Evaluation of Naturally Occurring HIF-1 Inhibitors for Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare and severe progressive disorder characterized by high pulmonary artery pressure. Chronic hypoxia causes a metabolic disorder and the Warburg effect in pulmonary arterial smooth muscle cells (PASMCs). Pyruvate dehydrogenase kinase 1 (PDK1) is a key enzyme in Warburg effect increased by hypoxia-inducible factor (HIF-1). We constructed a cell-based luciferase assay system for HIF-1 inhibitors. Using this system, six HIF-1 inhibitors were identified. Among these inhibitors, the effect of tagitinin C ( 1 ) on PASMC was investigated. Tagitinin C ( 1 ) clearly decreased the amount of HIF-1β and the HIF-1 target PDK1. This result indicates that HIF-1 inhibitors effectively decrease PDK1 activity, which is a cause of the metabolic disorder and Warburg effect observed in PASMCs. Identifying naturally occurring HIF-1 inhibitors could provide novel insights into the development of PAH medications.     

Self‐Degradable Lipid‐Like Materials Based on “Hydrolysis accelerated by the intra‐Particle Enrichment of Reactant (HyPER)” for Messenger RNA Delivery

RNA‐based therapeutics is a promising approach for curing intractable diseases by manipulating various cellular functions. For eliciting RNA (i.e., mRNA and siRNA) functions successfully, the RNA in the extracellular space must be protected and it must be delivered to the cytoplasm. In this study, the development of a self‐degradable lipid‐like material that functions to accelerate the collapse of lipid nanoparticles (LNPs) and the release of RNA into cytoplasm is reported. The self‐degradability is based on a unique reaction “Hydrolysis accelerated by intra‐Particle Enrichment of Reactant (HyPER).” In this reaction, a disulfide bond and a phenyl ester are essential structural components: concentrated hydrophobic thiols that are produced by the cleavage of the disulfide bonds in the LNPs drive an intraparticle nucleophilic attack to the phenyl ester linker, which results in further degradation. An oleic acid‐scaffold lipid‐like material that mounts all of these units (ssPalmO‐Phe) shows superior transfection efficiency to nondegradable or conventional materials. The insertion of the aromatic ring is unexpectedly revealed to contribute to the enhancement of endosomal escape. Since the intracellular trafficking is a sequential process that includes cellular uptake, endosomal escape, the release of mRNA, and translation, the improvement in each process synergistically enhances the gene expression.     

Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.     

Oxide-based inorganic/organic and nanoporous spherical particles: synthesis and functional properties

Abstract

This paper reviews the recent progress in the preparation of oxide-based and heteroatom-doped particles. Surfactant-templated oxide particles, e.g. silica and titania, are possible candidates for various potential applications such as adsorbents, photocatalysts, and optoelectronic and biological materials. We highlight nanoporous oxides of one element, such as silicon or titanium, and those containing multiple elements, which exhibit properties that are not achieved with individual components. Although the multicomponent nanoporous oxides possess a number of attractive functions, the origin of their properties is hard to determine due to compositional/structural complexity. Particles with a well-defined size and shape are keys for a quantitative and detailed discussion on the unique complex properties of the particles. From this viewpoint, we review the synthesis techniques of the oxide particles, which are functionalized with organic molecules or doped with heteroatoms, the physicochemical properties of the particles and the possibilities for their photofunctional applications as complex systems.     

Improving the creep properties of 9Cr-3W-3Co-NbV steels and their weld joints by the addition of boron

New ferritic steels with a controlled addition of boron have been developed recently for ultrasuper-critical fossil power plants. These steels possess excellent creep resistance compared to conventional steels like P91, P92, P122, etc., and this has been attributed to the delay in coarsening of the carbides during creep owing to partial replacement of carbon by boron in these carbides. However, the susceptibility of the weld joints of the boron-containing ferritic steels to type IV cracking, which significantly brings down the rupture life of the weld joints, has not been investigated so far. In the present work, the creep properties of recently developed 9Cr-3W-3Co-NbV steels with boron contents varying from 47 to 180 ppm and of their weld joints have been studied. Creep tests were carried out at 923 K in the stress range of 140 to 80 MPa. Specimens were examined for particle coarsening using field-emission scanning electron microscopy, and the boron content in the precipitates was estimated using field-emission auger electron spectroscopy (FE-AES). The grain size of the parent metal and the heat-affected zone (HAZ) were estimated using electron backscattered pattern (EBSP) imaging. Results showed that the creep properties of the steels with 90 and 130 ppm boron and of their weld joints are superior to those of the P92 steels and its weld joints. Further, no weld joints exhibited type IV cracking. No significant coarsening of the carbides was observed, not only in the parent metal but also in the HAZ of the steels with ≥90 ppm of boron. In addition to the delay in carbide coarsening, the large prior-austenite grain size of the parent metal and the absence of a conventional fine-grained HAZ (FGHAZ) in the weld joints also seem to have a beneficial effect on improving the creep properties of these steels and their weld joints.     

Application of TEPC microdosimetry to boron neutron capture therapy

Boron neutron capture therapy (BNCT) is a bimodal radiation therapy used primarily for highly malignant gliomas. Tissue-equivalent proportional counter (TEPC) microdosimetry has proven an ideal dosimetry technique for BNCT, facilitating accurate separation of the photon and neutron absorbed dose components, assessment of radiation quality and measurement of the BNC dose. A miniature dual-TEPC system has been constructed to facilitate microdosimetry measurements with excellent spatial resolution in high-flux clinical neutron capture therapy beams. A 10B-loaded TEPC allows direct measurement of the secondary charged particle spectrum resulting from the BNC reaction. A matching TEPC fabricated from brain-tissue-equivalent plastic allows evaluation of secondary charged particle spectra from photon and neutron interactions in normal brain tissue. Microdosimetric measurements performed in clinical BNCT beams using these novel miniature TEPCs are presented, and the advantages of this technique for such applications are discussed.     

Materials in harnessing solar power

Harnessing renewable solar energy through different technologies is greatly dependent on the advancement of solar grade materials’ science and engineering. In this article, the prominent solar energy technologies, namely solar photovoltaic and concentrated solar power and other relevant technologies, and aspects related to various solar grade materials, influence of nanomaterials on enhancement of solar energy harvest, technology–market relations, development of hybrid systems etc., are discussed. The inspiration to write this article is not only to review the existing technologies to harvest solar energy but also to highlight the pertinent and possible solutions thereof, especially from materials perspective.     

Central-tendency estimation and nearest-estimate classification of event related potentials

Event related potentials (ERPs) are modeled as random vectors in order to determine multivariate central-tendency (C-T) estimates of ERPs such as the arithmetic mean, geometric mean, harmonic mean, median, tri-mean, trimmed-mean, and the Winsorized mean. Additionally, it is shown that the C-T estimates can be used to implement various forms of minimum-distance classifiers for individual channels and for single-channel heterogeneous, multi-channel homogeneous, and multi-channel heterogeneous-homogenous ERP classification through decision fusion. The study also focuses on answering the following related questions: (a) How do the C-T ERP estimates compare with each other? (b) How do the performances of nearest-estimate classifiers compare with each other? (c) For a given ERP channel, do the heterogeneous nearest-estimate classifiers offer complementary information for improving performance through decision fusion? (d) Do the homogeneous nearest-estimate classifiers of different channels offer complementary information for improving performance through decision fusion? (e) Can the performance be improved by fusing the decisions of all or a selected subset of the entire classifier ensemble? These questions are answered by designing estimation and classification experiments using real 6-channel ERPs. It is shown that although the operations to compute the vector C-T estimates can be quite different, the ERP estimates are similar with respect to their overall waveform shapes and peak latencies. Furthermore, the results of the classification experiments show that by fusing homogeneous nearest-estimate classifier decisions across multiple channels, the classification accuracy can be improved significantly when compared with the accuracies of individual channel classifiers.     

Charge transporting block copolymer for morphological control in light emitting device based on polymer blends

Bipolar charge transporting block copolymer composing of carbazole and oxadiazole monomers as hole and electron transporting units, respectively, was synthesized by nitroxide mediated radical polymerization. It is found that the current efficiency significantly increased with the addition of the block copolymer in the device based on polymer blend system. AFM measurement revealed that a phase-separated structure in the polymer blend layer changed to suitable morphology in the presence of block copolymer.