Publications by authors named "Hiroko Koyama"

Background: Heat shock proteins (HSPs) are present throughout the brain. They function as molecular chaperones, meaning they help with the folding and unfolding of large protein complexes. These chaperones are vital in the development of neuropathological conditions such as Alzheimer's disease and Lewy body disease, with HSP90, a specific subtype of HSP, playing a key role.

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Exosomes are small extracellular vesicles (EVs) found in culture supernatants, blood, and breast milk. The size of these nanocomplexes limits the methods of EV analyses. In this study, nitrobenzoxadiazole (NBD), a fluorophore, conjugated endosome-lysosome imager, GIF-2250 and its derivative, GIF-2276, were evaluated for exosome analyses.

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Background: Receptor interacting protein kinase 1 (RIPK1) is a serine/threonine kinase, which regulates programmed cell death and inflammation. Recently, the involvement of RIPK1 in the pathophysiology of Alzheimer's disease (AD) has been reported; RIPK1 is involved in microglia's phenotypic transition to their dysfunctional states, and it is highly expressed in the neurons and microglia in the postmortem brains in AD patients. They prompt neurodegeneration leading to accumulations of pathological proteins in AD.

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Article Synopsis
  • ARL-17477 is a selective inhibitor of neuronal nitric oxide synthase (NOS1) discovered in the 1990s, showing additional anticancer properties beyond its original function.
  • This compound demonstrates significant micromolar activity against various cancers, particularly effective against cancer stem-like and KRAS-mutant cells, while also functioning independently of NOS1.
  • The study reveals that ARL-17477 inhibits the autophagy-lysosomal system, leading to increased levels of key proteins, disturbed lysosomal function, and ultimately reduced tumor growth in vivo, suggesting its potential as a dual cancer therapeutic.
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Peretinoin is an acyclic retinoid that stimulates retinoic acid receptors (NR1Bs) and produces therapeutic effects on hepatocellular cancer. We have previously shown that NR1B agonists such as Am80 and all trans-retinoic acid suppress pathogenic events in intracerebral hemorrhage. The present study addressed the actions of peretinoin and Am80 against cytotoxicity of a blood protease thrombin on cortico-striatal slice cultures obtained from neonatal rat brains.

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Recently, retinoid actions on the central nervous system (CNS) have attracted considerable attention from the perspectives of brain disease diagnosis and drug development. Firstly, we successfully synthesized [C]peretinoin esters (methyl, ethyl, and benzyl) using a Pd(0)-mediated rapid C-[C]methylation of the corresponding stannyl precursors without geometrical isomerization in 82%, 66%, and 57% radiochemical yields (RCYs). Subsequent hydrolysis of the C-labeled ester produced [C]peretinoin in 13 ± 8% RCY (n = 3).

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Colony-stimulating factor 1 receptors (CSF1R) are expressed exclusively on microglia in the central nervous system. The receptors regulate immune responses by controlling the survival and activity of microglia and are intricately involved in the pathophysiology of Alzheimer's disease. In this study, we developed [C]NCGG401, a positron emission tomography (PET) ligand, targeting for CSF1R as an imaging biomarker for microglial pathophysiology in Alzheimer's disease.

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Article Synopsis
  • Tyrosinase is crucial for melanin synthesis but its transport within cells may be linked to conditions like albinism, although specific transport mechanisms are not fully understood.
  • The compound 4-OST significantly inhibits melanin production in melanoma cells by reducing the protein levels of tyrosinase without impacting its mRNA or activity; it also induces an increase in a lysosomal protein called cathepsin S.
  • Treatments with lysosome inhibitors, like chloroquine, can reverse the downregulation of tyrosinase caused by related compounds, suggesting 4-OST and GIF-2202 might redirect tyrosinase to lysosomes instead of melanosomes, providing insights into tyrosinase transport pathways.
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  • - Isoproterenol is a non-selective β receptor agonist used for treating bradycardia and asthma, but it may also help in Alzheimer's by blocking tau protein aggregation.
  • - The study utilized PET imaging and biodistribution analysis in rodents to examine how well isoproterenol penetrates the brain and how it is processed by the body.
  • - Results indicated that isoproterenol has a higher concentration in the brain than in plasma, is metabolized quickly in the bloodstream, and is primarily excreted through urine, highlighting its potential therapeutic use and safety concerns.
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(R,S)-Isoproterenol inhibits the formation of toxic granular tau oligomers associated with neuronal loss and development of cognitive disorders, and is an attractive drug candidate for Alzheimer's disease. To elucidate its behavior in the brain by positron emission tomography, we synthesize (R,S)-[C]isoproterenol by reductive alkylation of (R,S)-norepinephrine with [2-C]acetone, which was in turn synthesized in situ under improved conditions afforded a decay-corrected radiochemical yield of 54%. The reductive alkylation using NaBH(OAc) as reducing agent in the presence of benzoic acid in DMSO/DMF (60:40 v/v) at 100 °C for 10 min gave (R,S)-[C]isoproterenol in an 87% radio-high performance liquid chromatography (HPLC) analytical yield.

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Various 3-arylmethyl-2-oxindole derivatives were synthesized by the Knoevenagel condensation of oxindole and aromatic aldehydes followed by palladium-mediated hydrogenation or hydride-reduction. Further substituted derivatives at C-3 and/or N-1 of the oxindole skeleton were prepared from the condensation products. Their protective effect against neuronal cell death induced by oxidative stress was evaluated by lactate dehydrogenase assay.

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In previous clinical trials, we showed that remote ischemic preconditioning (rIPC) reduced myocardial damage in children undergoing treatment for congenital heart defects and postoperative renal failure in patients undergoing abdominal aortic aneurysm surgery. In rabbit experiments, pre-treatment with plasma and plasma dialysate (obtained using 15-kDa cut-off dialysis membrane) from donor rabbits subjected to rIPC similarly protected against cardiac infarction. However, the protective substances containing in rIPC plasma have been unknown.

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Novel 3-[4-(dimethylamino)phenyl]alkyl-2-oxindole analogs were synthesized by either of the following two pathways: (1) a sequence of Knoevenagel condensation of oxindole with (4-dimethylamino)cinnamaldehyde-hydrogenation, or (2) alkylation of oxindole dianion with [(4-dimethylamino)phenyl]alkyl halides. Subsequent alkylation at C-3 and/or N-1 of the oxindole skeleton by anion-based methods provided additional substituted derivatives for structure-activity relationship studies. Their effects on neuronal cell death induced by oxidative stress were evaluated by lactate dehydrogenase assay.

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O-Benzylguanine (O-BG) is a substrate of O-methylguanine-DNA methyltransferase (MGMT), which is involved in drug resistance of chemotherapy in the majority of glioblastoma multiform. For clinical diagnosis, it is hoped that the MGMT expression level could be determined by a noninvasive method to understand the detailed biological properties of MGMT-specific tumors. We synthesized C-labeled O-[(3-methyl)benzyl]guanine ([C]mMeBG) as a positron emission tomography probe.

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The blood-brain barrier permeability of ginkgolide B was examined using positron emission tomography (PET) probes of a F-incorporated ginkgolide B ([F]-2) and a C-incorporated methylbenzyl-substituted ginkgolide B ([C]-3). PET studies in monkeys showed low uptake of [F]-2 into the brain, but small amounts of [C]-3 were accumulated in the parenchyma. Furthermore, when cyclosporine A was preadministered to rats, the accumulation of [F]-2 in the rat brain did not significantly change, however, the accumulation of [C]-3 was five times higher than that in the control rat.

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Neurofibrillary tangles, composed of hyperphosphorylated tau fibrils, are a pathological hallmark of Alzheimer's disease; the neurofibrillary tangle load correlates strongly with clinical progression of the disease. A growing body of evidence indicates that tau oligomer formation precedes the appearance of neurofibrillary tangles and contributes to neuronal loss. Here we show that tau oligomer formation can be inhibited by compounds whose chemical backbone includes 1,2-dihydroxybenzene.

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Amyloids are ordered protein aggregates composed of cross-β sheet structures. Amyloids include prions, defined as infectious proteins, which are responsible for mammalian transmissible spongiform encephalopathies, and fungal prions. Although the conventional view is that typical amyloids are associated with nontransmissible mammalian neurodegenerative diseases such as Alzheimer's disease, increasing evidence suggests that the boundary between transmissible and nontransmissible amyloids is ambiguous.

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The nucleosides zidovudine (AZT), stavudine (d4T), and telbivudine (LdT) are approved for use in the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. To promote positron emission tomography (PET) imaging studies on their pharmacokinetics, pharmacodynamics, and applications in cancer diagnosis, a convenient one-pot method for Pd(0)-Cu(I) co-mediated rapid C-C coupling of [(11)C]methyl iodide with stannyl precursor was successfully established and applied to synthesize the PET tracers [(11)C]zidovudine, [(11)C]stavudine, and [(11)C]telbivudine. After HPLC purification and radiopharmaceutical formulation, the desired PET tracers were obtained with high radioactivity (6.

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Positron emission tomography is a noninvasive method for monitoring drug (or diagnostic) behavior and its localization on the target molecules in the living systems, including the human body, using a short-lived positron-emitting radionuclide. New methodologies for introducing representative short-lived radionuclides, (11)C and (18)F, into the carbon frameworks of biologically active organic compounds have been established by developing rapid C-[(11)C]methylations and C-[(18)F]fluoromethylations using rapid Pd(0)-mediated cross-coupling reactions between [(11)C]methyl iodide (sp(3)-hybridized carbon) and an excess amount of organotributylstannane or organoboronic acid ester having sp(2) (phenyl, heteroaromatic, or alkenyl), sp(alkynyl), or sp(3) (benzyl and cinnamyl)-hybridized carbons; and [(18)F]fluoromethyl halide (iodide or bromide) and an organoboronic acid ester, respectively. These rapid reactions provide a firm foundation for an efficient and general synthesis of short-lived (11)C- or (18)F-labeled PET molecular probes to promote in vivo molecular imaging studies.

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Article Synopsis
  • Retinoids are compounds that include natural vitamin A and synthetic versions, known for regulating important biological processes.
  • This study focused on creating a special form of retinoic acid, labeled with a carbon isotope, for tracking its effects in medical treatments.
  • The newly synthesized (11)C-labeled all-trans-retinoic acid (ATRA) can help researchers visualize and compare its therapeutic effects against an artificial retinoid in treating acute promyelocytic leukemia using PET imaging.
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Influenza viruses have developed resistance to current drugs, creating a need for new antiviral targets and new drugs to treat influenza virus infections. In this study, computational and experimental screening of an extensive compound library identified THC19, which was able to suppress influenza virus replication. This compound had no cytotoxic effects and did not disrupt cell cycle progression or induce apoptosis in MDCK cells as confirmed by WST-1 assays, flow cytometry analysis, and caspase-3 assays.

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The DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT, AGT) is a determinant of the resistance of tumor cells to alkylating anticancer agents that target the O(6) position of guanine. MGMT promoter methylation in tumors is regarded as the most common predictor of the responsiveness of glioblastoma to alkylating agents. However, MGMT promoter methylation status has been investigated mainly by methylation-specific PCR, which is a qualitative and subjective assay.

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SAR studies for the exploration a novel class of anti-human immunodeficiency virus type 1 (HIV-1) agents based on the hematoxylin structure (1) are described. The systematic deoxygenations of 1 including asymmetric synthesis were conducted to obtain a compound showing high potencies for inhibiting the nuclear import and viral replication as anti-HIV-1 agent. Among all, C-3-deoxygenated analog 16 exhibited most promising biological activities as anti-HIV-1 agent such as lower cytotoxicity (16:1; >80:40 μM), stronger inhibition of nuclear import (0.

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Dengue virus (DENV) is the etiologic agent for dengue fever, for which there is no approved vaccine or specific anti-viral drug. As a remedy for this, we explored the use of compounds that interfere with the action of required host factors and describe here the characterization of a kinase inhibitor (SFV785), which has selective effects on NTRK1 and MAPKAPK5 kinase activity, and anti-viral activity on Hepatitis C, DENV and yellow fever viruses. SFV785 inhibited DENV propagation without inhibiting DENV RNA synthesis or translation.

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