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Delphinidin, a plant anthocyanidin, suppresses disuse muscle atrophy in mice. However, its effect on muscle fiber type shift is unclear. To examine whether delphinidin affects skeletal muscle fiber type, differentiated C2C12 cells were treated with delphinidin. Results revealed that delphinidin upregulated the mRNA expression of myosin heavy chain type I (MyHCI), troponin C1, troponin I1, and MyHCIIx and increased slow MyHC protein level in C2C12 myotubes. Delphinidin also enhanced succinic dehydrogenase (SDH) activities and suppressed lactate dehydrogenase (LDH) activity. Adenosine monophosphate–activated protein kinase (AMPK) inhibition attenuated delphinidin-induced MyHCI upregulation and MyHCIIb downregulation. We investigated the effect of delphinidin on the upstream factors involved in AMPK activation. Delphinidin increased liver kinase B1 (LKB1) phosphorylation and nuclear respiratory factor 1 (NRF1) and calcium/calmodulin-dependent protein kinase 2 (CaMKK2) protein levels. In conclusion, delphinidin induced muscle fiber type conversion from fast-twitch to slow-twitch muscles through the AMPK signaling pathway.

(−)‐Epigallocatechin‐3‐O‐gallate (EGCG) is one of the major components of green tea polyphenol. Previous studies have shown that EGCG induces cancer‐specific cell death in vitro and in vivo without causing severe side effects. However, the anti‐cancer effect of EGCG alone is limited. 5,7‐dimethoxyflavone (5,7‐DMF), one of the principal functional components of black ginger (Kaempferia parviflora), also exerts anti‐cancer effects. Here, we show that 5,7‐DMF synergistically enhances the anti‐cancer effect of EGCG in multiple myeloma cells by potentiating EGCG‐induced intracellular cyclic guanosine monophosphate (cGMP) production. Moreover, the combination of EGCG and 5,7‐DMF induces apoptotic cell death in multiple myeloma cells, and this is accompanied by activation of the cGMP/acid sphingomyelinase (ASM)/cleaved caspase‐3 pathway. In conclusion, we have shown that 5,7‐DMF enhances the anti‐cancer effect of EGCG by upregulating cGMP in multiple myeloma cells.

Summary: Cirrhosis is becoming one of the most common diseases worldwide. Abnormal upregulation of transforming growth factor β (TGF-β) signaling plays a pivotal role in the excess activation of hepatic stellate cells. However, an efficient countermeasure against abnormal hepatic stellate cell activation is yet to be established because TGF-β signaling is involved in several biological processes. Herein, we demonstrated the antifibrotic effect of miR-12135, a microRNA with unknown function upregulated by isoflavone. Comprehensive transcriptome assay demonstrated that miR-12135 suppressed Integrin Subunit Alpha 11 (ITGA11) and that ITGA11 expression is correlated with alpha smooth muscle actin expression in patients with cirrhosis. miR-12135 suppressed the expression level of ITGA11 and liver fibrosis. Importantly, ITGA11 is overexpressed in activated hepatic stellate cells, whereas ITGA11 knockout mice are viable and fertile. In conclusions, the miR-12135/ITGA11 axis can be an ideal therapeutic target to suppress fibrosis by precisely targeting abnormally upregulated TGF-β signaling in hepatic stellate cells.

Abstract Lung fibrosis, including idiopathic pulmonary fibrosis, is an intractable disease accompanied by an irreversible dysfunction in the respiratory system. Its pathogenesis involves the transforming growth factorβ (TGFβ)-induced overproduction of the extracellular matrix from fibroblasts; however, limited countermeasures have been established. In this study, we identified osa-miR172d-5p, a plant-derived microRNA (miR), as a potent anti-fibrotic miR. In silico analysis followed by an in vitro assay based on human lung fibroblasts demonstrated that osa-miR172d-5p suppressed the gene expression of TGF-β activated kinase 1 (MAP3K7) binding protein 1 (Tab1). It also suppressed the TGFβ-induced fibrotic gene expression in human lung fibroblasts. To assess the anti-fibrotic effect of osa-miR172d-5p, we established bleomycin-induced lung fibrosis models to demonstrate that osa-miR172d-5p ameliorated lung fibrosis. Moreover, it suppressed Tab1 expression in the lung tissues of bleomycin-treated mice. In conclusion, osa-miR172d-5p could be a potent candidate for the treatment of lung fibrosis, including idiopathic pulmonary fibrosis.

Epigallocatechin 3-O-gallate (EGCG) is a predominant component in green tea with various health benefits. The 67 kDa laminin receptor (67LR) is a nonintegrin cell surface receptor that is overexpressed in various types of cancer; 67LR was identified a cell surface EGCG target that plays a pivotal role in tumor growth, metastasis, and resistance to chemotherapy. However, the plasma concentration of EGCG is limited, and its molecular mechanisms remain unelucidated in colon cancer. In this study, we found that the phosphodiesterase 5 (PDE5) inhibitor, vardenafil (VDN), potentiates EGCG-induced apoptotic cell death in colon cancer cells. The combination of EGCG and VDN induced apoptosis via activation of the endothelial nitric oxide synthase/cyclic guanosine monophosphate/protein kinase Cδ signaling pathway. In conclusion, the PDE5 inhibitor, VDN, may reduce the intracellular PDE5 enzyme activity that potentiates EGCG-induced apoptotic cell death in Caco-2 cells. These results suggest that PDE5 inhibitors can be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death. Therefore, EGCG may be employed as a therapeutic candidate for colon cancer.

Abstract Split-virus vaccine serves as a major countermeasure against influenza virus, but its effectiveness and protective action are not complete. We previously demonstrated the effect of Benifuuki, a green tea cultivar in Japan, on enhancing the split-virus vaccine–elicited immune response. However, little is known about the detail mechanisms. Here, we show that EGCG3”Me intake significantly potentiated the vaccine-elicited hemagglutination inhibition titer increase. Flow cytometry analysis revealed the increased Toll-like receptor 5 (TLR5) expression after EGCG3”Me treatment in lamina propria dendritic cells (LPDCs) and macrophages, which play crucial roles in the humoral immune system. TLR5 expression correlated with the level of interleukin-6 (IL-6)/C–C chemokine type receptor 5, which are important mediators of the humoral immunity. Taken together, In vivo and ex vivo studies showed that EGCG3”Me potentiated the split-virus vaccine–elicited immune response accompanied with the upregulation of TLR5 in intestine and splenocyte macrophages.

Abstract Green tea, a widely consumed beverage in Asia, contains green tea catechins effective against obesity, especially epigallocatechin-3-O-gallate (EGCG), but must be consumed in an impractically huge amount daily to elicit its biological effect. Meanwhile, citrus polyphenols have various physiological effects that could enhance EGCG functionality. Here we investigated the antiobesity effect of a combination of EGCG and α-glucosyl hesperidin, a citrus polyphenol, at doses that have not been previously reported to exert antiobesity effects by themselves in any clinical trial. In a randomized, placebo-controlled, double-blinded, and parallel-group-designed clinical trial, 60 healthy Japanese males and females aged 30–75 years consumed green tea combined with α-glucosyl hesperidin (GT-gH), which contained 178 mg α-glucosyl hesperidin and 146 mg EGCG, for 12 weeks. Physical, hematological, blood biochemical, and urine examinations showed that GT-gH is safe to use. At week 12, GT-gH prevented weight gain and reduced body mass index (BMI) compared with the placebo. Especially in those aged

The body is equipped with a “food factor-sensing system” that senses food factors, such as polyphenols, sulfur-containing compounds, and vitamins, taken into the body, and plays an essential role in manifesting their physiological effects. For example, (−)-epigallocatechin-3-O-gallate (EGCG), the representative catechin in green tea (Camellia sinensi L.), exerts various effects, including anti-cancer, anti-inflammatory, and anti-allergic effects, when sensed by the cell surficial protein 67-kDa laminin receptor (67LR). Here, we focus on three representative effects of EGCG and provide their specific signaling mechanisms, the 67LR-mediated EGCG-sensing systems. Various components present in foods, such as eriodictyol, hesperetin, sulfide, vitamin A, and fatty acids, have been found to act on the food factor-sensing system and affect the functionality of other foods/food factors, such as green tea extract, EGCG, or its O-methylated derivative at different experimental levels, i.e., in vitro, animal models, and/or clinical trials. These phenomena are observed by increasing or decreasing the activity or expression of EGCG-sensing-related molecules. Such functional interaction between food factors is called “functional food pairing”. In this review, we introduce examples of functional food pairings using EGCG.

Abstract Although understanding their chemical composition is vital for accurately predicting the bioactivity of multicomponent drugs, nutraceuticals, and foods, no analytical approach exists to easily predict the bioactivity of multicomponent systems from complex behaviors of multiple coexisting factors. We herein represent a metabolic profiling (MP) strategy for evaluating bioactivity in systems containing various small molecules. Composition profiles of diverse bioactive herbal samples from 21 green tea extract (GTE) panels were obtained by a high-throughput, non-targeted analytical procedure. This employed the matrix-assisted laser desorption ionization–mass spectrometry (MALDI–MS) technique, using 1,5-diaminonaphthalene (1,5-DAN) as the optical matrix for detecting GTE-derived components. Multivariate statistical analyses revealed differences among the GTEs in their antioxidant activity, oxygen radical absorbance capacity (ORAC). A reliable bioactivity-prediction model was constructed to predict the ORAC of diverse GTEs from their compositional balance. This chemometric procedure allowed the evaluation of GTE bioactivity by multicomponent rather than single-component information. The bioactivity could be easily evaluated by calculating the summed abundance of a few selected components that contributed most to constructing the prediction model. 1,5-DAN-MALDI–MS-MP, using diverse bioactive sample panels, represents a promising strategy for screening bioactivity-predictive multicomponent factors and selecting effective bioactivity-predictive chemical combinations for crude multicomponent systems.

Epigallocatechin-3-O-gallate (EGCG) is one of the major bioactive compounds known to be present in green tea. We previously reported that EGCG shows selective toxicity through activation of the protein kinase B (Akt)/cyclic guanosine monophosphate (cGMP)/acid sphingomyelinase (ASM) axis via targeting its receptor 67-kDa laminin receptor (67LR), which is overexpressed in cancer. However, little is known about upstream mechanisms of EGCG-elicited ASM activation. In this study we show that the proto-oncogene tyrosine-protein kinase Src, also known as c-src, plays a crucial role in the anticancer effect of EGCG. We showed that EGCG elicits phosphorylation of Src at Tyr 416, a crucial phosphorylation site for its activity, and that the pharmacological inhibition of Src impedes the upstream events in EGCG-induced cell death signaling including upregulation of Akt activity, increase in cGMP levels, and activation of ASM. Moreover, focal adhesion kinase (FAK), which is involved in the phosphorylation of Src, is colocalized with 67LR. EGCG treatment enhanced interaction of FAK and 67LR. Consistent with these findings, pharmacological inhibition of FAK significantly neutralized EGCG-induced upregulation of Akt activity and activation of ASM. Taken together, FAK/Src play crucial roles in the upstream signaling of EGCG.

Understanding the spatial distribution of bioactive small molecules is indispensable for elucidating their biological or pharmaceutical roles. Mass spectrometry imaging (MSI) enables determination of the distribution of ionizable molecules present in tissue sections of whole-body or single heterogeneous organ samples by direct ionization and detection. This emerging technique is now widely used for in situ label-free molecular imaging of endogenous or exogenous small molecules. MSI allows the simultaneous visualization of many types of molecules including a parent molecule and its metabolites. Thus, MSI has received much attention as a potential tool for pathological analysis, understanding pharmaceutical mechanisms, and biomarker discovery. On the other hand, several issues regarding the technical limitations of MSI are as of yet still unresolved. In this review, we describe the capabilities of the latest matrix-assisted laser desorption/ionization (MALDI)-MSI technology for visualizing in situ metabolism of endogenous metabolites or dietary phytochemicals (food factors), and also discuss the technical problems and new challenges, including MALDI matrix selection and metabolite identification, that need to be addressed for effective and widespread application of MSI in the diverse fields of biological, biomedical, and nutraceutical (food functionality) research.

Low-molecular-weight phytochemicals have health benefits and reduce the risk of diseases, but the mechanisms underlying their activities have remained elusive because of the lack of a methodology that can easily visualize the exact behavior of such small molecules. Recently, we developed an in situ label-free imaging technique, called mass spectrometry imaging, for visualizing spatially-resolved biotransformations based on simultaneous mapping of the major bioactive green tea polyphenol and its phase II metabolites. In addition, we established a mass spectrometry-based metabolic profiling technique capable of evaluating the bioactivities of diverse green tea extracts, which contain multiple phytochemicals, by focusing on their compositional balances. This methodology allowed us to simultaneously evaluate the relative contributions of the multiple compounds present in a multicomponent system to its bioactivity. This review highlights small molecule-sensing techniques for visualizing the complex behaviors of herbal components and linking such information to an enhanced understanding of the functionalities of multicomponent medicinal herbs.

The maturity of green coffee beans is the most influential determinant of the quality and flavor of the resultant coffee beverage. However, the chemical compounds that can be used to discriminate the maturity of the beans remain uncharacterized. We herein analyzed four distinct stages of maturity (immature, semi-mature, mature and overripe) of nine different varieties of green Coffea arabica beans hand-harvested from a single experimental field in Hawaii. After developing a high-throughput experimental system for sample preparation and liquid chromatography-mass spectrometry (LC-MS) measurement, we applied metabolic profiling, integrated with chemometric techniques, to explore the relationship between the metabolome and maturity of the sample in a non-biased way. For the multivariate statistical analyses, a partial least square (PLS) regression model was successfully created, which allowed us to accurately predict the maturity of the beans based on the metabolomic information. As a result, tryptophan was identified to be the best contributor to the regression model; the relative MS intensity of tryptophan was higher in immature beans than in those after the semi-mature stages in all arabica varieties investigated, demonstrating a universal discrimination factor for diverse arabica beans. Therefore, typtophan, either alone or together with other metabolites, may be utilized for traders as an assessment standard when purchasing qualified trading green arabica bean products. Furthermore, our results suggest that the tryptophan metabolism may be tightly linked to the development of coffee cherries and/or beans.

BACKGROUND: Aspirin-induced enteropathy is now increasingly being recognized although the pathogenesis of small intestinal damage induced by aspirin is not well understood and related risk factors have not been established. AIM: To investigate pharmacogenomic profile of low dose aspirin (LDA)-induced small bowel bleeding. METHODS: Genome-wide analysis of single nucleotide polymorphisms (SNPs) was performed using the Affymetrix DMET™ Plus Premier Pack. Genotypes of candidate genes associated with small bowel bleeding were determined using TaqMan SNP Genotyping Assay kits and direct sequencing. RESULTS: In the validation study in overall 37 patients with small bowel bleeding and 400 controls, 4 of 27 identified SNPs: CYP4F11 (rs1060463) GG (p=0.003), CYP2D6 (rs28360521) GG (p=0.02), CYP24A1 (rs4809957) T allele (p=0.04), and GSTP1 (rs1695) G allele (p=0.04) were significantly more frequent in the small bowel bleeding group compared to the controls. After adjustment for significant factors, CYP2D6 (rs28360521) GG (OR 4.11, 95% CI. 1.62 -10.4) was associated with small bowel bleeding. CONCLUSIONS: CYP4F11 and CYP2D6 SNPs may identify patients at increased risk for aspirin-induced small bowel bleeding.

BACKGROUND: We previously identified the 67-kDa laminin receptor (67LR) as the cell-surface receptor conferring the major green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) responsiveness to cancer cells. However, the underlying mechanism for interaction between EGCG and 67LR remains unclear. In this study, we investigated the possible role of EGCG-67LR interaction responsible for its bioactivities. METHODOLOGY/PRINCIPAL FINDINGS: We synthesized various peptides deduced from the extracellular domain corresponding to the 102-295 region of human 67LR encoding a 295-amino acid. The neutralizing activity of these peptides toward EGCG cell-surface binding and inhibition of cancer cell growth were assayed. Both activities were inhibited by a peptide containing the 10-amino acid residues, IPCNNKGAHS, corresponding to residues 161-170. Furthermore, mass spectrometric analysis revealed the formation of a EGCG-LR161-170 peptide complex. A study of the amino acid deletion/replacement of the peptide LR161-170 indicated that the 10-amino acid length and two basic amino acids, K(166) and H(169), have a critical role in neutralizing EGCG's activities. Moreover, neutralizing activity against the anti-proliferation action of EGCG was observed in a recombinant protein of the extracellular domain of 67LR, and this effect was abrogated by a deletion of residues 161-170. These findings support that the 10 amino-acid sequence, IPCNNKGAHS, might be the functional domain responsible for the anti-cancer activity of EGCG. CONCLUSIONS/SIGNIFICANCE: Overall, our results highlight the nature of the EGCG-67LR interaction and provide novel structural insights into the understanding of 67LR-mediated functions of EGCG, and could aid in the development of potential anti-cancer compounds for chemopreventive or therapeutic uses that can mimic EGCG-67LR interactions.

BACKGROUND: Green tea has various health promotion effects. Although there are numerous tea cultivars, little is known about the differences in their nutraceutical properties. Metabolic profiling techniques can provide information on the relationship between the metabolome and factors such as phenotype or quality. Here, we performed metabolomic analyses to explore the relationship between the metabolome and health-promoting attributes (bioactivity) of diverse Japanese green tea cultivars. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the ability of leaf extracts from 43 Japanese green tea cultivars to inhibit thrombin-induced phosphorylation of myosin regulatory light chain (MRLC) in human umbilical vein endothelial cells (HUVECs). This thrombin-induced phosphorylation is a potential hallmark of vascular endothelial dysfunction. Among the tested cultivars, Cha Chuukanbohon Nou-6 (Nou-6) and Sunrouge (SR) strongly inhibited MRLC phosphorylation. To evaluate the bioactivity of green tea cultivars using a metabolomics approach, the metabolite profiles of all tea extracts were determined by high-performance liquid chromatography-mass spectrometry (LC-MS). Multivariate statistical analyses, principal component analysis (PCA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA), revealed differences among green tea cultivars with respect to their ability to inhibit MRLC phosphorylation. In the SR cultivar, polyphenols were associated with its unique metabolic profile and its bioactivity. In addition, using partial least-squares (PLS) regression analysis, we succeeded in constructing a reliable bioactivity-prediction model to predict the inhibitory effect of tea cultivars based on their metabolome. This model was based on certain identified metabolites that were associated with bioactivity. When added to an extract from the non-bioactive cultivar Yabukita, several metabolites enriched in SR were able to transform the extract into a bioactive extract. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that metabolic profiling is a useful approach for nutraceutical evaluation of the health promotion effects of diverse tea cultivars. This may propose a novel strategy for functional food design.

Quercetin, a flavonol present in many vegetables and fruits, has been identified as a chemoprevention agent in several cancer models. However, the molecular mechanism of quercetin's anticancer activity is not entirely understood. MicroRNAs (miRNAs), small noncoding RNAs, have been reported to play key roles in various biological processes by regulating their target genes. We hypothesized that quercetin can exert an anticancer effect through the regulation of miRNAs. To test this hypothesis, we investigated the effects of quercetin on the expression of tumor-suppressive miRNAs in cervical cancer. Quercetin up-regulated the in vivo and in vitro expression of tumor-suppressive miRNAs miR-26b, miR-126, and miR-320a. Quercetin suppressed the level of β-catenin, encoded by catenin beta 1 (CTNNB1), by up-regulating miR-320a in HeLa cells. Moreover, quercetin increased the expression of mir-26b, mir-126, and mir-320a precursors in HeLa cells. The results from this study show that quercetin has the potential to prevent cervical cancer by regulating the expression of tumor-suppressive miRNAs. [ABSTRACT FROM AUTHOR]

Oxidative stress is associated with aging and pathologies such as cardiovascular diseases, Alzheimer's disease, and cancer. Glutathione S-transferase (GST), a family of detoxification enzymes, plays a crucial role in countering oxidative stress. Therefore, there is a need for the development of physiologically functional foods and agricultural products, which enhance GST activity. Sesamin and episesamin are major lignans in refined sesame oil that exhibit beneficial properties including antioxidative stress effects. A previous study showed that sesamin upregulated GST activity. This study aimed to elucidate the mechanism underlying the GST activity enhancement elicited by sesame lignans. C57BL/6J mice were orally administered 20 mg/kg body weight sesame lignans (sesamin:episesamin=1:1) for 7 days. Oral administration of sesame lignans increased the GST activity in the mouse liver. Furthermore, the lignans upregulated GSTA1, GSTA4, and GSTM4 protein expression. Microarray analysis revealed that sesame lignans changed the expression of various microRNAs (miRNAs) (84 upregulated, 19 downregulated). We also found 16 miRNAs, including miR-669c-3p, that may negatively regulate GST expression among the 19 miRNAs with reduced expression caused by the sesame lignans. miR-669c is reportedly negatively correlated with GST. Additionally, we transfected NMuLi cells with an miR-669c-3p mimic and evaluated the effect of miR-669c-3p on GST mRNA and protein expressions. The results showed that the miR-669c-3p mimic suppressed the mRNA and protein levels of GSTA4 and GSTM4. In conclusion, sesame lignans increased GST protein expression and activity and downregulated miRNAs, including miR-669c-3p, which is a possible suppressor of GST. [ABSTRACT FROM AUTHOR]

The article focuses on the small molecule-sensing strategy and techniques for green tea's functionality. Topics discussed include identification of a epigallocatechin gallate (EGCG)-sensing receptor and signaling molecules, analytical techniques for detection of complex behaviors of dietary factors in the body and food, and benefits of phytochemicals, which include health maintenance, disease risk reduction, and chemotherapy.

Summary: Mass spectrometry imaging (MSI) visualizes the simultaneous lateral distribution of multiple compounds on sample surface. However, it is still difficult to visualize biological indices such as energy charge index from multiple compounds because of the lack of publicly available tools. Here we present MSIdV, a visualization tool for biological indices calculated from mass spectrometry imaging data, which can effectively scan a series of mass spectra and process, calculate and visualize user-defined index measures accurately with a number of signal processing features. [ABSTRACT FROM AUTHOR]

Although understanding the high-resolution spatial distribution of bioactive small molecules is indispensable for elucidating their biological or pharmacological effects, there has been no analytical technique that can easily detect the naïve molecular localization in mammalian tissues. We herein present a novel in situ label-free imaging technique for visualizing bioactive small molecules, using a polyphenol. We established a 1,5-diaminonaphthalene (1,5-DAN)-based matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) technique for visualizing epigallocatechin-3-O-gallate (EGCG), the major bioactive green tea polyphenol, within mammalian tissue micro-regions after oral dosing. Furthermore, the combination of this label-free MALDI-MSI method and a standard-independent metabolite identification method, an isotopic fine structure analysis using ultrahigh-resolution mass spectrometer, allows for the visualization of spatially-resolved biotransformation based on simultaneous mapping of EGCG and its phase II metabolites. Although this approach has limitations of the detection sensitivity, it will overcome the drawbacks associated with conventional molecular imaging techniques, and could contribute to biological discovery [ABSTRACT FROM AUTHOR]

Little is known about the role of the M cells of human nasopharyngeal lymphoid tissue in the sampling of viruses that cause respiratory infections. To clarify whether M cells could function as a gateway for influenza virus into human nasopharyngeal lymphoid tissue, excised adenoid tissue was incubated in media containing influenza A virus for 30, 60, and 90 min, respectively. Transmission electron microscopic observation revealed that many influenza viruses adhered to M cell surfaces and were taken up into the cytoplasmic vesicles of M cells after 30 min incubation; the viruses had been transported into enfolded lymphoid cells after 60 min incubation. By staining M cells with Sambucus nigra lectin, which specifically recognizes the NeuAca2,6 Gal linkage of sialoprotein, it was also found that abundant receptors for the human influenza virus are present on the M cell surface. Our findings indicated that M cells of human nasopharyngeal tonsils function as a major port for influenza A virus entry and that the virus could be efficiently transferred to enfolded macrophages and lymphoid cells by M cells. The transport of influenza viruses to lymphoid cells by M cells may promote antigen delivery to the immune system, and these findings may be important for systemic delivery of those influenza viruses that have the capacity to productively infect cells outside of the respiratory tract. [ABSTRACT FROM AUTHOR]

Strictinin has been shown to suppress interleukin (IL)-4-induced signal transducer and activator of transcription (STAT)-6 phosphorylation, which is a critical event for IgE class switching. However, it is unclear how strictinin inhibits STAT6 activation. Strictinin inhibited STAT6 phosphorylation by suppressing IL-4 receptor α (IL-4Rα) activation. Strictinin was bound to the cell surface and only localized in non-lipid raft fraction of the cells where IL-4Rα was also located. In addition, strictinin directly bound to IL-4Rα and inhibited binding of IL-4 to IL-4Rα. These results suggest that IL-4Rα locating in non-lipid raft region is a target molecule for strictinin in inhibiting STAT6 activation. [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) reduces the synthesis of pituitary gonadotropins in a fetal age-specific manner. The pituitary synthesis of gonadotropins is regulated by the hypothalamus and, thus, needs the differentiation and development of the hypothalamus requiring a number of factors including energy supply and neurotransmitters. To investigate the mechanism whereby TCDD reduces fetal gonadotropins, we carried out a comparative study on the metabolomes of the hypothalamus and pituitary using fetal and mature Wistar rats. Male fetuses at gestational day (GD)20 were removed from dams treated orally with TCDD (1 µg/kg) at GD15, and the metabolome profiles were analyzed by gas chromatography-mass spectrometry (GC-MS). The principal component analysis of GC-MS data revealed that TCDD caused a change in the profile of fetal metabolome more markedly in the hypothalamus than in the pituitary. In sharp contrast, TCDD did not cause any marked alteration in hypothalamic as well as pituitary metabolomes in male rats born of untreated dams and treated with TCDD at postnatal day 49. It was also demonstrated that a number of fetal hypothalamic components, including glutamine and γ-aminobutyric acid, are reduced by TCDD. These results demonstrate a possibility that TCDD may reduce the metabolic activity of the hypothalamus in a fetus-specific fashion, resulting in the reduced synthesis of gonadotropins. [ABSTRACT FROM AUTHOR]