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.     

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 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.     

The induction of apoptosis in pre-malignant keratinocytes by omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is inhibited by albumin

The long chain omega-3 polyunsaturated fatty acids (PUFA) have been reported to exert anti-cancer effects. At this study we tested the effect of the omega-3 PUFA, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), on pre-malignant keratinocytes growth in the well-characterised human pre-malignant epidermal cell line, HaCaT and attempted to identify a PUFA serum antagonist. Both EPA and DHA inhibited HaCaT growth and induced apoptosis. At the 10% (v/v) foetal bovine serum (FBS) medium, limited growth inhibition (3–20% for 50 μM DHA and EPA respectively) and negligible apoptosis were observed with PUFA use. However, at 3% (v/v) FBS medium, 30–50 μM of PUFA caused impressive levels of growth inhibition (82–83% for 50 μM DHA and EPA respectively) and increase of apoptosis (8–19% increase in 72 h). None of the numerous serum growth factors present in FBS or the antioxidant n-tert-butyl-α-phenylnitrone could inhibit the PUFA-induced cytotoxicity. In contrast, bovine and human albumin (0.1–0.3%, w/v) significantly antagonized the growth inhibitory and apoptosis-inducing effects of PUFA. In conclusion, we have shown for the first time that omega-3 PUFA inhibit the growth and induce apoptosis of pre-malignant keratinocytes and identified albumin as a major antagonistic factor in serum that could limit their effectiveness at pharmacologically-achievable doses.     

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。     

Bioequivalence of two omega-3 fatty acid ethyl ester formulations: a case of clinical pharmacology of dietary supplements

AIM

To evaluate the bioequivalence of two omega-3 long chain polyunsaturated fatty acid (n-3 LC-PUFA) ethyl ester preparations, previously shown not to be bioequivalent in healthy subjects, with the objective of providing a guideline for future work in this area.

METHOD

A randomized double-blind crossover protocol was chosen. Volunteers with the lowest blood concentrations of n-3 LC-PUFA were selected. They received the ethyl esters in a single high dose (12 g) and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) blood concentrations were analyzed after fingerprick collection at intervals up to 24 h.

RESULTS

Differently from a prior study, the pharmacokinetic analysis indicated a satisfactory bioequivalence: for the AUC(0,24 h) 90% CI of the ratio between the two formulations were in the range for bioequivalence (for EPA 0.98, 1.04 and for DHA 0.99, 1.04) and the same was true for C_max and t_max (90% CI were 0.95, 1.14 and 1.10, 1.25 for EPA and 0.88, 1.02 and 0.84, 1.24 for DHA).

CONCLUSION

This study shows that, in order to obtain reliable bioequivalence data of products present in the daily diet, certain conditions should be met. Subjects should have low, homogeneous baseline concentrations and not be exposed to food items containing the product under evaluation, e.g. fish. Finally, as in the case of omega-3 fatty acids, selected doses should be high, eventually with appropriate conditions of intake.     

杨树皮不饱和脂肪酸对实验性高脂血症大鼠血脂的影响

目的评价杨树皮不饱和脂肪酸对实验性高脂血症大鼠血脂的影响。方法将雄性大鼠60只,随机分成6组,即:基础饲料对照组(1),病理模型组(2),杨树皮不饱和脂肪酸高剂量组(3)、中剂量组(4)、低剂量组(5)及烟酸阳性对照组(6),连续给药15d,末次给药后14h分离血清,测定血清中TC、TG、LDL-C、HDL-C的浓度。结果杨树皮不饱和脂肪酸能显著降低实验性高脂血症大鼠的血清总胆固醇(TC)、甘油三脂(TG)和低密度脂蛋白的胆固醇(LDL-C)水平,而对血清中高密度脂蛋白的胆固醇(HDL-C)含量有升高作用。结论杨树皮不饱和脂肪酸具有调节血清TC、TG、HDL-C的作用。     

Vitamin E supplementation modulates the biological effects of omega-3 fatty acids in naturally aged rats

Omega-3 fatty acids are well-known class of nutraceuticals with established health benefits. Recently, the oxidation products of these fatty acids are gaining attention, as they are likely to disturb body redox balance. Therefore, the efficacy of omega-3 fats under conditions of diminished antioxidant status, such as aging, is always a concern. Present study assessed the effects of omega-3 fats (DHA and EPA) together with or without vitamin-E in naturally aged rats. It was found that in omega-3 fats alone consumed rats the lipid profile was improved, while in omega-3 fat with vitamin-E-consumed group (OMVE), the hepato protective and antioxidant properties were pronounced, especially the redox status of brain tissue. It is possible that vitamin-E might have reduced the peroxidation of omega-3 fats, thereby allowing their synergistic effects. Hence, the use of vitamin-E along with omega-3 fat may be beneficial under aged conditions.     

Omega-3 fatty acid supplementation in schizophrenic patients

There is evidence that certain n3 and n6 essential fatty acids (EFAs) are depleted in cell membranes from red blood cells (RBC) and brains of patients suffering from schizophrenia. If these findings are of primary significance, then the possibility is raised of modifying schizophrenic symptomatology by dietary supplementation with fatty acids. We have carried out detailed analysis of dietary fatty acid intake of 20 schizophrenic patients. It was found that a greater intake of n3 fatty acids and particularly eicosapentenoic (EPA) in the normal diet, was associated with less severe schizophrenic symptoms and particularly less positive symptoms, as well as less tardive dyskinesia (TD). Furthermore, supplementation of the diet for 6 weeks with 10 g/day of concentrated fish oil (MaxEPA) resulted in significant amelioration of both schizophrenic symptoms and TD. Multiple regression analysis showed that improvement in schizophrenic symptoms was importantly related to the increased level of n3 fatty acids in RBC membranes.     

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.     

Epigenetic regulation of gene expression and M2 macrophage polarization as new potential omega-3 polyunsaturated fatty acid targets in colon inflammation and cancer

Introduction: It has become increasingly clear that dietary habits may affect the risk/progression of chronic diseases with a pathogenic inflammatory component, such as colorectal cancer. Considerable attention has been directed toward the ability of nutritional agents to target key molecular pathways involved in these inflammatory-related diseases.

Areas covered: ω-3 Polyunsaturated fatty acids (PUFA) and their oxidative metabolites have attracted considerable interest as possible anti-inflammatory and anti-cancer agents, especially in areas such as the large bowel, where the influence of orally introduced substances is high and tumors show deranged PUFA patterns. On this basis, we have analyzed pre-clinical findings that have recently revealed new insight into the molecular pathways targeted by ω-3 PUFA.

Expert opinion: The findings analyzed herein demonstrate that ω-3 PUFA may exert beneficial effects by targeting the epigenetic regulation of gene expression and altering M2 macrophage polarization during the inflammatory response. These mechanisms need to be better explored in the large bowel, and further studies could better clarify their role and the potential of dietary interventions with ω-3 PUFA in the large bowel. The epigenomic mechanism is discussed in view of the potential of ω-3 PUFA to enhance the efficacy of other agents used in the therapy of colorectal cancer.     

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。     

Combination of arginine and omega-3 fatty acids enteral nutrition in critically ill and surgical patients: a meta-analysis

Immunonutrients may improve outcomes in critically ill and surgical patients. The objective of this meta-analysis was to determine if the combination of arginine and omega-3 fatty acids impacts infection rate, hospital length of stay and mortality in critically ill or surgical patients. In total, 23 studies met all of the criteria. Immunonutrition with arginine and omega-3 fatty acids was administered either pre- or post-operatively or during intensive care unit stay in seven, ten and six studies, respectively. Infection rate and length of stay were significantly lower in patients receiving immunonutrition compared with the control group. In a subgroup analysis, these differences were maintained in the pre- and post-operative populations, but were not significant in the critically ill population. Mortality was not significantly different between the immunonutrition and control groups.     

Role of omega-6 and omega-3 fatty acids in fetal programming

Maternal nutrition plays a critical role in fetal development and can influence adult onset of disease. Linoleic acid (LA) and alpha-linolenic acid (ALA) are major omega-6 (n-6) and n-3 polyunsaturated fatty acids (PUFA), respectively, that are essential in our diet. LA and ALA are critical for the development of the fetal neurological and immune systems. However, in recent years, the consumption of n-6 PUFA has increased gradually worldwide, and elevated n-6 PUFA consumption may be harmful to human health. Consumption of diets with high levels of n-6 PUFA before or during pregnancy may have detrimental effects on fetal development and may influence overall health of offspring in adulthood. This review discusses the role of n-6 PUFA in fetal programming, the importance of a balance between n-6 and n-3 PUFAs in the maternal diet, and the need of further animal models and human studies that critically evaluate both n-6 and n-3 PUFA contents in diets.     

Hepatoprotective role of bis-demethoxy curcumin analog on the expression of matrix metalloproteinase induced by alcohol and polyunsaturated fatty acid in rats

Liver fibrosis is one of the major health problems worldwide. Chronic alcohol abuse is one of the main causes of fibrosis. Ingestion of polyunsaturated fatty acids (PUFA) along with alcohol further aggravates the toxicity of alcohol. Fibrosis results due to increased deposition of extra cellular matrix (ECM). The degree of abnormal ECM degradation depends on the ratio of active matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The present work studied the influence of bis-desmethoxy curcumin analog (BDMC-A) on the expression of MMPs and TIMPs during alcohol and ΔPUFA induced liver toxicity. Male albino Wistar rats were used for the study. The MMP expression was found to be increased in alcohol as well as ΔPUFA treated rats and decreased in alcohol + ΔPUFA treated rats. The levels of TIMPs and the collagen were increased in alcohol, ΔPUFA, and alcohol + ΔPUFA groups. Administration of BDMC-A significantly decreased the levels of collagen and TIMPs; and positively modulated the expression of MMPs. From this study, it is concluded that BDMC-A influences MMPs, TIMPs expression, and acts as an efficient anti-fibrotic agent.