Publications by authors named "Hideaki Abe"

41 Publications

A 3-styrylchromone converted from trimebutine 3D pharmacophore possesses dual suppressive effects on RAGE and TLR4 signaling pathways.

Biochem Biophys Res Commun 2021 Jun 7;566:1-8. Epub 2021 Jun 7.

Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, 278-8510, Japan. Electronic address:

Receptor for advanced glycation end-products (RAGE) and Toll-like receptors (TLRs) are potential therapeutic targets in the treatment of acute and chronic inflammatory diseases. We previously reported that trimebutine, a spasmolytic drug, suppresses RAGE pro-inflammatory signaling pathway in macrophages. The aim of this study was to convert trimebutine to a new small molecule using in silico 3D pharmacophore similarity search, and dissect the mechanistic anti-inflammatory basis. Of note, a unique 3-styrylchromone (3SC), 7-methoxy-3-trimethoxy-SC (7M3TMSC), converted from trimebutine 3D pharmacophore potently suppressed both high mobility group box 1-RAGE and lipopolysaccharide-TLR4 signaling pathways in macrophage-like RAW264.7 cells. More importantly, 7M3TMSC inhibited the phosphorylation of extracellular signaling-regulated kinase 1 and 2 (ERK1/2) and downregulated the production of cytokines, such as interleukin-6. Furthermore, 3D pharmacophore-activity relationship analyses revealed that the hydrogen bond acceptors of the trimethoxy groups in a 3-styryl moiety and the 7-methoxy-group in a chromone moiety in this compound are significant in the dual anti-inflammatory activity. Thus, 7M3TMSC may provide an important scaffold for the development of a new type of anti-inflammatory dual effective drugs targeting RAGE/TLR4-ERK1/2 signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2021.05.096DOI Listing
June 2021

Low Detection Rate of H3K27M Mutations in Cerebrospinal Fluid Obtained from Lumbar Puncture in Newly Diagnosed Diffuse Midline Gliomas.

Diagnostics (Basel) 2021 Apr 9;11(4). Epub 2021 Apr 9.

Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.

Recent studies have suggested the feasibility of detecting H3K27M mutations in the cerebrospinal fluid of diffuse midline glioma (DMG) patients. However, cerebrospinal fluid from patients in these studies were collected mainly during biopsy, ventriculo-peritoneal shunt procedures or postmortem. We assessed circulating tumor DNA (ctDNA) extracted from cerebrospinal fluid (CSF) and plasma in a series of 12 radiographically suspected and/or pathologically confirmed diffuse midline glioma patients and assessed for K27M mutation using digital droplet PCR. In 10 patients, CSF was obtained by lumbar puncture at presentation. A definitive detection of K27M mutation was achieved in only one case (10%); K27M mutation was suspected in three other cases (30%). K27M mutation was detected in two patients in CSF obtained by ventricular tap during a ventriculo-peritoneal shunt for obstructive hydrocephalus. Cases in which a definitive assessment was possible (definite K27M or definite wildtype) tended to be younger (median 7.5 years vs. 40.5 years; = 0.07) and have a higher concentration of CSF protein (median 123 mg/dL vs. 27.5 mg/dL; = 0.21) compared to nondefinite cases. Low proliferation and apoptotic rates seemed to be characteristics of DMG unfavorable for liquid biopsy. More advanced lesions with necrosis and evidence of dissemination were unlikely to be candidates for lumbar puncture due to the fear of exacerbating obstructive hydrocephalus. Methods to safely sample CSF and a more sensitive detection of ctDNA are necessary for reliable liquid biopsy of DMG at presentation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/diagnostics11040681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070169PMC
April 2021

A Unique Anti-Cancer 3-Styrylchromone Suppresses Inflammatory Response via HMGB1-RAGE Signaling.

Medicines (Basel) 2021 Mar 24;8(4). Epub 2021 Mar 24.

Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba 278-8510, Japan.

High mobility group box 1 (HMGB1)-receptor for advanced glycation endo-products (RAGE) axis serves as a key player in linking inflammation and carcinogenesis. Recently, papaverine was revealed to suppress the HMGB1-RAGE inflammatory signaling pathway and cancer cell proliferation. Therefore, a dual suppressor targeting this axis is expected to become a new type of therapeutic agent to treat cancer. Papaverine 3D pharmacophore mimetic compounds were selected by the LigandScout software from our in-house, anti-cancer chemical library and assessed for their anti-inflammatory activities by a HMGB1-RAGE-mediated interleukin-6 production assay using macrophage-like RAW264.7 cells. Molecular-biological analyses, such as Western blotting, were performed to clarify the mechanism of action. A unique 6-methoxy-3-hydroxy-styrylchromone was found to possess potent anti-inflammatory and anti-cancer activities via the suppression of the HMGB1-RAGE-extracellular signal-regulated kinase 1/2 signaling pathway. Furthermore, the 3D pharmacophore-activity relationship analyses revealed that the hydroxyl group at the C4' position of the benzene ring in a 3-styryl moiety was significant in its dual suppressive effects. These findings indicated that this compound may provide a valuable scaffold for the development of a new type of anti-cancer drug possessing anti-inflammatory activity and as a tool for understanding the link between inflammation and carcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/medicines8040017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064355PMC
March 2021

Epidemiology of coronavirus disease 2019 in Yamagata Prefecture, Japan, January-May 2020: The importance of retrospective contact tracing.

Jpn J Infect Dis 2021 Mar 31. Epub 2021 Mar 31.

Yamagata Prefectural Institute of Public Health, Japan.

Public health interventions have served an important role in controlling coronavirus disease 2019 (COVID-19), a rapidly spreading infectious disease. To contribute to future COVID-19 countermeasures, we aimed at verifying the results of countermeasures achieved by public health centers (PHCs) against the first wave of COVID-19 in Yamagata Prefecture, Japan. During January-May 2020, 1,253 patients suspected of SARS-CoV-2 infection were invited for testing. Simultaneously, based on retrospective contact tracings, PHCs investigated the infection sources and transmission routes of laboratory-confirmed COVID-19 cases and tested 928 contacts. Consequently, 69 cases were confirmed during March 31 - May 4, 58 (84.1%; 95% confidence interval 75.5-92.7) of whom were found from contacts. The spread of infection was triggered by cases harboring epidemiological links outside of Yamagata. Then, the number of cases increased rapidly. However, PHCs identified epidemiological links in 61 (88.4%; 95% confidence interval 80.8-96.0) of the 69 cases and transmission chains up to the fifth generation. Finally, the spread of infection ended after approximately one month. Our results indicate that the identification of infection sources and active case finding from contacts based on retrospective contact tracing was likely to be an effective strategy to end the first wave of COVID-19 in Yamagata.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7883/yoken.JJID.2020.1073DOI Listing
March 2021

A genome-wide investigation of adaptive signatures in protein-coding genes related to tool behaviour in New Caledonian and Hawaiian crows.

Mol Ecol 2021 02 23;30(4):973-986. Epub 2020 Dec 23.

Department of Anatomy, University of Otago, Dunedin, New Zealand.

Very few animals habitually manufacture and use tools. It has been suggested that advanced tool behaviour co-evolves with a suite of behavioural, morphological and life history traits. In fact, there are indications for such an adaptive complex in tool-using crows (genus Corvus species). Here, we sequenced the genomes of two habitually tool-using and ten non-tool-using crow species to search for genomic signatures associated with a tool-using lifestyle. Using comparative genomic and population genetic approaches, we screened for signals of selection in protein-coding genes in the tool-using New Caledonian and Hawaiian crows. While we detected signals of recent selection in New Caledonian crows near genes associated with bill morphology, our data indicate that genetic changes in these two lineages are surprisingly subtle, with little evidence at present for convergence. We explore the biological explanations for these findings, such as the relative roles of gene regulation and protein-coding changes, as well as the possibility that statistical power to detect selection in recently diverged lineages may have been insufficient. Our study contributes to a growing body of literature aiming to decipher the genetic basis of recently evolved complex behaviour.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/mec.15775DOI Listing
February 2021

Trimebutine attenuates high mobility group box 1-receptor for advanced glycation end-products inflammatory signaling pathways.

Biochem Biophys Res Commun 2020 12 8;533(4):1155-1161. Epub 2020 Oct 8.

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan; Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, 278-8510, Japan. Electronic address:

We previously identified papaverine as an inhibitor of receptor for advanced glycation end-products (RAGE) and showed its suppressive effect on high mobility group box 1 (HMGB1)-mediated responses to inflammation. Here, we found trimebutine to be a 3D pharmacophore mimetics of papaverine. Trimebutine was revealed to have more potent suppressive effects on HMGB1-induced production of pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α in macrophage-like RAW264.7 cells and mouse bone marrow primarily differentiated macrophages than did papaverine. However, the inhibitory effect of trimebutine on the interaction of HMGB1 and RAGE was weaker than that of papaverine. Importantly, mechanism-of-action analyses revealed that trimebutine strongly inhibited the activation of RAGE downstream inflammatory signaling pathways, especially the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), which are mediator/effector kinases recruited to the intracellular domain of RAGE. Consequently, the activation of Jun amino terminal kinase, which is an important effector kinase for the up-regulation of pro-inflammatory cytokines, was inhibited. Taken together, these results suggest that trimebutine may exert its suppressive effect on the HMGB1-RAGE inflammatory signal pathways by strongly blocking the recruitment of ERK1/2 to the intracellular tail domain of RAGE in addition to its weak inhibition of the extracellular interaction of HMGB1 with RAGE. Thus, trimebutine may provide a unique scaffold for the development of novel dual inhibitors of RAGE for inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.09.126DOI Listing
December 2020

Endoscopic Management for Recurrent Hydrocephalus Associated with Neurosarcoidosis.

World Neurosurg 2020 12 2;144:121-124. Epub 2020 Sep 2.

Department of Neurosurgery, Akita University Graduate School of Medicine, Akita, Japan.

Background: Recurrent hydrocephalus may occur as a complication of neurosarcoidosis with chronic inflammation. We present a case that required a combination of multistage endoscopic diversion of the cerebrospinal fluid pathway and shunt surgery.

Case Description: A 34-year-old man presented with progressive nausea and vomiting. Magnetic resonance imaging revealed hydrocephalus with leptomeningeal enhancement along the base of the fourth ventricle and the bilateral foramina of Luschka. Concurrent endoscopic third ventriculostomy and biopsy were performed. The diagnosis was neurosarcoidosis. Immediately after the procedure, the endoscopic third ventriculostomy stoma was occluded, and a right ventriculoperitoneal shunt was urgently performed. However, left unilateral hydrocephalus developed during the late phase of immunosuppressive therapy for neurosarcoidosis. Endoscopic septostomy with repositioning of the ventricular catheter was indicated. Intraoperative findings included a white pasty tissue with nodules that covered the ventricular wall close to the foramen of Monro and sealed the side holes of the catheter. Chemotherapy with a tumor necrosis factor-α inhibitor was initiated after the surgical procedure. The patient had an uneventful course without recurrence of hydrocephalus for >6 months.

Conclusions: Endoscopic diversion of the cerebrospinal fluid pathway should be actively considered for treating hydrocephalus without a shunt and performing biopsy simultaneously. Even if a subsequent shunt is needed, complex hydrocephalus can be avoided with a combination of endoscopic techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2020.08.177DOI Listing
December 2020

Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors.

Molecules 2020 Aug 10;25(16). Epub 2020 Aug 10.

Department of Gene Regulation, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan.

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole-piperidine ()- and azaindole-piperazine ()-motif compounds, which were modified from the well-known NAMPT inhibitor FK866 (). Notably, displayed considerably stronger enzyme inhibitory activity and cellular potency than did and . The main reason for this phenomenon was revealed to be due to apparent electronic repulsion between the replaced nitrogen atom (N1) of piperazine in and the Nδ atom of His191 in NAMPT by our in silico binding mode analyses. Indeed, had a lower binding affinity score than did and , although these inhibitors took similar stable chair conformations in the tunnel region. Taken together, these observations indicate that the electrostatic enthalpy potential rather than entropy effects inside the tunnel cavity has a significant impact on the different binding affinity of from that of in the disparate enzymatic and cellular potencies. Thus, it is better to avoid or minimize interactions with His191 in designing further effective NAMPT inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules25163633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464552PMC
August 2020

The tuatara genome reveals ancient features of amniote evolution.

Nature 2020 08 5;584(7821):403-409. Epub 2020 Aug 5.

Department of Anatomy, University of Otago, Dunedin, New Zealand.

The tuatara (Sphenodon punctatus)-the only living member of the reptilian order Rhynchocephalia (Sphenodontia), once widespread across Gondwana-is an iconic species that is endemic to New Zealand. A key link to the now-extinct stem reptiles (from which dinosaurs, modern reptiles, birds and mammals evolved), the tuatara provides key insights into the ancestral amniotes. Here we analyse the genome of the tuatara, which-at approximately 5 Gb-is among the largest of the vertebrate genomes yet assembled. Our analyses of this genome, along with comparisons with other vertebrate genomes, reinforce the uniqueness of the tuatara. Phylogenetic analyses indicate that the tuatara lineage diverged from that of snakes and lizards around 250 million years ago. This lineage also shows moderate rates of molecular evolution, with instances of punctuated evolution. Our genome sequence analysis identifies expansions of proteins, non-protein-coding RNA families and repeat elements, the latter of which show an amalgam of reptilian and mammalian features. The sequencing of the tuatara genome provides a valuable resource for deep comparative analyses of tetrapods, as well as for tuatara biology and conservation. Our study also provides important insights into both the technical challenges and the cultural obligations that are associated with genome sequencing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2561-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116210PMC
August 2020

MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas.

Front Oncol 2019 21;9:1568. Epub 2020 Jan 21.

Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.

Diffuse midline gliomas (DMGs) show resistance to many chemotherapeutic agents including temozolomide (TMZ). Histone gene mutations in DMGs trigger epigenetic changes including DNA hypomethylation, one of which is a frequent lack of O6-methyl-guanine-DNA methyltransferase () promoter methylation, resulting in increased MGMT expression. We established the NGT16 cell line with K27M and G328E gene mutations from a DMG patient and used this cell line and other DMG cell lines with gene mutation (SF7761, SF8628, JHH-DIPG1) to analyze promoter methylation, MGMT protein expression, and response to TMZ. Three out of 4 DMG cell lines (NGT16, SF8628, and JHH-DIPG1) had unmethylated promoter, increased MGMT expression, and showed resistance to TMZ treatment. SF7761 cells with gene mutation showed promoter methylation, lacked MGMT expression, and sensitivity to TMZ treatment. NGT16 line showed response to ALK2 inhibitor K02288 treatment . We confirmed that MGMT expression contributes to TMZ resistance in DMG cell lines. There is an urgent need to develop new strategies to treat TMZ-resistant DMGs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.01568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985080PMC
January 2020

Structural insights into the active site of poly(ADP-ribose) glycohydrolase using docking modes of 6-hydroxy-3H-xanthen-3-one derivative inhibitors.

Bioorg Med Chem 2020 02 6;28(3):115249. Epub 2019 Dec 6.

Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, 2641 Yamazaki Noda, Chiba 278-8510, Japan. Electronic address:

Poly(ADP-ribose) glycohydrolase (PARG) plays an essential role in poly(ADP-ribose) (PAR) turnover, and thereby regulating DNA transactions, such as DNA repair, replication, transcription and recombination. Here, we examined the inhibitory activities of 6-hydroxy-3H-xanthene-3-one (HXO) derivatives and analyzed their binding modes in the active site of PARG by in silico docking study. Among the derivatives, Rose Bengal was found to be the most potent inhibitor of PARG and its halogen groups were revealed to cooperatively potentiate the inhibitory activity. Importantly, the binding mode of Rose Bengal occupied the active site of PARG revealed the presence of unique "Sandwich" residues of Asn869 and Tyr792, which enable the inhibitor to bind tightly with the active pocket. This sandwich interaction could stabilize the π-π interactions of HXO scaffold with Phe902 and Tyr795. In addition, to increase the binding affinity, the iodine and chlorine atoms of this inhibitor could contribute to the inducing of favorable disorders, which promote an entropy boost on the active site of PARG for structural plasticity, and making the stable configuration of HXO scaffold in the active site, respectively, as judged by the analysis of binding free energy. These results provide new insights into the active site of PARG and an additional opportunity for designing selective PARG inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2019.115249DOI Listing
February 2020

Targeting poly(ADP-ribose) glycohydrolase to draw apoptosis codes in cancer.

Biochem Pharmacol 2019 09 6;167:163-172. Epub 2019 Jun 6.

Hinoki Shinyaku Co., Ltd., 9-6 Nibancho, Chiyoda-ku, Tokyo 102-0084, Japan.

Poly(ADP-ribosyl)ation is a unique post-translational modification of proteins. The metabolism of poly(ADP-ribose) (PAR) is tightly regulated mainly by poly(ADP-ribose) polymerases (PARP) and poly(ADP-ribose) glycohydrolase (PARG). Accumulating evidence has suggested the biological functions of PAR metabolism in control of many cellular processes, such as cell proliferation, differentiation and death by remodeling chromatin structure and regulation of DNA transaction, including DNA repair, replication, recombination and transcription. However, the physiological roles of the catabolism of PAR catalyzed by PARG remain less understood than those of PAR synthesis by PARP. Noteworthy biochemical studies have revealed the importance of PAR catabolic pathway generating nuclear ATP via the coordinated actions of PARG and ADP-ribose pyrophosphorylase (ADPRPPL) for the driving of DNA repair and the maintenance of DNA replication apparatus while repairing DNA damage. Furthermore, genetic studies have shown the value of PARG as a therapeutic molecular target for PAR-mediated diseases, such as cancer, inflammation and many pathological conditions. In this review, we present the current knowledge of de-poly(ADP-ribosyl)ation catalyzed by PARG focusing on its role in DNA repair, replication and apoptosis. Furthermore, the induction of apoptosis code of DNA replication catastrophe by synthetic lethality of PARG inhibition and the recent progresses regarding the development of small molecule PARG inhibitors and their therapeutic potentials in cancer chemotherapy are highlighted in this review.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2019.06.004DOI Listing
September 2019

Papaverine identified as an inhibitor of high mobility group box 1/receptor for advanced glycation end-products interaction suppresses high mobility group box 1-mediated inflammatory responses.

Biochem Biophys Res Commun 2019 04 27;511(3):665-670. Epub 2019 Feb 27.

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan; Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan. Electronic address:

The interaction of high mobility group box 1 (HMGB1), which is secreted from immune and dying cells during cellular infection and injury, and receptor for advanced glycation end-products (RAGE) appears to be critical for acute and chronic inflammatory disorders. Here we designed a unique cyclic β-hairpin peptide (Pepb2), which mimics the predicted RAGE-binding domain of HMGB1. Pepb2 competitively inhibited HMGB1/RAGE interaction. We then identified papaverine as a Pepb2 mimetic by in silico 3D-structural similarity screening from the DrugBank library. Papaverine was found to directly inhibit HMGB1/RAGE interaction. It also suppressed the HMGB1-mediated production of pro-inflammatory cytokines, IL-6 and TNF-α, in mouse macrophage-like RAW264.7 cells and bone marrow-derived macrophages. In addition, papaverine attenuated mortality in cecal ligation puncture-induced sepsis model mice. Taken together, these findings indicate that papaverine could become a useful therapeutic against HMGB1/RAGE-mediated sepsis and other inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2019.01.136DOI Listing
April 2019

EGFRvIII Is Expressed in Cellular Areas of Tumor in a Subset of Glioblastoma.

Neurol Med Chir (Tokyo) 2019 Mar 21;59(3):89-97. Epub 2019 Feb 21.

Department of Pathology, Brain Research Institute, University of Niigata.

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific cell surface antigen often expressed in glioblastoma and has drawn much attention as a possible therapeutic target. We performed immunohistochemistry on histology sections of surgical specimens taken from 67 cases with glioblastoma, isocitrate dehydrogenase-wild type, and evaluated the morphological characteristics and distribution of the EGFRvIII-positive tumor cells. We then evaluated the localization of EGFRvIII-expression within the tumor and peritumoral areas. EGFRvIII immunopositivity was detected in 15 specimens taken from 13 patients, including two recurrent specimens taken from the same patient at relapse. Immunofluorescence staining demonstrated that EGFRvIII-positive cells were present in cells positive for glial fibrillary acidic protein (GFAP), and some showed astrocytic differentiation with multiple fine processes and others did not shown. The EGFRvIII-positive cells were located in cellular areas of the tumor, but not in the invading zone. In the two recurrent cases, EGFRvIII-positive cells were markedly decreased in one case and retained in the other. With regard to overall survival, univariate analysis indicated that EGFRvIII-expression in patients with glioblastoma was not significantly associated with a favorable outcome. Double-labeling immunofluorescence staining of EGFRvIII and GFAP showed that processes of large, well differentiated, GFAP-positive glia extend to and surround less differentiated, EGFRvIII-positive glial cells in cellular areas of tumor. However, in the tumor periphery, EGFRvIII-positive tumor cells were not observed. This finding suggests that EGFRvIII is involved in tumor proliferation, but that invading glioma cells lose their EGFRvIII expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2176/nmc.oa.2018-0078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434422PMC
March 2019

MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas and MGMT Silencing to Temozolomide Sensitivity in IDH-Mutant Gliomas.

Neurol Med Chir (Tokyo) 2018 Jul 31;58(7):290-295. Epub 2018 May 31.

Department of Neurosurgery, Brain Research Institute, Niigata University.

Histone H3 mutations are frequently found in diffuse midline gliomas (DMGs), which include diffuse intrinsic pontine gliomas and thalamic gliomas. These tumors have dismal prognoses. Recent evidence suggests that one reason for the poor prognoses is that O-methylguanine-DNA methyltransferase (MGMT) promoter frequently lacks methylation in DMGs. This review compares the epigenetic changes brought about by histone mutations to those by isocitrate dehydrogenase-mutant gliomas, which frequently have methylated MGMT promoters and are known to be sensitive to temozolomide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2176/nmc.ra.2018-0044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048353PMC
July 2018

Microsatellite Polymorphisms Adjacent to the Oxytocin Receptor Gene in Domestic Cats: Association with Personality?

Front Psychol 2017 18;8:2165. Epub 2017 Dec 18.

Department of Psychology, Graduate School of Letters, Kyoto University, Kyoto, Japan.

A growing number of studies have explored the oxytocin system in humans and non-human animals, and some have found important genetic polymorphisms in the oxytocin receptor gene () associated with the bonding system, social behaviors, and personality in several species. Although single nucleotide polymorphisms in have been well-examined in various species, microsatellites (or short tandem repeats) adjacent to have rarely been studied, despite some suggestions that microsatellite polymorphisms near genes might play a role in genetic transcription and translation. In this study, we surveyed microsatellites in the upstream, intron, and downstream regions of in domestic cats (). We succeeded in amplifying 5 out of 10 regions, and recognized these five regions as polymorphic. We compared allele frequencies in these five regions between mongrel cats in Japan ( = 100) and cats of 10 pure breeds ( = 40). There were significant differences in allele frequencies between the two populations in all microsatellite regions. Additionally, the owners of mongrel cats answered a comprehensive personality questionnaire, and factor analysis extracted four factors (Openness, Friendliness, Roughness, and Neuroticism). We examined the association between the microsatellite genotypes, age, sex, neutering status, and personality scores. Compared to their counterparts, younger cats tended to score higher on Openness, male cats scored higher on Friendliness, and female and neutered cats scored higher on Roughness. When we divided the sample into three groups depending on the length of alleles, we found a marginally significant association between Friendliness and MS3. Additionally, we found a sex-mediated effect of genotypes in MS4 on Friendliness, resulting in different effects on females and males. Our findings that mongrel cats had longer alleles in MS3 and MS4 than purebred cats, and that those cats tended to score higher on Friendliness, supported the previous findings. However, future studies such as comparison between purebred cats with apparently different origin or personality are required to determine the association of genetic variants in the with personality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyg.2017.02165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741686PMC
December 2017

Reliable diagnosis of IDH-mutant glioblastoma by 2-hydroxyglutarate detection: a study by 3-T magnetic resonance spectroscopy.

Neurosurg Rev 2018 Apr 27;41(2):641-647. Epub 2017 Sep 27.

Department of Neurosurgery, Brain Research Institute, University of Niigata, Niigata, Japan.

We have previously reported that reliable detection of 2-hydroxyglutarate (2HG) in isocitrate dehydrogenase (IDH)-mutant WHO grade 2 and 3 gliomas is possible utilizing 3.0-T single-voxel magnetic resonance spectroscopy (SVMRS). We set out to determine whether the same method could be applied to detect 2HG in IDH-mutant glioblastoma. Forty-four patients harboring glioblastoma underwent pre-operative MRS evaluation to detect 2HG and other metabolites. Presence of IDH-mutations was determined by IDH1 R132H immunohistochemical analysis and DNA sequencing of surgically obtained tissues. Six out of 44 (13.6%) glioblastomas were IDH-mutant. IDH-mutant glioblastoma exhibited significantly higher accumulation of 2HG (median 3.191 vs. 0.000 mM, p < 0.0001, Mann-Whitney test). A cutoff of 2HG = 0.897 mM achieved high sensitivity (100.0%) and specificity (92.59%) in determining IDH-mutation in glioblastoma. Glioblastoma with high 2HG accumulation did not have significantly longer overall survival than glioblastoma with low 2HG accumulation (p = 0.107, log-rank test). Non-invasive and reliable detection of 2HG in IDH-mutant glioblastoma was possible by 3.0-T SVMRS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10143-017-0908-yDOI Listing
April 2018

Gene expression patterns of chicken neuregulin 3 in association with copy number variation and frameshift deletion.

BMC Genet 2017 07 21;18(1):69. Epub 2017 Jul 21.

Wildlife Research Center, Kyoto University, 2-24 Tanaka-Sekiden-cho, Sakyo, Kyoto, 606-8203, Japan.

Background: Neuregulin 3 (NRG3) plays a key role in central nervous system development and is a strong candidate for human mental disorders. Thus, genetic variation in NRG3 may have some impact on a variety of phenotypes in non-mammalian vertebrates. Recently, genome-wide screening for short insertions and deletions in chicken (Gallus gallus) genomes has provided useful information about structural variation in functionally important genes. NRG3 is one such gene that has a putative frameshift deletion in exon 2, resulting in premature termination of translation. Our aims were to characterize the structure of chicken NRG3 and to compare expression patterns between NRG3 isoforms.

Results: Depending on the presence or absence of the 2-bp deletion in chicken NRG3, 3 breeds (red junglefowl [RJF], Boris Brown [BB], and Hinai-jidori [HJ]) were genotyped using flanking primers. In the commercial breeds (BB and HJ), approximately 45% of individuals had at least one exon 2 allele with the 2-bp deletion, whereas there was no deletion allele in RJF. The lack of a homozygous mutant indicated the existence of duplicated NRG3 segments in the chicken genome. Indeed, highly conserved elements consisting of exon 1, intron 1, exon 2, and part of intron 2 were found in the reference RJF genome, and quantitative PCR detected copy number variation (CNV) between breeds as well as between individuals. The copy number of conserved elements was significantly higher in chicks harboring the 2-bp deletion in exon 2. We identified 7 novel transcript variants using total mRNA isolated from the amygdala. Novel isoforms were found to lack the exon 2 cassette, which probably harbored the premature termination codon. The relative transcription levels of the newly identified isoforms were almost the same between chick groups with and without the 2-bp deletion, while chicks with the deletion showed significant suppression of the expression of previously reported isoforms.

Conclusions: A putative frameshift deletion and CNV in chicken NRG3 are structural mutations that occurred before the establishment of commercial chicken lines. Our results further suggest that the putative frameshift deletion in exon 2 may potentially affect the expression level of particular isoforms of chicken NRG3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12863-017-0537-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521077PMC
July 2017

Structural insight into the active site of mushroom tyrosinase using phenylbenzoic acid derivatives.

Bioorg Med Chem Lett 2017 07 26;27(13):2868-2872. Epub 2017 Apr 26.

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki Noda, Chiba 278-8510, Japan; Genome and Drug Research Center, Tokyo University of Science, 2641 Yamazaki Noda, Chiba 278-8510, Japan. Electronic address:

So far, many inhibitors of tyrosinase have been discovered for cosmetic and clinical agents. However, the molecular mechanisms underlying the inhibition in the active site of tyrosinase have not been well understood. To explore this problem, we examined here the inhibitory effects of 4'-hydroxylation and methoxylation of phenylbenzoic acid (PBA) isomers, which have a unique scaffold to inhibit mushroom tyrosinase. The inhibitory effect of 3-PBA, which has the most potent inhibitory activity among the isomers, was slightly decreased by 4'-hydroxylation and further decreased by 4'-methoxylation against mushroom tyrosinase. Surprisingly, 4'-hydroxylation but not methoxylation of 2-PBA appeared inhibitory activity. On the other hand, both 4'-hydroxylation and methoxylation of 4-PBA increased the inhibitory activity against mushroom tyrosinase. In silico docking analyses using the crystallographic structure of mushroom tyrosinase indicated that the carboxylic acid or 4'-hydroxyl group of PBA derivatives could chelate with cupric ions in the active site of mushroom tyrosinase, and that the interactions of Asn260 and Phe264 in the active site with the adequate-angled biphenyl group are involved in the inhibitory activities of the modified PBAs, by parallel and T-shaped π-π interactions, respectively. Furthermore, Arg268 could fix the angle of the aromatic ring of Phe264, and Val248 is supposed to interact with the inhibitors as a hydrophobic manner. These results may enhance the structural insight into mushroom tyrosinase for the creation of novel tyrosinase inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2017.04.074DOI Listing
July 2017

New Insights into the Roles of NAD+-Poly(ADP-ribose) Metabolism and Poly(ADP-ribose) Glycohydrolase.

Curr Protein Pept Sci 2016 ;17(7):668-682

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.

Accumulating evidence has suggested the fundamental functions of NAD+-poly(ADP-ribose) metabolism in cellular and physiological processes, including energy homeostasis, signal transduction, DNA transaction, genomic stability and cell death or survival. The NAD+ biosynthesis and poly(ADP-ribose) [(ADP-R)n] turnover are tightly controlled by several key enzymes, such as nicotinamide phosphoribosyltransferase (NmPRT), nicotinamide mononucleotide adenylyltransferases (NMNATs), poly(ADP-ribose) polymerase (PARP), poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose pyrophosphorylase (ADPRPPL). Many researches investigating the roles of these enzymes in cells have revealed the physiological and pathological importance, and thereby the therapeutical values. Among these enzymes, the polymer degrading enzyme PARG has not yet been intensively studied, because of the low cellular content, lack of cell-available PARG chemical inhibitors and PARG genetic models. So, the biological roles of (ADP-R)n catabolism by PARG are still being elucidated as compared to those of synthesis by PARP. However, recent studies delineate that PARG-dependent (ADP-R)n degradation is critical for many pathological conditions, and thus PARG is an important target for chemical therapeutics for several diseases. This review will present the recent progresses about the roles of NAD+-(ADP-R)n metabolism and the structures and functions of PARG, with a focus on its role in DNA repair and cell death by apoptosis in relation to central regulatory network, and the therapeutic potentials of PARG inhibitors in cancer chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389203717666160419150014DOI Listing
February 2017

Discovery of a new type of scaffold for the creation of novel tyrosinase inhibitors.

Bioorg Med Chem 2016 09 28;24(18):4509-4515. Epub 2016 Jul 28.

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Genome and Drug Research Center, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan. Electronic address:

Tyrosinase is known as the key enzyme for melanin biosynthesis, which is effective in preventing skin injury by ultra violet (UV). In past decades, tyrosinase has been well studied in the field of cosmetics, medicine, agriculture and environmental sciences, and a lot of tyrosinase inhibitors have been developed for their needs. Here, we searched for new types of tyrosinase inhibitors and found phenylbenzoic acid (PBA) as a unique scaffold. Among three isomers of PBA, 3-phenylbenzoic acid (3-PBA) was revealed to be the most potent inhibitor against mushroom tyrosinase (IC50=6.97μM, monophenolase activity; IC50=36.3μM, diphenolase activity). The kinetic studies suggested that the apparent inhibition modes for the monophenolase and diphenolase activities were noncompetitive and mixed type inhibition, respectively. Analyses by in silico docking studies using the crystallographic structure of mushroom tyrosinase indicated that the carboxylic acid group of the 3-PBA could adequately bind to two cupric ions in the tyrosinase. To prove this hypothesis, we examined the effect of modification of the carboxylic acid group of the 3-PBA on its inhibitory activity. As expected, the esterification abrogated the inhibitory activity. These observations suggest that 3-PBA is a useful lead compound for the generation of novel tyrosinase inhibitors and provides a new insight into the molecular basis of tyrosinase catalytic mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2016.07.060DOI Listing
September 2016

Evolutionary Footprints of Short Tandem Repeats in Avian Promoters.

Sci Rep 2016 Jan 14;6:19421. Epub 2016 Jan 14.

Department of Anatomy, University of Otago, Dunedin 9054, New Zealand.

Short tandem repeats (STRs) or microsatellites are well-known sequence elements that may change the spacing between transcription factor binding sites (TFBSs) in promoter regions by expansion or contraction of repetitive units. Some of these mutations have the potential to contribute to phenotypic diversity by altering patterns of gene expression. To explore how repetitive sequence motifs within promoters have evolved in avian lineages under mutation-selection balance, more than 400 evolutionary conserved STRs (ecSTRs) were identified in this study by comparing the 2 kb upstream promoter sequences of chicken against those of other birds (turkey, duck, zebra finch, and flycatcher). The rate of conservation was significantly higher in AG dinucleotide repeats than in AC or AT repeats, with the expansion of AG motifs being noticeably constrained in passerines. Analysis of the relative distance between ecSTRs and TFBSs revealed a significantly higher rate of conserved TFBSs in the vicinity of ecSTRs in both chicken-duck and chicken-passerine comparisons. Our comparative study provides a novel insight into which intrinsic factors have influenced the degree of constraint on repeat expansion/contraction during avian promoter evolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep19421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725869PMC
January 2016

Abundance, arrangement, and function of sequence motifs in the chicken promoters.

BMC Genomics 2014 Oct 15;15:900. Epub 2014 Oct 15.

Department of Anatomy, University of Otago, Dunedin, New Zealand.

Background: Eukaryotic promoters are regions containing various sequence motifs necessary to control gene transcription. Much evidence has emerged showing that structural and/or contextual changes in regulatory elements can critically affect cis-regulatory activity. As sequence motifs can be key factors in maintaining complex promoter architectures, one effective approach to further understand the evolution of promoter regions in vertebrates is to compare the abundance and distribution patterns of sequence motifs in these regions between divergent species. When compared with mammals, the chicken (Gallus gallus) has a very different genome composition and sufficient genomic information to make it a good model for the exploration of promoter structure and evolution.

Results: More than 10% of chicken genes contained short tandem repeat (STR) in the region 2 kb upstream of promoters, but the total number of STRs observed in chicken is approximately half of that detected in human promoters. In terms of the STR motif frequencies, chicken promoter regions were more similar to other avian and mammalian promoters than these were to the entire chicken genome. Unlike other STRs, nearly half of the trinucleotide repeats found in promoters partly or entirely overlapped with CpG islands, indicating potential association with nucleosome positions. Moreover, the chicken promoters are abundant with sequence motifs such as poly-A, poly-G and G-quadruplexes, especially in the core region, that are otherwise rare in the genome. Most of sequence motifs showed strong functional enrichment for particular gene ontology (GO) categories, indicating roles in regulation of transcription and gene expression, as well as immune response and cognition.

Conclusions: Chicken promoter regions share some, but not all, of the structural features observed in mammalian promoters. The findings presented here provide empirical evidence suggesting that the frequencies and locations of STR motifs have been conserved through promoter evolution in a lineage-specific manner. Correlation analysis between GO categories and sequence motifs suggests motif-specific constraints acting on gene function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2164-15-900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203960PMC
October 2014

Structure-activity relationships of the thujaplicins for inhibition of human tyrosinase.

Bioorg Med Chem 2014 Nov 21;22(21):6193-200. Epub 2014 Sep 21.

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki Noda, Chiba 278-8510, Japan; Genome and Drug Research Center, Tokyo University of Science, 2641 Yamazaki Noda, Chiba 278-8510, Japan. Electronic address:

Tyrosinase inhibitors have become increasingly critical agents in cosmetic, agricultural, and medicinal products. Although a large number of tyrosinase inhibitors have been reported, almost all the inhibitors were unfortunately evaluated by using commercial available mushroom tyrosinase. Here, we examined the inhibitory effects of three isomers of thujaplicin (α, β, and γ) on human tyrosinase and analyzed their binding modes using homology model and docking studies. As the results, γ-thujaplicin was found to strongly inhibit human tyrosinase with the IC50 of 1.15 μM, extremely superior to a well-known tyrosinase inhibitor kojic acid (IC50 = 571.17 μM). MM-GB/SA binding free energy decomposition analyses suggested that the potent inhibitory activity of γ-thujaplicin may be due to the interactions with His367, Ile368, and Val377 (hot spot amino acid residues) in human tyrosinase. Furthermore, the binding mode of α-thujaplicin indicated that Val377 and Ser380 may cause van der Waals clashes with the isopropyl group of α-thujaplicin. These results provide a novel structural insight into the hot spot of human tyrosinase for the specific binding of γ-thujaplicin and a way to optimize not only thujaplicins but also other lead compounds as specific inhibitors for human tyrosinase in a rational manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2014.08.027DOI Listing
November 2014

Short copy number variations potentially associated with tonic immobility responses in newly hatched chicks.

PLoS One 2013 25;8(11):e80205. Epub 2013 Nov 25.

Wildlife Research Center, Kyoto University, Kyoto, Japan ; Department of Anatomy, University of Otago, Dunedin, New Zealand.

Introduction: Tonic immobility (TI) is fear-induced freezing that animals may undergo when confronted by a threat. It is principally observed in prey species as defence mechanisms. In our preliminary research, we detected large inter-individual variations in the frequency and duration of freezing behavior among newly hatched domestic chicks (Gallus gallus). In this study we aim to identify the copy number variations (CNVs) in the genome of chicks as genetic candidates that underlie the behavioral plasticity to fearful stimuli.

Methods: A total of 110 domestic chicks were used for an association study between TI responses and copy number polymorphisms. Array comparative genomic hybridization (aCGH) was conducted between chicks with high and low TI scores using an Agilent 4 × 180 custom microarray. We specifically focused on 3 genomic regions (>60 Mb) of chromosome 1 where previous quantitative trait loci (QTL) analysis showed significant F-values for fearful responses.

Results: ACGH successfully detected short CNVs within the regions overlapping 3 QTL peaks. Eleven of these identified loci were validated by real-time quantitative polymerase chain reaction (qPCR) as copy number polymorphisms. Although there wkas no significant p value in the correlation analysis between TI scores and the relative copy number within each breed, several CNV loci showed significant differences in the relative copy number between 2 breeds of chicken (White Leghorn and Nagoya) which had different quantitative characteristics of fear-induced responses.

Conclusion: Our data shows the potential CNVs that may be responsible for innate fear response in domestic chicks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080205PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839970PMC
January 2015

Tandem duplications in the C-terminal domain of the mesotocin receptor exclusively identified among East Eurasian thrushes.

J Mol Evol 2013 Dec 6;77(5-6):260-7. Epub 2013 Nov 6.

Wildlife Research Center, Kyoto University, 2-24 Tanaka-Sekiden-cho, Sakyo-ku, Kyoto, 606-8203, Japan.

Mesotocin is a neurohypophyseal hormone found in some non-mammalian vertebrates, including birds, reptiles, and amphibians. In this study, we identified and characterized 18-amino acid duplications in the C-terminal domain of the mesotocin receptor (MTR), specifically found in Turdus thrushes (Aves: Passeriforms: Turdidae). These duplicated elements are located in the distal part of the C-terminal tails of MTR and consist of amino acids that are highly conserved among major vertebrates. Intraspecific polymorphisms in a variable number of tandem duplications are commonly found in East Eurasian Turdus, but not in any other genus of Turdidae. Moreover, the genus Turdus can be further classified into 2 groups according to the presence or absence of a 3-amino acid deletion just adjacent to the putative palmitoylation site in the cytoplasmic C-terminal tail. The phylogeny presented here strongly supports the conspecific group of 4 East Eurasian thrushes (Turdus pallidus, T. chrysolaus, T. obscurus, and T. celaenops). Our findings, therefore, provide a new synapomorphy that can be used for phylogenetic assumptions and shed a light on the history of diversification within Eurasian Turdus clades.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00239-013-9590-zDOI Listing
December 2013

Differences in responses to repeated fear-relevant stimuli between Nagoya and White Leghorn chicks.

Behav Processes 2013 Oct 13;99:95-9. Epub 2013 Jul 13.

Wildlife Research Center, Kyoto University, Sakyo, Kyoto 606-8203, Japan.

Freezing responses to fearful stimuli are crucial for survival among all animal species within a prey-predator system. Generally, the degree of fearfulness correlates with intensity, duration, and frequency of freezing behaviours in response to fear-relevant stimuli. The present study examines innate fear responses to human handling in 144 newly hatched chicks through a tonic immobility (TI) test. Two fear responses-freezing duration and number of TI inductions-were examined. Individual variations in innate fear were investigated in chicks 1-2 days post-hatching when the restraint procedure was successively repeated 3 times within each day. Chicks showed sensitivity to fearful stimuli and considerable inter-individual variation in freezing duration and number of attempts required to induce TI. Moreover, differences were observed between breeds; White Leghorn chicks showed relatively low fear levels with gradual increases in TI duration, whereas Nagoya chicks showed extended TI duration and habituation to fearful stimuli. Our results suggest that TI reactions among newly hatched chicks are an innately determined behaviour specific to a breed or strain of chicken. Further, fearful responses among newborn chicks are not simple, but complex behaviours that involve multiple factors, such as breed-specific contextual fear learning and habituation/sensitisation processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.beproc.2013.07.004DOI Listing
October 2013

Nitric oxide induces vascular endothelial growth factor expression in the rat placenta in vivo and in vitro.

Biosci Biotechnol Biochem 2013 7;77(5):971-6. Epub 2013 May 7.

Graduate School of Veterinary Medicine, Azabu University, Fuchinobe, Chuo-ku, Sagamihara, Japan.

We investigated the role of nitric oxide (NO) in vascular endothelial growth factor (VEGF) expression in the rat placenta. A nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine-methyl ester (L-NAME), was constantly infused into pregnant rats 6-24 h before sacrifice on gestational day (GD) 15.5. NO production declined to about 15% of the control level as monitored by NO trapping and electron paramagnetic resonance spectroscopy. VEGF mRNA expression was temporally decreased by L-NAME, but recovered to normal levels after 24 h of treatment, whereas hypoxia inducible factor (HIF)-1α and induced NOS (iNOS) expression increased. VEGF expression decreased significantly in placental explants after 6 h of co-treatment with L-NAME and lipopolysaccharide, an iNOS inducer. Our data indicate that NO induce VEGF expression in vivo and in vitro in the rat placenta, suggesting that peaked NO production was maintained by a reciprocal relationship between NO and VEGF via HIF-1α.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1271/bbb.120923DOI Listing
December 2013

Characterization of the intronic VNTR polymorphisms found in a paralog of chicken serotonin transporter gene.

Anim Sci J 2013 Apr 3;84(4):281-8. Epub 2012 Dec 3.

Wildlife Research Center, Kyoto University, Kyoto 606-8203, Japan.

Polymorphisms in the neurotransmitter-related genes can be a major source of behavioral variations. We searched for polymorphic sites in chicken neurotransmitter-related genes and identified two variable number of tandem repeat (VNTR) loci encompassing the paralog of chicken serotonin transporter gene (5-HTT). Both intronic VNTR were highly polymorphic across chicken breeds and the other Galliformes species, even though predominant alleles were considerably different among breeds. One VNTR locus contained sequences complementary to a conserved motif of CCCTC-binding factor (CTCF) within each repetitive unit, indicating that transcription of chicken 5-HTT paralog may be regulated by the CTCF protein. It is of great interest to contrast these results with previous knowledge on the human 5-HTT that also has CTCF binding sites in the repetitive units of intronic VNTR. Additionally, we measured the degree of impulsiveness in domestic chicks for their preference of immediate/small to large/delayed rewards. A significant difference in the impulsiveness score was detected between two chicken breeds (White Leghorn vs. Boris Brown; P < 0.01), as well as between White Leghorn chicks with different 5-HTT genotypes. These findings imply the possibility that 5-HTT VNTR genotypes may have some impact on chicks' impulsive choice by modifying the serotonergic neurotransmission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/asj.12011DOI Listing
April 2013