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Journal of Translational Medicine Jan 2023Astronauts undergo significant microgravity-induced bone loss during space missions, which has become one of the three major medical problems hindering human's long-term...
BACKGROUND
Astronauts undergo significant microgravity-induced bone loss during space missions, which has become one of the three major medical problems hindering human's long-term space flight. A risk-free and antiresorptive drug is urgently needed to prevent bone loss during space missions. D-mannose is a natural C-2 epimer of D-glucose and is abundant in cranberries. This study aimed to investigate the protective effects and potential mechanisms of D-mannose against bone loss under weightlessness.
METHODS
The hind legs of tail-suspended (TS) rats were used to mimic weightlessness on Earth. Rats were administered D-mannose intragastrically. The osteoclastogenic and osteogenic capacity of D-mannose in vitro and in vivo was analyzed by micro-computed tomography, biomechanical assessment, bone histology, serum markers of bone metabolism, cell proliferation assay, quantitative polymerase chain reaction, and western blotting. RNA-seq transcriptomic analysis was performed to detect the underlying mechanisms of D-mannose in bone protection.
RESULTS
The TS rats showed lower bone mineral density (BMD) and poorer bone morphological indices. D-mannose could improve BMD in TS rats. D-mannose inhibited osteoclast proliferation and fusion in vitro, without apparent effects on osteoblasts. RNA-seq transcriptomic analysis showed that D-mannose administration significantly inhibited the cell fusion molecule dendritic cell-specific transmembrane protein (DC-STAMP) and two indispensable transcription factors for osteoclast fusion (c-Fos and nuclear factor of activated T cells 1 [NFATc1]). Finally, TS rats tended to experience dysuria-related urinary tract infections (UTIs), which were suppressed by treatment with D-mannose.
CONCLUSION
D-mannose protected against bone loss and UTIs in rats under weightlessness. The bone protective effects of D-mannose were mediated by inhibiting osteoclast cell fusion. Our findings provide a potential strategy to protect against bone loss and UTIs during space missions.
Topics: Rats; Humans; Animals; Weightlessness; Mannose; X-Ray Microtomography; Osteoclasts; Bone Density; Bone Diseases, Metabolic; Bone Resorption
PubMed: 36617569
DOI: 10.1186/s12967-022-03870-1 -
Cellular and Molecular Life Sciences :... Aug 2013Glycosylation of proteins is arguably the most prevalent co- and post-translational modification. It is responsible for increased heterogeneity and functional diversity... (Review)
Review
Glycosylation of proteins is arguably the most prevalent co- and post-translational modification. It is responsible for increased heterogeneity and functional diversity of proteins. Here we discuss the importance of one type of glycosylation, specifically O-mannosylation and its relationship to a number of human diseases. The most widely studied O-mannose modified protein is alpha-dystroglycan (α-DG). Recent studies have focused intensely on α-DG due to the severity of diseases associated with its improper glycosylation. O-mannosylation of α-DG is involved in cancer metastasis, arenavirus entry, and multiple forms of congenital muscular dystrophy [1, 2]. In this review, we discuss the structural and functional characteristics of O-mannose-initiated glycan structures on α-DG, enzymes involved in the O-mannosylation pathway, and the diseases that are a direct result of disruptions within this pathway.
Topics: Animals; Arenaviridae Infections; Dystroglycans; Glycosylation; Humans; Mannose; Muscular Dystrophies; Neoplasm Metastasis; Neoplasms
PubMed: 23115008
DOI: 10.1007/s00018-012-1193-0 -
International Journal of Molecular... Jan 2024The mannose receptor (MR, CD 206) is an endocytic receptor primarily expressed by macrophages and dendritic cells, which plays a critical role in both endocytosis and... (Review)
Review
The mannose receptor (MR, CD 206) is an endocytic receptor primarily expressed by macrophages and dendritic cells, which plays a critical role in both endocytosis and antigen processing and presentation. MR carbohydrate recognition domains (CRDs) exhibit a high binding affinity for branched and linear oligosaccharides. Furthermore, multivalent mannose presentation on the various templates like peptides, proteins, polymers, micelles, and dendrimers was proven to be a valuable approach for the selective and efficient delivery of various therapeutically active agents to MR. This review provides a detailed account of the most relevant and recent aspects of the synthesis and application of mannosylated bioactive formulations for MR-mediated delivery in treatments of cancer and other infectious diseases. It further highlights recent findings related to the necessary structural features of the mannose-containing ligands for successful binding to the MR.
Topics: Mannose Receptor; Mannose; Receptors, Cell Surface; Mannose-Binding Lectins; Lectins, C-Type; Ligands
PubMed: 38338648
DOI: 10.3390/ijms25031370 -
Proceedings of the Japan Academy.... 2022Pradimicins (PRMs) are an exceptional family of natural products that specifically bind d-mannose (Man). In the past decade, their scientific significance has increased...
Pradimicins (PRMs) are an exceptional family of natural products that specifically bind d-mannose (Man). In the past decade, their scientific significance has increased greatly, with the emergence of biological roles of Man-containing glycans. However, research into the use of PRMs has been severely limited by their inherent tendency to form water-insoluble aggregates. Recently, we have established a derivatization strategy to suppress PRM aggregation, providing an opportunity for practical application of PRMs in glycobiological research. This article first outlines the challenges in studying Man-binding mechanisms and structural modifications of PRMs, and then describes our approach to address them. We also present our recent attempts toward the development of PRM-based research tools.
Topics: Anthracyclines; Biological Products; Humans; Mannose
PubMed: 35013028
DOI: 10.2183/pjab.98.002 -
Biochimica Et Biophysica Acta.... Nov 2020Mannose transporters constitute a superfamily (Man-PTS) of the Phosphoenolpyruvate Carbohydrate Phosphotransferase System (PTS). The membrane complexes are homotrimers... (Review)
Review
Mannose transporters constitute a superfamily (Man-PTS) of the Phosphoenolpyruvate Carbohydrate Phosphotransferase System (PTS). The membrane complexes are homotrimers of protomers consisting of two subunits, IIC and IID. The two subunits without recognizable sequence similarity assume the same fold, and in the protomer are structurally related by a two fold pseudosymmetry axis parallel to membrane-plane (Liu et al. (2019) Cell Research 29 680). Two reentrant loops and two transmembrane helices of each subunit together form the N-terminal transport domain. Two three-helix bundles, one of each subunit, form the scaffold domain. The protomer is stabilized by a helix swap between these bundles. The two C-terminal helices of IIC mediate the interprotomer contacts. PTS occur in bacteria and archaea but not in eukaryotes. Man-PTS are abundant in Gram-positive bacteria living on carbohydrate rich mucosal surfaces. A subgroup of IICIID complexes serve as receptors for class IIa bacteriocins and as channel for the penetration of bacteriophage lambda DNA across the inner membrane. Some Man-PTS are associated with host-pathogen and -symbiont processes.
Topics: Bacterial Proteins; Bacteriocins; Bacteriophages; Gram-Positive Bacteria; Mannose; Phosphotransferases; Protein Conformation, alpha-Helical; Protein Domains
PubMed: 32710850
DOI: 10.1016/j.bbamem.2020.183412 -
International Journal of Biological... Nov 2019Carbohydrate-binding proteins, also known as lectins, are valuable tools for biotechnology, including pharmacological uses. Mannose lectins obtained from plant and... (Review)
Review
Carbohydrate-binding proteins, also known as lectins, are valuable tools for biotechnology, including pharmacological uses. Mannose lectins obtained from plant and animal sources are applied to protection and characterization of autoimmune diseases as well as defense proteins against pathogens. The presence of mannose-binding lectins in plants that also recognize glucose could be entitled Man/Glc lectins; such specificity has allowed employing these vegetal lectins for several applications. Animal mannose-binding lectins are synthesized in the liver and secreted into the blood stream where both concentration and activity are greatly affected due to gene polymorphisms; these serum proteins play important roles in the immune system by recognizing mannose-like carbohydrate ligands found exclusively on pathogenic microorganisms. Mannose lectins already showed strong binding to relevant bacteria, viruses, protozoa and helminth species, initiating potent host defense mechanisms by inducing growth inhibition or death of such organisms; the ability to prevent the formation or destruction of microbial biofilms has also been reported. Mannose-binding lectins have attracted considerable attention against carcinogenesis and atherogenesis. The aim of this review article is to approach biotechnology characteristics of these lectins from different sources and microorganism/cell surface interactions with mannose; in addition, aspects of mechanisms associated to lectin antipathogenic activities are described.
Topics: Animals; Anti-Infective Agents; Antineoplastic Agents, Phytogenic; Binding Sites; Biotechnology; Cell Proliferation; Glycosylation; Lectins; Mannose; Mannose-Binding Lectins; Models, Molecular; Plant Lectins; Plants; Protein Binding
PubMed: 31400430
DOI: 10.1016/j.ijbiomac.2019.08.059 -
Proceedings of the National Academy of... Nov 2021Inflammation drives the pathology of many neurological diseases. d-mannose has been found to exert an antiinflammatory effect in peripheral diseases, but its effects on...
Inflammation drives the pathology of many neurological diseases. d-mannose has been found to exert an antiinflammatory effect in peripheral diseases, but its effects on neuroinflammation and inflammatory cells in the central nervous system have not been studied. We aimed to determine the effects of d-mannose on key macrophage/microglial functions-oxidative stress and phagocytosis. In murine experimental autoimmune encephalomyelitis (EAE), we found d-mannose improved EAE symptoms compared to phosphate-buffered saline (PBS)-control mice, while other monosaccharides did not. Multiagent molecular MRI performed to assess oxidative stress (targeting myeloperoxidase [MPO] using MPO-bis-5-hydroxytryptamide diethylenetriaminepentaacetate gadolinium [Gd]) and phagocytosis (using cross-linked iron oxide [CLIO] nanoparticles) in vivo revealed that d-mannose-treated mice had smaller total MPO-Gd areas than those of PBS-control mice, consistent with decreased MPO-mediated oxidative stress. Interestingly, d-mannose-treated mice exhibited markedly smaller CLIO areas and much less T2 shortening effect in the CLIO lesions compared to PBS-control mice, revealing that d-mannose partially blocked phagocytosis. In vitro experiments with different monosaccharides further confirmed that only d-mannose treatment blocked macrophage phagocytosis in a dose-dependent manner. As phagocytosis of myelin debris has been known to increase inflammation, decreasing phagocytosis could result in decreased activation of proinflammatory macrophages. Indeed, compared to PBS-control EAE mice, d-mannose-treated EAE mice exhibited significantly fewer infiltrating macrophages/activated microglia, among which proinflammatory macrophages/microglia were greatly reduced while antiinflammatory macrophages/microglia increased. By uncovering that d-mannose diminishes the proinflammatory response and boosts the antiinflammatory response, our findings suggest that d-mannose, an over-the-counter supplement with a high safety profile, may be a low-cost treatment option for neuroinflammatory diseases such as multiple sclerosis.
Topics: Animals; Drug Evaluation, Preclinical; Encephalomyelitis, Autoimmune, Experimental; Female; Mannose; Mice, Inbred C57BL; Molecular Imaging; Oxidative Stress; Phagocytosis; Mice
PubMed: 34702739
DOI: 10.1073/pnas.2107663118 -
International Journal of Molecular... Jan 2019To date, a number of mannose-binding lectins have been isolated and characterized from plants and fungi. These proteins are composed of different structural scaffold... (Review)
Review
To date, a number of mannose-binding lectins have been isolated and characterized from plants and fungi. These proteins are composed of different structural scaffold structures which harbor a single or multiple carbohydrate-binding sites involved in the specific recognition of mannose-containing glycans. Generally, the mannose-binding site consists of a small, central, carbohydrate-binding pocket responsible for the "broad sugar-binding specificity" toward a single mannose molecule, surrounded by a more extended binding area responsible for the specific recognition of larger mannose-containing -glycan chains. Accordingly, the mannose-binding specificity of the so-called mannose-binding lectins towards complex mannose-containing -glycans depends largely on the topography of their mannose-binding site(s). This structure⁻function relationship introduces a high degree of specificity in the apparently homogeneous group of mannose-binding lectins, with respect to the specific recognition of high-mannose and complex -glycans. Because of the high specificity towards mannose these lectins are valuable tools for deciphering and characterizing the complex mannose-containing glycans that decorate both normal and transformed cells, e.g., the altered high-mannose -glycans that often occur at the surface of various cancer cells.
Topics: Binding Sites; Fungi; Mannose; Mannose-Binding Lectins; Models, Molecular; Oligosaccharides; Plants; Protein Binding; Protein Conformation; Structure-Activity Relationship
PubMed: 30634645
DOI: 10.3390/ijms20020254 -
Frontiers in Immunology 2022D-mannose can be transported into a variety of cells glucose transporter (GLUT), and supraphysiological levels of D-mannose impairs tumor growth and modulates immune...
D-mannose can be transported into a variety of cells glucose transporter (GLUT), and supraphysiological levels of D-mannose impairs tumor growth and modulates immune cell function through mechanisms such as interference with glycolysis and induction of oxidative stress. Blood-stage mainly depends on glycolysis for energy supply and pathological immune response plays a vital role in cerebral malaria. However, it is not clear whether mannose affects malaria blood-stage infection. Here, we fed D-mannose to -infected mice and found weight loss and reduced parasitemia without apparent side effects. Compromised parasitemia in C57BL/6 mice was accompanied by an increase in splenic macrophages compared to an untreated group. When mannose was applied to a rodent experimental cerebral malaria (ECM) model, the incidence of ECM decreased. Expression of activation marker CD69 on T cells in peripheral blood and the brain were reduced, and cerebral migration of activated T cells was prevented by decreased expression of CXCR3. These findings suggest that mannose inhibits infection by regulating multiple host immune responses and could serve as a potential strategy for facilitating malaria treatment.
Topics: Animals; Glucose Transport Proteins, Facilitative; Immunity; Malaria, Cerebral; Mannose; Mice; Mice, Inbred C57BL; Parasitemia; Parasites; Plasmodium berghei
PubMed: 36211381
DOI: 10.3389/fimmu.2022.859228 -
Postgraduate Medical Journal Mar 2000Four types of carbohydrate-deficient glycoprotein syndrome have been described, and the cause of two of them has been found. The symptoms and signs of these syndromes... (Review)
Review
Four types of carbohydrate-deficient glycoprotein syndrome have been described, and the cause of two of them has been found. The symptoms and signs of these syndromes are described, with variations that occur at different ages. The commonest is type Ia with an autosomal recessive form of inheritance, and the gene responsible has been mapped to 16p. The typical pathology is atrophy of the cerebellum and brainstem, sometimes also involving the cortex, although both the pathology and the biochemical deficiencies vary between different types of syndrome. The diagnosis depends firstly on recognising the clinical features, including the presence of complications such as thyroid disorders. Then biochemical tests can be carried out, especially chromatographic carbohydrate-deficient transferrin assay and isoelectric focusing of serum transferrin. The prognosis depends on the complications, renal, hepatic, and cardiac, but affected children will be severely handicapped. Therefore treatment consists mainly of coping with the complications, and supporting the child and the family. Oral infusion of mannose can be effective in type Ib disease.
Topics: Adult; Child, Preschool; Congenital Disorders of Glycosylation; Humans; Infant; Mannose; Prognosis
PubMed: 10684323
DOI: 10.1136/pmj.76.893.145