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Renata S, Verma N, Peddinti RK. Surface-enhanced Raman spectroscopy as effective tool for detection of sialic acid as cancer biomarker. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 329:125631. [PMID: 39736186 DOI: 10.1016/j.saa.2024.125631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 12/07/2024] [Accepted: 12/17/2024] [Indexed: 01/01/2025]
Abstract
Sialic acid, a negatively charged nine-carbon monosaccharide, is mainly located at the terminal end of glycan chains on glycoproteins and glycolipids of cell surface and most secreted proteins. Elevated levels of sialylated glycans have been known as a hallmark in numerous cancers. As a result, sialic acid acts as a useful and accessible cancer biomarker for early cancer detection and monitoring the disease development during cancer treatment which is crucial in elevating the survival rate. The detection of sialic acid has been done by many tools including surface-enhanced Raman spectroscopy (SERS) which gained incredible attention due to its high selectivity and sensitivity. However, currently, comprehensive reviews of sialic acid detection and imaging as a cancer biomarker using SERS are still lacking. Here, we present the significant breakthroughs in SERS-based detection of sialic acid levels on cells, tissues, and body fluids due to the presence of cancer, different cancer metastasis stages, and in response to the external stimuli. This review covers the SERS substrate and novel SERS strategies, using lectin, boronic acid, metabolic glycan labelling and label-free methods, for sialic acid detection as cancer biomarker. The remaining challenges to detect sialic acid and prospect of future development of SERS for other carbohydrate-based cancer biomarker, for instance fucose, are also discussed.
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Affiliation(s)
- Septila Renata
- Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India.
| | - Nitish Verma
- Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India; Department of Chemistry, University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190 Vienna, Austria
| | - Rama Krishna Peddinti
- Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India.
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Goyal P, Dhanabalan K, Scalise M, Friemann R, Indiveri C, Dobson RCJ, Vinothkumar KR, Ramaswamy S. Molecular determinants of Neu5Ac binding to a tripartite ATP independent periplasmic (TRAP) transporter. eLife 2025; 13:RP98158. [PMID: 39912804 PMCID: PMC11801797 DOI: 10.7554/elife.98158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2025] Open
Abstract
N -Acetylneuraminic acid (Neu5Ac) is a negatively charged nine-carbon amino sugar that is often the peripheral sugar in human cell-surface glycoconjugates. Some bacteria scavenge, import, and metabolize Neu5Ac or redeploy it on their cell surfaces for immune evasion. The import of Neu5Ac by many bacteria is mediated by tripartite ATP-independent periplasmic (TRAP) transporters. We have previously reported the structures of SiaQM, a membrane-embedded component of the Haemophilus influenzae TRAP transport system, (Currie et al., 2024). However, none of the published structures contain Neu5Ac bound to SiaQM. This information is critical for defining the transport mechanism and for further structure-activity relationship studies. Here, we report the structures of Fusobacterium nucleatum SiaQM with and without Neu5Ac. Both structures are in an inward (cytoplasmic side) facing conformation. The Neu5Ac-bound structure reveals the interactions of Neu5Ac with the transporter and its relationship with the Na+ binding sites. Two of the Na+-binding sites are similar to those described previously. We identify a third metal-binding site that is further away and buried in the elevator domain. Ser300 and Ser345 interact with the C1-carboxylate group of Neu5Ac. Proteoliposome-based transport assays showed that Ser300-Neu5Ac interaction is critical for transport, whereas Ser345 is dispensable. Neu5Ac primarily interacts with residues in the elevator domain of the protein, thereby supporting the elevator with an operator mechanism. The residues interacting with Neu5Ac are conserved, providing fundamental information required to design inhibitors against this class of proteins.
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Affiliation(s)
- Parveen Goyal
- Biochemical Sciences Division, CSIR-National Chemical LaboratoryPuneIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
- Institute for Stem Cell Science and Regenerative MedicineBengaluruIndia
| | | | - Mariafrancesca Scalise
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of CalabriaArcavacata di RendeItaly
| | - Rosmarie Friemann
- Centre for Antibiotic Resistance Research (CARe) at University of GothenburgGothenburgSweden
| | - Cesare Indiveri
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of CalabriaArcavacata di RendeItaly
- CNR, Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), via AmendolaBariItaly
| | - Renwick CJ Dobson
- Biomolecular Interaction Centre, Maurice Wilkins Centre for Biodiscovery, MacDiarmid Institute for Advanced Materials and Nanotechnology, and School of Biological Sciences, University of CanterburyChristchurchNew Zealand
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, ParkvilleMelbourneAustralia
| | - Kutti R Vinothkumar
- National Centre for Biological Sciences TIFR, GKVK Campus, Bellary RoadBengaluruIndia
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Ng MP, Chan WC, Tan ML, Tan CH, Tiong SYX, Sim KS, Tan KW. Sialic acid detection and theranostic activity of phenylboronic acid-based fluorescent probe in human colorectal adenocarcinoma HT-29 cells. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 325:125116. [PMID: 39276466 DOI: 10.1016/j.saa.2024.125116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 09/02/2024] [Accepted: 09/07/2024] [Indexed: 09/17/2024]
Abstract
A new probe, 4-(((3',6'-bis(diethylamino)-3-oxospiro[isoindoline-1,9'-xanthen]-2-yl)imino)methyl)phenyl)boronic acid (R4B) was prepared by facile condensation of 4-formylphenylboronic acid and rhodamine B hydrazide. R4B was characterized by spectroscopic methods and single crystal X-ray diffraction. The sensor R4B solution turned pink and emitted orange fluorescence only in the presence of sialic acid but remained colorless and non-fluorescent otherwise. The sugar recognition performance was investigated via UV-vis and fluorescence spectroscopic studies. Our results revealed that R4B has good affinity and selectivity for sialic acid over common monosaccharides, with a detection limit as low as 10-7 M. Furthermore, R4B selectively inhibited growth of human colorectal adenocarcinoma HT-29 (IC50 <20 µM) without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with R4B suppressed HT-29 colony formation via mitochondrial apoptosis in a time-dependent manner. Cellular imaging studies also revealed the ability of R4B as a fluorescence dye to detect intracellular sialic acid and showed mitochondria-tracking ability in HT-29 cells. In summary, R4B is a potential theranostic for the detection of intracellular sialic acid during the early incubation period, followed by induction of cancer apoptotic cell death at a later treatment point.
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Affiliation(s)
- Min Phin Ng
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Wei Chuen Chan
- School of Foundation Studies, Xiamen University Malaysia, Bandar Serenia, 43900 Sepang, Selangor, Malaysia
| | - Min Li Tan
- Department of Chemistry, Faculty of Science, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Chun Hoe Tan
- Department of Biotechnology, Faculty of Applied Sciences, Lincoln University College, 47301 Petaling Jaya, Selangor, Malaysia
| | - Sheena Yin Xin Tiong
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, 50603 Kuala Lumpur, Malaysia; Molecular Brain Science, Division of Developmental Neuroscience, Department of Child Development, United Graduate School of Child Development (UGSCD), Osaka University, Suita, Japan
| | - Kae Shin Sim
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Kong Wai Tan
- Department of Chemistry, Faculty of Science, Universiti Malaya, 50603 Kuala Lumpur, Malaysia.
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Hunter CD, Cairo CW. Detection Strategies for Sialic Acid and Sialoglycoconjugates. Chembiochem 2024; 25:e202400402. [PMID: 39444251 DOI: 10.1002/cbic.202400402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 08/01/2024] [Indexed: 10/25/2024]
Abstract
Glycoconjugates are a vast class of biomolecules implicated in biological processes important for human health and disease. The structural complexity of glycoconjugates remains a challenge to deciphering their precise biological roles and for their development as biomarkers and therapeutics. Human glycoconjugates on the outside of the cell are modified with sialic (neuraminic) acid residues at their termini. The enzymes that install sialic acids are sialyltransferases (SiaTs), a family of 20 different isoenzymes. The removal and degradation of sialic acids is mediated by neuraminidase (NEU; sialidase) enzymes, of which there are four isoenzymes. In this review, we discuss chemical and biochemical approaches for the detection and analysis of sialoglycoconjugate (SGC) structures and their enzymatic products. The most common methods include affinity probes and synthetic substrates. Fluorogenic and radiolabelled substrates are also important tools for many applications, including screening for enzyme inhibitors. Strategies that give insight into the native substrate-specificity of enzymes that regulate SGCs (SiaT & NEU) are necessary to improve our understanding of the role of sialic acid metabolism in health and disease.
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Affiliation(s)
- Carmanah D Hunter
- Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada
| | - Christopher W Cairo
- Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada
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Kanagaraj R, Krishnan V, Senthil Kumar S, Veerapandian M. β-Cyclodextrin-Tethered Butein, a Greener Redox-Active Biomaterial for Electrochemical Enzymatic Sensing of Sialic Acid. ACS APPLIED BIO MATERIALS 2024; 7:4602-4610. [PMID: 38869946 DOI: 10.1021/acsabm.4c00474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2024]
Abstract
Biocompatible, industrially scalable, and opto/electrochemically active biomaterials are promising for biosensor platform design and application. Herein, cyclic oligosaccharide, β-cyclodextrin (BCD), is conjugated with Butein, a chalcone-type polyphenol, via dehydration reaction of the hydroxyl groups of BCD and the benzoyl ring of Butein. Functional group changes in the conjugated BCD-Butein were comprehensively studied using UV-visible absorbance, Fourier transform-infrared, and X-ray photoelectron spectroscopic techniques. The electrochemical characteristics of BCD-Butein were explored using cyclic voltammetry, showing the reversible redox behavior (2e-/2H+) attributed to the catecholic OH group of Butein. The BCD-Butein-modified electrode exhibits a surface-confined redox process (R2 = 0.99, Ipa and Ipc) at the interface, suitable for external mediatorless sensor studies. An enzymatic biomolecular sensor has been constructed using BCD-Butein-modified glassy carbon and a screen-printed electrode targeting sialic acid as the model clinical biomarker. With the enzyme sialic acid aldolase, BCD-Butein-modified substrate exhibited a selective conversion of sialic acid to N-acetyl-d-mannosamine and pyruvate, with a wide linear detection range (1-100 nM), the lowest detection limit of 0.2 nM, and a quantification limit of 0.69 nM, convenient for clinical threshold diagnosis.
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Affiliation(s)
- Ramya Kanagaraj
- Electrodics and Electrocatalysis Division, CSIR-Central Electrochemical Research Institute (CECRI), Karaikudi 630 003, Tamil Nadu, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201 002, India
| | - Vinoth Krishnan
- Electrodics and Electrocatalysis Division, CSIR-Central Electrochemical Research Institute (CECRI), Karaikudi 630 003, Tamil Nadu, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201 002, India
| | - Shanmugam Senthil Kumar
- Electrodics and Electrocatalysis Division, CSIR-Central Electrochemical Research Institute (CECRI), Karaikudi 630 003, Tamil Nadu, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201 002, India
| | - Murugan Veerapandian
- Electrodics and Electrocatalysis Division, CSIR-Central Electrochemical Research Institute (CECRI), Karaikudi 630 003, Tamil Nadu, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201 002, India
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Sebzda T, Karwacki J, Cichoń A, Modrzejewska K, Heimrath J, Łątka M, Gnus J, Gburek J. Association of Serum Proteases and Acute Phase Factors Levels with Survival Outcomes in Patients with Colorectal Cancer. Cancers (Basel) 2024; 16:2471. [PMID: 39001534 PMCID: PMC11240471 DOI: 10.3390/cancers16132471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 06/27/2024] [Accepted: 07/03/2024] [Indexed: 07/16/2024] Open
Abstract
Colorectal cancer (CRC) represents a substantial burden on global healthcare, contributing to significant morbidity and mortality worldwide. Despite advances in screening methodologies, its incidence remains high, necessitating continued efforts in early detection and treatment. Neoplastic invasion and metastasis are primary determinants of CRC lethality, emphasizing the urgency of understanding underlying mechanisms to develop effective therapeutic strategies. This study aimed to explore the potential of serum biomarkers in predicting survival outcomes in CRC patients, with a focus on cathepsin B (CB), leukocytic elastase (LE), total sialic acid (TSA), lipid-associated sialic acid (LASA), antitrypsin activity (ATA), C-reactive protein (CRP), and cystatin C (CC). We recruited 185 CRC patients and 35 healthy controls, assessing demographic variables, tumor characteristics, and 7 serum biomarker levels, including (1) CB, (2) LE, (3) TSA, (4) LASA, (5) ATA, (6) CRP, and (7) CC. Statistical analyses included ANOVA with Tukey's post hoc tests and MANOVA for continuous variables. Student's t-test was used for dependent samples, while non-parametric tests like Mann-Whitney U and Wilcoxon signed-rank tests were applied for variables deviating from the normal distribution. Categorical variables were assessed using chi-square and Kruskal-Wallis tests. Spearman's rank correlation coefficient was utilized to examine variable correlations. Survival analysis employed the Kaplan-Meier method with a log-rank test for comparing survival times between groups. Significant associations were observed between CB (p = 0.04), LE (p = 0.01), and TSA (p = 0.008) levels and survival outcomes in CRC patients. Dukes' classification stages also showed a significant correlation with survival (p = 0.001). However, no significant associations were found for LASA, ATA, CRP, and CC. Multivariate analysis of LE, TSA, and ATA demonstrated a notable correlation with survival (p = 0.041), notwithstanding ATA's lack of significance in univariate analysis (p = 0.13). CB, LE, and TSA emerged as promising diagnostic markers with prognostic value in CRC, potentially aiding in early diagnosis and treatment planning. Further research is needed to validate these findings and explore additional prognostic indicators.
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Affiliation(s)
- Tadeusz Sebzda
- Department of Pathophysiology, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Jakub Karwacki
- Department of Pathophysiology, Wroclaw Medical University, 50-368 Wroclaw, Poland;
- University Center of Excellence in Urology, Department of Minimally Invasive and Robotic Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Anna Cichoń
- Regional Specialist Hospital of St. Barbara, 41-200 Sosnowiec, Poland;
| | | | | | - Mirosław Łątka
- Department of Biomedical Engineering, Wroclaw University of Science and Technology, 50-370 Wroclaw, Poland;
| | - Jan Gnus
- Department of Physiotherapy, Wroclaw Medical University, 50-355 Wroclaw, Poland;
| | - Jakub Gburek
- Department of Pharmaceutical Biochemistry, Wroclaw Medical University, 50-556 Wroclaw, Poland
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Naber A, Demus D, Slieker RC, Nicolardi S, Beulens JWJ, Elders PJM, Lieverse AG, Sijbrands EJG, ‘t Hart LM, Wuhrer M, van Hoek M. Apolipoprotein-CIII O-Glycosylation Is Associated with Micro- and Macrovascular Complications of Type 2 Diabetes. Int J Mol Sci 2024; 25:5365. [PMID: 38791405 PMCID: PMC11121677 DOI: 10.3390/ijms25105365] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 05/10/2024] [Accepted: 05/12/2024] [Indexed: 05/26/2024] Open
Abstract
Apolipoprotein-CIII (apo-CIII) inhibits the clearance of triglycerides from circulation and is associated with an increased risk of diabetes complications. It exists in four main proteoforms: O-glycosylated variants containing either zero, one, or two sialic acids and a non-glycosylated variant. O-glycosylation may affect the metabolic functions of apo-CIII. We investigated the associations of apo-CIII glycosylation in blood plasma, measured by mass spectrometry of the intact protein, and genetic variants with micro- and macrovascular complications (retinopathy, nephropathy, neuropathy, cardiovascular disease) of type 2 diabetes in a DiaGene study (n = 1571) and the Hoorn DCS cohort (n = 5409). Mono-sialylated apolipoprotein-CIII (apo-CIII1) was associated with a reduced risk of retinopathy (β = -7.215, 95% CI -11.137 to -3.294) whereas disialylated apolipoprotein-CIII (apo-CIII2) was associated with an increased risk (β = 5.309, 95% CI 2.279 to 8.339). A variant of the GALNT2-gene (rs4846913), previously linked to lower apo-CIII0a, was associated with a decreased prevalence of retinopathy (OR = 0.739, 95% CI 0.575 to 0.951). Higher apo-CIII1 levels were associated with neuropathy (β = 7.706, 95% CI 2.317 to 13.095) and lower apo-CIII0a with macrovascular complications (β = -9.195, 95% CI -15.847 to -2.543). In conclusion, apo-CIII glycosylation was associated with the prevalence of micro- and macrovascular complications of diabetes. Moreover, a variant in the GALNT2-gene was associated with apo-CIII glycosylation and retinopathy, suggesting a causal effect. The findings facilitate a molecular understanding of the pathophysiology of diabetes complications and warrant consideration of apo-CIII glycosylation as a potential target in the prevention of diabetes complications.
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Affiliation(s)
- Annemieke Naber
- Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (A.N.)
| | - Daniel Demus
- Center for Proteomics and Metabolomics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands (M.W.)
| | - Roderick C. Slieker
- Department of Cell and Chemical Biology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
- Department of Epidemiology and Data Science, Amsterdam UMC, Location Vrije Universiteit Amsterdam, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Simone Nicolardi
- Center for Proteomics and Metabolomics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands (M.W.)
| | - Joline W. J. Beulens
- Department of Epidemiology and Data Science, Amsterdam UMC, Location Vrije Universiteit Amsterdam, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
- Amsterdam Public Health, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Petra J. M. Elders
- Department of General Practice, Amsterdam Public Health Institute, Amsterdam UMC, Location VUmc, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Aloysius G. Lieverse
- Department of Internal Medicine, Maxima Medical Center, P.O. Box 90052, 5600 PD Eindhoven, The Netherlands
| | - Eric J. G. Sijbrands
- Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (A.N.)
| | - Leen M. ‘t Hart
- Department of Cell and Chemical Biology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
- Department of Epidemiology and Data Science, Amsterdam UMC, Location Vrije Universiteit Amsterdam, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
- Amsterdam Public Health, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Department of Biomedical Data Science, Section Molecular Epidemiology, Leiden University Medical Center, Postal Zone S5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands (M.W.)
| | - Mandy van Hoek
- Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (A.N.)
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Lado-Baleato Ó, Torre J, O’Flaherty R, Alonso-Sampedro M, Carballo I, Fernández-Merino C, Vidal C, Gude F, Saldova R, González-Quintela A. Age-Related Changes in Serum N-Glycome in Men and Women-Clusters Associated with Comorbidity. Biomolecules 2023; 14:17. [PMID: 38254617 PMCID: PMC10813383 DOI: 10.3390/biom14010017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/17/2023] [Accepted: 12/18/2023] [Indexed: 01/24/2024] Open
Abstract
(1) Aim: To describe, in a general adult population, the serum N-glycome in relation to age in men and women, and investigate the association of N-glycome patterns with age-related comorbidity; (2) Methods: The serum N-glycome was studied by hydrophilic interaction chromatography with ultra-performance liquid chromatography in 1516 randomly selected adults (55.3% women; age range 18-91 years). Covariates included lifestyle factors, metabolic disorders, inflammatory markers, and an index of comorbidity. Principal component analysis was used to define clusters of individuals based on the 46 glycan peaks obtained in chromatograms; (3) Results: The serum N-glycome changed with ageing, with significant differences between men and women, both in individual N-glycan peaks and in groups defined by common features (branching, galactosylation, sialylation, fucosylation, and oligomannose). Through K-means clustering algorithm, the individuals were grouped into a cluster characterized by abundance of simpler N-glycans and a cluster characterized by abundance of higher-order N-glycans. The individuals of the first cluster were older, showed higher concentrations of glucose and glycation markers, higher levels of some inflammatory markers, lower glomerular filtration rate, and greater comorbidity index; (4) Conclusions: The serum N-glycome changes with ageing with sex dimorphism. The N-glycome could be, in line with the inflammaging hypothesis, a marker of unhealthy aging.
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Affiliation(s)
- Óscar Lado-Baleato
- Research Methodology Group, Health Research Institute of Santiago de Compostela (IDIS), Galician Health Service, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (Ó.L.-B.); (J.T.); (M.A.-S.); (I.C.); (C.F.-M.); (C.V.); (F.G.)
- ISCIII Support Platforms for Clinical Research, Health Research Institute of Santiago de Compostela (IDIS), Galician Health Service, University of Santiago de Compostel, 15706 Santiago de Compostela, Spain
| | - Jorge Torre
- Research Methodology Group, Health Research Institute of Santiago de Compostela (IDIS), Galician Health Service, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (Ó.L.-B.); (J.T.); (M.A.-S.); (I.C.); (C.F.-M.); (C.V.); (F.G.)
| | - Róisín O’Flaherty
- GlycoScience Group, National Institute for Bioprocessing Research and Training, Fosters Avenue, A94 X099 Dublin, Ireland (R.S.)
- Department of Chemistry, Maynooth University, W23 F2K8 Maynooth, Ireland
| | - Manuela Alonso-Sampedro
- Research Methodology Group, Health Research Institute of Santiago de Compostela (IDIS), Galician Health Service, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (Ó.L.-B.); (J.T.); (M.A.-S.); (I.C.); (C.F.-M.); (C.V.); (F.G.)
| | - Iago Carballo
- Research Methodology Group, Health Research Institute of Santiago de Compostela (IDIS), Galician Health Service, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (Ó.L.-B.); (J.T.); (M.A.-S.); (I.C.); (C.F.-M.); (C.V.); (F.G.)
| | - Carmen Fernández-Merino
- Research Methodology Group, Health Research Institute of Santiago de Compostela (IDIS), Galician Health Service, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (Ó.L.-B.); (J.T.); (M.A.-S.); (I.C.); (C.F.-M.); (C.V.); (F.G.)
- Primary Care, Santiago de Compostela Area, 15706 Santiago de Compostela, Spain
| | - Carmen Vidal
- Research Methodology Group, Health Research Institute of Santiago de Compostela (IDIS), Galician Health Service, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (Ó.L.-B.); (J.T.); (M.A.-S.); (I.C.); (C.F.-M.); (C.V.); (F.G.)
| | - Francisco Gude
- Research Methodology Group, Health Research Institute of Santiago de Compostela (IDIS), Galician Health Service, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (Ó.L.-B.); (J.T.); (M.A.-S.); (I.C.); (C.F.-M.); (C.V.); (F.G.)
- Primary Care, Santiago de Compostela Area, 15706 Santiago de Compostela, Spain
| | - Radka Saldova
- GlycoScience Group, National Institute for Bioprocessing Research and Training, Fosters Avenue, A94 X099 Dublin, Ireland (R.S.)
- UCD School of Medicine, College of Health and Agricultural Science, University College Dublin, D04 V1W8 Dublin, Ireland
| | - Arturo González-Quintela
- Research Methodology Group, Health Research Institute of Santiago de Compostela (IDIS), Galician Health Service, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (Ó.L.-B.); (J.T.); (M.A.-S.); (I.C.); (C.F.-M.); (C.V.); (F.G.)
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Choi JJ, Koscik RL, Jonaitis EM, Panyard DJ, Morrow AR, Johnson SC, Engelman CD, Schmitz LL. Assessing the Biological Mechanisms Linking Smoking Behavior and Cognitive Function: A Mediation Analysis of Untargeted Metabolomics. Metabolites 2023; 13:1154. [PMID: 37999250 PMCID: PMC10673384 DOI: 10.3390/metabo13111154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 11/10/2023] [Accepted: 11/11/2023] [Indexed: 11/25/2023] Open
Abstract
(1) Smoking is the most significant preventable health hazard in the modern world. It increases the risk of vascular problems, which are also risk factors for dementia. In addition, toxins in cigarettes increase oxidative stress and inflammation, which have both been linked to the development of Alzheimer's disease and related dementias (ADRD). This study identified potential mechanisms of the smoking-cognitive function relationship using metabolomics data from the longitudinal Wisconsin Registry for Alzheimer's Prevention (WRAP). (2) 1266 WRAP participants were included to assess the association between smoking status and four cognitive composite scores. Next, untargeted metabolomic data were used to assess the relationships between smoking and metabolites. Metabolites significantly associated with smoking were then tested for association with cognitive composite scores. Total effect models and mediation models were used to explore the role of metabolites in smoking-cognitive function pathways. (3) Plasma N-acetylneuraminate was associated with smoking status Preclinical Alzheimer Cognitive Composite 3 (PACC3) and Immediate Learning (IMM). N-acetylneuraminate mediated 12% of the smoking-PACC3 relationship and 13% of the smoking-IMM relationship. (4) These findings provide links between previous studies that can enhance our understanding of potential biological pathways between smoking and cognitive function.
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Affiliation(s)
- Jerome J. Choi
- Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA; (J.J.C.); (A.R.M.)
| | - Rebecca L. Koscik
- Wisconsin Alzheimer’s Institute, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA; (R.L.K.); (E.M.J.)
- Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Erin M. Jonaitis
- Wisconsin Alzheimer’s Institute, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA; (R.L.K.); (E.M.J.)
- Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Daniel J. Panyard
- Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA 94305, USA;
| | - Autumn R. Morrow
- Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA; (J.J.C.); (A.R.M.)
| | - Sterling C. Johnson
- Wisconsin Alzheimer’s Institute, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA; (R.L.K.); (E.M.J.)
- Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI 53792, USA
- William S. Middleton Memorial Veterans Hospital, Middleton, WI 53705, USA
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Corinne D. Engelman
- Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA; (J.J.C.); (A.R.M.)
| | - Lauren L. Schmitz
- La Follette School of Public Affairs, University of Wisconsin-Madison, Madison, WI 53706, USA;
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10
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Clark ND, Pham C, Kurniyati K, Sze CW, Coleman L, Fu Q, Zhang S, Malkowski MG, Li C. Functional and structural analyses reveal that a dual domain sialidase protects bacteria from complement killing through desialylation of complement factors. PLoS Pathog 2023; 19:e1011674. [PMID: 37747935 PMCID: PMC10553830 DOI: 10.1371/journal.ppat.1011674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 10/05/2023] [Accepted: 09/08/2023] [Indexed: 09/27/2023] Open
Abstract
The complement system is the first line of innate immune defense against microbial infections. To survive in humans and cause infections, bacterial pathogens have developed sophisticated mechanisms to subvert the complement-mediated bactericidal activity. There are reports that sialidases, also known as neuraminidases, are implicated in bacterial complement resistance; however, its underlying molecular mechanism remains elusive. Several complement proteins (e.g., C1q, C4, and C5) and regulators (e.g., factor H and C4bp) are modified by various sialoglycans (glycans with terminal sialic acids), which are essential for their functions. This report provides both functional and structural evidence that bacterial sialidases can disarm the complement system via desialylating key complement proteins and regulators. The oral bacterium Porphyromonas gingivalis, a "keystone" pathogen of periodontitis, produces a dual domain sialidase (PG0352). Biochemical analyses reveal that PG0352 can desialylate human serum and complement factors and thus protect bacteria from serum killing. Structural analyses show that PG0352 contains a N-terminal carbohydrate-binding module (CBM) and a C-terminal sialidase domain that exhibits a canonical six-bladed β-propeller sialidase fold with each blade composed of 3-4 antiparallel β-strands. Follow-up functional studies show that PG0352 forms monomers and is active in a broad range of pH. While PG0352 can remove both N-acetylneuraminic acid (Neu5Ac) and N-glycolyl-neuraminic acid (Neu5Gc), it has a higher affinity to Neu5Ac, the most abundant sialic acid in humans. Structural and functional analyses further demonstrate that the CBM binds to carbohydrates and serum glycoproteins. The results shown in this report provide new insights into understanding the role of sialidases in bacterial virulence and open a new avenue to investigate the molecular mechanisms of bacterial complement resistance.
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Affiliation(s)
- Nicholas D. Clark
- Department of Structural Biology, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, the State University of New York, Buffalo, New York, United States of America
| | - Christopher Pham
- Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Kurni Kurniyati
- Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Ching Wooen Sze
- Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Laurynn Coleman
- Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Qin Fu
- Proteomics Facility, Institute of Biotechnology, Cornell University, Ithaca, New York, United States of America
| | - Sheng Zhang
- Proteomics Facility, Institute of Biotechnology, Cornell University, Ithaca, New York, United States of America
| | - Michael G. Malkowski
- Department of Structural Biology, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, the State University of New York, Buffalo, New York, United States of America
| | - Chunhao Li
- Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia, United States of America
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11
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Zhang H, Yu H, Deng M, Ren Z, Li Z, Zhang L, Li J, Wang E, Wang X, Li J. Highly sensitive and real-time detection of sialic acid using a solution-gated graphene transistor functionalized with carbon quantum dots. Microchem J 2023. [DOI: 10.1016/j.microc.2023.108676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
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12
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Suzzi S, Croese T, Ravid A, Gold O, Clark AR, Medina S, Kitsberg D, Adam M, Vernon KA, Kohnert E, Shapira I, Malitsky S, Itkin M, Brandis A, Mehlman T, Salame TM, Colaiuta SP, Cahalon L, Slyper M, Greka A, Habib N, Schwartz M. N-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer's disease mouse model. Nat Commun 2023; 14:1293. [PMID: 36894557 PMCID: PMC9998639 DOI: 10.1038/s41467-023-36759-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 02/16/2023] [Indexed: 03/11/2023] Open
Abstract
Systemic immunity supports lifelong brain function. Obesity posits a chronic burden on systemic immunity. Independently, obesity was shown as a risk factor for Alzheimer's disease (AD). Here we show that high-fat obesogenic diet accelerated recognition-memory impairment in an AD mouse model (5xFAD). In obese 5xFAD mice, hippocampal cells displayed only minor diet-related transcriptional changes, whereas the splenic immune landscape exhibited aging-like CD4+ T-cell deregulation. Following plasma metabolite profiling, we identified free N-acetylneuraminic acid (NANA), the predominant sialic acid, as the metabolite linking recognition-memory impairment to increased splenic immune-suppressive cells in mice. Single-nucleus RNA-sequencing revealed mouse visceral adipose macrophages as a potential source of NANA. In vitro, NANA reduced CD4+ T-cell proliferation, tested in both mouse and human. In vivo, NANA administration to standard diet-fed mice recapitulated high-fat diet effects on CD4+ T cells and accelerated recognition-memory impairment in 5xFAD mice. We suggest that obesity accelerates disease manifestation in a mouse model of AD via systemic immune exhaustion.
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Grants
- R01 DK095045 NIDDK NIH HHS
- R01 DK099465 NIDDK NIH HHS
- the Vera and John Schwartz Family Center for Metabolic Biology.
- the National Institutes of Health (NIH) grants DK095045 and DK099465, the Cure Alzheimer’s Fund, the Chan Zuckerberg Foundation, and the Carlos Slim Foundation.
- the Israel Science Foundation (ISF) research grant no. 1709/19, the European Research Council grant 853409, the MOST-IL-China research grant no. 3-15687, and the Myers Foundation. N.H. holds the Goren-Khazzam chair in neuroscience.
- the Advanced European Research Council grants 232835 and 741744, the European Seventh Framework Program HEALTH-2011 (279017), the Israel Science Foundation (ISF)-research grant no. 991/16, the ISF-Legacy Heritage Bio-medical Science Partnership research grant no. 1354/15, and the Thompson Foundation and Adelis Foundation.
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Affiliation(s)
- Stefano Suzzi
- Weizmann Institute of Science, Department of Brain Sciences, Rehovot, Israel.
| | - Tommaso Croese
- Weizmann Institute of Science, Department of Brain Sciences, Rehovot, Israel
| | - Adi Ravid
- The Hebrew University of Jerusalem, Edmond & Lily Safra Center for Brain Sciences, Jerusalem, Israel
| | - Or Gold
- The Hebrew University of Jerusalem, Edmond & Lily Safra Center for Brain Sciences, Jerusalem, Israel
| | - Abbe R Clark
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Sedi Medina
- Weizmann Institute of Science, Department of Brain Sciences, Rehovot, Israel
| | - Daniel Kitsberg
- The Hebrew University of Jerusalem, Edmond & Lily Safra Center for Brain Sciences, Jerusalem, Israel
| | - Miriam Adam
- The Hebrew University of Jerusalem, Edmond & Lily Safra Center for Brain Sciences, Jerusalem, Israel
| | - Katherine A Vernon
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Eva Kohnert
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Inbar Shapira
- The Hebrew University of Jerusalem, Edmond & Lily Safra Center for Brain Sciences, Jerusalem, Israel
| | - Sergey Malitsky
- Weizmann Institute of Science, Life Sciences Core Facilities, Rehovot, Israel
| | - Maxim Itkin
- Weizmann Institute of Science, Life Sciences Core Facilities, Rehovot, Israel
| | - Alexander Brandis
- Weizmann Institute of Science, Life Sciences Core Facilities, Rehovot, Israel
| | - Tevie Mehlman
- Weizmann Institute of Science, Life Sciences Core Facilities, Rehovot, Israel
| | - Tomer M Salame
- Weizmann Institute of Science, Life Sciences Core Facilities, Rehovot, Israel
| | - Sarah P Colaiuta
- Weizmann Institute of Science, Department of Brain Sciences, Rehovot, Israel
| | - Liora Cahalon
- Weizmann Institute of Science, Department of Brain Sciences, Rehovot, Israel
| | - Michal Slyper
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Anna Greka
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
| | - Naomi Habib
- The Hebrew University of Jerusalem, Edmond & Lily Safra Center for Brain Sciences, Jerusalem, Israel.
| | - Michal Schwartz
- Weizmann Institute of Science, Department of Brain Sciences, Rehovot, Israel.
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13
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Fakhari S, Waszkiewicz N. Old and New Biomarkers of Alcohol Abuse: Narrative Review. J Clin Med 2023; 12:jcm12062124. [PMID: 36983134 PMCID: PMC10054673 DOI: 10.3390/jcm12062124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/03/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023] Open
Abstract
The harmful use of alcohol is responsible for 5.1% of the global burden of disease, and the early detection of alcohol problems may prevent its development and progression. Therefore, the aim of the study is to review traditional and new biomarkers associated with alcohol use. The nature and practical application and limitations of alcohol biomarkers in the diagnosis and monitoring of drinking are reviewed. Despite the limited specificity and sensitivity in alcohol drinking detection, traditional biomarkers are useful in clinical practice, and new generations of biomarkers, e.g., proteomic markers, are in need of further investigation. Traditional biomarkers are broadly available and cost-efficient, providing valuable data on the complications of drinking and prognosis, as well as on concurrent conditions affected by drinking. The most important challenge in the future will be to translate methodically advanced methods of detecting alcohol markers into simpler and cheaper methods. Larger population studies are also needed to test the usefulness of these potential markers of alcohol use.
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Affiliation(s)
- Sara Fakhari
- Department of Psychiatry, Mazowieckie Specjalistyczne Centrum Zdrowia w Pruszkowie, 05-800 Pruszków, Poland
- Correspondence: ; Tel.: +48-69-6963901
| | - Napoleon Waszkiewicz
- Department of Psychiatry, Medical University of Bialystok, 15-089 Bialystok, Poland
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14
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Donoghue SE, Heath O, Pitt J, Hong KM, Fuller M, Smith J. Free urinary sialic acid levels may be elevated in patients with pneumococcal sepsis. Clin Chem Lab Med 2022; 60:1855-1858. [PMID: 36000484 DOI: 10.1515/cclm-2022-0473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/16/2022] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Urine free sialic acid (UFSA) is an important diagnostic biomarker for sialuria (GNE variants) and infantile sialic acid storage disease/Salla disease (SLC17A5 variants). Traditionally, UFSA has been measured using specific single-plex methodology in relatively small cohorts of patients with clinical symptoms suggestive of these disorders. The use of multiplex tandem mass spectrometry urine screening (UMSMS) has meant that UFSA can be measured semi-quantitatively in a much larger cohort of patients being investigated for suspected metabolic disorders. We hypothesised that the neuraminidase of Streptococcus pneumoniae may release free sialic acid from endogenous sialylated glycoconjugates and result in increased UFSA levels. METHODS We conducted a retrospective review of clinical records of patients who were identified as having S. pneumoniae infection and who also had UMSMS at the time of their acute infection. RESULTS We identified three cases of increased UFSA detected by UMSMS screening that were secondary to S. pneumoniae sepsis. Additional testing ruled out genetic causes of increased UFSA in the first patient. All three patients had overwhelming sepsis with multiorgan dysfunction which was fatal. Glycosylation abnormalities consistent with the removal of sialic acid were demonstrated in serum transferrin patterns in one patient. CONCLUSIONS We have demonstrated in a retrospective cohort that elevation of UFSA levels have been observed in cases of S. pneumoniae sepsis. This expands our knowledge of UFSA as a biomarker in human disease. This research demonstrates that infection with organisms with neuraminidase activity should be considered in patients with unexplained increases in UFSA.
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Affiliation(s)
- Sarah E Donoghue
- Department of Metabolic Medicine, The Royal Children's Hospital, Melbourne, VIC, Australia.,Department of Biochemical Genetics, Victorian Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, VIC, Australia
| | - Oliver Heath
- Department of Metabolic Medicine, The Royal Children's Hospital, Melbourne, VIC, Australia
| | - James Pitt
- Department of Biochemical Genetics, Victorian Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, VIC, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
| | - Kai Mun Hong
- Department of Biochemical Genetics, Victorian Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, VIC, Australia
| | - Maria Fuller
- Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.,Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Joel Smith
- Laboratory Services, Royal Children's Hospital, Melbourne, VIC, Australia.,Department of Pathology, Royal Melbourne Hospital, Melbourne, VIC, Australia
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15
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Rosenau J, Grothaus IL, Yang Y, Kumar ND, Ciacchi LC, Kelm S, Waespy M. N-glycosylation modulates enzymatic activity of Trypanosoma congolense trans-sialidase. J Biol Chem 2022; 298:102403. [PMID: 35995210 PMCID: PMC9493392 DOI: 10.1016/j.jbc.2022.102403] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 11/24/2022] Open
Abstract
Trypanosomes cause the devastating disease trypanosomiasis, in which the action of trans-sialidase (TS) enzymes harbored on their surface is a key virulence factor. TS enzymes are N-glycosylated, but the biological functions of their glycans have remained elusive. In this study, we investigated the influence of N-glycans on the enzymatic activity and structural stability of TconTS1, a recombinant TS from the African parasite Trypanosoma congolense. We expressed the enzyme in Chinese hamster ovary Lec1 cells, which produce high-mannose type N-glycans similar to the TS N-glycosylation pattern in vivo. Our MALDI-TOF mass spectrometry data revealed that up to eight putative N-glycosylation sites were glycosylated. In addition, we determined that N-glycan removal via endoglycosidase Hf treatment of TconTS1 led to a decrease in substrate affinity relative to the untreated enzyme but had no impact on the conversion rate. Furthermore, we observed no changes in secondary structure elements of hypoglycosylated TconTS1 in CD experiments. Finally, our molecular dynamics simulations provided evidence for interactions between monosaccharide units of the highly flexible N-glycans and some conserved amino acids located at the catalytic site. These interactions led to conformational changes, possibly enhancing substrate accessibility and enzyme–substrate complex stability. The here-observed modulation of catalytic activity via N-glycans represents a so-far-unknown structure–function relationship potentially inherent in several members of the TS enzyme family.
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Affiliation(s)
- Jana Rosenau
- University of Bremen, Centre for Biomolecular Interactions Bremen, Faculty for Biology and Chemistry, 28359 Bremen, Germany
| | - Isabell Louise Grothaus
- University of Bremen, Centre for Biomolecular Interactions Bremen, Faculty for Biology and Chemistry, 28359 Bremen, Germany; University of Bremen, Hybrid Materials Interfaces Group, Faculty of Production Engineering, Bremen Center for Computational Materials Science, Center for Environmental Research and Sustainable Technology (UFT), and MAPEX Center for Materials and Processes, 28359 Bremen, Germany
| | - Yikun Yang
- University of Bremen, Centre for Biomolecular Interactions Bremen, Faculty for Biology and Chemistry, 28359 Bremen, Germany
| | - Nilima Dinesh Kumar
- University of Bremen, Centre for Biomolecular Interactions Bremen, Faculty for Biology and Chemistry, 28359 Bremen, Germany
| | - Lucio Colombi Ciacchi
- University of Bremen, Hybrid Materials Interfaces Group, Faculty of Production Engineering, Bremen Center for Computational Materials Science, Center for Environmental Research and Sustainable Technology (UFT), and MAPEX Center for Materials and Processes, 28359 Bremen, Germany
| | - Sørge Kelm
- University of Bremen, Centre for Biomolecular Interactions Bremen, Faculty for Biology and Chemistry, 28359 Bremen, Germany
| | - Mario Waespy
- University of Bremen, Centre for Biomolecular Interactions Bremen, Faculty for Biology and Chemistry, 28359 Bremen, Germany.
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16
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Černocká H, Římánková L, Ostatná V. Fetuin and asialofetuin at charged surfaces: Influence of sialic acid presence. J Electroanal Chem (Lausanne) 2021. [DOI: 10.1016/j.jelechem.2021.115801] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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17
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Harris JC, Leggio L, Farokhnia M. Blood Biomarkers of Alcohol Use: A Scoping Review. CURRENT ADDICTION REPORTS 2021; 8:500-508. [PMID: 37274945 PMCID: PMC10237590 DOI: 10.1007/s40429-021-00402-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/28/2021] [Indexed: 11/24/2022]
Abstract
Purpose of Review Understanding whether a person has consumed alcohol or not, as well as quantitative assessment of alcohol use, are often based on self-reported measures, which may be subject to recall bias, among other challenges. Although not without limitations, blood biomarkers may complement self-reported assessments to provide a more accurate determination of the presence and quantity of alcohol use. The aim of this review is to provide a critical overview of the current knowledge and research on biomarkers of alcohol use, with a particular focus on blood tests. Recent Findings This scoping review summarizes the published work on blood tests currently used in clinical practice, including phosphatidyl ethanol (PEth), fatty acid ethyl ester (FAEE), carbohydrate-deficient transferrin (CDT), total serum sialic acid (TSA), mean corpuscular volume (MCV), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and cholesteryl ester transfer protein (CETP). Emerging blood biomarkers with a potential use to assess alcohol drinking are also briefly reviewed, including N-Acetyl-β-Hexosaminidase (Beta-Hex), macrophage migration inhibitory factor (MIF), and D-dopachrome tautomerase (DDT). We discuss the aforementioned biomarkers in the context of their clinical implications, characteristics, strengths, and limitations. Summary The available blood biomarkers considerably vary in the time period in which they detect alcohol use and the amount of alcohol they are sensitive to. While currently available biomarkers provide useful information, especially in combination with self-reported measures, future work is needed to identify more sensitive and specific blood biomarkers for different levels and patterns of alcohol use. Integration of such biomarkers into clinical practice and research will increase the accuracy and richness of the data and may guide more effective and targeted strategies for prevention, diagnosis, and treatment of excessive alcohol use.
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Affiliation(s)
- Julia C. Harris
- Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, MD 21224, USA
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, MD 21224, USA
- Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
- Department of Behavioral and Social Sciences, Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA
- Department of Medicine, Division of Addiction Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
- Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA
| | - Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, MD 21224, USA
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21224, USA
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18
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Lin S, Cheng Z, Li Q, Wang R, Yu F. Toward Sensitive and Reliable Surface-Enhanced Raman Scattering Imaging: From Rational Design to Biomedical Applications. ACS Sens 2021; 6:3912-3932. [PMID: 34726891 DOI: 10.1021/acssensors.1c01858] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Early specific detection through indicative biomarkers and precise visualization of lesion sites are urgent requirements for clinical disease diagnosis. However, current detection and optical imaging methods are insufficient for these demands. Molecular imaging technologies are being intensely studied for reliable medical diagnosis. In the past several decades, molecular imaging with surface-enhanced Raman scattering (SERS) has significant advances from analytical chemistry to medical science. SERS is the inelastic scattering generated from the interaction between photons and substances, presenting molecular structure information. The outstanding SERS virtues of high sensitivity, high specificity, and resistance to biointerference are highly advantageous for biomarker detection in a complex biological matrix. In this work, we review recent progress on the applications of SERS imaging in clinical diagnostics. With the assistance of SERS imaging, the detection of disease-related proteins, nucleic acids, small molecules, and pH of the cellular microenvironment can be implemented for adjuvant medical diagnosis. Moreover, multimodal imaging integrates the high penetration and high speed of other imaging modalities and imaging precision of SERS imaging, resulting in final complete and accurate imaging outcomes and exhibiting robust potential in the discrimination of pathological tissues and surgical navigation. As a promising molecular imaging technology, SERS imaging has achieved remarkable performance in clinical diagnostics and the biomedical realm. It is expected that this review will provide insights for further development of SERS imaging and promote the rapid progress and successful translation of advanced molecular imaging with clinical diagnostics.
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Affiliation(s)
- Shanshan Lin
- Key Laboratory of Hainan Trauma and Disaster Rescue, Laboratory of Neurology, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou 571199, China
- Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Hainan Functional Materials and Molecular Imaging, College of Pharmacy, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, China
| | - Ziyi Cheng
- Key Laboratory of Hainan Trauma and Disaster Rescue, Laboratory of Neurology, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou 571199, China
- Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Hainan Functional Materials and Molecular Imaging, College of Pharmacy, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, China
| | - Qifu Li
- Key Laboratory of Hainan Trauma and Disaster Rescue, Laboratory of Neurology, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou 571199, China
| | - Rui Wang
- Key Laboratory of Hainan Trauma and Disaster Rescue, Laboratory of Neurology, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou 571199, China
- Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Hainan Functional Materials and Molecular Imaging, College of Pharmacy, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, China
| | - Fabiao Yu
- Key Laboratory of Hainan Trauma and Disaster Rescue, Laboratory of Neurology, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou 571199, China
- Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Hainan Functional Materials and Molecular Imaging, College of Pharmacy, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, China
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19
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Huang G, Chen Q, Hu J, Mao J, He Y, Bai H, Tang G. Chitosan-derived nanoparticles impede signal transduction in T790M lung cancer therapy. Biomater Sci 2021; 9:7412-7419. [PMID: 34751282 DOI: 10.1039/d1bm01133b] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treated patients ultimately develop disease progression, about 50% of which are involved in the emergence of a p.Thr790Met (T790M) mutation acquiring drug resistance. In order to solve the aforementioned problem, a therapeutic nanoparticles DGA is developed to overcome EGFR-T790M resistance via downstream anti-apoptotic signal transduction blocking by a combination with persuading mitochondrial dysfunction and inhibiting miRNA expression. As the concept of design, chitosan-derived nanocarrier DCAFP, capable of persuading mitochondrial dysfunction, is demonstrated to convey gefitinib (GFT) and miR21 inhibitor (anti-miR21) to form DGA nanoparticles. The superior accumulation of antitumor therapeutics and synergistic blocking of downstream signal transduction by mitochondrial dysfunction and miRNA regulation lead to high sensitivity of DGA nanoparticles to EGFR-T790M mutated non-small cell lung cancer (NSCLC) cells with significant inhibition of tumor cell growth. The in vivo study demonstrates superior safety and antitumor efficacy of EGFRT790M mutated lung cancer mouse models. These results highlight the promise of DGA nanoparticles for enhancing GFT sensitivity to EGFRT790M NSCLC.
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Affiliation(s)
- Guojun Huang
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China. .,Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Qi Chen
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China. .,Institute of Translational Medicine, and the Second Affiliated Hospital, Zhejiang University School of medicine, Hangzhou 310009, China
| | - Jiawei Hu
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
| | - Jianming Mao
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
| | - Yunhong He
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
| | - Hongzhen Bai
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
| | - Guping Tang
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
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20
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Sebzda T, Gnus J, Dziadkowiec B, Latka M, Gburek J. Diagnostic usefulness of selected proteases and acute phase factors in patients with colorectal adenocarcinoma. World J Gastroenterol 2021; 27:6673-6688. [PMID: 34754160 PMCID: PMC8554409 DOI: 10.3748/wjg.v27.i39.6673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/07/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Uncontrolled growth and loss of control over basic metabolic functions, leading to invasive proliferation and metastases, are the salient traits of malignant tumors in general and colorectal cancer in particular. Invasion and metastases hinder effective tumor treatment. While surgical techniques and radiotherapy can be used to remove tumor focus, only chemotherapy can eliminate dispersed neoplastic cells. However, the efficacy of the latter method is limited in the advanced stages of the disease. Therefore, recognition of the mechanisms involved in neoplastic cell spreading is indispensable for developing effective therapies.
AIM To use a number of biomarkers involved in cancer progression and identify a panel that could be used for effective early diagnosis.
METHODS We recruited 185 patients with colorectal adenocarcinoma (98 men, 87 women with median age 63). Thirty-five healthy controls were sex and age-matched. Dukes’ staging was as follows: A = 22, B = 52, C = 72, D = 39. We analyzed patients' blood serum before surgery. We determined: (1) Cathepsin B (CB) with Barrett's method (fluorogenic substrate); (2) Leukocytic elastase (LE) in a complex with alpha 1 trypsin inhibitor (AAT) using the immunoenzymatic MERCK test; (3) Total sialic acid (TSA) with the colorimetric periodate-resorcinol method; (4) Lipid-bound sialic acid (LASA) with the colorimetric Taut's method; and (5) The antitrypsin activity (ATA) employing the colorimetric test.
RESULTS In patients, the values of the five biochemical parameters were as follows: CB = 16.1 ± 8.8 mU/L, LE = 875 ± 598 µg/L, TSA = 99 ± 31 mg%, LASA = 0.68 ± 0.33 mg%, and ATA = 3211 ± 1504 U/mL. Except for LASA, they were significantly greater than those of controls: CB = 11.4 ± 6.5 mU/L, LE = 379 ± 187 µg/L, TSA = 71.4 ± 15.1 mg%, LASA = 0.69 ± 0.28 mg%, and ATA = 2016 ± 690 U/mL. For CB and LASA, the differences between the four Dukes’ stages and controls were not statistically significant. The inter-stage differences for CB and LASA were also absent. The receiver operating characteristic (ROC) analysis revealed the potential diagnostic value of CB, TSA, and ATA. The area under ROC, sensitivity, and specificity for these three parameters were: 0.85, 72%, 90%; 0.75, 66%, 77%; and 0.77, 63%, 84%, respectively. The sensitivity and specificity for the three-parameter panel CB-TSA-ATA were equal to 88.2% and 100%, respectively.
CONCLUSION The increased value of CB, TSA, and ATA parameters are associated with tumor biology, invasion, and metastasis of colorectal cancer. The presented evidence suggests the potential value of the CB-TSA-ATA biochemical marker panel in early diagnostics.
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Affiliation(s)
- Tadeusz Sebzda
- Department of Pathophysiology, Wroclaw Medical University, Wroclaw 50-368, Poland
| | - Jan Gnus
- Department of Physiotherapy, Wroclaw Medical University, Wroclaw 50-355, Poland
| | - Barbara Dziadkowiec
- Department of Pathophysiology, Wroclaw Medical University, Wroclaw 50-368, Poland
| | - Miroslaw Latka
- Department of Biomedical Engineering, Wroclaw University of Science and Technology, Wroclaw 50-370, Poland
| | - Jakub Gburek
- Department of Pharmaceutical Biochemistry, Wroclaw Medical University, Wroclaw 50-556, Poland
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21
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Tran C, Turolla L, Ballhausen D, Buros SC, Teav T, Gallart-Ayala H, Ivanisevic J, Faouzi M, Lefeber DJ, Ivanovski I, Giangiobbe S, Caraffi SG, Garavelli L, Superti-Furga A. The fate of orally administered sialic acid: First insights from patients with N-acetylneuraminic acid synthase deficiency and control subjects. Mol Genet Metab Rep 2021; 28:100777. [PMID: 34258226 PMCID: PMC8251509 DOI: 10.1016/j.ymgmr.2021.100777] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/15/2021] [Accepted: 06/15/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND In NANS deficiency, biallelic mutations in the N-acetylneuraminic acid synthase (NANS) gene impair the endogenous synthesis of sialic acid (N-acetylneuraminic acid) leading to accumulation of the precursor, N-acetyl mannosamine (ManNAc), and to a multisystemic disorder with intellectual disability. The aim of this study was to determine whether sialic acid supplementation might be a therapeutic avenue for NANS-deficient patients. METHODS Four adults and two children with NANS deficiency and four adult controls received oral NeuNAc acid (150 mg/kg/d) over three days. Total NeuNAc, free NeuNAc and ManNAc were analyzed in plasma and urine at different time points. RESULTS Upon NeuNAc administration, plasma free NeuNAc increased within hours (P < 0.001) in control and in NANS-deficient individuals. Total and free NeuNAc concentrations also increased in the urine as soon as 6 h after beginning of oral administration in both groups. NeuNAc did not affect plasma and urinary ManNAc, that remained higher in NANS deficient subjects than in controls (day 1-3; all P < 0.01). Oral NeuNAc was well tolerated with no significant side effects. DISCUSSION Orally administered free NeuNAc was rapidly absorbed but also rapidly excreted in the urine. It did not change ManNAc levels in either patients or controls, indicating that it may not achieve enough feedback inhibition to reduce ManNAc accumulation in NANS-deficient subjects. Within the limitations of this study these results do not support a potential for oral free NeuNAc in the treatment of NANS deficiency but they provide a basis for further therapeutic approaches in this condition.
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Affiliation(s)
- Christel Tran
- Center for Molecular Diseases, Division of Genetic Medicine, University of Lausanne and University Hospital of Lausanne, Switzerland
| | - Licia Turolla
- Medical Genetics Unit, Azienda ULSS 2, Treviso, Italy
| | - Diana Ballhausen
- Pediatric Metabolic Unit, Pediatrics, Woman-Mother-Child Department, University of Lausanne and University Hospital of Lausanne, Switzerland
| | | | - Tony Teav
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Switzerland
| | - Hector Gallart-Ayala
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Switzerland
| | - Julijana Ivanisevic
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Switzerland
| | - Mohamed Faouzi
- Division of Biostatistics, Center for Primary Care and Public Health (Unisanté), University of Lausanne, Switzerland
| | - Dirk J. Lefeber
- Translational Metabolic Laboratory, Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Ivan Ivanovski
- Medical Genetics Unit, Maternal and Child Health Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- Institute of Medical Genetics, University of Zurich, Switzerland
| | - Sara Giangiobbe
- Medical Genetics Unit, Maternal and Child Health Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Stefano Giuseppe Caraffi
- Medical Genetics Unit, Maternal and Child Health Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Livia Garavelli
- Medical Genetics Unit, Maternal and Child Health Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Andrea Superti-Furga
- Center for Molecular Diseases, Division of Genetic Medicine, University of Lausanne and University Hospital of Lausanne, Switzerland
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22
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Seo N, Ko J, Lee D, Jeong H, Oh MJ, Kim U, Lee DH, Kim J, Choi YJ, An HJ. In-depth characterization of non-human sialic acid (Neu5Gc) in human serum using label-free ZIC-HILIC/MRM-MS. Anal Bioanal Chem 2021; 413:5227-5237. [PMID: 34235565 DOI: 10.1007/s00216-021-03495-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/16/2021] [Accepted: 06/21/2021] [Indexed: 01/22/2023]
Abstract
Sialic acid Neu5Gc, a non-human glycan, is recognized as a new harmful substance that can cause vascular disease and cancer. Humans are unable to synthesize Neu5Gc due to a genetic defect that converts Neu5Ac to Neu5Gc, but Neu5Gc is often observed in human biological samples. Therefore, the demand for accurately measuring the amount of Neu5Gc present in human blood or tissues is rapidly increasing, but there is still no method to reliably quantify trace amounts of a non-human sugar. In particular, selective isolation and detection of Neu5Gc from human serum is analytically challenging due to the presence of excess sialic acid Neu5Ac, which has physicochemical properties very similar to Neu5Gc. Herein, we developed the label-free approach based on ZIC-HILIC/MRM-MS that can enrich sialic acids released from human serum and simultaneously monitor Neu5Ac and Neu5Gc. The combination of complete separation of Neu5Gc from abundant Neu5Ac by hydrophilic and electrostatic interactions with selective monitoring of structure-specific cross-ring cleavage ions generated by negative CID-MS/MS was remarkably effective for quantification of Neu5Ac and Neu5Gc at the femtomole level. Indeed, we were able to successfully determine the absolute quantitation of Neu5Gc from 30 healthy donors in the range of 3.336 ± 1.252 pg/μL (mean ± SD), 10,000 times lower than Neu5Ac. In particular, analysis of sialic acids in protein-free serum revealed that both Neu5Ac and Neu5G are mostly bound to proteins and/or lipids, but not in free form. In addition, the correlation between expression level of Neu5Gc and biological factors such as BMI, age, and sex was investigated. This method can be widely used in studies requiring sialic acid-related measurements such as disease diagnosis or prediction of immunogenicity in biopharmaceuticals as it is both fast and highly sensitive.
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Affiliation(s)
- Nari Seo
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 34134, Republic of Korea.,Asia Glycomics Reference Site, Daejeon, 34134, Republic of Korea
| | - Jaekyoung Ko
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 34134, Republic of Korea.,Asia Glycomics Reference Site, Daejeon, 34134, Republic of Korea
| | - Daum Lee
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 34134, Republic of Korea.,Asia Glycomics Reference Site, Daejeon, 34134, Republic of Korea
| | - Heejin Jeong
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 34134, Republic of Korea.,Asia Glycomics Reference Site, Daejeon, 34134, Republic of Korea
| | - Myung Jin Oh
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 34134, Republic of Korea.,Asia Glycomics Reference Site, Daejeon, 34134, Republic of Korea
| | - Unyong Kim
- Biocomplete Co., Ltd., Seoul, 08389, Republic of Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Budang Hospital, Seongnam, 13620, Republic of Korea
| | - Jaehan Kim
- Department of Food and Nutrition, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Yoon Jin Choi
- Department of Internal Medicine, Seoul National University Budang Hospital, Seongnam, 13620, Republic of Korea. .,Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
| | - Hyun Joo An
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 34134, Republic of Korea. .,Asia Glycomics Reference Site, Daejeon, 34134, Republic of Korea.
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23
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Kiran I, Ekin S, Vural Ö. Low vitamin B 12 level in relation to trace element, total sialic acid and antioxidant enzymes in children with vitamin B 12 deficiency anemia. INT J VITAM NUTR RES 2021; 93:132-141. [PMID: 34100302 DOI: 10.1024/0300-9831/a000716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
In this study, children with vitamin B12 deficiency anemia (V-B12DA) and control subjects were evaluated for erythrocyte glutathione peroxidase, catalase and superoxide dismutase enzyme activities, glutathione, malondialdehyde, serum total sialic acid, total antioxidant status, cobalt, chromium, copper, selenium, vanadium, zinc, iron, lead, magnesium, calcium, sodium, potassium, chloride, phosphorus levels, and the associations of these variables were assessed. The study included 50 children with V-B12DA and 50 control subjects. It was found that the V-B12DA group was significantly lower than the control group, with regard to the mean±the standard error of the mean levels of cobalt (0.089±0.009; 0.058±0.0063 μmol/L, p<0.01), selenium (2.19±0.087; 1.88±0.057 μmol/L, p<0.01), vanadium (1.31±0.053; 1.18±0.035 μmol/L, p<0.05), magnesium (3.02±0.15; 2.73±0.068 μmol/L, p<0.05), zinc (50.76±1.96; 42.23± 1.53 μmol/L, p<0.001), and vitamin B12 (427.20±21.45; 157.08±3.96 pg/mL, p<0.001). Moreover, a significant elevation in total sialic acid (1.44±0.050; 1.61±0.043 mmol/L, p<0.01), and mean corpuscular volume (MCV) (75.37±0.95; 79.91±1.14 fL, p<0.01). It was observed that in the V-B12DA, significantly linear correlations were observed between cobalt - vitamin B12 (r=0.334; p=0.025), vanadium - MCV (r=0.315; p=0.017), vitamin B12 - MCV (r=-0.297; p=0.026). The findings of the study indicated that the levels of cobalt, vanadium significantly associated with traditional vitamin B12-deficiency parameters. Vitamin B12 and MCV should be measured together with cobalt, vanadium for monitoring the vitamin B12 deficiency anemia.
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Affiliation(s)
- Isa Kiran
- Division of Blood and Transfusion, University of Health Sciences, Van Training and Research Hospital, Van, Turkey
| | - Suat Ekin
- Department of Chemistry, Division of Biochemistry, Faculty of Science, Van Yuzuncu Yil University, Van, Turkey
| | - Özge Vural
- Division of Pediatric Hematology and Oncology, Faculty of Medicine, Gazi University Ankara, Turkey
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24
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Villacrés C, Tayi VS, Butler M. Strategic feeding of NS0 and CHO cell cultures to control glycan profiles and immunogenic epitopes of monoclonal antibodies. J Biotechnol 2021; 333:49-62. [PMID: 33901620 DOI: 10.1016/j.jbiotec.2021.04.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 04/03/2021] [Accepted: 04/18/2021] [Indexed: 01/12/2023]
Abstract
The control of glycosylation profiles is essential to the consistent manufacture of therapeutic monoclonal antibodies that may be produced from a variety of cell lines including CHO and NS0. Of particular concern is the potential for generating non-human epitopes such as N-glycolylneuraminic acid (Neu5Gc) and Galα1-3 Gal that may be immunogenic. We have looked at the effects of a commonly used media supplements of manganese, galactose and uridine (MGU) on Mab production from CHO and NS0 cells in enhancing galactosylation and sialylation as well as the generation of these non-human glycan epitopes. In the absence of the MGU supplement, the humanized IgG1 antibody (Hu1D10) produced from NS0 cells showed a low level of mono- and di-sialylated structures (SI:0.09) of which 75 % of sialic acid was Neu5Gc. The chimeric human-llama Mab (EG2-hFc) produced from CHO cells showed an equally low level of sialylation (SI: 0.12) but the Neu5Gc content of sialic acid was negligible (<3%). Combinations of the MGU supplements added to the production cultures resulted in a substantial increase in the galactosylation of both Mabs (up to GI:0.78 in Hu1D10 and 0.81 in EG2-hFc). However, the effects on sialylation differed between the two Mabs. We observed a slight increase in sialylation of the EG2-hFc Mab by a combination of MG but it appeared that one of the components (uridine) was inhibitory to sialylation. On the other hand, MG or MGU increased sialylation of Hu1D10 substantially (SI:0.72) with an increase that could be attributed predominantly to the formation of Neu5Ac rather than Neu5Gc. The increased level of galactosylation observed with MG or MGU was attributed to an activation of the galactosyl transferase enzymes through enhanced intracellular levels of UDP-Gal and the availability of Mn2+ as an enzymic co-factor. However, this effect not only increased the desirable beta 1-4 Gal linkage to GlcNAc but unfortunately in NS0 cells increased the formation of Galα1-3 Gal which was shown to increase x3 in the presence of combinations of the MGU supplements. Supplementation of media with fetal bovine serum (FBS) increased the availability of free Neu5Ac which resulted in a significant increase in the sialylation of Hu1D10 from NS0 cells. This also resulted in a significant decrease in the proportion of Neu5Gc in the measured sialic acid from the Mab.
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Affiliation(s)
- Carina Villacrés
- Department of Microbiology, University of Manitoba, Winnipeg, MB, R3T2N2, Canada
| | - Venkata S Tayi
- Department of Microbiology, University of Manitoba, Winnipeg, MB, R3T2N2, Canada
| | - Michael Butler
- Department of Microbiology, University of Manitoba, Winnipeg, MB, R3T2N2, Canada; National Institute for Bioprocessing Research & Training (NIBRT), Fosters Avenue, Dublin, A94 X099, Ireland.
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25
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Rashed AA, Ahmad H, Abdul Khalid SK, Rathi DNG. The Potential Use of Sialic Acid From Edible Bird's Nest to Attenuate Mitochondrial Dysfunction by In Vitro Study. Front Pharmacol 2021; 12:633303. [PMID: 33912049 PMCID: PMC8072155 DOI: 10.3389/fphar.2021.633303] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 02/22/2021] [Indexed: 01/03/2023] Open
Abstract
Edible bird's nest (EBN) is one of the expensive functional foods in herbal medicine. One of the major glyconutrients in EBN is sialic acid, which has a beneficial effect on neurological and intellectual capability in mammals. The aims of this research were to study the effects of sialic acid from EBN on cell viability and to determine its effect on mitochondria membrane potential (MtMP) in Caco-2, SK-N-MC, SH-SY5Y, and PC-12 cell lines. Fourteen samples of raw EBN were collected from four different states in Malaysia. The confluency of the epithelial monolayers measurement of the tight junction for all the cell lines was determined using transepithelial electrical resistance (TEER), and the sialic acid uptake study in cell lines was determined by using ultra-high performance liquid chromatography (UHPLC). The MTT assay was conducted for cell viability study. The MtMP in cell lines was determined using the Mito Probe JC-1 Assay by flow cytometer analysis. We have recorded a statistically significant difference between the uptake of sialic acid from EBN and the standard solution. A higher amount of sialic acid was absorbed by the cells from extract of EBN compared to the standard solution. The amounts of sialic acid uptake in Caco-2, SK-N-MC, SH-SY5Y, and PC-12 cell lines were (0.019 ± 0.001), (0.034 ± 0.006), (0.021 ± 0.002), and (0.025 ± 0.000) µmol/L, respectively. The MTT results indicated that the concentration of sialic acid increased the cell viability and showed no cytotoxicity effects on cell lines when they were exposed to the sialic acid extract and sialic acid standard at all the tested concentrations. The number of active mitochondria was found to be significantly higher in SH-SY5Y cell lines with a 195% increase when treated with sialic acid from EBN. Although many researchers around the globe use SH-SY5Y and SK-N-MC for Alzheimer's disease (AD) study, based on our finding, SH-SY5Y was found to be the most suitable cell line for AD study by in vitro works where it has a known relationship with mitochondrial dysfunction.
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Affiliation(s)
- Aswir Abd Rashed
- Nutrition, Metabolism and Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health, Shah Alam, Malaysia
| | - Hafandi Ahmad
- Departments of Veterinary Preclinical Sciences, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
| | - Siti Khadijah Abdul Khalid
- Nutrition, Metabolism and Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health, Shah Alam, Malaysia
| | - Devi-Nair Gunasegavan Rathi
- Nutrition, Metabolism and Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health, Shah Alam, Malaysia
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26
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Siddiqui SS, Dhar C, Sundaramurthy V, Sasmal A, Yu H, Bandala-Sanchez E, Li M, Zhang X, Chen X, Harrison LC, Xu D, Varki A. Sialoglycan recognition is a common connection linking acidosis, zinc, and HMGB1 in sepsis. Proc Natl Acad Sci U S A 2021; 118:e2018090118. [PMID: 33658363 PMCID: PMC7958265 DOI: 10.1073/pnas.2018090118] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Blood pH is tightly maintained between 7.35 and 7.45, and acidosis (pH <7.3) indicates poor prognosis in sepsis, wherein lactic acid from anoxic tissues overwhelms the buffering capacity of blood. Poor sepsis prognosis is also associated with low zinc levels and the release of High mobility group box 1 (HMGB1) from activated and/or necrotic cells. HMGB1 added to whole blood at physiological pH did not bind leukocyte receptors, but lowering pH with lactic acid to mimic sepsis conditions allowed binding, implying the presence of natural inhibitor(s) preventing binding at normal pH. Testing micromolar concentrations of divalent cations showed that zinc supported the robust binding of sialylated glycoproteins with HMGB1. Further characterizing HMGB1 as a sialic acid-binding lectin, we found that optimal binding takes place at normal blood pH and is markedly reduced when pH is adjusted with lactic acid to levels found in sepsis. Glycan array studies confirmed the binding of HMGB1 to sialylated glycan sequences typically found on plasma glycoproteins, with binding again being dependent on zinc and normal blood pH. Thus, HMGB1-mediated hyperactivation of innate immunity in sepsis requires acidosis, and micromolar zinc concentrations are protective. We suggest that the potent inflammatory effects of HMGB1 are kept in check via sequestration by plasma sialoglycoproteins at physiological pH and triggered when pH and zinc levels fall in late stages of sepsis. Current clinical trials independently studying zinc supplementation, HMGB1 inhibition, or pH normalization may be more successful if these approaches are combined and perhaps supplemented by infusions of heavily sialylated molecules.
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Affiliation(s)
- Shoib S Siddiqui
- Department of Medicine, University of California San Diego, La Jolla, CA 92093
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093
- Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093
| | - Chirag Dhar
- Department of Medicine, University of California San Diego, La Jolla, CA 92093
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093
- Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093
| | - Venkatasubramaniam Sundaramurthy
- Department of Medicine, University of California San Diego, La Jolla, CA 92093
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093
- Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093
| | - Aniruddha Sasmal
- Department of Medicine, University of California San Diego, La Jolla, CA 92093
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093
- Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093
| | - Hai Yu
- Department of Chemistry, University of California, Davis, CA 95616
| | - Esther Bandala-Sanchez
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
| | - Miaomiao Li
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, NY 14214
| | - Xiaoxiao Zhang
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, NY 14214
| | - Xi Chen
- Department of Chemistry, University of California, Davis, CA 95616
| | - Leonard C Harrison
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
| | - Ding Xu
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, NY 14214
| | - Ajit Varki
- Department of Medicine, University of California San Diego, La Jolla, CA 92093;
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093
- Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093
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27
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Cao Y, Han S, Zhang H, Wang J, Jiang QY, Zhou Y, Yu YJ, Wang J, Chen F, Ng DKP. Detection of cell-surface sialic acids and photodynamic eradication of cancer cells using dye-modified polydopamine-coated gold nanobipyramids. J Mater Chem B 2021; 9:5780-5784. [PMID: 34269776 DOI: 10.1039/d1tb01274f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
A nanoprobe based on polydopamine-coated gold nanobipyramids surface modified with molecules of a phenylboronic acid-substituted distyryl boron dipyrromethene has been fabricated and characterised using various physical and spectroscopic methods. It serves as an ultrasensitive sensor for sialic acids on the surface of cancer cells based on its dual surface-enhanced Raman scattering and fluorescence response. This biomarker can also trigger the photodynamic activity of these nanobipyramids, effectively eradicating the cancer cells mainly through apoptosis as shown by various bioassays.
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Affiliation(s)
- Yue Cao
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China. and Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
| | - Shenghua Han
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
| | - Han Zhang
- Department of Physics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
| | - Jie Wang
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
| | - Qiao-Yan Jiang
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
| | - Yimin Zhou
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
| | - You-Jia Yu
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
| | - Jianfang Wang
- Department of Physics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
| | - Feng Chen
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
| | - Dennis K P Ng
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
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28
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Organic electrochemical transistor for sensing of sialic acid in serum samples. Anal Chim Acta 2020; 1128:231-237. [DOI: 10.1016/j.aca.2020.07.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/30/2020] [Accepted: 07/02/2020] [Indexed: 12/19/2022]
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Guruaribam VD, Sarumathi T. Relevance of serum and salivary sialic acid in oral cancer diagnostics. J Cancer Res Ther 2020; 16:401-404. [PMID: 32719243 DOI: 10.4103/jcrt.jcrt_512_19] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
To review the relevance of sialic acid as a tumour marker in oral cancer. Tumour marker are useful in the screening for early malignancy. Sialic acids are important in determining the surface properties of cells and has been implicated in cellular invasiveness, adhesiveness, and immunogenicity. Sialic acids are commonly found at the outermost end of glycan chains of all cell types. Increase in the levels of sialic acid in oral cancer indicates its importance as a tumour marker.Both serum and salivary sialic acid levels can be used as a screening tool and a diagnostic aid for oral cancer. Salivary sialic acid can be used as a non-invasive, cost effective and reliable diagnostic methods for screening and monitoring of oral cancer. In patients with oral cancer, glycoprotein metabolism is altered. Increase in the levels of sialic acid in oral cancer indicate its importance as a tumour marker. Changes in the serum is reflected in saliva. Salivary sialic acid can be used as non-invasive, cost effective and reliable diagnostic methods for screening and monitoring of oral cancer. Early the diagnosis, better the prognosis.
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Affiliation(s)
- Victoria Devi Guruaribam
- Department of Oral Medicine Diagnosis and Radiology, Sree Balaji Dental College and Hospital, BIHER, Chennai, Tamil Nadu, India
| | - T Sarumathi
- Department of Oral Medicine Diagnosis and Radiology, Sree Balaji Dental College and Hospital, BIHER, Chennai, Tamil Nadu, India
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30
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Fuentes F, Carrillo N, Wilkins KJ, Blake J, Leoyklang P, Gahl WA, Kopp JB, Huizing M. Elevated plasma free sialic acid levels in individuals with reduced glomerular filtration rates. ACTA ACUST UNITED AC 2020; 1:957-961. [PMID: 33969317 DOI: 10.34067/kid.0002122020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Federico Fuentes
- Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Nuria Carrillo
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Kenneth J Wilkins
- Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jodi Blake
- Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Petcharat Leoyklang
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - William A Gahl
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Jeffrey B Kopp
- Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Marjan Huizing
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
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31
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Olaru OG, Constantin GI, Pena CM. Variation of total serum sialic acid concentration in postmenopausal women. Exp Ther Med 2020; 20:2455-2459. [PMID: 32765733 DOI: 10.3892/etm.2020.8873] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/01/2020] [Indexed: 11/06/2022] Open
Abstract
Given its location and ubiquitous distribution, sialic acid can mediate or modulate a wide variety of physiological and pathological processes; however, there is scarce data regarding the associations between sialic acid serum levels and sex, age and menopause. The present study evaluated the age-related changes in serum sialic acid (SA) levels in 97 elderly subjects, including men and postmenopausal women. A significant increase in serum levels of sialic acid in postmenopausal women and a significant decrease in men were observed in an age-dependent manner. Furthermore, in postmenopausal women, positive correlations were observed between the total serum sialic acid level and age in all decades and subgroups. The total serum concentration of sialic acid in the postmenopausal women group exhibited a particular pattern; significantly lower levels were observed in subjects in the intermediate postmenopausal period compared with those in the first decade of post menopause and then higher levels again as the women get older (late climax), thus the concentration increased according to the age of the individual.
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Affiliation(s)
- Octavian Gabriel Olaru
- Department of Obstetrics and Gynecology, 'Carol Davila' University of Medicine and Pharmacy, 040292 Bucharest, Romania
| | - Gianina Ioana Constantin
- Department of Biology of Aging Research, 'Ana Aslan' National Institute of Gerontology and Geriatrics, 011241 Bucharest, Romania
| | - Catalina Monica Pena
- Department of Biology of Aging Research, 'Ana Aslan' National Institute of Gerontology and Geriatrics, 011241 Bucharest, Romania
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32
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Zernia S, van der Heide NJ, Galenkamp NS, Gouridis G, Maglia G. Current Blockades of Proteins inside Nanopores for Real-Time Metabolome Analysis. ACS NANO 2020; 14:2296-2307. [PMID: 32003969 PMCID: PMC7045694 DOI: 10.1021/acsnano.9b09434] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 01/31/2020] [Indexed: 05/14/2023]
Abstract
Biological nanopores are emerging as powerful and low-cost sensors for real-time analysis of biological samples. Proteins can be incorporated inside the nanopore, and ligand binding to the protein adaptor yields changes in nanopore conductance. In order to understand the origin of these conductance changes and develop sensors for detecting metabolites, we tested the signal originating from 13 different protein adaptors. We found that the quality of the protein signal depended on both the size and charge of the protein. The engineering of a dipole within the surface of the adaptor reduced the current noise by slowing the protein dynamics within the nanopore. Further, the charge of the ligand and the induced conformational changes of the adaptor defined the conductance changes upon metabolite binding, suggesting that the protein resides in an electrokinetic minimum within the nanopore, the position of which is altered by the ligand. These results represent an important step toward understanding the dynamics of the electrophoretic trapping of proteins inside nanopores and will allow developing next-generation sensors for metabolome analysis.
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Affiliation(s)
- Sarah Zernia
- Groningen
Biomolecular Sciences & Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
| | - Nieck Jordy van der Heide
- Groningen
Biomolecular Sciences & Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
| | - Nicole Stéphanie Galenkamp
- Groningen
Biomolecular Sciences & Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
| | - Giorgos Gouridis
- Rega
Institute for Medical Research, Laboratory of Molecular Bacteriology, KU Leuven, Herestraat 49, Box 1037, 3000 Leuven, Belgium
| | - Giovanni Maglia
- Groningen
Biomolecular Sciences & Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
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33
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Muda NM, Nasreen M, Dhouib R, Hosmer J, Hill J, Mahawar M, Schirra HJ, McEwan AG, Kappler U. Metabolic analyses reveal common adaptations in two invasive Haemophilus influenzae strains. Pathog Dis 2020; 77:5420469. [PMID: 30915434 DOI: 10.1093/femspd/ftz015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 03/19/2019] [Indexed: 01/22/2023] Open
Abstract
Non-typeable Haemophilus influenzae (NTHi) is a major pathogen in upper and lower respiratory tract infections in humans, and is increasingly also associated with invasive disease. We have examined two unrelated NTHi invasive disease isolates, R2866 and C188, in order to identify metabolic and physiological properties that distinguish them from respiratory tract disease isolates such as Hi2019. While the general use of the Hi metabolic network was similar across all three strains, the two invasive isolates secreted increased amounts of succinate, which can have anti-inflammatory properties. In addition, they showed a common shift in their carbon source utilization patterns, with strongly enhanced metabolism of nucleoside substrates, glucose and sialic acid. The latter two are major compounds present in blood and cerebrospinal fluid (CSF). Interestingly, C188 and R2866 also shared a reduced ability to invade or survive intracellularly in 16HBE14 bronchial epithelial cells relative to Hi2019 (4-fold (4 h), 25-fold (24 h) reduction). Altered metabolic properties, such as the ones observed here, could arise from genomic adaptations that NTHi undergo during infection. Together these data indicate that shifts in substrate preferences in otherwise conserved metabolic pathways may underlie strain niche specificity and thus have the potential to alter the outcomes of host-NTHi interactions.
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Affiliation(s)
- Noor Marian Muda
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, Centre for Metals in Biology, The University of Queensland, St. Lucia QLD 4072, Australia
| | - Marufa Nasreen
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, Centre for Metals in Biology, The University of Queensland, St. Lucia QLD 4072, Australia
| | - Rabeb Dhouib
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, Centre for Metals in Biology, The University of Queensland, St. Lucia QLD 4072, Australia
| | - Jennifer Hosmer
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, Centre for Metals in Biology, The University of Queensland, St. Lucia QLD 4072, Australia
| | - Julian Hill
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, Centre for Metals in Biology, The University of Queensland, St. Lucia QLD 4072, Australia
| | - Manish Mahawar
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, Centre for Metals in Biology, The University of Queensland, St. Lucia QLD 4072, Australia.,Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243122, India
| | - Horst Joachim Schirra
- Centre for Advanced Imaging, The University of Queensland, St. Lucia QLD 4072, Australia
| | - Alastair G McEwan
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, Centre for Metals in Biology, The University of Queensland, St. Lucia QLD 4072, Australia
| | - Ulrike Kappler
- School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, Centre for Metals in Biology, The University of Queensland, St. Lucia QLD 4072, Australia
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34
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Saeui CT, Cho KC, Dharmarha V, Nairn AV, Galizzi M, Shah SR, Gowda P, Park M, Austin M, Clarke A, Cai E, Buettner MJ, Ariss R, Moremen KW, Zhang H, Yarema KJ. Cell Line-, Protein-, and Sialoglycosite-Specific Control of Flux-Based Sialylation in Human Breast Cells: Implications for Cancer Progression. Front Chem 2020; 8:13. [PMID: 32117864 PMCID: PMC7013041 DOI: 10.3389/fchem.2020.00013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 01/07/2020] [Indexed: 12/11/2022] Open
Abstract
Sialylation, a post-translational modification that impacts the structure, activity, and longevity of glycoproteins has been thought to be controlled primarily by the expression of sialyltransferases (STs). In this report we explore the complementary impact of metabolic flux on sialylation using a glycoengineering approach. Specifically, we treated three human breast cell lines (MCF10A, T-47D, and MDA-MB-231) with 1,3,4-O-Bu3ManNAc, a "high flux" metabolic precursor for the sialic acid biosynthetic pathway. We then analyzed N-glycan sialylation using solid phase extraction of glycopeptides (SPEG) mass spectrometry-based proteomics under conditions that selectively captured sialic acid-containing glycopeptides, referred to as "sialoglycosites." Gene ontology (GO) analysis showed that flux-based changes to sialylation were broadly distributed across classes of proteins in 1,3,4-O-Bu3ManNAc-treated cells. Only three categories of proteins, however, were "highly responsive" to flux (defined as two or more sialylation changes of 10-fold or greater). Two of these categories were cell signaling and cell adhesion, which reflect well-known roles of sialic acid in oncogenesis. A third category-protein folding chaperones-was unexpected because little precedent exists for the role of glycosylation in the activity of these proteins. The highly flux-responsive proteins were all linked to cancer but sometimes as tumor suppressors, other times as proto-oncogenes, or sometimes both depending on sialylation status. A notable aspect of our analysis of metabolically glycoengineered breast cells was decreased sialylation of a subset of glycosites, which was unexpected because of the increased intracellular levels of sialometabolite "building blocks" in the 1,3,4-O-Bu3ManNAc-treated cells. Sites of decreased sialylation were minor in the MCF10A (<25% of all glycosites) and T-47D (<15%) cells but dominated in the MDA-MB-231 line (~60%) suggesting that excess sialic acid could be detrimental in advanced cancer and cancer cells can evolve mechanisms to guard against hypersialylation. In summary, flux-driven changes to sialylation offer an intriguing and novel mechanism to switch between context-dependent pro- or anti-cancer activities of the several oncoproteins identified in this study. These findings illustrate how metabolic glycoengineering can uncover novel roles of sialic acid in oncogenesis.
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Affiliation(s)
- Christopher T Saeui
- Department of Biomedical Engineering, Translational Tissue Engineering Center, The Johns Hopkins University, Baltimore, MD, United States
| | - Kyung-Cho Cho
- Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Vrinda Dharmarha
- Department of Biomedical Engineering, Translational Tissue Engineering Center, The Johns Hopkins University, Baltimore, MD, United States
| | - Alison V Nairn
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, United States
| | - Melina Galizzi
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, United States
| | - Sagar R Shah
- Department of Biomedical Engineering, Translational Tissue Engineering Center, The Johns Hopkins University, Baltimore, MD, United States
| | - Prateek Gowda
- Department of Biomedical Engineering, Translational Tissue Engineering Center, The Johns Hopkins University, Baltimore, MD, United States
| | - Marian Park
- Department of Biomedical Engineering, Translational Tissue Engineering Center, The Johns Hopkins University, Baltimore, MD, United States
| | - Melissa Austin
- Department of Biomedical Engineering, Translational Tissue Engineering Center, The Johns Hopkins University, Baltimore, MD, United States
| | - Amelia Clarke
- Department of Biomedical Engineering, Translational Tissue Engineering Center, The Johns Hopkins University, Baltimore, MD, United States
| | - Edward Cai
- Department of Biomedical Engineering, Translational Tissue Engineering Center, The Johns Hopkins University, Baltimore, MD, United States
| | - Matthew J Buettner
- Department of Biomedical Engineering, Translational Tissue Engineering Center, The Johns Hopkins University, Baltimore, MD, United States
| | - Ryan Ariss
- Department of Biomedical Engineering, Translational Tissue Engineering Center, The Johns Hopkins University, Baltimore, MD, United States
| | - Kelley W Moremen
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, United States
| | - Hui Zhang
- Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Kevin J Yarema
- Department of Biomedical Engineering, Translational Tissue Engineering Center, The Johns Hopkins University, Baltimore, MD, United States.,Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, The Johns Hopkins University, Baltimore, MD, United States.,Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, United States
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35
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Wang N, Wang M, Yu Y, Yang G, Su X. Label-free fluorescence assay based on near-infrared B,N-doped carbon dots as a fluorescent probe for the detection of sialic acid. NEW J CHEM 2020. [DOI: 10.1039/c9nj05981d] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
A simple and sensitive sensing strategy for sialic acid activity detection on the basis of novel near-infrared B,N co-doped carbon dots was constructed.
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Affiliation(s)
- Nan Wang
- Department of Analytical Chemistry
- College of Chemistry
- Jilin University
- Changchun 130012
- China
| | - Mengke Wang
- Department of Analytical Chemistry
- College of Chemistry
- Jilin University
- Changchun 130012
- China
| | - Yang Yu
- State Key Lab of Supramolecular Structure and Materials
- College of Chemistry
- Jilin University
- Changchun
- P. R. China
| | - Guojian Yang
- State Key Lab of Supramolecular Structure and Materials
- College of Chemistry
- Jilin University
- Changchun
- P. R. China
| | - Xingguang Su
- Department of Analytical Chemistry
- College of Chemistry
- Jilin University
- Changchun 130012
- China
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36
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Arda-Pirincci P, Sacan O, Ozal-Coskun C, Aykol-Celik G, Karabulut-Bulan O, Yanardag R, Bolkent S. Galectin-1 exhibits a protective effect against hepatotoxicity induced by dextran sulfate sodium in mice. Hum Exp Toxicol 2019; 39:423-432. [PMID: 31789064 DOI: 10.1177/0960327119891224] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Galectin-1 is an important mediator that regulates the T-cell-mediated immune response. It has many other biological functions such as cell growth, immunomodulation, and wound healing. The aim of this study was to reveal the role of galectin-1 on liver morphology, cell proliferation, apoptosis, inflammatory and anti-inflammatory mediators, oxidative stress, and antioxidant system in colitis-mediated hepatotoxicity induced by dextran sulfate sodium (DSS). In the present study, adult mice were divided into four groups: The control group intraperitoneally injected with phosphate buffer saline (I), the group which was orally administered with DSS (II), the control group which was injected with galectin-1 (III), and the group which was given DSS and galectin-1 (IV). DSS administration caused degenerative changes and diffuse necrotic damage, an increase in caspase-3 and cyclooxygenase-2 expression, the levels of lipid peroxidation and tumor necrosis factor-alpha, lactate dehydrogenase, and myeloperoxidase activities, and a decrease in cell proliferation, interleukin-10 levels, and antioxidant system parameters in liver tissues. Treatment of DSS group with galectin-1 reversed these effects and prevented liver damage. This study showed that galectin-1 has proliferative, antiapoptotic, anti-inflammatory, and antioxidant effects against DSS-induced liver injury in mice. It is expected considering all results of this study that galectin-1 may be useful as a protective agent against liver toxicity.
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Affiliation(s)
- P Arda-Pirincci
- Division of Molecular Biology, Department of Biology, Faculty of Science, Istanbul University, Istanbul, Turkey
| | - O Sacan
- Division of Biochemistry, Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - C Ozal-Coskun
- Section of Biology, Institute of Graduate Studies in Sciences, Istanbul University, Istanbul, Turkey
| | - G Aykol-Celik
- Section of Biology, Institute of Graduate Studies in Sciences, Istanbul University, Istanbul, Turkey
| | - O Karabulut-Bulan
- Division of General Biology, Department of Biology, Faculty of Science, Istanbul University, Istanbul, Turkey
| | - R Yanardag
- Division of Biochemistry, Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - S Bolkent
- Division of Molecular Biology, Department of Biology, Faculty of Science, Istanbul University, Istanbul, Turkey
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37
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Suresh R, Jayachandran P, Fenol A, Biswas R, Krishnan S, Kumar KA, Divakar DD, Vellappally S. Effect of Non-Surgical Periodontal Therapy on the Serum Sialic Acid Levels in Diabetic Patients with Periodontitis. ACTA MEDICA (HRADEC KRÁLOVÉ) 2019; 62:109-116. [PMID: 31663504 DOI: 10.14712/18059694.2019.134] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Sialic acid (SA), a family of acetylated derivatives of neuraminic acid, an acute phase reactant by itself. It usually occurs as a terminal component at the non-reducing end of carbohydrate chains of glycoproteins and glycolipids. SA participates in multiple physiological functions, such as cell-to-cell interactions, cell migration and proliferation. Diabetes mellitus (DM) is a chronic metabolic disorder characterized by rise in blood glucose level. Periodontitis is a chronic inflammatory disease of the periodontal tissue, leading to destruction of bone surrounding the tooth and ultimately tooth loss. There is a two way relationship between diabetes mellitus and periodontitis. Periodontitis is the sixth complication of diabetes along with retinopathy, nephropathy, neuropathy, macrovascular disease, and altered wound healing. Inflammatory mediators like interleukin-6 and tumor necrosis factor-alpha produced during periodontal inflammation can interfere with the actions of insulin receptors and worsen the glycemic control of diabetic patients. Periodontitis is a major cause of tooth loss, affecting over 300 million people and bacteria associated with periodontitis are also linked with systemic problems like endocarditis, atherosclerosis. Recent work has highlighted a major role for the host sugar sialic acid in the biofilm physiology and host-pathogen interactions of T. forsithya, a key periodontal pathogen. There exists a need for a biomarker, for early detection of disease evolution and more robust therapy efficacy measurements. Serum sialic acids were estimated in Indian population by diphenylamine method and Thiobarbituric acid method. The average values were 68 ± 2.6 mg percent by DPA method and 56 ± 5 mg percent by TBA (thiobarbituric acid assay) method. Age and sex showed no influence on serum sialic acid level. Objectives of the present study was to compare (TSSA) level in healthy subjects, subjects with (CMP) with and without (NIDDM) and its effect on non-surgical periodontal therapy. In the present study, the participants were divided into three groups: Group A, B and C. Group A consists of systemically healthy subjects, Group B consists of subjects with (CMP) while Group C consists of subjects with (CMP) with (NIDDM) and results of this study indicated that, at baseline, there were significant differences between Group A, B and Group C with respect to all the clinical parameters, including (GI), (OHI-S), (PPD), (CAL), (TSSA) and (HbA1c) levels. Thus (TSSA) level could be considered as novel biomarker in the progression of periodontal disease and diabetic status. Periodontitis could be considered as a potential, modifiable, and independent risk factor for the development of diabetes. Early detection of elevated (TSSA) level may help in interpreting the progression of periodontitis, risk of development of diabetes mellitus in future and also to prevent complications.
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Affiliation(s)
- Reshma Suresh
- Department of Periodontics, Amrita School of Dentistry, Amrita vishwa vidhyapeetham, Ponekara, Edapally, Cochin, India.
| | - Perayil Jayachandran
- Department of Periodontics, Amrita School of Dentistry, Amrita vishwa vidhyapeetham, Ponekara, Edapally, Cochin, India
| | - Angel Fenol
- Department of Periodontics, Amrita School of Dentistry, Amrita vishwa vidhyapeetham, Ponekara, Edapally, Cochin, India
| | - Raja Biswas
- Nano Science and Molecular Biology, Amrita institute of medical science, Cochin, India
| | - Sajitha Krishnan
- Department of Biochemistry, Amrita Institute of Medical Science, Cochin, India
| | - K Aswini Kumar
- Department of Prosthodontics, Amrita School of Dentistry, Cochin, India
| | - Darshan Devang Divakar
- Dental Biomaterials Research Chair, Dental Health Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Sajith Vellappally
- Division of Preventive Dentistry, Dental Health Department College of Applied Medical Science, King Saud University, Riyadh, Saudi Arabia
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38
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Zhang M, Wang Q, Xu Y, Guo L, Lai Z, Li Z. Graphitic carbon nitride quantum dots as analytical probe for viewing sialic acid on the surface of cells and tissues. Anal Chim Acta 2019; 1095:204-211. [PMID: 31864624 DOI: 10.1016/j.aca.2019.10.031] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 10/10/2019] [Accepted: 10/16/2019] [Indexed: 12/25/2022]
Abstract
The abnormal expression of sialic acids (SAs) on cells and tissues is closely related to various pathophysiological states. Here we applied phenylboronic acid (PBA) functionalized graphitic carbon nitride fluorescent quantum dots (PCQDs) with sizes from 3 to 5 nm in efficient and selective labeling SAs on the surface of living cells and tissues. With abundant PBA in their structure, the water soluble PCQDs showed the relative SA level on the cell surface via selectively and efficiently staining different cell lines in 30 min and revealed that M1 macrophages may express more SAs on their surfaces compared with M0 and M2. The distinct demarcation of cancerous and para-noncancerous areas on cancer tissue sections was showed by PCQDs staining. PCQDs with their high selectivity, stable photoluminescence, low cost, and nontoxicity can be an ideal SA fluorescent probe for living cells and tissues.
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Affiliation(s)
- Mo Zhang
- Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China
| | - Qing Wang
- Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China
| | - Yupin Xu
- Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China
| | - Lei Guo
- Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China
| | - Zhizhen Lai
- Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China
| | - Zhili Li
- Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
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Gurung MK, Altermark B, Helland R, Smalås AO, Ræder ILU. Features and structure of a cold active N-acetylneuraminate lyase. PLoS One 2019; 14:e0217713. [PMID: 31185017 PMCID: PMC6559660 DOI: 10.1371/journal.pone.0217713] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 05/16/2019] [Indexed: 11/23/2022] Open
Abstract
N-acetylneuraminate lyases (NALs) are enzymes that catalyze the reversible cleavage and synthesis of sialic acids. They are therefore commonly used for the production of these high-value sugars. This study presents the recombinant production, together with biochemical and structural data, of the NAL from the psychrophilic bacterium Aliivibrio salmonicida LFI1238 (AsNAL). Our characterization shows that AsNAL possesses high activity and stability at alkaline pH. We confirm that these properties allow for the use in a one-pot reaction at alkaline pH for the synthesis of N-acetylneuraminic acid (Neu5Ac, the most common sialic acid) from the inexpensive precursor N-acetylglucosamine. We also show that the enzyme has a cold active nature with an optimum temperature for Neu5Ac synthesis at 20°C. The equilibrium constant for the reaction was calculated at different temperatures, and the formation of Neu5Ac acid is favored at low temperatures, making the cold active enzyme a well-suited candidate for use in such exothermic reactions. The specific activity is high compared to the homologue from Escherichia coli at three tested temperatures, and the enzyme shows a higher catalytic efficiency and turnover number for cleavage at 37°C. Mutational studies reveal that amino acid residue Asn 168 is important for the high kcat. The crystal structure of AsNAL was solved to 1.65 Å resolution and reveals a compact, tetrameric protein similar to other NAL structures. The data presented provides a framework to guide further optimization of its application in sialic acid production and opens the possibility for further design of the enzyme.
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Affiliation(s)
- Man Kumari Gurung
- The Norwegian Structural Biology Center (NorStruct), Department of Chemistry, UiT- The Arctic University of Norway, Tromsø, Norway
| | - Bjørn Altermark
- The Norwegian Structural Biology Center (NorStruct), Department of Chemistry, UiT- The Arctic University of Norway, Tromsø, Norway
| | - Ronny Helland
- The Norwegian Structural Biology Center (NorStruct), Department of Chemistry, UiT- The Arctic University of Norway, Tromsø, Norway
| | - Arne O. Smalås
- The Norwegian Structural Biology Center (NorStruct), Department of Chemistry, UiT- The Arctic University of Norway, Tromsø, Norway
| | - Inger Lin U. Ræder
- The Norwegian Structural Biology Center (NorStruct), Department of Chemistry, UiT- The Arctic University of Norway, Tromsø, Norway
- * E-mail:
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Shahvali S, Shahesmaeili A, Sanjari M, Karami-Mohajeri S. The correlation between blood oxidative stress and sialic acid content in diabetic patients with nephropathy, hypertension, and hyperlipidemia. Diabetol Int 2019; 11:19-26. [PMID: 31950000 DOI: 10.1007/s13340-019-00395-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 04/23/2019] [Indexed: 12/23/2022]
Abstract
This clinical study was designed to find out the correlation between oxidative stress and sialic acid (SA) content of plasma and RBCs in patients with type 2 diabetes. We evaluated SA concentration and oxidative stress biomarkers in healthy subjects and diabetic patients with and without complications in a cross-sectional survey. Significant changes in oxidative stress biomarkers and RBC-SA were revealed in the diabetic patients compared to those in the healthy group. Plasma SA significantly increased with an increase in lipid peroxidation of RBCs (LPO-RBC) (P < 0.001) in the diabetic patients without complication. RBC-SA significantly decreased with an elevation in LPO-RBC (P < 0.001) in all the diabetic patients and those with nephropathy. There was no significant correlation between plasma and RBC-SA and other oxidative stress biomarkers in the diabetic subjects. In multiple logistic regression analysis, RBC-SA was independently related to LPO-RBC in all the diabetic patients and those with nephropathy. We conclude that the induction of LPO-RBC in diabetic patients and those with nephropathy may influence the SA decomposition of RBC membrane, thereby altering its functions and transporter activities. Therefore, LPO-RBC and SA levels in RBCs can be used for prediction of diabetic nephropathy, and further studies to evaluate other factors contributing to desialylation of RBC membrane are justified.
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Affiliation(s)
- Sedigheh Shahvali
- 1Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.,2Pharmaceutics Research Center, Institute of Neuropharmacology, Faculty of Pharmacy, Kerman University of Medical Sciences, Haft Bagh-e-Alavi Highway, 7616911319 Kerman, Iran
| | - Armita Shahesmaeili
- 3Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Mojgan Sanjari
- 1Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Somayyeh Karami-Mohajeri
- 2Pharmaceutics Research Center, Institute of Neuropharmacology, Faculty of Pharmacy, Kerman University of Medical Sciences, Haft Bagh-e-Alavi Highway, 7616911319 Kerman, Iran
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Nontypeable Haemophilus influenzae Has Evolved Preferential Use of N-Acetylneuraminic Acid as a Host Adaptation. mBio 2019; 10:mBio.00422-19. [PMID: 31064827 PMCID: PMC6509186 DOI: 10.1128/mbio.00422-19] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Host-adapted bacterial pathogens such as NTHi cannot survive out of their host environment and have evolved host-specific mechanisms to obtain nutrients and evade the immune response. Relatively few of these host adaptations have been characterized at the molecular level. NTHi utilizes sialic acid as a nutrient and also incorporates this sugar into LOS, which is important in biofilm formation and immune evasion. In the present study, we showed that NTHi has evolved to preferentially utilize the Neu5Ac form of sialic acid. This adaptation is due to the substrate preference of the enzyme CMP-Neu5Ac synthetase, which synthesizes the activated form of Neu5Ac for macromolecule biosynthesis. This adaptation allows NTHi to evade killing by a human antibody response against the nonhuman sialic acid Neu5Gc. Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative bacterial pathogen that is adapted exclusively to human hosts. NTHi utilizes sialic acid from the host as a carbon source and as a terminal sugar on the outer membrane glycolipid lipooligosaccharide (LOS). Sialic acid expressed on LOS is critical in NTHi biofilm formation and immune evasion. There are two major forms of sialic acids in most mammals, N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), the latter of which is derived from Neu5Ac. Humans lack the enzyme to convert Neu5Ac to Neu5Gc and do not express Neu5Gc in normal tissues; instead, Neu5Gc is recognized as a foreign antigen. A recent study showed that dietary Neu5Gc can be acquired by NTHi colonizing humans and then presented on LOS, which acts as an antigen for the initial induction of anti-Neu5Gc antibodies. Here we examined Neu5Gc uptake and presentation on NTHi LOS. We show that, although Neu5Gc and Neu5Ac are utilized equally well as sole carbon sources, Neu5Gc is not incorporated efficiently into LOS. When equal amounts of Neu5Gc and Neu5Ac are provided in culture media, there is ∼4-fold more Neu5Ac incorporated into LOS, suggesting a bias in a step of the LOS biosynthetic pathway. CMP-Neu5Ac synthetase (SiaB) was shown to have ∼4,000-fold-higher catalytic efficiency for Neu5Ac than for Neu5Gc. These data suggest that NTHi has adapted preferential utilization of Neu5Ac, thus avoiding presentation of the nonhuman Neu5Gc in the bacterial cell surface. The selective pressure for this adaptation may represent the human antibody response to the Neu5Gc xenoantigen.
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A selective probe based on 3‑aminophenyl boronic acid assembly on dithiobis(succinimidylpropionate) functionalized gold nanoparticles for sialic acid detection in human serum. J Mol Liq 2019. [DOI: 10.1016/j.molliq.2019.02.112] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Johnson A, Baeten J, Patel K, Killian M, Sunny S, Suresh A, Uma K, Birur P, Kuriakose M, Kademani D. Evaluation of a Lectin-Based Imaging System for the Chairside Detection of Oral Dysplasia and Malignancy. J Oral Maxillofac Surg 2019; 77:1941-1951. [PMID: 31004587 DOI: 10.1016/j.joms.2019.03.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 03/14/2019] [Accepted: 03/14/2019] [Indexed: 02/04/2023]
Abstract
PURPOSE Currently available oral cancer screening adjuncts have not enhanced clinical screening methods because of high false positives and negatives, highlighting the need for a molecularly specific technique for accurate screening of suspicious oral lesions. The purpose of this study was to evaluate the in vivo screening accuracy of an oral lesion identification system that evaluates aberrant glycosylation patterns using a fluorescently labeled lectin (wheat germ agglutinin and fluorescein isothiocyanate [WGA-FITC]). MATERIALS AND METHODS The authors designed and implemented a prospective cohort study at 3 institutions composed of patients with and without suspicious oral lesions. Oral cavities were screened by clinical examination and with the oral lesion identification system according to a stepwise procedure that included the topical application and fluorescence visualization of a fluorescent nuclear stain and WGA-FITC. Tissue samples were obtained from all enrolled patients for histopathological diagnosis and were used to calculate sensitivity and specificity metrics (primary outcome variable) irrespective of the oral lesion identification system result. RESULTS The sample was composed of 97 patients; 86 had 100 clinically suspicious lesions and 11 without such lesions were included as a control group. Use of the oral lesion identification system resulted in 100, 100, and 74% sensitivity for cancer, high-grade dysplasia, and low-grade dysplasia, respectively, and a specificity of 80%. Clinical diagnosis yielded similar sensitivity values of 84, 100, and 88% for cancer, high-grade dysplasia, and low-grade dysplasia, respectively, and a specificity of 76%. Use of the oral lesion identification system enhanced the visualization of lesion dimensionality and borders. CONCLUSIONS The results of this study suggest the oral lesion identification system was a beneficial adjunct to standard clinical examination, because the system provided sensitivity and specificity values similar to or greater than clinical diagnosis.
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Affiliation(s)
| | - John Baeten
- Director of Engineering/Research and Development, Inter-Med, Inc, Racine, WI
| | - Ketan Patel
- Attending Surgeon, North Memorial Health Care, Robbinsdale, MN
| | - Molly Killian
- Clinical Research Coordinator, North Memorial Health Care, Robbinsdale, MN
| | - Sumsum Sunny
- Fellow, Mazumdar Shaw Cancer Center, Bangalore, India
| | - Amritha Suresh
- Research Scientist, Mazumdar Shaw Cancer Center, Bangalore, India
| | - K Uma
- Oral Pathologist, KLES Dental College, Bangalore, India
| | - Praveen Birur
- Professor and Department Head, Oral Medicine and Radiology, KLES Dental College, Bangalore, India
| | - Moni Kuriakose
- Professor and Director, Department of Surgical Oncology, Narayana Hrudayalaya Hospital, Bangalore, India; Professor of Oncology and Director of Head and Neck Oncology Research Program, Roswell Park Cancer Institute, Buffalo, NY
| | - Deepak Kademani
- Chief of Surgery, Chief and Fellowship Director, Oral and Maxillofacial Surgery, North Memorial Medical Center, Robbinsdale, MN.
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Lochmüller H, Behin A, Caraco Y, Lau H, Mirabella M, Tournev I, Tarnopolsky M, Pogoryelova O, Woods C, Lai A, Shah J, Koutsoukos T, Skrinar A, Mansbach H, Kakkis E, Mozaffar T. A phase 3 randomized study evaluating sialic acid extended-release for GNE myopathy. Neurology 2019; 92:e2109-e2117. [PMID: 31036580 PMCID: PMC6512882 DOI: 10.1212/wnl.0000000000006932] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 11/20/2018] [Indexed: 12/23/2022] Open
Abstract
Objective To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy. Methods UX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by upper extremity composite (UEC) score. Key secondary endpoints included change in lower extremity composite (LEC) score, knee extensor strength, and GNE myopathy–Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results. Results Eighty-nine patients were randomized (Ace-ER n = 45; placebo n = 44). Change from baseline to week 48 for UEC score between treatments did not differ (least square mean [LSM] Ace-ER −2.25 kg vs placebo −2.99 kg; LSM difference confidence interval [CI] 0.74 [−1.61 to 3.09]; p = 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) −1.49 (−5.83 to 2.86); knee extension strength −0.40 (−2.38 to 1.58); and GNEM-FAS mobility domain score −0.72 (−2.01 to 0.57). Gastrointestinal events were the most common AEs. Conclusions Ace-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy. Classification of evidence This study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.
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Affiliation(s)
- Hanns Lochmüller
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany.
| | - Anthony Behin
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Yoseph Caraco
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Heather Lau
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Massimiliano Mirabella
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Ivailo Tournev
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Mark Tarnopolsky
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Oksana Pogoryelova
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Catherine Woods
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Alexander Lai
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Jinay Shah
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Tony Koutsoukos
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Alison Skrinar
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Hank Mansbach
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Emil Kakkis
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
| | - Tahseen Mozaffar
- From the Institute of Genetic Medicine (H.L., O.P.), Newcastle University, Newcastle upon Tyne, UK; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa; Division of Neurology, Department of Medicine (H.L.), The Ottawa Hospital, Canada; APHP (A.B.), Centre de Référence de Pathologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Hadassah Clinical Research Center (Y.C.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Department of Neurology, Division of Neurogenetics (H.L.), NYU School of Medicine, New York, NY; Fondazione Policlinico Universitario A. Gemelli IRCCS (M.M.), Catholic University, Rome, Italy; Expert Center of Genetic Neurologic and Metabolic Disorders (I.T.), University Hospital Aleksandrovska, Sofia; Department of Neurology (I.T.), Medical University Sofia; Department of Cognitive Science and Psychology (I.T.), New Bulgarian University, Sofia, Bulgaria; Department of Pediatrics, Neuromuscular and Neurometabolic Clinic (M.T.), McMaster University Medical Center, Hamilton, Canada; Ultragenyx Pharmaceutical Inc. (C.W., A.L., J.S., T.K., A.S., H.M., E.K.), Novato, CA; and University of California Irvine (T.M.), Orange. H.L. is currently affiliated with the Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Germany
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Gruszewska E, Cylwik B, Gudowska M, Panasiuk A, Flisiak R, Chrostek L. The concentration of total sialic acid in chronic hepatitis B and C. Ann Clin Biochem 2018; 56:118-122. [PMID: 30027776 DOI: 10.1177/0004563218792292] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The synthesis and glycosylation of glycoproteins and glycolipids take place in the liver. Thus, liver diseases may affect serum concentrations of some carbohydrate derivatives, especially the concentration of sialic acid which is attached to the end of oligosaccharide chains. The aim of this study was to measure and compare the serum concentration of total sialic acid in chronic hepatitis B and C. The hypothesis is that both viruses responsible for the development of inflammation work differently at the cellular level. METHODS Serum samples were obtained from 90 patients suffering from liver diseases: 50 from chronic hepatitis B and 40 from chronic hepatitis C at the time of diagnosis. The total sialic acid concentration in the serum was measured according to the enzymatic method using a colorimetric procedure. RESULTS The mean total sialic acid concentration in patients with chronic hepatitis B was significantly lower than the mean concentration in the healthy group, while in patients with chronic hepatitis C, it was significantly higher than that in healthy people and in patients suffering from chronic hepatitis B. There were no significant differences in total sialic acid concentrations in patients with chronic hepatitis B and C according to the grade of portal/periportal activity, the grade of lobular activity and the stage of fibrosis. CONCLUSIONS We conclude that chronic viral hepatitis affects the total serum concentration of sialic acid. Moreover, the concentration of total sialic acid may be a useful marker to differentiate between chronic hepatitis B and C but is not useful for evaluation of the progression of these diseases.
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Affiliation(s)
- Ewa Gruszewska
- 1 Department of Biochemical Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | - Bogdan Cylwik
- 2 Department of Pediatric Laboratory Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | - Monika Gudowska
- 1 Department of Biochemical Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | - Anatol Panasiuk
- 3 Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
| | - Robert Flisiak
- 3 Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
| | - Lech Chrostek
- 1 Department of Biochemical Diagnostics, Medical University of Bialystok, Bialystok, Poland
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Colorimetric determination of sialic acid based on boronic acid-mediated aggregation of gold nanoparticles. Mikrochim Acta 2018; 185:409. [DOI: 10.1007/s00604-018-2951-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/03/2018] [Indexed: 10/28/2022]
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Elevated urinary total sialic acid and increased oxidative stress in patients with bladder cancer. ASIAN BIOMED 2018. [DOI: 10.2478/abm-2010-0092] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Abstract
Background: Increased production and release of sialic acid have been reported in many malignant conditions including bladder cancer. 8-hydroxydeoxyguanosine (8-OHdG) and malondialdehyde (MDA) have been widely used as oxidative stress biomarkers. Objective: Determine urinary levels of total sialic acid (TSA), 8-OHdG, and MDA in patients with urinary bladder cancer, and evaluate their clinical relevance. Patients and methods: Forty-five patients with histologically proven bladder cancer and 41 healthy subjects were recruited for the study. Morning urine samples were collected from all participants for measurements of TSA, 8-OHdG and MDA using thiobarbituric assay, competitive ELISA and spectrophotometry methods, respectively. Histological examination was performed for all patients. Results: Bladder cancer patients excreted urinary TSA, 8-OHdG, and MDA significantly higher than healthy controls. Based on receiver operating characteristic curve analysis, urinary TSA had adequate diagnostic potential to distinguish patients from healthy populations, and its cutoff value was chosen at 95.26 μg/g creatinine. Sensitivity, specificity, and accuracy of urinary TSA determination were 75.6%, 75.6%, and 75.6%, respectively. Both in patient and healthy groups, urinary TSA was linearly correlated with urinary 8-OHdG. Patients with highseverity grade (n=27) excreted urinary TSA significantly greater than those with low-severity grade (n=18). Conclusion: Urinary TSA, 8-OHdG, and MDA increased in patients with bladder cancer. The elevated urinary TSA was associated with enhanced oxidative stress. In addition, urinary TSA increased with progressiveness of the tumor.
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Metabolic flux-driven sialylation alters internalization, recycling, and drug sensitivity of the epidermal growth factor receptor (EGFR) in SW1990 pancreatic cancer cells. Oncotarget 2018; 7:66491-66511. [PMID: 27613843 PMCID: PMC5341816 DOI: 10.18632/oncotarget.11582] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 08/01/2016] [Indexed: 12/12/2022] Open
Abstract
In prior work we reported that advanced stage, drug-resistant pancreatic cancer cells (the SW1990 line) can be sensitized to the EGFR-targeting tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib by treatment with 1,3,4-O-Bu3ManNAc (Bioorg. Med. Chem. Lett. (2015) 25(6):1223-7). Here we provide mechanistic insights into how this compound inhibits EGFR activity and provides synergy with TKI drugs. First, we showed that the sialylation of the EGFR receptor was at most only modestly enhanced (by ∼20 to 30%) compared to overall ∼2-fold increase in cell surface levels of this sugar. Second, flux-driven sialylation did not alter EGFR dimerization as has been reported for cancer cell lines that experience increased sialylation due to spontaneous mutations. Instead, we present evidence that 1,3,4-O-Bu3ManNAc treatment weakens the galectin lattice, increases the internalization of EGFR, and shifts endosomal trafficking towards non-clathrin mediated (NCM) endocytosis. Finally, by evaluating downstream targets of EGFR signaling, we linked synergy between 1,3,4-O-Bu3ManNAc and existing TKI drugs to a shift from clathrin-coated endocytosis (which allows EGFR signaling to continue after internalization) towards NCM endocytosis, which targets internalized moieties for degradation and thereby rapidly diminishes signaling.
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Demir SS, Özcan HÇ, Balat Ö, Öztürk E, Uğur MG, Gündüz R, Taysi S. Assessment of total sialic acid levels in patients with hyperemesis gravidarum: a preliminary study. J OBSTET GYNAECOL 2018; 38:532-535. [PMID: 29390942 DOI: 10.1080/01443615.2017.1367765] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
To determine the levels of serum total sialic acid (TSA) in patients with hyperemesis gravidarum (HG) and their gestational age-matched controls. Thirty pregnant women with HG, and 30 healthy pregnant women at up to 14 weeks of gestation were enrolled in this preliminary study. Total sialic acid levels in maternal serum were measured using the quantitative sandwich ELISA method. We observed statistically significant difference in TSA levels between HG and the control groups (p = .003). The identification of the role of SA in the prediction, diagnosis and follow-up of HG warrants more comprehensive studies in the future. Impact Statement What is already known on this subject? The derivatives of neuraminic acid are collectively referred to as sialic acid (SA). Changes in SA levels are known to trigger various conditions and disorders, including inflammatory, cardiovascular, neurological and endocrine diseases. Although a sensitive test capable of identifying hyperemesis gravidarum (HG) would be useful for diagnosis purposes, such a test is currently not available. Studies focussing on identifying new potential indicators and biomarkers for HG - as well as identifying their relevance in establishing diagnosis and assessing disease severity - would not only assist in elucidating the underlying causes of this condition but would also contribute to the development of new diagnostic tests for HG. What the results of this study add? Total sialic acid levels are significantly higher in sera of the patients with HG. The present study is the first in the literature to assess total sialic acid levels in patients with HG and healthy pregnant women before 14 weeks of gestation. What the implications are of these findings for clinical practice and/or further research? Total sialic acid levels could give an idea to clinicians in the etiopathogenesis of HG. The identification of the role of sialic acid in the prediction, diagnosis and follow-up of HG warrants more comprehensive studies in the future.
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Affiliation(s)
| | - Hüseyin Çağlayan Özcan
- b Department of Obstetrics and Gynecology, School of Medicine , Gaziantep University , Gaziantep , Turkey
| | - Özcan Balat
- b Department of Obstetrics and Gynecology, School of Medicine , Gaziantep University , Gaziantep , Turkey
| | | | - Mete Gurol Uğur
- b Department of Obstetrics and Gynecology, School of Medicine , Gaziantep University , Gaziantep , Turkey
| | - Reyhan Gündüz
- b Department of Obstetrics and Gynecology, School of Medicine , Gaziantep University , Gaziantep , Turkey
| | - Seyithan Taysi
- d Department of Biochemistry, School of Medicine , Gaziantep University , Gaziantep , Turkey
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Feijoo-Carnero C, Rodríguez-Berrocal FJ, Páez de la Cadena M, Ayude D, de Carlos A, Martínez-Zorzano VS. Clinical Significance of Preoperative Serum Sialic Acid Levels in Colorectal Cancer: Utility in the Detection of Patients at High Risk of Tumor Recurrence. Int J Biol Markers 2018; 19:38-45. [PMID: 15077925 DOI: 10.1177/172460080401900105] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
This study was conducted to evaluate the significance of preoperative serum sialic acid levels in the diagnosis and prognosis of colorectal cancer (CRC). Total sialic acid (TSA) was determined by the thiobarbituric acid method and normalized to total protein (TP). A postoperative follow-up of CRC patients classified as Dukes’ stages A, B or C was performed and survival analysis was carried out to evaluate the impact of sialic acid levels on tumor recurrence. Our diagnostic studies indicate that TSA/TP is a better marker than either TSA or carcinoembryonic antigen (CEA), especially for the detection of CRC patients at an early stage. At a cutoff of 30.90 nmol/mg of protein, TSA/TP showed a sensitivity of 85% with a specificity of 97% to discriminate CRC patients from healthy donors. In survival analysis, both TSA and TSA/TP were found to be significant prognostic factors for tumor recurrence in CRC. Furthermore, TSA/TP could distinguish patients at high risk of recurrence within Dukes’ stage B and in multivariate analysis it was identified as the best independent prognostic factor. According to our results, preoperative serum TSA/TP content could supply additional information to that provided by Dukes’ stage about the prognosis of CRC patients.
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Affiliation(s)
- C Feijoo-Carnero
- Department of Biochemistry, Genetics and Immunology, University of Vigo, Vigo, Spain
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