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Introduction This study was designed to investigate the molecular epidemiology of Clostridioides difficile in South Korea, and to evaluate the risk factors of rifaximin-nonsusceptible C. difficile infections (CDI). Methods A total of 413 patients with CDI from two sentinel hospitals in South Korea were enrolled in this study. Putative clinical risk factors for CDI were identified using the digital medical records of the patients, and pathogen profiles, including antimicrobial susceptibility, toxin generation, and ribotype, were evaluated for each of the causative C. difficile isolates. Results A total of 81 (19.6%) C. difficile isolates were shown to be rifaximin-nonsusceptible with the most common ribotypes being described as 018 (56.8%, 46/81), 017 (16.0%, n = 13), and 027 (6.2%, n = 5). Rifaximin-nonsusceptible C. difficile isolates exhibited higher nonsusceptibility rates to most of the other drugs tested in this study when compared to the rifaximin-susceptible isolates. Previous history of pulmonary tuberculosis and prior rifaximin treatment were shown to be linked with the occurrence of rifaximin-nonsusceptible CDIs than those with susceptible CDIs. Conclusions The rifaximin-nonsusceptibility rates for the C. difficile isolates identified in this study were reasonably high with most of these resistant strains belonging to either the 018 or 017 RT. The widespread dissemination of these clones may be the result of the antimicrobial selection pressure introduced by the widespread use of rifaximin. These results suggest that a sustainable surveillance program for C. difficile infections and resistance is needed in order to better control CDIs and improve therapeutic efficacy.

Background and Objectives Mesenchymal stem cells (MSCs) elicit therapeutic effects against liver fibrosis in animal models. Human liver stem cells (HLSCs) are cells isolated from human liver tissue that have mesenchymal morphology and express MSC markers. HLSCs also possess intrahepatic stem cell properties. We introduce a rat model of liver fibrosis and trans-portal transplantation of HLSC to demonstrate alleviation of liver fibrosis. Methods and Results Liver fibrosis was induced by intraperitoneal injection of Carbon tetrachloride (CCl4). Sprague Dawley rats underwent simultaneous partial hepatectomy of the left hepatic lobe and HLSC transplantation via the portal vein. Gross appearance of the liver observed following CCl4 injection showed cholestasis and surface nodularity. Sirius red staining revealed deposition of collagen fibers in the extracellular matrix (ECM). Following HLSC transplantation, human albumin secreting cells were detected by immunohistochemistry in liver specimens. Quantitative measurements of fibrosis area stained by Sirius red were compared between baseline and post-HLSC transplant (1×107 cells) following 10 weeks of CCl4 treatment liver specimens. Fibrosis area (p

Retinyl palmitate (RP) was added in monoolein (MO) cubic phase including decanoyl poly(ethyleneimine) (DePEI) and decanoyl gelatin (DeGel) in its water channel. RP, DePEI, and DeGel was incorporated In the cubic phase without structural disintegration, as confirmed by transmission electron microscopy. Differential scanning calorimetric and polarized optical microscopic analysis showed that adding the additives reduces phase transition temperature of cubic phase by 2 °C to 3 °C. The time-dependent chemical stability of RP added in the cubic phase was analyzed for 4 weeks at 5 °C, 20 °C, 30 °C, and 40 °C, using RP loaded in o/w emulsion as a control. The chemical stability of RP added in cubic phase containing DePEI and DeGel was somewhat higher as compared to the RP added in the cubic phase without DeGel/DePEI, possibly because DeGel/DePEI complex might shield RP from its environment by blocking the water channels inside the cubic phase. Moreover, the chemical stability of RP added in the cubic phase was comparatively higher than RP added in o/w emulsion.

Background: Conventional diagnostic approaches for adrenal tumors require multi-step processes, including imaging studies and dynamic hormone tests. Therefore, this study aimed to discriminate adrenal tumors from a single blood sample based on the combination of liquid chromatography-mass spectrometry (LC-MS) and machine learning algorithms in serum profiling of adrenal steroids.Methods: The LC-MS-based steroid profiling was applied to serum samples obtained from patients with nonfunctioning adenoma (NFA, n=73), Cushing’s syndrome (CS, n=30), and primary aldosteronism (PA, n=40) in a prospective multicenter study of adrenal disease. The decision tree (DT), random forest (RF), and extreme gradient boost (XGBoost) were performed to categorize the subtypes of adrenal tumors.Results: The CS group showed higher serum levels of 11-deoxycortisol than the NFA group, and increased levels of tetrahydrocortisone (THE), 20α-dihydrocortisol, and 6β-hydroxycortisol were found in the PA group. However, the CS group showed lower levels of dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S) than both the NFA and PA groups. Patients with PA expressed higher serum 18-hydroxycortisol and DHEA but lower THE than NFA patients. The balanced accuracies of DT, RF, and XGBoost for classifying each type were 78%, 96%, and 97%, respectively. In receiver operating characteristics (ROC) analysis for CS, XGBoost, and RF showed a significantly greater diagnostic power than the DT. However, in ROC analysis for PA, only RF exhibited better diagnostic performance than DT.Conclusion: The combination of LC-MS-based steroid profiling with machine learning algorithms could be a promising one-step diagnostic approach for the classification of adrenal tumor subtypes.

As part of our continuous program to identify new potential candidates for controlling osteolytic bone diseases from natural products, the alkaloid fraction of barley (Hordeum vulgare var. hexastichon) grass (HVA) significantly inhibited RANKL-induced osteoclast formation and protected mice from LPS-induced bone loss. A phytochemical investigation of HVA afforded nine indole alkaloids, including one new compound [hordeumin A (1)] and eight known analogues (2-9). Of them, four (1, 2, 4, and 5) were anti-osteoclastogenic compounds. Of these four, compound 5 significantly suppressed RANKL-induced osteoclast formation, actin ring formation, and bone resorption in a concentration-dependent manner. It also suppressed the RANKL-induced NF-κB and MAPK signaling pathways and the activation of c-Fos and NFATc1. Compound 5 also reduced the expression levels of osteoclast-specific marker genes, including TRAP, CtsK, DC-STAMP, OSCAR, and MMP9. Our findings suggest that HVA and its alkaloid constituents could be valuable candidates for the prevention and treatment of osteolytic bone diseases.

Background: Although CREB phosphorylation is known to be essential in UVB/cAMP-stimulated melanogenesis, CREB null mice did not show identifiable pigmentation phenotypes. Here, we show that CREB-regulated transcription co-activator 3 (CRTC3) quantitatively regulates and orchestrates melanogenesis by directly targeting microphthalmia-associated transcription factor (MITF) and regulating the expression of most key melanogenesis-related genes. Methods: We analyzed CRTC3-null, KRT14-SCF transgenic, and their crossover mice. The molecular basis of CRTC3 effects on pigmentation was investigated by histology, melanin/tyrosinase assay, immunoblotting, shRNA, promoter assay, qRT-PCR, and subcellular localization. These analyses were carried out in primary cultured melanocytes, mouse cell lines, normal human cells, co-cultures, and ex vivo human skin. CRTC/CREB activity screening was performed to identify candidate agents for the regulation of melanogenesis. Results: The coat and skin color of CRTC3-null mice was paler due to a reduction in melanin deposition. Melanogenesis-related genes were reduced in CRTC3-deficient cultured melanocytes and tail skin of CRTC3-null mice. Notably, basal levels of MITF present in CRTC3-null mice were sufficient for melanocytic differentiation/survival. Thus CRTC3-null mice showed a comparable number of epidermal melanocytes compared to control mice. Stem cell factor (SCF) introduction by crossing with KRT14-SCF mice increased epidermal melanocytes and melanin deposition in control and CRTC3-null mice, but the skin color remained still light on the CRTC3-null background. Furthermore, we identified the therapeutic potential of altiratinib to inhibit melanogenesis in human melanocytes and human skin effectively and safely. Conclusion: CRTC3 appears to be a key sensor for melanogenesis and can be used as a reversible and tunable tool for selectively regulating melanogenesis without affecting melanocyte integrity. Thus, CRTC3 can also serve as a screening tool for the discovery of ideal melanogenesis-modulating small molecules.

By various chromatographic methods, 30 phloroglucinols (1−30) were isolated from a methanol extract of Dryopteris crassirhizoma, including two new dimeric phloroglucinols (13 and 25). The structures of the isolates were confirmed by HR−MS, 1D, and 2D NMR as well as by comparison with the literature. The protein tyrosine phosphatase 1B (PTP1B) effects of the isolated compounds (1–30) were evaluated using sodium orthovanadate and ursolic acid as a positive control. Among them, trimeric phloroglucinols 26–28 significantly exhibited the PTP1B inhibitory effects with the IC50 values of 1.19 ± 0.13, 1.00 ± 0.04, 1.23 ± 0.05 μM, respectively. In addition, the kinetic analysis revealed compounds 26–28 acted as competitive inhibitors against PTP1B enzyme with Ki values of 0.63, 0.61, 1.57 μM, respectively. Molecular docking simulations were performed to demonstrate that these active compounds can bind with the catalytic sites of PTP1B with negative binding energies and the results are in accordance with that of the kinetic studies. In vitro and in silico results suggest that D. crassirhizoma rhizomes together with compounds 26–28 are potential candidates for treating type 2 diabetes.

Low pH virus inactivation (VI) step is routinely used in antibody production manufacturing. In this work, a mimic of the VI step was developed to focus on evaluating adverse effects on product quality. A commercially available lab-scale glass reactor system was utilized to assess impacts of process and solution conditions on process-induced monoclonal antibody particle formation. Flow imaging was found to be more sensitive than light obscuration in detecting microparticles. NaOH as a base titrant increased protein microparticles more than Tris. Both stirring and NaCl accelerated particle formation, indicating that interfacial stress and protein colloidal stability were important factors. Polysorbate 80 was effective at suppressing particle formation induced by stirring. In contrast, trehalose led to higher microparticle levels suggesting a conformational stabilizer may have other adverse effects during titration with stirring. Additionally, conformational and colloidal stability of antibodies were characterized to investigate the potential roles of antibody physicochemical properties in microparticle formation during VI. The stability data were supportive in rationalizing particle formation behaviors, but they were not predictive of particle formation during the mimicked viral inactivation steps. Overall, the results demonstrate the value of testing various solution and processing conditions in a scaled-down system prior to larger-scale VI bioprocesses.

A protein precipitation technique was optimized to produce biophysically stable ‘protein microbeads’, applicable to highly concentrated protein formulation. Initially, production of BSA microbeads was performed using rapid dehydration by vortexing in organic solvents followed by cold ethanol treatment and a vacuum drying. Out of four solvents, n-octanol produced the most reversible microbeads upon reconstitution. A Shirasu porous glass (SPG) membrane emulsification technique was utilized to enhance the size distribution and manufacturing process of the protein microbeads with a marketized human IgG solution. Process variants such as dehydration time, temperature, excipients, drying conditions, and initial protein concentration were evaluated in terms of the quality of IgG microbeads and their reversibility. The hydrophobized SPG membrane produced a narrow size distribution of the microbeads, which were further enhanced by shorter dehydration time, low temperature, minimized the residual solvents, lower initial protein concentration, and addition of trehalose to the IgG solution. Final reversibility of the IgG microbeads with trehalose was over 99% at both low and high protein concentrations. Moreover, the formulation was highly stable under repeated mechanical shocks and at an elevated temperature compared to its liquid state. Its in vivo pharmacokinetic profiles in rats were consistent before and after the ‘microbeadification’.

Arabidopsis thaliana blue-light inhibitor of cryptochromes 1 (AtBIC1) suppresses the dimerization of cryptochromes, which is necessary for cryptochrome function in plants. Additionally, AtBIC1 interacts with brassinazole-resistant 1 (BZR1) and phytochrome-interacting factor 4 (PIF4) transcription factors for integrating brassinosteroid (BR) and light signaling to promote plant growth. Thus, AtBIC1 overexpression is postulated to facilitate a desirable plant architecture for a high yield of crops. We first confirmed the phenotypes of transgenic Arabidopsis plants overexpressing AtBIC1, showing increases in leaf growth, plant height, and seed productivity. Next, we applied the AtBIC1 overexpression approach to soybean as a target crop. The transgenic soybean plants overexpressing AtBIC1 exhibited a significantly tall phenotype (i.e., an increased plant height) but with reduced root growth. In particular, the transgenic soybean plants displayed altered plant architecture, such as greatly elongated hypocotyls, during growth under both greenhouse and field conditions. Due to the phenotype of increased plant height, the total seed weights from the transgenic soybean plants decreased. These results suggest that the greater growth of above-ground parts might result in diminished growth of underground parts (i.e., roots), reducing the seed productivity of soybean. Collectively, these results suggest that AtBIC1 overexpression functions similarly in elongated growth to increase plant heights in both Arabidopsis and soybean, whereas it functions differently in root growth between the two plants.

Tungsten carbide (WC) in Ni-based powders is a promising candidate for laser-based additive manufacturing because WC is an extremely hard material, whereas Ni is tough and weldable. However, WC par...

A new acetylene, (8S)-deca-4,6-diyne-1,8-di-O-β-D-glucopyranoside (4), and four known polyacetylenes (1–3 and 5), together with nine known flavonoids (6–14), were isolated from the flowers of Carthamus tinctorius L. The structures of the isolates were elucidated by using spectroscopic analysis, mainly 1D and 2D NMR, HR-MS, and comparison with literature data, as well as enzymatic hydrolysis and Mosher′s esterification methods. All isolated compounds were evaluated for their anti-allergic effects by analyzing the inhibition of interleukin-2 (IL-2) expression in Jurkat T cells. Among them, 6-hydroxykaempferol 3,6-diglucoside (7) inhibited IL-2 production in activated T cells.

Background Dexmedetomidine is known to protect against ischemia-reperfusion (IR) in various organs; however, the mechanisms of dexmedetomidine in the liver remain unclear. We investigated whether dexmedetomidine preconditioning leads to hepatic protection and whether nitric oxide was associated with this protective mechanism by employing N-nitro- l -arginine methyl ester ( l -NAME), a nitrous oxide synthase inhibitor. Methods Experiment 1 included 24 rats in 4 groups: sham, IR, 30 μg/kg of dexmedetomidine, and 50 μg/kg of dexmedetomidine. Experiment 2 included 36 rats in 6 groups: IR, 50 μg/kg of dexmedetomidine, 10 mg/kg of l -NAME, 10 mg/kg of l -NAME + 50 μg/kg of dexmedetomidine, 30 of mg/kg l -NAME, and 30 mg/kg of l -NAME + 50 μg/kg of dexmedetomidine. All drugs were administered intraperitoneally. The levels of serum transaminases, malondialdehyde, superoxide dismutase, tumor necrosis factor-α, nuclear factor-κB, and c-Jun N-terminal kinase were measured 6 hours after hepatic surgery. Results Dexmedetomidine demonstrated a dose-dependent decrease in serum transaminase levels. The 50-μg/kg dexmedetomidine group showed a significant decrease in malondialdehyde levels (P = .002), increase in superoxide dismutase levels (P = .002), and a significantly lower level of phosphorylated tumor necrosis factor-α, nuclear factor-κB, and c-Jun N-terminal kinase (P = .002, respectively) compared with the IR injury group. These protective effects of dexmedetomidine were partially reversed by pretreatment with l -NAME (P l -NAME). Conclusion In hepatic IR injury, dexmedetomidine might protect the liver via antioxidative and anti-inflammatory responses, and nitric oxide production could play a role in these protective mechanisms.

Renal fibrosis is a progressive and chronic process that influences kidneys with chronic kidney disease (CKD), irrespective of cause, leading to irreversible failure of renal function and end-stage kidney disease. Among the signaling related to renal fibrosis, transforming growth factor-β1 (TGF-β1) signaling is a major pathway that induces the activation of myofibroblasts and the production of extracellular matrix (ECM) molecules. Apamin, a component of bee venom (BV), has been studied in relation to various diseases. However, the effect of apamin on renal interstitial fibrosis has not been investigated. The aim of this study was to estimate the beneficial effect of apamin in unilateral ureteral obstruction (UUO)-induced renal fibrosis and TGF-β1-induced renal fibroblast activation. This study revealed that obstructive kidney injury induced an inflammatory response, tubular atrophy, and ECM accumulation. However, apamin treatment suppressed the increased expression of fibrotic-related genes, including α-SMA, vimentin, and fibronectin. Administration of apamin also attenuated the renal tubular cells injury and tubular atrophy. In addition, apamin attenuated fibroblast activation, ECM synthesis, and inflammatory cytokines such as TNF-α, IL-1β, and IL-6 by suppressing the TGF-β1-canonical and non-canonical signaling pathways. This study showed that apamin inhibits UUO-induced renal fibrosis in vivo and TGF-β1-induced renal fibroblasts activation in vitro. Apamin inhibited the inflammatory response, tubular atrophy, ECM accumulation, fibroblast activation, and renal interstitial fibrosis through suppression of TGF-β1/Smad2/3 and STAT3 signaling pathways. These results suggest that apamin might be a potential therapeutic agent for renal fibrosis. KEY MESSAGES: UUO injury can induce renal dysfunction; however, apamin administration prevents renal failure in UUO mice. Apamin inhibited renal inflammatory response and ECM deposition in UUO-injured mice. Apamin suppressed the activation of myofibroblasts in vivo and in vitro. Apamin has the anti-fibrotic effect on renal fibrosis via regulation of TGF-β1 canonical and non-canonical signaling.

A Gram-stain-negative, strictly aerobic, non-flagellated, rod-shaped bacterium, designated GSB7T, was isolated from seawater collected at the Yellow Sea coast of South Korea. Catalase and oxidase activities were positive. Growth occurred at pH 6.0–9.0 (optimum pH 7.0), 10–40 °C (optimum 30 °C) and with 0–8% NaCl (optimum 1–2%). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain GSB7T belonged to the genus Marivivens, showing the sequence similarities of 96.3, 96.1, and 96.0% with Marivivens niveibacter HSLHS2T, Limimaricola hongkongensis DSM17492T, Marivivens donghaensis AM-4T, respectively. The respiratory quinone was ubiquinone-10 and the major fatty acids were summed feature 8 (C18:1 ω7c and/or C18:1 ω6c), C18:1 ω7c 11-methyl, C16:0 and C10:0 3-OH. The polar lipids comprised phosphatidylglycerol, diphosphatidylglycerol, one unidentified aminolipid, and five unidentified lipids. The DNA G+C content calculated from the whole-genome sequence was 60.6 mol%. On the basis of phenotypic, chemotaxonomic and genotypic characteristics presented in this study, strain GSB7T is suggested to represent a novel species of the genus Marivivens, for which the name Marivivens aquimaris sp. nov. is proposed. The type strain is GSB7T (=KCTC 82026T=JCM 34042T).

Tonicity-responsive enhancer-binding protein (TonEBP; nuclear factor of activated T cells 5) is a transcription factor that responds to changes in osmolality. However, recent studies have shown that it also modulates immune responses under inflammatory conditions independently of hyperosmolality. Fibronectin fragments (FN-fs), which are abundant in the synovial fluid of patients with osteoarthritis (OA), induce expression of matrix metalloproteinases (MMPs) via the toll-like receptor-2 (TLR-2) signaling pathway. In this study we examined whether TonEBP is involved in 29-kDa FN-f-induced expression of MMPs. The expression of TonEBP was significantly higher in human osteoarthritis compared with normal cartilage samples. 29-kDa FN-f affected the expression of MMPs 1, 3, and 13 via TonEBP, and expression and nuclear accumulation of TonEBP were induced by activation of the phospholipase C/NF-κB/MAPK signaling pathway and, in particular, modulated by TLR-2. In addition, 29-kDa FN-f induced the expression of osmoregulatory genes, including Tau-T, SMIT, and AR, as well as voltage-dependent calcium channels via the TonEBP/TLR-2 signaling pathway. These results show that 29-kDa FN-f upregulates MMPs in chondrocytes via the TLR-2/TonEBP signaling pathway.

Despite the facile fabrication of geometry-controlled vertical silicon nanocolumn arrays (vSNAs), metal-assisted chemical etching (MACE) showed critical limitations for producing vSNAs, particularl...

Animal husbandry workers are exposed to various malodorous compounds in the workplace. Although these compounds cause severe nuisance, no systemic investigation of their effects on the immune system has been conducted. To address this issue, we evaluated the effects of inhalational exposure to ammonia, dimethyl disulfide, 3-methylindole (3-MI), and propionic acid (PA), representing four major groups of malodorous compounds, on humoral and cellular immunity in mice. Mice were exposed to the substances (low dose: 10 µL and high dose: 200 µL) for 10 min/day for 4 weeks in a modified standard mouse cage. Neutrophil% and splenic cytotoxic T cell% were significantly lower in the high-dose ammonia group than in the vehicle control. Exposure to ammonia and 3-MI increased immature thymic T lymphocyte% relative to control and concomitantly decreased both mature helper and cytotoxic T-cell populations in the thymus. In the ammonia exposure group, levels of serum immunoglobulin E and immunoglobulin A were elevated, and the IgG2a:IgG1 ratio in the serum was reduced in a dose-dependent manner. Splenic natural killer cell activity was significantly less in the PA exposure group than in the control. Overall, our findings suggest that inhalational exposure to these malodorous substances disturbs immune homeostasis in vivo.

Stimuli-responsive drug delivery systems can respond to specific external stimuli, resulting in improved treatment outcomes and reduced side effects from their controllable site-specific release ability. The aim of this study was to develop a thermo-responsive bubble-generating drug release platform by near-infrared (NIR) laser irradiation using melanin-perfluorohexane-methotrexate-polylactic acid (Mel @PFH@MTX-PLA) nanoparticles. Mel@PFH@MTX-PLA nanoparticles were successfully prepared without precipitation or aggregation. By adjusting the amount of perfluorohexane (PFH), a size of Mel@PFH@MTX-PLA nanoparticles with optimal conditions was about 52.75 ± 1.41 nm. Due to the photothermal conversion properties of melanin, the temperature of the Mel@PFH@MTX-PLA nanoparticles was increased to about 59.2 °C after 7 min of 808 nm NIR laser irradiation at a power density of 1.5 W/cm2. The NIR laser-induced temperature increase triggered additional drug release and caused the phase transition of PFH, resulting in dramatic bubble generation. The resultant Mel@PFH@MTX-PLA nanoparticles can be utilized in biomedical applications as promising carriers for localized and controlled drug delivery.

Hepatocellular carcinoma (HCC) has high fatality rate and limited therapeutic options. Here, we propose a new anti-HCC approach with high cancer-selectivity and efficient anticancer effects, based on adenovirus-mediated Tetrahymena group I trans-splicing ribozymes specifically inducing targeted suicide gene activity through HCC-specific replacement of telomerase reverse transcriptase (TERT) RNA. To confer potent anti-HCC effects and minimize hepatotoxicity, we constructed post-transcriptionally enhanced ribozyme constructs coupled with splicing donor and acceptor site and woodchuck hepatitis virus post-transcriptional regulatory element under the control of microRNA-122a (miR-122a). Adenovirus encoding post-transcriptionally enhanced ribozyme improved trans-splicing reaction and decreased human TERT (hTERT) RNA level, efficiently and selectively retarding hTERT-positive liver cancers. Adenovirus encoding miR-122a-regulated ribozyme caused selective liver cancer cytotoxicity, the efficiency of which depended on ribozyme expression level relative to miR-122a level. Systemic administration of adenovirus encoding the post-transcriptionally enhanced and miR-regulated ribozyme caused efficient anti-cancer effects at a single dose of low titers and least hepatotoxicity in intrahepatic multifocal HCC mouse xenografts. Minimal liver toxicity, tissue distribution, and clearance pattern of the recombinant adenovirus were observed in normal animals administered either systemically or via the hepatic artery. Post-transcriptionally regulated RNA replacement strategy mediated by a cancer-specific ribozyme provides a clinically relevant, safe, and efficient strategy for HCC treatment., Graphical Abstract, Hepatocellular carcinoma (HCC) has high fatality rate and limited therapeutic options. Han et al. developed a new suicide-gene therapeutic strategy for HCC with high cancer-selectivity and efficacy, based on hTERT RNA replacement through an adenovirus-mediated trans-splicing ribozyme under the post-transcriptionally enhanced regulation and normal liver-specific miR-122a control.

This study aimed to evaluate the impact of biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) on lipid profile and atherogenic index of plasma (AIP) in rheumatoid arthritis (RA) patients and to compare the occurrence of dyslipidemia between patients using bDMARDs, tsDMARDs, or conventional DMARDs (cDMARDs).Data on lipid profile, AIP, and occurrence of dyslipidemia were collected from the Korean College of Rheumatology BIOlogics registry. A comparison was conducted between patients using bDMARDs (tumor necrosis factor (TNF)-α inhibitor, tocilizumab, abatacept), Janus kinase inhibitors (JAKis), and cDMARDs. The Kaplan-Meier method was used to compare the occurrence of dyslipidemia between groups, and hazard ratios (HR) were calculated using the cox proportional hazard method.The data of 917, 826, 789, 691, and 520 RA patients were eligible for analysis at the baseline, 1-year, 2-year, 3-year, and 4-year follow-ups, respectively. Baseline total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were higher in the cDMARDs group, whereas AIP was comparable. During the 4-year follow-up, AIP was comparable between the groups. The occurrence of dyslipidemia did not show a significant difference when comparing the bDMARDs/tsDMARDs and cDMARDs groups (P=0.06) or the TNF-α inhibitor, tocilizumab, abatacept, JAKi, and cDMARD user groups (P=0.3). In the multivariate cox proportional hazard model, older age (HR=1.03, P=0.005) and concomitant hypertension (HR=2.21, P=0.013) were significantly associated with dyslipidemia occurrence.Long-term use of bDMARDs and tsDMARDs is relatively safe with regard to lipid profile, AIP, and the occurrence of dyslipidemia in RA patients. Key Points • The use of bDMARDs and tsDMARDs did not increase the risk of dyslipidemia than cDMARDs use in patients with RA. • AIP was comparable between bDMARDs user, tsDMARDs user, and cDMARDs user group in 4-year follow-up data. • Based on the present study, the long-term use of bDMARDs or tsDMARDs did not significantly deteriorate atherogenic lipid profile nor an increased risk of dyslipidemia in patients with RA.

Celery seeds were fractioned successively by organic solvents, and fractions were screened for their antioxidant properties. Metabolites of high antioxidative fractions were analyzed, and then anti-obesity properties and mechanisms of selected fractions were evaluated in 3T3-L1 adipocytes. Celery seed ethanol extract (CSE) and celery seed ethyl acetate fraction (CSEA) possessed higher in vitro antioxidant properties, including radical scavenging and total phenolic content, than that of hexane, butanol, and water fractions. Total of 43 and 19 metabolites were identified from CSE and CSEA, respectively, by gas chromatography-mass selective detector. Isoferulic acid and p-coumaric acid were only found in CSEA. CSEA possessed higher anti-adipogenesis in the 3T3-L1 cells than CSE by decreasing adipogenic hormones, including leptin and adiponectin. Expression levels of adipocyte-related transcription factors and genes such as C/EBPα, PPARγ, aP2, and FAS decreased to comparable levels of control. CSEA could be used as a natural ingredient with antioxidant and anti-obesity functionality.

Background Gene silencing using siRNA can be a new potent strategy to treat many incurable diseases at the genetic level, including cancer and viral infections. Treatments using siRNA essentially requires an efficient and safe method of delivering siRNA into cells while maintaining its stability. Thus, we designed novel synergistic fusion peptides, i.e., SPACE and oligoarginine. Results Among the novel fusion peptides and siRNAs, nanocomplexes have enhanced cellular uptake and gene silencing effect in vitro and improved retention and gene silencing effects of siRNAs in vivo. Oligoarginine could attract siRNAs electrostatically to form stable and self-assembled nanocomplexes, and the SPACE peptide could interact with the cellular membrane via hydrogen bonding. Therefore, nanocomplexes using fusion peptides showed improved and evident cellular uptake and gene silencing of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) via the lipid raft-mediated endocytosis pathway, especially to the HDFn cells of the skin, and all of the fusion peptides were biocompatible. Also, intratumorally injected nanocomplexes had increased retention time of siRNAs at the site of the tumor. Finally, nanocomplexes demonstrated significant in vivo gene silencing effect without overt tissue damage and immune cell infiltration. Conclusions The new nanocomplex strategy could become a safe and efficient platform for the delivery of siRNAs into cells and tissues to treat various target diseases through gene silencing.

Single-molecule force measurement techniques provide unique opportunities to investigate simple molecular interactions and complicated force-induced cell responses. This has revolutionized our understanding of how mechanical cues influence cell behaviors. Recent advances in DNA technologies have led to the development of tension sensors for high-throughput screening of pN scale forces with single-molecule precision. Thus, the emerging DNA-based mechano-sensors are replacing conventional single-molecule force spectroscopes. This review provides an overview of double-stranded DNA-based mechano-sensors, such as the tension gauge tether (TGT) and its derivatives, and their biophysical applications. First, we review the theoretical background of the force-induced rupture of DNA duplexes and force sensing mechanisms using DNA structures. Next, we survey the use of double-stranded DNA-based force sensors to study the role of mechanical forces, mostly receptor tensions, in signaling pathways.

With rapid advances in flexible electronics, transparent conductive electrodes (TCEs) have also been significantly developed as alternatives to the conventional indium tin oxide (ITO)-based material systems that exhibit low mechanical flexibility. Nanomaterial-based alternating materials, such as graphene, nanowire, and nanomesh, exhibit remarkable properties for TCE-based applications, such as high electrical conductivity, high optical transparency, and high mechanical stability. However, these nanomaterial-based systems lack scalability, which is a key requirement for practical applications, and exhibit a size-dependent property variation and inhomogeneous surface uniformity that limit reliable properties over a large area. Here, we exploited a conventional ITO-based material platform; however, we incorporated a transparent molecular adhesive, 4-aminopyridine (4-AP), to improve mechanical flexibility. While the presence of 4-AP barely affected optical transmittance and sheet resistance, it improved interfacial adhesion between the substrate and ITO as well as formed a wavy surface, which could improve the mechanical flexibility. Under various mechanical tests, ITO/4-AP/poly(ethylene terephthalate) (PET) exhibited remarkably improved mechanical flexibility as compared with that of ITO/PET. Furthermore, ITO/4-AP/PET was utilized for a flexible Joule heater application having spatial uniformity of heat generation, voltage-dependent temperature control, and mechanical flexibility under repeated bending tests. This molecular adhesive could overcome the current limitations of material systems for flexible electronics.

UV-responsive vesicle was prepared by incorporating azobenzene in the vesicular membrane composed of dimethylaminopropyl octadecanamide (DMAPODA) and stearic acid (SA). Azobenzene intercalated in the vesicular membrane underwent cis-to-trans isomerization under the UV irradiation, confirmed by UV spectroscopy. The phase transition temperature of vesicle was found to be around 51.2 °C by differential scanning calorimetry. Using a negative staining technique, the vesicles were found as circular and irregular-shaped particles on the TEM photo. The mean hydrodynamic diameter of vesicles increased from 199.4 to 1597.3 nm when the lipid/azobenzene ratio increased from 100/0 to 100/5. The zeta potential of DMAPODA/SA vesicle decreased from about + 60 mV to – 60 mV when the pH value of medium increased from 3.0 to 10.0, and the inclusion of azobenzene in the vesicular membrane had little effect on the zeta potential. UV irradiation markedly promoted the release of carboxylic fluorescein loaded in vesicle incorporating azobenzene, possibly because the cis-to-trans photoisomerization would disturb the well-ordered crystalline structure of the vesicular membrane.

Even though arginine hydrochloride has been recognized as a protein aggregation suppressor in the biopharmaceutical industry, its use has been questioned due to decreasing transition unfolding temperatures (Tm). Four compounds were designed to enhance the role of arginine by changing the length of the carbon chain with removal or N-acetylation of α-amino group. Biophysical properties were observed by differential scanning calorimetry (DSC), dynamic light scattering (DLS), size-exclusion chromatography (SEC), and flow imaging (FI). N-Acetyl-L-arginine (NALA) performed the best at minimizing decrease in Tm with arginine at different pH. NALA also demonstrated relatively higher colloidal stability than arginine hydrochloride, especially in the acidic pH, thereby reducing agitation stress of IgG. Moreover, NALA exhibited a cooperative effect with commercially used glycine buffer for IVIG to maintain the monomer contents with almost no change and suppressed larger particle formation after agitation with heat. The study concludes that the decreasing Tm of proteins by arginine hydrochloride is due to amide group in the α-carbon chain. Moreover, chemical modification on the group compared to removing it will be a breakthrough of arginine's limitations and optimize storage stability of protein therapeutics.

Background: Glioblastoma (GBM) is one of the most aggressive types of brain cancer. GBM progression is closely associated with microglia activation; therefore, understanding the regulation of the crosstalk between human GBM and microglia may help develop effective therapeutic strategies. Elucidation of efficient delivery of microRNA (miRNA) via extracellular vesicles (EVs) and their intracellular communications is required for therapeutic applications in GBM treatment. Methods: We used human GBM cells (U373MG) and human microglia. MiRNA-124 was loaded into HEK293T-derived EVs (miR-124 EVs). Various anti-tumor effects (proliferation, metastasis, chemosensitivity, M1/M2 microglial polarization, and cytokine profile) were investigated in U373MG and microglia. Anti-tumor effect of miR-124 EVs was also investigated in five different patient-derived GBM cell lines (SNU-201, SNU-466, SNU-489, SNU-626, and SNU-1105). A three-dimensional (3D) microfluidic device was used to investigate the interactive microenvironment of the tumor and microglia. Results: MiR-124 EVs showed highly efficient anti-tumor effects both in GBM cells and microglia. The mRNA expression levels of tumor progression and M2 microglial polarization markers were decreased in response to miR-124 EVs. The events were closely related to signal transducer and activator of transcription (STAT) 3 signaling in both GBM and microglia. In 3D microfluidic experiments, both U373MG and microglia migrated to a lesser extent and showed less-elongated morphology in the presence of miR-124 EVs compared to the control. Analyses of changes in cytokine levels in the microfluidic GBM-microglia environment showed that the treatment with miR-124 EVs led to tumor suppression and anti-cancer immunity, thereby recruiting natural killer (NK) cells into the tumor. Conclusions: In this study, we demonstrated that EV-mediated miR-124 delivery exerted synergistic anti-tumor effects by suppressing the growth of human GBM cells and inhibiting M2 microglial polarization. These findings provide new insights toward a better understanding of the GBM microenvironment and provide substantial evidence for the development of potential therapeutic strategies using miRNA-loaded EVs.

Carbon fixing materials are a new class of self-healing, self-reinforcing materials we have introduced that utilize ambient CO2 to chemically add to an ever extending carbon backbone. This class of materials can utilize biological or non-biological photocatalysts and support a wide range of potential backbone chemistries. However, there is no analysis to date that describes their fundamental limits in terms of chemical kinetics and mass transfer. In this computational study, we employ a reaction engineering, and materials science analysis to answer basic questions about the maximum growth rate, photocatalytic requirements and limits of applicable materials. Our proposed mathematical framework envelops three main functions required for carbon fixing materials: (1) adsorption of CO2 from air, (2) photocatalytic reduction of CO2 into selected monomers, and (3) polymerization of CO2-derived monomers. First, by performing a Damkohler number analysis, we derive criteria for the cross over from kinetic control to mass transfer limited growth, setting upper limits on performance of a potential photocatalyst. Next, we analyze photocatalytic reduction of CO2 to single carbon products, using known catalytic pathways and kinetic data. We identify formaldehyde as a C1 intermediate having unique potential for incorporation into the material backbone of carbon fixing materials. As an example, we find that a diamond-shaped reaction network graph for CO2 reduction, passing through CO and HCOOH intermediates, accurately describes kinetic data for cobalt-promoted TiO2 nanoparticles at room temperature and 1 atm CO2. Finally, as an applied case study, we consider and analyze the example of a carbon fixing poly(oxymethylene) system with embedded catalyst promoting the photocatalytic reduction of CO2 to formaldehyde. The latter then trimerizes to a trioxane monomer which subsequently polymerizes to polyoxymethylene. This reaction engineering analysis introduces benchmarks for carbon fixing materials with respect to achievable rates of photocatalysis, adsorption, and polymerization. These results should prove valuable for the design, evaluation, and benchmarking of this emergent and new class of environmentally sustainable materials.

Household products often contain an antimicrobial agent such as biocides, polyhexamethylene guanidine (PHMG), triclosan (TCS), and propylene glycol (PG) as an excipient to dissolve the active ingredients. The skin sensitization (SS) potentials of each of these substances or mixtures of PHMG or TCS with PG have not been investigated through in vitro alternative test methods. The in vitro alternative assay called human Cell Line Activation Test (h-CLAT) served to address these issues. The h-CLAT assay was conducted in accordance with OECD TG 442E. On three independent runs, all the three substances were predicted to be sensitizers according to the SS positivity with relative fluorescence intensity of CD86 ≥ 150% and/or CD54 ≥ 200% at any tested concentrations. Mixtures of PHMG or TCS with PG at ratios of 9:1, 4:1, or 1:4 weight/volume were all positive in terms of SS potential. Since humans can be occupationally or environmentally exposed to mixtures of excipients with active ingredients of biocides, the present study may give insights into further investigations of the SS potentials of various chemical mixtures.

Purpose Approval of eribulin for metastatic breast cancer was based on data primarily from Western patients, and there is a paucity of data on the effectiveness and safety of eribulin for Asian patients. To determine the effectiveness and safety of eribulin in Korean women with breast cancer in a real-world setting, we conducted a nationwide, multicenter, retrospective study. Methods Patients with locally advanced or metastatic breast cancer who were treated with eribulin in 14 centers throughout Korea were included in this study. Eribulin was generally administered at a dose of 1.23 mg/m2 (equivalent to 1.4 mg/m2 eribulin mesylate) by intravenous infusion for 2–5 min, or as a diluted solution, on Days 1 and 8 of every 21-day cycle. The primary endpoint was progression-free survival (PFS) rate at 6 months. Secondary endpoints included median PFS, overall survival (OS), time-to-treatment failure (TTF), tumor response rate, and incidence of hematologic treatment-emergent adverse events (TEAEs). Results The safety and full analysis populations included 398 and 360 (38 had no efficacy data) patients, respectively. The PFS rate at 6 months was 37.8%. Median PFS, OS, and TTF were 134, 631, and 120 days, respectively. Objective response rate, clinical benefit rate, and disease control rate were 18.1%, 50.6%, and 49.4%, respectively. Hematologic TEAEs were reported in 65.1% of patients; neutropenia (56.8%) and anemia (11.3%) were most common. Conclusion Real-world effectiveness and safety of eribulin in Korean breast cancer patients were consistent with previous reports; no new safety concerns were identified., Graphical abstract Image 1, Highlights • Metastatic breast cancer patients were treated with eribulin (1.23 mg/m2, IV). • Progression-free survival rate at 6 months was 37.8% in eribulin-treated patients. • Median progression-free and overall survivals were 134 and 631 days, respectively. • Hematologic treatment-emergent adverse events were reported in 65.1% of patients. • Effectiveness and safety of eribulin were consistent with previous reports.

Lactobacillus sanfranciscensis, Lactobacillus brevis, and Lactobacillus curvatus are frequently isolated from cereal-based fermented foods and are the dominant lactic acid bacteria in Korean sourdough. Detection of the individual species and their enumeration during fermentation are of great importance for maintaining the quality of bakery products. Here, we developed a species-specific quantitative polymerase chain reaction (qPCR) method to monitor the population of these three bacterial species during cocultivation in sourdough. Target genes, including those encoding nucleoside hydrolase, hypothetical protein, and glyoxalase, were selected by MegaBLAST for the detection of L. sanfranciscensis, L. brevis, and L. curvatus, respectively. The specificities of PCR primer sets were verified with qPCR; constant cycle threshold (Ct) values were obtained from mixed genomic DNAs (gDNAs) of target and non-target strains. The qPCR results were unaffected by the sourdough matrix. The cell numbers derived from qPCR were 10–65% higher than those obtained using a conventional plate-counting method. The qPCR standard curves for the three Lactobacillus species were established, and their populations were successfully enumerated during sourdough propagation. This method would enable quantification of three Lactobacillus species during cocultivation in sourdough and provide useful information on microbial commensalism that is essential to obtain high-quality bread.

Introduction: This study was conducted to evaluate the effect of short-term sunlight exposure on blood pressure (BP) and pulse rate (PR) in vitamin D3-insufficient, prehypertensive patients. Methods: Twenty prehypertensive male participants were prospectively enrolled in this pilot study. BP and PR were measured using 24-hour ambulatory BP monitoring and endocrine biomarkers were assessed. Results: Sunlight exposure decreased 24-hour systolic BP (SBP), diastolic BP (DBP), and PR (SBP: 132.6 mm Hg to 129.3 mm Hg, DBP: 77.6 mm Hg to 75.7 mm Hg, and PR: 76.1 bpm to 71.3 bpm, p values: 0.0011, 0.0012, and p values: 0.0015, 0.0003, and 3 were significantly increased (p = 0.0001) but aldosterone levels were significantly decreased (p = 0.0014) after sunlight exposure. In addition, an inverse relationship between 25-hydroxyvitamin D3 and aldosterone levels was observed (R = –0.4709, p = 0.0419). Discussion/Conclusion: The pilot study gives promising results that it is worthwhile to evaluate short-term sunlight exposure as a potentially effective approach in decreasing BP and PR in 25-hydroxyvitamin D3-insufficient prehypertensive patients in a larger trial with a control group.

Aryl hydrocarbon receptor nuclear translocator (ARNT) plays an essential role in maintaining cellular homeostasis in response to environmental stress. Under conditions of hypoxia or xenobiotic exposure, ARNT regulates the subset of genes involved in adaptive responses, by forming heterodimers with hypoxia-inducible transcription factors (HIF1α and HIF2α) or aryl hydrocarbon receptor (AhR). Here, we have shown that ARNT interacts with DDB1 and CUL4-associated factor 15 (DCAF15), and the aryl sulfonamides, indisulam and E7820, induce its proteasomal degradation through Cullin-RING finger ligase 4 containing DCAF15 (CRL4DCAF15) E3 ligase. Moreover, the two known neo-substrates of aryl sulfonamide, RNA-binding motif protein 39 (RBM39) and RNA-binding motif protein 23 (RBM23), are not required for ARNT degradation. In line with this finding, aryl sulfonamides inhibited the transcriptional activities of HIFs and AhR associated with ARNT. Our results collectively support novel regulatory roles of aryl sulfonamides in both hypoxic and xenobiotic responses.

Myristica fragrans Houtt. (Myristicaceae), an aromatic evergreen tree, is well known as a commercial source of mace (aril) and nutmeg (seed), which have long been widely used as spices in the culinary field. In addition, various parts of M. fragrans have been used in folk medicine for treating several diseases. Since its extensive uses in the culinary sector and folk medicine, M. fragrans has long attracted a great deal of attention from pharmacologists and chemists. Numerous studies have indicated that M. fragrans contains diverse phytochemicals such as lignans, neolignans, diphenylalkanes, phenylpropanoids, and terpenoids, which exhibit many of pharmacological activities. Among them, macelignan (1), meso-dihydroguaiaretic acid (2), myristicin (111), and malabaricone C (Mal C, 104) are the most active compounds. The aim of this review is to comprehensively summarize the phytochemical and pharmacological properties of M. fragrans that have reported to date.

Vesicles comprising dimethyl aminopropyl octadecanamide (DMAPODA), stearic acid (SA), and carboxyhexadecyl disulfide (CHDDS) were prepared as reduction-responsive carriers. Vesicular particles were found on TEM micrographs and the diameter fell within 100–400 nm. The hydrodynamic mean diameter increased with increasing the content of CHDDS. The zeta potential was lowered by the incorporation of CHDDS into the vesicular membrane. Vesicle whose DMAPODA/SA/ CHDDS molar ratio was 1/1/5 exhibited one endothermic peak around 50.9°C, indicating that the vesicular membrane was homogeneous in the composition. Strong signals were found in 500–540 cm-1 in the Raman spectrum of vesicles, suggesting that the disulfide lipid (i.e. CHDDS) was incorporated into the vesicular membranes. Vesicles containing CHDDS released rhodamine B in dithiothreitol (DTT, a reducing agent) concentration-dependent manner. The DTTsensitivity of the vesicles in terms of release was higher as the CHDDS content was higher.

Among the 2-arylbenzofuran derivatives isolated from Morus alba, the farnesylated 2-arylbenzofuran is a rarer constituent. The derivative has been reported to exert anti-obesity effect; however, its inhibitory effect on protein tyrosine phosphatase 1B (PTP1B) has not been investigated. In the previous study, the presence of the farnesyl group in the structure of 2-arylbenzofurans was found to have positive influences on their pancreatic lipase inhibitory activity. In the present study, we have confirmed the authenticity of the notation based on the PTP1B inhibitory activity of farnesylated 2-arylbenzofurans. Specifically, two farnesylated 2-arylbenzofurans [morusalfurans B (2) and C (3)] showed strong inhibitory effects on PTP1B with IC50 values of 8.92 and 7.26 µM, respectively, which was significantly higher than that of the positive controls [sodium orthovanadate (IC50 = 15.10 µM) and ursolic acid (IC50 = 11.34 µM)]. Besides, two 2-arylbenzofurans [morusalfurans A (1) and F (6)], one flavonoid [morusalnol B (9)], and one geranylated stilbene [morusibene A (11)] exhibited PTP1B inhibition with IC50 values ranging from 11.02 to 26.56 µM. Kinetic studies revealed compounds 2, 3, 6, and 11 as mixed type PTP1B inhibitors, while 1 and 9 are known as noncompetitive. Molecular docking simulations demonstrated that these active compounds can bind with the respective catalytic or/and allosteric sites of PTP1B with negative binding energies and the results are in accordance with that of the kinetic studies. To the best of our knowledge, this is the first time, the PTP1B inhibitory activity of eleven compounds (1–11), as well as the mechanism of action underlying the effects on PTP1B enzyme of the active compounds, were investigated. In vitro and in silico results suggest that the farnesylated 2-arylbenzofurans from M. alba may potentially be utilized as an effective treatment therapy for type 2 diabetes mellitus and its associated complications.

This study investigated the chemical profiles of fine urban road dust as a set of indicators for major air pollutants at sampling sites or as proxies for potential human health impacts. We examined the chemical compositions of fine particles (3, NOx, PM2.5, SOx, and volatile organic compounds. The elemental compositions, including metal contents and volatile or semi-volatile organic compound species were determined to constitute comprehensive chemical profiles of the solid road dust samples. The water-extractable organic compounds and fluorescent species of the size-fractionated re-suspended fine particulate matter (RPM) were also incorporated in the chemical profiles. The metal content and aliphatic hydrocarbons could partly distinguish emission sources, and clearer distinctions were achieved with the inclusion of fluorescence excitation-emission matrix (EEM) results. The dose–response test results showed positive correlations between cytotoxicity and relative abundance of hydrocarbons or metal contents of urban road dust. The set of chemical profiles suggested in this study could be further utilized for site identification or human health impact assessment using urban road dust.

Hydrocoptisonine is a new compound that has been isolated from the rhizomes of Coptis chinensis, which belongs to the Ranunculaceae family of Chinese medicines. Although studies on C. chinensis have been reported, the metabolic pathway of hydrocoptisonine in human liver microsomes (HLMs) remains unelucidated. We identified 13 metabolites in HLMs, including six Phase I metabolites and seven glucuronide conjugates, using a high-resolution quadrupole-orbitrap mass spectrometer. The major metabolic pathway was the O-demethylation and mono-hydroxylation of hydrocoptisonine in HLMs. Notably, M3 metabolite was O-demethylated in dioxolane structures (cyclohexa-3,5-diene-1,2-dione), which was mediated by cytochrome P450 1A2. The locations of hydroxylation and hydroxyl-glucuronidation were identified by analyzing the signature fragments generated as a result of tandem mass spectrometry, indicating hydroxylation at an aliphatic chain or aromatic ring. We determined whether the hydroxylation and glucuronidation occurred in an aromatic moiety (M5 and M12) or an aliphatic moiety (M6 and M13), respectively, based on signature fragments of the metabolites.

Background/Aims To investigate whether parapapillary choroidal microvasculature dropout (MvD) is associated with progressive retinal nerve fibre layer (RNFL) thinning in eyes with primary open-angle glaucoma (POAG) and disc haemorrhage (DH). Methods Parapapillary microvasculature was evaluated by swept-source optical coherence tomography (OCT) angiography (OCTA) in 50 eyes with POAG and DH, 1 year before, at the time of and 1 year after the detection of DH. MvD was defined as an area in the parapapillary deep layer of focal sectoral dropout with no visible microvascular network. Progressive changes in OCT RNFL thickness were compared in groups of eyes with and without MvD. Results Cumulative prevalence of MvD was 76.0% (38 eyes) at 1 year after detection of DH. All MvDs were detected in the same sectoral locations as DH. In eyes with MvD, global RNFL thickness and sectoral RNFL thickness at the location of DH were significantly reduced, both from 1 year before to the time of DH detection (both p Conclusion In eyes with POAG, RNFL thinning was spatially consistent and progressive at the location of MvD accompanied by subsequent DH and continued to progress after the occurrence of DH. When DH was not accompanied by MvD, progressive RNFL thinning was more likely to occur after the detection of DH.

The onion, known as the bulb onion or common onion, is not only a key ingredient in many tasty and healthy vegetarian meals but also many traditional medicines. Nine new flavonoids [cepaflavas A, B (5, 6), cepadials A-D (7-9 and 14), and cepabiflas A-C (10-12)] and six known compounds (1-4, 13, 15) were obtained from the outer skins of Allium cepa L. Among them, compounds 5, 6, and 9 might be artificial products formed during extraction and isolation. New compounds were structurally elucidated using various spectroscopy/spectrometry techniques, including NMR and HRMS, and computational methods. Their absolute configurations were determined using time-dependent density functional theory calculations, combined with ECD spectroscopy, optical rotation calculation, and statistical procedures (CP3 and DP4 analysis). The free radical scavenging assays revealed that the new compounds 10-12 possessed considerable antioxidant activities with IC50 values of 4.25-8.88 and 7.12-8.14 μM against DPPH and ABTS•+, respectively. Compounds 13-15 showed substantial inhibitory activities against both α-glucosidase and protein tyrosine phosphatase 1B (PTP1B), with IC50 values of 0.89-6.80 and 1.13-6.82 μM, respectively. On the basis of molecular docking studies, 13 and 15 were predicted to have high binding capacity and strong affinity toward the active site of PTP1B.

Cryopreservation is used for blastocyst preservation of most mammalian embryos and is an important technique for breeding. We aimed to compare the efficiency of the cryopreservation method using the standard Cryotop device and the ReproCarrier device, a domestic product manufactured in Korea. The efficacy of the two devices was analyzed based on the survival rate, intracellular levels of reactive oxygen species (ROS), and apoptosis of the vitrified bovine blastocysts. The survival rates of the vitrified-warmed blastocysts were similar between the ReproCarrier group (58.4 ± 17.7%) and Cryotop group (59.9 ± 14.1%). Intracellular ROS levels and apoptotic index were determined by DCFDA staining and TUNEL assay. Changes in intracellular ROS levels, number of total nuclei, and cellular apoptosis of vitrified blastocysts after cryopreservation were not significantly different between the two groups. These results indicate that the ReproCarrier device method is as effective as the standard Cryotop method for vitrification of bovine blastocysts in vitro.

Objective:To assess the prevalence of partially hydrogenated oils (PHO), hydrogenated oils (HO) and/or both in Canadian packaged foods in 2013 and 2017 and to determine the mean trans-fatty acid (TFA) content of products declaring such oils.Design:Repeated cross-sectional study of the Food Label Information Program.Setting:Food labels (n 32 875) were collected from top Canadian grocery retailers in 2013 and 2017. Proportions of products declaring PHO, HO and/or both in the Ingredients List were calculated by year and food category. The percentage contribution of TFA (g) to total fat (g) was calculated and compared against the voluntary TFA limits, defined as Results:The use of PHO, HO and/or both significantly decreased in Canadian foods from 2013 to 2017 (0·8 to 0·2 %, 5 to 2·4 % and 5·7 to 2·6 %, respectively, for PHO, HO and/or both). The mean TFA content of products containing PHO increased (0·34 to 0·57 g TFA/serving); although it was not statistically significant, it is still concerning that TFA content increased. The TFA content significantly decreased in foods with HO (0·24 to 0·16 g TFA/serving, P < 0·05) during 2013–2017.Conclusions:Products with PHO continue to be present in the Canadian marketplace, despite voluntary efforts to eliminate them. Products with HO should also be monitored, as they can also contribute to TFA content in foods.

Background/objectives Different fatty acids exert different health benefits. This study investigated the potential protective effects of perilla, olive, and safflower oils on high-fat diet-induced obesity and colon inflammation. Materials/methods Five-week old, C57BL/6J mice were assigned to 5 groups: low-fat diet (LFD), high-fat diet (HFD) and high-fat diet supplemented with-perilla oil (HPO), olive oil (HOO), and safflower oil (HSO). After 16 weeks of the experimental period, the mice were sacrificed, and blood and tissues were collected. The serum was analyzed for obesity- and inflammation-related biomarkers. Gene expression of the biomarkers in the liver, adipose tissue, and colon tissue was analyzed. Micro-computed tomography (CT) analysis was performed one week before sacrifice. Results Treatment with all the three oils significantly improved obesity-induced increases in body weight, liver weight, and epididymal fat weight as well as serum triglyceride and leptin levels. Treatment with perilla oil (PO) and safflower oil (SO) increased adiponectin levels. The micro-CT analysis revealed that PO and SO reduced abdominal fat volume considerably. The mRNA expression of lipogenic genes was reduced in all the three oil-supplemented groups and PO upregulated lipid oxidation in the liver. Supplementation of oils improved macroscopic score, increased colon length, and decreased serum endotoxin and proinflammatory cytokine levels in the colon. The abundance of Bifidobacteria was increased and that of Enterobacteriaceae was reduced in the PO-supplemented group. All three oils reduced proinflammatory cytokine levels, as indicated by the mRNA expression. In addition, PO increased the expression of tight junction proteins. Conclusions Taken together, our data indicate that the three oils exert similar anti-obesity effects. Interestingly, compared with olive oil and SO, PO provides better protection against high-fat diet-induced colon inflammation, suggesting that PO consumption helps manage inflammation-related diseases and provides omega-3 fatty acids needed by the body.

Even though butein can be a promising candidate for anti-inflammatory and anti-diabetic activities, it is poorly soluble limiting its availability for product development. Size reduction and solid dispersion (SD) were adopted independently to evaluate their feasibility for enhancement in solubility as well as bioavailability. To reduce the particle size, milling method was carried out under dry and wet conditions. For solid dispersion preparation, simple solvent evaporation method was used with hydrophilic excipients including PVP K-30 and Poloxamer 407. Physicochemical properties such as crystallinity, size, and kinetic solubility of prepared formulations were assessed using dynamic light scattering, X-ray powder diffraction, differential scanning calorimetry, and solubility. In vivo pharmacokinetic study was also conducted with selected samples. Butein is weakly basic with its pKa 6.76 and log P 3.81 based on the Henderson-Hasselbalch equation. High temperature and basic pH were degradative stresses as significant color change in solution. Milling decreased the size distribution down to 4.2 μm without dramatic change in the solubility. However, the solubility of solid dispersion increased from 3.15 up to 114.57 μg/mL, suggesting amorphous state increased solubility significantly. Its amorphous state was confirmed by DSC and PXRD. In addition, oral absorption of SD in vivo confirmed its enhanced pharmacokinetic parameters; faster Tmax, higher Cmax and AUC. Solid dispersion exhibited enhancement in pharmacokinetic parameters compared to size reduction, suggesting its feasibility for solid dispersion formulation.

이 연구는 농산물의 원산지에 따른 검출 농약을 조사하여 대한 민국의 수입 바나나 중 잔류농약 안전 관리 자료로 활용하고자 하였다. 미국, 일본, EU, 영국 및 대한민국의 2007에서 2018년까지 바나나 중 잔류농약 검사 결과를 활용하여 검출 농약, 검사 건수, 농약 검출 건수 및 검출량으로 정리하였다. 이들 바나나의 잔류농약 검사에서 검출된 농약은 총 109종이었으며, 전체 검사 건수는 206,894건이었다. 이 중 9,483건에서 잔류농약이 검출되었으며, 농약 검출률은 4.58%였다. 검출된 농약은 chlorpyrifos, imazalil, methyl-bromide, azoxystrobin, carbendazim, pretilachlor 및 thiabendazole 등 이었으며, 이 농약들의 검출률은 10.62-24.62% 범위였다. Chlorpyrifos가 검출 건수에서 가장 많이 검출되었으며, 다음으로 imazalil, azoxystrobin, thiabendazole, bifenthrin 및 carbendazim 순이었다. EU, 일본, 미국, 영국 및 대한민국의 잔류농약 검사에서 각각 85, 57, 23, 18 및 8종 농약이 검출되었다. Azoxystrobin, bifenthrin 및 chlorpyrifos는 모든 국가의 모니터링에서 검출되었다. 코스타리카 및 에콰도르산 바나나에서 각각 14 및 12종 농약이 검출되었다. Imazalil 및 thiabendazole은 각각 16 및 11개 원산지에서 검출되었다. Myclobutanil 및 iprodione은 각각 4 및 2개국산에서 검출되었다. Azoxystrobin 및 bifenthrin은 코스타리카산 바나나에서 각각 11.8 및 9.8% 검출 건수를 보였고, azoxystrobin의 검출률은 콜롬비아산에서 19%였다. 벨리즈산, 콜롬비아산 및 코스타리카산 바나나 중 chlorpyrifos는 각각 22.7, 13.3 및 10.8%의 검출률을 보였고, 콜롬비아산 및 코스타리카산 바나나 중 myclobutanil의 검출률은 각각 17.9 및 10.4%였다.

An efficient protocol for multiple shoot induction and plant regeneration from axillary bud culture of Magnolia ‘Vulcan’ was developed in the present study. Primary shoots were obtained from axillary bud explants cultured on Murashige and Skoog (MS) medium containing 1.0 mg/L 6-benzylaminopurine (BA). To induce multiple shoots effectively, primary shoot tips were cultured on MS medium supplemented with different concentrations of BA and zeatin at 0, 0.2, 0.5, and 1.0 mg/L. Of these treatments, the MS medium with 0.5 mg/L BA resulted in the highest number of shoots per explant with an average value of 5.9, and it produced the greatest shoot height at 4.8 cm after 12 weeks of culturing. In the rooting of in vitro produced shoots, the greatest percentage of explants forming roots (91.3%), number of roots per explant (9.7), and root length (2.8 cm) were obtained in half-strength MS medium supplemented with 6.0 mg/L indole-3-butyric acid (IBA). Regenerated plantlets were successfully acclimatized and hardened off inside the culture room with 87.5% survival rate. Plants were transferred to a greenhouse with a 97.2% survival rate. The highly efficient shoot multiplication and plant regeneration system reported herein can be used for large-scale clonal propagation of valuable Magnolia species or cultivars.