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Two-dimensional materials-based membranes continue attracting research interest due to the ultrafast permeance and effective molecular sieving. However, measuring the nanofiltration performance of an ultrafast membrane under long-term filtration remains elusive, particularly when considering the effects of concentration polarization and cake formation on the flux decline and rejection rate. To address this question, we designed an ultrafast graphene oxide (GO) membrane using small-flake graphene oxide (SFGO) on the lateral scale of ∼100 nm, which was prepared using sonication. The SFGO membrane exhibited ultrafast permeance of 720–5410 L m−2 h−1 bar−1 for several solvents (i.e., acetone, methanol, water, ethanol, and isopropyl alcohol), which could be attributed to the reduced diffusion length and increased effective membrane surface area. It was observed a drastic flux and rejection rate decline in both water and isopropyl alcohol in the filtration of several dye solutions using dead-end and cross-flow systems. This could be attributed to the concentration polarization and cake formation that occurred during the rapid accumulation of solute on the membrane surface due to the ultrafast solvent permeance.

We isolated S-formylglutathione hydrolase (scSFH) from Sphingobium chungbukense strain KCTC2955 and expressed it in Escherichia coli. The extracted scSFH showed activity toward p-nitrophenyl butyrate (p-NB), and a protein–substrate interaction was confirmed through 3D molecular docking simulation. The DNA sequence of the cloned scSFH gene (900 bp) has an open reading frame encoding 300 amino acids with a predicted molecular mass of 32.82 kDa; the sequence contains Ser-His-Asp conserved in the active site and a GHSMGG motif. The cloned scSFH gene successfully overproduced scSFH protein under the T7 promoter of the expression vectors pET21a and pGEX4T-1 in E. coli BL21(DE3). We analyzed E. coli-expressed scSFH protein for esterase activity using p-NB as a substrate. Furthermore, we confirmed the interaction between the scSFH protein and p-NB substrate. The scSFH protein of the SFH family was overexpressed in E. coli BL21(DE3) and purified using affinity Ni–NTA agarose resin. The activity of purified scSFH against p-NB was 6.87 mg L−1 for Km and 131.16 mg L−1 protein min−1 for Vmax. Additionally, we confirmed that the serine residue of the GHSMGG motif in the obtained protein interacts with p-NB through molecular docking prediction by the molecular operating environment. We identified a novel scSFH gene from S. chungbukense and overexpressed it in E. coli. The recombined scSFH protein showed activity toward p-NB, and the interaction was confirmed through 3D molecular docking prediction. This research could be applied to identify new genes and confirm their functions.

Sphinganine is a key precursor for the synthesis of ceramide during sphingolipid biosynthesis in eukaryotes. In the sphinganine biosynthetic pathway, serine palmitoyltransferase (SPT) and 3-ketosphinganine reductase (3KSR) catalyze the condensation of serine and palmitoyl-CoA to form 3-ketosphinganine, and the conversation of 3-ketosphinganine to dehydrosphingosine (DHS), respectively. Phytosphingosine among cosmeceutical ingredients exists primarily on the surface of the skin and serves as a potent anti-microbial and anti-inflammatory agent. To overexpressing produce phytosphingosine in bacteria, we designed and synthesized the oligonucleotide of two major genes (3KSR and SPT) involved in the biosynthesis of sphingolipid for industrial applications. The genes encoding SPT from the Gram-negative bacterium Sphingobium chungbukense DJ77 and 3KSR from the eukaryotic Saccharomyces cerevisiae were expressed in Escherichia coli BL21 (DE3) to produce DHS efficiently. Codon optimization was utilized for 3KSR expression in E. coli to facilitate the expression of eukaryotic proteins in the bacterial host. The synthetic 3KSR (3sKSR) protein activity was improved approximately 1.8 times compared to the wild-type 3KSR. Additionally, we successfully overexpressed the spt gene obtained from S. chungbukense DJ77, which can be used in efficient production of the sphenoid bases, with codon-optimized 3sKSR. The enhanced accumulation of DHS by SPT-3sKSR suggests that the codon-optimized enzyme (3sKSR) is more efficient for heterogeneous expression in E. coli. Our results demonstrate that sphingolipid metabolism can be configured in engineered E. coli by the simultaneous overexpression of two key enzymes, SPT and 3sKSR, thereby producing sphingosine.

Biogenic amines (BAs) produced by the action of bacterial amino acid decarboxylases in fermented foods cause various health problems in human. Despite the importance, detailed characterizations of the BA-producing decarboxylases are relatively less progressed than the studies on BA-producing bacteria, due to the time-consuming chromatography-based assay method. In this study, a simple and general colorimetric assay for aromatic amino acid decarboxylases coupled with an amine oxidase from Arthrobacter aurescens (AMAO) and horseradish peroxidase was developed using a tyrosine decarboxylase from Enterococcus faecium DSM20477 (EfmTDC) as a model enzyme. The activity profiles over pH and temperature and the kinetic analysis for EfmTDC revealed that the results by the colorimetric assay are compatible with those by the chromatographic assay. In addition, due to the broad substrate specificity of AMAO for histamine and 2-phenylethylamine, the colorimetric assay would be applicable to the characterization of other aromatic amino acid decarboxylases including histidine decarboxylases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10068-021-00938-4.

In the described experiments, we identify and clone a novel serine palmitoyltransferase (SPT) isolated from the gram-negative obligatory aerobic bacteria Sphingobium chungbukense strain KCTC2955. SPT catalyzes the first rate-limiting reaction in the de novo biosynthesis of sphingolipids, in S. chungbukense. The DNA sequence of the cloned SPT gene (1791 bp) has an open reading frame encoding 405 amino acids with a predicted molecular mass of 41 kDa; the sequence contains the consensus PLP-binding motif (GTFSKSXXXXGG) which is conserved among serine palmitoyltransferase. The ribosomal binding site GGGA lays 6 bp upstream of the ORF of 1218 bp, which is initiated by an ATG codon and terminated by TGA. The cloned SPT gene succeeded in overproducing the SPT protein under the T7 promoter of the expression vector pET 21a in Escherichia coli BL21(DE3), in which the product amounted to about 20–30% of the total protein isolated from the cell extract. Sphingobium SPT showed about a 68.4–89.3% homology with other enzymes in the serine palmitoyltransferase family, and amino acid residues proposed to be involved in catalysis were conserved. The activity of purified recombinant-SPT using Ni-NTA metal-affinity chromatography was measured via the radioactivity of the [3H]-3-ketodihydrosphingosone (KDS) formation using l-[3H]-serine. We have identified a novel SPT gene from S. chungbukense KCTC2955 and overexpressed the recombinant SPT in E. coli. This study is a first step in understanding the reaction mechanism of SPT in bacteria as well as the first focused on the genus Sphingobium.

Photobiomodulation (PBM) is a therapeutic approach to certain diseases based on light energy. Currently, stem cells (SCs) are being considered as putative treatments for previously untreatable diseases. One medical condition that could be treated using SCs is sensorineural hearing loss. Theoretically, if properly delivered and differentiated, SCs could replace lost hair cells in the cochlea. However, this is not currently possible due to the structural complexity and limited survival of SCs within the cochlea. PBM facilitates SC differentiation into other target cells in multiple lineages. Using light with a wavelength > 800 nm, which can penetrate the inner ear through the tympanic membrane, we assessed morphological changes of mouse embryonic stem cells (mESCs) during "otic organoid" generation, and within the scala media (SM) of the cochlea, after light energy stimulation. We observed enhanced differentiation, which was confirmed by an increased number of otic vesicles and increased cell attachment inside the SM. These results suggest that > 800-nm light affected the morphology of mESCs within otic organoids and SM of the cochlea. Based on our results, light energy could be used to enhance otic sensory differentiation, despite the structural complexity of the inner ear and limited survival time of SCs within the cochleae. Additional studies to refine the light energy delivery technology and maximize the effect on otic differentiation are required.

We describe the design of functional hierarchical pores in polymer monoliths on the basis of inverse, water-in-oil (w/o), high internal phase emulsions. The emulsion structure was formed and stabil...

People living near abandoned mines are at increased risk of exposure to toxic metals. We surveyed 4500 inhabitants with the mean age of 68.5 years old (male: 1768, female: 2732) living near 104 abandoned metal mines from 2013 to 2017 (the 2nd phase health survey in Korea). We conducted personal interviews, blood and urine sampling, and analyzed the concentrations of lead (Pb) and cadmium (Cd) in whole blood and Cd in urine using a graphite furnace atomic absorption spectrometer. The geometric means of blood Pb, blood Cd, and urine Cd were 2.27 μg/dL, 1.42 μg/L, and 1.66 μg/g creatinine, respectively. The level of metal exposure was lower than that reported from the first phase health survey in Korea (2008‒2011) but was higher than in the general population of Korea. Blood Pb was higher in males while blood Cd and urine Cd were significantly higher in females. Blood Pb was highest in the 40‒59 age group, while blood and urine Cd levels continuously increased until age 80 or older. The Cd levels in blood and urine were affected by consumption of locally produced rice and duration of residence near abandoned mines. Furthermore, negative correlations were observed between blood Pb and blood and urine Cd levels. Additionally, 252 of the 4500 subjects exceeded the thresholds of blood Cd or urine Cd levels. Together, these findings suggest that Cd has more sustainable and adverse health effects on the abandoned mine inhabitants, who are mostly aged. Therefore, continuous biomonitoring and risk assessment to environmental health risks are necessary for environmental pollution control and health promotion.

In response to the extensive utilization of ionic circuits, including in iontronics and wearable devices, a new method for fabricating a hydrogel-based ionic circuit on a polydimethylsiloxane (PDMS) microchip is reported. Prolonged UV/ozone oxidation combined with proper surface functionalizations and a novel microchip bonding method using thiol-epoxy click reaction enable the robust attachment of the photopolymerized hydrogel to the microchannel surface for eventual operation in electrolytes as an ionic circuit. The stretchable ionic diode constructed on the PDMS microchip shows a superior rectification ratio even under tensile stress and long-term storage stability. Furthermore, the combination of the ionic circuit and unique material properties of PDMS allows us to maximize the versatility and diversify the functionalities of the iontronic device, as demonstrated in a pressure-driven ionic switch and chip-integrated ionic regulator. Its iontronic signal transmission mimicking the excitatory and inhibitory synapses also evinces the potential of the hydrogel-based iontronics on the PDMS microchip as developed toward an aqueous neuromimetic information processor while opening up new opportunities for various bioinspired applications.

In this research, we report the rapid and reliable formation of high-performance nanoscale bilayer oxide dielectrics on silicon substrates via low-temperature deep ultraviolet (DUV) photoactivation. The optical analysis of sol-gel aluminum oxide films prepared at various concentrations reveals the processable film thickness with DUV photoactivation and its possible generalization to the formation of various metal oxide films on silicon substrates. The physicochemical and electrical characterizations confirm that DUV photoactivation accelerates the efficient formation of a highly dense aluminum oxide and aluminum silicate bilayer (17 nm) on heavily doped silicon at 150 °C within 5 min owing to the efficient thermal conduction on silicon, resulting in excellent dielectric properties in terms of low leakage current (∼10-8 A/cm2 at 1.0 MV/cm) and high areal capacitance (∼0.4 μF/cm2 at 100 kHz) with narrow statistical distributions. Additionally, the sol-gel bilayer oxide dielectrics are successfully combined with a sol-gel indium-gallium-zinc oxide semiconductor via two successive DUV photoactivation cycles, leading to the efficient fabrication of solution-processed oxide thin-film transistors on silicon substrates with an operational voltage below 0.5 V. We expect that in combination with large-area printing, the bilayer oxide dielectrics are beneficial for large-area solution-based oxide electronics on silicon substrates, while DUV photoactivation can be applied to various types of solution-processed functional metal oxides such as phase-transition memories, ferroelectrics, photocatalysts, charge-transporting interlayers and passivation layers, etc. on silicon substrates.

The oxygen evolution reaction (OER) is the key reaction in water splitting systems, but compared with the hydrogen evolution reaction (HER), the OER exhibits slow reaction kinetics. In this work, boron doping into nickel–iron layered double hydroxide (NiFe LDH) was evaluated for the enhancement of OER electrocatalytic activity. To fabricate boron-doped NiFe LDH (B:NiFe LDH), gaseous boronization, a gas–solid reaction between boron gas and NiFe LDH, was conducted at a relatively low temperature. Subsequently, catalyst activation was performed through electrochemical oxidation for maximization of boron doping and improved OER performance. As a result, it was possible to obtain a remarkably reduced overpotential of 229 mV at 10 mA cm−2 compared to that of pristine NiFe LDH (315 mV) due to the effect of facile charge-transfer resistance by boron doping and improved active sites by electrochemical oxidation.

In this study, we developed oral pemetrexed (PMX) for metronomic dosing to enhance antitumor immunity. PMX was electrostatically complexed with positively charged lysine-linked deoxycholic acid (DL) as an intestinal permeation enhancer, forming PMX/DL, to enhance its intestinal permeability. PMX/DL was also incorporated into a colloidal dispersion (CD) comprised of the block copolymer of poly(ethylene oxide) and poly(propylene oxide), and caprylocaproyl macrogol-8 glycerides (PMX/DL-CD). CD-containing PMX/DL complex in a 1:1 molar ratio [PMX/DL(1:1)-CD] showed 4.66- and 7.19-fold greater permeability than free PMX through the Caco-2 cell monolayer and rat intestine, respectively. This resulted in a 282% improvement in oral bioavailability in rats. In addition, low-dose metronomic PMX led to more immunogenic cell death in CT26.CL25 cells compared to high PMX concentrations at the maximum tolerated dose. In CT26.CL25 tumor-bearing mice, oral metronomic PMX/DL-CD elicited greater antitumor immunity not only by enhancing the number of tumor-infiltrating lymphocytes but also by suppressing T cell functions. Oral PMX/DL-CD substantially increased programmed cell death protein ligand-1 (PD-L1) expression on tumor cells compared to the control and PMX-IV groups. This increased antitumor efficacy in combination with anti-programmed cell death protein-1 (aPD-1) antibody in terms of tumor rejection and immunological memory compared to the combination of PMX-IV and aPD-1. These results suggest that oral metronomic scheduling of PMX/DL-CD in combination with immunotherapy has synergistic antitumor effects.

The electrochemical CO2 reduction reaction (CO2RR), which converts CO2 into value-added feedstocks and renewable fuels, has been increasingly studied as a next-generation energy and environmental solution. Here, we report that single-atom metal sites distributed around active materials can enhance the CO2RR performance by controlling the Lewis acidity-based local CO2 concentration. By utilizing the oxidation Gibbs free energy difference between silver (Ag), zinc (Zn), and carbon (C), we can produce Ag nanoparticle-embedded carbon nanofibers (CNFs) where Zn is atomically dispersed by a one-pot, self-forming thermal calcination process. The CO2RR performance of AgZn–CNF was investigated by a flow cell with a gas diffusion electrode (GDE). Compared to Ag–CNFs without Zn species (53% at −0.85 V vs. RHE), the faradaic efficiency (FE) of carbon monoxide (CO) was approximately 20% higher in AgZn–CNF (75% at −0.82 V vs. RHE) with 1 M KOH electrolyte.

The short release half-life of carbon monoxide (CO) is a major obstacle to the effective therapeutic use of carbon monoxide-releasing molecule-2 (CORM-2). The potential of CORM-2-entrapped ultradeformable liposomes (CORM-2-UDLs) to enhance the release half-life of CO and alleviate skin inflammation was investigated in the present study. CORM-2-UDLs were prepared by using soy phosphatidylcholine to form lipid bilayers and Tween 80 as an edge activator. The deformability of CORM-2-UDLs was measured and compared with that of conventional liposomes by passing formulations through a filter device at a constant pressure. The release profile of CO from CORM-2-UDLs was evaluated by myoglobin assay. In vitro and in vivo anti-inflammatory effects of CORM-2-UDLs were assessed in lipopolysaccharide-stimulated macrophages and TPA-induced ear edema model, respectively. The deformability of the optimized CORM-2-UDLs was 2.3 times higher than conventional liposomes. CORM-2-UDLs significantly prolonged the release half-life of CO from 30 s in a CORM-2 solution to 21.6 min. CORM-2-UDLs demonstrated in vitro anti-inflammatory activity by decreasing nitrite production and pro-inflammatory cytokine levels. Furthermore, CORM-2-UDLs successfully ameliorated skin inflammation by reducing ear edema, pathological scores, neutrophil accumulation, and inflammatory cytokines expression. The results demonstrate that CORM-2-UDLs could be used as promising therapeutics against acute skin inflammation., Graphical abstract The short release half-life of carbon monoxide is a major obstacle to the effective therapeutic use of carbon monoxide-releasing molecule-2 (CORM-2). Herein, CORM-2-entrapped ultradeformable liposomes (CORM-2-UDLs) were designed to prolong carbon monoxide release half-life and enhance skin permeation of CORM-2 for better anti-inflammatory effects in skin inflammation model.Image 1

Photocatalytic hydrogel composites were prepared by using multifunctional microporous polymer particles as a reinforcing agent and also as a catalytic species. A benzothiadiazole-based conjugated microporous polymer (BTCMP) was synthesized by the Sonogashira-Hagihara reaction between 4,7-dibromo-2,1,3-benzothiadiazole and 1,3,5-triethynylbenzene as insoluble particles. BTCMP particles were functionalized with acryl groups via the thiol-yne click reaction with 2-aminoethanethiol and subsequent reaction with acryloyl chloride. Acrylated BTCMP particles were polymerized with acrylamide in a glass mold to yield a highly elastic hydrogel composite sheet. The tensile test results showed that covalently incorporated BTCMP particles significantly enhanced the mechanical properties of the hydrogels compared with a pure polyacrylamide hydrogel. A possible application of the hydrogel composites for the removal of a dye in water was studied using methylene blue as an exemplary dye. The maximum methylene blue adsorption capacity of the hydrogel composite containing 2 wt% of BTCMP particles was 2.6 times higher than that of the pure Polyacrylamide hydrogel. The hydrogel composite with photocatalytic activity originated from benzothiadiazole groups degraded adsorbed methylene blue molecules in an aqueous solution upon UV irradiation. The hydrogel composite could be reused for the methylene blue removal without any significant decrease in adsorption capacity and catalytic activity.

Rudra Pangeni,1,* Laxman Subedi,2,* Saurav Kumar Jha,2 Seho Kweon,3 Seo-Hee Kang,4 Kwan-Young Chang,4 Jeong Uk Choi,5 Youngro Byun,3 Jin Woo Park1,2 1College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, 58554, Republic of Korea; 2Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Mokpo National University, Muan-gun, Jeonnam, 58554, Republic of Korea; 3Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; 4Global R&D Center, IcureBNP, Seoul 08511, Republic of Korea; 5College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea*These authors contributed equally to this workCorrespondence: Youngro ByunCollege of Pharmacy, Seoul National University, 1 Gwanak-Ro, Seoul 08826, Republic of KoreaTel +82 2 880 7866Fax +82 2 872 7864Email yrbyun@snu.ac.krJin Woo ParkCollege of Pharmacy and Natural Medicine Research Institute, Mokpo National University, 1666 Youngsan-Ro, Muan-gun, Jeonnam 58554, Republic of KoreaTel +82 61 450 2704Fax +82 61 450 2689Email jwpark@mokpo.ac.krObjective: The anticancer efficacy of orally administered chemotherapeutics is often constrained by low intestinal membrane permeability and oral bioavailability. In this context, we designed a solid oral formulation of oxaliplatin (OP), a third-generation cisplatin analog, to improve oral bioavailability and investigate its application in metronomic chemotherapy.Methods: An ion-pairing complex of OP with a permeation enhancer, Nα-deoxycholyl-l-lysyl-methylester (DLM), was successfully prepared and then mixed with dispersing agents (including poloxamer 188 and Labrasol) to form the solid, amorphous oral formulation OP/DLM (OP/DLM-SF; hereafter, ODSF).Results: The optimized powder formulation was sized in the nanoscale range (133± 1.47 nm). The effective permeability of OP increased by 12.4-fold after ionic complex formation with DLM and was further increased by 24.0-fold after incorporation into ODSF. ODSF exhibited respective increases of 128% and 1010% in apparent permeability across a Caco-2 monolayer, compared to OP/DLM and OP. Furthermore, inhibition of bile acid transporters by actinomycin D and caveola-mediated uptake by brefeldin in Caco-2 cell monolayers reduced the apparent permeability values of ODSF by 58.4% and 51.1%, respectively, suggesting predominant roles for bile acid transporters and caveola-mediated transport in intestinal absorption of ODSF. In addition, macropinocytosis and paracellular and transcellular passive transport significantly influenced the intestinal permeation of ODSF. The oral bioavailabilities of ODSF in rats and monkeys were 68.2% and 277% higher, respectively, than the oral bioavailability of free OP. In vivo analyses of anticancer efficacy in CT26 and HCT116 cell-bearing mice treated with ODSF demonstrated significant suppression of tumor growth, with respective maximal tumor volume reductions of 7.77-fold and 4.07-fold, compared to controls.Conclusion: ODSF exhibits therapeutic potential, constituting an effective delivery system that increases oral bioavailability, with applications to metronomic chemotherapy.Keywords: oxaliplatin, bile acid transporter-mediated permeation, oral bioavailability, metronomic dosing, colorectal cancer

Photobiomodulation (PBM) stimulates different types of stem cells to migrate, proliferate, and differentiate in vitro and in vivo. However, little is known about the effects of PBM on the differentiation of embryonic stem cells (ESCs) toward the otic lineage. Only a few reports have documented the in vitro differentiation of ESCs into inner-ear hair cells (HCs) due to the complexity of HCs compared with other target cell types. In this study, we determined the optimal condition to differentiate the ESCs into the otic organoid using different culture techniques and PBM parameters. The efficiency of organoid formation within the embryoid body (EB) was dependent on the cell density of the hanging drop. PBM, using 630 nm wavelength light-emitting diodes (LEDs), further improved the differentiation of inner-ear hair cell-like cells coupled with reactive oxygen species (ROS) overexpression. Transcriptome analysis showed the factors that are responsible for the effect of PBM in the formation of otic organoids, notably, the downregulation of neural development-associated genes and the hairy and enhancer of split 5 (Hes5) gene, which inhibits the differentiation of prosensory cells to hair cells. These data enrich the current differentiation protocols for generating inner-ear hair cells., Graphical Abstract, More effective and specified differentiation is required for stem cell differentiation into inner-ear hair cell-like cells. Photobiomodulation is known to enhance the differentiation in other target cell lineage. In this study, we determined more effective and specified otic-lineage differentiation by photobiomodulation and uncovered underlying molecular processes.

Opuntia humifusa, known as the eastern prickly pear cactus and locally called “Cheonnyuncho” in Korea, is cultivated widely on Jeju Island, Korea. Phytochemical analysis of the methanolic extract o...

Mitochondrial oxidative phosphorylation (OxPhos) is essential for energy production and survival. However, the tissue-specific and systemic metabolic effects of OxPhos function in adipocytes remain incompletely understood.We used adipocyte-specific Crif1 (also known as Gadd45gip1) knockout (AdKO) mice with decreased adipocyte OxPhos function. AdKO mice fed a normal chow or high-fat diet were evaluated for glucose homeostasis, weight gain and energy expenditure (EE). RNA sequencing of adipose tissues was used to identify the key mitokines affected in AdKO mice, which included fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). For in vitro analysis, doxycycline was used to pharmacologically decrease OxPhos in 3T3L1 adipocytes. To identify the effects of GDF15 and FGF21 on the metabolic phenotype of AdKO mice, we generated AdKO mice with global Gdf15 knockout (AdGKO) or global Fgf21 knockout (AdFKO).Under high-fat diet conditions, AdKO mice were resistant to weight gain and exhibited higher EE and improved glucose tolerance. In vitro pharmacological and in vivo genetic inhibition of OxPhos in adipocytes significantly upregulated mitochondrial unfolded protein response-related genes and secretion of mitokines such as GDF15 and FGF21. We evaluated the metabolic phenotypes of AdGKO and AdFKO mice, revealing that GDF15 and FGF21 differentially regulated energy homeostasis in AdKO mice. Both mitokines had beneficial effects on obesity and insulin resistance in the context of decreased adipocyte OxPhos, but only GDF15 regulated EE in AdKO mice.The present study demonstrated that the adipose tissue adaptive mitochondrial stress response affected systemic energy homeostasis via cell-autonomous and non-cell-autonomous pathways. We identified novel roles for adipose OxPhos and adipo-mitokines in the regulation of systemic glucose homeostasis and EE, which facilitated adaptation of an organism to local mitochondrial stress.

Although titanium-based implants are widely used in orthopedic and dental clinics, improved osseointegration at the bone-implant interface is still required. In this study, we developed a titanium alloy (Ti-6Al-4V, Ti) coated with epigallocatechin gallate (EGCG) and magnesium ions (Mg2+) in a metal-polyphenol network (MPN) formation. Specifically, Ti discs were coated with EGCG in MgCl2 by controlling their concentrations and pH, with the amount of coating increasing with the coating time. An in vitro culture of human adipose-derived stem cells (hADSCs) on the EGCG-Mg2+-coated Ti showed significantly enhanced ALP activity and mRNA expression of osteogenic markers. In addition, the EGCG-Mg2+-coated Ti enhanced the mineralization of hADSCs, significantly increasing the calcium content (22.2 ± 5.0 μg) compared with cells grown on Ti (13.5 ± 0.3 μg). Treatment with 2-APB, an inhibitor of Mg2+ signaling, confirmed that the enhancement of osteogenic differentiation in the hADSCs was caused by the synergistic influence of EGCG and Mg2+. The EGCG-Mg2+ coating significantly reduced the osteoclastic maturation of Raw264.7 cells, reducing tartrate-resistant acid phosphatase activity (5.4 ± 0.4) compared with that of cells grown on Ti (1.0 ± 0.5). When we placed Ti implants onto rabbit tibias, the bone-implant contact (%) was greater on the EGCG-Mg2+-coated Ti implants (8.1 ± 4.3) than on the uncoated implants (4.4 ± 2.0). Therefore, our MPN coating could be a reliable surface modification for orthopedic implants to enable the delivery of an osteoinductive metal ion (Mg2+) with the synergistic benefits of a polyphenol (EGCG).

Electrocatalysts for CO2 electroreduction require not only high-performance active materials to control the series reaction but also conductive and durable supports to ensure long-term stability under harsh operating conditions. Instead of conventional heterogeneous catalysts made by attaching metal on supports, we manufactured a self-formed tandem catalyst designed for a cascade electroreduction of CO2 to C2H4. Using oxygen partial pressure-controlled calcination, electrospun copper acetate/polyacrylonitrile nanofibers were successfully transformed into porous carbon nanofibers consisting of doped N and metallic Cu particles. Doped nitrogen atoms adjacent to Cu atoms trigger the reaction by increasing the amount of CO* on the Cu surfaces, which lowers the energy required for CO dimerization that is used for C2H4 production. The Cu-embedded N-doped carbon nanofibers exhibit a C2H4 faradaic efficiency of 62% at a potential of −0.57 V vs. RHE with high current density of 600 mA cm−2 and excellent long-term stability. DFT calculations suggest that the lowered overpotential originates from the decreased CO dimerization energy barrier due to the doped N triggering CO production around the Cu particles.

Centella asiatica (L.) Urb. (C. asiatica) has been widely treated for inflammation-related diseases in China for thousands of years. While C. asiatica showed relevant effects as traditional medicine, the mechanism of C. asiatica suppressing inflammation has not been thoroughly investigated. Therefore, this study was conducted to reveal the anti-inflammatory mechanism of methanol fraction from C. asiatica (MCA) at the molecular level in murine macrophages. Levels of inflammation-related mediators were observed with treatment of MCA. MCA significantly suppressed nitric oxide production and iNOS expression in RAW 264.7 macrophages. Prostaglandin E2 production was alleviated by MCA via the downregulation of cyclooxygenase-2. MCA treatment also reduced pro-inflammatory tumor necrosis factor-[Formula: see text] and interleukin (IL)-6 levels. LPS/D-GalN-induced acute hepatitis in mouse was alleviated by MCA treatment. In addition, MCA decreased the phosphorylation of inhibitory [Formula: see text]B[Formula: see text] (I[Formula: see text]B[Formula: see text]) at Ser32/36 and thereby blocked I[Formula: see text]B[Formula: see text] degradation. TXY motif phosphorylation in the activation loops of mitogen-activated protein kinases (MAPKs) was also suppressed by MCA treatment. Further investigation revealed that MCA inhibited transforming growth factor-[Formula: see text]-activated kinase 1 (TAK1) phosphorylation and IL-1 receptor-associated kinase (IRAK1) degradation, the upstream kinases activating nuclear factor [Formula: see text]B and MAPKs. Taken together, MCA exhibited anti-inflammatory properties via the downregulation of IRAK1-TAK1 signaling pathways.

Background Phosphatidylcholine (PC) and Omega-3 fatty acid (Omega-3) are promising therapeutic molecules for treating inflammatory bowel disease (IBD). Purpose Based on the IBD therapeutic potential of nanoparticles, we herein sought to develop Omega-3-incorporated PC nanoparticles (liposomes) as an orally administrable vehicle for treating IBD. Methods Liposomes prepared with or without Omega-3 incorporation were compared in terms of colloidal stability and anitiinflammatory effects. Results The incorporation of free Omega-3 (alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid) into liposomes induced time-dependent membrane fusion, resulting in particle size increase from nm to μm during storage. In contrast, krill oil incorporation into liposomes (KO liposomes) did not induce the fusion and the particle size maintained

Butyrates inhibit cell growth in colon cancer cells by inhibiting histone deacetylases. However, chronic exposure to butyrates induces butyrate resistance in colon cancer cells. The mechanism underlying the acquisition of resistance is not yet fully understood. Here, butyrate-resistant (BR) colon cancer cells were developed in HCT116, HT29, and SW480 human colon cancer cells and were confirmed by the increase in the inhibitory concentrations of cell growth by 50% (IC50) compared to their respective parental (PT) cells. Chronic exposure to butyrate induced autophagy via higher expression of Beclin-1 and LC3B-II. The AMP-activated protein kinase (AMPK) was downregulated along with the activation of Akt and mammalian target of rapamycin (mTOR) and decrease in acetyl-CoA carboxylase (ACC) in BR colon cancer cells compared to those in their respective PT cells. Activation of AMPK by AICAR treatment in BR colon cancer cells suppressed cell proliferation by inhibiting Akt and mTOR and activating ACC. Taken together, chronic exposure to butyrate increased butyrate resistance in human colon cancer by inducing protective autophagy through the downregulation of AMPK/ACC and activation of Akt/mTOR signaling. Activation of AMPK restored sensitivity to butyrate by the inhibition of Akt/mTOR, suggesting that AMPK could be a therapeutic target for BR colon cancers.

Uranium (U(VI)) and thorium (Th(IV)) ions produced by the nuclear and mining industries cause water pollution, thereby harming the environment and human health. In this study, gadolinium oxide-decorated polyvinyl alcohol-graphene oxide composite (PGO–Gd) was developed using a simple hydrothermal process to treat U(VI) and Th(IV) ions in water. The developed material was structurally characterized by highly advanced spectroscopy and microscopy techniques. The effects of pH, equilibration time and temperature on both radionuclides (U(VI) and Th(IV)) adsorption by PGO–Gd were examined. The PGO–Gd composite adsorbed both metal ions satisfactorily, with adsorption capacities of 427.50 and 455.0 mg g−1 at pH 4.0, respectively. The adsorption properties of both metal ions were found to be compatible with the Langmuir and pseudo–second-order kinetic models. Additionally, based on the thermodynamic characteristics, the adsorption was endothermic and spontaneous. Furthermore, the environmental viability of PGO–Gd and its application was demonstrated by studying its reusability in treating spiked surface water. PGO–Gd shows promise as an adsorbent in effectively removing both radionuclides from aqueous solutions.

Primary cilia are sensory organelles with a variety of receptors and channels on their membranes. Recently, primary cilia were proposed to be crucial sites for exocytosis and endocytosis of vesicles associated with endocytic control of various ciliary signaling pathways. Thyroglobulin (Tg) synthesis and Tg exocytosis/endocytosis are critical for the functions of thyroid follicular cells, where primary cilia are relatively well preserved. LRP2/megalin has been detected on the apical surface of absorptive epithelial cells, including thyrocytes. LRP2/megalin on thyrocytes serves as a Tg receptor and can mediate Tg endocytosis. In this study, we investigated the role of primary cilia in LRP2/megalin expression in thyroid gland stimulated with endogenous TSH using MMI-treated and Tg-Cre;Ift88flox/flox mice. LRP2/megalin expression in thyroid follicles was higher in MMI-treated mice than in untreated control mice. MMI-treated mice exhibited a significant increase in ciliogenesis in thyroid follicular cells relative to untreated controls. Furthermore, MMI-induced ciliogenesis accompanied increases in LRP2/megalin expression in thyroid follicular cells, in which LRP2/megalin was localized to the primary cilium. By contrast, in Tg-Cre;Ift88flox/flox mice, thyroid with defective primary cilia expressed markedly lower levels of LRP2/megalin. Serum Tg levels were elevated in MMI-treated mice and reduced in Tg-Cre;Ift88flox/flox mice. Taken together, these results indicate that defective ciliogenesis in murine thyroid follicular cells is associated with impaired LRP2/megalin expression and reduced serum Tg levels. Our results strongly suggest that primary cilia harbors LRP2/megalin, and are involved in TSH-mediated endocytosis of Tg in murine thyroid follicles.

Otic organoids have the potential to resolve current challenges in hearing loss research. The reproduction of the delicate and complex structure of the mammalian cochlea using organoids requires high efficiency and specificity. Recent attempts to strengthen otic organoids have focused on the effects of the Wnt signaling pathway on stem cell differentiation. One important aspect of this is the evaluation of undesirable effects of differentiation after Wnt activation. In the present study, we differentiated mouse embryonic stem cell embryoid bodies (EB) into otic organoids and observed two morphologies with different cell fates. EBs that underwent a core ejection process, or ‘enucleation,’ were similar to previously reported inner ear organoids. Meanwhile, EBs that retained their core demonstrated features characteristic of neural organoids. The application of a Wnt agonist during the maturation phase increased enucleation, as well as otic organoid formation, in turn leading to sensory hair cell-like cell generation. However, with a longer incubation period, Wnt activation also led to EBs with ‘beating’ organoids that exhibited spontaneous movement. This observation emphasizes the necessity of optimizing Wnt enhancement for the differentiation of specific cells, such as those found in the inner ear.

Polymorph conversion of transition metal dichalcogenides (TMDs) offers intriguing material phenomena that can be applied for tuning the intrinsic properties of 2D materials. In general, group VIB TMDs can have thermodynamically stable 2H phases and metastable 1T/T' phases. Herein, we report key principles to apply carbon monoxide (CO)-based gas-solid reactions for a universal polymorph conversion of group VIB TMDs without forming undesirable compounds. We found that the process conditions are strongly dependent on the reaction chemical potential of cations in the TMDs, which can be predicted by thermodynamic calculations, and that polymorphic conversion is triggered by S vacancy (VS) formation. Furthermore, we conducted DFT calculations for the reaction barriers of VS formation and S diffusion to reveal the polymorph conversion mechanism of WS2 and compared it with that of MoS2. We believe that phase engineering 2D materials via thermodynamically designed gas-solid reactions could be functionally used to achieve defect-related nanomaterials.

Continuous monitoring of hydrogen sulfide (H2S) in human breath for early stage diagnosis of halitosis is of great significance for prevention of dental diseases. However, fabrication of a highly selective and sensitive H2S gas sensor material still remains a challenge, and direct analysis of real breath samples has not been properly attempted, to the best of our knowledge. To address the issue, herein, we introduce facile cofunctionalization of WO3 nanofibers with alkaline metal (Na) and noble metal (Pt) catalysts via the simple addition of sodium chloride (NaCl) and Pt nanoparticles (NPs), followed by electrospinning process. The Na-doping and Pt NPs decoration in WO3 grains induces the partial evolution of the Na2W4O13 phase, causing the buildup of Pt/Na2W4O13/WO3 multi-interface heterojunctions that selectively interacts with sulfur-containing species. As a result, we achieved the highest-ranked sensing performances, that is, response (Rair/Rgas) = 780 @ 1 ppm and selectivity (RH2S/REtOH) = 277 against 1 ppm ethanol, among the chemiresistor-based H2S sensors, owing to the synergistic chemical and electronic sensitization effects of the Pt NP/Na compound cocatalysts. The as-prepared sensing layer was proven to be practically effective for direct, and quantitative halitosis analysis based on the correlation (accuracy = 86.3%) between the H2S concentration measured using the direct breath signals obtained by our test device (80 cases) and gas chromatography. This study offers possibilities for direct, highly reliable and rapid detection of H2S in real human breath without the need of any collection or filtering equipment.

We aimed to investigate if a home meal replacement (HMR), designed with a low ω-6/ω-3 fatty acid ratio, improves cardiometabolic parameters, including metabolic syndrome (MetS) in obese individuals. We conducted a monocentric, controlled, randomized crossover trial. The HMR contains higher protein and fat content, lower carbohydrate content, and a lower ω6FA/ω3FA ratio than the regular diet. Sixty-four participants were randomized into two groups and switched to the other group following a 4-week intervention. While subjects in the HMR group were provided three HMRs daily, those in the control group were requested to maintain their regular dietary pattern. We conducted paired t-tests, repeated measures analysis of variance, and McNemar tests before and after the intervention. Body mass index (BMI) and weight were lower in the HMR group after adjusting for age, sex, and total energy intake and significantly changed in the between-group differences. The waist circumference, systolic blood pressure, triglycerides, triglyceride–glucose index, and triglyceride to high-density lipoprotein cholesterol ratio were reduced in the HMR group (all p &lt, 0.05). The percentage of subjects with MetS significantly decreased from 39.1% at baseline to 28.1% post-intervention (p = 0.035). Using the HMR for 4 weeks reduced the BMI, weight, and MetS prevalence in individuals with obesity. This trial was registered at clinicaltrials.gov (NCT04552574).

For steady electroconversion to value-added chemical products with high efficiency, electrocatalyst reconstruction during electrochemical reactions is a critical issue in catalyst design strategies. Here, we report a reconstruction-immunized catalyst system in which Cu nanoparticles are protected by a quasi-graphitic C shell. This C shell epitaxially grew on Cu with quasi-graphitic bonding via a gas–solid reaction governed by the CO (g) - CO2 (g) - C (s) equilibrium. The quasi-graphitic C shell-coated Cu was stable during the CO2 reduction reaction and provided a platform for rational material design. C2+ product selectivity could be additionally improved by doping p-block elements. These elements modulated the electronic structure of the Cu surface and its binding properties, which can affect the intermediate binding and CO dimerization barrier. B-modified Cu attained a 68.1% Faradaic efficiency for C2H4 at −0.55 V (vs RHE) and a C2H4 cathodic power conversion efficiency of 44.0%. In the case of N-modified Cu, an improved C2+ selectivity of 82.3% at a partial current density of 329.2 mA/cm2 was acquired. Quasi-graphitic C shells, which enable surface stabilization and inner element doping, can realize stable CO2-to-C2H4 conversion over 180 h and allow practical application of electrocatalysts for renewable energy conversion., Surface reconstruction of electrocatalysts is an important issue for electroconversion of carbon dioxide to value-added chemical products. Here the authors address this issue by using copper nanoparticles protected by self-formed quasi graphitic carbon shell for stable CO2 to C2H4 conversion.

Interleukin-4 (IL-4) and IL-13 are the major T helper 2 (Th2) cytokines, and they are involved in the regulation of metabolism in the adipose tissue. The liver contains diverse innate and adaptive immune cells, but it remains to be determined whether Th2 cytokines modulate energy metabolism in the liver. Here, using gene expression data from the Gene Expression Omnibus (GEO) and the BXD mouse reference population, we determined that the Th2 cytokines IL-4 and IL-13 increase the secretion of fibroblast growth factor 21 (FGF21) in the liver. In vitro experiments confirmed that FGF21 was highly expressed in response to IL-4 and IL-13, and this response was abolished by the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) blockade. Moreover, FGF21 expression in response to Th2 cytokines was augmented by selective peroxisome proliferator-activated receptor α (PPARα) inhibition. In vivo administration of IL-4 increased FGF21 protein levels in the liver in a STAT6-dependent manner, but FGF21 secretion in response to IL-4 was not observed in the epididymal white adipose tissue (eWAT) despite the activation of STAT6. Intraperitoneal administration of IL-33, an activator of type 2 immune responses, significantly increased the level of FGF21 in the serum and liver after 24 h, but repeated administration of IL-33 attenuated this effect. Taken together, these data demonstrate that the IL-4/IL-13–STAT6 axis regulates metabolic homeostasis through the induction of FGF21 in the liver.

Prostate cancer (PCa) is the second most leading cause of death in males. Our previous studies have demonstrated that δ-catenin plays an important role in prostate cancer progression. However, the molecular mechanism underlying the regulation of δ-catenin has not been fully explored yet. In the present study, we found that δ-catenin could induce phosphorylation of p21Waf and stabilize p21 in the cytoplasm, thus blocking its nuclear accumulation for the first time. We also found that δ-catenin could regulate the interaction between AKT and p21, leading to phosphorylation of p21 at Thr-145 residue. Finally, EGF was found to be a key factor upstream of AKT/δ-catenin/p21 for promoting proliferation and metastasis in prostate cancer. Our findings provide new insights into molecular controls of EGF and the development of potential therapeutics targeting δ-catenin to control prostate cancer progression.

While cracks are usually considered detrimental, crack generation can be harnessed for various applications, for example in ceramic materials, via directing crack propagation and crack opening. Here, we find that electron beam irradiation prompts a crack suppression phenomenon in a copper (Cu) thin film on a polyimide substrate, allowing for the control of crack formation in terms of both location and shape. Under tensile strain, cracks form on the unirradiated region of the Cu film whereas cracks are prevented on the irradiated region. We attribute this to the enhancement of the adhesion at the Cu–polyimide interface by electrons transmitted through the Cu film. Finally, we selectively form conductive regions in a Cu film on a polyimide substrate under tension and fabricate a strain-responsive organic light-emitting device., Cracking in thin films is usually associated with failure. Here, the authors use an electron beam to selectively irradiate a copper thin film on a polymer substrate and introduce designed cracks under tension to make a strain responsive organic light-emitting device (OLED).

Rudra Pangeni,1,* Saurav Kumar Jha,1,* Ruby Maharjan,2 Jeong Uk Choi,2 Kwan-Young Chang,3 Young Kweon Choi,3 Youngro Byun,4 Jin Woo Park11Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea; 2Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; 3Global R&D Center, Icure BNP, Seoul 06170, Republic of Korea; 4Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea*These authors contributed equally to this workObjective: The rational combination of immunotherapy with standard chemotherapy shows synergistic clinical activities in cancer treatment. In the present study, an oral powder formulation of pemetrexed (PMX) was developed to enhance intestinal membrane permeability and investigate its application in metronomic chemotherapy in combination with immunotherapy.Methods: PMX was ionically complexed with a bile acid derivative (Nα-deoxycholyl-l-lysyl-methylester; DCK) as a permeation enhancer and mixed with dispersing agents, such as poloxamer 188 (P188) and Labrasol, to form an amorphous oral powder formulation of PMX/DCK (PMX/DCK-OP).Results: The apparent permeability (Papp) of PMX/DCK-OP across a Caco-2 cell monolayer was 2.46- and 8.26-fold greater than that of PMX/DCK and free PMX, respectively, which may have been due to the specific interaction of DCK with bile acid transporters, as well as the alteration of membrane fluidity due to Labrasol and P188. Furthermore, inhibition of bile acid transporters by actinomycin D in Caco-2 cell monolayers decreased the Papp of PMX/DCK-OP by 75.4%, suggesting a predominant role of bile acid transporters in the intestinal absorption of PMX/DCK-OP. In addition, caveola/lipid raft-dependent endocytosis, macropinocytosis, passive diffusion, and paracellular transport mechanisms significantly influenced the permeation of PMX/DCK-OP through the intestinal membrane. Therefore, the oral bioavailability of PMX/DCK-OP in rats was 19.8%±6.93%, which was 294% higher than that of oral PMX. Moreover, an in vivo anticancer efficacy study in B16F10 cell-bearing mice treated with a combination of oral PMX/DCK-OP and intraperitoneal anti-PD1 exhibited significant suppression of tumor growth, and the tumor volume was maximally inhibited by 2.03- and 3.16-fold compared to the oral PMX/DCK-OP and control groups, respectively.Conclusion: These findings indicated the therapeutic potential of a combination of low-dose oral chemotherapy and immunotherapy for synergistic anticancer efficacy.Keywords: pemetrexed, bile acid derivative, oral powder formulation, intestinal membrane permeability, oral delivery, oral metronomic chemotherapy &nbsp

BACKGROUND & AIMS There is no proven treatment for ursodeoxycholic acid (UDCA)-refractory primary biliary cholangitis (PBC) other than obeticholic acid. Although fibrates have been reported to improve biochemical parameters, the long-term effects remain unclear. This study evaluated the effect of fibrate on clinical outcomes of UDCA-refractory PBC. METHODS Patients whose alkaline phosphatase (ALP) was not normalized with at least 13 mg/kg of UDCA treatment for >1 year were included from two tertiary referral centres. The primary outcome was ALP normalization. Secondary outcomes included the development of cirrhosis and hepatic deterioration. Immortal time bias was adjusted using the Mantel-Byar method. RESULTS A total of 100 UDCA-refractory PBC patients were included: 71 patients received UDCA alone (the UDCA group) and 29 patients received UDCA plus additional fibrate treatment of 160 mg/d fenofibrate or 400 mg/d bezafibrate (the fibrate/UDCA group). During the follow-up period, the probability of ALP normalization was significantly higher in the fibrate/UDCA group (hazard ratio [HR] = 5.00, 95% confidence interval = 2.87-8.27, P

Soil dust emitted from large-scale construction sites in urban areas impacts air quality and creates a severe health threat to residents. Water spraying is commonly practiced to lower dust emission in construction sites, but its long-term effectiveness is questionable. In this study the utility of starch, polyvinyl alcohol (PVA), and a blend of starch and PVA in various proportions was investigated for the suppression of soil dust emissions at construction sites in Seoul. The efficiency of each dust suppressant was tested with test soil samples in a laboratory-scale wind tunnel box under different concentrations of suppressants and soil textures. Starch and PVA showed superior ability to suppress soil dust emissions compared to moistening bare soil, resulting in PM10 lower than the daily limit values of 30 μg/m3. PVA showed higher soil dust suppression capability for all conditions over starch. Test soils sprayed with dust suppressants significantly improved aggregate stability compared to untreated soils.