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PROF.SSA GABRIELA MAZZANTIgabriela.mazzanti@uniroma1.it

Dipartimento di Fisiologia e Farmacologia “Vittorio Erspamer”

Acidi grassi essenziali

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ACIDI GRASSI INSATURI

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Vie metaboliche degli acidi grassi polinsaturi

Acido eicosapentaenoico (EPA)

ACIDI GRASSI ESSENZIALI ω-3: OLIO DI PESCE

(SGOMBRO, SALMONE, ARINGA, TONNO, MERLUZZO)

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Possibili meccanismi alla base degli effetti sui fa ttori di rischio cardiovascolare

• Riduzione della produzione epatica delle VLDL (ricche di trigliceridi)

• Aumento della β ossidazione degli acidi grassi nel fegato• Miglioramento della funzione dell’endotelio e della

muscolatura liscia vasale con ridotta vasocostrizione• Ridotta aggregabilità piastrinica• Riduzione dei marker dell’infiammazione (NFK-beta, IL6,

TNF-alpha)

Omega-3 polyunsaturated fatty acids in the treatmen t of hypertriglyceridaemia .

Pirillo and Catapano Int J Cardiol. 2013 Jul 12

Hypertriglyceridaemia (HTG) is an independent risk factor for cardiovascular disease; high-risk patients with HTG , such as those with

metabolic syndrome or diabetes, may benefit from hy polipidaemic therapies. Several lipid-lowering drugs act by reducing triglyceride (TG) levels,

including fibrates, nicotinic acid and omega-3 fatty acids. The omega-3 polyunsaturated fatty acids eicosapentaenoic acid ( EPA) and

docosahexaenoic acid (DHA) dose-dependently reduce plasma TG levels; the effect tends to be greater in patients with hig her TG levels at baseline.Evidence from clinical trials suggests that EPA+DHA doses of ≥2g/day are

required to achieve significant effects. The optimal TG-lowering doses of EPA+DHA are 3-4g/day, with little evidence to support lipid-altering efficacy of doses of EPA and DHA <1g/day. Predicted changes in fasting serum TG levels at the recommended dietary intakes of EPA and/or DHA of 200-500mg/day are -

3.1% to -7.2%. Reductions of plasma TG levels at the optimal doses are from 25-35% up to 45% in the presence of severely elevated TG levels (≥500mg/dl; ≥5.65mmol/l), along with a reduction in non-high-density lipoprotein-cholesterol

(non-HDL-C) and an increase in HDL-C. This observation has also been confirmed in statin-treated patients

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Indications for Omega-3 Long Chain Polyunsaturated Fatty Acid in the Prevention and Treatment of Cardiovascular Disease

Nestel et al, Heart, Lung and Circulation (2015) 24, 769–779

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Omega-3 fatty acids: a review of the effects on adi ponectin and leptin and potential implications for obesity management

Gray et al., Eur J Clin Nutr. 2013 Oct 16.

An increase in adiposity is associated with altered levels of biologically active proteins. These include the hormones adipone ctin and leptin . The marked change in circulating concentrations of these hormones in obesity has

been associated with the development of insulin resistance and metabolic syndrome. Variations in dietary lipid consumption have also been shown to impact obesity. Specifically, omega-3 fatty acids have been correlated with the prevention of obesity and subsequent development of chronic disease sequalae. This review

explores animal and human data relating to the effects of omega-3 fatty acids (marine lipids) on adiponectin and leptin, considering plausible mechanisms and potential implications for obesity management. Current evidence suggests a

positive, dose-dependent relationship between omega -3 fatty acid intake and circulating levels of adiponectin. In obese subjects, this may translate into a reduced risk of developing cardiovascular disease, metabolic syndrome and

diabetes. In non-obese subjects, omega-3 is observed to decrease circulating levels of leptin; however, omega-3-associated increases in leptin levels have been observed in obese subjects . This may pose benefits in the prevention

of weight regain in these subjects following calori e restriction

Adiponectina: stimola ossidazione acidi grassi. Leptina: induce sazietà

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People with schizophrenia and depression have a low omega-3 index. Parletta et al. Prostaglandins Leukot Essent Fatty Acids. 2016 Jul;110:42-7

Cardiovascular disease (CVD) is higher in people with mental illness and is associated with a 30 year higher mortality rate in this population. Erythrocyte docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA) (omega-3 index)≤4% is a marker for increased mortality risk from CVD while >8% is protective. Omega-3 polyunsaturated fatty acids are also important for brain function and may ameliorate symptoms of mental illness. We investigated the erythrocyte omega-3 index in people with mental illness. One hundred and thirty adults aged 18-65 years (32.6% male) with schizophrenia (n=14) and depression (n=116) provided blood samples and completed physiological assessments and questionnaires. Both populations had risk factors for metabolic syndrome and CVD. The average omega-3 index was 3.95% (SD=1.06), compared to an estimated 5% in the Australian population. These data indicate an unfavourable omega-3 profile in people with mental illness that could contribute to higher CVD risk.

PLoS One. 2016 May 27;11(5):e0156432Omega-3 and Omega-6 Polyunsaturated Fatty Acid Levels a nd Correlations with Symptoms in Children with Attention Deficit Hyperactivity Disorder, Autistic Spectrum Disorder and TypicallyDeveloping Controls.Parletta N1, Niyonsenga T1, Duff J2,3.

BACKGROUND:There is evidence that children with Attention Deficit Hyperactivity Disorder (ADHD) and AutisticSpectrum Disorder (ASD) have lower omega-3 polyunsaturated fatty acid (n-3 PUFA) levels comparedwith controls and conflicting evidence regarding omega-6 (n-6) PUFA levels.OBJECTIVES:This study investigated whether erythrocyte n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were lower and n-6 PUFA arachidonic acid (AA) higher in children withADHD, ASD and controls, and whether lower n-3 and higher n-6 PUFAs correlated with poorer scoreson the Australian Twin Behaviour Rating Scale (ATBRS; ADHD symptoms) and Test of VariableAttention (TOVA) in children with ADHD, and Childhood Autism Rating Scale (CARS) in children withASD.RESULTS:Children with ADHD and ASD had lower DHA, EPA and AA, higher AA/EPA ratio and lower n-3/n-6 than controls (P<0.001 except AA between ADHD and controls: P = 0.047). Children with ASD hadlower DHA, EPA and AA than children with ADHD (P<0.001 for all comparisons). ATBRS scorescorrelated negatively with EPA (r = -.294, P<0.001), DHA (r = -.424, P<0.001), n-3/n-6 (r = -.477, P<0.001) and positively with AA/EPA (r = .222, P <.01). TOVA scores correlated positively with DHA (r = .610, P<0.001), EPA (r = .418, P<0.001) AA (r = .199, P<0.001), and n-3/n-6 (r = .509, P<0.001) and negatively with AA/EPA (r = -.243, P<0.001). CARS scores correlated significantly with DHA (r = .328, P = 0.002), EPA (r = -.225, P = 0.038) and AA (r = .251, P = 0.021).CONCLUSIONS:Children with ADHD and ASD had low levels of EPA, DHA and AA and high ratio of n-6/n-3 PUFAsand these correlated significantly with symptoms. Future research should further investigate abnormal fatty acid metabolism in these disorders

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Olio di pesce e dismenorrea

Supplementation with omega-3 polyunsaturated fatty acids in the

managment of dysmenorrhea in adolescentHarel et al, Am J Obstet Gynecol 1996; 174(4):1335-8

STUDY DESIGN: Forty-two adolescents with dysmenorrheawere randomly allocated to two groups. In the first group 21girls received fish oil (1080 mg icosapentaenoic acid, 720mg docosahexaenoic acid, and 1.5 mg vitamin E) daily for 2months followed by a placebo for an additional 2 months. Inthe second group 21 girls received placebo for the first 2months, followed by fish oil for 2 more months. The CoxMenstrual Symptom Scale was used to assess response totreatment.

RESULTS: There were no significant differences in the CoxMenstrual Symptom Scale between the two groups atbaseline after 2 months of placebo administration. After 2months of treatment with fish oil there was a markedreduction in the Cox Menstrual Symptom Scale from abaseline mean value of 69.9 to 44.0 (p < 0.0004).

CONCLUSIONS: This study suggests that dietarysupplementation with omega-3 fatty acids has a beneficialeffect on symptoms of dysmenorrhea in adolescents.

Menstrual pain in Danish women correlated with low n-3 polyunsaturated fatty acid intake

Deutch B, Eur J Clin Nutr 1995; 49(7): 508-16

SUBJECTS: The subjects were recruited by advertising (about220 volunteered); 181 healthy Danish women were selected,aged 20-45 years; they were not pregnant and did not use oralcontraceptives.

RESULTS: No correlations were found between socioeconomicor anthropometric data and menstrual problems. On thecontrary certain dietary habits, e.g. low intake of animal and fishproducts, and intakes of specific nutrients, were correlated withmenstrual pain. The average dietary n-3/n-6 ratio of womenwith menstrual pain was 0.24. It was significantly higher amongthose with low intake of B12 coincident with low intake of n-3(0.42, P < 0.001) (chi-square), with low n-3 intake coincidentwith low n-3/n-6 ratio (0.42, P < 0.005), and finally with lowintake of B12 coincident with low n-3/n-6 ratio (0.47, P < 0.001).

CONCLUSION: The results were highly significant and mutuallyconsistent and supported the hypothesis that a higher intake ofmarine n-3 fatty acids correlates with milder menstrual

symptoms.

Eicosapentaenoic acid is converted via ω-3 epoxygenation to the anti-inflammatory metabolite 12-hydroxy-17,18- epoxyeicos atetraenoic acid

Kubota et al, FASEB J. 2013 Oct 15.

Eicosapentaenoic acid (EPA) has beneficial effects in many inflammatory disorders. In this study, dietary EPA was converted to 17,18-

epoxyeicosatetraenoic acid (17,18- EpETE) by ω-3 epoxygenation in the mouse peritoneal cavity. Mediator lipidomics revealed a series of novel

oxygenated metabolites of 17,18-EpETE, and one of the major metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE),

displayed a potent anti-inflammatory action by limiting neutrophil infiltration in murine zymosan-induced peritonitis. 12-OH-17,18-EpETE inhibited

leukotriene B4-induced neutrophil chemotaxis and polarization in vitro in a low nanomolar range (EC50 0.6 nM). The complete structures of two natural isomers were assigned as 12S-OH-17R,18S-EpETE and 12S-OH-17S,18R-EpETE, using chemically synthesized stereoisomers. These natural isomers

displayed potent anti-inflammatory action, whereas the unnatural stereoisomers were essentially devoid of activity. These results demonstrate

that 17,18-EpETE derived from dietary EPA is converted to a potent bioactive metabolite 12-OH-17,18-EpETE, which may g enerate an

endogenous anti-inflammatory metabolic pathway

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ACIDI GRASSI ESSENZIALI ω-6

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OENOTHERA BIENNIS L. (Onagraceae)(Evening Primrose)

• Pianta erbacea originaria dell’America del Nord, diffusa nelle zone costiere, mediterranee ed atlantiche

• Parte utilizzata: olio dei semi

• Componenti principali: acidi grassi insaturi: oleico (6-11%), linoleico (65-80%), gamma-linolenico (8-14%).

Acido gamma linolenico (ω-6)

Acido linoleico (ω-6)

Acido oleico

BORAGO OFFICINALIS L. (Boraginaceae)

Pianta erbacea annua molto comune in Italia

Olio dei semi: ac. linoleico (30-40%), ac. oleico (15-19%), ac. gamma-linolenico (18-25%)

Acido gamma linolenico (ω-6)

Acido linoleico (ω-6)

Acido oleico

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ω-6 e dismenorrea

Metabolism of omega-6 polyunsaturated fatty acids i n women with dysmenorrhea

Chao-Chic Wu et al, Asia Pac J Clin Nutr 2008; 17(S1): 216-9

AIM: To compare the effect of dietary supplementation with PUFA (sunflower oil, borage oil, fish oil) for three months on RBC membrane fatty acid composition in healthy and dysmenorrheic houng women.

RESULTS: Conversion of linoleic acid, via gamma-linolenic acid, to dihomo-gamma-linolenic acid (a precursor of anti-inflammatory prostaglandin E1) in dysmenorrheic subjects was slower as compared to controls.

Vie metaboliche degli acidi grassi polinsaturi

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Olio di Enotera: basi dell’uso nella PMS

• Alcune donne affette da PMS sono carenti di ∆6-desaturasi

• La carenza di tale enzima compromette la produzione di PGE1 che attenua gli effetti della prolattina (Horrobin, J Reprod Med 1983; 28: 465-8)

• 7 studi placebo-controllati: risultati tendenzialmente positivi ma generalmente di scarsa qualità metodologica

• I due studi metodologicamente corretti non mostravano effetti positivi verso placebo

Farmacologia clinica dell’olio di Enotera nella PMS (Budeiri et al, Control Clin Trials 1996; 17: 60-8)

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Femicomfort in the treatment of premenstrual syndro mes: a double-blind, randomized and placebo controlled trial.Iran J Psychiatry. 2010;5(2):47-50 Kashani L, Saedi N, Akhondzadeh S.

Infertility Center of Arash Hospital, Tehran University of Medical Sciences, Tehran, Iran.

OBJECTIVE: Premenstrual syndromes (PMS) affecting 20-40% of women of reproductive age. The aim of this double blind and placebo controlled trial was to investigate whether femicofort a supplement contains Vitamin B6, Vitamin E and evening primrose oil could relieve symptoms of PMS.METHOD: This was a randomized and double blind clinical trial. Women aged 20 to 45 years with regular menstrual cycles and experience of PMS symptoms for at least 6 months were eligible for the study. Patients were randomized to receive femicomfort or placebo in a 1: 1 ratio using a computer-generated code. The assignments were kept in sealed, opaque envelopes until the point of analysis of data. In this double-blind, patients were randomly assigned to receive capsule of femicomfort (Group A) or capsule placebo for two menstrual cycles (cycles 3 and 4). The primary outcome measure was the Daily Symptom Report, a checklist of 17 premenstrual symptoms rated from 0 to 4 according to their severity throughout the menstrual cycle. Secondary outcome measure was Hamilton Depression Rating Scale (17-item).RESULTS: Femicomfort at this dose was found to be e ffective in relieving symptoms of PMS. The difference between the femicom fort and placebo in the frequency of side effects was not significant.CONCLUSION: The results of this study indicate the efficacy of femicomfort in the treatment of PMS

Evening primrose oil and borage oil in rheumatologi c conditionsBelch JJ, Hill A.

Am J Clin Nutr. 2000 Jan;71(1 Suppl):352S-6S.

Diets rich in arachidonic acid (20:4n-6) lead to the formation of 2-series prostaglandins (PGs) and 4-series leukotrienes (LTs), with proinflammatory effects. Nonsteroidal antiinflammatory drugs are used in rheumatoid arthritis to inhibit cyclooxygenase

(prostaglandin-endoperoxide synthase), thereby decreasing production of 2-series PGs. Lipoxygenase activity remains intact, however, allowing LT production (eg, synthesis of

LTB(4), a potent inflammatory mediator) to continue. Altering the essential fatty acid (EFA) content of the diet can modify some of these effects. Ingestion of a diet rich in evening primrose oil elevates concentrations of dihomo-gamma-linolenic a cid (DGLA; 20:3n-6), which results in the production of 1-series PGs, eg, PGE(1).

DGLA itself cannot be converted to LTs but can form a 15-hydroxyl derivative that blocks the transformation of arachidonic acid to LT s. Increasing DGLA intake may allow DGLA to act as a competitive inhibitor of 2-s eries PGs and 4-series LTs and thus suppress inflammation. The results of in vitro and animal work evaluating EFAs

in inflammatory situations are encouraging, which has stimulated clinical workers to evaluate these compounds in rheumatoid arthritis. Several well-controlled, randomized

clinical studies have now been completed in which various EFAs were evaluated as treatments. The results of most of these studies suggest some clinical benefit to these

treatments; these data are reviewed here

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Borage oil reduction of rheumatoid arthritis activi ty may be mediated by increased cAMP that suppresses tumor necrosis facto r-alpha

Kast, Int Immunopharmacol. 2001 Nov;1(12):2197-9.

Recent double blind studies have shown some benefit of borage oil in treatment of rheumatoid arthritis. Tumor necrosis factor-alpha has been shown

to be a central mediator of inflammatory and joint destructive processes in rheumatoid arthritis. In this paper, evidence from published research is

reviewed that indicates gamma linolenic acid component of borage oil increases prostaglandin E levels that increase cAMP levels that in turn

suppress tumor necrosis factor-alpha synthesis . If this biochemical path of borage oil is correct then (1) concomitant non-steroidal anti-inflammatory drug use would tend to undermine borage oil effects, and (2) borage oil would be

contraindicated in pregnancy given the teratogenic and labor inducing effects of prostaglandin E agonists

Borage oil in the treatment of atopic dermatitisFoster et al, Nutrition 2010 Jul-Aug;26(7-8):708-18

EFAs play a vital role in skin structure and physiology. EFA deficiency replicates the symptoms of atopic dermatitis, and patients with atopic dermatitis have been reported to have imbalances in EFA levels. Although direct proof is lacking, it has been hypothesized

that patients with atopic dermatitis have impaired activity of the delta-6 desaturase enzyme, affecting metabolism of linoleic acid to gamma-linolenic acid (GLA). However, to date, studies of EFA supplementation in atopic dermatitis, most commonly using evening

primrose oil, have produced conflicting results. Borage oil is of interest because it contains two to three times more GLA than evening primrose oil. This review identified 12 clinical

trials of oral or topical borage oil for treatment of atopic dermatitis and one preventive trial. All studies were controlled and most were randomized and double-blind, but many were

small and had other methodological limitations. The results of studies of borage oil for the treatment of atopic dermatitis were highly variable, with the effect reported to be significant in five studies, insignificant in five studies, and mixed in two studies. Borage oil given to at-

risk neonates did not prevent development of atopic dermatitis. However, the majority of studies showed at least a small degree of efficacy or were not able to exclude the

possibility that the oil produces a small benefit. Overall, the data suggest that nutritional supplementation with borage oil is unlikely to have a major clinical effect but may be useful

in some individual patients with less severe atopic dermatitis who are seeking an alternative treatment. Which patients are likely to respond cannot yet be identified. Borage

oil is well tolerated in the short term but no long-term tolerability data are available.

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Status epilepticus associated with borage oil inges tion.Al-Khamees et al. J Med Toxicol. 2011 Jun;7(2):154-7 Georgia Poison Center,

Grady Health System, Atlanta, GA, USA.

The use of herbal and complementary medicine is common. Many herbal products are known to produce serious

adverse effects. Borage oil is derived from the seeds of the borage plant (Borago officinalis) an abundant source of gamma-linolenic acid (GLA), and Borage oil has been

promoted as a treatment for rheumatoid arthritis, atopic dermatitis, diabetic neuropathy, and menopause-related

symptoms. We report a case of status epilepticus in a patient who consumed borage oil for one week.