Journal articles on the topic 'Specialized pre-resolving mediators (SPMs)'
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1
Kraft, Jamie D., Robert Blomgran, Iben Lundgaard, Marianne Quiding-Järbrink, Jonathan S. Bromberg, and Emma Börgeson. "Specialized Pro-Resolving Mediators and the Lymphatic System." International Journal of Molecular Sciences 22, no. 5 (March 9, 2021): 2750. http://dx.doi.org/10.3390/ijms22052750.
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Diminished lymphatic function and abnormal morphology are common in chronic inflammatory diseases. Recent studies are investigating whether it is possible to target chronic inflammation by promoting resolution of inflammation, in order to enhance lymphatic function and attenuate disease. Resolution of inflammation is an active process regulated by bioactive lipids known as specialized pro-resolving mediators (SPMs). SPMs can modulate leukocyte migration and function, alter cytokine/chemokine release, modify autophagy, among other immune-related activities. Here, we summarize the role of the lymphatics in resolution of inflammation and lymphatic impairment in chronic inflammatory diseases. Furthermore, we discuss the current literature describing the connection between SPMs and the lymphatics, and the possibility of targeting the lymphatics with innovative SPM therapy to promote resolution of inflammation and mitigate disease.
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Gila-Diaz, Andrea, Gloria Herranz Carrillo, Pratibha Singh, and David Ramiro-Cortijo. "Specialized Pro-Resolving Lipid Mediators in Neonatal Cardiovascular Physiology and Diseases." Antioxidants 10, no. 6 (June 8, 2021): 933. http://dx.doi.org/10.3390/antiox10060933.
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Cardiovascular disease remains a leading cause of mortality worldwide. Unresolved inflammation plays a critical role in cardiovascular diseases development. Specialized Pro-Resolving Mediators (SPMs), derived from long chain polyunsaturated fatty acids (LCPUFAs), enhances the host defense, by resolving the inflammation and tissue repair. In addition, SPMs also have anti-inflammatory properties. These physiological effects depend on the availability of LCPUFAs precursors and cellular metabolic balance. Most of the studies have focused on the impact of SPMs in adult cardiovascular health and diseases. In this review, we discuss LCPUFAs metabolism, SPMs, and their potential effect on cardiovascular health and diseases primarily focusing in neonates. A better understanding of the role of these SPMs in cardiovascular health and diseases in neonates could lead to the development of novel therapeutic approaches in cardiovascular dysfunction.
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Chiang, Nan, and Charles N. Serhan. "Specialized pro-resolving mediator network: an update on production and actions." Essays in Biochemistry 64, no. 3 (September 2020): 443–62. http://dx.doi.org/10.1042/ebc20200018.
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Abstract Today, persistent and uncontrolled inflammation is appreciated to play a pivotal role in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other diseases of public health concern (e.g. Coronavirus Disease 2019 (COVID-19) and periodontal disease). The ideal response to initial challenge in humans is a self-limited inflammatory response leading to complete resolution. The resolution phase is now widely recognized as a biosynthetically active process, governed by a superfamily of endogenous chemical mediators that stimulate resolution of inflammatory responses, namely specialized proresolving mediators (SPMs). Because resolution is the natural ideal response, the SPMs have gained attention. SPMs are mediators that include ω-6 arachidonic acid-derived lipoxins, ω-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-derived resolvins, protectins and maresins, cysteinyl-SPMs, as well as n-3 docosapentaenoic acid (DPA)-derived SPMs. These novel immunoresolvents, their biosynthetic pathways and receptors have proven to promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via specific cellular and molecular mechanisms. As of 17 August, 2020, PubMed.gov reported >1170 publications for resolvins, confirming their potent protective actions from many laboratories worldwide. Since this field is rapidly expanding, we provide a short update of advances within 2–3 years from human and preclinical animal studies, together with the structural–functional elucidation of SPMs and identification of novel SPM receptors. These new discoveries indicate that SPMs, their pathways and receptors could provide a basis for new approaches for treating inflammation-associated diseases and for stimulating tissue regeneration via resolution pharmacology and precision nutrition.
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Díaz del Campo, Lucía Serrano, Raquel Rodrigues-Díez, Mercedes Salaices, Ana M. Briones, and Ana B. García-Redondo. "Specialized Pro-Resolving Lipid Mediators: New Therapeutic Approaches for Vascular Remodeling." International Journal of Molecular Sciences 23, no. 7 (March 25, 2022): 3592. http://dx.doi.org/10.3390/ijms23073592.
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Vascular remodeling is a typical feature of vascular diseases, such as atherosclerosis, aneurysms or restenosis. Excessive inflammation is a key mechanism underlying vascular remodeling via the modulation of vascular fibrosis, phenotype and function. Recent evidence suggests that not only augmented inflammation but unresolved inflammation might also contribute to different aspects of vascular diseases. Resolution of inflammation is mediated by a family of specialized pro-resolving mediators (SPMs) that limit immune cell infiltration and initiate tissue repair mechanisms. SPMs (lipoxins, resolvins, protectins, maresins) are generated from essential polyunsaturated fatty acids. Synthases and receptors for SPMs were initially described in immune cells, but they are also present in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), where they regulate processes important for vascular physiology, such as EC activation and VSMC phenotype. Evidence from genetic models targeting SPM pathways and pharmacological supplementation with SPMs have demonstrated that these mediators may play a protective role against the development of vascular remodeling in atherosclerosis, aneurysms and restenosis. This review focuses on the latest advances in understanding the role of SPMs in vascular cells and their therapeutic effects in the vascular remodeling associated with different cardiovascular diseases.
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Valente, Mariarosaria, Marta Dentoni, Fabrizio Bellizzi, Fedra Kuris, and Gian Luigi Gigli. "Specialized Pro-Resolving Mediators in Neuroinflammation: Overview of Studies and Perspectives of Clinical Applications." Molecules 27, no. 15 (July 28, 2022): 4836. http://dx.doi.org/10.3390/molecules27154836.
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Specialized pro-resolving mediators (SPMs) are lipid mediators derived from poly-unsaturated fatty acids (PUFAs) which have been demonstrated to have an important role in the inflammation environment, preventing an overreaction of the organism and promoting the resolution of inflammation. Our purpose was to point out the current evidence for specialized pro-resolving mediators, focusing on their role in neuroinflammation and in major neurological diseases.
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Chávez-Castillo, Mervin, Ángel Ortega, Lorena Cudris-Torres, Pablo Duran, Milagros Rojas, Alexander Manzano, Bermary Garrido, et al. "Specialized Pro-Resolving Lipid Mediators: The Future of Chronic Pain Therapy?" International Journal of Molecular Sciences 22, no. 19 (September 26, 2021): 10370. http://dx.doi.org/10.3390/ijms221910370.
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Chronic pain (CP) is a severe clinical entity with devastating physical and emotional consequences for patients, which can occur in a myriad of diseases. Often, conventional treatment approaches appear to be insufficient for its management. Moreover, considering the adverse effects of traditional analgesic treatments, specialized pro-resolving lipid mediators (SPMs) have emerged as a promising alternative for CP. These include various bioactive molecules such as resolvins, maresins, and protectins, derived from ω-3 polyunsaturated fatty acids (PUFAs); and lipoxins, produced from ω-6 PUFAs. Indeed, SPMs have been demonstrated to play a central role in the regulation and resolution of the inflammation associated with CP. Furthermore, these molecules can modulate neuroinflammation and thus inhibit central and peripheral sensitizations, as well as long-term potentiation, via immunomodulation and regulation of nociceptor activity and neuronal pathways. In this context, preclinical and clinical studies have evidenced that the use of SPMs is beneficial in CP-related disorders, including rheumatic diseases, migraine, neuropathies, and others. This review integrates current preclinical and clinical knowledge on the role of SPMs as a potential therapeutic tool for the management of patients with CP.
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Kytikova, Oxana, Tatyana Novgorodtseva, Yulia Denisenko, Marina Antonyuk, and Tatyana Gvozdenko. "Pro-Resolving Lipid Mediators in the Pathophysiology of Asthma." Medicina 55, no. 6 (June 18, 2019): 284. http://dx.doi.org/10.3390/medicina55060284.
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Asthma is one of the most important medical and social problems of our time due to the prevalence and the complexity of its treatment. Chronic inflammation that is characteristic of asthma is accompanied by bronchial obstruction, which involves various lipid mediators produced from n-6 and n-3 polyunsaturated fatty acids (PUFAs). The review is devoted to modern ideas about the PUFA metabolites—eicosanoids (leukotrienes, prostaglandins, thromboxanes) and specialized pro-resolving lipid mediators (SPMs) maresins, lipoxins, resolvins, protectins. The latest advances in clinical lipidomics for identifying and disclosing the mechanism of synthesis and the biological action of SPMs have been given. The current views on the peculiarities of the inflammatory reaction in asthma and the role of highly specialized metabolites of arachidonic, eicosapentaenoic and docosahexaenoic acids in this process have been described. The possibility of using SPMs as therapeutic agents aimed at controlling the resolution of inflammation in asthma is discussed.
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Regidor, Pedro-Antonio, Xavier de la Rosa, Anna Müller, Manuela Mayr, Fernando Gonzalez Santos, Rafael Gracia Banzo, and Jose Miguel Rizo. "PCOS: A Chronic Disease That Fails to Produce Adequately Specialized Pro-Resolving Lipid Mediators (SPMs)." Biomedicines 10, no. 2 (February 16, 2022): 456. http://dx.doi.org/10.3390/biomedicines10020456.
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Introduction: Polycystic ovary syndrome (PCOS) is an endocrinological disorder that affects 5–15% of women of their reproductive age and is a frequent cause of infertility. Major symptoms include hyperandrogenism, ovulatory dysfunction, and often obesity and/or insulin resistance. PCOS also represents a state of chronic low-grade inflammation that is closely interlinked with the metabolic features. “Classical” pro-inflammatory lipid mediators such as prostaglandins (PG), leukotrienes (LT), or thromboxanes (TX) are derived from arachidonic acid (AA) and are crucial for the initial response. Resolution processes are driven by four families of so-called specialized pro-resolving mediators (SPMs): resolvins, maresins, lipoxins, and protectins. The study aimed to establish lipid mediator profiles of PCOS patients compared to healthy women to identify differences in their resolutive and pro-inflammatory lipid parameters. Material and Methods: Fifteen female patients (18–45 years) were diagnosed with PCOS according to Rotterdam criteria, and five healthy women, as a comparator group, were recruited for the study. The main outcome measures were: pro-inflammatory lipid mediators (PG, LT, TX) and their precursor AA, SPMs (resolvins, maresins, protectins, lipoxins), their precursors EPA, DHA, DPA, and their active biosynthesis pathway intermediates (18-HEPE, 17-HDHA, 14-HDHA). Results: The level of pro-inflammatory parameters in serum was significantly higher in PCOS-affected women. The ratio (sum of pro-inflammatory molecules)/(sum of SPMs plus hydroxylated intermediates) reflecting the inflammatory state was significantly lower in the group of healthy women. Conclusion: There is a strong pro-inflammatory state in PCOS patients. Further research will clarify whether supplementation with SPMs or their precursors may improve this state.
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Thornton, Julianne M., and Kingsley Yin. "Role of Specialized Pro-Resolving Mediators in Modifying Host Defense and Decreasing Bacterial Virulence." Molecules 26, no. 22 (November 18, 2021): 6970. http://dx.doi.org/10.3390/molecules26226970.
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Bacterial infection activates the innate immune system as part of the host’s defense against invading pathogens. Host response to bacterial pathogens includes leukocyte activation, inflammatory mediator release, phagocytosis, and killing of bacteria. An appropriate host response requires resolution. The resolution phase involves attenuation of neutrophil migration, neutrophil apoptosis, macrophage recruitment, increased phagocytosis, efferocytosis of apoptotic neutrophils, and tissue repair. Specialized Pro-resolving Mediators (SPMs) are bioactive fatty acids that were shown to be highly effective in promoting resolution of infectious inflammation and survival in several models of infection. In this review, we provide insight into the role of SPMs in active host defense mechanisms for bacterial clearance including a new mechanism of action in which an SPM acts directly to reduce bacterial virulence.
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Merularini, Saravanan, Madhuram Krishnamurthy, Ashok Leburu, Praveen Nehrudas, Selvendran K. Elangovan, and Naveen Kumar Venugopal. "Specialized pro-resolving lipid mediators: A future for conventional endodontics-A review." IP Indian Journal of Conservative and Endodontics 7, no. 3 (October 15, 2022): 105–8. http://dx.doi.org/10.18231/j.ijce.2022.023.
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Human dental pulp is a highly dynamic tissue that plays 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 progressive unresolved inflammation can lead to pulp tissue necrosis and subsequent apical periodontitis or it can develop into chronic inflammation and become a silent killer causing bone destruction. Considering the cause & effect model, the decision to perform pulp extirpation and endodontic treatment is justifiable only by the lack of therapeutic tools that limit the immune/inflammatory process. 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), which include several families of distinct local mediators (lipoxins, resolvins, protectins and Maresins). These immunoresolvents are distinct from immunosuppressive molecules as they not only dampen inflammation but also promote host defense. Experimental application of SPMs has shown promising result in wide range of inflammatory diseases. This article illustrates about the potential use of SPMs in dentistry
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Recchiuti, Antonio, Elisa Isopi, Mario Romano, and Domenico Mattoscio. "Roles of Specialized Pro-Resolving Lipid Mediators in Autophagy and Inflammation." International Journal of Molecular Sciences 21, no. 18 (September 10, 2020): 6637. http://dx.doi.org/10.3390/ijms21186637.
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Autophagy is a catabolic pathway that accounts for degradation and recycling of cellular components to extend cell survival under stress conditions. In addition to this prominent role, recent evidence indicates that autophagy is crucially involved in the regulation of the inflammatory response, a tightly controlled process aimed at clearing the inflammatory stimulus and restoring tissue homeostasis. To be efficient and beneficial to the host, inflammation should be controlled by a resolution program, since uncontrolled inflammation is the underlying cause of many pathologies. Resolution of inflammation is an active process mediated by a variety of mediators, including the so-called specialized pro-resolving lipid mediators (SPMs), a family of endogenous lipid autacoids known to regulate leukocyte infiltration and activities, and counterbalance cytokine production. Recently, regulation of autophagic mechanisms by these mediators has emerged, uncovering unappreciated connections between inflammation resolution and autophagy. Here, we summarize mechanisms of autophagy and resolution, focusing on the contribution of autophagy in sustaining paradigmatic examples of chronic inflammatory disorders. Then, we discuss the evidence that SPMs can restore dysregulated autophagy, hypothesizing that resolution of inflammation could represent an innovative approach to modulate autophagy and its impact on the inflammatory response.
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Ferreira, Inês, Filipa Falcato, Narcisa Bandarra, and Amélia P. Rauter. "Resolvins, Protectins, and Maresins: DHA-Derived Specialized Pro-Resolving Mediators, Biosynthetic Pathways, Synthetic Approaches, and Their Role in Inflammation." Molecules 27, no. 5 (March 3, 2022): 1677. http://dx.doi.org/10.3390/molecules27051677.
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Marine organisms are an important source of natural products with unique and diverse chemical structures that may hold the key for the development of novel drugs. Docosahexaenoic acid (DHA) is an omega-3 fatty acid marine natural product playing a crucial regulatory role in the resolution of inflammation and acting as a precursor for the biosynthesis of the anti-inflammatory specialized pro-resolving mediators (SPMs) resolvins, protectins, and maresins. These metabolites exert many beneficial actions including neuroprotection, anti-hypertension, or anti-tumorigenesis. As dysregulation of SPMs is associated with diseases of prolonged inflammation, the disclosure of their bioactivities may be correlated with anti-inflammatory and pro-resolving capabilities, offering new targets for drug design. The availability of these SPMs from natural resources is very low, but the evaluation of their pharmacological properties requires their access in larger amounts, as achieved by synthetic routes. In this report, the first review of the total organic syntheses carried out for resolvins, protectins, and maresins is presented. Recently, it was proposed that DHA-derived pro-resolving mediators play a key role in the treatment of COVID-19. In this work we also review the current evidence on the structures, biosynthesis, and functional and new-found roles of these novel lipid mediators of disease resolution.
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Regidor, Pedro-Antonio, Anna Mueller, Manuela Sailer, Fernando Gonzalez Santos, Jose Miguel Rizo, and Fernando Moreno Egea. "Chronic Inflammation in PCOS: The Potential Benefits of Specialized Pro-Resolving Lipid Mediators (SPMs) in the Improvement of the Resolutive Response." International Journal of Molecular Sciences 22, no. 1 (December 31, 2020): 384. http://dx.doi.org/10.3390/ijms22010384.
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PCOS as the most common endocrine disorder of women in their reproductive age affects between 5–15% of the female population. Apart from its cardinal symptoms, like irregular and anovulatory cycles, hyperandrogenemia and a typical ultrasound feature of the ovary, obesity, and insulin resistance are often associated with the disease. Furthermore, PCOS represents a status of chronic inflammation with permanently elevated levels of inflammatory markers including IL-6 and IL-18, TNF-α, and CRP. Inflammation, as discovered only recently, consists of two processes occurring concomitantly: active initiation, involving “classical” mediators including prostaglandins and leukotrienes, and active resolution processes based on the action of so-called specialized pro-resolving mediators (SPMs). These novel lipid mediator molecules derive from the essential ω3-poly-unsaturated fatty acids (PUFAs) DHA and EPA and are synthesized via specific intermediates. The role and benefits of SPMs in chronic inflammatory diseases like obesity, atherosclerosis, and Diabetes mellitus has become a subject of intense research during the last years and since PCOS features several of these pathologies, this review aims at summarizing potential roles of SPMs in this disease and their putative use as novel therapeutics.
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Rangarajan, Subhapradha, Davit Orujyan, Patrida Rangchaikul, and Mohamed M. Radwan. "Critical Role of Inflammation and Specialized Pro-Resolving Mediators in the Pathogenesis of Atherosclerosis." Biomedicines 10, no. 11 (November 6, 2022): 2829. http://dx.doi.org/10.3390/biomedicines10112829.
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Recent research on how the body resolves this inflammation is gaining traction and has shed light on new avenues for future management of cardiovascular diseases. In this narrative review, we discuss the pathophysiological mechanisms of atherosclerosis, the recent development in the understanding of a new class of molecules called Specialized Pro-resolving Mediators (SPMs), and the impact of such findings in the realm of cardiovascular treatment options. We searched the MEDLINE database restricting ourselves to original research articles as much as possible on the complex pathophysiology of atherosclerosis and the role of SPMs. We expect to see further research in translating these findings to bedside clinical trials in treating conditions with a pathophysiological basis of inflammation, such as coronary artery disease, asthma, and periodontal disease.
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Miyazawa, Keishi, Hisanori Fukunaga, Yasuko Tatewaki, Yumi Takano, Shuzo Yamamoto, Tatsushi Mutoh, and Yasuyuki Taki. "Alzheimer’s Disease and Specialized Pro-Resolving Lipid Mediators: Do MaR1, RvD1, and NPD1 Show Promise for Prevention and Treatment?" International Journal of Molecular Sciences 21, no. 16 (August 12, 2020): 5783. http://dx.doi.org/10.3390/ijms21165783.
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Alzheimer’s disease (AD) is a common neurodegenerative disease and a major contributor to progressive cognitive impairment in an aging society. As the pathophysiology of AD involves chronic neuroinflammation, the resolution of inflammation and the group of lipid mediators that actively regulate it—i.e., specialized pro-resolving lipid mediators (SPMs)—attracted attention in recent years as therapeutic targets. This review focuses on the following three specific SPMs and summarizes their relationships to AD, as they were shown to effectively address and reduce the risk of AD-related neuroinflammation: maresin 1 (MaR1), resolvin D1 (RvD1), and neuroprotectin D1 (NPD1). These three SPMs are metabolites of docosahexaenoic acid (DHA), which is contained in fish oils and is thus easily available to the public. They are expected to become incorporated into promising avenues for preventing and treating AD in the future.
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Ramon, Sesquile, Charles Serhan, David Topham, and Richard Phipps. "Endogenous specialized proresolving mediators enhance antigen-specific antibody response against influenza virus: A new class of adjuvant (P4285)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 123.6. http://dx.doi.org/10.4049/jimmunol.190.supp.123.6.
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Abstract Inflammation is a highly regulated process triggered by the presence of pathogens, injury or trauma. Specialized proresolving mediators (SPMs) are endogenous lipid-derived molecules, which regulate the resolution of inflammation. Resolving inflammation is critical for maintaining homeostasis while assuring immune protection against pathogens, such as influenza virus. We previously showed that the SPM 17-hydroxydosahexaenoic acid (17-HDHA) increased human B cell antibody production in vitro and promoted differentiation towards an antibody-secreting phenotype. Herein, we used a pre-clinical influenza virus immunization mouse model to study the effects of 17-HDHA in vivo. Mice immunized with influenza-derived hemagglutinin (HA) protein plus 17-HDHA have enhanced HA-specific IgM and IgG production compared to mice immunized with HA alone. Enhanced HA-specific antibody production was due to plasma cell increase in the bone marrow. HA-specific antibodies were protective against live influenza viral infection as they decreased morbidity and mortality following viral challenge. Our study shows that DHA-derived SPMs play an important role in enhancing B cell-mediated immunity. An enhanced antigen-specific immune response promotes faster pathogen clearance, and thus return to homeostasis. In addition, these new findings highlight the potential applications of SPMs as new endogenous and non-toxic adjuvants or vaccine “boosters”.
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Liotti, Federica, Maria Marotta, Rosa Marina Melillo, and Nella Prevete. "The Impact of Resolution of Inflammation on Tumor Microenvironment: Exploring New Ways to Control Cancer Progression." Cancers 14, no. 14 (July 8, 2022): 3333. http://dx.doi.org/10.3390/cancers14143333.
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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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Brennan, Eoin P., Muthukumar Mohan, Darrell Andrews, Madhura Bose, and Phillip Kantharidis. "Specialized pro-resolving mediators in diabetes: novel therapeutic strategies." Clinical Science 133, no. 21 (November 2019): 2121–41. http://dx.doi.org/10.1042/cs20190067.
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Abstract Diabetes mellitus (DM) is an important metabolic disorder characterized by persistent hyperglycemia resulting from inadequate production and secretion of insulin, impaired insulin action, or a combination of both. Genetic disorders and insulin receptor disorders, environmental factors, lifestyle choices and toxins are key factors that contribute to DM. While it is often referred to as a metabolic disorder, modern lifestyle choices and nutrient excess induce a state of systemic chronic inflammation that results in the increased production and secretion of inflammatory cytokines that contribute to DM. It is chronic hyperglycemia and the low-grade chronic-inflammation that underlies the development of microvascular and macrovascular complications leading to damage in a number of tissues and organs, including eyes, vasculature, heart, nerves, and kidneys. Improvements in the management of risk factors have been beneficial, including focus on intensified glycemic control, but most current approaches only slow disease progression. Even with recent studies employing SGLT2 inhibitors demonstrating protection against cardiovascular and kidney diseases, kidney function continues to decline in people with established diabetic kidney disease (DKD). Despite the many advances and a greatly improved understanding of the pathobiology of diabetes and its complications, there remains a major unmet need for more effective therapeutics to prevent and reverse the chronic complications of diabetes. More recently, there has been growing interest in the use of specialised pro-resolving mediators (SPMs) as an exciting therapeutic strategy to target diabetes and the chronic complications of diabetes.
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Jordan, Paul M., Emeline van Goethem, Andrea M. Müller, Kathrin Hemmer, Virginie Gavioli, Vincent Baillif, Yvonne Burmeister, et al. "The Natural Combination Medicine Traumeel (Tr14) Improves Resolution of Inflammation by Promoting the Biosynthesis of Specialized Pro-Resolving Mediators." Pharmaceuticals 14, no. 11 (November 3, 2021): 1123. http://dx.doi.org/10.3390/ph14111123.
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The resolution of inflammation is an integral part of the acute inflammatory response and eventually leads to the return to homeostasis. It is supported by specialized pro-resolving mediators (SPMs) that act as immunoresolvents via specific G-protein-coupled receptors. In contrast to classical non-steroidal anti-inflammatory drugs (NSAIDs) that suppress the formation of pro-inflammatory lipid mediators such as prostaglandins, novel pharmacotherapeutic concepts propose to foster the biosynthesis of beneficial SPMs. Here, we demonstrate that the natural combination medicine Traumeel (Tr14) improves resolution of inflammation by promoting SPM formation. Tr14 enhanced the biosynthesis of 12-/15-lipoxygenase (LOX) products and of SPMs in zymosan-induced mouse peritonitis as well as in human monocyte-derived macrophages challenged with Staphylococcus aureus. Importantly, in the peritonitis model, Tr14 supported the recruitment of innate leukocytes and the efferocytotic capacity of macrophages, and positively influenced the inflammation resolution index. Taken together, we suggest that based on these properties Tr14 may possess therapeutic potential as an enhancer for the resolution of inflammatory processes.
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Guzman Vazquez, S., Y. Escobar Juárez, A. Morales, O. diaz Alvarez, and H. Soto Molina. "PMS8 A SYSTEMATIC REVIEW OF SPECIALIZED PRO-RESOLVING LIPID MEDIATORS (SPMS) IN OSTEOARTHRITIS." Value in Health 23 (May 2020): S215. http://dx.doi.org/10.1016/j.jval.2020.04.695.
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Ramirez, Joel, Greg J. Zahner, Sukaynah A. Khetani, Kimberly A. Spaulding, Nancy K. Hills, and S. Marlene Grenon. "2204 Characterizing specialized pro-resolving lipid mediators and synthesis pathways in veterans with peripheral artery disease." Journal of Clinical and Translational Science 2, S1 (June 2018): 6–7. http://dx.doi.org/10.1017/cts.2018.53.
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OBJECTIVES/SPECIFIC AIMS: Specialized pro-resolving lipid mediators (SPM) actively counter proinflammatory cascades. A deficit of SPMs is one possible mechanism through which inflammation leads to the development of atherosclerotic disease. The purpose of this study is to characterize the profiles of intermediates of SPM synthesis pathways and end-product SPMs in the plasma of patients with peripheral artery disease (PAD). METHODS/STUDY POPULATION: A cross-sectional sample of 52 patients with PAD was recruited at the San Francisco Veterans Affairs Medical Center. PAD was defined as the presence of claudication symptoms and an ankle-brachial index <0.9, or a history of revascularization for claudication. Patients were excluded if they were taking immunosuppressive medications, had a severe acute illness (infection, surgery, illness, critical limb ischemia) within the last 30 days, or had severe hepatic, renal, or nonvascular inflammatory disease. Intermediates of SPM synthesis pathways and end-product SPMs were measured in plasma samples of patients by liquid chromatography-tandem mass spectrometry. RESULTS/ANTICIPATED RESULTS: The average age of the cohort was 69±6.3 and patient comorbidities reflected common comorbidities associated with PAD (hypertension 96%, hyperlipidemia 87%, diabetes mellitus 42%, coronary artery disease 34%). Rutherford categories, measurements of PAD symptom severity, ranged from 0 to III (0 10%, I 40%, II 27%, III 23%). Three EPA products were measured: 18-hydroxyeicosapentaenoic acid (18-HEPE), resolvin E1 (RvE1), and resolvin E2 (RvE2). 18-HEPE, an intermediate of SPM synthesis, was detectable in the plasma of every patient (median: 105 pg/mL, IQR: 54.9–195), whereas the SPM end-products, RvE1 and RvE2, were only detectable in 6 and 10 patients, respectively. In total, 7 DHA products were measured: 14-hydroxydocosahexaenoic acid (14-HDHA), 17-HDHA, resolvin D1 (RvD1), resolvin D2 (RvD2), protectin D1, protectin DX, and maresin 1. The intermediates 14-HDHA (median: 6546 pg/mL, IQR: 3329–12061) and 17-HDHA (median: 644 pg/mL, IQR: 340–1056) were detectable in the plasma of every patient. However, the end-products RvD1, RvD2, protectin D1, protecin DX, and maresin 1 were identified in less than half of the cohort. DISCUSSION/SIGNIFICANCE OF IMPACT: We report the presence of several intermediates of SPM synthesis pathways (18-HEPE, 14-HDHA, and 17-HDHA) in every patient but the presence of SPM end-products in only a limited portion of the cohort. These results suggest that some patients with PAD may have a deficit of SPMs. Further investigation is required to better understand the role of SPMs and mediators of resolution of inflammation in PAD.
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Molfino, Alessio, Maria Ida Amabile, Massimo Monti, and Maurizio Muscaritoli. "Omega-3 Polyunsaturated Fatty Acids in Critical Illness: Anti-Inflammatory, Proresolving, or Both?" Oxidative Medicine and Cellular Longevity 2017 (2017): 1–6. http://dx.doi.org/10.1155/2017/5987082.
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Prognosis and outcomes of critically ill patients are strictly related with inflammatory status. Inflammation involves a multitude of interactions between different cell types and chemical mediators. Omega-3 polyunsaturated fatty acids (PUFAs), mainly represented by eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are able to inhibit different pathways including leukocyte chemotaxis, adhesion molecule expression and interactions, and production of inflammatory cytokines, through the action of specialized proresolving mediators (SPMs). SPMs from omega-6 fatty acids, such as lipoxins, and from omega-3 fatty acids such as resolvins, protectins, and maresins, act in reducing/resolving the inflammatory process in critical diseases, stimulating the phases of resolution of inflammation. In this light, the resolution of inflammation is nowadays considered as an active process, instead of a passive process. In critical illness, SPMs regulate the excessive posttrauma inflammatory response, protecting organs from damage. This review focuses on the role of omega-3 PUFAs as pharma nutrition agents in acute inflammatory conditions, highlighting their effects as anti-inflammatory or proresolving agents.
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Guenard, Rebecca. "Lipid role in the immune system." INFORM International News on Fats, Oils, and Related Materials 32, no. 10 (November 1, 2021): 6–10. http://dx.doi.org/10.21748/inform.11.2021.06.
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The essential fatty acids react with enzymes to produce a group of compounds known as specialized pro-resolving mediators, or SPMs. Researchers continually discover new members of the four groups of precursors that comprise the SPM family, called lipoxins, resolvins, protectins, and maresins. These stereospecific molecules shut down inflammation and restore the body to homeostasis, a mechanism researchers are targeting for treatment as an alternative to anti-inflammatory pathways.
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Ungaro, Federica, Silvia D’Alessio, and Silvio Danese. "The Role of Pro-Resolving Lipid Mediators in Colorectal Cancer-Associated Inflammation: Implications for Therapeutic Strategies." Cancers 12, no. 8 (July 26, 2020): 2060. http://dx.doi.org/10.3390/cancers12082060.
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Inflammation is a recognized hallmark of cancer that contributes to the development and progression of colorectal cancer (CRC). Anti-inflammatory drugs currently used for the treatment of CRC show many adverse side effects that prompted researchers to propose the polyunsaturated fatty acids-derived specialized pro-resolving mediators (SPMs) as promoters of resolution of cancer-associated inflammation. SPMs were found to inhibit the CRC-associated pro-inflammatory milieu via specific G-coupled protein receptors, although clinical data are still lacking. This review aims to summarize the state-of-the-art in this field, ultimately providing insights for the development of innovative anti-CRC therapies that promote the endogenous lipid-mediated resolution of CRC-associated inflammation.
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Kang, Gyeoung Jin, Eun Ji Kim, and Chang Hoon Lee. "Therapeutic Effects of Specialized Pro-Resolving Lipids Mediators on Cardiac Fibrosis via NRF2 Activation." Antioxidants 9, no. 12 (December 10, 2020): 1259. http://dx.doi.org/10.3390/antiox9121259.
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Heart disease is the number one mortality disease in the world. In particular, cardiac fibrosis is considered as a major factor causing myocardial infarction and heart failure. In particular, oxidative stress is a major cause of heart fibrosis. In order to control such oxidative stress, the importance of nuclear factor erythropoietin 2 related factor 2 (NRF2) has recently been highlighted. In this review, we will discuss the activation of NRF2 by docosahexanoic acid (DHA), eicosapentaenoic acid (EPA), and the specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated lipids, including DHA and EPA. Additionally, we will discuss their effects on cardiac fibrosis via NRF2 activation.
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Yaeger, Michael J., Sky W. Reece, Brita Kilburg-Basnyat, Miles X. Hodge, Anandita Pal, Katelyn Dunigan-Russell, Bin Luo, et al. "Sex Differences in Pulmonary Eicosanoids and Specialized Pro-Resolving Mediators in Response to Ozone Exposure." Toxicological Sciences 183, no. 1 (June 27, 2021): 170–83. http://dx.doi.org/10.1093/toxsci/kfab081.
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Abstract Ozone (O3) is a criteria air pollutant known to increase the morbidity and mortality of cardiopulmonary diseases. This occurs through a pulmonary inflammatory response characterized by increased recruitment of immune cells into the airspace, pro-inflammatory cytokines, and pro-inflammatory lipid mediators. Recent evidence has demonstrated sex-dependent differences in the O3-induced pulmonary inflammatory response. However, it is unknown if this dimorphic response is evident in pulmonary lipid mediator metabolism. We hypothesized that there are sex-dependent differences in lipid mediator production following acute O3 exposure. Male and female C57BL/6J mice were exposed to 1 part per million O3 for 3 h and were necropsied at 6 or 24 h following exposure. Lung lavage was collected for cell differential and total protein analysis, and lung tissue was collected for mRNA analysis, metabololipidomics, and immunohistochemistry. Compared with males, O3-exposed female mice had increases in airspace neutrophilia, neutrophil chemokine mRNA, pro-inflammatory eicosanoids such as prostaglandin E2, and specialized pro-resolving mediators (SPMs), such as resolvin D5 in lung tissue. Likewise, precursor fatty acids (arachidonic and docosahexaenoic acid; DHA) were increased in female lung tissue following O3 exposure compared with males. Experiments with ovariectomized females revealed that loss of ovarian hormones exacerbates pulmonary inflammation and injury. However, eicosanoid and SPM production were not altered by ovariectomy despite depleted pulmonary DHA concentrations. Taken together, these data indicate that O3 drives an increased pulmonary inflammatory and bioactive lipid mediator response in females. Furthermore, ovariectomy increases susceptibility to O3-induced pulmonary inflammation and injury, as well as decreases pulmonary DHA concentrations.
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Poblete, Roy. "49193 The Association Between Specialized Pro-resolving Lipid Mediators and Markers of Neuroinflammation and Disease Severity in Acute Traumatic Brain Injury: A Prospective, Observational Cohort Study." Journal of Clinical and Translational Science 5, s1 (March 2021): 95–96. http://dx.doi.org/10.1017/cts.2021.646.
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ABSTRACT IMPACT: Characterizing specialized pro-resolving lipid mediators (SPMs) of inflammation in a cohort of adult patients with traumatic brain injury (TBI) will potentially identify novel biomarkers of disease and would generate hypotheses regarding the role of SPMs in the pathophysiology and recovery after brain injury OBJECTIVES/GOALS: Primary aim: evaluate the association between plasma and cerebrospinal fluid (CSF) SPM levels with inflammatory markers known to mediate blood brain barrier (BBB) disruption. Secondary aim: evaluate the association between SPM levels and disease severity, 14-day Glasgow Coma Scale score (GCS) and survival. METHODS/STUDY POPULATION: This is a single-center, prospective, observational cohort study (target N=50). Adult participants with moderate-to-severe non-penetrating TBI will have blood and CSF sampled serially for laboratory measures of SPMs (resolvins, protectins, lipoxins, maresins) and inflammatory peptides (TNF-α, IL-1β, IL-6, MMP-9, TIMP-1) by liquid chromatography’‘ mass spectrometry and RT-PCR & ELISA, respectively. Baseline patient characteristics, admission GCS, and 14-day GCS and mortality will be prospectively collected. To evaluate the association between SPMs and other continuous variables, Pearson’s and Spearman’s correlation will be used. Cox regression will be used to evaluate the association between SPM lipidomes and 14-day survival. RESULTS/ANTICIPATED RESULTS: As the primary outcome measure, the association between SPM levels with assayed inflammatory markers will be determined at 24 and 72 hours post-TBI. We hypothesize that SPMs will be negatively correlated with TNF-α, IL-1β, IL-6, MMP-9 and positively correlated with TIMP-1. As secondary outcome measures, the association between SPM levels with disease severity by admission GCS will be determined at 24 hours post-TBI, and the association between SPM levels and GCS and mortality will be determined at 14-days. We hypothesize that SPM levels will be positively associated with admission and 14-day GCS and will be independently associated with 14-day survival. DISCUSSION/SIGNIFICANCE OF FINDINGS: Using the SPM lipidome as a biomarker of disease is a novel tool for future translational research. It will inform a foundational mechanistic framework for TBI pathophysiology and attenuation of neuroinflammation post-TBI, providing rationale for pre-clinical and clinical research focused on novel therapeutics
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Tangeten, Cecilia, Karim Zouaoui Boudjeltia, Cedric Delporte, Pierre Van Antwerpen, and Keziah Korpak. "Unexpected Role of MPO-Oxidized LDLs in Atherosclerosis: In between Inflammation and Its Resolution." Antioxidants 11, no. 5 (April 28, 2022): 874. http://dx.doi.org/10.3390/antiox11050874.
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Inflammation and its resolution are the result of the balance between pro-inflammatory and pro-resolving factors, such as specialized pro-resolving mediators (SPMs). This balance is crucial for plaque evolution in atherosclerosis, a chronic inflammatory disease. Myeloperoxidase (MPO) has been related to oxidative stress and atherosclerosis, and MPO-oxidized low-density lipoproteins (Mox-LDLs) have specific characteristics and effects. They participate in foam cell formation and cause specific reactions when interacting with macrophages and endothelial cells. They also increase the production of intracellular reactive oxygen species (ROS) in macrophages and the resulting antioxidant response. Mox-LDLs also drive macrophage polarization. Mox-LDLs are known to be pro-inflammatory particles. However, in the presence of Mox-LDLs, endothelial cells produce resolvin D1 (RvD1), a SPM. SPMs are involved in the resolution of inflammation by stimulating efferocytosis and by reducing the adhesion and recruitment of neutrophils and monocytes. RvD1 also induces the synthesis of other SPMs. In vitro, Mox-LDLs have a dual effect by promoting RvD1 release and inducing a more anti-inflammatory phenotype macrophage, thereby having a mixed effect on inflammation. In this review, we discuss the interrelationship between MPO, Mox-LDLs, and resolvins, highlighting a new perception of the role of Mox-LDLs in atherosclerosis.
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AlZahrani, Shahd, Zakia Shinwari, Ameera Gaafar, Ayodele Alaiya, and Ahmed Al-Kahtani. "Anti-Inflammatory Effect of Specialized Proresolving Lipid Mediators on Mesenchymal Stem Cells: An In Vitro Study." Cells 12, no. 1 (December 28, 2022): 122. http://dx.doi.org/10.3390/cells12010122.
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An interconnection between tissue inflammation and regeneration has been established through the regulation of defense and repair mechanisms within diseased dental tissue triggered by the release of immune-resolvent mediators. To better our understanding of the role of specific pro-resolving mediators (SPMs) in inflamed human bone marrow-derived mesenchymal stem cells (hBMMSCs), we studied the effects of Resolvin E1 (RvE1) and Maresin 1 (MaR1) in lipopoly-saccharide (LPS) stimulated hBMMSCs. The hBMMSCs were divided into five different groups, each of which was treated with or without SPMs. Group-1: negative control (no LPS stimulation), Group-2: positive control (LPS-stimulated), Group-3: RvE1 100 nM + 1 μg/mL LPS, Group-4: MaR1 100 nM + 1 µg/mL LPS, and Group-5: RvE1 100 nM + MaR1100 nM + 1 μg/mL LPS. Cell proliferation, apoptosis, migration, colony formation, Western blotting, cytokine array, and LC/MS analysis were all performed on each group to determine the impact of SPMs on inflammatory stem cells. According to our data, RvE1 plus MaR1 effectively reduced inflammation in hBMMSCs. In particular, IL-4, 1L-10, and TGF-β1 activation and downregulation of RANKL, TNF-α, and IFN-γ compared to groups receiving single SPM were shown to be significantly different (Group 3 and 4). In addition, the LC/MS analysis revealed the differentially regulated peptide’s role in immunological pathways that define the cellular state against inflammation. Inflamed hBMMSCs treated with a combination of Resolvin E1 (RvE1) and Maresin 1 (MaR1) promoted the highest inflammatory resolution compared to the other groups; this finding suggests a potential new approach of treating bacterially induced dental infections.
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Miao, Zhijuan, Xin Tang, Marianne Schultzberg, Yuwu Zhao, and Xiuzhe Wang. "Plasma Resolvin D2 to Leukotriene B4 Ratio Is Reduced in Diabetic Patients with Ischemic Stroke and Related to Prognosis." BioMed Research International 2021 (February 26, 2021): 1–8. http://dx.doi.org/10.1155/2021/6657646.
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Background. Diabetes mellitus (DM) aggravates symptoms and prognosis of acute ischemic stroke (AIS), and inflammation plays an important role therein. Resolvin D2 (RvD2) is one of the specialized pro-resolving mediators (SPMs), while leukotriene B4 (LTB4) is a classic proinflammatory mediator. The ratio of RvD2 to LTB4 is an index of pro-resolving/proinflammatory balance. We aim to explore the role of RvD2/LTB4 ratio in ischemic stroke complicated with DM. Methods. The plasma levels of RvD2 and LTB4 were analyzed by enzyme immunoassay in stroke patients with DM (DM + AIS group) or without DM (nonDM+AIS group). Patients were followed up at 90 days after stroke onset, and modified Rankin Score (mRS) was assessed. The association of RvD2/LTB4 ratio with stroke severity and prognosis was also analyzed. Results. The plasma levels of RvD2 were positively correlated to LTB4. The RvD2/LTB4 ratio in DM + AIS group was lower than that in the nonDM+AIS group. No correlation was found between the RvD2/LTB4 ratio and infarct size or NIHSS score. The RvD2/LTB4 ratio at baseline was significantly lower in the poor prognosis group ( mRS ≥ 3 ) than that in the good prognosis group ( mRS ≤ 2 ). Conclusions. Our study indicated that the balance between pro-resolving and proinflammatory mediators was impaired by diabetes in ischemic stroke. The RvD2/LTB4 ratio may serve as a biomarker of prognosis for ischemic stroke.
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Hsiao, HsiMin, Thomas Thatcher, Richard Phipps, Charles Serhan, and Patricia Sime. "Resolvin D1 inhibits multiple pro-inflammatory signaling pathways in primary human lung cells exposed to diverse inflammatory stimuli (IRM9P.721)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 128.4. http://dx.doi.org/10.4049/jimmunol.192.supp.128.4.
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Abstract Resolution of inflammation is a bioactive process involving a new genus of lipid molecules called “specialized pro-resolving lipid mediators” (SPMs), mainly derived from dietary ω-3 polyunsaturated fatty acids, which actively antagonize inflammatory signaling pathways and promote resolution. Although it is broadly known that SPMs inhibit inflammation, the specific pathways and targets of many SPMs remained to be discovered. Here, we investigated the mechanism by which the SPM resolvin D1 (RvD1) inhibits pro-inflammatory signaling pathways using two distinct stimuli; IL-1β, which acts primarily via its own receptor, and poly(I:C), a double-stranded viral RNA mimetic that acts primarily through toll-like receptor (TLR)3. RvD1 inhibited production of pro-inflammatory mediators including IL-6 and IL-8, both primary human lung fibroblast and epithelial cell strains, when stimulated with either IL-1β or poly(I:C). RvD1 also blocked phosphorylation of ERK1/2 and translocation of NF-κB p65 in cells treated with both stimuli. Importantly, we found that RvD1 inhibited phosphorylation of TAK1, an upstream effector protein that regulates both the MAP-kinase and NF-κB pathways. These results demonstrate that RvD1 targets multiple pro-inflammatory signaling pathways and may have significant therapeutic potential in complex inflammatory diseases including pulmonary fibrosis, asthma and chronic obstructive pulmonary disease.
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Maner-Smith, Kristal M., Erin Ferranti, Anne Dunlop, Elizabeth Corwin, and Eric A. Ortlund. "African American Women with Cardiometabolic Complications of Pregnancy Have Decreased Serum Abundance of Specialized Pro-Resolving Lipid Mediators and Endocannabinoids." Nutrients 15, no. 1 (December 28, 2022): 140. http://dx.doi.org/10.3390/nu15010140.
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African American (AA) women experience higher rates of maternal morbidity and mortality compared to US women of other racial/ ethnic groups. Cardiometabolic complications of pregnancy (including gestational diabetes, gestational hypertension, and preeclampsia) are leading contributors to maternal morbidity and mortality. Marked changes in circulating lipids are known to accompany cardiometabolic complications of pregnancy. Serum concentrations of docosahexaenoic acid (DHA) have been shown to be inversely correlated with risk for preeclampsia. DHA is a biosynthetic precursor of a class of specialized pro-resolving mediators (SPMs), resolvins, that have anti-inflammatory properties and are also associated with hypertensive disorders of pregnancy. We employed targeted lipidomics to characterize the distribution of DHA-containing phospholipids and SPMs in maternal serum collected in early and late pregnancy (8–14 weeks and 24–30 weeks gestation, respectively) to identify key lipids that are dysregulated during pregnancy in AA women who develop cardiometabolic complications. We identified a lipid signature in early pregnancy serum samples of AA women that is predictive of cardiometabolic complications of pregnancy with 74% accuracy. These are Resolvin D1, Resolvin E1, 2-AG, PGE2-glyerol ester, and 36:6 PC. These findings suggest that there are blood-based markers detectable in early pregnancy that can potentially identify persons at risk and tailor clinical interventions.
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Navarini, L., M. Vomero, O. Berardiucrti, D. Currado, A. Marino, A. Biaggi, S. DI Donato, et al. "AB1182 SPECIALIZED PRO-RESOLVING MEDIATORS (SPMS) AND INFLAMMATORY NETWORKS IN PATIENTS AFFECTED BY ADULT ONSET STILL’S DISEASE (AOSD) AND COVID-19." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1705.2–1706. http://dx.doi.org/10.1136/annrheumdis-2022-eular.5053.
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BackgroundUncontrolled systemic inflammation characterizes COVID-19 and autoinflammatory diseases such as adult-onset Still’s disease (AOSD). Biosynthesis of pro-resolving mediators (SPMs), i.e. lipoxins (LX), resolvins (Rv), protectins (PD), and maresins (MaR), ensures inflammation shutdown and tissue repair, limiting neutrophils recruitment and stimulating macrophages to remove apoptotic cells. Among protectins, reduction of PD1 was found in the lungs of mice infected with the H5N1 influenza virus and experimental treatment with PD1 resulted in increased animals’ survival (Morita M et al 2013).ObjectivesWe investigated the effects of SPMs in pathogenesis and clinical evolution of AOSD and compared these data with mild and severe COVID-19. Finally, we analyzed the potential role of PD1 in modulating the inflammatory response of macrophages obtained from AOSD patients, COVID-19 patients and healthy donors (HDs).Methods21 patients hospitalized for COVID-19 (10 ICU and 11 hospitalized in medical clinical unit) and 13 patients with AOSD were enrolled. Plasma PD1 levels from patients and controls were analyzed by ELISA, and monocytes-derived macrophages were polarized into M1 and M2 phenotype. We analyzed the effect of PD-1 on macrophages differentiation. At 10 days, macrophages were analyzed for surface expression of subtypes markers by flow cytometry. Cytokines production was measured in supernatants by Bio-Plex Assays. Peripheral blood mononuclear cells (PBMCS) from 3 AOSD patients, 2 COVID-19 patients and 3 HDs were obtained. Next-generation deep sequencing was then performed to identify the differences in PBMCs transcripts profiles.ResultsAOSD patients with systemic scored (SS) ≥1 showed an increase of PD1 levels compared to AOSD patients with lower systemic score (p=0.04) (Figure 1A). Similarly, plasma levels of PD1 were increased in COVID-19 patients independently from their clinical subsets, compared to HDs (p=0.02). In vitro treatment with PD1 of monocytes-derived macrophages from AOSD and COVID-19 patients induced a significant increase of M2 polarization vs control (p<0.05) (Figure 1B). Furthermore, a significant release of IL-10 and CCL4 from M2 macrophages was observed when compared to control (p<0.05) (Figure 1C). In the transcriptomes from 3 AOSD patients (2 mild and 1 severe), 2 COVID-19 patients (1 mild and 1 ICU) and 2 HDs, we observed that genes involved in inflammation, lipid catabolism and monocytes activation were specifically dysregulated in AOSD and COVID-19 patients when compared to HDs. Among them pla2g15, pla2g12a, pla2g2d, involved in mobilization of SPMs precursors, were significant upregulated in patients compared to HDs (p<.01, |log2FoldChange|>1.2) (Figure 1D). The largest part of the genes involved in inflammation, lipid catabolism, and monocytes activation are less expressed in AOSD patients when compared to COVID19 patients, as reported in Table 1.Table 1.Gene symbolLog2 fold changepAdjusted pCounts COVID19Counts AOSDInflammation-related genesALOX50.980.0240.2116861.618562.92IL13RA11.280.0020.0537154.782938.95RTN30.720.0020.00699948.376045.92SSH21.056,78 E-70.0001618343.868848.67Lipid catabolism genesPLBD11.680.000110.008228051.888671.3CYP4F32.850.000340.0171996.63277.13STS1.530.0100.0361798.5623.9HADHA0.740.000140.009712766.447625.38Monocytes-related genesALDH21.462.48E-101.85E-079186.553340.87CD1632.379,99E-060.001466499.4512870.59MGST11.130.00260.0631385.54631.67RNASE42.480.00010.009286.6615.42Figure 1.ConclusionThe counterbalance by SPMs during inflammation is still a largely unexplored pathway. Our study suggests that an imbalance of SPMs in autoinflammatory diseases as well as COVID-19. The modulation of SPMs as observed in our experiments, might represent a new possible therapeutic strategy during AOSD and COVID-19.References[1]Morita M et al. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell. 2013;153:112-25.Disclosure of Interestsluca navarini Speakers bureau: AbbVie, Pfizer, MSD, UCB, GSK, BMS, Roche, Sanofi Aventis, Novartis, Janssen, Galapagos, Eli Lilly, Paid instructor for: AbbVie, Eli Lilly, Consultant of: Philogen, Grant/research support from: AbbVie, Marta Vomero: None declared, Onorina Berardiucrti: None declared, Damiano Currado: None declared, Annalisa Marino: None declared, Alice Biaggi: None declared, Stefano Di Donato: None declared, Francesco Ursini: None declared, Piero Ruscitti: None declared, Riccardo Meliconi: None declared, Paola Cipriani: None declared, Annamaria Iagnocco Speakers bureau: AbbVie, Pfizer, MSD, UCB, GSK, BMS, Roche, Sanofi Aventis, Novartis, Janssen, Galapagos, Eli Lilly, Antonella Afeltra Speakers bureau: AbbVie, Pfizer, MSD, UCB, GSK, BMS, Roche, Sanofi Aventis, Novartis, Janssen, Galapagos, Eli Lilly, Roberto Giacomelli Speakers bureau: AbbVie, Pfizer, MSD, UCB, GSK, BMS, Roche, Sanofi Aventis, Novartis, Janssen, Galapagos, Eli Lilly, SOBI, Consultant of: Philogen, Grant/research support from: AbbVie, SOBI
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Perniola, S., S. Alivernini, B. Tolusso, M. R. Gigante, M. Gessi, C. Di Mario, L. Petricca, et al. "AB0102 SPECIALIZED PRO-RESOLVING MEDIATOR RECEPTORS AS INFLAMMATORY RESOLUTION BIOMARKERS IN RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1350.3–1350. http://dx.doi.org/10.1136/annrheumdis-2020-eular.6303.
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Background:The regulation of inflammation is a dynamic process involving several molecules as lipid mediators. The Specialized Pro-resolving Mediators (SPMs), such as Resolvin (RvD and RvE), Protectins, Maresins and Lipoxin A4 (LXA4), are bioactive metabolites of omega-3 and omega-6 fatty acids which drive inflammatory resolution phase and promote tissue repair. ERV, ALX/FPR2 and BLT1 are SPM receptors. Although in Rheumatoid Arthritis (RA) lipid mediators role within pathophysiology is under definition, studies on SPMs receptors role are still lacking in this disease.Objectives:Purpose of this study is to define ERV, ALX/FPR2 and BLT1 expression in blood derived leukocytes and synovial cells and to correlate it to disease activity to define SPM receptors ad inflammatory resolution biomarkers in RA patients.Methods:A cohort of 52 RA patients was enrolled in the study of which 40 with active disease (DAS28= 5,35 (5,18-6,40)) and 12 in sustained remission status (DAS28= 2,1 (1,83-2,42)). Each enrolled patient underwent peripheral blood (PB) drawing and 46 of them underwent US-guided synovial tissue (ST) biopsy. FACS gating strategy was used for PB and ST processing to evaluate percentage of positive cells and the mean fluorescence intensity (MFI) of ERV+, ALX/FPR2+and BLT1+in CD45+CD3+, CD45+CD19+for PB and ST, CD45+CD14+and neutrophils for PB only and CD45-CD90+, CD45+CD64+CD11b+macrophages (distinct in CD206+and CD206-subpopulations) for ST only. Each included ST was stained with haematoxylin/eosin and categorized by a pathologist, blinded to clinical characteristics, using the Krenn Score (KS) to assess ST inflammation degree. As control group, 11 undifferentiated peripheral inflammatory arthritis (UPIA) patients were enrolled in the study.Results:Considering the whole RA cohort, DAS28 inversely correlated with BLT1+positive cells on ST-derived CD45+(r= -0.48; p= 0.048), CD3+(r= -0.56; p= 0.019) and CD19+(r= -0.49; p= 0.042) cells, in contrast with CD90+(r= 0.50; p= 0.041) cells. Similarly, both DAS28 and KS inversely correlated with ALX/FPR2+positive cells in ST-derived CD45+(r= -0.42, p= 0.050 and r= -0,41, p= 0,046 respectively) cells. Evaluating the MFI levels of the SPM receptors along all RA stages (naïve-to-treatment, resistant-to-treatment, sustained remission) compared with UPIA control group, interestingly ST-derived CD45+cells of remission RA were depleted of ERV1 compared to naïve-to-treatment RA (p=0.04), despite comparable ST inflammation. Furthermore, highest ERV1 expression was found in ST-derived CD45+CD3+and CD45+CD19+cells in naïve-to-treatment RA compared with UPIA patients (p= 0,045 and p= 0,012 respectively). Moreover, the lowest BLT1 level was found in remission RA CD3+cells compared with UPIA and naïve-to-treatment RA patients (p= 0,008 and p= 0,023 respectively).Conclusion:SPM receptors expression seem to be tightly related to disease activity in the synovial tissue, suggesting an important involvement in the inflammatory process in RA patient.References:[1]Serhan CN. Nature, 2014.[2]Alivernini S, et al. Arthritis Res Ther 2016[3]Krenn V et al. Histopathology, 2006.Disclosure of Interests:Simone Perniola: None declared, Stefano Alivernini: None declared, Barbara Tolusso: None declared, Maria Rita Gigante: None declared, Marco Gessi: None declared, Clara Di Mario: None declared, Luca Petricca: None declared, Annunziata Capacci: None declared, Anna Laura Fedele: None declared, Gianfranco Ferraccioli: None declared, Elisa Gremese Speakers bureau: Abbvie, BMS, Celgene, Jannsen, Lilly, MSD, Novartis, Pfizer, Sandoz, UCB
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Ontoria-Oviedo, Imelda, Elena Amaro-Prellezo, Delia Castellano, Elena Venegas-Venegas, Fernando González-Santos, Amparo Ruiz-Saurí, Beatriz Pelacho, Felipe Prósper, María Dolores Pérez del Caz, and Pilar Sepúlveda. "Topical Administration of a Marine Oil Rich in Pro-Resolving Lipid Mediators Accelerates Wound Healing in Diabetic db/db Mice through Angiogenesis and Macrophage Polarization." International Journal of Molecular Sciences 23, no. 17 (August 31, 2022): 9918. http://dx.doi.org/10.3390/ijms23179918.
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Impaired wound healing in patients with type 2 diabetes (DM2) is characterized by chronic inflammation, which delays wound closure. Specialized pro-resolving lipid mediators (SPMs) are bioactive molecules produced from essential polyunsaturated fatty acids (PUFAs), principally omega-3 docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). SPMs are potent regulators of inflammation and have been used to suppress chronic inflammation in peripheral artery disease, non-alcoholic fatty liver disease, and central nervous system syndromes. LIPINOVA® is a commercially available safe-grade nutritional supplement made from a fractionated marine lipid concentrate derived from anchovy and sardine oil that is rich in SPMs and EPA, as well as DHA precursors. Here, we assessed the effect of LIPINOVA® in wound dressing applications. LIPINOVA® showed biocompatibility with keratinocytes and fibroblasts, reduced the abundance of pro-inflammatory macrophages (Mφ1), and promoted in vitro wound closure. Daily application of the marine oil to open wounds made by punch biopsy in db/db mice promoted wound closure by accelerating the resolution of inflammation, inducing neoangiogenesis and Mφ1/Mφ2 macrophage polarization. In conclusion, LIPINOVA® displays pro-resolutive properties and could be exploited as a therapeutic agent for the treatment of diabetic ulcers.
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Dominguez, Edward C., Art J. Heires, Jacqueline Pavlik, Tricia D. Larsen, Stephanie Guardado, Joseph H. Sisson, Michelle L. Baack, Debra J. Romberger, and Tara M. Nordgren. "A High Docosahexaenoic Acid Diet Alters the Lung Inflammatory Response to Acute Dust Exposure." Nutrients 12, no. 8 (August 4, 2020): 2334. http://dx.doi.org/10.3390/nu12082334.
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Agricultural workers are at risk for the development of acute and chronic lung diseases due to their exposure to organic agricultural dusts. A diet intervention using the omega-3 fatty acid docosahexaenoic acid (DHA) has been shown to be an effective therapeutic approach for alleviating a dust-induced inflammatory response. We thus hypothesized a high-DHA diet would alter the dust-induced inflammatory response through the increased production of specialized pro-resolving mediators (SPMs). Mice were pre-treated with a DHA-rich diet 4 weeks before being intranasally challenged with a single dose of an extract made from dust collected from a concentrated swine feeding operation (HDE). This omega-3-fatty-acid-rich diet led to reduced arachidonic acid levels in the blood, enhanced macrophage recruitment, and increased the production of the DHA-derived SPM Resolvin D1 (RvD1) in the lung following HDE exposure. An assessment of transcript-level changes in the immune response demonstrated significant differences in immune pathway activation and alterations of numerous macrophage-associated genes among HDE-challenged mice fed a high DHA diet. Our data indicate that consuming a DHA-rich diet leads to the enhanced production of SPMs during an acute inflammatory challenge to dust, supporting a role for dietary DHA supplementation as a potential therapeutic strategy for reducing dust-induced lung inflammation.
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Balta, Maria G., Olav Schreurs, Rashi Halder, Thomas M. Küntziger, Frank Saetre, Inger Johanne S. Blix, Espen S. Baekkevold, Enrico Glaab, and Karl Schenck. "RvD1n-3 DPA Downregulates the Transcription of Pro-Inflammatory Genes in Oral Epithelial Cells and Reverses Nuclear Translocation of Transcription Factor p65 after TNF-α Stimulation." International Journal of Molecular Sciences 23, no. 23 (November 28, 2022): 14878. http://dx.doi.org/10.3390/ijms232314878.
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Specialized pro-resolving mediators (SPMs) are multifunctional lipid mediators that participate in the resolution of inflammation. We have recently described that oral epithelial cells (OECs) express receptors of the SPM resolvin RvD1n-3 DPA and that cultured OECs respond to RvD1n-3 DPA addition by intracellular calcium release, nuclear receptor translocation and transcription of genes coding for antimicrobial peptides. The aim of the present study was to assess the functional outcome of RvD1n-3 DPA–signaling in OECs under inflammatory conditions. To this end, we performed transcriptomic analyses of TNF-α-stimulated cells that were subsequently treated with RvD1n-3 DPA and found significant downregulation of pro-inflammatory nuclear factor kappa B (NF-κB) target genes. Further bioinformatics analyses showed that RvD1n-3 DPA inhibited the expression of several genes involved in the NF-κB activation pathway. Confocal microscopy revealed that addition of RvD1n-3 DPA to OECs reversed TNF-α-induced nuclear translocation of NF-κB p65. Co-treatment of the cells with the exportin 1 inhibitor leptomycin B indicated that RvD1n-3 DPA increases nuclear export of p65. Taken together, our observations suggest that SPMs also have the potential to be used as a therapeutic aid when inflammation is established.
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Trojan, Ewa, Natalia Bryniarska, Monika Leśkiewicz, Magdalena Regulska, Katarzyna Chamera, Magdalena Szuster-Głuszczak, Marcello Leopoldo, Enza Lacivita, and Agnieszka Basta-Kaim. "The Contribution of Formyl Peptide Receptor Dysfunction to the Course of Neuroinflammation: A Potential Role in the Brain Pathology." Current Neuropharmacology 18, no. 3 (February 14, 2020): 229–49. http://dx.doi.org/10.2174/1570159x17666191019170244.
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: Chronic inflammatory processes within the central nervous system (CNS) are in part responsible for the development of neurodegenerative and psychiatric diseases. These processes are associated with, among other things, the increased and disturbed activation of microglia and the elevated production of proinflammatory factors. Recent studies indicated that the disruption of the process of resolution of inflammation (RoI) may be the cause of CNS disorders. It is shown that the RoI is regulated by endogenous molecules called specialized pro-resolving mediators (SPMs), which interact with specific membrane receptors. Some SPMs activate formyl peptide receptors (FPRs), which belong to the family of seven-transmembrane G protein-coupled receptors. These receptors take part not only in the proinflammatory response but also in the resolution of the inflammation process. Therefore, the activation of FPRs might have complex consequences. : This review discusses the potential role of FPRs, and in particular the role of FPR2 subtype, in the brain under physiological and pathological conditions and their involvement in processes underlying neurodegenerative and psychiatric disorders as well as ischemia, the pathogenesis of which involves the dysfunction of inflammatory processes.
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Polinski, Kristen J., Michael Armstrong, Jonathan Manke, Jennifer Seifert, Tessa Crume, Fan Yang, Michael Clare-Salzler, V. Michael Holers, Nichole Reisdorph, and Jill M. Norris. "Collection and Storage of Human Plasma for Measurement of Oxylipins." Metabolites 11, no. 3 (February 26, 2021): 137. http://dx.doi.org/10.3390/metabo11030137.
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Oxylipins derived from omega-3 and -6 fatty acids are actively involved in inflammatory and immune processes and play important roles in human disease. However, as the interest in oxylipins increases, questions remain regarding which molecules are detectable in plasma, the best methods of collecting samples, and if molecules are stable during collection and storage. We thereby built upon existing studies by examining the stability of an expanded panel of 90 oxylipins, including specialized pro-resolving lipid mediators (SPMs), in human plasma (n = 5 subjects) during sample collection, processing, and storage at −80 °C. Oxylipins were quantified using liquid chromatography-tandem mass spectrometry (LC/MS/MS). Blood samples collected in ethylenediaminetetraacetic acid (EDTA) or heparin followed by up to 2 h at room temperature prior to processing showed no significant differences in oxylipin concentrations compared to immediately processed samples, including the SPMs lipoxin A4 and resolvin D1. The majority of molecules, including SPMs, remained stable following storage for up to 1 year. However, in support of previous findings, changes were seen in a small subset of oxylipins including 12-HETE, TXB2, 14-HDHA, and 18-HEPE. Overall, this study showed that accurate measurements of most oxylipins can be obtained from stored EDTA or heparin plasma samples using LC/MS/MS.
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Martinez, Renata M., Victor Fattori, Priscila Saito, Ingrid C. Pinto, Camilla C. A. Rodrigues, Cristina P. B. Melo, Allan J. C. Bussmann, et al. "The Lipoxin Receptor/FPR2 Agonist BML-111 Protects Mouse Skin Against Ultraviolet B Radiation." Molecules 25, no. 12 (June 26, 2020): 2953. http://dx.doi.org/10.3390/molecules25122953.
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Excessive exposure to UV, especially UVB, is the most important risk factor for skin cancer and premature skin aging. The identification of the specialized pro-resolving lipid mediators (SPMs) challenged the preexisting paradigm of how inflammation ends. Rather than a passive process, the resolution of inflammation relies on the active production of SPMs, such as Lipoxins (Lx), Maresins, protectins, and Resolvins. LXA4 is an SPM that exerts its action through ALX/FPR2 receptor. Stable ALX/FPR2 agonists are required because SPMs can be quickly metabolized within tissues near the site of formation. BML-111 is a commercially available synthetic ALX/FPR2 receptor agonist with analgesic, antioxidant, and anti-inflammatory properties. Based on that, we aimed to determine the effect of BML-111 in a model of UVB-induced skin inflammation in hairless mice. We demonstrated that BML-111 ameliorates the signs of UVB-induced skin inflammation by reducing neutrophil recruitment and mast cell activation. Reduction of these cells by BML-111 led to lower number of sunburn cells formation, decrease in epidermal thickness, collagen degradation, cytokine production (TNF-α, IL-1β, IL-6, TGF, and IL-10), and oxidative stress (observed by an increase in total antioxidant capacity and Nrf2 signaling pathway), indicating that BML-111 might be a promising drug to treat skin disorders.
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Hwang, Sung-Min, Gehoon Chung, Yong Ho Kim, and Chul-Kyu Park. "The Role of Maresins in Inflammatory Pain: Function of Macrophages in Wound Regeneration." International Journal of Molecular Sciences 20, no. 23 (November 21, 2019): 5849. http://dx.doi.org/10.3390/ijms20235849.
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Although acute inflammatory responses are host-protective and generally self-limited, unresolved and delayed resolution of acute inflammation can lead to further tissue damage and chronic inflammation. The mechanism of pain induction under inflammatory conditions has been studied extensively; however, the mechanism of pain resolution is not fully understood. The resolution of inflammation is a biosynthetically active process, involving specialized pro-resolving mediators (SPMs). In particular, maresins (MaRs) are synthesized from docosahexaenoic acid (DHA) by macrophages and have anti-inflammatory and pro-resolving capacities as well as tissue regenerating and pain-relieving properties. A new class of macrophage-derived molecules—MaR conjugates in tissue regeneration (MCTRs)—has been reported to regulate phagocytosis and the repair and regeneration of damaged tissue. Macrophages not only participate in the biosynthesis of SPMs, but also play an important role in phagocytosis. They exhibit different phenotypes categorized as proinflammatory M1-like phenotypes and anti-inflammatory M2 phenotypes that mediate both harmful and protective functions, respectively. However, the signaling mechanisms underlying macrophage functions and phenotypic changes have not yet been fully established. Recent studies report that MaRs help resolve inflammatory pain by enhancing macrophage phagocytosis and shifting cytokine release to the anti-inflammatory M2 phenotypes. Consequently, this review elucidated the characteristics of MaRs and macrophages, focusing on the potent action of MaRs to enhance the M2 macrophage phenotype profiles that possess the ability to alleviate inflammatory pain.
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Olivares-González, Lorena, Sheyla Velasco, Idoia Gallego, Marina Esteban-Medina, Gustavo Puras, Carlos Loucera, Alicia Martínez-Romero, María Peña-Chilet, José Luis Pedraz, and Regina Rodrigo. "An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in rd10 Mice." Antioxidants 12, no. 1 (December 30, 2022): 98. http://dx.doi.org/10.3390/antiox12010098.
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Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), on retinal degeneration and microglia activation in rd10 mice, a model of RP, as well as on LPS-stimulated BV2 cells. The EFA supplement was orally administered to mice from postnatal day (P)9 to P18. At P18, the electrical activity of the retina was examined by electroretinography (ERG) and innate behavior in response to light were measured. Retinal degeneration was studied via histology including the TUNEL assay and microglia immunolabeling. Microglia polarization (M1/M2) was assessed by flow cytometry, qPCR, ELISA and histology. Redox status was analyzed by measuring antioxidant enzymes and markers of oxidative damage. Interestingly, the EFA supplement ameliorated retinal dysfunction and degeneration by improving ERG recording and sensitivity to light, and reducing photoreceptor cell loss. The EFA supplement reduced inflammation and microglia activation attenuating M1 markers as well as inducing a shift to the M2 phenotype in rd10 mouse retinas and LPS-stimulated BV2 cells. It also reduced oxidative stress markers of lipid peroxidation and carbonylation. These findings could open up new therapeutic opportunities based on resolving inflammation with oral supplementation with SPMs such as the EFA supplement.
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Kolawole, Oluwafunke R., and Khosrow Kashfi. "NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase." International Journal of Molecular Sciences 23, no. 3 (January 27, 2022): 1432. http://dx.doi.org/10.3390/ijms23031432.
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Acute inflammation or resolved inflammation is an adaptive host defense mechanism and is self-limiting, which returns the body to a state of homeostasis. However, unresolved, uncontrolled, or chronic inflammation may lead to various maladies, including cancer. Important evidence that links inflammation and cancer is that nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, reduce the risk and mortality from many cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug developmental work focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in the colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, NSAIDs do not require the presence of COX-2 to prevent cancer. In this review, we highlight the effects of NSAIDs and selective COX-2 inhibitors (COXIBs) on targets beyond COX-2 that have shown to be important against many cancers. Finally, we hone in on specialized pro-resolving mediators (SPMs) that are biosynthesized locally and, in a time, -dependent manner to promote the resolution of inflammation and subsequent tissue healing. Different classes of SPMs are reviewed, highlighting aspirin’s potential in triggering the production of these resolution-promoting mediators (resolvins, lipoxins, protectins, and maresins), which show promise in inhibiting cancer growth and metastasis.
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Engert, L. C., M. Dubourdeau, J. M. Mullington, and M. Haack. "0275 Exposure to Experimentally Induced Sleep Disturbance Affects the Inflammatory Resolution Pathways in Healthy Humans." Sleep 43, Supplement_1 (April 2020): A104—A105. http://dx.doi.org/10.1093/sleep/zsaa056.273.
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Abstract Introduction Sleep disturbances are assumed to impair health through induction of low-grade systemic inflammation. Experimental studies have shown that such inflammatory upregulation does not normalize even after a couple of nights of recovery sleep. We hypothesized that sleep disturbances do not only affect inflammatory pathways, but also the recently detected inflammatory resolution pathways, which actively terminate inflammation. Mediators of inflammatory resolution mainly derive from omega-3 fatty acids converted to specialized pro-resolving mediators (SPMs), such as resolvins. We investigated SPMs in healthy humans exposed to a novel model of experimental insomnia. Methods Twenty-four individuals (age 18–42 years, 12 women) participated in a study consisting of two 19-day in-hospital protocols (insomnia/control). After three nights of baseline sleep (8h/night, 23:00-07:00), participants in the experimental insomnia condition were exposed to three cycles of three nights of disturbed sleep (delayed sleep-onset, hourly sleep disruption, advanced sleep-offset) followed by one night of 8h-recovery sleep. The protocol ended with three additional nights of recovery sleep. In the control condition, participants had an uninterrupted sleep opportunity (8h/night) across the 19-day protocol. Blood samples were taken at 11:00 at baseline, during experimental insomnia exposure, and after recovery sleep. Several SPMs were measured in plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Data were analyzed using linear mixed models. Results Exposure to experimental insomnia affected several SPMs compared to control sleep, including a decrease of resolvin D4 and E2 concentrations, which was still evident after the third recovery night (p<.05). Conclusion This is the first investigation on the effects of experimentally induced sleep disturbance on inflammatory resolution pathways. The results support that SPMs, particularly resolvin D4 and E2, are decreased by sleep disturbances, and do not normalize after a couple of nights of recovery sleep. Targeting these pathways by pharmacologically increasing SPMs may help to limit inflammatory consequences of sleep disturbances. Support NIH/NINDS R01-NS091177; NIH/National Center for Research Resources UL1-RR02758 and M01-RR01032 to the Harvard Clinical and Translational Science Center.
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Tylek, Kinga, Ewa Trojan, Monika Leśkiewicz, Magdalena Regulska, Natalia Bryniarska, Katarzyna Curzytek, Enza Lacivita, Marcello Leopoldo, and Agnieszka Basta-Kaim. "Time-Dependent Protective and Pro-Resolving Effects of FPR2 Agonists on Lipopolysaccharide-Exposed Microglia Cells Involve Inhibition of NF-κB and MAPKs Pathways." Cells 10, no. 9 (September 9, 2021): 2373. http://dx.doi.org/10.3390/cells10092373.
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Prolonged or excessive microglial activation may lead to disturbances in the resolution of inflammation (RoI). The importance of specialized pro-resolving lipid mediators (SPMs) in RoI has been highlighted. Among them, lipoxins (LXA4) and aspirin-triggered lipoxin A4 (AT-LXA4) mediate beneficial responses through the activation of N-formyl peptide receptor-2 (FPR2). We aimed to shed more light on the time-dependent protective and anti-inflammatory impact of the endogenous SPMs, LXA4, and AT-LXA4, and of a new synthetic FPR2 agonist MR-39, in lipopolysaccharide (LPS)-exposed rat microglial cells. Our results showed that LXA4, AT-LXA4, and MR-39 exhibit a protective and pro-resolving potential in LPS-stimulated microglia, even if marked differences were apparent regarding the time dependency and efficacy of inhibiting particular biomarkers. The LXA4 action was found mainly after 3 h of LPS stimulation, and the AT-LXA4 effect was varied in time, while MR-39′s effect was mainly observed after 24 h of stimulation by endotoxin. MR-39 was the only FPR2 ligand that attenuated LPS-evoked changes in the mitochondrial membrane potential and diminished the ROS and NO release. Moreover, the LPS-induced alterations in the microglial phenotype were modulated by LXA4, AT-LXA4, and MR-39. The anti-inflammatory effect of MR-39 on the IL-1β release was mediated through FPR2. All tested ligands inhibited TNF-α production, while AT-LXA4 and MR-39 also diminished IL-6 levels in LPS-stimulated microglia. The favorable action of LXA4 and MR-39 was mediated through the inhibition of ERK1/2 phosphorylation. AT-LXA4 and MR39 diminished the phosphorylation of the transcription factor NF-κB, while AT-LXA4 also affected p38 kinase phosphorylation. Our results suggest that new pro-resolving synthetic mediators can represent an attractive treatment option for the enhancement of RoI, and that FPR2 can provide a perspective as a target in immune-related brain disorders.
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Barnig, Cindy, Gaetan Lutzweiler, Margherita Giannini, Anne Lejay, Anne-Laure Charles, Alain Meyer, and Bernard Geny. "Resolution of Inflammation after Skeletal Muscle Ischemia–Reperfusion Injury: A Focus on the Lipid Mediators Lipoxins, Resolvins, Protectins and Maresins." Antioxidants 11, no. 6 (June 20, 2022): 1213. http://dx.doi.org/10.3390/antiox11061213.
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Skeletal muscle ischemia reperfusion is very frequent in humans and results not only in muscle destruction but also in multi-organ failure and death via systemic effects related to inflammation and oxidative stress. In addition to overabundance of pro-inflammatory stimuli, excessive and uncontrolled inflammation can also result from defects in resolution signaling. Importantly, the resolution of inflammation is an active process also based on specific lipid mediators including lipoxins, resolvins and maresins that orchestrate the potential return to tissue homeostasis. Thus, lipid mediators have received growing attention since they dampen deleterious effects related to ischemia–reperfusion. For instance, the treatment of skeletal muscles with resolvins prior to ischemia decreases polymorphonuclear leukocyte (PMN) infiltration. Additionally, remote alterations in lungs or kidneys are reduced when enhancing lipid mediators’ functions. Accordingly, lipoxins prevented oxidative-stress-mediated tissue injuries, macrophage polarization was modified and in mice lacking DRV2 receptors, ischemia/reperfusion resulted in excessive leukocyte accumulation. In this review, we first aimed to describe the inflammatory response during ischemia and reperfusion in skeletal muscle and then discuss recent discoveries in resolution pathways. We focused on the role of specialized pro-resolving mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) and their potential therapeutic applications.
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Nordgren, Tara M., Ann Anderson Berry, Matthew Van Ormer, Samuel Zoucha, Elizabeth Elliott, Rebecca Johnson, Elizabeth McGinn, et al. "Omega-3 Fatty Acid Supplementation, Pro-Resolving Mediators, and Clinical Outcomes in Maternal-Infant Pairs." Nutrients 11, no. 1 (January 5, 2019): 98. http://dx.doi.org/10.3390/nu11010098.
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Omega (n)-3 fatty acids are vital to neonatal maturation, and recent investigations reveal n-3 fatty acids serve as substrates for the biosynthesis of specialized pro-resolving lipid mediators (SPM) that have anti-inflammatory and immune-stimulating effects. The role SPM play in the protection against negative maternal-fetal health outcomes is unclear, and there are no current biomarkers of n-3 fatty acid sufficiency. We sought to ascertain the relationships between n-3 fatty acid intake, SPM levels, and maternal-fetal health outcomes. We obtained n-3 fatty acid intake information from 136 mothers admitted for delivery using a food frequency questionnaire and measured docosahexaenoic acid (DHA)-derived SPMs resolvin D1 (RvD1) and RvD2 in maternal and cord plasma. We found significantly elevated SPM in maternal versus cord plasma, and increased SPM levels were associated with at-risk outcomes. We also identified that increased DHA intake was associated with elevated maternal plasma RvD1 (p = 0.03; R2 = 0.18) and RvD2 (p = 0.04; R2 = 0.20) in the setting of neonatal intensive care unit (NICU) admission. These findings indicate that increased n-3 fatty acid intake may provide increased substrate for the production of SPM during high-risk pregnancy/delivery conditions, and that increased maternal plasma SPM could serve as a biomarker for negative neonatal outcomes.
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Olsen, Markus V., Anne V. Lyngstadaas, Jeffrey A. Bair, Robin R. Hodges, Tor P. Utheim, Charles N. Serhan, and Darlene A. Dartt. "Signaling Pathways Used by the Specialized Pro-Resolving Mediator Maresin 2 Regulate Goblet Cell Function: Comparison with Maresin 1." International Journal of Molecular Sciences 23, no. 11 (June 2, 2022): 6233. http://dx.doi.org/10.3390/ijms23116233.
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Specialized pro-resolving mediators (SPMs), including Maresins (MaR)-1 and 2, contribute to tear film homeostasis and resolve conjunctival inflammation. We investigated MaR2′s signaling pathways in goblet cells (GC) from rat conjunctiva. Agonist-induced [Ca2+]i and high-molecular weight glycoconjugate secretion were measured. MaR2 increased [Ca2+]i and stimulated secretion. MaR2 and MaR1 stimulate conjunctival goblet cell function, especially secretion, by activating different but overlapping GPCR and signaling pathways, and furthermore counter-regulate histamine stimulated increase in [Ca2+]i. Thus, MaR2 and MaR1 play a role in maintaining the ocular surface and tear film homeostasis in health and disease. As MaR2 and MaR1 modulate conjunctival goblet cell function, they each may have potential as novel, but differing, options for the treatment of ocular surface inflammatory diseases including allergic conjunctivitis and dry eye disease. We conclude that in conjunctival GC MaR2 and MaR1, both increase the [Ca2+]i and stimulate secretion to maintain homeostasis by using one set of different, but overlapping, signaling pathways to increase [Ca2+]i and another set to stimulate secretion. MaR2 also resolves ocular allergy.
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Ramon, Sesquile, Steven Baker, Julie Sahler, Eric Feldsott, Luis Martínez-Sobrido, David Topham, Charles Serhan, and Richard Phipps. "Vaccination with DHA-derived specialized proresolving mediators increases the antibody-mediated immune response against influenza virus (VAC2P.925)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 72.3. http://dx.doi.org/10.4049/jimmunol.192.supp.72.3.
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Abstract Influenza viruses remain a critical global health concern. More efficacious vaccines are needed to protect against influenza virus, yet few adjuvants are approved for routine use. Specialized proresolving mediators (SPMs) are powerful endogenous bioactive lipid regulators of inflammation, with great clinical translational properties. We previously identified endogenous levels of the SPM resolvin D1, protectin D1 and 17-hydroxydocosahexaenoic acid (17-HDHA) in the mouse spleen. Here, we investigated the ability of 17-HDHA to enhance the adaptive immune response using a pre-clinical influenza vaccination mouse model. Our findings revealed that mice immunized with influenza H1N1-derived HA protein plus 17-HDHA increased antigen specific antibody titers. 17-HDHA increased the number of plasma cells and HA-specific antibody-secreting cells in the bone marrow, but it did not affect the frequency of GC B cells or Tfh cells in the draining lymph node. Importantly, the 17-HDHA-mediated increased antibody production was more protective against live pH1N1 influenza virus infection in mice. This is the first report on the immuno-stimulatory effects of omega-3-derived SPMs on the humoral immune response. These findings illustrate a previously unknown biological relation between proresolution signals and the adaptive immune system. In addition, 17-HDHA as well as other immuno-stimulatory SPM have the potential to be used as novel endogenous adjuvants.
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Bennouna, Djawed, Melissa Solano, Tonya S. Orchard, A. Courtney DeVries, Maryam Lustberg, and Rachel E. Kopec. "The Effects of Doxorubicin-based Chemotherapy and Omega-3 Supplementation on Mouse Brain Lipids." Metabolites 9, no. 10 (September 29, 2019): 208. http://dx.doi.org/10.3390/metabo9100208.
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Chemotherapy-induced cognitive impairment affects ~30% of breast cancer survivors, but the effects on how chemotherapy impacts brain lipids, and how omega-3 polyunsaturated fatty acid supplementation may confer protection, is unknown. Ovariectomized mice were randomized to two rounds of injections of doxorubicin + cyclophosphamide or vehicle after consuming a diet supplemented with 2% or 0% EPA+DHA, and sacrificed 4, 7, and 14 days after the last injection (study 1, n = 120) or sacrificed 10 days after the last injection (study 2, n = 40). Study 1 whole brain samples were extracted and analyzed by UHPLC-MS/MS to quantify specialized pro-resolving mediators (SPMs). Lipidomics analyses were performed on hippocampal extracts from study 2 to determine changes in the brain lipidome. Study 1 results: only resolvin D1 was present in all samples, but no differences in concentration were observed (P > 0.05). Study 2 results: chemotherapy was positively correlated with omega-9 fatty acids, and EPA+DHA supplementation helped to maintain levels of plasmalogens. No statistically significant chemotherapy*diet effect was observed. Results demonstrate a limited role of SPMs in the brain post-chemotherapy, but a significant alteration of hippocampal lipids previously associated with other models of cognitive impairment (i.e., Alzheimer’s and Parkinson’s disease).