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Fisk HL, Shaikh SR. Emerging mechanisms of organ crosstalk: The role of oxylipins. NUTR BULL 2025; 50:12-29. [PMID: 39659132 DOI: 10.1111/nbu.12726] [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: 08/19/2024] [Revised: 10/22/2024] [Accepted: 11/20/2024] [Indexed: 12/12/2024]
Abstract
There is growing interest in the role of oxylipins in the pathophysiology of several diseases. This is accompanied by a limited but evolving evidence base describing augmented oxylipin concentrations in a range of complications including cardiovascular disease, obesity, liver disease and neurological disorders. Despite this, literature describing oxylipin profiles in blood and multiple organs is inconsistent and the mechanisms by which these profiles are altered, and the relationships between localised tissue and circulating oxylipins are poorly understood. Inflammation and immune response associated with disease requires communication across organs and physiological systems. For example, inflammation and comorbidities associated with obesity extend beyond the adipose tissue and affect the vascular, hepatobiliary and digestive systems amongst others. Communication between organs and physiological systems is implicated in the progression of disease as well as the maintenance of homeostasis. There is emerging evidence for the role of oxylipins as a mechanism of communication in organ crosstalk but the role of these in orchestrating multiple organ and system responses is poorly understood. Herein, we review evidence to support and describe the role of oxylipins in organ crosstalk via the cardiosplenic and gut-link axis. In addition, we review emerging mechanisms of oxylipin regulation, the gut microbiome and modification using nutritional intervention. Finally, we describe future perspectives for addressing challenges in measurement and interpretation of oxylipin research with focus on the host genome as a modifier of oxylipin profiles and response to dietary lipid intervention.
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Affiliation(s)
- Helena Lucy Fisk
- Faculty of Medicine, School of Human Development and Health, Southampton General Hospital, University of Southampton, Southampton, UK
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
| | - Saame Raza Shaikh
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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2
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Fukuishi N, Takahama K, Kurosaki H, Ono S, Asai H. The Role of Endogenous Specialized Proresolving Mediators in Mast Cells and Their Involvement in Inflammation and Resolution. Int J Mol Sci 2025; 26:1491. [PMID: 40003957 PMCID: PMC11855587 DOI: 10.3390/ijms26041491] [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: 01/15/2025] [Revised: 02/05/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Many polyunsaturated fatty acids within cells exhibit diverse physiological functions. Particularly, arachidonic acid is the precursor of highly bioactive prostaglandins and leukotrienes, which are pro-inflammatory mediators. However, polyunsaturated fatty acids, such as arachidonic, docosahexaenoic, and eicosapentaenoic acids, can be metabolized into specialized proresolving mediators (SPMs), which have anti-inflammatory properties. Given that pro-inflammatory mediators and SPMs are produced via similar enzymatic pathways, SPMs can play a crucial role in mitigating excessive tissue damage induced by inflammation. Mast cells are immune cells that are widely distributed and strategically positioned at interfaces with the external environment, such as the skin and mucosa. As immune system sentinels, they respond to harmful pathogens and foreign substances. Upon activation, mast cells release various pro-inflammatory mediators, initiating an inflammatory response. Furthermore, these cells secrete factors that promote tissue repair and inhibit inflammation. This dual function positions mast cells as central regulators, balancing between the body's defense mechanisms and the need to minimize tissue injury. This review investigates the production of SPMs by mast cells and their subsequent effects on these cells. By elucidating the intricate relationship between mast cells and SPMs, this review aims to provide a comprehensive understanding of the mechanism by which these cells regulate the delicate balance between tissue damage and repair at inflammatory sites, ultimately contributing to the resolution of inflammatory responses.
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Affiliation(s)
- Nobuyuki Fukuishi
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kinjo Gakuin University, Nagoya 463-8521, Japan; (H.K.); (S.O.); (H.A.)
| | - Kentaro Takahama
- Technology Center, Tokai National Higher Education and Research System, Nagoya 464-8601, Japan;
| | - Hiromasa Kurosaki
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kinjo Gakuin University, Nagoya 463-8521, Japan; (H.K.); (S.O.); (H.A.)
| | - Sayaka Ono
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kinjo Gakuin University, Nagoya 463-8521, Japan; (H.K.); (S.O.); (H.A.)
| | - Haruka Asai
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kinjo Gakuin University, Nagoya 463-8521, Japan; (H.K.); (S.O.); (H.A.)
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Kirchhoff R, Kampschulte N, Rothweiler C, Rohwer N, Weylandt K, Schebb NH. An Optimized Ex Vivo n-3 PUFA Supplementation Strategy for Primary Human Macrophages Shows That DHA Suppresses Prostaglandin E2 Formation. Mol Nutr Food Res 2025; 69:e202400716. [PMID: 39676434 PMCID: PMC11704825 DOI: 10.1002/mnfr.202400716] [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: 09/05/2024] [Revised: 10/25/2024] [Accepted: 11/18/2024] [Indexed: 12/17/2024]
Abstract
Evidence suggests beneficial effects of long-chain n-3 polyunsaturated fatty acids (PUFAs) in inflammatory diseases. However, the underlying mechanisms are still subject of research. For this purpose, we developed an ex vivo n-3 PUFA supplementation strategy. M2-like macrophages were supplemented for 2-3 days with 20-40 µM docosahexaenoic acid (DHA) during differentiation. Quality parameters include <3% oxylipins for PUFA-preparation, total fatty acids (FAs) <10 mM, and low oxylipins in plasma, n-3 PUFA <0.25 mM for the selection of donors of plasma as well as %n-6 in highly unsaturated fatty acids (HUFAs) ≥70% for donors of cells. Following supplementation, PUFA pattern of cells was shifted toward one described for blood and tissue from subjects with higher n-3 and lower n-6 PUFAs. This was accompanied by a decrease of arachidonic acid-derived oxylipins in a dose- and time-dependent manner in favor of n-3 PUFA ones. Stimulation with LPS resulted in decreased levels of pro-inflammatory prostaglandins in the DHA-supplemented cells, but no changes in cytokines. In vitro supplementation studies with n-3 PUFA need rigorous controls to exclude the background formation of oxylipins. By accounting for these possible confounders the described approach allows the mechanistic investigation of n-3 PUFAs in primary human immune cells, offering an alternative for intervention studies.
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Affiliation(s)
- Rebecca Kirchhoff
- Chair of Food Chemistry, School of Mathematics and Natural SciencesUniversity of WuppertalWuppertalGermany
| | - Nadja Kampschulte
- Chair of Food Chemistry, School of Mathematics and Natural SciencesUniversity of WuppertalWuppertalGermany
| | - Carina Rothweiler
- Chair of Food Chemistry, School of Mathematics and Natural SciencesUniversity of WuppertalWuppertalGermany
| | - Nadine Rohwer
- Division of Medicine, Department of Gastroenterology, Metabolism and OncologyUniversity Hospital Ruppin‐Brandenburg, Brandenburg Medical SchoolNeuruppinGermany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of TechnologyBrandenburg Medical School and University of PotsdamPotsdamGermany
- Department of Molecular ToxicologyGerman Institute of Human NutritionPotsdam‐Rehbruecke, NuthetalGermany
| | - Karsten‐Henrich Weylandt
- Division of Medicine, Department of Gastroenterology, Metabolism and OncologyUniversity Hospital Ruppin‐Brandenburg, Brandenburg Medical SchoolNeuruppinGermany
| | - Nils Helge Schebb
- Chair of Food Chemistry, School of Mathematics and Natural SciencesUniversity of WuppertalWuppertalGermany
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Cayer LGJ, Buhrke T, Roberts J, Nunnikhoven A, Sommerkorn K, Reinhold A, Braeuning A, Raju J, Aukema HM, Karakach T. An integrated multi-omics analysis of the effects of the food processing-induced contaminant 2-monochloropropane-1,3-diol (2-MCPD) in rat heart. Arch Toxicol 2024; 98:4033-4045. [PMID: 39316134 PMCID: PMC11496350 DOI: 10.1007/s00204-024-03856-6] [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: 06/26/2024] [Accepted: 08/29/2024] [Indexed: 09/25/2024]
Abstract
Many foods including edible oils contain 2-monochloropropane-1,3-diol (2-MCPD), a processing-induced chemical contaminant. Cardiotoxic effects have been shown to result from oral 2-MCPD exposure in rodents, but the underlying mechanisms of action remain poorly understood. We undertook a comprehensive multi-omics approach to assess changes at the transcriptomic, proteomic, and oxylipin levels in heart tissues from male F344 rats that were exposed to 0 or 40 mg/kg BW/day of 2-MCPD in the diet for 90 days, in a regulatory compliant rodent bioassay. Heart tissues were collected for RNA sequencing, quantitative PCR analysis, proteomic analysis via two-dimensional gel electrophoresis and mass spectrometry, and targeted lipidomic profiling by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Transcriptomic and proteomic data analyses revealed upregulation of immune/inflammatory response processes and downregulation of energy metabolism and cardiac structure and functions. Among differentially expressed gene-protein pairs, coronin-1A, a key leukocyte-regulating protein, emerged as markedly up-regulated. Oxylipin profiling highlighted a selective suppression of docosahexaenoic acid-derived metabolites, suggesting a disruption in cardioprotective lipid pathways. These findings suggest that 2-MCPD disrupts homeostasis through inflammatory activation and suppression of metabolic and cardiac function. This research provides insights into 2-MCPD's cardiotoxicity, emphasizing the need for further studies to support hazard characterization.
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Affiliation(s)
- Lucien G J Cayer
- Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada
- Canadian Centre for Agri-Food Research in Health and Medicine, St Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | - Thorsten Buhrke
- Department of Food Safety, German Federal Institute for Risk Assessment, Berlin, Germany
| | | | | | - Katharina Sommerkorn
- Department of Food Safety, German Federal Institute for Risk Assessment, Berlin, Germany
| | - Anna Reinhold
- Department of Food Safety, German Federal Institute for Risk Assessment, Berlin, Germany
| | - Albert Braeuning
- Department of Food Safety, German Federal Institute for Risk Assessment, Berlin, Germany
| | - Jayadev Raju
- Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada.
- Health Canada, Bureau of Chemical Safety, Ottawa, Canada.
| | - Harold M Aukema
- Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada
- Canadian Centre for Agri-Food Research in Health and Medicine, St Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | - Tobias Karakach
- Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada
- Pharmacology, Dalhousie University, Halifax, NS, Canada
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Wenderoth T, Feldotto M, Hernandez J, Schäffer J, Leisengang S, Pflieger FJ, Bredehöft J, Mayer K, Kang JX, Bier J, Grimminger F, Paßlack N, Rummel C. Effects of Omega-3 Polyunsaturated Fatty Acids on the Formation of Adipokines, Cytokines, and Oxylipins in Retroperitoneal Adipose Tissue of Mice. Int J Mol Sci 2024; 25:9904. [PMID: 39337391 PMCID: PMC11432517 DOI: 10.3390/ijms25189904] [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: 07/25/2024] [Revised: 09/04/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
Oxylipins and specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) are mediators that coordinate an active process of inflammation resolution. While these mediators have potential as circulating biomarkers for several disease states with inflammatory components, the source of plasma oxylipins/SPMs remains a matter of debate but may involve white adipose tissue (WAT). Here, we aimed to investigate to what extent high or low omega (n)-3 PUFA enrichment affects the production of cytokines and adipokines (RT-PCR), as well as oxylipins/SPMs (liquid chromatography-tandem mass spectrometry) in the WAT of mice during lipopolysaccharide (LPS)-induced systemic inflammation (intraperitoneal injection, 2.5 mg/kg, 24 h). For this purpose, n-3 PUFA genetically enriched mice (FAT-1), which endogenously synthesize n-3 PUFAs, were compared to wild-type mice (WT) and combined with n-3 PUFA-sufficient or deficient diets. LPS-induced systemic inflammation resulted in the decreased expression of most adipokines and interleukin-6 in WAT, whereas the n-3-sufficient diet increased them compared to the deficient diet. The n-6 PUFA arachidonic acid was decreased in WAT of FAT-1 mice, while n-3 derived PUFAs (eicosapentaenoic acid, docosahexaenoic acid) and their metabolites (oxylipins/SPMs) were increased in WAT by genetic and nutritional n-3 enrichment. Several oxylipins/SPMs were increased by LPS treatment in WAT compared to PBS-treated controls in genetically n-3 enriched FAT-1 mice. Overall, we show that WAT may significantly contribute to circulating oxylipin production. Moreover, n-3-sufficient or n-3-deficient diets alter adipokine production. The precise interplay between cytokines, adipokines, and oxylipins remains to be further investigated.
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Affiliation(s)
- Tatjana Wenderoth
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
| | - Martin Feldotto
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
| | - Jessica Hernandez
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
| | - Julia Schäffer
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
| | - Stephan Leisengang
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
- Center for Mind Brain and Behavior (CMMB), Universities Giessen and Marburg, 34032 Marburg, Germany
- Translational Neuroscience Network Giessen (TNNG), Justus Liebig University, 35392 Giessen, Germany
| | - Fabian Johannes Pflieger
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
| | - Janne Bredehöft
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
| | - Konstantin Mayer
- Department of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany;
| | - Jing X. Kang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical, Charlestown, MA 02129, USA;
| | - Jens Bier
- Cardio-Pulmonary Institute, Justus Liebig University, 35392 Giessen, Germany; (J.B.); (F.G.)
- Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany
| | - Friedrich Grimminger
- Cardio-Pulmonary Institute, Justus Liebig University, 35392 Giessen, Germany; (J.B.); (F.G.)
- Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany
| | - Nadine Paßlack
- Small Animal Clinic, Internal Medicine and Department of Veterinary Clinical Sciences, Justus Liebig University, 35392 Giessen, Germany;
| | - Christoph Rummel
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
- Center for Mind Brain and Behavior (CMMB), Universities Giessen and Marburg, 34032 Marburg, Germany
- Translational Neuroscience Network Giessen (TNNG), Justus Liebig University, 35392 Giessen, Germany
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Gamal RM, Hazem SH, Hamed MF, Abdelaziz RR. PI3K inhibitor "alpelisib" alleviates methotrexate induced liver injury in mice and potentiates its cytotoxic effect against MDA-MB-231 triple negative breast cancer cell line. Toxicol Appl Pharmacol 2024; 488:116979. [PMID: 38797265 DOI: 10.1016/j.taap.2024.116979] [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: 03/18/2024] [Revised: 05/15/2024] [Accepted: 05/23/2024] [Indexed: 05/29/2024]
Abstract
Hepatotoxicity is the main off-target effect of methotrexate (MTX) limiting its effective clinical use. Besides, MDA-MB231 breast cancer cells show chemoresistance, partly via PI3K/AKT pathway. Therefore, we investigated the ameliorative potentials of the PI3K inhibitor, alpelisib (ALP) on MTX-induced hepatotoxicity (in vivo) and the restraining potentials of ALP on MDA-MB231 chemoresistance to MTX (in vitro). Twenty-eight male BALB/c mice were divided into 4 groups. In treatment groups, mice were administered ALP (2.5 and 5 mg/kg) for 5 days and MTX (20 mg/kg) from day 2 till day 5. The results showed that ALP restored hepatic architecture, reduced immune cell infiltration (F4/80, Ly6G and MPO) and repressed the rise in liver enzymes (AST and ALT) induced by MTX. Additionally, ALP rectified the MTX-induced disruption of cellular oxidant status by boosting antioxidant defense systems (HO-1 and GSH) and repressing lipid peroxidation (MDA and 4-HNE). Finally, ALP curbed MTX-induced hepatocyte apoptosis (NF-κB and BAX) and shifted the cytokine milieu away from inflammation (IL-17, IL-22, IL-6 and IL- 10). The results of the in vitro experiments revealed that ALP alone and in combination with MTX, synergistically, reduced cancer cell viability (MTT assay), migration (wound healing assay) and their capacity to establish colonies (colony formation assay) as compared to MTX alone. RT-PCR revealed the antiproliferative (Bcl-2) and proapoptotic (BAX) potentials of ALP and ALP/MTX combination especially after 24 h. In conclusion, targeting PI3K/AKT pathway is a promising strategy in triple negative breast cancer patients by ameliorating hepatotoxicity and restraining chemoresistance to chemotherapy.
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Affiliation(s)
- Rana M Gamal
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Sara H Hazem
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Mohamed F Hamed
- Department of Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt.
| | - Rania R Abdelaziz
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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Strekalova T, Radford-Smith D, Dunstan IK, Gorlova A, Svirin E, Sheveleva E, Burova A, Morozov S, Lyundup A, Berger G, Anthony DC, Walitza S. Omega-3 alleviates behavioral and molecular changes in a mouse model of stress-induced juvenile depression. Neurobiol Stress 2024; 31:100646. [PMID: 38912378 PMCID: PMC11190747 DOI: 10.1016/j.ynstr.2024.100646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 04/29/2024] [Accepted: 05/19/2024] [Indexed: 06/25/2024] Open
Abstract
Introduction Depression is increasingly diagnosed in adolescence, necessitating specific prevention and treatment methods. However, there is a lack of animal models mimicking juvenile depression. This study explores a novel model using ultrasound (US) stress in juvenile mice. Methods We employed the US stress model in one-month-old C57/BL6 mice, exposing them to alternating ultrasound frequencies (20-25 kHz and 25-45 kHz) for three weeks. These frequencies correspond to negative and neutral emotional states in rodents and can induce a depressive-like syndrome. Concurrently, mice received either an omega-3 food supplement (FS) containing eicosapentaenoic acid (EPA; 0.55 mg/kg/day) and docosahexaenoic acid (DHA; 0.55 mg/kg/day) or a vehicle. Post-stress, we evaluated anxiety- and depressive-like behaviors, blood corticosterone levels, brain expression of pro-inflammatory cytokines, and conducted metabolome analysis of brain, liver and blood plasma. Results US-exposed mice treated with vehicle exhibited decreased sucrose preference, a sign of anhedonia, a key feature of depression, increased anxiety-like behavior, elevated corticosterone levels, and enhanced TNF and IL-1β gene expression in the brain. In contrast, US-FS mice did not display these changes. Omega-3 supplementation also reduced anxiety-like behavior in non-stressed mice. Metabolomic analysis revealed US-induced changes in brain energy metabolism, with FS increasing brain sphingomyelin. Liver metabolism was affected by both US and FS, while plasma metabolome changes were exclusive to FS. Brain glucose levels correlated positively with activity in anxiety tests. Conclusion Chronic omega-3 intake counteracted depressive- and anxiety-like behaviors in a US model of juvenile depression in mice. These effects likely stem from the anti-inflammatory properties of the supplement, suggesting potential therapeutic applications in juvenile depression.
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Affiliation(s)
- Tatyana Strekalova
- Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands
- Department of Pharmacology, Oxford University, Oxford, UK
| | | | | | - Anna Gorlova
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia
- RUDN University, 6 Miklukho-Maklaya Str, Moscow, Russia
| | - Evgeniy Svirin
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Elisaveta Sheveleva
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia
- Department of Normal Physiology, Sechenov Moscow State Medical University, Moscow, Russia
| | - Alisa Burova
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Sergey Morozov
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Aleksey Lyundup
- RUDN University, 6 Miklukho-Maklaya Str, Moscow, Russia
- Endocrinology Research Centre, Dmitry Ulyanov str. 19, Moscow, 117036, Russia
| | - Gregor Berger
- Department of Child and Adolescent Psychiatry and Psychotherapy, University of Zuerich, Zuerich, Switzerland
| | | | - Susanne Walitza
- Department of Child and Adolescent Psychiatry and Psychotherapy, University of Zuerich, Zuerich, Switzerland
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8
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Yadav D, Ostrea EM, Cheng CT, Kisseih E, Maddipati KR, Thomas RL. Effect of docosahexaenoic acid and olive oil supplementation on pup weight in alcohol-exposed pregnant rats. Front Pediatr 2024; 12:1334285. [PMID: 38638591 PMCID: PMC11024321 DOI: 10.3389/fped.2024.1334285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 03/20/2024] [Indexed: 04/20/2024] Open
Abstract
Background Low birth weight has been observed in offspring of alcoholic mothers due likely to unresolved inflammation and oxidative injury. Dietary lipids play a role in inflammation and its resolution. The primary objective was to investigate the effect of DHA and olive oil on the birth weight of pups born to alcohol-exposed dams. Methods Pregnant rats were randomized to the control or three treatment (alcohol) groups. From gestational days (GD) 8-19, the control group received daily olive oil and malto/dextrose, whereas groups 2 and 3 received olive oil and low-dose alcohol or high-dose alcohol, respectively. Group 4 received daily DHA and high-dose alcohol. The dam's blood was collected on GD 15 and 20 for cytokine analysis. Dams were sacrificed on GD 20. The mean birth weight of pups was compared by one-way ANOVA with post hoc Duncan's test. Results There was a significant increase in the pups' mean birth weight in the high-dose alcohol/DHA and high-dose alcohol/olive oil. Higher pro-inflammatory cytokines (IL-1β and IL-12p70) were noted in the alcohol-exposed dams. Conclusions DHA and olive oil supplementation in alcohol-exposed pregnant rats significantly increased their pups' birth weight despite having high pro-inflammatory cytokines. The mechanism of this effect remains to be determined.
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Affiliation(s)
- Deepak Yadav
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, United States
| | - Enrique M. Ostrea
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, United States
| | - Charlie T. Cheng
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, United States
| | - Esther Kisseih
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, United States
| | - Krishna R. Maddipati
- Bioactive Lipids Research Program, Wayne State University School of Medicine, Detroit, MI, United States
| | - Ronald L. Thomas
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, United States
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Liu H, Li N, Kuang G, Gong X, Wang T, Hu J, Du H, Zhong M, Guo J, Xie Y, Xiang Y, Wu S, Yuan Y, Yin X, Wan J, Li K. Protectin D1 inhibits TLR4 signaling pathway to alleviate non-alcoholic steatohepatitis via upregulating IRAK-M. Free Radic Biol Med 2024; 210:42-53. [PMID: 37984750 DOI: 10.1016/j.freeradbiomed.2023.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/09/2023] [Accepted: 11/15/2023] [Indexed: 11/22/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is a prevalent metabolic disease, characterized by the hepatic steatosis, inflammation, and fibrosis, which is lack of effective treatment currently. Protectin D1 (PTD1), a lipid mediator from omega-3 fatty acid docosahexaenoic acid (DHA), has displayed wide pharmacological actions including anti-inflammation in a variety of diseases, but the role of PTD1 on NASH remains unclear. In this study, using the methionine and choline deficient (MCD) fed NASH model, we explored the effect and underlying mechanism of PTD1 on NASH in mice. Our results showed PTD1 improved MCD-induced steatosis, hepatocellular injury, inflammation and fibrosis. Furthermore, PTD1 inhibited MCD-induced activation of TLR4 downstream molecules (TAK1, p38 and p65) without affecting the levels of TLR4 and phosphorylated IRAK-1. Notably, the levels of IRAK-M protein and the binding between IRAK-M and TRAF6 in the liver were also increased by PTD1 in NASH mice. Moreover, IRAK-M knockout remarkedly reverted the beneficial effects of PTD1 on the NASH in mice. Thus, these results demonstrated that PTD1 could protect mice from NASH by inhibiting the activation of TLR4 downstream signaling pathway, which might be related to the upregulation of IRAK-M, indicating that PTD1 may provide a new treatment for NASH.
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Affiliation(s)
- Hao Liu
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Nana Li
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Ge Kuang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Xia Gong
- Department of Anatomy, Chongqing Medical University, Chongqing, China
| | - Ting Wang
- Department of Orthopedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jun Hu
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Hui Du
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Minxuan Zhong
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Jiashi Guo
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Yao Xie
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Yang Xiang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Shengwang Wu
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yiling Yuan
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xinru Yin
- Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, China
| | - Jingyuan Wan
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China.
| | - Ke Li
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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10
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Patil J, Kumar N, Ravindra S S, Rao KG M, Bishnu A, S Rai K. Hepato-protective potential of Choline and DHA supplements in rats exposed to tobacco particulate matter-A histological study. RESEARCH JOURNAL OF PHARMACY AND TECHNOLOGY 2023:3787-3793. [DOI: 10.52711/0974-360x.2023.00625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Introduction: Smokeless tobacco is known to induce liver damage by decreasing its detoxifying capability. Chronic exposure to tobacco particulate matter in various forms jeopardizes the normal function of vital organs including the liver. The tobacco rolled in tendu leaf; known as ‘bidi’ is an unfiltered cigarette having tobacco content that is different from those used in cigarettes and is referred to as 'bidi tobacco'. Bidi smoking or chronic exposure to bidi tobacco causes multi-organ diseases. Choline and docosahexaenoic acid (C & DHA) are dietary components known to have hepato-protective action. But the combined action of choline and DHA on tobacco particulate-induced liver damage is largely unknown. The present study was designed to assess the hepato-protective potential of choline and DHA supplements to rat dams and pups exposed to tobacco particulate matter. Liver histological changes were analyzed from groups of Wistar rat dams and their pups [Unexposed Normal controls (NC) and those exposed to different tobacco particulate matters namely, tendu leaf smoke, tobacco dust, and bidi smoke] with or without supplementation of both choline and DHA. Results: Hepatocytic morphological architecture showed non-alcoholic fatty changes in all rats exposed to tobacco particulate matter and more so visibly higher in tobacco dust exposed groups compared to the same in age-matched NC group. These changes were ameliorated in rats supplemented with choline & DHA and exposed to tobacco particulate matter. Conclusion: Chronic exposure of mothers and their offspring to tobacco particulates causes non-alcoholic fatty liver disease with microstructural changes. Dietary supplementation of choline and DHA to rats exposed to tobacco particulate matter provides hepato-protection and ameliorates the hepatocytic morphological changes.
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Affiliation(s)
- Jyothsna Patil
- Department of Anatomy, #Former Faculty, Melaka Manipal Medical College, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India
| | - Naveen Kumar
- Department of Anatomy, RAK College of Medical Sciences, Ras Al-Khaimah Medical and Health Sciences University, UAE
| | - Swami Ravindra S
- Department of Anatomy, #Former Faculty, Melaka Manipal Medical College, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India
| | - Mohandas Rao KG
- Department of Anatomy, #Former Faculty, Melaka Manipal Medical College, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India
| | - Arijit Bishnu
- Senior Consultant, Department of Hemato-Oncology, Saroj Gupta Cancer Centre, Thakurpukur, Kolkata, India
| | - Kiranmai S Rai
- Department of Physiology, Melaka Manipal Medical College, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India
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11
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Xiao Y, Pietzner A, Rohwer N, Jung A, Rothe M, Weylandt KH, Elbelt U. Bioactive oxylipins in type 2 diabetes mellitus patients with and without hypertriglyceridemia. Front Endocrinol (Lausanne) 2023; 14:1195247. [PMID: 37664847 PMCID: PMC10472135 DOI: 10.3389/fendo.2023.1195247] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/20/2023] [Indexed: 09/05/2023] Open
Abstract
Objective Dyslipidemia, in particular elevated triglycerides (TGs) contribute to increased cardiovascular risk in type 2 diabetes mellitus (T2DM). In this pilot study we aimed to assess how increased TGs affect hepatic fat as well as polyunsaturated fatty acid (PUFA) metabolism and oxylipin formation in T2DM patients. Methods 40 patients with T2DM were characterized analyzing routine lipid blood parameters, as well as medical history and clinical characteristics. Patients were divided into a hypertriglyceridemia (HTG) group (TG ≥ 1.7mmol/l) and a normal TG group with TGs within the reference range (TG < 1.7mmol/l). Profiles of PUFAs and their oxylipins in plasma were measured by gas chromatography and liquid chromatography/tandem mass spectrometry. Transient elastography (TE) was used to assess hepatic fat content measured as controlled attenuation parameter (CAP) (in dB/m) and the degree of liver fibrosis measured as stiffness (in kPa). Results Mean value of hepatic fat content measured as CAP as well as body mass index (BMI) were significantly higher in patients with high TGs as compared to those with normal TGs, and correlation analysis showed higher concentrations of TGs with increasing CAP and BMI scores in patients with T2DM. There were profound differences in plasma oxylipin levels between these two groups. Cytochrome P450 (CYP) and lipoxygenase (LOX) metabolites were generally more abundant in the HTG group, especially those derived from arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), γ-linolenic acid (γ-LA), and α-linolenic acid (α-LA), and a strong correlation between TG levels and plasma metabolites from different pathways was observed. Conclusions In adult patients with T2DM, elevated TGs were associated with increased liver fat and BMI. Furthermore, these patients also had significantly higher plasma levels of CYP- and LOX- oxylipins, which could be a novel indicator of increased inflammatory pathway activity, as well as a novel target to dampen this activity.
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Affiliation(s)
- Yanan Xiao
- Division of Medicine, Department of Gastroenterology, Metabolism and Oncology, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany
- Medical Department, Division of Psychosomatic Medicine, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anne Pietzner
- Division of Medicine, Department of Gastroenterology, Metabolism and Oncology, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany
| | - Nadine Rohwer
- Division of Medicine, Department of Gastroenterology, Metabolism and Oncology, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Adelheid Jung
- Division of Medicine, Department of Gastroenterology, Metabolism and Oncology, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany
| | | | - Karsten H. Weylandt
- Division of Medicine, Department of Gastroenterology, Metabolism and Oncology, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Brandenburg Medical School and University of Potsdam, Potsdam, Germany
| | - Ulf Elbelt
- Division of Medicine, Department of Gastroenterology, Metabolism and Oncology, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany
- Medical Department, Division of Psychosomatic Medicine, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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12
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Shaker ME, Gomaa HAM, Hazem SH, Abdelgawad MA, El-Mesery M, Shaaban AA. Mitigation of acetaminophen-induced liver toxicity by the novel phosphatidylinositol 3-kinase inhibitor alpelisib. Front Pharmacol 2023; 14:1212771. [PMID: 37608890 PMCID: PMC10441125 DOI: 10.3389/fphar.2023.1212771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 07/26/2023] [Indexed: 08/24/2023] Open
Abstract
The sterile inflammatory response mediated by Toll-like receptors (TLRs) 4 and 9 is implicated in the massive hepatic damage caused by acetaminophen (APAP)-overdose. There is a crosstalk between TLR-dependent signaling with other intracellular kinases like phosphatidylinositol 3-kinases (PI3Ks). Nevertheless, the detailed role of PI3Kα is still unknown in hepatic sterile inflammation. Accordingly, the effect of the novel PI3Kα inhibitor alpelisib was investigated in the setting of APAP-driven sterile inflammation in the liver. This was examined by pretreating mice with alpelisib (5 and 10 mg/kg, oral) 2 h before APAP (500 mg/kg, i.p.)-intoxication. The results indicated that alpelisib dose-dependently lowered APAP-induced escalation in serum liver function biomarkers and hepatic necroinflammation score. Alpelisib also attenuated APAP-induced rise in cleaved caspase 3 and proliferating cell nuclear antigen (PCNA) in the liver hepatocytes, as indices for apoptosis and proliferation. Mechanistically, inhibition of PI3Kα by alpelisib limited APAP-induced overproduction of the pro-inflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in the blood circulation via switching off the activation of several signal transduction proteins, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription-3 (Stat-3), glycogen Synthase Kinase (GSK)-3β and nuclear factor (NF)-κB. Alpelisib also impaired APAP-instigated immune cell infiltration in the liver via reducing systemic granulocyte/macrophage-colony stimulating factor (GM-CSF) release and reversed APAP-induced abnormalities in the systemic and hepatic levels of the anti-inflammatory IL-10 and IL-22. In conclusion, selective modulation of the PI3Kα activity by alpelisib can hinder the inflammatory response and infiltration of immune cells occurring by APAP-hepatotoxicity.
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Affiliation(s)
- Mohamed E. Shaker
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Hesham A. M. Gomaa
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Sara H. Hazem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Mohamed A. Abdelgawad
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al-Jawf, Saudi Arabia
| | - Mohamed El-Mesery
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Ahmed A. Shaaban
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
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13
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Alba MM, Ebright B, Hua B, Slarve I, Zhou Y, Jia Y, Louie SG, Stiles BL. Eicosanoids and other oxylipins in liver injury, inflammation and liver cancer development. Front Physiol 2023; 14:1098467. [PMID: 36818443 PMCID: PMC9932286 DOI: 10.3389/fphys.2023.1098467] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/16/2023] [Indexed: 02/05/2023] Open
Abstract
Liver cancer is a malignancy developed from underlying liver disease that encompasses liver injury and metabolic disorders. The progression from these underlying liver disease to cancer is accompanied by chronic inflammatory conditions in which liver macrophages play important roles in orchestrating the inflammatory response. During this process, bioactive lipids produced by hepatocytes and macrophages mediate the inflammatory responses by acting as pro-inflammatory factors, as well as, playing roles in the resolution of inflammation conditions. Here, we review the literature discussing the roles of bioactive lipids in acute and chronic hepatic inflammation and progression to cancer.
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Affiliation(s)
- Mario M. Alba
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Brandon Ebright
- Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Brittney Hua
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Ielyzaveta Slarve
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Yiren Zhou
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Yunyi Jia
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Stan G. Louie
- Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Bangyan L. Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
- Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, Unites States
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14
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Velasque MJSG, Branchini G, Catarina AV, Bettoni L, Fernandes RS, Da Silva AF, Dorneles GP, da Silva IM, Santos MA, Sumienski J, Peres A, Roehe AV, Kohek MBDF, Porawski M, Nunes FB. Fish Oil - Omega-3 Exerts Protective Effect in Oxidative Stress and Liver Dysfunctions Resulting from Experimental Sepsis. J Clin Exp Hepatol 2023; 13:64-74. [PMID: 36647406 PMCID: PMC9840085 DOI: 10.1016/j.jceh.2022.07.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/24/2022] [Accepted: 07/03/2022] [Indexed: 01/19/2023] Open
Abstract
Background Sepsis is a severe global health problem, with high morbidity and mortality. In sepsis, one of the main affected organs is the liver. Hepatic alterations characterize a negative prognostic. Omega-3 fatty acids (ω3), eicosapentaenoic acid, and docosahexaenoic acid, are part of the main families of polyunsaturated fatty acids. ω3 has been used in studies as sepsis treatment and as a treatment for non-alcoholic liver disease. Aim We aimed to evaluate the effects of treatment with fish oil (FO) rich in ω3 on liver changes and damage resulting from experimental sepsis. Methodology A model of severe sepsis in Wistar rats was used. Oxidative stress in the liver tissue was evaluated by means of tests of thiobarbituric acid reactive substances, 2,7-dihydrodichlorofluorescein diacetate , catalase, and glutathione peroxidase, in the serum TBARS, DCF, thiols and, to assess liver dysfunction, alanine aminotransferase and aspartate aminotransferase. Hepatic tissue damage was evaluated using H&E histology. Results In assessments of oxidative stress in liver tissue, a protective effect was observed in the tests of TBARS, DCF, CAT, and GPx, when compared the sepsis versus sepsis+ω3 groups. Regarding the oxidative stress in serum, a protective effect of treatment with ω3 was observed in the TBARS, DCF, and thiols assays, in the comparison between the sepsis and sepsis+ω3 groups. ω3 had also a beneficial effect on biochemical parameters in serum in the analysis of ALT, creatinine, urea, and lactate, observed in the comparison between the sepsis and sepsis+ω3 groups. Conclusion The results suggest ω3 as a liver protector during sepsis with an antioxidant effect, alleviating injuries and dysfunctions.
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Key Words
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- CAT, catalase
- DCF, 2,7-dihydrodichlorofluorescein diacetate
- DHA, docosahexaenoic acid
- EPA, eicosapentaenoic acid
- FO, fish oil
- GPx, glutathione peroxidase
- GTO, oxaloacetic transaminase
- GTP, pyruvic transaminase
- HE, Hematoxylin and Eosin
- ICON, Intensive Care Over Nations
- ICU, intensive care unit
- IFN- γ, interferon gamma
- Liver injury
- RNS, reactive nitrogen species
- ROS, reactive oxygen species
- TBARS, Thiobarbituric Acid Reactive Substances
- TGF-β, transforming growth factor beta
- TNF-α, tumor necrosis factor alpha
- antioxidant
- inflammation
- omega-3
- oxidative stress
- sepsis
- ω3, omega-3
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Affiliation(s)
- Mary J. Soares Gonçalves Velasque
- Graduate Program in Pathology – Laboratory of Computational, Molecular, and Cellular Biophysics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Gisele Branchini
- Graduate Program in Pathology – Laboratory of Computational, Molecular, and Cellular Biophysics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Anderson V. Catarina
- Graduate Program in Pathology – Laboratory of Computational, Molecular, and Cellular Biophysics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Lais Bettoni
- Graduate Program in Pathology – Laboratory of Computational, Molecular, and Cellular Biophysics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Renata S. Fernandes
- Graduate Program in Health Sciences – Laboratory of Translational Physiology – Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | | | - Gilson P. Dorneles
- Laboratory of Cellular and Molecular Immunology – Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Igor Martins da Silva
- Laboratory of Cellular and Molecular Immunology – Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Maeli A. Santos
- Laboratory of Cellular and Molecular Immunology – Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Juliana Sumienski
- Laboratory of Immunology and Microbiology - Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil
| | - Alessandra Peres
- Laboratory of Cellular and Molecular Immunology – Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Adriana V. Roehe
- Graduate Program in Pathology – Laboratory of Pathology – Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Maria B. da Fonte Kohek
- Laboratory of Cellular and Molecular Immunology – Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Marilene Porawski
- Laboratory of Behavioral and Metabolic Physiology – Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Fernanda B. Nunes
- Graduate Program in Pathology – Laboratory of Computational, Molecular, and Cellular Biophysics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
- Laboratory of Inflammation and Cellular Biophysics - Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil
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15
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Vinokurtseva A, Armstrong JJ, Liu H, Hutnik CML. Differential effects of acetylsalicylic acid and mitomycin C on cytokine-induced Tenon's capsule myofibroblast transdifferentiation and activity: Implications for glaucoma surgery. Exp Eye Res 2022; 225:109284. [PMID: 36273575 DOI: 10.1016/j.exer.2022.109284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/08/2022] [Accepted: 10/13/2022] [Indexed: 12/29/2022]
Abstract
Inflammation-driven scarring is a major contributor to surgical failure after subconjunctival bleb forming glaucoma surgery. The current gold standard anti-scarring adjuvant mitomycin C (MMC) has variable effectiveness and is associated with significant risks. Acetylsalicylic acid (ASA), when delivered locally, repurposes the typically pro-inflammatory cyclooxygenase (COX-2) signaling for the resolution of inflammation and mitigating inflammation-mediated fibrosis. The aim of this study is to compare the effects of ASA and MMC in an in vitro model of subconjunctival scarring. Glaucoma patient-derived Tenon's capsule fibroblasts (HTCFs) were treated with TGFβ1 (2 ng/mL) plus or minus ASA (1600 μg/ml), or MMC (0.05, 0.1, 0.2 mg/mL). In vitro collagen contraction, MTT, LDH, immunofluorescence, and Western blot assays were performed. To elucidate the mechanistic effects of ASA in TGFβ1-induced HTCFs, liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to identify and measure pro-inflammatory and pro-resolving lipid mediator secretion. ASA was at least as effective as MMC in reducing TGFβ1-induced HTCF-mediated collagen contraction, metabolic activity, and pro-fibrotic protein expression, with less cytotoxicity. Within cytokine-activated HTCFs, ASA significantly impaired secretion of pro-inflammatory lipid mediators prostaglandin E2 and 6-keto-prostaglandin F1α and significantly increased secretion of the pro-resolving mediators 5-hydroxyeicosatetraenoic acid (HETE), 15-HETE and 18-hydroxyeicosapentaenoic acid (HEPE). ASA reduces cytokine-induced myofibroblast transdifferentiation in HTCFs, being non-inferior to MMC in vitro. ASA's effects are associated with a unique lipid mediator expression profile, suggesting that the ASA-induced resolution of inflammation may be a promising strategy to mitigate inflammation-mediated scarring and could offer a novel alternative as a surgical adjuvant.
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Affiliation(s)
- Anastasiya Vinokurtseva
- Department of Ophthalmology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
| | - James J Armstrong
- Department of Ophthalmology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada; Ivey Eye Institute, St. Joseph's Health Care, London, ON, Canada
| | - Hong Liu
- Department of Ophthalmology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
| | - Cindy M L Hutnik
- Department of Ophthalmology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada; Ivey Eye Institute, St. Joseph's Health Care, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
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16
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Production of C20 9S- and C22 11S-hydroxy fatty acids by cells expressing Shewanella hanedai arachidonate 9S-lipoxygenase. Appl Microbiol Biotechnol 2022; 107:247-260. [DOI: 10.1007/s00253-022-12285-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 10/24/2022] [Accepted: 11/08/2022] [Indexed: 11/29/2022]
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da Silva Batista E, Nakandakari SCBR, Ramos da Silva AS, Pauli JR, Pereira de Moura L, Ropelle ER, Camargo EA, Cintra DE. Omega-3 pleiad: The multipoint anti-inflammatory strategy. Crit Rev Food Sci Nutr 2022; 64:4817-4832. [PMID: 36382659 DOI: 10.1080/10408398.2022.2146044] [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] [Indexed: 11/17/2022]
Abstract
Omega 3 (ω3) fatty acids have been described since the 1980s as promising anti-inflammatory substances. Prostaglandin and leukotriene modulation were exhaustively explored as the main reason for ω3 beneficial outcomes. However, during the early 2000s, after the human genome decoding advent, the nutrigenomic approaches exhibited an impressive plethora of ω3 targets, now under the molecular point of view. Different G protein-coupled receptors (GPCRs) recognizing ω3 and its derivatives appear to be responsible for blocking inflammation and insulin-sensitizing effects. A new class of ω3-derived substances, such as maresins, resolvins, and protectins, increases ω3 actions. Inflammasome disruption, the presence of GPR120 on immune cell surfaces, and intracellular crosstalk signaling mediated by PPARγ compose the last discoveries regarding the multipoint anti-inflammatory targets for this nutrient. This review shows a detailed mechanistic proposal to understand ω3 fatty acid action over the inflammatory environment in the background of several chronic diseases.
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Affiliation(s)
- Ellencristina da Silva Batista
- Graduate Program of Health Sciences (PPGCS), Federal University of Sergipe, Aracaju, Sergipe, Brazil
- Nutritional Genomics Laboratory, LabGeN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- Nutrigenomics and Lipids Research Center, CELN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- Nutrition Department, Federal University of Sergipe, Lagarto, Sergipe, Brazil
| | - Susana Castelo Branco Ramos Nakandakari
- Nutritional Genomics Laboratory, LabGeN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- Nutrigenomics and Lipids Research Center, CELN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
| | | | - José Rodrigo Pauli
- Nutrigenomics and Lipids Research Center, CELN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, UNICAMP, São Paulo, Brazil
| | - Leandro Pereira de Moura
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, UNICAMP, São Paulo, Brazil
| | - Eduardo Rochete Ropelle
- Nutrigenomics and Lipids Research Center, CELN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, UNICAMP, São Paulo, Brazil
| | - Enilton A Camargo
- Graduate Program of Health Sciences (PPGCS), Federal University of Sergipe, Aracaju, Sergipe, Brazil
- Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil
| | - Dennys Esper Cintra
- Nutritional Genomics Laboratory, LabGeN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- Nutrigenomics and Lipids Research Center, CELN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- OCRC - Obesity and Comorbidities Research Center, UNICAMP, São Paulo, Brazil
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18
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Gagestein B, von Hegedus JH, Kwekkeboom JC, Heijink M, Blomberg N, van der Wel T, Florea BI, van den Elst H, Wals K, Overkleeft HS, Giera M, Toes REM, Ioan-Facsinay A, van der Stelt M. Comparative Photoaffinity Profiling of Omega-3 Signaling Lipid Probes Reveals Prostaglandin Reductase 1 as a Metabolic Hub in Human Macrophages. J Am Chem Soc 2022; 144:18938-18947. [PMID: 36197299 PMCID: PMC9585591 DOI: 10.1021/jacs.2c06827] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
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The fish oil constituent
docosahexaenoic acid (DHA, 22:6
n-3) is
a signaling lipid with anti-inflammatory properties. The molecular
mechanisms underlying the biological effect of DHA are poorly understood.
Here, we report the design, synthesis, and application of a complementary
pair of bio-orthogonal, photoreactive probes based on the polyunsaturated
scaffold DHA and its oxidative metabolite 17-hydroxydocosahexaenoic
acid (17-HDHA). In these probes, an alkyne serves as a handle to introduce
a fluorescent reporter group or a biotin-affinity tag via copper(I)-catalyzed
azide-alkyne cycloaddition. This pair of chemical probes was used
to map specific targets of the omega-3 signaling lipids in primary
human macrophages. Prostaglandin reductase 1 (PTGR1) was identified
as an interaction partner that metabolizes 17-oxo-DHA, an oxidative
metabolite of 17-HDHA. 17-oxo-DHA reduced the formation of pro-inflammatory
lipids 5-HETE and LTB4 in human macrophages and neutrophils. Our results
demonstrate the potential of comparative photoaffinity protein profiling
for the discovery of metabolic enzymes of bioactive lipids and highlight
the power of chemical proteomics to uncover new biological insights.
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Affiliation(s)
- Berend Gagestein
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Einsteinweg 55, Leiden 2333 CC, The Netherlands
| | - Johannes H von Hegedus
- Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
| | - Joanneke C Kwekkeboom
- Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
| | - Marieke Heijink
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
| | - Niek Blomberg
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
| | - Tom van der Wel
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Einsteinweg 55, Leiden 2333 CC, The Netherlands
| | - Bogdan I Florea
- Bio-Organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands
| | - Hans van den Elst
- Bio-Organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands
| | - Kim Wals
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Einsteinweg 55, Leiden 2333 CC, The Netherlands
| | - Herman S Overkleeft
- Bio-Organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands
| | - Martin Giera
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
| | - René E M Toes
- Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
| | - Andreea Ioan-Facsinay
- Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
| | - Mario van der Stelt
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Einsteinweg 55, Leiden 2333 CC, The Netherlands
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19
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Dalle C, Tournayre J, Mainka M, Basiak-Rasała A, Pétéra M, Lefèvre-Arbogast S, Dalloux-Chioccioli J, Deschasaux-Tanguy M, Lécuyer L, Kesse-Guyot E, Fezeu LK, Hercberg S, Galan P, Samieri C, Zatońska K, Calder PC, Fiil Hjorth M, Astrup A, Mazur A, Bertrand-Michel J, Schebb NH, Szuba A, Touvier M, Newman JW, Gladine C. The Plasma Oxylipin Signature Provides a Deep Phenotyping of Metabolic Syndrome Complementary to the Clinical Criteria. Int J Mol Sci 2022; 23:ijms231911688. [PMID: 36232991 PMCID: PMC9570185 DOI: 10.3390/ijms231911688] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/23/2022] [Accepted: 09/24/2022] [Indexed: 11/06/2022] Open
Abstract
Metabolic syndrome (MetS) is a complex condition encompassing a constellation of cardiometabolic abnormalities. Oxylipins are a superfamily of lipid mediators regulating many cardiometabolic functions. Plasma oxylipin signature could provide a new clinical tool to enhance the phenotyping of MetS pathophysiology. A high-throughput validated mass spectrometry method, allowing for the quantitative profiling of over 130 oxylipins, was applied to identify and validate the oxylipin signature of MetS in two independent nested case/control studies involving 476 participants. We identified an oxylipin signature of MetS (coined OxyScore), including 23 oxylipins and having high performances in classification and replicability (cross-validated AUCROC of 89%, 95% CI: 85–93% and 78%, 95% CI: 72–85% in the Discovery and Replication studies, respectively). Correlation analysis and comparison with a classification model incorporating the MetS criteria showed that the oxylipin signature brings consistent and complementary information to the clinical criteria. Being linked with the regulation of various biological processes, the candidate oxylipins provide an integrative phenotyping of MetS regarding the activation and/or negative feedback regulation of crucial molecular pathways. This may help identify patients at higher risk of cardiometabolic diseases. The oxylipin signature of patients with metabolic syndrome enhances MetS phenotyping and may ultimately help to better stratify the risk of cardiometabolic diseases.
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Affiliation(s)
- Céline Dalle
- UNH, INRAE, Université Clermont Auvergne, 63000 Clermont-Ferrand, France
| | - Jérémy Tournayre
- UNH, INRAE, Université Clermont Auvergne, 63000 Clermont-Ferrand, France
| | - Malwina Mainka
- Faculty of Mathematics and Natural Sciences, University of Wuppertal, 42119 Wuppertal, Germany
| | - Alicja Basiak-Rasała
- Department of Social Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Mélanie Pétéra
- Plateforme d’Exploration du Métabolisme, MetaboHUB Clermont, UNH, INRAE, Université Clermont Auvergne, 63000 Clermont-Ferrand, France
| | - Sophie Lefèvre-Arbogast
- Bordeaux Population Health Research Center, Université de Bordeaux, INSERMUMR 1219, 33076 Bordeaux, France
| | - Jessica Dalloux-Chioccioli
- MetaToul, MetaboHUB, Inserm/UPS UMR 1048-I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 31400 Toulouse, France
| | - Mélanie Deschasaux-Tanguy
- Nutritional Epidemiology Research Team (EREN), Sorbonne Paris Nord University, INSERM U1153, INRAE U1125, Cnam, Epidemiology and Statistics Research Center, University Paris Cité (CRESS), 93017 Bobigny, France
| | - Lucie Lécuyer
- Nutritional Epidemiology Research Team (EREN), Sorbonne Paris Nord University, INSERM U1153, INRAE U1125, Cnam, Epidemiology and Statistics Research Center, University Paris Cité (CRESS), 93017 Bobigny, France
| | - Emmanuelle Kesse-Guyot
- Nutritional Epidemiology Research Team (EREN), Sorbonne Paris Nord University, INSERM U1153, INRAE U1125, Cnam, Epidemiology and Statistics Research Center, University Paris Cité (CRESS), 93017 Bobigny, France
| | - Léopold K. Fezeu
- Nutritional Epidemiology Research Team (EREN), Sorbonne Paris Nord University, INSERM U1153, INRAE U1125, Cnam, Epidemiology and Statistics Research Center, University Paris Cité (CRESS), 93017 Bobigny, France
| | - Serge Hercberg
- Nutritional Epidemiology Research Team (EREN), Sorbonne Paris Nord University, INSERM U1153, INRAE U1125, Cnam, Epidemiology and Statistics Research Center, University Paris Cité (CRESS), 93017 Bobigny, France
| | - Pilar Galan
- Nutritional Epidemiology Research Team (EREN), Sorbonne Paris Nord University, INSERM U1153, INRAE U1125, Cnam, Epidemiology and Statistics Research Center, University Paris Cité (CRESS), 93017 Bobigny, France
| | - Cécilia Samieri
- Bordeaux Population Health Research Center, Université de Bordeaux, INSERMUMR 1219, 33076 Bordeaux, France
| | - Katarzyna Zatońska
- Department of Social Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Philip C. Calder
- Faculty of Medicine, School of Human Development and Health, University of Southampton, Southampton SO16 6YD, UK
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton SO16 6YD, UK
| | - Mads Fiil Hjorth
- Obesity and Nutritional Sciences, Novo Nordisk Foundation, 2900 Hellerup, Denmark
| | - Arne Astrup
- Obesity and Nutritional Sciences, Novo Nordisk Foundation, 2900 Hellerup, Denmark
| | - André Mazur
- UNH, INRAE, Université Clermont Auvergne, 63000 Clermont-Ferrand, France
| | - Justine Bertrand-Michel
- MetaToul, MetaboHUB, Inserm/UPS UMR 1048-I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, 31400 Toulouse, France
| | - Nils Helge Schebb
- Faculty of Mathematics and Natural Sciences, University of Wuppertal, 42119 Wuppertal, Germany
| | - Andrzej Szuba
- Department of Angiology, Hypertension and Diabetology, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Mathilde Touvier
- Nutritional Epidemiology Research Team (EREN), Sorbonne Paris Nord University, INSERM U1153, INRAE U1125, Cnam, Epidemiology and Statistics Research Center, University Paris Cité (CRESS), 93017 Bobigny, France
| | - John W. Newman
- Obesity and Metabolism Research Unit, United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA 95616, USA
- University of California Davis Genome Center, University of California, Davis, CA 95616, USA
- Department of Nutrition, University of California, Davis, CA 95616, USA
| | - Cécile Gladine
- UNH, INRAE, Université Clermont Auvergne, 63000 Clermont-Ferrand, France
- Correspondence: ; Tel.: +33-473-624-230
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20
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Quek SXZ, Tan EXX, Ren YP, Muthiah M, Loo EXL, Tham EH, Siah KTH. Factors early in life associated with hepatic steatosis. World J Hepatol 2022; 14:1235-1247. [PMID: 35978672 PMCID: PMC9258263 DOI: 10.4254/wjh.v14.i6.1235] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/01/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The rise in prevalence of non-alcoholic fatty liver disease (NAFLD) mirrors the obesity epidemic. NAFLD is insidious but may gradually progress from simple steatosis to steatohepatitis, fibrosis and cirrhosis and/or hepatocellular carcinoma. Intervention strategies to ameliorate developmental programming of NAFLD may be more efficacious during critical windows of developmental plasticity.
AIM To review the early developmental factors associated with NAFLD.
METHODS Databases MEDLINE via PubMed, and EMBASE and Reference Citation Analysis were searched and relevant publications up to April 30, 2021 were assessed. Original research studies that included risk factors associated with early development of NAFLD in human subjects were included. These factors include: Maternal factors, intrauterine and prenatal factors, post-natal factors, genetic and ethnic predisposition, childhood and adolescence environmental factors. Studies were excluded if they were review articles or animal studies, case reports or conference abstracts, or if NAFLD was not clearly defined and assessed radiologically.
RESULTS Of 1530 citations identified by electronic search, 420 duplicates were removed. Of the 1110 citations screened from title and abstract, 80 articles were included in the final analysis. Genetic polymorphisms such as patatin-like phospholipase domain-containing protein 3 (PNPLA3) and membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) were associated with increased risk of NAFLD. Familial factors such as maternal obesogenic environment and parental history of hepatic steatosis was associated with offspring NAFLD. Longer duration of exclusive breastfeeding in infancy was associated with a lower risk of developing NAFLD later in life while metabolic dysfunction and/or obesity in adolescence was associated with increased risk of NAFLD. Studies relating to socioeconomic factors and its association with NAFLD reported confounding results.
CONCLUSION Maternal metabolic dysfunction during pregnancy, being exclusively breastfed for a longer time postnatally, diet and physical activity in childhood and adolescence are potential areas of intervention to decrease risk of NAFLD.
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Affiliation(s)
- Sabrina Xin Zi Quek
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore 119228, Singapore
| | - Eunice Xiang-Xuan Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore 119228, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Yi Ping Ren
- Department of Medicine, National University Hospital, Singapore 119228, Singapore
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore 119228, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Evelyn Xiu Ling Loo
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore; Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore 119228, Singapore
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore 117609, Singapore
| | - Elizabeth Huiwen Tham
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore; Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore 119228, Singapore
| | - Kewin Tien Ho Siah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
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21
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Sprygin VG, Kushnerova NF, Fomenko SE. Effect of a Lipid Complex from the Marine Red Alga Ahnfeltia tobuchiensis on the Metabolic Responses of the Liver under Conditions of Experimental Toxic Hepatitis. BIOL BULL+ 2022. [DOI: 10.1134/s1062359022010149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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22
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Koelmel JP, Tan WY, Li Y, Bowden JA, Ahmadireskety A, Patt AC, Orlicky DJ, Mathé E, Kroeger NM, Thompson DC, Cochran JA, Golla JP, Kandyliari A, Chen Y, Charkoftaki G, Guingab‐Cagmat JD, Tsugawa H, Arora A, Veselkov K, Kato S, Otoki Y, Nakagawa K, Yost RA, Garrett TJ, Vasiliou V. Lipidomics and Redox Lipidomics Indicate Early Stage Alcohol-Induced Liver Damage. Hepatol Commun 2022; 6:513-525. [PMID: 34811964 PMCID: PMC8870008 DOI: 10.1002/hep4.1825] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 12/12/2022] Open
Abstract
Alcoholic fatty liver disease (AFLD) is characterized by lipid accumulation and inflammation and can progress to cirrhosis and cancer in the liver. AFLD diagnosis currently relies on histological analysis of liver biopsies. Early detection permits interventions that would prevent progression to cirrhosis or later stages of the disease. Herein, we have conducted the first comprehensive time-course study of lipids using novel state-of-the art lipidomics methods in plasma and liver in the early stages of a mouse model of AFLD, i.e., Lieber-DeCarli diet model. In ethanol-treated mice, changes in liver tissue included up-regulation of triglycerides (TGs) and oxidized TGs and down-regulation of phosphatidylcholine, lysophosphatidylcholine, and 20-22-carbon-containing lipid-mediator precursors. An increase in oxidized TGs preceded histological signs of early AFLD, i.e., steatosis, with these changes observed in both the liver and plasma. The major lipid classes dysregulated by ethanol play important roles in hepatic inflammation, steatosis, and oxidative damage. Conclusion: Alcohol consumption alters the liver lipidome before overt histological markers of early AFLD. This introduces the exciting possibility that specific lipids may serve as earlier biomarkers of AFLD than those currently being used.
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Affiliation(s)
- Jeremy P. Koelmel
- Department of Environmental Health SciencesYale School of Public HealthNew HavenCTUSA
- Department of Pathology, Immunology and Laboratory MedicineUniversity of FloridaGainesvilleFLUSA
| | - Wan Y. Tan
- Department of Environmental Health SciencesYale School of Public HealthNew HavenCTUSA
- Internal Medicine Residency ProgramDepartment of Internal MedicineNorwalk HospitalNorwalkCTUSA
| | - Yang Li
- Department of Pathology, Immunology and Laboratory MedicineUniversity of FloridaGainesvilleFLUSA
| | - John A. Bowden
- Department of ChemistryUniversity of FloridaGainesvilleFLUSA
- Center for Environmental and Human Toxicology and Department of Physiological SciencesUniversity of FloridaGainesvilleFLUSA
| | | | - Andrew C. Patt
- Division of Preclinical InnovationNational Center for Advancing Translational SciencesNational Institutes of HealthRockvilleMDUSA
| | - David J. Orlicky
- Department of PathologyUniversity of Colorado School of MedicineDenverCOUSA
| | - Ewy Mathé
- Division of Preclinical InnovationNational Center for Advancing Translational SciencesNational Institutes of HealthRockvilleMDUSA
| | - Nicholas M. Kroeger
- Computer and Information Science and EngineeringUniversity of FloridaGainesvilleFLUSA
| | - David C. Thompson
- Department of Clinical PharmacyUniversity of Colorado Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of ColoradoAuroraCOUSA
| | - Jason A. Cochran
- Department of Pathology, Immunology and Laboratory MedicineUniversity of FloridaGainesvilleFLUSA
- Computer and Information Science and EngineeringUniversity of FloridaGainesvilleFLUSA
| | - Jaya Prakash Golla
- Department of Environmental Health SciencesYale School of Public HealthNew HavenCTUSA
| | - Aikaterini Kandyliari
- Department of Environmental Health SciencesYale School of Public HealthNew HavenCTUSA
- Unit of Human NutritionDepartment of Food Science and Human NutritionAgricultural University of AthensAthensGreece
| | - Ying Chen
- Department of Environmental Health SciencesYale School of Public HealthNew HavenCTUSA
| | - Georgia Charkoftaki
- Department of Environmental Health SciencesYale School of Public HealthNew HavenCTUSA
| | - Joy D. Guingab‐Cagmat
- Department of Pathology, Immunology and Laboratory MedicineUniversity of FloridaGainesvilleFLUSA
| | - Hiroshi Tsugawa
- RIKEN Center for Sustainable Resource ScienceKanagawaJapan
- RIKEN Center for Integrative Medical SciencesKanagawaJapan
- Department of Biotechnology and Life ScienceTokyo University of Agriculture and TechnologyTokyoJapan
| | - Anmol Arora
- Department of Environmental Health SciencesYale School of Public HealthNew HavenCTUSA
- School of Clinical MedicineUniversity of CambridgeCambridgeUnited Kingdom
| | - Kirill Veselkov
- Department of Metabolism, Digestion and ReproductionImperial CollegeLondonUnited Kingdom
| | - Shunji Kato
- Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural ScienceTohoku UniversitySendaiJapan
| | - Yurika Otoki
- Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural ScienceTohoku UniversitySendaiJapan
| | - Kiyotaka Nakagawa
- Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural ScienceTohoku UniversitySendaiJapan
| | - Richard A. Yost
- Department of Pathology, Immunology and Laboratory MedicineUniversity of FloridaGainesvilleFLUSA
- Department of ChemistryUniversity of FloridaGainesvilleFLUSA
| | - Timothy J. Garrett
- Department of Pathology, Immunology and Laboratory MedicineUniversity of FloridaGainesvilleFLUSA
- Department of ChemistryUniversity of FloridaGainesvilleFLUSA
| | - Vasilis Vasiliou
- Department of Environmental Health SciencesYale School of Public HealthNew HavenCTUSA
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23
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Shaker ME, Hamed MF, Shaaban AA. Digoxin mitigates diethylnitrosamine-induced acute liver injury in mice via limiting production of inflammatory mediators. Saudi Pharm J 2022; 30:291-299. [PMID: 35498227 PMCID: PMC9051977 DOI: 10.1016/j.jsps.2022.01.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 01/12/2022] [Indexed: 01/21/2023] Open
Abstract
The cardiotonic digoxin has been recently shown to possess an anti-inflammatory potential in numerous metabolic and inflammatory disorders. However, data about digoxin’s impact in the setting of acute liver injury and sterile inflammation are still limited. Here, we investigated the potential effect of digoxin pretreatments (0.25 and 0.5 mg/kg, oral) on the severity of acute hepatotoxicity in mice challenged with a single dose of diethylnitrosamine (DN; 150 mg/kg, intraperitoneal) for 24 h. Our results indicated that digoxin pretreatments dose-dependently mitigated DN-induced rise of hepatocellular injury parameters and necroinflammation scores. Digoxin, particularly at dose of 0.5 mg/kg, boosted the number of PCNA positive hepatocytes, leading to improvement of the reparative potential in hepatocytes of DN-intoxicated livers. Digoxin’s ameliorative effect on DN-hepatotoxicity coincided with (i) lowering the increased hepatic production and release of the proinflammatory mediators IL-17A, IL-1β and TNF-α, and (ii) impeding the attraction and infiltration of monocytes to the liver, as denoted by decreasing serum MCP-1 and F4/80 immunohistochemical expression. These effects were attributed to reducing DN-induced activation of NF-κB and overexpression of CD98 in the liver. Meanwhile, DN elicited a decline in the hepatic production and release of the anti-inflammatory cytokines IL-22 and IL-6, which was intensified by digoxin, especially at a dose 0.5 mg/kg. In conclusion, digoxin conferred liver protection against DN-insult by impairing the overproduction of proinflammatory cytokines and infiltration of inflammatory cells to the liver.
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Affiliation(s)
- Mohamed E. Shaker
- Pharmacology Department, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf, Saudi Arabia
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
- Corresponding author at: Pharmacology Department, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf, Saudi Arabia.
| | - Mohamed F. Hamed
- Pathology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Ahmed A. Shaaban
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
- Pharmacology and Biochemistry Department, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
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24
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Aboraya DM, El Baz A, Risha EF, Abdelhamid FM. Hesperidin ameliorates cisplatin induced hepatotoxicity and attenuates oxidative damage, cell apoptosis, and inflammation in rats. Saudi J Biol Sci 2022; 29:3157-3166. [PMID: 35844386 PMCID: PMC9280168 DOI: 10.1016/j.sjbs.2022.01.052] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 01/19/2022] [Accepted: 01/23/2022] [Indexed: 12/25/2022] Open
Abstract
Cisplatin is one of the most widely used chemotherapeutic anti-cancer drugs that is associated with multiple systemic toxicities limiting its use. The present study aimed to evaluate the hepato-protective effect of hesperidin against cisplatin-induced toxicity. Thirty-two adult male albino rats were equally split into four groups, the first group served as control received normal saline, the second group (CIS) received a single intraperitoneal dose of cisplatin (7.5 mg/kg bw) on the 22nd day of the experiment, the third group (HES) treated once daily with hesperidin (200 mg/kg bw, orally) for 21 days, and the last group (HES + CIS) pretreated once daily with hesperidin followed by a single intraperitoneal dose of cisplatin. Twenty-four hours later, samples were collected for further investigations. CIS-intoxication resulted in a significant decrease in the erythrogram along with thrombocytopenia leukopenia, and lymphopenia. Furthermore, CIS administration significantly elevated serum activity of liver enzymes, total, and indirect bilirubin as well serum glucose, total cholesterol, and triglycerides levels, meanwhile serum total protein, and globulin levels were significantly reduced. The hepatic MDA was markedly elevated with a concomitant decline in the hepatic antioxidant enzymes and severe alterations in the hepatic tissue architecture in CIS-intoxicated rats. Additionally, CIS-induced overexpression of hepatic Bax, caspase-3, and TNF-α, with no effect on hepatic expression of IL-10. Interestingly, HES pretreatment improved the CIS-induced hemato-biochemical, molecular and histopathological alterations. In conclusion, hesperidin hepato-protective effects against CIS might be mediated by its antioxidant, anti-inflammatory, and anti-apoptotic properties.
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25
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Jeyakumar SM, Vajreswari A. Pharmaconutrition strategy to resolve SARS-CoV-2-induced inflammatory cytokine storm in non-alcoholic fatty liver disease: Omega-3 long-chain polyunsaturated fatty acids. World J Clin Cases 2021; 9:9333-9349. [PMID: 34877270 PMCID: PMC8610854 DOI: 10.12998/wjcc.v9.i31.9333] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/18/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammation is one of the primary factors associated with the causation and/or progression of several lifestyle disorders, including obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of disorders, and starts with simple steatosis, progresses to non-alcoholic steatohepatitis, and then advances to fibrosis, cirrhosis and finally, hepatocellular carcinoma, due to perpetual cycles of insults caused by inflammation and other cellular stress. Emerging evidence has documented that patients with NAFLD have severe coronavirus disease 2019 (COVID-19), and patients with COVID-19 have a higher liver injury and mortality. Although the exact cause or mechanism is not known, inflammatory cytokine storm is a characteristic feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and is known to be associated with higher mortality among COVID-19 patients. Therefore, the COVID-19 pandemic seems to be a major concern in NAFLD patients, who have contracted SARS-CoV-2 infection and develop COVID-19. This is evident in patients at any stage of the NAFLD spectrum, as the inflammatory cytokine storm may cause and/or aggravate the progression or severity of NAFLD. Thus, there is a need for resolution of the inflammatory cytokine storm in these patients. A large body of evidence has demonstrated the efficacy of omega-3 long-chain polyunsaturated fatty acids (ω-3 LCPUFA) in NAFLD conditions, due to their anti-inflammatory, immunomodulatory and anti-viral properties. Therefore, intervention with ω-3 LCPUFA, an effective pharmaconutrient along with the standard treatment for COVID-19 may be useful in the management of the NAFLD spectrum in COVID-19 patients with pre-existing NAFLD conditions by resolving the inflammatory cytokine storm and thereby attenuating its progression. Although there are challenges in implementation, optimistically they can be circumvented and the pharmaconutrition strategy may be potentially helpful in tackling both the pandemics; NAFLD and COVID-19 at least in this subset of patients.
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Affiliation(s)
- Shanmugam M Jeyakumar
- Department of Clinical Pharmacology, ICMR-National Institute for Research in Tuberculosis, Chennai 600031, Tamil Nadu, India
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26
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Han YH, Lee K, Saha A, Han J, Choi H, Noh M, Lee YH, Lee MO. Specialized Proresolving Mediators for Therapeutic Interventions Targeting Metabolic and Inflammatory Disorders. Biomol Ther (Seoul) 2021; 29:455-464. [PMID: 34162770 PMCID: PMC8411019 DOI: 10.4062/biomolther.2021.094] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/07/2021] [Accepted: 06/08/2021] [Indexed: 12/18/2022] Open
Abstract
Uncontrolled inflammation is considered the pathophysiological basis of many prevalent metabolic disorders, such as nonalcoholic fatty liver disease, diabetes, obesity, and neurodegenerative diseases. The inflammatory response is a self-limiting process that produces a superfamily of chemical mediators, called specialized proresolving mediators (SPMs). SPMs include the ω-3-derived family of molecules, such as resolvins, protectins, and maresins, as well as arachidonic acid-derived (ω-6) lipoxins that stimulate and promote resolution of inflammation, clearance of microbes, and alleviation of pain and promote tissue regeneration via novel mechanisms. SPMs function by binding and activating G protein-coupled receptors, such as FPR2/ALX, GPR32, and ERV1, and nuclear orphan receptors, such as RORα. Recently, several studies reported that SPMs have the potential to attenuate lipid metabolism disorders. However, the understanding of pharmacological aspects of SPMs, including tissue-specific biosynthesis, and specific SPM receptors and signaling pathways, is currently limited. Here, we summarize recent advances in the role of SPMs in resolution of inflammatory diseases with metabolic disorders, such as nonalcoholic fatty liver disease and obesity, obtained from preclinical animal studies. In addition, the known SPM receptors and their intracellular signaling are reviewed as targets of resolution of inflammation, and the currently available information on the therapeutic effects of major SPMs for metabolic disorders is summarized.
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Affiliation(s)
- Yong-Hyun Han
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Kyeongjin Lee
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Abhirup Saha
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Juhyeong Han
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Haena Choi
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Minsoo Noh
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Yun-Hee Lee
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Mi-Ock Lee
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.,Bio-MAX Institute, Seoul National University, Seoul 08826, Republic of Korea
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Krill Oil Treatment Increases Distinct PUFAs and Oxylipins in Adipose Tissue and Liver and Attenuates Obesity-Associated Inflammation via Direct and Indirect Mechanisms. Nutrients 2021; 13:nu13082836. [PMID: 34444996 PMCID: PMC8401900 DOI: 10.3390/nu13082836] [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: 06/30/2021] [Revised: 08/12/2021] [Accepted: 08/16/2021] [Indexed: 12/31/2022] Open
Abstract
The development of obesity is characterized by the metabolic overload of tissues and subsequent organ inflammation. The health effects of krill oil (KrO) on obesity-associated inflammation remain largely elusive, because long-term treatments with KrO have not been performed to date. Therefore, we examined the putative health effects of 28 weeks of 3% (w/w) KrO supplementation to an obesogenic diet (HFD) with fat derived mostly from lard. The HFD with KrO was compared to an HFD control group to evaluate the effects on fatty acid composition and associated inflammation in epididymal white adipose tissue (eWAT) and the liver during obesity development. KrO treatment increased the concentrations of EPA and DHA and associated oxylipins, including 18-HEPE, RvE2 and 14-HDHA in eWAT and the liver. Simultaneously, KrO decreased arachidonic acid concentrations and arachidonic-acid-derived oxylipins (e.g., HETEs, PGD2, PGE2, PGF2α, TXB2). In eWAT, KrO activated regulators of adipogenesis (e.g., PPARγ, CEBPα, KLF15, STAT5A), induced a shift towards smaller adipocytes and increased the total adipocyte numbers indicative for hyperplasia. KrO reduced crown-like structures in eWAT, and suppressed HFD-stimulated inflammatory pathways including TNFα and CCL2/MCP-1 signaling. The observed eWAT changes were accompanied by reduced plasma leptin and increased plasma adiponectin levels over time, and improved insulin resistance (HOMA-IR). In the liver, KrO suppressed inflammatory signaling pathways, including those controlled by IL-1β and M-CSF, without affecting liver histology. Furthermore, KrO deactivated hepatic REL-A/p65-NF-κB signaling, consistent with increased PPARα protein expression and a trend towards an increase in IkBα. In conclusion, long-term KrO treatment increased several anti-inflammatory PUFAs and oxylipins in WAT and the liver. These changes were accompanied by beneficial effects on general metabolism and inflammatory tone at the tissue level. The stimulation of adipogenesis by KrO allows for safe fat storage and may, together with more direct PPAR-mediated anti-inflammatory mechanisms, attenuate inflammation.
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28
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Clària J, Flores-Costa R, Duran-Güell M, López-Vicario C. Proresolving lipid mediators and liver disease. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:159023. [PMID: 34352389 DOI: 10.1016/j.bbalip.2021.159023] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 06/07/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023]
Abstract
Inflammation is a characteristic feature of virtually all acute and chronic liver diseases. It intersects different liver pathologies from the early stages of liver injury, when the inflammatory burden is mild-to-moderate, to very advanced stages of liver disease, when the inflammatory response is very intense and drives multiple organ dysfunction and failure(s). The current review describes the most relevant features of the inflammatory process in two different clinical entities across the liver disease spectrum, namely non-alcoholic steatohepatitis (NASH) and acute-on-chronic liver failure (ACLF). Special emphasis is given within these two disease conditions to gather the most relevant data on the specialized pro-resolving mediators that orchestrate the resolution of inflammation, a tightly controlled process which dysregulation commonly associates with chronic inflammatory conditions.
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Affiliation(s)
- Joan Clària
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS and CIBERehd, Barcelona, Spain; Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain; European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain.
| | - Roger Flores-Costa
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS and CIBERehd, Barcelona, Spain; European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain
| | - Marta Duran-Güell
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS and CIBERehd, Barcelona, Spain; European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain
| | - Cristina López-Vicario
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS and CIBERehd, Barcelona, Spain; European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain.
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29
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Rosa-Velazquez M, Jaborek JR, Pinos-Rodriguez JM, Relling AE. Maternal Supply of Fatty Acids during Late Gestation on Offspring's Growth, Metabolism, and Carcass Characteristics in Sheep. Animals (Basel) 2021; 11:719. [PMID: 33800817 PMCID: PMC8001004 DOI: 10.3390/ani11030719] [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: 01/29/2021] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 12/27/2022] Open
Abstract
Lambs born from dams supplemented with different sources of fatty acids (FA) during late gestation have a different growth rate and plasma glucose concentration. The main objectives of this experiment were to evaluate the effect of supplementing different sources of FA during late gestation on offspring plasma metabolite concentrations, growth, and on a glucose tolerance test (GTT) during the finishing phase. Fifty-four lambs (18 pens, 3 lambs/pen) were born from ewes supplemented during late gestation with one of three treatments: (1) no FA (NF); (2) a source of monounsaturated FA (PDS, 1.01% of Ca salts); or (3) a source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (EDS, 1.01% of Ca salts containing). At birth (day 0), supplementation ceased, and all ewes and lambs were placed in a common pen. On day 60, lambs were weaned, grouped by sex, blocked by body weight (BW), and placed on a common finishing diet for 54 days (FP). One lamb per pen was used for the GTT after the FP. There was a tendency for FA × Sex × Day interaction (p = 0.08) on lamb growth during the finishing period, with PDS females being heavier than PDS males, while EDS males were heavier than EDS females at day 60. There was a tendency for FA × Sex interaction (p = 0.06) for plasma insulin concentration for the GTT. Plasma insulin concentration of wethers increased as FA unsaturation degree increased during the GTT; the opposite happened with the plasma insulin concentration of female lambs. In conclusion, FA supplementation during late gestation tended to modified growth and insulin response to a GTT; these changes differed with the degree of FA unsaturation of the supplement and lamb sex.
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Affiliation(s)
- Milca Rosa-Velazquez
- Facultad de Medicina Veterinaria Zootecnia, Universidad Veracruzana, 91710 Veracruz, Mexico; (M.R.-V.); (J.M.P.-R.)
- Department of Animal Sciences, Ohio Agricultural Research and Development Center (OARDC), The Ohio State University, Wooster 44691, OH, USA;
| | - Jerad R. Jaborek
- Department of Animal Sciences, Ohio Agricultural Research and Development Center (OARDC), The Ohio State University, Wooster 44691, OH, USA;
| | - Juan Manuel Pinos-Rodriguez
- Facultad de Medicina Veterinaria Zootecnia, Universidad Veracruzana, 91710 Veracruz, Mexico; (M.R.-V.); (J.M.P.-R.)
| | - Alejandro Enrique Relling
- Department of Animal Sciences, Ohio Agricultural Research and Development Center (OARDC), The Ohio State University, Wooster 44691, OH, USA;
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30
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Leslie E, Lopez V, Anti NAO, Alvarez R, Kafeero I, Welsh DG, Romero M, Kaushal S, Johnson CM, Bosviel R, Blaženović I, Song R, Brito A, Frano MRL, Zhang L, Newman JW, Fiehn O, Wilson SM. Gestational long-term hypoxia induces metabolomic reprogramming and phenotypic transformations in fetal sheep pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 2021; 320:L770-L784. [PMID: 33624555 DOI: 10.1152/ajplung.00469.2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Gestational long-term hypoxia increases the risk of myriad diseases in infants including persistent pulmonary hypertension. Similar to humans, fetal lamb lung development is susceptible to long-term intrauterine hypoxia, with structural and functional changes associated with the development of pulmonary hypertension including pulmonary arterial medial wall thickening and dysregulation of arterial reactivity, which culminates in decreased right ventricular output. To further explore the mechanisms associated with hypoxia-induced aberrations in the fetal sheep lung, we examined the premise that metabolomic changes and functional phenotypic transformations occur due to intrauterine, long-term hypoxia. To address this, we performed electron microscopy, Western immunoblotting, calcium imaging, and metabolomic analyses on pulmonary arteries isolated from near-term fetal lambs that had been exposed to low- or high-altitude (3,801 m) hypoxia for the latter 110+ days of gestation. Our results demonstrate that the sarcoplasmic reticulum was swollen with high luminal width and distances to the plasma membrane in the hypoxic group. Hypoxic animals were presented with higher endoplasmic reticulum stress and suppressed calcium storage. Metabolically, hypoxia was associated with lower levels of multiple omega-3 polyunsaturated fatty acids and derived lipid mediators (e.g., eicosapentaenoic acid, docosahexaenoic acid, α-linolenic acid, 5-hydroxyeicosapentaenoic acid (5-HEPE), 12-HEPE, 15-HEPE, prostaglandin E3, and 19(20)-epoxy docosapentaenoic acid) and higher levels of some omega-6 metabolites (P < 0.02) including 15-keto prostaglandin E2 and linoleoylglycerol. Collectively, the results reveal broad evidence for long-term hypoxia-induced metabolic reprogramming and phenotypic transformations in the pulmonary arteries of fetal sheep, conditions that likely contribute to the development of persistent pulmonary hypertension.
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Affiliation(s)
- Eric Leslie
- Department of Health, Exercise, and Sport Sciences, University of New Mexico, Albuquerque, New Mexico
| | - Vanessa Lopez
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California
| | - Nana A O Anti
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California
| | - Rafael Alvarez
- Center for Health Disparities and Molecular Mechanisms, Loma Linda University School of Medicine, Loma Linda, California
| | - Isaac Kafeero
- Center for Health Disparities and Molecular Mechanisms, Loma Linda University School of Medicine, Loma Linda, California
| | - Donald G Welsh
- Robarts Research Institute, Western University, London, Ontario, Canada
| | - Monica Romero
- Advanced Imaging and Microscopy Core, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California
| | - Shawn Kaushal
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California
| | - Catherine M Johnson
- Department of Food Science and Nutrition, California Polytechnic State University, San Luis Obispo, California
| | - Remy Bosviel
- NIH West Coast Metabolomics Center, Genome Center, University of California, Davis, California
| | - Ivana Blaženović
- NIH West Coast Metabolomics Center, Genome Center, University of California, Davis, California
| | - Rui Song
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California
| | - Alex Brito
- Laboratory of Pharmacokinetics and Metabolomic Analysis, Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.,World-Class Research Center "Digital biodesign and personalized healthcare," I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Michael R La Frano
- Department of Food Science and Nutrition, California Polytechnic State University, San Luis Obispo, California.,Center for Health Research, California Polytechnic State University, San Luis Obispo, California.,Cal Poly Metabolomics Service Center, California Polytechnic State University, San Luis Obispo, California
| | - Lubo Zhang
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California
| | - John W Newman
- NIH West Coast Metabolomics Center, Genome Center, University of California, Davis, California.,Department of Nutrition, University of California, Davis, California.,USDA-ARS Western Human Nutrition Research Center, Davis, California
| | - Oliver Fiehn
- NIH West Coast Metabolomics Center, Genome Center, University of California, Davis, California.,West Coast Metabolomics Center, University of California, Davis, California
| | - Sean M Wilson
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California.,Advanced Imaging and Microscopy Core, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California
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31
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Wang T, Han Y, Li H, Wang Y, Xue T, Chen X, Chen W, Fan Y, Qiu X, Gong J, Xu Y, Wang J, Li W, Zhu T. Changes in bioactive lipid mediators in response to short-term exposure to ambient air particulate matter: A targeted lipidomic analysis of oxylipin signaling pathways. ENVIRONMENT INTERNATIONAL 2021; 147:106314. [PMID: 33326904 DOI: 10.1016/j.envint.2020.106314] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 11/13/2020] [Accepted: 11/25/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND Exposure to ambient air particulate matter (PM) is a risk factor for cardiometabolic diseases. The knowledge of the underlying mechanisms is still evolving, but systemic inflammation and oxidative stress are central to the ability of PM to induce cardiometabolic effects. Oxylipins derived from polyunsaturated fatty acids (PUFAs) are bioactive lipid mediators that have fundamental roles in the signaling of inflammatory events. However, the associations between oxylipins and short-term exposure to PM in humans are unknown. METHODS Using targeted lipidomic analyses, we measured 16 oxylipins derived from lipoxygenase (LOX), cytochrome P450 (CYP), and cyclooxygenase (COX) pathways and their parent PUFAs in serum samples of 110 adults enrolled in a panel study in Beijing, China. Each participant completed 2-7 clinical visits from 2013 to 2015. PM with aerodynamic diameter ≤ 2.5 μm (PM2.5) and ≤ 0.1 μm (ultrafine particles, UFPs) were continuously monitored at a station. Linear mixed-effects models were applied to examine the associations between changes in lipid mediators and exposure to ambient PM during the preceding 1 to 3 days before the clinical visit. RESULTS Serum concentrations of PUFAs, including omega-6 arachidonic acid (ARA) and omega-3 eicosapentaenoic acid (EPA), were significantly increased in association with interquartile range (IQR) increases in PM with different exposure windows (i.e., 1-3 days). Regarding oxylipins, significant PM-associated changes included increases in LOX-derived leukotriene B4 (LTB4), 12(S)-, 15(S)-hydroxyeicosatetraenoic acid (HETE), 12-hydroxyeicosapentaenoic acid (HEPE), and 17-hydroxydocosahexaenoic acid (HDHA); an increase in CYP-derived 5,6-dihydroxyeicosatrienoic acid (DHET); and a decrease in COX-derived prostaglandin E2. CONCLUSIONS Short-term exposure to PM was associated with PUFAs and oxylipins derived from LOX, CYP, and COX pathways in humans. Our findings provide mechanistic insight suggesting bioactive oxylipins might be used as biomarkers and have important implications as mediators of PM-associated systemic cardiometabolic effects.
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Affiliation(s)
- Teng Wang
- BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China.
| | - Yiqun Han
- BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China; Environmental Research Group, MRC Centre for Environment and Health, Imperial College London, London, UK.
| | - Haonan Li
- BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China.
| | - Yanwen Wang
- BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China; National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China.
| | - Tao Xue
- Institute of Reproductive and Child Health/Ministry of Health Key Laboratory of Reproductive Health and Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
| | - Xi Chen
- BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China; GRiC, Shenzhen Institute of Building Research Co., Ltd., Shenzhen, China.
| | - Wu Chen
- BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China.
| | - Yunfei Fan
- BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China.
| | - Xinghua Qiu
- BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China.
| | - Jicheng Gong
- BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China.
| | - Yifan Xu
- BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China.
| | - Junxia Wang
- BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China.
| | - Weiju Li
- Peking University Hospital, Peking University, Beijing, China.
| | - Tong Zhu
- BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China.
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Sezin T, Ferreirós N, Jennrich M, Ochirbold K, Seutter M, Attah C, Mousavi S, Zillikens D, Geisslinger G, Sadik CD. 12/15-Lipoxygenase choreographs the resolution of IgG-mediated skin inflammation. J Autoimmun 2020; 115:102528. [DOI: 10.1016/j.jaut.2020.102528] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 07/11/2020] [Accepted: 07/22/2020] [Indexed: 12/31/2022]
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Assessing the safety of transarterial locoregional delivery of low-density lipoprotein docosahexaenoic acid nanoparticles to the rat liver. Eur J Pharm Biopharm 2020; 158:273-283. [PMID: 33242579 DOI: 10.1016/j.ejpb.2020.10.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 09/14/2020] [Accepted: 10/25/2020] [Indexed: 11/22/2022]
Abstract
Hepatic-arterial infusion (HAI) of low-density lipoprotein (LDL) nanoparticles reconstituted with docosahexaenoic acid (DHA) (LDL-DHA) has been shown in a rat hepatoma model to be a promising treatment for hepatocellular carcinoma. To date, little is known regarding the safety of HAI of LDL-DHA to the liver. Therefore, we aimed to investigate the deposition, metabolism and safety of HAI of LDL-DHA (2, 4 or 8 mg/kg) in the rat. Following HAI, fluorescent labeled LDL nanoparticles displayed a biexponential plasma concentration time curve as the particles were rapidly extracted by the liver. Overall, increasing doses of HAI of LDL-DHA was well tolerated in the rat. Body weight, plasma biochemistry and histology were all unremarkable and molecular markers of inflammation did not increase with treatment. Lipidomics analyses showed that LDL-DHA was preferentially oxidized to the anti-inflammatory mediator, protectin DX. We conclude that HAI of LDL-DHA nanoparticles is not only safe, but provides potential hepatoprotective benefits.
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Rosa Velazquez M, Batistel F, Pinos Rodriguez JM, Relling AE. Effects of maternal dietary omega-3 polyunsaturated fatty acids and methionine during late gestation on fetal growth, DNA methylation, and mRNA relative expression of genes associated with the inflammatory response, lipid metabolism and DNA methylation in placenta and offspring's liver in sheep. J Anim Sci Biotechnol 2020; 11:111. [PMID: 33292515 PMCID: PMC7672917 DOI: 10.1186/s40104-020-00513-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 09/15/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Omega-3 PUFA or methionine (Met) supply during gestation alters offspring physiology. However, the effect of both nutrients on fetal development has not been explored. Our objective was to determine the effects of supplementation of these two nutrients during late gestation on fetal growth, DNA methylation, and mRNA expression of genes associated with the inflammatory response, and DNA methylation. Ewes (n = 5/treatment) were fed from day 100 to 145 of gestation one of the following treatments: 1) basal diet (NS) without fatty acids (FS) or methionine (MS) supplementation; 2) FS (10 g/kg Ca salts, source omega-3 PUFA); 3) MS (1 g/kg rumen protected methionine); and 4) FS and MS (FS-MS). On day 145, ewes were euthanized, and data from dams and fetus was recorded. Placenta (cotyledon), fetal liver, and blood samples were collected. RESULTS A treatments interaction on fetal liver weight, ewe body weight and body condition score (BCS) was observed; FS-MS were heavier (P < 0.01) than FS and MS, and FS-MS ewes had a better (P = 0.02) BCS than NS. Methionine increased (P = 0.03) ewe plasma glucose concentration. Fetal liver global DNA methylation increased (P < 0.01) in FS and MS. Dietary treatments modify the mRNA relative expression on some of the genes evaluated. In the fetal liver, FS increased (P = 0.04) the mRNA relative expression of arachidonate-5-lipoxygenase-activating-protein and tended to decrease (P = 0.06) methionine-adenosyltransferase-1A. Moreover, MS decreased (P = 0.04) DNA-methyltransferase-1 and tended to decrease (P = 0.08) free-fatty-acid-receptor-1 mRNA relative expression. Furthermore, FS-MS decreased mRNA relative expression of tumor-necrosis-factor-alpha (P = 0.05), peroxisome-proliferator-activated-receptor-delta (P = 0.03) and gamma (P = 0.04), tended to decrease (P ≤ 0.09) interleukin-6, fatty-acid-transport-protein-1, and delta-5-desaturase, and increased adenosylhomocysteinase (P = 0.04) mRNA relative expression. In cotyledon, FS tended to decrease fatty acid binding protein 4 (P = 0.09) mRNA relative expression. CONCLUSION Omega-3 PUFA and Met supplementation improves dam's performance in late gestation, which was positively correlated with an increase in offspring's liver development. Moreover, FS-MS decreased mRNA relative expression of proinflammatory cytokines, and lipogenic genes, and increased the expression on an enzyme that has an important role in methylation.
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Affiliation(s)
- Milca Rosa Velazquez
- Facultad de Medicina Veterinaria y Zootecnia, Universidad Veracruzana, 91710, Veracruz, Mexico.,Department of Animal Science, Ohio Agricultural Research and Development Center (OARDC), The Ohio State University, 114 Gerlaugh Hall, 1680 Madison Ave, Wooster, OH, 44691, USA
| | - Fernanda Batistel
- Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, 84322, USA
| | | | - Alejandro Enrique Relling
- Department of Animal Science, Ohio Agricultural Research and Development Center (OARDC), The Ohio State University, 114 Gerlaugh Hall, 1680 Madison Ave, Wooster, OH, 44691, USA.
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Wang Y, Li J, Subramaniyan I, do Vale GD, Chaudhary J, Anwar A, Wight-Carter M, McDonald JG, Putnam WC, Qin T, Zhang H, Corbin IR. An implanted port-catheter system for repeated hepatic arterial infusion of low-density lipoprotein-docosahexaenoic acid nanoparticles in normal rats: A safety study. Toxicol Appl Pharmacol 2020; 400:115037. [PMID: 32417438 DOI: 10.1016/j.taap.2020.115037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 04/27/2020] [Accepted: 05/09/2020] [Indexed: 11/25/2022]
Abstract
BACKGROUND In recent years, small animal arterial port-catheter systems have been implemented in rodents with reasonable success. The aim of the current study is to employ the small animal port-catheter system to evaluate the safety of multiple hepatic-artery infusions (HAI) of low-density lipoprotein-docosahexaenoic acid (LDL-DHA) nanoparticles to the rat liver. METHODS Wistar rats underwent surgical placement of indwelling HAI ports. Repeated administrations of PBS or LDL-DHA nanoparticles were performed through the port at baseline and days 3 and 6. Rats were sacrificed on day 9 at which point blood and various organs were collected for histopathology and biochemical analyses. RESULTS The port-catheter systems were implanted successfully and repeated infusions of PBS or LDL-DHA nanoparticles were tolerated well by all animals over the duration of the study. Measurements of serum liver/renal function tests, glucose and lipid levels did not differ between control and LDL-DHA treated rats. The liver histology was unremarkable in the LDL-DHA treated rats and the expression of hepatic inflammatory regulators (NF-κβ, IL-6 and CRP) were similar to control rats. Repeated infusions of LDL-DHA nanoparticles did not alter liver glutathione content or the lipid profile in the treated rats. The DHA extracted by the liver was preferentially metabolized to the anti-inflammatory DHA-derived mediator, protectin DX. CONCLUSION Our findings indicate that repeated HAI of LDL-DHA nanoparticles is not only well tolerated and safe in the rat, but may also be protective to the liver.
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Affiliation(s)
- Yuzhu Wang
- Department of Hepatobiliary and pancreatic surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, China; Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
| | - Junjie Li
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
| | - Indhumathy Subramaniyan
- Department of Pharmaceutical Sciences, Department of Pharmacy Practice within the Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, TX 75235, USA
| | | | - Jaideep Chaudhary
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
| | - Arnida Anwar
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
| | | | | | - William C Putnam
- Department of Pharmaceutical Sciences, Department of Pharmacy Practice within the Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, TX 75235, USA
| | - Tao Qin
- Department of Hepatobiliary and pancreatic surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, China
| | - Hongwei Zhang
- Department of Hepatobiliary and pancreatic surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, China
| | - Ian R Corbin
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Internal Medicine Division of Liver and Digestive Diseases, Dallas, TX 75390, USA; RadiologyUniversity of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
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Wang F, Huang S, Xia H, Yao S. Specialized pro-resolving mediators: It's anti-oxidant stress role in multiple disease models. Mol Immunol 2020; 126:40-45. [PMID: 32750537 DOI: 10.1016/j.molimm.2020.07.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 07/13/2020] [Accepted: 07/23/2020] [Indexed: 12/20/2022]
Abstract
Oxidative stress-related injury is a negative state caused by the imbalance between oxidation and antioxidant effects in the internal environment of the body. Oxidative stress has been confirmed to be an important factor in aging and a variety of diseases and the inhibition of inappropriate oxidative stress responses are important for maintaining normal physiological functions. Recently, considerable attention has been focused on specialized pro-resolving mediators(SPMs). SPMs are endogenous mediators derived from polyunsaturated fatty acids, which have multiple protective effects such as anti-inflammation, pro-resolution, and promoting tissue damage repair, etc. Moreover, the role of SPMs on oxidative stress has been extensively researched and provides a possible treatment method. In the current study, we review the positive role of SPMs in oxidative stress-related disease and outline the possible involved mechanism, thus providing the theoretical support for a better understanding of the roles of SPMs in oxidative stress and the theoretical basis for finding targets for the oxidative stress-related diseases.
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Affiliation(s)
- Fuquan Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shiqian Huang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Haifa Xia
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Shanglong Yao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Mariqueo TA, Zúñiga-Hernández J. Omega-3 derivatives, specialized pro-resolving mediators: Promising therapeutic tools for the treatment of pain in chronic liver disease. Prostaglandins Leukot Essent Fatty Acids 2020; 158:102095. [PMID: 32450460 DOI: 10.1016/j.plefa.2020.102095] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/02/2020] [Accepted: 03/23/2020] [Indexed: 12/12/2022]
Abstract
The main causes of liver injury are associated with inflammation and permanent damage. They can cause chronic liver disease (CLD), which is mainly related to viral hepatitis, alcohol consumption and non-alcoholic steatohepatitis, leading to fibrosis, cirrhosis and hepatocellular carcinoma. These conditions prevent the liver from working normally and make it begin to fail, which in turn may prompt a liver transplant. CLD and cirrhosis are the eleventh cause of death worldwide. At present, there are no approved pharmacological treatments to prevent, treat or resolve liver fibrosis. The prevalence of pain in the hepatic disease is elevated with ranges between 30% and 40%. Most of the pain drugs require hepatic function; therefore, the suitable control of pain is still a clinical challenge. Specialized pro-resolving mediators (SPM): lipoxins, resolvins, protectins and maresins, are potent endogenous molecules (nM concentrations) that modulate inflammatory body responses by reducing neutrophil infiltration, macrophage activity and pain sensitization. SPM have anti-inflammatory properties, stimulate tissue resolution, repair and regeneration, and exhibit anti-nociceptive actions. Furthermore, SPM were tried on different cellular, animal models and human observational data of liver injury, improving the pathogenesis of inflammation and fibrosis. In the present work, we will describe recent evidence that suggests that SPM can be used as a therapeutic option for CLD. Additionally, we will examine the role of SPM in the control of pain in pathologies associated with liver injury.
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Affiliation(s)
- T A Mariqueo
- Centro de Investigaciones Medicas, Escuela de Medicina, Universidad de Talca, Talca, Chile
| | - J Zúñiga-Hernández
- Centro de Investigaciones Medicas, Escuela de Medicina, Universidad de Talca, Talca, Chile.
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Sharma T, Mandal CC. Omega-3 fatty acids in pathological calcification and bone health. J Food Biochem 2020; 44:e13333. [PMID: 32548903 DOI: 10.1111/jfbc.13333] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 05/21/2020] [Accepted: 05/21/2020] [Indexed: 01/19/2023]
Abstract
Omega-3 fatty acids (ω-3FAs) such as Docosahexaenoic acid (DHA) and Eicosapentanoic acid (EPA), are active ingredient of fish oil, which have larger health benefits against various diseases including cardiovascular, neurodegenerative, cancers and bone diseases. Substantial studies documented a preventive role of omega-3 fatty acids in pathological calcification like vascular calcification and microcalcification in cancer tissues. In parallel, these fatty acids improve bone quality probably by preventing bone decay and augmenting bone mineralization. This study also addresses that the functions of ω-3FAs not only depend on tissue types, but also work through different molecular mechanisms for preventing pathological calcification in various tissues and improving bone health. PRACTICAL APPLICATIONS: Practical applications of the current study are to improve the knowledge about the supplementation of omega-3 fatty acids. This study infers that supplementation of omega-3 fatty acids aids in bone preservation in elder females at the risk of osteoporosis and also, on the contrary, omega-3 fatty acids interfere with pathological calcification of vascular cells and cancer cells. Omega-3 supplementation should be given to the cardiac patients because of its cardio protective role. In line with this, omega-3 supplementation should be included with chemotherapy for cancer patients as it can prevent osteoblastic potential of breast cancer patients, responsible for pathological mineralization, and blocks off target toxicities. Administration of omega-3 fatty acid with chemotherapy will not only improve survival of cancer patients, but also improve the bone quality. Thus, this study allows a better understanding on omega-3 fatty acids in combating pathological complications such as osteoporosis, vascular calcification, and breast microcalcification.
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Affiliation(s)
- Tanu Sharma
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, India
| | - Chandi C Mandal
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, India
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39
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Brown LH, Mutch DM. Mechanisms underlying N3-PUFA regulation of white adipose tissue endocrine function. Curr Opin Pharmacol 2020; 52:40-46. [PMID: 32504953 DOI: 10.1016/j.coph.2020.04.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/27/2020] [Accepted: 04/28/2020] [Indexed: 12/11/2022]
Abstract
Omega-3 polyunsaturated fatty acids (N3-PUFA) are widely reported to improve obesity-associated metabolic impairments, in part, through the regulation of adipokine and cytokine secretion from white adipose tissue (WAT). However, the precise underlying molecular mechanisms by which N3-PUFA influence WAT endocrine function remain poorly described. Available evidence supports that N3-PUFA and related bioactive lipid mediators regulate several intracellular pathways that converge on two important transcription factors: PPAR-γ and NF-κB. Further, N3-PUFA signaling through GPR120 appears integral for the regulation of adipokine and cytokine production. This review collates insights from in vitro and in vivo studies using genetic and chemical inhibition of key signaling proteins to describe the pathways by which N3-PUFA regulate WAT endocrine function. Existing gaps in knowledge and opportunities to advance our understanding in this area are also highlighted.
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Affiliation(s)
- Liam H Brown
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - David M Mutch
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
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40
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von Hegedus JH, Kahnt AS, Ebert R, Heijink M, Toes REM, Giera M, Ioan-Facsinay A. Toll-like receptor signaling induces a temporal switch towards a resolving lipid profile in monocyte-derived macrophages. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158740. [PMID: 32447052 DOI: 10.1016/j.bbalip.2020.158740] [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: 11/11/2019] [Revised: 05/11/2020] [Accepted: 05/13/2020] [Indexed: 12/20/2022]
Abstract
Inflammation is a tightly regulated process. During the past decade it has become clear that the resolution of inflammation is an active process and its dysregulation can contribute to chronic inflammation. Several cells and soluble mediators, including lipid mediators, regulate the course of inflammation and its resolution. It is, however, unclear which signals and cells are involved in initiating the resolution process. Macrophages are tissue resident cells and key players in regulating tissue inflammation through secretion of soluble mediators, including lipids. We hypothesize that persistent inflammatory stimuli can initiate resolution pathways in macrophages. In this study, we detected 21 lipids in LPS-stimulated human monocyte-derived macrophages by liquid chromatography coupled to tandem mass spectrometry. Cyclooxygenase-derived Prostaglandins were observed in the first six hours of stimulation. Interestingly, a switch towards 15-lipoxygenase products, such as the pro-resolving lipid precursors 15-HEPE and 17-HDHA was observed after 24 h. The RNA and protein expression of cyclooxygenase and 15-lipoxygenase were in line with this trend. Treatment with 17-HDHA increased IL-10 production of monocyte-derived macrophages and decreased LTB4 production by neutrophils, indicating the anti-inflammatory property of this lipid. These data reveal that monocyte-derived macrophages contribute to the resolution of inflammation in time by the production of pro-resolving lipids after an initial inflammatory stimulus.
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Affiliation(s)
| | - Astrid S Kahnt
- Institute of Pharmaceutical Chemistry/ZAFES, Goethe University, Frankfurt/Main, Germany
| | - Roland Ebert
- Institute of Pharmaceutical Chemistry/ZAFES, Goethe University, Frankfurt/Main, Germany
| | - Marieke Heijink
- Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, the Netherlands
| | - Rene E M Toes
- Leiden University Medical Center, Department of Rheumatology, Leiden, the Netherlands
| | - Martin Giera
- Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, the Netherlands
| | - Andreea Ioan-Facsinay
- Leiden University Medical Center, Department of Rheumatology, Leiden, the Netherlands
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Shoieb SM, El-Ghiaty MA, Alqahtani MA, El-Kadi AO. Cytochrome P450-derived eicosanoids and inflammation in liver diseases. Prostaglandins Other Lipid Mediat 2020; 147:106400. [DOI: 10.1016/j.prostaglandins.2019.106400] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 10/08/2019] [Accepted: 11/12/2019] [Indexed: 02/08/2023]
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Samra YA, Hamed MF, El-Sheakh AR. Hepatoprotective effect of allicin against acetaminophen-induced liver injury: Role of inflammasome pathway, apoptosis, and liver regeneration. J Biochem Mol Toxicol 2020; 34:e22470. [PMID: 32040233 DOI: 10.1002/jbt.22470] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 11/02/2019] [Accepted: 01/31/2020] [Indexed: 12/25/2022]
Abstract
Acetaminophen (APAP) overdose leads to liver injury. NLRP3 inflammasome is a key player in APAP-induced inflammation. Also, apoptosis and liver regeneration play an important role in liver injury. Therefore, we assessed allicin's protective effect on APAP-induced hepatotoxicity and studied its effect on NLRP3 inflammasome and apoptosis. Mice in the APAP group were injected by APAP (250 mg/kg, intraperitoneal). The allicin-treated group received allicin orally (10 mg/kg/d) during 7 days before APAP injection. Serum and hepatic tissues were separated 24 hours after APAP injection. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, alkaline phosphatase (ALP), and hepatic malondialdehyde (MDA) were assessed using the colorimetric method. Hepatic NLRP3 inflammasome, caspase-1, and interleukin-1β (IL-1β) were estimated using enzyme-linked immunosorbent assay. Hepatic Bcl-2 and Ki-67 were investigated by immunohistochemistry. APAP significantly increased AST, ALT, and ALP, whereas allicin significantly decreased their levels. Also, APAP significantly decreased albumin and allicin significantly improved it. APAP produced changes in liver morphology, including inflammation and massive coagulative necrosis. Allicin protected the liver from APAP-induced necrosis, apoptosis, and hepatocellular degeneration via increasing Bcl-2 and Ki-67 levels. APAP significantly increased the hepatic MDA, whereas allicin significantly prevented this increase. APAP markedly activated the NLRP3 inflammasome pathway and consequently increased the production of caspase-1 and IL-1β. Interestingly, we found that allicin significantly inhibited NLRP3 inflammasome activation, which resulted in decreased caspase-1 and IL-1β levels. Allicin has a hepatoprotective effect against APAP-induced liver injury via the decline of oxidative stress and inhibition of the inflammasome pathway and apoptosis. Therefore, allicin might be a novel tool to halt the progression of APAP-stimulated hepatotoxicity.
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Affiliation(s)
- Yara A Samra
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Mohamed F Hamed
- Department of Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmed R El-Sheakh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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A Nutraceutical Rich in Docosahexaenoic Acid Improves Portal Hypertension in a Preclinical Model of Advanced Chronic Liver Disease. Nutrients 2019; 11:nu11102358. [PMID: 31623374 PMCID: PMC6835927 DOI: 10.3390/nu11102358] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/25/2019] [Accepted: 09/29/2019] [Indexed: 02/06/2023] Open
Abstract
Inflammation and oxidative stress play a key role in the pathophysiology of advanced chronic liver disease (ACLD) and portal hypertension (PH). Considering the current lack of effective treatments, we evaluated an anti-inflammatory and antioxidant nutraceutical rich in docosahexaenoic acid (DHA) as a possible therapy for ACLD. We investigated the effects of two-week DHA supplementation (500 mg/kg) on hepatic fatty acids, PH, oxidative stress, inflammation, and hepatic stellate cell (HSC) phenotype in rats with ACLD. Additionally, the effects of DHA were evaluated in murine macrophages and human HSC. In contrast to vehicle-treated animals, cirrhotic rats receiving DHA reestablished a healthy hepatic fatty acid profile, which was associated with an improvement in PH. The mechanisms underlying this hemodynamic improvement included a reduction in oxidative stress and inflammation, as well as a marked HSC deactivation, confirmed in human HSC. Experiments with cultured macrophages showed that treatment with DHA protects against pro-inflammatory insults. The present preclinical study demonstrates that a nutraceutical rich in DHA significantly improves PH in chronic liver disease mainly by suppressing inflammation and oxidative stress-driven HSC activation, encouraging its evaluation as a new treatment for PH and cirrhosis.
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Morris JK, Piccolo BD, John CS, Green ZD, Thyfault JP, Adams SH. Oxylipin Profiling of Alzheimer's Disease in Nondiabetic and Type 2 Diabetic Elderly. Metabolites 2019; 9:metabo9090177. [PMID: 31491971 PMCID: PMC6780570 DOI: 10.3390/metabo9090177] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 08/27/2019] [Accepted: 09/03/2019] [Indexed: 01/02/2023] Open
Abstract
Oxygenated lipids, called “oxylipins,” serve a variety of important signaling roles within the cell. Oxylipins have been linked to inflammation and vascular function, and blood patterns have been shown to differ in type 2 diabetes (T2D). Because these factors (inflammation, vascular function, diabetes) are also associated with Alzheimer’s disease (AD) risk, we set out to characterize the serum oxylipin profile in elderly and AD subjects to understand if there are shared patterns between AD and T2D. We obtained serum from 126 well-characterized, overnight-fasted elderly individuals who underwent a stringent cognitive evaluation and were determined to be cognitively healthy or AD. Because the oxylipin profile may also be influenced by T2D, we assessed nondiabetic and T2D subjects separately. Within nondiabetic individuals, cognitively healthy subjects had higher levels of the nitrolipid 10-nitrooleate (16.8% higher) compared to AD subjects. AD subjects had higher levels of all four dihydroxyeicosatrienoic acid (DiHETrE) species: 14,15-DiHETrE (18% higher), 11,12 DiHETrE (18% higher), 8,9-DiHETrE (23% higher), and 5,6-DiHETrE (15% higher). Within T2D participants, we observed elevations in 14,15-dihydroxyeicosa-5,8,11-trienoic acid (14,15-DiHETE; 66% higher), 17,18-dihydroxyeicosa-5,8,11,14-tetraenoic acid (17,18-DiHETE; 29% higher) and 17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid (17-HDoHE; 105% higher) and summed fatty acid diols (85% higher) in subjects with AD compared to cognitively healthy elderly, with no differences in the DiHETrE species between groups. Although these effects were no longer significant following stringent adjustment for multiple comparisons, the consistent effects on groups of molecules with similar physiological roles, as well as clear differences in the AD-related profiles within nondiabetic and T2D individuals, warrant further research into these molecules in the context of AD.
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Affiliation(s)
- Jill K Morris
- Department of Neurology, University of Kansas Alzheimer's Disease Center, Kansas City, KS 66205, USA.
- University of Kansas Alzheimer's Disease Center, Fairway, KS 66205, USA.
| | - Brian D Piccolo
- Arkansas Children's Nutrition Center, Little Rock, AR 72205, USA.
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Casey S John
- Department of Neurology, University of Kansas Alzheimer's Disease Center, Kansas City, KS 66205, USA.
- University of Kansas Alzheimer's Disease Center, Fairway, KS 66205, USA.
| | - Zachary D Green
- University of Kansas Alzheimer's Disease Center, Fairway, KS 66205, USA.
| | - John P Thyfault
- Department of Molecular and Integrative Physiology, University of Kansas, Kansas City, KS 66045, USA.
- Kansas City VA Medical Center, Kansas City, MO 64128, USA.
| | - Sean H Adams
- Arkansas Children's Nutrition Center, Little Rock, AR 72205, USA.
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
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He J, Hong B, Bian M, Jin H, Chen J, Shao J, Zhang F, Zheng S. Docosahexaenoic acid inhibits hepatic stellate cell activation to attenuate liver fibrosis in a PPARγ-dependent manner. Int Immunopharmacol 2019; 75:105816. [PMID: 31437794 DOI: 10.1016/j.intimp.2019.105816] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 07/16/2019] [Accepted: 08/09/2019] [Indexed: 12/13/2022]
Abstract
Docosahexaenoic acid (DHA) has been found to have a hepatoprotective effect. In this study, we investigated the role of peroxisome proliferator-activated receptor γ (PPARγ) in DHA regulation of liver fibrosis. DHA was found to inhibit hepatic stellate cell (HSC)-LX2 cell viability and downregulate marker proteins of HSC activation. Furthermore, DHA induced cell cycle arrest at G1 phase in HSCs. Antagonism of PPARγ by GW9662 abrogated the effects of DHA on HSCs. Computer-aided molecular docking predicted that DHA bound to PPARγ via hydrogen bonding with residues Ser289, His323, Tyr473, and His499. We overexpressed Ser289 mutant PPARγ in HSC-LX2 cells and investigated fibrotic marker modulation, and found that DHA effects on HSCs were diminished. Thus, bonding with the Ser289 residue might be indispensable for DHA to activate PPARγ to exert its inhibiting effect on activated HSCs. Last, data from a CCl4-treated mouse model confirmed that PPARγ activation was required for DHA to attenuate liver fibrosis.
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Affiliation(s)
- Jianlin He
- Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, PR China; Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, PR China
| | - Bihong Hong
- Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, PR China
| | - Mianli Bian
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, PR China
| | - Huanhuan Jin
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, PR China; Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu 241000, PR China
| | - Junde Chen
- Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, PR China
| | - Jiangjuan Shao
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, PR China
| | - Feng Zhang
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, PR China.
| | - Shizhong Zheng
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, PR China.
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Fernández-Martínez E, Lira-Islas IG, Cariño-Cortés R, Soria-Jasso LE, Pérez-Hernández E, Pérez-Hernández N. Dietary chia seeds (Salvia hispanica) improve acute dyslipidemia and steatohepatitis in rats. J Food Biochem 2019; 43:e12986. [PMID: 31489674 DOI: 10.1111/jfbc.12986] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 06/27/2019] [Accepted: 06/30/2019] [Indexed: 02/06/2023]
Abstract
Chia seeds (Salvia hispanica L.) are rich in omega fatty acids. Dyslipidemia and steatohepatitis are diseases that require effective treatments in obese and non-obese patients. The aim was to evaluate the effect of chia intake on acute tyloxapol (TI)-induced dyslipidemia, on acute carbon tetrachloride (TC)-induced steatohepatitis, and on mixed damage (TC+TI) in non-obese rats. Four experimental groups were fed for 4 weeks a diet with established rodent food (DE), and four groups were fed a diet with 15% added chia (DC). Plasma samples were analyzed for total cholesterol, triglycerides, glucose, biochemical liver damage markers, and tumor necrosis factor-α (TNF-α). Liver samples were used to quantify glycogen, catalase, lipid peroxidation, and TNF-α. A histopathological analysis was performed. DC intake partially or totally prevented steatohepatitis, and reduced lipids in the dyslipidemic groups. The hypolipidemic and hepatoprotective effects of chia may be correlated to its high content of α-linolenic acid (omega-3) and phenolics. PRACTICAL APPLICATIONS: Metabolic syndrome is associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which are currently the most common causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. Dyslipidemia is a significant risk factor for NAFLD and NASH. Non-obese patients may have NAFLD or NASH. Metabolic syndrome and dyslipidemia are more strongly associated with NAFLD in non-obese than in obese patients. This is the first study evaluating the hypolipidemic and hepatoprotective effects of chia seed intake on acute dyslipidemia and/or steatohepatitis caused by the individual or combined administration of the inducers tyloxapol and carbon tetrachloride, respectively, in non-obese rats. The pharmacological effects of dietary chia are correlated to its high content of omega-3 and omega-6 (1:1), protein, dietary fiber, and phenolics. The results suggest that inclusion of chia in diets of non-obese patients with dyslipidemia and/or NAFLD/NASH may improve their health state and preventing cirrhosis or HCC.
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Affiliation(s)
- Eduardo Fernández-Martínez
- Laboratory of Medicinal Chemistry and Pharmacology, Centro de Investigación en Biología de la Reproducción, Área Académica de Medicina, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca, México
| | - Ivet G Lira-Islas
- Laboratory of Medicinal Chemistry and Pharmacology, Centro de Investigación en Biología de la Reproducción, Área Académica de Medicina, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca, México
| | - Raquel Cariño-Cortés
- Laboratory of Medicinal Chemistry and Pharmacology, Centro de Investigación en Biología de la Reproducción, Área Académica de Medicina, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca, México
| | - Luis E Soria-Jasso
- Laboratory of Medicinal Chemistry and Pharmacology, Centro de Investigación en Biología de la Reproducción, Área Académica de Medicina, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca, México
| | | | - Nury Pérez-Hernández
- Programa Institucional de Biomedicina Molecular, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Ciudad de México, México
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Jin A, Shi XC, Deng W, Sun J, Ji H. Ameliorative effect of docosahexaenoic acid on hepatocyte apoptosis and inflammation induced by oleic acid in grass carp, Ctenopharyngodon idella. FISH PHYSIOLOGY AND BIOCHEMISTRY 2019; 45:1091-1099. [PMID: 30903378 DOI: 10.1007/s10695-019-00623-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 02/19/2019] [Indexed: 06/09/2023]
Abstract
Our previous study has shown that overload of lipid accumulation results in cell apoptosis and inflammation in grass carp (Ctenopharyngodon idella). In this study, we investigated the potential protective effects of docosahexaenoic acid (DHA) on inhibiting oleic acid (OA)-induced apoptosis and inflammation in grass carp hepatocytes. Firstly, the hepatocyte of grass carp were treated with OA (800 μM) and different concentration (0, 50, 100 and 200 μM) of DHA for 24 h, the apoptotic ratio, gene expression levels of apoptosis such as caspase 3, caspase 8, and caspase 9, protein levels of Caspase3, and mRNA levels of inflammation genes such as nf-kb, tnf-α, and il-8 were detected. Furthermore, the mRNA levels of lipogenesis genes srebp1c, fas, acc, and scd and a key enzyme of lipolysis Atgl were also detected. These results showed that the cell apoptosis and the inflammation increased by OA were significantly attenuated by DHA (P < 0.05). Furthermore, DHA could significantly decrease fatty acid synthesis gene expression levels which were induced by OA (P < 0.05). However, the hepatocytes exposed with DHA had no significant influence on the expression of Atgl. Taken together, the study indicated that DHA protects the hepatocytes against apoptosis and inflammation induced by OA might via inhibiting fatty acid synthesis, instead of promoting lipolysis. These results call for further studies to assess the effectiveness of DHA.
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Affiliation(s)
- Ai Jin
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, People's Republic of China
| | - Xiao-Chen Shi
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, People's Republic of China
| | - Wei Deng
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, People's Republic of China
| | - Jian Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, People's Republic of China
| | - Hong Ji
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, People's Republic of China.
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Yang J, Fernández-Galilea M, Martínez-Fernández L, González-Muniesa P, Pérez-Chávez A, Martínez JA, Moreno-Aliaga MJ. Oxidative Stress and Non-Alcoholic Fatty Liver Disease: Effects of Omega-3 Fatty Acid Supplementation. Nutrients 2019; 11:E872. [PMID: 31003450 PMCID: PMC6521137 DOI: 10.3390/nu11040872] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/12/2019] [Accepted: 04/15/2019] [Indexed: 02/06/2023] Open
Abstract
Aging is a complex phenomenon characterized by the progressive loss of tissue and organ function. The oxidative-stress theory of aging postulates that age-associated functional losses are due to the accumulation of ROS-induced damage. Liver function impairment and non-alcoholic fatty liver disease (NAFLD) are common among the elderly. NAFLD can progress to non-alcoholic steatohepatitis (NASH) and evolve to hepatic cirrhosis or hepatic carcinoma. Oxidative stress, lipotoxicity, and inflammation play a key role in the progression of NAFLD. A growing body of evidence supports the therapeutic potential of omega-3 polyunsaturated fatty acids (n-3 PUFA), mainly docosahaexenoic (DHA) and eicosapentaenoic acid (EPA), on metabolic diseases based on their antioxidant and anti-inflammatory properties. Here, we performed a systematic review of clinical trials analyzing the efficacy of n-3 PUFA on both systemic oxidative stress and on NAFLD/NASH features in adults. As a matter of fact, it remains controversial whether n-3 PUFA are effective to counteract oxidative stress. On the other hand, data suggest that n-3 PUFA supplementation may be effective in the early stages of NAFLD, but not in patients with more severe NAFLD or NASH. Future perspectives and relevant aspects that should be considered when planning new randomized controlled trials are also discussed.
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Affiliation(s)
- Jinchunzi Yang
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
| | - Marta Fernández-Galilea
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- IDISNA, Navarra's Health Research Institute, 31008 Pamplona, Spain.
| | - Leyre Martínez-Fernández
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
| | - Pedro González-Muniesa
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- IDISNA, Navarra's Health Research Institute, 31008 Pamplona, Spain.
- CIBERobn Physiopathology of Obesity and Nutrition, Centre of Biomedical Research Network, ISCIII, 28029 Madrid, Spain.
| | - Adriana Pérez-Chávez
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
| | - J Alfredo Martínez
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- IDISNA, Navarra's Health Research Institute, 31008 Pamplona, Spain.
- CIBERobn Physiopathology of Obesity and Nutrition, Centre of Biomedical Research Network, ISCIII, 28029 Madrid, Spain.
| | - Maria J Moreno-Aliaga
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- IDISNA, Navarra's Health Research Institute, 31008 Pamplona, Spain.
- CIBERobn Physiopathology of Obesity and Nutrition, Centre of Biomedical Research Network, ISCIII, 28029 Madrid, Spain.
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Hansen TV, Vik A, Serhan CN. The Protectin Family of Specialized Pro-resolving Mediators: Potent Immunoresolvents Enabling Innovative Approaches to Target Obesity and Diabetes. Front Pharmacol 2019; 9:1582. [PMID: 30705632 PMCID: PMC6344435 DOI: 10.3389/fphar.2018.01582] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 12/31/2018] [Indexed: 12/17/2022] Open
Abstract
A western type diet and lifestyle play an important role in the development of chronic diseases, yet little insight into the precise cellular and biomolecular mechanisms has emerged. It is known that an unbalanced diet may result in obesity and diabetes. Sufficient amounts and proper balance of omega-6 and omega-3 polyunsaturated fatty acids is key for maintenance of health. The resolution of inflammation is now held to be a biosynthetically actively driven process precisely regulated and controlled by a superfamily of specialized pro-resolving mediators. Specialized pro-resolving mediators are biosynthesized from both omega-6 and omega-3 polyunsaturated fatty acids and are resolution agonists acting on distinct G-coupled protein receptors. These mediators display potent anti-inflammatory and pro-resolving bioactions with EC50-values in the low nanomolar to picomolar range. The protectin (PD) family of specialized pro-resolving mediators is biosynthesized from the two omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and n–3 docosapentaenoic acid (n–3 DPA). All of the PDs display interesting bioactions as anti-inflammatory and pro-resolving agents. This review covers the bioactions, G-coupled protein receptors pharmacology, biosynthesis, and medicinal chemistry of the PD family of specialized pro-resolving mediators with an emphasis on obesity and anti-diabetic effects. In order to enable drug development and medicinal chemistry efforts against these diseases, stereoselective total organic synthesis of each of these mediators is required for confirmation of structure, stereochemical biosynthesis, and their functions. We provide an overview of our ongoing efforts and the current knowledge.
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Affiliation(s)
- Trond Vidar Hansen
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, Oslo, Norway
| | - Anders Vik
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, Oslo, Norway
| | - Charles N Serhan
- Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, United States
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50
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Enguita M, Razquin N, Pamplona R, Quiroga J, Prieto J, Fortes P. The cirrhotic liver is depleted of docosahexaenoic acid (DHA), a key modulator of NF-κB and TGFβ pathways in hepatic stellate cells. Cell Death Dis 2019; 10:14. [PMID: 30622239 PMCID: PMC6325107 DOI: 10.1038/s41419-018-1243-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 10/15/2018] [Accepted: 10/16/2018] [Indexed: 02/06/2023]
Abstract
Liver cirrhosis results from chronic hepatic damage and is characterized by derangement of the organ architecture with increased liver fibrogenesis and defective hepatocellular function. It frequently evolves into progressive hepatic insufficiency associated with high mortality unless liver transplantation is performed. We have hypothesized that the deficiency of critical nutrients such as essential omega-3 fatty acids might play a role in the progression of liver cirrhosis. Here we evaluated by LC-MS/MS the liver content of omega-3 docosahexaenoic fatty acid (DHA) in cirrhotic patients and investigated the effect of DHA in a murine model of liver injury and in the response of hepatic stellate cells (HSCs) (the main producers of collagen in the liver) to pro-fibrogenic stimuli. We found that cirrhotic livers exhibit a marked depletion of DHA and that this alteration correlates with the progression of the disease. Administration of DHA exerts potent anti-fibrogenic effects in an acute model of liver damage. Studies with HSCs show that DHA inhibits fibrogenesis more intensely than other omega-3 fatty acids. Data from expression arrays revealed that DHA blocks TGFβ and NF-κB pathways. Mechanistically, DHA decreases late, but not early, SMAD3 nuclear accumulation and inhibits p65/RelA-S536 phosphorylation, which is required for HSC survival. Notably, DHA increases ADRP expression, leading to the formation of typical quiescence-associated perinuclear lipid droplets. In conclusion, a marked depletion of DHA is present in the liver of patients with advanced cirrhosis. DHA displays anti-fibrogenic activities on HSCs targeting NF-κB and TGFβ pathways and inducing ADPR expression and quiescence in these cells.
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Affiliation(s)
- Mónica Enguita
- Department of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain.,Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - Nerea Razquin
- Department of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain.,Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - Reinald Pamplona
- Department of Experimental Medicine, University of Lleida (IRB), Lleida, Spain
| | - Jorge Quiroga
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.,Liver Unit, Clínica Universidad de Navarra, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Pamplona, Spain
| | | | - Puri Fortes
- Department of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain. .,Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
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