Down-regulation of a signaling mediator in association with lowered plasma arachidonic acid levels in individuals with autism spectrum disorders

Neuroscience Letters 610 (2016) 223–228

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Research paper

Down-regulation of a signaling mediator in association with lowered plasma arachidonic acid levels in individuals with autism spectrum disorders Kunio Yui a,∗ , George Imataka b , Yohei Kawasaki c , Hiroshi Yamada c a

Research Institute of Pervasive Developmental Disorders, Ashiya University, 13-22 Rokurokusocho, Ashiya, 659-8511 Hyogo, Japan Department of Pediatrics, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, 321-0293 Tochigi, Japan c Department of Drug Evaluation and Information, School of Pharmaceutical Science University of Shizuoka, 52-1 Tada, Shizuoka 422-8526, Japan b

h i g h l i g h t s

g r a p h i c a l

a b s t r a c t

• Fatty acid levels and arachidonic • • • •

acid-related signaling mediators were assayed. DHA/arachidonic acid ratio was higher while arachidonic acid levels were lower. Plasma levels of signaling mediator ceruloplasmin was reduced. High DHA/arachidonic acid ratio contributed to downregulation of ceruloplasmin. Low ceruloplasmin contributes to abnormal behavior of autism spectrum disorders.

Downregulation of ceruloplasmin related to increased plasma DHA levels and reduced AA levels

Increased ratios of plasma DHA/AA

AA-related these fatty acids (5,8,11,14eicosatetraenoic acid, stearic acid, adrenic acid, and arachidic acid)

Reduced plasma AA levels

Downregulation of a mediator of AArelated eicosanoid signaling (Cp)

a r t i c l e

i n f o

Article history: Received 6 October 2015 Received in revised form 3 November 2015 Accepted 4 November 2015 Available online 10 November 2015 Keywords: Signaling mediators Competitive interaction Eicosapentaenoic acid Arachidonic acid Autism spectrum disorder

∗ Corresponding author. Fax: +81 792 23 1901. E-mail address: [email protected] (K. Yui). http://dx.doi.org/10.1016/j.neulet.2015.11.006 0304-3940/© 2015 Published by Elsevier Ireland Ltd.

a b s t r a c t Previous studies have indicated that the altered composition of polyunsaturated fatty acids (PUFAs) might contribute to the pathophysiology of autism spectrum disorder (ASD). We examined the relationship between the plasma fatty acid levels, expressed as ␮g/ml, and the plasma levels of biomarkers of AArelated signaling mediators, such as ceruloplasmin, transferrin and superoxide dismutase, and assessed the behavioral symptoms of 30 individuals with ASD (mean age, 13.6 ± 4.3 years old) compared with 20 age- and gender-matched normal controls (mean age, 13.2 ± 5.4 years old) using Aberrant Behavior Checklists (ABC). The plasma levels of EPA and the plasma ratios of EPA/AA were significantly higher, while the plasma levels of AA and metabolites, such as 5,8,11,14-eicosatetraenoic acid, adrenic acid, and ceruloplasmin (Cp), were significantly lower in the 30 individuals with ASD compared with the 20 normal controls. The ABC scores were significantly increased in the ASD group compared with those of the control group. Thus, the results of the present study revealed that reduced plasma levels of AA and metabolites in association with high plasma EPA/AA ratios might down-regulate AA-related signaling mediators, such as Cp. Subsequently, reduced plasma Cp levels might reduce the protective capacity for

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brain damage, resulting in the pathophysiology underlying the behavioral symptoms in individuals with ASD. These findings suggest that reduced plasma AA levels may downregulate Cp. © 2015 Published by Elsevier Ireland Ltd.

1. Introduction The altered metabolism of polyunsaturated fatty acids (PUFAs) might be involved in the pathophysiology of autism spectrum disorder (ASD) [1]. PUFAs are essential components of cell membranes, where the cell signaling machinery resides [2]. Docosahexaenoic acid (DHA, 22:6␻-3), eicosapentaenoic acid (EPA, 20:5␻-3) and arachidonic acid (AA, 20:4␻-6) play important roles in signal transduction [3]. EPA modulates prostaglandin E2 signaling [4], and DHA might alter downstream signaling [5]. Thus, ASD might be attributed to alterations in the composition of PUFA and related signaling mediators. Previous studies on ASD have shown reduced plasma DHA levels in ASD [6], changes in the plasma omega3/omega-6 ratio [7], or decreased erythrocyte AA and DHA levels [8]. However, the neurobiological basis underlying the relationship between the altered composition of PUFAs and the development of ASD symptoms remains unclear. However, two neurobiological aspects have been suggested. First, the relationship between omega-3 PUFAs and AA is antagonistic at high EPA and DHA concentrations [9]. Reducing omega-6 PUFAs increases the bioavailability of omega-3 PUFAs [10]. This antagonism significantly affects cell signaling [11]. Omega-3 PUFAs might attenuate both tissue AA levels and eicosanoid formation [12,13]. This competitive interaction between omega-3 PUFAs and AA reflects increased plasma omega3/omega-6 PUFA ratios [9]. Thus, the reduced AA levels associated with this competitive interaction might downregulate AA-related signaling mediators. Second, ceruloplasmin (Cp) [14], superoxide dismutase (SOD) [15] and transferrin (Tf) [16] act as signaling mediators in ASD. Cp is an important copper signaling biomarker [17] with a natural neuroprotective mechanism [18]. Cp reduces the synthesis of AA-derived eicosanoid mediator leukotrienes [19] and cyclooxygenase-2 [20]. EPA reduces the levels of Cp in branchoalveolar lavage fluid [21]. SOD is a biomarker of copper signaling [22], and both AA [23] and essential PUFAs increase the activity of SOD [24] (Cardoso). Tf is an iron-signaling mediator [25]. DHA elevates the levels of Tf receptor protein expression [26]. Thus, Cp, SOD and Tf are associated with AA, DHA and EPA activities. In previous ASD studies, changes in the blood SOD, TF and CP levels indicate altered antioxidant status [27,28] and copper dyshomeostasis [29]. Based on these aspects, we hypothesized that reduced plasma AA levels associated with the competitive interaction between increased plasma levels of omega-3 PUFAs (EPA and DHA) and reduced plasma levels of AA might correlate with the downregulation of AA-related signaling mediators and behavioral symptoms observed in individuals with ASD. Thus, we measured the plasma levels of the 22 fatty acids, expressed as the means ± SD ␮g/ml. Because multiple subfamilies of AA-derived eicosanoid signaling mediators are affected through multiple factors [30], we examined the plasma levels of some well-known signaling mediators, namely Cp, SOD and Tf. In addition, we controlled the dietary intake and assessed nutrient intake.

and July 2014. Diagnosis was performed based on DSM-IV-TR criteria, and two psychiatrists confirmed the results using the Autism Diagnostic Interview-Revised (ADI-R) [31]. Among the 50 individuals, 30 subjects were diagnosed with ASD (20 males and 10 females, mean age: 13.6 ± 4.3 years old, range: 6–21 years old), and the remaining 20 individuals were normal healthy controls (14 males and 6 females, mean age: 13.2 ± 5.4 years old, range: 5–21 years old). The 30 individuals with ASD exhibited the core symptoms of the DSM-IV-R diagnostic criteria for ASD, without any abnormal neurological symptoms, comorbid psychiatric disorders and chronic gastrointestinal disorders. The ASD and control groups were matched to 20 normal controls based on age, gender and full intelligent quotient (IQ) scores (Table 1). All participants showed no abnormalities in physical and clinical laboratory examinations. The IQ score was estimated using the Wechsler Intelligence Scale for children and adolescents aged 6–16 years old (WISC-III) [32] or the Wechsler Intelligence Scale for adults (WAIS-R) [33] (Table 1). The additional inclusion criteria included (a) a baseline verbal or full IQ score greater than 70 because subjects with high-functioning pervasive developmental disorders were required to have a total IQ score of at least 70 [34]; and (b) no treatment with medical drugs within the three months prior to the study. The present study was performed with the approval of the ethics committee of Fujimoto Medical Clinic in Kobe City, Japan. Written informed consent was obtained from the participants and/or their parents. 2.2. Controlling for dietary intake and assessment of nutrient intake All 50 participants received dietary control according to “Japanese Food Guide Spinning TOP” [35]. Moreover, a semiconstructive questionnaire for the assessment of dietary nutrient intake for Japanese individuals (DHQ support center, Tokyo, Japan) was performed using the junior high school version (DHQ15) [36]. The DHQ15 was administered one month prior to the start of the present study in 16 ASD individuals and 9 normal controls during January 2014 and December 2014. The mothers of these individuals also completed the DHQ15. The nutrient intake data were calculated using the computer program associated with the DHQ system. 2.3. Assessment of behavioral symptoms In the present study, the ABC used to assess the behavioral symptoms and evaluate treatment responses in behavioral intervention trials for individuals with normal IQ levels [37]. This test also appears to be capable of discriminating between several syndromes, such as disruptive behavior disorders and the behavioral symptoms of ASD [38]. 2.4. Assays of plasma levels of PUFAs, Cp, SOD and Tf

2. Patients and methods 2.1. Subjects A total of 50 young, healthy individuals were recruited from the medical care facility of Ashiya University between January 2012

2.4.1. Methods of blood sampling Plasma samples were obtained at 11:00–12:30 after supine rest and frozen at −80 ◦ C until further analysis. The plasma levels of fatty acids and signaling biomarkers were measured at SRL, Inc. (Tokyo, Japan).

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Table 1 Subject characteristics and plasma levels of signaling mediators, and the ABC subscale scores in the 30 individuals with ASD and 20 normal controls. Parameters

ASD (n = 30)

Controls (n = 20)

U

p value

Age (year) Sex (male/female) Full IQ

13.6 ± 4.3 10/20 99.7 ± 18.2

13.2 ± 5.4 6/14 117.2 ± 23.9

290.50 ␹2 = 0.00 106.00

0.85 1.00 0.09

Scores of autism diagnostic Interview-revised Domain A (social) Domain B (communication) Domain C (stereotyped) Plasma biomarkers levels Cp (mg/dl) Tf (mg/dl) SOD (U/ml) Scores of the ABC Irritability Social withdrawal Stereotypy Hyperactivity Inappropriate speech Total

17.0 ± 5.3 14.4 ± 4.9 7.2 ± 5.9 24.97 ± 5.00 267.07 ± 43.23 3.41 ± 2.67 13.90 22.87 5.87 19.23 5.30 67.20

± ± ± ± ± ±

9.28 9.14 50 10.80 4.36 28.72

N/A N/A N/A 28.20 ± 4.97 270.50 ± 36.75 3.84 ± 3.00 0.50 0.85 0.15 0.60 0.20 2.30

± ± ± ± ± ±

0.76 2.06 0.49 1.60 0.52 4.44

196.50 287.50 246.50 9.50 1.50 68.50 10.00 50.00 1.00

0.04* 0.80 0.29 0.000*** 0.000*** 0.000*** 0.000*** 0.000*** 0.000***

Values are means ± SD. Abbreviations used: AB —Aberrant Behavior Cheklist; Cp—ceruloplasmin; Tf—transferrin; SOD—superoxide dismutase. * P < 0.05, *** P < 0.001: significant differences in the 30 individuals with ASD as compared to in the 20 controls using Mann–Whitney-U test.

2.4.2. Plasma levels of PUFAs The composition of 22 fatty acids was determined as previously described [39]. After transmethylation with HCl-methanol, the PUFA composition was analyzed using gas chromatography (GC2010 Shimadzu Co., Japan). 2.4.3. Plasma levels of Cp A Bering BN IINephelometer (Siemens Healthcare Diagnostics K.K., USA) was used to estimate the plasma CP levels. 2.4.4. Plasma levels of SOD Human plasma was assayed using an SOD assay kit (Takara Bio, Tokyo) according to the cytochrome c method. 2.4.5. Plasma levels of Tf A standard turbidimetric assay and an automated biochemical analyzer (JCA-BM8000 series, JEOL Ltd., Tokyo, Japan) were used to assess the plasma Tf levels. 2.5. Statistical analysis The non-parametric Mann–Whitney U test was used for multiple comparisons of the plasma data between the ASD and control groups. Spearman’s rank correlation coefficients were used to determine the correlations between the plasma data and the ABC scores. Multiple linear regression analysis was used to confirm the relationships between plasma levels of PUFAs (AA, EPA and DHA), the plasma DHA/AA and EPA/AA ratios, and other main variables (two subject groups, the three signaling biomarkers and the total ABC score). The statistical analysis was conducted using SPSS version 18.0 (Fig. 1). 3. Results 3.1. Characteristics of the subjects The mean total ABC score was 67.20 ± 28.72 (Table 1). In a previous study, the total ABC score was 60.14 for children and adolescents with moderate to severe ASD [40]. Thus, the patients in the present study exhibited moderate to severe ASD symptoms. The IQ score in the ASD group showed a normal distribution

(range, 75–150; average score, 99.7 ± 18.2). The IQ score in highfunctioning ASD and individuals with Asperger’s disorder ranged from 76.3–120.29 and 110–119, respectively [41]. Thus, those individuals with the IQs of the ASD group might be diagnosed as high-functioning ASD. All of the ABC subscales and total scores were significantly higher in individuals with ASD compared with the control group (Table 1). 3.2. Assessment of nutrient intake There were no significant differences between the random subsamples of the two groups in the intake of essential fatty acids, such as ␣-linolenic acid (18:3␻-3) (P = 0.37), linoleic acid (18:2␻6) (P = 0.63), and omega-3 (P = 0.37) and omega-6 PUFAs (P = 0.07), AA (p = 0.18), EPA (P = 0.53), DHA (P = 0.73), iron (P = 0.23), copper (P = 0.95), and other nutrients (cholesterol, proteins, carbohydrates, fats, animal fats, saturated and unsaturated fatty acids, vitamin D, Vitamin B12, and folate). There was no significant correlation between nutrient intake and the plasma levels of PUFA variables in the random subsamples of 16 individuals with ASD (r = 0.04–0.66, P = 0.192–0.938). 3.3. Plasma levels of PUFAs and biomarkers Compared with the 20 normal controls, the plasma levels of EPA and plasma DHA/AA and EPA/AA ratios were significantly higher in the 30 individuals with ASD, while the plasma levels of AA, adrenic acid, 5,8,11,14-eicosatetraenoic acid and Cp were significantly lower (Table 2). The plasma AA and EPA levels and plasma ratios of DHA/AA and EPA/AA were significantly correlated with three of the five ABC subscale and total scores (all r values were greater than 0.29, P < 0.05, P < 0.01 or P < 0.001) for the entire population. Multiple linear regression analysis demonstrated that the plasma EPA/AA ratio (R2 = 0.331, P = 0.003) and plasma AA levels (R2 = 0.292, P = 0.008) were significantly associated with adjustments in the variables, signaling biomarkers and total ABC scores in the two subject groups. Using group as a dependent variable, we observed a significant contribution to the plasma AA levels (unstandardized coefficients, ˇ = 0.575 and P = 0.020). Thus, the plasma EPA/AA ratio and plasma AA levels are adequate parameters to distinguish the two groups.

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Fig. 1. Mean of measured plasma DHA/AA ratio and plasma levels of AA and Cp in the 30 individuals with ASD and the 20 normal control. Mean value for each group as designed by a line (left, ASD group; right, control group). Data on Cp in the control group were similar values and most of the total ABC score in the control groups were zero or very small values, and thus scatter plots lied one on another, and thus appeared to be decreased the number of cases. For drawing figure, we used Statistical Analysis System (SAS) software version 9.3 was used (SAS Institute Inc., Cary, NC, USA). Abbreviations used: ABC—Aberrant Behavior Checklist; DHA—docosahesaenoic acid; AA—arachidonic acid; Cp—ceruloplasmin.

4. Discussion The estimated range of gender differences in ASD have been reported as 2:1–7.1 [42]. The estimates of ASD individuals with severe intellectual disability versus high-functioning ASD range from 2:1 [43]–2.3:1 [44]. As the AD group was diagnosed with high-functioning ASD, the gender difference of 2:1 might reflect the high-functioning IQ levels. There were no significant differences in the assessment of the daily nutrient intake between random subsamples of the two groups. There was no significant correlation between the nutrient intake and plasma levels of PUFA variables in random subsamples of 16 individuals with ASD. Thus, the altered composition of fatty acids observed in the present study might not reflect nutrient intake. Plasma PUFA levels reflect changes in brain PUFAS levels [45]. 5,8,11,14-eicosatetraenoic acid is a new arachidonate metabolite [46] (Bednar). AA serves as a major precursor for adrenic acid [47], and reduced plasma adrenic acid levels might therefore reflect low plasma AA levels. Collectively, the levels of plasma AA and associated metabolites were significantly reduced in the ASD group compared with the control group, likely reflecting decreased AA biosynthesis. The decreased biosynthesis of AA might depend on transcriptional factors [48]. Notably, in the metabolism of EPA and DHA, there is limited conversion of EPA to DHA [49], potentially

reflecting no significant difference in plasma DHA between the two groups. The plasma AA and plasma DHA/AA ratio were significantly correlated with three of the five ABC subscales and total scores. Notably, multiple linear regression analysis revealed that the plasma EPA/AA ratio and plasma AA levels were adequate to distinguish the two groups. Collectively, the reduced plasma levels of AA and associated metabolites might lead to the downregulation of Cp. Cp has neuroprotective properties [18] and is involved in the etiologies of several neurological diseases [50]. Thus, reduced plasma Cp levels might contribute to the pathophysiology of the behavioral symptoms observed in the 30 individuals with ASD. Previous studies have shown altered PUFA compositions in autistic children aged 3–17 years old [6,7,51]. In the present study, a competitive interaction was observed in ASD individuals with an average age of 13.6 years. At higher ages, omega-3 PUFAs protect against neurodegeneration [52]. Therefore, the difference in the results between these two studies might reflect an age-dependent PUFA metabolic mechanism. In this study, the concentrations of eicosanoid family members (e.g., cleukotriene [53]) were not measured. Further studies should measure plasma levels of PUFA-related eicosanoid family members such as prosdtaglandin E2 [54] (Chen) or 18 eicosanoids (Rago) [55]. In conclusion, the present study revealed that the reduced levels of plasma AA and associated metabolites and high plasma EPA/AA

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Table 2 Plasma levels of fatty acid profiles of the 30 individuals with ASD and the 20 normal controls. Parameters Plasma PUFA levels (␮g/ml) Omega-3 series C18:3␻3 (ALA) C20:5␻3 (EPA) C22:5␻3 (DPA) C22:6␻3 (DHA) Omega-6 series C18:2␻6 (LA) C18:3␻6 (GLA) C20:2␻6 (DGLA) C20:2␻6 C20:4␻6 (AA) C22:4␻6 (adrenic acid) Ratios of plasma levels of PUFAs DHA/AA EPA/AA Monounsaturated fatty acids C16:1␻7 C18:1␻9 C20:1␻9 C20:3␻9 (5-8-11-14 Eicosatetraenoic acid) C22:1␻9 C24:1␻9 Saturated fatty acids C12 C14 C16 C18 (stearic acid) C20 (arachidic acid) C22 C24

Controls (n = 20)

ASD (n = 30)

18.79 30.02 12.67 89.94

± ± ± ±

11.92 20.49 5.18 31.37

706.13 7.25 36.84 4.80 139.55 4.26

± ± ± ± ± ±

145.74 4.07 35.30 1.32 37.89 0.43

0.66 ± 0.23 0.26 ± 0.17 40.63 504.17 4.02 1.71

± ± ± ±

22.67 210.91 2.22 0.87

1.58 ± 1.22 28.48 ± 5.93 3.68 22.53 572.40 7.84 7.39 17.19 14.40

± ± ± ± ± ± ±

3.58 16.45 206.68 0.49 1.93 4.52 4.69

U

p value

1 7.27 21.25 12.21 80.00

± ± ± ±

6.58 13.24 3.24 29.33

293.00 138.00 280.50 256.00

0.89 0.01* 0.70 0.38

769.02 8.72 30.09 5.07 180.08 5.80

± ± ± ± ± ±

186.69 3.92 9.55 0.89 39.89 1.75

206.00 229.00 226.50 309.00 138.00 155.00

0.06 0.16 0.15 0.84 0.01* 0.004**

0.45 ± 015 0.10 ± 0.07

116.50 85.50

0.000*** 0.000***

± ± ± ±

222.00 221.00 273.50 191.00

0.12 0.12 0.60 0.03*

270.00 234.50

0.53 0.20

292.00 256.50 221.00 240.50 295.50 263.50 274.50

0.87 0.39 0.12 0.24 0.93 0.47 0.61

45.66 538.12 3.76 2.26

17.55 190.62 0.95 0.87

1.38 ± 0.91 30.54 ± 6.14 4.33 22.16 607.94 7.48 7.10 17.78 15.29

± ± ± ± ± ± ±

7.23 9.83 130.21 0.55 1.23 3.57 3.08

Values are mean ± SD ␮g/ml. * P < 0.05. ** P < 0.01, *** P < 0.001, significant differences in the 30 individuals with ASD as compared to in the 20 controls using Mann–Whitney-U test.

ratios might down-regulate plasma Cp levels, thereby reducing the protective capacity of the brain against damage. Although there are likely many other factors and steps between Cp and behavioral symptoms in the 30 individuals with ASD, these findings could be associated with the pathophysiology of the behavioral symptoms observed in individuals with ASD. From a clinical perspective, it is plausible that the reduced AA revels or increased plasma EPA/AA ratio might be risk factors for the development of behavioral symptoms in young individuals with ASD. Conflict of interest The authors declare that they have no conflicts of interests. Acknowledgments The authors would like to thank Professor Kenji Hashimoto (Division of Clinical Neuroscience, Center for Forensic Mental Health, Chiba University, Japan). Kunio Yui received a Grantin-Aid for Scientific Research on Innovative Areas (Grant no. 21200017) (2010–2012) and a Grant-in-Aid for Scientific Research (C) (2014–2016) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. References [1] C. Wong, D.A. Crawford, Lipid signaling in the pathology of autism spectrum disorders, in: V.B. Patel, V.R. Preedy, C.R. Martin (Eds.), Comprehensive Guide to Autism, Springer Publishing, New York (USA), 2014, pp. 1259–1283.

[2] D. Holowka, K. Korzeniowski, K.L. Bryant, B. Baird, Polyunsaturated fatty acids inhibit stimulated coupling between the ER Ca2+ sensor STIM1 and the Ca2+ channel protein Orai1 in a process that correlates with inhibition of stimulated STIM1 oligomerization, Biochim. Biophys. 1841 (2014) 1210–1216. [3] J. Tamiji, D.A. Crawford, The neurobiology of lipid metabolism in autism spectrum disorders, Neurosignals 18 (2010) 98–112. [4] G. Hawcroft, P.M. Loadman, A. Belluzzi, M.A. Hull, Effect of eicosapentaenoic acid on E-type prostaglandin synthesis and EP4 receptor signaling in human colorectal cancer cells, Neoplasia (2010) 618–627. [5] K. Gharami, M. Das, S. Das, Essential role of docosahexaenoic acid towards development of a smarter brain, Neurochem. Int. (2015), http://dx.doi.org/10. 1016/j.neuint.2015.08.014, S0197-0186(15) 30041-3. [6] S. Vancassel, G. Durand, C. Barthélémy, B. Lejeune, J. Martineau, D. Guilloteau, C. Andrès, S. Chalon, Plasma fatty acid levels in autistic children, Prostaglandins Leukot. Essent. Fatty Acids 65 (2001) 1–7. [7] A.K. El-Ansary, A.G. Bacha, L.Y. Al-Ayahdi, Impaired plasma phospholipids and relative amounts of essential polyunsaturated fatty acids in autistic patients from Saudi Arabia, Lipids Health Dis. (2011) http://www.ncbi.nlm.nihgov/ pmc/articles/PMC3107801/. [8] S.A. Brigandi, H. Shao, S.Y. Qian, Y. Shen, B.L. Wu, Kang: Autistic children exhibit decreased levels of essential fatty acids in red blood cells, Int. J. Mol. Sci. 16 (2015) 10061–10076. [9] R.S. Luxwolda, E.N. Smit, F.V. Velzing-Aarts, D.A. Dijck-Brouwer, F.A. Muskiet, The relation between the omega-3 index and arachidonic acid is bell shaped: synergistic at low EPA+DHA status and antagonistic at high EPA+DHA status, Prostaglandins Leukot. Essent. Fatty Acids 8 (2011) 171–178. [10] A.Y. Taha, Y. Cheon, K.F. Faurot, B. Macintosh, S.F. Majchrzak-Hong, J.D. Mann, J.R. Hibbeln, A. Ringel, C.E. Ramsden, Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools, Prostaglandins Leukot. Essent. Fatty Acids 90 (2014) 151–157. [11] O. Obajimi, K.D. Black, D.J. MacDonald, R.M. Boyle, I. Glen, B.M. Ross, Differential effects of eicosapentaenoic and docosahexaenoic acids upon oxidant-stimulated release and uptake of arachidonic acid in human lymphoma U937 cells, Pharmacol. Res. 52 (2005) 183–191. [12] K. Morbtaten, T.M. Haug, C.R. Kleiveland, T. Lea, Omega-3 and omega-6 PUFAs induce the same GPR120-mediated signaling events, but with different kinetics and intensity in Caco-2 cells, Lipids Health Dis. 12 (2013) 101.

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[13] C.P. Calder, Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale, Biochimie 91 (2009) 791–795. [14] A. Sidhu, P.J. Miller, A.D. Hollenbach, FOXO1 stimulates ceruloplasmin promoter activity in human hepatoma cells treated with IL-6, Biochem. Biophys. Res. Commun. 404 (2011) 963–967. [15] C.K. Tsang, Y. Liu, J. Thoma, Y. Zhang, X.F. Zheng, Superoxide dismutase 1 acts as a nuclear transcription factor to regulate oxidative stress resistance, Nat. Commun. 5 (2014) 3446. [16] J. Jian, Q. Yang, X. Huang, Src regulates Tyr (20) phosphorylation of transferrin receptor-1 and potentiates breast cancer cell survival, J. Biol. Chem. 286 (2011) 35708–35715. [17] M. Barbariga, F. Curnis, A. Spitaleri, A. Andolfo, C. Zucchell, M. Lazzaro, G. Magnani, G. Musco, A. Corti, M. Alessio, Oxidation-induced structural changes of ceruloplasmin foster NGR motif deamidation that promotes integrin binding and signaling, J. Biol. Chem. 289 (2014) 3736–3748. [18] S. Ayton, M. Zhang, B.R. Roberts, L.Q. Lam, M. Lind, C. McLean, A.I. Bush, T. Frugier, P.J. Crack, J.A. Duce, Ceruloplasmin and ␤-amyloid precursor protein confer neuroprotection in traumatic brain injury and lower neuronal iron, Free Radic. Biol. Med. 69 (2014) 331–337. [19] A.V. Sokov, E.A. Golenkina, V.A. Kostevich, V.B. Vasilyev, G.F. Sud’ina: interaction of ceruloplasmin and 5-lipoxygenase, Biochemistry (Mosc.) 75 (2010) 1464–1469. [20] K.H. Lee, S.J. Yun, K.N. Nam, Y.S. Gho, E.H. Lee, Activation of microglial cells by ceruloplasmin, Brain Res. 1171 (2007) 1–8. [21] E.R. Pacht, S.J. DeMichele, J.L. Nelson, J. Hart, A.K. Wennberg, J.E. Gadek, Enteral nutrition with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants reduces alveolar inflammatory mediators and protein influx in patients with acute respiratory distress syndrome, Crit. Care Med. 31 (2003) 491–500. [22] T. Fukai, Superoxide dismutases: role in redox signaling, vascular function, and diseases, Antioxid. Redox Signal. 15 (2011) 1583–1606. [23] J. Du, X. Li, C. Lin, X. He, Protective effects of arachidonic acid against paraquat-induced pulmonary injury, Inflammation 38 (2015) 1458–1463. [24] H.D. Cardoso, E.F. dos Santos Junior, D.F. de Santana, C. Gonc¸alves-Pimentel, M.K. Angelim, A.R. Isaac, C.J. Lagranha, R.C. Guedes, E.I. Beltrão, E. Morya, M.C. Rodrigues, B.L. Andrade-da-Costa, Omega-3 deficiency and neurodegeneration in the substantia nigra: involvement of increased nitric oxide production and reduced BDNF expression, Biochim. Biophys. Acta 840 (2014) 1902–1912. [25] S. Kasibhatla, K.A. Jessen, S. Maliartchouk, J.Y. Wang, N.M. English, J. Drewe, L. Qiu, S.P. Archer, A.E. Ponce, N. Sirisoma, S. Jiang, H.Z. Zhang, S.X. Cai, K.R. Gehlsen, D.R. Green, B. Tseng, A role for transferrin receptor in triggering apoptosis when targeted with gambogic acid, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 12095–12100. [26] E. Schonfeld, I. Yasharel, E. Yavin, A. Brand, Docosahexaenoic acid enhances iron uptake by modulating iron transporters and accelerates apoptotic death in PC12 cells, Neurochem. Res. 2 (2007) 1673–1684. [27] N.A. Meguid, A.A. Dardir, E.R. Abdel-Raouf, A. Hashish, Evaluation of oxidative stress in autism: defective antioxidant enzymes and increased lipid peroxidation, Biol. Trace Elem. Res. 143 (2011) 58–65. [28] M. Parellada, C. Moreno, K. Mac-Dowell, L.C. Leza, M. Giraldez, C. Bailón, C. Castro, P. Miranda-Azpiazu, D. Fraguas, C. Arango, Plasma antioxidant capacity is reduced in Asperger syndrome, J. Psychiatr. Res. 46 (2012) 394–401. [29] A. Chauhan, V. Chauhan, W.T. Brown, L. Cohen, Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin-the antioxidant proteins, Life Sci. 75 (2004) 2539–2549. [30] A.N. Hata, R.M. Breyer, Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation, Pharmacol. Ther. 103 (2004) 147–166. [31] M. Rutter, A. Le Couteur, C. Lord, ADI-R Autism Diagnostic Interview Revised Manual, Western Psychological Services, Los Angeles, 2003. [32] D. Wechsler, Wechsler Intelligence Scale for Children-Revised Manual. The Psychological Corporation, New York, NY, 1974. [33] D. Wechsler, Wechsler Adult Intelligence Scale-Revised Manual. The Psychological Corporation, San Antonio, TX, 1981. [34] T. Koyama, Y. Kamio, N. Inada, H. Kurita, Sex differences in WISC-III profiles of children with high-functioning pervasive developmental disorders, J. Autism Dev. Disord. 39 (2009) 135–141. [35] Ministry of Health, Labour and Welfare, and Ministry of Agriculture, Forestry and Fishers, Japanese Food Guide. Ministry of Health, Labour and Welfare, and Ministry of Agriculture, Forestry and Fishers, Tokyo, 2012. [36] M. Okuda, S. Sasaki, N. Bando, M. Hashimoto, I. Kunitsugu, S. Sugiyama, J. Terao, T. Hobara, Carotenoid, tocopherol, and fatty acid biomarkers and

[37]

[38] [39]

[40]

[41]

[42]

[43]

[44] [45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

dietary intake estimated by using a brief self-administered diet history questionnaire for older Japanese children and adolescents, Nutr. Sci. Vitaminol. 5 (2009) 231–241. E. Hollander, W. Chaplin, L. Soorya, S. Wasserman, S. Novotny, J. Rusoff, N. Feirsen, L. Pepa, E. Anagnostou, Divalproex sodium vs. placebo for the treatment of irritability in children and adolescents with autism spectrum disorders, Neuropsychopharmacology 35 (2009) 990–998. K. Karabekiroglu, M.G. Aman, Validity of the aberrant behavior checklist in a clinical sample of toddlers, Child Psychiatry Hum. Dev. 40 (2009) 99–110. H. Hamazaki, M. Itomura, T. Hamazaki, S. Sawazaki, Effects of cooking plant oils on recurrent aphthous stomatitis: a randomized, placebo-controlled, double-blind trial, Nutrition 22 (2006) 534–536. K. Singh, S.L. Connors, E.A. Macklin, K.D. Smith, J.W. Fahey, P. Talalay, A.W. Zimmerman, Sulforaphane treatment of autism disorder (ASD), Pro.c Natl. Acad. Sci. U. S. A. 111 (2014) 15550–15555. H.M. Chiang, L.Y. Tsai, Y.K. Cheung, A. Brown, H.A. Li, A meta-analysis of differences in IQ profiles between individuals with Asperger’s disorder and high-functioning autism, J. Autism Dev. Disord. 44 (2014) (2014) 1577–1596. A.K. Halladay, S. Bishop, J.N. Constantino, A.M. Daniels, K. Koenig, K. Palmer, D. Messinger, K. Pelphrey, S.J. Sanders, A.T. Singer, J.L. Taylor, P. Szatmari, Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority, Mol. Autism 6 (2015) 36, http://dx.doi.org/10.1186/s13229-015-0019-y. S.E. Bryson, E.A. Bradley, A. Thompson, A. Wainwright, Prevalence of autism among adolescents with intellectual disabilities, Can. J. Psychiatry 53 (2008) 449–459. D.M. Werling, D.H. Geschwind, Sex differences in autism spectrum disorders, Curr. Opin. Neurol. 26 (2013) 146–153. M.E. Sublette, F. Bosetti, J.C. DeMar, K. Ma, J.M. Bell, S. Fagin-Jones, M.J. Russ, S.I. Rapoport, Plasma free polyunsaturated fatty acid levels are associated with symptom severity in acute mania, Bipolar Disord. 9 (2007) 759–765. M.M. Bednar, C.E. Gross, M.K. Balazy, Y. Belosludtsev, D.T. Colella, J.R. Falck, M. Balazy, 16(R)-hydroxy-5,8,11,14-eicosatetraenoic acid, a new arachidonate metabolite in human polymorphonuclear leukocytes, Biochem. Pharmacol. 60 (2000) 447–455. P.G. Kopf, D.X. Zhang, K.M. Gauthier, K. Nithipatikom, X.Y. Yi, J.R. Falck, W.B. Campbell, Adrenic acid metabolites as endogenous endothelium-derived and zona glomerulosa-derived hyperpolarizing factors, Hypertension 55 (2010) 547–554. A.C. Seegmiller, Abnormal unsaturated fatty acid metabolism in cystic fibrosis: biochemical mechanisms and clinical implications, Int. J. Mol. Sci. 15 (2014) 16083–16099. K.M. LinderborgG. Kaur, E. Miller, P.J. Meikle, A.E. Larsen, J.M. Weir, A. Nuora, C.K. Barlow, H.P. Kallio, D. Cameron-Smith, A.J. Sinclair, Postprandial metabolism of docosapentaenoic acid (DPA, 22:5n-3) and eicosapentaenoic acid (EPA, 20:5n-3) in humans, Prostaglandins. Leukot. Essent. Fatty Acids 88 (2013) 313–319. R. Squitti, R. Ghidoni, M. Siott, M. Ventriglia, L. Benussi, A. Paterlini, M. Magri, G. Binetti, E. Cassetta, D. Caprara, F. Vernieri, P.M. Rossini, P Pasqualetti: value of serum nonceruloplasmin copper for prediction of mild cognitive impairment conversion to Alzheimer disease, Ann. Neurol. 75 (2014) 574–580. A.K. El-Ansary, A.G. Bacha, L.Y. Al-Ayahdi, Plasma fatty acids as diagnostic markers in autistic patients from Saudi Arabia, Lipids Health Dis. 10 (2011) 62, http://dx.doi.org/10.1186/1476-511X-10-62. J.E. Karr, J.E. Alexander, R.G. Winningham, Omega-3 polyunsaturated fatty acids and cognition throughout the lifespan: a review, Nutr. Neurosci. 14 (2011) 216–225. S. Adel, K.R. Kakularam, T. Horn, P. Reddanna, H. Kuhn, D. Heydeck, Leukotriene signaling in the extinct human subspecies Homo denisovan and Homo neanderthalensis. Structural and functional comparison with Homo sapiens, Arch. Biochem. Biophys. 565 (2015) 17–24. J.H. Chen, C.J. Perry, Y.C. Tsui, M.M. Staron, I.A. Parish, C.X. Dominguez, D.W. Rosenberg, S.M. Kaech, Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection, Nat. Med. 21 (2015) 327–334. B. Rago, C. Fu, Development of a high-throughput ultra performance liquid chromatography-mass spectrometry assay to profile 18 eicosanoids as exploratory biomarkers for atherosclerotic diseases, J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 936 (2013) 25–32.