Search

BACKGROUND & AIMS: Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production. METHODS: Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histological and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in two distinct human pancreatitis cohorts. RESULTS: Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss-of-ERRγ in primary acini abrogates mRNA expression and protein levels of mitochondrial oxidative phosphorylation (OXPHOS) complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, ER stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared to normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants (SNVs) for ERRγ that associated with chronic pancreatitis. CONCLUSIONS: Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.

Supplementary Figures

Supplementary tables

Purpose:New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy–refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRγ) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC50 = 0.006 μmol/L), selective, and orally available ERRγ inverse agonist for NIS enhancement in ATC.Experimental Design:We sought to identify better ERRγ-targeting ligands and explored the crystal structure of ERRγ in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression, as well as radioiodine avidity was examined. ATC tumor–bearing mice were orally administered with DN200434, followed by 124I-positron emission tomography/CT (PET/CT). For radioiodine therapy, ATC tumor–bearing mice treated with DN200434 were administered 131I (beta ray–emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histologic analysis was performed to evaluate ERRγ expression status in normal tissue and ATC tissue, respectively.Results:DN200434–ERRγ complex crystallographic studies revealed that DN200434 binds to key ERRγ binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by 124I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histologic findings of patients with ATC showed higher ERRγ expression in tumors than in normal tissue, supporting ERRγ as a therapeutic target for ATC.Conclusions:DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers.

Janus kinase 1 (JAK1) plays a key role in most cytokine-mediated inflammatory and autoimmune responses through JAK/STAT signaling; thus, JAK1 inhibition is a promising therapeutic strategy for several diseases. Analysis of the binding modes of current JAK inhibitors to JAK isoforms allowed the design of N-alkyl-substituted 1-H-pyrrolo[2,3-b] pyridine carboxamide as a JAK1-selective scaffold, and the synthesis of various methyl amide derivatives provided 4-((cis-1-(4-chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31g) as a potent JAK1-selective inhibitor. In particular, the (S,S)-enantiomer of 31g (38a) exhibited excellent potency for JAK1 and selectivity over JAK2, JAK3, and TYK2. On investigating the effect of 31g on hepatic fibrosis, it was found that it reduces the proliferation and fibrogenic gene expression of TGF-β-induced hepatic stellate cells (HSCs). Specifically, 31g significantly inhibited TGF-β-induced migration of HSCs at 0.25 μM in wound-healing assays.

G protein-coupled receptors (GPCRs) play crucial roles in numerous physiological and pathological processes. Mutations in GPCRs that result in loss of function or alterations in signaling can lead to inherited or acquired diseases. Herein, studying prokineticin receptor 2 (PROKR2), we initially identify distinct interactomes for wild-type (WT) versus a mutant (P290S) PROKR2 that causes hypogonadotropic hypogonadism. We then find that both the WT and mutant PROKR2 are targeted for endoplasmic reticulum (ER)-associated degradation, but the mutant is degraded to a greater extent. Further analysis revealed that both forms can also leave the ER to reach the Golgi. However, whereas most of the WT is further transported to the cell surface, most of the mutant is retrieved to the ER. Thus, the post-ER itinerary plays an important role in distinguishing the ultimate fate of the WT versus the mutant. We have further discovered that this post-ER itinerary reduces ER stress induced by the mutant PROKR2. Moreover, we extend the core findings to another model GPCR. Our findings advance the understanding of disease pathogenesis induced by a mutation at a key residue that is conserved across many GPCRs and thus contributes to a fundamental understanding of the diverse mechanisms used by cellular quality control to accommodate misfolded proteins.

The sphingosine-1-phosphate-1 (S1P

Hybrids of carbon-based materials and metals/metal oxides have emerged as promising candidates for electrochemical electrodes. While porous and inter-connected networks are necessary for a high specific area and an outstanding electrochemical resistance, the fabrication of rationally designed hybrids requires complex procedures. Herein, we report sol-gel-driven combustion waves (CWs) for one-step transformation from Mn(NO3)2/multi-walled carbon nanotube (MWCNT) into MnO2-X/MWCNT hybrids capable of electrochemical activation. A solidified Mn(NO3)2/MWCNT/nitrocellulose (NC) mixture was prepared by applying drop-casting/drying processes to a precursor solution. The sol-gel-driven CWs, induced through the exothermic reaction of NC, conducted a rapid thermochemical transformation into MnO2-X/MWCNT hybrids. Electrochemical activation using cyclic voltammetry methods resulted in the anodizing and oxidizing of MnO2-X/MWCNT hybrids, thereby presenting porous and inter-connected MnO2/MWCNT electrodes consisting of plate-like MnO2 structures and embedded MWCNTs, as well as the increasing capacitance by 42.5%. Owing to the extended surface area of the porous MnO2 having the conductive networks of entangled MWCNTs among plate-like structures, MnO2/MWCNT supercapacitor electrodes exhibited a highly enhanced specific capacitance (∼259.6 F/g) and an outstanding long-term capacitance retention over 10,000 charge-discharge cycles (∼91% at 100 mV/s). The fabrication strategy using sol-gel-driven CWs enables a facile, new synthesis method for versatile hybrids of carbon-based materials and metals/metal oxides.

As a potential treatment of type 2 diabetes, a novel PPARγ non-TZD full agonist, compound 18 (BR102375) was identified from the original lead BR101549 by the SAR efforts of the labile metabolite control through bioisosteres approach. In vitro assessments of BR102375 demonstrated its activating potential of PPARγ comparable to Pioglitazone as well as the induction of related gene expressions. Further in vivo evaluation of BR102375 in diabetic rodent models successfully proved its glucose lowering effect as a potential antidiabetic agent, but the anticipated suppression of weight gain was not evident. The X-ray co-crystal analysis of BR102375-PPARγ LBD unexpectedly revealed binding modes totally different from those of BR101549, which was found, instead, closely resembled to those of TZD full agonists.

Hybrids of micro/nanostructured metals/metal oxides and carbon-based materials are promising candidates for electrochemical electrodes. However, their fabrication requires complex procedures involving the interfaces and grain boundaries between constituent materials that degrade the overall performances. Herein, we report one-step electric-field driven combustion waves to fabricate the completely wetted hybrids of single-crystalline, spherical silver micro/nanoparticles and carbon nanotube webs, thereby significantly improving the contact interfaces and reducing the grain boundaries. The electric fields across the layered films of nitrocellulose, silver oxide nanoparticles and carbon nanotubes enable the combustion waves of ultrafast heating–cooling which facilitates the relocation of reduced and liquefied silver along the fiber-like networks and formation of single-crystalline silver particles, while the carbon nanotubes were mostly preserved without oxidization. These hybrids exhibited outstanding specific capacitance (1083 F g−1) and capacitance retention (95% after 10 000 cycles) as supercapacitor electrodes. Furthermore, the symmetric/solid-state/flexible supercapacitors using the electrodes showed remarkable electrochemical performances (458 F g−1, 100% after 10 000 cycles) and stability under harsh mechanical strains, such as bending and twisting (∼97%). This fabrication strategy enables scalable synthesis processes for functional hybrids having unique interfacial and grain boundaries.

Biporous structures at the nano–microscale are promising candidates for controlling phase change heat transfer, through their enhanced capillary wicking and fluid transportation. However, existing methods for fabricating biporous structures involve complex process which is not suitable for small-scale thermal devices such as heat pipes, owing to their confined and non-flat inner structures. Herein, we report the biporous structures inside copper-sintered heat pipes, enabled by layer-by-layer (LbL) assembled multi-walled carbon nanotube (MWCNT)-polyethyleneimine (PEI) coating for enhanced thermal performance. The repetitive filling and removing of the oppositely charged solutions with MWCNT-PEI and carboxylic-functionalized MWCNTs assembled the nanoporous MWCNT-PEI coatings (10, 20, and 40 bilayers) on the microporous copper-sintered inner surfaces. The fiber-like MWCNT networks structurally manipulated morphology and thickness of biporous structures, while the hydrophilic PEI shells chemically optimized wettability. A reduced thermal resistance (∼14.3%) was observed for MWCNT-PEI coating in 10 bilayers, due to the enhanced capillary wicking, interfacial contact areas, and bubble dynamics, whereas the 40 bilayers did not exhibit improved thermal performance owing to the redundant nanoporous layers causing reduced volume of microporous structures and increased thermal resistance. The LbL-assembled MWCNT-PEI coatings would act as functional layers to improve the performance of miniaturized and thin-film-based thermal devices.

Janus kinase 1 (JAK1) plays a key role in most cytokine-mediated inflammatory and autoimmune responses through JAK/STAT signaling; thus, JAK1 inhibition is a promising therapeutic strategy for several diseases. Analysis of the binding modes of current JAK inhibitors to JAK isoforms allowed the design of

Small molecule modulators of mitochondrial function have been attracted much attention in recent years due to their potential therapeutic applications for neurodegenerative diseases. The mitochondrial translocator protein (TSPO) is a promising target for such compounds, given its involvement in the formation of the mitochondrial permeability transition pore in response to mitochondrial stress. In this study, we performed a ligand-based pharmacophore design and virtual screening, and identified a potent hit compound, 7 (VH34) as a TSPO ligand. After validating its biological activity against amyloid-β (Aβ) induced mitochondrial dysfunction and in acute and transgenic Alzheimer’s disease (AD) model mice, we developed a library of analogs, and we found two most active compounds, 31 and 44, which restored the mitochondrial membrane potential, ATP production, and cell viability under Aβ-induced mitochondrial toxicity. These compounds recovered learning and memory function in acute AD model mice with improved pharmacokinetic properties.

Reduction-oxidation controls and synthesis of organic-inorganic hybrid structures are key features associated with their electrochemical properties. However, they involve bulky setup and long-time processes that incur high-cost. Herein, we report one-step combustion waves (CWs) for the fabrication of hybrid-porous palladium/palladium oxides/carbon (Pd/PdxOy@C) nanostructures with controllable atomic composition and their application as a high-performance pH sensor. Hybrid composites of Pd/formaldehyde (FA)/nitrocellulose (NC) were prepared as precursors. Self-propagating CWs through the NC networks carried out the transformation from Pd to PdO2 in the higher oxidation state and the formation of a carbon layer, while the fast release of chemicals in CWs developed the porous nanostructures with large surface areas. The flexible pH sensor using the synthesized Pd/PdxOy@C powders exhibited the outstanding specific voltage potential (2.08 V/mg at pH 2.83) and sensitivity (167 mV/mg pH). It showed no hysteresis during cycling of pH values and high stability over 4 h (voltage change

Multifunctionalities with self-powered capability are crucial for miniaturized, scattered devices to sense temperature and dynamics of fluids, which are intrinsic parameters to monitor environmental or industrial features. Herein, we present flexible-detachable dual-output fluid sensors employing the structural design of thermoelectric materials (SDTMs) that are artificially patterned TMs. The SDTMs enable the successive thermoelectric waves as the raw voltage signals with two distinct peaks that can reflect fluid temperature and dynamics, in contact with working fluids. The 1st-peak voltage provides the precise sensing of fluid temperature, while the duration between 1st- and 2nd-peaks indicates the moving velocity. A flexible-detachable SDTM-based sensor comprising of pre-designed Bi2Te3 pattern between cellulose and PET substrates performs high-resolution sensing of temperature and velocity ( 93%) of sensing under transfers between flat and curved surfaces. Furthermore, a scalable sensor array (4-by-4 SDTMs array at 16 pixels) is developed as a large-area device for real-time detection of fluid temperature and dynamics at multiple positions, accompanying with self-power generation of 42 μW/cm2. The new methodology using SDTMs can contribute to developing next-generation sensors having advanced features, such as multi-detection and diversely integrated flexible-detachable functions.

We demonstrate a metal-free triboelectric energy harvester consisted of MWCNT mesh film and PDMS layer. Upon touch from a finger, the single electrode-mode energy harvester generates up to 27.0 W/m2 output power at 10 MΩ matched impedance. The device generates stable power upon touch by bare fingers or gloved fingers. Using copper counter electrode results in decreased power output, due to the weaker tendency in triboelectrification. The power output also scales with the pressure applied by the finger. The intertwined, condensed MWCNT network acts as a flexible yet effective current collector, with resistance across the device less than 10 Ω. This current collector possesses strong corrosion resistance and stability against potential oxidation, while its metal counterpart may undergo oxidation over extended exposure to air or frequent fracture upon straining. The flexible device form may be applied to various curved or irregular surfaces that undergo frequent human touches.

Hybrid foam structures of metal and carbon are extensively used for electrochemical applications. However, their fabrication involves solution- or vacuum-processing, which damages the metal backbones or increases the fabrication time and cost. Herein, we report a tunable method for the scalable fabrication of core–shell metal–carbon hybrid foams using structure-guided combustion waves (SGCWs) and their application for the synthesis of core–shell Ni–MnO2 hybrid foams as binder-free supercapacitor electrodes. SGCWs passing through the hybrids of nickel foams and chemical fuels, prepared by a wet impregnation method, enabled the direct fabrication of carbon coatings on the surfaces of the inner nickel backbones and yielded core–shell Ni@C. The incompletely combusted carbonaceous fuels in a few seconds, which were formed in the narrowly confined foam structures reaching 430 °C, acted as amorphous carbon coatings, while the total amount and uniformity of the carbon content could be controlled by the number of times SGCWs were applied. The developed carbon coatings were used as templates for MnO2 shells to synthesize core–shell Ni@MnO2 hybrid foams as binder-free supercapacitor electrodes. The core–shell Ni@MnO2 foams fabricated by applying SGCWs three times exhibited a high specific capacitance of up to 660 F g−1 and stable capacitance retention (∼95.4% over more than 10 000 cycles) because of their lower serial resistance and optimal diffusion during the redox reaction. This tunable fabrication method using SGCWs in a vacuum-free, open-air environment enables the synthesis of scalable carbon coatings on metal- or ceramic-based foams for electrochemical applications.

Metabolomics combined with high-resolution mass spectrometry (HR-MS) and multivariate data analysis has broad applications in the study of xenobiotic metabolism. Although information about xenobiotic metabolism is essential to understand toxic mechanisms, pharmacokinetic parameters and excretion pathways, it is limited to predict all generated metabolites in biological fluids. Here, we revisited sildenafil metabolism in human liver microsomes using a metabolomics approach to achieve a global picture of sildenafil phase 1 metabolism. Finally, 12 phase 1 metabolites were identified in human liver microsomes; M1-M5 were previously known metabolites. The chemical structures of the novel metabolites were elucidated by MS2 fragmentation using an HR-MS system as follows: M6, reduced sildenafil; M7, N,N-deethylation and mono-oxidation; M8, demethanamine, N,N-deethylation and mono-hydroxylation; M9, demethanamine and N,N-deethylation; M10 and M11, mono-oxidation in the piperazine ring after N-demethylation; and M12, mono-oxidation. All metabolites, except M1, were formed by CYP3A4 and CYP3A5. In conclusion, we successfully updated the metabolic pathway of sildenafil in human liver, including 7 novel metabolites using metabolomics combined with HR-MS and multivariate data analysis.

Precise phase-transformation can facilitate control of the properties of various materials, while an organic coating surrounding inorganic materials can yield useful characteristics. Herein, we demonstrate facile, selective manipulation of micro-nanostructured bismuth oxide (Bi 2 O 3 ) for phase transformation from microflower-like β -Bi 2 O 3 to micropill-like α -Bi 2 O 3 , with carbon-coating layer deposition, using structure-guided combustion waves (SGCWs). Microflower-like β-Bi 2 O 3 are synthesized as core materials and nitrocellulose is coated on their surfaces for the formation of core-shell hybrid structures of Bi 2 O 3 and chemical fuel. The SGCWs, which propagate along the core-material and fuel interfaces, apply high thermal energy (550–600 °C) and deposit incompletely combusted carbonaceous fuel on the microflower-like β-Bi 2 O 3 to enable transformation to α -phase and carbon-coating-layer synthesis. SGCW-induced improvements to the electrochemical characteristics of the developed micropill-like α -Bi 2 O 3 @C, compared with the microflower-like β-Bi 2 O 3 , are investigated. The enhanced stability from the α -phase Bi 2 O 3 and micropill-like structures during charge-discharge cycling improves the specific capacitance, while the carbon-coating layers facilitate increased electrical conductivity. SGCW-based methods exhibit high potential for selective phase manipulation and synthesis of carbon coatings surrounding micro-nanomaterials. They constitute a low-cost, fast, large-scale process for metal oxides, ceramics, and hybrid materials, implemented through control of the processing parameters by tuning the temperature, chemical fuel, and ambient conditions.

Peroxisome proliferator-activated receptor delta (PPARδ) is considered as a promising biological target for the development of new drugs to treat metabolic syndrome including hyperlipidemia. In this study, a simple and efficient method for the preparation of a unique dimethyl thiazoline containing intermediate (13) of new PPARδ agonists as GW501516 analogue is described. The intermediate 13 was readily obtained by coupling reaction of 4-(chloromethyl)-5,5-dimethyl-2-(4-(trifluoromethyl)phenyl)-4,5-dihydrothiazole (11) with 4-mercapto-2-methylphenol (12) in the presence of tetrabutylammonium hydrogensulfate (TBAHS) and Cs2CO3 in DMF at 80 °C for 1 h. This unique intermediate could be useful for the synthesis of various novel PPARδ agonists to understand the structural and biological significance of PPARδ.

Angiogenesis is the process of new blood vessel formation. Excessive angiogenesis is a critical factor in the progression of cancer, macular degeneration, and other chronic inflammatory diseases. When investigating the effects of crude extracts of cultured marine microorganisms, an extract of the cultured Streptomyces sp. YP127 strain was found to inhibit human umbilical vein endothelial cell (HUVEC) tube formation. Bioassay-guided fractionation and spectroscopic data analyses led to the identification of napyradiomycin A1 (1) as an antiangiogenic component of the extract. Compound 1 inhibited HUVEC tube formation in a concentration-dependent manner. It inhibited endothelial cell proliferation but did not affect human dermal fibroblast proliferation. Compound 1 also suppressed migration and invasion of vascular endothelial cells. In addition, compound 1 suppressed vascular endothelial cadherin expression and increased the permeability of the endothelial cell membrane. These results suggested that compound 1 modulates cell permeability and inhibits the angiogenesis of endothelial cells.

Micro–nanostructured metal oxides can facilitate the development of electrochemical electrodes with enhanced features for supercapacitors and batteries. However, the fabrication of electrodes using precisely controlled metal oxides generally requires high-cost, multi-step procedures, which limits the scalability. Herein, we report that a direct current-field-driven combustion wave (DC-CW) enables the one-step fabrication of high-performance supercapacitor electrodes from hybrid nanostructures comprising reduced manganese oxides and multi-walled carbon nanotubes (MWCNTs). A layered film of MnO2 nanoparticles (NPs) and MWCNTs on a nitrocellulose membrane is prepared and subsequently subjected to a DC-electric field, thereby igniting and propagating CWs throughout the film surface within one second. The underlying mechanism of the DC-CW process is elucidated by comparative analysis of the electrodes generated by the laser irradiation-driven combustion wave process without the DC-field and the as-prepared MnO2/MWCNT film. The MnxOy/MWCNT hybrids via DC-CWs exhibit higher specific capacitance (757 F g−1) and capacitance retention (100%) than the other two systems over 10 000 charge–discharge cycles, due to the improved inter-conductivity and substantial contact interfaces in heterogeneously mixed, less agglomerated nanostructures. The DC-CWs may enable various manipulation methods of micro–nanostructured metal oxides and their hybrid structures via a low-cost, fast, and scalable process for high-performance electrochemical electrodes.

The manipulation of micro/nanostructured metal oxides is crucial to advancing their diverse applications, including as electrodes in supercapacitors or batteries, catalysts, and pigments. However, controlling the physicochemical properties of metal oxides requires complex procedures with bulky setups that incur high costs and long processing times. Herein, we present a facile one-step manipulation of the reduced states of manganese oxides and the synthesis of carbon coatings surrounding them, using structure-guided combustion waves (SGCWs), which is induced by incomplete combustion through the chemical fuel-wrapped materials. Controlled oxygen release from MnO2 using SGCWs in air and in an Ar atmosphere enabled direct fabrication of reduced Mn2O3/Mn3O4/MnO and MnO, respectively. Furthermore, control of the incompletely combusted carbonaceous fuel facilitated the synthesis of carbon coating layers to form Mn2O3/Mn3O4/MnO@C and MnO@C. These core–shell nanostructures of reduced manganese oxides and carbon layers were applied as supercapacitor electrodes. These electrodes showed better specific capacitance (maximum 438 F g−1 at 10 mV s−1 scan rate for Mn2O3/Mn3O4/MnO@C) and improved stability in charge–discharge performance compared with bare MnO2, due to the carbon coatings enhancing electrical conductivity in the percolation network of electrodes and facilitating the reversible redox reaction without degradation during cycling operations. SGCWs are applicable for fast, low-cost, and large-scale fabrication of reduced metal oxides and organic material coatings, which could significantly contribute to electrochemical applications.

A cytotoxic alkaloidal meroterpenoid, saccharoquinoline (1), has been isolated from the fermentation broth of the marine-derived bacterium Saccharomonospora sp. CNQ-490. The planar structure of 1 was elucidated by 1D, 2D NMR, and MS spectroscopic data analyzes, while the relative configuration of 1 was defined through the interpretation of NOE spectroscopic data. Saccharoquinoline (1) is composed of a drimane-type sesquiterpene unit in combination with an apparent 6,7,8-trihydroxyquinoline-2-carboxylic acid. This combination of biosynthetic pathways was observed for the first time in natural microbial products. Saccharoquinoline (1) was found to have cytotoxicity against the HCT-116 cancer cell line by inducing G1 arrest, which leads to cell growth inhibition.

An inverse agonist of estrogen-related receptor-γ (ERRγ), an orphan nuclear receptor encoded by Esrrg, enhances sodium iodide symporter-mediated radioiodine uptake in anaplastic thyroid cancer (ATC) cells, thereby facilitating responsiveness to radioiodine therapy in vitro. We synthesized potent, selective, and orally bioavailable ERRγ-inverse agonists and evaluated their activity by analyzing in vitro pharmacology and absorption, distribution, metabolism, excretion, and toxicity profiles. X-ray crystallographic analysis of the ligand and ERRγ complex showed that 35 completely binds to the target protein (PDB 6A6K). Our results showed improved radioiodine avidity in ATC cells through compound 35-mediated upregulation of iodide-handling genes, leading to enhanced responsiveness to radioiodine therapy in vitro. Importantly, in vivo 124I-positron emission tomography/computed tomography imaging revealed that 35 increases radioiodine avidity in CAL62 tumors. Collectively, these results demonstrated that 35 can...

A cytotoxic alkaloidal meroterpenoid, saccharoquinoline (1), has been isolated from the fermentation broth of the marine-derived bacterium Saccharomonospora sp. CNQ-490. The planar structure of 1 was elucidated by 1D, 2D NMR, and MS spectroscopic data analyzes, while the relative configuration of 1 was defined through the interpretation of NOE spectroscopic data. Saccharoquinoline (1) is composed of a drimane-type sesquiterpene unit in combination with an apparent 6,7,8-trihydroxyquinoline-2-carboxylic acid. This combination of biosynthetic pathways was observed for the first time in natural microbial products. Saccharoquinoline (1) was found to have cytotoxicity against the HCT-116 cancer cell line by inducing G1 arrest, which leads to cell growth inhibition.

Transglutaminase 2 (TGase2, TG2) activity has been implicated in the pathogenesis of a number of unrelated disorders, including celiac, neurological, and renal diseases, and various forms of cancer. It has been suggested that TGase2 activity, such as cross-linking, deamidation, and GTP-related activity, is associated with each disease. Continuing efforts to develop small molecule TG2 inhibitors are ongoing. To develop a new class of TG2 inhibitors, the factors impeding the development of TG2 inhibitors have been identified. Additionally, the conformational effect of TG2 enzyme in regard to its pathological roles, in vitro screening methods, recently discovered TG2 inhibitors, and preclinical evaluations are discussed with a brief summary of current TG2 inhibitor pipelines under the clinical setting.

We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had comparable potency to 3 and were far more selective for ERRγ over the ERRα, -β, and ERα. The in vivo pharmacokinetic profiles of 6g and 10b were further evaluated, as they possessed superior in vitro ADMET profiles compared to the other compounds. Additionally, we observed a significant increase of fully glycosylated NIS protein, key protein for radioiodine therapy in anaplastic thyroid cancer (ATC), in 6g- or 10b-treated CAL62 cells, which indicated that these compounds could be promising enhancers for restoring NIS protein function in ATC cells. Thus, 6g and 10b possess advantageous druglike properties and can be used to potentially treat various ERRγ-related disorders.

The application of micro/nanostructured materials to combustion enables distinctive chemical reactions that can be used to modulate the reaction rates. Simultaneously, combustion is capable of changing the intrinsic properties of micro/nanostructured materials based on chemical interactions in high-temperature conditions. In this work, we investigate the structural–chemical transition of copper oxide microstructures exposed to interfacially driven combustion waves. The high thermal energy and exchange of chemical compounds resulting from the instant combustion waves cause direct transition without any further processes. The precise characterization of the structural and chemical transitions in the copper oxide microstructures and chemical fuels confirm that the self-propagating combustion waves in the layered composites of Cu/Cu 2 O/CuO microparticle-based films and the chemical fuel layers yield the direct synthesis of Cu(OH) 2 flower-like structures and nanowires. The propagation of combustion waves at the interface induces an increase of the surface temperatures over 650 °C and the direct interaction between the copper oxide and chemical compounds of the fuel layers. Further application of these interfacially driven combustion waves will contribute to the development of one-step, fast, low-cost methods for the synthesis of micro/nanostructured materials.

Estrogen-related receptor gamma (ERRγ) is the NR3B subgroup of associated transcription factors. In this report, a new generation of a potent and selective ERRγ inverse agonist (25) with good biocompatibility was proposed. We also explored the potential of the newly developed compound 25 in the PDTC model to expand the original indications from ATC. In addition, an X-ray crystallographic study of the ligand and ERRγ co-complex showed that 25 completely binds to the target protein (PDB 6KNR ). Its medicinal chemistry, including a distinctive structural study to in vivo results, denotes that 25 may be directed towards the development of a pivotal treatment for ERRγ-related cancers.

Hybrids of micro/nanostructured metals/metal oxides have great potential to provide high performance in electrochemical applications such as supercapacitors. However, their synthesis routes involve complex procedures that limit scalable fabrication. Herein, we report a combustion-driven synthesis route for tunable TiO2/RuO2 hybrid composites as high-performance electrode materials for supercapacitors. Self-propagating combustion waves passing through precursors consisting of TiO2 nanoparticles and combustible nitrocellulose directly fabricated carbon templates as sacrificial layers for the outermost functional metal oxides, while the initial mass loading of nitrocellulose manipulated the residual hybrids. Through substituting the pre-formed carbon templates with RuO2, tunable TiO2/RuO2 hybrid composites of core–shell TiO2@RuO2 nanostructures or RuO2 clusters with embedded TiO2 nanoparticles were selectively obtained. The developed hybrids exhibited outstanding specific capacitances (~1200 F/g at 0.5 A/g) and capacitance retentions (~95.2% after 10,000 cycles) as supercapacitor electrodes, whereas the commercial RuO2-based electrode showed a lower specific capacitance (~600 F/g) and faster degradation of stability (~72%). An optimal thickness of hydrous RuO2 could facilitate inter-diffusion and proton transport for the high specific capacitances, while the amorphous nature of the outermost RuO2 and the inner TiO2 stability could provide robustness against the harsh stresses during charge–discharge cycles. This work can provide new strategies for the scalable fabrication of hybridized metal oxides such as core–shell nanostructures and nanoclusters, which would be useful for electrochemical devices, catalysts, and electromagnetic shielding.

Purpose: New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy–refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRγ) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC50 = 0.006 μmol/L), selective, and orally available ERRγ inverse agonist for NIS enhancement in ATC. Experimental Design: We sought to identify better ERRγ-targeting ligands and explored the crystal structure of ERRγ in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression, as well as radioiodine avidity was examined. ATC tumor–bearing mice were orally administered with DN200434, followed by 124I-positron emission tomography/CT (PET/CT). For radioiodine therapy, ATC tumor–bearing mice treated with DN200434 were administered 131I (beta ray–emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histologic analysis was performed to evaluate ERRγ expression status in normal tissue and ATC tissue, respectively. Results: DN200434–ERRγ complex crystallographic studies revealed that DN200434 binds to key ERRγ binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by 124I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histologic findings of patients with ATC showed higher ERRγ expression in tumors than in normal tissue, supporting ERRγ as a therapeutic target for ATC. Conclusions: DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers.

SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2) is a lipid phosphatase that produce phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) from phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3), and is involved in many diseases such as neurodegenerative diseases. A recent report demonstrating that SHIP2 inhibition decreased tau hyperphosphorylation induced by amyloid β and rescued memory impairment in a transgenic Alzheimer's disease mouse model indicates SHIP2 can be a promising therapeutic target for Alzheimer's disease. In the present study, we have developed novel, potent SHIP2 inhibitors by extensive structural elaboration of crizotinib discovered from a high-throughput screening. Our representative compound 43 potently inhibited SHIP2 activity as well as GSK3β activation in HT22 neuronal cells. It was also shown that 43 has favorable physicochemical properties, especially high brain penetration. Considering SHIP2 is one of key signal mediators for tau hyperphosphorylation, our potent SHIP2 inhibitor 43 may function as a promising lead compound for the treatment of Alzheimer's disease.

In this study, we designed and synthesized several novel “Y”-shaped biaryl PPARδ agonists. Structure-activity relationship (SAR) studies demonstrated that compound 3a was the most active agonist with an EC 50 of 2.6 nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC 50 = 0.7 nM) shows much more potent activity than S isomer (EC 50 = 6.1 nM). Molecular docking studies between the PPAR ligand binding domain and enantiospecific R and S isomers of compound 3a were performed. In vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) and in vivo PK profiles show that compound 3a possesses superior drug-like properties including good bioavailability. Our overall results clearly demonstrate that this orally administrable PPARδ agonist 3a is a viable drug candidate for the treatment of various PPARδ-related disorders.

The study of combustion at the interfaces of materials and chemical fuels has led to developments in diverse fields such as materials chemistry and energy conversion. Recently, it has been suggested that thermopower waves can utilize chemical-thermal-electrical-energy conversion in hybrid structures comprising nanomaterials and combustible fuels to produce enhanced combustion waves with concomitant voltage generation. In this study, this is the first time that the direct phase transformation of Co-doped ZnO via instant combustion waves and its applications to thermopower waves is presented. It is demonstrated that the chemical combustion waves at the surfaces of Co3O4-ZnO multipod nanostructures (deep brown in color) enable direct phase transformations to newly formed CoO-ZnO(1-x) nanoparticles (olive green in color). The oxygen molecules are released from Co3O4-ZnO to CoO-ZnO(1-x) under high-temperature conditions in the reaction front regime in combustion, whereas the CoO-ZnO multipod nanoparticles do not undergo any transformations and thus do not experience any color change. This oxygen-release mechanism is applicable to thermopower waves, enhances the self-propagating combustion velocity, and forms lattice defects that interrupt the charge-carrier movements inside the nanostructures. The chemical transformation and corresponding energy transport observed in this study can contribute to diverse potential applications, including direct-combustion synthesis and energy conversion.

Understanding the chemical–thermal–electrical energy conversion in micro/nanostructures is crucial for making breakthroughs in new fields related to energy research, as well as in improving the existing energy technologies. Thermopower wave utilizing this chemical–thermal–electrical energy conversion in hybrid structures of nanomaterials and combustible fuel has recently attracted much attention as an enhanced combustion wave with the concomitant voltage generation. In this study, we have explored thermopower waves in the hybrid composite of the chemical fuel and surface-oxidized copper sub-microparticles (SCuMPs) films during combustion. Here, we have demonstrated that the manipulations of micro/nanostructures in SCuMPs films by annealing are capable of converting the energy released during chemical combustion to a significantly large amount of thermal and electrical energy (average combustion velocity 32.6 mm s−1, output voltages up to 6.2 V; average 2.02 V) in comparison with the as-prepared SCuMPs films (19.2 mm s−1, up to 1.0 V; average 0.75 V) from thermopower waves. Owing to the inter grain boundary fusions and inner/surface nanowire-bonding by annealing, the chemical combustion rate, the corresponding thermal transport, and the electrical energy generation were greatly enhanced in the micro/nanostructured films. This work can contribute to the enhanced combustion wave and voltage generation in thermopower waves as well as further understanding of the fundamental phenomena in chemical–thermal–electrical energy conversions using micro/nanostructured materials.

This study investigates a novel and practical technique to improve the critical heat flux (CHF) of thermal devices by bonding a film of single-walled carbon nanotubes (SWCNTs) to metal surfaces. Various SWCNT film layers in thicknesses of 296, 613, 845, and 1432 nm were fabricated by vacuum filtration. Experimental work of surface characterization and pool boiling heat transfer was conducted with bare stainless steel grade 316 heaters and SWCNT-coated heaters in the deionized water under atmospheric pressure. Surface characterization of the CNT adhesion showed that SWCNT adhesion to the metal surface exhibited properties of a smooth porous medium with smaller roughness compared to the bare SS316 substrate. Wall superheat and applied heat flux were measured and high speed images of boiling process were captured at a rate of 1500 frames/s during respective tests. The CHF with the random SWCNT network-coated heater was observed to increase by up to 55% compared to the bare SS316 heater. The increased porosity with the adhesion of a random SWCNT network is believed responsible for the enhanced CHF. However, nucleate boiling heat transfer coefficient with SWCNT-coated heaters was reduced compared to the bare heaters due to the lower surface roughness.

Core-shell nanostructures of metal oxides and carbon-based materials have emerged as outstanding electrode materials for supercapacitors and batteries. However, their synthesis requires complex procedures that incur high costs and long processing times. Herein, a new route is proposed for synthesizing triple-core-shell nanoparticles of TiO

Transglutaminase 2 (TGase2, TG2) activity has been implicated in the pathogenesis of a number of unrelated disorders, including celiac, neurological, and renal diseases, and various forms of cancer. It has been suggested that TGase2 activity, such as cross-linking, deamidation, and GTP-related activity, is associated with each disease. Continuing efforts to develop small molecule TG2 inhibitors are ongoing. To develop a new class of TG2 inhibitors, the factors impeding the development of TG2 inhibitors have been identified. Additionally, the conformational effect of TG2 enzyme in regard to its pathological roles, in vitro screening methods, recently discovered TG2 inhibitors, and preclinical evaluations are discussed with a brief summary of current TG2 inhibitor pipelines under the clinical setting.

The development of new energy sources and harvesting methods has increased with the rapid development of multiscale wireless and portable systems. A thermopower wave (TW) is a potential portable energy source that exhibits a high power density. TWs generate electrical energy via the transport of charges inside micro- or nanostructured materials. This transport is induced by self-propagating combustion. Despite the high specific power of TWs, the generation of energy by TWs is transient, making a TW device a one-time use source, which is a critical limitation on the further advancement of this technology. Herein, we first report the development of a hybrid supercapacitor charging system driven by consecutive TWs to accumulate multiple amounts of energy generated by the repetitive combustion of the chemical fuel. In this study, hybrid layers composed of a supercapacitor (poly(vinyl alcohol)/MnO2/nickel) and solid fuel layer (nitrocellulose film) were fabricated as one integrated platform. Combustion was ini...

The fashion industry is one of the most labor intensive industries, and employs over 25 million workers in over 100 countries (Reinhard, Schmidt, Rutzel, & Zentgraf, 2013). There have been many concerns regarding the poor working conditions of garment workers, including their long working hours, forced overtime, and hazardous working environments, especially in developing countries. In Korea, competition has intensified within the industry with the emergence of global fashion companies, which has caused many fashion companies to move their production bases overseas in search of cheaper labor (Son, 2007). Thus, the labor problems that have arisen in the fashion industry are mostly about low wages and the poor working conditions of production workers. However, what about the labor problems of fashion industry workers other than those in production factories? Lee, Kim, Shin, Yoon, Lee, Chang, Chung, and Choi (2009) noted in their study that white-collar workers in fashion companies in Korea work longer hours, receive fewer benefits, and have a higher turnover rate than workers in other industries. In 2015, the poor working environment and low or absent wages of fashion industry interns came under public scrutiny (Kim, 2015; Kwon, 2016). In addition, there were cases in which body size was specified when hiring fashion designers, which raised the question of discrimination based on physical appearance (Kim, 2015). These employment conditions are important factors that influence fashion design majors entering the job market. Hence, regarding this and the physical body size discrimination of fashion designers in the Korean fashion industry, the aims of this paper are twofold: 1) to examine the present situation of physical discrimination by analyzing fashion companies’ job advertisements and 2) to explore fashion major undergraduates’ opinions about job criteria that indicate potential physical discrimination. Two approaches were used in this exploratory study to examine potential hiring discrimination tied to job applicants’ body size; 1) investigation of job advertisements by fashion companies and 2) focus group interviews with fashion majors seniors or graduates looking for a work as fashion designers. First, job advertisements for fashion designers placed on major fashion recruiting sites (e.g., www.saramin.co.kr, www.fashionscout.co.kr, and http://cafe.naver.com/fashionworking) in 2015 were reviewed to determine the current situation of which physical conditions or specific body measurements are set as job requirements or preferred qualifications when hiring fashion designers (n=201). Next, five focus group interviews with seven university seniors each(n=35) were conducted. No fashion companies that were looking for experienced fashion designers only (n=65) included a physical body-size requirement in the job advertisement. Thus 136 fashion designer interns or entry-level fashion designer advertisements were used in further analysis. According to the analysis of the “job requirements”, among those 136 advertisements, 51.5% required education and only 16.2% required a related major along with education, 10.3% required fitting capable size (e.g. female fitting size 55) and 13.2% even presented detailed body measurements (e.g. height 175–178 cm). Among the “preferred” qualifications mentioned in the advertisements, fitting capable size accounted for 6.6%, detailed body measurements accounted for 2%. Analysis results showed that physical conditions capable of fitting were presented more frequently than major as requirements or preferred qualifications, indicating that physical conditions capable of fitting was one of the most important factors for hiring fashion designers. Based on the five focus group interviews, participants’ opinion toward body size requirements in job advertisements were summarized into five themes: 1) Discontent over the unreasonable standard— “Why do I have to have a model figure to become a fashion designer?”; 2) Adapting to given circumstances— “I will lose weight to become a fashion designer”; 3) Frustration over reality that can’t be changed with effort— “I can lose weight, but I can’t get any taller”; and 4) Setting practical alternatives—“I can be a children’s clothing designer instead of women’s”. Most respondents shared a sense of discontent over such hiring requirements and unreasonable discrimination on the grounds of appearance, but they also showed reluctant acceptance of the unreasonable discrimination practiced by employers in the fierce job market. The physical restrictions set as requirements by fashion companies fundamentally deny opportunities to some applicants. Importantly, the outright specification of a physical condition that cannot be overcome through personal effort or improved by the cultivation of skills as a hiring requirement is an infringement upon personal rights. The fashion industry should make efforts to improve its awareness of fashion designers as specialists equipped with design competencies instead of treating them as fitting models simply to save costs.