Publications by authors named "Akemi Suzuki"

112 Publications

Assessing an alpha-defensin lateral flow device for diagnosing septic arthritis: reporting on a false-negative case and a false-positive case.

Mod Rheumatol Case Rep 2020 01 28;4(1):156-160. Epub 2019 Oct 28.

Department of Orthopaedic Surgery, Faculty of Medicine, Yamagata University, Yamagata, Japan.

Alpha-defensin (αD), an antimicrobial peptide released by neutrophils in response to bacterial pathogens, was proposed as a novel diagnostic biomarker in synovial fluid. Several reports have shown that αD can serve as a reliable biomarker in the diagnosis of periprosthetic joint infection (PJI). We assessed whether αD could also serve to diagnosis of septic arthritis, a similarly difficult to diagnose PJI. To our knowledge, besides PJI, few reports exist assessing the utility of αD for septic arthritis. We have attempted to diagnose several cases of suspected septic arthritis using the Synovasure αD detection lateral flow device. We report a false-positive case and a false-negative case. The false-negative case we experienced was caused by , which is coagulase-negative, and possibly represents a low virulence micro-organism infection. The false-positive case was ultimately diagnosed as seronegative rheumatoid arthritis and possessed calcium pyrophosphate depositions. False positives have been suggested to occur in conditions where neutrophils are mobilised. As for PJI, in cases where diagnosis is difficult, αD can be an additional diagnostic indicator. However, making a definitive diagnosis using the αD lateral flow device alone was found to be difficult. The utility of αD in assessing septic arthritis is inconclusive; therefore, larger prospective clinical studies should be considered for a better assessment.
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http://dx.doi.org/10.1080/24725625.2019.1683134DOI Listing
January 2020

Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity.

EMBO J 2020 06 7;39(12):e101732. Epub 2020 May 7.

Department of Medical Biotechnology and Translational Medicine, University of Milan, Milano, Italy.

Innate immune signaling via TLR4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear. GM3 ganglioside in human serum is composed of a variety of fatty acids, including long-chain (LCFA) and very-long-chain (VLCFA). Analysis of circulating levels of human serum GM3 species from patients at different stages of insulin resistance and chronic inflammation reveals that levels of VLCFA-GM3 increase significantly in metabolic disorders, while LCFA-GM3 serum levels decrease. Specific GM3 species also correlates with disease symptoms. VLCFA-GM3 levels increase in the adipose tissue of obese mice, and this is blocked in TLR4-mutant mice. In cultured monocytes, GM3 by itself has no effect on TLR4 activation; however, VLCFA-GM3 synergistically and selectively enhances TLR4 activation by LPS/HMGB1, while LCFA-GM3 and unsaturated VLCFA-GM3 suppresses TLR4 activation. GM3 interacts with the extracellular region of TLR4/MD2 complex to modulate dimerization/oligomerization. Ligand-molecular docking analysis supports that VLCFA-GM3 and LCFA-GM3 act as agonist and antagonist of TLR4 activity, respectively, by differentially binding to the hydrophobic pocket of MD2. Our findings suggest that VLCFA-GM3 is a risk factor for TLR4-mediated disease progression.
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http://dx.doi.org/10.15252/embj.2019101732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298289PMC
June 2020

Characterization of a novel glycolipid with a difucosylated H-antigen in human blood group O erythrocytes with monoclonal antibody HMMC-1 and its detection in human uterine cervical carcinoma tissues.

Glycoconj J 2019 06 16;36(3):219-226. Epub 2019 May 16.

Laboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Health and Nutrition, 7-6-8 Asagi-Saito, Osaka, Ibaraki, 567-0085, Japan.

Humanized monoclonal antibody HMMC-1 established by immunizing transchromosomal mice with a human uterine endometrial cancer cell line has been found to react with the H-antigen carried on core l O-glycans through cotransfection of glycosyltransferases for O-glycans and inhibition of antibody-binding with synthetic oligosaccharides. However, direct binding analysis of an antibody against glycosphingolipids from human erythrocytes with different ABO blood groups revealed that it was able to bind selectively with polar glycolipids in blood group O, but not blood group A, B and AB erythrocytes. Unexpectedly, typical monofucosylated H-glycolipids, IVFucα-nLcCer and VIFucα-nLcCer, which are the precursors for A and B-glycolipids, and were present not only in blood group O, but also A, B and AB-erythrocytes, were not the antigens for the HMMC-1 antibody. The antigen comprised less than 0.001% of the total glycolipids in blood group O-erythrocytes, and was purified by conventional silica gel column chromatography. Structural determination by permethylation, GC-MS, and ESI-TOFMS demonstrated that the structure was a novel glycolipid with a difucosylated H-antigen, Fucα1-2Galβ1-4GlcNAcβ1-3Gal(2-1αFuc)β1-4GlcNAcβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glcβ1-1'Cer, VI,VIII(Fucα)-nLcCer, whose terminal difucosylated structure was the epitope of the HMMC-1 antibody. The HMMC-1 glycolipid was detected in five out of 29 tissues from patients suffering from uterine cervical carcinomas, irrespective of their ABO-blood groups.
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http://dx.doi.org/10.1007/s10719-019-09873-3DOI Listing
June 2019

Effects of Maternal Flaxseed Supplementation on Female Offspring of Diabetic Rats in Serum Concentration of Glucose, Insulin, and Thyroid Hormones.

Int J Vitam Nutr Res 2019 Jul 8;89(1-2):45-54. Epub 2019 Apr 8.

1Laboratory of Experimental Nutrition, Department of Nutrition and Dietetics, Fluminense Federal University, Rio de Janeiro, Brazil.

: This study aimed to evaluate the effect of maternal consumption of flaxseed flour and oil on serum concentrations of glucose, insulin, and thyroid hormones of the adult female offspring of diabetic rats. : Wistar rats were induced to diabetes by a high-fat diet (60%) and streptozotocin (35 mg/kg). Rats were mated and once pregnancy was confirmed, were divided into the following groups: Control Group (CG): casein-based diet; High-fat Group (HG): high-fat diet (49%); High-fat Flaxseed Group (HFG): high-fat diet supplemented with 25% flaxseed flour; High-fat Flaxseed Oil group (HOG): high-fat diet, where soya oil was replaced with flaxseed oil. After weaning, female pups (n = 6) from each group were separated, received a commercial rat diet and were sacrificed after 180 days. Serum insulin concentrations were determined by ELISA, the levels of triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone (TSH) were determined by chemiluminescence. : There was a significant reduction in body weight at weaning in HG (-31%), HFG (-33%) and HOG (44%) compared to CG (p = 0.002), which became similar by the end of 180 days. Blood glucose levels were reduced in HFG (-10%, p = 0.044) when compared to CG, and there was no significant difference between groups in relation to insulin, T3, T4, and TSH after 180 days. : Maternal severe hyperglycemia during pregnancy and lactation resulted in a microsomal offspring. Maternal consumption of flaxseed reduces blood glucose levels in adult offspring without significant effects on insulin levels and thyroid hormones.
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http://dx.doi.org/10.1024/0300-9831/a000259DOI Listing
July 2019

Overexpression of HexCer and LacCer containing 2-hydroxylated fatty acids in cholangiocarcinoma and the association of the increase of LacCer (d18:1-h23:0) with shorter survival of the patients.

Glycoconj J 2019 04 19;36(2):103-111. Epub 2019 Mar 19.

Department of Biochemistry and Research Group for Glycosciences and Glycotechnology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.

Alteration of glycosphingolipid (GSL) synthesis is observed in many types of cancer. In this study, we have analyzed the expression of sphingolipids and GSLs in cholangiocarcinoma (CCA) tissues and adjacent normal liver tissues. Neutral lipids were extracted from tissue samples using mild-alkaline treatment method followed by TLC and LC-MS analysis. The expression of ceramides, hexosylceramides (HexCer), and lactosylceramides (LacCer) was altered in CCA tissues, 61.1% (11/18) of them showing an increase whereas 38.9% (7/18) showing a decrease, compared with the adjacent normal tissue. Cers and GSLs containing 2-hydroxylated fatty acids except one LacCer molecular species were overexpressed in CCA tissues, and the increase of LacCer (d18:1-h23:0) was correlated with shorter survival of CCA patients, suggesting the involvement of GSL synthesis and fatty acid hydroxylation in progression of CCA. Taken together, we have demonstrated in this study the increase of GSL synthesis and fatty hydroxylation in CCA, which probably be used as a target for CCA treatment.
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http://dx.doi.org/10.1007/s10719-019-09864-4DOI Listing
April 2019

Globo-series glycosphingolipids enhance Toll-like receptor 4-mediated inflammation and play a pathophysiological role in diabetic nephropathy.

Glycobiology 2019 03;29(3):260-268

Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Alteration of glycosphingolipid (GSL) expression plays key roles in the pathogenesis and pathophysiology of many important human diseases, including cancer, diabetes and glycosphingolipidosis. Inflammatory processes are involved in development and progression of diabetic nephropathy, a major complication of type 2 diabetes mellitus. GSLs are known to play roles in inflammatory responses in various diseases, and levels of renal GSLs are elevated in mouse models of diabetic nephropathy; however, little is known regarding the pathophysiological role of these GSLs in this disease process. We studied proinflammatory activity of GSLs in diabetic nephropathy using spontaneously diabetic mouse strain KK. Mice were fed a high-fat diet (HFD) (60% kcal from fat) or normal diet (ND) (4.6% kcal from fat) for a period of 8 wk. HFD-feeding resulted in quantitative and qualitative changes of renal globo-series GSLs (particularly Gb3Cer), upregulation of TNF-α, and induction of renal inflammation. Gb3Cer/Gb4Cer treatment enhanced inflammatory responses via TLR4 in TLR4/MD-2 complex expressing cells, including HEK293T, mouse bone marrow-derived macrophages (BMDMs) and human monocytes. Our findings suggest that HFD-induced increase of Gb3Cer/Gb4Cer positively modulate TLR4-mediated inflammatory response, and that such GSLs play an important pathophysiological role in diabetic nephropathy.
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http://dx.doi.org/10.1093/glycob/cwy105DOI Listing
March 2019

Abnormal immunolabelling of SMAD4 in cell block specimens to distinguish malignant and benign pancreatic cells.

Cytopathology 2019 03 18;30(2):201-208. Epub 2018 Dec 18.

Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku, Tokyo, Japan.

Background: Accurate diagnosis of malignant and benign pancreatic lesions can be challenging, especially with endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) samples that are small and/or degraded. In the present study, we determined how to best evaluate abnormal SMAD4 expression by immunohistochemical staining on cell block specimens from EUS-FNA samples.

Results: In surgically resected pancreas, when abnormal SMAD4 immunolabelling was evaluated as negative SMAD4 expression, the sensitivity was low (33%), but when it was evaluated as decreased SMAD4 expression, the sensitivity improved (53%). Specificity and positive predictive value were high for both evaluations. There were no false-positive cases. In cell block specimens, decreased SMAD4 expression showed 47% sensitivity and 72% specificity, while negative SMAD4 expression showed lower sensitivity (20%) and higher specificity (100%). Both evaluations in cell block specimens showed lower sensitivity and specificity compared to resected specimens. False-positive and -negative rates were higher for cell blocks than for resected specimens.

Conclusions: Decreased SMAD4 immunolabelling provided improved sensitivity as compared to negative SMAD4 immunolabelling; therefore, it is important to compare SMAD4 expression in a sample to its expression in normal cells. Abnormal SMAD4 labelling showed low sensitivity and high specificity; therefore, SMAD4 staining using EUS-FNA samples might be helpful to detect malignancies that possess SMAD4 gene abnormalities.
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http://dx.doi.org/10.1111/cyt.12653DOI Listing
March 2019

The regulatory roles of glycosphingolipid-enriched lipid rafts in immune systems.

FEBS Lett 2018 12 27;592(23):3921-3942. Epub 2018 Oct 27.

Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Lipid rafts formed by glycosphingolipids (GSLs) on cellular membranes play important roles in innate and adaptive immunity. Lactosylceramide (LacCer) forms lipid rafts on plasma and granular membranes of human neutrophils. These LacCer-enriched lipid rafts bind directly to pathogenic components, such as pathogenic fungi-derived β-glucan and Mycobacteria-derived lipoarabinomannan via carbohydrate-carbohydrate interactions, and mediate innate immune responses to these pathogens. In contrast, a-series and o-series gangliosides form distinct rafts on CD4 and CD8 T cell subsets, respectively, contributing to the respective functions of these cells and stimulating adaptive immune responses through T cell receptors. These findings suggest that gangliosides play indispensable roles in T cell selection and activation. This Review introduces the involvement of GSL-enriched lipid rafts in innate and adaptive immunity.
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http://dx.doi.org/10.1002/1873-3468.13275DOI Listing
December 2018

Mass Spectrometry of Gangliosides.

Methods Mol Biol 2018 ;1804:207-221

Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.

This chapter describes protocols for mass spectrometry (MS) applied to the characterization of ganglioside structures and the determination of ganglioside contents. Matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) are often used to ionize biological materials and this chapter covers three protocols for atmospheric pressure MALDI MS (AP-MALDI MS), liquid chromatography-ESI MS (LC-ESI MS), and LC-ESI MS with multiple reaction monitoring (MRM). Purified gangliosides were used in AP-MALDI MS analyses while crude preparations of gangliosides were subjected to LC-ESI MS and LC-ESI MS with MRM. The LC protocol includes conditions for both reversed-phase and normal-phase column chromatography.
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http://dx.doi.org/10.1007/978-1-4939-8552-4_9DOI Listing
March 2019

Induction of ganglioside synthesis in Drosophila brain accelerates assembly of amyloid β protein.

Sci Rep 2018 05 29;8(1):8345. Epub 2018 May 29.

Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Morioka 7-430, Obu, Aichi, 474-8511, Japan.

The assembly and deposition of amyloid β protein (Aβ) is a fundamental event during the early stages of Alzheimer's disease (AD) and cerebral amyloid angiopathy. A growing body of evidence indicates that gangliosides form a pathological platform for the generation of ganglioside-bound Aβ, which facilitates the assembly of soluble Aβs; however, the molecular mechanisms underlying the binding of Aβ to gangliosides in the brain remain unclear due to the lack of an in vivo system that may address this issue. In insects, including the fruit fly Drosophila melanogaster, gangliosides are not intrinsically present at a detectable level. We herein demonstrate that ganglioside expression is inducible in Drosophila via the expression of transgenes of ganglioside synthesis enzymes and the feeding of exogenous sialic acid, and also that the induction of ganglioside synthesis significantly accelerates Aβ assembly in vivo. Our results support the hypothesis that gangliosides are responsible for Aβ assembly in vivo and also provide an opportunity to develop a valuable model for basic research as well as a therapeutic strategy for AD.
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http://dx.doi.org/10.1038/s41598-018-26294-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974419PMC
May 2018

Biology of GM3 Ganglioside.

Prog Mol Biol Transl Sci 2018 3;156:151-195. Epub 2018 Feb 3.

Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.

Since the successful molecular cloning in 1998 of GM3 synthase (GM3S, ST3GAL5), the enzyme responsible for initiating biosynthesis of all complex gangliosides, the efforts of our research group have been focused on clarifying the physiological and pathological implications of gangliosides, particularly GM3. We have identified isoforms of GM3S proteins having distinctive lengths of N-terminal cytoplasmic tails, and found that these cytoplasmic tails define subcellular localization, stability, and in vivo activity of GM3S isoforms. Our studies of the molecular pathogenesis of type 2 diabetes, focused on interaction between insulin receptor and GM3 in membrane microdomains, led to a novel concept: type 2 diabetes and certain other lifestyle-related diseases are membrane microdomain disorders resulting from aberrant expression of gangliosides. This concept has enhanced our understanding of the pathophysiological roles of GM3 and related gangliosides in various diseases involving chronic inflammation, such as insulin resistance, leptin resistance, and T-cell function and immune disorders (e.g., allergic asthma). We also demonstrated an essential role of GM3 in murine and human auditory systems; a common pathological feature of GM3S deficiency is deafness. This is the first direct link reported between gangliosides and auditory functions.
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http://dx.doi.org/10.1016/bs.pmbts.2017.10.004DOI Listing
February 2019

Recurrent patellar dislocation with spontaneous valgus knee deformity treated by distal femoral osteotomy alone: A report of two cases.

J Orthop Sci 2020 Mar 2;25(2):359-363. Epub 2017 Sep 2.

Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jos.2017.08.009DOI Listing
March 2020

The 2016 Tamio Yamakawa award.

Glycoconj J 2017 02;34(1)

Japan Consortium for Glycobiology and Glycotechnology, RIKEN, Wako, Japan.

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http://dx.doi.org/10.1007/s10719-016-9756-1DOI Listing
February 2017

N-Glycoform-dependent interactions of megalin with its ligands.

Biochim Biophys Acta Gen Subj 2017 Jan 20;1861(1 Pt A):3106-3118. Epub 2016 Oct 20.

Institute of Glycoscience, Tokai University, 4-1-1 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan; Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsusima, Aoba, Sendai, Miyagi 981-8558, Japan.

Background: Megalin is a 600-kDa single-spanning transmembrane glycoprotein and functions as an endocytic receptor, distributed not only in the kidney but also in other tissues. Structurally and functionally distinct ligands for megalin have been identified. Megalin has 30 potential N-glycosylation sites in its extracellular domain. We found that megalin interacts with its ligands in a glycoform-dependent manner.

Methods: Distribution of megalin and glycans was histochemically analyzed in mouse kidneys. Kidney absorption of Cy5-labeled ligands was examined in vivo. Megalin-ligand interactions were analyzed using ligand blotting and ELISA.

Results: Megalins expressed on renal proximal convoluted tubules (PCTs) and proximal straight tubules (PSTs) have different N-glycans. PCT megalin stained with Lens culinaris agglutinin (LCA), which recognizes core-fucosyl N-glycans catalyzed by α1,6-fucosyltransferase (Fut8). In contrast, PST megalin stained with wheat germ agglutinin (WGA), which recognizes hybrid-type N-glycans. Retinol-binding protein-Cy5 (RBP-Cy5) was endocytosed by megalin on PCTs but minimally endocytosed by PSTs. BSA-Cy5 was endocytosed nearly equally by both tubules. The purified LCA-positive glycoform megalin had higher binding activity for RBP and vitamin D-binding protein than did WGA-positive glycoform megalin. Both glycoforms had nearly the same BSA- and kanamycin-binding activities. RBP-binding analysis of megalin lacking core fucose, in Fut8 mouse kidneys, had significantly decreased binding activity.

Conclusions: N-Glycosylation of megalin can modulate its ligand-binding activity. Core fucosylation, in particular, is a modification crucial for megalin-RBP interactions.

General Significance: Cell type-specific glycoforms of megalin exist in the proximal tubular cells and modulate ligand absorption capacity.
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http://dx.doi.org/10.1016/j.bbagen.2016.10.015DOI Listing
January 2017

Probable transfusion-transmitted Zika virus in Brazil.

Transfusion 2016 07 21;56(7):1684-8. Epub 2016 Jun 21.

Hematology and Transfusion Center, Universidade Estadual de Campinas-UNICAMP, Campinas, SP, Brazil.

Background: Zika virus (ZIKV) is an emerging arthropod-borne flavivirus transmitted by Aedes mosquitoes. Recent commentaries regarding ZIKV routes of transmission describe a potential transmission by transfusion. Herein, we report a probable case of transfusion-transmitted ZIKV infection through a platelet transfusion that was detected from postdonation information.

Case Report: A blood donor made a voluntary telephone report to the blood donor facility 3 days after donation and informed the facility of a febrile illness (fever, malaise, and headaches). Due to the ongoing dengue epidemic, the initial clinical investigation included dengue among other possible diagnoses. The serology and molecular laboratory results excluded dengue infection. However, stored samples from the donation were positive for ZIKV on reverse transcription-polymerase chain reaction (RT-PCR) analysis. A retrospective investigation demonstrated that the platelet concentrate, which was part of a pool, had been transfused after a liver transplantation. A physician had evaluated the patient 4 days after surgery. Laboratory investigation showed enzyme-linked immunosorbent assay results that were negative for dengue immunoglobulin M antibodies; however, the results were positive for hemagglutination inhibition antibodies against flavivirus. ZIKV RT-PCR and virus isolation analyses in cell cultures from recipient serum were both positive. The sequencing confirmed ZIKV in the donor and patient samples. Ten partial nucleotide sequences from the ZIKV strain that were detected in the donor were aligned and compared with the ZIKV genome detected in the recipient, revealing a 99.8% homology between the two strains.

Conclusions: This is a case of probable transmission of ZIKV through blood transfusion. The patient had been transfused with the blood product from an infected donor, most likely in the incubation period after ZIKV infection but prior to clinical disease onset. This report emphasizes the importance of postdonation information and recipient investigations during outbreaks of potentially blood-borne infections.
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http://dx.doi.org/10.1111/trf.13681DOI Listing
July 2016

Zika virus in the Americas: Early epidemiological and genetic findings.

Science 2016 Apr 24;352(6283):345-349. Epub 2016 Mar 24.

Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Pará State, Brazil.

Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015, and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. We performed next-generation sequencing to generate seven Brazilian ZIKV genomes sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Results of phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, which we estimated to have occurred between May and December 2013, more than 12 months before the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV-endemic areas, as well as with reported outbreaks in the Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however, no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this correlation does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology of this emerging virus in the Americas.
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http://dx.doi.org/10.1126/science.aaf5036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918795PMC
April 2016

First Complete Genome Sequence of Zika Virus (Flaviviridae, Flavivirus) from an Autochthonous Transmission in Brazil.

Genome Announc 2016 Mar 3;4(2). Epub 2016 Mar 3.

Department of Internal Medicine, Division of Infectious Diseases, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

We report here the genome sequence of Zika virus, strain ZikaSPH2015, containing all structural and nonstructural proteins flanked by the 5' and 3' untranslated region. It was isolated in São Paulo state, Brazil, in 2015, from a patient who received a blood transfusion from an asymptomatic donor at the time of donation.
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http://dx.doi.org/10.1128/genomeA.00032-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777745PMC
March 2016

Immunization of A4galt-deficient mice with glycosphingolipids from renal cell cancers resulted in the generation of anti-sulfoglycolipid monoclonal antibodies.

Glycoconj J 2016 Apr 16;33(2):169-80. Epub 2016 Feb 16.

Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-0065, Japan.

In this study, we immunized Gb3/CD77 synthase gene (A4galt) knockout (KO) mice with glycosphingolipids (GSLs) extracted from 3 renal cell cancer (RCC) cell lines to raise monoclonal antibodies (mAbs) reactive with globo-series GSLs specifically expressed in RCCs. Although a number of mAbs reactive with globo-series GSLs were generated, they reacted with both RCC cell lines and normal kidney cells. When we analyzed recognized antigens by mAbs that were specifically reactive with RCC, but not with normal kidney cells at least on the cell surface, many of them turned out to be reactive with sulfoglycolipids. Eight out of 11 RCC-specific mAbs were reactive with SM2 alone, and the other 3 mAbs were more broadly reactive with sulfated glycolipids, i.e. SM3 and SM4 as well as SM2. In the immunohistochemistry, these anti-sulfoglycolipids mAbs showed RCC-specific reaction, with no or minimal reaction with adjacent normal tissues. Thus, immunization of A4galt KO mice with RCC-derived GSLs resulted in the generation of anti sulfated GSL mAbs, and these mAbs may be applicable for the therapeutics for RCC patients.
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http://dx.doi.org/10.1007/s10719-016-9654-6DOI Listing
April 2016

Pinhal Virus, a New Arenavirus Isolated from Calomys tener in Brazil.

Vector Borne Zoonotic Dis 2015 Nov 26;15(11):694-700. Epub 2015 Oct 26.

3 Faculdade de Medicina de Ribeirão Preto-Ribeirão Preto/SP , Brazil .

Arenavirus Sabiá was originally isolated from a fatal human infection in Brazil, and after the occurrence of the second fatal human case in São Paulo state, epidemiologic and virologic studies were performed in the area where the patient lived, aiming at the identification of the Sabiá natural rodent reservoir. A broadly cross-reactive enzyme-linked immunosorbent assay (ELISA) was used to screen for antibody-positive samples. Antibodies to arenavirus were detected in two of the 55 samples of Calomys tener, and from these results, samples of rodents were analyzed by a broad RT-PCR assay. RT-PCR amplification detected arenavirus sequences in five of the 55 C. tener samples, and sequencing showed that this virus is a distinct form of Sabiá virus. Thus, we describe here the evidence for the circulation of a new arenavirus in Brazil (proposed name Pinhal virus) and its genetic characterization compared to other arenaviruses. This study also suggests C. tener as a probable rodent reservoir for this virus and associates this new virus with the lineage C of New World arenaviruses. Although we have defined some characteristics of this virus, so far, there is no evidence of its involvement in human disease.
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http://dx.doi.org/10.1089/vbz.2014.1708DOI Listing
November 2015

Clinicopathological Features of 15 Occult and 178 Clinical Pancreatic Ductal Adenocarcinomas in 8339 Autopsied Elderly Patients.

Pancreas 2016 Feb;45(2):234-40

From the *Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku; †Department of Pathology and Integrative Oncological Pathology, Nippon Medical School, Bunkyo-ku; ‡Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku; and §Research Team for Geriatric Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku, Tokyo, Japan.

Objective: The aim of the study was to investigate the clinicopathological features of pancreatic cancer at different stages using autopsy results.

Methods: We retrospectively evaluated 8399 consecutive cases of autopsy performed between 1972 and 2013 at our geriatric hospital.

Results: Macroscopic pancreatic lesions were detected in 6.13% of the cases. Primary and secondary pancreatic tumors were observed in 2.88% and 2.10% of the cases, respectively. Most primary tumors were invasive ductal adenocarcinomas (193 cases [2.31%]; mean patient age, 78.09 years) with a peak incidence at 50 to 59 years. Occult invasive ductal adenocarcinoma was discovered incidentally in 15 cases, with distant metastasis present in 26.67% of those. Microscopically, occult and advanced tumors exhibited similar characteristics such as hyalinized fibrous stroma, necrosis, invasion into vessels, peripancreatic fat tissues, and extrapancreatic nerve plexus. Mucin 1 and 2 immunohistochemical expression levels were also similar. Occult cancer incidence increased with age. Patients aged 85 years or older had shorter survival, a small tumor size, and a low incidence of lymph node metastasis. Approximately 8% of pancreatic invasive ductal adenocarcinomas progressed asymptomatically and were discovered incidentally at autopsy.

Conclusions: Pancreatic cancers in elderly patients tend to progress asymptomatically, but once symptoms develop, they are more often fatal than those in younger patients.
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http://dx.doi.org/10.1097/MPA.0000000000000447DOI Listing
February 2016

Identification of Ganglioside GM3 Molecular Species in Human Serum Associated with Risk Factors of Metabolic Syndrome.

PLoS One 2015 23;10(6):e0129645. Epub 2015 Jun 23.

Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, Sendai, Japan.

Serum GM3 molecular species were quantified in 125 Japanese residents using tandem mass spectrometry multiple reaction monitoring. Individuals were categorized by the presence or absence of metabolic disease risk factors including visceral fat accumulation, hyperglycemia and dyslipidemia. A total of 23 GM3 molecular species were measured, of these, eight were found to be significantly elevated in individuals with visceral fat accumulation and metabolic disease, defined as the presence of hyperglycemia and dyslipidemia. All of the GM3 molecular species were composed of the sphingoid base sphingosine (d18:1 (Δ4)) and, interestingly, six of the eight elevated GM3 molecular species contained a hydroxylated ceramide moiety. The hydroxylated GM3 species were, in order of decreasing abundance, d18:1-h24:0 ≈ d18:1-h24:1 > d18:1-h22:0 » d18:1-h20:0 > d18:1-h21:0 > d18:1-h18:1. Univariate and multiple linear regression analyses were conducted using a number of clinical health variables associated with obesity, type 2 diabetes, metabolic disease, atherosclerosis and hypertension. GM3(d18:1-h24:1) was identified as the best candidate for metabolic screening, proving to be significantly correlated with intima-media thickness, used for the detection of atherosclerotic disease in humans, and a number of metabolic disease risk factors including autotaxin, LDL-c and homeostatic model assessment insulin resistance (HOMA-IR).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129645PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477979PMC
April 2016

Maternal use of flaxseed oil during pregnancy and lactation prevents morphological alterations in pancreas of female offspring from rat dams with experimental diabetes.

Int J Exp Pathol 2015 Apr 25;96(2):94-102. Epub 2015 Mar 25.

Laboratory of Experimental Nutrition, Department of Nutrition and Dietetics, Nutrition College, Fluminense Federal University, Niterói, Brazil.

Nutritional recommendations have promoted the increased need to consume n-3 polyunsaturated fatty acids. Flaxseed is the richest dietary source of n-3 fatty acids among plant sources and is widely used for its edible oil. This study aimed to investigate whether maternal use of flaxseed oil has effects on pancreas morphology in the female offspring of diabetic mothers. Female Wistar rats (n = 12) were induced into diabetes by a high-fat diet and low dose of streptozotocin. After confirmation of the diabetes, rats were mated, and once pregnancy was confirmed, they were allocated into three groups (n = 6): high-fat group (HG); flaxseed oil group (FOG); and control group (CG) (non-diabetic rats). At weaning, female offspring (n = 6/group) received standard chow diet. The animals were euthanized at 180 days. Pancreas was collected for histomorphometric and immunohistochemistry analysis. HG showed hypertrophy of pancreatic islets (P < 0.0001), whereas FOG offspring had islets with smaller diameters compared to HG (P < 0.0001). HG offspring showed higher percentage of larger (P = 0.0061) and lower percentage of smaller islets (P = 0.0036). HG showed lower islet insulin immunodensity at 180 days (P < 0.0001), whereas FOG was similar to CG (P < 0.0001). Flaxseed oil reduced the damage caused by maternal hyperglycaemia, promoting normal pancreas histomorphometry and β-cell mass in female offspring.
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http://dx.doi.org/10.1111/iep.12126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459801PMC
April 2015

Imbalance in fatty-acid-chain length of gangliosides triggers Alzheimer amyloid deposition in the precuneus.

PLoS One 2015 23;10(3):e0121356. Epub 2015 Mar 23.

Department of Drug Discovery, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Aichi, Japan; Department of Alzheimer's Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Aichi, Japan.

Amyloid deposition, a crucial event of Alzheimer's disease (AD), emerges in distinct brain regions. A key question is what triggers the assembly of the monomeric amyloid ß-protein (Aß) into fibrils in the regions. On the basis of our previous findings that gangliosides facilitate the initiation of Aß assembly at presynaptic neuritic terminals, we investigated how lipids, including gangliosides, cholesterol and sphingomyelin, extracted from synaptic plasma membranes (SPMs) isolated from autopsy brains were involved in the Aß assembly. We focused on two regions of the cerebral cortex; precuneus and calcarine cortex, one of the most vulnerable and one of the most resistant regions to amyloid deposition, respectively. Here, we show that lipids extracted from SPMs isolated from the amyloid-bearing precuneus, but neither the amyloid-free precuneus nor the calcarine cortex, markedly accelerate the Aß assembly in vitro. Through liquid chromatography-mass spectrometry of the lipids, we identified an increase in the ratio of the level of GD1b-ganglioside containing C20:0 fatty acid to that containing C18:0 as a cause of the enhanced Aß assembly in the precuneus. Our results suggest that the local glycolipid environment play a critical role in the initiation of Alzheimer amyloid deposition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121356PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370507PMC
February 2016

Ganglioside GM3 is essential for the structural integrity and function of cochlear hair cells.

Hum Mol Genet 2015 May 4;24(10):2796-807. Epub 2015 Feb 4.

Division of Glycopathology, Institute of Molecular Biomembranes and Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Aoba-ku, Sendai, Miyagi 981-8558, Japan,

GM3 synthase (ST3GAL5) is the first biosynthetic enzyme of a- and b-series gangliosides. Patients with GM3 synthase deficiency suffer severe neurological disability and deafness. Eight children (ages 4.1 ± 2.3 years) homozygous for ST3GAL5 c.694C>T had no detectable GM3 (a-series) or GD3 (b-series) in plasma. Their auditory function was characterized by the absence of middle ear muscle reflexes, distortion product otoacoustic emissions and cochlear microphonics, as well as abnormal auditory brainstem responses and cortical auditory-evoked potentials. In St3gal5(-/-) mice, stereocilia of outer hair cells showed signs of degeneration as early as postnatal Day 3 (P3); thereafter, blebs devoid of actin or tubulin appeared at the region of vestigial kinocilia, suggesting impaired vesicular trafficking. Stereocilia of St3gal5(-/-) inner hair cells were fused by P17, and protein tyrosine phosphatase receptor Q, normally linked to myosin VI at the tapered base of stereocilia, was maldistributed along the cell membrane. B4galnt1(-/-) (GM2 synthase-deficient) mice expressing only GM3 and GD3 gangliosides had normal auditory structure and function. Thus, GM3-dependent membrane microdomains might be essential for the proper organization and maintenance of stereocilia in auditory hair cells.
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http://dx.doi.org/10.1093/hmg/ddv041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425844PMC
May 2015

Maternal exposure to diets containing flaxseed flour or flaxseed oil during pregnancy and lactation protects the aortic remodeling in adult male offspring of diabetic rat dams.

J Sci Food Agric 2015 Nov 5;95(14):2973-80. Epub 2015 Jan 5.

Laboratory of Experimental Nutrition (LabNE), College of Nutrition, Federal Fluminense University (UFF), Niterói, RJ, Brazil.

Background: Diabetes during pregnancy is associated with cardiovascular complications in the fetus and extends into adulthood. Therapeutic applications of flaxseed have been studied in cardiovascular disorders, because its oilseed is the best plant source of omega-3 fatty acid, which is currently considered by researchers to be an essential protective against cardiovascular disease. The aim of this study was to evaluate the influence of flaxseed flour and oil on cardiovascular biochemical parameters and the histoarchitecture of the aorta in adult rats which were offspring of diabetic mothers.

Results: At 100 days of age in offspring it was observed that maternal consumption of a high-fat diet containing flaxseed oil (FOG) and flaxseed flour (FFG) did not affect the serum concentration of monocyte chemoattractant protein-1, vascular endothelial growth factor, cholesterol, triglycerides, high-density-, low-density- or very-low-density-lipoprotein cholesterol. However, the thickness of the intima media layer of the aorta was significantly smaller in FOG and FFG groups; the lumen area was similar among the groups; and a higher percentage of elastic fiber was found in FOG and FFG groups.

Conclusion: These data suggest that the use of both flaxseed flour and its oil reduces the remodeling of the aorta; however; it has not been possible to modify the cardiovascular biochemical parameters.
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http://dx.doi.org/10.1002/jsfa.7041DOI Listing
November 2015

Effect of maternal use of flaxseed oil during pregnancy and lactation on glucose metabolism and pancreas histomorphometry of male offspring from diabetic rats.

Diabetes Res Clin Pract 2014 Dec 5;106(3):634-42. Epub 2014 Oct 5.

Laboratory of Experimental Nutrition, Department of Nutrition and Dietetics, Nutrition College, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil.

Aim: Investigate if the maternal use of flaxseed oil prevents pancreatic alterations in the offspring of diabetic mothers.

Methods: Diabetes was induced in female wistar rats (n=12) by a high-fat diet and low-dose of streptozotocin. After the confirmation of the diabetes (glucose >300 mg/dL), rats were mated and once pregnancy was confirmed, they were allocated into three groups (n=6): high-fat group (HFG); flaxseed oil group (FOG); and control group (CG) (nondiabetic rats). At weaning, male offspring (n=12/group) received a standard chow diet. The animals were euthanized in two phases: at 100 and at 180 days, (n=6/group). The pancreas was collected for histomorphometric and immunohistochemistry analysis.

Results: HFG showed hypertrophy of pancreatic islets at 100 and at 180 days (p<0.0001), while the FOG offspring had islets with smaller diameters compared to HFG at both phases of sacrifice (p<0.0001). HFG had a lower percentage of small islets when compared to CG and FOG, which had a higher percentage when compared to HFG (p=0.0053) at 100 days. At 180 days HFG showed higher percentage of larger islets (p=0.00137) and lower percentage of smaller islets (p=0.00112), when compared to FOG. HFG showed lower islet insulin immunodensity at 100 days (p<0.0001) and 180 days (p<0.0001), whereas FOG was similar to CG (p<0.0001) at 100 days and higher at 180 days (p<0.0001).

Conclusions: Flaxseed oil reduced the damage caused by maternal hyperglycemia, promoting normal pancreas histomorphometry and β cell mass.
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http://dx.doi.org/10.1016/j.diabres.2014.09.022DOI Listing
December 2014

The use of flaxseed flour during pregnancy and lactation reverses lower birth weight in offspring from diabetic mothers but averts the development during lactation.

Nutr Hosp 2014 Oct 1;30(4):831-6. Epub 2014 Oct 1.

Laboratory of Experimental Nutrition. Federal Fluminense University, Rio de Janeiro, Brazil..

Unlabelled: Diabetes is a complication which occurring during gestation might substantially influence the development of offspring during fetal life and postnatally. Flaxseed is a source of omega-3, that the appropriate supply during gestation and lactation are determinant for a suitable perinatal growth and development. The present study aimed to assess beneficial effects of the use of flaxseed flour during pregnancy and lactation on body development from birth to weaning of offspring from diabetic mothers.

Methods: twelve rats from a total of eighteen were induced to diabetes by high-fat diet during four weeks, also receiving one lower dose of streptozotocin. After confirmation of diabetes (glucose>300 mg/dL), they were mated and when pregnancy was confirmed, they were divided in 3 groups: high-fat group (HFG), high-fat flaxseed flour group (HFFFG) and control group (CG), receiving high- fat diet, high-fat diet added flaxseed flour and control diet, respectively. They were fed this way during whole gestation and lactation. The body development of offspring was measured weekly since the first day after birth until weaning.

Results: At birth, the average body mass of offspring from diabetics mothers who received only high-fat diet was 23,6% lighter than body mass of offspring from non-diabetics mothers (p<0,05), while the animals from diabetic mothers who consumed flaxseed flour during pregnancy and lactation showed the same body mass than the control group. During all experiment HFFFG group showed decreased body mass (about 20%, p<0,05)in comparison with control group.

Conclusion: The treatment with flaxseed flour was capable of avoiding lower birth weight in offspring from diabetic mothers. However, the consumption of flaxseed flour by mothers during lactation yielded decrease offspring weight at weaning.
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http://dx.doi.org/10.3305/nh.2014.30.4.7637DOI Listing
October 2014

Distinct selectivity of gangliosides required for CD4⁺ T and CD8⁺ T cell activation.

Biochim Biophys Acta 2015 Jan 3;1851(1):98-106. Epub 2014 Sep 3.

Institute of Glycoscience, Tokai University, Hiratsuka, Kanagawa 259-1292, Japan.

T cells compose a crucial part of the immune system and require activation. The first step of T cell activation is triggered by the movement of one of their surface molecules, known as T cell receptor, into localized regions of cell membrane known as lipid rafts. Molecules called gangliosides are known to be major components of lipid rafts, but their role in T-cell activation remains to be elucidated. This review summarizes recent findings that different types of T cells require distinct ganglioside types for the activation. Control of ganglioside expression would offer a strategy targeting for specific T-cell subpopulations to treat immune diseases. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics.
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http://dx.doi.org/10.1016/j.bbalip.2014.07.013DOI Listing
January 2015

[Yellow fever: reemerging in the state of Sao Paulo, Brazil, 2009].

Rev Saude Publica 2013 Oct;47(5):881-9

Objective: To describe the investigation of a sylvatic yellow fever outbreak in the state of Sao Paulo and the main control measures undertaken.

Methods: This is a descriptive study of a sylvatic yellow fever outbreak in the Southwestern region of the state from February to April 2009. Suspected and confirmed cases in humans and in non-human primates were evaluated. Entomological investigation in sylvatic environment involved capture at ground level and in the tree canopy to identify species and detect natural infections. Control measures were performed in urban areas to control Aedes aegypti . Vaccination was directed at residents living in areas with confirmed viral circulation and also at nearby cities according to national recommendation.

Results: Twenty-eight human cases were confirmed (39.3% case fatality rate) in rural areas of Sarutaiá, Piraju, Tejupá, Avaré and Buri. The deaths of 56 non-human primates were also reported, 91.4% were Allouatta sp. Epizootics was confirmed in two non-human primates in the cities of Itapetininga and Buri. A total of 1,782 mosquitoes were collected, including Haemagogus leucocelaenus , Hg. janthinomys/capricornii , and Sabethes chloropterus, Sa. purpureus and Sa. undosus . Yellow fever virus was isolated from a group of Hg. Leucocelaenus from Buri. Vaccination was carried out in 49 cities, with a total of 1,018,705 doses. Nine serious post-vaccination adverse events were reported.

Conclusions: The cases occurred between February and April 2009 in areas with no recorded yellow fever virus circulation in over 60 years. The outbreak region occurred outside the original recommended vaccination area with a high percentage of susceptible population. The fast adoption of control measures interrupted the human transmission within a month and the confirmation of viral circulation in humans, monkeys and mosquitoes. The results allowed the identification of new areas of viral circulation but further studies are required to clarify the dynamics of the spread of this disease.
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http://dx.doi.org/10.1590/s0034-8910.2013047004341DOI Listing
October 2013

Influence of APOE genotype and the presence of Alzheimer's pathology on synaptic membrane lipids of human brains.

J Neurosci Res 2014 May 21;92(5):641-50. Epub 2014 Jan 21.

Department of Drug Discovery, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Japan.

The APOE genotype is the major risk factor for Alzheimer's disease (AD); however, it remains unclarified how the ε4 allele accelerates whereas the ε2 allele suppresses AD development, compared with the more common ε3 allele. On the basis of the previous finding that the assembly of the amyloid-β protein (Aβ) into fibrils in the brain, an early and invariable pathological feature of AD, depends on the lipid environment, we determined the levels of synaptic membrane lipids in aged individuals of different APOE genotypes. In the comparison between amyloid-free ε2/ε3 and ε3/ε3 brains, the presence of the ε2 allele significantly decreased the level of cholesterol. Alternatively, in the comparison among ε3/ε3 brains, the presence of AD pathology substantially decreased the levels of cholesterol. This study suggests that the ε2 allele suppresses the initiation of AD development by lowering the cholesterol levels in synaptic membranes.
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http://dx.doi.org/10.1002/jnr.23341DOI Listing
May 2014
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