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This study aimed to determine the anti-inflammatory activities and bioactive compounds of soymilk yogurt prepared using Lactiplantibacillus plantarumTOKAI 17 or Pediococcus pentosaceusTOKAI 759 m. Mice were divided into five groups: normal diet (ND), soymilk, soymilk yogurt using L. plantarumTOKAI 17 (SY 17) or P. pentosaceusTOKAI 759 m (SY 759 m), and 0.5 × 109cells of each starter strain (BC 17 or BC759m). In the SY 759 m group, the serum pro-inflammatory cytokine levels and the cytotoxicity of natural killer cells were attenuated compared to the ND group. In the cecum microbiota, the abundances of butyrate-producing bacteria increased in the SY 759 m and BC 17 groups. Furthermore, SY 759 m metabolites contained high levels of aglycone isoflavone, adenine and showed a significant decrease in CCL-2 and interleukin-6 production in lipopolysaccharide-induced macrophage. In conclusion, soymilk yogurt produced using P. pentosaceusTOKAI 759 m modulates the gut microbiota and can potentially prevent pro-inflammatory cytokine production.Graphical AbstractSoymilk yogurt using Pediococcus pentosaceusTOKAI 759 m contained rich aglycone isoflavones and adenine. It modulated the gut microbiota and prevented pro-inflammatory cytokine production.

Indoxyl sulfate (IS), a uremic toxin, is a physiologically active sulfated metabolite, specifically in kidney failure patients. Our previous studies have shown that IS downregulates phagocytic immune function in a differentiated HL-60 human macrophage cell model. However, it remains unclear whether IS exerts similar effects on macrophage function in other cell types or in lipopolysaccharide (LPS)-sensitive immune cell models. Therefore, this study aimed to investigate the effects of IS on intracellular oxidation levels and phagocytic activity in a differentiated U937 human macrophage cell model, both in the absence and presence of LPS. Our results demonstrated that IS significantly increases intracellular oxidation levels and decreases phagocytic activity, particularly in cells activated by LPS. Furthermore, we found that 2-acetylphenothiazine, an NADH oxidase inhibitor, attenuates the effects of IS in LPS-activated macrophage cells. Representative antioxidants, trolox, α-tocopherol, and ascorbic acid, significantly mitigated the effects of IS on the macrophages responding to LPS.Graphical AbstractRegulatory effects of antioxidants on IS-enhanced intracellular oxidation and impaired phagocytic activity in differentiated U937 human macrophages.

AbstractIntroductionCytosolic sulfotransferases (SULTs)-mediated sulfation is critically involved in the metabolism of key endogenous compounds, such as catecholamines and thyroid/steroid hormones, as well as a variety of drugs and other xenobiotics. Studies performed in the past three decades have yielded a good understanding about the enzymology of the SULTs and their structural biology, phylogenetic relationships, tissue/organ-specific/developmental expression, as well as the regulation of the SULTgene expression. An emerging area is related to the functional impact of the SULTgenetic polymorphisms.Areas coveredThe current review aims to summarize our current knowledge about the above-mentioned aspects of the SULT research. An emphasis is on the information concerning the effects of the polymorphisms of the SULTgenes on the functional activity of the SULT allozymes and the associated physiological, pharmacological, and clinical implications.Expert opinionElucidation of how SULTSNPs may influence the drug-sulfating activity of SULT allozymes will help understand the differential drug metabolism and eventually aid in formulating personalized drug regimens. Moreover, the information concerning the differential sulfating activities of SULT allozymes toward endogenous compounds may allow for the development of strategies for mitigating anomalies in the metabolism of these endogenous compounds in individuals with certain SULTgenotypes.

ABSTRACTIndoxyl sulfate (IS), a uremic toxin, is a sulfate-conjugated metabolite originated from tryptophan. Accumulating uremic toxins may worsen renal diseases and further complicate related disorders including impaired immune functions under oxidative stress conditions. However, it has remained unclear whether or not IS can directly cause the cellular immune dysfunction. We investigated the effects of IS on the intracellular oxidation level and phagocytic activity in a HL-60-differantiated human macrophage cell model. Incubation of the cells in the presence of IS resulted in increasing intracellular oxidation level and decreasing phagocytic activity. In addition to inhibitors for NADH oxidase (NOX), organic anion transporting polypeptide2B1 (OATP2B1), protein kinase C (PKC), and phosphoinositide 3-kinase (PI3K), a representative antioxidant Trolox, was also shown to significantly relieve the IS-induced oxidation and restore weakened phagocytosis. Collectively, IS may directly down-regulate the phagocytic immune function of macrophages through the oxidation mechanisms including OATP2B1, PKC, PI3K, and NOX pathways.AbbreviationsCKD: Chronic kidney disease; IS: Indoxyl sulfate; ROS: Reactive oxygen species; NOX: NADH oxidase; OATP2B1: Organic anion transporting polypeptide2B1; PKC: Protein kinase C; PI3K: Phosphoinositide 3-kinase; 2-APT: 2-acetylphenothiazine

ABSTRACTWe investigated the content of phenolic compounds and antioxidant capacity of two batches of non-heated and heated leaves of the yacon cultivar “Andes no yuki”, grown in Japan. Lyophilized yacon leaves heated at 160°C for 20 min and 100°C for 60 min had a 1.96 to 9.69-times higher total phenolic content than that of the non-heated leaves. Heated leaves exhibited a 1.98 to 4.07-times higher antioxidant capacity than that of the non-heated leaves in three different free radical scavenging assays. Heated leaves were more efficient at attenuating the superoxide anion radical production in human granulocytic cells than the non-heated leaves. High-performance liquid chromatography analysis revealed that, in the heated leaves, the caffeic acid content was 2.13 to 3.64-times higher and the chlorogenic acid content was slightly lower than those in the non-heated leaves. Hence, heat processing may affect the active constituent contents in yacon leaves, potentiating its antioxidant capacity.Abbreviations:ABTS+: 2,2′-azinobis(2-ethylbenzothiazoline-6-sulfonic acid) cation; DPPH: 1,1-diphenyl-2-picrylhydrazyl, HPLC: high-performance liquid chromatography; NBT: nitroblue tetrazolium; O2−: superoxide anion; PMA: phorbol 12-myristate 13-acetate; PMS: phenazine methosulfate; TEAC: Trolox equivalent antioxidant capacity

ABSTRACTThis study aimed to investigate the unique antioxidative effects of Japanese moringa products, herbal leaf tea and stem tea, using established free radical assays, focusing on superoxide anion (O2−) radical generation systems. Hot-water extracts from moringa teas resulted in different but lower scavenging activities than Trolox in four synthetic free radical models. Interestingly, these extracts further showed higher O2−radical scavenging effects than Trolox in the phenazine methosulfate-NADH-nitroblue tetrazolium and xanthine oxidase assay systems. Incubating human neutrophils in the presence of these tea extracts rather than Trolox effectively suppressed cellular O2−radical generation. Among the eight known phenolic constituents of moringa leaves, caffeic acid and chlorogenic acid may be responsible for the O2–specific radical scavenging capacity stronger than that of Trolox. These results suggest that moringa herbal teas are a good source of natural antioxidants for preventing O2−radical-mediated disorders.Abbreviations:O2−: superoxide anion; ROS: reactive oxygen species; H2O2: hydrogen peroxide; XOD: xanthine oxidase; DPPH: 1,1-diphenyl-2-picrylhydrazyl; ABTS+: 2,2′-azinobis(2-ethylbenzothiazoline-6-sulfonic acid) cation; CPZ+: chlorpromazine cation; PMS: phenazine methosulfate; NBT: nitroblue tetrazolium; PMA: phorbol 12-myristate 13-acetate

In this study, we aimed to identify starter strains of lactic acid bacteria (LAB) to produce soymilk yogurt that can decrease the risk of diabetes mellitus (DM) and its complications. The inhibition assays of the dipeptidyl peptidase IV (DPP- IV) and advanced glycation end products (AGEs) formation were conducted using 70% ethanol (EtOH) extraction of freeze-dried soymilk yogurt. Soymilk yogurt produced using Weissella confusaTOKAI 2 showed the highest inhibition rate in the α-amylase inhibition assay, while soymilk yogurt produced using Lactiplantibacillus plantarumTOKAI 17 showed the highest inhibition rates in the α-glucosidase and DPP-Ⅳ inhibition assays, respectively. Soymilk yogurt produced using Streptococcus macedonicusTOKAI 4 showed the highest inhibitory activities in Nω-(carboxymethyl) arginine (CMA) and Nε-(carboxymethyl) lysine (CML) formation, respectively. Furthermore, soymilk yogurt prepared using Lb. plantarumTOKAI 17 and Lactiplantibacillus pentosusTOKAI 35 exhibited higher proportions of aglycone isoflavones than soymilk and showed a higher fluorescent AGEs inhibitory activity than that of soymilk (p < 0.05). Interestingly, the inhibition assay assessing fluorescent AGEs formation using isoflavones indicated that aglycone-type isoflavones, such as genistein and daidzein, had higher inhibitory activities than that of glycosides (p < 0.05). These results indicate that soymilk yogurt produced using Lb. plantarumTOKAI 17 and Lb. pentosusTOKAI 35 had inhibitory effects on α-glucosidase, DPP-Ⅳ, and AGEs formation in vitro, and that aglycone isoflavones might inhibit the formation of fluorescent AGEs.

Despite their high degree of identity and even higher homology, the two Kat3 transcriptional coactivators, CBP and p300, have distinct functions, particularly within the Wnt/β-catenin signaling cascade. ICG-001, by directly binding to CBP but not p300, inhibits CBP/β-catenin transcription and has served as an invaluable chemical genomic tool to dissect the Wnt signaling cascade and the divergent roles of these two coactivators. However, to date no direct antagonist of the p300/β-catenin interaction has been reported. We now report the identification and validation of the first highly specific, direct p300/β-catenin antagonists, YH249/250 and their ability to maintain pluripotency in ESC.

Tocopherols are essential micronutrients for mammals widely known as potent lipid-soluble antioxidants that are present in cell membranes. Recent studies have demonstrated that most of the carboxychromanol (CEHC), a tocopherol metabolite, in the plasma exists primarily in sulfate- and glucuronide-conjugated forms. To gain insight into the enzymatic sulfation of tocopherols and their metabolites, a systematic investigation was performed using all 14 known human cytosolic sulfotransferases (SULTs). The results showed that the members of the SULT1 family displayed stronger sulfating activities toward tocopherols and their metabolites. These enzymes showed a substrate preference for γ-tocopherol over α-tocopherol and for γ-CEHC over other CEHCs. Using A549 human lung epithelial cells in a metabolic labeling study, a similar trend in the sulfation of tocopherols and CEHCs was observed. Collectively, the results obtained indicate that SULT-mediated enzymatic sulfation of tocopherols and their metabolites is a significant pathway for regulation of the homeostasis and physiological functions of these important compounds.

Cadherin family is classified into classical cadherins, desmosomal cadherins and protocadherins (PCDHs). Genomic structures distinguish between PCDHs and other cadherins, and between clustered and non-clustered PCDHs. The phylogenetic analysis with full sequences of non-clustered PCDHs enabled them to be further classified into three subgroups: δ1 (PCDH1, PCDH7, PCDH9, PCDH11 and PCDH20), δ2 (PCDH8, PCDH10, PCDH12, PCDH17, PCDH18 and PCDH19) and ε (PCDH15, PCDH16, PCDH21 and MUCDHL). ε-PCDH members except PCDH21 have either higher or lower numbers of cadherin repeats than those of other PCDHs. Non-clustered PCDHs are expressed predominantly in the nervous system and have spatiotemporally diverse expression patterns. Especially, the region-specific expressions of non-clustered PCDHs have been observed in cortical area of early postnatal stage and in caudate putaman and/or hippocampal formation of mature brains, suggesting that non-clustered PCDHs play roles in the circuit formation and maintenance. The non-clustered PCDHs appear to have homophilic/heterophilc cell-cell adhesion properties, and each member has diverse cell signaling partnership distinct from those of other members (PCDH7/TAF1; PCDH8/TAO2β; PCDH10/Nap1; PCDH11/β-catenin; PCDH18/mDab1). Furthermore, each PCDH has several isoforms with differential cytoplasmic sequences, suggesting that one PCDH isoform could activate intracellular signaling differential from other isoforms. These facts suggest that non-clustered PCDHs play roles as a mediator of a regulator of other molecules as well as cell-cell adhesion. Furthermore, some non-clustered PCDHs have been considered to be involved in neuronal diseases such as autism-spectrum disorders, schizophrenia, and female-limited epilepsy and cognitive impairment, suggesting that they play multiple, tightly regulated roles in normal brain function. In addition, some non-clustered PCDHs have been suggested as candidate tumor suppressor genes in several tissues. Although molecular adhesive and regulatory properties of some PCDHs began to be unveiled, the endeavor to understand the molecular mechanism of non-clustered PCDH is still in its infancy and requires future study.

Cytosolic sulfotransferases (SULTs) are traditionally known as the Phase II drug-metabolizing or detoxifying enzymes that serve for the detoxification of drugs and other xenobiotics. These enzymes in general catalyze the transfer of a sulfonate group from the active sulfate, 3-phophoadenosine 5-phosphosulfate (PAPS), to low-molecular weight substrate compounds containing hydroxyl or amino group(s). Despite considerable efforts made in recent years, some fundamental aspects of the SULTs, particularly their ontogeny, cell type/tissue/organ-specific distribution, and physiological relevance, particularly their involvement in drug metabolism and detoxification, still remain poorly understood. To better understand these fundamental issues, we have embarked on developing the zebrafish as a model for studies concerning the SULTs. To date, fifteen zebrafish SULTs have been cloned, expressed, purified, and characterized. These zebrafish SULTs, which fall into four major SULT gene families, exhibited differential substrate specificities and distinct patterns of expression at different stages during embryogenesis, through larval development, and on to maturity. The information obtained, as summarized in this review, provides a foundation for further investigation into the physiological and pharmacological involvement of the SULTs using the zebrafish as a model.

Multiplexing characteristics of a dc-removed coaxial holographic storage system were evaluated for what is believed to be the first time. Our dc-removed coaxial system achieved 3.5 times higher raw data density than a conventional coaxial system that involved dc recording. The increase of the data density was due not only to less M/# consumption but also to the effects of signal amplification and noise reduction by use of the positive and negative images reconstructed from the same holograms.

To establish the zebrafish as a model for investigating the drug metabolism through sulfation, we had embarked on establishing a complete repertoire of the zebrafish Phase II cytosolic sulfotransferases (SULTs). By searching the expressed sequence tag database, a zebrafish cDNA encoding a putative cytosolic sulfotransferase (SULT) was identified. Based on the sequence analysis, this zebrafish SULT was found to belong to the SULT3 gene family. The recombinant protein of the zebrafish SULT, designated SULT3 ST3, was expressed in and purified from BL21 (DE3) Escherichia coli cells transformed with the pGEX-2TK expression vector harboring SULT3 ST3 cDNA. Upon enzymatic characterization, purified SULT3 ST3 displayed sulfating activity toward hydroxysteroids, particularly pregnenolone and dehydroepiandrosterone (DHEA), as well as several drugs among various endogenous and xenobiotic compounds tested as substrates. The pH-dependence and kinetic constants of this enzyme with DHEA were determined. The regulatory effects of various divalent metal cations on the DHEA-sulfating activity of SULT3 ST3 were quantitatively evaluated. A reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed developmental stage-dependent expression of SULT3 ST3 during embryonic development and throughout the larval stage onto maturity. Collectively, these results suggest a possible involvement of the newly discovered SULT3 ST3 in the metabolism of hydroxysteroids and xenobiotics including drugs in zebrafish.

A method for simultaneous detection and quantification is presented to determine the presence of isoflavones and bisphenol A in a biological sample. A coulometric array detector was used with reversed-phase high-performance liquid chromatography (HPLC). Daidzein (1), glycitein (2), genistein (3) and their glucoside conjugates, daidzin (4), glycitin (5) and genistin (6), were measured as phytochemicals. Also assayed here was equol (7), a metabolite from compound 1, and bisphenol A (8), an industrial chemical that acts as an endocrine disrupter. All chemicals were simultaneously detected by using a 600-mV single detection voltage with high efficacy. A mixture of 1, 3and 8was orally administered to rats, and the levels of these three chemicals in the serum were clearly increased after a 4 kU β-glucuronidase treatment. The levels of compounds 1and 3in the serum were detected at 1665 and 2040 ng/ml, while 8was at a low level of 417 ng/ml. Compound 7in the serum was not detected until after enzymatic hydrolysis (72 ng/ml). These results suggest that this analytical method would be useful for metabolic and pharmacokinetic studies on isoflavones and bisphenol A.

The role of glutamate receptors in the inferior colliculus (IC) in audiogenic and audiogenic-like seizures was investigated in adult rats with transient neonatal hypothyroidism by 0.02% propylthiouracil (PTU) treatment through mother's milk (PTU rats) and in naive rats treated intracisternally with N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA), or cyclothiazide, an inhibitor of rapid AMPA receptor desensitization. All rats showed audiogenic or audiogenic-like seizures characterized by running fit (RF) and generalized tonic–clonic seizures (GTCS). While systemically administered MK-801 inhibited GTCS, intracisternally administered NBQX inhibited RF and GTCS in both audiogenic and audiogenic-like seizures. Auditory stimulation shortened the latency to GTCS induced by AMPA, but not NMDA, at a subclinical dose and further elongated the shortened duration of RF, but not GTCS, induced by MK-801 pretreatment. Furthermore, Northern blot analysis was used to evaluate the expression of the immediate-early gene c-fosin the IC following induction of audiogenic or audiogenic-like seizures. The significant induction of c-fosmRNA by audiogenic seizures in PTU rats or by AMPA- or cyclothiazide-induced seizures in naive rats was prominent in the IC. MK-801 suppressed c-fosmRNA expression in the IC induced by audiogenic seizures in PTU rats or by AMPA-induced seizures in naive rats. NBQX suppressed the expression of c-fosmRNA in the IC induced by AMPA-induced seizures but did not suppress c-fosmRNA in PTU rats or rats with cyclothiazide-induced seizures. Auditory stimuli failed to affect c-fosmRNA induction by AMPA. The present study suggests that audiogenic-like seizures can be reproduced by glutamate receptor agonists in which AMPA receptors are primarily linked to the initiation of audiogenic seizures (RF) while NMDA receptors presumably located within the IC are involved in the propagation of GTCS in audiogenic seizures.

The aim of this study was to compare the disposition of the tricyclic antidepressant clomipramine (C) in Japanese and Swedish patients receiving continuous treatment. Therapeutic drug monitoring data for C and the active metabolite N-desmethylclomipramine (DC) in Japanese patients receiving monotherapy (N = 12) and in those receiving C plus benzodiazepines (BZDs) (N = 96) as well as in Swedes receiving C monotherapy (N = 131) and in those receiving C plus BZDs (N = 43) were used. A population kinetic approach with Bayesian feedback was used to estimate the individual clearance values for C. The relationships between kinetic variables and covariates were evaluated by linear multiple regression. The median (25% and 75% quartiles, respectively) oral clearance of C was 12.7 L/hr (11.6, 30.6) in Japanese patients receiving C monotherapy, 18.1 L/hr (5.6, 31.8) in Japanese patients receiving C plus BZDs, 62.7 L/hr (40.0, 90.6) in Swedish patients receiving C monotherapy, and 56.5 L/hr (34.3, 74.1) in Swedish patients receiving C plus BZDs. When combining all populations in a linear multiple regression, clearance was correlated with ethnic group (p< 0.00001) and age (p< 0.0005), but it was uncorrelated with gender, body weight, and administration of BZDs. The C/DC plasma concentration ratios were 1.08 in Japanese patients receiving C monotherapy, 0.90 in Japanese patients receiving C plus BZDs, 0.51 in Swedish patients receiving C monotherapy, and 0.49 in Swedish patients receiving C plus BZDs. Thus, the lower oral clearance of C in Japanese patients compared with that in Swedish patients is not accounted for by the lower body weight in Japanese patients or by concomitant treatment with BZDs and is therefore likely to be a true ethnic difference. The higher C/DC ratio implicates a more pronounced serotonergic than noradrenergic effect in Japanese patients than in Swedish patients.

The extract from bulbs of Scilla scilloidesexhibited inhibitory effects in lipoxygenase and hyaluronidase assays and various oxidation models in vitro. Incubating the cells in the presence of this extract ameliorated t-butyl hydroperoxide-induced cytotoxicity from 27% to 57% in a macrophage model. The results may indicate the potential role of S. scilloidesfor its anti-inflammatory and antioxidative effects.

A fabrication method for square lens arrays together with their application to integral photography is presented. Our square lens arrays are fabricated by a technique similar to the fabrication of cylindrical lens arrays that was reported in Opt. Rev. 19(2012) 287. This technique features the easy control of the pitch and radius of curvature of the lens arrays. The lens pitches in both transverse and longitudinal directions are controlled by adjusting the interval of partition walls created by scratching a polymeric substrate with a sharp edge. The radius of curvature is controlled by adjusting the volume of the ultra-violet curable polymer deposited into square apertures formed by the partition walls. The vertices of the partition walls prevent the spreading of the polymer owing to the pinning effect. It is also demonstrated that our square lens array succeeded in realizing three-dimensional integral printing.

A method of reconstructing positive and negative images simultaneously from the same dc-removed coaxial Fourier hologram with the same reference pattern is presented. The simultaneous reconstruction is possible by making the polarization of the additional dc component of the signal beam perpendicular to the polarization of the reconstructed signal beam, in which separately detected s- and p-polarization components create contrast-reversed images. This method provides an aspect of designing dc-removed coaxial holographic storage systems for realizing optical noise reduction and less consumption of dynamic range of the recording medium.

A method of reconstructing positive and negative images from Fourier holograms recorded without the dc components is demonstrated by use of a coaxial holographic storage system. Reconstructed images are obtained by adding a phase-modulated dc component of the signal beam on reading. Contrast reversal of the reconstructed images can be achieved by reversing the readout reference pattern. This method can realize not only optical noise reduction but also less consumption of the dynamic range of the recording medium, potentially contributing to increasing the number of multiplexed holograms.

A technique of recovering the data pages from Fourier holograms recorded without the dc components is demonstrated theoretically and experimentally by use of a coaxial holographic storage system. A reconstructed image is obtained by adding a phase-modulated dc component of the signal beam on reading. The bit error rate of the reconstructed image is comparable with that for the hologram recorded with the dc component as well. Since high intensities of the dc components are not recorded in this technique, the dynamic range of the recording media can be saved, which potentially contributes to increasing the number of multiplexed holograms.

A technique for reconstructing positive and negative images from an identical intensity-modulated hologram is demonstrated theoretically and experimentally by use of a coaxial holographic storage system. Negative images are obtained by adding a phase-modulated dc component of signal beam on reading. By comparing positive and negative images, the bit error rate (BER) is improved by two orders of magnitude. This technique can reduce optical noise of reconstructed images to attain low BERs.

An application of pinned cylindrical lens arrays (CLAs) reported in Opt. Rev. 19(2012) 287 to three-dimensional prints is presented for the first time. This lens fabrication method features the easy control of the pitch and radius of curvature of the lens arrays by taking advantage of the pinning effect that the partition walls created on a polymeric substrate by scratching with a cutter blade prevent the ultraviolet curable polymer dispensed between the walls from spreading. It is demonstrated in this paper that a three-dimensional print was realized successfully with the pinned CLA fabricated with our method.