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Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Cross-Field Chemistry".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 63176

Special Issue Editors

Prof. Dr. George Kokotos

E-Mail Website
Guest Editor
Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece
Interests: design, synthesis and study of enzyme inhibitors; inhibitors of phospholipase A2; inhibitors of autotaxin; synthesis and study of bioactive lipids; synthesis of small molecules exhibiting anti-inflammatory and cytotoxic activity; organocatalysis; biotransformations in organic synthesis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Jesús Balsinde

E-Mail Website
Guest Editor
1. Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), 47003 Valladolid, Spain
2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
Interests: inflammation; innate immunity; lipid mediators; phospholipases; lipins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Edward A. Dennis received his B.A. from Yale University in 1963 and his Ph.D. from Harvard University in 1968. Following the completion of his postdoctoral fellowship at Harvard Medical School, he was appointed (1970) assistant professor at the University of California, San Diego (UCSD). He became Professor in 1981 and then Distinguished Professor in 2004 in the Department of Chemistry and Biochemistry and Department of Pharmacology at the School of Medicine of UCSD. He has since served as Chair of the Department of Chemistry and Biochemistry, Editor-in-Chief of the Journal of Lipid Research (2003–2018) and Director of the LIPID MAPS NIH Glue Grant Consortium (2003–2014). He was the recipient of the American Society of Biochemistry and Molecular Biology’s Avanti Award in Lipid Enzymology in 2000, the European Federation for Lipid Science and Technology’s European Lipid Science Award in 2008, the American Chemical Society, San Diego Section, Distinguished Scientist Award in 2016, and the Bert Vallee Award in Biomedical Science from the American Society of Biochemistry and Molecular Biology (2020).

Prof. Dennis’ career research focus has been on the structure, function, mechanism, and inhibition of the enzyme phospholipase A2 as well as on signal transduction, inflammation, lipid metabolism, eicosanoid action, and lipidomics. Since phospholipase A2 releases arachidonic acid, it is partially responsible for the regulation of eicosanoid cascade and prostaglandin production. The regulation of the production of these compounds has been shown to be important in inflammatory diseases, including cancer, diabetes, and degenerative diseases. Thus, understanding how phospholipase A2 functions and how to control its activity offer important avenues for developing novel pharmacological agents for controlling numerous diseases.

Molecules is pleased to announce a Special Issue honoring Prof. Edward A. Dennis, on the occasion of his 80th birthday, for his outstanding achievements in lipid chemistry and biochemistry. This Special Issue is dedicated to all aspects of lipid chemistry and biochemistry, in particular to lipid metabolizing enzymes, such as phospholipases and lipases, lipid analysis including cutting-edge lipidomics, lipid signaling, and bioactive lipids, and lipids in health and disease.

It is a pleasure to invite you to submit a manuscript to this Honorary Special Issue. Regular articles, communications, and reviews are all welcome.

Prof. Dr. George Kokotos
Prof. Dr. Jesús Balsinde 
Guest Editors

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Keywords

  • Phospholipase A2
  • Lipidomics
  • Fatty acids
  • Eicosanoids
  • Lipid analysis
  • Lipid synthesis
  • Inhibitors of lipases, phospholipases, autotaxin
  • Lipid signaling
  • Food lipids
  • Lipids and health

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Published Papers (15 papers)

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Research

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10 pages, 3694 KiB  
Article
Phosphorylation of cPLA2α at Ser505 Is Necessary for Its Translocation to PtdInsP2-Enriched Membranes
by Javier Casas, Jesús Balsinde and María A. Balboa
Molecules 2022, 27(7), 2347; https://doi.org/10.3390/molecules27072347 - 6 Apr 2022
Cited by 4 | Viewed by 2032
Abstract
Group IVA cytosolic phospholipase A2α (cPLA2α) is a key enzyme in physiology and pathophysiology because it constitutes a rate-limiting step in the pathway for the generation of pro- and anti-inflammatory eicosanoid lipid mediators. cPLA2α activity is tightly [...] Read more.
Group IVA cytosolic phospholipase A2α (cPLA2α) is a key enzyme in physiology and pathophysiology because it constitutes a rate-limiting step in the pathway for the generation of pro- and anti-inflammatory eicosanoid lipid mediators. cPLA2α activity is tightly regulated by multiple factors, including the intracellular Ca2+ concentration, phosphorylation reactions, and cellular phosphatidylinositol (4,5) bisphosphate levels (PtdInsP2). In the present work, we demonstrate that phosphorylation of the enzyme at Ser505 is an important step for the translocation of the enzyme to PtdInsP2–enriched membranes in human cells. Constructs of eGFP-cPLA2 mutated in Ser505 to Ala (S505A) exhibit a delayed translocation in response to elevated intracellular Ca2+, and also in response to increases in intracellular PtdInsP2 levels. Conversely, translocation of a phosphorylation mimic mutant (S505E) is fully observed in response to cellular increases in PtdInsP2 levels. Collectively, these results suggest that phosphorylation of cPLA2α at Ser505 is necessary for the enzyme to translocate to internal membranes and mobilize arachidonic acid for eicosanoid synthesis. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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16 pages, 5461 KiB  
Article
Inhibition of Cytosolic Phospholipase A2α Induces Apoptosis in Multiple Myeloma Cells
by Nur Mahammad, Felicity J. Ashcroft, Astrid J. Feuerherm, Samah Elsaadi, Esten N. Vandsemb, Magne Børset and Berit Johansen
Molecules 2021, 26(24), 7447; https://doi.org/10.3390/molecules26247447 - 9 Dec 2021
Cited by 5 | Viewed by 3587
Abstract
Cytosolic phospholipase A2α (cPLA2α) is the rate-limiting enzyme in releasing arachidonic acid and biosynthesis of its derivative eicosanoids. Thus, the catalytic activity of cPLA2α plays an important role in cellular metabolism in healthy as well as cancer cells. There is mounting evidence suggesting [...] Read more.
Cytosolic phospholipase A2α (cPLA2α) is the rate-limiting enzyme in releasing arachidonic acid and biosynthesis of its derivative eicosanoids. Thus, the catalytic activity of cPLA2α plays an important role in cellular metabolism in healthy as well as cancer cells. There is mounting evidence suggesting that cPLA2α is an interesting target for cancer treatment; however, it is unclear which cancers are most relevant for further investigation. Here we report the relative expression of cPLA2α in a variety of cancers and cancer cell lines using publicly available datasets. The profiling of a panel of cancer cell lines representing different tissue origins suggests that hematological malignancies are particularly sensitive to the growth inhibitory effect of cPLA2α inhibition. Several hematological cancers and cancer cell lines overexpressed cPLA2α, including multiple myeloma. Multiple myeloma is an incurable hematological cancer of plasma cells in the bone marrow with an emerging requirement of therapeutic approaches. We show here that two cPLA2α inhibitors AVX420 and AVX002, significantly and dose-dependently reduced the viability of multiple myeloma cells and induced apoptosis in vitro. Our findings implicate cPLA2α activity in the survival of multiple myeloma cells and support further studies into cPLA2α as a potential target for treating hematological cancers, including multiple myeloma. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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17 pages, 2496 KiB  
Article
Alterations in β-Cell Sphingolipid Profile Associated with ER Stress and iPLA2β: Another Contributor to β-Cell Apoptosis in Type 1 Diabetes
by Tomader Ali, Xiaoyong Lei, Suzanne E. Barbour, Akio Koizumi, Charles E. Chalfant and Sasanka Ramanadham
Molecules 2021, 26(21), 6361; https://doi.org/10.3390/molecules26216361 - 21 Oct 2021
Cited by 4 | Viewed by 2295
Abstract
Type 1 diabetes (T1D) development, in part, is due to ER stress-induced β-cell apoptosis. Activation of the Ca2+-independent phospholipase A2 beta (iPLA2β) leads to the generation of pro-inflammatory eicosanoids, which contribute to β-cell death and T1D. ER stress [...] Read more.
Type 1 diabetes (T1D) development, in part, is due to ER stress-induced β-cell apoptosis. Activation of the Ca2+-independent phospholipase A2 beta (iPLA2β) leads to the generation of pro-inflammatory eicosanoids, which contribute to β-cell death and T1D. ER stress induces iPLA2β-mediated generation of pro-apoptotic ceramides via neutral sphingomyelinase (NSMase). To gain a better understanding of the impact of iPLA2β on sphingolipids (SLs), we characterized their profile in β-cells undergoing ER stress. ESI/MS/MS analyses followed by ANOVA/Student’s t-test were used to assess differences in sphingolipids molecular species in Vector (V) control and iPLA2β-overexpressing (OE) INS-1 and Akita (AK, spontaneous model of ER stress) and WT-littermate (AK-WT) β-cells. As expected, iPLA2β induction was greater in the OE and AK cells in comparison with V and WT cells. We report here that ER stress led to elevations in pro-apoptotic and decreases in pro-survival sphingolipids and that the inactivation of iPLA2β restores the sphingolipid species toward those that promote cell survival. In view of our recent finding that the SL profile in macrophages—the initiators of autoimmune responses leading to T1D—is not significantly altered during T1D development, we posit that the iPLA2β-mediated shift in the β-cell sphingolipid profile is an important contributor to β-cell death associated with T1D. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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12 pages, 2273 KiB  
Article
ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo
by Bisera Stepanovska Tanturovska, Aleksandra Zivkovic, Faik Imeri, Thomas Homann, Burkhard Kleuser, Holger Stark and Andrea Huwiler
Molecules 2021, 26(17), 5134; https://doi.org/10.3390/molecules26175134 - 24 Aug 2021
Cited by 6 | Viewed by 2390
Abstract
Sphingosine 1-phosphate (S1P) is an extensively studied signaling molecule that contributes to cell proliferation, survival, migration and other functions through binding to specific S1P receptors. The cycle of S1P1 internalization upon S1P binding and recycling to the cell surface when local S1P [...] Read more.
Sphingosine 1-phosphate (S1P) is an extensively studied signaling molecule that contributes to cell proliferation, survival, migration and other functions through binding to specific S1P receptors. The cycle of S1P1 internalization upon S1P binding and recycling to the cell surface when local S1P concentrations are low drives T cell trafficking. S1P1 modulators, such as fingolimod, disrupt this recycling by inducing persistent S1P1 internalization and receptor degradation, which results in blocked egress of T cells from the secondary lymphoid tissues. The approval of these compounds for the treatment of multiple sclerosis has placed the development of S1PR modulators in the focus of pharmacological research, mostly for autoimmune indications. Here, we report on a novel anellated bismorpholino derivative of oxy-fingolimod, named ST-2191, which exerts selective S1P1 agonist and functional antagonist potency. ST-2191 is also effective in reducing the lymphocyte number in mice, and this effect is not dependent on phosphorylation by sphingosine kinase 2 for activity. These data show that ST-2191 is a novel S1P1 modulator, but further experiments are needed to analyze the therapeutic impact of ST-2191 in animal models of autoimmune diseases. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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Review

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15 pages, 3002 KiB  
Review
The Role of Diacylglycerol Kinase in the Amelioration of Diabetic Nephropathy
by Daiki Hayashi and Yasuhito Shirai
Molecules 2022, 27(20), 6784; https://doi.org/10.3390/molecules27206784 - 11 Oct 2022
Cited by 7 | Viewed by 3243
Abstract
The drastic increase in the number of patients with diabetes and its complications is a global issue. Diabetic nephropathy, the leading cause of chronic kidney disease, significantly affects patients’ quality of life and medical expenses. Furthermore, there are limited drugs for treating diabetic [...] Read more.
The drastic increase in the number of patients with diabetes and its complications is a global issue. Diabetic nephropathy, the leading cause of chronic kidney disease, significantly affects patients’ quality of life and medical expenses. Furthermore, there are limited drugs for treating diabetic nephropathy patients. Impaired lipid signaling, especially abnormal protein kinase C (PKC) activation by de novo-synthesized diacylglycerol (DG) under high blood glucose, is one of the causes of diabetic nephropathy. DG kinase (DGK) is an enzyme that phosphorylates DG and generates phosphatidic acid, i.e., DGK can inhibit PKC activation under diabetic conditions. Indeed, it has been proven that DGK activation ameliorates diabetic nephropathy. In this review, we summarize the involvement of PKC and DGK in diabetic nephropathy as therapeutic targets, and its mechanisms, by referring to our recent study. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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25 pages, 3804 KiB  
Review
The Role and Regulation of Thromboxane A2 Signaling in Cancer-Trojan Horses and Misdirection
by Anthony W. Ashton, Yunjia Zhang, Rosanna Cazzolli and Kenneth V. Honn
Molecules 2022, 27(19), 6234; https://doi.org/10.3390/molecules27196234 - 22 Sep 2022
Cited by 13 | Viewed by 5016
Abstract
Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including breast, prostate, lung, and colorectal cancers. Several processes involved in cancer development, such as cell growth, [...] Read more.
Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including breast, prostate, lung, and colorectal cancers. Several processes involved in cancer development, such as cell growth, migration, and angiogenesis, are regulated by the arachidonic acid derivative thromboxane A2 (TXA2). Higher levels of circulating TXA2 are observed in patients with multiple cancers, and this is accompanied by overexpression of TXA2 synthase (TBXAS1, TXA2S) and/or TXA2 receptors (TBXA2R, TP). Overexpression of TXA2S or TP in tumor cells is generally associated with poor prognosis, reduced survival, and metastatic disease. However, the role of TXA2 signaling in the stroma during oncogenesis has been underappreciated. TXA2 signaling regulates the tumor microenvironment by modulating angiogenic potential, tumor ECM stiffness, and host immune response. Moreover, the by-products of TXA2S are highly mutagenic and oncogenic, adding to the overall phenotype where TXA2 synthesis promotes tumor formation at various levels. The stability of synthetic enzymes and receptors in this pathway in most cancers (with few mutations reported) suggests that TXA2 signaling is a viable target for adjunct therapy in various tumors to reduce immune evasion, primary tumor growth, and metastasis. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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20 pages, 4977 KiB  
Review
Phosphatidylcholine Cation—Tyrosine π Complexes: Motifs for Membrane Binding by a Bacterial Phospholipase C
by Mary F. Roberts, Anne Gershenson and Nathalie Reuter
Molecules 2022, 27(19), 6184; https://doi.org/10.3390/molecules27196184 - 21 Sep 2022
Cited by 5 | Viewed by 1905
Abstract
Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes are a virulence factor in many Gram-positive organisms. The specific activity of the Bacillus thuringiensis PI-PLC is significantly increased by adding phosphatidylcholine (PC) to vesicles composed of the substrate phosphatidylinositol, in part because the inclusion of PC reduces [...] Read more.
Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes are a virulence factor in many Gram-positive organisms. The specific activity of the Bacillus thuringiensis PI-PLC is significantly increased by adding phosphatidylcholine (PC) to vesicles composed of the substrate phosphatidylinositol, in part because the inclusion of PC reduces the apparent Kd for the vesicle binding by as much as 1000-fold when comparing PC-rich vesicles to PI vesicles. This review summarizes (i) the experimental work that localized a site on BtPI-PLC where PC is bound as a PC choline cation—Tyr-π complex and (ii) the computational work (including all-atom molecular dynamics simulations) that refined the original complex and found a second persistent PC cation—Tyr-π complex. Both complexes are critical for vesicle binding. These results have led to a model for PC functioning as an allosteric effector of the enzyme by altering the protein dynamics and stabilizing an ‘open’ active site conformation. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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15 pages, 1825 KiB  
Review
Targeting Ceramides and Adiponectin Receptors in the Islet of Langerhans for Treating Diabetes
by Wen-hong Li
Molecules 2022, 27(18), 6117; https://doi.org/10.3390/molecules27186117 - 19 Sep 2022
Cited by 6 | Viewed by 3062
Abstract
Ceramides belong to the sphingolipid family and represent the central hub of the sphingolipid network. In obesity, oversupply of saturated fatty acids including palmitate raises ceramide levels which can be detrimental to cells. Elevated ceramides can cause insulin resistance, endoplasmic reticulum stress, and [...] Read more.
Ceramides belong to the sphingolipid family and represent the central hub of the sphingolipid network. In obesity, oversupply of saturated fatty acids including palmitate raises ceramide levels which can be detrimental to cells. Elevated ceramides can cause insulin resistance, endoplasmic reticulum stress, and mitochondrial dysfunction. Studies over the last few decades have highlighted the role played by ceramides in pancreatic islet β-cell apoptosis, especially under glucolipotoxic and inflammatory conditions. This review focuses on ceramides and adiponectin receptor signaling, summarizing recent advancements in our understanding of their roles in islet β-cells and the discovery of zinc-dependent lipid hydrolase (ceramidase) activity of adiponectin receptors. The therapeutic potential of targeting these events to prevent islet β-cell loss for treating diabetes is discussed. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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24 pages, 2356 KiB  
Review
Liquid Chromatography-Mass Spectrometry (LC-MS) Derivatization-Based Methods for the Determination of Fatty Acids in Biological Samples
by Christiana Mantzourani and Maroula G. Kokotou
Molecules 2022, 27(17), 5717; https://doi.org/10.3390/molecules27175717 - 5 Sep 2022
Cited by 21 | Viewed by 8517
Abstract
Fatty acids (FAs) play pleiotropic roles in living organisms, acting as signaling molecules and gene regulators. They are present in plants and foods and may affect human health by food ingestion. As a consequence, analytical methods for their determination in biological fluids, plants [...] Read more.
Fatty acids (FAs) play pleiotropic roles in living organisms, acting as signaling molecules and gene regulators. They are present in plants and foods and may affect human health by food ingestion. As a consequence, analytical methods for their determination in biological fluids, plants and foods have attracted high interest. Undoubtedly, mass spectrometry (MS) has become an indispensable technique for the analysis of FAs. Due to the inherent poor ionization efficiency of FAs, their chemical derivatization prior to analysis is often employed. Usually, the derivatization of the FA carboxyl group aims to charge reversal, allowing detection and quantification in positive ion mode, thus, resulting in an increase in sensitivity in determination. Another approach is the derivatization of the double bond of unsaturated FAs, which aims to identify the double bond location. The present review summarizes the various classes of reagents developed for FA derivatization and discusses their applications in the liquid chromatography-MS (LC-MS) analysis of FAs in various matrices, including plasma and feces. In addition, applications for the determination of eicosanoids and fatty acid esters of hydroxy fatty acids (FAHFAs) are discussed. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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16 pages, 9838 KiB  
Review
Designing Dual Inhibitors of Autotaxin-LPAR GPCR Axis
by Souvik Banerjee, Suechin Lee, Derek D. Norman and Gabor J. Tigyi
Molecules 2022, 27(17), 5487; https://doi.org/10.3390/molecules27175487 - 26 Aug 2022
Cited by 15 | Viewed by 4747
Abstract
The ATX-LPA-LPAR1 signaling pathway plays a universal role in stimulating diverse cellular responses, including cell proliferation, migration, survival, and invasion in almost every cell type. The ATX-LPAR1 axis is linked to several metabolic and inflammatory diseases including cancer, fibrosis, and rheumatoid arthritis. Numerous [...] Read more.
The ATX-LPA-LPAR1 signaling pathway plays a universal role in stimulating diverse cellular responses, including cell proliferation, migration, survival, and invasion in almost every cell type. The ATX-LPAR1 axis is linked to several metabolic and inflammatory diseases including cancer, fibrosis, and rheumatoid arthritis. Numerous selective ATX or LPAR1 inhibitors have been developed and so far, their clinical efficacy has only been evaluated in idiopathic pulmonary fibrosis. None of the ATX and LPAR1 inhibitors have advanced to clinical trials for cancer and rheumatoid arthritis. Nonetheless, several research groups, including ours, have shown considerable benefit of simultaneous ATX and LPAR1 inhibition through combination therapy. Recent research suggests that dual-targeting therapies are superior to combination therapies that use two selective inhibitors. However, limited reports are available on ATX-LPAR1 dual inhibitors, potentially due to co-expression of multiple different LPARs with close structural similarities at the same target. In this review, we discuss rational design and future directions of dual ATX-LPAR1 inhibitors. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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20 pages, 2699 KiB  
Review
Current Knowledge on Mammalian Phospholipase A1, Brief History, Structures, Biochemical and Pathophysiological Roles
by Shun Yaginuma, Hiroki Kawana and Junken Aoki
Molecules 2022, 27(8), 2487; https://doi.org/10.3390/molecules27082487 - 12 Apr 2022
Cited by 19 | Viewed by 5432
Abstract
Phospholipase A1 (PLA1) is an enzyme that cleaves an ester bond at the sn-1 position of glycerophospholipids, producing a free fatty acid and a lysophospholipid. PLA1 activities have been detected both extracellularly and intracellularly, which are well conserved [...] Read more.
Phospholipase A1 (PLA1) is an enzyme that cleaves an ester bond at the sn-1 position of glycerophospholipids, producing a free fatty acid and a lysophospholipid. PLA1 activities have been detected both extracellularly and intracellularly, which are well conserved in higher eukaryotes, including fish and mammals. All extracellular PLA1s belong to the lipase family. In addition to PLA1 activity, most mammalian extracellular PLA1s exhibit lipase activity to hydrolyze triacylglycerol, cleaving the fatty acid and contributing to its absorption into the intestinal tract and tissues. Some extracellular PLA1s exhibit PLA1 activities specific to phosphatidic acid (PA) or phosphatidylserine (PS) and serve to produce lysophospholipid mediators such as lysophosphatidic acid (LPA) and lysophosphatidylserine (LysoPS). A high level of PLA1 activity has been detected in the cytosol fractions, where PA-PLA1/DDHD1/iPLA1 was responsible for the activity. Many homologs of PA-PLA1 and PLA2 have been shown to exhibit PLA1 activity. Although much has been learned about the pathophysiological roles of PLA1 molecules through studies of knockout mice and human genetic diseases, many questions regarding their biochemical properties, including their genuine in vivo substrate, remain elusive. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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15 pages, 923 KiB  
Review
Macrophage-Mediated Immune Responses: From Fatty Acids to Oxylipins
by Barbara Balestrieri, David Di Costanzo and Daniel F. Dwyer
Molecules 2022, 27(1), 152; https://doi.org/10.3390/molecules27010152 - 28 Dec 2021
Cited by 17 | Viewed by 5606
Abstract
Macrophages have diverse functions in the pathogenesis, resolution, and repair of inflammatory processes. Elegant studies have elucidated the metabolomic and transcriptomic profiles of activated macrophages. However, the versatility of macrophage responses in inflammation is likely due, at least in part, to their ability [...] Read more.
Macrophages have diverse functions in the pathogenesis, resolution, and repair of inflammatory processes. Elegant studies have elucidated the metabolomic and transcriptomic profiles of activated macrophages. However, the versatility of macrophage responses in inflammation is likely due, at least in part, to their ability to rearrange their repertoire of bioactive lipids, including fatty acids and oxylipins. This review will describe the fatty acids and oxylipins generated by macrophages and their role in type 1 and type 2 immune responses. We will highlight lipidomic studies that have shaped the current understanding of the role of lipids in macrophage polarization. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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26 pages, 5836 KiB  
Review
Nitro Fatty Acids (NO2-FAs): An Emerging Class of Bioactive Fatty Acids
by Giorgos S. Koutoulogenis and George Kokotos
Molecules 2021, 26(24), 7536; https://doi.org/10.3390/molecules26247536 - 13 Dec 2021
Cited by 17 | Viewed by 5706
Abstract
Unsaturated nitro fatty acids (NO2-FAs) constitute a category of molecules that may be formed endogenously by the reaction of unsaturated fatty acids (UFAs) with secondary species of nitrogen monoxide and nitrite anions. The warhead of NO2-FAs is a nitroalkene [...] Read more.
Unsaturated nitro fatty acids (NO2-FAs) constitute a category of molecules that may be formed endogenously by the reaction of unsaturated fatty acids (UFAs) with secondary species of nitrogen monoxide and nitrite anions. The warhead of NO2-FAs is a nitroalkene moiety, which is a potent Michael acceptor and can undergo nucleophilic attack from thiol groups of biologically relevant proteins, showcasing the value of these molecules regarding their therapeutic potential against many diseases. In general, NO2-FAs inhibit nuclear factorκ-B (NF-κB), and simultaneously they activate nuclear factor (erythroid derived)-like 2 (Nrf2), which activates an antioxidant signaling pathway. NO2-FAs can be synthesized not only endogenously in the organism, but in a synthetic laboratory as well, either by a step-by-step synthesis or by a direct nitration of UFAs. The step-by-step synthesis requires specific precursor compounds and is in position to afford the desired NO2-FAs with a certain position of the nitro group. On the contrary, the direct nitration of UFAs is not a selective methodology; thus, it affords a mixture of all possible nitro isomers. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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20 pages, 1269 KiB  
Review
Human Group IIA Phospholipase A2—Three Decades on from Its Discovery
by Kieran F. Scott, Timothy J. Mann, Shadma Fatima, Mila Sajinovic, Anshuli Razdan, Ryung Rae Kim, Adam Cooper, Aflah Roohullah, Katherine J. Bryant, Kasuni K. Gamage, David G. Harman, Fatemeh Vafaee, Garry G. Graham, W. Bret Church, Pamela J. Russell, Qihan Dong and Paul de Souza
Molecules 2021, 26(23), 7267; https://doi.org/10.3390/molecules26237267 - 30 Nov 2021
Cited by 12 | Viewed by 5043
Abstract
Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine [...] Read more.
Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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11 pages, 247 KiB  
Commentary
Outtakes from My Journey through the World of LIPID MAPS
by Edward A. Dennis
Molecules 2022, 27(12), 3885; https://doi.org/10.3390/molecules27123885 - 17 Jun 2022
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Abstract
My laboratory’s research on lipids has focused on phospholipases and lipidomics and in many ways has evolved in parallel to the evolution of the lipid field over the past half century. I have reviewed our research elsewhere. Herein, I describe the “side stories” [...] Read more.
My laboratory’s research on lipids has focused on phospholipases and lipidomics and in many ways has evolved in parallel to the evolution of the lipid field over the past half century. I have reviewed our research elsewhere. Herein, I describe the “side stories” or “outtakes” that parallel the main story that focuses on our laboratory’s research. I will emphasize the importance of community activities and describe how I came to initiate and lead the international effort on the Lipid Metabolites and Pathways Strategy (LIPID MAPS). Several of these side activities had a significant effect on discoveries in my laboratory research and its evolution as well as contributing significantly to the development of the LIPID MAPS initiative. These included experience and influences from serving as Editor-in-Chief of the Journal of Lipid Research and Chair and President of the Keystone Symposia on Cell and Molecular Biology as well as other experiences in organizing lipid conferences, teaching on lipid structure and mechanism, and earlier formative administrative and leadership experiences. The relevant influences are summarized herein. Full article
(This article belongs to the Special Issue Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday)
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