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New Insights on Roles of Glycoconjugates in Health and Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 16060

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Special Issue Editor

Prof. Dr. Kazunori Hamamura

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Guest Editor

Department of Pharmacology, School of Dentistry, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan
Interests: glycosylation; glycosphingolipids; bone metabolism; malignant properties
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Glycosylation is a biological process that attaches carbohydrates to proteins and lipids. Glycoconjugates have been considered to play important roles in the maintenance of the homeostasis of organisms and in the pathogenesis of various diseases. For instance, glycosphingolipids consist of carbohydrate chains and ceramide and regulate bone metabolism and endocrine metabolism. On the other hand, they are involved in nerve degeneration and the promotion of the malignant properties of cancer cells. As one of the mechanisms, the localization of glycosphingolipids in lipid raft regulates the interaction of membrane molecules to control cellular signalling. As for glycoproteins, it has been known that the fucosylation of N-glycans and O-glycans on various receptors leads to the regulation of signalling in cancer cells.

This Special Issue, entitled New Insights on Roles of Glycoconjugates in Health and Diseases, will cover research topics and current review articles in the field.

Prof. Dr. Kazunori Hamamura
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

glycosylation
glycoconjugates
glycolipids
gangliosides
glycoproteins

Published Papers (7 papers)

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Research

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20 pages, 2245 KiB

Open AccessArticle

Brain N-Glycosylation and Lipidomic Profile Changes Induced by a High-Fat Diet in Dyslipidemic Hamsters

by Beatrix Paton, Elisabet Foguet-Romero, Manuel Suarez, Jordi Mayneris-Perxachs, Noemí Boqué, Antoni Caimari, Núria Canela and Pol Herrero

Int. J. Mol. Sci. 2023, 24(3), 2883; https://doi.org/10.3390/ijms24032883 - 2 Feb 2023

Cited by 1 | Viewed by 1645

Abstract

The consumption of diets rich in saturated fats is known to be associated with higher mortality. The adoption of healthy habits, for instance adhering to a Mediterranean diet, has proved to exert a preventive effect towards cardiovascular diseases and dyslipidemia. Little is known about how a suboptimal diet can affect brain function, structure, and the mechanisms involved. The aims of this study were to examine how a high-fat diet can alter the brain N-glycan and lipid profile in male Golden Syrian hamsters and to evaluate the potential of a Mediterranean-like diet to reverse this situation. During twelve weeks, hamsters were fed a normal fat diet (CTRL group), a high-fat diet (HFD group), and a high-fat diet followed by a Mediterranean-like diet (MED group). Out of seventy-two identified N-glycans, fourteen were significant (p < 0.05) between HFD and CTRL groups, nine between MED and CTRL groups, and one between MED and HFD groups. Moreover, forty-nine lipids were altered between HFD and CTRL groups, seven between MED and CTRL groups, and five between MED and HFD groups. Our results suggest that brain N-glycan composition in high-fat diet-fed hamsters can produce events comparable to those found in some neurodegenerative diseases, and may promote brain ageing. Full article

(This article belongs to the Special Issue New Insights on Roles of Glycoconjugates in Health and Diseases)

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17 pages, 2868 KiB

Open AccessArticle

In Vivo and In Silico Analgesic Activity of Ficus populifolia Extract Containing 2-O-β-D-(3′,4′,6′-Tri-acetyl)-glucopyranosyl-3-methyl Pentanoic Acid

by Hamdoon A. Mohammed, Amr S. Abouzied, Salman A. A. Mohammed and Riaz A. Khan

Int. J. Mol. Sci. 2023, 24(3), 2270; https://doi.org/10.3390/ijms24032270 - 23 Jan 2023

Cited by 5 | Viewed by 2109

Abstract

Natural product-based structural templates have immensely shaped small molecule drug discovery, and new biogenic natural products have randomly provided the leads and molecular targets in anti-analgesic activity spheres. Pain relief achieved through opiates and non-steroidal anti-inflammatory drugs (NSAIDs) has been under constant scrutiny owing to their tolerance, dependency, and other organs toxicities and tissue damage, including harm to the gastrointestinal tract (GIT) and renal tissues. A new, 3′,4′,6′-triacetylated-glucoside, 2-O-β-D-(3′,4′,6′-tri-acetyl)-glucopyranosyl-3-methyl pentanoic acid was obtained from Ficus populifolia, and characterized through a detailed NMR spectroscopic analysis, i.e., ¹H-NMR, ¹³C-DEPT-135, and the 2D nuclear magnetic resonance (NMR) correlations. The product was in silico investigated for its analgesic prowess, COX-2 binding feasibility and scores, drug likeliness, ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, possible biosystem’s toxicity using the Discovery Studio^®, and other molecular studies computational software programs. The glycosidic product showed strong potential as an analgesic agent. However, an in vivo evaluation, though at strong levels of pain-relieving action, was estimated on the compound’s extract owing to the quantity and yield issues of the glycosidic product. Nonetheless, the F. populifolia extract showed the analgesic potency in eight-week-old male mice on day seven of the administration of the extract’s dose in acetic acid-induced writhing and hot-plate methods. Acetic acid-induced abdominal writhing for all the treated groups decreased significantly (p < 0.0001), as compared to the control group (n = 6) by 62.9%, 67.9%, and 70.9% of a dose of 100 mg/kg (n = 6), 200 mg/kg (n = 6), and 400 mg/kg (n = 6), respectively. Similarly, using the analgesia meter, the reaction time to pain sensation increased significantly (p < 0.0001), as compared to the control (n = 6). The findings indicated peripheral and central-nervous-system-mediated analgesic action of the product obtained from the corresponding extract. Full article

(This article belongs to the Special Issue New Insights on Roles of Glycoconjugates in Health and Diseases)

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14 pages, 3022 KiB

Open AccessArticle

Lung Tumor Cells with Different Tn Antigen Expression Present Distinctive Immunomodulatory Properties

by Valeria da Costa, Karina V. Mariño, Santiago A. Rodríguez-Zraquia, María Florencia Festari, Pablo Lores, Monique Costa, Mercedes Landeira, Gabriel A. Rabinovich, Sandra J. van Vliet and Teresa Freire

Int. J. Mol. Sci. 2022, 23(19), 12047; https://doi.org/10.3390/ijms231912047 - 10 Oct 2022

Cited by 4 | Viewed by 1983

Abstract

Lung cancer is the first leading cause of cancer-related deaths in the world. Aberrant glycosylation in lung tumors leads to the expression of tumor-associated carbohydrate structures, such as the Tn antigen, consisting of N-acetyl-galactosamine (GalNAc) linked to a serine or threonine residue in proteins (α-GalNAc-O-Ser/Thr). The Tn antigen can be recognized by the Macrophage Galactose/GalNAc lectin (MGL), which mediates various immune regulatory and tolerogenic functions, mainly by reprogramming the maturation of function of dendritic cells (DCs). In this work, we generated two different Tn-expressing variants from the Lewis-type lung murine cancer cell line LL/2, which showed different alterations in the O-glycosylation pathways that influenced the interaction with mouse MGL2 and the immunomodulatory properties of DCs. Thus, the identification of the biological programs triggered by Tn⁺ cancer cells might contribute to an improved understanding of the molecular mechanisms elicited by MGL-dependent immune regulatory circuits. Full article

(This article belongs to the Special Issue New Insights on Roles of Glycoconjugates in Health and Diseases)

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18 pages, 4623 KiB

Open AccessArticle

Attenuation of Bone Formation through a Decrease in Osteoblasts in Mutant Mice Lacking the GM2/GD2 Synthase Gene

by Eri Sasaki, Kazunori Hamamura, Yoshitaka Mishima, Koichi Furukawa, Mayu Nagao, Hanami Kato, Kosuke Hamajima, Takuma Sato, Ken Miyazawa, Shigemi Goto and Akifumi Togari

Int. J. Mol. Sci. 2022, 23(16), 9044; https://doi.org/10.3390/ijms23169044 - 12 Aug 2022

Cited by 2 | Viewed by 1661

Abstract

The ganglioside GD1a has been reported to promote the differentiation of mesenchymal stem cells to osteoblasts in cell culture systems. However, the involvement of gangliosides, including GD1a, in bone formation in vivo remains unknown; therefore, we herein investigated their roles in GM2/GD2 synthase-knockout (GM2/GD2S KO) mice without GD1a. The femoral cancellous bone mass was analyzed using three-dimensional micro-computed tomography. A histomorphometric analysis of bone using hematoxylin and eosin (HE) and tartrate-resistant acid phosphatase was performed to examine bone formation and resorption, respectively. Calcein double labeling was also conducted to evaluate bone formation. Although no significant differences were observed in bone mass or resorption between GM2/GD2S KO mice and wild-type (WT) mice, analyses of the parameters of bone formation using HE staining and calcein double labeling revealed less bone formation in GM2/GD2S KO mice than in WT mice. These results suggest that gangliosides play roles in bone formation. Full article

(This article belongs to the Special Issue New Insights on Roles of Glycoconjugates in Health and Diseases)

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15 pages, 3115 KiB

Open AccessArticle

Cancer Malignancy Is Correlated with Upregulation of PCYT2-Mediated Glycerol Phosphate Modification of α-Dystroglycan

by Fumiko Umezawa, Makoto Natsume, Shigeki Fukusada, Kazuki Nakajima, Fumiya Yamasaki, Hiroto Kawashima, Chu-Wei Kuo, Kay-Hooi Khoo, Takaya Shimura, Hirokazu Yagi and Koichi Kato

Int. J. Mol. Sci. 2022, 23(12), 6662; https://doi.org/10.3390/ijms23126662 - 15 Jun 2022

Cited by 3 | Viewed by 2737

Abstract

The dystrophin–glycoprotein complex connects the cytoskeleton with base membrane components such as laminin through unique O-glycans displayed on α-dystroglycan (α-DG). Genetic impairment of elongation of these glycans causes congenital muscular dystrophies. We previously identified that glycerol phosphate (GroP) can cap the core part of the α-DG O-glycans and terminate their further elongation. This study examined the possible roles of the GroP modification in cancer malignancy, focusing on colorectal cancer. We found that the GroP modification critically depends on PCYT2, which serves as cytidine 5′-diphosphate-glycerol (CDP-Gro) synthase. Furthermore, we identified a significant positive correlation between cancer progression and GroP modification, which also correlated positively with PCYT2 expression. Moreover, we demonstrate that GroP modification promotes the migration of cancer cells. Based on these findings, we propose that the GroP modification by PCYT2 disrupts the glycan-mediated cell adhesion to the extracellular matrix and thereby enhances cancer metastasis. Thus, the present study suggests the possibility of novel approaches for cancer treatment by targeting the PCYT2-mediated GroP modification. Full article

(This article belongs to the Special Issue New Insights on Roles of Glycoconjugates in Health and Diseases)

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Review

Jump to: Research

13 pages, 2986 KiB

Open AccessReview

The Regulatory Roles of Cerebellar Glycosphingolipid Microdomains/Lipid Rafts

by Keisuke Komatsuya, Norihito Kikuchi, Tetsuya Hirabayashi and Kohji Kasahara

Int. J. Mol. Sci. 2023, 24(6), 5566; https://doi.org/10.3390/ijms24065566 - 14 Mar 2023

Cited by 3 | Viewed by 2154

Abstract

Lipid rafts are dynamic assemblies of glycosphingolipids, sphingomyelin, cholesterol, and specific proteins which are stabilized into platforms involved in the regulation of vital cellular processes. Cerebellar lipid rafts are cell surface ganglioside microdomains for the attachment of GPI-anchored neural adhesion molecules and downstream signaling molecules such as Src-family kinases and heterotrimeric G proteins. In this review, we summarize our recent findings on signaling in ganglioside GD3 rafts of cerebellar granule cells and several findings by other groups on the roles of lipid rafts in the cerebellum. TAG-1, of the contactin group of immunoglobulin superfamily cell adhesion molecules, is a phosphacan receptor. Phosphacan regulates the radial migration signaling of cerebellar granule cells, via Src-family kinase Lyn, by binding to TAG-1 on ganglioside GD3 rafts. Chemokine SDF-1α, which induces the tangential migration of cerebellar granule cells, causes heterotrimeric G protein Goα translocation to GD3 rafts. Furthermore, the functional roles of cerebellar raft-binding proteins including cell adhesion molecule L1, heterotrimeric G protein Gsα, and L-type voltage-dependent calcium channels are discussed. Full article

(This article belongs to the Special Issue New Insights on Roles of Glycoconjugates in Health and Diseases)

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19 pages, 1601 KiB

Open AccessReview

Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG)

by Sandra Brasil, Mariateresa Allocca, Salvador C. M. Magrinho, Inês Santos, Madalena Raposo, Rita Francisco, Carlota Pascoal, Tiago Martins, Paula A. Videira, Florbela Pereira, Giuseppina Andreotti, Jaak Jaeken, Kristin A. Kantautas, Ethan O. Perlstein and Vanessa dos Reis Ferreira

Int. J. Mol. Sci. 2022, 23(15), 8725; https://doi.org/10.3390/ijms23158725 - 5 Aug 2022

Cited by 6 | Viewed by 2923

Abstract

Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid glycosylation and glycosylphosphatidylinositol anchor biosynthesis. The (re)use of known drugs for novel medical purposes, known as drug repositioning, is growing for both common and rare disorders. The latest innovation concerns the rational search for repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, drug repositioning accelerates the overall drug discovery process while saving costs. This is particularly valuable for rare diseases. AI tools have proven their worth in diagnosis, in disease classification and characterization, and ultimately in therapy discovery in rare diseases. The availability of biomarkers and reliable disease models is critical for research and development of new drugs, especially for rare and heterogeneous diseases such as CDG. This work reviews the literature related to repositioned drugs for CDG, discovered by serendipity or through a systemic approach. Recent advances in biomarkers and disease models are also outlined as well as stakeholders’ views on AI for therapy discovery in CDG. Full article

(This article belongs to the Special Issue New Insights on Roles of Glycoconjugates in Health and Diseases)

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