Omega 3-fatty acids: health benefits and cellular mechanisms of action

Epidemiological evidence has established that ingestion of long-chain polyunsaturated omega-3 fatty acids (omega-3 PUFAs), abundant in fish oils, have profound effects on many human disorders and diseases, including cardiovascular disease and cancer. Here we briefly review the dietary recommendations and the food sources that are naturally enriched by these fatty acids. There are also a number of products including eggs, bread, and cereals available to supplement omega-3 fatty acid dietary intake. Some of these supplements are proposed to aid different pathological conditions. While the beneficial effects of omega-3 fatty acids can no longer be doubted, their molecular mechanism of action remains elusive. Without question, the action of omega-3 fatty acids is complex and involves a number of integrated signaling pathways. This review focuses on one of the possible cellular mechanisms by which the omega-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may function. Studies with cancer cells suggest that DHA induces cell cycle arrest and apoptosis by activating protein phosphatases, leading to dephosphorylation of retinoblastoma protein (pRB). Protein phosphatases are also involved with the protein Bcl2, which regulates the release of cytochrome c from mitochondria, and eventually, activation of the apoptotic enzyme caspase 3.     

Effects of polyunsaturated fatty acids on calcium response and degranulation from RBL-2H3 cells

To investigate the biological activity of various polyunsaturated fatty acids (PUFAs) on the allergic reaction, we examined the effects of six PUFAs and two saturated fatty acids on calcium response and degranulation from rat basophilic leukemia (RBL-2H3) cells. Between 20 and 40 microM of six PUFAs (omega-6 series: arachidonic acid [AA, C20:4], gamma-linolenic acid [gamma-LN, C18:3] and linoleic acid [LA, C18:2]; omega-3 series: alpha-linolenic acids [alpha-LN, C18:3] and eicosapentaenoic acid [EPA, C20:5]; and omega-9 series: oleic acid [OLE, C18:1]), or two saturated fatty acids (stearic acid [STA, C18:0] and arachidic acid [AD, C20:0]) were used to examine the effects on calcium response and degranulation from RBL-2H3 cells. Calcium response was monitored using the fluorescent calcium indicator fura-2, while degranulation was monitored by measuring histamine release from the cells. Three omega-6 PUFAs (AA, alpha-LN and LA) dose-dependently increased the cytosolic free-calcium concentration and histamine release from RBL-2H3 cells. This phenomenon was specific to the omega-6 PUFAs, the omega-3 PUFAs (alpha-LA and EPA), omega-9 PUFA (OLE) and the saturated fatty acids (STA and AD) had no effect. The increase in the cytosolic free-calcium concentration caused by the omega-6 PUFAs depended on the existence of external calcium, cell viability and the cellular IP(3) levels remained unchanged throughout the experiment. These results suggest that omega-6 PUFAs work as direct mediators of calcium signaling pathways in RBL-2H3 cells.     

CD4+CD25+ regulatory T-cell therapy for allergy, autoimmune disease and transplant rejection

Naturally occurring CD4+CD25+ regulatory T cells (Tregs) play a critical role in the control of periphery tolerance to self-antigens. Interestingly, they also control immune responses to allergens and transplant antigens. Recent studies in animal models have shown that adoptive transfer of CD4+CD25+ Tregs can prevent or even cure allergic and autoimmune diseases, and appear to induce transplantation tolerance. Thus, adoptive cell therapy using patient-specific CD4+CD25+ Tregs has been emerged as individualized medicine for the treatment of inflammatory disease including allergy, autoimmune disease and transplant rejection. Furthermore, strategies to activate and expand antigen-specific CD4+CD25+ Tregs in vivo using pharmacological agents may represent a novel avenue for drug development.     

PPARγ功能与疾病关系研究进展

过氧化物酶体增殖物激活受体γ(peroxisome prolifera-tor-activated receptor gamma(PPARγ)对脂质代谢、脂肪形成、细胞分裂和凋亡等多种生物学过程具有调节作用。近年来的研究发现,配体激活PPARγ具有抗肥胖、高血压、动脉粥样硬化、糖尿病、肿瘤等疾病的有益作用,使得围绕PPARγ受体功能和配体筛选研究成为生物医学和药理学研究的前沿热点,并有望成为治疗上述顽疾的新的药物靶标。该文就PPARγ与疾病关系的研究进展做一综述。     

Gamma linolenic acid: an antiinflammatory omega-6 fatty acid

Inflammation plays an important role in health and disease. Most of the chronic diseases of modern society, including cancer, diabetes, heart disease, arthritis, Alzheimer's disease, etc. have inflammatory component. At the same time, the link between diet and disease is also being recognized. Amongst dietary constituents, fat has gained most recognition in affecting health. Saturated and trans fatty acids have been implicated in obesity, heart disease, diabetes and cancer while polyunsaturated fatty acids (PUFAs) generally have a positive effect on health. The PUFAs of omega-3 and omega-6 series play a significant role in health and disease by generating potent modulatory molecules for inflammatory responses, including eicosanoids (prostaglandins, and leukotrienes), and cytokines (interleukins) and affecting the gene expression of various bioactive molecules. Gamma linolenic acid (GLA, all cis 6, 9, 12-Octadecatrienoic acid, C18:3, n-6), is produced in the body from linoleic acid (all cis 6,9-octadecadienoic acid), an essential fatty acid of omega-6 series by the enzyme delta-6-desaturase. Preformed GLA is present in trace amounts in green leafy vegetables and in nuts. The most significant source of GLA for infants is breast milk. GLA is further metabolized to dihomogamma linlenic acid (DGLA) which undergoes oxidative metabolism by cyclooxygenases and lipoxygenases to produce anti-inflammatory eicosanoids (prostaglandins of series 1 and leukotrienes of series 3). GLA and its metabolites also affect expression of various genes where by regulating the levels of gene products including matrix proteins. These gene products play a significant role in immune functions and also in cell death (apoptosis). The present review will emphasize the role of GLA in modulating inflammatory response, and hence its potential applications as an anti-inflammatory nutrient or adjuvant.     

Omega-3 fatty acids: from biochemistry to their clinical use in the prevention of cardiovascular disease

Omega-3 and omega-6 Polyunsaturated fatty acids (PUFA) are the major families of PUFA that can be found as components of the human diet. After ingestion, both omega-3 and omega-6 PUFA are distributed to every cell in the body where they are involved in a myriad of physiological processes, including regulation of cardiovascular, immune, hormonal, metabolic, neuronal, and visual functions. At the cell level, these effects are mediated by changes in membrane phospholipids structure, interference with eicosanoid intracellular signaling, and regulation of gene expression. Two long-chain omega-3 PUFAs, the docosahexaenoic (DHA) and eicosapentaenoic (EPA) acid, are found in fatty fish and other marine sources and might be the putative dietary components thought to modify the cardiovascular risk in subjects consuming high amounts of such food. Evidence of an inverse relationship between fatty fish intake and cardiovascular risk has, in fact, emerged in studies performed more than twenty years ago in Eskimos and has been subsequently confirmed in other ethnic groups. The benefits of omega-3 PUFA might relate principally to prevention of coronary heart disease, coronary artery restenosis after angioplasty, and sudden arrhythmic death. In this brief review, we will cover the general biochemical aspects of omega-3 PUFA, summarize the evidence relating these fatty acids with control of cardiovascular risk factors and prevention of cardiovascular events, and overview the most recent and relevant patents that are related to these issues. More specifically, we will deal with the possibility to use PUFA in association with other molecules that can potentiate their antiinflammatory and antiatherogenic effects.     

Isoliquiritigenin suppresses tumor necrosis factor-α-induced inflammation via peroxisome proliferator-activated receptor-γ in intestinal epithelial cells

Intestinal epithelial cells play an important role in the mucosal immune reaction in inflammatory bowel diseases via the expression of inflammatory mediators, such as cyclooxygenase-2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1). Isoliquiritigenin (ISL; 4,2′,4′-trihydroxychalcone) has been shown to exhibit anti-inflammatory properties in murine macrophage cells. In the present study, we evaluated the anti-inflammatory properties of ISL in intestinal epithelial cells and determined its mechanism of action. ISL suppressed the expression of COX-2 and ICAM-1 in tumor necrosis factor-α (TNF-α) stimulated intestinal epithelium HT-29 cells. It also induced peroxisome proliferator-activated receptor-γ (PPARγ) protein expression. Moreover, using a PPARγ antagonist, GW9662, we found that the regulation of COX-2 and ICAM-1 expression by ISL in TNF-α-stimulated HT-29 cells is mediated via PPARγ expression. A signal transduction study revealed that ISL significantly attenuates TNF-α-mediated JNK phosphorylation. ISL-induced ERK1/2 phosphorylation was associated with PPARγ expression. Additionally, both the inhibitory effect on COX-2 and ICAM-1 expression and the induction of PPARγ expression by ISL in TNF-α-stimulated HT-29 cells was abolished by the addition of U0126, a specific ERK1/2 inhibitor. Collectively, ISL-induced PPARγ mediated, at least partially, the suppression of intestinal inflammation. These results suggest that ISL may be beneficial for the treatment of mucosal inflammation.     

Formation of cyclic deoxyguanosine adducts from omega-3 and omega-6 polyunsaturated fatty acids under oxidative conditions

The discovery of the cyclic 1,N(2)-propanodeoxyguanosine adducts of acrolein (Acr), crotonaldehyde (Cro), and t-4-hydroxy-2-nonenal (HNE) as endogenous DNA lesions from lipid peroxidation has raised questions regarding the role of different types of fatty acids as sources for their formation. In this study, we carried out reactions at pH 7 and 37 degrees C with deoxyguanosine 5'-monophosphate and omega-3 polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA), linolenic acid (LNA), and eicosapentaenoic acid (EPA); or omega-6 PUFAs, including linoleic acid (LA) and arachidonic acid (AA), each in the presence of ferrous sulfate. The formation of Acr, Cro, and HNE-derived 1,N(2)-propanodeoxyguanosine adducts (Acr-, Cro-, and HNE-dG) in the incubation mixture was determined by reversed-phase HPLC analysis. The results showed that Acr and Cro adducts are primarily derived from omega-3 PUFAs, although Acr adducts are also formed, to a lesser extent, from oxidized AA and LA. HNE-dG adducts were detected exclusively in incubations with AA. The kinetics of the formation of these adducts was determined during incubations for 2 weeks and 5 days. The rate of Acr adduct formation was about 5-10-fold that of Cro adducts, depending on the type of PUFAs, and the rate of formation of HNE adducts from AA was also considerably slower than that of Acr adducts. Unlike other cyclic adducts, the formation of Acr adducts was independent of types of PUFAs, but its yield was proportional to the number of double bonds in the fatty acid. Only one of the isomeric Acr adducts was detected, and its stereoselective formation is consistent with that observed previously in vivo. Two previously unknown cyclic adducts, one derived from pentenal and the other from heptenal, were also detected as products from omega-3 and omega-6 fatty acids, respectively. This study demonstrated the specificity for the formation of the cyclic adducts of Acr, Cro, and HNE and other related enals by oxidation of omega-3 and omega-6 PUFAs. These results may be important for the understanding of the specific roles of different types of fatty acids in tumorigenesis.     

Clinical Trials Reports: Ongoing and planned clinical trials of antiarrhythmic drugs:Cardiovascular & Renal

The discovery that the insulin-sensitising thiazolidinediones (TZDs), specific peroxisome proliferator-activated receptor-γ (PPARγ) agonists, have antiproliferative, anti-inflammatory and immunomodulatory effects has led to the evaluation of their potential use in the treatment of diabetic complications and inflammatory, proliferative diseases in non-insulin-resistant, euglycaemic individuals. Apart from improving insulin resistance, plasma lipids and systemic inflammatory markers, ameliorating atherosclerosis and preventing coronary artery restenosis in diabetic subjects, currently approved TZDs have been shown to improve psoriasis and ulcerative colitis in euglycaemic human subjects. These data imply that the activation of PPAR-γ may improve cardiovascular risk factors and cardiovascular outcomes in both insulin-resistant diabetic and non-diabetic individuals. Through their immunomodulatory and anti-inflammatory actions, TZDs and other PPAR-γ agonists may prove to be effective in treating diseases unrelated to insulin resistance, such as autoimmune (e.g., multiple sclerosis), atopic (e.g., asthma, atopic dermatitis) and other inflammatory diseases (e.g., psoriasis, ulcerative colitis). Newer and safer selective PPAR-γ agonists are presently under development. Furthermore, of considerable interest is the recent discovery that a unique subset of currently prescribed antihypertensive angiotensin II Type 1 receptor antagonists has selective PPAR-γ-modulating activity. These discoveries pave the way for the development of drugs for treating chronic multigenic cardiovascular and metabolic diseases, for which therapy is presently insufficient or non-existent. The potential utility of the currently available TZDs rosiglitazone and pioglitazone and PPAR-γ-modulating angiotensin II Type 1 receptor antagonists in treating cardiovascular, metabolic and inflammatory diseases in insulin resistant and euglycaemic states is of immense clinical potential and should be investigated.     

Submaximal PPARγ activation and endothelial dysfunction: new perspectives for the management of cardiovascular disorders

PPARγ activation plays an important role in glucose metabolism by enhancing insulin sensitization. PPARγ is a primary target for thiazolidinedione-structured insulin sensitizers like pioglitazone and rosiglitazone employed for the treatment of type 2 diabetes mellitus. Additionally, PPARγ activation inhibits adhesion cascades and detrimental vascular inflammatory events. Importantly, activation of PPARγ plays a distinctive role in regulating the physiology and expression of endothelial nitric oxide synthase (eNOS) in the endothelium, resulting in enhanced generation of vascular nitric oxide. The PPARγ activation-mediated vascular anti-inflammatory and direct endothelial functional regulatory actions could, therefore, be beneficial in improving the vascular function in patients with atherosclerosis and hypertension with or without diabetes mellitus. Despite the disappointing cardiac side effect profile of rosiglitazone-like PPARγ full agonists, the therapeutic potential of novel pharmacological agents targeting PPARγ submaximally cannot be ruled out. This review discusses the potential regulatory role of PPARγ on eNOS expression and activation in improving the function of vascular endothelium. We argue that partial/submaximal activation of PPARγ could be a major target for vascular endothelial functional improvement. Interestingly, newly synthesized partial agonists of PPARγ such as balaglitazone, MBX-102, MK-0533, PAR-1622, PAM-1616, KR-62776 and SPPARγM5 are devoid of or have a reduced tendency to cause the adverse effects associated with full agonists of PPARγ. We propose that the vascular protective properties of pharmacological agents, which submaximally activate PPARγ, should be investigated. Moreover, the therapeutic opportunities of agents that submaximally activate PPARγ in preventing vascular endothelial dysfunction (VED) and VED-associated cardiovascular disorders are discussed.     

过氧化物酶体增殖物激活受体-γ与胰腺疾病的关系

过氧化物酶体增殖物激活受体γ（peroxisome proliferator activated receptor γ,PPARγ）是一类依赖配体活化的转录因子,属于Ⅱ型核激素受体超家族成员。PPAR-γ是近年来国内外研究的一个热点,现已明确其在细胞增殖分化、炎症反应、糖代谢及脂类代谢具有重要的调节作用。本文就PPARγ与胰腺疾病的关系作一综述。     

Fish oil fatty acids as cardiovascular drugs

Starting in the 1970s the hypothesis that the low mortality from coronary heart disease among the Greenland Eskimos was due to their high consumption of n-3 fish oil fatty acids, initiated many studies to find if the n-3 polyunsaturated fatty acids in fish oils (PUFAs) could prevent cardiac atherosclerosis. To date this possibility has not achieved clinical recognition. The recent literature shows an increase of intervention studies to learn if the fish oil fatty acids can reduce mortality from sudden cardiac death, and the mechanism(s) of such a protective effect. Indeed the most definite beneficial cardiac action of these n-3 PUFAs seems now to be their ability in the short term to prevent sudden cardiac death. It is apparent that over long periods of time the n-3 fish oil fatty acids also prevent atherosclerosis. Definition of the fatty acids to which I will be referring in the text: n-6 (omega-6) polyunsaturated fatty acids; linoleic acid (18:2n-6, LA); arachidonic acid (C20:4n-6, AA). n-3 (omega-3) fatty acids; alpha-linolenic acid (18:3n-3, ALA); eicosapentaenoic acid (20:5n-3, EPA); docosahexaenoic acid (C22:6n-3, DHA). The bold, underlined abbreviation will appear in the text to identify the fatty acid being discussed.     

Dietary n − 6 and n − 3 polyunsaturated fatty acids: From biochemistry to clinical implications in cardiovascular prevention

Linoleic acid (LA) and alpha linolenic acid (ALA) belong to the n − 6 (omega-6) and n − 3 (omega-3) series of polyunsaturated fatty acids (PUFA), respectively. They are defined “essential” fatty acids since they are not synthesized in the human body and are mostly obtained from the diet. Food sources of ALA and LA are most vegetable oils, cereals and walnuts. This review critically revises the most significant epidemiological and interventional studies on the cardioprotective activity of PUFAs, linking their biological functions to biochemistry and metabolism. In fact, a complex series of desaturation and elongation reactions acting in concert transform LA and ALA to their higher unsaturated derivatives: arachidonic acid (AA) from LA, eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) from ALA. EPA and DHA are abundantly present in fish and fish oil. AA and EPA are precursors of different classes of pro-inflammatory or anti-inflammatory eicosanoids, respectively, whose biological activities have been evoked to justify risks and benefits of PUFA consumption. The controversial origin and clinical role of the n − 6/n − 3 ratio as a potential risk factor in cardiovascular diseases is also examined. This review highlights the important cardioprotective effect of n − 3 in the secondary prevention of sudden cardiac death due to arrhythmias, but suggests caution to recommend dietary supplementation of PUFAs to the general population, without considering, at the individual level, the intake of total energy and fats.     

A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease

Non‐alcoholic fatty liver disease is becoming a major health burden, as prevalence increases and there are no approved treatment options. Thiazolidinediones target the nuclear receptor peroxisome proliferator‐activated receptor γ (PPARγ) and have been investigated in several clinical trials for their potential in treating non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH). PPARγ has specialized roles in distinct tissues and cell types, and although the primary function of PPARγ is in adipose tissue, where the highest expression levels are observed, hepatic expression levels of PPARγ are significantly increased in patients with NAFLD. Thus, NAFLD patients receiving treatment with PPARγ agonists might have a liver response apart from the one in adipose tissue. Owing to the different roles of PPARγ, new treatment strategies include development of compounds harnessing the beneficial effects of PPARγ while restricting PPARγ unwanted effects such as adipogenesis resulting in weight gain. Furthermore, dual or pan agonists targeting two or more of the PPARs have shown promising results in pre‐clinical research and some are currently proceeding to clinical trials. This MiniReview explores adipose‐ and liver‐specific actions of PPARγ, and how this knowledge may contribute in the search for new treatment modalities in NAFLD/NASH.     

Clinical potential of omega-3 fatty acids in the treatment of schizophrenia

The phospholipids in the neuronal membranes of the brain are rich in highly unsaturated essential fatty acids (EFAs). It has been hypothesised that abnormalities of phospholipid metabolism are present in patients with schizophrenia and that the EFAs omega-3 polyunsaturated fatty acids, and eicosapentaenoic acid (EPA) in particular, may have a role in treating this illness. Considerable preclinical and clinical evidence provides support for this proposal. An epidemiological study reported a better outcome for patients with schizophrenia in countries where the diet is rich in unsaturated fatty acids. Evidence of abnormalities of EFAs has been found in erythrocyte membranes and cultured skin fibroblasts of patients with schizophrenia, and abnormal retinal function and niacin skin flush tests (markers of omega-3 polyunsaturated fatty acid depletion) have also been reported. Case reports and an open-label clinical trial reported efficacy for EPA in schizophrenia. Four randomised, controlled trials of EPA versus placebo as supplemental medication have now been reported. Two of these trials showed significant benefit with EPA on the positive and negative symptom scale total scores, whereas the other two did not show any effects on this primary efficacy measure. One study also reported a beneficial effect on dyskinesia. In the only published trial in which EPA was used as monotherapy versus placebo in schizophrenia, some evidence was found to suggest antipsychotic activity. Taken together, there is considerable evidence to suggest abnormalities of EFAs in cell membranes of patients with schizophrenia, and there is preliminary evidence that EPA is an effective adjunct to antipsychotics.     

Omega-3 fatty acids in the treatment of psychiatric disorders

The importance of omega-3 fatty acids for physical health is now well recognised and there is increasing evidence that omega-3 fatty acids may also be important to mental health. The two main omega-3 fatty acids in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have important biological functions in the CNS. DHA is a major structural component of neuronal membranes, and changing the fatty acid composition of neuronal membranes leads to functional changes in the activity of receptors and other proteins embedded in the membrane phospholipid. EPA has important physiological functions that can affect neuronal activity. Epidemiological studies indicate an association between depression and low dietary intake of omega-3 fatty acids, and biochemical studies have shown reduced levels of omega-3 fatty acids in red blood cell membranes in both depressive and schizophrenic patients.Five of six double-blind, placebo-controlled trials in schizophrenia, and four of six such trials in depression, have reported therapeutic benefit from omega-3 fatty acids in either the primary or secondary statistical analysis, particularly when EPA is added on to existing psychotropic medication. Individual clinical trials have suggested benefits of EPA treatment in borderline personality disorder and of combined omega-3 and omega-6 fatty acid treatment for attention-deficit hyperactivity disorder. The evidence to date supports the adjunctive use of omega-3 fatty acids in the management of treatment unresponsive depression and schizophrenia. As these conditions are associated with increased risk of coronary heart disease and diabetes mellitus, omega-3 fatty acids should also benefit the physical state of these patients. However, as the clinical research evidence is preliminary, large, and definitive randomised controlled trials similar to those required for the licensing of any new pharmacological treatment are needed.