Omega- fatty acids for inflammation -
On a cellular level, RvDs increased serotonin levels in a model of depression, and decreased gliosis in neurodegenerative disorders. Protectins prevented neurite and dendrite retraction and apoptosis in models of neurodegeneration, while maresins reduced cell death across all studies.
In terms of mechanisms, all SPMs down-regulated pro-inflammatory cytokines. Our review indicates a potential promising approach for tailored therapy with n-3 PUFAs-derived metabolites in the treatment of psychiatric, neurodegenerative, and neurological conditions. Over the last few decades, inflammation has been identified as one of the main pathophysiological mechanisms underlying psychiatric conditions 1 , 2.
Indeed, over-expression of distinct pro-inflammatory cytokines, including interleukin 1 beta IL-1β , IL-6, and tumor necrosis factor alpha TNF-α , has been associated with several neuropsychiatric disorders, such as depression 3 , 4 , as well as neurodegenerative diseases, like Alzheimer's AD and Parkinson's PD 5 , 6.
In particular, patients with major depressive disorder MDD exhibit both increased immune activation and aberrant regulation of brain plasticity 7 , which has been linked with abnormal cellular immunity 8.
Similar abnormalities have also been reported in PD and AD, which are characterized by a dysregulated immune response, due to hyper-stimulation of microglia to activate distinct inflammatory signaling pathways 9 related to aggregates of alpha-synuclein and beta-amyloid protein, respectively 10 , In all these conditions, the presence of pro-inflammatory cytokines leads to the impairment of microglial function, including phagocytosis of debris, and propagation of inflammation This is accompanied by an insufficient compensatory and regulatory function of anti-inflammatory cytokines, including IL-4, IL, and IL, which are produced by alternatively activated M2 microglia Conversely, classically activated M1 microglia have been shown to be increased in the brain of patients 13 , Despite the role of inflammation in the context of both psychiatric and neurodegenerative disorders 15 , 16 , there is still a lack of effective anti-inflammatory strategies that are safe for everyday use and display a clear mechanism of action.
Recently, increasing attention has been given to potentially anti-inflammatory nutritional interventions, particularly omega-3 polyunsaturated fatty acids n-3 PUFAs , like eicosapentaenoic acid EPA and docosahexaenoic acid DHA , which have been known to reduce depressive symptoms in patients 17 , 18 and animal models 19 , as well as cognitive symptoms EPA has been found to be present at lower levels in patients with interferon-alpha-induced depression 21 , the development of which has been shown to be prevented by EPA treatment 22 , supporting n-3 PUFAs anti-inflammatory properties Although the exact mechanisms underlying their mode of action remain unknown, n-3 PUFAs are important in regulating immune responses by inhibiting activation of pro-inflammatory pathways and reducing cytokine expression This function has been suggested to be mediated by the production of distinct n-3 PUFAs-derived metabolites, defined as specialized pro-resolving mediators SPMs , including resolvins D RvD and E RvE series, maresins MaR and protectins PD , which become elevated upon exposure to an inflammatory challenge in order to re-establish internal immune homeostasis In particular, SPMs are produced upon metabolism of n-3 PUFAs by specific enzymes including lipoxygenases, 5-lipoxygenase-1 5-LOX , LOX, and LOX, cyclooxygenases, primarily COX-2, and cytochrome P enzymes Figure 1.
These enzymatic transformations occur rapidly within the organism and genetic variants of the involved enzymes have been associated with increased risk of developing interferon-alpha-induced depression 26 , which suggests that the anti-inflammatory effects of n-3 PUFAs may indeed stem from SPMs actions.
Figure 1. Metabolism of DHA and EPA to SPMs through enzymatic transformation. SPMs are produced upon metabolism of n-3 PUFAs by specific lipoxygenase and cyclooxygenase enzymes.
Respectively, the enzymes lipoxygenase-1 LOX and lipoxygenase LOX are responsible for initiating the conversion of DHA to protectin-1 PD1 , and maresin 1 and 2 MaR1, MaR2 , whereas LOX, cyclooxygenase 2 COX-2 and cytochrome P are responsible for the conversion of DHA to resolvins D series RvD , and of EPA to resolvins E series RvE.
Downstream, metabolism of RvD and RvE are dependent on 5-lipoxygenase 5-LOX. Aspirin-acetylated COX-2 followed by 5-lipoxygenase 5-LOX transformation generates aspirin-triggered isomers of RvDs AT-RvD.
Research into the effectiveness of SPMs treatment has been carried out in various models of peripheral and central inflammation. For example, RvDs and protectins have been shown to improve inflammatory outcomes in animal models of colitis and obesity-induced diabetes, where a reduction in cytokine levels, including IL-6, were reported in macrophages derived from bone marrow tissue 27 , 28 , as well as in adipose tissue With respect to the CNS, evidence has shown that protectins and resolvins are produced in the brain, as shown by studies using brain tissue homogenates 30 , 31 , neuron-glia cultures or hippocampal tissue In a model of inflammatory pain, RvDs and RvEs were found to reduce pain behaviors through central actions Additionally, maresins have been demonstrated to attenuate mechanical allodynia 34 , 35 , a process involving central sensitization, and decreased levels of IL-1β, IL-6, and TNF-α in spinal cord tissue in models of neuropathic pain.
Taken together, these findings therefore suggest the potential involvement of SPMs in other disorders within the CNS.
Given the need to elucidate the mechanisms whereby n-3 PUFAs-derived metabolites exert their anti-inflammatory actions and the potential role of SPMs in reducing CNS inflammation, it appears relevant to summarize the evidence provided thus far on their effects in the context of psychiatric, neurodegenerative, and neurological disorders, in addition to uncovering mechanisms specific to these conditions.
Overall, 25 articles were obtained from the PubMed database, including ex vivo, in vivo , and in vitro studies investigating resolvins RvD1, RvD2, RvE1, RvE2, RvE3 , protectins PD1, NPD1 , and maresins MaR1, MaR2 in relation to psychiatric, neurodegenerative, and neurological disorders affecting cognition, and in which neuroinflammation is part of the pathophysiology.
Studies excluded from the search were or contained one or more of the following: not published in English language, did not look at the specific effects of treatment with resolvin, proctectin, or maresin, were not measuring psychiatric, neurological, neuroinflammatory, or cognitive outcomes.
In this section of the review we summarize behavioral, cellular, and molecular outcomes identified in ex vivo, in vivo , and in vitro studies which used treatment with resolvins, protectins and maresins in the context of psychiatric, neurodegenerative, and neurological disorders Table 1.
Table 1. Behavioral, cellular and molecular outcomes identified upon treatment with SPMs. Models of depression.
While depression has a wide range of symptoms, from persistent sad mood to appetite or sleep changes 60 , it was assessed by behavioral despair, measured using the immobility time in the forced swim test FST or tail suspension test TST in most of the studies.
In a mouse chronic unpredictable stress CUS model 39 intracranial RvD1 administration decreased behavioral despair in the FST. This was also found in a rat post-myocardial infarct model of depression, where depression-like behaviors are increased after occlusion of the left anterior descending coronary artery However, neither peripheral nor central RvD1 administration improved FST immobility in a mouse fibromyalgia-induced depression model 38 , where mice develop depression-like behavior after reserpine injection.
In the TST, intracranial RvD1 also reduced behavioral despair in both CUS 39 and lipopolysaccharide LPS -induced mouse models of depression Social behavior, commonly affected in depression, was enhanced by intracranial injection of RvD1 in a rat model of depression Models of neurodegenerative and neurological disorders.
The behavioral outcomes of aspirin-triggered isomer of RvD1 AT-RvD1 administration were investigated in two in vivo studies. Peripheral AT-RvD1 injection ameliorated sensorimotor function and memory after traumatic brain injury TBI in mice, confirming the hypothesis that reducing the prolonged inflammation caused by TBI would in consequence limit the impact seen in neurological functions Peripheral AT-RvD1 administration was also beneficial on cognitive impairment and fear-associated freezing in mice with surgery-induced cognitive decline, mimicking the cognitive dysfunctions observed in some patients after orthopedic surgery Only one of the studies previously mentioned investigated the cellular effects of AT-RvD1 in the context of depression.
In vivo , intravenous AT-RvD1 administration increased levels of cortical dopamine and glutamate, and limited serotonin depletion in a mouse model of fibromyalgia-associated depression, suggesting a positive effect of treatment on neurotransmitter imbalance in depression Three studies investigated the effects of RvD1 in macrophages isolated from peripheral blood mononuclear cells PBMC of AD patients treated with n-3 PUFAs supplementation.
In one study, RvD1 incubation of PBMC from AD patients improved phagocytosis of Aβ peptides on a trend level In another, RvD1 significantly increased phagocytosis and decreased apoptosis in PBMC In vivo , peripheral AT-RvD1 administration prevented astrogliosis and improved short and long-term potentiation in the hippocampus of mice with cognitive decline In vitro , embryonic human microglia incubated with Aβ 42 peptides and exposed to RvD1 had decreased expression of microglia pro-inflammatory markers CD11b and CD40 In the selected papers, only one in vivo study using a mouse model of depression examined the mechanisms underlying the actions of RvD1.
Out of the five studies investigating the mechanisms of RvD1 in neurodegenerative and neurological disorders, two were ex vivo , one was in vivo and two were in vitro. In PBMC from AD patients, RvD1 treatment decreased the transcription of immune genes and the secretion of cytokines, such as IL-1β, IL, or IL-6 In the same study, inhibition of the G protein-coupled receptor 32 GRP32 prevented RvD1-induced phagocytosis of Aβ In another study using PBMC from AD patients receiving oral nutritional intervention with n-3 PUFAs, cell treatment with RvD1 lowered p-PERK and caspase-3 expression on a trend level In vivo , IL-6 was decreased by peripheral RvD1 injection, along with the n-6 PUFAs-derived SPM lipoxin LXA 4 in the plasma of mice with surgery-induced cognitive decline In vitro , RvD1 reduced TNF-α protein expression, but not IL-6, and prevented high levels of NF-κB p50 in a PD model of rat adrenal phaeochromocytoma cells The expression of GRP32 was also confirmed in human bone-marrow derived neuroblastoma cells In three mouse models of depression, RvD2 was shown to have positive effects on depressive-like behavior, however, only one study also investigated cellular outcomes.
Central RvD2 administration was reported to improve FST and TST scores in LPS-induced 36 and in a CUS model of depression Similarly, in a model of fibromyalgia-associated depression, intravenous RvD2 prevented immobility in the FST With respect to cellular findings, RvD2 administration partially prevented total brain serotonin loss and increased glutamate levels To our knowledge, only one study described findings on the behavioral and cellular effects of RvD2 administration in neurodegenerative disorders.
In a LPS-induced PD model, intracranial addition of RvD2 to apomorphine, a non-selective dopamine receptor agonist, improved motor function of rats more efficiently, when compared with apomorphine alone Regarding cellular findings, RvD2 effectively reduced the number of activated microglia and increased the ramified phenotype in the substantia nigra of rats with PD.
This was also shown in a primary culture of cortical microglia from neonatal rats Among the studies previously mentioned, only one investigated the mechanisms underlying the effects of treatment with RvD2 in a model of depression. In one study, RvD2 was reported to exert its beneficial actions through microglia in LPS-induced PD models.
Specifically, RvD2 decreased transcription of several cytokines such as IL, IL-6, TNF-α, and IL-1β in the cytoplasm in an in vitro model of PD using rat primary cortical microglia. The expression of these cytokines was also reduced in the plasma of PD rats after central injection of RvD2.
Moreover, RvD2 effectively prevented an up-regulation of NF-κB p65 subunit and IκBα in ventral mesencephalon microglia of PD rats The evidence summarized in this section highlights the role of RvDs in reducing depression-like behavior in models of depression, and in decreasing glial inflammatory processes in neurogenerative models.
RvE series were shown to have beneficial effects in mice when injected centrally. Administration of RvE1, RvE2, and RvE3 improved behavioral despair in the TST in a LPS-induced model of depression 48 , This was also demonstrated in the FST, but only in respects of intracranial RvE1 and RvE2 injection One in vivo study investigated the behavioral effects of RvE1, and two in vivo studies investigated the cellular effects.
In a mouse model of TBI, peripheral RvE1 administration affected sleep during the first 12 h post-injury. Specifically, an overall increase in number, but not length, of sleep bouts in both light and dark periods was seen upon RvE1 administration On a cellular level, RvE1 administration increased the number of ramified microglia and decreased the number of rod microglia in the primary somatosensory cortex of mice In addition, intraperitoneal injection of RvE1 with LXA 4 decreased microgliosis and astrogliosis in the cortex and hippocampus of AD mice One in vivo study proposed two different mechanisms of actions for RvEs using a model of LPS-induced depression in mice.
Firstly, intracranial injection of RvE1 and RvE2 produced anti-depressant effects similar to those observed by activating ChemR23, a G-coupled receptor activated by chemerin 62 and RvE1 63 , suggesting the involvement of this receptor in depression.
Secondly, inhibition of the mTORC1 pathway was able to prevent the anti-depressant effects of RvE1 In an in vivo transgenic mouse model of AD, RvE1 was shown to exert its effects through down-regulation of various pro-inflammatory factors.
Specifically, peripheral RvE1 injection reduced levels of IL-6, IL-1β, IL, granulocyte-macrophage colony-stimulating factor GM-CSF , IFN-γ, TNF-α, monocyte chemoattractant protein 1 MCP-1 , macrophage inflammatory protein MIP -1a, and MIP1b in the prefrontal cortex The evidence summarized in this section supports the potential of RvEs, similar to RvDs, to alleviate depression-like behavior, which would occur via mTORC1 activation.
In terms of neurodegenerative disorders, studies clearly present RvEs as beneficial agents against the increased levels of cytokines and pro-inflammatory factors present in those conditions. Behavioral effects of PD1 administration were measured in three in vivo studies, one in the context of epilepsy and two in the context of stroke, both conditions which are associated with increased central inflammation affecting neurogenesis-related cognitive processes.
Intracranial PD1 administration improved cognitive function, specifically non-spatial recognition memory, in the novel object recognition task in kainic acid-induced epilepsy in mice PD1 also reduced frequency and seizure duration and prevented weight loss Additionally, intravenous injection of PD1 and its aspirin-triggered isomer AT-PD1 improved neurological recovery in rat models of ischemic stroke using middle cerebral artery occlusion 51 , Cellular outcomes were investigated in nine studies both in vivo and in vitro , predominantly using models of AD and ischemia.
Intravenous administration of PD1 in vivo reduced immunoglobulin G IgG immunoreactivity in the cortex, subcortex, and whole right hemisphere of rats subject to ischemic stroke It also inhibited astrocyte and microglia activation in the penumbra of ischemic rats Likewise, intracranial infusion of PD1 in epileptic mice decreased astrogliosis and microgliosis in the hippocampus, and increased neuroblasts migration in the hilus In a mouse model of TBI, intracranial administration of PD1 also improved parenchymal cell survival In vitro , PD1 treatment decreased Aβ 42 production 56 and prevented Aβ 42 -induced apoptosis and increased cell viability in two human models of AD, both using cortical neuron-glia co-culture 32 , This was also observed upon treatment with protectin isomer, PDX, in a human bone-marrow derived neuroblastoma cell model of AD In a rat dopaminergic mesencephalon neurons model of PD, PD1 treatment decreased dendritic retraction and increased neuronal survival Finally, in an in vitro model of ischemia, PDX also increased proliferation of mice subventricular zone neural progenitors One in vivo and two in vitro studies investigated the mechanisms of PD1.
In vivo , transcription and expression of IL-1β and TNF-α were reduced in the hippocampus upon PD1 intracranial administration in a murine model of epilepsy In an in vitro model of AD, PD1 administration reduced Aβ 42 production through repression of pro-inflammatory molecules, including COX-2 and TNF-α Furthermore, PD1 enhanced expression of anti-apoptotic proteins of the B-cell lymphoma 2 Bcl-2 gene family 32 and reduced caspase-3 activity in cortical human neuronal cells in vitro Based on the evidence summarized in this section, protectins are especially useful in reducing behavioral deficits observed in neurological disorders, most likely via reducing microgliosis and pro-inflammatory cytokines levels.
One in vivo study investigated the behavioral effects of treatment with MaR1, whereas three in vitro studies assessed cellular outcomes. In an in vivo mouse model of stroke, intracranial administration of MaR1 reduced neurological impairments over time On a cellular level, administration of MaR1 protected against brain cell death and inhibited the degradation of postsynaptic density protein 95 PSD95 and synapsin.
Furthermore, MaR1 administration also inhibited neutrophil infiltration and glial activation in the cortex In vitro , MaR1 treatment prevented cell death in human bone-marrow derived neuroblastoma cell models of ALS and AD 46 , MaR1 also stimulated an increase of Aβ 42 phagocytosis in embryonic human microglial cells All three studies previously mentioned investigated the mechanisms of action of PD1.
In an in vivo mouse model of stroke, expression of TNF-α, IL-1β, and MCP-1 in the cortex was reduced by intracranial administration of MaR1. Furthermore, MaR1 decreased NF-κB activation through down-regulation of p65 phosphorylation Similar effects were seen in vitro , with MaR1 treatment decreasing levels of phosphorylated NF-κB in human bone-marrow derived neuroblastoma cells MaR1 treatment of embryonic human microglia also induced a reduction in pro-inflammatory markers including CD11b, major histocompatibility complex class II MHC-II , CD86, CD40, and CD33 The limited evidence available on maresins suggests that they might benefit neurological conditions, specifically by reducing cell death and inflammatory factors, which may be related to decreased NF-κB pathway activation.
This review summarizes evidence on the beneficial effects of resolvins, protectins and maresins, in the treatment of psychiatric, neurodegenerative, and neurological disorders Figure 2. Overall, treatment with both RvD and RvE improved depressive-like behaviors in various animal models of depression, whereas PD1 and MaR1 ameliorated neurological function.
On a cellular level, RvD1 and RvD2 increased serotonin levels in a model of depression, and decreased gliosis in neurodegenerative disorders. In contrast, PD1 and PDX prevented neurite and dendrite retraction and apoptosis in models of neurodegeneration, while MaR1 reduced cell death across all studies.
In terms of mechanisms, all SPMs down-regulated pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α.
These findings suggest that not only do SPMs have anti-inflammatory properties across different models, but also possess characteristic therapeutic effects depending on the condition.
Figure 2. Comparison of behavioral, cellular, and molecular findings upon treatment with SPMs in the context of psychiatric, neurodegenerative, and neurological disorders. Despite the scarce number of studies conducted in psychiatric disorders, differences among specific SPMs could be drawn on several levels.
In particular, RvD1 and RvEs were the most effective in improving depressive symptoms across several mouse models 36 , 39 , 48 , This could be explained by their mechanistic actions, which were notably distinct between psychiatric and neurological conditions.
The mTORC1 pathway, which is a key signaling pathway in the effectiveness of antidepressants 64 , was found to underlie the behavioral effects of resolvins 36 , Moreover, all of these are key elements involved in neurogenesis 66 , which is impaired by pro-inflammatory cytokines 67 and has been shown to be rescued by n-3 PUFAs treatment after IL-1β challenge in vitro With respect to neurodegenerative disorders, none of the SPMs could be distinguished in terms of better therapeutic effects.
While apoptosis or gliosis were equally reduced by RvD1, RvE1, PD1, and MaR1 in in vivo and in vitro models, the benefits observed in ex vivo studies using patient-derived cells remained on a trend level 41 or were restricted to specific sub-groups Although it is difficult to disentangle the underlying cause of these seemingly puzzling findings, the situation can be closely related to the reality of research into AD therapy.
Many anti-inflammatory drugs appear promising at pre-clinical stages but are not effective in clinical trials, presumably due to the complexity of the disorder and the number of interacting factors Further investigation is thus necessary to achieve a clearer understanding of SPMs in neurodegenerative disorders.
Although, maresins and protectins have not been examined in the context of depression, the evidence was conclusive in neurological disorders, where they appear to have a greater potential. PD1, PDX, and MaR1 improved neurological function in animal models of ischaemia, and TBI 51 , 53 , In line with this, PD1 limited cell death, highlighting its neuroprotective abilities.
MaR1 likely had a greater effect in these conditions due to its presence in macrophages and its more potent role in dampening the activation of microglia 69 , which are more acutely and severely triggered in those conditions.
Additionally, MaR1 promotes tissue regeneration, which could be of increased therapeutic value in ischemic stroke Thus, the ability of specific metabolites to improve behavioral, cellular and mechanistic components differentially in psychiatric and neurodegenerative disorders could be a basis for new personalized therapeutic strategies.
Although current pharmacotherapies for AD and PD appear to slow the progression of cognitive impairment, the benefits have often found to be marginal and non-sustained Additionally, up to one third of MDD patients fail to respond to first-line pharmacological treatment 71 , which has been associated with elevated plasma pro-inflammatory factors expression N-3 PUFAs have been approved as safe when administered in doses up to 3 g per day and minor side-effects are rare Recent reviews and meta-analysis have reported a clinical efficacy of n-3 PUFAs treatment, which might be partly attributable to SPMs, in MDD and AD patients 76 , More interestingly, the majority of the animal studies so far only used males, which have recently been shown to have higher baseline levels of n-3 PUFAs metabolites than females in brain tissue The single study using female mice reported positive effects of RvE1 on inflammatory factors, however, this does not allow for direct comparison between sexes With women being at increased risk of developing MDD and AD 79 , 80 , further insight into this question is necessary as they might even more particularly benefit from this type of intervention.
Based on the findings from our review, personalized SPMs treatment could be a therapeutic possibility. RvD1, RvD2, or RvE1 could prove to be beneficial in psychiatric conditions, like depression, while MaR1 or PD1 would be optimally targeted toward neurological conditions.
Although more studies are required to determine their exact influence and production in the brain, our review indicates a potential promising approach for tailored therapy with SPMs. With further research, this could lead to subsequent dietary recommendations and nutritional interventions in the treatment of psychiatric, neurodegenerative or neurological conditions, as n-3 PUFAs have been demonstrated to raise specific SPMs levels This review has few limitations that must be considered, such as the number of studies meeting the inclusion criteria and the prominence of cognitive and neurological compared with psychiatric studies.
Additionally, dosage and route of administration between metabolites was also variable. Nonetheless, this is the first review to compare the effects of SPMs in the context of psychiatric, neurodegenerative and neurological disorders and sheds light on the differential mechanisms mediating their beneficial properties.
Further research is needed to elucidate the exact mechanisms of action of these metabolites, as well as the extent of their anti-inflammatory properties, in order to discern which disorder they should optimally target.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Amor S, Peferoen LAN, Vogel DYS, Breur M, van der Valk P, Baker D, et al. There have been a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches.
Many of the placebo-controlled trials of fish oil in chronic inflammatory diseases reveal significant benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs. Abstract Among the fatty acids, it is the omega-3 polyunsaturated fatty acids PUFA which possess the most potent immunomodulatory activities, and among the omega-3 PUFA, those from fish oil-eicosapentaenoic acid EPA and docosahexaenoic acid DHA --are more biologically potent than alpha-linolenic acid ALA.
Publication types Review. Substances Anti-Inflammatory Agents Cytokines Fatty Acids, Omega-3 Fatty Acids, Omega-6 Fatty Acids, Unsaturated Fish Oils Prostaglandins alpha-Linolenic Acid Docosahexaenoic Acids Eicosapentaenoic Acid.
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