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Liquid Biopsies for Pancreatic Cancer: A Step Towards Early Detection
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Joseph Carmicheal, Rahat Jahan, Koelina Ganguly, Ashu Shah, Sukhwinder Kaur
Lipids being an integral part of malignant processes, cancer lipidomics has emerged as a promising arm of metabolomics-based biomarker studies. A wide range of glycerophospholipids and sphingolipids are essential for membrane biosynthesis in proliferating cancer cells, their eventual metastasis, and signal transduction properties. Thus, serum levels of phosphatidylcholines and their derivatives have been found to be upregulated in different malignancies including liver, breast, brain, and prostate [31, 32]. Besides their expression level, the active derivatives of some sphingolipids are well implicated in cancer cell growth and migration. For example, Sphingosine-1 phosphate (SW), an active lysolipid formed by Sphingosine Kinase Type 1 enzyme, was found to induce breast cancer cell MCF-7 growth, transformation, and angiogenesis [33]. Interestingly, S1P was observed to be shed from the tumor cells and was found at elevated levels in ovarian cancer patient’s serum [34]. These findings elucidate the universality of metabolomic profiling that is not inherently specific to pancreatic cancer but has broad application potential.
Lymphocyte trafficking from inductive sites to effector sites
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Valerie Verhasselt, William Agace, Oliver Pabst, Andrew Stagg
In most cases, naive T cells will not find their cognate antigen:MHC on the surface of DCs and will leave the lymph nodes within a few hours via the efferent lymph. Depending on the particular situation, lymphocytes in lymph will directly reenter the circulation or enter the subcapsular region of higher-order lymph nodes. In contrast, if activated, T cells are initially retained within the lymph node, where they undergo rapid clonal expansion. A subset of these cells subsequently migrates via the efferent lymph back to the circulation, from where they can seed other organs. The underlying cellular and molecular mechanisms regulating the egress of lymphocytes from lymph nodes are only beginning to emerge. A key factor in the regulation of lymphocyte egress is the lysophospholipid sphingosine-1-phosphate (S1P). S1P concentrations are higher in blood and lymph than in lymph nodes, and these differential levels of S1P are needed to drive lymphocyte exit. S1P is produced by sphingosine kinases through the phosphorylation of sphingosine and is degraded by sphingosine lyase. Thus, S1P concentrations in tissues, lymph, and blood are regulated by the differential activity of the respective S1P-producing and/or -degrading enzymes as well as S1P release from intracellular stores. High S1P levels in lymph are maintained by the expression of sphingosine kinase in lymphatic endothelial cells, whereas high S1P concentrations in blood rely on S1P release from red blood cells.
Immunologically Mediated Diseases and Allergic Reactions
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Kim A. Campbell, Caroline C. Whitacre
Mast cells and basophils are activated by antigen-bridged IgE molecules bound to FcεRJ molecules on their surface. The biochemical events that occur following receptor cross-linking and which result in mast cell degranulation are not completely understood or have only been partially elucidated. However, it is clear that several intracellular signal transduction pathways are activated. While FcεRJ subunits lack any known enzymatic activity, this receptor associates with protein tyrosine kinases, and protein tyrosine phosphorylation is essential for FcεRJ-mediated degranulation. Tyrosine phosphorylation of phospholipase C induces the breakdown of membrane phosphatidylinositoi 4,5-bisphosphate, resulting in the formation of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (TP3). IP3 and DAG serve as second messenger molecules, which release cytoplasmic calcium from internal stores and activate protein kinase C, respectively Activation of PKC and a rise in Ca2-concentration leads to maximal mast cell secretory activity; however, IP3 alone does not account for the elevation of intracellular calcium. It has recently been shown that FcεRJ activates a sphingosine kinase pathway to mobilize calcium. Many of the regulatory functions of calcium are mediated through the Ca2--binding protein calmodulin. Ca ′-calmodulin complexes are involved in the disassembly of the cytoskeleton, which allows granules to fuse with the plasma membrane and release their preformed mediators into the extracellular environment. In addition, Ca2--calmodulin complexes mediate activation of phospholipase A2, which is important for generation of arachidonic acid, an important intermediate in lipid (prostaglandin and leukotriene) biosynthesis. Lastly, crosslinking FcεRI activates the adenylate cyclase pathway, which results in the conversion of ATP to cAMP and subsequent activation of protein kinase A. Both cAMP and protein kinase A may also be involved in the regulation of degranulation processes.
Molecular Targets of Curcumin and Its Therapeutic Potential for Ovarian Cancer
Published in Nutrition and Cancer, 2022
Malihe Mohamadian, Afsane Bahrami, Maryam Moradi Binabaj, Fereshteh Asgharzadeh, Gordon A. Ferns
Sphingosine kinase 1 (SphK1), a kinase that regulates the balance between ceramide/sphingosine and S1P amounts, controls cellular behaviors and may support tumor progression, including tumor formation, proliferation, metastasis, and invasion of malignant cells. SphK1 also is an important enzyme amplified within the neoplastic transformation. It has been demonstrated that SKI-II, an SphK1 inhibitor, combined with curcumin had a synergistic anti-cell proliferation impact in OC cell lines including SKOV3, CaOV3, and A2780. Moreover, curcumin-induced mitochondrial apoptosis pathways are facilitated by SKI-II which significantly increased curcumin-induced caspase-3 and PARP cleavage, as well as cytochrome c release. The results of the current study also showed that ceramide formation, p38 activation, and Akt inhibition mediated by curcumin are assisted in a synergistic way when SphK1 is inhibited via SKI-II. These findings imply that SKI-II potentiates curcumin-induced growth inhibition and apoptosis in OC cells (106).
Targeted pharmacotherapy for ischemia reperfusion injury in acute myocardial infarction
Published in Expert Opinion on Pharmacotherapy, 2020
Amit Rout, Udaya S Tantry, Marko Novakovic, Ajaypaul Sukhi, Paul A Gurbel
Cangrelor is a potent, intravenously administered, direct-acting P2Y12 antagonist with a potent antiplatelet effect, rapid onset and quick, reversible action. A cardioprotective effect of cangrelor beyond potent inhibition of platelets was demonstrated in two animal studies. Administration of cangrelor shortly before IRI in rabbits reduced infarct size by approximately 30%, and this effect was dose-dependent and correlated with platelet inhibition. However, delaying the cangrelor administration by 10 minutes after the onset of reperfusion eliminated the cardioprotective effect [74]. In a primate model, cangrelor started just prior to reperfusion, and ischemic preconditioning significantly decreased infarct to the same extent [75]. Sphingosine kinase activity is suggested as one of the pathways of cardioprotection by cangrelor [76].
HDL therapy today: from atherosclerosis, to stent compatibility to heart failure
Published in Annals of Medicine, 2019
C.R. Sirtori, M. Ruscica, L. Calabresi, G. Chiesa, R. Giovannoni, J.J. Badimon
A significant role of the sphingomyelin (SM) species, representing 5–10% in weight of total has been recognised in a number of recent reports. The SM derivative sphingosine-1-phosphate (S1P) in particular follows phosphorylation of cell membrane derived sphingosine through SphK1 (sphingosine kinase 1) and SphK2 (sphingosine kinase 2) [10]. S1P rapidly reaches high plasma concentrations being bound to albumin or HDL. This bioactive PL can influence the quality and quantity of HDL dependent function, particularly with the binding partner apolipoprotein M; ApoM deficient mice do not carry S1P and show a functional deficiency of HDL [11]. Cellular protection may be exerted also by way of opening of the mitochondrial channels, exerted by S1P, apo AI, clusterin and miRNA [12,13]. The mechanism appears to be that of induction of STAT3, subsequently bound by mitochondria, decreasing the permeability transition pore and preventing apoptosis [14].