Publications by authors named "Noriaki Hirayama"

Article Synopsis
  • Platelet C-type lectin-like receptor 2 (CLEC-2) activates platelets when bound to its ligand, podoplanin (PDPN), which is found in inflammatory and cancer cells, increasing the risk of blood clots and tumor spread.
  • Researchers discovered new compounds (diphenyl-tetrazol-propanamide derivatives) that inhibit the PDPN-CLEC-2 interaction and also block collagen-induced platelet aggregation, showcasing their potential as antiplatelet agents.
  • These compounds may need modifications for clinical use, but they hold promise in treating conditions related to arterial thrombosis, venous thromboembolism (VTE), and cancer metastasis by targeting dual platelet activation pathways.
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Cluster of differentiation 4 (CD4) molecule expressed on the leukocytes is known to function as a co-receptor for class II major histocompatibility complex (MHC) binding to T cell receptor (TCR) on helper T cells. We previously identified two CD4 alleles (CD4.A and CD4.

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Article Synopsis
  • Podoplanin (PDPN) is a glycoprotein linked to tumor markers, platelet activation, and the process of epithelial-to-mesenchymal transition (EMT), which enhances tumor invasiveness but its exact role in these processes is not fully understood.
  • In experimental methods, researchers used PDPN gene knockout and anti-PDPN antibodies on TE11A esophageal carcinoma cells to evaluate their effects on EMT-related gene expression and how they influenced cellular invasiveness and motility.
  • Findings revealed that PDPN deficiency hindered cellular motility and invasiveness despite some EMT-like gene expression changes, indicating that PDPN may help maintain an epithelial state in these cancer cells.
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While pregnancy-related proteins (PRP) are known to contribute to immunotolerance during pregnancy, their significance to development of invasive placenta is unclear. We compared PRP expression in humans and the common marmoset (Callithrix jacchus), a new-world monkey. Invasive placenta was observed at the maternal-foetal interface of marmoset placenta from green fluorescent protein (GFP)-expressing foetus and wild type mother.

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Podoplanin, a transmembrane glycoprotein, is overexpressed in certain types of tumors and induces platelet aggregation by binding to C-type lectin-like receptor 2 (CLEC-2) on the platelet membrane. Activated platelets release granule components, which in turn, trigger epithelial-mesenchymal transition and confer invasive capacity to the tumor cells. Therefore, blocking the podoplanin-CLEC-2 interaction by a small-molecule compound is a potential therapeutic strategy to prevent cancer metastasis and invasion.

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Intervertebral discs (IVD) degeneration, which is caused by ageing or mechanical stress, leads to IVD disease, including back pain and sciatica. The cytokine interleukin (IL)-17A is elevated in NP cells during IVD disease. Here we explored the pharmacotherapeutic potential of IL-17A for the treatment of IVD disease using small-molecule inhibitors that block binding of IL-17A to the IL-17A receptor (IL-17RA).

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Human leukocyte antigen (HLA)-DRB1*01:01 has been shown to be involved in nevirapine-induced hepatic hypersensitivity reactions. In the present study, in silico docking simulations and molecular dynamics simulations were performed to predict the interaction mode of nevirapine with the peptide binding groove of HLA-DRB1*01:01 and its possible effect on the position and orientation of the ligand peptide derived from hemagglutinin (HA). In silico analyses suggested that nevirapine interacts with HLA-DRB1*01:01 around the P4 pocket within the peptide binding groove and the HA peptide stably binds on top of nevirapine at the groove.

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Hematopoietic stem and progenitor cells (HSPCs) reside in the supportive stromal niche in bone marrow (BM); when needed, however, they are rapidly mobilized into the circulation, suggesting that HSPCs are intrinsically highly motile but usually stay in the niche. We questioned what determines the motility of HSPCs. Here, we show that transforming growth factor (TGF)-β-induced intracellular plasminogen activator inhibitor (PAI)-1 activation is responsible for keeping HSPCs in the BM niche.

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A number of autoimmune diseases are associated with the genotypes of human leukocyte antigen class II (HLA), some of which present peptides derived from self-proteins, resulting in clonal expansion of self-reactive T cells. Therefore, selective inhibition of self-peptide loading onto such disease-associated HLA could ameliorate the diseases. To effectively identify such compounds, in this study, we established, for the first time, a cell- and 96-well microplate-based high-throughput screening system for inhibitors of antigen presentation.

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Idiosyncratic ximelagatran-induced hepatotoxicity has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01 and ximelagatran has been reported to inhibit the binding of the ligand peptide to HLA-DRB1*07:01 in vitro. In order to predict the possible interaction modes of ximelagatran with HLA-DR molecules, in silico docking simulations were performed. Molecular dynamics (MD) simulations were also performed to predict the effect of ximelagatran on the binding mode of the ligand peptide to HLA-DRB1*07:01.

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Idiosyncratic drug toxicities (IDTs) caused by certain drugs are a significant cause of morbidity and mortality for patients. As IDTs are not normally detected even during clinical trials, it is difficult to foresee the risk during the early stage of drug development. Prediction of potential IDTs at the earliest possible opportunity is highly desirable.

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The class I major histocompatibility complex (MHC) presents self-developed peptides to specific T cells to induce cytotoxity against infection. The MHC proteins are encoded by multiple loci that express numerous alleles to preserve the variability of the antigen-presenting ability in each species. The mechanism regulating MHC mRNA and protein expression at each locus is difficult to analyze because of the structural and sequence similarities between alleles.

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Recent studies showed that head and neck squamous cell carcinoma (HNSCC) including oral squamous cell carcinoma (OSCC) of Caucasian, Chinese and Indian patients frequently have NOTCH1 mutations. We found eight of 84 OSCC in Japanese patients have point mutations (9.5%) correspond to the ligand binding region of NOTCH1 protein.

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Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron degenerative disease. Given that oxidative stress and resulting chronic neuronal inflammation are thought to be central pathogenic, anti-oxidative agents and modulators of neuronal inflammation could be potential therapies for ALS. We report here that the novel small molecular compound, 2-[mesityl(methyl)amino]-N-[4-(pyridin-2-yl)-1H-imidazol-2-yl] acetamide trihydrochloride (WN1316) selectively suppresses oxidative stress-induced cell death and neuronal inflammation in the late-stage ALS mice.

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Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug hypersensitivities with high mortality. Typical over-the-counter drugs of cold medicines are suggested to be causative. As multiple ingredients are generally contained in cold medicines, it is of particular interest to investigate which ingredients are responsible for SJS/TEN.

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The plasma membrane Na(+)/H(+) exchanger 1 (NHE1) is rapidly activated in response to various stimuli. The membrane-proximal cytoplasmic region (∼60 residues), termed the lipid-interacting domain (LID), is an important regulatory domain of NHE1. Here, we used a pharmacological approach to further characterize the role of LID in the regulation of NHE1.

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Since binding of a drug molecule to human serum albumin (HSA) significantly affects the pharmacokinetics of the drug, it is highly desirable to predict the binding affinity of the drug. Profen drugs are a widely used class of nonsteroidal anti-inflammatory drugs and it has been reported that several members of the profen class specifically bind to one of the main binding sites named site II. The actual binding mode of only ibuprofen has been directly confirmed by X-ray crystallography.

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Bilirubin is an endogenous product of heme degradation in mammals. Bilirubin has long been considered as a cytotoxic waste product that needs to be excreted. However, increasing evidence suggests that bilirubin possesses multiple biological activities.

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The three-dimensional (3D) structures of human leukocyte antigen (HLA) molecules are indispensable for the studies on the functions at molecular level. We have developed a homology modeling system named HLA-modeler specialized in the HLA molecules. Segment matching algorithm is employed for modeling and the optimization of the model is carried out by use of the PFROSST force field considering the implicit solvent model.

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Antioxidant defense is crucial in restoring cellular redox homeostasis. Recent findings have suggested that oxidative stress plays pivotal roles in the pathogenesis of many neurodegenerative diseases. Thus, an anti-oxidative stress remedy might be a promising means for the treatment of such disorders.

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3D-QSAR approach has been widely applied and proven to be useful in the case where no reliable crystal structure of the complex between a biologically active molecule and the receptor is available. At the same time, however, it also has highlighted the sensitivity of this approach. The main requirement of the traditional 3D-QSAR method is that molecules should be correctly overlaid in what is assumed to be the bioactive conformation.

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Alpha sphere filter (ASF) method is a novel previrtual screening method to undertake a rapid virtual screening of a huge chemical space. The small-molecule binding site of a target molecule can be characterized by a set of alpha spheres generated at the site. Two types of pseudomolecules representing molecules that likely fit into the binding site were molded from the set of alpha spheres.

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We identified specific amino acid propensities at the interfaces of antigen-antibody interactions in non-redundant qualified antigen-antibody complex structures from Protein Data Bank. Propensities were expressed by the frequency of each of the 20 x 20 standard amino acid pairs that appeared at the interfaces of the complexes and were named the antibody-specific epitope propensity (ASEP) index. Using this index, we developed a novel method of predicting epitope residues for individual antibodies by narrowing down candidate epitope residues which was predicted by the conventional method.

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