Saki Kakutani

Chymase Participates in Chronic Dermatitis by Inducing Eosinophil Infiltration

An epicutaneous application of 2,4-dinitrofluorobenzene (DNFB) to a mouse ear caused a transient skin swelling, and the repetition of the challenge enlarged the contact dermatitis. The repeated challenge with DNFB also induced eosinophil infiltration on the application site. Administration of a chymase inhibitor significantly inhibited the ear swelling as well as eosinophil accumulation. An intradermal injection of human chymase to the mouse ear also elicited transient skin swelling and eosinophil infiltration, both of which were augmented in proportion to the number of injections. Human serum albumin and heat-inactivated chymase failed to induce such skin reactions, suggesting the participation of proteolytic activity of the enzyme. In addition, chymase stimulated eosinophil migration in vitro in a concentration-dependent manner. Taken together, these observations suggest that mast cell chymase may contribute to development of the DNFB-induced dermatitis, probably by promoting eosinophil infiltration. It is therefore possible that chymase plays a role in pathogenesis of chronic dermatitis such as atopic dermatitis.

Supplementation of arachidonic acid-enriched oil increases arachidonic acid contents in plasma phospholipids, but does not increase their metabolites and clinical parameters in Japanese healthy elderly individuals: a randomized controlled study

BackgroundThe importance of arachidonic acid (ARA) among the elderly has recently gained increased attention. The effects of ARA supplementation in the elderly are not fully understood, although ARA is considered to be associated with various diseases. We investigate whether ARA supplementation to Japanese elderly subjects affects clinical parameters involved in cardiovascular, inflammatory, and allergic diseases. We also examine the levels of ARA metabolites such as prostanoids during intervention.MethodsWe conducted a randomized, double-blind and placebo-controlled parallel group intervention trial. ARA-enriched oil (240 or 720 mg ARA per day) or placebo was administered to Japanese healthy men and women aged 55-70 years for 4 weeks followed by a 4-week washout period. The fatty acid contents of plasma phospholipids, clinical parameters, and ARA metabolites were determined at baseline, 2, 4, and 8 weeks.ResultsThe ARA content in plasma phospholipids in the ARA-administrated groups increased dose-dependently and was almost the same at 2 weeks and at 4 weeks. The elevated ARA content decreased to nearly baseline during a 4-week washout period. During the supplementation and washout periods, no changes were observed in eicosapentaenoic acid and docosahexaenoic acid contents. There were no changes in clinical blood parameters related to cardiovascular, inflammatory and allergic diseases. ARA supplementation did not alter the level of ARA metabolites such as urinary 11-dehydro thromboxane B2, 2,3-dinor-6-keto prostaglandin (PG) F1α and 9,15-dioxo-11α-hydroxy-13,14-dihydro-2,3,4,5-tetranor-prostan-1,20-dioic acid (tetranor-PGEM), and plasma PGE2 and lipoxin A4. ARA in plasma phospholipids was not correlated with ARA metabolite levels in the blood or urine.ConclusionThese results indicate that ARA supplementation, even at a relatively high dose, does not increase ARA metabolites, and suggest that it does not induce cardiovascular, inflammatory or allergic diseases in Japanese elderly individuals.

Role of mast cell chymase in allergen-induced biphasic skin reaction

Intradermal injection of human chymase (EC 3.4.21.39) into the mouse ear elicited an edematous skin reaction in a biphasic manner, with a transient reaction peaking at 1 hr, followed by a delayed response persisting for at least 24hr. The kinetics of this reaction was analogous to the biphasic skin reaction induced by ascaris extract in actively sensitized mice. A similarity between the two dermatitis models was also shown by histological analysis, i.e. accumulation of inflammatory cells was observed exclusively in the later phases of the skin reaction. A chymase inhibitor, SUN-C8077 [3-(3-aminophenylsulfonyl)-7-chloroquinazorine 2,4(1H, 3H)-dione], significantly inhibited both the early- and late-phase responses of the skin reaction induced by ascaris extract. These findings suggest that chymase may play an important role in the allergen-induced biphasic skin reaction. A histamine receptor antagonist, homochlorcyclizine, inhibited the early-phase but not the late-phase of the chymase-induced skin reaction. In addition, human chymase showed chemotactic activity to human polymorphonuclear leukocytes in vitro. Mast cell chymase may participate in the two phases of allergic skin inflammation by two distinct mechanisms, i.e. histamine- and leukocyte-dependent mechanisms, respectively.

Arachidonic acid and cancer risk: a systematic review of observational studies

BackgroundAn n-6 essential fatty acid, arachidonic acid (ARA) is converted into prostaglandin E2, which is involved in tumour extension. However, it is unclear whether dietary ARA intake leads to cancer in humans. We thus systematically evaluated available observational studies on the relationship between ARA exposure and the risk of colorectal, skin, breast, prostate, lung, and stomach cancers.MethodsWe searched the PubMed database for articles published up to May 17, 2010. 126 potentially relevant articles from the initial search and 49,670 bibliographies were scrutinised to identify eligible publications by using predefined inclusion criteria. A comprehensive literature search yielded 52 eligible articles, and their reporting quality and methodological quality was assessed. Information on the strength of the association between ARA exposure and cancer risk, the dose-response relationship, and methodological limitations was collected and evaluated with respect to consistency and study design.ResultsFor colorectal, skin, breast, and prostate cancer, 17, 3, 18, and 16 studies, respectively, were identified. We could not obtain eligible reports for lung and stomach cancer. Studies used cohort (n = 4), nested case-control (n = 12), case-control (n = 26), and cross-sectional (n = 12) designs. The number of subjects (n = 15 - 88,795), ARA exposure assessment method (dietary intake or biomarker), cancer diagnosis and patient recruitment procedure (histological diagnosis, cancer registries, or self-reported information) varied among studies. The relationship between ARA exposure and colorectal cancer was inconsistent based on ARA exposure assessment methodology (dietary intake or biomarker). Conversely, there was no strong positive association or dose-response relationship for breast or prostate cancer. There were limited numbers of studies on skin cancer to draw any conclusions from the results.ConclusionsThe available epidemiologic evidence is weak because of the limited number of studies and their methodological limitations, but nonetheless, the results suggest that ARA exposure is not associated with increased breast and prostate cancer risk. Further evidence from well-designed observational studies is required to confirm or refute the association between ARA exposure and risk of cancer.

Dihomo-γ-linolenic acid prevents the development of atopic dermatitis through prostaglandin D1 production in NC/Tnd mice

BACKGROUND Atopic dermatitis (AD) is a chronic and relapsing skin disorder with pruritic skin symptoms. We previously reported that dihomo-γ-linolenic acid (DGLA) prevented the development of AD in NC/Tnd mice, though the mechanism remained unclear. OBJECTIVE We attempted to investigate the mechanism of preventive effect of DGLA on AD development in NC/Tnd mice. METHODS The clinical outcomes of NC/Tnd mice that were given diets containing DGLA, arachidonic acid, or eicosapentaenoic acid were compared. Lipid mediator contents in the skin in each group were also quantified. In addition, release of lipid mediators from RBL-2H3 mast cells treated with either DGLA or prostaglandin D1 (PGD1) was measured. Furthermore, effect of PGD1 on gene expression of thymic stromal lymphopoietin (TSLP) in PAM212 keratinocyte cells was determined. RESULTS Only DGLA containing diet suppressed the development of dermatitis in vivo. By quantifying the 20-carbon fatty acid-derived eicosanoids in the skin, the application of DGLA was found to upregulate PGD1, which correlated with a better outcome in NC/Tnd mice. Moreover, we confirmed that mast cells produced PGD1 after DGLA exposure, thereby exerting a suppressive effect on immunoglobulin E-mediated degranulation. PGD1 also suppressed gene expression of TSLP in keratinocytes. CONCLUSION These results suggest that oral administration of DGLA causes preventive effects on AD development in NC/Tnd mice by regulating the PGD1 supply.

Oral Supplementation with Dihomo-γ-linolenic Acid-Enriched Oil Altered Serum Fatty Acids in Healthy Men

Dihomo-gamma-linolenic acid (DGLA)-enriched oil (50 or 150 mg as free DGLA) was administered to healthy men for 4 weeks. The DGLA content in serum phospholipids dose-dependently increased and returned to the initial level after a 4-week washout. No side effects or changes in platelet aggregation were observed. These results indicate that oral supplementation with DGLA oil can safely increase serum DGLA content.

Uptake of dihomo-γ-linolenic acid by murine macrophages increases series-1 prostaglandin release following lipopolysaccharide treatment

Administration of dihomo-gamma-linolenic acid is useful for atopic dermatitis and atherosclerosis in mice; however, the metabolites of dihomo-gamma-linolenic acid have been little studied. We employed a method which enabled simultaneous analysis of nine prostaglandins using liquid chromatography-tandem mass spectrometry, and determined the concentrations of prostaglandins in the supernatants of cultures of mouse peritoneal macrophages stimulated with lipopolysaccharide after pre-incubation with dihomo-gamma-linolenic acid, arachidonic acid, or eicosapentaenoic acid. Accumulated prostaglandin concentrations from mouse macrophages with dihomo-gamma-linolenic acid uptake increased in a dihomo-gamma-linolenic acid concentration-dependent fashion. These increases were mainly due to prostaglandin D(1) and prostaglandin E(1). The order of accumulated prostaglandin concentrations was dihomo-gamma-linolenic acid>arachidonic acid>eicosapentaenoic acid in supernatants with the same concentration of polyunsaturated fatty acid. Since mouse macrophages can clearly produce series-1 prostaglandins, they must be formed in vivo. These findings suggest that the effects of dihomo-gamma-linolenic acid on diseases may be due to series-1 prostaglandins.

Cross-sectional association between serum concentrations of n-3 long-chain PUFA and depressive symptoms: results in Japanese community dwellers.

The effect of n-3 long-chain PUFA (n-3 LCPUFA) on depression in healthy subjects is unclear, and most of the previous studies have focused on populations eating Western diets with lower fish intake. The present study investigated the association between blood levels of n-3 LCPUFA and depressive symptoms in Japanese community dwellers with higher n-3 LCPUFA blood levels. A cross-sectional study was conducted from 2006 to 2008, including 1050 men and 1073 women aged 40 years or older from the National Institute for Longevity Sciences – the Longitudinal Study of Aging. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms. Multiple logistic regression analysis was performed to estimate the OR and 95 % CI for a CES-D score ≥16. Serum concentrations of n-3 PUFA, but not n-6 PUFA, were inversely associated with depressive symptoms. Compared with the lowest quintile, the adjusted OR for serum EPA at the fourth and fifth quintiles were 0·55 (95 % CI 0·35, 0·85) and 0·64 (95 % CI 0·42, 0·98), respectively, and at the fifth quintile for DHA it was 0·58 (95 % CI 0·37, 0·92), for the presence of depressive symptoms (P for trend=0·013 and 0·011, respectively). Serum levels of EPA and DHA were inversely associated with depressive symptoms in Japanese community dwellers with higher blood levels of n-3 LCPUFA, suggesting that n-3 LCPUFA intakes corresponding to higher levels in a Japanese population may have implications for a lower prevalence of depression.

Arachidonic Acid and Cerebral Ischemia Risk: A Systematic Review of Observational Studies

Background: Arachidonic acid (ARA) is a precursor of various lipid mediators. ARA metabolites such as thromboxane A2 cause platelet aggregation and vasoconstriction, thus may lead to atherosclerotic disease. It is unclear whether dietary ARA influences the ARA-derived lipid mediator balance and the risk for atherosclerotic diseases, such as cerebral ischemia. Considering the function of ARA in atherosclerosis, it is reasonable to focus on the atherothrombotic type of cerebral ischemia risk. However, no systematic reviews or meta-analyses have been conducted to evaluate the effect of habitual ARA exposure on cerebral ischemia risk. We aimed to systematically evaluate observational studies available on the relationship between ARA exposure and the atherothrombotic type of cerebral ischemia risk in free-living populations. Summary: The PubMed database was searched for articles registered up to June 24, 2014. We designed a PubMed search formula as follows: key words for humans AND brain ischemia AND study designs AND ARA exposure. Thirty-three articles were reviewed against predefined criteria. There were 695 bibliographies assessed from the articles that included both ARA and cerebral ischemia descriptions. Finally, we identified 11 eligible articles and categorized them according to their reporting and methodological quality. We used the Strengthening the Reporting of Observational Studies in Epidemiology Statement (STROBE) checklist to score the reporting quality. The methodological quality was qualitatively assessed based on the following aspects: subject selection, ARA exposure assessment, outcome diagnosis, methods for controlling confounders, and statistical analysis. We did not conduct a meta-analysis due to the heterogeneity among the studies. All eligible studies measured blood ARA levels as an indicator of exposure. Our literature search did not identify any articles that evaluated dietary ARA intake and tissue ARA as assessments of exposure. Seven of the 11 eligible articles were considered to be of low quality. No articles reported a dose-dependent positive association between an increased cerebral ischemia risk and ARA exposure. However, most studies did not assess the risk in each subtype of cerebral ischemia, thus various etiological types of cerebral ischemia risk were involved in their results. Key Messages: We did not find a positive association between ARA exposure and cerebral ischemia risk. Eligible studies reported inconsistent findings: cerebral ischemia risk did not change or significantly decreased. We could not draw any conclusions due to the limited number of eligible high-quality studies. Further evidence from well-designed observational studies is required. Simultaneously, in order to develop effective preventive measures against cerebral ischemia, it is imperative to establish standardized definitions, nomenclatures, classifications, and diagnostic procedures.

Arachidonic acid intake and asthma risk in children and adults: a systematic review of observational studies

The effect of arachidonic acid (ARA) intake on asthma risk is unclear. The objective of the present review was to systematically evaluate available observational studies on the relationship between ARA exposure and asthma risk in children and adults. A PubMed search was conducted on 22 October 2013 and seventy-three publications were checked against predefined criteria for eligibility. To identify additional eligible publications, potentially relevant articles were searched from bibliographies of articles on ARA and asthma. A total of 2924 citations were scrutinised. Finally, fourteen articles were included. A quality assessment was conducted based on the reporting and methodological quality. A meta-analysis was not conducted; therefore, a qualitative assessment is presented. Three high-, two medium- and ten low-quality studies were reviewed. Eleven studies, including two high- and two medium-quality studies, did not find a significant association between ARA exposure and asthma risk. In contrast, one high-quality study indicated a significant trend toward reducing asthma risk in children with decreasing maternal ARA intake (Ptrend = 0·025), and one low-quality study reported a significant trend of increasing asthma risk with higher blood ARA levels (Ptrend = 0·007). In two low-quality studies, asthma patients had significantly lower blood ARA levels than controls (both P < 0·05). These studies did not sufficiently demonstrate any relationships between ARA exposure and asthma risk because of the limited number of studies and their methodological limitations. They seem to suggest that ARA exposure is not consistently associated with asthma risk. Nevertheless, further evidence is required to prove or disprove the association.