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BACKGROUND Artemisia capillaris is among the most abundantly used traditional medicines, utilized in East Asia to treat diverse illnesses, including gastrointestinal tract diseases. We previously reported that an aqueous extract of A. capillaris (AEAC) inhibited gastric inflammation induced by HCl/ethanol via reactive oxygen species scavenging and NF-κB downregulation. To date, the pharmacological potential of AEAC for promoting mucosal integrity has not been studied. RESULTS Here, we report that a single treatment with AEAC increased mucus production, and repeated administration of AEAC abolished HCl/ethanol-induced mucosal injury in vivo. Single- and multiple-dose AEAC treatments measurably increased the expression of mucosal stabilizing factors in vivo, including mucin (MUC) 5 AC, MUC6, and trefoil factor (TFF) 1 and TFF2 (but not TFF3). AEAC also induced mucosal stabilizing factors in both SNU-601 cells and RGM cells through phosphorylation of extracellular signal-regulated kinases. CONCLUSION Taken together, our results suggest that AEAC protects against HCl/ethanol-induced gastritis by upregulating MUCs and TFFs and stabilizing the mucosal epithelium. © 2021 Society of Chemical Industry.

The relationship between the process condition of wire-drawing and the microstructural evolution during the subsequent annealing was investigated for the production of high-purity copper wires. Three wire-drawing process conditions were considered according to the reduction in the area per pass and the die angle, and their effects on the evolution of the grain structure and texture during annealing were investigated. Strain distributions, calculated using the finite element method, showed that the shear strain near the wire surface varies according to the process condition. The electron backscatter diffraction results indicate that the location on the cross-section of the wire, where secondary recrystallization initiates during annealing, is closely related to the shear strain during wire-drawing. Meanwhile, the effect of shear deformation on the grain structure and texture after primary recrystallization is insignificant. Drawing process conditions with a small reduction in the area per pass and die angle resulted in a relatively small shear strain and gave rise to the onset of secondary recrystallization at the central region of the wires. In contrast, the condition with a large reduction in the area per pass and die angle led to a high shear strain and the onset of secondary recrystallization at the peripheral region of the wire. The observed primary and secondary recrystallization behavior during annealing was explained from the viewpoint of dynamic material phenomena and inhomogeneity in the local recrystallization texture, regulated by the extent of shear deformation during wire-drawing.

Hypoxia‐inducible factor‐1 (HIF‐1) plays an important role in cellular responses to hypoxia, including the transcriptional activation of several genes involved in tumor angiogenesis. Melatonin, also known as N‐acetyl‐5‐methopxytryptamine, is produced naturally by the pineal gland and has anti‐angiogenic effects in cancer through its ability to modulate HIF‐1α activity. However, the use of melatonin as a therapeutic is limited by its low oral bioavailability and short half‐life. Here, we synthesized melatonin‐like molecules with enhanced HIF‐1α targeting activity and less toxicity and investigated their effects on tumor growth and angiogenesis, as well as the underlying molecular mechanisms. Among melatonin derivatives, N‐butyryl‐5‐methoxytryptamine (NB‐5‐MT) showed the most potent HIF‐1α targeting activity. This molecule was able to (a) reduce the expression of HIF‐1α at the protein level, (b) reduce the transcription of HIF‐1α target genes, (c) reduce reactive oxygen species (ROS) generation, (d) decrease angiogenesis in vitro and in vivo, and (e) suppress tumor size and metastasis. In addition, NB‐5‐MT showed improved anti‐angiogenic activity compared with melatonin due to its enhanced cellular uptake. NB‐5‐MT is thus a promising lead for the future development of anticancer compounds with HIF‐1α targeting activity. Given that HIF‐1α is overexpressed in the majority of human cancers, the melatonin derivative NB‐5‐MT could represent a novel potent therapeutic agent for cancer.

This study was designed to determine whether α-humulene, a major constituent in many plants used in fragrances, has a protective role against gastric injury in vivo and in vitro. A rat model of hydrochloric acid (HCl)/ethanol-induced gastritis and human mast cells (HMC-1) were used to investigate the mucosal protective effect of α-humulene. α-Humulene significantly inhibited gastric lesions in HCl/ethanol-induced acute gastritis and decreased gastric acid secretion pyloric ligation-induced gastric ulcers in vivo. In addition, α-humulene reduced the amount of reactive oxygen species and malondialdehyde through upregulation of prostaglandin E2 (PGE2) and superoxide dismutase (SOD). In HMC-1 cells, α-humulene decreased intracellular calcium and increased intracellular cyclic adenosine monophosphate (cAMP) levels, resulting in low histamine levels. α-Humulene also reduced the expression levels of cytokine genes such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF) by downregulating nuclear factor-κB (NF-κB) nuclear translocation. Finally, α-humulene upregulated the expression levels of mucin 5AC (Muc5ac), Muc6, trefoil factor 1 (Tff1), trefoil factor 2 (Tff2), and polymeric immunoglobulin receptor (pigr). α-Humulene may attenuate HCl/ethanol-induced gastritis by inhibiting histamine release and NF-κB activation and stimulating antioxidants and mucosal protective factors, particularly Muc5ac and Muc6. Therefore, these data suggest that α-humulene is a potential drug candidate for the treatment of stress-induced or alcoholic gastritis.

In bottom-up multi-person pose estimation, grouping joint candidates into the appropriately structured corresponding instance of a person is challenging. In this paper, a new bottom-up method, the Partitioned CenterPose (PCP) Network, is proposed to better cluster the detected joints. To achieve this goal, we propose a novel approach called Partition Pose Representation (PPR) which integrates the instance of a person and its body joints based on joint offset. PPR leverages information about the center of the human body and the offsets between that center point and the positions of the body’s joints to encode human poses accurately. To enhance the relationships between body joints, we divide the human body into five parts, and then, we generate a sub-PPR for each part. Based on this PPR, the PCP Network can detect people and their body joints simultaneously, then group all body joints according to joint offset. Moreover, an improved l1 loss is designed to more accurately measure joint offset. Using the COCO keypoints and CrowdPose datasets for testing, it was found that the performance of the proposed method is on par with that of existing state-of-the-art bottom-up methods in terms of accuracy and speed.

Through silicon via (TSV) is one of the most important technologies in 3-dimensional wafer/chip stacking. However, there are some issues related to defect-free TSV filling and Cu pumping. In this study, a defect-free TSV filling was achieved using iodide ions. The working mechanism of iodide ions in TSV filling was systemically investigated by electrochemical measurements; It was found that the formation of CuI on the electrode surface is a key process for inhibiting Cu ion reduction. This inhibition effect of iodide ions enables defect-free TSV filling. Furthermore, the study of microstructure of the filled Cu revealed that the electrochemical reduction of CuI during the TSV filling forms small Cu grains in TSV. The small Cu grains cause Cu pumping in subsequent processes, which damages semiconductor devices. We achieved a defect-free TSV filling with enlarged Cu grains using a two-step filling method that effectively promotes the direct reduction of Cu ions rather than electrochemical reduction of CuI.

Kushen (Radix Sophorae flavescentis) is used to treat ulcerative colitis, tumors, and pruritus. Recently, phaseolin, formononetin, matrine, luteolin, and quercetin, through a network pharmacology approach, were tentatively identified as five bioactive constituents responsible for the anti-inflammatory effects of S. flavescentis. However, the role of phaseolin (one of the primary components of S. flavescentis) in the direct regulation of inflammation and inflammatory processes is not well known. In this study, the beneficial role of phaseolin against inflammation was explored in lipopolysaccharide (LPS)-induced inflammation models of RAW 264.7 macrophages and zebrafish larvae. Phaseolin inhibited LPS-mediated production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), without affecting cell viability. In addition, phaseolin suppressed pro-inflammatory mediators such as cyclooxygenase 2 (COX-2), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in a dose-dependent manner. Furthermore, phaseolin reduced matrix metalloproteinase (MMP) activity as well as macrophage adhesion in vitro and the recruitment of leukocytes in vivo by downregulating Ninjurin 1 (Ninj1), an adhesion molecule. Finally, phaseolin inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB). In view of the above, our results suggest that phaseolin could be a potential therapeutic candidate for the management of inflammation.

Slow-cycling cancer cells (SCCs) with a quiescence-like phenotype are believed to perpetrate cancer relapse and progression. However, the mechanisms that mediate SCC-derived tumor recurrence are poorly understood. Here, we investigated the mechanisms underlying cancer recurrence after chemotherapy, focusing on the interplay between SCCs and the tumor microenvironment. We established a preclinical model of SCCs by exposing non-small-cell lung cancer (NSCLC) cells to either the proliferation-dependent dye carboxyfluorescein diacetate succinimidyl ester (CFSE) or chemotherapeutic drugs. An RNA sequencing analysis revealed that the established SCCs exhibited the upregulation of a group of genes, especially epidermal growth factor (EGF). Increases in the number of vascular endothelial growth factor receptor (VEGFR)-positive vascular endothelial cells and epidermal growth factor receptor (EGFR) activation were found in NSCLC cell line- and patient-derived xenograft tumors that progressed upon chemotherapy. EGFR tyrosine kinase inhibitors effectively suppressed the migration and tube formation of vascular endothelial cells. Furthermore, activating transcription factor 6 (ATF6) induced the upregulation of EGF, and its antagonism effectively suppressed these SCC-mediated events and inhibited tumor recurrence after chemotherapy. These results suggest that the ATF6-EGF signaling axis in SCCs functions to trigger the angiogenesis switch in residual tumors after chemotherapy and is thus a driving force for the switch from SCCs to actively cycling cancer cells, leading to tumor recurrence.

Fluorine is a unique atom that imparts distinct properties to bioactive molecules upon incorporation. Herein, we prepare and study fluorinated derivatives of the nanomolar affine peripherally restricted dual CB1R/CB2R agonist; CRA13 and its analogs. Binding affinity evaluation relative to CRA13 proved the stronger binding affinity of compound 7c to CB1R and CB2R by 6.95 and 5.64 folds. Physicochemical properties evaluation proved compound 7c improved lipophilicity profile suggesting some enhanced BBB penetration relative to CRA13. Radiosynthesis of 18F-labeled compound 7c was conducted conveniently affording pure hot ligand. In vivo PET study investigation demonstrated efficient distribution of 18F-labeled compound 7c in peripheral tissues visualizing peripheral CB1R/CB2R generating time-activity-curves showing good standard uptake values. Despite enhanced BBB penetration and increased cannabinoid receptors binding affinity, low brain uptake of 7c was observed. In silico docking study explained the measured binding affinities of compounds 7a-d to CB1R. While most of previous efforts aimed to develop central cannabinoid PET imaging agents, 18F-labeled compound 7c might be a promising agent serving as a universal CB1R/CB2R PET imaging agents for diagnosis and therapy of various diseases correlated with peripheral cannabinoid system. It might also serve as a lead compound for development of PET imaging of peripheral and central cannabinoid systems.

Due to its tentacle poison and huge body, giant jellyfish (Nemopilema nomurai) poses challenging issues to the environment and ecosystems. Here we developed, upcycling a giant jellyfish extract as a reducing agent, a green synthetic method of gold nanoparticles (JF-AuNPs) which possess biological activities. The colloidal solutions of JF-AuNPs were blue, violet, purple and pink depending on the extract concentration. UV-visible spectra exhibited two surface plasmon resonance bands at 5 4 0 ∼ 550 nm and 810 nm. Spherical shapes with an average size of 35.2 ± 8.7 nm and triangular nanoplates with an average height of 70.5 ± 30.3 nm were observed. A face-centered cubic structure was confirmed by high-resolution X-ray diffraction. JF-AuNPs exhibited significant cytotoxic effect against HeLa cancer cells but not against normal cells such as NIH-3T3 and Raw 264.7 cells. In HeLa cells, JF-AuNPs decreased the phosphorylation of AKT and ERK, which are crucial for cell proliferation. Also, JF-AuNPs decreased NO secretion and iNOS expression levels, resulting in anti-inflammatory effects in LPS-inflamed macrophages. Collectively, we established a green synthesis of anti-tumorigenic and anti-inflammatory JF-AuNPs using the extract of jellyfish sea wastes. Thus, beneficial effects of JF-AgNPs must be weighed in further studies in vivo and it can be potent nanomedicine for future applications.

Spermidine is a naturally occurring polyamine compound that has recently emerged with anti-aging properties and suppresses inflammation and oxidation. However, its mechanisms of action on anti-inflammatory and antioxidant effects have not been fully elucidated. In this study, the potential of spermidine for reducing pro-inflammatory and oxidative effects in lipopolysaccharide (LPS)-stimulated macrophages and zebrafish was explored. Our data indicate that spermidine significantly inhibited the production of pro-inflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2), and cytokines including tumor necrosis factor-α and interleukin-1β in RAW 264.7 macrophages without any significant cytotoxicity. The protective effects of spermidine accompanied by a marked suppression in their regulatory gene expression at the transcription levels. Spermidine also attenuated the nuclear translocation of NF-κB p65 subunit and reduced LPS-induced intracellular accumulation of reactive oxygen species (ROS) in RAW 264.7 macrophages. Moreover, spermidine prevented the LPS-induced NO production and ROS accumulation in zebrafish larvae and was found to be associated with a diminished recruitment of neutrophils and macrophages. Although more work is needed to fully understand the critical role of spermidine on the inhibition of inflammation-associated migration of immune cells, our findings clearly demonstrate that spermidine may be a potential therapeutic intervention for the treatment of inflammatory and oxidative disorders.

This work examines the filling of Through Silicon Vias (TSV) by Ni deposition from a NiSO4 + NiCl2 + H3BO3 electrolyte containing a branched polyethyleneimine suppressor. Feature filling occurs due to the interaction of transport limited suppressor adsorption and its consumption by potential dependent metal deposition. The interaction between surface topography and suppressor transport yields a sharp transition from passive to active deposition within the TSV. The transition is associated with significant incorporation of the suppressor, or its components, within the Ni deposit that results in grain refinement evident by electron backscatter diffraction (EBSD). Potential waveforms that progressively shift the location of the passive-active transition upward to optimize feature filling were examined. The evolution of feature filling and deposit microstructure are compared to predictions of a three-dimensional model that reflect critical behavior associated with suppressor-derived, S-shaped negative differential resistance (S-NDR). The model uses adsorption and consumption kinetics obtained from voltammetric measurements of the critical potential associated with suppression breakdown. Good agreement between experiment and simulation is demonstrated.

Mammalian claudin-5 (cldn5), a zebrafish cldn5a homolog, is essential to blood-brain barrier (BBB) integrity. Previously, the existence of an endothelial tight junction-based BBB with cldn5a expression in the cerebral microvessels was reported in zebrafish. However, the role of cldn5a in the cerebral microvessels of developing zebrafish has not been elucidated. Here, we further investigated the functional integrity of cldn5a in developing zebrafish by injecting cldn5a morpholinos. At 7 days post-fertilization, cldn5a immunoreactivity was detected on the brain surface, ventricular ependyma, and cerebral mircovessels but disappeared following cldna5a knockdown. Cldn5a morphants showed size-selective leakage of tracers through the BBB and downregulated expression of glucose transporter 1 (glut1) in the cerebral microvessels. In addition, leakiness in the blood-cerebrospinal fluid barrier was observed, implying the overall abnormal development of blood-neural barriers. The results of our study suggest that cldn5a is required for building and maintaining the blood-neural barrier during zebrafish development.

The microstructure of copper filled through silicon vias deposited in a CuSO(4) + H(2)SO(4) electrolyte containing micromolar concentrations of deposition rate suppressing poloxamine and chloride additives is explored using electron backscatter diffraction. Regions with distinct microstructures are observed in the vias, including conformal deposition and seam formation localized adjacent to the bottom that can transition to bottom-up filling higher in the features. The presence and extent of each microstructure depends on applied potential as well as additive concentration. Deposition in the presence of higher chloride concentration yields a strong (110) growth texture in regions where bottom-up filling exhibits a horizontal growth front profile while (110) textured or untextured growth is observed for different conditions where upward growth proceeds with a v-notch profile.

Fucoidan, a sulfated polysaccharide, is an active component found in various species of seaweed. Although this compound has a strong anti-inflammatory activity, the underlying mechanisms exerted by fucoidan have not been fully elucidated. In the present study, the anti-inflammatory effects of fucoidan on lipopolysaccharide (LPS)-stimulated macrophages and zebrafish larvae were examined. The present data indicated that fucoidan significantly suppressed the secretion of pro-inflammatory mediators including nitric oxide (NO ) and prostaglandin E2 (PGE2), and cytokines, such as tumor necrosis factor-α and interleukin-1β in RAW 264.7 macrophages without any significant cytotoxicity, the protective effects of which were accompanied by a marked reduction in their regulatory gene expression at the transcription levels. Fucoidan also inhibited translocation of the nuclear factor-kappa B from the cytoplasm to the nucleus and attenuated LPS-induced production of intracellular reactive oxygen species (ROS) in RAW 264.7 macrophages. Moreover, fucoidan reduced NO and PGE2 production and ROS accumulation in LPS-stimulated zebrafish larvae, which was associated with a diminished recruitment of neutrophils and macrophages. Based on the results of this study, we suggest that fucoidan has excellent potential as a therapeutic agent for inflammatory disorders.

Gallium nitride (GaN) nanowires are one of the most promising photoelectrode materials due to their high stability in acidic and basic electrolytes, and tunable band edge potentials. In this study, GaN nanowire arrays (GaN NWs) were prepared by molecular beam epitaxy (MBE); their large surface area enhanced the solar to hydrogen conversion efficiency. More significantly, graphene was grown by chemical vapor deposition (CVD), which enhanced the electron transfer between NWs for water splitting and protected the GaN NW surface. Structural characterizations of the prepared composite were performed using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The photocurrent density of Gr/GaN NWs exhibited a two-fold increase over pristine GaN NWs and sustained water splitting up to 70 min. These improvements may accelerate possible applications for hydrogen generation with high solar to hydrogen conversion efficiency.

Tacrolimus is widely used as an immunosuppressant to reduce the risk of rejection after organ transplantation, but its cytotoxicity is problematic. Nargenicin A1 is an antibiotic extracted from Nocardia argentinensis and is known to have antioxidant activity, though its mode of action is unknown. The present study was undertaken to evaluate the protective effects of nargenicin A1 on DNA damage and apoptosis induced by tacrolimus in hirame natural embryo (HINAE) cells. We found that reduced HINAE cell survival by tacrolimus was due to the induction of DNA damage and apoptosis, both of which were prevented by co-treating nargenicin A1 or N-acetyl-l-cysteine, a reactive oxygen species (ROS) scavenger, with tacrolimus. In addition, apoptosis induction by tacrolimus was accompanied by increases in ROS generation and decreases in adenosine triphosphate (ATP) levels caused by mitochondrial dysfunction, and these changes were significantly attenuated in the presence of nargenicin A1, which further indicated tacrolimus-induced apoptosis involved an oxidative stress-associated mechanism. Furthermore, nargenicin A1 suppressed tacrolimus-induced B-cell lymphoma-2 (Bcl-2) down-regulation, Bax up-regulation, and caspase-3 activation. Collectively, these results demonstrate that nargenicin A1 protects HINAE cells against tacrolimus-induced DNA damage and apoptosis, at least in part, by scavenging ROS and thus suppressing the mitochondrial-dependent apoptotic pathway.

During spinal cord development, Sonic hedgehog (Shh), secreted from the floor plate, plays an important role in the production of motor neurons by patterning the ventral neural tube, which establishes MN progenitor identity. It remains unknown, however, if Shh signaling plays a role in generating columnar diversity of MNs that connect distinct target muscles. Here, we report that Shh, expressed in MNs, is essential for the formation of lateral motor column (LMC) neurons in vertebrate spinal cord. This novel activity of Shh is mediated by its downstream effector ARHGAP36, whose expression is directly induced by the MN-specific transcription factor complex Isl1-Lhx3. Furthermore, we found that AKT stimulates the Shh activity to induce LMC MNs through the stabilization of ARHGAP36 proteins. Taken together, our data reveal that Shh, secreted from MNs, plays a crucial role in generating MN diversity via a regulatory axis of Shh-AKT-ARHGAP36 in the developing mouse spinal cord.

Arbutin, a natural polyphenol, possesses numerous biological activities including whitening, anti-oxidant, anti-cancer, anti-inflammatory activities, as well as strong reducing power, making it an ideal bioactive ingredient for preparing gold nanoparticles (GNPs). Previously, we developed a novel green, mild synthetic method for GNPs using glycosides such as arbutin as reducing agents and stabilizers. Herein, we optimized the synthetic method for glycoside–GNPs using arbutin, methyl β-d-glucoside, and phenyl β-d-glucoside and validated their whitening efficacy in vitro and in vivo. The resulting glycoside–GNPs were predominantly mono-dispersed and spherical (10.30–17.13 nm diameter). Compared with arbutin itself, arbutin–GNP complexes (GNP-A1 and GNP-P2) displayed enhanced whitening capabilities. Furthermore, GNP-P2 exhibited enhanced anti-inflammatory activity and lacked the toxicity associated with arbutin. Bioactive glycoside–GNP complexes may open new directions for cosmeceuticals, and GNP-P2 may serve as a useful whitening ingredient in future cosmeceutical applications.

Microstructural and morphological evolution during bottom-up Cu filling of annular through silicon vias (TSV) in a CuSO4–H2SO4–Cl-–poloxamine electrolyte is examined. Deposition proceeds in two distinct stages beginning with a passive-to-active state transition on the via sidewalls whose depth and ultimate thickness depends on the polymer flux. Growth is conformal or tapered with columnar grains whose width and texture differ between the outer and inner sidewalls of the annulus due to area reduction and expansion respectively. The outer sidewall and bottom surface have a preferred texture; ⟨111⟩//ND (via normal) and ⟨110⟩//CD (via circumferential). With time the sidewalls passivate while further deposition is localized to the via bottom. Bottom-up growth then fills the TSV with the formation and selective expansion of the ⟨110⟩//ND textured grains. At higher suppressor concentrations the initial onset and transient period of sidewall deposition is displaced to greater depth and the subsequent shift to bottom-up filling with large ⟨110⟩//ND texture grains occurs earlier. The dominant ⟨110⟩//ND texture during bottom-up filling is congruent with Cl− stabilized texture development. The absence of suppression indicates that the polymeric suppressor does not adsorb on the active upward propagating surface.

Here we developed a novel green synthesis method for gold nanoparticles (CGA-AuNPs) using chlorogenic acid (CGA) as reductants without the use of other chemicals and validated the anti-inflammatory efficacy of CGA-AuNPs in vitro and in vivo . The resulting CGA-AuNPs appeared predominantly spherical in shape with an average diameter of 22.25 ± 4.78 nm. The crystalline nature of the CGA-AuNPs was confirmed by high-resolution X-ray diffraction and by selected-area electron diffraction analyses. High-resolution liquid chromatography/electrospray ionization mass spectrometry revealed that the caffeic acid moiety of CGA forms quinone structure through a two-electron oxidation causing the reduction of Au 3 + to Au 0 . When compared to CGA, CGA-AuNPs exhibited enhanced anti-inflammatory effects on NF-κB-mediated inflammatory network, as well as cell adhesion. Collectively, green synthesis of CGA-AuNPs using bioactive reductants and mechanistic studies based on mass spectrometry may open up new directions in nanomedicine and CGA-AuNPs can be an anti-inflammatory nanomedicine for future applications. From the Clinical Editor Gold nanoparticles (Au NPs) have been shown to be very useful in many applications due to their easy functionalization capability. In this article, the authors demonstrated a novel method for the synthesis of gold nanoparticles using chlorogenic acid (CGA) as reductants. In-vitro experiments also confirmed biological activity of the resultant gold nanoparticles. Further in-vivo studies are awaited.

To examine whether quercetin interacts with vitamin D receptor, we investigated the effects of quercetin on vitamin D receptor activity in human intestinal Caco-2 cells. The effects of quercetin on the expression of the vitamin D receptor target genes, vitamin D 3 24-hydroxylase, cytochrome P450 3A4, multidrug resistance protein 1, and transient receptor potential vanilloid type 6 were measured using quantitative polymerase chain reaction. The vitamin D receptor siRNA was used to assess the involvement of the vitamin D receptor. Vitamin D receptor activation using a vitamin D responsive element-mediated cytochrome P450 3A4 reporter gene assay was investigated in Caco-2 cells transfected with human vitamin D receptor. We also studied the magnitude of the vitamin D receptor activation and/or synergism between 1 α ,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] and quercetin-like flavonoids. Slight but significant increases in the mRNA expression of cytochrome P450 3A4, vitamin D 3 24-hydroxylase, multidrug resistance protein 1, and transient receptor potential vanilloid type 6 were observed after 3 days of continual quercetin treatment. The silencing effect of vitamin D receptor by vitamin D receptor siRNA in Caco-2 cells significantly attenuated the induction of the vitamin D receptor target genes. Moreover, quercetin significantly enhanced cytochrome P450 3A4 reporter activity in Caco-2 cells in a dose-dependent manner, and the expression of exogenous vitamin D receptor further stimulated the vitamin D receptor activity. Quercetin-like flavonoids such as kaempferol stimulated the vitamin D receptor activity in a manner similar to that seen with quercetin. Taken together, the data indicates that quercetin upregulates cytochrome P450 3A4 and multidrug resistance protein 1 expression in Caco-2 cells likely via a vitamin D receptor-dependent pathway.

Pad discoloration is caused by Ni corrosion during electroless nickel immersion gold (ENIG) treatment, and here it was investigated by SEM, XPS and cross-sectional EDS analysis. Interestingly, we found that the corrosion occurred at two different sites. For relatively thinner Ni layers, the Ni corrosion occurred at the nodule boundary, whereas thicker Ni deposits caused pit corrosions. The electroless Ni had an amorphous structure and had isotropic surface energy. In other words, the domain boundary energy between two Ni nodules did not change during Ni growth. However, the intersection angle of the two surfaces gradually increases during film growth, and the cusp stress between the two nodules also decreases gradually during Ni growth. Hence, the corrosion mode changed from nodule boundary corrosion to pit corrosion. Promoting Ni nucleation as well as increasing the Ni thickness is expected to suppress the pad discoloration by reducing the nodule boundary corrosion.

Histone deacetylases (HDACs) are considered promising targets in the treatment of hematologic malignancies and several types of solid tumors, including non-small cell lung cancer (NSCLC). However, the efficacy of HDAC inhibitors in solid tumors is marginal, and the mechanisms underlying resistance to HDAC inhibitors are largely unknown. Here, we demonstrate the involvement of type 1 insulin-like growth factor receptor (IGF-1R) signaling in resistance to HDAC inhibitors in NSCLC. Using MTT and soft-agar colony formation assays, we selected NSCLC cell lines that exhibited intrinsic resistance to vorinostat. Treatment with vorinostat activated IGF-1R signaling in vorinostat-resistant but not vorinostat-sensitive NSCLC cells. Other HDAC inhibitors, including trichostatin A, sodium butyrate, and depsipeptide, also activated IGF-1R signaling in vorinostat-resistant NSCLC cells. Blockade of IGF-1R signaling via IGF-1R monoclonal antibodies (mAbs) or through knockdown of IGF-1R via RNA interference sensitized vorinostat-resistant cells to HDAC inhibition. Finally, IGF-1R mAbs sensitized xenograft tumors of vorinostat-resistant cells to vorinostat treatment in vivo. These findings suggest that IGF-1R activation is generally involved in resistance to HDAC inhibitors and that targeting IGF-1R is an effective strategy for overcoming resistance to HDAC inhibitors in NSCLC.

Copper electrodeposits annealed at 80 °C were investigated by electrical resistance measurement, X-ray diffraction and electron backscattered diffraction analyses. The decrease of electrical resistivity had a linear relationship with the re-crystallized area. Interestingly, the texture coefficient of (200) orientation increased as the re-crystallization occurred. Such appearance of (200) texture during annealing seemed to be related to the residual strain in the copper electrodeposits. It is possible to evaluate the progress of grain growth by measuring the electrical resistivity or texture coefficient in copper electrodeposits. †(Received July 23, 2013)

3-Fluoromethamphetamine (3-FMA) is an illegal designer drug of methamphetamine (MA) derivative. Up to date, little is known about the neurotoxic potential of 3-FMA. In the present study, we investigated the role of dopamine receptors in neurotoxicity induced by 3-FMA in comparison with MA (35 mg/kg, i.p.) as a control drug. Here we found that 3-FMA (40, 60 or 80 mg/kg, i.p.) produced mortality in a dose-dependent manner in mice. Treatment with 3-FMA (40 mg/kg, i.p.) resulted in significant hyperthermia, oxidative stress and microgliosis (microglial differentiation into M1 phenotype) followed by pro-apoptotic changes and the induction of terminal deoxynucleotidyl transferase dUDP nick end labeling (TUNEL)-positive cells. Moreover, 3-FMA significantly produced dopaminergic impairments [i.e., increase in dopamine (DA) turnover rate and decreases in DA level, and in the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT-2)] with behavioral impairments. These dopaminergic neurotoxic effects of 3-FMA were comparable to those of MA. SCH23390, a dopamine D1 receptor antagonist, but not sulpiride, a dopamine D2 receptor antagonist significantly attenuated 3-FMA-induced neurotoxicity. Although both SCH23390 and sulpiride attenuated MA-induced dopaminergic neurotoxicity, sulpiride is more effective than SCH23390 on the dopaminergic neurotoxicity. Interestingly, SCH23390 treatment positively modulated 3-FMA-induced microglial activation (i.e., SCH23390 inhibited M1 phenotype from 3-FMA insult, but activated M2 phenotype). Therefore, our results suggest that the activation of dopamine D1 receptor is critical to 3-FMA-induced neurotoxicity, while both dopamine D1 and D2 receptors (dopamine D2 receptor > dopamine D1 receptor) mediate MA-induced dopaminergic neurotoxicity.

The recent mass emergence of Nomura's jellyfish (Nemopilema nomurai) has caused much economic and environmental damage. However, there is no innovative strategy to dispose of or utilize these jellyfish. Some reports suggest that the jellyfish may be bioactive resources and a source of important compounds with antibacterial activity. Here, we examined the effect of an aqueous extract of Nomura's jellyfish (AENJ) on lipopolysaccharide (LPS)-stimulated Raw 264.7 macrophages and a zebrafish model of inflammation and analyzed the underlying molecular mechanisms. AENJ downregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA levels in LPS-stimulated Raw 264.7 macrophages, with no apparent cytotoxic effects. However, AENJ had no effect on expression of other inflammation-related genes such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and MCP-1. Furthermore, AENJ reduced expression of nerve injury-induced protein 1 (Ninj1), which is an important adhesion molecule, thereby reducing cell adhesion to the extracellular matrix (ECM) in vitro. The inhibitory effect of AENJ on leukocytes was confirmed in LPS-microinjected zebrafish larvae; AENJ reduced the number of the infiltrate accumulating at the site of inflammation. In addition, AENJ suppressed the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 in LPS-stimulated Raw 264.7 cells. Finally, AENJ blocked nuclear translocation of nuclear factor kappa B (NF-κB), a key transcription factor for inflammatory responses, in Raw 264.7 cells in a dose-dependent manner. Collectively, the data suggest that AENJ inhibits expression of COX and iNOS by blocking NF-κB signaling pathways and suppresses the activity of macrophages by downregulating Ninj1 and MMPs. Therefore, AENJ may be a useful preventive neutraceutical, or therapeutic agent against inflammatory disorders.

Artemisia capillaris, also called “InJin” in Korean, has been used as traditional oriental medicine in Korea because of its various pharmacological activities. These include hepatoprotective, analgesic, and antipyretic activities. The present study was designed to validate the beneficial effects of the aqueous extract of A. capillaris (AEAC) against acute gastric mucosal injury and investigate the underlying molecular mechanisms. The pharmacological efficacy of AEAC was evaluated using the gastric ulcer index and histological examination. AEAC decreased gastric mucosal lesions mediated by HCl/ethanol in vivo in a dose-dependent manner. Interestingly, the mucosal damage was almost prevented by pretreatment with 200 or 400 mg/kg AEAC. However, AEAC did not have acid-neutralizing activity in vitro and did not prevent histamine secretion in HMC-1 mast cells. In the gastric mucosa, AEAC also significantly inhibited lipid peroxide formation through superoxide dismutase (SOD) activation. Moreover, AEAC strongly reduced the generation of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and interleukin-1β (IL-1β), through nuclear factor kappa B (NF-κB) downregulation. Taken together, our findings suggest that AEAC inhibits inflammation and maintains oxidant/antioxidant homeostasis, resulting in a gastro-protective effect against HCl/ethanol-induced gastric damage. Therefore, AEAC might be a promising drug or useful neutraceutical for treatment of gastritis and gastric ulcer.

Microstructure and composition analysis was performed on the nitrided Ti–6Al–4V alloy by using coupled techniques of X-ray diffraction analysis and glow discharge spectroscopy. Titanium nitride (TiN x ) appeared at the outmost surface, but the low solubility of Al in the TiN x phase made Al atom to move inward. Such Al-rich phase as Ti 3 Al compound was formed by Al accumulation at the boundary between TiN x and α(N)-Ti phase (N diffusion zone). Interestingly, the Ti 3 Al had very low concentration of N, and it may inhibit N atom from diffusing inward as a diffusion barrier. The flat region of V concentration profile with about 2 at% also appeared in the region of α(N)-Ti phase because there was a solubility limit of less than 2 at% V in the α-Ti phase (hcp).

Asymmetric synthesis of α-quaternary chiral lactam derivatives as novel anticancer agents and evaluation of their cytotoxic potentials and spectrums are reported. Among the developed lactam derivatives, the most active new compounds (S)-4m and (S)-4n synthesized via asymmetric phase-transfer catalytic alkylation in very high optical yields (98 % ee) show promising in vitro anticancer activities with low micromolar IC50 values against colon, uterus, lung, and breast human cancer cells.

The microstructures of the P-GaN (250 nm)/GaN cap (~ 35 nm)/7 pairs of InGaN/GaN MQWs (multi-quantum wells)/n-GaN (3 μm)/HT (high temperature)-GaN (3 μm)/LT (low temperature)-GaN buffer (5 nm) on c-plane convex patterned sapphire substrate were analyzed using transmission electron microscopy (TEM). High density of dislocations in the LT-GaN buffer layer at both flat and convex patterned regions was observed to form. At the flat region, some of high dislocations formed at LT-GaN buffer grew over, bended to from stair-like dislocations extended along the edge of the convex pattern and then transformed to TDs (threading dislocations) extending through the InGaN/GaN epitaxial layers. However, few TDs reached the top of the epitaxial layers. Quantitative analysis revealed that the dislocation density has been drastically reduced to ~ 106 cm− 2, reducing formation of V-defects at the 7 pairs of multi-quantum-wells near the surface.

We proposed an indium-tin-oxide (ITO) based gas sensor which can operate at room temperature. ITO nano-crystal was screen printed on a quartz substrate. To improve the sensitivity and to decrease the resistivity of the printed ITO layer, pressurized annealing was adopted. Resistivity of the printed ITO gas sensor decreased from 3.5 kΩcm to 1.56 Ωcm by pressurized annealing. We could observe room temperature operation of the printed ITO gas sensor by using various gases such as Ar, N2, O2 and CH4. (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

A simple procedure for measuring lipoprotein lipase activity was developed by using newly formulated substrate with turbidimetry method. The activity of lipoprotein lipase was expressed as Y (value) (%) that was calculated by measuring UV absorbance (600 nm) at two time points (30 sec and 15 min). Lipid emulsions as the substrate and other factors affecting the lipolytic activity of lipase were studied. The optimal conditions for an in vitro experiment were found to be with LIPOMCT as lipid substrate at 37°C in tris-HCl buffer (pH 7.4) in the presence of BSA. To evaluate an in vivo applicability, low molecular weight heparin (LMWH)-containing drug, Sulodexide, was administered to the rats. The serum from LMWH-administered rats was incubated in an optimized analytical condition without BSA. As expected, increasing the amount of LMWH administered led to higher lipase activity. The newly developed method was successfully applied to an in vivo model suggesting the potential to be applicable for the pharmacodynamic studies of commercially available products of LPL analogues in human subjects, and for the diagnosis of acute pancreatitis in the clinical laboratory.

We investigated the nucleation and growth behavior of GaN on various powders by hydride vapor phase epitaxy. In relative comparison, the nucleation tendency of GaN on each powder can be summarized as AlN > LaN, TiN, NbN > ZrN > ZrB2 > VN, BeO, indicating that the number of nucleation sites increased from right to left. LaN and NbN have not yet been reported as buffer materials for GaN growth. Of these, NbN is expected to be a good buffer material because the interatomic distance on the NbN (111) plane has only 2% difference from that on the GaN (0001) plane.

The developing embryo naturally experiences relatively low oxygen conditions in vivo. Under in vitro hypoxia, mouse embryonic stem cells (mESCs) lose their self-renewal activity and display an early differentiated morphology mediated by the hypoxia-inducible factor-1α (HIF-1α). Previously, we demonstrated that histone deacetylase (HDAC) is activated by hypoxia and increases the protein stability and transcriptional activity of HIF-1α in many human cancer cells. Furthermore HDAC1 and 3 mediate the differentiation of mECSs and hematopoietic stem cells. However, the role of HDACs and their inhibitors in hypoxia-induced early differentiation of mESCs remains largely unknown. Here, we examined the effects of several histone deacetylase inhibitors (HDA-CIs) on the self-renewal properties of mESCs under hypoxia. Inhibition of HDAC under hypoxia effectively decreased the HIF-1α protein levels and substantially improved the expression of the LIF-specific receptor (LIFR) and phosphorylated-STAT3 in mESCs. In particular, valproic acid (VPA), a pan HDACI, showed dramatic changes in HIF-1α protein levels and LIFR protein expression levels compared to other HDACIs, including sodium butyrate (SB), trichostatin A (TSA), and apicidin (AP). Importantly, our RT-PCR data and alkaline phosphatase assays indicate that VPA helps to maintain the self-renewal activity of mESCs under hypoxia. Taken together, these results suggest that VPA may block the early differentiation of mESCs under hypoxia via the destabilization of HIF-1α.