Mechanism of pathogenesis of Jingfang Mixture in intervention of chronic spontaneous urticaria based on serum metabolomics / 中国中药杂志

This study aims to clarify the effect of Jingfang Mixture on the treatment of chronic urticarial and its mechanism, and investigate the regulatory effect of chronic urticaria on the metabolic disorder of endogenous metabolites in the blood. The mice were randomly divided into normal group, model group, and Jingfang Mixture group, and modeling and administration continued for 21 d. The changes in endogenous small molecules in rat serum were determined by ultra-high performance liquid chromatography-electrospray ionization-Q Exactive-Orbitrap-mass spectrometry(UHPLC-ESI-QE-Orbitrap-MS) metabolomics technology. The change trend of endogenous metabolites in rat serum was analyzed to find potential biomarkers. The results showed that Jingfang Mixture regulate 16 biomarkers, mainly including taurine, glutamate, succinic acid, docosahexaenoic acid, and arachidonic acid. Metabolic pathway analysis was carried out by MetaboAnalyst, and P<0.01 was taken as the potential key metabolic pathway. Ten metabolic pathways were closely related to the treatment of chronic urticarial by Jingfang Mixture, mainly involved in the glutamate metabolism, taurine and hypotaurine metabolism, arginine and proline metabolism, arachidonic acid metabolism, tricarboxylic acid cycle, unsaturated fatty acid biosynthesis, glutathione metabolism, phenylalanine metabolism, alanine, aspartic acid, and glutamate metabolism, and butyric acid metabolism. Glutamate metabolism and butyric acid metabolism involved more metabolic pathways than others. Therefore, it was speculated that Jingfang Mixture had a balanced regulating effect on the related metabolic pathways which caused the serum disorder in the rats with urticaria, and tended to regulate the metabolic differential to the normal level in the rats with urticaria. This paper provides references for studying the mechanism of Jingfang Mixture from the perspective of endogenous metabolites and metabolic pathways in vivo. At the same time, the endogenous substances explored in this paper can be used as important biomarkers for the prevention of urticaria.

Compatibility mechanism of Trichosanthis Fructus-Allii Macrostemonis Bulbus combination against atherosclerosis: based on metabolomics and network pharmacology / 中国中药杂志

This study aims to investigate the compatibility mechanism of Trichosanthis Fructus-Allii Macrostemonis Bulbus combination against atherosclerosis(AS) in apolipoprotein E-deficient(ApoE~(-/-)) mice. To be specific, high-fat diet was used to induce AS in mice. The pathological morphology of mice aorta was evaluated based on hematoxylin-eosin(HE) staining and Masson staining. The metabolic profiling of mouse serum samples was performed with ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Multiple statistical analysis methods including partial least squares-discriminant analysis and orthogonal partial least squares-discriminant analysis were employed to screen potential biomarkers in mice. With the techniques in network pharmacology, the metabolites related to AS and the targets in the metabolic pathways were screened out. The results showed that Trichosanthis Fructus alone and the pair all reduced the plaque area of aortic sinus(P<0.05) and collagen area(P<0.05). Compared with the Trichosanthis Fructus alone and Allii Macrostemonis Bulbus alone, the combination significantly decreased the plaque area of aortic sinus(P<0.05) and collagen area(P<0.05). Metabolomics revealed 16 biomarkers in mice. Trichosanthis Fructus re-gulated the abnormal levels of 4 metabolites in glycerophosphatide metabolic pathway. Allii Macrostemonis Bulbus modulated the abnormal levels of 2 metabolites in arachidonic acid metabolic pathway and the combination recovered the levels of 8 metabolites in glycerophosphatide, linoleic acid, arachidonic acid, and pyrimidine metabolic pathways. Network pharmacology suggested that Trichosanthis Fructus regulated 24 targets which related to 2 AS-associated metabolites and involved glycerophosphatide metabolic pathway. Allii Macroste-monis Bulbus modulated 40 targets which related to 2 AS-associated metabolites and involved the arachidonic acid metabolic pathway. The combination regulated 57 targets which related to 6 AS-metabolites and involved linoleic acid metabolic pathway, glycerophosphatide metabolic pathway, and arachidonic acid metabolic pathway. These results indicate that the Trichosanthis Fructus-Allii Macrostemonis Bulbus combination enhances the regulation of linoleic acid metabolism, glycerophosphatide metabolism, and arachido-nic acid metabolism, thereby synergistically alleviating lipid disorder and inflammatory response in AS mice.

Arachidonic acid metabolism in liver glucose and lipid homeostasis / 生理学报

Arachidonic acid (AA) is an ω-6 polyunsaturated fatty acid, which mainly exists in the cell membrane in the form of phospholipid. Three major enzymatic pathways including the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 monooxygenase (CYP450) pathways are involved in AA metabolism leading to the generation of a variety of lipid mediators such as prostaglandins, leukotrienes, hydroxyeicosatetraenoic acids (HETEs) and epoxyeicoastrienoic acids (EETs). These bioactive AA metabolites play an important role in the regulation of many physiological processes including the maintenance of liver glucose and lipid homeostasis. As the central metabolic organ, the liver is essential in metabolism of carbohydrates, lipids and proteins, and its dysfunction is associated with the pathogenesis of many metabolic diseases such as type 2 diabetes mellitus, dyslipidemia and nonalcoholic fatty liver disease (NAFLD). This article aims to provide an overview of the enzymatic pathways of AA and discuss the role of AA-derived lipid mediators in the regulation of hepatic glucose and lipid metabolism and their associations with the pathogenesis of major metabolic disorders.

The roles of cytochrome P450 metabolites of arachidonic acid in the regulation of vascular function / 生理学报

Arachidonic acids (AA) widely exist in multiple organs and can be metabolized into small lipid molecules with strong biological functions through several pathways. Among them, epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), which are produced by cytochrome P450 enzymes, have attracted a lot of attentions, especially in vascular homeostasis. The regulation of vascular function is the foundation of vascular homeostasis, which is mainly achieved by manipulating the vascular structure and biological function. In the past 30 years, the roles of EETs and 20-HETE in the regulation of vascular function have been widely explored. In this review, we discussed the effects of EETs and 20-HETE on angiogenesis and vascular inflammation, respectively. Generally, EETs can dilate blood vessels and inhibit vascular inflammation, while 20-HETE can induce vasoconstriction and vascular inflammation. Interestingly, both EETs and 20-HETE can promote angiogenesis. In addition, the roles of EETs and 20-HETE in several vascular diseases, such as hypertension and cardiac ischemia, were discussed. Finally, the therapeutic perspectives of EETs and 20-HETE for vascular diseases were also summarized.

Research progress of eicosanoid metabolomics in cardiovascular diseases / 生理学报

Eicosanoids are oxidized derivatives of 20-carbon polyunsaturated fatty acids (PUFAs). In recent years, the role and mechanism of eicosanoids in cardiovascular diseases have attracted extensive attention. Substrate PUFAs including arachidonic acid are metabolized by cyclooxygenase, lipoxygenase, cytochrome P450 oxidase enzymes, or non-enzymatic auto-oxidation. Eicosanoid metabolomics is an effective approach to study the complex metabolic network of eicosanoids. In this review, we discussed the biosynthesis and functional activities of eicosanoids, the strategies of eicosanoid metabolomics, and applications and research progress of eicosanoid metabolomics in cardiovascular diseases, which might offer new insights and strategies for the treatment of cardiovascular diseases.

Identification of dysregulated microRNAs involved in arachidonic acid metabolism regulation in dilated cardiomyopathy-mediated heart failure patients / 生理学报

Heart failure (HF), a clinical syndrome with high morbidity and mortality, is becoming a growing public health problem. Dilated cardiomyopathy (DCM) is one of the major causes of HF, yet the molecular mechanisms underlying DCM-mediated HF are not completely understood. Previous studies have shown that dysregulation of arachidonic acid (AA) metabolism could contribute to the development of HF. To explore the roles of microRNAs (miRNAs) in regulating AA metabolism in HF, we used two public datasets to analyze the expression changes of miRNAs in the patients of DCM-mediated HF. A total of 101 and 88 miRNAs with significant abundance alterations in the two dataset were obtained, respectively. Around 1/3 of these miRNAs were predicted to target AA metabolic pathway genes. We also investigated the distribution of known single nucleotide polymorphisms (SNPs) within the sequences of miRNAs dysregulated in DCM-mediated HF patients, and identified miRNAs harboring high number of SNPs in either the seed regions or the entire sequences. These information could provide clues for further functional studies of miRNAs in the pathogeny of DCM-mediated HF.

Effect of arachidonic acid cytochrome P450ω hydroxylase Cyp4a14 gene knockout on skeletal muscle regeneration after injury / 生理学报

The objective of this study was to explore the roles of arachidonic acid cytochrome P450ω hydroxylase CYP4A14 in skeletal muscle regeneration after injury. Wild-type (WT) control mice and Cyp4a14 knockout (A14

Arachidonic acid Alox15/12-HETE signaling inhibits vascular calcification / 生理学报

This study aims to explore the effects of arachidonic acid lipoxygenase metabolism in vascular calcification. We used 5/6 nephrectomy and high-phosphorus feeding to establish a model of vascular calcification in mice. Six weeks after nephrectomy surgery, vascular calcium content was measured, and Alizarin Red S and Von Kossa staining were applied to detect calcium deposition in aortic arch. Control aortas and calcified aortas were collected for mass spectrometry detection of arachidonic acid metabolites, and active molecules in lipoxygenase pathway were analyzed. Real-time quantitative PCR was used to detect changes in the expression of lipoxygenase in calcified aortas. Lipoxygenase inhibitor was used to clarify the effect of lipoxygenase metabolic pathways on vascular calcification. The results showed that 6 weeks after nephrectomy surgery, the aortic calcium content of the surgery group was significantly higher than that of the sham group (P < 0.05). Alizarin Red S staining and Von Kossa staining showed obvious calcium deposition in aortic arch from surgery group, indicating formation of vascular calcification. Nine arachidonic acid lipoxygenase metabolites were quantitated using liquid chromatography/mass spectrometry (LC-MS) analysis. The content of multiple metabolites (12-HETE, 11-HETE, 15-HETE, etc.) was significantly increased in calcified aortas, and the most abundant and up-regulated metabolite was 12-HETE. Furthermore, we examined the mRNA levels of metabolic enzymes that produce 12-HETE in calcified blood vessels and found the expression of arachidonate lipoxygenase-15 (Alox15) was increased. Blocking Alox15/12-HETE by Alox15 specific inhibitor PD146176 significantly decreased the plasma 12-HETE content, promoted calcium deposition in aortic arch and increased vascular calcium content. These results suggest that the metabolism of arachidonic acid lipoxygenase is activated in calcified aorta, and the Alox15/12-HETE signaling pathway may play a protective role in vascular calcification.

Intervenções baseadas na restauração da função vascular como terapias adjuvantes para malária cerebral experimental / Interventions based on the restoration of vascular function as adjuvant therapies for experimental cerebral malaria

A malária cerebral (MC) é uma das complicações mais graves e letais da infecção por Plasmodium falciparum. O principal tratamento para a MC é o artesunato por via intravenosa, mesmo assim, 15- 25% dos pacientes tratados ainda morrem. A disfunção vascular, com vasoconstrição, leva a diminuição no fluxo sanguíneo cerebral, isquemia, hipóxia tecidual e morte na MC. O óxido nítrico (NO) e metabólitos do ácido araquidônico (AA) são importantes reguladores fisiológicos do fluxo sanguíneo cerebral por suas propriedades vasodilatadoras e vasoconstritoras. Utilizando a técnica de laser speckle com contraste de imagem nós mostramos aqui que animais infectados por Plasmodium berghei ANKA (PbA) que desenvolveram malária cerebral experimental (MCE) apresentaram marcante diminuição no fluxo sanguíneo cerebral e que a administração de L-arginina em combinação com artesunato induziu imediata reversão na isquemia cerebral a curto prazo (1 hora), mas o efeito retrocedeu 3 e 6 horas após o tratamento. O aumento no fluxo sanguíneo cerebral, mesmo que transiente, foi associado a aumentada sobrevida desses animais. L-arginina mais artesunato não foi capaz de reverter a quebra da barreira hematoencefálica presente em animais MCE. Camundongos com MCE apresentaram maior produção de metabólitos do AA com um perfil vasoconstritor, com níveis aumentados de 8-isoprostanos, 20-HETE, 14,15-DHET e níveis diminuídos de 14,15-EET, enquanto camundongos infectados por Plasmodium berghei NK65, uma cepa que não causa MC, mostraram um perfil vasodilatador, com níveis normais de 20-HETE e 14,15-DHET e aumento das concentrações de PGE2

O tratamento de animais que desenvolveram MCE com HET0016 e ozagrel diminuiu as concentrações cerebrais de 20-HETE e 8-isoprostanos, respectivamente. Apesar dos níveis de TXA2 não estarem aumentados em animais com MCE, o tratamento com ozagrel diminuiu a produção desse eicosanoide vasoconstritor no cérebro e aumentou a sobrevida de animais com MCE quando combinado com artesunato. Assim como L-arginina, ozagrel não reverteu a quebra da barreira hematoencefálica na dose testada. A produção de PGE2 no cérebro de animais com MCE não aumentou após tratamento com ozagrel. Utilizando um sistema de miografia pressurizado nós observamos que as artérias cerebrais de animais com MCE apresentaram resposta vasodilatadora dependente (estímulo com metacolina) de endotélio, bem como resposta vasoconstritora à serotonina, semelhante a resposta de artérias cerebrais de animais controles não infectados. Além disso, utilizando ensaio DAF-2 para avaliar a produção de NO, nós observamos que a produção de NO induzida por metacolina foi semelhante em artérias cerebrais oriundas de animais controles e de animais com MCE. Surpreendentemente, ao incubar artérias cerebrais de animais com MCE e de animais controles em plasma de animais com MCE, nós observamos que o plasma por si só aumentou a produção basal de NO pelas artérias de ambos os grupos. Esses resultados mostram que a disfunção vascular observada na MCE não é intrínseca do vaso já que a vasorreatividade e a produção de NO estão preservadas nas artérias cerebrais de animais com MCE, mas pode estar relacionada a um fator tecidual. Metabólitos do AA podem desempenhar um papel na disfunção cerebrovascular e a inibição da produção de eicosanoides vasoconstritores pode ser benéfica em animais com MC. (AU)

Dietary intake of n-3 and n-6 polyunsaturated fatty acids in Korean toddlers 12–24 months of age with comparison to the dietary recommendations

BACKGROUND/OBJECTIVES: Adequate dietary fatty acid intake is important for toddlers between 12–24 months of age, as this is a period of dietary transition in conjunction with rapid growth and development; however, actual fatty acid intake during this period seldom has been explored. This study was conducted to assess the intake status of n-3 and n-6 polyunsaturated fatty acids by toddlers during the 12–24-month period using 2010–2015 Korea National Health and Nutrition Examination Survey data. SUBJECTS/METHODS: Twenty-four-hour dietary recall data of 12–24-month-old toddlers (n = 544) was used to estimate the intakes of α-linolenic acid (ALA; 18:3n-3), eicosapentaenoic acid (EPA; 20:5n-3), docosahexaenoic acid (DHA; 22:6n-3), linoleic acid (LA; 18:2n-6), and arachidonic acid (AA; 20:4n-6), as well as the major dietary sources of each. The results were compared with the expected intake for exclusively breastfed infants in the first 6 months of life and available dietary recommendations. RESULTS: Mean daily intakes of ALA, EPA, DHA, LA, and AA were 529.9, 22.4, 37.0, 3907.6, and 20.0 mg/day, respectively. Dietary intakes of these fatty acids fell below the expected intake for 0–5-month-old exclusively breastfed infants. In particular, DHA and AA intakes were 4 to 5 times lower. The dietary assessment indicated that the mean intake of essential fatty acids ALA and LA was below the European and the FAO/WHO dietary recommendations, particularly for DHA, which was approximately 30% and 14–16% lower, respectively. The key sources of the essential fatty acids, DHA, and AA were soy (28.2%), fish (97.3%), and animals (53.7%), respectively. CONCLUSIONS: Considering the prevailing view of DHA and AA requirements on early brain development, there remains considerable room for improvement in their intakes in the diets of Korean toddlers. Further studies are warranted to explore how increasing dietary intakes of DHA and AA could benefit brain development during infancy and early childhood.

The serum arachidonic acid/eicosapentaenoic acid ratio in children with healthy weight and obesity

The western diet is characterized by a high consumption of n-6 polyunsaturated fatty acids (PUFAs) and reduced n-3PUFAs, this phenomenon has been parallel to the increase in the prevalence of obesity. The studies that have analyzed the association between serum PUFAs and the influence on the development of adiposity in children is limited and the findings are controversial. The present study compared the ARA/EPA (arachidonic/eicosapentaenoic) PUFA ratio in children with healthy weight vs. obesity in a cross-sectional study. Thirty children were diagnosed with obesity and 32 children with healthy weight determined through the age-specific body mass index (BMI) Z score, according to the WHO. The variables included were weight, BMI, waist circumference (WC), and the serum ARA/EPA ratio. The Student's t test and Pearson correlation were performed and statistical significance was set at a p <0.05. The project was approved by the local ethics committee of the hospital Instituto Mexicano del Seguro Social. The serum ARA/EPA ratio was significantly higher in children with obesity compared with healthy weight (9.0 vs 5.4; p = 0.012). A statistically significant difference was observed between healthy weight boys and obese boys (p=0.003). Furthermore, the ARA/EPA ratio correlated positively with weight (r=0.336; p=0.008), BMI (r=0.373; p=0.003), WC (r=0.319; p=0.012) and cardio-metabolic risk (r=0.302; p=0.017). When performing a multivariate regression analysis, we identified that BMI was the only variable that remained significant and predicted the ARA/EPA ratio. In conclusion, the serum ARA/EPA ratio differed significantly in relation to weight and was higher in the obese children(AU)

La dieta occidental se caracteriza por un alto consumo de ácidos grasos poliinsaturados n-6(AGPI) y AGPIn-3 reducidos, fenómeno que ha sido paralelo al aumento en la prevalencia de la obesidad. Los estudios que han analizado la asociación entre AGPN en suero y adiposidad en niños son limitados y con hallazgos inconsistentes. El presente estudio comparó la relación ARA/EPA (ácido araquidónico/eicosapentaenoico) AGPI en niños con peso normal vs. obesidad. Es un estudio transversal donde treinta niños fueron diagnosticados con obesidad y 32 niños con peso normal determinado mediante el puntaje z del IMC para la edad, de acuerdo a la OMS. Las variables incluidas fueron peso, IMC, circunferencia de cintura (CC) y la relación ARA/EPA en suero. Se realizó prueba de t de Student y correlación de Pearson, la significación estadística se estableció en p <0,05. El proyecto fue aprobado por el comité de ética local del Hospital del Instituto Mexicano del Seguro Social. La relación ARA/EPA en suero fue significativamente mayor en niños con obesidad en comparación con el peso normal (9,0 frente a 5,4; p = 0,012). Además, la relación ARA/EPA se correlacionó positivamente con el peso (r = 0.336; p = 0.008), IMC (r = 0.373; p = 0.003), CC (r = 0.319; p = 0.012). Al realizar un análisis de regresión multivariable, identificamos que el IMC fue la variable predictora que permaneció significativa. En conclusión, la relación de suero ARA/EPA fue significativamente mayor en los niños con obesidad(AU)

Eicosanoids and cancer

Eicosanoids are 20-carbon bioactive lipids derived from the metabolism of polyunsaturated fatty acids, which can modulate various biological processes including cell proliferation, adhesion and migration, angiogenesis, vascular permeability and inflammatory responses. In recent years, studies have shown the importance of eicosanoids in the control of physiological and pathological processes associated with several diseases, including cancer. The polyunsaturated fatty acid predominantly metabolized to generate 2-series eicosanoids is arachidonic acid, which is the major n-6 polyunsaturated fatty acid found in animal fat and in the occidental diet. The three main pathways responsible for metabolizing arachidonic acid and other polyunsaturated fatty acids to generate eicosanoids are the cyclooxygenase, lipoxygenase and P450 epoxygenase pathways. Inflammation plays a decisive role in various stages of tumor development including initiation, promotion, invasion and metastasis. This review will focus on studies that have investigated the role of prostanoids and lipoxygenase-derived eicosanoids in the development and progression of different tumors, highlighting the findings that may provide insights into how these eicosanoids can influence cell proliferation, cell migration and the inflammatory process. A better understanding of the complex role played by eicosanoids in both tumor cells and the tumor microenvironment may provide new markers for diagnostic and prognostic purposes and identify new therapeutic strategies in cancer treatment.

Anti-platelet effects of epigallocatechin-3-gallate in addition to the concomitant aspirin, clopidogrel or ticagrelor treatment

BACKGROUND/AIMS: Although epigallocatechin-3-gallate (EGCG), which is found in high contents in the dried leaves of green tea, has been reported to have an anti-platelet effect, synergistic effects of EGCG in addition to current anti-platelet medications remains to be elucidated. METHODS: Blood samples were obtained from 40 participants who took aspirin (ASA, n = 10), clopidogrel (CPD, n = 10), ticagrelor (TCG, n = 10) and no anti-platelet medication (Control, n = 10). Ex vivo platelet aggregation and adhesion under various stimulators were analyzed by multiple electrode aggregometry (MEA) and Impact-R systems. PAC-1 and P-selectin expressions in human platelets were analyzed by flow cytometry. RESULTS: In MEA analysis, adenosine diphosphate (ADP) and thrombin receptor activating peptide (TRAP)-induced platelet aggregations were lower in the CPD and the TCG groups; arachidonic acid (AA)-induced platelet aggregation was lower in the ASA group, whereas collagen (COL)-induced platelet aggregations were comparable among four groups. EGCG significantly reduced ADP- and COL-induced platelet aggregation in dose-dependent manner (ADP, p = 0.04; COL, p < 0.01). There were no additional suppressions of platelet aggregation stimulated by AA in the ASA group, and by ADP in the CPD and TCG groups. Moreover, EGCG suppressed shear stress-induced platelet adhesion on Impact-R, and had no effect on P-selectin and PAC-1 expressions. CONCLUSIONS: Ex vivo treatment of EGCG inhibited platelet adhesion and aggregation without changes in P-selectin and PAC-1 expression. There was no additional suppressions in platelet aggregation stimulated by AA in the ASA group and ADP in the CPD and TCG groups.

Efectos neuroprotectores del ácido araquidónico y del ácido docosahexaenoico en las etapas extremas de la vida: Una visión integradora / Neuroprotective effects of arachidonic and docosahexaenoic acid in the extreme stages of life: An integrative view

RESUMEN El estudio focalizado en dilucidar el rol neuroprotector del ARA y del DHA a lo largo del ciclo vital ha cobrado cada vez más interés puesto que se continúan descubriendo mecanismos mediante los cuales estos ácidos grasos poliinsaturados de cadena larga (AGPICL) modulan el metabolismo. Tanto el ARA como el DHA se encuentran depositados en los lípidos de las membranas de las células que forman la materia gris y representan aproximadamente el 25% del contenido total de ácidos grasos cerebrales. El ARA y el DHA tienen efectos sobre el crecimiento y la diferenciación neuronal a través de la modulación de las propiedades físicas de la membrana, de la transducción de señales asociada a proteínas G y la modulación de la expresión génica, adquiriendo un rol relevante en la neuro-génesis y el desarrollo cerebral. Además, se les atribuye un rol neuroprotector en patologías neurodegenerativas como la enfermedad de Alzheimer y la enfermedad de Parkinson, pudiendo disminuir la disfunción mitocondrial, la neuro-inflamación y el estrés oxidativo, expresiones características de estas patologías. La presente revisión analiza y discute acerca del rol del ARA y del DHA en la neuro-protección y en la neurodegeneración a través de una visión integradora.

ABSTRACT The study focused on elucidating the neuro-protective effects of ARA and DHA throughout the life cycle has become of increasingly interest since the continue discovering of mechanisms by which these long-chain polyunsaturated fatty acids (LCPUFA) modulate the metabolism. Both ARA and DHA are deposited into the membrane lipids of the cells that form the gray matter of the brain and represent approximately 25% of the total content of cerebral fatty acids. ARA and DHA have effects on the growth and neuronal differentiation through the modulation of the physical properties of the membrane, the signal transduction associated to G proteins and by the modulation of gene expression, acquiring a relevant role in neurogenesis and brain development. In addition, it is attributed to these fatty acids a neuro-protective role in neurodegenerative pathologies such as Alzheimer's disease and Parkinson's disease by decreasing the mitochondrial dysfunction, neuroinflammation and oxidative stress, characteristic of these pathologies. This review analyzes and discusses the role of ARA and DHA in neuro-protection and neuro-degeneration through an integrative vision.

Nonsteroidal anti-inflammatory drug hypersensitivity in the Asia-Pacific

Nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity reactions (HSRs) are often nonimmunologically mediated reactions which present with immediate HSR type manifestations. These are mediated by cyclooxygenase inhibition resulting in shunting towards the excessive production of leukotrienes. Important disease associations include asthma, nasal polyposis, and chronic spontaneous urticaria, especially among adults. The European Network on Drug Allergy/Global Allergy and Asthma European Network 2013 classification of NSAID HSR comprises nonselective HSR i.e., NSAID exacerbated respiratory disease (NERD), NSAIDs exacerbated cutaneous disease (NECD), NSAIDs induced urticarial-angioedema (NIUA); and selective (allergic) HSR i.e., single NSAID induced urticaria/angioedema or anaphylaxis, NSAIDs-induced delayed HSR. Much of the literature on genetic associations with NSAID HSR originate from Korea and Japan; where genetic polymorphisms have been described in genes involved in arachidonic acid metabolism, basophil/mast cell/eosinophil activation, various inflammatory mediators/cytokines, and different HLA genotypes. The Asian phenotype for NSAID HSR appears to be predominantly NIUA with overlapping features in some adults and children. NECD also appears to be more common than NERD, although both are not common in the Asian paediatric population. Between adults and children, children seem to be more atopic, although over time when these children grow up, it is likely that the prevalence of atopic adults with NSAID HSR will increase. Low-dose aspirin desensitization has been shown to be effective in the treatment of coronary artery disease, especially following percutaneous coronary intervention.

Erythrocyte Membrane Unsaturated (Mono and Poly) Fatty Acids Profile in Newly Diagnosed Basal Cell Carcinoma Patients

Studies have reported different changes in the fatty acid composition of red blood cell (RBC) total lipids in patients with various types of cancer. It has been indicated that n-3/n-6 ratio plays a key role in the general consequence of skin photocarcinogenesis. However, to our knowledge there was no study examining the unsaturated fatty acid profile in basal cell carcinoma (BCC) patients. So, we explore the fatty acid composition of RBCs in newly diagnosed BCC patients in a hospital-based case-control study. This study has been conducted on new case BCC patients in Razi Hospital, Tehran, Iran. Fatty acid concentration in erythrocyte membranes defined as relative values after extraction, purification and preparation, by gas chromatography.Analysis revealed that heptadecenoic acid (p = 0.010) and oleic acid (p < 0.001) was significantly higher in BCC patients in comparison with control group. Among polyunsaturated fatty acids (PUFAs), linoleic acid (LA), and arachidonic acid (AA) were significantly higher in BCC patients (p < 0.001). It has been indicated that n-3 was significantly lower (p = 0.040) and n-6 was significantly higher (p = 0.002) in BCC patients. In addition, total PUFA (p < 0.001) and n-6 PUFAs/n-3 PUFAs (p = 0.002) were significantly higher in BCC patients compared to the control group. Here we indicated that new case BCC patient had significantly higher n-6 PUFA and lower n-3 along with other differences in unsaturated fatty acid in comparison with healthy subjects. Our study provides evidence that lipids are important in BCC development.

Role of cytochrome P450 epoxygenase-dependent arachidonic acid metabolites in kidney physiology and diseases / 生理学报

Kidney diseases are important causes of mortality world widely. Renal microvascular dysfunction plays a pivotal role in the development of kidney diseases. Pharmacological and biochemical tools have been used to conduct detailed studies on the metabolization of arachidonic acid by cytochrome P450 (CYP450) in renal microvasculature. CYP450 epoxygenase metabolites epoxyeicosatrienoic acids (EETs) are mainly produced in renal microvessels. EETs exhibit renoprotective effects through vasodilation, anti-hypertension, anti-apoptosis and anti-inflammation, and were reported as therapeutic targets of renal diseases. However, the ability of the kidney in generating EETs is reduced in renal diseases. Recently, the studies from transgenic animal overexpressing CYP450 epoxygenases and application of soluble epoxide hydrolase inhibitors revealed that increasing of EETs exhibits renoprotective effects in vivo. The present review focuses on the protective mechanisms of EETs in kidney physiology and diseases.

In vivo anti-inflammatory and anti-platelet aggregation activities of longissiminone A, isolated from Usnea longissima

Secondary metabolite, longissiminone A [1] was isolated from a lichen, Usnea longissima. It was screened for its' in vivo anti-inflammatroy and anti-platelet aggregation activities. Compound 1 showed moderate in vivo anti-inflammatory activity as well as moderately active against the aggregation induced by arachidonic acid at different doses

Antiplatelet Therapy Combinations and Thrombogenicity in Patients with Non-Valvular Atrial Fibrillation

BACKGROUND AND OBJECTIVES: Combination antiplatelet therapy reduces the risk of ischemic stroke compared with aspirin monotherapy in non-valvular atrial fibrillation (NVAF) patients. The underlying mechanism, however, remains unclear. In addition, the association between platelet inhibition and thrombogenicity in NVAF has not been evaluated. SUBJECTS AND METHODS: We randomized 60 patients with NVAF that were taking 100 mg of aspirin daily (>1 month) to adding 75 mg of clopidogrel daily (CLPD group), 100 mg of cilostazol twice daily (CILO group), or 1000 mg of omega-3 polyunsaturated fatty acid twice daily (PUFA group). Biomarkers (von Willebrand factor antigen [vWF:Ag], fibrinogen, D-dimer, and high-sensitivity C-reactive protein [hs-CRP]) and platelet reactivity (PR), which were the levels stimulated by adenosine diphosphate (ADP), thrombin-receptor agonist peptide, collagen, and arachidonic acid, were measured at baseline and 30-day follow-up. RESULTS: Combination antiplatelet therapy significantly reduced vWF:Ag and fibrinogen levels (7.7 IU/dL, p=0.015 and 15.7 mg/dL, p=0.005, respectively), but no changes were found in D-dimer and hs-CRP levels. The CLPD and CILO groups showed fibrinogen and vWF:Ag level reductions (24.9 mg/dL, p=0.015 and 9.3 IU/dL, p=0.044, respectively), whereas the PUFA group did not show any differences in biomarkers. Irrespective of regimen, the changes in fibrinogen and vWF:Ag levels were mainly associated with the change in ADP-mediated PR (r=0.339, p=0.008 and r=0.322, p=0.012, respectively). CONCLUSION: In patients with NVAF, combination antiplatelet therapy showed reductions for vWF:Ag and fibrinogen levels, which may be associated with the inhibitory levels of ADP-mediated PR. The clinical implications of these findings need to be evaluated in future trials.

Effects of host modulation by nonsteroidal anti-inflammatory drugs on periodontal disease: a systematic review and meta-analysis

PURPOSE: Nonsteroidal anti-inflammatory drugs that prohibit biosynthesis of arachidonic acid metabolites have been considered potent host modulation agents. The aim of this review was to determine the effect of nonsteroidal anti-inflammatory drugs adjunctive with nonsurgical periodontal treatment in patients with periodontal disease. MATERIALS AND METHODS: Three electronic databases were searched to identify relevant studies. The methodological quality and mean differences of the change in clinical attachment level and probing depth were analyzed according to Cochrane review methods. RESULTS: Twelve studies were included in the methodological assessment and nine studies were suitable for inclusion in the meta-analysis. The mean difference in the clinical attachment level gain did not differ significantly between the nonsteroidal anti-inflammatory drugs and control groups at any observation time. The highest mean difference in clinical attachment level gain was 0.30 mm at 4 weeks (95% confidence interval = -0.37 to 0.97). There was a significant mean difference in the probing depth reduction, of 0.34 mm (95% confidence interval = 0.29 to 0.40) at 6 weeks. CONCLUSION: Therefore, nonsteroidal anti-inflammatory drugs have additional therapeutic effect when administrated with nonsurgical periodontal treatment.