation. This research has found a complex system of genetics and signaling that helps determine how organisms develop and function. This review provides an overview of what is known about hedgehog genetics and signaling, followed by an in-depth discussion of the role of hedgehog signaling in craniofacial development and carcinogenesis.

scholarly journals Activation of the receptor tyrosine kinase RET improves long-term hematopoietic stem cell outgrowth and potency

Blood ◽  
2020 ◽  
Vol 136 (22) ◽  
pp. 2535-2547 ◽  
Author(s):  
W. Grey ◽  
R. Chauhan ◽  
M. Piganeau ◽  
H. Huerga Encabo ◽  
M. Garcia-Albornoz ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Culture Conditions ◽  
Cellular Growth ◽  
Great Promise ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Intracellular Signaling Pathway ◽  
Wide Range

Abstract Expansion of human hematopoietic stem cells (HSCs) is a rapidly advancing field showing great promise for clinical applications. Recent evidence has implicated the nervous system and glial family ligands (GFLs) as potential drivers of hematopoietic survival and self-renewal in the bone marrow niche; how to apply this process to HSC maintenance and expansion has yet to be explored. We show a role for the GFL receptor, RET, at the cell surface of HSCs in mediating sustained cellular growth, resistance to stress, and improved cell survival throughout in vitro expansion. HSCs treated with the key RET ligand/coreceptor complex, glial-derived neurotrophic factor and its coreceptor, exhibit improved progenitor function at primary transplantation and improved long-term HSC function at secondary transplantation. Finally, we show that RET drives a multifaceted intracellular signaling pathway, including key signaling intermediates protein kinase B, extracellular signal-regulated kinase 1/2, NF-κB, and p53, responsible for a wide range of cellular and genetic responses that improve cell growth and survival under culture conditions.

scholarly journals Lack of Platelet-Activating Factor Receptor Attenuates Experimental Food Allergy but Not Its Metabolic Alterations regarding Adipokine Levels

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Nathália Vieira Batista ◽  
Roberta Cristelli Fonseca ◽  
Denise Perez ◽  
Rafaela Vaz Sousa Pereira ◽  
Juliana de Lima Alves ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Food Allergy ◽  
Inflammatory Process ◽  
Platelet Activating Factor ◽  
Oral Challenge ◽  
Tissue Loss ◽  
Lack Of Information ◽  
Paf Receptor ◽  
Rolling Leukocytes

Platelet-activating factor (PAF) is known to be an important mediator of anaphylaxis. However, there is a lack of information in the literature about the role of PAF in food allergy. The aim of this work was to elucidate the participation of PAF during food allergy development and the consequent adipose tissue inflammation along with its alterations. Our data demonstrated that, both before oral challenge and after 7 days receiving ovalbumin (OVA) diet, OVA-sensitized mice lacking the PAF receptor (PAFR) showed a decreased level of anti-OVA IgE associated with attenuated allergic markers in comparison to wild type (WT) mice. Moreover, there was less body weight and adipose tissue loss in PAFR-deficient mice. However, some features of inflamed adipose tissue presented by sensitized PAFR-deficient and WT mice after oral challenge were similar, such as a higher rate of rolling leukocytes in this tissue and lower circulating levels of adipokines (resistin and adiponectin) in comparison to nonsensitized mice. Therefore, PAF signaling through PAFR is important for the allergic response to OVA but not for the adipokine alterations caused by this inflammatory process. Our work clarifies some effects of PAF during food allergy along with its role on the metabolic consequences of this inflammatory process.

scholarly journals Signaling through mitogen-activated protein kinase and Rac/Rho does not duplicate the effects of activated Ras on skeletal myogenesis.

1997 ◽  
Vol 17 (7) ◽  
pp. 3547-3555 ◽  
Author(s):  
M B Ramocki ◽  
S E Johnson ◽  
M A White ◽  
C L Ashendel ◽  
S F Konieczny ◽  
...  
Keyword(s):  
Map Kinase ◽  
Signaling Pathways ◽  
Transcriptional Activation ◽  
Intracellular Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Negative Effects ◽  
Intracellular Signaling Pathway ◽  
Helix Loop Helix ◽  
Mitogen Activated Protein

The ability of basic helix-loop-helix muscle regulatory factors (MRFs), such as MyoD, to convert nonmuscle cells to a myogenic lineage is regulated by numerous growth factor and oncoprotein signaling pathways. Previous studies have shown that H-Ras 12V inhibits differentiation to a skeletal muscle lineage by disrupting MRF function via a mechanism that is independent of the dimerization, DNA binding, and inherent transcriptional activation properties of the proteins. To investigate the intracellular signaling pathway(s) that mediates the inhibition of MRF-induced myogenesis by oncogenic Ras, we tested two transformation-defective H-Ras 12V effector domain variants for their ability to alter terminal differentiation. H-Ras 12V,35S retains the ability to activate the Raf/MEK/mitogen-activated protein (MAP) kinase cascade, whereas H-Ras 12V,40C is unable to interact directly with Raf-1 yet still influences other signaling intermediates, including Rac and Rho. Expression of each H-Ras 12V variant in C3H10T1/2 cells abrogates MyoD-induced activation of the complete myogenic program, suggesting that MAP kinase-dependent and -independent Ras signaling pathways individually block myogenesis in this model system. However, additional studies with constitutively activated Rac1 and RhoA proteins revealed no negative effects on MyoD-induced myogenesis. Similarly, treatment of Ras-inhibited myoblasts with the MEK1 inhibitor PD98059 revealed that elevated MAP kinase activity is not a significant contributor to the H-Ras 12V effect. These data suggest that an additional Ras pathway, distinct from the well-characterized MAP kinase and Rac/Rho pathways known to be important for the transforming function of activated Ras, is primarily responsible for the inhibition of myogenesis by H-Ras 12V.

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