Omega-3 fatty acids and hypertension in humans

1. Population studies and clinical trials provide compelling evidence that omega-3 (omega3) fatty acids have cardioprotective effects. The strongest evidence is from DART and GISSI-P, two secondary prevention trials in patients with previous myocardial infarctions. Data from these trials support a reduction in ventricular fibrillation as a primary mechanism for the decreased incidence of myocardial infarction. 2. Evidence suggests that w3 fatty acids may also provide protection against stroke, particularly ischaemic stroke. 3. The cardioprotective effects of omega3 fatty acids relate to improvements in blood pressure, cardiac function, arterial compliance and vascular function, as well as improved lipid metabolism, antiplatelet and anti-inflammatory effects. 4. Clinical trials in humans have shown that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have different haemodynamic properties. Docosahexaenoic acid may be more favourable in lowering blood pressure and heart rate, as well as improving vascular function. However, the effects of EPA and DHA may also differ depending on the target population.     

Omega-3 polyunsaturated fatty acids for major depressive disorder

Introduction: Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) are not synthesized by the human body; they must be derived from dietary sources and they have been known to be involved with neurological, cardiovascular, cerebrovascular, autoimmune and metabolic diseases, and cognitive disorder as well as mood disorders.

Areas covered: A number of epidemiological and preclinical studies have proven the potential benefit and critical role of omega-3 PUFA in the development and management of major depressive disorder (MDD). In addition, recently independent clinical trials and meta-analyses have also provided superidority of omega-3 PUFA over placebo as monotherapy or augmentation agent in the treatment of MDD. This article presents a brief overview of the evidence to date about the clinical application and biological mechanisms of omega-3 PUFA in the treatment of MDD.

Expert opinion: Given the potential action mechanism, clinical benefits and currently available clinical trial data, omega-3 PUFAs may deserve greater attention and wider application for treatment of MDD. However, the practical utility of omega-3 PUFA as one of promising alternative agent for treatment of MDD still have many questions unresolved to be fully addressed in near future.     

n-3多不饱和脂肪酸类药物在心血管疾病中的临床应用进展

许多临床试验表明n-3多不饱和脂肪酸(n-3 PUFAs)对于冠心病、血脂异常和心力衰竭等人群均具有保护作用,而且已有建议推荐心肌梗死后患者和高甘油三酯血症人群口服此类提纯药物。但在应用过程中,仍有一些值得临床关注的问题,如药物安全性、药物成分和用量等。笔者认为,随着对n-3 PUFAs药物的深入研究,其将有更广阔的应用前景。     

n-3系多烯酸摄取量的探讨

n-3系多烯酸具有防治心血管疾病、促进脑组织及视网膜的正常生长发育等生理作用,因此越来越引起人们摄取的兴趣。从目前的膳食结构来看,摄取n-3系多烯酸是十分必要的。如何正确的摄取,以充分发挥n-3系多烯酸对人体的健康作用及避免不良反应是人们摄取及开发这方面的保健食品和药物时值得注意的问题。     

Omega-3 polyunsaturated fatty acids alleviate hydrogen sulfide-induced blood-testis barrier disruption in the testes of adult mice

Hydrogen sulfide (H₂S), a gaseous intracellular signal transducer, participates in multiple physiological and pathological conditions, including reproductive conditions, and disrupts spermatogenesis. The blood-testis barrier (BTB) plays a vital role in spermatogenesis. However, the effect of H₂S on the BTB and the underlying mechanism remain unclear. Herein, we examined the effect of H₂S and omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on the BTB and testicular functions. ICR male mice were randomly divided into the following groups: control, H₂S exposure, and H₂S exposure with ω-3 PUFAs intervention. The sperm parameters (sperm concentration and sperm motility) declined in the H₂S group and improved in the ω-3 intervention group. BTB integrity was severely disrupted by H₂S, and the BTB-related gene levels (ZO-1, Occludin, Claudin 11) decreased; ω-3 supplementation could alleviate BTB disruption by upregulating BTB-related genes, and TM4 Sertoli cells had a similar trend in vitro. p38 MAPK phosphorylation was upregulated in the Na₂S treatment group and downregulated after ω-3 cotreatment. These findings suggest that H₂S can impair the BTB and that ω-3 PUFAs supplementation can attenuate H₂S toxicity in the male reproductive system. Our study elucidated the relationship between a gasotransmitter (H₂S) and the BTB and identified the potential therapeutic effect of ω-3 PUFAs.     

饱和脂肪酸与心血管疾病关系的研究进展

摘要： 关于饱和脂肪酸 （SFA） 对心血管疾病的作用现在观点不一, 食物种类来源、 SFA碳链的奇偶和链长是很大的影响因素。本文回顾了饱和脂肪酸对心血管疾病危险因素的影响, 除了中链饱和脂肪酸 （MCSFA）, 其余类型的 SFA可使血压升高, SFA对血管功能中度有害, 随着摄入时间的延长, 乳制品导致血脂异常的风险将增大, 纯棕榈油和椰子油对降低血脂有帮助, 摄入SFA碳链的奇偶和长度不同的SFA, 罹患2型糖尿病的风险不同; 同时总结了SFA 对心血管疾病 （CVD） 患病风险的影响, 总体SFA的摄入会增加CVD的风险, 但不同食物有不同的影响, 富含SFA的椰子油会导致心肌纤维化, 乳制品尤其是奶酪的摄入可降低CVD的发病风险, 红肉对心血管健康中度有害。     

Early modifications of fatty acid composition in plasma phospholipids,platelets and mononucleates of healthy volunteers after low doses of n-3 polyunsaturated fatty acids

Objectives Although previous data suggested that only doses of 4 g/day or higher of n-3 polyunsaturated fatty acids (PUFA) have had a beneficial effect in the prevention of atherosclerosis and cardiovascular diseases, the GISSI-Prevenzione Study in a 3-year trial showed that 1 g/day reduced total and cardiovascular mortality in over 11,000 post-infarction patients. The aim of this study was to investigate the time course and the extent of incorporation of n-3 fatty acids in plasma and blood cells after 1 g/day of n-3 PUFA, the dose effective in the GISSI-Prevenzione in comparison with higher doses.Methods Thirty-six healthy volunteers were given 1, 2 and 4 g/day of n-3 PUFA ethyl esters for 12 weeks, followed by a 4-week washout. Blood was collected at weeks 0, 1, 2, 4, 8, 12 and 16 and used for lipid profile analysis and measurement of fatty acid composition in plasma phospholipids, platelets and mononucleates.Results Total n-3 PUFA increased by 2.0-, 2.2- and 2.9-fold versus baseline after 12-week treatment with 1, 2 and 4 g respectively. A statistically significant raise of total n-3 PUFA was seen in platelets and mononucleates. Among individual n-3 PUFA, 22:5 n-3 was enriched early and dose dependently in plasma phospholipids, platelets and mononucleates; the raise of 22:6 n-3 was less marked especially in platelets and mononucleates.Conclusions One gram per day of n-3 PUFA induces fast (within 1 week) and striking changes in blood composition of PUFA that may well explain their beneficial effects against cardiovascular diseases.Delia Di Stasi and Roberto Bernasconi contributed equally to this work.     

Lipidomics reveals the dynamics of lipid profile altered by omega-3 polyunsaturated fatty acid supplementation in healthy people

Glycerophospholipids (GPs) and sphingolipids (SPs) are important lipid components in the body and play biological functions. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are important nutrients, and their supplements are commonly used for preventing some diseases. However, the effect of n-3 PUFAs on the human glycerophospholipidome and sphingolipidome is unclear. We used targeted lipidomics to study the GP and SP profile of healthy individuals after supplementation with n-3 PUFAs for 3, 7, 14 and 21 days. Fuzzy c-means clustering was used to cluster the lipid species into six classes reflecting different changed-content patterns after n-3 PUFA supplementation. Among the species with significantly changed content, lysophospholipids were the most sensitive; their content started to increase on day 3. The content of phosphatidylserines increased at a later stage. The content of most of the phosphatidylcholines and alkylphosphatidylcholines decreased on day 21. A correlation network analysis of lipid species suggested that some enzymes involved in the metabolism of lysophospholipids and phosphatidylserines were regulated by n-3 PUFAs. Levels of creatine kinase-MB (CK-MB), urea, glucose, triglycerides and total bilirubin were altered by n-3 PUFA at 21 days. Correlation analysis revealed that the level of CK-MB was negatively correlated with those of species in lysophosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine and phosphatidylserine classes, which were increased by n-3 PUFA supplementation. With the analysis in this work, we demonstrated the regular pattern of n-3 PUFAs on GP and SP metabolism, which provides a pharmacological basis for n-3 PUFAs for clinical application.     

Docosahexaenoic Acid Suppresses Neuroinflammatory Responses and Induces Heme Oxygenase-1 Expression in BV-2 Microglia: Implications of Antidepressant Effects for Omega-3 Fatty Acids

Accumulating evidence suggests that the pathophysiology of depression might be associated with neuroinflammation, which could be attenuated by pharmacological treatment for depression. Omega-3 polyunsaturated fatty acids (PUFAs) are anti-inflammatory and exert antidepressant effects. The aim of this study was to identify the molecular mechanisms through which docosahexaenoic acid (DHA), the main omega-3 PUFA in the brain, modulates oxidative reactions and inflammatory cytokine production in microglial and neuronal cells. The results of this study showed that DHA reduced expressions of tumor necrosis factor-α, interleukin-6, nitric oxide synthase, and cyclo-oxygenase-2, induced by interferon-γ, and induced upregulation of heme oxygenase-1 (HO-1) in BV-2 microglia. The inhibitory effect of DHA on nitric oxide production was abolished by HO-1 inhibitor zinc protoporphyrin IX. In addition, DHA caused AKT and ERK activation in a time-dependent manner, and the DHA-induced HO-1 upregulation could be attenuated by PI-3 kinase/AKT and MEK/ERK inhibitors. DHA also increased IKKα/β phosphorylation, IκBα phosphorylation, and IκBα degradation, whereas both nuclear factor-κB and IκB protease inhibitors could inhibit DHA-induced HO-1 expressions. The other major n-3 PUFA, eicosapentaenoic acid, showed similar effects of DHA on inflammation and HO-1 in repeated key experiments. In connecting with inflammation hypothesis of depression and clinical studies supporting the antidepressant effects of omega-3 PUFAs, this study provides a novel implication of the antidepressant mechanisms of DHA.     

The pleiotropic effects of statins and omega-3 fatty acids against sepsis: a new perspective

The available therapeutic options for sepsis are restricted by their effectiveness and high cost. Emerging preliminary data suggest that statins and omega-3 fatty acids (OM3FA) may be associated with improved outcomes in terms of prevention and treatment of sepsis. We sought to review the current evidence on the effectiveness of their combined administration against sepsis, by carrying out a review of PubMed and Scopus databases for relevant studies, without imposing language or time restrictions. No clinical studies were identified regarding the effect of the combination treatment with statins and OM3FA on sepsis in terms of prevention or treatment. However, there is experimental evidence that both statins and OM3FA inhibit the inflammatory process at different levels, but also enhance inhibition at those levels that are common. There are also preliminary data supporting the beneficial effect of this combination on platelet function and other haemostatic mechanisms. Appropriately designed and powered clinical trials are warranted to investigate the effectiveness and safety of the combined administration of statins and OM3FA for the prevention and treatment of sepsis.     

The omega-3 polyunsaturated fatty acid eicosapentaenoic acid inhibits mouse MC-26 colorectal cancer cell liver metastasis via inhibition of PGE2-dependent cell motility

BACKGROUND AND PURPOSE

The omega-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) has antineoplastic activity at early stages of colorectal carcinogenesis, relevant to chemoprevention of colorectal cancer (CRC). We tested the hypothesis that EPA also has anti-CRC activity at later stages of colorectal carcinogenesis, relevant to treatment of metastatic CRC, via modulation of E-type PG synthesis.

EXPERIMENTAL APPROACH

A BALB/c mouse model, in which intrasplenic injection of syngeneic MC-26 mouse CRC cells leads to development of liver metastases, was used. Dietary EPA was administered in the free fatty acid (FFA) form for 2 weeks before and after ultrasound-guided intrasplenic injection of 1 × 10⁶ MC-26 cells (n= 16 each group).

KEY RESULTS

Treatment with 5% (w w^-1) EPA-FFA was associated with a reduced MC-26 mouse CRC cell liver tumour burden compared with control animals (median liver weight 1.03 g vs. 1.62 g; P < 0.034). Administration of 5% EPA-FFA was also linked to a significant increase in tumour EPA incorporation and lower intratumoural PGE₂ levels (with concomitant increased production of PGE₃). Liver tumours from 5% EPA-FFA- treated mice demonstrated decreased 5-bromo-2-deoxyuridine-positive CRC cell proliferation and reduced phosphorylated ERK 1/2 expression at the invasive edge of tumours. A concentration-dependent reduction in MC-26 CRC cell Transwell® migration following EPA-FFA treatment (50–200 µM) in vitro was rescued by exogenous PGE₂ (10 µM) and PGE₁-alcohol (1 µM).

CONCLUSIONS AND IMPLICATIONS

EPA-FFA inhibits MC-26 CRC cell liver metastasis. EPA incorporation is associated with a ‘PGE₂ to PGE₃ switch’ in liver tumours. Inhibition of PGE₂-EP₄ receptor-dependent CRC cell motility probably contributes to the antineoplastic activity of EPA.     

Oxidative stress,polyunsaturated fatty acidsderived oxidation products and bisretinoids as potential inducers of CNS diseases: focus on age-related macular degeneration

Many pathologies of the central nervous system (CNS) originate from excess of reactive free radicals, notably reactive oxygen species (ROS), and oxidative stress. A phenomenon which usually runs in parallel with oxidative stress is unsaturated lipid peroxidation, which, via a chain reaction, contributes to the progression of disbalanced redox homeostasis. Among long-chain (LC) polyunsaturated fatty acids (PUFAs) abundantly occurring in the CNS, docosahexaenoic acid (DHA), a member of ω-3 LC-PUFAs, deserves special attention, as it is avidly retained and uniquely concentrated in the nervous system, particularly in retinal photoreceptors and synaptic membranes; owing to the presence of the six double bonds between carbon atoms in its polyene chain (C=C), DHA is exquisitely sensitive to oxidative damage. In addition to oxidative stress and LC-PUFAs peroxidation, other stress-related mechanisms may also contribute to the development of various CNS malfunctions, and a good example of such mechanisms is the process of lipofuscin formation occurring particularly in the retina, an integral part of the CNS. The retinal lipofuscin is formed and accumulated by the retinal pigment epithelial (RPE) cells as a consequence of both visual process taking place in photoreceptor-RPE functional complex and metabolic insufficiency of RPE lysosomal compartment. Among various retinal lipofuscin constituents, bisretinoids, originating from all-trans retinal substrate – a photometabolite of visual pigment cofactor 11-cis-retinal (responsible for photon capturing), are endowed with cytotoxic and complement-activating potential which increases upon illumination and oxidation. This survey deals with oxidative stress, PUFAs (especially DHA) peroxidation products of carboxyalkylpyrrole type and bisretinoids as potential inducers of the CNS pathology. A focus is put on vision-threatening disease, i.e., age-related macular degeneration (AMD), as an example of the CNS disorder whose pathogenesis has strong background in both oxidative stress and lipid peroxidation products.     

n－3多烯脂肪酸在创伤感染中的作用

为探讨ｎ－３多烯脂肪酸在创伤感染中所起的作用，采用盲肠结扎穿孔诱发大鼠脓毒血症，食道插管灌入液体鱼油治疗。研究结果，术前接受４ｗｋ鱼油治疗组与脓毒症组比较，前者动物枯否细胞释放的细胞因子，炎性介质及氧自由基产物明显减少，膜磷脂成分及花生四烯酸含量明显增加；同时观察到肝细胞膜脂流动性明显升高，相变温度明显降低，内皮素含量明显减少。提示，ｎ－３多烯脂肪酸有调节创伤感染动物巨噬细胞的生物学功能，减轻肝细胞和血管内皮细胞损伤的作用。     

n－3多烯脂肪酸在创伤感染中的作用

为探讨ｎ－３多烯脂肪酸在创伤感染中所起的作用，采用盲肠结扎穿孔诱发大鼠脓毒血症，食道插管灌入液体鱼油治疗。研究结果，术前接受４ｗｋ鱼油治疗组与脓毒症组比较，前者动物枯否细胞释放的细胞因子，炎性介质及氧自由基产物明显减少，膜磷脂成分及花生四烯酸含量明显增加；同时观察到肝细胞膜脂流动性明显升高，相变温度明显降低，内皮素含量明显减少。提示，ｎ－３多烯脂肪酸有调节创伤感染动物巨噬细胞的生物学功能，减轻肝细胞和血管内皮细胞损伤的作用。     

Omega-3 fatty acids induce Ca2+ mobilization responses in human colon epithelial cell lines endogenously expressing FFA4

Aim:

Free fatty acid receptor 4 (FFA4; formerly known as GPR120) is the G protein-coupled receptor (GPCR) for omega-3 polyunsaturated fatty acids. FFA4 has been found to express in the small intestines and colons of mice and humans. In this study we investigate the effects of omega-3 polyunsaturated fatty acids on FFA4 in human colon epithelial cells in vitro.

Methods:

HCT116 and HT-29 human colon epithelial cell lines endogenously expressing FFA4 were used. Intracellular Ca²⁺ concentration ([Ca²⁺]_i) was measured in fura 2-AM-loaded cells with fluorescence spectrophotometry. RT-PCR and immunohistochemistry were used to detect FFA4.

Results:

Ten to 100 μmol/L of omega-3 polyunsaturated fatty acids α-linolenic acid (αLA) or eicosapentaenoic acid (EPA) induced dose-dependent [Ca²⁺]_i increase in HCT116 and HT-29 cells, whereas docosahexaenoic acid (DHA) had no effect. In addition, the omega-6 fatty acids linoleic acid and γ-linoleic acid also dose-dependently increase [Ca²⁺]_i, but the mono-unsaturated fatty acid oleic acid and saturated fatty acids such as stearic acid and palmitic acid had no effect. In HCT116 and HT-29 cells, the αLA-induced [Ca²⁺]_i increase was partially inhibited by pretreatment with EGTA, phospholipase C inhibitor edelfosine, cADPR inhibitors 8-bro-cADPR or DAB, and abolished by pretreatment with Ca²⁺ATPase inhibitor thapsigargin, but was not affected by G_i/o protein inhibitor PTX or IP₃R inhibitor 2-APB.

Conclusion:

Omega-3 and omega-6 long-chain polyunsaturated fatty acids (C18-20) induce Ca²⁺ mobilization responses in human colonic epithelial cells in vitro through activation of FFA4 and PTX-insensitive G_i/o protein, followed by Ca²⁺ release from thapsigargin-sensitive Ca²⁺ stores and Ca²⁺ influx across the plasma membrane.