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Supplementation with an enriched marine oil upregulates peripheral blood specialized pro-resolving mediators (SPM) concentrations in healthy volunteers. Blood was collected from healthy volunteers pre (0 h) then 2, 4, 6, and 24 h after the administration of 1.5, 3, and 4.5 g of an enriched marine oil supplement or placebo. Plasma was obtained, and lipid mediators were extracted, identified, and quantified using LC-MS/MS based lipid mediator profiling. A, Cumulative SPM (left) and leukotrienes and prostaglandin (right) concentrations. B, Cumulative concentrations for the distinct lipid mediator families identified in plasma. Results are mean, n=22 volunteers. Statistical differences were assessed using 2-way ANOVA and Dunnett post hoc test with P value correction conducted using Benjamini Hochberg correction. cysLT indicates cysteinyl leukotrienes; LTB 4 metabolome, leukotriene B 4 metabolome; LX, lipoxins; MaR, maresins; MaR n-3 DPA , n-3 DPA-derived MaR; MCTR, maresin conjugates in tissue regeneration; PCTR, protectin conjugates in tissue regeneration; PD, protectins; PD n-3 DPA , n-3 DPA-derived PD; PG, prostaglandins; RvD, D-series resolvins; RvD n-3 DPA , n-3 DPA-derived RvD; RvE, E-series resolvin; and RvT, 13-series resolvins.
Source publication
Rationale:
Specialized pro-resolving mediators (SPM-lipoxins, resolvins, protectins, and maresins) are produced via the enzymatic conversion of essential fatty acids, including the omega-3 fatty acids docosahexaenoic acid and n-3 docosapentaenoic acid. These mediators exert potent leukocyte directed actions and control vascular inflammation. Suppl...
Contexts in source publication
Context 1
... we found a temporal regulation of plasma SPM by enriched marine oil supplementation, which was also dose-dependent ( Figure 1). Cumulative plasma pro-resolving lipid mediator concentrations were found to increase at the 2-hour interval in a dose-dependent manner, reaching statistical significance in volunteers given the 3 and 4.5 g doses when compared with both presupplementation concentrations and to lipid mediator concentrations measured at this interval in the placebo group ( Figure 1A and Online Table IV). ...
Context 2
... we found a temporal regulation of plasma SPM by enriched marine oil supplementation, which was also dose-dependent ( Figure 1). Cumulative plasma pro-resolving lipid mediator concentrations were found to increase at the 2-hour interval in a dose-dependent manner, reaching statistical significance in volunteers given the 3 and 4.5 g doses when compared with both presupplementation concentrations and to lipid mediator concentrations measured at this interval in the placebo group ( Figure 1A and Online Table IV). Supplementation was found to increase the circulating concentrations of mediators from all omega-3 fatty acid metabolomes measured, with marked increases in n-3 DPA and the EPA metabolomes including the vasculoprotective RvD n-3 DPA Table IV). ...
Context 3
... SPM are also involved in regulating vascular inflammatory responses where alterations in the production of the DHA-derived RvD1, RvD2, and MaR1 are linked with increased vascular leukocyte activation. 13,14 Results from the present findings demonstrate that supplementation with marine oils can increase plasma SPM concentrations and reduce peripheral blood monocyte and platelet diurnal activation (Figures 1 through 3). Of note, supplementation was also found to increase peripheral blood platelet-neutrophil heterotypic aggregates as measured by an increase in CD41 expression (Figure 3). ...
Context 4
... from the present studies support this hypothesis given that while increases in peripheral blood SPM concentrations were rapid, reaching a maximum around 2-to -4 hour post supplementation, changes in the responses of peripheral blood monocytes in particular were still present 24 hours after supplementation (Figures 1 through 4). Transcriptomic analysis provides further support to this hypothesis, given that we observed significant changes in the expression of genes that are linked with key pathways in the regulation of host immune responses, including leukocyte tethering, aggregation, and energy generation (Figure 7). ...
Context 5
... we found a temporal regulation of plasma SPM by enriched marine oil supplementation, which was also dose-dependent ( Figure 1). Cumulative plasma pro-resolving lipid mediator concentrations were found to increase at the 2-hour interval in a dose-dependent manner, reaching statistical significance in volunteers given the 3 and 4.5 g doses when compared with both presupplementation concentrations and to lipid mediator concentrations measured at this interval in the placebo group ( Figure 1A and Online Table IV). ...
Context 6
... we found a temporal regulation of plasma SPM by enriched marine oil supplementation, which was also dose-dependent ( Figure 1). Cumulative plasma pro-resolving lipid mediator concentrations were found to increase at the 2-hour interval in a dose-dependent manner, reaching statistical significance in volunteers given the 3 and 4.5 g doses when compared with both presupplementation concentrations and to lipid mediator concentrations measured at this interval in the placebo group ( Figure 1A and Online Table IV). Supplementation was found to increase the circulating concentrations of mediators from all omega-3 fatty acid metabolomes measured, with marked increases in n-3 DPA and the EPA metabolomes including the vasculoprotective RvD n-3 DPA Table IV). ...
Context 7
... SPM are also involved in regulating vascular inflammatory responses where alterations in the production of the DHA-derived RvD1, RvD2, and MaR1 are linked with increased vascular leukocyte activation. 13,14 Results from the present findings demonstrate that supplementation with marine oils can increase plasma SPM concentrations and reduce peripheral blood monocyte and platelet diurnal activation (Figures 1 through 3). Of note, supplementation was also found to increase peripheral blood platelet-neutrophil heterotypic aggregates as measured by an increase in CD41 expression (Figure 3). ...
Context 8
... from the present studies support this hypothesis given that while increases in peripheral blood SPM concentrations were rapid, reaching a maximum around 2-to -4 hour post supplementation, changes in the responses of peripheral blood monocytes in particular were still present 24 hours after supplementation (Figures 1 through 4). Transcriptomic analysis provides further support to this hypothesis, given that we observed significant changes in the expression of genes that are linked with key pathways in the regulation of host immune responses, including leukocyte tethering, aggregation, and energy generation (Figure 7). ...
Citations
... Concentration of resolvin D1, resolvin E1, and maresin 1 were higher with intakes of ω-3 LC-PUFAs greater than 1 g. Interventions included single administration of ω-3 LC-PUFAs [119][120][121] or administration for a short period of time such as one week [122][123][124]. Population samples from healthy and chronically ill individuals older than 65 years were studied [124][125][126][127][128][129][130][131]. ...
Age-related changes in organ function, immune dysregulation, and the effects of senescence explain in large part the high prevalence of infections, including respiratory tract infections in older persons. Poor nutritional status in many older persons increases susceptibility to infection and worsens prognosis. Interestingly, there is an association between the amount of saturated fats in the diet and the rate of community-acquired pneumonia. Polyunsaturated fatty acids, particularly omega-3 long chain polyunsaturated fatty acids (ω-3 LC-PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have well-known anti-inflammatory, immunomodulatory, and antimicrobial effects, which may, in theory, be largely induced by PUFAs-derived lipids such as specialized pro-resolving mediators (SPMs). In adults, preliminary results of studies show that ω-3 LC-PUFAs supplementation can lead to SPM generation. SPMs have a crucial role in the resolution of inflammation, a factor relevant to survival from infection independent of the pathogen’s virulence. Moreover, the immune system of older adults appears to be more sensitive to ω-3 PUFAs. This review explores the effects of ω-3 LC-PUFAs, and PUFA bioactive lipid-derived SPMs in respiratory tract infections and the possible relevance of these data to infectious disease outcomes in the older population. The hypothesis that PUFAs have beneficial effects via SPM generation will need to be confirmed by animal experiments and patient-derived data.
... These SPMs actively mediate downregulation and resolution of the inflammatory process [34]. Hence, an intake of fish oil supplements containing n-3 LCPUFAs increases concentrations of SPMs in peripheral blood and mediates translational changes in immune cells [36]. However, the exact mechanisms of SPMs remain unclear and multifaceted. ...
Background
Oxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors’ quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN.
Methods
The OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months.
The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy.
Discussion
If readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival.
Trial registration
ClinicalTrial.gov identifier: NCT05404230
Protocol version: 1.2, April 25th. 2023
... Among PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both omega-3 PUFAs, have been associated with reducing the risk of cardiovascular diseases, improving cognitive function, and mitigating inflammation. Similarly, arachidonic acid (ARA), an omega-6 PUFA, plays a pivotal role in various cellular processes, including immune responses (Souza et al., 2020). However, the human body is incapable of de novo synthesis of PUFAs, necessitating their inclusion in dietary intake. ...
... These observations support the hypothesis that supplementing with omega-3 fatty acids will increase SPM amounts in circulation as well as in organs and tissues, and their protective actions are mediated via the upregulation of SPM biosynthesis. Recent studies have described that after supplementation of omega-3-rich oils, SPM amounts are elevated in plasma [34]. Nonetheless, the interrelationship between supplementation and increased concentrations of SPMs, their biosynthesis in organs, and reprogramming of the immune systems is not well understood yet. ...
... It is now well appreciated how important it is to treat impaired resolution and regulate inflammation [4,60]. There is also growing evidence that supplementation with SPMs is a valid source of these active lipid mediators that will increase circulation to reset or reprogram the immune system [34]. In another study, it was observed that oral supplementation of SPM-enriched oil improved quality of life, reduced pain intensity or interference, and improved mood within 4 weeks of intervention in adults with chronic pain [61], and it was recently reviewed by Ji R.R. [62]. ...
Omega-3 polyunsaturated fatty acids (PUFAs) play a vital role in human health, well-being, and the management of inflammatory diseases. Insufficient intake of omega-3 is linked to disease development. Specialized pro-resolving mediators (SPMs) are derived from omega-3 PUFAs and expedite the resolution of inflammation. They fall into categories known as resolvins, maresins, protectins, and lipoxins. The actions of SPMs in the resolution of inflammation involve restricting neutrophil infiltration, facilitating the removal of apoptotic cells and cellular debris, promoting efferocytosis and phagocytosis, counteracting the production of pro-inflammatory molecules like chemokines and cytokines, and encouraging a pro-resolving macrophage phenotype. This is an experimental pilot study in which ten healthy subjects were enrolled and received a single dose of 6 g of an oral SPM-enriched marine oil emulsion. Peripheral blood was collected at baseline, 3, 6, 9, 12, and 24 h post-administration. Temporal increases in plasma and serum SPM levels were found by using LC-MS/MS lipid profiling. Additionally, we characterized the temporal increases in omega-3 levels and established fundamental pharmacokinetics in both aforementioned matrices. These findings provide substantial evidence of the time-dependent elevation of SPMs, reinforcing the notion that oral supplementation with SPM-enriched products represents a valuable source of essential bioactive SPMs.
... These observations support the hypothesis that supplementing with omega-3 fatty acid, will increase SPMs amounts in circulation as well as in organs, tissues and their protective actions are mediated via the upregulation of SPM biosynthesis. Recent studies have described that after supplementation of omega-3 rich oils, elevate SPMs amounts in plasma [34]. Nonetheless, the interrelationship between supplementation and increased concentrations of SPMs, their biosynthesis in organs and reprogramming of the immune systems is not well understood yet. ...
... It is now well appreciated how important is to treat impaired resolution and regulate inflammation [4,56]. There is also growing evidence that supplementation of SPMs is a valid source of these active lipid mediators that will increase in circulation to reset or reprogram the immune 20 system [34]. In another study they observed that oral supplementation of SPM-enriched oil improved quality of life, reduced pain intensity or interference, and improved mood within 4 weeks of intervention in adults with chronic pain [57]. ...
Omega-3 polyunsaturated fatty acids (PUFA) play a pivotal role in health, wellbeing, and inflammatory diseases in humans. Lack of omega-3 consumption is associated with diseases. Specialized Pro-resolving Mediators (SPM) are produced from Omega-3-PUFAs and accelerate resolution of inflammation. They are classified as resolvins, maresins, protectins, and lipoxins. SPMs actions in resolution consist in limiting neutrophilic infiltration, promote the clearance of apoptotic cell and cellular debris, enhancing efferocytosis and phagocytosis, counter regulate the production of pro-inflammatory mediators such as chemokines and cytokines, and promote pro-resolving macrophage phenotype. We identified temporal plasma and serum increases of SPMs after 6 g of oral supplementation of SPM-enriched emulsion in ten healthy subjects. We also described temporal increases of omega-3, as well as pharmacokinetics fundamentals in plasma and serum using LC-MS/MS lipid profiling. These results provide evidence of temporal increases of SPMs that together support the idea that given oral supplementation is a good source of essential bioactive SPMs.
... Previous studies showed that DPA supplement could increase the level of resolvins, protectins, and maresins in body, which was a small molecule with strong antioxidant effect, leading to reprogramming of peripheral white blood cells and significant enrichment of genes involved in immune regulation and peripheral blood cell reaction. Compared with other PUFAs, DPA may play a stronger role in regulating the body's immune capacity and cardiovascular inflammation [25][26][27]. In one study, supplementation with MAT9001 (a fatty acid formula rich in EPA and DPA) was found to have a better effect than ethyl eicosapentaenoate, resulting in higher levels of PUFAs in the blood circulation, lower triglycerides and high sensitivity C-reactive protein without increasing LDL [28]. ...
Background
The relationship between marine polyunsaturated fatty acid (PUFA) intake and cardiovascular disease and mortality in dyslipidemic patients is unclear. Men with dyslipidemia have a higher risk of cardiovascular disease than women, and PUFA supplementation may be more beneficial in men.
Objective
The purpose of this study was to assess the relationship between different types of marine polyunsaturated fatty acids intakes and cardiovascular disease, all-cause mortality, and cardiovascular mortality in adult U.S. males with dyslipidemia.
Methods
The study ultimately included 11,848 adult men with dyslipidemia who were screened from the National Health and Nutrition Examination Survey (NHANES) between 2001 and 2016. This was linked to the 2019 National Death Index (NDI) records to establish a prospective cohort. In the study, a logistic regression model was established to assess the relationship between PUFA intake and prevalent CVD, and a Cox proportional hazards regression model was established to assess the relationship between PUFA intake and death.
Results
In the fully adjusted models, compared with participants in the lowest tertile, participants with the highest DPA intake were associated with a lower risk of CVD (CVD: OR = 0.71, 95%CI: 0.55, 0.91; angina: OR = 0.54, 95%CI: 0.38, 0.79; stroke: OR = 0.62, 95%CI: 0.43, 0.89), but not with three subtypes of congestive heart failure, coronary heart disease, and myocardial infarction. And the highest tertile level of DPA intake can reduce all-cause mortality (HR = 0.77, 95%CI: 0.64, 0.91) and CVD mortality (HR = 0.68, 95%CI: 0.52, 0.90).
Conclusions
Cardiovascular disease risk, all-cause mortality, and CVD mortality were inversely associated with dietary DPA intake but not EPA and DHA intakes in U.S. male participants with dyslipidemia.
... This point is particularly interesting, since EPA and DHA in the phospholipid membrane of leukocytes serve as precursors for the synthesis of specialized proresolving mediators (SPMs), such as resolvins (E and D), maresins, and protectins, in the context of an established inflammatory process. The synthesis and circulating levels of these SPMs have been reported to occur in a dosedependent manner, which leads to a reprogramming of peripheral blood cells; thus, SPMs have an important role in the regulation of persistent inflammation due to their capacity to inhibit microglia activation and reduce proinflammatory cytokines through the MAPK, NF-κB, PI3K/Akt, and caspase-3 signaling pathways [43]. However, the levels of these proresolution markers were not measured since they are beyond the scope of this research. ...
The n-3 polyunsaturated fatty acids (PUFAs) can reduce inflammatory markers and may therefore be useful in obesity management. The aim of this study was to analyze the effect of supplementation with n-3 PUFAs on total fatty acid profile in red blood cells (RBCs), as well as biochemical and inflammatory markers, in subjects with obesity. The study consisted in a randomized placebo-controlled, double-blind clinical trial involving 41 subjects with obesity during a 4-month follow-up. Individuals were randomly assigned to two groups: n-3 PUFA supplementation (1.5 g fish oil) and placebo (1.5 g sunflower oil). Anthropometric, biochemical, dietetic, cytokine and total fatty acid profiles in RBCs were measured. Both groups increased their PUFA intake and DHA incorporation in RBCs. However, the placebo group showed a reduction in serum IL-8 and MCP-1 at the end of the study. A multiple linear regression model adjusted by body fat mass and sex showed that an increase in DHA in RBCs decreased the serum IL-8 levels in both study groups at the end of the study. Our results highlight the role of dietary DHA and n-3 supplementation usefulness in exerting beneficial anti-inflammatory effects.
... 14S-HpDHA (≥1 µM), the precursor of maresin, also reduced the aggregation of platelets by 90%, implying that the intake of DHA may be beneficial in treatment [5]. However, in terms of the supplementation of n-3 fatty acids, whether it increases the concentration of endogenous maresin-associated products in the blood or tissue when fighting against bacteria, in the model of Alzheimer's disease, or during human pregnancy in different stages, still needs further investigation [172][173][174][175][176]. Ingestion of fish oil can also upregulate peripheral blood MaR2 and MaR2n-3 DPA levels (4.5 g total fatty acids, 2-4 h), and the concentration of MaR1n-3 DPA (4.5 g total fatty acids) was negatively correlated with the expression of monocyte activation marker CD49d [177]. For patients with obesity, after consuming 2 g/d of marine oil for about one month, the plasma level of MaR1 increased 4.7-fold, and B cell IgG decreased [178]. ...
Maresins are lipid mediators derived from omega-3 fatty acids with anti-inflammatory and pro-resolving properties, capable of promoting tissue regeneration and potentially serving as a therapeutic agent for chronic inflammatory diseases. The aim of this review was to systematically investigate preclinical and clinical studies on maresin to inform translational research. Two independent reviewers performed comprehensive searches with the term “Maresin (NOT) Review” on PubMed. A total of 137 studies were included and categorized into 11 human organ systems. Data pertinent to clinical translation were specifically extracted, including delivery methods, optimal dose response, and specific functional efficacy. Maresins generally exhibit efficacy in treating inflammatory diseases, attenuating inflammation, protecting organs, and promoting tissue regeneration, mostly in rodent preclinical models. The nervous system has the highest number of original studies (n = 25), followed by the cardiovascular system, digestive system, and respiratory system, each having the second highest number of studies (n = 18) in the field. Most studies considered systemic delivery with an optimal dose response for mouse animal models ranging from 4 to 25 μg/kg or 2 to 200 ng via intraperitoneal or intravenous injection respectively, whereas human in vitro studies ranged between 1 and 10 nM. Although there has been no human interventional clinical trial yet, the levels of MaR1 in human tissue fluid can potentially serve as biomarkers, including salivary samples for predicting the occurrence of cardiovascular diseases and periodontal diseases; plasma and synovial fluid levels of MaR1 can be associated with treatment response and defining pathotypes of rheumatoid arthritis. Maresins exhibit great potency in resolving disease inflammation and bridging tissue regeneration in preclinical models, and future translational development is warranted.
... With limited pharmacological options, in many cases joint replacement is considered as the only treatment option [2,3,7,34]. Recently, SPMs administered orally to healthy individuals, peripheral artery disease patients, and obese patients have been shown to: Increase SPMs levels in peripheral blood, activate downstream lipid mediator pathways, dampen inflammation, and induce a more proresolution phenotype in circulating leukocytes and macrophages [35][36][37]. There is also clinical evidence showing the efficacy of 17-HDHA and 18-HEPE in improving QoL and reducing pain in adults with chronic pain [38]. ...
Background
Specialized pro-resolving mediators (SPMs), including 18-HEPE, 17-HDHA, and 14-HDHA are recognized as potentially therapeutic in inflammatory diseases because SPMs regulate the inflammation process, which leads to, for example; swelling and the sensation of pain. In osteoarthritis (OA), chronic pain is described as the symptom that reduces patients´ quality of life (QoL). The GAUDI study evaluated the efficacy of SPMs supplementation in reducing pain in the symptomatic knee of OA patients.
Methods
This randomized, multicenter, double-blind, and placebo-controlled parallel-group pilot study was performed in Spain and conducted on adults 18–68 years old diagnosed with symptomatic knee OA. Patients were enrolled in the study for up to 24 weeks, which included a 12-week intervention period and a follow-up visit on week 24. The primary endpoint was pain change measured through a Visual Analog Scale (VAS). Secondary endpoints included: Pain change evaluation, stiffness, and function according to the WOMAC index; assessment of constant, intermittent, and total pain according to the OMERACT-OARSI score; evaluation of changes in health-related QoL parameters; the use or not of concomitant, rescue, and anti-inflammatory medication; and safety and tolerability assessments.
Results
Patients were enrolled in the study from May 2018 to September 2021. VAS pain score was evaluated in the per protocol population (n = 51 patients), in which we observed a statistically significant reduction after 8 weeks (p = 0.039) and 12 weeks (p = 0.031) of treatment in patients consuming SPMs (n = 23 subjects) vs. placebo (n = 28 subjects). In line with the OMERACT-OARSI score, intermittent pain was reduced after 12 weeks with statistical significance (p = 0.019) in patients treated with SPMs (n = 23 subjects) vs. placebo (n = 28 subjects). Functional status as WOMAC score did not significantly change after SPMs or placebo consumption. Notably, patients consuming SPMs showed improvements in all five aspects of the EUROQoL-5, including a significant improvement in the usual-activities dimension. None of the patients required rescue medication, nor were any adverse events reported.
Conclusions
These findings suggest that sustained SPMs consumption reduces pain in OA patients while also improving their Quality of Life. These results also support the safety profile of SPMs supplementation.
Trial registration NCT05633849. Registered 1 December 1 2022. Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT05633849
... By supplementing enriched marine oil supplements, the concentration of SPMs in the peripheral blood of RA patients increased and the peripheral blood cells were reprogrammed. SPMs have a guiding role in mediating the immune response of this supplement (157). After supplementation with n-3 PUFA, LTB4 levels were decreased in RA subjects (155,158). ...
As a chronic progressive autoimmune disease, rheumatoid arthritis (RA) is characterized by mainly damaging the synovium of peripheral joints and causing joint destruction and early disability. RA is also associated with a high incidence rate and mortality of cardiovascular disease. Recently, the relationship between lipid metabolism and RA has gradually attracted attention. Plasma lipid changes in RA patients are often detected in clinical tests, the systemic inflammatory status and drug treatment of RA patients can interact with the metabolic level of the body. With the development of lipid metabolomics, the changes of lipid small molecules and potential metabolic pathways have been gradually discovered, which makes the lipid metabolism of RA patients or the systemic changes of lipid metabolism after treatment more and more comprehensive. This article reviews the lipid level of RA patients, as well as the relationship between inflammation, joint destruction, cardiovascular disease, and lipid level. In addition, this review describes the effect of anti-rheumatic drugs or dietary intervention on the lipid profile of RA patients to better understand RA.
