Cooperative contributions of Interferon regulatory factor 1 (IRF1) and IRF8 to interferon-γ-mediated cytotoxic effects on oligodendroglial progenitor cells

<p>Abstract</p> <p>Background</p> <p>Administration of exogenous interferon-γ (IFNγ) aggravates the symptoms of multiple sclerosis (MS), whereas interferon-β (IFNβ) is used for treatment of MS patients. We previously demonstrated that IFNγ induces apoptosis of oligodendroglial progenitor cells (OPCs), suggesting that IFNγ is more toxic to OPCs than IFNβ. Thus we hypothesized that a difference in expression profiles between IFNγ-inducible and IFNβ-inducible genes in OPCs would predict the genes responsible for IFNγ-mediated cytotoxic effects on OPCs. We have tested this hypothesis particularly focusing on the interferon regulatory factors (IRFs) well-known transcription factors up-regulated by IFNs.</p> <p>Methods</p> <p>Highly pure primary rat OPC cultures were treated with IFNγ and IFNβ. Cell death and proliferation were assessed by MTT reduction, caspse-3-like proteinase activity, Annexin-V binding, mitochondrial membrane potential, and BrdU-incorporation. Induction of all nine IRFs was comprehensively compared by quantitative PCR between IFNγ-treated and IFNβ-treated OPCs. IRFs more strongly induced by IFNγ than by IFNβ were selected, and tested for their ability to induce OPC apoptosis by overexpression and by inhibition by dominant-negative proteins or small interference RNA either in the presence or absence of IFNγ.</p> <p>Results</p> <p>Unlike IFNγ, IFNβ did not induce apoptosis of OPCs. Among nine IRFs, IRF1 and IRF8 were preferentially up-regulated by IFNγ. In contrast, IRF7 was more robustly induced by IFNβ than by IFNγ. Overexpressed IRF1 elicited apoptosis of OPCs, and a dominant negative IRF1 protein partially protected OPCs from IFNγ-induced apoptosis, indicating a substantial contribution of IRF1 to IFNγ-induced OPC apoptosis. On the other hand, overexpression of IRF8 itself had only marginal proapoptotic effects. However, overexpressed IRF8 enhanced the IFNγ-induced cytotoxicity and the proapoptotic effect of overexpressed IRF1, and down-regulation of IRF8 by siRNA partially but significantly reduced preapoptotic cells after treatment with IFNγ, suggesting that IRF8 cooperatively enhances IFNγ-induced OPC apoptosis.</p> <p>Conclusions</p> <p>This study has identified that IRF1 and IRF8 mediate IFNγ-signaling leading to OPC apoptosis. Therapies targeting at these transcription factors and their target genes could reduce IFNγ-induced OPC loss and thereby enhance remyelination in MS patients.</p

PROTEIN: A Visual Interface for Classification of Partial Reliefs

ABSTRACT 3D structure of proteins deeply takes part in the expression of the protein. Molecular surfaces of the protein generally have very complex and bumpy shapes. It is well-known that functions of proteins strongly appear in the bumpy parts of the molecular surfaces. We propose a visual interface to effectively visualize the partial reliefs of molecular surfaces of proteins. This technique assumes that molecule surfaces are approximated as triangular meshes. It first extracts groups of triangles forming partial reliefs, and calculates their feature values as histograms. It finally clusters the partial reliefs according to the histogram. The presented technique then visualizes the clustering results applying a hierarchical data visualization technique &quot;HeiankyoView&quot;, as a visual interface to explore the clustered partial reliefs

Sodium benzoate attenuates 2,8-dihydroxyadenine nephropathy by inhibiting monocyte/macrophage TNF-α expression

Sodium benzoate (SB), a known D-amino acid oxidase (DAO) enzyme inhibitor, has an anti-inflammatory effect, although its role in renal damage has not been explored. 2,8-dihydroxyadenine crystal induced chronic kidney disease, in which TNF-α is involved in the pathogenesis, was established by oral adenine administration in C57BL/6JJcl mice (AdCKD) with or without SB to investigate its renal protective effects. SB significantly attenuated AdCKD by decreasing serum creatinine and urea nitrogen levels, and kidney interstitial fibrosis and tubular atrophy scores. The survival of AdCKD mice improved 2.6-fold by SB administration. SB significantly decreased the number of infiltrating macrophages observed in the positive F4/80 immunohistochemistry area and reduced the expression of macrophage markers and inflammatory genes, including TNF-α, in the kidneys of AdCKD. Human THP-1 cells stimulated with either lipopolysaccharide or TNF-α showed increased expression of inflammatory genes, although this was significantly reduced by SB, confirming the anti-inflammatory effects of SB. SB exhibited renal protective effects in AdCKD in DAO enzyme deficient mice, suggesting that anti-inflammatory effect of SB was independent of DAO enzyme activity. Moreover, binding to motif DNA sequence, protein level, and mRNA level of NF-κB RelB were significantly inhibited by SB in AdCKD kidneys and lipopolysaccharide treated THP-1 cells, respectively. We report that anti-inflammatory property of SB is independent of DAO enzymatic activity and is associated with down regulated NF-κB RelB as well as its downstream inflammatory genes such as TNF-α in AdCKD

A FORTRAN data processing system for the epidemiological data on rheumatic diseases - Part 1. Basic programs for deposit and retrieval of data

A set of FORTRAN programs for small computer is described for deposit and retrieval of the epidemiological data, which have been compiled at the Kami-hojo-cho district in Feb. 1972and Feb. 1975. A data file is constructed on a magnetic disk. The following items are recorded and registered on the disk for every person: identification number, full name in Japanese alphabet, sex, date of birth, weight, height, blood pressures, chemical characterics of blood serum and urine, and various complaints of clinical significance (fever, morning stiffness, arthralgia, joint swelling, myalgia, cutaneous rash, aphthous stomatitis, dry eyes, dry mouth, joint deformity, subcutaneous nodules, lymph and parotid gland enlargement, struma, heart murmur, and neulogical findings). All information per one person requires only two IBM cards due to compact encoding of original records. The encode-decode procedures are explained also in the text

Trisomy 9 Mosaicism Diagnosed In Utero

We present three cases of trisomy 9 mosaicism diagnosed by amniocentesis with ongoing pregnancies after referral to our center due to fetal abnormalities. Two cases were associated with severe fetal growth restriction (FGR), each of which resulted in an intrauterine fetal demise (IUFD) in the third trimester. The other case involved mild FGR with a congenital diaphragmatic hernia and resulted in a live birth with severe development delay. A major prenatal finding of trisomy 9 mosaicism is FGR. Fetuses with trisomy 9 mosaicism can rarely survive in the case of severe FGR

Fluorescence and chemiluminescence behavior of distyrylbenzene bearing two arms of dipicolylaminomethyl groups: Interactions with zinc ion and ATP

Available online 31 January 2018.The absorption and fluorescence spectral study of the distyrylbenzene bearing two arms of the dipicolylaminomethyl groups, the effective ligands for Zn2+, was studied in the presence of Zn2+ and ATP. Upon complexation of the distyrylbenzene with zinc ions in acetonitrile, enhancement of the fluorescence intensity was observed due to inhibition of intramolecular PET (photo-induced electron transfer) quenching, but no effect was found in aqueous media because the equilibrium laid to the free form of the ligands. In contrast, the addition of ATP disodium salt was effective to enhance the fluorescence intensity of the combination of the distyrylbenzne and Zn2+ in aqueous media. This assembly was applied to the peroxyoxalate chemiluminescence system and a significant increase in the intensity was observed, which provides a potential detection for ATP by chemiluminescence. (C) 2018 Elsevier B.V. All rights reserved.ArticleSPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY. 195:223-229 (2018)journal articl

Prenatal and Lactational Exposure to Bisphenol A in Mice Alters Expression of Genes Involved in Cortical Barrel Development without Morphological Changes

It has been reported that premature infants in neonatal intensive care units are exposed to a high rate of bisphenol A (BPA), an endocrine disrupting chemical. Our previous studies demonstrated that corticothalamic projection was disrupted by prenatal exposure to BPA, which persisted even in adult mice. We therefore analyzed whether prenatal and lactational exposure to low doses of BPA affected the formation of the cortical barrel, the barreloid of the thalamus, and the barrelette of the brainstem in terms of the histology and the expression of genes involved in the barrel development. Pregnant mice were injected subcutaneously with 20 µg/kg of BPA daily from embryonic day 0 (E0) to postnatal 3 weeks (P3W), while the control mice received a vehicle alone. The barrel, barreloid and barrelette of the adult mice were examined by cytochrome C oxidase (COX) staining. There were no significant differences in the total and septal areas and the patterning of the posterior medial barrel subfield (PMBSF), barreloid and barrelette, between the BPA-exposure and control groups in the adult mice. The developmental study at postnatal day 1 (PD1), PD4 and PD8 revealed that the cortical barrel vaguely appeared at PD4 and completely formed at PD8 in both groups. The expression pattern of some genes was spatiotemporally altered depending on the sex and the treatment. These results suggest that the trigeminal projection and the thalamic relay to the cortical barrel were spared after prenatal and lactational exposure to low doses of BPA, although prenatal exposure to BPA was previously shown to disrupt the corticothalamic projection

Different Patterns of Vascular Response Between Patients With or Without Diabetes Mellitus After Drug-Eluting Stent Implantation Optical Coherence Tomographic Analysis

ObjectivesWe performed this study to investigate with optical coherence tomography (OCT) the vascular response after sirolimus-eluting stent (SES) implantation between patients with and those without diabetes mellitus (DM).BackgroundThe difference in vascular response after SES implantation between patients with and those without DM has not been fully evaluated with OCT.MethodsOptical coherence tomography was performed to examine 74 nonrestenotic SES implanted in 63 patients (32 with DM and 31 without DM) at 9 months after SES implantation. For struts showing neointimal coverage, the neointimal thickness on the luminal side of each strut section was measured, and neointimal characteristics were classified into high, low, and layered signal pattern.ResultsBaseline patient characteristics and lesion and procedural characteristics data were similar between the 2 groups. In total, 11,422 struts were analyzed. High signal neointima was observed in 90.2 ± 13.9%, low signal neointima in 7.3 ± 10.0%, and layered neointima in 2.7 ± 5.8%/stents. There was higher incidence of low signal neointima (10.5 ± 10.3% vs. 4.5 ± 5.6%, p = 0.003), neointimal thickness was larger (median: 106.8 μm, interquartile range: 79.3 to 130.4 μm vs. median: 83.5 μm, interquartile range: 62.3 to 89.3 μm; p < 0.0001), and neointimal coverage of stent struts was higher (92.1 ± 6.2% vs. 87.2 ± 11.9%; p = 0.03) in DM patients.ConclusionsHigh signal neointimal pattern was predominantly observed, and low or layered signal pattern was observed in some cases. In DM patients, low signal neointima was observed with high frequency. Neointimal coverage and neointimal thickness was also higher in DM patients as compared with non-DM patients

Viral entry and translation in brain endothelia provoke influenza-associated encephalopathy

The version of record of this article, first published in Acta Neuropathologica, is available online at Publisher’s website: https://doi.org/10.1007/s00401-024-02723-z.Influenza-associated encephalopathy (IAE) is extremely acute in onset, with high lethality and morbidity within a few days, while the direct pathogenesis by influenza virus in this acute phase in the brain is largely unknown. Here we show that influenza virus enters into the cerebral endothelium and thereby induces IAE. Three-weeks-old young mice were inoculated with influenza A virus (IAV). Physical and neurological scores were recorded and temporal-spatial analyses of histopathology and viral studies were performed up to 72 h post inoculation. Histopathological examinations were also performed using IAE human autopsy brains. Viral infection, proliferation and pathogenesis were analyzed in cell lines of endothelium and astrocyte. The effects of anti-influenza viral drugs were tested in the cell lines and animal models. Upon intravenous inoculation of IAV in mice, the mice developed encephalopathy with brain edema and pathological lesions represented by micro bleeding and injured astrocytic process (clasmatodendrosis) within 72 h. Histologically, massive deposits of viral nucleoprotein were observed as early as 24 h post infection in the brain endothelial cells of mouse models and the IAE patients. IAV inoculated endothelial cell lines showed deposition of viral proteins and provoked cell death, while IAV scarcely amplified. Inhibition of viral transcription and translation suppressed the endothelial cell death and the lethality of mouse models. These data suggest that the onset of encephalopathy should be induced by cerebral endothelial infection with IAV. Thus, IAV entry into the endothelium, and transcription and/or translation of viral RNA, but not viral proliferation, should be the key pathogenesis of IAE