Noriyuki Nishida

Nagasaki University · Graduate School of Biomedical Sciences

Background/Objectives: Sporadic Creutzfeldt–Jakob disease (sCJD) is a fatal neurodegenerative disorder traditionally diagnosed based on the World Health Organization (WHO) criteria in 1998. Recently, Hermann et al. proposed updated diagnostic criteria incorporating advanced biomarkers to enhance early detection of sCJD. This study aimed to evaluate...

We report the structural functionalization of the terminal amino group of N¹‐(7‐chloroquinolin‐4‐yl) butane‐1,4‐diamine, leading to a series of 7‐chloro‐4‐aminoquinoline derivatives, and their evaluation as potent anti‐malarial and anti‐viral agents. Some compounds exhibited promising anti‐malarial effects against the Plasmodium falciparum 3D7 (chl...

Stem cell therapy for ischemic stroke holds great promise for the treatment of neurological impairment and has moved from the laboratory into early clinical trials. The mechanism of action of stem cell therapy includes the bystander effect and cell replacement. The bystander effect plays an important role in the acute to subacute phase, and cell re...

Prions are unconventional pathogens that encode the pathogenic information in conformations of the constituent abnormal isoform of prion protein (PrPSc), independently of the nucleotide genome. Therefore, conformational diversity of PrPSc underlies the existence of many prion strains and species barriers of prions, although the conformational infor...

Prion diseases are fatal neurodegenerative disorders caused by the deposition of scrapie prion protein aggregates (PrPSc) in the brain. We previously reported that styrylchromone (SC) and benzofuran (BF) derivatives have potential as imaging probes for PrPSc. To further improve their properties, we designed and synthesized 2-(benzofuran-2-yl)-chrom...

Prion diseases are fatal neurodegenerative diseases characterized by the deposition of abnormal prion protein aggregates (PrPSc) in the brain. In this study, we developed hydroxyethylamino-substituted styrylchromone (SC) and 2-(2-(pyridin-3-yl)vinyl)-4H-chromen-4-one (VPC) derivatives for single-photon emission computed tomography (SPECT) imaging o...

Background The neuropathology of sporadic Creutzfeldt–Jakob disease (sCJD) is usually investigated using formalin-fixed and formic acid-treated brain tissue. However, formalin and formic acid treatment can interfere with immunostaining of abnormal prion protein. Therefore, there is a need for biochemical methods other than immunostaining to investi...

Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy are characterized by aggregation of abnormal α-synuclein (α-syn) and collectively referred to as α-synucleinopathy. Because these diseases have different prognoses and treatments, it is desirable to diagnose them early and accurately. However, it is difficult to accurately...

Sporadic Creutzfeldt-Jakob disease is a fatal neurodegenerative disease caused by misfolded prion proteins (PrPSc). Effective therapeutics are currently not available and accurate diagnosis can be challenging. Clinical diagnostic criteria use a combination of characteristic neuropsychiatric symptoms, CSF proteins 14-3-3, MRI, and EEG. Supportive bi...

We report the general autopsy findings of abnormal prion protein (PrP) deposits with their seeding activities, as assessed by the real-time quaking-induced conversion (RT-QuIC) method, in a 72-year-old female patient with sporadic Creutzfeldt-Jakob disease (sCJD). At 68 years of age, she presented with gait disturbance and visual disorders. Electro...

Prion diseases are characterized by the accumulation of amyloid fibrils. The causative agent is an infectious amyloid that is comprised solely of misfolded prion protein (PrPSc). Prions can convert normal cellular prion protein (PrPC) to proteinase-resistant PrP (PrP-res) in vitro; however, the intermediate steps involved in this spontaneous conver...

The defining characteristic of prion diseases is conversion of a cellular prion protein (PrPC) to an abnormal prion protein (PrPSc). The exogenous attachment of PrPSc to the surface of a target cell is critical for infection. However, the initial interaction of PrPSc with the cell surface is poorly characterized. In the current study, we specifical...

Introduction: Prion diseases are fatal neurodegenerative disorders caused by the deposition of abnormal prion protein aggregates (PrPSc) in the central nervous system. This study aimed to evaluate the use of iodinated pyridyl benzofuran (IPBF) derivatives as single-photon emission computed tomography (SPECT) probes for the detection of cerebral Pr...

The accumulation of abnormal prion protein (PrPSc) produced by the structure conversion of PrP (PrPC) in the brain induces prion disease. Although the conversion process of the protein is still not fully elucidated, it has been known that the intramolecular chemical bridging in the most fragile pocket of PrP, known as the “hot spot,” stabilizes the...

The original version of this article unfortunately contained an error in affiliation of Yuhtaka Fukuda.

Prions are misfolded proteins involved in neurodegenerative diseases of high interest in veterinary and public health. In this work, we report the chemical space exploration around the anti-prion compound BB 0300674 in order to gain an understanding of its Structure Activity Relationships (SARs). A series of 43 novel analogues, based on four differ...

Human prion diseases are etiologically categorized into three forms: sporadic, genetic, and infectious. Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common type of human prion disease that manifests as subacute progressive dementia. No effective therapy for sCJD is currently available. Potential therapeutic compounds are frequently tested...

Background The prognosis of intrahepatic cholangiocarcinoma (ICC) is based on tumor localization; however, the mechanism remains unknown. Therefore, we investigated the biological characteristics of perihilar and peripheral ICC in a mouse model. Methods The model was established by the administration of three oncogenic plasmids harboring myristoyl...

Real-time quaking-induced conversion (RT-QUIC) assays using Escherichia coli-derived purified recombinant prion protein (rPrP) enable us to amplify a trace amount of the abnormal form of PrP (PrPSc) from specimens. This technique can be useful for the early diagnosis of both human and animal prion diseases and the assessment of prion contamination....

The emergence of resistance to currently available anti-influenza drugs has heightened the need for antivirals with novel mechanisms of action. The influenza A virus (IAV) nucleoprotein (NP) is highly conserved and essential for the formation of viral ribonucleoprotein (vRNP), which serves as the template for replication and transcription. Recently...

Cellular prion protein (PrP) is a membrane protein that is highly conserved among mammals and mainly expressed on the cell surface of neurons. Despite its reported interactions with various membrane proteins, no functional studies have so far been carried out on it, and its physiological functions remain unclear. Neuronal cell death has been observ...

In prion diseases, the causative agent is thought to be solely composed of misfolded prion proteins (PrPSc). It has been shown that PrPSc can convert host-encoded normal isoform of prion protein (PrPC), but the spontaneous emergence of PrPSc is still enigmatic. Certain amyloidogenic proteins have recently been shown to undergo liquid phase separati...

Prions are unconventional pathogen without nucleotide genome and their pathogenic properties are defined by the primary structure and the conformation of the constituent abnormal isoform (PrP Sc ) of prion protein (PrP). A polymorphic codon 129 of human PrP that is valine (V129) or methionine (M129) is particularly influential on properties of PrP...

Human prion diseases are neurodegenerative disorders caused by prion protein. Although infectivity was historically detected only in the central nervous system and lymphoreticular tissues of patients with sporadic Creutzfeldt-Jakob disease, recent reports suggest that the seeding activity of Creutzfeldt-Jakob disease prions accumulates in various n...

Prions are unconventional pathogens that encode the pathogenic information in conformations of the constituent abnormal isoform of prion protein (PrP Sc ), independently of the nucleotide genome. Therefore, conformational diversity of PrP Sc underlies the existence of many prion strains and species barriers of prions, although the conformational in...

Mechanism of strain diversity of prions is a long-standing conundrum, because prions consist solely of abnormal isoform of prion protein (PrP Sc ) devoid of genetic material. Pathogenic properties of prions are determined by conformations of the constituent PrP Sc according to the protein-only hypothesis, and alterations to even a single residue ca...

Infectious prions comprising abnormal prion protein, which is produced by structural conversion of normal prion protein, are responsible for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease in humans. Prions are infectious agents that do not possess a genome and the pathogenic protein was not thought to evoke any immune...

Prion diseases are fatal neurodegenerative disorders associated with the deposition of abnormal prion protein aggregates (PrPSc) in the brain tissue. Here, we report the development of ¹²⁵I-labeled iodobenzofuran (IBF) derivatives as single photon emission computed tomography (SPECT) imaging probes to detect cerebral PrPSc deposits. We synthesized...

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases that lack therapeutic solutions. Here, we show that the molecular chaperone (N,N′-([cyclohexylmethylene]di-4,1-phenylene)bis(2-[1-pyrrolidinyl]acetamide)), designed via docking simulations, molecular dynamics simulations and quantum chemical calculations, slows do...

The mechanism of prion strain diversity remains unsolved. Investigation of inheritance and diversification of protein-based pathogenic information demands the identification of the detailed structures of abnormal isoforms of the prion protein (PrPSc); however, achieving purification is difficult without affecting infectivity. Similar prion-like pro...

Prion diseases are transmissible neurodegenerative disorders of humans and animals, which are characterized by the aggregation of abnormal prion protein (PrPSc) in the central nervous system. Although several small compounds that bind to normal PrP (PrPC) have been shown to inhibit structural conversion of the protein, an effective therapy for huma...

The mechanism of strain diversity of prions still remains unsolved, because the investigation of inheritance and diversification of the protein-based pathogenic information demands identification of the detailed structures of abnormal isoform of prion protein (PrP Sc ), while it is difficult to purify for analysis without affecting the infectious n...

Prions are composed solely of the pathological isoform (PrPSc) of the normal cellular prion protein (PrPC). Identification of different PrPSc structures is crucially important for understanding prion biology because the pathogenic properties of prions are hypothesized to be encoded in the structures of PrPSc However, these structures remain yet to...

The high propensity of influenza viruses to develop resistance to antiviral drugs necessitates the continuing search for new therapeutics. Peanut skins, which are low-value byproducts of the peanut industry, are known to contain high levels of polyphenols. In this study, we investigated the antiviral activity of ethanol extracts of peanut skins aga...

Diversity of prion strains is one of the most mysterious traits of prions because they are mere aggregates of abnormally-folded forms of single protein species, prion protein (PrP Sc ), without genome. Although the strain-specific properties are hypothesized to be enciphered in the strain-specific structures of PrP Sc instead of nucleotide genome,...

Background: Immune complexes (ICs) may clearly reflect immunological abnormalities caused by disease, especially for autoimmune diseases. Although ICs have been detected in cerebrospinal fluid (CSF) from patients with CNS autoimmune diseases, identities of antigens in such ICs have not been comprehensively determined. Methods: We used immune com...

The prion-like seeding of misfolded α-synuclein (αSyn) involved in the pathogenesis of Lewy body diseases (LBD) remains poorly understood at the molecular level. Using the real-time quaking-induced conversion (RT-QUIC) seeding assay, we investigated whether brain tissues from cases of dementia with Lewy bodies (DLB), which contain serine 129 (Ser12...

Influenza virus infections are serious public health concerns throughout the world. The development of compounds with novel mechanisms of action is urgently required due to the emergence of viruses with resistance to the currently-approved anti-influenza viral drugs. We performed in silico screening using a structure-based drug discovery algorithm...

Cell transplantation therapy offers great potential to improve impairments after stroke. However, the importance of donor age on therapeutic efficacy is unclear. We investigated the regenerative capacity of transplanted cells focusing on donor age (young vs. old) for ischaemic stroke. The quantities of human mesenchymal stem cell (hMSC) secreted br...

Sporadic human prion diseases are defined on the basis of clinical features, with periodic sharp discharge (PSD) on electroencephalograms (EEG), a positive 14-3-3 protein assay of CSF samples, and abnormal signals on cerebral cortex on diffusion-weighted (DWI) MR images. It is essential to detect the abnormal prion protein in neuropathological or i...

There exist many phenotypically-varied prion strains, like viruses, despite the absence of conventional genetic material which codes the phenotypic information. As prion is composed solely of the pathological isoform (PrP Sc ) of prion protein (PrP), the strain-specific traits are hypothesized to be enciphered in the structural details of PrP Sc ....

Influenza viruses have acquired resistance to approved neuraminidase-targeting drugs, increasing the need for new drug targets for the development of novel anti-influenza drugs. Nucleoprotein (NP) is an attractive target since it has an indispensable role in virus replication and its amino acid sequence is well conserved. In this study, we aimed to...

Chemical names of NUD compounds. (PDF)

Purification of recombinant NP. Samples were analyzed by 10% SDS-PAGE, followed by CBB staining (A) and western blotting (B) using anti-NP antibody (GTX125989, GeneTex, Inc. (Irvine, CA)). Lysate of E.coli harboring pET14b-NP plasmid without (lane 1) or with (lane 2) IPTG induction and purified NP sample (lane 3) were used. The position of His-tagg...

Correlation between the in silico binding score and SPR binding of NUDs to NP. The in silico binding score of NUDs 1?24 to NP was calculated using the NUDE system as described in the ?materials and methods section?, and the in vitro binding properties were assessed by an SPR assay. Recombinant NP was immobilized on a sensor chip and 10 ?M of the co...

Prions are unique infectious agents, consisting solely of abnormally-folded prion protein (PrPSc). However, they possess virus-like features, including strain diversity, the ability to adapt to new hosts and to be altered evolutionarily. Because prions lack genetic material (DNA and RNA), these biological phenomena have been attributed to the struc...

Detailed information about the neural network secondary structure prediction. (DOC)

Pβ-, Pc- and relative ΔPβ-graphs of PrPs of representative prion-resistant species imply existence of respective ways of resistance. A. Pβ-graphs of PrP from representative prion-resistant species, except for mouse. Mouse is presented as an example of prion-susceptible species for comparison. Dog1 and Dog2, canine PrP registered in GenBank as AF022...

Pβ values show fair correlation with aggregation efficiencies of substitution-mutant Aβ42 and Pβmax/Pcmax show even better correlation. A. Examples of Pβ and Pc graphs of mutant Aβ42. Pβmax, the highest Pβ value in the region of residues 17–23. Pcmax, the highest Pc value in the region of residues 13–19. The curves labeled with square brackets, e.g...

Relations between Pβ and Pc values and aggregation propensity using the data from Aβ42-GFP fusion protein experiments. (DOC)

Tables A to H, presenting Pβ and Pc values of PrPs from various species, Aβ42 and tau-derived peptides. (XLS)

Background and purpose: Cell transplantation therapy holds great potential to improve impairments after stroke. However, the importance of donor age on therapeutic efficacy is uncertain. We investigate regenerative capacity of transplanted cells focusing on donor age (young vs. old) for ischemic stroke. Methods: The value of platelet-derived growth...

Prion diseases are caused by deposition of abnormal prion protein aggregates (PrP(Sc)) in the central nervous system. This study aimed to develop in vivo imaging probes that can detect cerebral PrP(Sc) deposits. We synthesized several quinacrine-based acridine (AC) derivatives with 2,9-substitution and radioiodinated them. The AC derivatives were e...

Prion is a unique infectious agent which consists solely of abnormally-folded prion protein (PrP Sc ) but possesses virus-like features, e.g. existence of strain diversity, adaptation to new hosts and evolutionary changes. These biological phenomena were attributed to the structural properties of PrP Sc due to lack of genetic material of prion. The...

Human prion diseases are neurodegenerative disorders caused by abnormally folded prion proteins in the central nervous system. These proteins can be detected using the quaking-induced conversion assay. Compared with other bioassays, this assay is extremely sensitive and was used in the present study to determine prion distribution in sporadic Creut...

Supplementary material

None of effective and efficient therapeutic agents for prion disease is available. In this manuscript, we describe the drug discovery against prion disease using novel screening system. In this system, we performed docking simulation using original calculation system, termed DEGIMA supercomputer, and searched candidate compounds as anti-prion drug...

Removal of pathogenic organisms from reprocessed surgical instruments is essential to prevent iatrogenic infections. Some bacteria can make persistent biofilms on medical devices. Contamination of non-disposable equipment with prions also represents a serious risk to surgical patients. Efficient disinfection of prions from endoscopes and other inst...

Accidental transmission of prions during neurosurgery has been reported as a consequence of re-using contaminated surgical instruments. Several decontamination methods have been studied using the 263K-hamster prion; however, no studies have directly evaluated human prions. A newly developed in vitro amplification system, designated real-time quakin...

Prion diseases are fatal neurodegenerative diseases characterised by deposition of amyloid plaques containing abnormal prion protein aggregates (PrP(Sc)). This study aimed to evaluate the potential of radioiodinated flavonoid derivatives for single photon emission computed tomography (SPECT) imaging of PrP(Sc). In vitro binding assays using recombi...

Prion diseases are neurodegenerative disorders caused by the accumulation of abnormal prion protein (PrPSc) in the central nervous system. With the aim of elucidating the mechanism underlying the accumulation and degradation of PrPSc, we investigated the role of autophagy in its degradation, using cultured cells stably infected with distinct prion...

Intrahepatic cholangiocarcinomas develop through a multi-step carcinogenesis. Precancerous lesions are defined as biliary intraepithelial neoplasia. Sex determining region Y-box9 (Sox9) is required for the normal differentiation of the biliary tract. To evaluate the Sox9 expression in carcinogenesis and its correlation with clinicopathological feat...

A major unsolved issue of prion biology is the existence of multiple strains with distinct phenotypes and this strain phenomenon is postulated to be associated with the conformational diversity of the abnormal prion protein (PrP(Sc)). Real-time quaking-induced conversion (RT-QUIC) assay that uses Escherichia coli-derived recombinant prion protein (...

The infectious agents of the transmissible spongiform encephalopathies are composed of amyloidogenic prion protein, PrPSc. Real-time quaking-induced conversion can amplify very small amounts of PrPSc seeds in tissues/body fluids of patients or animals. Using this in vitro PrP-amyloid amplification assay, we quantitated the seeding activity of affec...