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1
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Qaderi K, Shahmoradi A, Thyagarajan A, Sahu RP. Impact of targeting the platelet-activating factor and its receptor in cancer treatment. Mil Med Res 2025; 12:10. [PMID: 40033370 PMCID: PMC11877967 DOI: 10.1186/s40779-025-00597-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 01/26/2025] [Indexed: 03/05/2025] Open
Abstract
The lipid mediator platelet-activating factor (PAF) and its receptor (PAFR) signaling play critical roles in a wide range of physiological and pathophysiological conditions, including cancer growth and metastasis. The ability of PAFR to interact with other oncogenic signaling cascades makes it a promising target for cancer treatment. Moreover, numerous natural and synthetic compounds, characterized by diverse pharmacological activities such as anti-inflammatory and anti-tumor effects, have been explored for their potential as PAF and PAFR antagonists. In this review, we provide comprehensive evidence regarding the PAF/PAFR signaling pathway, highlighting the effectiveness of various classes of PAF and PAFR inhibitors and antagonists across multiple cancer models. Notably, the synergistic effects of PAF and PAFR antagonists in enhancing the efficacy of chemotherapy and radiation therapy in several experimental cancer models are also discussed. Overall, the synthesis of literature review indicates that targeting the PAF/PAFR axis represents a promising approach for cancer treatment and also exerts synergy with chemotherapy and radiation therapy.
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Affiliation(s)
- Kimya Qaderi
- Department of Molecular and Cell Biology, College of Life Sciences, University of Leicester, University Road, Leicester, LE1 7RH, UK
| | - Arvin Shahmoradi
- Department of Laboratory Medicine, Faculty of Paramedical, Kurdistan University of Medical Sciences, Sanandaj, 66177-13446, Kurdistan, Iran
| | - Anita Thyagarajan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH, 45435, USA
| | - Ravi P Sahu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH, 45435, USA.
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2
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Jokesch P, Holzer L, Jantscher L, Guttzeit S, Übelhart R, Oskolkova O, Bochkov V, Gesslbauer B. Identification of plasma proteins binding oxidized phospholipids using pull-down proteomics and OxLDL masking assay. J Lipid Res 2025; 66:100704. [PMID: 39566852 PMCID: PMC11696850 DOI: 10.1016/j.jlr.2024.100704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/08/2024] [Accepted: 11/05/2024] [Indexed: 11/22/2024] Open
Abstract
Oxidized phospholipids (OxPLs) are increasingly recognized as toxic and proinflammatory mediators, which raises interest in the mechanisms of their detoxification. Circulating OxPLs are bound and neutralized by plasma proteins, including both antibodies and non-immunoglobulin proteins. The latter group of proteins is essentially not investigated because only three OxPC-binding plasma proteins are currently known. The goal of this work was to characterize a broad spectrum of plasma proteins selectively binding OxPLs. Using pull-down-proteomic analysis, we found about 150 non-immunoglobulin proteins preferentially binding oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphatidylcholine (OxPAPC) as compared to non-oxidized PAPC. To test if candidate proteins indeed can form a barrier isolating OxPLs from recognition by other proteins, we applied an immune masking assay. Oxidized LDL (OxLDL) immobilized in multiwell plates was used as a carrier of OxPLs, while mAbs recognizing OxPC or OxPE were used as "detectors" showing if OxPLs on the surface of OxLDL are physically accessible to external binding partners. Using an orthogonal combination of pull-down and masking assays we confirmed that previously described OxPL-binding proteins (non-fractionated IgM, CFH, and Apo-M) indeed can bind to and mask OxPC and OxPE on liposomes and OxLDL. Furthermore, we identified additional plasma proteins selectively binding and masking OxPC including Apo-D, Apo-H, pulmonary surfactant-associated protein B, and antithrombin-III. We hypothesize that in addition to circulating antibodies, multiple non-immunoglobulin plasma proteins can also bind OxPLs and modulate their recognition by innate and adaptive immunity.
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Affiliation(s)
- Philipp Jokesch
- Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria
| | - Lisa Holzer
- Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria
| | - Lydia Jantscher
- Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria
| | | | | | - Olga Oskolkova
- Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria
| | - Valery Bochkov
- Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria; Field of Excellence BioHealth - University of Graz, Graz, Austria.
| | - Bernd Gesslbauer
- Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.
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3
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Chistyakov DV, Tiulina VV, Gancharova OS, Baksheeva VE, Goriainov SV, Shebardina NG, Ivlev VA, Komarov SV, Shevelyova MP, Tikhomirova NK, Philippov PP, Vasil'ev VG, Sergeeva MG, Permyakov SE, Iomdina EN, Tsvetkov PO, Senin II, Zernii EY. Targeting Oxidative Stress and Inflammation in the Eye: Insights from a New Model of Experimental Autoimmune Uveitis. Int J Mol Sci 2024; 25:12910. [PMID: 39684616 DOI: 10.3390/ijms252312910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/12/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Autoimmune uveitis is a relapsing blind-causing ocular condition with complex pathogenesis that is not completely understood. There is a high demand for accurate animal models of experimental autoimmune uveitis (EAU) suitable for elucidating the molecular mechanisms of the disease and testing new therapeutic approaches. Here, we demonstrated that photoreceptor Ca2+/Zn2+-sensor protein recoverin is a uveoretinal antigen in albino rabbits provoking typical autoimmune chorioretinitis 2-4 weeks after immunization. The pathologic process in recoverin-induced EAU shared features with human disease and included lymphocytic infiltration of the retina, Dalen-Fuchs nodules and foci of subtotal or total retinal atrophy, manifested as a decrease in amplitude of the a-wave of the electroretinogram. In some cases, changes in the retinal vascular pattern and subretinal hemorrhages were also observed. These signs were accompanied by a gradual accumulation of serum antibodies against recoverin. Biochemical examination of the aqueous humor (AH) revealed typical characteristics of inflammation and oxidative stress, including increased levels of TNF-α and IL-6 and decreased levels of IL-10, as well as decreased total antioxidant activity, superoxide dismutase and glutathione peroxidase activities, and increased zinc concentration. Consistently, metabolomic and targeted lipidomic analysis of AH showed high lactate and low ascorbic acid levels in early EAU; increased levels of key pro-inflammatory signaling lipids such as PGE2, TXB2, 11-HETE and Lyso-PAF; and reduced levels of the anti-inflammatory fatty acid DHA in advanced stages of the disease. Uveitic AH became enriched with recoverin, confirming disruption of the blood-ocular barrier and photoreceptor damage. Notably, the application of mitochondria-targeted antioxidant therapy impeded EAU progression by maintaining local antioxidant activity and suppressing TNF-α, IL-6 and PGE2 signaling. Overall, our results demonstrate that recoverin-induced EAU in rabbits represents an accurate model of human autoimmune posterior uveitis and suggest new directions for its therapy that can be trialed using the developed model.
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Affiliation(s)
- Dmitry V Chistyakov
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- Pharmacy Resource Center, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Veronika V Tiulina
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Olga S Gancharova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Viktoriia E Baksheeva
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Sergei V Goriainov
- Pharmacy Resource Center, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Natalia G Shebardina
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Vasily A Ivlev
- Pharmacy Resource Center, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Sergey V Komarov
- Skryabin Moscow State Academy of Veterinary Medicine and Biotechnology, 109472 Moscow, Russia
| | - Marina P Shevelyova
- Institute for Biological Instrumentation, Russian Academy of Sciences, 142292 Pushchino, Russia
| | - Natalia K Tikhomirova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Pavel P Philippov
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Vasiliy G Vasil'ev
- Pharmacy Resource Center, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Marina G Sergeeva
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Sergei E Permyakov
- Institute for Biological Instrumentation, Russian Academy of Sciences, 142292 Pushchino, Russia
| | - Elena N Iomdina
- Helmholtz National Medical Research Center of Eye Diseases, 105062 Moscow, Russia
| | - Philipp O Tsvetkov
- CNRS, UMR 7051, INP, Inst Neurophysiopathol, Faculté des Sciences Médicales et Paramédicales, Aix Marseille Univ, 13005 Marseille, France
| | - Ivan I Senin
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Evgeni Yu Zernii
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
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Sahebkar A, Reiner Ž, Almahmeed W, Jamialahmadi T, Simental-Mendía LE. Effect of Statin Treatment on Lipoprotein-Associated Phospholipase A2 Mass and Activity: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Trials. Cardiovasc Drugs Ther 2024:10.1007/s10557-024-07634-5. [PMID: 39466484 DOI: 10.1007/s10557-024-07634-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/16/2024] [Indexed: 10/30/2024]
Abstract
PURPOSE The goal of this meta-analysis was to establish whether statin treatment reduces Lp-PLA2 mass concentration and/or activity. METHODS PubMed, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar databases were searched using MESH terms and keywords. Randomized controlled trials (RCT) with either parallel or cross-over design examining the effect of statins on Lp-PLA2 mass and/or activity were included in meta-analysis. RESULTS Out of 256 articles, 10 RCT were selected for meta-analysis. Statin therapy significantly reduced both Lp-PLA2 mass (WMD -44.46 ng/mL; 95%CI -59.01, -29.90; p < 0.001; I2 = 93%) and activity (WMD -39.37 nmol/min/mL; 95%CI -69.99, -8.75; p = 0.01; I2 = 100%). The sensitivity analysis was robust for Lp-PLA2 mass and was also positive for two studies concerning Lp-PLA2 activity. CONCLUSION Statin therapy significantly reduced both Lp-PLA2 mass and activity.
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Affiliation(s)
- Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Željko Reiner
- Department of Internal Medicine, University Hospital Center Zagreb, University of Zagreb, Kišpatićeva 12, Zagreb, Croatia
- Polish Mother's Memorial Hospital Research Institute, Lodz, 93-338, Poland
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Tannaz Jamialahmadi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Luis E Simental-Mendía
- Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Durango, Mexico.
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Carvalho NS, Nardini V, Veronezes RM, Maciel JB, Trabuco AC, De Carvalho MF, Fontanari C, Sartim MA, de Moraes LAB, Faccioli LH. Characterizing lipid constituents of B. moojeni snake venom: a comparative approach for chemical and biological investigations. Arch Toxicol 2024; 98:3491-3502. [PMID: 38951190 DOI: 10.1007/s00204-024-03809-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 06/19/2024] [Indexed: 07/03/2024]
Abstract
Snake venoms are complex mixtures majorly composed of proteins with well-studied biological effects. However, the exploration of non-protein components, especially lipids, remains limited despite their potential for discovering bioactive molecules. This study compares three liquid-liquid lipid extraction methods for both chemical and biological analyses of Bothrops moojeni snake venom. The methods evaluated include the Bligh and Dyer method (methanol, chloroform, water), considered standard; the Acunha method, a modification of the Bligh and Dyer protocol; and the Matyash method (MTBE/methanol/water), featuring an organic phase less dense than the aqueous phase. Lipidomic analysis using liquid chromatography with high-resolution mass spectrometry (LC-HRMS) system revealed comparable values of lipid constituents' peak intensity across different extraction methods. Our results show that all methods effectively extracted a similar quantity of lipid species, yielding approximately 17-18 subclasses per method. However, the Matyash and Acunha methods exhibited notably higher proportions of biologically active lipids compared to the Bligh and Dyer method, particularly in extracting lipid species crucial for cellular structure and function, such as sphingomyelins and phosphatidylinositol-phosphate. In conclusion, when selecting a lipid extraction method, it is essential to consider the study's objectives. For a biological approach, it is crucial to evaluate not only the total quantity of extracted lipids but also their quality and biological activity. The Matyash and Acunha methods show promise in this regard, potentially offering a superior option for extracting biologically active lipids compared to the Bligh and Dyer method.
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Affiliation(s)
- Nathalia Santos Carvalho
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Viviani Nardini
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Raul Moyses Veronezes
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Jéssica Burlamaque Maciel
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
- Graduate Program in Tropical Medicine, Department of Teaching and Research, Dr. Heitor Vieira Dourado Tropical Medicine Foundation, Superior School of Health Sciences, Amazonas State University, Manaus, Amazonas, Brazil
| | - Amanda Cristina Trabuco
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Mirian Félix De Carvalho
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Caroline Fontanari
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Marco Aurélio Sartim
- Graduate Program in Tropical Medicine, Department of Teaching and Research, Dr. Heitor Vieira Dourado Tropical Medicine Foundation, Superior School of Health Sciences, Amazonas State University, Manaus, Amazonas, Brazil
- Department of Research and Development, Nilton Lins Foundation, Manaus, Brazil
| | - Luiz Alberto Beraldo de Moraes
- Department of Chemistry, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of Sao Paulo, Sao Paulo, Brazil
| | - Lúcia Helena Faccioli
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
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Chakraborty A, Kamat SS. Lysophosphatidylserine: A Signaling Lipid with Implications in Human Diseases. Chem Rev 2024; 124:5470-5504. [PMID: 38607675 DOI: 10.1021/acs.chemrev.3c00701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2024]
Abstract
Lysophosphatidylserine (lyso-PS) has emerged as yet another important signaling lysophospholipid in mammals, and deregulation in its metabolism has been directly linked to an array of human autoimmune and neurological disorders. It has an indispensable role in several biological processes in humans, and therefore, cellular concentrations of lyso-PS are tightly regulated to ensure optimal signaling and functioning in physiological settings. Given its biological importance, the past two decades have seen an explosion in the available literature toward our understanding of diverse aspects of lyso-PS metabolism and signaling and its association with human diseases. In this Review, we aim to comprehensively summarize different aspects of lyso-PS, such as its structure, biodistribution, chemical synthesis, and SAR studies with some synthetic analogs. From a biochemical perspective, we provide an exhaustive coverage of the diverse biological activities modulated by lyso-PSs, such as its metabolism and the receptors that respond to them in humans. We also briefly discuss the human diseases associated with aberrant lyso-PS metabolism and signaling and posit some future directions that may advance our understanding of lyso-PS-mediated mammalian physiology.
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Affiliation(s)
- Arnab Chakraborty
- Department of Biology, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune 411008, Maharashtra, India
| | - Siddhesh S Kamat
- Department of Biology, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune 411008, Maharashtra, India
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Riera-Ferrer E, Mazanec H, Mladineo I, Konik P, Piazzon MC, Kuchta R, Palenzuela O, Estensoro I, Sotillo J, Sitjà-Bobadilla A. An inside out journey: biogenesis, ultrastructure and proteomic characterisation of the ectoparasitic flatworm Sparicotyle chrysophrii extracellular vesicles. Parasit Vectors 2024; 17:175. [PMID: 38570784 PMCID: PMC10993521 DOI: 10.1186/s13071-024-06257-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 03/21/2024] [Indexed: 04/05/2024] Open
Abstract
BACKGROUND Helminth extracellular vesicles (EVs) are known to have a three-way communication function among parasitic helminths, their host and the host-associated microbiota. They are considered biological containers that may carry virulence factors, being therefore appealing as therapeutic and prophylactic target candidates. This study aims to describe and characterise EVs secreted by Sparicotyle chrysophrii (Polyopisthocotyla: Microcotylidae), a blood-feeding gill parasite of gilthead seabream (Sparus aurata), causing significant economic losses in Mediterranean aquaculture. METHODS To identify proteins involved in extracellular vesicle biogenesis, genomic datasets from S. chrysophrii were mined in silico using known protein sequences from Clonorchis spp., Echinococcus spp., Fasciola spp., Fasciolopsis spp., Opisthorchis spp., Paragonimus spp. and Schistosoma spp. The location and ultrastructure of EVs were visualised by transmission electron microscopy after fixing adult S. chrysophrii specimens by high-pressure freezing and freeze substitution. EVs were isolated and purified from adult S. chrysophrii (n = 200) using a newly developed ultracentrifugation-size-exclusion chromatography protocol for Polyopisthocotyla, and EVs were characterised via nanoparticle tracking analysis and tandem mass spectrometry. RESULTS Fifty-nine proteins involved in EV biogenesis were identified in S. chrysophrii, and EVs compatible with ectosomes were observed in the syncytial layer of the haptoral region lining the clamps. The isolated and purified nanoparticles had a mean size of 251.8 nm and yielded 1.71 × 108 particles · mL-1. The protein composition analysis identified proteins related to peptide hydrolases, GTPases, EF-hand domain proteins, aerobic energy metabolism, anticoagulant/lipid-binding, haem detoxification, iron transport, EV biogenesis-related, vesicle-trafficking and other cytoskeletal-related proteins. Several identified proteins, such as leucyl and alanyl aminopeptidases, calpain, ferritin, dynein light chain, 14-3-3, heat shock protein 70, annexin, tubulin, glutathione S-transferase, superoxide dismutase, enolase and fructose-bisphosphate aldolase, have already been proposed as target candidates for therapeutic or prophylactic purposes. CONCLUSIONS We have unambiguously demonstrated for the first time to our knowledge the secretion of EVs by an ectoparasitic flatworm, inferring their biogenesis machinery at a genomic and transcriptomic level, and by identifying their location and protein composition. The identification of multiple therapeutic targets among EVs' protein repertoire provides opportunities for target-based drug discovery and vaccine development for the first time in Polyopisthocotyla (sensu Monogenea), and in a fish-ectoparasite model.
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Affiliation(s)
- Enrique Riera-Ferrer
- Fish Pathology Group, Institute of Aquaculture Torre de La Sal, Consejo Superior de Investigaciones Científicas (IATS, CSIC), Ribera de Cabanes, 12595, Castellón, Spain
| | - Hynek Mazanec
- Laboratory of Helminthology, Institute of Parasitology, Biology Centre, Czech Academy of Sciences, (BC CAS), České Budějovice, Czech Republic
| | - Ivona Mladineo
- Laboratory of Functional Helminthology, Institute of Parasitology, Biology Centre Czech Academy of Sciences (BC CAS), České Budějovice, Czech Republic
| | - Peter Konik
- Faculty of Science, University of South Bohemia, Branišovská 1160/31, 370 05, České Budějovice, Czech Republic
| | - M Carla Piazzon
- Fish Pathology Group, Institute of Aquaculture Torre de La Sal, Consejo Superior de Investigaciones Científicas (IATS, CSIC), Ribera de Cabanes, 12595, Castellón, Spain
| | - Roman Kuchta
- Laboratory of Helminthology, Institute of Parasitology, Biology Centre, Czech Academy of Sciences, (BC CAS), České Budějovice, Czech Republic
| | - Oswaldo Palenzuela
- Fish Pathology Group, Institute of Aquaculture Torre de La Sal, Consejo Superior de Investigaciones Científicas (IATS, CSIC), Ribera de Cabanes, 12595, Castellón, Spain
| | - Itziar Estensoro
- Fish Pathology Group, Institute of Aquaculture Torre de La Sal, Consejo Superior de Investigaciones Científicas (IATS, CSIC), Ribera de Cabanes, 12595, Castellón, Spain.
| | - Javier Sotillo
- Parasitology Reference and Research Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Ariadna Sitjà-Bobadilla
- Fish Pathology Group, Institute of Aquaculture Torre de La Sal, Consejo Superior de Investigaciones Científicas (IATS, CSIC), Ribera de Cabanes, 12595, Castellón, Spain
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Mendoza-Martínez GD, Orzuna-Orzuna JF, Roque-Jiménez JA, Gloria-Trujillo A, Martínez-García JA, Sánchez-López N, Hernández-García PA, Lee-Rangel HA. A Polyherbal Mixture with Nutraceutical Properties for Ruminants: A Meta-Analysis and Review of BioCholine Powder. Animals (Basel) 2024; 14:667. [PMID: 38473052 PMCID: PMC11154432 DOI: 10.3390/ani14050667] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/09/2024] [Accepted: 02/14/2024] [Indexed: 03/14/2024] Open
Abstract
BioCholine Powder is a polyherbal feed additive composed of Achyrantes aspera, Trachyspermum ammi, Azadirachta indica, and Citrullus colocynthis. The objective of this study was to analyze published results that support the hypothesis that the polyherbal product BioCholine Powder has rumen bypass choline metabolites through a meta-analysis and effect size analysis (ES). Using Scopus, Web of Science, ScienceDirect, PubMed, and university dissertation databases, a systematic search was conducted for experiments published in scientific documents that evaluated the effects of BioCholine supplementation on the variables of interest. The analyzed data were extracted from twenty-one publications (fifteen scientific articles, three abstracts, and three graduate dissertations available in institutional libraries). The studies included lamb growing-finishing, lactating ewes and goats, calves, and dairy cows. The effects of BioCholine were analyzed using random effects statistical models to compare the weighted mean difference (WMD) between BioCholine-supplemented ruminants and controls (no BioCholine). Heterogeneity was explored, and three subgroup analyses were performed for doses [(4 (or 5 g/d), 8 (10 g/d)], supplementation in gestating and lactating ewes (pre- and postpartum supplementation), and blood metabolites by species and physiological state (lactating goats, calves, lambs, ewes). Supplementation with BioCholine in sheep increased the average daily lamb gain (p < 0.05), final body weight (p < 0.01), and daily milk yield (p < 0.05) without effects on intake or feed conversion. Milk yield was improved in small ruminants with BioCholine prepartum supplementation (p < 0.10). BioCholine supplementation decreased blood urea (p < 0.01) and increased levels of the liver enzymes alanine transaminase (ALT; p < 0.10) and albumin (p < 0.001). BioCholine doses over 8 g/d increased blood glucose, albumin (p < 0.10), cholesterol, total protein, and globulin (p < 0.05). The ES values of BioCholine in retained energy over the control in growing lambs were +7.15% NEm (p < 0.10) and +9.25% NEg (p < 0.10). In conclusion, adding BioCholine Powder to domestic ruminants' diets improves productive performance, blood metabolite indicators of protein metabolism, and liver health, showing its nutraceutical properties where phosphatidylcholine prevails as an alternative that can meet the choline requirements in ruminants.
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Affiliation(s)
- Germán David Mendoza-Martínez
- Departamento de Producción Agrícola y Animal, Universidad Autónoma Metropolitana—Xochimilco, Mexico City 04960, Mexico; (G.D.M.-M.); (J.A.R.-J.); (A.G.-T.); (J.A.M.-G.); (N.S.-L.)
| | | | - José Alejandro Roque-Jiménez
- Departamento de Producción Agrícola y Animal, Universidad Autónoma Metropolitana—Xochimilco, Mexico City 04960, Mexico; (G.D.M.-M.); (J.A.R.-J.); (A.G.-T.); (J.A.M.-G.); (N.S.-L.)
- Instituto de Ciencias Agrícolas, Universidad Autónoma de Baja California, Ejido Nuevo León, Mexicali 21705, Mexico
| | - Adrián Gloria-Trujillo
- Departamento de Producción Agrícola y Animal, Universidad Autónoma Metropolitana—Xochimilco, Mexico City 04960, Mexico; (G.D.M.-M.); (J.A.R.-J.); (A.G.-T.); (J.A.M.-G.); (N.S.-L.)
| | - José Antonio Martínez-García
- Departamento de Producción Agrícola y Animal, Universidad Autónoma Metropolitana—Xochimilco, Mexico City 04960, Mexico; (G.D.M.-M.); (J.A.R.-J.); (A.G.-T.); (J.A.M.-G.); (N.S.-L.)
| | - Nallely Sánchez-López
- Departamento de Producción Agrícola y Animal, Universidad Autónoma Metropolitana—Xochimilco, Mexico City 04960, Mexico; (G.D.M.-M.); (J.A.R.-J.); (A.G.-T.); (J.A.M.-G.); (N.S.-L.)
| | | | - Héctor Aaron Lee-Rangel
- Facultad de Agronomía y Veterinaria, Centro de Biociencias, Instituto de Investigaciones en Zonas Desérticas, Universidad Autónoma de San Luis Potosí, S.L.P., Soledad de Graciano Sánchez 78000, Mexico;
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9
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Valentine WJ, Shimizu T, Shindou H. Lysophospholipid acyltransferases orchestrate the compositional diversity of phospholipids. Biochimie 2023; 215:24-33. [PMID: 37611890 DOI: 10.1016/j.biochi.2023.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/14/2023] [Accepted: 08/19/2023] [Indexed: 08/25/2023]
Abstract
Lysophospholipid acyltransferases (LPLATs), in concert with glycerol-3-phosphate acyltransferases (GPATs) and phospholipase A1/2s, orchestrate the compositional diversity of the fatty chains in membrane phospholipids. Fourteen LPLAT enzymes which come from two distinct families, AGPAT and MBOAT, have been identified, and in this mini-review we provide an overview of their roles in de novo and remodeling pathways of membrane phospholipid biosynthesis. Recently new nomenclature for LPLATs has been introduced (LPLATx, where x is a number 1-14), and we also give an overview of key biological functions that have been discovered for LPLAT1-14, revealed primarily through studies of LPLAT-gene-deficient mice as well as by linkages to various human diseases.
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Affiliation(s)
- William J Valentine
- Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, 187-8502, Japan.
| | - Takao Shimizu
- Department of Lipid Signaling, National Center for Global Health and Medicine (NCGM), Shinjuku-ku, Tokyo, 162-8655, Japan; Institute of Microbial Chemistry, Shinagawa-ku, Tokyo, 141-0021, Japan
| | - Hideo Shindou
- Department of Lipid Life Science, National Center for Global Health and Medicine (NCGM), Shinjuku-ku, Tokyo, 162-8655, Japan; Department of Lipid Medical Science, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan.
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10
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Ali O, Szabó A. Review of Eukaryote Cellular Membrane Lipid Composition, with Special Attention to the Fatty Acids. Int J Mol Sci 2023; 24:15693. [PMID: 37958678 PMCID: PMC10649022 DOI: 10.3390/ijms242115693] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/24/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Biological membranes, primarily composed of lipids, envelop each living cell. The intricate composition and organization of membrane lipids, including the variety of fatty acids they encompass, serve a dynamic role in sustaining cellular structural integrity and functionality. Typically, modifications in lipid composition coincide with consequential alterations in universally significant signaling pathways. Exploring the various fatty acids, which serve as the foundational building blocks of membrane lipids, provides crucial insights into the underlying mechanisms governing a myriad of cellular processes, such as membrane fluidity, protein trafficking, signal transduction, intercellular communication, and the etiology of certain metabolic disorders. Furthermore, comprehending how alterations in the lipid composition, especially concerning the fatty acid profile, either contribute to or prevent the onset of pathological conditions stands as a compelling area of research. Hence, this review aims to meticulously introduce the intricacies of membrane lipids and their constituent fatty acids in a healthy organism, thereby illuminating their remarkable diversity and profound influence on cellular function. Furthermore, this review aspires to highlight some potential therapeutic targets for various pathological conditions that may be ameliorated through dietary fatty acid supplements. The initial section of this review expounds on the eukaryotic biomembranes and their complex lipids. Subsequent sections provide insights into the synthesis, membrane incorporation, and distribution of fatty acids across various fractions of membrane lipids. The last section highlights the functional significance of membrane-associated fatty acids and their innate capacity to shape the various cellular physiological responses.
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Affiliation(s)
- Omeralfaroug Ali
- Agrobiotechnology and Precision Breeding for Food Security National Laboratory, Institute of Physiology and Animal Nutrition, Department of Animal Physiology and Health, Hungarian University of Agriculture and Life Sciences, Guba Sándor Str. 40, 7400 Kaposvár, Hungary;
| | - András Szabó
- Agrobiotechnology and Precision Breeding for Food Security National Laboratory, Institute of Physiology and Animal Nutrition, Department of Animal Physiology and Health, Hungarian University of Agriculture and Life Sciences, Guba Sándor Str. 40, 7400 Kaposvár, Hungary;
- HUN-REN-MATE Mycotoxins in the Food Chain Research Group, Hungarian University of Agriculture and Life Sciences, Guba Sándor Str. 40, 7400 Kaposvár, Hungary
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11
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Zhang Y, Jen FEC, Fox KL, Edwards JL, Jennings MP. The biosynthesis and role of phosphorylcholine in pathogenic and nonpathogenic bacteria. Trends Microbiol 2023; 31:692-706. [PMID: 36863982 PMCID: PMC10272106 DOI: 10.1016/j.tim.2023.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 01/18/2023] [Accepted: 01/23/2023] [Indexed: 03/03/2023]
Abstract
Phosphorylcholine (ChoP) can be found in all life forms. Although this molecule was first thought to be uncommon in bacteria, it is now appreciated that many bacteria express ChoP on their surface. ChoP is usually attached to a glycan structure, but in some cases, it is added as a post-translational modification to proteins. Recent findings have demonstrated the role of ChoP modification and phase variation (ON/OFF switching) in bacterial pathogenesis. However, the mechanisms of ChoP synthesis are still unclear in some bacteria. Here, we review the literature and examine the recent developments in ChoP-modified proteins and glycolipids and of ChoP biosynthetic pathways. We discuss how the well-studied Lic1 pathway exclusively mediates ChoP attachment to glycans but not to proteins. Finally, we provide a review of the role of ChoP in bacterial pathobiology and the role of ChoP in modulating the immune response.
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Affiliation(s)
- Yuan Zhang
- Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, QLD 4222, Australia
| | - Freda E-C Jen
- Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, QLD 4222, Australia
| | - Kate L Fox
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
| | - Jennifer L Edwards
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43210, USA
| | - Michael P Jennings
- Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, QLD 4222, Australia.
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12
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de Carvalho JCS, da Silva-Neto PV, Toro DM, Fuzo CA, Nardini V, Pimentel VE, Pérez MM, Fraga-Silva TFC, Oliveira CNS, Degiovani AM, Ostini FM, Feitosa MR, Parra RS, da Rocha JJR, Feres O, Vilar FC, Gaspar GG, Santos IKFM, Fernandes APM, Maruyama SR, Russo EMS, Bonato VLD, Cardoso CRB, Dias-Baruffi M, Faccioli LH, Sorgi CA, on behalf of the ImmunoCovid Study Group. The Interplay among Glucocorticoid Therapy, Platelet-Activating Factor and Endocannabinoid Release Influences the Inflammatory Response to COVID-19. Viruses 2023; 15:573. [PMID: 36851787 PMCID: PMC9959303 DOI: 10.3390/v15020573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/06/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
COVID-19 is associated with a dysregulated immune response. Currently, several medicines are licensed for the treatment of this disease. Due to their significant role in inhibiting pro-inflammatory cytokines and lipid mediators, glucocorticoids (GCs) have attracted a great deal of attention. Similarly, the endocannabinoid (eCB) system regulates various physiological processes including the immunological response. Additionally, during inflammatory and thrombotic processes, phospholipids from cell membranes are cleaved to produce platelet-activating factor (PAF), another lipid mediator. Nonetheless, the effect of GCs on this lipid pathway during COVID-19 therapy is still unknown. This is a cross-sectional study involving COVID-19 patients (n = 200) and healthy controls (n = 35). Target tandem mass spectrometry of plasma lipid mediators demonstrated that COVID-19 severity affected eCBs and PAF synthesis. This increased synthesis of eCB was adversely linked with systemic inflammatory markers IL-6 and sTREM-1 levels and neutrophil counts. The use of GCs altered these lipid pathways by reducing PAF and increasing 2-AG production. Corroborating this, transcriptome analysis of GC-treated patients blood leukocytes showed differential modulation of monoacylglycerol lipase and phospholipase A2 gene expression. Altogether, these findings offer a breakthrough in our understanding of COVID-19 pathophysiology, indicating that GCs may promote additional protective pharmacological effects by influencing the eCB and PAF pathways involved in the disease course.
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Affiliation(s)
- Jonatan C. S. de Carvalho
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto-FFCLRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-901, SP, Brazil
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-903, SP, Brazil
| | - Pedro V. da Silva-Neto
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-903, SP, Brazil
- Programa de Pós-Graduação em Imunologia Básica e Aplicada-PPGIBA, Instituto de Ciências Biológicas, Universidade Federal do Amazonas-UFAM, Manaus 69080-900, AM, Brazil
| | - Diana M. Toro
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-903, SP, Brazil
- Programa de Pós-Graduação em Imunologia Básica e Aplicada-PPGIBA, Instituto de Ciências Biológicas, Universidade Federal do Amazonas-UFAM, Manaus 69080-900, AM, Brazil
| | - Carlos A. Fuzo
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-903, SP, Brazil
| | - Viviani Nardini
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-903, SP, Brazil
| | - Vinícius E. Pimentel
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-903, SP, Brazil
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-900, SP, Brazil
| | - Malena M. Pérez
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-903, SP, Brazil
| | - Thais F. C. Fraga-Silva
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-900, SP, Brazil
| | - Camilla N. S. Oliveira
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-903, SP, Brazil
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-900, SP, Brazil
| | - Augusto M. Degiovani
- Hospital Santa Casa de Misericórdia de Ribeirão Preto, Ribeirao Preto 14085-000, SP, Brazil
| | - Fátima M. Ostini
- Hospital Santa Casa de Misericórdia de Ribeirão Preto, Ribeirao Preto 14085-000, SP, Brazil
| | - Marley R. Feitosa
- Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirao Preto 14048-900, SP, Brazil
| | - Rogerio S. Parra
- Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirao Preto 14048-900, SP, Brazil
| | - José J. R. da Rocha
- Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirao Preto 14048-900, SP, Brazil
| | - Omar Feres
- Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirao Preto 14048-900, SP, Brazil
| | - Fernando C. Vilar
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirao Preto 14049-900, SP, Brazil
| | - Gilberto G. Gaspar
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirao Preto 14049-900, SP, Brazil
| | - Isabel K. F. M. Santos
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-900, SP, Brazil
| | - Ana P. M. Fernandes
- Departamento de Enfermagem Geral e Especializada, Escola de Enfermagem de Ribeirão Preto-EERP, Universidade de São Paulo-USP, Ribeirao Preto 14040-902, SP, Brazil
| | - Sandra R. Maruyama
- Departamento de Genética e Evolução, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos-UFSCar, Sao Carlos 13565-905, SP, Brazil
| | - Elisa M. S. Russo
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-903, SP, Brazil
| | - Vânia L. D. Bonato
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-900, SP, Brazil
| | - Cristina R. B. Cardoso
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-903, SP, Brazil
| | - Marcelo Dias-Baruffi
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-903, SP, Brazil
| | - Lúcia H. Faccioli
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-903, SP, Brazil
| | - Carlos A. Sorgi
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto-FFCLRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-901, SP, Brazil
- Programa de Pós-Graduação em Imunologia Básica e Aplicada-PPGIBA, Instituto de Ciências Biológicas, Universidade Federal do Amazonas-UFAM, Manaus 69080-900, AM, Brazil
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirao Preto 14040-900, SP, Brazil
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PLA2G7/PAF-AH as Potential Negative Regulator of the Wnt Signaling Pathway Mediates Protective Effects in BRCA1 Mutant Breast Cancer. Int J Mol Sci 2023; 24:ijms24010882. [PMID: 36614323 PMCID: PMC9821466 DOI: 10.3390/ijms24010882] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/23/2022] [Accepted: 12/29/2022] [Indexed: 01/05/2023] Open
Abstract
Past studies have confirmed that aberrant activation of the Wnt/β-catenin signaling is associated with tumorigenesis and metastasis in breast cancer, while the role of platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in this signaling pathway remains unclear. In this study, we analyze the functional impact of PAF-AH on BRCA1 mutant breast cancer and explore its relationship to the Wnt signaling pathway. By performing immunohistochemistry, PAF-AH expression and β-catenin expression were examined in both BRCA1 WT and BRCA1 mutant breast cancer specimens. The BRCA1 mutant breast cancer cell line HCC1937 was used for in vitro experiments to assess the impact of PAF-AH on cellular functions. The intracellular distribution of β-catenin depending on PLA2G7/PAF-AH expression was investigated by immunocytochemistry. Significantly higher nuclear expression levels of PAF-AH were found in BRCA1 mutant tissue specimens than in BRCA1 WT samples. Cell viability, proliferation, and the motility rate of HCC1937 were significantly enhanced after PLA2G7 silencing, which indicated a protective role of PAF-AH in breast cancer. Nuclear PAF-AH expressed correlatedly with membranous β-catenin. PLA2G7 silencing provoked the β-catenin translocation from the membrane to the nucleus and activated Wnt signaling downstream genes. Our data showed a protective effect of high PAF-AH expression in BRCA1 mutant breast cancer. PAF-AH may achieve its protective effect by negatively regulating the Wnt pathway. In conclusion, our research sheds new light on the regulatory pathways in BRCA1 mutant breast cancer.
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English CJ, Lohning AE, Mayr HL, Jones M, Reidlinger DP. Interrelationships among platelet-activating factor and lipoprotein-associated phospholipase A 2 activity and traditional cardiovascular risk factors. Biofactors 2022; 49:457-471. [PMID: 36538603 DOI: 10.1002/biof.1928] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 12/01/2022] [Indexed: 12/24/2022]
Abstract
Traditionally cardiovascular disease (CVD) risk has been assessed through blood lipids and inflammatory marker C-reactive protein (hsCRP). Recent clinical interest in novel pro-inflammatory markers platelet-activating factor (PAF) and lipoprotein-associated phospholipase A2 (Lp-PLA2 ) recognizes that vascular damage can exist in the absence of traditional risk factors. This cross-sectional study investigated the potential relationship between circulating PAF, Lp-PLA2 , hsCRP, and traditional risk factors for CVD. One hundred adults (49 ± 13 years, 31% male) with variable CVD risk were recruited. Fasting inflammatory markers PAF, Lp-PLA2 and hsCRP and total, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol, and triglycerides were measured. Blood pressure, body mass index, and waist circumference were measured. Medical and physical activity data were self-reported. Linear and multiple regressions were performed. PAF, Lp-PLA2 , and hsCRP independently correlated with several CVD risk factors. PAF was correlated significantly with risk factors in an unexpected way; there was a medium positive correlation between PAF and HDL cholesterol (r = 0.394, p < 0.001) and medium negative correlations with Total:HDL cholesterol; (r = -0.436, p < 0.001) systolic blood pressure; (r = -0.307, p = 0.001); BMI (r = -0.381, p < 0.001); and waist circumference (r = -0.404, p < 0.001). There were large positive correlations between Lp-PLA2 and LDL (r = 0.525, p < 0.001) and non-HDL cholesterol (r = 0.508, p < 0.001). There were large positive correlations between hsCRP and Total:HDL cholesterol (r = 0.524, p < 0.001); BMI (r = 0.668, p < 0.001); and waist circumference (r = 0.676, p < 0.001). PAF, Lp-PLA2 , and hsCRP are implicated in the pathophysiology of inflammation in CVD; however, the relationships between each marker and traditional risk factors were different suggesting they may be involved in different atherogenic pathways.
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Affiliation(s)
- Carolyn J English
- Bond University, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
| | - Anna E Lohning
- Bond University, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
| | - Hannah L Mayr
- Bond University, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
- Department of Nutrition and Dietetics, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
- Centre for Functioning and Health Research, Metro South Hospital and Health Service, Brisbane, Queensland, Australia
| | - Mark Jones
- Institute of Evidence-Based Healthcare, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
| | - Dianne P Reidlinger
- Bond University, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
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15
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Sigurjónsson S, Lúthersson E, Magnússon CD, Gudmundsson HG, Das E, Haraldsson GG. Asymmetric Synthesis of Methoxylated Ether Lipids: Total Synthesis of n-3 Polyunsaturated Docosahexaenoic Acid-Like Methoxylated Ether Lipid. J Org Chem 2022; 87:14623-14635. [PMID: 36279500 DOI: 10.1021/acs.joc.2c01991] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The first total synthesis of a docosahexaenoic acid (DHA)-like methoxylated ether lipid (MEL) is reported. This compound constitutes an all-cis methylene skipped hexaene framework identical to that present in DHA, the well-known omega-3 polyunsaturated fatty acid. The polyene C22 hydrocarbon chain, bearing a methoxyl group in the 2-position and R-configuration at the resulting chiral center, is attached by an ether linkage to the pro-S hydroxymethyl group (sn-1 position) of a glycerol backbone. The asymmetric synthesis is highly convergent and based on the polyacetylene approach involving iterative copper-promoted coupling reactions of propargyl bromides with terminal alkynes and semihydrogenation of the resulting hexayne. Starting from enantiopure R-solketal and racemic epichlorohydrin, the targeted MEL was accomplished in an 8.2% yield over eight steps (longest linear sequence) involving an enantio- and diastereopure glyceryl glycidyl ether key C6-building blocks from which the polyynes were constructed.
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Affiliation(s)
| | - Einar Lúthersson
- Science Institute, University of Iceland, Dunhaga 3, 107 Reykjavik, Iceland
| | - Carlos D Magnússon
- Science Institute, University of Iceland, Dunhaga 3, 107 Reykjavik, Iceland.,Department of Science and Mathematics, Volda University College, P.O. Box 500, 6101 Volda, Norway
| | | | - Erika Das
- Science Institute, University of Iceland, Dunhaga 3, 107 Reykjavik, Iceland
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Lawanprasert A, Pimcharoen S, Sumner SE, Watson CT, Manning KB, Kirimanjeswara GS, Medina SH. Heparin-Peptide Nanogranules for Thrombosis-Actuated Anticoagulation. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2203751. [PMID: 36192159 PMCID: PMC9671832 DOI: 10.1002/smll.202203751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/25/2022] [Indexed: 06/16/2023]
Abstract
Despite nearly a century of clinical use as a blood thinner, heparin's rapid serum clearance and potential to induce severe bleeding events continue to urge the development of more effective controlled delivery strategies. Subcutaneous depots that steadily release the anticoagulant into circulation represent a promising approach to reducing overdose frequency, sustaining therapeutic concentrations of heparin in plasma, and prolonging anticoagulant activity in a safe and effective manner. Subcutaneously deliverable heparin-peptide nanogranules that allow for long-lasting heparin bioavailability in the circulatory system, while enabling on-demand activation of heparin's anticoagulant effects in the thrombus microenvironment, are reported. Biophysical studies demonstrate this responsive behavior is due to the sequestration of heparin within self-assembling peptide nanofibrils and its mechanically actuated decoupling to elicit antithrombotic effects at the clotting site. In vivo studies show these unique properties converge to allow subcutaneous nanogranule depots to extend heparin serum concentrations for an order of magnitude longer than standard dosing regimens while enabling prolonged and controlled anticoagulant activity. This biohybrid delivery system demonstrates a potentially scalable platform for the development of safer, easier to administer, and more effective antithrombotic nanotechnologies.
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Affiliation(s)
- Atip Lawanprasert
- Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, 16802-4400, USA
| | - Sopida Pimcharoen
- Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, 16802-4400, USA
| | - Sarah E Sumner
- Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA, 16802-4400, USA
| | - Connor T Watson
- Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, 16802-4400, USA
| | - Keefe B Manning
- Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, 16802-4400, USA
| | - Girish S Kirimanjeswara
- Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA, 16802-4400, USA
- Center for Infectious Disease Dynamics, Pennsylvania State University, University Park, PA, 16802-4400, USA
- Center for Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, PA, 16802-4400, USA
| | - Scott H Medina
- Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, 16802-4400, USA
- Huck Institutes of the Life Sciences, Penn State University, University Park, PA, 16802-4400, USA
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17
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Designer phospholipids – structural retrieval, chemo-/bio- synthesis and isotopic labeling. Biotechnol Adv 2022; 60:108025. [DOI: 10.1016/j.biotechadv.2022.108025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 07/12/2022] [Accepted: 07/26/2022] [Indexed: 11/23/2022]
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TAKENOUCHI S, KOBAYASHI Y, SHINOZAKI T, KOBAYASHI K, NAKAMURA T, YONEZAWA T, MURATA T. The urinary lipid profile in cats with idiopathic cystitis. J Vet Med Sci 2022; 84:689-693. [PMID: 35387958 PMCID: PMC9177401 DOI: 10.1292/jvms.22-0049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/24/2022] [Indexed: 11/22/2022] Open
Abstract
Although feline idiopathic cystitis (FIC) distresses of many cats, its pathogenesis is unknown and the diagnosis is challenging. Polyunsaturated fatty acids (PUFAs) are metabolized into various lipid mediators. Lipid mediators such as prostaglandins (PGs) modulate inflammation and many of them are excreted into the urine. Thus, the investigation of the urinary lipid profile may reveal pathogenesis and help diagnosis of FIC. We collected urine samples from five FIC cats by spontaneous urination and analyzed 158 types of lipid mediators in urines using liquid chromatography-mass spectrometry. The urinary levels of PUFAs were higher in FIC compared to those of the healthy group. The excretions of a major inflammatory mediator, PGD2, were less in FIC. Other well-known inflammatory mediators such as PGE2, PGI2, and their metabolites did not show a difference. In contrast, the levels of PGF2α and its 2 metabolites and PGF3α were higher in FIC. These results may provide new insights into the future management of cat FIC.
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Affiliation(s)
- Shinya TAKENOUCHI
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Yui KOBAYASHI
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | | | - Koji KOBAYASHI
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Tatsuro NAKAMURA
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Tomohiro YONEZAWA
- Department of Veterinary Clinical Pathobiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Takahisa MURATA
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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English CJ, Mayr HL, Lohning AE, Reidlinger DP. The association between dietary patterns and the novel inflammatory markers platelet-activating factor and lipoprotein-associated phospholipase A2: a systematic review. Nutr Rev 2022; 80:1371-1391. [PMID: 34651191 PMCID: PMC9086773 DOI: 10.1093/nutrit/nuab051] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
CONTEXT Atherosclerosis is a disease of chronic inflammation. Recent research has identified 2 novel inflammatory biomarkers: platelet-activating factor (PAF) and lipoprotein-associated phospholipase A2 (Lp-PLA2). Diet has been proposed as a mediator of inflammation, but to date, the focus for these novel biomarkers has been on individual foods and nutrients rather than overall dietary patterns. OBJECTIVE To systematically review the literature on the association between dietary patterns and PAF and Lp-PLA2. DATA SOURCES The PubMed, Embase, CINAHL, and Cochrane CENTRAL literature databases were searched. DATA ANALYSIS Study quality was evaluated using the Quality Criteria Checklist. Sixteen studies (n = 4 observational and n = 12 interventional) were included and assessed for associations between dietary patterns and PAF and Lp-PLA2. CONCLUSION Study quality varied from neutral (n = 10) to positive (n = 6). Mediterranean, heart healthy, and vegetarian dietary patterns were associated with improved levels of PAF and Lp-PLA2. Conversely, Western dietary patterns were less favorable. A range of well-established, healthier dietary patterns may lower inflammation and the risk of atherosclerosis. More well-designed studies are needed to confirm these findings and identify other dietary patterns that improve inflammation.
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Affiliation(s)
- Carolyn J English
- Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
| | - Hannah L Mayr
- Faculty of Health Sciences and Medicine, Bond University, Robina , Queensland, Australia
- Department of Nutrition and Dietetics, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Anna E Lohning
- Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
| | - Dianne P Reidlinger
- Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
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20
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Frommeyer TC, Gilbert MM, Brittain GV, Wu T, Nguyen TQ, Rohan CA, Travers JB. UVB-Induced Microvesicle Particle Release and Its Effects on the Cutaneous Microenvironment. Front Immunol 2022; 13:880850. [PMID: 35603177 PMCID: PMC9120817 DOI: 10.3389/fimmu.2022.880850] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/04/2022] [Indexed: 12/14/2022] Open
Abstract
Ultraviolet B radiation (UVB) has profound effects on human skin that results in a broad spectrum of immunological local and systemic responses and is the major cause of skin carcinogenesis. One important area of study in photobiology is how UVB is translated into effector signals. As the skin is exposed to UVB light, subcellular microvesicle particles (MVP), a subtype of bioactive extracellular vesicles, are released causing a variety of local and systemic immunological effects. In this review, we highlight keratinocyte MVP release in keratinocytes in response to UVB. Specifically, Platelet-activating factor receptor agonists generated by UVB result in MVP released from keratinocytes. The downstream effects of MVP release include the ability of these subcellular particles to transport agents including the glycerophosphocholine-derived lipid mediator Platelet-activating factor (PAF). Moreover, even though UVB is only absorbed in the epidermis, it appears that PAF release from MVPs also mediates systemic immunosuppression and enhances tumor growth and metastasis. Tumor cells expressing PAF receptors can use this mechanism to evade chemotherapy responses, leading to treatment resistance for advanced cancers such as melanoma. Furthermore, novel pharmacological agents provide greater insight into the UVB-induced immune response pathway and a potential target for pharmacological intervention. This review outlines the need to more clearly elucidate the mechanism linking UVB-irradiation with the cutaneous immune response and its pathological manifestations. An improved understanding of this process can result in new insights and treatment strategies for UVB-related disorders from carcinogenesis to photosensitivity.
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Affiliation(s)
- Timothy C. Frommeyer
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
| | - Michael M. Gilbert
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
| | - Garrett V. Brittain
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
| | - Tongfan Wu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
| | - Trang Q. Nguyen
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
| | - Craig A. Rohan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Department of Dermatology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Department of Medicine, Dayton Veterans Administration Medical Center, Dayton, OH, United States
| | - Jeffrey B. Travers
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Department of Dermatology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Department of Medicine, Dayton Veterans Administration Medical Center, Dayton, OH, United States
- *Correspondence: Jeffrey B. Travers,
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21
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Macroalgal Proteins: A Review. Foods 2022; 11:foods11040571. [PMID: 35206049 PMCID: PMC8871301 DOI: 10.3390/foods11040571] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/31/2022] [Accepted: 02/08/2022] [Indexed: 12/11/2022] Open
Abstract
Population growth is the driving change in the search for new, alternative sources of protein. Macroalgae (otherwise known as seaweeds) do not compete with other food sources for space and resources as they can be sustainably cultivated without the need for arable land. Macroalgae are significantly rich in protein and amino acid content compared to other plant-derived proteins. Herein, physical and chemical protein extraction methods as well as novel techniques including enzyme hydrolysis, microwave-assisted extraction and ultrasound sonication are discussed as strategies for protein extraction with this resource. The generation of high-value, economically important ingredients such as bioactive peptides is explored as well as the application of macroalgal proteins in human foods and animal feed. These bioactive peptides that have been shown to inhibit enzymes such as renin, angiotensin-I-converting enzyme (ACE-1), cyclooxygenases (COX), α-amylase and α-glucosidase associated with hypertensive, diabetic, and inflammation-related activities are explored. This paper discusses the significant uses of seaweeds, which range from utilising their anthelmintic and anti-methane properties in feed additives, to food techno-functional ingredients in the formulation of human foods such as ice creams, to utilising their health beneficial ingredients to reduce high blood pressure and prevent inflammation. This information was collated following a review of 206 publications on the use of seaweeds as foods and feeds and processing methods to extract seaweed proteins.
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22
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Gijbels A, Schutte S, Esser D, Wopereis S, Gonzales GB, Afman LA. Effects of a 12-week whole-grain or refined wheat intervention on plasma acylcarnitines, bile acids and signaling lipids, and association with liver fat: A post-hoc metabolomics study of a randomized controlled trial. Front Nutr 2022; 9:1026213. [PMID: 36330140 PMCID: PMC9624226 DOI: 10.3389/fnut.2022.1026213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/14/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND We previously showed that whole-grain wheat (WGW) consumption had beneficial effects on liver fat accumulation, as compared to refined wheat (RW). The mechanisms underlying these effects remain unclear. OBJECTIVE In this study, we investigated the effects of WGW vs. RW consumption on plasma metabolite levels to explore potential underlying mechanisms of the preventive effect of WGW consumption on liver fat accumulation. METHODS Targeted metabolomics of plasma obtained from a concluded 12-week double-blind, randomized controlled trial was performed. Fifty overweight or obese men and women aged 45-70 years with mildly elevated levels of plasma cholesterol were randomized to either 98 g/d of WGW or RW products. Before and after the intervention, a total of 89 fasting plasma metabolite concentrations including acylcarnitines, trimethylamine-N-oxide (TMAO), choline, betaine, bile acids, and signaling lipids were quantified by UPLC-MS/MS. Intrahepatic triglycerides (IHTG) were quantified by 1H-MRS, and multiple liver markers, including circulating levels of β-hydroxybutyrate, alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (γ-GT), serum amyloid A (SAA), and C-reactive protein, were assessed. RESULTS The WGW intervention increased plasma concentrations of four out of 52 signaling lipids-lysophosphatidic acid C18:2, lysophosphatidylethanolamine C18:1 and C18:2, and platelet-activating factor C18:2-and decreased concentrations of the signaling lipid lysophosphatidylglycerol C20:3 as compared to RW intervention, although these results were no longer statistically significant after false discovery rate (FDR) correction. Plasma concentrations of the other metabolites that we quantified were not affected by WGW or RW intervention. Changes in the above-mentioned metabolites were not correlated to change in IHTG upon the intervention. CONCLUSION Plasma acylcarnitines, bile acids, and signaling lipids were not robustly affected by the WGW or RW interventions, which makes them less likely candidates to be directly involved in the mechanisms that underlie the protective effect of WGW consumption or detrimental effect of RW consumption on liver fat accumulation. CLINICAL TRIAL REGISTRATION [www.ClinicalTrials.gov], identifier [NCT02385149].
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Affiliation(s)
- Anouk Gijbels
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, Netherlands
| | - Sophie Schutte
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, Netherlands
| | - Diederik Esser
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, Netherlands
| | - Suzan Wopereis
- Research Group Microbiology and Systems Biology, TNO, Netherlands Organization for Applied Scientific Research, Zeist, Netherlands
| | - Gerard Bryan Gonzales
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, Netherlands
| | - Lydia A. Afman
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, Netherlands
- *Correspondence: Lydia A. Afman,
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23
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Hayashi D, Mouchlis VD, Dennis EA. Each phospholipase A 2 type exhibits distinct selectivity toward sn-1 ester, alkyl ether, and vinyl ether phospholipids. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159067. [PMID: 34634490 PMCID: PMC9188868 DOI: 10.1016/j.bbalip.2021.159067] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/28/2021] [Accepted: 10/05/2021] [Indexed: 01/03/2023]
Abstract
Glycerophospholipids are major components of cell membranes and have enormous variation in the composition of fatty acyl chains esterified on the sn-1 and sn-2 position as well as the polar head groups on the sn-3 position of the glycerol backbone. Phospholipase A2 (PLA2) enzymes constitute a superfamily of enzymes which play a critical role in metabolism and signal transduction by hydrolyzing the sn-2 acyl chains of glycerophospholipids. In human cell membranes, in addition to the conventional diester phospholipids, a significant amount is the sn-1 ether-linked phospholipids which play a critical role in numerous biological activities. However, precisely how PLA2s distinguish the sn-1 acyl chain linkage is not understood. In the present study, we expanded the technique of lipidomics to determine the unique in vitro specificity of three major human PLA2s, including Group IVA cytosolic cPLA2, Group VIA calcium-independent iPLA2, and Group V secreted sPLA2 toward the linkage at the sn-1 position. Interestingly, cPLA2 prefers sn-1 vinyl ether phospholipids known as plasmalogens over conventional ester phospholipids and the sn-1 alkyl ether phospholipids. iPLA2 showed similar activity toward vinyl ether and ester phospholipids at the sn-1 position. Surprisingly, sPLA2 preferred ester phospholipids over alkyl and vinyl ether phospholipids. By taking advantage of molecular dynamics simulations, we found that Trp30 in the sPLA2 active site dominates its specificity for diester phospholipids.
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24
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Costa KA, Lacerda DR, Silveira ALM, Martins LB, Oliveira MC, Rezende BM, Menezes-Garcia Z, Mügge FLB, Silva AM, Teixeira MM, Rouault C, Pinho V, Marcelin G, Clément K, Ferreira AVM. PAF signaling plays a role in obesity-induced adipose tissue remodeling. Int J Obes (Lond) 2022; 46:68-76. [PMID: 34493775 DOI: 10.1038/s41366-021-00961-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 08/16/2021] [Accepted: 08/26/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND/OBJECTIVES Platelet-activating factor receptor (PAFR) activation controls adipose tissue (AT) expansion in animal models. Our objective was twofold: (i) to check whether PAFR signaling is involved in human obesity and (ii) investigate the PAF pathway role in hematopoietic or non-hematopoietic cells to control adipocyte size. MATERIALS/SUBJECTS AND METHODS Clinical parameters and adipose tissue gene expression were evaluated in subjects with obesity. Bone marrow (BM) transplantation from wild-type (WT) or PAFR-/- mice was performed to obtain chimeric PAFR-deficient mice predominantly in hematopoietic or non-hematopoietic-derived cells. A high carbohydrate diet (HC) was used to induce AT remodeling and evaluate in which cell compartment PAFR signaling modulates it. Also, 3T3-L1 cells were treated with PAF to evaluate fat accumulation and the expression of genes related to it. RESULTS PAFR expression in omental AT from humans with obesity was negatively correlated to different corpulence parameters and more expressed in the stromal vascular fraction than adipocytes. Total PAFR-/- increased adiposity compared with WT independent of diet-induced obesity. Differently, WT mice receiving PAFR-/--BM exhibited similar adiposity gain as WT chimeras. PAFR-/- mice receiving WT-BM showed comparable augmentation in adiposity as total PAFR-/- mice, demonstrating that PAFR signaling modulates adipose tissue expansion through non-hematopoietic cells. Indeed, the PAF treatment in 3T3-L1 adipocytes reduced fat accumulation and expression of adipogenic genes. CONCLUSIONS Therefore, decreased PAFR signaling may favor an AT accumulation in humans and animal models. Importantly, PAFR signaling, mainly in non-hematopoietic cells, especially in adipocytes, appears to play a significant role in regulating diet-induced AT expansion.
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Affiliation(s)
- Kátia A Costa
- Immunometabolism, Department of Nutrition, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Débora R Lacerda
- Immunometabolism, Department of Nutrition, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Ana L M Silveira
- Immunometabolism, Department of Nutrition, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Laís B Martins
- Immunometabolism, Department of Nutrition, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Marina C Oliveira
- Immunometabolism, Department of Nutrition, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Barbara M Rezende
- Department of Basic Nursing, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Zélia Menezes-Garcia
- Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Fernanda L B Mügge
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Aristóbolo M Silva
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Mauro M Teixeira
- Immunopharmacology, Department of Immunology and Biochemistry, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Christine Rouault
- Sorbonne Université, INSERM, Nutrition and obesities: systemic approaches (Nutriomics), Paris, France.,Assistance Publique Hôpitaux de Paris, Nutrition Departments, CRNH Ile de France, Pitié-Salpêtrière Hospital, Paris, France
| | - Vanessa Pinho
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Geneviève Marcelin
- Sorbonne Université, INSERM, Nutrition and obesities: systemic approaches (Nutriomics), Paris, France.,Assistance Publique Hôpitaux de Paris, Nutrition Departments, CRNH Ile de France, Pitié-Salpêtrière Hospital, Paris, France
| | - Karine Clément
- Sorbonne Université, INSERM, Nutrition and obesities: systemic approaches (Nutriomics), Paris, France.,Assistance Publique Hôpitaux de Paris, Nutrition Departments, CRNH Ile de France, Pitié-Salpêtrière Hospital, Paris, France
| | - Adaliene V M Ferreira
- Immunometabolism, Department of Nutrition, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
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25
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He Y, He Z, Zhang X, Liu S. Platelet-activating factor acetyl hydrolase IB2 dysregulated cell proliferation in ovarian cancer. Cancer Cell Int 2021; 21:697. [PMID: 34930255 PMCID: PMC8690939 DOI: 10.1186/s12935-021-02406-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/09/2021] [Indexed: 11/10/2022] Open
Abstract
Background Ovarian cancer is the leading cause of death from gynaecologic illnessed worldwide. Platelet-activating factor acetyl hydrolase IB2 (PAF-AH IB2) is an intracellular serine esterase that hydrolyzes platelet-activating factor, a G-protein-like trimer with two catalytic subunits and one regulatory subunit. The regulatory role of PAF-AH IB2 in the oncogenesis of ovarian cancer is not well understood. Methods In this study, the TCGA dataset and clinical cancer tissue microarray were utilized to investigate abnormal overexpression of PAF-AH IB2 in ovarian cancer. To investigate the impact on the cell proliferation, migration, and tumorigenicity in vitro, PAF-AH IB2 stable knocking down (KD) ovarian cancer cells were established by ShRNA. The whole transcription profiling, tyrosine kinase profiling and standard cell functional assays were integrated to explore the biological importance and mechanism of PAF-AH IB2 modulated in ovarian cancer. Results PAF-AH IB2 was identified significantly overexpression in four subtypes of ovarian cancer. In vitro, PAF-AH IB2 KD significantly inhibited cancer cell proliferation, migration, and tumorigenicity, activated caspases and caused cell cycle arrest, and made the cells more sensitive to PAF. PAF-AH 1B2 KD cells down-regulated several key regulators of the multiple tyrosine kinases-mediated signaling pathway, suggesting a novel interaction network between the growth factor receptors pathway and PAF-AH 1B2 mediated PAF signalling. Conclusions These findings revealed a previously undiscovered role for PAF-AH IB2 as a potenial therapy target and essential signaling mediators in ovarian cancer pathogenesis, as well as new possible preventive and therapeutic strategies to inhibit this enzyme in clinical treatment for ovarian cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02406-9.
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Affiliation(s)
- YingYing He
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, #132 Lanhei Road, Panlong District, Kunming, 650201, Yunnan, People's Republic of China.,School of Chemical Science & Technology, Yunnan University, Kunming, 650091, Yunnan, China
| | - Zhicheng He
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, #132 Lanhei Road, Panlong District, Kunming, 650201, Yunnan, People's Republic of China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaoyu Zhang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, #132 Lanhei Road, Panlong District, Kunming, 650201, Yunnan, People's Republic of China
| | - Shubai Liu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, #132 Lanhei Road, Panlong District, Kunming, 650201, Yunnan, People's Republic of China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
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26
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Sakr F, Dyrba M, Bräuer AU, Teipel S. Association of Lipidomics Signatures in Blood with Clinical Progression in Preclinical and Prodromal Alzheimer's Disease. J Alzheimers Dis 2021; 85:1115-1127. [PMID: 34897082 DOI: 10.3233/jad-201504] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Lipidomics may provide insight into biochemical processes driving Alzheimer's disease (AD) pathogenesis and ensuing clinical trajectories. OBJECTIVE To identify a peripheral lipidomics signature associated with AD pathology and investigate its potential to predict clinical progression. METHODS We used Bayesian elastic net regression to select plasma lipid classes associated with the CSF pTau/Aβ42 ratio as a biomarker of AD pathology in preclinical and prodromal AD cases from the ADNI cohort. Consensus clustering of the selected lipid classes was used to identify lipidomic endophenotypes and study their association with clinical progression. RESULTS In the APOE4-adjusted model, ether-glycerophospholipids, lyso-glycerophospholipids, free-fatty acids, cholesterol esters, and complex sphingolipids were found to be associated with the CSF pTau/Aβ 42 ratio. We found an optimal number of five lipidomic endophenotypes in the prodromal and preclinical cases, respectively. In the prodromal cases, these clusters differed with respect to the risk of clinical progression as measured by clinical dementia rating score conversion. CONCLUSION Lipid alterations can be captured at the earliest phases of AD. A lipidomic signature in blood may provide a dynamic overview of an individual's metabolic status and may support identifying different risks of clinical progression.
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Affiliation(s)
- Fatemah Sakr
- Department of Psychosomatic Medicine, University Medicine Rostock, Rostock, Germany.,German Centre for Neurodegenerative Diseases (DZNE), Rostock, Germany.,Anatomy Research Group, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg, Germany
| | - Martin Dyrba
- German Centre for Neurodegenerative Diseases (DZNE), Rostock, Germany
| | - Anja U Bräuer
- Anatomy Research Group, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg, Germany.,Research Centre for Neurosensory Science, Carl von Ossietzky University Oldenburg, Oldenburg, Germany
| | - Stefan Teipel
- Department of Psychosomatic Medicine, University Medicine Rostock, Rostock, Germany.,German Centre for Neurodegenerative Diseases (DZNE), Rostock, Germany
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Proteomic Research on the Antitumor Properties of Medicinal Mushrooms. Molecules 2021; 26:molecules26216708. [PMID: 34771120 PMCID: PMC8588050 DOI: 10.3390/molecules26216708] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/27/2021] [Accepted: 11/02/2021] [Indexed: 12/22/2022] Open
Abstract
Medicinal mushrooms are increasingly being recognized as an important therapeutic modality in complementary oncology. Until now, more than 800 mushroom species have been known to possess significant pharmacological properties, of which antitumor and immunomodulatory properties have been the most researched. Besides a number of medicinal mushroom preparations being used as dietary supplements and nutraceuticals, several isolates from mushrooms have been used as official antitumor drugs in clinical settings for several decades. Various proteomic approaches allow for the identification of a large number of differentially regulated proteins serendipitously, thereby providing an important platform for a discovery of new potential therapeutic targets and approaches as well as biomarkers of malignant disease. This review is focused on the current state of proteomic research into antitumor mechanisms of some of the most researched medicinal mushroom species, including Phellinus linteus, Ganoderma lucidum, Auricularia auricula, Agrocybe aegerita, Grifola frondosa, and Lentinus edodes, as whole body extracts or various isolates, as well as of complex extract mixtures.
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28
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Pereira-Dutra FS, Bozza PT. Lipid droplets diversity and functions in inflammation and immune response. Expert Rev Proteomics 2021; 18:809-825. [PMID: 34668810 DOI: 10.1080/14789450.2021.1995356] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Lipid droplets (LDs) are dynamic and evolutionary conserved lipid-enriched organelles composed of a core of neutral lipids surrounded by a monolayer of phospholipids associated with a diverse array of proteins that are cell- and stimulus-regulated. Far beyond being simply a deposit of neutral lipids, accumulating evidence demonstrate that LDs act as spatial and temporal local for lipid and protein compartmentalization and signaling organization. AREAS COVERED This review focuses on the progress in our understanding of LD protein diversity and LD functions in the context of cell signaling and immune responses, highlighting the relationship between LD composition with the multiple roles of this organelle in immunometabolism, inflammation and host-response to infection. EXPERT OPINION LDs are essential platforms for various cellular processes, including metabolic regulation, cell signaling, and immune responses. The functions of LD in infection and inflammatory disease are associated with the dynamic and complexity of their proteome. Our contemporary view place LDs as critical regulators of different inflammatory and infectious diseases and key markers of leukocyte activation.
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Affiliation(s)
- Filipe S Pereira-Dutra
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Patrícia T Bozza
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
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29
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Abhilasha KV, Sumanth MS, Thyagarajan A, Sahu RP, Kemparaju K, Marathe GK. Reversible cross-tolerance to platelet-activating factor signaling by bacterial toxins. Platelets 2021; 32:960-967. [PMID: 32835559 DOI: 10.1080/09537104.2020.1810652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Bacterial toxins signaling through Toll-like receptors (TLRs) are implicated in the pathogenesis of many inflammatory diseases. Among the toxins, lipopolysaccharide (LPS) exerts its action via TLR-4 while lipoteichoic acid (LTA) and bacterial lipoproteins such as Braun lipoprotein (BLP) or its synthetic analogue Pam3CSK4 act through TLR-2. Part of the TLR mediated pathogenicity is believed to stem from endogenously biosynthesized platelet-activating factor (PAF)- a potent inflammatory phospholipid acting through PAF-receptor (PAF-R). However, the role of PAF in inflammatory diseases like endotoxemia is controversial. In order to test the direct contribution of PAF in TLR-mediated pathogenicity, we intraperitoneally injected PAF to Wistar albino mice in the presence or absence of bacterial toxins. Intraperitoneal injection of PAF (5 μg/mouse) causes sudden death of mice, that can be delayed by simultaneously or pre-treating the animals with high doses of bacterial toxins- a phenomenon known as endotoxin cross-tolerance. The bacterial toxins- induced tolerance to PAF can be reversed by increasing the concentration of PAF suggesting the reversibility of cross-tolerance. We did similar experiments using human platelets that express both canonical PAF-R and TLRs. Although bacterial toxins did not induce human platelet aggregation, they inhibited PAF-induced platelet aggregation in a reversible manner. Using rabbit platelets that are ultrasensitive to PAF, we found bacterial toxins (LPS and LTA) and Pam3CSK4 causing rabbit platelet aggregation via PAF-R dependent way. The physical interaction of PAF-R and bacterial toxins is also demonstrated in a human epidermal cell line having stable PAF-R expression. Thus, we suggest the possibility of direct physical interaction of bacterial toxins with PAF-R leading to cross-tolerance.
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Affiliation(s)
| | | | - Anita Thyagarajan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA
| | - Ravi Prakash Sahu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA
| | - Kempaiah Kemparaju
- Department of Studies in Biochemistry, University of Mysore, Mysuru, India.,Department of Studies in Molecular Biology, University of Mysore, Mysuru, India
| | - Gopal Kedihithlu Marathe
- Department of Studies in Biochemistry, University of Mysore, Mysuru, India.,Department of Studies in Molecular Biology, University of Mysore, Mysuru, India
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30
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Liang Y, Tang Z, Jiang Y, Ai C, Peng J, Liu Y, Chen J, Xin X, Lei B, Zhang J, Cai Z. Lipid metabolism disorders associated with dioxin exposure in a cohort of Chinese male workers revealed by a comprehensive lipidomics study. ENVIRONMENT INTERNATIONAL 2021; 155:106665. [PMID: 34098336 DOI: 10.1016/j.envint.2021.106665] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 05/23/2021] [Accepted: 05/23/2021] [Indexed: 06/12/2023]
Abstract
Dioxins, environmentally stable and ubiquitous, have been found to induce metabolic changes especially in lipids and be related to multiple diseases. However, limited study is available on lipid alternations related to human exposure to dioxins. This study aims to explore the serum lipidomic characterization and to understand the underlying mechanisms of adverse health risks associated with dioxin exposure. A lipidomic study integrating nontargeted lipidomics, and targeted free fatty acid (FFA) and acyl-coenzyme A (acyl-CoA) analyses were conducted to investigate the 94 serum samples from two groups of male workers with remarkably different dioxin concentrations. The obtained results exhibited distinct lipidomic signatures between the high and low exposed groups. A total of 37 lipids were identified with the significant changes. The results revealed that dioxin exposure caused accumulations of triglyceride (TG), ceramide (Cer) and sphingoid (So), remodeling of glycerophospholipid (GP), imbalanced FFA metabolism, as well as upregulation of platelet-activating factor (PAF). These findings implied the associations between dioxin exposure and potential adverse health risks including inflammation, apoptosis, cardiovascular diseases (CVDs), and liver diseases. This study is the first to explain the associations between dioxin exposure and health effects at the level of lipid metabolism.
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Affiliation(s)
- Yanshan Liang
- Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, China; State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong Special Administrative Region
| | - Zhi Tang
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China; Department of Environmental and Occupational Health, School of Public Health, Guangdong Medical University, Dongguan, China
| | - Yousheng Jiang
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
| | - Chunyan Ai
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
| | - Jinling Peng
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
| | - Yuan Liu
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
| | - Jinru Chen
- Songgang Preventive Health Center of Baoan District, Shenzhen, 518105, China
| | - Xiong Xin
- Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, China
| | - Bo Lei
- Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, China
| | - Jianqing Zhang
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China.
| | - Zongwei Cai
- Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, China; State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong Special Administrative Region.
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31
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Yang S, Wang YL, Lyu Y, Jiang Y, Xiang J, Ji S, Kang S, Lyu X, He C, Li P, Liu B, Wu C. mGWAS identification of six novel single nucleotide polymorphism loci with strong correlation to gastric cancer. Cancer Metab 2021; 9:34. [PMID: 34565479 PMCID: PMC8474935 DOI: 10.1186/s40170-021-00269-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 09/08/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Metabolite genome-wide association studies (mGWAS) are key for understanding the genetic regulation of metabolites in complex diseases including cancers. Although mGWAS has revealed hundreds of metabolomics quantitative trait loci (mQTLs) in the general population, data relating to gastric cancer (GC) are still incomplete. METHODS We identified mQTLs associated with GC by analyzing genome-wide and metabolome-wide datasets generated from 233 GC patients and 233 healthy controls. RESULTS Twenty-two metabolites were statistically different between GC cases and healthy controls, and all of them were associated with the risk of gastric cancer. mGWAS analyses further revealed that 9 single nucleotide polymorphisms (SNPs) were significantly associated with 3 metabolites. Of these 9 SNPs, 6 loci were never reported in the previous mGWAS studies. Surprisingly, 4 of 9 SNPs were significantly enriched in genes involved in the T cell receptor signaling pathway. CONCLUSIONS Our study unveiled several novel GC metabolite and genetic biomarkers, which may be implicated in the prevention and diagnosis of gastric cancer.
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Affiliation(s)
- Shuangfeng Yang
- School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, China
| | - Yuan-Liang Wang
- School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, China
| | - Yanping Lyu
- School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, China
| | - Yu Jiang
- School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, China
| | - Jianjun Xiang
- School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, China
| | - Shumi Ji
- School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, China
| | - Shuling Kang
- School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, China
| | - Xuejie Lyu
- School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, China
| | - Chenzhou He
- School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, China
| | - Peixin Li
- School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, China
| | - Baoying Liu
- School of Public Health, Fujian Medical University, Fuzhou, China.
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, China.
| | - Chuancheng Wu
- School of Public Health, Fujian Medical University, Fuzhou, China.
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, China.
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32
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Comparative Computational Modeling of the Bat and Human Immune Response to Viral Infection with the Comparative Biology Immune Agent Based Model. Viruses 2021; 13:v13081620. [PMID: 34452484 PMCID: PMC8402910 DOI: 10.3390/v13081620] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/05/2021] [Accepted: 08/13/2021] [Indexed: 12/22/2022] Open
Abstract
Given the impact of pandemics due to viruses of bat origin, there is increasing interest in comparative investigation into the differences between bat and human immune responses. The practice of comparative biology can be enhanced by computational methods used for dynamic knowledge representation to visualize and interrogate the putative differences between the two systems. We present an agent based model that encompasses and bridges differences between bat and human responses to viral infection: the comparative biology immune agent based model, or CBIABM. The CBIABM examines differences in innate immune mechanisms between bats and humans, specifically regarding inflammasome activity and type 1 interferon dynamics, in terms of tolerance to viral infection. Simulation experiments with the CBIABM demonstrate the efficacy of bat-related features in conferring viral tolerance and also suggest a crucial role for endothelial inflammasome activity as a mechanism for bat systemic viral tolerance and affecting the severity of disease in human viral infections. We hope that this initial study will inspire additional comparative modeling projects to link, compare, and contrast immunological functions shared across different species, and in so doing, provide insight and aid in preparation for future viral pandemics of zoonotic origin.
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Teixeira SC, da Silva MS, Gomes AAS, Moretti NS, Lopes DS, Ferro EAV, Rodrigues VDM. Panacea within a Pandora's box: the antiparasitic effects of phospholipases A 2 (PLA 2s) from snake venoms. Trends Parasitol 2021; 38:80-94. [PMID: 34364805 DOI: 10.1016/j.pt.2021.07.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 10/20/2022]
Abstract
Parasitic diseases affect millions of individuals worldwide, mainly in low-income regions. There is no cure for most of these diseases, and the treatment relies on drugs that have side effects and lead to drug resistance, emphasizing the urgency to find new treatments. Snake venom has been gaining prominence as a rich source of molecules with antiparasitic potentials, such as phospholipases A2 (PLA2s). Here, we compile the findings involving PLA2s with antiparasitic activities against helminths, Plasmodium, Toxoplasma, and trypanosomatids. We indicate their molecular features, highlighting the possible antiparasitic mechanisms of action of these proteins. We also demonstrate interactions between PLA2s and some parasite membrane components, shedding light on potential targets for drug design that may provide better treatment for the illnesses caused by parasites.
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Affiliation(s)
- Samuel Cota Teixeira
- Department of Immunology, Institute of Biomedical Science, Federal University of Uberlândia, Uberlândia (UFU), MG, Brazil.
| | - Marcelo Santos da Silva
- DNA Replication and Repair Laboratory (DRRL), Department of Chemical and Biological Sciences, Biosciences Institute, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | | | - Nilmar Silvio Moretti
- Laboratório de Biologia Molecular de Patógenos (LBMP), Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil
| | - Daiana Silva Lopes
- Multidisciplinary Institute of Health, Anísio Teixeira Campus, Federal University of Bahia (UFBA), Vitória da Conquista, BA, Brazil
| | - Eloisa Amália Vieira Ferro
- Department of Immunology, Institute of Biomedical Science, Federal University of Uberlândia, Uberlândia (UFU), MG, Brazil
| | - Veridiana de Melo Rodrigues
- Laboratory of Biochemistry and Animal Toxins, Institute of Biotechnology, Federal University of Uberlândia (UFU), Uberlândia, MG, Brazil.
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Lindhout IA, Murray TE, Richards CM, Klegeris A. Potential neurotoxic activity of diverse molecules released by microglia. Neurochem Int 2021; 148:105117. [PMID: 34186114 DOI: 10.1016/j.neuint.2021.105117] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 05/18/2021] [Accepted: 06/24/2021] [Indexed: 01/02/2023]
Abstract
Microglia are the professional immune cells of the brain, which support numerous physiological processes. One of the defensive functions provided by microglia involves secretion of cytotoxins aimed at destroying invading pathogens. It is also recognized that the adverse activation of microglia in diseased brains may lead to secretion of cytotoxic molecules, which could be damaging to the surrounding cells, including neurons. Several of these toxins, such as reactive oxygen and nitrogen species, L-glutamate, and quinolinic acid, are widely recognized and well-studied. This review is focused on a structurally diverse group of less-established microglia neurotoxins, which were selected by applying the two criteria that these molecules 1) can be released by microglia, and 2) have the potential to be directly harmful to neurons. The following 11 molecules are discussed in detail: amyloid beta peptides (Aβ); cathepsin (Cat)B and CatD; C-X-C motif chemokine ligand (CXCL)10 and CXCL12 (5-67); high mobility group box (HMGB)1; lymphotoxin (LT)-α; matrix metalloproteinase (MMP)-2 and MMP-9; platelet-activating factor (PAF); and prolyl endopeptidase (PEP). Molecular mechanisms of their release by microglia and neurotoxicity, as well as available evidence implicating their involvement in human neuropathologies are summarized. Further studies on several of the above molecules are warranted to confirm either their microglial origin in the brain or direct neurotoxic effects. In addition, investigations into the differential secretion patterns of neurotoxins by microglia in response to diverse stimuli are required. This research could identify novel therapeutic targets for neurological disorders involving adverse microglial activation.
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Affiliation(s)
- Ivan A Lindhout
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, British Columbia, V1V 1V7, Canada
| | - Taryn E Murray
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, British Columbia, V1V 1V7, Canada
| | - Christy M Richards
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, British Columbia, V1V 1V7, Canada
| | - Andis Klegeris
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, British Columbia, V1V 1V7, Canada.
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35
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Gene Expression Profile in Different Age Groups and Its Association with Cognitive Function in Healthy Malay Adults in Malaysia. Cells 2021; 10:cells10071611. [PMID: 34199148 PMCID: PMC8304476 DOI: 10.3390/cells10071611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 06/13/2021] [Accepted: 06/21/2021] [Indexed: 11/16/2022] Open
Abstract
The mechanism of cognitive aging at the molecular level is complex and not well understood. Growing evidence suggests that cognitive differences might also be caused by ethnicity. Thus, this study aims to determine the gene expression changes associated with age-related cognitive decline among Malay adults in Malaysia. A cross-sectional study was conducted on 160 healthy Malay subjects, aged between 28 and 79, and recruited around Selangor and Klang Valley, Malaysia. Gene expression analysis was performed using a HumanHT-12v4.0 Expression BeadChip microarray kit. The top 20 differentially expressed genes at p < 0.05 and fold change (FC) = 1.2 showed that PAFAH1B3, HIST1H1E, KCNA3, TM7SF2, RGS1, and TGFBRAP1 were regulated with increased age. The gene set analysis suggests that the Malay adult's susceptibility to developing age-related cognitive decline might be due to the changes in gene expression patterns associated with inflammation, signal transduction, and metabolic pathway in the genetic network. It may, perhaps, have important implications for finding a biomarker for cognitive decline and offer molecular targets to achieve successful aging, mainly in the Malay population in Malaysia.
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36
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Amunugama K, Pike DP, Ford DA. The lipid biology of sepsis. J Lipid Res 2021; 62:100090. [PMID: 34087197 PMCID: PMC8243525 DOI: 10.1016/j.jlr.2021.100090] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 01/12/2023] Open
Abstract
Sepsis, defined as the dysregulated immune response to an infection leading to organ dysfunction, is one of the leading causes of mortality around the globe. Despite the significant progress in delineating the underlying mechanisms of sepsis pathogenesis, there are currently no effective treatments or specific diagnostic biomarkers in the clinical setting. The perturbation of cell signaling mechanisms, inadequate inflammation resolution, and energy imbalance, all of which are altered during sepsis, are also known to lead to defective lipid metabolism. The use of lipids as biomarkers with high specificity and sensitivity may aid in early diagnosis and guide clinical decision making. In addition, identifying the link between specific lipid signatures and their role in sepsis pathology may lead to novel therapeutics. In this review, we discuss the recent evidence on dysregulated lipid metabolism both in experimental and human sepsis focused on bioactive lipids, fatty acids, and cholesterol as well as the enzymes regulating their levels during sepsis. We highlight not only their potential roles in sepsis pathogenesis but also the possibility of using these respective lipid compounds as diagnostic and prognostic biomarkers of sepsis.
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Affiliation(s)
- Kaushalya Amunugama
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA; Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Daniel P Pike
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA; Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - David A Ford
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA; Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO, USA.
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37
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Dalmaso B, da Silva-Junior IA, Fragel-Madeira L, Jancar S, Del Debbio CB. Platelet activating factor in the eye: Physiological roles, diseases and future perspectives. Prostaglandins Other Lipid Mediat 2021; 153:106522. [PMID: 33358892 DOI: 10.1016/j.prostaglandins.2020.106522] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 12/03/2020] [Accepted: 12/18/2020] [Indexed: 01/09/2023]
Abstract
Platelet Activating Factor (PAF) is a known phospholipid mediator of inflammation. Since its first description in 1972, it has emerged as a key regulator of vital cellular signaling functions, as proliferation, cell adhesion, and apoptosis. Evidence suggests that interactions between PAF and its receptor (PAFR) play a critical role in nervous system tissues, including the retina. The retina is a very important constituent of the visual system, along with the cornea, sclera, choroid, iris, and ciliary body, that acts synergistically to provide vision and to maintain optical homeostasis. There is evidence that PAF may regulate a wide range of physiological functions in the visual system tissues, such as eye development, inflammation, epithelial wound healing, and synapsis. Due to their multiple functions, PAF and PAFR also have important pathological and clinical implications in ocular disorders such as Choroidal Neovascularization (CNV), Age Macular Degeneration, (AMD), Diabetic Retinopathy (DR), transplant responses, and pharmacological interactions. Studies with PAFR antagonists have shown promising results such as inhibition of neovascularization and chloroquine-induced retinopathies, as well as reducing inflammation and retinal cell death. Due to the importance of PAFR signaling in the visual system and ophthalmology research, this review aims to provide a general overview of current and future perspectives about PAF in eye biology.
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Affiliation(s)
- Barbara Dalmaso
- Department of Cell and Developmental Biology, Biomedical Sciences Institute, University of Sao Paulo, São Paulo, Brazil
| | | | - Lucianne Fragel-Madeira
- Department of Neurobiology, Institute of Biology, Fluminense Federal University, Rio de Janeiro, Brazil
| | - Sonia Jancar
- Department of Immunology, Biomedical Sciences Institute, University of Sao Paulo, São Paulo, Brazil
| | - Carolina Beltrame Del Debbio
- Department of Cell and Developmental Biology, Biomedical Sciences Institute, University of Sao Paulo, São Paulo, Brazil.
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38
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Sato A, Watanabe H, Yamazaki M, Sakurai E, Ebina K. Interaction of Native- and Oxidized-Low-Density Lipoprotein with Human Estrogen Sulfotransferase. Protein J 2021; 40:192-204. [PMID: 33665770 DOI: 10.1007/s10930-021-09971-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2021] [Indexed: 12/11/2022]
Abstract
Cytosolic estrogen sulfotransferase (SULT1E) mainly catalyzes the sulfate conjugation of estrogens, which decrease atherosclerosis progression. Recently we reported that a YKEG sequence in human SULT1E1 (hSULT1E1) corresponding to residues 61-64 can bind specifically to oxidized low-density lipoprotein (Ox-LDL), which plays a major role in the pathogenesis of atherosclerosis; its major oxidative lipid component lysophosphatidylcholine (LPC), and its structurally similar lipid, platelet-activating factor (PAF). In this study, we investigated the effect of Ox-LDL on the sulfating activity of hSULT1E1. In vivo experiments using a mouse model of atherosclerosis showed that the protein expression of SULT1E1 was higher in the aorta of mice with atherosclerosis compared with that in control animals. Results from a sulfating activity assay of hSULT1E1 using 1-hydroxypyrene as the substrate demonstrated that Ox-LDL, LPC, and PAF markedly decreased the sulfating activity of hSULT1E1, whereas native LDL and 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) as one of the oxidized phosphatidylcholines showed the opposite effect. The sulfating activity greatly changed in the presence of LPC, PAF, and POVPC in their concentration-dependen manner (especially above their critical micelle concentrations). Moreover, Ox-LDL specifically recognized dimeric hSULT1E1. These results suggest that the effects of Ox-LDL and native LDL on the sulfating activity of hSULT1E1 might be helpful in elucidating the novel mechanism underlying the pathogenesis of atherosclerosis, involving the relationship between estrogen metabolism, LDL, and Ox-LDL.
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Affiliation(s)
- Akira Sato
- Department of Pharmaceutical Health Science, Faculty of Pharmacy, Iryo Sosei University, 5-5-1, Chuodai-Iino, Iwaki, Fukushima, 970-8551, Japan. .,Graduate School of Life Science and Technology, Iryo Sosei University, 5-5-1, Chuodai-Iino, Iwaki, Fukushima, 970-8551, Japan.
| | - Hinako Watanabe
- Department of Pharmaceutical Health Science, Faculty of Pharmacy, Iryo Sosei University, 5-5-1, Chuodai-Iino, Iwaki, Fukushima, 970-8551, Japan
| | - Miyuki Yamazaki
- Department of Pharmaceutical Health Science, Faculty of Pharmacy, Iryo Sosei University, 5-5-1, Chuodai-Iino, Iwaki, Fukushima, 970-8551, Japan
| | - Eiko Sakurai
- Department of Pharmaceutical Health Science, Faculty of Pharmacy, Iryo Sosei University, 5-5-1, Chuodai-Iino, Iwaki, Fukushima, 970-8551, Japan.,Graduate School of Life Science and Technology, Iryo Sosei University, 5-5-1, Chuodai-Iino, Iwaki, Fukushima, 970-8551, Japan
| | - Keiichi Ebina
- Department of Pharmaceutical Health Science, Faculty of Pharmacy, Iryo Sosei University, 5-5-1, Chuodai-Iino, Iwaki, Fukushima, 970-8551, Japan.,Graduate School of Life Science and Technology, Iryo Sosei University, 5-5-1, Chuodai-Iino, Iwaki, Fukushima, 970-8551, Japan
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Díaz Galván C, Méndez Olvera ET, Martínez Gómez D, Gloria Trujillo A, Hernández García PA, Espinosa Ayala E, Palacios Martínez M, Lara Bueno A, Mendoza Martínez GD, Velázquez Cruz LA. Influence of a Polyherbal Mixture in Dairy Calves: Growth Performance and Gene Expression. Front Vet Sci 2021; 7:623710. [PMID: 33575280 PMCID: PMC7870704 DOI: 10.3389/fvets.2020.623710] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/21/2020] [Indexed: 11/23/2022] Open
Abstract
A polyherbal feed mixture containing (Achyrantes aspera, Trachyspermum ammi, Citrullus colocynthis, Andrographis paniculata, and Azadirachta indica) was evaluated in growing calves through blood chemistry, blood biometry, and gene expression during the pre-ruminant to weaning period. Forty Holstein calves (initial BW 45.6 ± 3.2 kg; 22.8 ± 0.9 days post birth) from a dairy farm were randomly assigned to the following treatments: 0, 3, 4, and 5 g/d of a polyherbal mixture, dosed in colloid gels with gelatin. Calves were housed in individual outdoor boxes with ad libitum access to a 21.5% CP calf starter and water and fed individually with a mixture of milk and a non-medicated milk replacer (22% CP). Blood samples were collected on day 59 for blood chemistry, blood biometry, and gene expression analysis in leukocyte through microarray assays. Immunoglobulins were quantified by enzyme-linked immunosorbent assay. The animals treated with the polyherbal mixture showed a quadratic effect on final body weight, daily weight gain, final hip height, and final thoracic girth. The best performance results were obtained with a treatment dose of 4 g/d. The serum IgG increased linearly with the treatment doses. Gene set enrichment analysis of upregulated genes revealed that the three biological processes with higher fold change were tight junction, mucin type O-Glycan biosynthesis, and intestinal immune network for IgA production. Also, these upregulated genes influenced arachidonic acid metabolism, and pantothenate and CoA biosynthesis. Gene ontology enrichment analysis indicated that the pathways enriched were PELP1 estrogen receptor interacting protein pathways, nuclear receptors in lipid metabolism and toxicity, tight junction, ECM-receptor interaction, thyroid hormone signaling pathways, vascular smooth muscle contraction, ribosome function, glutamatergic synapse pathway, focal adhesion, Hippo, calcium, and MAPK signaling pathways.
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Affiliation(s)
- Cesar Díaz Galván
- Doctorado en Ciencias Agropecuarias, Universidad Autónoma Metropolitana Xochimilco, Ciudad de México, Mexico
| | - Estela Teresita Méndez Olvera
- Laboratorio de Biología Molecular, Departamento de Producción Agrícola y Animal, Universidad Autónoma Metropolitana Xochimilco, Ciudad de México, Mexico
| | - Daniel Martínez Gómez
- Laboratorio de Microbiología Agropecuaria, Universidad Autónoma Metropolitana Xochimilco, Ciudad de México, Mexico
| | - Adrián Gloria Trujillo
- Departamento de Producción Agrícola y Animal, Universidad Autónoma Metropolitana Xochimilco, Ciudad de México, Mexico
| | | | - Enrique Espinosa Ayala
- Centro Universitario UAEM Amecameca, Universidad Autónoma del Estado de México, Amecameca, Mexico
| | - Monika Palacios Martínez
- Departamento de Producción Agrícola y Animal, Universidad Autónoma Metropolitana Xochimilco, Ciudad de México, Mexico
| | | | - Germán David Mendoza Martínez
- Departamento de Producción Agrícola y Animal, Universidad Autónoma Metropolitana Xochimilco, Ciudad de México, Mexico
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Bioactive Ether Lipids: Primordial Modulators of Cellular Signaling. Metabolites 2021; 11:metabo11010041. [PMID: 33430006 PMCID: PMC7827237 DOI: 10.3390/metabo11010041] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/01/2021] [Accepted: 01/03/2021] [Indexed: 12/14/2022] Open
Abstract
The primacy of lipids as essential components of cellular membranes is conserved across taxonomic domains. In addition to this crucial role as a semi-permeable barrier, lipids are also increasingly recognized as important signaling molecules with diverse functional mechanisms ranging from cell surface receptor binding to the intracellular regulation of enzymatic cascades. In this review, we focus on ether lipids, an ancient family of lipids having ether-linked structures that chemically differ from their more prevalent acyl relatives. In particular, we examine ether lipid biosynthesis in the peroxisome of mammalian cells, the roles of selected glycerolipids and glycerophospholipids in signal transduction in both prokaryotes and eukaryotes, and finally, the potential therapeutic contributions of synthetic ether lipids to the treatment of cancer.
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Klein M, Dao V, Khan F. A Review of Platelet-Activating Factor As a Potential Contributor to Morbidity and Mortality Associated with Severe COVID-19. Clin Appl Thromb Hemost 2021; 27:10760296211051764. [PMID: 34755565 PMCID: PMC8586171 DOI: 10.1177/10760296211051764] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 09/19/2021] [Accepted: 09/21/2021] [Indexed: 01/18/2023] Open
Abstract
The precise mechanisms of pathology in severe COVID-19 remains elusive. Current evidence suggests that inflammatory mediators are responsible for the manifestation of clinical symptoms that precedes a fatal response to infection. This review examines the nature of platelet activating factor and emphasizes the similarities between the physiological effects of platelet activating factor and the clinical complications of severe COVID-19.
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Affiliation(s)
- Mark Klein
- Minneapolis Veterans Affairs Healthcare System, Minneapolis, MN, 55417, USA
- University of Minnesota, MN, USA
| | - Vinh Dao
- Minneapolis Veterans Affairs Healthcare System, Minneapolis, MN, 55417, USA
| | - Fatima Khan
- Minneapolis Veterans Affairs Healthcare System, Minneapolis, MN, 55417, USA
- University of Minnesota, MN, USA
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Marathe GK, Chaithra VH, Ke LY, Chen CH. Effect of acyl and alkyl analogs of platelet-activating factor on inflammatory signaling. Prostaglandins Other Lipid Mediat 2020; 151:106478. [PMID: 32711129 DOI: 10.1016/j.prostaglandins.2020.106478] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 07/20/2020] [Accepted: 07/20/2020] [Indexed: 01/11/2023]
Abstract
Platelet-activating factor (PAF), a bioactive ether phospholipid with significant pro-inflammatory properties, was identified almost half a century ago. Despite extensive study of this autocoid, therapeutic strategies for targeting its signaling components have not been successful, including the recent clinical trials with darapladib, a drug that targets plasma PAF-acetylhydrolase (PAF-AH). We recently provided experimental evidence that the previously unrecognized acyl analog of PAF, which is concomitantly produced along with PAF during biosynthesis, dampens PAF signaling by acting both as a sacrificial substrate for PAF-AH and probably as an endogenous PAF-receptor antagonist/partial agonist. If this is the scenario in vivo, PAF-AH needs to catalyze the selective hydrolysis of alkyl-PAF and not acyl-PAF. Accordingly, different approaches are needed for treating inflammatory diseases in which PAF signaling is implicated. The interplay between acyl-PAF, alkyl-PAF, PAF-AH, and PAF-R is complex, and the outcome of this interplay has not been previously appreciated. In this review, we discuss this interaction based on our recent findings. It is very likely that the relative abundance of acyl and alkyl-PAF and their interactions with PAF-R in the presence of their hydrolyzing enzyme PAF-AH may exert a modulatory effect on PAF signaling during inflammation.
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Affiliation(s)
- Gopal Kedihithlu Marathe
- Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysuru, 570006, Karnataka, India; Department of Studies in Molecular Biology, University of Mysore, Manasagangothri, Mysuru, 570006, Karnataka, India.
| | | | - Liang-Yin Ke
- College of Health Sciences, Kaohsiung Medical University, Vascular and Medicinal Research, Kaohsiung, 80708, Taiwan.
| | - Chu-Huang Chen
- Vascular and Medicinal Research, Texas Heart Institute, Houston, Texas 77030, USA.
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Mendoza-Almanza G, Burciaga-Hernández L, Maldonado V, Melendez-Zajgla J, Olmos J. Role of platelets and breast cancer stem cells in metastasis. World J Stem Cells 2020; 12:1237-1254. [PMID: 33312396 PMCID: PMC7705471 DOI: 10.4252/wjsc.v12.i11.1237] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/23/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
The high mortality rate of breast cancer is mainly caused by the metastatic ability of cancer cells, resistance to chemotherapy and radiotherapy, and tumor regression capacity. In recent years, it has been shown that the presence of breast cancer stem cells is closely associated with the migration and metastatic ability of cancer cells, as well as with their resistance to chemotherapy and radiotherapy. The tumor microenvironment is one of the main molecular factors involved in cancer and metastatic processes development, in this sense it is interesting to study the role of platelets, one of the main communicator cells in the human body which are activated by the signals they receive from the microenvironment and can generate more than one response. Platelets can ingest and release RNA, proteins, cytokines and growth factors. After the platelets interact with the tumor microenvironment, they are called "tumor-educated platelets." Tumor-educated platelets transport material from the tumor microenvironment to sites adjacent to the tumor, thus helping to create microenvironments conducive for the development of primary and metastatic tumors. It has been observed that the clone capable of carrying out the metastatic process is a cancer cell with stem cell characteristics. Cancer stem cells go through a series of processes, including epithelial-mesenchymal transition, intravasation into blood vessels, movement through blood vessels, extravasation at the site of the establishment of a metastatic focus, and site colonization. Tumor-educated platelets support all these processes.
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Affiliation(s)
| | | | - Vilma Maldonado
- Laboratorio de Epigenética, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Melendez-Zajgla
- Génómica funcional del cáncer, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Olmos
- Biotecnología Marina, Centro de Investigación Científica y de Estudios Superiores de Ensenada, Ensenada 22860, Mexico
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Papadopoulos S, Kazepidou E, Antonelou MH, Leondaritis G, Tsapinou A, Koulouras VP, Avgeropoulos A, Nakos G, Lekka ME. Secretory Phospholipase A 2-IIA Protein and mRNA Pools in Extracellular Vesicles of Bronchoalveolar Lavage Fluid from Patients with Early Acute Respiratory Distress Syndrome: A New Perception in the Dissemination of Inflammation? Pharmaceuticals (Basel) 2020; 13:ph13110415. [PMID: 33238426 PMCID: PMC7700412 DOI: 10.3390/ph13110415] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 01/08/2023] Open
Abstract
Secretory phospholipase-IIA A2 (sPLA2-IIA) is expressed in a variety of cell types under inflammatory conditions. Its presence in the bronchoalveolar lavage (BAL) fluid of patients with acute respiratory distress syndrome (ARDS) is associated with the severity of the injury. Exosomal type extracellular vesicles, (EVs), are recognized to perform intercellular communication. They may alter the immune status of recipient target cells through cargo shuttling. In this work, we characterized the exosomal type EVs isolated from BAL fluid of patients with early and late ARDS as compared to control/non-ARDS patients, through morphological (confocal and electron microscopy) and biochemical (dynamic light scattering, qRT-PCR, immunoblotting) approaches. We provide evidence for the presence of an sPLA2-IIA-carrying EV pool that coprecipitates with exosomes in the BAL fluid of patients with ARDS. PLA2G2A mRNA was present in all the samples, although more prominently expressed in early ARDS. However, the protein was found only in EVs from early phase ARDS. Under both forms, sPLA2-IIA might be involved in inflammatory responses of recipient lung cells during ARDS. The perception of the association of sPLA2-IIA to the early diagnosis of ARDS or even with a mechanism of development and propagation of lung inflammation can help in the adoption of appropriate and innovative therapeutic strategies.
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Affiliation(s)
- Stylianos Papadopoulos
- Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, 451 10 Ioannina, Greece; (S.P.); (E.K.); (A.T.)
| | - Eleftheria Kazepidou
- Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, 451 10 Ioannina, Greece; (S.P.); (E.K.); (A.T.)
| | - Marianna H. Antonelou
- Section of Cell Biology & Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), Panepistimioupolis, 15784 Athens, Greece;
| | - George Leondaritis
- Laboratory of Pharmacology, School of Medicine, University of Ioannina, 451 10 Ioannina, Greece;
| | - Alexia Tsapinou
- Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, 451 10 Ioannina, Greece; (S.P.); (E.K.); (A.T.)
| | - Vasilios P. Koulouras
- Department of Intensive Care Medicine, School of Medicine, University of Ioannina, 451 10 Ioannina, Greece; (V.P.K.); (G.N.)
| | | | - George Nakos
- Department of Intensive Care Medicine, School of Medicine, University of Ioannina, 451 10 Ioannina, Greece; (V.P.K.); (G.N.)
| | - Marilena E. Lekka
- Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, 451 10 Ioannina, Greece; (S.P.); (E.K.); (A.T.)
- Correspondence: ; Tel.: +30-6972247374
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Demopoulos C, Antonopoulou S, Theoharides TC. COVID-19, microthromboses, inflammation, and platelet activating factor. Biofactors 2020; 46:927-933. [PMID: 33296106 DOI: 10.1002/biof.1696] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023]
Abstract
Recent articles report elevated markers of coagulation, endothelial injury, and microthromboses in lungs from deceased COVID-19 patients. However, there has been no discussion of what may induce intravascular coagulation. Platelets are critical in the formation of thrombi and their most potent trigger is platelet activating factor (PAF), first characterized by Demopoulos and colleagues in 1979. PAF is produced by cells involved in host defense and its biological actions bear similarities with COVID-19 disease manifestations. PAF can also stimulate perivascular mast cell activation, leading to inflammation implicated in severe acute respiratory syndrome (SARS). Mast cells are plentiful in the lungs and are a rich source of PAF and of inflammatory cytokines, such as IL-1β and IL-6, which may contribute to COVID-19 and especially SARS. The histamine-1 receptor antagonist rupatadine was developed to have anti-PAF activity, and also inhibits activation of human mast cells in response to PAF. Rupatadine could be repurposed for COVID-19 prophylaxis alone or together with other PAF-inhibitors of natural origin such as the flavonoids quercetin and luteolin, which have antiviral, anti-inflammatory, and anti-PAF actions.
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Affiliation(s)
- Constantinos Demopoulos
- Laboratory of Biochemistry, Faculty of Chemistry, National & Kapodistrian University, Athens, Greece
| | - Smaragdi Antonopoulou
- Laboratory of Biology, Biochemistry and Microbiology, Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Theoharis C Theoharides
- Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, USA
- School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA
- Department of Internal Medicine, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts, USA
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46
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Gozari M, Alborz M, El-Seedi HR, Jassbi AR. Chemistry, biosynthesis and biological activity of terpenoids and meroterpenoids in bacteria and fungi isolated from different marine habitats. Eur J Med Chem 2020; 210:112957. [PMID: 33160760 DOI: 10.1016/j.ejmech.2020.112957] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/16/2020] [Accepted: 10/17/2020] [Indexed: 02/06/2023]
Abstract
The marine environment with its vast biological diversity encompasses many organisms that produce bioactive natural products. Marine microorganisms are rich sources of compounds from many structural classes with a multitude of biological activities. The biosynthesis of microbial natural products depends on a variety of biotic and abiotic factors in the marine environment, including temperature, nutrients, salinity and interaction with other microorganisms. Terpenoids, as one of the most important groups of natural products in terrestrial microorganisms are important metabolites for marine microorganisms. Here, we have reviewed the chemistry, biosynthesis and pharmacological activities of terpenoids, extracted from marine microbes, and then survey their potential applications in drug development. We also discussed the different habitats in which marine microorganisms are found including sediments, the flora, such as seaweeds, sea grasses, and mangroves as well as the fauna like sponges and corals. Amongst these habitats, marine sediments are the major source for terpenoids producing microorganisms. The marine bacteria produce mostly meroterpenoids, while the fungi are well known for production of isoprenoids. Interestingly, marine-derived microbial terpenoids have some structural characteristics such as halogenation, which are catalyzed by specific enzymes with distinct substrate specificity. These compounds have anticancer, antibacterial, antifungal, antimalarial and anti-inflammatory properties. The information collected here might provide useful clues for developing new medications.
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Affiliation(s)
- Mohsen Gozari
- Persian Gulf and Oman Sea Ecological Research Center, Iranian Fisheries Science Research Institute, Agricultural Research, Education and Extension Organization, Bandar Abbas, Iran
| | - Maryam Alborz
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hesham R El-Seedi
- Pharmacognosy Group, Department of Pharmaceutical Biosciences, BMC, Uppsala University, SE-751 23, Uppsala, Sweden; International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, PR China
| | - Amir Reza Jassbi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Gupta P, Agarwal R, Bhaskaran S, Garg S, Mehndiratta M, Radhakrishnan G, Singh A, Agarwal R, Narang D. Evaluation of maternal plasma platelet activating factor acetylhydrolase activity and mRNA expression in pre-eclampsia: a case control study. J OBSTET GYNAECOL 2020; 41:726-732. [PMID: 33073639 DOI: 10.1080/01443615.2020.1789956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Preeclampsia (PE) remains a leading cause of maternal morbidity and mortality all over the world. However, its aetiology and pathophysiology remain elusive. Platelet activating factor (PAF) is produced in response to oxidative stress and is a potent hypotensive agent. PAF acetylhydrolase (PAF-AH) inactivates PAF and is seen to decrease in normotensive women. The role of PAF-AH in preeclampsia has been in investigational literature, so far. The few studies done have shown a positive association of elevated levels of PAF-AH with preeclampsia. However, this marker has not been studied in the Indian population to-date and such studies are needed to elucidate the pathogenesis of this condition. Our study aimed to determine the PAF-AH activity by spectrophotometric assay in maternal plasma of 73 PE patients versus 73 normotensive controls and plasma PAF-AH mRNA expression to know the aberration of PAF-AH activity at the genetic level. Relative mRNA expression was calculated by Δ DCT method and a fold change was calculated by 2-ΔDCT. We found that the mean plasma PAF-AH activity levels among cases was significantly higher than the normotensive controls. However, the mRNA expression of the PAF-AH gene was similar between the cases and controls, as well as between severe and non-severe preeclampsia (true fold change =1). To conclude, PAF-AH appears to be increased in women with preeclampsia and hence may contribute to pathophysiology and severity. However, a larger sample size will be required to reiterate this association. Recently, PAF-AH inhibitors such as Darapladib has been tested as a therapeutic option in atherosclerosis. After studying the role of PAF-AH in the pathogenesis of PE, PAF-AH inhibitors may be used as a therapeutic tool in the future in PE.IMPACT STATEMENTWhat is already known on this subject? Platelet activating factor (PAF) is produced in response to oxidative stress and is a potent hypotensive agent. PAF acetylhydrolase (PAF-AH) hydrolyses and inactivates PAF and is seen to decrease in normotensive women. The role of platelet activating factor-acetylhydrolase (PAF-AH) in preeclampsia has been investigational so far. Few studies done have shown a positive association of elevated levels of PAF-AH in preeclamptic women.What do the results of this study add? Our study aimed to determine the activity of PAF-AH in maternal plasma of PE patients versus normal pregnancy and plasma PAF-AH mRNA expression to know the aberration of PAF-AH activity at the level of the gene. We found that plasma PAF-AH activity among preeclamptics was significantly higher than in the controls with a possible role in early-onset preeclampsia (<32 weeks), in the Indian population. This marker has never been studied in this population earlier. The results of our study re-emphasised its role in the pathogenesis of preeclampsia.What are the implications of these findings for clinical practice and/or further research? Such studies are important to not only give us a greater understanding of the various pathways involved in this multifactorial dreaded condition, but can also offer us a marker for early identification of women at risk. Recently, PAF-AH inhibitors like Darapladib has been tested as a therapeutic option in atherosclerosis. After studying the role of PAF-AH in the pathogenesis of PE, PAF-AH inhibitors may be used as a therapeutic tool in the future in PE.
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Affiliation(s)
- Preeti Gupta
- Department of Obstetrics and Gynaecology, UCMS and Guru Teg Bahadur Hospital, Delhi, India
| | - Rachna Agarwal
- Department of Obstetrics and Gynaecology, UCMS and Guru Teg Bahadur Hospital, Delhi, India
| | - Sruthi Bhaskaran
- Department of Obstetrics and Gynaecology, UCMS and Guru Teg Bahadur Hospital/UCMS, Delhi, India
| | - Seema Garg
- Department of Biochemistry, AIIMS, Nagpur, India
| | - Mohit Mehndiratta
- Department of Biochemistry, UCMS and Guru Teg Bahadur Hospital/UCMS, Delhi, India
| | - Gita Radhakrishnan
- Department of Obstetrics and Gynaecology, UCMS and Guru Teg Bahadur Hospital/UCMS, Delhi, India
| | - Alpana Singh
- Department of Obstetrics and Gynaecology, UCMS and Guru Teg Bahadur Hospital/UCMS, Delhi, India
| | - Richa Agarwal
- Department of Obstetrics and Gynaecology, UCMS and Guru Teg Bahadur Hospital/UCMS, Delhi, India
| | - Divya Narang
- Department of Biochemistry, UCMS and Guru Teg Bahadur Hospital, Delhi, India
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A lipidomics approach reveals new insights into Crotalus durissus terrificus and Bothrops moojeni snake venoms. Arch Toxicol 2020; 95:345-353. [PMID: 32880718 DOI: 10.1007/s00204-020-02896-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/27/2020] [Indexed: 12/15/2022]
Abstract
Snakebite envenomation causes > 81,000 deaths and incapacities in another 400,000 people worldwide every year. Snake venoms are complex natural secretions comprised of hundreds of different molecules with a wide range of biological functions that after injection cause local and systemic manifestations. Although several studies have investigated snake venoms, the majority have focused on the protein portion (toxins), without significant attention paid to the lipid fraction. Therefore, an untargeted lipidomic approach based on liquid chromatography with high-resolution mass spectrometry (LC-HRMS) was applied to investigate the lipid constituents of venoms of the snake species Crotalus durissus terrificus and Bothrops moojeni. Phosphatidylcholines (PC), Lyso-PCs, phosphatidylethanolamines (PE), Lyso-PE, phosphatidylserine (PS), phosphatidylinositol (PI), ceramides (Cer), and sphingomyelin (SM) species were detected in the analyzed snake venoms. The identified lipids included bioactive compounds such as platelet-activating factor (PAF) precursor, PAF-like molecules, plasmalogens, ceramides, and sphingomyelins with long fatty acid chain lengths, which may be associated with the systemic responses triggered by C. d. terrificus and B. moojeni envenomation. These responses include platelet aggregation, activation of intercellular adhesion molecule 1 (ICAM1), apoptosis, as well as the production of pro-inflammatory lipid mediators, cytokines, and reactive species. The newly proposed lipidomics strategy provided valuable information regarding the lipid profiles of viperid venoms, which could lead to increased understanding of the complex pathology promoted by snakebite envenomation.
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Kahremany S, Hofmann L, Gruzman A, Cohen G. Advances in Understanding the Initial Steps of Pruritoceptive Itch: How the Itch Hits the Switch. Int J Mol Sci 2020; 21:ijms21144883. [PMID: 32664385 PMCID: PMC7402353 DOI: 10.3390/ijms21144883] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/07/2020] [Accepted: 07/08/2020] [Indexed: 02/07/2023] Open
Abstract
Pruritoceptive (dermal) itch was long considered an accompanying symptom of diseases, a side effect of drug applications, or a temporary sensation induced by invading pruritogens, as produced by the stinging nettle. Due to extensive research in recent years, it was possible to provide detailed insights into the mechanism of itch mediation and modulation. Hence, it became apparent that pruritus is a complex symptom or disease in itself, which requires particular attention to improve patients’ health. Here, we summarize recent findings in pruritoceptive itch, including how this sensation is triggered and modulated by diverse endogenous and exogenous pruritogens and their receptors. A differentiation between mediating pruritogen and modulating pruritogen seems to be of great advantage to understand and decipher the molecular mechanism of itch perception. Only a comprehensive view on itch sensation will provide a solid basis for targeting this long-neglected adverse sensation accompanying numerous diseases and many drug side effects. Finally, we identify critical aspects of itch perception that require future investigation.
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Affiliation(s)
- Shirin Kahremany
- Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel; (L.H.); (A.G.)
- The Skin Research Institute, The Dead Sea and Arava Science Center, Masada 86910, Israel;
- Correspondence:
| | - Lukas Hofmann
- Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel; (L.H.); (A.G.)
| | - Arie Gruzman
- Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel; (L.H.); (A.G.)
| | - Guy Cohen
- The Skin Research Institute, The Dead Sea and Arava Science Center, Masada 86910, Israel;
- Ben-Gurion University of the Negev, Eilat Campus, Eilat 8855630, Israel
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50
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Sato A, Yamazaki M, Watanabe H, Sakurai E, Ebina K. Human estrogen sulfotransferase and its related fluorescently labeled decapeptides specifically interact with oxidized low-density lipoprotein. J Pept Sci 2020; 26:e3274. [PMID: 32633098 DOI: 10.1002/psc.3274] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/16/2020] [Accepted: 06/12/2020] [Indexed: 12/24/2022]
Abstract
Estrogen sulfotransferase (SULT1E) mainly catalyzes the sulfation of estrogens, which are known to prevent the pathogenesis of atherosclerosis. Recently, we found that peptides with a YKDG sequence specifically bind to oxidized low-density lipoprotein (Ox-LDL), which plays a major role in the pathogenesis of atherosclerosis. Here, we investigated the interaction between human SULT1E1 (hSULT1E1), which has a YKEG sequence (residues 61-64) unlike other human SULTs, and Ox-LDL. Results from polyacrylamide gel electrophoresis and western blotting demonstrated that hSULT1E1 specifically binds to Ox-LDL and its major lipid component (lysophosphatidylcholine; LPC), and platelet-activating factor (PAF), which bears a marked resemblance to LPC in terms of structure and activity. Moreover, an N-terminally fluorescein isothiocyanate (FITC)-labeled decapeptide (MIYKEGDVEK; FITC-hSULT1E1-P10) corresponding to residues 59-68 of hSULT1E1 specifically binds to Ox-LDL, LPC, and PAF. Unveiling the specific interaction between hSULT1E1 and Ox-LDL, LPC, and PAF provides important information regarding the mechanisms underlying various diseases caused by Ox-LDL, LPC, and PAF, such as atherosclerosis. In addition, FITC-hSULT1E1-P10 could be used as an efficient fluorescent probe for the detection of Ox-LDL, LPC, and PAF, which could facilitate the mechanistic study, identification, diagnosis, prevention, and treatment of atherosclerosis.
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Affiliation(s)
- Akira Sato
- Department of Pharmaceutical Health Science, Faculty of Pharmacy, Iryo Sosei University, Iwaki, Fukushima, Japan.,Graduate School of Life Science and Technology, Iryo Sosei University, Iwaki, Fukushima, Japan
| | - Miyuki Yamazaki
- Department of Pharmaceutical Health Science, Faculty of Pharmacy, Iryo Sosei University, Iwaki, Fukushima, Japan
| | - Hinako Watanabe
- Department of Pharmaceutical Health Science, Faculty of Pharmacy, Iryo Sosei University, Iwaki, Fukushima, Japan
| | - Eiko Sakurai
- Department of Pharmaceutical Health Science, Faculty of Pharmacy, Iryo Sosei University, Iwaki, Fukushima, Japan.,Graduate School of Life Science and Technology, Iryo Sosei University, Iwaki, Fukushima, Japan
| | - Keiichi Ebina
- Department of Pharmaceutical Health Science, Faculty of Pharmacy, Iryo Sosei University, Iwaki, Fukushima, Japan.,Graduate School of Life Science and Technology, Iryo Sosei University, Iwaki, Fukushima, Japan
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