Inhibition of the mitochondrial permeability transition pore as a promising target for protecting auditory function in cisplatin-induced hearing loss.

mPTP is a multi-protein complex that opens in mitochondria during cell death. Cisplatin-induced hearing loss is also known to be caused by mPTP opening. Thus, our study evaluated the protective effect of a novel mPTP inhibitor named DBP-iPT against cisplatin-induced hearing loss.

DDQ-catalyzed oxidative α-allylation of isochromans under aerobic conditions.

The allylation of isochromans at the α-position aerobic DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) catalysis is described. This process involves the DDQ oxidation of various isochromans under mild conditions to generate oxocarbenium intermediates, which are effectively stabilized in equilibration in the presence of acid before undergoing allylation. Molecular oxygen and -butyl nitrite are employed as an environmentally benign oxidant and mediator, respectively, in the catalytic cycle.

Visible-Light-Induced DDQ-Catalyzed Fluorocarbamoylation Using CFSONa and Oxygen.

The synthesis of carbamoyl fluorides via visible-light induced DDQ catalysis of secondary amines is described. This protocol employs sodium trifluorosulfinate and molecular oxygen for the generation of carbonyl difluoride, which is reacted with amines to afford the corresponding carbamoyl fluorides efficiently. Moreover, carbamoyl fluorides are easily transformed to synthetically useful carbonyl compounds under mild reaction conditions.

Synthesis and biological evaluation of indane-based fluorescent probes for detection of amyloid-β aggregates in Alzheimer's disease.

In this article, the development of fluorescent imaging probes for the detection of Alzheimer's disease (AD)-associated protein aggregates is described. Indane derivatives with a donor-π-acceptor (D-π-A) structure were designed and synthesized. The probes were evaluated for their ability to bind to β-amyloid (Aβ) protein aggregates, which are a key pathological hallmark of AD.

Correction: Kim et al. Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice. 2021, , 1954.

In the original publication [...

Novel potent blockers for TWIK-1/TREK-1 heterodimers as potential antidepressants.

TREK-1 (TWIK-related potassium channel-1) is a subunit of the two-pore domain potassium (K2p) channel and is widely expressed in the brain. TREK-1 knockout mice were shown to have antidepressant-like effects, providing evidence for the channel's potential as a therapeutic target. However, currently there is no good pharmacological inhibitor specifically targeting TREK-1 containing K2p channels that also displays similar antidepressant-like effects.

DS86760016, a Leucyl-tRNA Synthetase Inhibitor, Is Active against Mycobacterium abscessus.

Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. Epetraborole, a benzoxaborole, is a clinical candidate developed for Gram-negative infections and has been confirmed to exhibit favorable activity against a well known pulmonary pathogen, Mycobacterium abscessus. However, according to ClinicalTrials.

Dynamic Nuclear Polarization of Selectively Si-Enriched Core@shell Silica Nanoparticles.

Si silica nanoparticles (SiO NPs) are promising magnetic resonance imaging (MRI) probes that possess advantageous properties for in vivo applications, including suitable biocompatibility, tailorable properties, and high water dispersibility. Dynamic nuclear polarization (DNP) is used to enhance Si MR signals via enhanced nuclear spin alignment; to date, there has been limited success employing DNP for SiO NPs due to the lack of endogenous electronic defects that are required for the process. To create opportunities for SiO-based Si MRI probes, we synthesized variously featured SiO NPs with selective Si isotope enrichment on homogeneous and core@shell structures (shell thickness: 10 nm, core size: 40 nm), and identified the critical factors for optimal DNP signal enhancement as well as the effective hyperpolarization depth when using an exogenous radical.

Stereoselective synthesis of 1,6-diazecanes by a tandem aza-Prins type dimerization and cyclization process.

We report the stereocontrolled synthesis of 1,6-diazecanes a tandem aza-Prins type reaction of -acyliminium ions with allylsilanes. It involves an aza-Prins type dimerization and cyclization in a single-step operation. This reaction represents the first example of 10-membered N-heterocycle synthesis using an aza-Prins reaction.

Hyperpolarized Si magnetic resonance spectroscopy of selectively radical-embedded silica nanoparticles.

The embedding of radicals at different locations within core@shell silica nanoparticles contributes to enhanced polarization capability and can be self-polarized without adding external radicals. With grafting the radical source homogenously inside of the nanoparticles, a significant Si hyperpolarization signal enhancement of 49.4 was obtained.

Stereoselective Synthesis of Benzo[]quinolizidines via Aerobic DDQ-Catalyzed Allylation and Reductive Cyclization.

Stereoselective synthesis of C-substituted benzo[]quinolizidines via redox-controlled catalytic C-C-bond-forming reactions was carried out. Aerobic DDQ-catalyzed allylation of -Cbz tetrahydroisoquinolines efficiently provided α-allylated products , which were transformed to enones via cross-metathesis reactions using the second-generation Hoveyda-Grubbs catalyst. Palladium-catalyzed hydrogenation of prompted alkene reduction, protecting group removal, and intramolecular reductive amination in one step to afford the desired benzo[]quinolizidines as single diastereomers.

Zero Energy Heating of Solvent with Network-Structured Solar-Thermal Material: Eco-Friendly Palladium Catalysis of the Suzuki Reaction.

Solar-thermal materials absorb sunlight and convert it into heat, which is released into the surrounding medium. Utilization of solar energy for solvent heating can be a potential method of eco-friendly organic reactions. However, to date, significant heating of the entire volume of a solvent by 1 sun illumination has not been reported.

One-pot bifunctionalization of silica nanoparticles conjugated with bioorthogonal linkers: application in dual-modal imaging.

Covalent surface modification of silica nanoparticles (SNPs) offers great potential for the development of multimodal nanomaterials for biomedical applications. Herein, we report the synthesis of covalently conjugated bifunctional SNPs and their application to multimodal imaging. Bis(methallyl)silane 15 with cyclopropene and maleimide, designed as a stable bifunctional linker, was efficiently synthesized by traceless Staudiger ligation, and subsequently introduced onto the surface of monodispersed SNPs Sc(OTf)-catalyzed siloxane formation.

Discovery of Rv3364c-Derived Small Molecules as Potential Therapeutic Agents to Target SNX9 for Sepsis.

The serine protease inhibitor Rv3364c of (MTB) is highly expressed in cells during MTB exposure. In this study, we showed that the WLVSKF motif of Rv3364c interacts with the BAR domain of SNX9 and inhibits endosome trafficking to interact with p47phox, thereby suppressing TLR4 inflammatory signaling in macrophages. Derived from the structure of this Rv3364c peptide motif, 2,4-diamino-6-(4--butylphenyl)-1,3,5-trazine, as a WLVSKF peptide-mimetic small molecule has been identified.

Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice.

The run/cysteine-rich-domain-containing Beclin1-interacting autophagy protein (Rubicon) is essential for the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by interacting with p22phox to trigger the production of reactive oxygen species (ROS) in immune cells. In a previous study, we demonstrated that the interaction of Rubicon with p22phox increases cellular ROS levels. The correlation between Rubicon and mitochondrial ROS (mtROS) is poorly understood.

Si Isotope-Enriched Silicon Nanoparticles for an Efficient Hyperpolarized Magnetic Resonance Imaging Probe.

Silicon particles have garnered attention as promising biomedical probes for hyperpolarized Si magnetic resonance imaging and spectroscopy. However, due to the limited levels of hyperpolarization for nanosized silicon particles, microscale silicon particles have primarily been the focus of dynamic nuclear polarization (DNP) applications, including magnetic resonance imaging (MRI). To address these current challenges, we developed a facile synthetic method for partially Si-enriched porous silicon nanoparticles (NPs) (160 nm) and examined their usability in hyperpolarized Si MRI agents with enhanced signals in spectroscopy and imaging.

Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington's disease mouse model.

The present study describes evaluation of epigenetic regulation by a small molecule as the therapeutic potential for treatment of Huntington's disease (HD). We identified 5-allyloxy-2-(pyrrolidin-1-yl)quinoline (APQ) as a novel SETDB1/ESET inhibitor using a combined and cell based screening system. APQ reduced SETDB1 activity and H3K9me3 levels in a HD cell line model.

Cell-penetrating peptide-conjugated lipid/polymer hybrid nanovesicles for endoplasmic reticulum-targeting intracellular delivery.

The endoplasmic reticulum (ER) apparatus is a part of the secretory pathway that transports proteins to the plasma membrane through vesicle trafficking, enabling post-translational modification of the newly synthesized proteins. Several diseases such as inflammation, neurodegenerative disorder, and bipolar disorder are closely associated with dysfunction of the ER stress response. Herein, we present an ER-targeting, intracellular delivery approach that utilized cell-penetrating peptide (CPP)-conjugated lipid/polymer hybrid nanovehicles (LPNVs).

Performance of a novel fluorogenic probe assay for the detection of extended-spectrum-β-lactamase or plasmid AmpC β-lactamase-producing Enterobacterales directly from simulated blood culture bottles.

Resistance to third generation cephalosporins is widely disseminated in Enterobacteriaceae mainly because of extended-spectrum-β-lactamases (ESBL), plasmid AmpC β-lactamases (PABL), and hyper-production of chromosomal AmpC β-lactamases. Here, we evaluated the performance of rapid test using novel fluorogenic probe assay in simulated blood cultures and compared the results with the phenol red assay using a total of 172 characterized isolates (39 ESBL producers, 13 PABL producers, and 120 susceptible isolates). We prepared a pellet by centrifugation and washing, which can also be used for identification with MALDI-TOF directly from positive blood cultures.

Identification of highly potent and selective inhibitor, TIPTP, of the p22phox-Rubicon axis as a therapeutic agent for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity. The NADPH oxidase complex (NOX) produces reactive oxygen species (ROS) that are among the key markers for determining RA's pathophysiology. Therefore, understanding ROS-regulated molecular pathways and their interaction is necessary for developing novel therapeutic approaches for RA.

Development of carbapenem-based fluorogenic probes for the clinical screening of carbapenemase-producing bacteria.

This report describes the synthesis of a library of fluorogenic carbapenemase substrates consisting of carbapenem derivatives, fluorescence dyes, and active cleavable linkers and their evaluation for specifically detecting carbapenemase-producing organisms (CPOs). We synthesized a series of compounds having three different types of linkers such as benzyl ether, carbamate, and amine using hydroxymethyl carbapenem 7a and hydroxyallyl carbapenem 7b as key intermediates. Probe 1b exhibited high stability and a prompt turn-on fluorescence signal upon hydrolysis by carbapenemases.

Performance of a Novel Fluorogenic Assay for Detection of Carbapenemase-Producing from Bacterial Colonies and Directly from Positive Blood Cultures.

Rapid and accurate detection of carbapenemase-producing (CPE) is critical for appropriate treatment and infection control. We compared a rapid fluorogenic assay using a carbapenem-based fluorogenic probe with other phenotypic assays: modified carbapenem inactivation method (mCIM), Carba NP test (CNP), and carbapenemase inhibition test (CIT). A total of 217 characterized isolates of were included as follows: 63 CPE; 48 non-carbapenemase-producing carbapenem-resistant (non-CP-CRE); 53 extended-spectrum β-lactamase producers; and 53 third-generation-cephalosporin-susceptible isolates.

Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT Agonists.

Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT agonists. To improve selectivity for 5-HT over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-position or 4-position and varying cyclic amines at the 2-position. The in vitro cell-based assay and binding assay identified compounds and as potent 5-HT agonists.

Discovery of β-Arrestin Biased Ligands of 5-HTR.

Though many studies have been published about therapeutic potentials of selective 5-HTR ligands, there have been few biased ligands of 5-HTR. The development of potent and selective biased ligands of 5-HTR would be of great help in understanding the relationship between pharmacological effects and G protein/β-arrestin signaling pathways of 5-HTR. In order to identify 5-HTR ligands with biased agonism, we designed and synthesized a series of tetrahydroazepine derivatives 1 and 2 with arylpyrazolo moiety or arylisoxazolo moiety.