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β‐Carotene (BC) is a strong antioxidant, but its therapeutic application has been limited by its poor aqueous solubility. Protein‐based nanoparticles (NPs) have been used to increase the aqueous solubility of hydrophobic drugs. In this study, bovine serum albumin (BSA) was used to prepare NPs to encapsulate BC using a high‐speed homogenizer. After homogenization, BC‐BSA‐NPs were formed and the encapsulated BC was dissolved in phosphate‐buffered saline at pH 7.4. Various characterization methods, including dynamic light scattering, transmission electron microscopy, and spectrophotometry, indicated that BC‐BSA‐NPs were spherical with an average size of 112 nm and encapsulated BC with high efficiency. BC encapsulated in NPs was stable during the preparation process and was continuously released in PBS at 37 °C for 3 days. The 2,2‐diphenyl‐1‐picrylhydrazyl and ferric reducing antioxidant power assays demonstrated good antioxidant activity of BC‐BSA‐NPs. These results suggest that BSA‐NPs are a promising nanocarrier for the delivery of BC. [ABSTRACT FROM AUTHOR]

PTEN is a tumor suppressor found mutated in many cancers. From a synthetic lethality drug screen with PTEN-isogenic colorectal cancer cells, we found that mutant-PTEN cells were resistant to dual inhibitors of FLT3 and aurora kinase-A, including KW2449 and ENMD-2076. KW2449 significantly reduced the viability of wildtype-PTEN cells causing apoptosis, while little effect was observed in mutant-PTEN counterparts. Transcriptome profiling showed that members of PI3K-AKT signaling pathway were strongly changed in cells after KW2449 treatment, indicating a potential role of the pathway in drug resistance. We found that KW2449 caused a dose-dependent, biphasic induction of AKT phosphorylation at Ser473 in mutant-PTEN cells. Co-treatment with the inhibitors of its upstream signaling completely abolished the reactivation of AKT phosphorylation by KW2449 and reversed the drug resistant phenotype. These data suggest that reactivation of AKT phosphorylation at Ser473 is a key factor to confer drug resistant phenotype of mutant-PTEN cells to the dual inhibitors and that proper drug combinations that shut down AKT reactivation is necessary for the effective treatment of mutant-PTEN cancer with the dual inhibitors in clinical settings. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder afflicting from infancy to adults with itching, scratching, and lichenification. We aimed to investigate the effects of esculetin from Fraxinus rhynchophylla on atopic skin inflammation. For induction of atopic skin inflammation, we exposed the ears of female BALB/c mice to house dust mite ( Dermatophagoides farinae extract, DFE) and 2,4-dinitrochlorobenzene (DNCB) for 4 weeks. Oral administration of esculetin reduced the symptoms of DFE/DNCB-induced atopic skin inflammation, which were evaluated based on ear swelling and number of scratch bouts. The immunoglobulin (Ig) E, IgG2a, and histamine levels in serum were decreased and inflammatory cell infiltration in skin tissue was reduced by the esculetin. It suppressed production of Th1, Th2 and Th17-related cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-4, IL-13, IL-31 and IL-17 in the ear tissue. Furthermore, we investigated the effects of esculetin on activated keratinocytes, which are representative cells used for studying the pathogenesis of acute and chronic atopic skin inflammation. As results, esculetin suppressed gene expression of Th1, Th2 and Th17 cytokines and the activation of nuclear factor-κB and signal transducer and activator of transcription 1 in TNF-α/IFN-γ-stimulated keratinocytes. Taken together, these results imply that esculetin attenuated atopic skin inflammation, suggesting that esculetin could be a potential therapeutic candidate for the treatment of AD. [ABSTRACT FROM AUTHOR]

Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type C1 (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents. [ABSTRACT FROM AUTHOR]

During the screening of the cytotoxicity of rare Korean endemic plants, the extract of Thuja koraiensis Nakai displayed potent cytotoxicity against the adenocarcinomic human alveolar basal epithelial A549 cell line. Through a series of separations via column chromatography, three undescribed abietanes, an undescribed labdane along with a labdane, and a biflavonoid were purified from methylene chloride (CH 2 Cl 2) fraction possessing a potent cytotoxic effect. Extensive 1D and 2D NMR spectroscopic data analyses, in combination with quantum chemical calculations were conducted to establish the planar and absolute configurations of thujakoraienes A–C. The chemical structure of thujakoraiene D was elucidated by spectroscopic data analysis and competing enantioselective acylation. Thujakoraienes A and C along with 7,7″-di- O -methylamentoflavone, showed cytotoxic effects on A549 cells, with IC 50 values of 64.86, 47.97, and 16.14 μM, respectively. Finally, thujakoraiene C and 7,7″-di- O -methylamentoflavone were identified as potent cytotoxic compounds in A549 cells, followed by an additional cytotoxicity test in the normal human lung fibroblast MRC-5 cell line. This is the first study on the non-volatile chemicals in the extract of T. koraiensis and comparison of chemical profiles of T. orientalis and T. koraiensis. Four undescribed diterpenoids together with a diterpene and a biflavonoid were isolated from Korean rare endemic plant Thuja koraiensis. ECD calculation combined with NMR data analysis or chemical derivatization were used to structural assignment. Some of the isolated compounds showed cytotoxicity in A549 cell line. [Display omitted] • Non-volatile chemical constituents of Thuja koraiensis reported for the first time. • Four undescribed diterpenoids were isolated from Thuja koraiensis. • The configurations were confirmed by ECD calculation or chemical derivatization. • Two compounds showed cytotoxicity against A549 cell line. [ABSTRACT FROM AUTHOR]

Herbal medicines were subjected to enzyme reaction by using a commercial glycosidase AMG-300L, and were evaluated for enhancement of their antioxidative activities. The methanolic extract of Gentianae Scabrae Radix (GSR) showed the most dramatic changes after enzyme reaction, as seen in the high-performance liquid chromatography profiles and an increase in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging effect. Trifloroside ( 1, TF) was identified as being significantly decreased by enzyme reaction, whereas deglucosyltrifloroside ( 2, DTF) increased. The optimal reaction time to induce DTF was 24 h at 30°C. The content increased from 1.00 ± 0.29 mg/g of extract (gex) to 2.80 ± 0.85 mg/gex after 24 h of enzyme reaction. DTF showed better antioxidative effect than TF in the DPPH, Trolox equivalent antioxidant capacity, and reactive oxygen species (ROS) in HT22 cell assays. In addition, when HT22 cells were stressed by 5 mM glutamate, 50 μM of DTF significantly inhibited the glutamate-induced lactate dehydrogenase leakage, Ca2+ influx, lipid peroxidation, and intracellular ROS production. These data demonstrated that the enzyme-treated GSR and its increased level of antioxidant DTF could be useful as a starting point in the discovery of functional foods to prevent various oxidative stresses, especially neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

It is becoming increasingly important to investigate drug metabolites to evaluate their toxic or preventive effects after administration of the parent compound. In our previous study, isoliquiritigenin isolated from Glycyrrhizae Radix effectively protected mouse-derived hippocampal neuronal cells (HT22) against 5 mM glutamate-induced oxidative stress. However, there is little information on the protective effects of the metabolites of isoliquiritigenin on HT22 cells. In this study, isoliquiritigenin and its Phase I metabolites were prepared and their neuroprotective activities on glutamate-treated HT22 cells were compared. The prepared metabolites were liquiritigenin ( 1 ), 2′,4,4′,5′-tetrahydroxychalcone ( 2 ), sulfuretin ( 3 ), butein ( 4 ), davidigenin ( 5 ), and cis -6,4′-dihydroxyaurone ( 6 ). Among the six metabolites, 4 showed better neuroprotective effects than the parent compound, isoliquiritigenin. Our study suggests that the neuroprotective effect of isoliquiritigenin could be elevated by its active metabolite 4 , which is a chalcone containing a catechol group in the B ring. [ABSTRACT FROM AUTHOR]

The ubiquitous nuclear protein, high mobility group box-1 (HMGB1) functions as a late mediator of sepsis. A new rarely occurring C -methylrotenoid, named boeravinone X (comp 1 ), was isolated and identified from Abronia nana suspension cultures during our continuous works on the discovery of anti-septic natural products. Here, we investigated the antiseptic effects and underlying mechanisms of comp 1 against HMGB1-mediated septic responses. According to the results, comp 1 effectively inhibited lipopolysaccharide (LPS)-induced release of HMGB1, and suppressed HMGB1-mediated septic responses, such as hyperpermeability, adhesion and migration of leukocytes, and expression of cell adhesion molecules. And, comp 1 suppressed the production of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), and the activation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) by HMGB1. Collectively, these results indicate that comp 1 could be potential therapeutic agents for the treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway. [ABSTRACT FROM AUTHOR]

Polyozellus multiplex (Thelephoraceae) is a wild mushroom in Korea and Japan and is usually harvested in early autumn for food. Polyozellin, a major constituent of the edible mushroom P multiplex , has been known to exhibit biological activities such as antioxidative and anti-inflammatory effects. Transforming growth factor β–induced protein (TGFBIp) is an extracellular matrix protein whose expression in several cell types is greatly increased by TGF-β. TGFBIp is released by human umbilical vein endothelial cells and functions as a mediator of experimental sepsis. We hypothesized that polyozellin could reduce TGFBIp-mediated severe inflammatory responses in human endothelial cells and mice. Here, we investigated the antiseptic effects and underlying mechanisms of polyozellin against TGFBIp-mediated septic responses. Polyozellin effectively inhibited lipopolysaccharide-induced release of TGFBIp and suppressed TGFBIp-mediated septic responses. In addition, polyozellin suppressed cecal ligation and puncture–induced sepsis lethality and pulmonary injury. In conclusion, polyozellin suppressed TGFBIp-mediated and cecal ligation and puncture–induced septic responses. Therefore, polyozellin could be a potential therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the TGFBIp signaling pathway. [ABSTRACT FROM AUTHOR]

Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). Polyozellin, a major constituent of a Korea edible mushroom Polyozellus multiplex , has been known to exhibit the biological activities such as anti-oxidative and anti-inflammatory effects. However, little is known about the effects of polyozellin on EPCR shedding. We investigated this issue by monitoring the effects of polyozellin on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-α-, interleukin (IL)-1β-induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-mediated EPCR shedding in mice and underlying mechanism. Data demonstrate that polyozellin induced potent inhibition of PMA-, TNF-α-, IL-1β- (in HUVECs), and CLP-induced EPCR shedding (in mice) via inhibition of phosphorylation of mitogen-activated protein kinases (MAPKs) such as p38, janus kinase (JNK), and extracellular signal-regulated kinase (ERK) 1/2. Polyozellin also inhibited the expression and activity of PMA-induced TACE in HUVECs suggesting that p38, ERK1/2, and JNK could be the molecular targets of POZ. These results demonstrate the potential of polyozellin as an anti-EPCR shedding reagent against PMA-mediated and CLP-mediated EPCR shedding. [ABSTRACT FROM AUTHOR]

Aim and objective: The ubiquitous nuclear protein, high-mobility group box 1 (HMGB1), is released by activated macrophages and human umbilical vein endothelial cells (HUVECs) and functions as a late mediator of experimental sepsis. Polyozellin, which has been reported to have a variety of biological activities including antioxidant and anticancer activity, is the major active compound found in edible mushroom ( Polyozellus multiplex). In this study, we investigated the antiseptic effects and underlying mechanisms of polyozellin against HMGB1-mediated septic responses in HUVECs and mice. Methods: The anti-inflammatory activities of polyozellin were determined by measuring permeability, human neutrophil adhesion and migration, and activation of proinflammatory proteins in HMGB1-activated HUVECs and mice. Results: According to the results, polyozellin effectively inhibited lipopolysaccharide (LPS)-induced release of HMGB1, and suppressed HMGB1-mediated septic responses, such as hyperpermeability, adhesion and migration of leukocytes, and expression of cell adhesion molecules. In addition, polyozellin suppressed the production of tumor necrosis factor-α and interleukin (IL)-6, and the activation of nuclear factor-κB and extracellular signal-regulated kinases 1/2 by HMGB1. Conclusion: Collectively, these results indicate that P. multiplex containing polyozellin could be commercialized as functional food for preventing and treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Strain HD1 with antifungal activity was isolated from kimchi and identified as Lactobacillus plantarum. Antifungal compounds from Lb. plantarum HD1 were active against food- and feed-borne filamentous fungi and yeasts in a spot-on-the-lawn assay. Antifungal activity of Lb. plantarum HD1 was stronger against filamentous fungi than yeast. Antifungal compounds were purified using solid phase extraction (SPE) and recycling preparative-HPLC. Structures of the antifungal compounds were elucidated by electrospray ionization-mass spectrometry and nuclear magnetic resonance. Active compounds from Lb. plantarum HD1 were identified as 5-oxododecanoic acid (MW 214), 3-hydroxy decanoic acid (MW 188), and 3-hydroxy-5-dodecenoic acid (MW 214). To investigate the potential application of these antifungal compounds for reduction of fungal spoilage in foods, Korean draft rice wine was used as a food model. White film-forming yeasts were observed in control draft rice wine after 11 days of incubation. However, film-forming yeasts were not observed in draft rice wine treated with SPE-prepared culture supernatant of Lb. plantarum HD1 (equivalent to 2.5% addition of culture supernatant) until 27 days of incubation. The addition of antifungal compounds to Korean draft rice wine extended shelf-life up to 27 days at 10 °C without any sterilization process. Therefore, the antifungal activity of Lb. plantarum HD1 may lead to the development of powerful biopreservative systems capable of preventing food- and feed-borne fungal spoilage. [Copyright &y& Elsevier]

Abstract: Suspension cultures of Abronia nana were established to produce C-methylisoflavones. A new C-methylrotenoid, named abronione A (2), was isolated along with three known rotenoids, boeravinone D (1), boeravinone A methyl ether (3), and mirabijalone D (4). The IC50 values of compounds 1, 2, and 4 on β-secretase (BACE1) were 4.77, 62.21, and 4.24μM, respectively, whereas 3 was inactive. At concentrations up to 1.0mM, the compounds did not inhibit other proteases such as trypsin, chymotrypsin, and elastase, indicating that they were specific inhibitors of β-secretase. Compounds 1 and 4 were non-competitive inhibitors based on the Dixon plot and with K i values of 5.01 and 4.28μM, respectively. At 50μM, compound 4 inhibited Aβ1–42 production by 43.7% in APPSW-N2a cells. [Copyright &y& Elsevier]

Abstract: The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc; medullary dorsal horn) receives and processes orofacial nociceptive inputs, and serotonergic fibers involved in the descending modulation of nociception are more densely distributed in the superficial laminae of the Vc. This study investigated the direct effects of 5-HT1A/7 receptor agonist 8-OH-DPAT on SG neurons of the Vc to assess functional expression of the 5-HT7 receptor using gramicidin-perforated patch-clamp in postnatal day (PND) 5-84 male mice. Of the 70 SG neurons tested, bath application of 8-OH-DPAT (30μM) induced depolarization (n=33), hyperpolarization (n=16) or no response (n=21). In another 10 SG neurons, 8-OH-DPAT in the presence of 5-HT1A receptor antagonist WAY-100635 (1μM) elicited either depolarization (n=6) or no response (n=4); hyperpolarization was not observed. The 8-OH-DPAT-induced depolarization was significantly blocked by the selective 5-HT7 receptor antagonist SB-269970 (10μM; n=8), but not by WAY-100635 (1μM; n=5). The depolarizing effect of 8-OH-DPAT was maintained in the presence of TTX, CNQX, AP5, picrotoxin, and strychnine, indicating direct postsynaptic action of 8-OH-DPAT on SG neurons (n=6). 5-HT7 receptor mRNA was also detected in five of 21 SG neurons by single-cell RT-PCR. The mean amplitude of 8-OH-DPAT-induced depolarization in PND 5-21 mice (n=21) was significantly larger than that in PND 22-84 mice (n=12), although the proportion of SG neurons responding to 8-OH-DPAT by depolarization did not differ significantly between two age groups of mice. These results indicate that 5-HT7 receptors are functionally expressed in a subpopulation of SG neurons of the Vc and activation of 5-HT7 receptors plays an important role in modulating orofacial nociceptive processing in the SG neurons of the Vc. [Copyright &y& Elsevier]

Highlights: [•] Liquiritigenin (LIQ) was isolated as an active compound from licorice roots. [•] LIQ effectively reduced the early apoptosis in glutamate-treated HT22 cells. [•] Ca2+ influx, ROS production, and lipid peroxidation were inhibited by LIQ. [•] LIQ suppressed the mitochondrial stress and MAPKs phosphorylation. [•] LIQ might be useful for the development of drugs for neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the effect of pH on the complexation of quercetin and polyamidoamaine (PAMAM) dendrimers, which can exert antioxidant activity in aqueous solution. The therapeutic use of quercetin has been limited due to its low water solubility and bioavailability. In this study, quercetin was complexed with generation 4 PAMAM (G4) in different buffers at pH 4–9, with pH 6 showing the best results in terms of solubility and stability. The solubility of quercetin in 0.1 M phosphate buffer at pH 6.0 containing 1% G4 was over 1 mg/ml. The antioxidant and neuroprotective activities of water‐soluble G4–quercetin complex (G4‐Q) were comparable to those of free quercetin dissolved in methanol. In conclusion, this study indicates that the complexation of quercetin with PAMAM dendrimers was optimized at pH 6 and the complex exhibits good water solubility, strong antioxidant activity, and neuroprotective activity. [ABSTRACT FROM AUTHOR]

Highlights: [•] EPCR shedding is involved in the vascular inflammation. [•] EPCR shedding is mediated by PMA activation. [•] RA inhibited the PMA and CLP-induced EPCR shedding by suppressing TACE expression. [•] RA reduced PMA-stimulated phosphorylation of p38, ERK1/2 and JNK. [ABSTRACT FROM AUTHOR]

In the course of screening for neuroprotective natural products, Magnoliae Cortex showed potent inhibition of hippocampal neuronal HT22 cell death. Obovatol, honokiol, and magnolol were isolated from the ethanolic extract of Magnoliae Cortex. Isolated compounds obovatol, honokiol, and magnolol were protective against 5mM glutamate-induced cell death. When cells were stressed using glutamate, cell viability decreased to 16.98±4.58% over the control (100.00±10.15%). In contrast, 10μM obovatol, 10μM honokiol, and 50μM magnolol increased cell viability to 91.80±1.70%, 93.59±1.93%, and 85.36±7.40%, respectively. The neuroprotective effects of obovatol and honokiol were attributable to the inhibition of intracellular reactive oxygen species production, followed by protection of the mitochondrial membrane potential (ΔΨm ), recovery of Bcl-2 and Bid levels, inhibition of apoptosis-inducing factor expression, and phosphorylation of mitogen-activated protein kinases such as p38 kinases, extracellular signal-regulated kinases, and c-Jun N-terminal kinases. On the contrary, magnolol did not show any significant effect on the ΔΨm and apoptotic factors. Among three compounds, obovatol most strongly scavenged 2,2-diphenyl-1-picrylhydrazyl radicals and inhibited the elevation of intracellular reactive oxygen species levels in glutamate-stressed HT22 cells. These data suggest that obovatol and honokiol may have clinical applications for preventing neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

High mobility group box 1 (HMGB1) protein is a crucial cytokine that mediates response to infection, injury, and inflammation. Rosmarinic acid (RA) is an important component of the leaves of Perilla frutescens and has neuroprotective, anti-microbial, anti-oxidant, and anti-cancer effects but little is known of its effects on HMGB1-mediated inflammatory response. Here, we investigated this issue by monitoring the effects of RA on the lipopolysaccharide (LPS) or cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated modulation of inflammatory responses. RA potently inhibited the release of HMGB1 and down-regulated HMGB1-dependent inflammatory responses in human endothelial cells. RA also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. Furthermore, RA reduced CLP-induced HMGB1 release and sepsis-related mortality. Given these results, RA should be viewed as a candidate therapeutic agent for the treatment of various inflammatory diseases via inhibition of the HMGB1 signaling pathway. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Ischemic stroke is caused by brain injury due to prolonged ischemia by occlusion of cerebral arteries. In this study, we isolated active compounds from an ethanol extract of Aurantii Immatri Pericarpium (HY5356). We first showed by DNA fragmentation assay that HY5356 improved human hepatocellular carcinoma cells (HepG2) under hypoxic conditions by inhibiting apoptosis. When HY5356 was fractionated with dichloromethane (MC), ethyl acetate (EA) and n-butanol (BU), the MC fraction improved cell viability at the lowest concentration (100μg/ml). Intraperitoneal injection of HY5356 (200mg/kg) or the MC fraction (200mg/kg) to rats prior to occlusion attenuated brain injury significantly in a rat model of ischemia–reperfusion. Adopting cell viability under hypoxic conditions as an activity screening system, we isolated nobiletin and tangeretin as active compounds. The results suggest that intake of Aurantii Immatri Pericarpium containing nobiletin and tangeretin as active compounds might be beneficial for preventing ischemic stroke. [Copyright &y& Elsevier]

Oleanolic acid (OA) is a triterpenoid known for its anti-inflammatory and anti-cancer properties; however, the anti-inflammatory effects of OA on lipopolysaccharide (LPS)-mediated pro-inflammatory responses have not been studied. Here, we first investigated the possible anti-inflammatory effects of OA against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) induced by LPS and the associated signaling pathways. We found that OA inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion/transendothelial migration of monocytes to HUVECs. OA also suppressed acetic acid-induced hyperpermeability and carboxymethylcellulose-induced leukocyte migration in vivo. Further studies revealed that OA suppressed the production of tumor necrosis factor-α and activation of nuclear factor-κB by LPS. Collectively, these results suggest that OA has anti-inflammatory effects by inhibiting hyperpermeability, the expression of CAMs, and the adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapeutic agent for vascular inflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract: Yellow onion (Allium cepa) extract showed enhanced antioxidative effects in 2,2-diphenyl-1-picrylhydrazyl (DPPH), Trolox equivalent antioxidant capacity (TEAC) and 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate and acetyl ester (CM-H2DCFDA) assay after being treated with a crude enzyme extract from soybean paste fungi, Aspergillus kawachii. HPLC analysis showed two increased and two decreased peaks after enzyme treatment. The decreased peaks were identified as quercetin-3,4′-di-O-β-d-glucoside (1) and quercetin-4′-O-β-d-glucoside (2), and peaks that increased were quercetin-3-O-β-d-glucoside (3) and quercetin (4), respectively. It was expected that 3 and 4 were originated from the glucosidic cleavage of their glucosides, 1 and 2. Among the increased compounds, only quercetin (4) showed strong antioxidative activity in the DPPH assay. In addition, the protective effect against glutamate-induced neurotoxicity in HT22 cells was increased when treated with 25μg/ml of fermented onion. The enhanced neuroprotective effect was also originated from the increased quercetin content. As a consequence, fermentation raised the quercetin content in onion, and subsequently increased the antioxidative and neuroprotective activities. [Copyright &y& Elsevier]

In this study, we investigated the effects of CCL2 on constitutive apoptosis of normal and asthmatic neutrophils. CCL2 blocked the constitutive apoptosis of normal neutrophils through CCR2. CCL2 also induced elevation of the cytosolic Ca2+ concentration but had no effect on normal neutrophil chemotaxis. Constitutive apoptosis, calcium influx, and cell migration of asthmatic neutrophils were not affected by CCL2 stimulation. Supernatant collected from CCL2-treated normal neutrophils inhibited the constitutive apoptosis of normal neutrophils. Anti-apoptotic signaling mediated by CCL2 was found to be associated with the PI3K/Akt/ERK/NF-κB cascade in normal neutrophils. Both the cleavage of procaspase 3 and procaspase 9 and the decrease of in Mcl-1 expression were delayed by CCL2 stimulation. Inhibition of NF-κB blocked constitutive apoptosis of neutrophils from asthmatic patients via inhibition of the cleavage of procaspase 3 and procaspase 9, in contrast to normal neutrophils. NF-κB was involved in CCL2-induced anti-apoptotic signaling in normal neutrophils, whereas NF-κB functioned as a basal pro-apoptotic factor in asthmatic neutrophils. A better understanding of the difference in the regulation of neutrophil apoptosis due to CCL2 between normal individuals and asthmatics will enable elucidation of the role of CC chemokine in neutrophils and a framework for understanding the pathogenesis of asthma. J. Cell. Physiol. 227: 2567-2577, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Glutamate-mediated excitotoxicity, which is associated with reactive oxygen species (ROS), is hypothesized to be a major contributor to pathological cell death in the mammalian central nervous system, and to be involved in many acute and chronic brain diseases. Here, we showed that isoliquiritigenin (ISL) isolated from Glycyrrhiza uralensis (Gu), one of the most frequently prescribed oriental herbal medicines, protected HT22 hippocampal neuronal cells from glutamate-induced oxidative stress. In addition, we clarified the molecular mechanisms by which it protects against glutamate-induced neuronal cell death. ISL reversed glutamate-induced ROS production and mitochondrial depolarization, as well as glutamate-induced changes in expression of the apoptotic regulators Bcl-2 and Bax. Pretreatment of HT22 cells with ISL suppresses the release of apoptosis-inducing factor from mitochondria into the cytosol. Taken together, our results suggest that ISL may protect against mitochondrial dysfunction by limiting glutamate-induced oxidative stress. In conclusion, our results demonstrated that ISL isolated from Gu has protective effects against glutamate-induced mitochondrial damage and hippocampal neuronal cell death. We expect ISL to be useful in the development of drugs to prevent or treat neurodegenerative diseases. [Copyright &y& Elsevier]

Abstract: As a late mediator of inflammation, high mobility group box 1 (HMGB1) protein up-regulates pro-inflammatory cytokines in several inflammatory diseases. Further, high plasma levels of HMGB1 correlate with poor prognosis and increased mortality in patients with severe inflammation. Oleanolic acid (OA), a triterpenoid known for its anti-inflammatory and anti-cancer properties, is commonly present in several medicinal plants but the effects of OA on HMGB1-mediated pro-inflammatory responses of human endothelial cells is not well-studied. In this study, we investigated this question by monitoring the effect of OA on lipopolysaccharide (LPS)-mediated release of HMGB1 and the HMGB1-mediated modulation of inflammatory responses in human umbilical vein endothelial cells (HUVECs). OA potently inhibited the release of HMGB1 by HUVECs as well as down-regulated HMGB1-dependent adhesion and migration of the monocytic cell line THP-1 to activated HUVECs. OA also down-regulated the cell surface expression of the receptor of HMGB1, thereby inhibiting HMGB1-dependent pro-inflammatory responses by inhibiting activation of nuclear factor-κB (NF-κB) and production of tumor necrosis factor-α (TNF-α) by HMGB1. Given these results, OA showed anti-inflammatory activities and could be a candidate as a therapeutic agent for various inflammatory diseases through the inhibition of the HMGB1 signaling pathway. [Copyright &y& Elsevier]

Abstract: The trigeminal subnucleus caudalis (Vc) is the critical brainstem relay site of orofacial nociceptive processing to higher brain centers. The descending serotonergic pathway from the brainstem exerts inhibitory or facilitatory effects on nociceptive transmission in the spinal dorsal horn and the Vc, and SG neurons of the Vc exhibit hyperpolarization, no response or depolarization in response to 5-hydroxytryptamine (5-HT) application. In this study, we examined age-related changes in the effects of 5-HT on SG neurons of the Vc using immature, peripubertal and adult male mice and gramicidin-perforated patch recordings under the current-clamp mode. In the three age groups, hyperpolarization was the major response in SG neurons exhibiting membrane potential changes in response to 5-HT application. The proportion of the SG neurons responding to 5-HT by hyperpolarization was significantly higher in the immature (20/27) than in the adult mice (10/26; P <0.05). The proportion of SG neurons showing no response to 5-HT was significantly higher in the peripubertal (11/21) and the adult mice (13/26) compared with the immature mice (5/27). The amplitude of 5-HT-induced hyperpolarization significantly decreased with increasing postnatal age (correlation coefficient=−0.43, P <0.05). The mean amplitude of 5-HT-induced hyperpolarization was significantly higher in the immature mice (−9.7±1.1mV, n =20) than in the peripubertal (−5.3±1.0mV, n =10) and the adult mice (−5.4±0.9mV, n =10; both P <0.05). These results suggest that the descending serotonergic modulatory influence over the orofacial nociceptive processing in the Vc may change during postnatal development and postnatal age of three weeks is a critical period for changes in 5-HT-induced hyperpolarizing effects in mice. [Copyright &y& Elsevier]

Abstract: Aim of the study: In the present study, we investigated whether the Lagerstroemia indica Linn (LI) extract has an anti-inflammatory effect on lung inflammation in ovalbumin-induced asthmatic mice. Materials and methods: The LI extract was obtained from dried and powdered whole plants of LI using 80% ethanol. ELISA was performed to evaluate cytokine concentration. BALB/c mice were used as a mouse model of asthma after asthmatic induction by ovalbumin sensitization and inhalation. We examined the effects of the LI extract on leukocyte infiltration and mucus secretion using cell count and histological stain. Results: The amount of cytokines, such as interleukin (IL)-2, IL-4, IL-5, IL-13, and TNF-α, was increased in Jurkat cells using the extract from house dust mites. Increased cytokine concentrations were inhibited by the LI extract. The LI extract suppressed the increased expression of IL-6 after treatment with mite extract of EoL-1 cells and THP-1 cells. In an in vivo experiment using asthmatic mice, the LI extract significantly inhibited leukocytosis and eosinophilia in bronchoalveolar lavage (BAL) fluid and lung tissue samples. The LI extract inhibited the increase in mucus secretion by goblet cells, blocked the production of reactive oxygen species in BAL fluid cells, and blocked the protein expression of IL-5 in BAL fluid. The concentration of ovalbumin-specific IgE in BAL fluid was weakly inhibited by the LI extract. Conclusions: These results suggest that the LI extract may be used as a valuable agent for treating allergic diseases such as asthma due to its anti-inflammatory property. [Copyright &y& Elsevier]

Abstract: Hydroquinone (HQ) is a benzene metabolite that is involved in hematopoiesis via its accumulation into bone marrow. HQ also acts as a toxic agent that influences various immune responses. Both neutrophils and eosinophils function as important leukocytes in immunological regulation and immune diseases. In this study, we examined the toxic effects of HQ on the apoptosis of human neutrophils and eosinophils isolated from the blood of healthy donors. HQ markedly increased the apoptosis of neutrophils and eosinophils in a concentration- and a time-dependent manner. The pro-apoptotic effect is involved in activation of caspase 9 and caspase 3. Reactive oxygen species (ROS) production was enhanced after HQ treatment in a dose-dependent manner. In addition, HQ upregulated the release of IL-8 and MCP-1 from neutrophils and eosinophils, respectively. Taken together, the results of this study demonstrated that HQ strongly induces the apoptosis of neutrophils and eosinophils through the caspase 9/3-dependent pathway and the increased ROS production. HQ exerts a cytotoxic effect in human neutrophils and eosinophils and may impair the regulation of immune responses. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: Asthma is a disease marked by airway inflammation. Petasites japonicus (Pj) is known as an herb for treating asthma, oxidant stress and gastric ulcer in traditional Oriental medicine. In this study, the inhibitory effects of Pj extract on asthmatic responses were examined both in vitro and in vivo. Materials and methods: The Pj extract was acquired from whole plants of Petasites japonicus using 80% ethanol. Cytotoxicity of the Pj extract on Jurkat cells and THP-1 cells was determined using MTT assay. ELISA was performed to determine the expression levels of cytokines, chemokines, and IgE. BALB/c mice were used for an OVA-induced asthmatic mouse model. Reactive oxygen species (ROS) production was stained with 2′,7′-dichlorofluorescein diacetate and measured by fluorescence-activated cell sorting analysis. The effects of the Pj extract on leukocyte infiltration and mucus production were determined using periodic acid-Schiff staining as well as hematoxylin and eosin staining. Results: The Pj extract inhibits the increased release of interleukin (IL)-2, IL-4, IL-5, IL-13, and TNF-α due to house dust mite in Jurkat cells and blocks IL-6 expression in THP-1 cells without cytotoxicity. In the asthmatic mouse model, the Pj extract inhibits eosinophil infiltration, mucus hypersecretion, and IL-5 level in bronchoalveolar lavage (BAL) fluid, and it has a scavenging effect on ROS production of cells in BAL fluid. Conclusion: The Pj extract has suppressive properties for the pathogenesis of airway inflammation and may be used as a potent agent for the treatment of asthma. [Copyright &y& Elsevier]

Abstract: Idiopathic hypereosinophilc syndrome is a disorder associated with clonally eosinophilic proliferation. The importance of FIP1-like-1-platelet-derived growth factor receptor-α (FIP1L1-PDGFRA) in the pathogenesis and classification of HES has been recently reported. In this study, we investigated the contribution of monocyte chemoattractant protein-1 (MCP-1)/CCL2 to chemotactic activity and protein kinase C delta (PKCδ in the human eosinophilic leukemia cell line EoL-1. These cells express CCR2 protein among the CC chemokine receptors (CCR1-5). MCP-1 induces strong migration of EoL-1 cells and the chemotaxis signal in response to MCP-1 involves a Gi/Go protein, phospholipase C (PLC), PKCδ, p38 MAPK and NF-κB. MCP-1 activates p38 MAPK via Gi/Go protein, PLC and PKCδ cascade. MCP-1 also induces NF-κB translocation and the activation is inhibited by PKCδ activation. The increase in the basal expression and activity of PKCδ in EoL-1 cells, compared to normal eosinophils, inhibits apoptosis in EoL-1 cells. Anti-apoptotic mechanism of PKCδ is related to inhibition of caspase 3 and caspase 9, but not to FIP1L1-PDGFRA. PKCδ functions as an anti-apoptotic molecule, and is involved in EoL-1 cell movement stimulated by MCP-1. This study contributes to an understanding of MCP-1 in eosinophil biology and pathogenic mechanism of eosinophilic disorders. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Duchesnea chrysantha (D. chrysantha) is a herb with anti-oxidative, anti-inflammatory and immune-enhancing properties. Aim of the study: Asthma is an inflammatory disease of the lungs, and the hallmarks of the disease are increased inflammatory cell infiltration into the airways and poor respiratory function. Although there is the possibility that D. chrysantha may have an inhibitory effect on lung inflammation, the effects of D. chrysantha on asthma have not been fully investigated. In the present study, we investigated the anti-inflammatory activity of D. chrysantha extract (Dc extract) on lung inflammation in a murine model of ovalbumin-induced asthma. Materials and methods: Dc extract was obtained from dried and powdered whole plants of D. chrysantha using 80% ethanol. BALB/c mice induced by ovalbumin sensitization and nebulization were used as a mouse model of asthma. RT-PCR and ELISA were performed to measure mRNA and protein expression of cytokines. We examined the effects of Dc extract on leukocyte infiltration and mucus secretion using periodic acid-Schiff staining as well as hematoxylin and eosin staining. Results: Dc extract significantly inhibited leukocytosis and eosinophilia in the bronchoalveolar lavage (BAL) fluid (p <0.01). Dc extract significantly reduced the elevated infiltration of inflammatory cells (p <0.05) and inhibited the increased mucus secretion, despite the absence of significant value. Although Dc extract weakly inhibited the mRNA expression of IL-4, IL-5, IL-13, and eotaxin, it strongly inhibited the protein expression of IL-5 (p <0.05) and eotaxin (p <0.01) in BAL fluid. Ovalbumin-specific IgE levels in the serum and BAL fluid were blocked by Dc extract (p <0.05). Conclusions: These results suggest the possibility that Dc extract can exert suppressive effects on asthma and may provide evidence that Dc extract is a useful agent for the treatment of allergic airway disease. [Copyright &y& Elsevier]

Abstract: Background: National health in the United States is influenced by the dietary norms brought into the country by an increasing number of immigrants. Objectives: This cross-sectional study aimed to document dietary changes and disease prevalence in relation to the length of residence in the United States for Korean Americans in Michigan. Design: Of 1,860 questionnaires mailed out, 637 (34.3%) were returned with respondent-reported information, including demographics, weight and height, chronic diseases, and dietary patterns. Subjects/setting: Included in the final analyses were 497 first-generation Korean-American immigrants (263 men, 234 women, aged 30 to 87 years). Statistical analyses performed: Analysis of covariance with the Tukey test and logistic regression models provided sex-specific analysis of dietary changes and disease patterns. All statistical analyses were adjusted for age. Results: Chronic diseases reported most frequently by men and women, respectively, were hypertension, digestive diseases, arthritis, and diabetes. Length of residence in the United States (≤15 years, 16 to 25 years, or ≥26 years) was inversely associated with the prevalence of digestive diseases in men (P=0.017) and women (P=0.001), and positively with respiratory diseases in men and thyroid disease in women (P<0.05). Length of residence in the United States was inversely associated with intake of rice/rice dishes in both men (servings per week, P<0.001) and women (P=0.012). The prevalence of digestive diseases associated inversely with length of residence and positively with servings of rice/rice dishes consumed for Korean-American men. The age-adjusted odds ratio for digestive diseases was highest among men who had the shortest length of residence in the United States (≤15 years) and greater consumption of rice/rice dishes (>2 servings per day) (odds ratio 12.10; P=0.03). Conclusions: Dietary changes of Korean-American immigrants in the United States over time were associated with changes in their chronic disease patterns. These findings may help food and nutrition professionals who work with minority immigrants because they identify factors that affect changes in dietary patterns and work toward preventing diet-related diseases. Prospective studies could address underlying mechanisms of the observed diet–disease relationship with subsequent generations of Korean Americans, as well as various ethnic minority immigrants in the United States. [Copyright &y& Elsevier]

Abstract: Objective: This study was undertaken to test the hypothesis that specific meal and snack patterns are associated with selected nutrient intakes in US adults. Design: Using the 24-hour dietary recall from the Third National Health and Nutrition Examination Survey, meal and snack patterns were described in relation to nutrient intakes. Subjects: The study included US adults aged 20 years or older (n=15,978). Statistical Analyses Performed: All statistical analyses accounted for the survey design and sample weights. Linear regression analyses controlled for confounding factors, including energy intakes. Wald F tests were used for determination of significance between means of nutrient intakes by daily eating frequency or meal pattern groups. Results: Daily eating frequency was positively related to carbohydrate, folic acid, vitamin C, calcium, magnesium, iron, potassium, and fiber intakes and inversely related to protein, total fat, cholesterol, and sodium intakes. Meal patterns were further categorized into the five most commonly reported meal and snack combinations by population percentages including breakfast (B), lunch (L), dinner (D), and ≥2 snacks (S) (31.6%); B, L, D and 1 S (15.4%); B, D and ≥2 S (13.1%); B, L, D (8.3%); and L, D and ≥2 S (7.6%). Groups reporting B, L, D and 1 S and B, L, D and ≥2 S had the highest intakes of all micronutrients examined except cholesterol, vitamin B-6, and sodium. Breakfast skippers (L, D and ≥2 S) had the lowest intakes of all micronutrients examined except sodium. Conclusions: Findings from this cross-sectional survey suggest that meal and snack patterns may be markers for nutrient intakes and therefore diet quality. Complete nutrient intakes should be considered in investigations of meal patterns and health outcomes. [Copyright &y& Elsevier]

The Arabidopsis wall-associated receptor kinase, WAK1, is a member of WAK family that links the plasma membrane to the extracellular matrix. A glycine-rich secreted protein, AtGRP-3, was previously shown to regulate WAK1 functions through binding to the extracellular domain of WAK1. In this study, we sought to determine the downstream molecules of the AtGRP-3/WAK1 signaling pathway, by using two-dimensional gel electrophoresis combined with Edman sequencing and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). We report here that a chloroplast protein, oxygen-evolving enhancer protein 2 (OEE2), specifically interacts with the cytoplasmic kinase domain of WAK1 and becomes phosphorylated in an AtGRP-3-dependent manner. The phosphorylation of OEE2 is also induced in Arabidopsis by treatment with avirulent Pseudomonas syringae. Taken together, these results suggest that OEE2 activity is regulated by AtGRP-3/WAK1. [Copyright &y& Elsevier]

Mast cells play a crucial role in allergic diseases via the release of inflammatory mediators, particularly histamine and pro-inflammatory cytokines. Avenanthramide (Avn) C, a polyphenol found mainly in oats, is known to exhibit various biological properties. In this study, we aimed to evaluate the effectiveness of Avn C from germinated oats against mast cell-mediated allergic inflammation. For the in vitro study, RBL-2H3, mouse bone marrow-derived mast cells and rat peritoneal mast cells were used. Avn C (1–100 nM) inhibited the immunoglobulin (Ig)E-stimulated mast cells degranulation by suppressing phosphorylation of phosphoinositide 3-kinase and phospholipase Cγ1 and decreasing intracellular calcium levels. It inhibited IgE-stimulated secretion of inflammatory cytokines via suppression of FcεRI-mediated signaling proteins Lyn, Syk, Akt, and nuclear factor-κB. To verify the effects of Avn C in vivo, ovalbumin-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis (PCA) models were used. Oral administration of Avn C dose-dependently attenuated the ASA reactions, as evidenced by the inhibition of hypothermia and reduction of elevated serum histamine, IgE, and interleukin-4 levels. Avn C also inhibited the PCA reactions, such as ear swelling and plasma extravasation. Our results suggested that Avn C from germinated oats might be a possible therapeutic candidate for mast cell-mediated allergic inflammation. [ABSTRACT FROM AUTHOR]

Cholesterol is an essential structural component of cellular membranes. In addition to the structural role, it also serves as a precursor to a variety of steroid hormones and has diverse functions in intracellular signal transduction. As one of its functions in cell signaling, recent evidence suggests that cholesterol plays a key role in regulating angiogenesis. This review discusses the role of cholesterol in angiogenesis, with a particular emphasis on cholesterol trafficking in endothelial cell signaling. Small molecule inhibitors of cholesterol trafficking and their preclinical and clinical development targeting angiogenesis and cancer are also discussed. [ABSTRACT FROM AUTHOR]

In this paper, a fuzzy-innovation based adaptive extended Kalman filter (FI-AKF) is proposed to improve the performance of the GNSS/INS fusion system, which is degraded due to satellite signal cutoff and attenuation and inaccurate modeling in dense urban environments. The information used for sensor fusion is obtained from real-time kinematic (RTK), micro-electro-mechanical system based inertial measumrement unit (MEMS-IMU), and on-board diagnostics (OBD). The fuzzy logic system is proposed to adaptively update the measurement covariance matrix of the RTK according to the position dilution of precision (PDOP), the number of receivable satellites, and the innovation of the extended Kalman filter (EKF). In addition, the driving state of the vehicle is defined as stop, straight run, left/right turn, and the like. To reduce the heading estimation error of the Kalman filter, the estimated heading is corrected according to the driving state. Also, the measurement covariance matrices of IMU and OBD are applied adaptively considering the characteristics of each sensor according to the driving state. In order to analyze the performance of the proposed FI-AKF positioning system in a dense urban environment, a computer simulation is performed. The proposed FI-AKF is compared to the performance of the existing extended Kalman filter and the innovation-based adaptive extended Kalman filter. In addition, we conduct a performance comparison experiment with a commercial positioning system in the field test. Through each experiment, it is confirmed that the proposed FI-AKF system has higher positioning performance than the comparison positioning systems in a dense urban environment. [ABSTRACT FROM AUTHOR]

Abstract: Glutamate is the predominant excitatory amino acid neurotransmitter in the mammalian central nervous system (CNS). Glutamate transporter EAAT2/GLT-1 is the physiologically dominant astroglial protein that inactivates synaptic glutamate. Previous studies have shown that EAAT2 dysfunction leads to excessive extracellular glutamate and may contribute to various neurological disorders including amyotrophic lateral sclerosis (ALS). The recent discovery of the neuroprotective properties of ceftriaxone, a beta lactam antibiotic, suggested that increasing EAAT2/GLT-1 gene expression might be beneficial in ALS and other neurological/psychiatric disorders by augmenting astrocytic glutamate uptake. Here we report our efforts to develop a new screening assay for identifying compounds that activate EAAT2 gene expression. We generated fetal derived-human immortalized astroglial cells that are stably expressing a firefly luciferase reporter under the control of the human EAAT2 promoter. When screening a library of 1040 FDA approved compounds and natural products, we identified harmine, a naturally occurring beta-carboline alkaloid, as one of the top hits for activating the EAAT2 promoter. We further tested harmine in our in vitro cell culture systems and confirmed its ability to increase EAAT2/GLT1 gene expression and functional glutamate uptake activity. We next tested its efficacy in both wild type animals and in an ALS animal model of disease and demonstrated that harmine effectively increased GLT-1 protein and glutamate transporter activity in vivo. Our studies provide potential novel neurotherapeutics by modulating the activity of glutamate transporters via gene activation. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’. [Copyright &y& Elsevier]

Neuregulin (NRG)-1 plays fundamental roles in several organ systems after binding to its receptors, ErbB2 and ErbB4. This study examines the role of NRG-1 in atopic dermatitis (AD), a chronic skin disease that causes dryness, pruritus, and inflammation. In mice administered Der p 38, the skin presents AD-like symptoms including filaggrin downregulation and infiltration of neutrophils and eosinophils. Noticeably, there is an increased expression of NRG-1, ErbB2, and ErbB4 in the skin. Upregulation of these proteins is significantly correlated to the clinical skin severity score. In human keratinocyte HaCaT cells, exposure to Der p 38 decreased filaggrin expression, and NRG-1 alone had no effect on the expression. However, co-treatment of Der p 38 with NRG-1 enhanced the filaggrin expression decreased by Der p 38. Pre-treatment with AG879 (an ErbB2 inhibitor) or ErbB4 siRNA blocked the recovery of filaggrin expression in the cells after co-treatment with Der p 38 and NRG-1. Der p 38 treatment enhanced the secretion of interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1). Co-treatment of Der p 38 with NRG-1 lowered the cytokine secretion increased by Der p 38, although NRG-1 alone was not effective on cytokine alteration. Neutrophil apoptosis was not altered by NRG-1 or supernatants of cells treated with NRG-1, but the cell supernatants co-treated with Der p 38 and NRG-1 blocked the anti-apoptotic effects of Der p 38-treated supernatants on neutrophils, which was involved in the activation of caspase 9 and caspase 3. Taken together, we determined that NRG-1 has anti-inflammatory effects in AD triggered by Der p 38. These results will pave the way to understanding the functions of NRG-1 and in the future development of AD treatment. [ABSTRACT FROM AUTHOR]

Glycyrrhizae Radix is widely used as herbal medicine and is effective against inflammation, various cancers, and digestive disorders. We aimed to develop a sensitive and simultaneous analytical method for detecting glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin, the four marker components of Glycyrrhizae Radix extract (GRE), in rat plasma using liquid chromatography-tandem mass spectrometry and to apply this analytical method to pharmacokinetic studies. Retention times for glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin were 7.8 min, 4.1 min, 3.1 min, and 2.0 min, respectively, suggesting that the four analytes were well separated without any interfering peaks around the peak elution time. The lower limit of quantitation was 2 ng/mL for glycyrrhizin and 0.2 ng/mL for isoliquiritigenin, liquiritigenin, and liquiritin; the inter- and intra-day accuracy, precision, and stability were less than 15%. Plasma concentrations of glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin were quantified for 24 h after a single oral administration of 1 g/kg GRE to four rats. Among the four components, plasma concentration of glycyrrhizin was the highest and exhibited a long half-life (23.1 ± 15.5 h). Interestingly, plasma concentrations of isoliquiritigenin and liquiritigenin were restored to the initial concentration at 4–10 h after the GRE administration, as evidenced by liquiritin biotransformation into isoliquiritigenin and liquiritigenin, catalyzed by fecal lysate and gut wall enzymes. In conclusion, our analytical method developed for detecting glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin could be successfully applied to investigate their pharmacokinetic properties in rats and would be useful for conducting further studies on the efficacy, toxicity, and biopharmaceutics of GREs and their marker components. [ABSTRACT FROM AUTHOR]

Glutamate-induced neurotoxicity is related to excessive oxidative stress accumulation and results in the increase of neuronal cell death. In addition, glutamate has been reported to lead to neurodegenerative diseases, including Parkinson's and Alzheimer's diseases.It is well known that Fraxinus rhynchophylla contains a significant level of oleuropein (Ole), which exerts various pharmacological effects. However, the mechanism of neuroprotective effects of Ole is still poorly defined. In this study, we aimed to investigate whether Ole prevents glutamate-induced toxicity in HT-22 hippocampal neuronal cells. The exposure of the glutamate treatment caused neuronal cell death through an alteration of Bax/Bcl-2 expression and translocation of mitochondrial apoptosis-inducing factor (AIF) to the cytoplasm of HT-22 cells. In addition, glutamate induced an increase in dephosphorylation of dynamin-related protein 1 (Drp1), mitochondrial fragmentation, and mitochondrial dysfunction. The pretreatment of Ole decreased Bax expression, increased Bcl-2 expression, and inhibited the translocation of mitochondrial AIF to the cytoplasm. Furthermore, Ole amended a glutamate-induced mitochondrial dynamic imbalance and reduced the number of cells with fragmented mitochondria, regulating the phosphorylation of Drp1 at amino acid residue serine 637. In conclusion, our results show that Ole has a preventive effect against glutamate-induced toxicity in HT-22 hippocampal neuronal cells. Therefore, these data imply that Ole may be an efficient approach for the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Selective estrogen receptor modulators (SERM) including tamoxifen are known to inhibit angiogenesis. However, the underlying mechanism, which is independent of their action on the estrogen receptor (ER), has remained largely unknown. In the present study, we found that tamoxifen and other SERM inhibited cholesterol trafficking in endothelial cells, causing a hyper-accumulation of cholesterol in late endosomes/lysosomes. Inhibition of cholesterol trafficking by tamoxifen was accompanied by abnormal subcellular distribution of vascular endothelial growth factor receptor-2 (VEGFR2) and inhibition of the terminal glycosylation of the receptor. Tamoxifen also caused perinuclear positioning of lysosomes, which in turn trapped the mammalian target of rapamycin (mTOR) in the perinuclear region of endothelial cells. Abnormal distribution of VEGFR2 and mTOR and inhibition of VEGFR2 and mTOR activities by tamoxifen were significantly reversed by addition of cholesterol–cyclodextrin complex to the culture media of endothelial cells. Moreover, high concentrations of tamoxifen inhibited endothelial and breast cancer cell proliferation in a cholesterol-dependent, but ER-independent, manner. Together, these results unraveled a previously unrecognized mechanism of angiogenesis inhibition by tamoxifen and other SERM, implicating cholesterol trafficking as an attractive therapeutic target for cancer treatment. [ABSTRACT FROM AUTHOR]

Abstract: Thin films were deposited onto silica–alumina powders by plasma polymerization of 1,2-diaminocyclohexane to prepare amine-immobilized solid base catalysts. The existence of amine moieties in the films was confirmed by solid-state 13C NMR, FT/IR, and XPS analyses. The silica–alumina powders deposited with the films showed strong base catalytic activity when evaluated based on the adsorption/desorption pattern of acidic gases (NO2 and CO2) and the conversion of benzaldehyde in Knoevenagel condensation reaction between benzaldehyde and ethylcynoacetate. Adsorbed acidic gases still remained even at 400°C due to strong chemisorptions. When the plasma polymerization was carried out by a two-step process, the conversion was as high as 91.2% and adhesion of the films could be improved. The conversion was 82.0% even after the repeated use for 3 times when the films were deposited by the two-step process. [Copyright &y& Elsevier]

Abstract: Asthma is a disease marked by chronic lung inflammation and the number of patients suffering from asthma increases annually. Both β-sitosterol (BS) and β-sitosterol glucoside exist in a variety of plants and have anti-tumor, anti-microbial, and immunomodulatory activities. However, the precise role of BS and β-sitosterol glucoside in asthma has not been well understood. The aim of this study was to investigate the inhibitory effects of BS and lactose-BS (L-BS) on the pathophysiological process in ovalbumin-induced asthmatic mice. The total cells and eosinophils in the bronchoalveolar lavage (BAL) fluid markedly decreased (p <0.05) after L-BS or BS administration (1 mg/kg; i.p.), and the ROS production also decreased in comparison to the asthma control. Histopathological features were detected by performing histochemisty, including H&E and alcian blue & P.A.S staining. Both L-BS and BS mitigated the inflammation by eosinophil infiltration and mucus hypersecretion by goblet hyperplasia. These effects of L-BS were superior to those of BS. L-BS and BS inhibited the increased mRNA and protein expression of IL-4 and IL-5 in the lung tissue and BAL fluid, respectively. The IgE concentration in the BAL fluid and serum was measured by performing ELISA and the ovalbumin-specific IgE in the BAL fluid was uniquely inhibited by L-BS (p <0.05). The splenocytes were isolated from the normal and asthmatic mice and incubated in the absence and presence of 100 μg/ml ovalbumin, respectively. L-BS blocked the survival rate of the splenocytes of the mice (p <0.01). This finding indicates the possibility of L-BS and BS as potential therapeutic molecules in asthma and may contribute to the need to improve current therapeutic drugs. [Copyright &y& Elsevier]

Memory deterioration in Alzheimer's disease (AD) is thought to be underpinned by aberrant amyloid β (Aβ) accumulation, which contributes to synaptic plasticity impairment. Avenanthramide-C (Avn-C), a polyphenol compound found predominantly in oats, has a range of biological properties. Herein, we performed methanolic extraction of the Avns-rich fraction (Fr. 2) from germinated oats using column chromatography, and examined the effects of Avn-C on synaptic correlates of memory in a mouse model of AD. Avn-C was identified in Fr. 2 based on 1H-NMR analysis. Electrophysiological recordings were performed to examine the effects of Avn-C on the hippocampal long-term potentiation (LTP) in a Tg2576 mouse model of AD. Avn-C from germinated oats restored impaired LTP in Tg2576 mouse hippocampal slices. Furthermore, Avn-C-facilitated LTP was associated with changes in the protein levels of phospho-glycogen synthase kinase-3β (p-GSK3β-S9) and cleaved caspase 3, which are involved in Aβ-induced synaptic impairment. Our findings suggest that the Avn-C extract from germinated oats may be beneficial for AD-related synaptic plasticity impairment and memory decline. [ABSTRACT FROM AUTHOR]

It is difficult to treat allergic diseases including asthma completely because its pathogenesis remains unclear. House dust mite (HDM) is a critical allergen and Toll-like receptor (TLR) 4 is a member of the toll-like receptor family, which plays an important role in allergic diseases. The purpose of this study was to characterize a novel allergen, Der f 38 binding to TLR4, and unveil its role as an inducer of allergy. Der f 38 expression was detected in the body and feces of Dermatophagoides farinae (DF). Electron microscopy revealed that it was located in the granule layer, the epithelium layer, and microvilli of the posterior midgut. The skin prick test showed that 60% of allergic subjects were Der f 38-positive. Der f 38 enhanced surface 203c expression in basophils of Der f 38-positive allergic subjects. By analysis of the model structure of Der p 38, the expected epitope sites are exposed on the exterior side. In animal experiments, Der f 38 triggered an infiltration of inflammatory cells. Intranasal (IN) administration of Der f 38 increased neutrophils in the lung. Intraperitoneal (IP) and IN injections of Der f 38 induced both eosinophils and neutrophils. Increased total IgE level and histopathological features were found in BALB/c mice treated with Der f 38 by IP and IN injections. TLR4 knockout (KO) BALB/c mice exhibited less inflammation and IgE level in the sera compared to wild type (WT) mice. Der f 38 directly binds to TLR4 using biolayer interferometry. Der f 38 suppressed the apoptosis of neutrophils and eosinophils by downregulating proteins in the proapoptotic pathway including caspase 9, caspase 3, and BAX and upregulating proteins in the anti-apoptotic pathway including BCL-2 and MCL-1. These findings might shed light on the pathogenic mechanisms of allergy to HDM. [ABSTRACT FROM AUTHOR]

Simple Summary: The current study aimed to investigate the effects of a combination of two plant extracts Mentha arvensis and Geranium thunbergii in drinking water. A complete randomized design was performed to study the effects on production performance, egg quality parameters, sensory qualities, proximate analysis, and cholesterol content of egg yolk and immunity parameters in laying hens. The data suggested that the supplementation of plant extracts could improve the laying performance, egg quality and immunity, and decrease the egg yolk cholesterol content in a dose-dependent manner. This study examined the effects of Mentha arvensis (MA) and Geranium thunbergii (GT) extracts in drinking water on the production performance, egg quality, cholesterol content of egg yolk, proximate composition, and sensory qualities of egg and immunity parameters in laying hens. Ninety-six 28-week-old Hy-Line Brown layers were randomly divided into four dietary treatments for 16 weeks. The dietary treatments were (1) control, (2) T1 (0.01% 1 MA:1 GT), (3) T2 (0.05% 1 MA:1 GT), and (4) T3 (0.1% 1 MA:1 GT). Egg production increased significantly with increasing levels of MA and GT. The egg weight was increased in T2, and the feed intake was highest in T2 and T3 (p < 0.05). The Haugh unit and egg shape index were significantly better in T3 and the control than with other treatments (p < 0.05). The content of yolk cholesterol was significantly lower (p < 0.05) in T2 and T3. On the other hand, there were no significant differences in the egg proximate composition. A significant increase in the serum interleukin 6 (IL-6), tumor necrosis factor (TNFα) and immunoglobulins (IgG and IgA) concentration was observed in the birds fed plant extracts when compared to the control. On average, T2 and T3 showed significantly lower (p < 0.05) concentrations of NH3 gas from the feces as compared to the control. This study suggests that MA and GT supplementation could improve the laying performance, egg quality, and immunity, and decrease the egg yolk cholesterol content in a dose-dependent manner. [ABSTRACT FROM AUTHOR]