Sialic acid: an attractive biomarker with promising biomedical applications

Aida Doostkam; Leila Malekmakan; Alireza Hosseinpour; Sahar Janfeshan; Jamshid Roozbeh; Fatemeh Masjedi

Detalles de publicación y publicación

Asian Biomedicine

Detalles de la revista

Formato: Revista
eISSN: 1875-855X
Primera edición: 01 Jun 2007
Calendario de la edición: 6 veces al año
Idiomas: Inglés

Sialic acid was discovered in the 20th century in bovine submaxillary mucin, and its family contains more than 50 members [1]. The current narrative review considers sialic acid as a family of 9-carbon-containing monosaccharides.

Sialic acids form the terminus of glycoproteins, glycolipids (specifically in the nervous system), and oligosaccharides, which are widely distributed on vertebrate cell surfaces. They are neuraminic acid derivatives that modulate various physiological and pathological processes. The most familiar member of this group is N-acetylneuraminic acid (Neu5Ac or NANA) [2] (Figure 1A).

(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.

Although sialic acid is widely expressed on the plasma membrane of normal cells, it is upregulated in some pathological conditions, including cancers, infections, neurological disorders, cardiovascular diseases (CVD), and diabetic nephropathy [3, 4]. Serum sialic acid level is correlated with the severity of various diseases, and it may provide a marker for inflammation, disease severity, and tumor progression. However, this needs to be further elucidated, and more studies must be conducted to demonstrate the possibility of sialic acid as a general inflammatory marker [5].

Some studies have investigated sialic acid effects in various pathological conditions, and so we explored the role of sialic acid in the pathophysiology of neoplasms and other diseases.

Search methodology

For this narrative review, 2 coauthors (AD and AH) searched electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar, to find the relevant articles with time limitations (1991–2022). The keywords searched for were “sialic acid”, “neuraminic acids”, “viral infections”, “cardiovascular diseases”, “diabetic nephropathy”, “cancer”, “malignancy”, “serum marker”, “drug development”, and “drug target”. Then, these articles were screened based on their titles. All reviews, original articles, and clinical trial articles only in English were included. After finding the articles, each was screened to exclude irrelevant and duplicate studies. Next, the relevant articles were reviewed carefully, and the references were searched to find more articles.

Among a total of 2478 articles that were identified in databases, 131 full-text articles were chosen for careful review. Of the 131 studies we reviewed, 22 were regarding sialic acids as viral receptors [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26], and 29 were regarding immune system evasion of cancers through sialic acid modification [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]. Sialic acids and CVD were indicated in 12 articles [56,57,58,59,60,61,62,63,64,65,66,67], while 8 highlighted sialic acid as a predictor of diabetic complications [4, 68,69,70,71,72,73,74]. There were 9 articles regarding the role of sialic acids in the central nervous system [75,76,77,78,79,80,81,82,83]. Sialic acid as a promising target for novel therapeutic drugs was pursued in 12 studies [26, 41, 82, 84,85,86,87,88,89,90,91,92].

Sialic acids

N-Acetylneuraminic acid (Neu5Ac) is the most abundant member of the sialic acid family in mammals and is considered an α-keto acid (keto-aldononulosonic acid) [1, 2]. It is made in the eukaryotic cell cytoplasm and is activated by binding to cytosine 5′-monophosphate (CMP) in the nucleus and forming CMP-Neu5Ac. Next, CMP-Neu5Ac is transferred to the end of glycoconjugates by sialyltransferases in the Golgi apparatus and consequently expressed on the cell membrane [2] (Figure 1B).

Postglycosylation modifications of sialoglycoconjugates help Neu5Ac increase sialic acid diversity. These modifications include O-acetylation, O-methylation, sulfation, phosphorylation, and lactylation [1]. Approximately 70% of cellular sialic acid concentration is expressed on the plasma membrane, and the rest is predominantly found in the smooth endoplasmic reticulum [3]. Moreover, sialic acids can be detected in body fluids such as serum, urine, breast milk, and human tissues, including the stomach, intestines, and salivary glands. Sialic acids are bound to plasma proteins such as fibrinogen, haptoglobin, and transferrin. They are also widely distributed in the erythrocytes, leukocytes, platelets, and vascular endothelial cells [2]. The fundamental role of the sialic acid family in many physiological and pathological processes, including cellular recognition and communication, cellular development, mediating bacterial and viral infection, tumor growth and metastasis, and immunology, has been well established [3]. Sialic acids can have contradictory roles. First, they can function as antirecognition agents by masking normal cellular recognition sites and dampening the immune system. Furthermore, they can act as a ligand for many molecules such as lectins, antibodies, viruses, and bacteria by facilitating cell recognition and adhesion [1, 6, 7, 93, 94] (Figure 1C).

Sialic acids as viral receptors

Sialic acids were introduced as the first class of viral receptors, facilitating viral entrance and initiation of infection in a wide range of human and animal host cells [6]. Many viruses such as influenza, parainfluenza, mumps, corona, noro, rota, and DNA tumor viruses bind to sialylated structures like glycoproteins and gangliosides on their host cell membrane [6, 7]. In the viral attachment process, a particular binding site or packet on the viral protein recognizes one or more sialic acid derivatives [8,9,10,11]. Natural sialyl conjugates are α2-3- or α2-6-linked to Gal and GalNAc, 2-6-linked to GlcNAc, or α2-8-linked to the second sialyl residue [12,13,14,15]. Among viral attachment proteins, hemagglutinin is one of the most important on the surface of influenza and coronaviruses [16, 17]. Human influenza viruses predominantly bind to Neu5Acα2-6Gal on epithelial cells in the human airway epithelium [18].

By contrast, avian influenza viruses preferentially recognize Neu5Acα2-3-Gal on the intestinal and respiratory tract cells of birds [14, 15]. Murine coronaviruses recognize 4-O-acetyl-N-acetylneuraminic acid [19, 20], Sendai virus and human parainfluenza virus 1 (HPIV1) bind to α2-3 linkages [21], and HPIV3 has α2-6 specificity [22]. In addition to viral attachment proteins, viral enzymes such as neuraminidase (sialidase) and esterases, especially acetyl esterases, promote viral release at the end of the life cycle and prevent clumping of virions by removing receptors from the cell surface and viral glycoproteins, respectively [23, 24]. Sialic acids are essential for the entry of coronaviruses to target cells, and these viruses seem to have 2 domains for binding to the host cell [25]. This 2-step process begins primarily with viral binding to sialic acids on the cell surface. This step facilitates adherence to protein receptors and later stages of viral infection [26]. A study of the difference in immune-inflammatory markers between groups of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection revealed that serum level of sialic acid is markedly higher in severe cases than in those without severe infection [5]. Viruses with specific binding to sialyl derivatives, and their attachment proteins, are listed in Table 1.

Table 1

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]

Neu5Ac, N-acetylneuraminic acid; Gal, galactose; GalNAc, N-acetyl galactose; GlcNAc, N-acetyl glucose, HA, hemagglutinin; NA, neuraminidase; HEF, hemagglutinin–esterase (acetylesterase)-fusion, HE, hemagglutinin–esterase (acetylesterase); TGEV, transmissible gastroenteritis virus; BCoV, bovine coronavirus; HCoVOC43, human coronavirus OC43; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; IBV, infectious bronchitis virus; HPIV1, human parainfluenza virus 1; VP1, viral protein 1; VP4, viral protein 4; DAF/CD55, complement regulatory protein decay-accelerating factor; GM1, monosialotetrahexosylganglioside; DAF, decay-accelerating factor.

Therefore, sialic acid derivatives have a critical role in many critical viral infections. Targeting sialic acid production and virus–sialic acid interaction may provide new insights into therapeutic options for viral infections.

Immune system evasion of cancers through sialic acid modification and potential cancer treatment strategies targeting sialic acids

Upregulation of sialic acids in cancerous cells can play a fundamental role in immune system dampening, progression of tumor growth, and metastasis [27]. This enhanced glycosylation level results in dysregulation of enzymes modifying sialic acids, such as sialyltransferases and sialidases [28]. Sialyltranferases are enzymes that transfer sialic acids to the terminus of glycoconjugates. The overexpression of specific sialyltransferases is correlated with hypersialylation and poor prognosis in cancer progression [29, 30]. Moreover, sialidases can catalyze the removal of sialic acids from glycoconjugates. Hence, decreased expression of sialidases can contribute to increased levels of sialic acids on cell surfaces [31]. Accumulating evidence clarifies the potential role of hypersialylated cell membranes of malignant cells in modulating and evading the immune system. The innate immune system includes lymphocytes known as natural killer (NK) cells, which are critical players in targeting malignant cells by releasing granzymes and perforins. NK cells can also activate the adaptive immune system by releasing various cytokines, including tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFNγ), which promote T-cell effector functions to eradicate malignant cells [32, 33]. Tumor cells are proposed to evade the immune system through interactions between their hypersialylated membranes and sialic acid-binding immunoglobulin-like lectins (Siglecs) through the sialic acid–Siglec axis. Siglec-7 and Siglec-9 are 2 inhibitory receptors causing cellular inactivation, expressed by NK cells. The dense layer of sialic acids on the surface of tumor cells engages these inhibitory receptors. This modulates the immune system by overall reducing and inhibiting NK cell activities [28, 34,35,36]. As a result, the abnormal glycosylation of tumor cells and subsequent immune system evasion seems to help the tumor to invade local tissue, entering the blood or lymphatic system, with consequent extravasation, leading to metastasis [37].

The high density of sialic acids expressed on cell membranes of cancer cells confers a negative charge on the membrane [38]. This charge inhibits interactions between cells and might facilitate cell detachment from the tumor mass and their subsequent metastasis into the bloodstream [39]. Sialic acids limit the alternative complement pathway by binding to factor H, an essential regulator of the alternative pathway [40]; adding sialic acids to nanoparticles may dampen the innate immune response as suggested because these negatively charged nanoparticles evade being engulfed by macrophages in vitro. Sialic acids inhibit the expression of activated macrophage markers, CD14 and CD86, and cause the macrophages to stay silent and inactivated. Moreover, sialic acid-coated nanoparticles suppressed the formation of markers of inflammation such as TNF-α and IL-6 [41]. Thus, higher levels of sialic acids on tumor cells may dampen the immune system, thereby facilitating metastasis. Targeting the sialic acid-coated cancer cells is a potential therapeutic strategy for cancer treatment. Measuring sialic acid levels in patients with cancer may give us a better understanding of tumor and metastatic progress.

Siglecs are also expressed on cancerous cells and normal immune cells, playing a potentially vital role in dampening the immune response and molding the behavior of tumor cells. The expression of Siglecs on tumor cells is enhanced and mutated in malignancies such as endometrial carcinoma, melanoma, and non-small-cell lung cancer. mRNA levels of Siglec family genes are highly correlated with immune response. In head and neck squamous cell carcinoma, thyroid carcinoma, and thymoma, the expression of Siglec family genes is negatively associated with infiltration of B cells and cytotoxic T cells, while in cervical squamous cell carcinoma, robust expressions of Siglec genes seem to be positively linked with infiltration of adaptive immune cells [42, 43]. Siglec-15 has received substantial attention as a possible pillar of cancer therapy. Siglec-15 is expressed on many malignant cells besides its regular expression in macrophages and myeloid cells. It appears to play a crucial role in suppressing the immune response in the tumor microenvironment (TME). Instead of systemically stimulating the immune system, selective blockade of Siglec-15 by monoclonal antibodies or genetic manipulation of Siglec-15 genes has raised hopes of bringing new insights into selectively targeting cancer cells [44,45,46]. Treatment with anti-Siglec-15 antibody promoted the formation of osteoblasts in cultures of mouse bone marrow cells in the presence of receptor activator of nuclear factor-k B ligand and macrophage colony-stimulating factor [47].

CMP-sialic acid is a putative primary metabolite responsible for the sialylation of cancer cells and causing metastatic breast cancer. To prevent metastatic breast cancer, rather than targeting specific classes of sialyltransferases, a proposed method is to knock down CMAS, the underlying gene in the sialic acid pathway [48, 49].

A potential role of immunotherapeutic agents in altering glycosylation in cancer treatment is proposed. The ganglioside GD2 is expressed abundantly in neuroblastomas, in contrast with normal healthy tissues that do not contain high levels of GD2 on their cell surfaces. Immunotherapeutic agents such as a monoclonal anti-GD2 antibody (dinutuximab) induce NK cells to attack neuroblastoma cells by activating the antibody-dependent cell-mediated cytotoxicity (ADCC) pathway. This targeting depends on the recognition of aberrant GD2 sialylation on the malignant cells. Synergistic GD2 upregulation by Ac₅Neu5Ac, a sialic acid analog, and histone deacetylase inhibitors (HDI) suggested that combined sialic acid analogs and HDIs may boost anti-GD2 monoclonal antibody therapy for neuroblastomas [50, 51]. A further strategy to suppress tumor growth includes blocking sialic acid expression of malignant cells by injecting a fluorinated sialic acid mimetic into the tumor bulk. Blocking sialic acid expression by neuroblastoma and melanoma cells by intratumoral injection of Ac₅3F_axNeu5Ac, a fluorinated sialic acid derivative, attenuated the tumor growth in vivo by the direct inhibition of sialyltransferases. The dense layer of sialic acids on the malignant cell membranes helps the tumor evade the immune system and causes metastasis formation. Ac₅3F_axNeu5Ac can potentiate the immune response in the TME by inducing activated immune cells, including dendritic cells and CD8⁺ cells, and by decreasing the number of regulatory cells such as myeloid regulatory cells and regulatory T cells [52].

Another novel immunotherapeutic strategy targets the CD24-Siglec10 signaling pathway through anti-CD24 monoclonal antibodies or genetic ablation of Siglec-10 genes. Several neoplasms express an extensive amount of CD24. Upregulated expression of CD24 on cancer cells is closely related to the prognosis of ovarian cancer [53] and triple-negative breast cancer [54]. A higher expression of CD24 in cancerous cells than in other cell clusters has proposed CD24 as a tumor-specific antigen in the mentioned malignancies. Moreover, tumor-associated macrophages (TAM) appear to express Siglec-10 genes profoundly, proposing the CD24-Siglec10 inhibitory signaling cascade as a potential strategy for cancers to evade inflammatory responses efficiently. It has been shown that blocking the CD24-Siglec10 signaling pathway components by monoclonal antibodies against CD24 and Siglec10 or genetic ablation of involved genes can robustly increase the phagocytic activity by TAM and destroy malignant cells by enhancing immune responses in the TME [55]. Overall, studies have delineated the potential role of exploiting sialic acids by tumors to dampen inflammatory responses and progress and form metastasis. Thus, targeting signaling mechanisms involved in this process through genetic ablation and monoclonal antibodies is a potential strategy for cancer treatment. This idea should encourage future studies to target sialic acids and the involved signaling cascades as the leading players in cancer progression.

Sialic acids and CVD

Coronary artery disease (CAD) is the most prevalent cause of death globally. Inflammation, fibrinolysis, and oxidative stress seem to be the leading causes of plaque disruption and subsequently lead to CAD. Thus, markers that participate in these pathophysiological pathways may be used as prognostic factors [5, 56]. Sialic acids, which are also expressed on circulatory molecules, may affect the pathogenesis, progression, predictions, and severity of the atherosclerotic process and CVD [57].

Raised serum sialic acid levels in patients with CAD compared with healthy controls has a significant correlation with CVD risk factors. Therefore, serum sialic acid levels may be considered a strong predictor of CVD severity and mortality [56, 58]. Sialic acid is also a marker of vascular involvement in the atherosclerotic processes, probably related to an inflammatory response of the arterial wall [58, 59]. Zhang et al. analyzed the plasma metabolites in 2324 patients who had coronary angiography, and they confirmed a significant increase in Neu5Ac plasma levels correlated with CAD progression. They also performed a study in vitro. They found that administration of Neu5Ac led to increased levels of lactate dehydrogenase and creatine kinase-MB and apoptosis in neonatal rat ventricular myocytes. Their results suggest that the administration of neuraminidase-1 inhibitors, including oseltamivir and zanamivir, as used against the influenza virus, can act as cardioprotective agents, potentially preventing CAD progression and myocardial injury [60]. The mechanism involved in the rise in serum sialic acid among CVD patients may be various, including oxidative stress and inflammation, which can act in atherosclerosis and CVD [61].

Sialic acid is associated with the formation of inflammatory cytokines such as interleukin-6 (IL-6) and TNF-α [62, 63]. There is a significant increase in acute-phase reactants containing sialic acids. Therefore, like C-reactive protein (CRP), sialic acid could be used as an associated factor to predict CVD. Sialic acid has not only been suggested as the most stable acute-phase marker, but it has also been proposed as a suitable marker of the overall acute-phase response in indicating CVD [62, 64]. Moreover, due to the increased sialylation of plasma proteins during an inflammatory response, protein-bound sialic acid increases and reflects the clustering of cardiovascular risk factors. Sialic acid could scavenge reactive oxygen species (ROS), which subsequently prevent alteration of biological macromolecules, such as desialylation, which is a possible primary step of atherogenic modification. This occurs by the glycosidic bonding of sialic acid as a potential target for superoxide and other related ROS [65]. Desialylation may lead to cellular dysfunction and uptake of circulatory sialoglycoprotein by the hepatocyte sialoglycoprotein receptor. Remarkably, although CVD progression is accompanied by desialylation in glycoconjugates, serum total sialic acid (TSia) seems to rise [66]. Moreover, sialic acid-free low-density lipoprotein (LDL) tends to increase and accumulate in endothelium and smooth muscle cells, suggesting that low sialic acid content of LDLs may be atherogenic. Thus, it can be assumed that increased sialic acid levels can be a risk factor for CVD unless the levels reflect LDL-unbound sialic acid [66, 67]. CVD is a leading cause of morbidity and mortality worldwide, and there is also an increased incidence of its risk factors. Some clinical and epidemiological studies of CVD have shown that sialic acid has the best sensitivity and specificity and produces the least number of false negatives and false positives of other sensitive biomarkers such as highly sensitive CRP, oxidation of LDL, malondialdehyde, plasminogen activator inhibitor, and vitronectin, suggesting the value of sialic acid as a biomarker in clinical monitoring. Serum levels are significantly higher in patients with CAD than in healthy controls [56].

Sialic acid as a predictor of diabetic complications

The serum TSia level and plasma sialic acid (PSia) are increased to more than the normal range in type 2 diabetic (T2D) patients. TSia level in patients with diabetic nephropathy rises significantly compared with non-nephropathic patients [4, 68,69,70,71]. High concentrations of sialic acid derivatives are found in the vascular endothelium of the retina, kidneys, heart, and brain. Consequently, micro- and macrovascular complications in patients with T2D lead to increased TSia levels, and this causes retinopathy, nephropathy, and neuropathy [68, 71]. Furthermore, infiltrating immune cells such as macrophages and endothelial cells produce inflammatory factors such as cytokines in injured tissues. Next, the acute-phase response stimulates the secretion of glycoproteins containing sialic acids from the liver into the blood circulation, leading to increased TSia level and urinary excretion of sialic acid [68, 69, 72]. Oxidative stress during diabetic nephropathy causes lipid peroxidation of the red blood cell membranes, followed by desialylation. Removal of sialic acid moieties from the erythrocyte membranes increases PSia level and causes cell aggregation [73, 74]. Overall, TSia and PSia levels may provide valuable risk factors to predict diabetes-induced nephropathy early and may help to manage diabetic patients (Figure 2).

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

Role of sialic acids in the central nervous system

Glycosylation is essential for brain activity, and any change in this process can induce nervous system disorders [75]. Sialylation is a type of glycosylation abundantly found in brain tissue. Siglecs are expressed on the surface of neural cells and play important roles in neuroinflammation [76]. Sialoglycans are essential for the development of the nervous system. There are 2 families of sialoglycans in the brain: gangliosides and polysialic acid. Gangliosides are the most common form of sialoglycans in neurons. They participate in interactions between axons and myelin, regeneration of axons, and the excitability of nerve cells.

Polysialic acid modulates interactions between cells, matrix, and different molecules in the cellular environment. It is involved in brain development, neuroplasticity, and polymorphisms [77]. There is a correlation between psychiatric disorders such as schizophrenia, autism, and bipolar disorder and the genes responsible for synthesizing polysialic acid [77]. Neurological disorders affect sialylation during the inflammatory reaction of microglia. Chronic stress seems to lower the sialidase activity, which is associated with increased polysialic acid expression [78]. Sialidase enzymatic activity changes during epileptic seizures in the brain [79], and memory processing is based on the negative charge of the sialic acids expressed on the cellular membrane [80]. Sialidase prevents the release of glutamate from hippocampal neurons and synaptic vesicles by regulating calcium signaling during neurotransmission [81]. Deficiencies of lysosomal sialidases can cause the accumulation and amyloidogenic processing of an oversialylated amyloid precursor protein, and extracellular release of neurotoxic amyloid-β peptides, which are related to the pathogenesis of Alzheimer disease [82]. Sialidases may enhance GM1 ganglioside expression and be neuroprotective in a murine model of Parkinson disease [83]. Finding altered sialylation and sialidase activity in nervous system disorders may encourage future studies to elucidate the pathophysiology of sialic acids in neurological disorders and identify therapeutic drugs targeting these activities.

Sialic acids as promising targets for novel therapeutic drugs

Angiogenesis plays an essential role in developing various diseases, including neoplasms [84]. Sialic acids are widely expressed in endothelial cells, and they are linked with various gangliosides involved in angiogenesis and neovascularization. Thus, sialic acids may be used to develop anti-angiogenic strategies for neoplasms. These strategies include inhibiting sialidases, sialyltransferases, and enzymes involved in the synthesis of gangliosides, complete desialylation of the endothelial cells, and removal of sialic acid-mimicking compounds leading to the formation of angiogenic growth factors [84,85,86]. The chemotherapeutic agent, etoposide, has limited applications because of its severe adverse effects and poor solubility. Inhalable aminophenyl boronic acid–human serum albumin nanocomposites have provided a technique for the systemic delivery of etoposide to treat lung cancer. Intratumoral transport of aminophenyl boronic acid could be facilitated by binding to sialic acids. Hence, its tumor-targeting effect and cytotoxicity are improved against lung cancer cells compared with untargeted nanoparticles or free drugs [87]. Phenyl boronic acid arrangement could help nanoparticles target malignant cells more efficiently and extend the time they are retained in the TME due to the interaction between hypersialylated cancer cells and phenylboronic acid groups [88, 89]. The importance of finding suitable sites for modifying sialic acid, changing drugs/carrier linkage, and optimizing the density of sialic acid modified in the drug-delivery systems is emphasized [89]. Quercetin 7-O-sialic acid (QA) may outperform quercetin in preventing oxidative and inflammatory processes, promoting cholesterol efflux, and protecting molecules against the desialylation process. Moreover, QA significantly decreases the expression of TNF-α, monocyte chemoattractant protein-1, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1. The addition of N-acetylneuraminic acid to quercetin increases the solubility of quercetin by adding carboxyl groups, which may increase the possibility of potentially using QA for therapeutic approaches and has therefore been proposed to prevent or treat CVD [90]. Modification of sialic acids by gold nanoparticles may allow them to evade the reticuloendothelial system by inhibiting immune responses and increasing tumor accumulation via its active targeting ability [42]. Sialic acid-based micelles with bone repairing activities have the potential to treat rheumatoid arthritis. Methotrexate treatment of arthritis is associated with high toxicity and serious adverse effects, and inhibits bone regeneration on previously formed erosions in patients. A sialic acid-dextran-octadecanoic acid (SA-Dex-OA) conjugate was synthesized to form micelles. The conjugate dramatically corrected aggregation and transportation by combining sialic acid and E-selectin receptors in inflamed cells. MTX-loaded SA-Dex-OA micelles have been shown to suppress the inflammatory response, in addition to decreasing the adverse effects of MTX [91]. Doxorubicin-loaded SA-Dex-OA micelles have been proposed to target hepatocellular carcinoma. SA-Dex-OA micelles have multifold accumulation in TMEs and mediate doxorubicin delivery into tumor cells more effectively than micelles without sialic acid modification. Thus, sialic acid-functionalized micelles with double targeting effects have the potential for liver cancer treatment [92].

Sialylation promotes amyloid-β interaction, internalization, and transportation to the brain. Selective desialylation of amyloid-β is a potential target for sialidases as potential therapeutic agents for Alzheimer disease [83].

The essential role of sialic acids in coronavirus infections has been highlighted [26]. Blocking sialic acids or desialylation of cell membranes may be a therapeutic target in preventing and treating coronavirus infections. Exploiting sialic acid modification in different diseases and cancers seems to be a promising strategy for novel drugs designed with nanotechnology. Drugs, potential therapeutic targets, therapeutic effects, and mechanism of action of sialic acid in various diseases are listed in Table 2.

Table 2

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., Ac5₃F_ax 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]

SA, sialic acid; LFA, Limacus flavus agglutinin; CAD, coronary artery disease; CVD, cardiovascular diseases; TNF-α, tumor necrosis factor-α; MCP-1, monocyte chemoattractant protein-1; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; mPEG, methoxy polyethylene glycol; AuNPs, gold nanoparticles; EPI-SL, SA-stearic acid conjugates and epirubicin-loaded liposomes; N/Ms, neutrophils and monocytes; PSA-TPGS, polysialic acid and d-α-tocopheryl polyethylene glycol 1000 succinate conjugates; ABC, accelerated blood clearance; BS-NPs, biodegradable silica nanoparticles; GSH, glutathione; Siglec-10, sialic acid-binding immunoglobulin-type lectins; TNBC, triple-negative breast cancer; SAPPM, sialic acid-polyethylene glycolpoly (lactic-co-glycolic acid); DDS, drug-delivery system; SCI, spinal cord injury; Ac3ManNAc, 1,3,4-O-acetylated N-acetylmannosamine; ManNAc-6-P, N-acetylmannosamine 6-phosphate, PBN, peripheral blood neutrophil; HDI, histone deacetylase inhibitors.

Targeted drug-delivery systems may play a vital role in therapy for diseases and cancers by causing fewer adverse effects and enhanced antitumor activity than traditional medications.

Tissue specificity of sialic acids in various diseases

Any disease that causes vascular damage can elevate the sialic acid level. Correlation between different conditions such as viral infections, nervous system disorders, cancers, thromboembolism, diabetic nephropathy, and increased sialic acid levels has been found [5, 68]. Free and bound sialic acid (TSia) has been measured in serum, plasma, and tissue homogenates by various methods (Table 3). Most of these methods are research methods, and among them, enzyme-linked immunosorbent assay (ELISA) and high-performance liquid chromatography (HPLC) are more specific and more accurate than others and may be used in clinical applications. There are diagnostic parameters for sialic acids based on target disease and tissue (Table 4). However, the level of total serum sialic acid seems to be an unspecific and general marker, and it can increase in a variety of conditions.

Table 3

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]

SA, sialic acid; MBTH, 3-methyl-2-benzothiazolone hydrazone assay, HPLC, high-performance liquid chromatography; ELISA, enzyme-linked immunosorbentassay.

Table 4

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]
Oral squamous cell carcinoma	Spectrophotometric method	Blood	93.33	100	>4.23 μg/mL	98.3	[131]

SA, sialic acid; AUC, area under the receiver operating characteristic curve; HPLC, high-performance liquid chromatography; COVID-19; coronavirus disease 2019; ELISA, enzyme-linked immunosorbent assay.

Measuring tissue-specific sialic acids may provide new insights into distinguishing the origin of elevated sialic acids in the serum [3]. The possibility of tissue specificity of sialic acids warrants further investigation.

Conclusions

Sialic acids may play an important role in the pathophysiology of many diseases, including infection, malignancy, CVD, neurological disorders, and diabetic nephropathy. Abnormal overexpression of sialic acids on malignant cells and their interaction with immune cells seem to allow tumors to evade the immune system. However, routine measurement of serum sialic acid is not recommended as a classic marker of inflammation, although serum sialic acid may be better than measuring other acute-phase reactants, including CRP. We suggest that serum sialic acid level could be employed as a general and routine marker of severity in various diseases, especially neoplasms and infection; tissue specificity of sialic acids may suggest the organs involved. The potential of sialic acid as a crucial routine marker in different pathological conditions warrants exploration. Sialic acid and associated enzymes are promising therapeutic targets for improving anticancer and antiviral drugs and medications for CVD, neurological disorders, and diabetic complications.

Figuras y tablas

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]
Oral squamous cell carcinoma	Spectrophotometric method	Blood	93.33	100	>4.23 μg/mL	98.3	[131]

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., Ac5₃F_ax 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]

Referencias

[1] Park SS. Post-glycosylation modification of sialic acid and its role in virus pathogenesis. Vaccines (Basel). 2019; 7:171. doi: 10.3390/vaccines7040171 ParkSS Post-glycosylation modification of sialic acid and its role in virus pathogenesis Vaccines (Basel) 2019 7 171 10.3390/vaccines7040171 696318931683930 Abierto DOI Search in Google Scholar

[2] Zhang C, Chen J, Liu Y, Xu D. Sialic acid metabolism as a potential therapeutic target of atherosclerosis. Lipids Health Dis. 2019; 18:173. doi: 10.1186/s12944-019-1113-5 ZhangC ChenJ LiuY XuD Sialic acid metabolism as a potential therapeutic target of atherosclerosis Lipids Health Dis 2019 18 173 10.1186/s12944-019-1113-5 674506131521172 Abierto DOI Search in Google Scholar

[3] Schauer R, Kamerling JP. Exploration of the sialic acid world. In: Baker DC, editor. Sialic acids, Part I: Historical background and development, and chemical synthesis. San Diego: Academic Press; 2018, p. 1–213. (Demchenko A, Knirel YA, Stütz AE, Vliegenthart JFG, Yu B, series advisors. Adv Carbohydr Chem Biochem., vol. 75). SchauerR KamerlingJP Exploration of the sialic acid world In: BakerDC editor. Sialic acids, Part I: Historical background and development, and chemical synthesis San Diego Academic Press 2018 1 213 (Demchenko A, Knirel YA, Stütz AE, Vliegenthart JFG, Yu B, series advisors. Adv Carbohydr Chem Biochem., vol. 75). 10.1016/bs.accb.2018.09.001711206130509400 Search in Google Scholar

[4] Roozbeh J, Merat A, Bodagkhan F, Afshariani R, Yarmohammadi H. Significance of serum and urine neuraminidase activity and serum and urine level of sialic acid in diabetic nephropathy. Int Urol Nephrol. 2011; 43:1143–8. RoozbehJ MeratA BodagkhanF AfsharianiR YarmohammadiH Significance of serum and urine neuraminidase activity and serum and urine level of sialic acid in diabetic nephropathy Int Urol Nephrol 2011 43 1143 8 10.1007/s11255-010-9891-821207147 Search in Google Scholar

[5] Zhu Z, Cai T, Fan L, Lou K, Hua X, Huang Z, Gao G. Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019. Int J Infect Dis. 2020; 95:332–9. ZhuZ CaiT FanL LouK HuaX HuangZ GaoG Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019 Int J Infect Dis 2020 95 332 9 10.1016/j.ijid.2020.04.041719500332334118 Search in Google Scholar

[6] Matrosovich M, Herrler G, Klenk HD. Sialic acid receptors of viruses. In: Gerardy-Schahn R, Delannoy P, von Itzstein M, editors. Sialoglyco chemistry and biology II: tools and techniques to identify and capture sialoglycans. Heidelberg: Springer-Verlag; 2015, p. 1–28. (H. Bayley H, Houk KN, Hughes G, Hunter CA, Ishihara K, M.J. Krische MJ, et al., series editors. Top Curr Chem., vol. 367). MatrosovichM HerrlerG KlenkHD Sialic acid receptors of viruses In: Gerardy-SchahnR DelannoyP von ItzsteinM editors. Sialoglyco chemistry and biology II: tools and techniques to identify and capture sialoglycans Heidelberg Springer-Verlag 2015 1 28 (H. Bayley H, Houk KN, Hughes G, Hunter CA, Ishihara K, M.J. Krische MJ, et al., series editors. Top Curr Chem., vol. 367). 10.1007/128_2013_466712018323873408 Search in Google Scholar

[7] Wasik BR, Barnard KN, Parrish CR. Effects of sialic acid modifications on virus binding and infection. Trends Microbiol. 2016; 24:991–1001. WasikBR BarnardKN ParrishCR Effects of sialic acid modifications on virus binding and infection Trends Microbiol 2016 24 991 1001 10.1016/j.tim.2016.07.005512396527491885 Search in Google Scholar

[8] von Itzstein M., editor. Influenza virus sialidase – A drug discovery target. Basel: Springer; 2014, p. 1–178. (Parnham MJ, Bruinvels J., series editors., Milestones Drug Ther.). von ItzsteinM. editor. Influenza virus sialidase – A drug discovery target Basel Springer 2014 1 178 (Parnham MJ, Bruinvels J., series editors., Milestones Drug Ther.). Search in Google Scholar

[9] Wu NC, Wilson IA. Structural biology of influenza hemagglutinin: an amaranthine adventure. Viruses. 2020; 12:1053. doi: 10.3390/v12091053 WuNC WilsonIA Structural biology of influenza hemagglutinin: an amaranthine adventure Viruses 2020 12 1053 10.3390/v12091053 755119432971825 Abierto DOI Search in Google Scholar

[10] Benton DJ, Wharton SA, Martin SR, McCauley JW. Role of neuraminidase in influenza A(H7N9) virus receptor binding. J Virol. 2017; 91:e02293–16. doi: 10.1128/jvi.02293-16 BentonDJ WhartonSA MartinSR McCauleyJW Role of neuraminidase in influenza A(H7N9) virus receptor binding J Virol 2017 91 e02293 16 10.1128/jvi.02293-16 Abierto DOI Search in Google Scholar

[11] Wen F, Wan X-F. Influenza neuraminidase: underrated role in receptor binding. Trends Microbiol. 2019; 27:477–9. WenF WanX-F Influenza neuraminidase: underrated role in receptor binding Trends Microbiol 2019 27 477 9 10.1016/j.tim.2019.03.001652746530930001 Search in Google Scholar

[12] Imai M, Kawaoka Y. The role of receptor binding specificity in interspecies transmission of influenza viruses. Curr Opin Virol. 2012; 2:160–7. ImaiM KawaokaY The role of receptor binding specificity in interspecies transmission of influenza viruses Curr Opin Virol 2012 2 160 7 10.1016/j.coviro.2012.03.003 Search in Google Scholar

[13] Matrosovich M, Tuzikov A, Bovin N, Gambaryan A, Klimov A, Castrucci MR, et al. Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals. J Virol. 2000; 74:8502–12. MatrosovichM TuzikovA BovinN GambaryanA KlimovA CastrucciMR Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals J Virol 2000 74 8502 12 10.1128/JVI.74.18.8502-8512.2000 Search in Google Scholar

[14] Rogers GN, Paulson JC. Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin. Virology. 1983; 127:361–73. RogersGN PaulsonJC Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin Virology 1983 127 361 73 10.1016/0042-6822(83)90150-2 Search in Google Scholar

[15] Connor RJ, Kawaoka Y, Webster RG, Paulson JC. Receptor specificity in human, avian, and equine H2 and H3 influenza virus isolates. Virology. 1994; 205:17–23. ConnorRJ KawaokaY WebsterRG PaulsonJC Receptor specificity in human, avian, and equine H2 and H3 influenza virus isolates Virology 1994 205 17 23 10.1006/viro.1994.16157975212 Search in Google Scholar

[16] Wang M, Veit M. Hemagglutinin-esterase-fusion (HEF) protein of influenza C virus. Protein Cell. 2016; 7:28–45. WangM VeitM Hemagglutinin-esterase-fusion (HEF) protein of influenza C virus Protein Cell 2016 7 28 45 10.1007/s13238-015-0193-x470715526215728 Search in Google Scholar

[17] Kim C-H. SARS-CoV-2 Evolutionary adaptation toward host entry and recognition of receptor O-acetyl sialylation in virus-host interaction. Int J Mol Sci. 2020; 21:4549. doi: 10.3390/ijms21124549 KimC-H SARS-CoV-2 Evolutionary adaptation toward host entry and recognition of receptor O-acetyl sialylation in virus-host interaction Int J Mol Sci 2020 21 4549 10.3390/ijms21124549 735254532604730 Abierto DOI Search in Google Scholar

[18] Bolton MJ, Ort JT, McBride R, Swanson NJ, Wilson J, Awofolaju M, et al. Antigenic and virological properties of an H3N2 variant that continues to dominate the 2021–22 Northern Hemisphere influenza season. Cell Rep. 2022; 39:110897. doi: 10.1016/j.celrep.2022.110897 BoltonMJ OrtJT McBrideR SwansonNJ WilsonJ AwofolajuM Antigenic and virological properties of an H3N2 variant that continues to dominate the 2021–22 Northern Hemisphere influenza season Cell Rep 2022 39 110897 10.1016/j.celrep.2022.110897 915308335649381 Abierto DOI Search in Google Scholar

[19] Klausegger A, Strobl B, Regl G, Kaser A, Luytjes W, Vlasak R. Identification of a coronavirus hemagglutinin-esterase with a substrate specificity different from those of influenza C virus and bovine coronavirus. J Virol. 1999; 73:3737–43. KlauseggerA StroblB ReglG KaserA LuytjesW VlasakR Identification of a coronavirus hemagglutinin-esterase with a substrate specificity different from those of influenza C virus and bovine coronavirus J Virol 1999 73 3737 43 10.1128/JVI.73.5.3737-3743.199910415010196267 Search in Google Scholar

[20] Smits SL, Gerwig GJ, van Vliet AL, Lissenberg A, Briza P, Kamerling JP, et al. Nidovirus sialate-O-acetylesterases: evolution and substrate specificity of coronaviral and toroviral receptor-destroying enzymes. J Biol Chem. 2005; 280:6933–41. SmitsSL GerwigGJ van VlietAL LissenbergA BrizaP KamerlingJP Nidovirus sialate-O-acetylesterases: evolution and substrate specificity of coronaviral and toroviral receptor-destroying enzymes J Biol Chem 2005 280 6933 41 10.1074/jbc.M409683200806279315507445 Search in Google Scholar

[21] Markwell MA, Svennerholm L, Paulson JC. Specific gangliosides function as host cell receptors for Sendai virus. Proc Natl Acad Sci U S A. 1981; 78:5406–10. MarkwellMA SvennerholmL PaulsonJC Specific gangliosides function as host cell receptors for Sendai virus Proc Natl Acad Sci U S A 1981 78 5406 10 10.1073/pnas.78.9.54063487546272300 Search in Google Scholar

[22] Suzuki T, Portner A, Scroggs RA, Uchikawa M, Koyama N, Matsuo K, et al. Receptor specificities of human respiroviruses. J Virol. 2001; 75:4604–13. SuzukiT PortnerA ScroggsRA UchikawaM KoyamaN MatsuoK Receptor specificities of human respiroviruses J Virol 2001 75 4604 13 10.1128/JVI.75.10.4604-4613.2001 Search in Google Scholar

[23] Palese P, Tobita K, Ueda M, Compans RW. Characterization of temperature sensitive influenza virus mutants defective in neuraminidase. Virology. 1974; 61:397–410. PaleseP TobitaK UedaM CompansRW Characterization of temperature sensitive influenza virus mutants defective in neuraminidase Virology 1974 61 397 410 10.1016/0042-6822(74)90276-1 Search in Google Scholar

[24] Vlasak R, Luytjes W, Spaan W, Palese P. Human and bovine coronaviruses recognize sialic acid-containing receptors similar to those of influenza C viruses. Proc Natl Acad Sci U S A. 1988; 85:4526–9. VlasakR LuytjesW SpaanW PaleseP Human and bovine coronaviruses recognize sialic acid-containing receptors similar to those of influenza C viruses Proc Natl Acad Sci U S A 1988 85 4526 9 10.1073/pnas.85.12.45262804633380803 Search in Google Scholar

[25] Heida R, Bhide YC, Gasbarri M, Kocabiyik Ö, Stellacci F, Huckriede ALW, et al. Advances in the development of entry inhibitors for sialic-acid-targeting viruses. Drug Discov Today. 2021; 26:122–37. HeidaR BhideYC GasbarriM KocabiyikÖ StellacciF HuckriedeALW Advances in the development of entry inhibitors for sialic-acid-targeting viruses Drug Discov Today 2021 26 122 37 10.1016/j.drudis.2020.10.009757731633099021 Search in Google Scholar

[26] Qing E, Hantak M, Perlman S, Gallagher T. Distinct roles for sialoside and protein receptors in coronavirus infection. mBio. 2020; 11:e02764–19. doi: 10.1128/mBio.02764-19 QingE HantakM PerlmanS GallagherT Distinct roles for sialoside and protein receptors in coronavirus infection mBio 2020 11 e02764 19 10.1128/mBio.02764-19 701865832047128 Abierto DOI Search in Google Scholar

[27] Munkley J, Scott E. Targeting aberrant sialylation to treat cancer. Medicines (Basel). 2019; 6:102. doi: 10.3390/medicines6040102 MunkleyJ ScottE Targeting aberrant sialylation to treat cancer Medicines (Basel) 2019 6 102 10.3390/medicines6040102 696394331614918 Abierto DOI Search in Google Scholar

[28] Daly J, Carlsten M, O’Dwyer M. Sugar free: novel immunotherapeutic approaches targeting Siglecs and sialic acids to enhance natural killer cell cytotoxicity against cancer. Front Immunol. 2019; 10:1047. doi: 10.3389/fimmu.2019.01047 DalyJ CarlstenM O’DwyerM Sugar free: novel immunotherapeutic approaches targeting Siglecs and sialic acids to enhance natural killer cell cytotoxicity against cancer Front Immunol 2019 10 1047 10.3389/fimmu.2019.01047 652179731143186 Abierto DOI Search in Google Scholar

[29] Glavey SV, Manier S, Natoni A, Sacco A, Moschetta M, Reagan MR, et al. The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma. Blood. 2014; 124:1765–76. GlaveySV ManierS NatoniA SaccoA MoschettaM ReaganMR The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma Blood 2014 124 1765 76 10.1182/blood-2014-03-560862416210725061176 Search in Google Scholar

[30] Chang L-Y, Liang S-Y, Lu S-C, Tseng HC, Tsai H-Y, Tang C-J, et al. Molecular basis and role of Siglec-7 ligand expression on chronic lymphocytic leukemia B cells. Front Immunol. 2022; 13:840388. doi: 10.3389/fimmu.2022.840388 ChangL-Y LiangS-Y LuS-C TsengHC TsaiH-Y TangC-J Molecular basis and role of Siglec-7 ligand expression on chronic lymphocytic leukemia B cells Front Immunol 2022 13 840388 10.3389/fimmu.2022.840388 919529435711441 Abierto DOI Search in Google Scholar

[31] Miyagi T. Aberrant expression of sialidase and cancer progression. Proc Jpn Acad Ser B Phys Biol Sci. 2008; 84:407–18. MiyagiT Aberrant expression of sialidase and cancer progression Proc Jpn Acad Ser B Phys Biol Sci 2008 84 407 18 10.2183/pjab.84.407372054519075514 Search in Google Scholar

[32] Topham NJ, Hewitt EW. Natural killer cell cytotoxicity: how do they pull the trigger? Immunology. 2009; 128:7–15. TophamNJ HewittEW Natural killer cell cytotoxicity: how do they pull the trigger? Immunology 2009 128 7 15 10.1111/j.1365-2567.2009.03123.x274713419689731 Search in Google Scholar

[33] Paust S, Senman B, von Andrian UH. Adaptive immune responses mediated by natural killer cells. Immunol Rev. 2010; 235:286–96. PaustS SenmanB von AndrianUH Adaptive immune responses mediated by natural killer cells Immunol Rev 2010 235 286 96 10.1111/j.0105-2896.2010.00906.x291163320536570 Search in Google Scholar

[34] Shao J-Y, Yin W-W, Zhang Q-F, Liu Q, Peng M-L, Hu H-D, et al. Siglec-7 defines a highly functional natural killer cell subset and inhibits cell-mediated activities. Scand J Immunol. 2016; 84:182–90. ShaoJ-Y YinW-W ZhangQ-F LiuQ PengM-L HuH-D Siglec-7 defines a highly functional natural killer cell subset and inhibits cell-mediated activities Scand J Immunol 2016 84 182 90 10.1111/sji.1245527312286 Search in Google Scholar

[35] Lübbers J, Rodríguez E, van Kooyk Y. Modulation of immune tolerance via Siglec-sialic acid interactions. Front Immunol. 2018; 9:2807. doi: 10.3389/fimmu.2018.02807 LübbersJ RodríguezE van KooykY Modulation of immune tolerance via Siglec-sialic acid interactions Front Immunol 2018 9 2807 10.3389/fimmu.2018.02807 629387630581432 Abierto DOI Search in Google Scholar

[36] Varchetta S, Mele D, Oliviero B, Mantovani S, Ludovisi S, Cerino A, et al. Unique immunological profile in patients with COVID-19. Cell Mol Immunol. 2021; 18:604–12. VarchettaS MeleD OlivieroB MantovaniS LudovisiS CerinoA Unique immunological profile in patients with COVID-19 Cell Mol Immunol 2021 18 604 12 10.1038/s41423-020-00557-9755723033060840 Search in Google Scholar

[37] Häuselmann I, Borsig L. Altered tumor-cell glycosylation promotes metastasis. Front Oncol. 2014; 4:28. doi: 10.3389/fonc.2014.00028 HäuselmannI BorsigL Altered tumor-cell glycosylation promotes metastasis Front Oncol 2014 4 28 10.3389/fonc.2014.00028 392313924592356 Abierto DOI Search in Google Scholar

[38] Yang H, Lu L, Chen X. An overview and future prospects of sialic acids. Biotechnol Adv. 2021; 46:107678. doi: 10.1016/j.biotechadv.2020.107678 YangH LuL ChenX An overview and future prospects of sialic acids Biotechnol Adv 2021 46 107678 10.1016/j.biotechadv.2020.107678 33285252 Abierto DOI Search in Google Scholar

[39] Fuster MM, Esko JD. The sweet and sour of cancer: glycans as novel therapeutic targets. Nat Rev Cancer. 2005; 5:526–42. FusterMM EskoJD The sweet and sour of cancer: glycans as novel therapeutic targets Nat Rev Cancer 2005 5 526 42 10.1038/nrc164916069816 Search in Google Scholar

[40] Kajander T, Lehtinen MJ, Hyvärinen S, Bhattacharjee A, Leung E, Isenman DE, et al. Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement. Proc Natl Acad Sci U S A. 2011; 108:2897–902. KajanderT LehtinenMJ HyvärinenS BhattacharjeeA LeungE IsenmanDE Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement Proc Natl Acad Sci U S A 2011 108 2897 902 10.1073/pnas.1017087108304113421285368 Search in Google Scholar

[41] Kim Y-H, Min KH, Wang Z, Kim J, Jacobson O, Huang P, et al. Development of sialic acid-coated nanoparticles for targeting cancer and efficient evasion of the immune system. Theranostics. 2017; 7:962–73. KimY-H MinKH WangZ KimJ JacobsonO HuangP Development of sialic acid-coated nanoparticles for targeting cancer and efficient evasion of the immune system Theranostics 2017 7 962 73 10.7150/thno.19061538125828382168 Search in Google Scholar

[42] Chen Z, Yu M, Guo L, Zhang B, Liu S, Zhang W, et al. Tumor derived SIGLEC family genes may play roles in tumor genesis, progression, and immune microenvironment regulation. Front Oncol. 2020; 10:586820. doi: 10.3389/fonc.2020.586820 ChenZ YuM GuoL ZhangB LiuS ZhangW Tumor derived SIGLEC family genes may play roles in tumor genesis, progression, and immune microenvironment regulation Front Oncol 2020 10 586820 10.3389/fonc.2020.586820 768100333240817 Abierto DOI Search in Google Scholar

[43] Huang P-J, Low P-Y, Wang I, Hsu S-TD, Angata T. Soluble Siglec-14 glycan-recognition protein is generated by alternative splicing and suppresses myeloid inflammatory responses. J Biol Chem. 2018; 293:19645–58. HuangP-J LowP-Y WangI HsuS-TD AngataT Soluble Siglec-14 glycan-recognition protein is generated by alternative splicing and suppresses myeloid inflammatory responses J Biol Chem 2018 293 19645 58 10.1074/jbc.RA118.005676631413730377253 Search in Google Scholar

[44] Wang J, Sun J, Liu LN, Flies DB, Nie X, Toki M, et al. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nat Med. 2019; 25:656–66. WangJ SunJ LiuLN FliesDB NieX TokiM Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy Nat Med 2019 25 656 66 10.1038/s41591-019-0374-x717592030833750 Search in Google Scholar

[45] Cao G, Xiao Z, Yin Z. Normalization cancer immunotherapy: blocking Siglec-15! Signal Transduct Target Ther. 2019; 4:10. doi: 10.1038/s41392-019-0045-x CaoG XiaoZ YinZ Normalization cancer immunotherapy: blocking Siglec-15! Signal Transduct Target Ther 2019 4 10 10.1038/s41392-019-0045-x 647300131016034 Abierto DOI Search in Google Scholar

[46] Liu Y, Li X, Zhang C, Zhang H, Huang Y. LINC00973 is involved in cancer immune suppression through positive regulation of Siglec-15 in clear-cell renal cell carcinoma. Cancer Sci. 2020; 111:3693–704. doi: 10.1111/cas.14611 LiuY LiX ZhangC ZhangH HuangY LINC00973 is involved in cancer immune suppression through positive regulation of Siglec-15 in clear-cell renal cell carcinoma Cancer Sci 2020 111 3693 704 10.1111/cas.14611 754100132780490 Abierto DOI Search in Google Scholar

[47] Udagawa N, Koide M, Nakamura M, Nakamichi Y, Yamashita T, Uehara S, et al. Osteoclast differentiation by RANKL and OPG signaling pathways. J Bone Miner Metab. 2021; 39:19–26. UdagawaN KoideM NakamuraM NakamichiY YamashitaT UeharaS Osteoclast differentiation by RANKL and OPG signaling pathways J Bone Miner Metab 2021 39 19 26 10.1007/s00774-020-01162-633079279 Search in Google Scholar

[48] Kohnz RA, Roberts LS, DeTomaso D, Bideyan L, Yan P, Bandyopadhyay S, et al. Protein sialylation regulates a gene expression signature that promotes breast cancer cell pathogenicity. ACS Chem Biol. 2016; 11:2131–9. KohnzRA RobertsLS DeTomasoD BideyanL YanP BandyopadhyayS Protein sialylation regulates a gene expression signature that promotes breast cancer cell pathogenicity ACS Chem Biol 2016 11 2131 9 10.1021/acschembio.6b00433499406027380425 Search in Google Scholar

[49] Teoh ST, Ogrodzinski MP, Ross C, Hunter KW, Lunt SY. Sialic acid metabolism: a key player in breast cancer metastasis revealed by metabolomics. Front Oncol. 2018; 8:174. doi: 10.3389/fonc.2018.00174 TeohST OgrodzinskiMP RossC HunterKW LuntSY Sialic acid metabolism: a key player in breast cancer metastasis revealed by metabolomics Front Oncol 2018 8 174 10.3389/fonc.2018.00174 598544929892572 Abierto DOI Search in Google Scholar

[50] van den Bijgaart RJE, Kroesen M, Wassink M, Brok IC, Kers-Rebel ED, Boon L, et al. Combined sialic acid and histone deacetylase (HDAC) inhibitor treatment up-regulates the neuroblastoma antigen GD2. J Biol Chem. 2019; 294:4437–49. van den BijgaartRJE KroesenM WassinkM BrokIC Kers-RebelED BoonL Combined sialic acid and histone deacetylase (HDAC) inhibitor treatment up-regulates the neuroblastoma antigen GD2 J Biol Chem 2019 294 4437 49 10.1074/jbc.RA118.002763643306130670592 Search in Google Scholar

[51] Büll C, Heise T, Beurskens DMH, Riemersma M, Ashikov A, Rutjes FPJT, et al. Sialic acid glycoengineering using an unnatural sialic acid for the detection of sialoglycan biosynthesis defects and on-cell synthesis of Siglec ligands. ACS Chem Biol. 2015; 10:2353–63. BüllC HeiseT BeurskensDMH RiemersmaM AshikovA RutjesFPJT Sialic acid glycoengineering using an unnatural sialic acid for the detection of sialoglycan biosynthesis defects and on-cell synthesis of Siglec ligands ACS Chem Biol 2015 10 2353 63 10.1021/acschembio.5b0050126258433 Search in Google Scholar

[52] Büll C, Boltje TJ, Balneger N, Weischer SM, Wassink M, van Gemst JJ, et al. Sialic acid blockade suppresses tumor growth by enhancing T-cell-mediated tumor immunity. Cancer Res. 2018; 78:3574–88. BüllC BoltjeTJ BalnegerN WeischerSM WassinkM van GemstJJ Sialic acid blockade suppresses tumor growth by enhancing T-cell-mediated tumor immunity Cancer Res 2018 78 3574 88 10.1158/0008-5472.CAN-17-337629703719 Search in Google Scholar

[53] Nakamura K, Terai Y, Tanabe A, Ono YJ, Hayashi M, Maeda K, et al. CD24 expression is a marker for predicting clinical outcome and regulates the epithelial-mesenchymal transition in ovarian cancer via both the Akt and ERK pathways. Oncol Rep. 2017;37:3189–200. NakamuraK TeraiY TanabeA OnoYJ HayashiM MaedaK CD24 expression is a marker for predicting clinical outcome and regulates the epithelial-mesenchymal transition in ovarian cancer via both the Akt and ERK pathways Oncol Rep 2017 37 3189 200 10.3892/or.2017.5583544239928440503 Search in Google Scholar

[54] Kristiansen G, Winzer K-J, Mayordomo E, Bellach J, Schlüns K, Denkert C, et al. CD24 expression is a new prognostic marker in breast cancer. Clin Cancer Res. 2003; 9:4906–13. KristiansenG WinzerK-J MayordomoE BellachJ SchlünsK DenkertC CD24 expression is a new prognostic marker in breast cancer Clin Cancer Res 2003 9 4906 13 Search in Google Scholar

[55] Barkal AA, Brewer RE, Markovic M, Kowarsky M, Barkal SA, Zaro BW, et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature. 2019; 572(7769):392–6. BarkalAA BrewerRE MarkovicM KowarskyM BarkalSA ZaroBW CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy Nature 2019 572 7769 392 6 10.1038/s41586-019-1456-0669720631367043 Search in Google Scholar

[56] Abolhasani S, Shahbazloo SV, Saadati HM, Mahmoodi N, Khanbabaei N. Evaluation of serum levels of inflammation, fibrinolysis and oxidative stress markers in coronary artery disease prediction: a cross-sectional study. Arq Bras Cardiol. 2019; 113:667–74. [article in English and Portuguese] AbolhasaniS ShahbazlooSV SaadatiHM MahmoodiN KhanbabaeiN Evaluation of serum levels of inflammation, fibrinolysis and oxidative stress markers in coronary artery disease prediction: a cross-sectional study Arq Bras Cardiol 2019 113 667 74 [article in English and Portuguese] 10.5935/abc.20190159702086431482948 Search in Google Scholar

[57] Bakri RS, Afzali B, Covic A, Sriskantharan R, Bharma-Ariza P, Park WH, et al. Cardiovascular disease in renal allograft recipients is associated with elevated sialic acid or markers of inflammation. Clin Transplant. 2004; 18:201–4. BakriRS AfzaliB CovicA SriskantharanR Bharma-ArizaP ParkWH Cardiovascular disease in renal allograft recipients is associated with elevated sialic acid or markers of inflammation Clin Transplant 2004 18 201 4 10.1111/j.1399-0012.2004.00156.x15016136 Search in Google Scholar

[58] Christ ER, Cummings MH, Lumb PJ, Crook MA, Sönksen PH, Russell-Jones DL. Growth hormone (GH) replacement therapy reduces serum sialic acid concentrations in adults with GH-deficiency: a double-blind placebo-controlled study. Clin Endocrinol (Oxf). 1999; 51:173–9. ChristER CummingsMH LumbPJ CrookMA SönksenPH Russell-JonesDL Growth hormone (GH) replacement therapy reduces serum sialic acid concentrations in adults with GH-deficiency: a double-blind placebo-controlled study Clin Endocrinol (Oxf) 1999 51 173 9 10.1046/j.1365-2265.1999.00751.x10468987 Search in Google Scholar

[59] Masuda H, Wakabayashi R, Wakabayashi I. Serum sialic acid and ankle versus brachial arterial-pressure ratio in NIDDM. Scand J Clin Lab Invest. 1998; 58:433–39. MasudaH WakabayashiR WakabayashiI Serum sialic acid and ankle versus brachial arterial-pressure ratio in NIDDM Scand J Clin Lab Invest 1998 58 433 39 10.1080/003655198501864279819193 Search in Google Scholar

[60] Zhang L, Wei T-T, Li Y, Li J, Fan Y, Huang F-Q, et al. Functional metabolomics characterizes a key role for N-acetylneuraminic acid in coronary artery diseases. Circulation. 2018; 137:1374–90. ZhangL WeiT-T LiY LiJ FanY HuangF-Q Functional metabolomics characterizes a key role for N-acetylneuraminic acid in coronary artery diseases Circulation 2018 137 1374 90 10.1161/CIRCULATIONAHA.117.03113929212895 Search in Google Scholar

[61] Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003; 107:499–511. PearsonTA MensahGA AlexanderRW AndersonJL CannonRO3rd CriquiM Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association Circulation 2003 107 499 511 10.1161/01.CIR.0000052939.59093.45 Search in Google Scholar

[62] Nigam PK, Narain VS, Kumar A. Sialic acid in cardiovascular diseases. Indian J Clin Biochem. 2006; 21:54–61. NigamPK NarainVS KumarA Sialic acid in cardiovascular diseases Indian J Clin Biochem 2006 21 54 61 10.1007/BF02913067345378423105570 Search in Google Scholar

[63] Baumann H, Gauldie J. The acute phase response. Immunol Today. 1994; 15:74–80. BaumannH GauldieJ The acute phase response Immunol Today 1994 15 74 80 10.1016/0167-5699(94)90137-6 Search in Google Scholar

[64] Romero R, Lens XM, Novoa D, Arcocha V, Alonso R, Arza MD, et al. Sialic acid is a predictor of cardiovascular complications in renal transplantation recipients. Nephron. 1993; 65:489–90. RomeroR LensXM NovoaD ArcochaV AlonsoR ArzaMD Sialic acid is a predictor of cardiovascular complications in renal transplantation recipients Nephron 1993 65 489 90 10.1159/0001875458290012 Search in Google Scholar

[65] Ogasawara Y, Namai T, Yoshino F, Lee M-C-i, Ishii K. Sialic acid is an essential moiety of mucin as a hydroxyl radical scavenger. FEBS Lett. 2007; 581:2473–7. OgasawaraY NamaiT YoshinoF LeeM-C-i IshiiK Sialic acid is an essential moiety of mucin as a hydroxyl radical scavenger FEBS Lett 2007 581 2473 7 10.1016/j.febslet.2007.04.06217485090 Search in Google Scholar

[66] Tertov VV, Sobenin IA, Orekhov AN. Characterization of desialylated low-density lipoproteins which cause intracellular lipid accumulation. Int J Tissue React. 1992; 14:155–62. TertovVV SobeninIA OrekhovAN Characterization of desialylated low-density lipoproteins which cause intracellular lipid accumulation Int J Tissue React 1992 14 155 62 Search in Google Scholar

[67] Knuiman MW, Watts GF, Divitini ML. Is sialic acid an independent risk factor for cardiovascular disease? A 17-year follow-up study in Busselton, Western Australia. Ann Epidemiol. 2004; 14:627–32. KnuimanMW WattsGF DivitiniML Is sialic acid an independent risk factor for cardiovascular disease? A 17-year follow-up study in Busselton, Western Australia Ann Epidemiol 2004 14 627 32 10.1016/j.annepidem.2003.09.01715380792 Search in Google Scholar

[68] Prajna K, Kumar JA, Rai S, Shetty SK, Rai T, Shrinidhi, et al. Predictive value of serum sialic acid in type-2 diabetes mellitus and its complication (nephropathy). J Clin Diagn Res. 2013; 7:2435–7. doi: 10.7860/jcdr/2013/6210.3567 PrajnaK KumarJA RaiS ShettySK RaiT Shrinidhi Predictive value of serum sialic acid in type-2 diabetes mellitus and its complication (nephropathy) J Clin Diagn Res 2013 7 2435 7 10.7860/jcdr/2013/6210.3567 387988624392365 Abierto DOI Search in Google Scholar

[69] Nayak SB, Bhaktha G. Relationship between sialic acid and metabolic variables in Indian type 2 diabetic patients. Lipids Health Dis. 2005; 4:15. doi: 10.1186/1476-511x-4-15 NayakSB BhakthaG Relationship between sialic acid and metabolic variables in Indian type 2 diabetic patients Lipids Health Dis 2005 4 15 10.1186/1476-511x-4-15 Abierto DOI Search in Google Scholar

[70] Varma V, Varma M, Varma A, Kumar R, Bharosay A, Vyas S. Serum total sialic acid and highly sensitive C-reactive protein: prognostic markers for the diabetic nephropathy. J Lab Physicians. 2016; 8:25–9. doi: 10.4103/0974-2727.176230 VarmaV VarmaM VarmaA KumarR BharosayA VyasS Serum total sialic acid and highly sensitive C-reactive protein: prognostic markers for the diabetic nephropathy J Lab Physicians 2016 8 25 9 10.4103/0974-2727.176230 478576127013809 Abierto DOI Search in Google Scholar

[71] Shivananda Nayak B, Duncan H, Lalloo S, Maraj K, Matmungal V, Matthews F, et al. Correlation of microalbumin and sialic acid with anthropometric variables in type 2 diabetic patients with and without nephropathy. Vasc Health Risk Manag. 2008; 4:243–7. Shivananda NayakB DuncanH LallooS MarajK MatmungalV MatthewsF Correlation of microalbumin and sialic acid with anthropometric variables in type 2 diabetic patients with and without nephropathy Vasc Health Risk Manag 2008 4 243 7 10.2147/VHRM.2.94.134.1572 Search in Google Scholar

[72] Animaw W, Seyoum Y. Increasing prevalence of diabetes mellitus in a developing country and its related factors. PLoS One. 2017; 12:e0187670. doi: 10.1371/journal.pone.0187670 AnimawW SeyoumY Increasing prevalence of diabetes mellitus in a developing country and its related factors PLoS One 2017 12 e0187670 10.1371/journal.pone.0187670 567540229112962 Abierto DOI Search in Google Scholar

[73] Rogers ME, Williams DT, Niththyananthan R, Rampling MW, Heslop KE, Johnston DG. Decrease in erythrocyte glycophorin sialic acid content is associated with increased erythrocyte aggregation in human diabetes. Clin Sci (Lond). 1992; 82:309–13. RogersME WilliamsDT NiththyananthanR RamplingMW HeslopKE JohnstonDG Decrease in erythrocyte glycophorin sialic acid content is associated with increased erythrocyte aggregation in human diabetes Clin Sci (Lond) 1992 82 309 13 10.1042/cs08203091312416 Search in Google Scholar

[74] 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. 2020; 11:19–26. doi: 10.1007/s13340-019-00395-9 ShahvaliS ShahesmaeiliA SanjariM Karami-MohajeriS The correlation between blood oxidative stress and sialic acid content in diabetic patients with nephropathy, hypertension, and hyperlipidemia Diabetol Int 2020 11 19 26 10.1007/s13340-019-00395-9 Abierto DOI Search in Google Scholar

[75] Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurology of inherited glycosylation disorders. Lancet Neurol. 2012; 11:453–66. FreezeHH EklundEA NgBG PattersonMC Neurology of inherited glycosylation disorders Lancet Neurol 2012 11 453 66 10.1016/S1474-4422(12)70040-6 Search in Google Scholar

[76] Siddiqui SS, Matar R, Merheb M, Hodeify R, Vazhappilly CG, Marton J, et al. Siglecs in brain function and neurological disorders. Cells. 2019; 8:1125. doi: 10.3390/cells8101125 SiddiquiSS MatarR MerhebM HodeifyR VazhappillyCG MartonJ Siglecs in brain function and neurological disorders Cells 2019 8 1125 10.3390/cells8101125 Abierto DOI Search in Google Scholar

[77] Schnaar RL, Gerardy-Schahn R, Hildebrandt H. Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol Rev. 2014; 94:461–518. SchnaarRL Gerardy-SchahnR HildebrandtH Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration Physiol Rev 2014 94 461 518 10.1152/physrev.00033.2013 Search in Google Scholar

[78] Wielgat P, Walesiuk A, Braszko JJ. Effects of chronic stress and corticosterone on sialidase activity in the rat hippocampus. Behav Brain Res. 2011; 222:363–7. WielgatP WalesiukA BraszkoJJ Effects of chronic stress and corticosterone on sialidase activity in the rat hippocampus Behav Brain Res 2011 222 363 7 10.1016/j.bbr.2011.03.070 Search in Google Scholar

[79] Boyzo A, Ayala J, Gutiérrez R, Hernández-RJ. Neuraminidase activity in different regions of the seizing epileptic and non-epileptic brain. Brain Res. 2003; 964:211–7. BoyzoA AyalaJ GutiérrezR HernándezRJ Neuraminidase activity in different regions of the seizing epileptic and non-epileptic brain Brain Res 2003 964 211 7 10.1016/S0006-8993(02)03985-9 Search in Google Scholar

[80] Minami A, Meguro Y, Ishibashi S, Ishii A, Shiratori M, Sai S, et al. Rapid regulation of sialidase activity in response to neural activity and sialic acid removal during memory processing in rat hippocampus. J Biol Chem. 2017; 292:5645–54. MinamiA MeguroY IshibashiS IshiiA ShiratoriM SaiS Rapid regulation of sialidase activity in response to neural activity and sialic acid removal during memory processing in rat hippocampus J Biol Chem 2017 292 5645 54 10.1074/jbc.M116.764357539256028213516 Search in Google Scholar

[81] Minami A, Ishii A, Shimba S, Kano T, Fujioka E, Sai S, et al. Down-regulation of glutamate release from hippocampal neurons by sialidase. J Biochem. 2018; 163:273–80. MinamiA IshiiA ShimbaS KanoT FujiokaE SaiS Down-regulation of glutamate release from hippocampal neurons by sialidase J Biochem 2018 163 273 80 10.1093/jb/mvy00329319803 Search in Google Scholar

[82] Annunziata I, Patterson A, Helton D, Hu H, Moshiach S, Gomero E, et al. Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis. Nat Commun. 2013; 4:2734. doi: 10.1038/ncomms3734 AnnunziataI PattersonA HeltonD HuH MoshiachS GomeroE Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis Nat Commun 2013 4 2734 10.1038/ncomms3734 401546324225533 Abierto DOI Search in Google Scholar

[83] Schneider JS, Seyfried TN, Choi H-S, Kidd SK. Intraventricular sialidase administration enhances GM1 ganglioside expression and is partially neuroprotective in a mouse model of Parkinson's disease. PLoS One. 2015; 10:e0143351. doi: 10.1371/journal.pone.0143351 SchneiderJS SeyfriedTN ChoiH-S KiddSK Intraventricular sialidase administration enhances GM1 ganglioside expression and is partially neuroprotective in a mouse model of Parkinson's disease PLoS One 2015 10 e0143351 10.1371/journal.pone.0143351 466804926629687 Abierto DOI Search in Google Scholar

[84] De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017; 17:457–74. De PalmaM BiziatoD PetrovaTV Microenvironmental regulation of tumour angiogenesis Nat Rev Cancer 2017 17 457 74 10.1038/nrc.2017.5128706266 Search in Google Scholar

[85] Chiodelli P, Urbinati C, Paiardi G, Monti E, Rusnati M. Sialic acid as a target for the development of novel antiangiogenic strategies. Future Med Chem. 2018; 10:2835–54. ChiodelliP UrbinatiC PaiardiG MontiE RusnatiM Sialic acid as a target for the development of novel antiangiogenic strategies Future Med Chem 2018 10 2835 54 10.4155/fmc-2018-029830539670 Search in Google Scholar

[86] Szabo R, Skropeta D. Advancement of sialyltransferase inhibitors: therapeutic challenges and opportunities. Med Res Rev. 2017; 37:219–70. SzaboR SkropetaD Advancement of sialyltransferase inhibitors: therapeutic challenges and opportunities Med Res Rev 2017 37 219 70 10.1002/med.2140727678392 Search in Google Scholar

[87] Elgohary MM, Helmy MW, Abdelfattah E-ZA, Ragab DM, Mortada SM, Fang J-Y, Elzoghby AO. Targeting sialic acid residues on lung cancer cells by inhalable boronic acid-decorated albumin nanocomposites for combined chemo/herbal therapy. J Control Release. 2018; 285:230–43. ElgoharyMM HelmyMW AbdelfattahE-ZA RagabDM MortadaSM FangJ-Y ElzoghbyAO Targeting sialic acid residues on lung cancer cells by inhalable boronic acid-decorated albumin nanocomposites for combined chemo/herbal therapy J Control Release 2018 285 230 43 10.1016/j.jconrel.2018.07.01430009892 Search in Google Scholar

[88] Wang X, Tang H, Wang C, Zhang J, Wu W, Jiang X. Phenylboronic acid-mediated tumor targeting of chitosan nanoparticles. Theranostics. 2016; 6:1378–92. WangX TangH WangC ZhangJ WuW JiangX Phenylboronic acid-mediated tumor targeting of chitosan nanoparticles Theranostics 2016 6 1378 92 10.7150/thno.15156492450627375786 Search in Google Scholar

[89] Wang J, Wu W, Zhang Y, Wang X, Qian H, Liu B, Jiang X. The combined effects of size and surface chemistry on the accumulation of boronic acid-rich protein nanoparticles in tumors. Biomaterials. 2014; 35:866–78. WangJ WuW ZhangY WangX QianH LiuB JiangX The combined effects of size and surface chemistry on the accumulation of boronic acid-rich protein nanoparticles in tumors Biomaterials 2014 35 866 78 10.1016/j.biomaterials.2013.10.02824157313 Search in Google Scholar

[90] Tian H, Liu Q, Qin S, Zong C, Zhang Y, Yao S, et al. Synthesis and cardiovascular protective effects of quercetin 7-O-sialic acid. J Cell Mol Med. 2017; 21:107–20. TianH LiuQ QinS ZongC ZhangY YaoS Synthesis and cardiovascular protective effects of quercetin 7-O-sialic acid J Cell Mol Med 2017 21 107 20 10.1111/jcmm.12943519294327511707 Search in Google Scholar

[91] Xu X-L, Li W-S, Wang X-J, Du Y-L, Kang X-Q, Hu J-B, et al. Endogenous sialic acid-engineered micelles: a multifunctional platform for on-demand methotrexate delivery and bone repair of rheumatoid arthritis. Nanoscale. 2018; 10:2923–35. XuX-L LiW-S WangX-J DuY-L KangX-Q HuJ-B Endogenous sialic acid-engineered micelles: a multifunctional platform for on-demand methotrexate delivery and bone repair of rheumatoid arthritis Nanoscale 2018 10 2923 35 10.1039/C7NR08430G Search in Google Scholar

[92] Zhu M-L, Xu X-L, Wang X-J, Zhang N-N, Lu K-J, Qi J, et al. Sialic-acid-anchored micelles: a hierarchical targeting device for enhanced tumor tissue accumulation and cellular internalization. Mol Pharm. 2018; 15:4235–46. ZhuM-L XuX-L WangX-J ZhangN-N LuK-J QiJ Sialic-acid-anchored micelles: a hierarchical targeting device for enhanced tumor tissue accumulation and cellular internalization Mol Pharm 2018 15 4235 46 10.1021/acs.molpharmaceut.8b0064930110551 Search in Google Scholar

[93] Lin C-H, Yeh Y-C, Yang KD. Functions and therapeutic targets of Siglec-mediated infections, inflammations and cancers. J Formos Med Assoc. 2021; 120:5–24. LinC-H YehY-C YangKD Functions and therapeutic targets of Siglec-mediated infections, inflammations and cancers J Formos Med Assoc 2021 120 5 24 10.1016/j.jfma.2019.10.01931882261 Search in Google Scholar

[94] Khairnar A, Sunsunwal S, Babu P, Ramya TNC. Novel serine/threonine-O-glycosylation with N-acetylneuraminic acid and 3-deoxy-D-manno-octulosonic acid by bacterial flagellin glycosyltransferases. Glycobiology. 2021; 31:288–306. KhairnarA SunsunwalS BabuP RamyaTNC Novel serine/threonine-O-glycosylation with N-acetylneuraminic acid and 3-deoxy-D-manno-octulosonic acid by bacterial flagellin glycosyltransferases Glycobiology 2021 31 288 306 10.1093/glycob/cwaa084 Search in Google Scholar

[95] King AMQ, Adams MJ, Lefkowitz E, Carstens EB, editors. Virus taxonomy: classification and nomenclature of viruses. Ninth Report of the International Committee on Taxonomy of Viruses. San Diego: Elsevier Academic Press; 2011, p. 1327. KingAMQ AdamsMJ LefkowitzE CarstensEB editors. Virus taxonomy: classification and nomenclature of viruses. Ninth Report of the International Committee on Taxonomy of Viruses San Diego Elsevier Academic Press 2011 1327 Search in Google Scholar

[96] Herrler G, Klenk HD. Structure and function of the HEF glycoprotein of influenza C virus. Adv Virus Res. 1991; 40:213–34. HerrlerG KlenkHD Structure and function of the HEF glycoprotein of influenza C virus Adv Virus Res 1991 40 213 34 10.1016/S0065-3527(08)60280-8 Search in Google Scholar

[97] Rosenberg A, editor. Biology of the sialic acids. New York: Springer Science; 1995. RosenbergA editor. Biology of the sialic acids New York Springer Science 1995 10.1007/978-1-4757-9504-2 Search in Google Scholar

[98] Hellebø A, Vilas U, Falk K, Vlasak R. Infectious salmon anemia virus specifically binds to and hydrolyzes 4-O-acetylated sialic acids. J Virol. 2004; 78:3055–62. HellebøA VilasU FalkK VlasakR Infectious salmon anemia virus specifically binds to and hydrolyzes 4-O-acetylated sialic acids J Virol 2004 78 3055 62 10.1128/JVI.78.6.3055-3062.200435376514990724 Search in Google Scholar

[99] Falk K, Aspehaug V, Vlasak R, Endresen C. Identification and characterization of viral structural proteins of infectious salmon anemia virus. J Virol. 2004; 78:3063–71. FalkK AspehaugV VlasakR EndresenC Identification and characterization of viral structural proteins of infectious salmon anemia virus J Virol 2004 78 3063 71 10.1128/JVI.78.6.3063-3071.200435376714990725 Search in Google Scholar

[100] Schultze B, Krempl C, Ballesteros ML, Shaw L, Schauer R, Enjuanes L, Herrler G. Transmissible gastroenteritis coronavirus, but not the related porcine respiratory coronavirus, has a sialic acid (N-glycolylneuraminic acid) binding activity. J Virol. 1996; 70:5634–7. SchultzeB KremplC BallesterosML ShawL SchauerR EnjuanesL HerrlerG Transmissible gastroenteritis coronavirus, but not the related porcine respiratory coronavirus, has a sialic acid (N-glycolylneuraminic acid) binding activity J Virol 1996 70 5634 7 10.1128/jvi.70.8.5634-5637.19961905248764078 Search in Google Scholar

[101] Noda M, Koide F, Asagi M, Inaba Y. Physicochemical properties of transmissible gastroenteritis virus hemagglutinin. Arch Virol. 1988; 99:163–72. NodaM KoideF AsagiM InabaY Physicochemical properties of transmissible gastroenteritis virus hemagglutinin Arch Virol 1988 99 163 72 10.1007/BF0131106770869462835945 Search in Google Scholar

[102] Schultze B, Herrler G. Bovine coronavirus uses N-acetyl-9-O-acetylneuraminic acid as a receptor determinant to initiate the infection of cultured cells. J Gen Virol. 1992; 73(Pt 4):901–6. SchultzeB HerrlerG Bovine coronavirus uses N-acetyl-9-O-acetylneuraminic acid as a receptor determinant to initiate the infection of cultured cells J Gen Virol 1992 73 Pt 4 901 6 10.1099/0022-1317-73-4-9011321878 Search in Google Scholar

[103] Li B, Wang L, Ge H, Zhang X, Ren P, Guo Y, et al. Identification of potential binding sites of sialic acids on the RBD domain of SARS-CoV-2 spike protein. Front Chem. 2021; 9:659764. doi: 10.3389/fchem.2021.659764 LiB WangL GeH ZhangX RenP GuoY Identification of potential binding sites of sialic acids on the RBD domain of SARS-CoV-2 spike protein Front Chem 2021 9 659764 10.3389/fchem.2021.659764 834143434368076 Abierto DOI Search in Google Scholar

[104] Winter C, Schwegmann-Weßels C, Cavanagh D, Neumann U, Herrler G. Sialic acid is a receptor determinant for infection of cells by avian Infectious bronchitis virus. J Gen Virol. 2006; 87(Pt 5): 1209–16. WinterC Schwegmann-WeßelsC CavanaghD NeumannU HerrlerG Sialic acid is a receptor determinant for infection of cells by avian Infectious bronchitis virus J Gen Virol 2006 87 Pt 5 1209 16 10.1099/vir.0.81651-016603523 Search in Google Scholar

[105] Sherman MB, Williams AN, Smith HQ, Nelson C, Wilen CB, Fremont DH, et al. Bile salts alter the mouse norovirus capsid conformation: possible implications for cell attachment and immune evasion. J Virol. 2019; 93:e00970–19. doi: 10.1128/jvi.00970-19 ShermanMB WilliamsAN SmithHQ NelsonC WilenCB FremontDH Bile salts alter the mouse norovirus capsid conformation: possible implications for cell attachment and immune evasion J Virol 2019 93 e00970 19 10.1128/jvi.00970-19 674423031341042 Abierto DOI Search in Google Scholar

[106] Taube S, Perry JW, Yetming K, Patel SP, Auble H, Shu L, et al. Ganglioside-linked terminal sialic acid moieties on murine macrophages function as attachment receptors for murine noroviruses. J Virol. 2009; 83:4092–101. TaubeS PerryJW YetmingK PatelSP AubleH ShuL Ganglioside-linked terminal sialic acid moieties on murine macrophages function as attachment receptors for murine noroviruses J Virol 2009 83 4092 101 10.1128/JVI.02245-08266849719244326 Search in Google Scholar

[107] Alexander DA, Dimock K. Sialic acid functions in enterovirus 70 binding and infection. J Virol. 2002; 76:11265–72. AlexanderDA DimockK Sialic acid functions in enterovirus 70 binding and infection J Virol 2002 76 11265 72 10.1128/JVI.76.22.11265-11272.200213675812388686 Search in Google Scholar

[108] Nokhbeh MR, Hazra S, Alexander DA, Khan A, McAllister M, Suuronen EJ, et al. Enterovirus 70 binds to different glycoconjugates containing α2,3-linked sialic acid on different cell lines. J Virol. 2005; 79:7087–94. NokhbehMR HazraS AlexanderDA KhanA McAllisterM SuuronenEJ Enterovirus 70 binds to different glycoconjugates containing α2,3-linked sialic acid on different cell lines J Virol 2005 79 7087 94 10.1128/JVI.79.11.7087-7094.2005111209915890948 Search in Google Scholar

[109] Dukhinova M, Veremeyko T, Yung AWY, Kuznetsova IS, Lau TYB, Kopeikina E, et al. Fresh evidence for major brain gangliosides as a target for the treatment of Alzheimer's disease. Neurobiol Aging. 2019; 77:128–43. DukhinovaM VeremeykoT YungAWY KuznetsovaIS LauTYB KopeikinaE Fresh evidence for major brain gangliosides as a target for the treatment of Alzheimer's disease Neurobiol Aging 2019 77 128 43 10.1016/j.neurobiolaging.2019.01.02030797170 Search in Google Scholar

[110] Ding J, Sui D, Liu M, Su Y, Wang Y, Liu M, et al. Sialic acid conjugate-modified liposomes enable tumor homing of epirubicin via neutrophil/monocyte infiltration for tumor therapy. Acta Biomater. 2021; 134:702–15. DingJ SuiD LiuM SuY WangY LiuM Sialic acid conjugate-modified liposomes enable tumor homing of epirubicin via neutrophil/monocyte infiltration for tumor therapy Acta Biomater 2021 134 702 15 10.1016/j.actbio.2021.07.06334339869 Search in Google Scholar

[111] Sun J, Tian Q, Liu M, Su Y, Liu X, Deng Y, et al. Evaluation of the antitumor effect and immune response of micelles modified with a polysialic acid-d-α-tocopheryl polyethylene glycol 1000 succinate conjugate. AAPS PharmSciTech. 2021; 22:223. doi: 10.1208/s12249-021-02047-1 SunJ TianQ LiuM SuY LiuX DengY Evaluation of the antitumor effect and immune response of micelles modified with a polysialic acid-d-α-tocopheryl polyethylene glycol 1000 succinate conjugate AAPS PharmSciTech 2021 22 223 10.1208/s12249-021-02047-1 34409520 Abierto DOI Search in Google Scholar

[112] Xu Q, Shan Y, Wang N, Liu Y, Zhang M, Ma M. Sialic acid involves in the interaction between ovomucin and hemagglutinin and influences the antiviral activity of ovomucin. Int J Biol Macromol. 2018; 119:533–9. XuQ ShanY WangN LiuY ZhangM MaM Sialic acid involves in the interaction between ovomucin and hemagglutinin and influences the antiviral activity of ovomucin Int J Biol Macromol 2018 119 533 9 10.1016/j.ijbiomac.2018.07.186712466030071221 Search in Google Scholar

[113] Wang X-J, Shu G-F, Xu X-L, Peng C-H, Lu C-Y, Cheng X-Y, et al. Combinational protective therapy for spinal cord injury medicated by sialic acid-driven and polyethylene glycol based micelles. Biomaterials. 2019; 217:119326. doi: 10.1016/j.biomaterials.2019.119326 WangX-J ShuG-F XuX-L PengC-H LuC-Y ChengX-Y Combinational protective therapy for spinal cord injury medicated by sialic acid-driven and polyethylene glycol based micelles Biomaterials 2019 217 119326 10.1016/j.biomaterials.2019.119326 31288173 Abierto DOI Search in Google Scholar

[114] Morozzi C, Sedláková J, Serpi M, Avigliano M, Carbajo R, Sandoval L, et al. Targeting GNE myopathy: a dual prodrug approach for the delivery of N-acetylmannosamine 6-phosphate. J Med Chem. 2019; 62:8178–93. MorozziC SedlákováJ SerpiM AviglianoM CarbajoR SandovalL Targeting GNE myopathy: a dual prodrug approach for the delivery of N-acetylmannosamine 6-phosphate J Med Chem 2019 62 8178 93 10.1021/acs.jmedchem.9b0083331386361 Search in Google Scholar

[115] Lai X, Wang S, Hu M, Sun Y, Chen M, Liu M, et al. Dual targeting single arrow: neutrophil-targeted sialic acid-modified nanoplatform for treating comorbid tumors and rheumatoid arthritis. Int J Pharm. 2021; 607:121022. doi: 10.1016/j.ijpharm.2021.121022 LaiX WangS HuM SunY ChenM LiuM Dual targeting single arrow: neutrophil-targeted sialic acid-modified nanoplatform for treating comorbid tumors and rheumatoid arthritis Int J Pharm 2021 607 121022 10.1016/j.ijpharm.2021.121022 Abierto DOI Search in Google Scholar

[116] Svennerholm L. Quantitative estimation of sialic acids. II. A colorimetric resorcinol-hydrochloric acid method. Biochim Biophys Acta. 1957; 24:604–11. SvennerholmL Quantitative estimation of sialic acids. II. A colorimetric resorcinol-hydrochloric acid method Biochim Biophys Acta 1957 24 604 11 10.1016/0006-3002(57)90254-8 Search in Google Scholar

[117] Warren L. The thiobarbituric acid assay of sialic acids. J Biol Chem. 1959; 234:1971–5. WarrenL The thiobarbituric acid assay of sialic acids J Biol Chem 1959 234 1971 5 10.1016/S0021-9258(18)69851-5 Search in Google Scholar

[118] Roboz J, Suttajit M, Bekesi JG. Elimination of 2-deoxyribose interference in the thiobarbituric acid determination of N-acetylneuraminic acid in tumor cells by pH-dependent extraction with cyclohexanone. Anal Biochem. 1981; 110:380–8. RobozJ SuttajitM BekesiJG Elimination of 2-deoxyribose interference in the thiobarbituric acid determination of N-acetylneuraminic acid in tumor cells by pH-dependent extraction with cyclohexanone Anal Biochem 1981 110 380 8 10.1016/0003-2697(81)90207-4 Search in Google Scholar

[119] Durand G, Feger J, Coignoux M, Agneray J, Pays M. Rapid estimation of small amounts of formaldehyde liberated during periodate oxidation of a sialoglycoprotein. Anal Biochem. 1974; 61:232–6. DurandG FegerJ CoignouxM AgnerayJ PaysM Rapid estimation of small amounts of formaldehyde liberated during periodate oxidation of a sialoglycoprotein Anal Biochem 1974 61 232 6 10.1016/0003-2697(74)90349-2 Search in Google Scholar

[120] Massamiri Y, Durand G, Richard A, Féger J, Agneray J. Determination of erythrocyte surface sialic acid residues by a new colorimetric method. Anal Biochem. 1979; 97:346–51. MassamiriY DurandG RichardA FégerJ AgnerayJ Determination of erythrocyte surface sialic acid residues by a new colorimetric method Anal Biochem 1979 97 346 51 10.1016/0003-2697(79)90084-8 Search in Google Scholar

[121] Yao K, Ubuka T. Determination of sialic acids by acidic ninhydrin reaction. Acta Med Okayama. 1987; 41:237–41. YaoK UbukaT Determination of sialic acids by acidic ninhydrin reaction Acta Med Okayama 1987 41 237 41 Search in Google Scholar

[122] Yao K, Ubuka T, Masuoka N, Kinuta M, Ikeda T. Direct determination of bound sialic acids in sialoglycoproteins by acidic ninhydrin reaction. Anal Biochem. 1989; 179:332–5. YaoK UbukaT MasuokaN KinutaM IkedaT Direct determination of bound sialic acids in sialoglycoproteins by acidic ninhydrin reaction Anal Biochem 1989 179 332 5 10.1016/0003-2697(89)90138-3 Search in Google Scholar

[123] Mudd AT, Salcedo J, Alexander LS, Johnson SK, Getty CM, Chichlowski M, et al. Porcine milk oligosaccharides and sialic acid concentrations vary throughout lactation. Front Nutr. 2016; 3:39. doi: 10.3389/fnut.2016.00039 MuddAT SalcedoJ AlexanderLS JohnsonSK GettyCM ChichlowskiM Porcine milk oligosaccharides and sialic acid concentrations vary throughout lactation Front Nutr 2016 3 39 10.3389/fnut.2016.00039 Abierto DOI Search in Google Scholar

[124] Sugahara K, Sugimoto K, Nomura O, Usui T. Enzymatic assay of serum sialic acid. Clin Chim Acta. 1980; 108:493–8. SugaharaK SugimotoK NomuraO UsuiT Enzymatic assay of serum sialic acid Clin Chim Acta 1980 108 493 8 10.1016/0009-8981(80)90360-5 Search in Google Scholar

[125] Taniuchi K, Chifu K, Hayashi N, Nakamachi Y, Yamaguchi N, Miyamoto Y, et al. A new enzymatic method for the determination of sialic acid in serum and its application for a marker of acute phase reactants. Kobe J Med Sci. 1981; 27:91–102. TaniuchiK ChifuK HayashiN NakamachiY YamaguchiN MiyamotoY A new enzymatic method for the determination of sialic acid in serum and its application for a marker of acute phase reactants Kobe J Med Sci 1981 27 91 102 Search in Google Scholar

[126] Li W, Liu Y, Zheng X, Gao J, Wang L, Li Y. Investigation of the potential use of sialic acid as a biomarker for rheumatoid arthritis. Ann Clin Lab Sci. 2019; 49:224–31. LiW LiuY ZhengX GaoJ WangL LiY Investigation of the potential use of sialic acid as a biomarker for rheumatoid arthritis Ann Clin Lab Sci 2019 49 224 31 Search in Google Scholar

[127] Hernández-Arteaga AC, de Jesús Zermeño-Nava J, Martínez-Martínez MU, Hernández-Cedillo A, Ojeda-Galván HJ, José-Yacamán M, Navarro-Contreras HR. Determination of salivary sialic acid through nanotechnology: a useful biomarker for the screening of breast cancer. Arch Med Res. 2019; 50:105–10. Hernández-ArteagaAC de Jesús Zermeño-NavaJ Martínez-MartínezMU Hernández-CedilloA Ojeda-GalvánHJ José-YacamánM Navarro-ContrerasHR Determination of salivary sialic acid through nanotechnology: a useful biomarker for the screening of breast cancer Arch Med Res 2019 50 105 10 10.1016/j.arcmed.2019.05.01331495386 Search in Google Scholar

[128] Zermeño-Nava JJ, Martínez-Martínez MU, Rámirez-de-Ávila AL, Hernández-Arteaga AC, García-Valdivieso MG, Hernández-Cedillo A, et al. Determination of sialic acid in saliva by means of surface-enhanced Raman spectroscopy as a marker in adnexal mass patients: ovarian cancer vs benign cases. J Ovarian Res. 2018; 11:61. doi: 10.1186/s13048-018-0433-9 Zermeño-NavaJJ Martínez-MartínezMU Rámirez-de-ÁvilaAL Hernández-ArteagaAC García-ValdiviesoMG Hernández-CedilloA Determination of sialic acid in saliva by means of surface-enhanced Raman spectroscopy as a marker in adnexal mass patients: ovarian cancer vs benign cases J Ovarian Res 2018 11 61 10.1186/s13048-018-0433-9 605837130041680 Abierto DOI Search in Google Scholar

[129] Sun Y, Sun C, Zhang E. Expression of serum sialic acid, early antigen-IgA, and viral capsid antigen-IgA in nasopharynx cancer patients: the diagnostic implication of combined assays. Med Sci Monit. 2015; 21:4068–73. SunY SunC ZhangE Expression of serum sialic acid, early antigen-IgA, and viral capsid antigen-IgA in nasopharynx cancer patients: the diagnostic implication of combined assays Med Sci Monit 2015 21 4068 73 10.12659/MSM.894951469962026709095 Search in Google Scholar

[130] Haroun RA, Osman WH, Eessa AM. Evaluation of serum total sialic acid in moderate COVID-19 patients with and without gastrointestinal tract manifestations. Tissue Cell. 2022; 74:101679. doi: 10.1016/j.tice.2021.101679 HarounRA OsmanWH EessaAM Evaluation of serum total sialic acid in moderate COVID-19 patients with and without gastrointestinal tract manifestations Tissue Cell 2022 74 101679 10.1016/j.tice.2021.101679 859839634801789 Abierto DOI Search in Google Scholar

[131] Rasool M, Khan SR, Malik A, Khan KM, Zahid S, Manan A, et al. Comparative studies of salivary and blood sialic acid, lipid peroxidation and antioxidative status in oral squamous cell carcinoma (OSCC). Pak J Med Sci. 2014; 30:466–71. RasoolM KhanSR MalikA KhanKM ZahidS MananA Comparative studies of salivary and blood sialic acid, lipid peroxidation and antioxidative status in oral squamous cell carcinoma (OSCC) Pak J Med Sci 2014 30 466 71 10.12669/pjms.303.4985404848724948960 Search in Google Scholar

Asian Biomedicine

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 y
Jamshid Roozbeh y
Fatemeh Masjedi
Fatemeh Masjedi

Publicado en línea: 31 Aug 2022

Volumen & Edición: Volumen 16 (2022) - Edición 4 (August 2022)

Páginas: 153 - 167

Detalles de publicación y publicación

Asian Biomedicine

Vista previa del PDF

Artículo

Figure 1

Figure 2

Figuras y tablas

Figure 1

Figure 2

Diagnostic parameters for sialic acid

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

Various methods for sialic acid detection

Viruses with specific binding to sialic acid derivatives

Referencias

Artículos Recientes

Planifique su conferencia remota con Sciendo

Asian Biomedicine

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 yJamshid Roozbeh yFatemeh MasjediFatemeh Masjedi

Publicado en línea: 31 Aug 2022

Volumen & Edición: Volumen 16 (2022) - Edición 4 (August 2022)

Páginas: 153 - 167

Detalles de publicación y publicación

Asian Biomedicine

Vista previa del PDF

Artículo

Figure 1

Figure 2

Figuras y tablas

Figure 1

Figure 2

Diagnostic parameters for sialic acid

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

Various methods for sialic acid detection

Viruses with specific binding to sialic acid derivatives

Referencias

Artículos Recientes

Planifique su conferencia remota con Sciendo

Aida Doostkam,
Aida Doostkam,
Leila Malekmakan,
Leila Malekmakan,
Alireza Hosseinpour,
Alireza Hosseinpour,
Sahar Janfeshan,
Sahar Janfeshan,
Jamshid Roozbeh y
Jamshid Roozbeh y
Fatemeh Masjedi
Fatemeh Masjedi