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Yousef MS, Akthar I, Ma D, Haneda S, Kusama K, Shimada M, Imakawa K, Miyamoto A. Platelet secretions exert anti-inflammatory effects in vitro on neutrophils and uterine epithelia in cattle: a possible role in amplifying the uterine immune network toward pregnancy. Front Immunol 2025; 16:1560996. [PMID: 40230844 PMCID: PMC11994593 DOI: 10.3389/fimmu.2025.1560996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 03/17/2025] [Indexed: 04/16/2025] Open
Abstract
Background Platelet derivatives improve the uterine immune environment and increase pregnancy success in humans and animals. Platelet-conditioned media (PCM) contain all molecules derived from platelets in vitro (platelet secretions). The present study aimed to investigate the immunological impacts of platelet secretions on polymorphonuclear neutrophils (PMNs) and bovine endometrial epithelial cells (BEECs), in vitro. Methods Platelets (10×107 platelets/mL) from Holstein dairy cows were incubated for 0.5 h or lysed to obtain the PCM and platelet lysate (Lysate), respectively. PMNs were stimulated with PCM for 3h. While BEECs were exposed to PCM or Lysate for 24 h. Real-time PCR was performed to detect the expression of targeted genes (cytokines), including TNFA, IL1B and PGES1. Lipoxin A4 (LXA4; anti-inflammatory mediator) and PGE2 concentrations in the supernatants of PMNs cultured with PCM were measured via ELISA. Cell proliferation in BEECs was assessed using the Cell Counting Kit-8 (CCK-8). Additionally, uterine explants were prepared and processed for immunofluorescence to determine the expression of the LXA4 receptor. Results In PMNs, platelet secretions downregulated the mRNA expression of pro-inflammatory cytokines (TNFA and IL1B) and increased LXA4 production. In both PMNs and BEECs, platelet secretions upregulated PGES1 expression and PGE2 production. In BEECs, platelet secretions and Lysate upregulated TGFB1. While Lysate suppressed IL1B mRNA expression. Further, platelet secretions showed an anti-proliferative effect in BEECs and increased the LXA4 receptor protein expression in the endometrial epithelia. Conclusions Our findings reveal for the first time that platelet secretions directly act on PMNs and BEECs in vitro, thereby assisting the uterine immune network to shift anti-inflammatory environment toward pregnancy. The present study can explain, in part, the successful applications of platelet derivatives in reproductive medicine.
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Affiliation(s)
- Mohamed Samy Yousef
- Global Agromedicine Research Center (GAMRC), Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
- Department of Theriogenology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
| | - Ihshan Akthar
- Global Agromedicine Research Center (GAMRC), Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
| | - Dongxue Ma
- Global Agromedicine Research Center (GAMRC), Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
| | - Shingo Haneda
- Department of Clinical Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
| | - Kazuya Kusama
- Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Masayuki Shimada
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan
| | - Kazuhiko Imakawa
- Research Institute of Agriculture, Tokai University, Kumamoto, Japan
| | - Akio Miyamoto
- Global Agromedicine Research Center (GAMRC), Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
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Liu X, Tang Y, Luo Y, Gao Y, He L. Role and mechanism of specialized pro-resolving mediators in obesity-associated insulin resistance. Lipids Health Dis 2024; 23:234. [PMID: 39080624 PMCID: PMC11290132 DOI: 10.1186/s12944-024-02207-9] [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: 03/15/2024] [Accepted: 07/07/2024] [Indexed: 08/02/2024] Open
Abstract
With the changing times, obesity has become a characteristic epidemic in the context of the current era. Insulin resistance (IR) is most commonly caused by obesity, and IR is a common basis of the pathogenesis of many diseases such as cardiovascular disease, nonalcoholic fatty liver disease, and type 2 diabetes, which seriously threaten human life, as well as health. A major pathogenetic mechanism of obesity-associated IR has been found to be chronic low-grade inflammation in adipose tissue. Specialized pro-resolving mediators (SPMs) are novel lipid mediators that both function as "stop signals" for inflammatory reaction and promote inflammation to subside. In this article, we summarize the pathogenesis of obesity-associated IR and its treatments and outline the classification and biosynthesis of SPMs and their mechanisms and roles in the treatment of obesity-associated IR in order to explore the potential of SPMs for treating metabolic diseases linked with obesity-associated IR.
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Affiliation(s)
- Xinru Liu
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu Tang
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuanyuan Luo
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yongxiang Gao
- College of International Education, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Lisha He
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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Kawashima H, Yoshizawa K. The physiological and pathological properties of Mead acid, an endogenous multifunctional n-9 polyunsaturated fatty acid. Lipids Health Dis 2023; 22:172. [PMID: 37838679 PMCID: PMC10576882 DOI: 10.1186/s12944-023-01937-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 10/08/2023] [Indexed: 10/16/2023] Open
Abstract
Mead acid (MA, 5,8,11-eicosatrienoic acid) is an n-9 polyunsaturated fatty acid (PUFA) and a marker of essential fatty acid deficiency, but nonetheless generally draws little attention. MA is distributed in various normal tissues and can be converted to several specific lipid mediators by lipoxygenase and cyclooxygenase. Recent pathological and epidemiological studies on MA raise the possibility of its effects on inflammation, cancer, dermatitis and cystic fibrosis, suggesting it is an endogenous multifunctional PUFA. This review summarizes the biosynthesis, presence, metabolism and physiological roles of MA and its relation to various diseases, as well as the significance of MA in PUFA metabolism.
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Affiliation(s)
- Hiroshi Kawashima
- Research Institute, Suntory Global Innovation Center Ltd, Seika, Kyoto, Japan.
| | - Katsuhiko Yoshizawa
- Department of Innovative Food Sciences, School of Food Sciences and Nutrition, Mukogawa Women's University, Nishinomiya, Hyogo, Japan
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Edwards-Glenn JM, Fontes MT, Waigi EW, Costa TJ, Maiseyeu A, Webb RC, McCarthy CG, Wenceslau CF. Specialized Pro-resolving Mediator Improves Vascular Relaxation via Formyl Peptide Receptor-2. Am J Hypertens 2023; 36:542-550. [PMID: 37439351 PMCID: PMC10502783 DOI: 10.1093/ajh/hpad062] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 06/29/2023] [Accepted: 07/11/2023] [Indexed: 07/14/2023] Open
Abstract
BACKGROUND The resolution of inflammation is an active phenomenon important for switching off inflammatory processes once the harmful stimuli are removed and facilitate the return to homeostasis. Specialized pro-resolving mediators (SPMs), such as lipoxin A4, resolvin D1, and resolvin E1, derived from ω-3 or ω-6 polyunsaturated fatty acids, are crucial for the resolution of inflammation. We hypothesized that SPMs are decreased in hypertension which contributes to the acetylcholine-induced contraction in resistance arteries, which are well known to be mediated by leukotrienes and prostaglandins. Moreover, treatment with SPMs will decrease this contraction via formyl peptide receptor-2 (FPR-2) in resistance arteries from spontaneously hypertensive rats (SHR). METHODS AND RESULTS We performed a comprehensive eicosanoid lipid panel analysis, and our data showed for the first time that precursors of SPMs are decreased in SHR, limiting the production of SPMs and resolution of inflammation in vivo. This phenomenon was associated with an increase in lipid peroxidation in resistance arteries. Although SPMs did not abolish acetylcholine-induced contraction, these lipid mediators improved endothelial function in arteries from SHR via FPR-2 activation at nanomolar concentrations. SPMs also buffered TNF-α-induced reactive oxygen species generation in endothelial cells from C57Bl/6 mice. CONCLUSIONS We suggest that FPR-2 and SPMs could be revealed as a new target or therapeutic agent to improve vascular function in arteries from hypertensive rats.
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Affiliation(s)
- Jonnelle M Edwards-Glenn
- Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Milene T Fontes
- Cardiovascular Translational Research Center, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
| | - Emily W Waigi
- Cardiovascular Translational Research Center, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
| | - Tiago J Costa
- Cardiovascular Translational Research Center, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
| | - Andrei Maiseyeu
- Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - R Clinton Webb
- Cardiovascular Translational Research Center, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
- Biomedical Engineering Program, College of Engineering and Computing, University of South Carolina, Columbia, South Carolina, USA
| | - Cameron G McCarthy
- Cardiovascular Translational Research Center, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
- Biomedical Engineering Program, College of Engineering and Computing, University of South Carolina, Columbia, South Carolina, USA
| | - Camilla F Wenceslau
- Cardiovascular Translational Research Center, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
- Biomedical Engineering Program, College of Engineering and Computing, University of South Carolina, Columbia, South Carolina, USA
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Park S, Cathey AL, Hao W, Zeng L, Pennathur S, Aung MT, Rosario-Pabón Z, Vélez-Vega CM, Cordero JF, Alshawabkeh A, Watkins DJ, Meeker JD. Associations of phthalates, phthalate replacements, and their mixtures with eicosanoid biomarkers during pregnancy. ENVIRONMENT INTERNATIONAL 2023; 178:108101. [PMID: 37487376 PMCID: PMC10733973 DOI: 10.1016/j.envint.2023.108101] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/25/2023] [Accepted: 07/17/2023] [Indexed: 07/26/2023]
Abstract
Humans are exposed to complex mixtures of phthalates. Gestational exposure to phthalates has been linked to preeclampsia and preterm birth through potential pathways such as endocrine disruption, oxidative stress, and inflammation. Eicosanoids are bioactive signaling lipids that are related to a variety of homeostatic and inflammatory processes. We investigated associations between urinary phthalates and their mixtures with plasma eicosanoid levels during pregnancy using the PROTECT cohort in Puerto Rico (N = 655). After adjusting for covariates, we estimated pair-wise associations between the geometric mean of individual phthalate metabolite concentrations across pregnancy and eicosanoid biomarkers using multivariable linear regression. We used bootstrapping of adaptive elastic net regression (adENET) to evaluate phthalate mixtures associated with eicosanoids and subsequently create environmental risk scores (ERS) to represent weighted sums of phthalate exposure for each individual. After adjusting for false-discovery, in single-pollutant analysis, 14 of 20 phthalate metabolites or parent compound indices showed significant and primarily negative associations with multiple eicosanoids. In our mixture analysis, associations with several metabolites of low molecular weight phthalates - DEP, DBP, and DIBP - became prominent. Additionally, MEHHTP and MECPTP, metabolites of a new phthalate replacement, DEHTP, were selected as important predictors for determining the concentrations of multiple eicosanoids from different pathway groups. A unit increase in phthalate ERS derived from bootstrapping of adENET was positively associated with several eicosanoids mainly from Cytochrome P450 pathway. For example, an increase in ERS was associated with 11(S)-HETE (β = 1.6, 95% CI: 0.020, 3.180), (±)11,12-DHET (β = 2.045, 95% CI: 0.250, 3.840), 20(S)-HETE (β = 0.813, 95% CI: 0.147, 1.479), and 9 s-HODE (β = 2.381, 95% CI: 0.657, 4.104). Gestational exposure to phthalates and phthalate mixtures were associated with eicosanoid levels during pregnancy. Results from the mixture analyses underscore the complexity of physiological impacts of phthalate exposure and call for further in-depth studies to examine these relationships.
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Affiliation(s)
- Seonyoung Park
- Department of Environmental Health Sciences, University of Michigan, School of Public Health, Ann Arbor, MI, USA
| | - Amber L Cathey
- Department of Environmental Health Sciences, University of Michigan, School of Public Health, Ann Arbor, MI, USA
| | - Wei Hao
- Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA
| | - Lixia Zeng
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Subramaniam Pennathur
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Max T Aung
- Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
| | - Zaira Rosario-Pabón
- Graduate School of Public Health, Medical Sciences Campus, University of Puerto Rico, San Juan, PR, USA
| | - Carmen M Vélez-Vega
- Graduate School of Public Health, Medical Sciences Campus, University of Puerto Rico, San Juan, PR, USA
| | - José F Cordero
- Department of Epidemiology and Biostatistics, University of Georgia, Athens, GA, USA
| | | | - Deborah J Watkins
- Department of Environmental Health Sciences, University of Michigan, School of Public Health, Ann Arbor, MI, USA
| | - John D Meeker
- Department of Environmental Health Sciences, University of Michigan, School of Public Health, Ann Arbor, MI, USA.
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Rasquel-Oliveira FS, Silva MDVD, Martelossi-Cebinelli G, Fattori V, Casagrande R, Verri WA. Specialized Pro-Resolving Lipid Mediators: Endogenous Roles and Pharmacological Activities in Infections. Molecules 2023; 28:5032. [PMID: 37446699 DOI: 10.3390/molecules28135032] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/07/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
During an infection, inflammation mobilizes immune cells to eliminate the pathogen and protect the host. However, inflammation can be detrimental when exacerbated and/or chronic. The resolution phase of the inflammatory process is actively orchestrated by the specialized pro-resolving lipid mediators (SPMs), generated from omega-3 and -6 polyunsaturated fatty acids (PUFAs) that bind to different G-protein coupled receptors to exert their activity. As immunoresolvents, SPMs regulate the influx of leukocytes to the inflammatory site, reduce cytokine and chemokine levels, promote bacterial clearance, inhibit the export of viral transcripts, enhance efferocytosis, stimulate tissue healing, and lower antibiotic requirements. Metabolomic studies have evaluated SPM levels in patients and animals during infection, and temporal regulation of SPMs seems to be essential to properly coordinate a response against the microorganism. In this review, we summarize the current knowledge on SPM biosynthesis and classifications, endogenous production profiles and their effects in animal models of bacterial, viral and parasitic infections.
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Affiliation(s)
- Fernanda S Rasquel-Oliveira
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, Brazil
| | - Matheus Deroco Veloso da Silva
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, Brazil
| | - Geovana Martelossi-Cebinelli
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, Brazil
| | - Victor Fattori
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Rubia Casagrande
- Department of Pharmaceutical Sciences, Center of Health Science, Londrina State University, Londrina 86038-440, Paraná, Brazil
| | - Waldiceu A Verri
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, Brazil
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Yang H, Rothenberger E, Zhao T, Fan W, Kelly A, Attaya A, Fan D, Panigrahy D, Deng J. Regulation of inflammation in cancer by dietary eicosanoids. Pharmacol Ther 2023:108455. [PMID: 37257760 DOI: 10.1016/j.pharmthera.2023.108455] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/16/2023] [Accepted: 05/22/2023] [Indexed: 06/02/2023]
Abstract
BACKGROUND Cancer is a major burden of disease worldwide and increasing evidence shows that inflammation contributes to cancer development and progression. Eicosanoids are derived from dietary polyunsaturated fatty acids, such as arachidonic acid (AA), and are mainly produced by a series of enzymatic pathways that include cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 epoxygenase (CYP). Eicosanoids consist of at least several hundred individual molecules and play important roles in the inflammatory response and inflammation-related cancers. SCOPE AND APPROACH Dietary sources of AA and biosynthesis of eicosanoids from AA through different metabolic pathways are summarized. The bioactivities of eicosanoids and their potential molecular mechanisms on inflammation and cancer are revealed. Additionally, current challenges and limitations in eicosanoid research on inflammation-related cancer are discussed. KEY FINDINGS AND CONCLUSIONS Dietary AA generates a large variety of eicosanoids, including prostaglandins, thromboxane A2, leukotrienes, cysteinyl leukotrienes, lipoxins, hydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatrienoic acids (EETs). Eicosanoids exert different bioactivities and mechanisms involved in the inflammation and related cancer developments. A deeper understanding of eicosanoid biology may be advantageous in cancer treatment and help to define cellular targets for further therapeutic development.
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Affiliation(s)
- Haixia Yang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
| | - Eva Rothenberger
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Tong Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Wendong Fan
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Abigail Kelly
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Ahmed Attaya
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710069, China
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Jianjun Deng
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710069, China; State Key Laboratory of Vegetable Biobreeding, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
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8
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Stotts C, Corrales-Medina VF, Rayner KJ. Pneumonia-Induced Inflammation, Resolution and Cardiovascular Disease: Causes, Consequences and Clinical Opportunities. Circ Res 2023; 132:751-774. [PMID: 36927184 DOI: 10.1161/circresaha.122.321636] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
Pneumonia is inflammation in the lungs, which is usually caused by an infection. The symptoms of pneumonia can vary from mild to life-threatening, where severe illness is often observed in vulnerable populations like children, older adults, and those with preexisting health conditions. Vaccines have greatly reduced the burden of some of the most common causes of pneumonia, and the use of antimicrobials has greatly improved the survival to this infection. However, pneumonia survivors do not return to their preinfection health trajectories but instead experience an accelerated health decline with an increased risk of cardiovascular disease. The mechanisms of this association are not well understood, but a persistent dysregulated inflammatory response post-pneumonia appears to play a central role. It is proposed that the inflammatory response during pneumonia is left unregulated and exacerbates atherosclerotic vascular disease, which ultimately leads to adverse cardiac events such as myocardial infarction. For this reason, there is a need to better understand the inflammatory cross talk between the lungs and the heart during and after pneumonia to develop therapeutics that focus on preventing pneumonia-associated cardiovascular events. This review will provide an overview of the known mechanisms of inflammation triggered during pneumonia and their relevance to the increased cardiovascular risk that follows this infection. We will also discuss opportunities for new clinical approaches leveraging strategies to promote inflammatory resolution pathways as a novel therapeutic target to reduce the risk of cardiac events post-pneumonia.
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Affiliation(s)
- Cameron Stotts
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (C.S., K.J.R).,Centre for Infection, Immunity, and Inflammation, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (C.S., V.F.C.-M.).,University of Ottawa Heart Institute, Ottawa, ON, Canada (C.S., K.J.R)
| | - Vicente F Corrales-Medina
- Centre for Infection, Immunity, and Inflammation, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (C.S., V.F.C.-M.).,Department of Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (V.F.C-M).,Ottawa Hospital Research Institute, Ottawa, ON, Canada (V.F.C.-M)
| | - Katey J Rayner
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (C.S., K.J.R).,University of Ottawa Heart Institute, Ottawa, ON, Canada (C.S., K.J.R)
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Chen R, Li J, Zhou J, Wang Y, Zhao X, Li N, Liu W, Liu C, Zhou P, Chen Y, Yan S, Song L, Yan H, Zhao H. Prognostic impacts of Lipoxin A4 in patients with acute myocardial infarction: A prospective cohort study. Pharmacol Res 2023; 187:106618. [PMID: 36549409 DOI: 10.1016/j.phrs.2022.106618] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 11/28/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Lipoxin A4 (LXA4) is one of the specialized pro-resolving lipid mediators proved to suppress the progression of atherosclerosis in vivo, but its clinical impacts in atherosclerotic patients is unclear. In this study, we assessed the prognostic impacts of LXA4 in patients with acute myocardial infarction (AMI). A total of 1569 consecutive AMI patients were prospectively recruited from March 2017 to January 2020. Plasma samples of AMI patients were collected, and LXA4 levels were determined using enzyme-linked immunosorbent assay. The primary outcome was major adverse cardiovascular event (MACE), a composite of all-cause death, recurrent MI, ischemic stroke, or ischemia-driven revascularization. Cox regression was used to assess associations between LXA4 and clinical outcomes. Overall, the median level of LXA4 was 5.637 (3.047-9.014) ng/mL for AMI patients. During a median follow-up of 786 (726-1108) days, high LXA4 (≥ 5.637 ng/mL) was associated with lower risk of MACE (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: 0.60-0.89, P = 0.002), which was sustained in propensity score matching (HR: 0.73, 95% CI: 0.60-0.90, P = 0.004) and inverse probability weighting analysis (HR: 0.74, 95% CI: 0.61-0.90, P = 0.002). Combined with pro-inflammatory biomarker, patients with high levels of LXA4 (≥ 5.637 ng/mL) but low levels of high-sensitivity C-reactive protein (< 5.7 mg/L) acquired the lowest risk of MACE (HR: 0.68, 95% CI: 0.51-0.92, P = 0.012). In sum, high levels of LXA4 were associated with lower risk of recurrent ischemic events for AMI patients, which could serve as new therapeutic target to tackle cardiovascular inflammation.
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Affiliation(s)
- Runzhen Chen
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, China; Coronary Heart Disease Center, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Jiannan Li
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jinying Zhou
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Ying Wang
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoxiao Zhao
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Nan Li
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Weida Liu
- Medical Research Center, Peking Union Medical College Hospital, Beijing, China
| | - Chen Liu
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Coronary Heart Disease Center, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Peng Zhou
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Coronary Heart Disease Center, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yi Chen
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Coronary Heart Disease Center, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Shaodi Yan
- Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, China
| | - Li Song
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, China; Coronary Heart Disease Center, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Hongbing Yan
- Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, China; Coronary Heart Disease Center, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China.
| | - Hanjun Zhao
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Coronary Heart Disease Center, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China.
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10
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Sandeep B, Xiao Z, Zhao F, Feng Q, Gao K. Role of Platelets in Acute Lung Injury After Extracorporeal Circulation in Cardiac Surgery Patients: A Systemic Review. Curr Probl Cardiol 2022; 47:101088. [PMID: 34936908 DOI: 10.1016/j.cpcardiol.2021.101088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 12/15/2021] [Indexed: 11/15/2022]
Abstract
In vitro circulation (cardiopulmonary bypass, CPB) has been widely used in heart surgery. In the past, it was believed that the reduction of platelet count and impaired platelet function during cardiac surgery were the main causes of acute lung injury (ALI). ALI is a life-threatening clinical syndrome in critically ill patients due to an uncontrolled systemic inflammatory response resulting from direct injury to the lung or indirect injury in the setting of a systemic process. Platelets have an emerging and incompletely understood role in a myriad of ALI after extracorporeal circulation in cardiac surgery patients. An electronic literature search was performed using Pubmed, Scopus and Cinahl investigating ALI, pathogenesis, and role of platelets, treatment and management for ALI patients. Many studies have shown that in vitro circulation is a nonphysiological process that can lead to a decrease in the number of platelets and impaired platelet function, as well as varying degrees of lung damage. The relationship between the effects of in vitro circulation on platelets and acute lung injury is still controversial. This review article discusses the role of platelets in lung injury after cardiopulmonary bypass and resent development in the management of ALI.
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Affiliation(s)
- Bhushan Sandeep
- Department of Cardiothoracic Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, China
| | - Zongwei Xiao
- Department of Cardiothoracic Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, China
| | - Fengying Zhao
- Department of Intensive Care Unit, Chengdu Second People's Hospital, Chengdu, Sichuan, China
| | - Qianru Feng
- Department of Intensive Care Unit, Chengdu Second People's Hospital, Chengdu, Sichuan, China
| | - Ke Gao
- Department of Cardiothoracic Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, China.
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11
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Contursi A, Tacconelli S, Hofling U, Bruno A, Dovizio M, Ballerini P, Patrignani P. Biology and pharmacology of platelet-type 12-lipoxygenase in platelets, cancer cells, and their crosstalk. Biochem Pharmacol 2022; 205:115252. [PMID: 36130648 DOI: 10.1016/j.bcp.2022.115252] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/08/2022] [Accepted: 09/12/2022] [Indexed: 11/26/2022]
Abstract
Platelet-type lipoxygenase (pl12-LOX), encoded by ALOX12, catalyzes the production of the lipid mediator 12S-hydroperoxyeicosa-5,8,10,14-tetraenoic acid (12S-HpETE), which is quickly reduced by cellular peroxidases to form 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12S-HETE). Platelets express high levels of pl12-LOX and generate considerable amounts of 12S-HETE from arachidonic acid (AA; C20:4, n-6). The development of sensitive chiral liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods has allowed the accurate quantification of 12S-HETE in biological samples. Moreover, advances in the knowledge of the mechanism of action of 12S-HETE have been achieved. The orphan G-protein-coupled receptor 31 (GPR31) has been identified as the high-affinity 12S-HETE receptor. Moreover, upon platelet activation, 12S-HETE is produced, and significant amounts are found esterified to membrane phospholipids (PLs), such as phosphatidylethanolamine (PE) and phosphatidylcholine (PC), promoting thrombin generation. Platelets play many roles in cancer metastasis. Among them, the platelets' ability to interact with cancer cells and transfer platelet molecules by the release of extracellular vesicles (EVs) is noteworthy. Recently, it was found that platelets induce epithelial-mesenchymal transition(EMT) in cancer cells, a phenomenon known to confer high-grade malignancy, through the transfer of pl12-LOX contained in platelet-derived EVs. These cancer cells now generate 12-HETE, considered a key modulator of cancer metastasis. Interestingly, 12-HETE was mainly found esterified in plasmalogen phospholipids of cancer cells. This review summarizes the current knowledge on the regulation and functions of pl12-LOX in platelets and cancer cells and their crosstalk.Novel approaches to preventing cancer and metastasis by the pharmacological inhibition of pl12-LOX and the internalization of mEVs are discussed.
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Affiliation(s)
- Annalisa Contursi
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy
| | - Stefania Tacconelli
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy
| | - Ulrika Hofling
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy
| | - Annalisa Bruno
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy
| | - Melania Dovizio
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy
| | - Patrizia Ballerini
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Innovative Technologies in Medicine and Dentistry, "G. d'Annunzio" University, Chieti, Italy
| | - Paola Patrignani
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy.
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12
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Wach J, Güresir Á, Vatter H, Herrlinger U, Becker A, Toma M, Hölzel M, Güresir E. Low-Dose Acetylsalicylic Acid Treatment in Non-Skull-Base Meningiomas: Impact on Tumor Proliferation and Seizure Burden. Cancers (Basel) 2022; 14:cancers14174285. [PMID: 36077817 PMCID: PMC9454729 DOI: 10.3390/cancers14174285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/26/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
MIB-1 index is an important predictor of meningioma progression and was found to be correlated with COX-2 expression. However, the impact of low-dose acetylsalicylic acid (ASA) on MIB-1 index and clinical symptoms is unclear. Between 2009 and 2022, 710 patients with clinical data, tumor-imaging data, inflammatory laboratory (plasma fibrinogen, serum C-reactive protein) data, and neuropathological reports underwent surgery for primary cranial WHO grade 1 and 2 meningioma. ASA intake was found to be significantly associated with a low MIB-1 labeling index in female patients ≥ 60 years. Multivariable analysis demonstrated that female patients ≥ 60 years with a non-skull-base meningioma taking ASA had a significantly lower MIB-1 index (OR: 2.6, 95%: 1.0–6.6, p = 0.04). Furthermore, the intake of ASA was independently associated with a reduced burden of symptomatic epilepsy at presentation in non-skull-base meningiomas in both genders (OR: 3.8, 95%CI: 1.3–10.6, p = 0.03). ASA intake might have an anti-proliferative effect in the subgroup of elderly female patients with non-skull-base meningiomas. Furthermore, anti-inflammatory therapy seems to reduce the burden of symptomatic epilepsy in non-skull-base meningiomas. Further research is needed to investigate the role of anti-inflammatory therapy in non-skull-base meningiomas.
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Affiliation(s)
- Johannes Wach
- Department of Neurosurgery, University Hospital Bonn, 53127 Bonn, Germany
- Correspondence: ; Tel.: +49-228-287-16521
| | - Ági Güresir
- Department of Neurosurgery, University Hospital Bonn, 53127 Bonn, Germany
| | - Hartmut Vatter
- Department of Neurosurgery, University Hospital Bonn, 53127 Bonn, Germany
| | - Ulrich Herrlinger
- Division of Clinical Neurooncology, Department of Neurology and Centre of Integrated Oncology, University Hospital Bonn, 53127 Bonn, Germany
| | - Albert Becker
- Department of Neuropathology, University Hospital Bonn, 53127 Bonn, Germany
| | - Marieta Toma
- Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany
| | - Michael Hölzel
- Institute of Experimental Oncology, University Hospital Bonn, 53127 Bonn, Germany
| | - Erdem Güresir
- Department of Neurosurgery, University Hospital Bonn, 53127 Bonn, Germany
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13
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Henriksen HH, Marín de Mas I, Herand H, Krocker J, Wade CE, Johansson PI. Metabolic systems analysis identifies a novel mechanism contributing to shock in patients with endotheliopathy of trauma (EoT) involving thromboxane A2 and LTC 4. Matrix Biol Plus 2022; 15:100115. [PMID: 35813244 PMCID: PMC9260291 DOI: 10.1016/j.mbplus.2022.100115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 06/10/2022] [Accepted: 06/14/2022] [Indexed: 11/17/2022] Open
Abstract
Purpose Endotheliopathy of trauma (EoT), as defined by circulating levels of syndecan-1 ≥ 40 ng/mL, has been reported to be associated with significantly increased transfusion requirements and a doubled 30-day mortality. Increased shedding of the glycocalyx points toward the endothelial cell membrane composition as important for the clinical outcome being the rationale for this study. Results The plasma metabolome of 95 severely injured trauma patients was investigated by mass spectrometry, and patients with EoT vs. non-EoT were compared by partial least square-discriminant analysis, identifying succinic acid as the top metabolite to differentiate EoT and non-EoT patients (VIP score = 3). EoT and non-EoT patients' metabolic flux profile was inferred by integrating the corresponding plasma metabolome data into a genome-scale metabolic network reconstruction analysis and performing a functional study of the metabolic capabilities of each group. Model predictions showed a decrease in cholesterol metabolism secondary to impaired mevalonate synthesis in EoT compared to non-EoT patients. Intracellular task analysis indicated decreased synthesis of thromboxanA2 and leukotrienes, as well as a lower carnitine palmitoyltransferase I activity in EoT compared to non-EoT patients. Sensitivity analysis also showed a significantly high dependence of eicosanoid-associated metabolic tasks on alpha-linolenic acid as unique to EoT patients. Conclusions Model-driven analysis of the endothelial cells' metabolism identified potential novel targets as impaired thromboxane A2 and leukotriene synthesis in EoT patients when compared to non-EoT patients. Reduced thromboxane A2 and leukotriene availability in the microvasculature impairs vasoconstriction ability and may thus contribute to shock in EoT patients. These findings are supported by extensive scientific literature; however, further investigations are required on these findings.
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Key Words
- AA, Arachidonic acid
- CPT1, Carnitine palmitoyltransferase I
- EC, Endothelial cell
- EC-GEM, Genome-scale metabolic model of the microvascular endothelial cell
- ELISA, Enzyme-linked immunosorbent assay
- Eicosanoid
- Endotheliopathy
- EoT, Endotheliopathy of trauma
- FBA, Flux balance analysis
- GEMs, Genome-scale metabolic models
- Genome-scale metabolic model
- HMG-CoA, Hydroxymethylglutaryl-CoA
- ISS, Injury Severity Score
- LTC4, Leukotriene C4
- Metabolomics
- PCA, Principal Component Analysis
- PLS-DA, Partial least square-discriminant analysis
- Systems biology
- Trauma
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Affiliation(s)
- Hanne H. Henriksen
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- CAG Center for Endotheliomics, Copenhagen University Hospital, Rigshospitalet, Denmark
| | - Igor Marín de Mas
- CAG Center for Endotheliomics, Copenhagen University Hospital, Rigshospitalet, Denmark
- Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark
| | - Helena Herand
- CAG Center for Endotheliomics, Copenhagen University Hospital, Rigshospitalet, Denmark
- Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark
| | - Joseph Krocker
- Center for Translational Injury Research, Department of Surgery, University of Texas Health Science Center, Houston, TX, USA
| | - Charles E. Wade
- Center for Translational Injury Research, Department of Surgery, University of Texas Health Science Center, Houston, TX, USA
| | - Pär I. Johansson
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- CAG Center for Endotheliomics, Copenhagen University Hospital, Rigshospitalet, Denmark
- Center for Translational Injury Research, Department of Surgery, University of Texas Health Science Center, Houston, TX, USA
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14
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Liotti F, Marotta M, Melillo RM, Prevete N. The Impact of Resolution of Inflammation on Tumor Microenvironment: Exploring New Ways to Control Cancer Progression. Cancers (Basel) 2022; 14:3333. [PMID: 35884394 PMCID: PMC9316558 DOI: 10.3390/cancers14143333] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/06/2022] [Accepted: 07/07/2022] [Indexed: 12/23/2022] Open
Abstract
Non-resolving inflammation is an enabling feature of cancer. A novel super-family of lipid mediators termed Specialized Pro-resolving Mediators (SPMs) have a role as bioactive molecules mediating the resolution of inflammation in cancer biology. SPMs are derived from ω-3 and ω-6 polyunsaturated fatty acids through the activity of lipoxygenases. SPMs have been described to directly modulate cancer progression by interfering with the epithelial to mesenchymal transition and invasion of cancer cells. SPMs have also been demonstrated to act on several components of the tumor microenvironment (TME). Consistently with their natural immunomodulatory and anti-inflammatory properties, SPMs are able to reprogram macrophages to favor phagocytosis of cell debris, which are an important source of pro-inflammatory and pro-angiogenic signals; sustain a direct cytotoxic immune response against cancer cells; stimulate neutrophils anti-tumor activities; and inhibit the development of regulatory T and B cells, thus indirectly leading to enhanced anti-tumor immunity. Furthermore, the resolution pathways exert crucial anti-angiogenic functions in lung, liver, and gastrointestinal cancers, and inhibit cancer-associated fibroblast differentiation and functions in hepatocellular carcinoma and pancreatic cancer. The present review will be focused on the potential protective effects of resolution pathways against cancer, exerted by modulating different components of the TME.
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Affiliation(s)
- Federica Liotti
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (F.L.); (M.M.)
- Institute of Experimental Endocrinology and Oncology (IEOS), CNR, 80131 Naples, Italy
| | - Maria Marotta
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (F.L.); (M.M.)
| | - Rosa Marina Melillo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (F.L.); (M.M.)
- Institute of Experimental Endocrinology and Oncology (IEOS), CNR, 80131 Naples, Italy
| | - Nella Prevete
- Institute of Experimental Endocrinology and Oncology (IEOS), CNR, 80131 Naples, Italy
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy
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15
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Dubé L, Spahis S, Lachaîne K, Lemieux A, Monhem H, Poulin SM, Randoll C, Travaillaud E, Ould-Chikh NEH, Marcil V, Delvin E, Levy E. Specialized Pro-Resolving Mediators Derived from N-3 Polyunsaturated Fatty Acids: Role in Metabolic Syndrome and Related Complications. Antioxid Redox Signal 2022; 37:54-83. [PMID: 35072542 DOI: 10.1089/ars.2021.0156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Significance: Metabolic syndrome (MetS) prevalence continues to grow and represents a serious public health issue worldwide. This multifactorial condition carries the risk of hastening the development of type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). Another troubling aspect of MetS is the requirement of poly-pharmacological therapy not devoid of side effects. Therefore, there is an urgent need for prospecting alternative nutraceuticals as effective therapeutic agents for MetS. Recent Advances: Currently, there is an increased interest in understanding the regulation of metabolic derangements by specialized pro-resolving lipid mediators (SPMs), especially those derived from the long chain n-3 polyunsaturated fatty acids. Critical Issues: The SPMs are recognized as efficient modulators that are capable of inhibiting the production of pro-inflammatory cytokines, blocking neutrophil activation/recruitment, and inducing non-phlogistic (anti-inflammatory) activation of macrophage engulfment and removal of apoptotic inflammatory cells and debris. The aim of the present review is precisely to first underline key concepts relative to SPM functions before focusing on their status and actions on MetS components (e.g., obesity, glucose dysmetabolism, hyperlipidemia, hypertension) and complications such as T2D, NAFLD, and CVD. Future Directions: Valuable data from preclinical and clinical investigations have emphasized the SPM functions and influence on oxidative stress- and inflammation-related MetS. Despite these promising findings obtained without compromising host defense, additional efforts are needed to evaluate their potential therapeutic applications and further develop practical tools to monitor their bioavailability to cope with cardiometabolic disorders. Antioxid. Redox Signal. 37, 54-83.
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Affiliation(s)
- Laurent Dubé
- Research Centre, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada.,Department of Nutrition, Université de Montréal, Montreal, Canada
| | - Schohraya Spahis
- Research Centre, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada.,Department of Nutrition, Université de Montréal, Montreal, Canada.,Institute of Nutrition and Functional Foods, Laval University, Quebec City, Canada
| | - Karelle Lachaîne
- Department of Nutrition, Université de Montréal, Montreal, Canada
| | | | - Hanine Monhem
- Department of Nutrition, Université de Montréal, Montreal, Canada
| | | | - Carolane Randoll
- Department of Nutrition, Université de Montréal, Montreal, Canada
| | - Eva Travaillaud
- Department of Nutrition, Université de Montréal, Montreal, Canada
| | | | - Valérie Marcil
- Research Centre, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada.,Department of Nutrition, Université de Montréal, Montreal, Canada.,Institute of Nutrition and Functional Foods, Laval University, Quebec City, Canada
| | - Edgard Delvin
- Research Centre, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada.,Department of Biochemistry, Université de Montréal, Montreal, Canada
| | - Emile Levy
- Research Centre, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada.,Department of Nutrition, Université de Montréal, Montreal, Canada.,Institute of Nutrition and Functional Foods, Laval University, Quebec City, Canada.,Department of Pediatrics, Gastroenterology & Hepatology Unit, Université de Montréal, Montreal, Canada
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16
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Artru F, McPhail MJW, Triantafyllou E, Trovato FM. Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids. Front Immunol 2022; 13:867261. [PMID: 35432367 PMCID: PMC9008479 DOI: 10.3389/fimmu.2022.867261] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/08/2022] [Indexed: 12/30/2022] Open
Abstract
Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described.
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Affiliation(s)
- Florent Artru
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Mark J W McPhail
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Evangelos Triantafyllou
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
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17
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Behavioral, Anti-Inflammatory, and Neuroprotective Effects of a Novel FPR2 Agonist in Two Mouse Models of Autism. Pharmaceuticals (Basel) 2022; 15:ph15020161. [PMID: 35215274 PMCID: PMC8875614 DOI: 10.3390/ph15020161] [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: 12/31/2021] [Revised: 01/25/2022] [Accepted: 01/26/2022] [Indexed: 02/01/2023] Open
Abstract
Autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental conditions characterized by social deficits, repetitive stereotyped behaviors, and altered inflammatory responses. Accordingly, children with ASD show decreased plasma levels of lipoxin A4 (LXA4), a mediator involved in the resolution of inflammation, which is the endogenous ligand of the formyl peptide receptor 2 (FPR2). To investigate the role of FPR2 in ASDs, we have used a new ureidopropanamide derivative able to activate the receptor, named MR-39. The effects of MR-39 (10 mg/kg, for 8 days) on hippocampal pro-inflammatory profile, neuronal plasticity, and social behavior were evaluated in two validated animal models of ASD: BTBR mouse strain and mice prenatally exposed to valproic acid (VPA). Primary cultures of hippocampal neurons from BTBR mice were also used to evaluate the effect of MR-39 on neurite elongation. Our results show that MR-39 treatment reduced several inflammatory markers, restored the low expression of LXA4, and modulated FPR2 expression in hippocampal tissues of both ASD animal models. These findings were accompanied by a significant positive effect of MR-39 on social behavioral tests of ASD mice. Finally, MR-39 stimulates neurite elongation in isolated hippocampal neurons of BTBR mice. In conclusion, these data indicate FPR2 as a potential target for an innovative therapeutical approach for the cure of ASD.
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18
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Cecconello C, Clària Ribas P, Norling LV. Resolving acute inflammation; what happens when inflammation goes haywire? How can it get back in line? DIET, INFLAMMATION, AND HEALTH 2022:113-162. [DOI: 10.1016/b978-0-12-822130-3.00018-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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19
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Sandeep B, Xiao Z, Zhao F, Feng Q, Gao K. Role of Platelets in Acute Lung Injury After Extracorporeal Circulation in Cardiac Surgery Patients: A Systemic Review. Curr Probl Cardiol 2021. [DOI: https://doi.org/10.1016/j.cpcardiol.2021.101088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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20
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Podstawka J, Sinha S, Hiroki CH, Sarden N, Granton E, Labit E, Kim JH, Andonegui G, Lou Y, Snarr BD, Sheppard DC, Rosin NL, Biernaskie J, Yipp BG. Marginating transitional B cells modulate neutrophils in the lung during inflammation and pneumonia. J Exp Med 2021; 218:e20210409. [PMID: 34313733 PMCID: PMC8318832 DOI: 10.1084/jem.20210409] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 06/04/2021] [Accepted: 07/06/2021] [Indexed: 12/25/2022] Open
Abstract
Pulmonary innate immunity is required for host defense; however, excessive neutrophil inflammation can cause life-threatening acute lung injury. B lymphocytes can be regulatory, yet little is known about peripheral transitional IgM+ B cells in terms of regulatory properties. Using single-cell RNA sequencing, we discovered eight IgM+ B cell subsets with unique gene regulatory networks in the lung circulation dominated by transitional type 1 B and type 2 B (T2B) cells. Lung intravital confocal microscopy revealed that T2B cells marginate in the pulmonary capillaries via CD49e and require CXCL13 and CXCR5. During lung inflammation, marginated T2B cells dampened excessive neutrophil vascular inflammation via the specialized proresolving molecule lipoxin A4 (LXA4). Exogenous CXCL13 dampened excessive neutrophilic inflammation by increasing marginated B cells, and LXA4 recapitulated neutrophil regulation in B cell-deficient mice during inflammation and fungal pneumonia. Thus, the lung microvasculature is enriched in multiple IgM+ B cell subsets with marginating capillary T2B cells that dampen neutrophil responses.
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Affiliation(s)
- John Podstawka
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Sarthak Sinha
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Carlos H. Hiroki
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Nicole Sarden
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Elise Granton
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Elodie Labit
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Jung Hwan Kim
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Graciela Andonegui
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Yuefei Lou
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Brendan D. Snarr
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
| | - Donald C. Sheppard
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
- Division of Infectious Diseases, McGill University Health Centre, Montreal, Quebec, Canada
- Department of Medical Microbiology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Nicole L. Rosin
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Jeff Biernaskie
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Bryan G. Yipp
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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21
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Giménez-Bastida JA, González-Sarrías A, Laparra-Llopis JM, Schneider C, Espín JC. Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review. Int J Mol Sci 2021; 22:7937. [PMID: 34360703 PMCID: PMC8348464 DOI: 10.3390/ijms22157937] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/20/2021] [Accepted: 07/21/2021] [Indexed: 12/15/2022] Open
Abstract
5-Lipoxygenase (5-LOX) plays a key role in inflammation through the biosynthesis of leukotrienes and other lipid mediators. Current evidence suggests that dietary (poly)phenols exert a beneficial impact on human health through anti-inflammatory activities. Their mechanisms of action have mostly been associated with the modulation of pro-inflammatory cytokines (TNF-α, IL-1β), prostaglandins (PGE2), and the interaction with NF-κB and cyclooxygenase 2 (COX-2) pathways. Much less is known about the 5-lipoxygenase (5-LOX) pathway as a target of dietary (poly)phenols. This systematic review aimed to summarize how dietary (poly)phenols target the 5-LOX pathway in preclinical and human studies. The number of studies identified is low (5, 24, and 127 human, animal, and cellular studies, respectively) compared to the thousands of studies focusing on the COX-2 pathway. Some (poly)phenolics such as caffeic acid, hydroxytyrosol, resveratrol, curcumin, nordihydroguaiaretic acid (NDGA), and quercetin have been reported to reduce the formation of 5-LOX eicosanoids in vitro. However, the in vivo evidence is inconclusive because of the low number of studies and the difficulty of attributing effects to (poly)phenols. Therefore, increasing the number of studies targeting the 5-LOX pathway would largely expand our knowledge on the anti-inflammatory mechanisms of (poly)phenols.
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Affiliation(s)
- Juan Antonio Giménez-Bastida
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain;
| | - Antonio González-Sarrías
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain;
| | - José Moisés Laparra-Llopis
- Group of Molecular Immunonutrition in Cancer, Madrid Institute for Advanced Studies in Food (IMDEA-Food), 28049 Madrid, Spain;
| | - Claus Schneider
- Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, TN 37232, USA;
| | - Juan Carlos Espín
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain;
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22
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Aubeux D, Peters OA, Hosseinpour S, Tessier S, Geoffroy V, Pérez F, Gaudin A. Specialized pro-resolving lipid mediators in endodontics: a narrative review. BMC Oral Health 2021; 21:276. [PMID: 34030680 PMCID: PMC8142493 DOI: 10.1186/s12903-021-01619-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 05/09/2021] [Indexed: 02/06/2023] Open
Abstract
Endodontics is the branch of dentistry concerned with the morphology, physiology, and pathology of the human dental pulp and periradicular tissues. Human dental pulp is a highly dynamic tissue equipped with a network of resident immunocompetent cells that play major roles in the defense against pathogens and during tissue injury. However, the efficiency of these mechanisms during dental pulp inflammation (pulpitis) varies due to anatomical and physiological restrictions. Uncontrolled, excessive, or unresolved inflammation can lead to pulp tissue necrosis and subsequent bone infections called apical periodontitis. In most cases, pulpitis treatment consists of total pulp removal. Although this strategy has a good success rate, this treatment has some drawbacks (lack of defense mechanisms, loss of healing capacities, incomplete formation of the root in young patients). In a sizeable number of clinical situations, the decision to perform pulp extirpation and endodontic treatment is justifiable by the lack of therapeutic tools that could otherwise limit the immune/inflammatory process. In the past few decades, many studies have demonstrated that the resolution of acute inflammation is necessary to avoid the development of chronic inflammation and to promote repair or regeneration. This active process is orchestrated by Specialized Pro-resolving lipid Mediators (SPMs), including lipoxins, resolvins, protectins and maresins. Interestingly, SPMs do not have direct anti-inflammatory effects by inhibiting or directly blocking this process but can actively reduce neutrophil infiltration into inflamed tissues, enhance efferocytosis and bacterial phagocytosis by monocytes and macrophages and simultaneously inhibit inflammatory cytokine production. Experimental clinical application of SPMs has shown promising result in a wide range of inflammatory diseases, such as renal fibrosis, cerebral ischemia, marginal periodontitis, and cancer; the potential of SPMs in endodontic therapy has recently been explored. In this review, our objective was to analyze the involvement and potential use of SPMs in endodontic therapies with an emphasis on SPM delivery systems to effectively administer SPMs into the dental pulp space.
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Affiliation(s)
- Davy Aubeux
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, 44042, Nantes, France
- Université de Nantes, UFR Odontologie, 44042, Nantes, France
| | - Ove A Peters
- School of Dentistry, The University of Queensland, Brisbane, Australia
| | | | - Solène Tessier
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, 44042, Nantes, France
- Université de Nantes, UFR Odontologie, 44042, Nantes, France
| | - Valérie Geoffroy
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, 44042, Nantes, France
- Université de Nantes, UFR Odontologie, 44042, Nantes, France
| | - Fabienne Pérez
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, 44042, Nantes, France
- Université de Nantes, UFR Odontologie, 44042, Nantes, France
- CHU Nantes, PHU4 OTONN44093, Nantes, France
| | - Alexis Gaudin
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, 44042, Nantes, France.
- Université de Nantes, UFR Odontologie, 44042, Nantes, France.
- CHU Nantes, PHU4 OTONN44093, Nantes, France.
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23
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Tiberi M, Chiurchiù V. Specialized Pro-resolving Lipid Mediators and Glial Cells: Emerging Candidates for Brain Homeostasis and Repair. Front Cell Neurosci 2021; 15:673549. [PMID: 33981203 PMCID: PMC8107215 DOI: 10.3389/fncel.2021.673549] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022] Open
Abstract
Astrocytes and oligodendrocytes are known to play critical roles in the central nervous system development, homeostasis and response to injury. In addition to their well-defined functions in synaptic signaling, blood-brain barrier control and myelination, it is now becoming clear that both glial cells also actively produce a wide range of immune-regulatory factors and engage in an intricate communication with neurons, microglia or with infiltrated immune cells, thus taking a center stage in both inflammation and resolution processes occurring within the brain. Resolution of inflammation is operated by the superfamily of specialized pro-resolving lipid mediators (SPMs), that include lipoxins, resolvins, protectins and maresins, and that altogether activate a series of cellular and molecular events that lead to spontaneous regression of inflammatory processes and restoration of tissue homeostasis. Here, we review the manifold effects of SPMs on modulation of astrocytes and oligodendrocytes, along with the mechanisms through which they either inhibit inflammatory pathways or induce the activation of protective ones. Furthermore, the possible role of SPMs in modulating the cross-talk between microglia, astrocytes and oligodendrocytes is also summarized. This SPM-mediated mechanism uncovers novel pathways of immune regulation in the brain that could be further exploited to control neuroinflammation and neurodegeneration.
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Affiliation(s)
- Marta Tiberi
- Laboratory of Resolution of Neuroinflammation, European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy
| | - Valerio Chiurchiù
- Laboratory of Resolution of Neuroinflammation, European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy.,Institute of Translational Pharmacology, National Research Council, Rome, Italy
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24
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Intrinsic exercise capacity induces divergent vascular plasticity via arachidonic acid-mediated inflammatory pathways in female rats. Vascul Pharmacol 2021; 140:106862. [PMID: 33872803 DOI: 10.1016/j.vph.2021.106862] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/03/2021] [Accepted: 04/07/2021] [Indexed: 12/31/2022]
Abstract
Metabolic syndrome prevalence has increased among US adults, particularly among non-hispanic white and black women. Sedentary behavior often leads to chronic inflammation, a triggering factor of metabolic syndrome. Given that intrinsic exercise capacity is genetically inherited, we questioned if low-grade chronic inflammation would be present in a female rat model of low intrinsic exercise capacity-induced metabolic syndrome, while beneficial increase of resolution of inflammation would be present in a female rat model of high intrinsic exercise capacity. In the vascular system, two primary markers for inflammation and resolution of inflammation are cyclooxygenase (COX) and lipoxygenase (LOX), respectively. Our study focused on the novel hypothesis that untrained, inherited exercise capacity induces divergent vascular plasticity via changes in the delicate balance between COX and LOX inflammatory mediators. We used divergent rat strains with low (LCR) and high (HCR) aerobic running capacity. By using animals with contrasting intrinsic exercise capacities, it is possible to determine the exact triggers that lead to inherited vascular plasticity in female rats. We observed that female LCR displayed increased periovarian fat pad and body weight, which is congruent with their obesity-presenting phenotype. Furthermore, LCR presented with vascular hypocontractility and increased COX and LOX-derived pro-inflammatory factors. On the other hand, HCR presented with a "shutdown" of COX-induced vasoconstriction and enhanced resolution of inflammation to maintain vascular tone and homeostasis. In conclusion, LCR display low-grade chronic inflammation via increased COX activity. These results provide mechanistic clues as to why lower intrinsic aerobic capacity correlates with a predisposition to risk of vascular disease. Conversely, being born with higher intrinsic aerobic capacity is a significant factor for improved vascular physiology in female rats.
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25
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Lipoxin A4 regulates microglial M1/M2 polarization after cerebral ischemia-reperfusion injury via the Notch signaling pathway. Exp Neurol 2021; 339:113645. [PMID: 33600815 DOI: 10.1016/j.expneurol.2021.113645] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 01/30/2021] [Accepted: 02/12/2021] [Indexed: 11/23/2022]
Abstract
Microglia are rapidly activated after acute ischemic stroke, and the polarization of microglial is associated with the prognosis of acute ischemic stroke. Lipoxin A4 (LXA4), an anti-inflammatory agent, has a protective effect against ischemic stroke. However, the role of LXA4 on the polarization of microglial after acute ischemic stroke remains undetermined. We hypothesized that LXA4 may exert the neuroprotective effect though regulating the polarization of microglial. In this study, clinical features of acute ischemic stroke were simulated using a rat model of model of middle cerebral artery occlusion (MCAO) in vivo and the BV2 microglia oxygen-glucose deprivation/reoxygenation model (OGD/R) in vitro. The protective effects of LXA4 on cerebral ischemia-reperfusion injury were determined using TTC staining, HE staining, and TUNEL staining. The expression of targeted genes was assayed using quantitative real-time PCR (qRT-PCR), immunofluorescence, and western blot to investigated the regulation of LXA4 on microglia polarization after acute ischemic stroke. We found that LXA4 exerted protective effects on focal cerebral ischemia-reperfusion injury and reduced the expression of the pro-inflammatory cytokines IL-1β and TNF-α. Furthermore, LXA4 inhibited the expression of Notch-1, Hes1, iNOS and CD32 all of which are associated with the differentiation into M1 microglia. By contrast, LXA4 upregulated the expression of Hes5, Arg-1 and CD206 all of which are associated with M2 phenotype in microglia. In addition, blocking the Notch signaling pathway with the inhibitor DAPT significantly mitigated the effect of LXA4 on microglia differentiation. These data suggest that LXA4 may regulate the polarization of microglia after cerebral ischemia-reperfusion injury through the Notch signaling pathway.
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26
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Morris G, Bortolasci CC, Puri BK, Olive L, Marx W, O'Neil A, Athan E, Carvalho A, Maes M, Walder K, Berk M. Preventing the development of severe COVID-19 by modifying immunothrombosis. Life Sci 2021; 264:118617. [PMID: 33096114 PMCID: PMC7574725 DOI: 10.1016/j.lfs.2020.118617] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/01/2020] [Accepted: 10/13/2020] [Indexed: 01/10/2023]
Abstract
BACKGROUND COVID-19-associated acute respiratory distress syndrome (ARDS) is associated with significant morbidity and high levels of mortality. This paper describes the processes involved in the pathophysiology of COVID-19 from the initial infection and subsequent destruction of type II alveolar epithelial cells by SARS-CoV-2 and culminating in the development of ARDS. MAIN BODY The activation of alveolar cells and alveolar macrophages leads to the release of large quantities of proinflammatory cytokines and chemokines and their translocation into the pulmonary vasculature. The presence of these inflammatory mediators in the vascular compartment leads to the activation of vascular endothelial cells platelets and neutrophils and the subsequent formation of platelet neutrophil complexes. These complexes in concert with activated endothelial cells interact to create a state of immunothrombosis. The consequence of immunothrombosis include hypercoagulation, accelerating inflammation, fibrin deposition, migration of neutrophil extracellular traps (NETs) producing neutrophils into the alveolar apace, activation of the NLRP3 inflammazome, increased alveolar macrophage destruction and massive tissue damage by pyroptosis and necroptosis Therapeutic combinations aimed at ameliorating immunothrombosis and preventing the development of severe COVID-19 are discussed in detail.
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Affiliation(s)
- Gerwyn Morris
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Chiara C Bortolasci
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Deakin University, Centre for Molecular and Medical Research, School of Medicine, Geelong, Australia
| | | | - Lisa Olive
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; School of Psychology, Deakin University, Geelong, Australia
| | - Wolfgang Marx
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Adrienne O'Neil
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Melbourne School of Population and Global Health, Melbourne, Australia
| | - Eugene Athan
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Barwon Health, Geelong, Australia
| | - Andre Carvalho
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, University of Toronto, Toronto, Canada; Centre for Addiction and Mental Health (CAMH), Toronto, Canada
| | - Michael Maes
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, King Chulalongkorn University Hospital, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
| | - Ken Walder
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Deakin University, Centre for Molecular and Medical Research, School of Medicine, Geelong, Australia
| | - Michael Berk
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia.
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27
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Lee CH. Role of specialized pro-resolving lipid mediators and their receptors in virus infection: a promising therapeutic strategy for SARS-CoV-2 cytokine storm. Arch Pharm Res 2021; 44:84-98. [PMID: 33398691 PMCID: PMC7781431 DOI: 10.1007/s12272-020-01299-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023]
Abstract
Unexpected viral infections outbreaks, significantly affect human health, leading to increased mortality and life disruption. Among them is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged as a deadly pandemic, calling for intense research efforts on its pathogenicity mechanism and development of therapeutic strategies. In the SARS-CoV-2 cytokine storm, systemic inflammation has been associated with severe illness and mortality. Recent studies have demonstrated special pro-resolving lipids mediators (SPMs) lipoxins, resolvins, maresins, and protectins as potential therapeutic options for abnormal viral-triggered inflammation. Pro-resolving lipids mediators have shown great promise for the treatment of Herpes simplex virus, respiratory syncytial virus, human immunodeficiency virus, and hepatitis C virus. Based on this, studies are being conducted on their therapeutic effects in SARS-CoV-2 infection. In this review, we discussed SPMs and reviewed evidence from recent studies on SPMs as therapeutic options for viral infections, including SARS-CoV2. Based on our analysis of the previous study, we argue that SPMs are a potential treatment for SARS-CoV-2 infection and other viral infections. We expect further research on how SPMs modulate viral-triggered inflammation through G-protein-coupled receptors (GPCRs), and chemical stability and druggability of SPMs.
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Affiliation(s)
- Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul, 100-715, Republic of Korea.
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28
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Regulska M, Szuster-Głuszczak M, Trojan E, Leśkiewicz M, Basta-Kaim A. The Emerging Role of the Double-Edged Impact of Arachidonic Acid- Derived Eicosanoids in the Neuroinflammatory Background of Depression. Curr Neuropharmacol 2020; 19:278-293. [PMID: 32851950 PMCID: PMC8033972 DOI: 10.2174/1570159x18666200807144530] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 06/18/2020] [Accepted: 07/31/2020] [Indexed: 12/14/2022] Open
Abstract
Eicosanoids are arachidonic acid (AA) derivatives belonging to a family of lipid signalling mediators that are engaged in both physiological and pathological processes in the brain. Recently, their implication in the prolonged inflammatory response has become a focus of particular interest because, in contrast to acute inflammation, chronic inflammatory processes within the central nervous system (CNS) are crucial for the development of brain pathologies including depression. The synthesis of eicosanoids is catalysed primarily by cyclooxygenases (COX), which are involved in the production of pro-inflammatory AA metabolites, including prostaglandins and thromboxanes. Moreover, eicosanoid synthesis is catalysed by lipoxygenases (LOXs), which generate both leukotrienes and anti-inflammatory derivatives such as lipoxins. Thus, AA metabolites have double- edged pro-inflammatory and anti-inflammatory, pro-resolving properties, and an imbalance between these metabolites has been proposed as a contributor or even the basis for chronic neuroinflammatory effects. This review focuses on important evidence regarding eicosanoid-related pathways (with special emphasis on prostaglandins and lipoxins) that has added a new layer of complexity to the idea of targeting the double-edged AA-derivative pathways for therapeutic benefits in depression. We also sought to explore future research directions that can support a pro-resolving response to control the balance between eicosanoids and thus to reduce the chronic neuroinflammation that underlies at least a portion of depressive disorders.
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Affiliation(s)
- Magdalena Regulska
- Immunoendocrinology Laboratory, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343 Krakow, Poland
| | - Magdalena Szuster-Głuszczak
- Immunoendocrinology Laboratory, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343 Krakow, Poland
| | - Ewa Trojan
- Immunoendocrinology Laboratory, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343 Krakow, Poland
| | - Monika Leśkiewicz
- Immunoendocrinology Laboratory, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343 Krakow, Poland
| | - Agnieszka Basta-Kaim
- Immunoendocrinology Laboratory, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343 Krakow, Poland
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29
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Kumar A, Behl T, Jamwal S, Kaur I, Sood A, Kumar P. Exploring the molecular approach of COX and LOX in Alzheimer's and Parkinson's disorder. Mol Biol Rep 2020; 47:9895-9912. [PMID: 33263931 DOI: 10.1007/s11033-020-06033-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 11/24/2020] [Indexed: 01/02/2023]
Abstract
Neuroinflammation is well established biomarker for the major neurodegenerative like Alzheimer's disease (AD) and Parkinson's disease (PD). Cytokines/chemokines excite phospholipase A2 and cyclooxygenases (COX), facilitating the release of arachidonic acid (AA) and docosahexaenoic acid (DHA) from membrane glycerophospholipids, in which the former is oxidized to produce pro-inflammatory eicosanoids (prostaglandins, leukotrienes and thromboxane's), which intensify the neuroinflammatory events in the brain. Similarly, resolvins and neuroprotectins are the metabolized products of docosahexaenoic acid, which exert an inhibitory effect on the production of eicosanoids. Furthermore, an oxidized product of arachidonic acid, lipoxin, is generated via 5-lipoxygenase (5-LOX) pathway, and contributes to the resolution of inflammation, along with anti-inflammatory actions. Moreover, DHA and its lipid mediators inhibit neuroinflammatory responses by blocking NF-κB, inhibiting eicosanoid production, preventing cytokine secretion and regulating leukocyte trafficking. Various epidemiological studies reported, elevated levels of COX-2 enzyme in patients with AD and PD, indicating its role in progression of the disease. Similarly, enhanced levels of 5-LOX and 12/15-LOX in PD models represent their role brain disorders, where the former is expressed in AD patients and the latter exhibits it involvement in PD. The present review elaborates the role of AA, DHA, eicosanoids and docosanoids, along with COX and LOX pathway which provides an opportunity to the researchers to understand the role of these lipid mediators in neurological disorders (AD and PD). The information gathered from the review will aid in facilitating the development of appropriate therapeutic options targeting COX and LOX pathway.
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Affiliation(s)
- Arun Kumar
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Sumit Jamwal
- Department of Psychiatry, Yale School of Medicine, Yale University, New Haven, CT, 06511, USA
| | - Ishnoor Kaur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Archit Sood
- Institute of Plant Sciences, Volcani Center, Agricultural Research Organisation (ARO), Rishon LeTsiyon, Israel
| | - Puneet Kumar
- Department of Pharmacology, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, 151001, India
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30
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Wang Y, Leppert A, Tan S, van der Gaag B, Li N, Schultzberg M, Hjorth E. Maresin 1 attenuates pro-inflammatory activation induced by β-amyloid and stimulates its uptake. J Cell Mol Med 2020; 25:434-447. [PMID: 33225628 PMCID: PMC7810927 DOI: 10.1111/jcmm.16098] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 10/13/2020] [Accepted: 10/29/2020] [Indexed: 12/15/2022] Open
Abstract
Alzheimer's disease (AD) is the most common dementia, characterized by pathological accumulation of β‐amyloid (Aβ) and hyperphosphorylation of tau protein, together with a damaging chronic inflammation. The lack of effective treatments urgently warrants new therapeutic strategies. Resolution of inflammation, associated with beneficial and regenerative activities, is mediated by specialized pro‐resolving lipid mediators (SPMs) including maresin 1 (MaR1). Decreased levels of MaR1 have been observed in AD brains. However, the pro‐resolving role of MaR1 in AD has not been fully investigated. In the present study, human monocyte‐derived microglia (MdM) and a differentiated human monocyte cell line (THP‐1 cells) exposed to Aβ were used as models of AD neuroinflammation. We have studied the potential of MaR1 to inhibit pro‐inflammatory activation of Aβ and assessed its ability to stimulate phagocytosis of Aβ42. MaR1 inhibited the Aβ42‐induced increase in cytokine secretion and stimulated the uptake of Aβ42 in both MdM and differentiated THP‐1 cells. MaR1 was also found to decrease chemokine secretion and reduce the associated increase in the activation marker CD40. Activation of kinases involved in transduction of inflammation was not affected by MaR1, but the activity of nuclear factor (NF)‐κB was decreased. Our data show that MaR1 exerts effects that indicate a pro‐resolving role in the context of AD and thus presents itself as a potential therapeutic target for AD.
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Affiliation(s)
- Ying Wang
- Department of Neurobiology, Care Sciences & Society, Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden
| | - Axel Leppert
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - Shuai Tan
- Department of Medicine, Clinical Pharmacology Group, Karolinska University Hospital, Solna, Sweden
| | - Bram van der Gaag
- Department of Neurobiology, Care Sciences & Society, Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden
| | - Nailin Li
- Department of Medicine, Clinical Pharmacology Group, Karolinska University Hospital, Solna, Sweden
| | - Marianne Schultzberg
- Department of Neurobiology, Care Sciences & Society, Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden
| | - Erik Hjorth
- Department of Neurobiology, Care Sciences & Society, Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden
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31
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Romp E, Arakandy V, Fischer J, Wolz C, Siegmund A, Löffler B, Tuchscherr L, Werz O, Garscha U. Exotoxins from Staphylococcus aureus activate 5-lipoxygenase and induce leukotriene biosynthesis. Cell Mol Life Sci 2020; 77:3841-3858. [PMID: 31807813 PMCID: PMC11105070 DOI: 10.1007/s00018-019-03393-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 11/14/2019] [Accepted: 11/22/2019] [Indexed: 11/29/2022]
Abstract
Massive neutrophil infiltration is an early key event in infectious inflammation, accompanied by chemotactic leukotriene (LT)B4 generation. LTB4 biosynthesis is mediated by 5-lipoxygenase (5-LOX), but which pathogenic factors cause 5-LOX activation during bacterial infections is elusive. Here, we reveal staphylococcal exotoxins as 5-LOX activators. Conditioned medium of wild-type Staphylococcus aureus but not of exotoxin-deficient strains induced 5-LOX activation in transfected HEK293 cells. Two different staphylococcal exotoxins mimicked the effects of S. aureus-conditioned medium: (1) the pore-forming toxin α-hemolysin and (2) amphipathic α-helical phenol-soluble modulin (PSM) peptides. Interestingly, in human neutrophils, 5-LOX activation was exclusively evoked by PSMs, which was prevented by the selective FPR2/ALX receptor antagonist WRW4. 5-LOX activation by PSMs was confirmed in vivo as LT formation in infected paws of mice was impaired in response to PSM-deficient S. aureus. Conclusively, exotoxins from S. aureus are potent pathogenic factors that activate 5-LOX and induce LT formation in neutrophils.
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Affiliation(s)
- Erik Romp
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743, Jena, Germany
| | - Vandana Arakandy
- Institute of Medical Microbiology, University Hospital Jena, 07747, Jena, Germany
| | - Jana Fischer
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743, Jena, Germany
| | - Christiane Wolz
- Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, 72076, Tuebingen, Germany
| | - Anke Siegmund
- Institute of Medical Microbiology, University Hospital Jena, 07747, Jena, Germany
| | - Bettina Löffler
- Institute of Medical Microbiology, University Hospital Jena, 07747, Jena, Germany
| | - Lorena Tuchscherr
- Institute of Medical Microbiology, University Hospital Jena, 07747, Jena, Germany
| | - Oliver Werz
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743, Jena, Germany
| | - Ulrike Garscha
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743, Jena, Germany.
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Liang H, Ding X, Li H, Li L, Sun T. Association Between Prior Aspirin Use and Acute Respiratory Distress Syndrome Incidence in At-Risk Patients: A Systematic Review and Meta-Analysis. Front Pharmacol 2020; 11:738. [PMID: 32508656 PMCID: PMC7248262 DOI: 10.3389/fphar.2020.00738] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 05/04/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Recent studies have shown that prior antiplatelet drug use could ameliorate the risk and mortality of acute respiratory distress syndrome (ARDS). However, the connection between prior acetylsalicylic acid (aspirin) use and the risk of ARDS is unknown. Our primary objective was to perform a meta-analysis on the currently available studies to assess the association between aspirin use prior to ARDS onset and ARDS incidence in at-risk patients. METHODS Two investigators separately searched four research databases: MEDLINE, EMBASE, Cochrane Library, and Web of Science for relevant articles from the earliest available data through to July 14, 2019. In this paper, we performed a meta-analysis of the fixed effects model using the inverse variance-weighted average method to calculate the pooled odds ratios (ORs) and 95% confidence intervals (CIs). The primary outcome was risk of ARDS, and the secondary outcome was the hospital mortality of at-risk patients. RESULTS This article included seven studies altogether, enrolling 6,764 at-risk patients. Our meta-analysis revealed that, compared to non-aspirin use, prior aspirin use was linked with a significantly lower incidence of ARDS in at-risk patients (OR, 0.78; 95% CI, 0.64-0.96; P = 0.018) with low statistical heterogeneity (I 2 = 1.7%). Additionally, difference between prior aspirin use and non-aspirin use was not remarkable for hospital mortality in at-risk patients (OR, 0.88; 95% CI, 0.73-1.07; P = 0.204), and this analysis did not involve statistical heterogeneity (I 2 = 0%). CONCLUSIONS This article indicates an association between prior aspirin use and a lower incidence of ARDS in at-risk patients, suggesting that aspirin use could potentially lower the risk of ARDS, and the investigation of such an effect is an interesting area for future clinical studies.
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Affiliation(s)
- Huoyan Liang
- General ICU, First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
| | - Xianfei Ding
- General ICU, First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
| | - Hongyi Li
- General ICU, First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
| | - Lifeng Li
- Cancer Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Tongwen Sun
- General ICU, First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
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Hromcik F, Vokurka J, Gopfert E, Faldyna M, Hermanova M, Kyr M, Vicenova M, Izakovicova Holla L. Granulation tissue enriched by aspirin and omega-3 fatty acids in healing experimental periodontal lesion. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2020; 165:216-223. [PMID: 32091012 DOI: 10.5507/bp.2020.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 01/22/2020] [Indexed: 01/03/2023] Open
Abstract
AIMS Granulation tissue (GT) and specialized pro‑resolving mediators such as lipoxins and resolvins are key elements in the successful resolution of periodontitis. Aspirin‑triggered lipoxins and resolvins are even more powerful than their natural analogues. Their biosynthesis can be accelerated by omega-3 fatty acids. The aim of this study was to evaluate the use of GT enriched by aspirin and omega-3 fatty acids during the surgical treatment of periodontitis in an experimental animal model (rabbit). METHODS In each of 24 rabbits, two experimental periodontal defects were created. In total, 47 defects were treated with open-flap debridement and one of three procedures: (1) GT extracted and soaked with aspirin and omega-3 fatty acids (ASA+OMEGA3 group); (2) GT soaked with saline (PLACEBO group); or (3) GT left untreated (CONTROL group). Then, the GT was replaced in situ. Primary evaluated criteria were the probing pocket depth (PPD) and the clinical attachment level (CAL). Necropsies were harvested 2, 6, and 12 weeks after surgery. The samples were used for histological and molecular biological assessment. RESULTS A trend of greater PPD and CAL in the ASA+OMEGA3 group was observed at 6 weeks. However, there was no significant difference between them. During the observation period, tissue levels of FGF-7, IL-1β and TIMP-1 showed a statistically significant decrease (P<0.05). For the other variables, the ASA+OMEGA3 group was comparable with the PLACEBO and CONTROL groups. CONCLUSION This experiment did not demonstrate the superiority of the proposed approach. However, the enriched granulation tissue did not impair healing outcomes.
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Affiliation(s)
- Filip Hromcik
- Clinic of Dentistry, St. Anne's Faculty Hospital, Pekarska 53, 656 91, Brno, Czech Republic.,Faculty of Medicine, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic
| | - Jan Vokurka
- Clinic of Dentistry, St. Anne's Faculty Hospital, Pekarska 53, 656 91, Brno, Czech Republic.,Faculty of Medicine, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic
| | - Eduard Gopfert
- Veterinary Research Institute, Hudcova 70, 621 00, Brno, Czech Republic
| | - Martin Faldyna
- Veterinary Research Institute, Hudcova 70, 621 00, Brno, Czech Republic
| | - Marketa Hermanova
- Faculty of Medicine, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.,First Department of Pathology, St. Anne's Faculty Hospital, Pekarska 53, 656 91, Brno, Czech Republic
| | - Michal Kyr
- Faculty of Medicine, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.,Department of Pediatric Oncology, University Hospital Brno, Cernopolni 9, 613 00, Brno, Czech Republic
| | - Monika Vicenova
- Veterinary Research Institute, Hudcova 70, 621 00, Brno, Czech Republic
| | - Lydie Izakovicova Holla
- Clinic of Dentistry, St. Anne's Faculty Hospital, Pekarska 53, 656 91, Brno, Czech Republic.,Faculty of Medicine, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic
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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: 33] [Impact Index Per Article: 6.6] [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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35
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Park J, Langmead CJ, Riddy DM. New Advances in Targeting the Resolution of Inflammation: Implications for Specialized Pro-Resolving Mediator GPCR Drug Discovery. ACS Pharmacol Transl Sci 2020; 3:88-106. [PMID: 32259091 DOI: 10.1021/acsptsci.9b00075] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Indexed: 12/19/2022]
Abstract
Chronic inflammation is a component of numerous diseases including autoimmune, metabolic, neurodegenerative, and cancer. The discovery and characterization of specialized pro-resolving mediators (SPMs) critical to the resolution of inflammation, and their cognate G protein-coupled receptors (GPCRs) has led to a significant increase in the understanding of this physiological process. Approximately 20 ligands, including lipoxins, resolvins, maresins, and protectins, and 6 receptors (FPR2/ALX, GPR32, GPR18, chemerin1, BLT1, and GPR37) have been identified highlighting the complex and multilayered nature of resolution. Therapeutic efforts in targeting these receptors have proved challenging, with very few ligands apparently progressing through to preclinical or clinical development. To date, some knowledge gaps remain in the understanding of how the activation of these receptors, and their downstream signaling, results in efficient resolution via apoptosis, phagocytosis, and efferocytosis of polymorphonuclear leukocytes (mainly neutrophils) and macrophages. SPMs bind and activate multiple receptors (ligand poly-pharmacology), while most receptors are activated by multiple ligands (receptor pleiotropy). In addition, allosteric binding sites have been identified signifying the capacity of more than one ligand to bind simultaneously. These fundamental characteristics of SPM receptors enable alternative targeting strategies to be considered, including biased signaling and allosteric modulation. This review describes those ligands and receptors involved in the resolution of inflammation, and highlights the most recent clinical trial results. Furthermore, we describe alternative mechanisms by which these SPM receptors could be targeted, paving the way for the identification of new therapeutics, perhaps with greater efficacy and fidelity.
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Affiliation(s)
- Julia Park
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Christopher J Langmead
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Darren M Riddy
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
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Fu T, Mohan M, Brennan EP, Woodman OL, Godson C, Kantharidis P, Ritchie RH, Qin CX. Therapeutic Potential of Lipoxin A 4 in Chronic Inflammation: Focus on Cardiometabolic Disease. ACS Pharmacol Transl Sci 2020; 3:43-55. [PMID: 32259087 DOI: 10.1021/acsptsci.9b00097] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Indexed: 02/07/2023]
Abstract
Several studies have shown that failure to resolve inflammation may contribute to the progression of many chronic inflammatory disorders. It has been suggested targeting the resolution of inflammation might be a novel therapeutic approach for chronic inflammatory diseases, including inflammatory bowel disease, diabetic complications, and cardiometabolic disease. Lipoxins [LXs] are a class of endogenously generated mediators that promote the resolution of inflammation. Biological actions of LXs include inhibition of neutrophil infiltration, promotion of macrophage polarization, increase of macrophage efferocytosis, and restoration of tissue homeostasis. Recently, several studies have demonstrated that LXs and synthetic analogues protect tissues from acute and chronic inflammation. The mechanism includes down-regulation of pro-inflammatory cytokines and chemokines (e.g., interleukin-1β and tumor necrosis factor-α), inhibition of the activation of the master pro-inflammatory pathway (e.g., nuclear factor κ-light-chain-enhancer of activated B cells pathway) and increased release of the pro-resolving cytokines (e.g., interleukin-10). Three generations of LXs analogues are well described in the literature, and more recently a fourth generation has been generated that appears to show enhanced potency. In this review, we will briefly discuss the potential therapeutic opportunity provided by lipoxin A4 as a novel approach to treat chronic inflammatory disorders, focusing on cardiometabolic disease and the current drug development in this area.
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Affiliation(s)
- Ting Fu
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Muthukumar Mohan
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria 3800, Australia
| | - Eoin P Brennan
- UCD Diabetes Complications Research Centre, UCD Conway Institute, UCD School of Medicine, University College Dublin, Dublin, 4, Ireland
| | - Owen L Woodman
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
| | - Catherine Godson
- UCD Diabetes Complications Research Centre, UCD Conway Institute, UCD School of Medicine, University College Dublin, Dublin, 4, Ireland
| | - Phillip Kantharidis
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria 3800, Australia
| | - Rebecca H Ritchie
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria 3800, Australia.,Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia.,Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Cheng Xue Qin
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia.,Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria 3800, Australia
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Konieczka P, Barszcz M, Kowalczyk P, Szlis M, Jankowski J. The potential of acetylsalicylic acid and vitamin E in modulating inflammatory cascades in chickens under lipopolysaccharide-induced inflammation. Vet Res 2019; 50:65. [PMID: 31533824 PMCID: PMC6751615 DOI: 10.1186/s13567-019-0685-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 08/11/2019] [Indexed: 02/07/2023] Open
Abstract
Distinct enzymes, including cyclooxygenase 1 and 2 (COX-1 and COX-2), lipoxygenase (LOXs), and cytochrome P450 monooxygenase (CYP450), produce different stress mediators and mediate inflammation in birds. Bioactive agents such as acetylsalicylic acid (ASA) and vitamin E (vE) may affect enzyme activities and could be used in poultry production to control the magnitude of acute phase inflammation. Here, we characterized COX, LOX, and CYP450 mRNA expression levels in chicken immune tissues in response to Escherichia coli lipopolysaccharide (LPS) challenge and investigated whether ASA and vE could alter gene expression. Additionally, for the first time in chickens, we evaluated oxygen consumption by platelet mitochondria as a biomarker of mitochondria function in response to ASA- and vE. LPS challenge compromised bird growth rates, but neither dietary ASA nor vE significantly ameliorated this effect; however, gradually increasing dietary vE levels were more effective than basal levels. ASA regulated arachidonic acid metabolism, providing an eicosanoid synthesis substrate, whereas gradually increasing vE levels evoked aspirin resistance during challenge. Gene expression in immune tissues was highly variable, indicating a complex regulatory network controlling inflammatory pathways. However, unlike COX-1, COX-2 and CYP450 exhibited increased mRNA expression in some cases, suggesting an initiation of novel anti-inflammatory and pro-resolving signals during challenge. Measuring oxygen consumption rate, we revealed that neither the ASA nor vE levels applied here exerted toxic effects on platelet mitochondria.
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Affiliation(s)
- Paweł Konieczka
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110, Jabłonna, Poland. .,Department of Poultry Science, University of Warmia and Mazury in Olsztyn, 10-719, Olsztyn, Poland.
| | - Marcin Barszcz
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110, Jabłonna, Poland
| | - Paweł Kowalczyk
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110, Jabłonna, Poland
| | - Michał Szlis
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110, Jabłonna, Poland
| | - Jan Jankowski
- Department of Poultry Science, University of Warmia and Mazury in Olsztyn, 10-719, Olsztyn, Poland
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Satish M, Agrawal DK. Pro-resolving lipid mediators in the resolution of neointimal hyperplasia pathogenesis in atherosclerotic diseases. Expert Rev Cardiovasc Ther 2019; 17:177-184. [PMID: 30582389 PMCID: PMC6679914 DOI: 10.1080/14779072.2019.1563483] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 12/21/2018] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Despite advances in drug eluting technologies, neointimal hyperplasia (NIH) and restenosis still plagues endovascular therapy in atherosclerotic diseases. By appreciating atherosclerosis and NIH as complex inflammatory processes, specialized pro-resolving mediators (SPMs) are a superfamily of endogenous unsaturated fatty-acid derived lipids with the potential for inflammatory resolution. Areas covered: Inquiry into SPMs in this context is a novel approach and is the focus of this review, with emphasis on our understanding with NIH. Prior mechanistic understandings of SPM deficiency with atherosclerosis has offered insight, as well as the complexity and diversity of the SPM superfamily. Therapeutic investigation using SPMs to combat NIH is also evaluated here. Expert commentary: Endogenous deficiency of SPMs synthesis by 12/15-lipoxygenase underlies resolution deficits in atherosclerosis and NIH. Upstream PDGF inhibition by SPMs, most notably RvD1 and LXA4, confers a multifactorial attenuation of NIH that involves interconnected anti-inflammatory efforts, most notably switch pro-resolving smooth muscle cells (vSMCs) and macrophages. The ALX/FPR2 is one receptor system identified on vSMCs that interacts with these SPMs to promote NIH resolution. Therapeutically, while shown to be promising with less stent burden or cytotoxicity, SPMs must be balanced by necessary mechanistic, pharmacokinetic and anatomical considerations.
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Affiliation(s)
- Mohan Satish
- Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE USA
| | - Devendra K Agrawal
- Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE USA
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Weylandt KH, Schmöcker C, Ostermann AI, Kutzner L, Willenberg I, Kiesler S, Steinhagen-Thiessen E, Schebb NH, Kassner U. Activation of Lipid Mediator Formation Due to Lipoprotein Apheresis. Nutrients 2019; 11:nu11020363. [PMID: 30744123 PMCID: PMC6412478 DOI: 10.3390/nu11020363] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 02/02/2019] [Accepted: 02/05/2019] [Indexed: 12/21/2022] Open
Abstract
Lipoprotein apheresis reliably reduces low-density lipoprotein (LDL) cholesterol in patients with atherosclerotic disease and therapy-refractory hypercholesterolemia or elevated lipoprotein (a) (Lp(a)). Besides lowering lipoproteins and triglycerides, apheresis also decreases levels of essential omega-6 and omega-3 polyunsaturated fatty acids (n-6 and n-3 PUFAs) in blood plasma. In contrast, heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) lipid apheresis might increase the formation of potentially pro-inflammatory and pro-thrombotic lipid mediators derived from n-6 and n-3 PUFAs. The study presented here analyzed lipid mediator profiles in the plasma of patients with hyperlipidemia treated by one of three different apheresis methods, either HELP, direct absorption (DA), or membrane filtration (MDF), in a direct pre- and post-apheresis comparison. Using gas chromatography and liquid chromatography tandem mass spectrometry (LC-MS/MS) we were able to analyze fatty acid composition and the formation of lipid mediators called oxylipins. Our data illustrate—particularly in HELP-treated patients—significant decreases of essential omega-6 and omega-3 polyunsaturated fatty acids in blood plasma but significant increases of PUFA-derived lipoxygenase-, as well as cyclooxygenase- and cytochrome P450-derived lipid mediators. Given that n-3 PUFAs in particular are presumed to be cardioprotective and n-3 PUFA-derived lipid mediators might limit inflammatory reactions, these data indicate that n-3 PUFA supplementation in the context of lipid apheresis treatment might have additional benefits through apheresis-triggered protective n-3 PUFA-derived lipid mediators.
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Affiliation(s)
- Karsten-H Weylandt
- Medical Department, Divisions of Hepatology, Gastroenterology, Oncology, Hematologyand Diabetes, Ruppiner Kliniken, Brandenburg Medical School, 16816 Neuruppin, Germany.
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Medical Department, Division of Hepatology and Gastroenterology (including Metabolic Diseases), Campus Virchow Klinikum, 13353 Berlin, Germany.
| | - Christoph Schmöcker
- Medical Department, Divisions of Hepatology, Gastroenterology, Oncology, Hematologyand Diabetes, Ruppiner Kliniken, Brandenburg Medical School, 16816 Neuruppin, Germany.
| | - Annika I Ostermann
- Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, 30173 Hannover, Germany.
| | - Laura Kutzner
- Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, 30173 Hannover, Germany.
| | - Ina Willenberg
- Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, 30173 Hannover, Germany.
| | - Stefanie Kiesler
- Medical Department, Divisions of Hepatology, Gastroenterology, Oncology, Hematologyand Diabetes, Ruppiner Kliniken, Brandenburg Medical School, 16816 Neuruppin, Germany.
| | - Elisabeth Steinhagen-Thiessen
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Medical Department, Division of Hepatology and Gastroenterology (including Metabolic Diseases), Campus Virchow Klinikum, 13353 Berlin, Germany.
| | - Nils Helge Schebb
- Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, 30173 Hannover, Germany.
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, 42119 Wuppertal, Germany.
| | - Ursula Kassner
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Medical Department, Division of Hepatology and Gastroenterology (including Metabolic Diseases), Campus Virchow Klinikum, 13353 Berlin, Germany.
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Gao Y, Su J, Zhang Y, Chan A, Sin JH, Wu D, Min K, Gronert K. Dietary DHA amplifies LXA 4 circuits in tissues and lymph node PMN and is protective in immune-driven dry eye disease. Mucosal Immunol 2018; 11:1674-1683. [PMID: 30104626 PMCID: PMC6279588 DOI: 10.1038/s41385-018-0070-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 07/02/2018] [Accepted: 07/10/2018] [Indexed: 02/04/2023]
Abstract
Recently identified regulatory PMN control immune-driven dry eye disease (DED) in females by producing the arachidonic acid (ω-6)-derived specialized pro-resolving mediator (SPM), LXA4, in lymph nodes. Dietary ω-3 docosahexaenoic acid (DHA) is protective in DED but mechanisms of action remain elusive. DHA is converted to ω-3 SPMs by PMN via the same lipoxygenases (LOX) that generate LXA4. We investigated if dietary DHA amplifies SPM formation and affects T effector cell function and/or regulatory PMN in DED. DED was induced in mice on a DHA-enriched or ω-3-deficient diet. DHA deficiency amplified DED with marked sex-specific differences. Dietary DHA protection against dry eye disease correlated with increased PMN levels in lymph nodes, ocular tissues, and unexpectedly, selective amplification of LXA4 tissue levels. Dietary DHA increased 12/15-LOX and decreased 5-LOX expression in lymph nodes and isolated lymph node PMN, which correlated with amplified LXA4 formation. Acute DHA treatment rescued DHA-deficient females from exaggerated DED by amplifying lymph node LXA4 formation, increasing Treg and decreasing TH1 and TH17 effector cells. Our results identify DHA regulation of LXA4 producing PMN in ocular tissues and lymph nodes in health and immune disease as novel mechanism and determinant for T-cell responses to routine ocular injury or stress signals.
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Affiliation(s)
- Yuan Gao
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
- Vision Science Program, University of California Berkeley, Berkeley, CA, 94720, USA
- School of Optometry, University of California Berkeley, Berkeley, CA, 94720, USA
| | - John Su
- Vision Science Program, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Yibing Zhang
- Vision Science Program, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Allison Chan
- Vision Science Program, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Jun Hyung Sin
- Vision Science Program, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Di Wu
- Vision Science Program, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Kyungi Min
- Vision Science Program, University of California Berkeley, Berkeley, CA, 94720, USA
| | - Karsten Gronert
- Vision Science Program, University of California Berkeley, Berkeley, CA, 94720, USA.
- School of Optometry, University of California Berkeley, Berkeley, CA, 94720, USA.
- Infectious Disease and Immunity Program, University of California Berkeley, Berkeley, CA, 94720, USA.
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Toewe A, Balas L, Durand T, Geisslinger G, Ferreirós N. Simultaneous determination of PUFA-derived pro-resolving metabolites and pathway markers using chiral chromatography and tandem mass spectrometry. Anal Chim Acta 2018; 1031:185-194. [DOI: 10.1016/j.aca.2018.05.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/04/2018] [Accepted: 05/06/2018] [Indexed: 10/17/2022]
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Bali SK, Madaiah H, Dharmapalan J, Janarthanam S, Tarannum F. Effect of systemic long-term, low-dose aspirin on periodontal status and soluble CD14 in gingival crevicular fluid: a case-control study. JOURNAL OF INVESTIGATIVE AND CLINICAL DENTISTRY 2018; 9:e12353. [PMID: 30062853 DOI: 10.1111/jicd.12353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/18/2018] [Indexed: 06/08/2023]
Abstract
AIM In the present study, we evaluated the effect of systemic long-term, low-dose aspirin on the periodontal status and gingival crevicular fluid (GCF) concentrations of aspirin-triggered lipoxins (ATL) and soluble CD14 (sCD14). METHODS The study group consisted of 45 patients who were on long-term, low-dose aspirin therapy, and the control group included patients not on aspirin therapy. Mean bleeding index, plaque index (PI), probing depth (PD), and clinical attachment loss (CAL) were recorded. GCF samples were analyzed for concentrations of ATL, and sCD14 using enzyme-linked immunosorbent assay method. RESULTS The means of PI, PD, and CAL were higher for the control group compared to the study group. The mean concentration of ATL was significantly higher for the study group (49.13 ± 37.39 ng/mL). The mean concentration of sCD14 was higher in the control group (5.75 ± 3.91 μg/mL). There was a negative correlation in the study group between concentrations of ATL with PD (r = -0.54) and CAL (r = -0.123). There was a positive correlation between sCD14 and CAL (r = 0.047) in the study group. A negative correlation was also observed between concentrations of sCD14 and ATL (r = -0.134) in the study group. CONCLUSION The results indicate better periodontal status among long-term aspirin users compared to non-aspirin users.
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Affiliation(s)
- Sumeet K Bali
- Department of Periodontics, M.R. Ambedkar Dental College and Hospital, Bangalore, Karnataka, India
| | - Hemalata Madaiah
- Department of Periodontics, M.R. Ambedkar Dental College and Hospital, Bangalore, Karnataka, India
| | - Jayanthi Dharmapalan
- Department of Periodontics, M.R. Ambedkar Dental College and Hospital, Bangalore, Karnataka, India
| | - Sanghamitra Janarthanam
- Department of Periodontics, M.R. Ambedkar Dental College and Hospital, Bangalore, Karnataka, India
| | - Fouzia Tarannum
- Department of Periodontics, M.R. Ambedkar Dental College and Hospital, Bangalore, Karnataka, India
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Saito P, Melo CPB, Martinez RM, Fattori V, Cezar TLC, Pinto IC, Bussmann AJC, Vignoli JA, Georgetti SR, Baracat MM, Verri WA, Casagrande R. The Lipid Mediator Resolvin D1 Reduces the Skin Inflammation and Oxidative Stress Induced by UV Irradiation in Hairless Mice. Front Pharmacol 2018; 9:1242. [PMID: 30429790 PMCID: PMC6220064 DOI: 10.3389/fphar.2018.01242] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 10/12/2018] [Indexed: 12/19/2022] Open
Abstract
UV irradiation-induced oxidative stress and inflammation contribute to the development of skin diseases. Therefore, targeting oxidative stress and inflammation might contribute to reduce skin diseases. Resolvin D1 (RvD1) is a bioactive metabolite generated during inflammation to actively orchestrate the resolution of inflammation. However, the therapeutic potential of RvD1 in UVB skin inflammation remains undetermined, which was, therefore, the aim of the present study. The intraperitoneal treatment with RvD1 (3-100 ng/mouse) reduced UVB irradiation-induced skin edema, myeloperoxidase activity, matrix metalloproteinase 9 activity, and reduced glutathione depletion with consistent effects observed with the dose of 30 ng/mouse, which was selected to the following experiments. RvD1 inhibited UVB reduction of catalase activity, and hydroperoxide formation, superoxide anion production, and gp91phox mRNA expression. RvD1 also increased the Nrf2 and its downstream targets NQO1 and HO-1 mRNA expression. Regarding cytokines, RvD1 inhibited UVB-induced production of IL-1β, IL-6, IL-33, TNF-α, TGF-β, and IL-10. These immuno-biochemical alterations by RvD1 treatment had as consequence the reduction of UVB-induced epidermal thickness, sunburn and mast cell counts, and collagen degradation. Therefore, RvD1 inhibited UVB-induced skin oxidative stress and inflammation, rendering this resolving lipid mediator as a promising therapeutic agent.
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Affiliation(s)
- Priscila Saito
- Laboratory of Oxidative Stress and Inflammation, Department of Pharmaceutical Sciences, Londrina State University, Londrina, Brazil
| | - Cristina P. B. Melo
- Laboratory of Oxidative Stress and Inflammation, Department of Pharmaceutical Sciences, Londrina State University, Londrina, Brazil
| | - Renata M. Martinez
- Laboratory of Oxidative Stress and Inflammation, Department of Pharmaceutical Sciences, Londrina State University, Londrina, Brazil
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Londrina State University, Londrina, Brazil
| | - Victor Fattori
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Londrina State University, Londrina, Brazil
| | - Talita L. C. Cezar
- Laboratory of Oxidative Stress and Inflammation, Department of Pharmaceutical Sciences, Londrina State University, Londrina, Brazil
| | - Ingrid C. Pinto
- Laboratory of Oxidative Stress and Inflammation, Department of Pharmaceutical Sciences, Londrina State University, Londrina, Brazil
| | - Allan J. C. Bussmann
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Londrina State University, Londrina, Brazil
| | - Josiane A. Vignoli
- Department of Biochemistry and Biotechnology, Londrina State University, Londrina, Brazil
| | - Sandra R. Georgetti
- Laboratory of Oxidative Stress and Inflammation, Department of Pharmaceutical Sciences, Londrina State University, Londrina, Brazil
| | - Marcela M. Baracat
- Laboratory of Oxidative Stress and Inflammation, Department of Pharmaceutical Sciences, Londrina State University, Londrina, Brazil
| | - Waldiceu A. Verri
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Londrina State University, Londrina, Brazil
| | - Rubia Casagrande
- Laboratory of Oxidative Stress and Inflammation, Department of Pharmaceutical Sciences, Londrina State University, Londrina, Brazil
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Dobrian AD, Morris MA, Taylor-Fishwick DA, Holman TR, Imai Y, Mirmira RG, Nadler JL. Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications. Pharmacol Ther 2018; 195:100-110. [PMID: 30347209 DOI: 10.1016/j.pharmthera.2018.10.010] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
12-lipoxygenase (12-LOX) is one of several enzyme isoforms responsible for the metabolism of arachidonic acid and other poly-unsaturated fatty acids to both pro- and anti-inflammatory lipid mediators. Mounting evidence has shown that 12-LOX plays a critical role in the modulation of inflammation at multiple checkpoints during diabetes development. Due to this, interventions to limit pro-inflammatory 12-LOX metabolites either by isoform-specific 12-LOX inhibition, or by providing specific fatty acid substrates via dietary intervention, has the potential to significantly and positively impact health outcomes of patients living with both type 1 and type 2 diabetes. To date, the development of truly specific and efficacious inhibitors has been hampered by homology of LOX family members; however, improvements in high throughput screening have improved the inhibitor landscape. Here, we describe the function and role of human 12-LOX, and mouse 12-LOX and 12/15-LOX, in the development of diabetes and diabetes-related complications, and describe promise in the development of strategies to limit pro-inflammatory metabolites, primarily via new small molecule 12-LOX inhibitors.
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Affiliation(s)
- A D Dobrian
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, United States
| | - M A Morris
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, United States
| | - D A Taylor-Fishwick
- Department of Microbiology, Cell and Molecular Biology, Eastern Virginia Medical School, Norfolk, VA, United States
| | - T R Holman
- Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, United States
| | - Y Imai
- University of Iowa Carver College of Medicine, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa, city, IA, United States
| | - R G Mirmira
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - J L Nadler
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, United States.
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Doyle R, Sadlier DM, Godson C. Pro-resolving lipid mediators: Agents of anti-ageing? Semin Immunol 2018; 40:36-48. [PMID: 30293857 DOI: 10.1016/j.smim.2018.09.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 09/14/2018] [Accepted: 09/24/2018] [Indexed: 12/11/2022]
Abstract
Inflammation is an essential response to injury and its timely and adequate resolution permits tissue repair and avoidance of chronic inflammation. Ageing is associated with increased inflammation, sub-optimal resolution and these act as drivers for a number of ageing-associated pathologies. We describe the role played by specialised proresolving lipid mediators (SPMs) in the resolution of inflammation and how insufficient levels of these mediators, or compromised responsiveness may play a role in the pathogenesis of many ageing-associated pathologies, e.g. Alzheimer's Disease, atherosclerosis, obesity, diabetes and kidney disease. Detailed examination of the resolution phase of inflammation highlights the potential to harness these lipid mediators and or mimetics of their bioactions, in particular, their synthetic analogues to promote effective resolution of inflammation, without compromising the host immune system.
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Affiliation(s)
- Ross Doyle
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland; Mater Misericordiae University Hospital, Eccles St., Inns Quay, Dublin 7, Ireland.
| | - Denise M Sadlier
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland; Mater Misericordiae University Hospital, Eccles St., Inns Quay, Dublin 7, Ireland
| | - Catherine Godson
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
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Conte MS, Desai TA, Wu B, Schaller M, Werlin E. Pro-resolving lipid mediators in vascular disease. J Clin Invest 2018; 128:3727-3735. [PMID: 30168805 PMCID: PMC6118638 DOI: 10.1172/jci97947] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Unresolved inflammation is central to the pathophysiology of commonly occurring vascular diseases such as atherosclerosis, aneurysm, and deep vein thrombosis - conditions that are responsible for considerable morbidity and mortality. Surgical or catheter-based procedures performed on affected blood vessels induce acute-on-chronic inflammatory responses. The resolution of vascular inflammation is an important driver of vessel wall remodeling and functional recovery in these clinical settings. Specialized pro-resolving lipid mediators (SPMs) derived from omega-3 polyunsaturated fatty acids orchestrate key cellular processes driving resolution and a return to homeostasis. The identification of their potent effects in classic animal models of sterile inflammation triggered interest in their vascular properties. Recent studies have demonstrated that SPMs are locally synthesized in vascular tissues, have direct effects on vascular cells and their interactions with leukocytes, and play a protective role in the injury response. Early translational work has established the potential for SPMs as vascular therapeutics, and as candidate biomarkers in vascular disease. Further investigations are needed to understand the molecular and cellular mechanisms of resolution in the vasculature, to improve tools for clinical measurement, and to better define the potential for "resolution therapeutics" in vascular patients.
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Affiliation(s)
- Michael S. Conte
- Division of Vascular and Endovascular Surgery, Department of Surgery, and Cardiovascular Research Institute, UCSF, San Francisco, California, USA
| | - Tejal A. Desai
- Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, California, USA
| | - Bian Wu
- Division of Vascular and Endovascular Surgery, Department of Surgery, and Cardiovascular Research Institute, UCSF, San Francisco, California, USA
| | - Melinda Schaller
- Division of Vascular and Endovascular Surgery, Department of Surgery, and Cardiovascular Research Institute, UCSF, San Francisco, California, USA
| | - Evan Werlin
- Division of Vascular and Endovascular Surgery, Department of Surgery, and Cardiovascular Research Institute, UCSF, San Francisco, California, USA
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Yu H, Ni YN, Liang ZA, Liang BM, Wang Y. The effect of aspirin in preventing the acute respiratory distress syndrome/acute lung injury: A meta-analysis. Am J Emerg Med 2018; 36:1486-1491. [PMID: 29804790 DOI: 10.1016/j.ajem.2018.05.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 04/19/2018] [Accepted: 05/12/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The effects of aspirin in preventing the occurrence of acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) among adult patients are controversial. We aimed to further determine the effectiveness of aspirin in reducing the rate of ARDS/ALI. METHODS The Pubmed, Embase, Medline, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL) as well as the Information Sciences Institute (ISI) Web of Science were searched for all controlled studies that research the role of aspirin in adult patients who have the risk of ARDS/ALI. The outcomes were the ARDS/ALI rate and the mortality. Cochrane systematic review software, Review Manager (RevMan), the R software for statistical computing version 3.2.0, and the metafor package were used to test the hypothesis by Mann-Whitney U test. The heterogeneity test and sensitivity analyses were conducted, and random-effects or fixed-effects model was applied to calculate odds ratio (OR) and mean difference (MD) for dichotomous and continuous data, respectively. RESULTS Six trials involving 6562 patients were pooled in our final study. No significant heterogeneity was found in outcome measures. Aspirin could reduce the rate of ARDS/ALI (OR 0.71, 95% confidence interval (CI) 0.58-0.86) but not the mortality (OR 0.87, 95% CI 0.71-1.07). CONCLUSIONS In patients with risk of ARDS/ALI, aspirin could provide protective effect on the rate of ARDS/ALI, but it could not reduce the mortality.
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Affiliation(s)
- He Yu
- Department of Critical Care Medicine, West China School of Medicine, West China Hospital, Sichuan University, China
| | - Yue-Nan Ni
- Department of Respiratory and Critical Care Medicine, West China School of Medicine, West China Hospital, Sichuan University, China
| | - Zong-An Liang
- Department of Respiratory and Critical Care Medicine, West China School of Medicine, West China Hospital, Sichuan University, China
| | - Bin-Miao Liang
- Department of Respiratory and Critical Care Medicine, West China School of Medicine, West China Hospital, Sichuan University, China.
| | - Yanmei Wang
- Sichuan 2nd Hospital of Traditional Chinese Medicine, 610041, China.
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49
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Das UN. Arachidonic acid in health and disease with focus on hypertension and diabetes mellitus: A review. J Adv Res 2018; 11:43-55. [PMID: 30034875 PMCID: PMC6052660 DOI: 10.1016/j.jare.2018.01.002] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 01/01/2018] [Accepted: 01/02/2018] [Indexed: 02/06/2023] Open
Abstract
Arachidonic acid (AA 20:4n-6) is an essential component of cell membranes and modulates cell membrane fluidity. AA is metabolized by cyclo-oxygenase (COX), lipoxygenase (LOX) and cytochrome P450 enzymes to form several metabolites that have important biological actions. Of all the actions, role of AA in the regulation of blood pressure and its ability to prevent both type 1 and type 2 diabetes mellitus seems to be interesting. Studies showed that AA and its metabolites especially, lipoxin A4 (LXA4) and epoxyeicosatrienoic acids (EETs), potent anti-inflammatory metabolites, have a crucial role in the pathobiology of hypertension and diabetes mellitus. AA, LXA4 and EETs regulate smooth muscle function and proliferation, voltage gated ion channels, cell membrane fluidity, membrane receptors, G-coupled receptors, PPARs, free radical generation, nitric oxide formation, inflammation, and immune responses that, in turn, participate in the regulation blood pressure and pathogenesis of diabetes mellitus. In this review, role of AA and its metabolites LXA4 and EETs in the pathobiology of hypertension, pre-eclampsia and diabetes mellitus are discussed. Based on several lines of evidences, it is proposed that a combination of aspirin and AA could be of benefit in the prevention and management of hypertension, pre-eclampsia and diabetes mellitus.
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50
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Chiurchiù V, Leuti A, Maccarrone M. Bioactive Lipids and Chronic Inflammation: Managing the Fire Within. Front Immunol 2018; 9:38. [PMID: 29434586 PMCID: PMC5797284 DOI: 10.3389/fimmu.2018.00038] [Citation(s) in RCA: 295] [Impact Index Per Article: 42.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 01/05/2018] [Indexed: 12/14/2022] Open
Abstract
Inflammation is an immune response that works as a contained fire that is pre-emptively sparked as a defensive process during infections or upon any kind of tissue insult, and that is spontaneously extinguished after elimination or termination of the damage. However, persistent and uncontrolled immune reactions act as a wildfire that promote chronic inflammation, unresolved tissue damage and, eventually, chronic diseases. A wide network of soluble mediators, among which endogenous bioactive lipids, governs all immune processes. They are secreted by basically all cells involved in inflammatory processes and constitute the crucial infrastructure that triggers, coordinates and confines inflammatory mechanisms. However, these molecules are also deeply involved in the detrimental transition from acute to chronic inflammation, be it for persistent or excessive action of pro-inflammatory lipids or for the impairment of the functions carried out by resolving ones. As a matter of fact, bioactive lipids have been linked, to date, to several chronic diseases, including rheumatoid arthritis, atherosclerosis, diabetes, cancer, inflammatory bowel disease, systemic lupus erythematosus, and multiple sclerosis. This review summarizes current knowledge on the involvement of the main classes of endogenous bioactive lipids—namely classical eicosanoids, pro-resolving lipid mediators, lysoglycerophospholipids/sphingolipids, and endocannabinoids—in the cellular and molecular mechanisms that lead to the pathogenesis of chronic disorders.
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Affiliation(s)
- Valerio Chiurchiù
- Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.,European Center for Brain Research (CERC), Santa Lucia Foundation (IRCCS), Rome, Italy
| | - Alessandro Leuti
- Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.,European Center for Brain Research (CERC), Santa Lucia Foundation (IRCCS), Rome, Italy
| | - Mauro Maccarrone
- Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.,European Center for Brain Research (CERC), Santa Lucia Foundation (IRCCS), Rome, Italy
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