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Gong Y, Xu R, Gao G, Li S, Liu Y. The role of fatty acid metabolism on B cells and B cell-related autoimmune diseases. Inflamm Res 2025; 74:75. [PMID: 40299047 DOI: 10.1007/s00011-025-02042-3] [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: 02/08/2025] [Revised: 04/08/2025] [Accepted: 04/15/2025] [Indexed: 04/30/2025] Open
Abstract
Fatty acid metabolism plays a critical role in regulating immune cell function, including B cells, which are central to humoral immunity and the pathogenesis of autoimmune diseases. Emerging evidence suggests that fatty acid metabolism influences B cell development, activation, differentiation, and antibody production, thereby impacting B cell-related autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). In this review, we discuss the mechanisms by which fatty acid metabolism modulates B cell biology, including energy provision, membrane composition, and signaling pathways. We highlight how alterations in fatty acid synthesis, oxidation, and uptake affect B cell function and contribute to autoimmune pathogenesis. Additionally, we explore the therapeutic potential of targeting fatty acid metabolism in B cells to treat autoimmune diseases. Understanding the interplay between fatty acid metabolism and B cell immunity may provide novel insights into the development of precision therapies for B cell-mediated autoimmune disorders.
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Affiliation(s)
- Yanmei Gong
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Jinan, Shandong, China
| | - Ruiqi Xu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Jinan, Shandong, China
| | - Guohui Gao
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Jinan, Shandong, China
| | - Simiao Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Jinan, Shandong, China
| | - Ying Liu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Jinan, Shandong, China.
- Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China, China.
- Shandong Provincial Medicine and Health Key Laboratory of Neuroimmunology, Jinan, Shandong, China.
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Ioannidis O, Cheva A, Varnalidis I, Koutelidakis I, Papaziogas V, Christidis P, Anestiadou E, Aggelopoulos K, Mantzoros I, Pramateftakis MG, Kotidis E, Driagka B, Aggelopoulos S, Giamarellos-Bourboulis EJ. The Combined Administration of Eicosapentaenoic Acid (EPA) and Gamma-Linolenic Acid (GLA) in Experimentally Induced Colitis: An Experimental Study in Rats. J Clin Med 2024; 13:6661. [PMID: 39597805 PMCID: PMC11594508 DOI: 10.3390/jcm13226661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 10/11/2024] [Accepted: 10/18/2024] [Indexed: 11/29/2024] Open
Abstract
Background/Objectives: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited effective treatments, prompting the need for investigation of novel therapeutic approaches. Eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) have demonstrated potential anti-inflammatory properties, but their combined effects on UC have not been thoroughly investigated. This study aimed to evaluate the effect of the combined administration of EPA and GLA on clinical and histopathologic features of experimental UC models. Methods: Thirty-six male Wistar rats were randomized in three groups (DSS group, Ensure Plus group, and Oxepa group), with twelve rats in each group. Experimental colitis was induced by administrating dextran sulfate sodium (DSS) 8%. The DSS group received tap water, the Ensure Plus group was given a high caloric diet, and the Oxepa group received a special diet containing high levels of EPA and GLA. Disease activity index (DAI) and microscopic activity index (MAI) were measured. Inflammatory markers were calculated both in blood and large intestine, liver, spleen, and lung tissue samples. Neutrophil and macrophage populations were assessed with immunohistochemistry. Results: No significant differences in the DAI index were found between the groups, but the MAI revealed statistically significant differences (p < 0.001). While no significant differences were observed in tumor necrosis factor-alpha (TNF-α) levels, interleukin-17 (IL-17) levels in the large intestine showed statistically significant differences (p = 0.05), with the Ensure Plus and Oxepa groups displaying lower levels compared to the DSS group (p = 0.021 and p = 0.043, respectively). Significant differences in neutrophil infiltration were found in both the large intestine (p < 0.001) and lungs (p = 0.002), with the Oxepa group showing fewer cells. Similarly, significant differences in macrophage infiltration were observed in the large intestine (p = 0.038) and spleen (p < 0.001), with the Oxepa group having lower macrophage counts. Conclusions: In conclusion, the combination of EPA and GLA demonstrates local anti-inflammatory effects and improves the histopathological outcomes in UC.
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Affiliation(s)
- Orestis Ioannidis
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Angeliki Cheva
- Pathology Department, Faculty of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Ioannis Varnalidis
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Ioannis Koutelidakis
- 2nd Department of Surgery, G.Gennimatas General Hospital, Aristotle University of Thessaloniki, 54635 Thessaloniki, Greece; (I.K.); (V.P.)
| | - Vasileios Papaziogas
- 2nd Department of Surgery, G.Gennimatas General Hospital, Aristotle University of Thessaloniki, 54635 Thessaloniki, Greece; (I.K.); (V.P.)
| | - Panagiotis Christidis
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Elissavet Anestiadou
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Konstantinos Aggelopoulos
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Ioannis Mantzoros
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Manousos George Pramateftakis
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Efstathios Kotidis
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Barbara Driagka
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Stamatios Aggelopoulos
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Evangelos J. Giamarellos-Bourboulis
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens Medical School, “Attikon” Hospital, 12462 Athens, Greece;
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Jia H, Dong N. Effects of bile acid metabolism on intestinal health of livestock and poultry. J Anim Physiol Anim Nutr (Berl) 2024; 108:1258-1269. [PMID: 38649786 DOI: 10.1111/jpn.13969] [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: 09/01/2022] [Revised: 01/27/2024] [Accepted: 04/08/2024] [Indexed: 04/25/2024]
Abstract
Bile acids are synthesised in the liver and are essential amphiphilic steroids for maintaining the balance of cholesterol and energy metabolism in livestock and poultry. They can be used as novel feed additives to promote fat utilisation in the diet and the absorption of fat-soluble substances in the feed to improve livestock performance and enhance carcass quality. With the development of understanding of intestinal health, the balance of bile acid metabolism is closely related to the composition and growth of livestock intestinal microbiota, inflammatory response, and metabolic diseases. This paper systematically reviews the effects of bile acid metabolism on gut health and gut microbiology in livestock. In addition, our paper summarised the role of bile acid metabolism in performance and disease control.
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Affiliation(s)
- Hongpeng Jia
- The Laboratory of Molecular Nutrition and Immunity, Institute of Animal Nutrition, Northeast Agricultural University, Harbin, China
| | - Na Dong
- The Laboratory of Molecular Nutrition and Immunity, Institute of Animal Nutrition, Northeast Agricultural University, Harbin, China
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Wu M, Ge Y, Wang E, Liao Q, Ren Z, Yu Y, Zhu G, Liu C, Zhang M, Su H, Shen H, Chen Y, Wang L, Wang Y, Li M, Bian Z, Chai J, Ye RD, Lu J. Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation. EMBO Mol Med 2023; 15:e17815. [PMID: 37994307 PMCID: PMC10701612 DOI: 10.15252/emmm.202317815] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 10/20/2023] [Accepted: 10/24/2023] [Indexed: 11/24/2023] Open
Abstract
Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation. Here, we report the identification of columbamine (COL) which enhances macrophage-mediated efferocytosis and attenuates intestinal inflammation in a murine colitis model. COL enhances efferocytosis by promoting LC3-associated phagocytosis (LAP), a non-canonical form of autophagy. Transcriptome analysis and pharmacological characterization revealed that COL is a biased agonist that occupies a part of the ligand binding pocket of formyl peptide receptor 2 (FPR2), a G-protein coupled receptor involved in inflammation regulation. Genetic ablation of the Fpr2 gene or treatment with an FPR2 antagonist abolishes COL-induced efferocytosis, anti-colitis activity and LAP. Taken together, our study identifies FPR2 as a potential target for modulating LC3-associated efferocytosis to alleviate intestinal inflammation and highlights the therapeutic value of COL, a natural and biased agonist of FPR2, in the treatment of inflammatory bowel disease.
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Affiliation(s)
- Ming‐Yue Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacau SARChina
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital)Third Military Medical University (Army Medical University)ChongqingChina
| | - Yun‐Jun Ge
- Kobilka Institute of Innovative Drug Discovery, School of MedicineThe Chinese University of Hong KongShenzhenChina
- Department of Basic Medical Science, Wuxi School of MedicineJiangnan UniversityWuxiChina
| | - Er‐Jin Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacau SARChina
| | - Qi‐Wen Liao
- Kobilka Institute of Innovative Drug Discovery, School of MedicineThe Chinese University of Hong KongShenzhenChina
| | - Zheng‐Yu Ren
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacau SARChina
| | - Yang Yu
- Engineering Research Center of Cell and Therapeutic Antibody Medicine, Ministry of Education, School of PharmacyShanghai Jiao Tong UniversityShanghaiChina
| | - Guoyuan Zhu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and HealthMacau University of Science and TechnologyMacau SARChina
| | - Chun‐Ping Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacau SARChina
- Department of Cardiovascular MedicineThe Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhouChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchUniversity of MacauMacau SARChina
| | - Meng‐Ni Zhang
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital)Third Military Medical University (Army Medical University)ChongqingChina
| | - Huanxing Su
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacau SARChina
| | - Han‐Ming Shen
- Faculty of Health SciencesUniversity of MacauMacau SARChina
| | - Ye Chen
- Integrative Microecology Center, Department of Gastroenterology, Shenzhen HospitalSouthern Medical UniversityShenzhen, GuangzhouChina
| | - Lei Wang
- Department of Cardiovascular MedicineThe Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhouChina
| | - Yi‐Tao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacau SARChina
| | - Min Li
- School of Chinese MedicineHong Kong Baptist UniversityHongkong SARChina
| | - Zhaoxiang Bian
- School of Chinese MedicineHong Kong Baptist UniversityHongkong SARChina
| | - Jin Chai
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital)Third Military Medical University (Army Medical University)ChongqingChina
| | - Richard D Ye
- Kobilka Institute of Innovative Drug Discovery, School of MedicineThe Chinese University of Hong KongShenzhenChina
- The Second Affiliated Hospital, School of MedicineThe Chinese University of Hong KongShenzhenChina
| | - Jia‐Hong Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacau SARChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchUniversity of MacauMacau SARChina
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Park SW, Kim DY, Bak GT, Hyun DS, Kim SK. Relation of Dietary n-3 and n-6 Fatty Acid Intakes to Metabolic Syndrome in Middle-Aged People Depending on the Level of HbA1c: A Review of National Health and Nutrition Survey Data from 2014 to 2016. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58081017. [PMID: 36013484 PMCID: PMC9413490 DOI: 10.3390/medicina58081017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/21/2022] [Accepted: 07/25/2022] [Indexed: 11/16/2022]
Abstract
Background and Objectives: The relation of dietary n-6 fatty acid to metabolic syndrome has not been examined and clearly defined. To improve health in the general population, this study was to investigate the role of n-3 and n-6 fatty acids in the reduction in metabolic syndrome and to observe changes in the effects of these fatty acids depending on the level of insulin resistance. Materials and Methods: This cross-sectional study utilized national health and nutrition survey data from 2014 to 2016. From the data, a relation of n-3 and n-6 fatty acid intakes to metabolic syndrome and Hemoglobin A1c (HbA1c)’s role in the relation was evaluated and analyzed for 4852 patients between 40 and 64 years old. Intake frequency of 112 nutrition and daily consumption amounts were identified, and intakes of n-3 and n-4 fatty acids were calculated from this data. Metabolic syndrome was determined for each participant using diagnostic standards for the Asian population published by the National Cholesterol Education Program. Results: Among the total 4852 subjects, 1583 (32.6%) had metabolic syndrome; 736 of 1875 (39.3%) males and 847 of 2977 (28.5%) females had the syndrome. In males, when their HbA1c was low (<5.4%), intakes of both n-3 and n-6 fatty acids were related to a 43−63% decreased prevalence of metabolic syndrome with significance, and a similar negative tendency was also observed in females. On the contrary, for both males and females, no statistically significant correlation was present when HbA1c was high. Conclusion: It was considered that consistent and regular dietary intakes of n-3 and n-6 fatty acids may contribute greatly to prevent or treat metabolic syndrome in healthy males with normal insulin sensitivity, but the effect of their dietary intakes was found to be limited in a group with strong insulin resistance. The conclusion of this study presents a valuable reference and knowledge to provide nutritional education to the general population.
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Affiliation(s)
- Seo-Woo Park
- Department of Preventive Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea; (S.-W.P.); (D.-Y.K.); (G.-T.B.)
| | - Do-Yeong Kim
- Department of Preventive Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea; (S.-W.P.); (D.-Y.K.); (G.-T.B.)
| | - Gyeong-Tae Bak
- Department of Preventive Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea; (S.-W.P.); (D.-Y.K.); (G.-T.B.)
| | - Dae-Sung Hyun
- Department of Preventive Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea; (S.-W.P.); (D.-Y.K.); (G.-T.B.)
- Institute of Occupational and Environmental Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea
- Correspondence: (D.-S.H.); (S.-K.K.)
| | - Sung-Kyung Kim
- Institute of Occupational and Environmental Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea
- Department of Occupational and Environmental Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea
- Correspondence: (D.-S.H.); (S.-K.K.)
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Kikut J, Drozd A, Mokrzycka M, Grzybowska-Chlebowczyk U, Ziętek M, Szczuko M. Are EPA and DHA Derivatives Involved in IBD Remission? J Clin Med 2022; 11:jcm11092388. [PMID: 35566515 PMCID: PMC9104684 DOI: 10.3390/jcm11092388] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/10/2022] [Accepted: 04/22/2022] [Indexed: 12/10/2022] Open
Abstract
Recently, an increase in the incidence of inflammatory bowel disease (IBD) has been observed among children and adolescents. Although the pathogenesis of IBD is not fully elucidated currently, actual research focuses on the occurrence of imbalance between pro- and anti-inflammatory molecules and future identification of the role of cytokines in IBD therapy. The purpose of this study was to compare the concentrations of eicosapentaenoic and docosahexaenoic acid derivatives during both phases of Crohn’s disease (CD) and ulcerative colitis (UC). The study included 64 adolescent patients with CD (n = 34) and UC (n = 30) aged 13.76 ± 2.69 and 14.15 ± 3.31, respectively. Biochemical analysis was performed on a liquid chromatography apparatus. A statistically significant lower concentration of resolvin E1 (RvE1) was observed in the CD group relative to UC. In the active phase of CD, a statistically significantly higher concentration of protectin DX (PDX) was observed relative to remission CD. Comparing the active phase of both diseases, a statistically significantly higher concentration of resolvin E1 (RvE1) was observed in UC relative to CD. Comparing the remission phase of both diseases showed statistically significantly higher PDX levels in CD relative to UC. Our study adds to the knowledge on the involvement of anti-inflammatory lipid mediators in both IBD entities. In conclusion, it seems that the marker differentiating both disease entities in the active phase may be RvE1, while in the remission phase, PDX. In CD remission, the greatest involvement was observed towards PDX, whereas in UC, MaR1, RvE1 and 18RS-HEPE seem to be the most involved in remission.
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Affiliation(s)
- Justyna Kikut
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland; (J.K.); (A.D.)
- Department of Pediatrics, Hemato-Oncology and Pediatric Gastroenterology, Independent Public Clinical Hospital No.1, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland;
| | - Arleta Drozd
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland; (J.K.); (A.D.)
| | - Małgorzata Mokrzycka
- Department of Pediatrics, Hemato-Oncology and Pediatric Gastroenterology, Independent Public Clinical Hospital No.1, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland;
| | - Urszula Grzybowska-Chlebowczyk
- Department of Pediatrics, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, 40-752 Katowice, Poland;
| | - Maciej Ziętek
- Department of Perinatology, Obstetrics and Gynecology, Pomeranian Medical University in Szczecin, 72-010 Police, Poland;
| | - Małgorzata Szczuko
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland; (J.K.); (A.D.)
- Correspondence:
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Abdolmaleki F, Kovanen PT, Mardani R, Gheibi-Hayat SM, Bo S, Sahebkar A. Resolvins: Emerging Players in Autoimmune and Inflammatory Diseases. Clin Rev Allergy Immunol 2020; 58:82-91. [PMID: 31267470 DOI: 10.1007/s12016-019-08754-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Resolvins, belonging to the group of specialized proresolving mediators (SPMs), are metabolic products of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and are synthesized during the initial phases of acute inflammatory responses to promote the resolution of inflammation. Resolvins are produced for termination of neutrophil infiltration, stimulation of the clearance of apoptotic cells by macrophages, and promotion of tissue remodeling and homeostasis. Metabolic dysregulation due to either uncontrolled activity of pro-inflammatory responses or to inefficient resolution of inflammation results in chronic inflammation and may also lead to atherosclerosis or other chronic autoimmune diseases such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, vasculitis, inflammatory bowel diseases, and type 1 diabetes mellitus. The pathogenesis of such diseases involves a complex interplay between the immune system and, environmental factors (non-infectious or infectious), and critically depends on individual susceptibility to such factors. In the present review, resolvins and their roles in the resolution of inflammation, as well as the role of these mediators as potential therapeutic agents to counteract specific chronic autoimmune and inflammatory diseases are discussed.
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Affiliation(s)
- Fereshte Abdolmaleki
- Cellular and Molecular Research Center, School of Paramedical Sciences, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | - Rajab Mardani
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
| | | | - Simona Bo
- Department of Medical Sciences, AOU Città della Salute e della Scienza di Torino, University of Turin, Torino, Italy
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran.
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Keely SJ, Steer CJ, Lajczak-McGinley NK. Ursodeoxycholic acid: a promising therapeutic target for inflammatory bowel diseases? Am J Physiol Gastrointest Liver Physiol 2019; 317:G872-G881. [PMID: 31365646 DOI: 10.1152/ajpgi.00163.2019] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The secondary bile acid ursodeoxycholic acid (UDCA) has long been known to have medicinal properties. As the therapeutically active component of bear bile, it has been used for centuries in traditional Chinese medicine to treat a range of conditions, while manufactured UDCA has been used for decades in Western medicine to treat cholestatic liver diseases. The beneficial qualities of UDCA are thought to be due to its well-established cytoprotective and anti-inflammatory actions. In addition to its established role in treating liver diseases, UDCA is now under investigation for numerous conditions associated with inflammation and apoptosis, including neurological, ocular, metabolic, and cardiovascular diseases. Here, we review the growing evidence base from in vitro and in vivo models to suggest that UDCA may also have a role to play in the therapy of inflammatory bowel diseases.
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Affiliation(s)
- Stephen J Keely
- Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Clifford J Steer
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota Medical School, Minneapolis, Minnesota.,Department of Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Natalia K Lajczak-McGinley
- Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
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The Lipid Status in Patients with Ulcerative Colitis: Sphingolipids are Disease-Dependent Regulated. J Clin Med 2019; 8:jcm8070971. [PMID: 31277430 PMCID: PMC6678307 DOI: 10.3390/jcm8070971] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 06/13/2019] [Accepted: 07/02/2019] [Indexed: 02/06/2023] Open
Abstract
The factors that contribute to the development of ulcerative colitis (UC), are still not fully identified. Disruption of the colon barrier is one of the first events leading to invasion of bacteria and activation of the immune system. The colon barrier is strongly influenced by sphingolipids. Sphingolipids impact cell-cell contacts and function as second messengers. We collected blood and colon tissue samples from UC patients and healthy controls and investigated the sphingolipids and other lipids by LC-MS/MS or LC-QTOFMS. The expression of enzymes of the sphingolipid pathway were determined by RT-PCR and immunohistochemistry. In inflamed colon tissue, the de novo-synthesis of sphingolipids is reduced, whereas lactosylceramides are increased. Reduction of dihydroceramides was due to posttranslational inhibition rather than altered serine palmitoyl transferase or ceramide synthase expression in inflamed colon tissue. Furthermore, in human plasma from UC-patients, several sphinglipids change significantly in comparison to healthy controls. Beside sphingolipids free fatty acids, lysophosphatidylcholines and triglycerides changed significantly in the blood of colitis patients dependent on the disease severity. Our data indicate that detraction of the sphingolipid de novo synthesis in colon tissue might be an important trigger for UC. Several lipids changed significantly in the blood, which might be used as biomarkers for disease control; however, diet-related variabilities need to be considered.
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10
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Yang M, Li L, Soh Y, Heo SM. Effects of omega-3 fatty acids and aspirin on Porphyromonas gingivalis-induced periodontitis in rats. J Periodontol 2019; 90:1307-1319. [PMID: 31106412 DOI: 10.1002/jper.19-0063] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 03/29/2019] [Accepted: 04/04/2019] [Indexed: 12/23/2022]
Abstract
BACKGROUND Periodontitis is a common chronic inflammatory disease caused by bacteria which can result in periodontal tissue inflammation, as well as alveolar bone resorption. The purpose of this study was to evaluate the effects of omega-3 fatty acids plus aspirin (ASA) on ligature-induced periodontitis in rats. METHODS Ninety-six male Sprague-Dawley (SD) rats (age 6 weeks) were randomly divided into eight groups (n = 12 each) and had ligatures placed for 7 days, followed by daily treatment with specific drug regimens for 14 days. The rats were sacrificed 20 days after drug treatment, and their maxillary were subjected to histomorphometric analysis. RAW264.7 cells were cultured with lipopolysaccharide (LPS) or receptor activator (NF)-κB ligand (RANKL), and treated with various concentrations of omega-3 and ASA. Then, cyclooxygenase (COX-2), inducible nitric oxide synthase (iNOS) protein expression and receptor activator of nuclear factor κ B (RANK), tartrate-resistant acid phosphatase (TRAP), matrix metalloproteinase-9 (MMP-9), MMP-2, and Cathepsin-K gene expression were detected. RESULTS The administration of omega-3 fatty acids and aspirin significantly inhibited tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in serum of rats. Histomorphometric analysis showed omega-3 fatty acids plus aspirin promoted alveolar bone increase. Omega-3 fatty acids only, aspirin only, or omega-3 fatty acids plus aspirin also inhibited the protein expressions of COX-2 and iNOS in LPS-stimulated RAW264.7 cells. In addition, omega-3 combined with ASA also inhibited the RANKL-induced gene expressions of MMPs in dose-dependent manners. CONCLUSION These results demonstrate that omega-3 fatty acids plus aspirin could decrease alveolar bone loss, while simultaneously increasing the protection against periodontal inflammation.
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Affiliation(s)
- Ming Yang
- Department of Periodontology, School of Dentistry, Chonbuk National University, Jeon-Ju, South Korea.,Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeon-Ju, South Korea.,Department of Periodontology, School of Dentistry, Beihua University, Jilin City, Jilin, China
| | - Liang Li
- Department of Dental Pharmacology, School of Dentistry, Chonbuk National University, Jeon-Ju, South Korea
| | - Yunjo Soh
- Department of Dental Pharmacology, School of Dentistry, Chonbuk National University, Jeon-Ju, South Korea
| | - Seok-Mo Heo
- Department of Periodontology, School of Dentistry, Chonbuk National University, Jeon-Ju, South Korea.,Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeon-Ju, South Korea
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11
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Günay S, Taşova F, Yılmaz HE, Paköz ZB, Çekiç C. Serum Resolvin E1 Levels and Its Relationship with Disease Activity in Ulcerative Colitis. Gastroenterol Res Pract 2019; 2019:6258327. [PMID: 30906319 PMCID: PMC6393930 DOI: 10.1155/2019/6258327] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 01/08/2019] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Resolvins originate from ω-3 PUFA (polyunsaturated fatty acid) precursors and play a role in the resolution of inflammation. The aim of this study was to determine the serum Resolvin E1 levels in patients with ulcerative colitis (UC) and to evaluate the relationship between the serum Resolvin E1 levels and ulcerative colitis disease activity. METHODS In this observational study, serum samples were collected from 51 patients with UC and 30 healthy controls for the determination of Resolvin E1 levels. Firstly, we compared the serum Resolvin E1 levels between the UC patients and the control group. Subsequently, Resolvin E1 levels were analyzed in patients with active UC and UC in remission. Finally, the correlation between Resolvin E1 and C-reactive protein (CRP) and partial Mayo score (p-MS) was analyzed to determine the efficacy of Resolvin E1 in predicting disease activity. RESULTS Serum Resolvin E1 level was determined in the UC group (3126 ± 1413 ng/ml) and in the control group (2758 ± 1065 ng/ml) (p = 0.187). Serum Resolvin E1 levels were determined in patients with active UC (3114 ± 1166 ng/ml) and patients in remission (3132 ± 1520 ng/ml) (p = 0.749). In the UC group, a low-grade positive significant association was found between Resolvin E1 and CRP (r = 0.303, p = 0.031). There was no significant association between Resolvin E1 and partial Mayo score (r = -0.207, p = 0.146). CONCLUSIONS There was no sufficient evidence that Resolvin E1 was an appropriate inflammatory marker to determine disease activity in UC.
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Affiliation(s)
- Süleyman Günay
- Department of Gastroenterology, Katip Çelebi University, Atatürk Education and Research Hospital, İzmir, Turkey
| | - Ferda Taşova
- Department of Internal Medicine, Katip Çelebi University, Atatürk Education and Research Hospital, İzmir, Turkey
| | - Huriye Erbak Yılmaz
- Department of Biochemistry, Katip Çelebi University, Atatürk Education and Research Hospital, İzmir, Turkey
| | - Zehra Betül Paköz
- Department of Gastroenterology, Tepecik Education and Research Hospital, İzmir, Turkey
| | - Cem Çekiç
- Department of Gastroenterology, Katip Çelebi University, Atatürk Education and Research Hospital, İzmir, Turkey
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12
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Wu D, Lewis ED, Pae M, Meydani SN. Nutritional Modulation of Immune Function: Analysis of Evidence, Mechanisms, and Clinical Relevance. Front Immunol 2019; 9:3160. [PMID: 30697214 PMCID: PMC6340979 DOI: 10.3389/fimmu.2018.03160] [Citation(s) in RCA: 264] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 12/21/2018] [Indexed: 12/12/2022] Open
Abstract
It is well-established that the nutritional deficiency or inadequacy can impair immune functions. Growing evidence suggests that for certain nutrients increased intake above currently recommended levels may help optimize immune functions including improving defense function and thus resistance to infection, while maintaining tolerance. This review will examine the data representing the research on prominent intervention agents n-3 polyunsaturated fatty acids (PUFA), micronutrients (zinc, vitamins D and E), and functional foods including probiotics and tea components for their immunological effects, working mechanisms, and clinical relevance. Many of these nutritive and non-nutritive food components are related in their functions to maintain or improve immune function including inhibition of pro-inflammatory mediators, promotion of anti-inflammatory functions, modulation of cell-mediated immunity, alteration of antigen-presenting cell functions, and communication between the innate and adaptive immune systems. Both animal and human studies present promising findings suggesting a clinical benefit of vitamin D, n-3 PUFA, and green tea catechin EGCG in autoimmune and inflammatory disorders, and vitamin D, vitamin E, zinc, and probiotics in reduction of infection. However, many studies report divergent and discrepant results/conclusions due to various factors. Chief among them, and thus call for attention, includes more standardized trial designs, better characterized populations, greater consideration for the intervention doses used, and more meaningful outcome measurements chosen.
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Affiliation(s)
- Dayong Wu
- Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States
| | - Erin D Lewis
- Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States
| | - Munyong Pae
- Department of Food and Nutrition, Chungbuk National University, Cheongju, South Korea
| | - Simin Nikbin Meydani
- Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States
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13
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Hegyi P, Maléth J, Walters JR, Hofmann AF, Keely SJ. Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease. Physiol Rev 2018; 98:1983-2023. [PMID: 30067158 DOI: 10.1152/physrev.00054.2017] [Citation(s) in RCA: 193] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid to and from the luminal contents. At the same time, epithelial cells are responsible for forming a physical and biochemical barrier that prevents the entry into the body of harmful agents, such as bacteria and their toxins. Dysregulation of epithelial transport and barrier function is associated with the pathogenesis of a number of conditions throughout the intestine, such as inflammatory bowel disease, chronic diarrhea, pancreatitis, reflux esophagitis, and cancer. Driven by discovery of specific receptors on intestinal epithelial cells, new insights into mechanisms that control their synthesis and enterohepatic circulation, and a growing appreciation of their roles as bioactive bacterial metabolites, bile acids are currently receiving a great deal of interest as critical regulators of epithelial function in health and disease. This review aims to summarize recent advances in this field and to highlight how bile acids are now emerging as exciting new targets for disease intervention.
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Affiliation(s)
- Peter Hegyi
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
| | - Joszef Maléth
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
| | - Julian R Walters
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
| | - Alan F Hofmann
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
| | - Stephen J Keely
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
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14
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Ananthakrishnan AN, Khalili H, Song M, Higuchi L, Lochhead P, Richter JM, Chan AT. Genetic Polymorphisms in Fatty Acid Metabolism Modify the Association Between Dietary n3: n6 Intake and Risk of Ulcerative Colitis: A Prospective Cohort Study. Inflamm Bowel Dis 2017; 23:1898-1904. [PMID: 28991856 PMCID: PMC5675119 DOI: 10.1097/mib.0000000000001236] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION High intake of dietary n-3 polyunsaturated fatty acids (PUFA) is associated with a decreased risk of ulcerative colitis (UC) and Crohn's disease (CD). However, results have been heterogeneous suggesting that genetic variations in PUFA metabolism may modify this risk. METHODS We conducted a case-control study nested within 2 prospective cohorts, the Nurses' Health Study (NHS) and NHS II. Among women providing blood (n = 62,437) or buccal cells (n = 59,543) for genotyping, we confirmed new diagnoses of CD or UC. Dietary intake was assessed 4 years before diagnosis. Confirmed cases were matched 1:2 to controls. Subjects were genotyped for single nucleotide polymorphisms at CYP4F3, FADS1, and FADS2 loci. Conditional logistic regression models examined the interaction between genotype, n3:n6 PUFA intake and risk of CD and UC. RESULTS Our study included 101 CD and 139 UC patients matched to 495 controls. On multivariable analysis, high intake of n3:n6 PUFA (above median) demonstrated a trend toward reduced risk of UC (Odds ratio [OR] 0.71, 95% confidence interval [CI], 0.47-1.09, P = 0.11). High n3:n6 PUFA intake was associated with a reduced risk of UC in individuals with the GG/AG genotype at a single nucleotide polymorphism in CYP4F3 (OR 0.57, 95% CI, 0.32-0.99) but not those with the AA genotype (OR 0.95, 95% CI, 0.47-1.93) (P-interaction = 0.049). No gene-diet interactions were noted for CD. CONCLUSIONS The association between dietary n3:n6 PUFA intake and risk of UC may be modified variants at CYP4F3. Further gene-environment studies of the association between diet and IBD risk are warranted.
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Affiliation(s)
- Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA
| | - Hamed Khalili
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA
| | - Mingyang Song
- Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA
| | - Leslie Higuchi
- Division of Gastroenterology and Nutrition, Children's Hospital Boston and Harvard Medical School, Boston, MA
| | - Paul Lochhead
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA
| | - James M Richter
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA
- Channing Division of Network Medicine, Department of Medicine, Brigham and women's Hospital, Boston, MA
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15
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Navarini L, Afeltra A, Gallo Afflitto G, Margiotta DPE. Polyunsaturated fatty acids: any role in rheumatoid arthritis? Lipids Health Dis 2017; 16:197. [PMID: 29017507 PMCID: PMC5634864 DOI: 10.1186/s12944-017-0586-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 10/02/2017] [Indexed: 12/12/2022] Open
Abstract
Background Polyunsaturated fatty acids (PUFAs) are members of the family of fatty acids and are included in the diet. Particularly, western diet is usually low in n-3 PUFAs and high in n-6 PUFAs. PUFAs play a central role in the homeostasis of immune system: n-6 PUFAs have predominantly pro-inflammatory features, while n-3 PUFAs seem to exert anti-inflammatory and pro-resolving properties. Rheumatoid arthritis (RA) is a chronic inflammatory arthritis in which many inflammatory pathways contribute to joint and systemic inflammation, disease activity, and structural damage. Research on PUFAs could represent an important opportunity to better understand the pathogenesis and to improve the management of RA patients. Methods We searched PubMed, Embase, EBSCO-Medline, Cochrane Central Register of Controlled Trials (CENTRAL), CNKI and Wanfang to identify primary research reporting the role of n-3 PUFAs in rheumatoid arthritis both in humans and in animal models up to the end of March 2017. Results Data from animal models allows to hypothesize that n-3 PUFAs supplementation may represent an interesting perspective in future research as much in prevention as in treating RA. In humans, several case-control and prospective cohort studies suggest that a high content of n-3 PUFAs in the diet could have a protective role for incident RA in subjects at risk. Moreover, n-3 PUFAs supplementation has been assessed as a valuable therapeutic option also for patients with RA, particularly in order to improve the pain symptoms, the tender joint count, the duration of morning stiffness and the frequency of NSAIDs assumption. Conclusions n-3 PUFAs supplementation could represent a promising therapeutic option to better control many features of RA. The impact of n-3 PUFAs on radiographic progression and synovial histopathology has not been yet evaluated, as well as their role in early arthritis and the combination with biologics.
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Affiliation(s)
- Luca Navarini
- Unit of Allergology, Immunology, Rheumatology, Department of Medicine, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128, Rome, Italy.
| | - Antonella Afeltra
- Unit of Allergology, Immunology, Rheumatology, Department of Medicine, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128, Rome, Italy
| | - Gabriele Gallo Afflitto
- Unit of Allergology, Immunology, Rheumatology, Department of Medicine, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128, Rome, Italy
| | - Domenico Paolo Emanuele Margiotta
- Unit of Allergology, Immunology, Rheumatology, Department of Medicine, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128, Rome, Italy
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16
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Lance KD, Chatterjee A, Wu B, Mottola G, Nuhn H, Lee PP, Sansbury BE, Spite M, Desai TA, Conte MS. Unidirectional and sustained delivery of the proresolving lipid mediator resolvin D1 from a biodegradable thin film device. J Biomed Mater Res A 2016; 105:31-41. [PMID: 27508346 DOI: 10.1002/jbm.a.35861] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 07/24/2016] [Accepted: 08/08/2016] [Indexed: 12/20/2022]
Abstract
Resolvin D1 (RvD1) belongs to a family of endogenously derived proresolving lipid mediators that have been shown to attenuate inflammation, activate proresolution signaling, and promote homeostasis and recovery from tissue injury. In this study we present a poly(lactic-co-glycolic acid) (PLGA) based thin-film device composed of layers of varying ratios of lactic and glycolic acid that elutes RvD1 unidirectionally to target tissues. The device demonstrated sustained release in vitro for 56 days with an initial burst of release over 14 days. The asymmetric design of the device released 98% of RvD1 through the layer with the lowest molar ratio of lactic acid to glycolic acid, and the remainder through the opposite side. We validated structural integrity of RvD1 released from the device by mass spectrometry and investigated its bioactivity on human vascular endothelial (EC) and smooth muscle cells (VSMC). RvD1 released from the device attenuated VSMC migration, proliferation, and TNF-α induced NF-κB activation, without evidence of cytotoxicity. Delivery of RvD1 to blood vessels was demonstrated ex vivo in a flow chamber system using perfused rabbit aortas and in vivo in a rat carotid artery model, with the devices applied as an adventitial wrap. Our results demonstrate a novel approach for sustained, local delivery of Resolvin D1 to vascular tissue at therapeutically relevant levels. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 31-41, 2017.
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Affiliation(s)
- Kevin D Lance
- UC Berkeley-UCSF Graduate Group in Bioengineering, San Francisco, California, 94158.,Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, 94158
| | - Anuran Chatterjee
- Cardiovascular Research Institute (CVRI) and Department of Surgery, University of California San Francisco, San Francisco, California, 94143
| | - Bian Wu
- Cardiovascular Research Institute (CVRI) and Department of Surgery, University of California San Francisco, San Francisco, California, 94143
| | - Giorgio Mottola
- Cardiovascular Research Institute (CVRI) and Department of Surgery, University of California San Francisco, San Francisco, California, 94143
| | - Harald Nuhn
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, 94158
| | - Phin Peng Lee
- UC Berkeley-UCSF Graduate Group in Bioengineering, San Francisco, California, 94158
| | - Brian E Sansbury
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine HIM 830, Boston, Massachusetts, 02115
| | - Matthew Spite
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine HIM 830, Boston, Massachusetts, 02115
| | - Tejal A Desai
- UC Berkeley-UCSF Graduate Group in Bioengineering, San Francisco, California, 94158.,Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, 94158
| | - Michael S Conte
- Cardiovascular Research Institute (CVRI) and Department of Surgery, University of California San Francisco, San Francisco, California, 94143
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17
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Marion-Letellier R, Savoye G, Ghosh S. Polyunsaturated fatty acids and inflammation. IUBMB Life 2015; 67:659-67. [DOI: 10.1002/iub.1428] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 07/15/2015] [Indexed: 01/12/2023]
Affiliation(s)
- Rachel Marion-Letellier
- INSERM Unit UMR1073, Rouen University and Rouen University Hospital; 22, Boulevard Gambetta Rouen Cedex 76183 France
| | - Guillaume Savoye
- INSERM Unit UMR1073, Rouen University and Rouen University Hospital; 22, Boulevard Gambetta Rouen Cedex 76183 France
- Department of Gastroenterology; Rouen University Hospital; 1 Rue De Germont Rouen Cedex 76031 France
| | - Subrata Ghosh
- Division of Gastroenterology; University of Calgary; AB Canada
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18
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Miklavcic JJ, Hart TDL, Lees GM, Shoemaker GK, Schnabl KL, Larsen BMK, Bathe OF, Thomson ABR, Mazurak VC, Clandinin MT. Increased catabolism and decreased unsaturation of ganglioside in patients with inflammatory bowel disease. World J Gastroenterol 2015; 21:10080-10090. [PMID: 26401073 PMCID: PMC4572789 DOI: 10.3748/wjg.v21.i35.10080] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Revised: 03/27/2015] [Accepted: 05/04/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether accelerated catabolism of ganglioside and decreased ganglioside content contribute to the etiology of pro-inflammatory intestinal disease.
METHODS: Intestinal mucosa from terminal ileum or colon was obtained from patients with ulcerative colitis or inflammatory Crohn’s disease (n = 11) undergoing bowel resection and compared to control samples of normal intestine from patients with benign colon polyps (n = 6) and colorectal cancer (n = 12) in this observational case-control study. Gangliosides and phospholipids of intestinal mucosa were characterized by class and ceramide or fatty acid composition using liquid chromatography triple-quad mass spectrometry. Content and composition of ganglioside classes GM1, GM3, GD3, GD1a, GT1 and GT3 were compared among subject groups. Content and composition of phospholipid classes phosphatidylcholine (PC) and phosphatidylethanolamine were compared among subject groups. Unsaturation index of individual ganglioside and phospholipid classes was computed and compared among subject groups. Ganglioside catabolism enzymes beta-hexosaminidase A (HEXA) and sialidase-3 (NEU3) were measured in intestinal mucosa using western blot and compared among subject groups.
RESULTS: Relative GM3 ganglioside content was 2-fold higher (P < 0.05) in intestine from patients with inflammatory bowel disease (IBD) compared to control intestine. The quantity of GM3 and ratio of GM3/GD3 was also higher in IBD intestine than control tissue (P < 0.05). Control intestine exhibited 3-fold higher (P < 0.01) relative GD1a ganglioside content than IBD intestine. GD3 and GD1a species of ganglioside containing three unsaturated bonds were present in control intestine, but were not detected in IBD intestine. The relative content of PC containing more than two unsaturated bonds was 30% lower in IBD intestine than control intestine (P < 0.05). The relative content of HEXA in IBD intestine was increased 1.7-fold (P < 0.05) and NEU3 was increased 8.3-fold (P < 0.01) compared to normal intestine. Intestinal mucosa in IBD is characterized by increased GM3 content, decreased GD1a, and a reduction in polyunsaturated fatty acid constituents in GD3, GD1a and PC.
CONCLUSION: This study suggests a new paradigm by proposing that IBD occurs as a consequence of increased metabolism of specific gangliosides.
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Effects of arachidonic acid intake on inflammatory reactions in dextran sodium sulphate-induced colitis in rats. Br J Nutr 2015; 114:734-45. [PMID: 26234346 DOI: 10.1017/s000711451500224x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The aim of this study was to investigate the effects of the administration of oral arachidonic acid (AA) in rats with or without dextran sulphate sodium (DSS)-induced inflammatory bowel disease. Male Wistar rats were administered AA at 0, 5, 35 or 240 mg/kg daily by gavage for 8 weeks. Inflammatory bowel disease was induced by replacing drinking water with 3 % DSS solution during the last 7 d of the AA dosing period. These animals passed loose stools, diarrhoea and red-stained faeces. Cyclo-oxygenase-2 concentration and myeloperoxidase activity in the colonic tissue were significantly increased in the animals given AA at 240 mg/kg compared with the animals given AA at 0 mg/kg. Thromboxane B2 concentration in the medium of cultured colonic mucosae isolated from these groups was found to be dose-dependently increased by AA, and the increase was significant at 35 and 240 mg/kg. Leukotriene B4 concentration was also significantly increased and saturated at 5 mg/kg. In addition, AA at 240 mg/kg promoted DSS-induced colonic mucosal oedema with macrophage infiltration. In contrast, administration of AA for 8 weeks, even at 240 mg/kg, showed no effects on the normal rats. These results suggest that in rats with bowel disease AA metabolism is affected by oral AA, even at 5 mg/kg per d, and that excessive AA may aggravate inflammation, whereas AA shows no effects in rats without inflammatory bowel disease.
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20
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Porter E, Ma DC, Alvarez S, Faull KF. Antimicrobial lipids: Emerging effector molecules of innate host defense. World J Immunol 2015; 5:51-61. [DOI: 10.5411/wji.v5.i2.51] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 06/28/2015] [Accepted: 07/17/2015] [Indexed: 02/05/2023] Open
Abstract
The antimicrobial properties of host derived lipids have become increasingly recognized and evidence is mounting that antimicrobial lipids (AMLs), like antimicrobial peptides, are effector molecules of the innate immune system and are regulated by its conserved pathways. This review, with primary focus on the human body, provides some background on the biochemistry of lipids, summarizes their biological functions, expands on their antimicrobial properties and site-specific composition, presents modes of synergism with antimicrobial peptides, and highlights the more recent reports on the regulation of AML production as well as bacterial resistance mechanisms. Based on extant data a concept of innate epithelial defense is proposed where epithelial cells, in response to microbial products and proinflammatory cytokines and through activation of conserved innate signaling pathways, increase their lipid uptake and up-regulate transcription of enzymes involved in lipid biosynthesis, and induce transcription of antimicrobial peptides as well as cytokines and chemokines. The subsequently secreted antimicrobial peptides and lipids then attack and eliminate the invader, assisted by or in synergism with other antimicrobial molecules delivered by other defense cells that have been recruited to the site of infection, in most of the cases. This review invites reconsideration of the interpretation of cholesteryl ester accumulation in macrophage lipid droplets in response to infection as a solely proinflammatory event, and proposes a direct antimicrobial role of lipid droplet- associated cholesteryl esters. Finally, for the interested, but new- to- the-field investigator some starting points for the characterization of AMLs are provided. Before it is possible to utilize AMLs for anti-infectious therapeutic and prophylactic approaches, we need to better understand pathogen responses to these lipids and their role in the pathogenesis of chronic infectious disease.
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Liu J, Ma DWL. The role of n-3 polyunsaturated fatty acids in the prevention and treatment of breast cancer. Nutrients 2014; 6:5184-223. [PMID: 25412153 PMCID: PMC4245586 DOI: 10.3390/nu6115184] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 10/28/2014] [Accepted: 11/04/2014] [Indexed: 02/07/2023] Open
Abstract
Breast cancer (BC) is the most common cancer among women worldwide. Dietary fatty acids, especially n-3 polyunsaturated fatty acids (PUFA), are believed to play a role in reducing BC risk. Evidence has shown that fish consumption or intake of long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are beneficial for inhibiting mammary carcinogenesis. The evidence regarding α-linolenic acid (ALA), however, remains equivocal. It is essential to clarify the relation between ALA and cancer since ALA is the principal source of n-3 PUFA in the Western diet and the conversion of ALA to EPA and DHA is not efficient in humans. In addition, the specific anticancer roles of individual n-3 PUFA, alone, have not yet been identified. Therefore, the present review evaluates ALA, EPA and DHA consumed individually as well as in n-3 PUFA mixtures. Also, their role in the prevention of BC and potential anticancer mechanisms of action are examined. Overall, this review suggests that each n-3 PUFA has promising anticancer effects and warrants further research.
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Affiliation(s)
- Jiajie Liu
- Department of Human Health & Nutritional Sciences, College of Biological Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada.
| | - David W L Ma
- Department of Human Health & Nutritional Sciences, College of Biological Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada.
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Suthar SK, Sharma M. Recent Developments in Chimeric NSAIDs as Safer Anti-Inflammatory Agents. Med Res Rev 2014; 35:341-407. [DOI: 10.1002/med.21331] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Sharad Kumar Suthar
- Department of Pharmacy; Jaypee University of Information Technology; Waknaghat 173234 India
| | - Manu Sharma
- Department of Pharmacy; Jaypee University of Information Technology; Waknaghat 173234 India
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Denison H, Nilsson C, Löfgren L, Himmelmann A, Mårtensson G, Knutsson M, Al-Shurbaji A, Tornqvist H, Eriksson JW. Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial. Diabetes Obes Metab 2014; 16:334-43. [PMID: 24118885 DOI: 10.1111/dom.12221] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 08/21/2013] [Accepted: 09/30/2013] [Indexed: 02/02/2023]
Abstract
AIM Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight or obese men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor. METHODS Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 h after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying. RESULTS Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at the end of treatment. With AZD7687 doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea. CONCLUSIONS Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.
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Abstract
In the healthy gastrointestinal tract, homeostasis is an active process that requires a careful balance of host responses to the enteric luminal contents. Intestinal macrophages and dendritic cells (DCs) comprise a unique group of tissue immune cells that are ideally situated at the interface of the host and the enteric luminal environment to appropriately respond to microbes and ingested stimuli. However, intrinsic defects in macrophage and DC function contribute to the pathogenesis of inflammatory bowel diseases, as highlighted by recent genome-wide association studies. Gastrointestinal macrophages and DCs participate in inflammatory bowel disease development through inappropriate responses to enteric microbial stimuli, inefficient clearance of microbes from host tissues, and impaired transition from appropriate proinflammatory responses to anti-inflammatory responses that promote resolution. By understanding how intestinal macrophages and DCs initiate chronic inflammation, new pathogenesis-based therapeutic strategies to treat human inflammatory bowel diseases will be elucidated.
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Biasi F, Leonarduzzi G, Oteiza PI, Poli G. Inflammatory bowel disease: mechanisms, redox considerations, and therapeutic targets. Antioxid Redox Signal 2013; 19:1711-47. [PMID: 23305298 PMCID: PMC3809610 DOI: 10.1089/ars.2012.4530] [Citation(s) in RCA: 221] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Oxidative stress is thought to play a key role in the development of intestinal damage in inflammatory bowel disease (IBD), because of its primary involvement in intestinal cells' aberrant immune and inflammatory responses to dietary antigens and to the commensal bacteria. During the active disease phase, activated leukocytes generate not only a wide spectrum of pro-inflammatory cytokines, but also excess oxidative reactions, which markedly alter the redox equilibrium within the gut mucosa, and maintain inflammation by inducing redox-sensitive signaling pathways and transcription factors. Moreover, several inflammatory molecules generate further oxidation products, leading to a self-sustaining and auto-amplifying vicious circle, which eventually impairs the gut barrier. The current treatment of IBD consists of long-term conventional anti-inflammatory therapy and often leads to drug refractoriness or intolerance, limiting patients' quality of life. Immune modulators or anti-tumor necrosis factor α antibodies have recently been used, but all carry the risk of significant side effects and a poor treatment response. Recent developments in molecular medicine point to the possibility of treating the oxidative stress associated with IBD, by designing a proper supplementation of specific lipids to induce local production of anti-inflammatory derivatives, as well as by developing biological therapies that target selective molecules (i.e., nuclear factor-κB, NADPH oxidase, prohibitins, or inflammasomes) involved in redox signaling. The clinical significance of oxidative stress in IBD is now becoming clear, and may soon lead to important new therapeutic options to lessen intestinal damage in this disease.
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Affiliation(s)
- Fiorella Biasi
- 1 Department of Clinical and Biological Sciences, University of Turin , San Luigi Gonzaga Hospital, Orbassano, Italy
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Acetylsalicylic Acid reduces the severity of dextran sodium sulfate-induced colitis and increases the formation of anti-inflammatory lipid mediators. BIOMED RESEARCH INTERNATIONAL 2013; 2013:748160. [PMID: 24083240 PMCID: PMC3780524 DOI: 10.1155/2013/748160] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 07/19/2013] [Indexed: 12/16/2022]
Abstract
The role of non-steroidal anti-inflammatory drugs in inflammatory bowel disease is controversial, as they have been implicated in disease aggravation. Different from other cyclooxygenase inhibitors, acetylsalicylic acid (ASA) enhances the formation of anti-inflammatory and proresolution lipoxins derived from arachidonic acid as well as resolvins from omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA). In this study, we examined the effect of ASA on murine dextran sodium sulfate colitis. A mouse magnetic resonance imaging (MRI) protocol and post mortem assessment were used to assess disease severity, and lipid metabolites were measured using liquid chromatography-coupled tandem mass spectrometry. Decreased colitis activity was demonstrated by phenotype and MRI assessment in mice treated with ASA, and confirmed in postmortem analysis. Analysis of lipid mediators showed sustained formation of lipoxin A4 and an increase of DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA) after treatment with ASA. Furthermore, in vitro experiments in RAW264.7 murine macrophages demonstrated significantly increased phagocytosis activity after incubation with 17-HDHA, supporting its proresolution effect. These results show a protective effect of ASA in a murine colitis model and could give a rationale for a careful reassessment of ASA therapy in patients with inflammatory bowel disease and particularly ulcerative colitis, possibly combined with DHA supplementation.
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Haworth O, Levy BD. Lipoxins, resolvins and protectins: new leads for the treatment of asthma. Expert Opin Drug Discov 2013; 3:1209-22. [PMID: 23489078 DOI: 10.1517/17460441.3.10.1209] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND The pathobiology of asthma is characterized by the production of pro-inflammatory eicosanoids that play important roles in regulating airway responses. Recognition of the biosynthetic pathways and sites of action for 5-lipoxygenase-derived leukotrienes has led to the successful development of two different classes of asthma therapeutics. OBJECTIVES In this review, we describe structurally distinct lipid mediators derived from arachidonic acid and ω-3 fatty acids that have anti-inflammatory and pro-resolving actions. These counter-regulatory lipid mediators are generated in the airway during asthma and defects in their production are associated with disease severity. CONCLUSION These natural small molecules are rapidly inactivated, but serve as rationale templates for the design of stable analogues with protective actions that could serve as new therapeutic leads for asthma.
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Affiliation(s)
- Oliver Haworth
- Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts, MA 02115, USA +1 617 525 8362 ; +1 617 264 5133 ;
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Keinan D, Leigh NJ, Nelson JW, De Oleo L, Baker OJ. Understanding resolvin signaling pathways to improve oral health. Int J Mol Sci 2013; 14:5501-18. [PMID: 23528855 PMCID: PMC3634469 DOI: 10.3390/ijms14035501] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2012] [Revised: 02/19/2013] [Accepted: 02/22/2013] [Indexed: 12/15/2022] Open
Abstract
The discovery of resolvins has been a major breakthrough for understanding the processes involved in resolution of inflammation. Resolvins belong to a family of novel lipid mediators that possess dual anti-inflammatory and pro-resolution actions. Specifically, they protect healthy tissue during immune-inflammatory responses to infection or injury, thereby aiding inflammation resolution and promoting tissue healing. One of the major concerns in modern medicine is the management and treatment of oral diseases, as they are related to systemic outcomes impacting the quality of life of many patients. This review summarizes known signaling pathways utilized by resolvins to regulate inflammatory responses associated with the oral cavity.
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Affiliation(s)
- David Keinan
- Department of Periodontics and Endodontics, School of Dental Medicine, University at Buffalo, the State University of New York, Buffalo, NY 14214-3932, USA; E-Mail:
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, Buffalo, NY 14214-3932, USA; E-Mails: (N.J.L.); (J.W.N.); (L.D.O.)
| | - Noel J. Leigh
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, Buffalo, NY 14214-3932, USA; E-Mails: (N.J.L.); (J.W.N.); (L.D.O.)
| | - Joel W. Nelson
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, Buffalo, NY 14214-3932, USA; E-Mails: (N.J.L.); (J.W.N.); (L.D.O.)
| | - Laura De Oleo
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, Buffalo, NY 14214-3932, USA; E-Mails: (N.J.L.); (J.W.N.); (L.D.O.)
| | - Olga J. Baker
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, Buffalo, NY 14214-3932, USA; E-Mails: (N.J.L.); (J.W.N.); (L.D.O.)
- To whom correspondence should be addressed; E-Mail: ; Tel.: +1-716-829-3667; Fax: +1-716-829-3942
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Polyunsaturated fatty acids in inflammatory bowel diseases: a reappraisal of effects and therapeutic approaches. Inflamm Bowel Dis 2013; 19:650-61. [PMID: 23328774 DOI: 10.1097/mib.0b013e3182810122] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recent epidemiological studies highlight the key role of the type of consumed unsaturated fatty acid and the development of ulcerative colitis (UC). We aimed to review the potential mechanisms behind the antiinflammatory effects of unsaturated fatty acids on intestinal inflammation, to discuss their potential limitations, and to propose a new reappraisal of polyunsaturated fatty acids (PUFAs) in the pathophysiology of inflammatory bowel disease (IBD). A literature search using PubMed was carried out to identify relevant studies (basic science, epidemiological studies, or clinical trials) with unsaturated fatty acids and IBD. Only articles published in English were included. IBD patients exhibit an altered lipid metabolism. While in vitro and in vivo studies have demonstrated the antiinflammatory properties of n-3 polyunsaturated fatty acids in experimental models IBD, results of clinical trials have been disappointing. In addition, the impact of fatty acid on innate immunity as an alternative therapeutic approach is explored. This may offer insight into therapeutic avenues for designing n-3 PUFA diet therapy for IBD.
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Abstract
BACKGROUND & AIM Despite their well known anti-inflammatory actions, the clinical usefulness of omega-3 PUFA in inflammatory bowel disease is controversial. We aimed to systematically review the available data on the performance of omega-3 PUFA as therapeutic agents in these patients. METHODS Electronic databases were systematically searched for RCT of fish oil or omega-3 PUFA therapy in both active and inactive ulcerative colitis or Crohn's disease, without limitation on either the length of therapy or the form it was given, including nutritional supplements and enteral formula diets. Eligible articles were assessed for methodological quality on the basis of the adequacy of the randomisation process, concealment of allocation, blinding of intervention and outcome, possible biases, and completeness of follow-up. The five-point Oxford quality score was calculated. RESULTS A total of 19 RCT were finally selected for this review. Overall, available data do not allow to support the use of omega-3 PUFA supplementation for the treatment of both active and inactive inflammatory bowel disease. Negative results are quite consistent in trials assessing the use of omega-3 PUFA to maintain disease remission, particularly ulcerative colitis, and to a lesser extent Crohn's disease. Trials on their use in active disease do not allow to draw firm conclusions mainly because the heterogeneity of design (ulcerative colitis) or their short number (Crohn's disease). In most trials, the appropriateness of the selected placebo is questionable. CONCLUSION The present systematic review does not allow to make firm recommendations about the usefulness of omega-3 PUFA in inflammatory bowel disease.
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Abstract
Polymorphonuclear leukocytes or neutrophils play a critical role in the maintenance of intestinal homeostasis. They have elegant defense mechanisms to eliminate microbes that have translocated across a single layer of mucosal epithelial cells that form a critical barrier between the gut lumen and the underlying tissue. During the inflammatory response, neutrophils also contribute to the recruitment of other immune cells and facilitate mucosal healing by releasing mediators necessary for the resolution of inflammation. Although the above responses are clearly beneficial, excessive recruitment and accumulation of activated neutrophils in the intestine under pathological conditions such as inflammatory bowel disease is associated with mucosal injury and debilitating disease symptoms. Thus, depending on the circumstances, neutrophils can be viewed as either good or bad. In this article, we summarize the beneficial and deleterious roles of neutrophils in the intestine during health and disease and provide an overview of what is known about neutrophil function in the gut.
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Dietary ganglioside reduces proinflammatory signaling in the intestine. J Nutr Metab 2012; 2012:280286. [PMID: 22506104 PMCID: PMC3306953 DOI: 10.1155/2012/280286] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Revised: 10/07/2011] [Accepted: 10/07/2011] [Indexed: 12/31/2022] Open
Abstract
Gangliosides are integral to the structure and function of cell membranes. Ganglioside composition of the intestinal brush border and apical surface of the colon influences numerous cell processes including microbial attachment, cell division, differentiation, and signaling. Accelerated catabolism of ganglioside in intestinal disease results in increased proinflammatory signaling. Restoring proper structure and function to the diseased intestine can resolve inflammation, increase resistance to infection, and improve gut integrity to induce remission of conditions like necrotizing enterocolitis (NEC) and Crohn's disease (CD). Maintaining inactive state of disease may be achieved by reducing the rate that gangliosides are degraded or by increasing intake of dietary ganglioside. Collectively, the studies outlined in this paper indicate that the amount of gangliosides GM3 and GD3 in intestinal mucosa is decreased with inflammation, low level of GM3 is associated with higher production of proinflammatory signals, and ganglioside content of intestinal mucosa can be increased by dietary ganglioside.
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Shores DR, Binion DG, Freeman BA, Baker PR. New insights into the role of fatty acids in the pathogenesis and resolution of inflammatory bowel disease. Inflamm Bowel Dis 2011; 17:2192-204. [PMID: 21910181 PMCID: PMC4100336 DOI: 10.1002/ibd.21560] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Accepted: 10/05/2010] [Indexed: 12/12/2022]
Abstract
Dietary and endogenously modified lipids modulate inflammation by functioning as intra- and intercellular signaling molecules. Proinflammatory lipid mediators such as the eicosanoids compete against the signaling actions of newly discovered modified fatty acids that act to resolve inflammation. In inflammatory bowel disease, multiple aberrancies in lipid metabolism have been discovered, which shed further light on the pathogenesis of intestinal inflammation. Mechanisms by which lipids modulate inflammation, abnormalities of lipid metabolism in the setting of inflammatory bowel disease, and potential therapeutic application of lipid derivatives in this setting are discussed.
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Affiliation(s)
- Darla R. Shores
- Division of Pediatric Gastroenterology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - David G. Binion
- Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Bruce A. Freeman
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Paul R.S. Baker
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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López-Posadas R, Ballester I, Mascaraque C, Suárez MD, Zarzuelo A, Martínez-Augustin O, Sánchez de Medina F. Flavonoids exert distinct modulatory actions on cyclooxygenase 2 and NF-kappaB in an intestinal epithelial cell line (IEC18). Br J Pharmacol 2010; 160:1714-26. [PMID: 20649574 DOI: 10.1111/j.1476-5381.2010.00827.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Cyclooxygenase 2 (COX-2) is involved in inflammatory bowel disease, but the effect of flavonoids at the intestinal epithelial level is unknown. We aimed to characterize the effect and structure-activity relationship of nine selected flavonoids on COX-2 expression in intestinal epithelial cell (IEC)18 cells. We also investigated the signal transduction pathway(s) responsible for the effects observed. EXPERIMENTAL APPROACH Intestinal epithelial cell 18, a non-tumour cell line with intestinal epithelial phenotype, was used. COX-2 was measured by Western blot and the involvement of the NF-kappaB pathway assessed by Western blot, pharmacological inhibition, luciferase reporter assays and nuclear translocation experiments. KEY RESULTS The effect of flavonoids on COX-2 expression depended on the experimental conditions tested [non-stimulated and lipopolysaccharide (LPS)-stimulated]. Flavonoids caused an increase in COX-2 expression and NF-kappaB-dependent gene transcription under basal conditions. Conversely, under LPS stimulation flavonoids increased, decreased or did not affect COX-2 levels depending on the specific type. Variable effects were observed on extracellular signal regulated kinase/p38/c-Jun N-terminal kinase phosphorylation and p50/65 nuclear translocation. CONCLUSION AND IMPLICATIONS The effect of flavonoids on COX-2 expression depended on the balance of the interference with IkappaB-alpha phosphorylation and other signalling targets, and therefore depends on the experimental conditions and on the type of flavonoids. This is expected to result in different effects in inflammatory conditions. In general, flavonoids may limit epithelial COX-2 expression in inflammatory conditions while favouring it when inflammation is not present.
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Affiliation(s)
- R López-Posadas
- Department of Pharmacology, School of Pharmacy, University of Granada, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Granada, Spain
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Sea-cod oil supplementation alters the course of Streptococcus pneumoniae infection in BALB/c mice. Eur J Clin Microbiol Infect Dis 2010; 30:393-400. [DOI: 10.1007/s10096-010-1099-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Revised: 10/10/2010] [Accepted: 10/11/2010] [Indexed: 01/09/2023]
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Das UN. A defect in Δ6 and Δ5 desaturases may be a factor in the initiation and progression of insulin resistance, the metabolic syndrome and ischemic heart disease in South Asians. Lipids Health Dis 2010; 9:130. [PMID: 21062475 PMCID: PMC2987992 DOI: 10.1186/1476-511x-9-130] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Accepted: 11/09/2010] [Indexed: 02/03/2023] Open
Abstract
The high incidence of insulin resistance and the metabolic syndrome in South Asians remains unexplained. I propose that a defect in the activity of Δ6 and Δ5 desaturases and consequent low plasma and tissue concentrations of polyunsaturated fatty acids such as γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and formation of their anti-inflammatory products prostaglandin E1 (PGE1), prostacyclin (PGI2), PGI3, lipoxins, resolvins, protectins, maresins and nitrolipids could be responsible for the high incidence of insulin resistance, the metabolic syndrome and ischemic heart disease (IHD) in South Asians. This proposal is supported by the observation that South Asian Indians have lower plasma and tissue concentrations of GLA, DGLA, AA, EPA and DHA, the precursors of PGE1, PGI2, PGI3, lipoxins, resolvins, protectins, and nitrolipids, the endogenous molecules that prevent platelet aggregation, vasoconstriction, thrombus formation, leukocyte activation and possess anti-inflammatory action and thus, are capable of preventing the development of insulin resistance, atherosclerosis, hypertension, type 2 diabetes mellitus and premature ischemic heart disease. Genetic predisposition, high carbohydrate intake, lack of exercise, tobacco use and low birth weight due to maternal malnutrition suppress the activity of Δ6 and Δ5 desaturases that leads to low plasma and tissue concentrations of polyunsaturated fatty acids and their products. This implies that adequate provision of polyunsaturated fatty acids and co-factors needed for their metabolism, and efforts to enhance the formation of their beneficial metabolites PGE1, PGI2, PGI3, lipoxins, resolvins, protectins, maresins and nitrolipids could form a novel approach in the prevention and management of these diseases in this high-risk population.
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Affiliation(s)
- Undurti N Das
- UND Life Sciences, 13800 Fairhill Road, #321, Shaker Heights, OH 44120, USA.
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Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev 2010; 68:280-9. [PMID: 20500789 DOI: 10.1111/j.1753-4887.2010.00287.x] [Citation(s) in RCA: 718] [Impact Index Per Article: 47.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are precursors of potent lipid mediators, termed eicosanoids, which play an important role in the regulation of inflammation. Eicosanoids derived from n-6 PUFAs (e.g., arachidonic acid) have proinflammatory and immunoactive functions, whereas eicosanoids derived from n-3 PUFAs [e.g., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] have anti-inflammatory properties, traditionally attributed to their ability to inhibit the formation of n-6 PUFA-derived eicosanoids. While the typical Western diet has a much greater ratio of n-6 PUFAs compared with n-3 PUFAs, research has shown that by increasing the ratio of n-3 to n-6 fatty acids in the diet, and consequently favoring the production of EPA in the body, or by increasing the dietary intake of EPA and DHA through consumption of fatty fish or fish-oil supplements, reductions may be achieved in the incidence of many chronic diseases that involve inflammatory processes; most notably, these include cardiovascular diseases, inflammatory bowel disease (IBD), cancer, and rheumatoid arthritis, but psychiatric and neurodegenerative illnesses are other examples.
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Affiliation(s)
- Rebecca Wall
- Alimentary Pharmabiotic Centre (APC), County Cork, Ireland
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El-Sharkawy H, Aboelsaad N, Eliwa M, Darweesh M, Alshahat M, Kantarci A, Hasturk H, Van Dyke TE. Adjunctive treatment of chronic periodontitis with daily dietary supplementation with omega-3 Fatty acids and low-dose aspirin. J Periodontol 2010; 81:1635-43. [PMID: 20572767 DOI: 10.1902/jop.2010.090628] [Citation(s) in RCA: 136] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Host modulatory therapy has been proposed as a treatment for periodontal diseases. Omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were shown to have therapeutic anti-inflammatory and protective actions in inflammatory diseases including periodontitis. The goal of this study was to test an innovative strategy for periodontal treatment in a clinical experiment. METHODS Eighty healthy subjects (40 in each group) with advanced chronic periodontitis were enrolled in Mansoura, Egypt, in a parallel-design, double-masked clinical study. The control group was treated with scaling and root planing (SRP) and a placebo, whereas the ω-3 group was treated with SRP followed by dietary supplementation of fish oil (900 mg EPA + DHA) and 81 mg aspirin daily. Saliva samples were obtained from all patients at baseline and 3 and 6 months for evaluation of receptor activator of nuclear factor-kappa B ligand (RANKL) and matrix metalloproteinase-8 (MMP-8). Plaque and gingival indices, bleeding on probing, probing depths, and attachment levels were recorded at the same time points. RESULTS Statistical analyses demonstrated a significant reduction in probing depths and a significant attachment gain after 3 and 6 months in the ω-3 group compared to baseline and the control group (P <0.05). Salivary RANKL and MMP-8 levels showed significant reductions in the ω-3 group in response to treatment at 3 and 6 months and compared to the control group at 6 months (P <0.01). Supplementation with ω-3 + aspirin resulted in a significant shift in the frequency of pockets with probing depths <4 mm (P <0.05). CONCLUSION The results of this preliminary clinical study suggest that dietary supplementation with ω-3 PUFAs and 81 mg aspirin may provide a sustainable, low-cost intervention to augment periodontal therapy.
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Affiliation(s)
- Hesham El-Sharkawy
- Department of Oral Medicine and Periodontology, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
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Metabolism and biological production of resolvins derived from docosapentaenoic acid (DPAn-6). Biochem Pharmacol 2009; 79:251-60. [PMID: 19679107 DOI: 10.1016/j.bcp.2009.08.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2009] [Revised: 07/28/2009] [Accepted: 08/04/2009] [Indexed: 11/21/2022]
Abstract
17S-HDPAn-6 (17S-hydroxydocosa-4Z,7Z,10Z,13Z,15E-pentaenoic acid) and 10S,17S-HDPAn-6 (10S,17S-dihydroxydocosa-4Z,7Z,11E,13Z,15E-pentaenoic acid) are potent anti-inflammatory resolvins derived from DPAn-6 (docosapentaenoic acid n-6) and are analogous in structure and action to DHA (docosahexaenoic acid)-derived resolvins. These resolvins have proven to be potential drug candidates, albeit with therapeutic profiles that need optimization. The main objectives of this study were to evaluate key features of DPAn-6 derived resolvins that are important for therapeutic efficacy, demonstrate that these DPAn-6 resolvins could be produced naturally, and could therefore have physiological significance. Here we demonstrate biological production, examine pharmacokinetic profiles and identify key routes of metabolic inactivation of DPAn-6 derived resolvins. We compare their metabolic stability to a known resolvin, 17S-HDHA (17S-hydroxydocosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid) and show that order of their stabilities is 10S,17S-HDPAn-6>17S-HDPAn-6>17S-HDHA. We show that both these compounds are not strong inhibitors of cytochrome-P450 enzymes. We evaluate activity of compounds in the delayed-type hypersensitivity model, results of which show that compounds need optimization for enhanced duration and magnitude of action. Analysis of the metabolic stability and identification of metabolites of these compounds could play an important role in the design of better analogs with longer durations of action and hence better efficacy.
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Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention. Biochem Pharmacol 2008; 77:937-46. [PMID: 19022225 DOI: 10.1016/j.bcp.2008.10.020] [Citation(s) in RCA: 514] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2008] [Revised: 10/20/2008] [Accepted: 10/21/2008] [Indexed: 11/20/2022]
Abstract
Linoleic acid (LA) and alpha linolenic acid (ALA) belong to the n-6 (omega-6) and n-3 (omega-3) series of polyunsaturated fatty acids (PUFA), respectively. They are defined "essential" fatty acids since they are not synthesized in the human body and are mostly obtained from the diet. Food sources of ALA and LA are most vegetable oils, cereals and walnuts. This review critically revises the most significant epidemiological and interventional studies on the cardioprotective activity of PUFAs, linking their biological functions to biochemistry and metabolism. In fact, a complex series of desaturation and elongation reactions acting in concert transform LA and ALA to their higher unsaturated derivatives: arachidonic acid (AA) from LA, eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) from ALA. EPA and DHA are abundantly present in fish and fish oil. AA and EPA are precursors of different classes of pro-inflammatory or anti-inflammatory eicosanoids, respectively, whose biological activities have been evoked to justify risks and benefits of PUFA consumption. The controversial origin and clinical role of the n-6/n-3 ratio as a potential risk factor in cardiovascular diseases is also examined. This review highlights the important cardioprotective effect of n-3 in the secondary prevention of sudden cardiac death due to arrhythmias, but suggests caution to recommend dietary supplementation of PUFAs to the general population, without considering, at the individual level, the intake of total energy and fats.
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Vassiliou EK, Kesler OM, Tadros JH, Ganea D. Bone Marrow-Derived Dendritic Cells Generated in the Presence of Resolvin E1 Induce Apoptosis of Activated CD4+ T Cells. THE JOURNAL OF IMMUNOLOGY 2008; 181:4534-44. [DOI: 10.4049/jimmunol.181.7.4534] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Hong S, Porter TF, Lu Y, Oh SF, Pillai PS, Serhan CN. Resolvin E1 metabolome in local inactivation during inflammation-resolution. THE JOURNAL OF IMMUNOLOGY 2008; 180:3512-9. [PMID: 18292578 DOI: 10.4049/jimmunol.180.5.3512] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Resolvin E1 (RvE1; 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is a potent anti-inflammatory and proresolving mediator derived from the omega-3 eicosapentaenoic acid. In this study, we report the RvE1 metabolome, namely, the metabolic products derived from RvE1. RvE1 was converted to several novel products by human polymorphonuclear leukocytes and whole blood as well as in murine inflammatory exudates, spleen, kidney, and liver. The potential activity of each of the newly identified products was directly compared with that of RvE1. The new RvE1 products elucidated included 19-hydroxy-RvE1, 20-carboxy-RvE1, and 10,11-dihydro-RvE1. Metabolomic profiles of RvE1 were species-, tissue-, and cell type-specific. Direct comparisons of the bioactions between isolated RvE1 metabolic products indicated that 10,11-dihydro-RvE1, 18-oxo-RvE1, and 20-carboxy-RvE1 displayed reduced bioactivity in vivo. At concentrations as low as 1 nM, RvE1 enhanced macrophage phagocytosis, a proresolving activity that was reduced by metabolic inactivation. These results document novel metabolic products of RvE1 that impact its actions and that both omega-1 hydroxylation and reduction of conjugated double bonds in RvE1 are new pathways of four main routes of RvE1 metabolism in mammalian tissues. Together, these findings indicate that, during inflammation and its controlled resolution, specific tissues inactivate proresolving signals, i.e., RvE1, to permit the coordinated return to homeostasis. Moreover, the RvE1 metabolome may serve as a biomarker of these processes.
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Affiliation(s)
- Song Hong
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
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Chen Y, Wang J, Nie R, Zhou S. Endogenous pro-resolving and anti-inflammatory lipid mediators: The new hope of atherosclerotic diseases. Med Hypotheses 2008; 71:237-40. [DOI: 10.1016/j.mehy.2008.03.026] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2008] [Revised: 03/05/2008] [Accepted: 03/10/2008] [Indexed: 12/17/2022]
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