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Sialic acid: an attractive biomarker with promising biomedical applications

Aida Doostkam
Aida Doostkam
, 
Leila Malekmakan
Leila Malekmakan
, 
Alireza Hosseinpour
Alireza Hosseinpour
, 
Sahar Janfeshan
Sahar Janfeshan
, 
Jamshid Roozbeh
Jamshid Roozbeh
 oraz 
Fatemeh Masjedi
Fatemeh Masjedi
   | 31 sie 2022
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Article Category: Review
Data publikacji: 31 sie 2022
Zakres stron: 153 - 167
DOI: https://doi.org/10.2478/abm-2022-0020
Słowa kluczowe
© 2022 Aida Doostkam et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

Figure 1

(A) Chemical structure of the 3 main sialic acids, N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid (Neu5Gc), and deaminoneuraminic acid (KDN). (B) Sialic acids are transferred onto acceptor glycans via sialyl transferase enzymes that use the activated cytidine-5′-monophosphate-sialic acid (CMP-Sia) as a donor molecule. Sialyl residues may be added terminally to galactose residues in α-2,3 or α-2,6 linkage, or to sialic acid residues in α-2,8 connection. Such glycan chains may be attached to glycoproteins via asparagine (N-glycan) or serine or threonine residues (O-glycans). Sialic acids may be released via hydrolytic enzymes called neuraminidases. (C) Examples of pathobiological interactions involving sialic acids with viruses, bacteria, hormones, and toxins. Gal, galactose; GalNAc, N-acetylgalactosamine; Man, mannose; Glc, glucose; GlcNAc, N-acetylglucosamine; Fuc, fucose.
(A) Chemical structure of the 3 main sialic acids, N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid (Neu5Gc), and deaminoneuraminic acid (KDN). (B) Sialic acids are transferred onto acceptor glycans via sialyl transferase enzymes that use the activated cytidine-5′-monophosphate-sialic acid (CMP-Sia) as a donor molecule. Sialyl residues may be added terminally to galactose residues in α-2,3 or α-2,6 linkage, or to sialic acid residues in α-2,8 connection. Such glycan chains may be attached to glycoproteins via asparagine (N-glycan) or serine or threonine residues (O-glycans). Sialic acids may be released via hydrolytic enzymes called neuraminidases. (C) Examples of pathobiological interactions involving sialic acids with viruses, bacteria, hormones, and toxins. Gal, galactose; GalNAc, N-acetylgalactosamine; Man, mannose; Glc, glucose; GlcNAc, N-acetylglucosamine; Fuc, fucose.

Figure 2

Flowchart showing that increased sialic acid level in plasma predicts diabetic nephropathy. RBC, red blood cell.
Flowchart showing that increased sialic acid level in plasma predicts diabetic nephropathy. RBC, red blood cell.

Diagnostic parameters for sialic acid

Target disease Detection methods for SA Target tissue Sensitivity (%) Specificity (%) Cut-off AUC (%) Refs.
Breast cancer Surface-enhancedRaman spectroscopy Saliva 80 93 12 mg/dL 95 [127]
Breast cancer Surface-enhancedRaman spectroscopy Saliva 80 100 15.5 mg/dL 94.05 [128]
Rheumatoid arthritis HPLC Serum 84.2 92 766.70 μg/mL 92.1 [126]
Nasopharynx cancer Enzymatic method Serum 30.95 83.33 ≥650 mg/dL 80.7 [129]
COVID-19 and gastrointestinal tract ELISA Serum 76.2 73.7 74.55 mg/dL 84 [130]
Oral squamous cell carcinoma Spectrophotometric method Saliva 100 100 >0.30 μg/mL 100 [131]
Blood 93.33 100 >4.23 μg/mL 98.3

Potential therapeutic targets and effects and mechanism of action of sialic acid in various diseases

Disease Drug or potential therapeutic target Therapeutic effects Mechanism of action Refs.
Alzheimer disease Human β-amyloid SA-binding lectin LFA Decrease in amyloid plaque deposition in the brain, reducing neuroinflammation Binding to gangliosides in neuronal lipid rafts and inhibiting the binding of amyloid peptides [109]
CVD

Quercetin 7-O-SA

Neuraminidase inhibitors (oseltamivir and zanamivir)

 Antioxidation, antiinflammation, cholesterol efflux, promotion of biomolecule protection, prevention of CAD progression Antioxidant, antiatherosclerosis, decreased hydrogen peroxide, reduced expression of TNF-α, MCP-1, ICAM-1, VCAM-1, reducing Neu5Ac levels by inhibiting its regulatory enzyme (neuraminidase) [90, 60]
Cancer

SA/mPEG AuNPs

EPI-SL

PSA-TPGS

SA-imprinted BS-NPs

Blockade of CD24-Siglec-10 interaction in TNBC and ovarian cancer

Combination of sialic acid analog, HDI, and anti-GD2 antibody (dinutuximab) in neuroblastoma

Fluorinated sialic acids (e.g., Ac53Fax Neu5Ac)

 Inhibiting the evasion of the immune response, improvement of the tumor-targeting efficiency and antitumor activity, improvement in immune responses, enhancement of cell cytotoxicity, clearance of cancer cells by macrophages, localized blockade of tumor antigens

Evasion of the reticuloendothelial system

Enhancement endocytosis of liposomes by circulating N/Ms

ABC phenomenon weakness

Cleavage of intracellular GSH

Enhancement of phagocytic activity using monoclonal antibodies targeting CD24-Siglec-10 interaction in ovarian cancer and TNBC

Concurrent increase of sialyltransferase expression involved in GD2 synthesis and blockade of GD2 in neuroblastoma

Repeated injection of fluorinated sialic acids can directly inhibit tumor-associated sialyltransferases in melanoma and neuroblastoma

 [41, 50, 52, 55, 110, 111]
Viral infection (chicken new castle, influenza virus, coronavirus, and rotavirus)

Ovomucin

Oseltamivir

 Antiviral activity

Unknown

Neuraminidase inhibitors

 [93, 112]
Neurological Disorders

SAPPM copolymer for delivering DDS in SCI

Ac3ManNAc for delivering ManNAc-6-P in GNE myopathy

 Neuroregeneration, increased neuroprotective capacity, providing substrate for sialic acid biosynthesis

Enhancing the distribution of DDS via binding to E-selectin in SCI

Increase in sialic acid levels via providing the deficient substrate in GNE (IBM2) myopathy

 [76, 113, 114]
Rheumatoid arthritis and comorbid tumors Sialic acid-modified doxorubicin hydrochloride liposome (DOX-SAL) Accumulation reduction of inflammatory neutrophils at the disease site Induction of PBN apoptosis by binding to L-selectin [115]

Various methods for sialic acid detection

Method Example Advantages Disadvantages Refs.
Biochemical assay Resorcinol assay Assays bound and free SA Considerable interferences by pentoses, hexoses, and uronic acids [116]
Periodate–thiobarbituric acid assay Assays free SA Considerable interferences by 2-deoxyribose, unsaturated fatty acids, lactose, and maltose Bound SA not detected [117]
Roboz assay Assays bound and free SAEliminates interferences such as deoxyribose, fatty acids, and some neutral carbohydrates Slight turbidity in the assay solution [118]
Periodic acid/MBTH Assays total SA without release sialic acids by acid hydrolysis or neuraminidase treatment, Considerable interferences [119, 120]
Acidic ninhydrin assay Assays bound and free SA Considerable interferences [121, 122]
Enzymatic and fluorometric assay Measurement total [123]
Neu5Ac
Simple and convenient
No significant cross-reactivity or interference
Enzymatic and calorimetric assay Measurement total [123,124,125]
Neu5Ac
Simple and convenient
No significant cross-reactivity or interference
HPLC fluorescent detection High specificity Expensive, research use only [125]
ELISA and calorimetric assay High specificity Research use only [56]

Viruses with specific binding to sialic acid derivatives

Virus name Viral genus Viral family Genome type Envelope Sialic acid receptor Viral attachment protein Host(s) Refs.
Influenza A virus Alphainfluenza-virus Orthomyxoviridae ssRNA Yes Neu5Acα2-3/6Gal, Neu5Acα23/6GalNAc, Neu5Acα2-6GlcNAc HA, NA Birds and mammals [8, 13,14,15, 95]
Influenza B virus Betainfluenza-virus Orthomyxoviridae ssRNA Yes Neu5Acα2-3/6Gal, Neu5Acα23/6GalNAc, Neu5Acα2-6GlcNAc HA, NA Human and seals [8, 13,14,15, 95]
Influenza C virus Gammainfluenza-virus Orthomyxoviridae ssRNA Yes N-Acetyl-9-O-acetylneuraminic acid (Neu5,9Ac2) HEF Human [95,96,97]
Salmon isavirus Isa-virus Orthomyxoviridae ssRNA Yes 4-O-5-N-Acetylneuraminic acid (Neu4,5Ac2) HE Fish [95, 98, 99]
TGEV Alphacorona-virus Coronaviridae ssRNA Yes α2-3-linked N-glycolylneuraminic acid HA Pigs [6, 100, 101]
BCoV, HCoVOC43 Betacorona-virus Coronaviridae ssRNA Yes 9-O-Acetylated sialic acid HE, S protein Bovine and Human [6, 102]
SARS-CoV-2 Betacorona-virus Coronaviridae ssRNA Yes N-Acetylneuraminic acid S protein Human [103]
IBV Gammacorona-virus Coronaviridae ssRNA Yes α-2-3-Linked sialic acid HA Birds [6, 104]
Bovine torovirus Toro-virus Coronaviridae ssRNA Yes Neu5,9Ac2 and N-acetyl-7,9-O-acetylneuraminic acid HE Bovine [6, 20]
HPIV1 Respiro-virus Paramyxoviridae ssRNA Yes α-2-3-Linked sialic acid HA, NA Human [6]
Murine norovirus Noro-virus Caliciviridae ssRNA No Terminal sialic acid in GD1a VP1 Murine [105, 106]
Enterovirus 70 Entero-virus Picornaviridae ssRNA No O-Linked glycans containing sialic acid α2-3-linked to galactose (DAF/CD55) Human [107, 108]
Human rotavirus Rota-virus Reoviridae dsRNA No GM1 VP4 Human [6]
Murine polyomavirus Alphapolyoma-virus Polyomaviridae dsDNA No Neu5Acα2-3-Gal VP1 Murine [6]
eISSN:
1875-855X
Język:
Angielski
Częstotliwość wydawania:
6 razy w roku
Dziedziny czasopisma:
Medicine, Assistive Professions, Nursing, Basic Medical Science, other, Clinical Medicine
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