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Cellular Physiology and Biochemistry :... Nov 2023Microglial cells play a crucial role in the development of neuroinflammation in response to harmful stimuli, such as infection, ischemia or injury. Their chronic...
BACKGROUND/AIMS
Microglial cells play a crucial role in the development of neuroinflammation in response to harmful stimuli, such as infection, ischemia or injury. Their chronic activation, however, is associated with a progression of neurodegenerative diseases. Therefore, looking for potential factors limiting microglial activation, the effect of docosahexaenoic acid (DHA) on the inflammatory response and TREM2-dependent phagocytic activity in microglia was investigated.
METHODS
In LPS-induced primary microglia preincubated with DHA, or without preincubation the expression of ATF3 and TREM2 genes and TREM2, Syk, Akt proteins were determined by RT-PCR and WB, respectively. Cell viability was assayed by MTT and cytokine and chemokine expression was determined by the Proteome Profiler assay. Moreover, the phagocytic activity of microglia was assayed using immunofluorescence.
RESULTS
We found that DHA significantly increased the expression of ATF3 , and decreased the levels of CINC-1, CINC-2αβ, CINC-3 chemokines, IL-1α and IL-1β cytokines, and ICAM-1 adhesion protein. Additionally, preincubation of microglia with DHA resulted in increased Src/Syk kinases activation associated with increased phagocytic microglia activity.
CONCLUSION
These findings indicate that DHA efficiently inhibits ATF3-dependent release of proinflammatory mediators and enhances phagocytic activity of microglia. The study provides a new mechanism of DHA action in reactive microglia, which may help limit neuronal damage caused by the pro-inflammatory milieu in the brain.
Topics: Humans; Microglia; Docosahexaenoic Acids; Lipopolysaccharides; Activating Transcription Factor 3; Phagocytosis; Cytokines; Inflammation
PubMed: 37962278
DOI: 10.33594/000000668 -
Marine Drugs Oct 2022Alzheimer's disease (AD) is a complex and progressive disease, which affects millions of people around the world. Despite the many efforts over the years to find... (Review)
Review
Alzheimer's disease (AD) is a complex and progressive disease, which affects millions of people around the world. Despite the many efforts over the years to find efficient therapeutics, there is no cure yet. Nonetheless, many compounds have been proven to decrease Alzheimer's symptoms. After a short overview of the hypotheses considered in AD drug development and the drugs approved for AD treatment, which lead to symptom release, we focus on the valorization of natural marine sources that decrease AD symptoms, particularly on docosahexaenoic acid (DHA), an important component in membrane phospholipids and the most abundant n-3 polyunsaturated fatty acids (PUFA) found in gray matter of the brain and in retina and on the DHA-containing phospholipids (DHA-PLs) present in marine sources, namely fish, krill, mollusks and in fisheries and aquaculture by-products. DHA-PLs' bioactivities are presented, namely their properties in anti-neurodegeneration, neuroinflammation, as anticancer agents, as well as their benefits to obesity and visual problems. Fisheries and aquaculture by-products are also highlighted as they have a high content of DHA and DHA-rich phospholipids, can be extracted by green methodologies and should be considered in a circular economy for a healthy sustainable future.
Topics: Animals; Docosahexaenoic Acids; Phospholipids; Eicosapentaenoic Acid; Fish Oils; Euphausiacea; Alzheimer Disease
PubMed: 36354985
DOI: 10.3390/md20110662 -
International Journal of Molecular... Jan 2023Being the most common cause of implant failure, peri-implantitis is defined as a pathological condition associated with the occurrence of peri-implant plaque,...
Being the most common cause of implant failure, peri-implantitis is defined as a pathological condition associated with the occurrence of peri-implant plaque, characterized by peri-implant mucosal inflammation and progressive loss of the supporting bone tissue attributed to the persistence of pro-inflammatory cytokines. Docosahexaenoic acid (DHA), which is a type of omega-3 polyunsaturated fatty acid, is generally used for the treatment of many inflammatory diseases. However, a suitable form for dosing and its therapeutic effect on peri-implantitis remain unclear. In this study, a novel nanostructured lipid carrier (NLC) loaded with squalene and DHA was fabricated (DHA-loaded NLC). The encapsulation efficiency and drug loading efficiency values of the DHA-loaded NLC were 78.13% ± 1.85% and 28.09% ± 0.48%, respectively. The release of DHA was gradual and steady until 144 h. In addition, the free-radical-scavenging rate of DHA-loaded NLC (0.57 ± 0.03) was much higher than that of sole DHA (0.17 ± 0.003). By inhibiting nuclear factor-κB p65 nuclear translocation, DHA-loaded NLC prevented the activation of nuclear factor-κB downstream inflammatory pathways and exerted anti-inflammatory effects on macrophages. Moreover, DHA-loaded NLC showed better effects on preventing alveolar bone resorption of rat peri-implantitis model than sole DHA. Hence, DHA-loaded NLC enhanced the anti-inflammatory bioavailability of DHA, offering a novel approach for the treatment of peri-implantitis.
Topics: Animals; Rats; Anti-Inflammatory Agents; Docosahexaenoic Acids; Drug Carriers; Nanostructures; NF-kappa B; Peri-Implantitis; Lipids
PubMed: 36768193
DOI: 10.3390/ijms24031872 -
International Journal of Molecular... Sep 2023Polyunsaturated fatty acids (PUFAs) undergo lipid peroxidation and conversion into malondialdehyde (MDA). MDA reacts with acetaldehyde to form malondialdehyde-modified...
Lipid Peroxidation of the Docosahexaenoic Acid/Arachidonic Acid Ratio Relating to the Social Behaviors of Individuals with Autism Spectrum Disorder: The Relationship with Ferroptosis.
Polyunsaturated fatty acids (PUFAs) undergo lipid peroxidation and conversion into malondialdehyde (MDA). MDA reacts with acetaldehyde to form malondialdehyde-modified low-density lipoprotein (MDA-LDL). We studied unsettled issues in the association between MDA-LDL and the pathophysiology of ASD in 18 individuals with autism spectrum disorders (ASD) and eight age-matched controls. Social behaviors were assessed using the social responsiveness scale (SRS). To overcome the problem of using small samples, adaptive Lasso was used to enhance the interpretability accuracy, and a coefficient of variation was used for variable selections. Plasma levels of the MDA-LDL levels (91.00 ± 16.70 vs. 74.50 ± 18.88) and the DHA/arachidonic acid (ARA) ratio (0.57 ± 0.16 vs. 0.37 ± 0.07) were significantly higher and the superoxide dismutase levels were significantly lower in the ASD group than those in the control group. Total SRS scores in the ASD group were significantly higher than those in the control group. The unbeneficial DHA/ARA ratio induced ferroptosis via lipid peroxidation. Multiple linear regression analysis and adaptive Lasso revealed an association of the DHA/ARA ratio with total SRS scores and increased MDA-LDL levels in plasma, resulting in neuronal deficiencies. This unbeneficial DHA/ARA-ratio-induced ferroptosis contributes to autistic social behaviors and is available for therapy.
Topics: Humans; Docosahexaenoic Acids; Arachidonic Acid; Autism Spectrum Disorder; Lipid Peroxidation; Ferroptosis; Lipoproteins, LDL; Malondialdehyde
PubMed: 37834244
DOI: 10.3390/ijms241914796 -
Journal of Cardiovascular Pharmacology... Nov 2021Atherosclerotic cardiovascular disease is a significant cause of morbidity and mortality worldwide. While use of statin therapy has improved management of lipids, an... (Review)
Review
BACKGROUND
Atherosclerotic cardiovascular disease is a significant cause of morbidity and mortality worldwide. While use of statin therapy has improved management of lipids, an unmet need in reducing residual atherosclerotic cardiovascular disease risk and ischemic events persists. We provide an overview of the pharmacology of omega-3 fatty acids, omega-3 fatty acid cardiovascular outcomes trials, landmark clinical data and pharmacology of icosapent ethyl (a stable and highly purified ethyl ester of eicosapentaenoic acid), and the critical differences between fish oil supplements and prescription omega-3 fatty acids.
METHOD
A PubMed literature review was conducted in April 2020 to identify articles discussing omega-3 fatty acid cardiovascular outcomes trials, pharmacology of icosapent ethyl, and the evaluation of fish oil dietary supplements and prescription omega-3 fatty acids.
RESULTS
Both eicosapentaenoic acid and docosahexaenoic acid have been widely associated with positive health benefits; however, data are inconsistent regarding the benefit of combination eicosapentaenoic acid and docosahexaenoic acid in patients with cardiovascular disease. Eicosapentaenoic acid, and specifically icosapent ethyl, has demonstrated atherosclerotic cardiovascular disease risk reduction among statin-treated patients. Important clinical differences exist between dietary supplement and prescription omega-3 fatty acid products.
CONCLUSIONS
As research regarding the optimal management of dyslipidemia continues, additional therapy beyond statins is necessary to reduce atherosclerotic cardiovascular disease risk. In large cardiovascular outcomes trials, eicosapentaenoic acid has demonstrated cardiovascular benefit. Icosapent ethyl possesses a favorable efficacy and safety profile and should be considered as an adjunct to statin therapy to reduce ischemic event risk.
Topics: Atherosclerosis; Cardiovascular Diseases; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Humans; Pharmacists
PubMed: 34191622
DOI: 10.1177/10742484211023715 -
Toxicologic Pathology Dec 2019Two environmental factors, crystalline silica (cSiO), a toxic airborne particle encountered occupationally, and docosahexaenoic acid (DHA), a dietary omega-3 highly... (Review)
Review
Two environmental factors, crystalline silica (cSiO), a toxic airborne particle encountered occupationally, and docosahexaenoic acid (DHA), a dietary omega-3 highly unsaturated fatty acid (HUFA), have the potential to influence the development of systemic lupus erythematosus (lupus). Using the NZBWF1 mouse, which spontaneously develops lupus, we found that intranasal exposure to cSiO significantly decreases latency and promotes rapid progression of the disease. Specifically, cSiO induces the development of ectopic lymphoid structures (ELS) containing germinal centers in the lungs that yield vigorous and diverse autoantibody responses locally and systemically. Transcriptomic analysis revealed that cSiO promotes a robust type I interferon gene signature that likely precipitates ELS neogenesis. Intriguingly, dietary supplementation with human-relevant doses of DHA impedes cSiO-induced gene expression, ELS neogenesis, autoantibody elevation, and glomerulonephritis in this lupus-prone mouse model. Together, our findings point to the feasibility of enhancing tissue omega-3 HUFAs as a personalized nutritional intervention to impede onset and progression of environment-triggered autoimmune disease.
Topics: Air Pollutants; Animals; Autoimmunity; Dietary Supplements; Disease Models, Animal; Docosahexaenoic Acids; Gene-Environment Interaction; Humans; Lupus Erythematosus, Systemic; Particulate Matter; Silicon Dioxide
PubMed: 31725357
DOI: 10.1177/0192623319878398 -
Marine Drugs Aug 2023Epilepsy is a chronic neurological disorder that is more prevalent in children, and recurrent unprovoked seizures can lead to cognitive impairment. Numerous studies have...
Epilepsy is a chronic neurological disorder that is more prevalent in children, and recurrent unprovoked seizures can lead to cognitive impairment. Numerous studies have reported the benefits of docosahexaenoic acid (DHA) on neurodevelopment and cognitive ability, while comparatively less attention has been given to eicosapentaenoic acid (EPA). Additionally, little is known about the effects and mechanisms of DHA and EPA in relation to seizure-induced cognitive impairment in the young rodent model. Current research indicates that ferroptosis is involved in epilepsy and cognitive deficiency in children. Further investigation is warranted to determine whether EPA or DHA can mitigate seizure-induced cognitive deficits by inhibiting ferroptosis. Therefore, this study was conducted to compare the effects of DHA and EPA on seizure-induced cognitive deficiency and reveal the underlying mechanisms focused on ferroptosis in a pentylenetetrazol (PTZ)-kindling young mice model. Mice were fed a diet containing DHA-enriched ethyl esters or EPA-enriched ethyl esters for 21 days at the age of 3 weeks and treated with PTZ (35 mg/kg, i.p.) every other day 10 times. The findings indicated that both EPA and DHA exhibited ameliorative effects on seizure-induced cognitive impairment, with EPA demonstrating a superior efficacy. Further mechanism study revealed that supplementation of DHA and EPA significantly increased cerebral DHA and EPA levels, balanced neurotransmitters, and inhibited ferroptosis by modulating iron homeostasis and reducing lipid peroxide accumulation in the hippocampus through activating the Nrf2/Sirt3 signal pathway. Notably, EPA exhibited better an advantage in ameliorating iron dyshomeostasis compared to DHA, owing to its stronger upregulation of Sirt3. These results indicate that DHA and EPA can efficaciously alleviate seizure-induced cognitive deficiency by inhibiting ferroptosis in PTZ-kindled young mice.
Topics: Humans; Child; Animals; Mice; Infant, Newborn; Pentylenetetrazole; Docosahexaenoic Acids; Eicosapentaenoic Acid; Sirtuin 3; Seizures; Cognition; Disease Models, Animal
PubMed: 37755077
DOI: 10.3390/md21090464 -
International Journal of Molecular... Feb 2018A large body of evidence supports the cardioprotective effects of the long-chain omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA), and... (Review)
Review
A large body of evidence supports the cardioprotective effects of the long-chain omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). There is increasing interest in the independent effects of EPA and DHA in the modulation of cardiometabolic risk factors. This systematic review aims to appraise the latest available evidence of the differential effects of EPA and DHA on such risk factors. A systematic literature review was conducted up to May 2017. Randomised controlled trials were included if they met strict eligibility criteria, including EPA or DHA > 2 g/day and purity ≥ 90%. Eighteen identified articles were included, corresponding to six unique studies involving 527 participants. Both EPA and DHA lowered triglyceride concentration, with DHA having a greater triglyceride-lowering effect. Whilst total cholesterol levels were largely unchanged by EPA and DHA, DHA increased high-density lipoprotein (HDL) cholesterol concentration, particularly HDL₂, and increased low-density lipoprotein (LDL) cholesterol concentration and LDL particle size. Both EPA and DHA inhibited platelet activity, whilst DHA improved vascular function and lowered heart rate and blood pressure to a greater extent than EPA. The effects of EPA and DHA on inflammatory markers and glycaemic control were inconclusive; however both lowered oxidative stress. Thus, EPA and DHA appear to have differential effects on cardiometabolic risk factors, but these need to be confirmed by larger clinical studies.
Topics: Antioxidants; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Hypoglycemic Agents; Metabolic Syndrome; Randomized Controlled Trials as Topic
PubMed: 29425187
DOI: 10.3390/ijms19020532 -
Applied and Environmental Microbiology Mar 2022The heterotrophic marine microalgae sp. is an important industrial producer of docosahexaenoic acid (DHA). Increased production of DHA and lipids in sp. has been...
The heterotrophic marine microalgae sp. is an important industrial producer of docosahexaenoic acid (DHA). Increased production of DHA and lipids in sp. has been achieved by standard fermentation optimization and metabolic engineering methods; however, regulatory mechanisms for DHA and lipid biosynthesis remain unknown. In this study, the CH zinc finger protein LipR was identified in sp. ATCC 20888 by transcriptional analysis. Deletion of the gene significantly (0.001) increased production of total lipids and DHA by 33% and 48%, respectively. LipR repressed DHA and lipid production by directly inhibiting transcription of polyunsaturated fatty acid (PUFA) and fatty acid synthase (FAS) genes (, , , and ). Specific binding of LipR to 9-bp recognition sequence 5'-(C/A)(A/G)CCATCTT-3' in upstream regions of target genes was demonstrated by electrophoretic mobility shift assays (EMSAs) and DNase I footprinting assays. Expression of several key genes (, , , , , , and ) related to levels of precursors and NADPH, and to triacylglycerol storage rate, were also directly repressed by LipR. Our findings, taken together, indicate that the evolutionarily unique regulator LipR is an essential repressor of DHA and saturated fatty acid biosynthesis in sp. Regulatory mechanisms for DHA and saturated fatty acid biosynthesis in the heterotrophic marine microalgae sp. are unclear. We demonstrate here that deletion of the gene () encoding the CH zinc finger protein LipR promotes DHA and saturated fatty acid production in this genus. LipR acts as a key repressor of such production by binding to 9-bp consensus sequence 5'-(C/A)(A/G)CCATCTT-3' in the upstream regions of polyunsaturated fatty acid and fatty acid synthase genes (, , , and ), and genes related to levels of precursors and NADPH (, , , , , and ), and to triacylglycerol storage rate (). This is the first demonstration that a regulator inhibits synthesis of DHA and lipids in sp. by directly controlling transcription of PUFA synthase and genes. Manipulation of the gene provides a potential strategy for enhancing accumulation of polyunsaturated fatty acids and lipids in thraustochytrids.
Topics: Docosahexaenoic Acids; Fatty Acids; Fatty Acids, Unsaturated; Stramenopiles; Zinc Fingers
PubMed: 35108079
DOI: 10.1128/aem.02063-21 -
Marine Drugs Sep 2021Thraustochytrids are unicellular, heterotrophic marine eukaryotes. Some species are known to store surplus carbon as intracellular lipids, and these also contain the... (Review)
Review
Thraustochytrids are unicellular, heterotrophic marine eukaryotes. Some species are known to store surplus carbon as intracellular lipids, and these also contain the long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA). Most vertebrates are unable to synthesize sufficient amounts of DHA, and this fatty acid is essential for, e.g., marine fish, domesticated animals, and humans. Thraustochytrids may also produce other commercially valuable fatty acids and isoprenoids. Due to the great potential of thraustochytrids as producers of DHA and other lipid-related molecules, a need for more knowledge on this group of organisms is needed. This necessitates the ability to do genetic manipulation of the different strains. Thus far, this has been obtained for a few strains, while it has failed for other strains. Here, we systematically review the genetic transformation methods used for different thraustochytrid strains, with the aim of aiding studies on strains not yet successfully transformed. The designs of transformation cassettes are also described and compared. Moreover, the potential problems when trying to establish transformation protocols in new thraustochytrid species/strains are discussed, along with suggestions utilized in other organisms to overcome similar challenges. The approaches discussed in this review could be a starting point when designing protocols for other non-model organisms.
Topics: Animals; Aquatic Organisms; Docosahexaenoic Acids; Genetic Engineering; Microalgae
PubMed: 34564177
DOI: 10.3390/md19090515