Role of Neu4L sialidase and its substrate ganglioside GD3 in neuronal apoptosis induced by catechol metabolites

Hasegawa, Takafumi; Sugeno, Naoto; Takeda, Atsushi; Matsuzaki-Kobayashi, Michiko; Kikuchi, Akio; Furukawa, Koichi; Miyagi, Taeko; Itoyama, Yasuto

doi:10.1016/j.febslet.2006.12.046

Cited by 45 publications

(34 citation statements)

References 51 publications

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“…These Neu4 isoforms are also differentially expressed in a tissue-specific manner. In the brain, muscle and kidney, they contain both the long and short forms, while in the liver and the colon they are predominantly the short form as revealed by RT-PCR [46]. Both isoforms of Neu4 possess broad substrate specificity, including activity towards mucin.…”

Section: Discussionmentioning

confidence: 97%

Thymoquinone from nutraceutical black cumin oil activates Neu4 sialidase in live macrophage, dendritic, and normal and type I sialidosis human fibroblast cells via GPCR Gαi proteins and matrix metalloproteinase-9

et al. 2010

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Anti-inflammatory activities of thymoquinone (TQ) have been demonstrated in in vitro and in vivo studies. However, the precise mechanism(s) of TQ in these anti-inflammatory activities is not well understood. Using a newly developed assay to detect sialidase activity in live macrophage cells (Glycoconj J doi: 10.1007/s10719-009-9239-8 ), here we show that TQ has no inhibitory effect on endotoxin lipopolysaccharide (LPS) induced sialidase activity in live BMC-2 macrophage cells. In contrast, the parent black seed oil (BSO) and another constituent of BSO para-cymene (p-CY) completely block LPS induced sialidase activity. All of these compounds had no effect on cell viability. On the other hand, TQ induces a vigorous sialidase activity in live BMC-2 macrophage cells in a dose dependent manner as well in live DC-2.4 dendritic cells, HEK-TLR4/MD2, HEK293, SP1 mammary adenocarcinoma cells, human WT and 1140F01 and WG0544 type I sialidosis fibroblast cells. Tamiflu (oseltamivir phosphate) inhibits TQ-induced sialidase activity in live BMC-2 cells with an IC(50) of 0.0194 microM compared to an IC(50) of 19.1 microM for neuraminidase inhibitor DANA (2-deoxy-2,3-dehydro-N-acetylneuraminic acid). Anti-Neu1, -2 and -3 antibodies have no inhibition of TQ-induced sialidase activity in live BMC-2 and human THP-1 macrophage cells but anti-Neu4 antibodies completely block this activity. There is a vigorous sialidase activity associated with TQ treated live primary bone marrow (BM) macrophage cells derived from WT and hypomorphic cathepsin A mice with a secondary Neu1 deficiency (NeuI KD), but not from Neu4 knockout (Neu4 KO) mice. Pertussis toxin (PTX), a specific inhibitor of Galphai proteins of G-protein coupled receptor (GPCR) and the broad range inhibitors of matrix metalloproteinase (MMP) galardin and piperazine applied to live BMC-2, THP-1 and primary BM macrophage cells completely block TQ-induced sialidase activity. These same inhibitory effects are not observed with the GM1 ganglioside specific cholera toxin subunit B (CTXB) as well as with CTX, tyrosine kinase inhibitor K252a, and the broad range GPCR inhibitor suramin. The specific inhibitor of MMP-9, anti-MMP-9 antibody and anti-Neu4 antibody, but not the specific inhibitor of MMP-3 completely block TQ-induced sialidase activity in live THP-1 cells, which express Neu4 and MMP-9 on the cell surface. Neu4 sialidase activity in cell lysates from TQ-treated live THP-1 cells desialylates natural gangliosides and mucin substrates. RT-PCR and western blot analyses reveal no correlation between mRNA and protein values for Neu3 and Neu4 in human monocytic THP-1 cells, suggesting for the first time a varied post-transcriptional mechanism for these two mammalian sialidases independent of TQ activation. Our findings establish an unprecedented activation of Neu4 sialidase on the cell surface by thymoquinone, which is derived from the nutraceutical black cumin oil. The potentiation of GPCR-signaling by TQ via membrane targeting of Galphai subunit proteins and matrix metalloproteinas...

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Section: Discussionmentioning

confidence: 97%

Thymoquinone from nutraceutical black cumin oil activates Neu4 sialidase in live macrophage, dendritic, and normal and type I sialidosis human fibroblast cells via GPCR Gαi proteins and matrix metalloproteinase-9

et al. 2010

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“…We have recently reported that in SAECs, at the mRNA level, NEU2 and 4 are expressed at 7.7 and 13.8%, respectively, relative to NEU3 (31). Furthermore, compared with NEU3 (36,63), the catalytic activities of NEU1, 2, and 4 for gangliosides are less clear (19,56,65).…”

Section: Resultsmentioning

confidence: 99%

Human airway epithelia express catalytically active NEU3 sialidase

Lillehoj

Hyun²,

Feng

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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acids on glycoconjugates play a pivotal role in many biological processes. In the airways, sialylated glycoproteins and glycolipids are strategically positioned on the plasma membranes of epithelia to regulate receptor-ligand, cell-cell, and host-pathogen interactions at the molecular level. We now demonstrate, for the first time, sialidase activity for ganglioside substrates in human airway epithelia. Of the four known mammalian sialidases, NEU3 has a substrate preference for gangliosides and is expressed at mRNA and protein levels at comparable abundance in epithelia derived from human trachea, bronchi, small airways, and alveoli. In small airway and alveolar epithelia, NEU3 protein was immunolocalized to the plasma membrane, cytosolic, and nuclear subcellular fractions. Small interfering RNA-induced silencing of NEU3 expression diminished sialidase activity for a ganglioside substrate by Ͼ70%. NEU3 immunostaining of intact human lung tissue could be localized to the superficial epithelia, including the ciliated brush border, as well as to nuclei. However, NEU3 was reduced in subepithelial tissues. These results indicate that human airway epithelia express catalytically active NEU3 sialidase.

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“…Several sialidases are expressed in the human brain and are suggested to be involved in the mitochondrial apoptotic pathway in neuronal cell death (Yamaguchi et al, 2005;Hasegawa et al, 2007). Inhibition of sialidases in the brain may be associated with the abnormal behavior following oseltamivir medication.…”

Section: Active Efflux Of Oseltamivir By P-gp At the Bbbmentioning

confidence: 99%

P-glycoprotein Restricts the Penetration of Oseltamivir Across the Blood-Brain Barrier

Ose

Kusuhara²,

Yamatsugu³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Oseltamivir is an ethyl ester prodrug of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), the anti-influenza drug. Abnormal behavior has been suspected to be associated with oseltamivir medication in Japan. The purpose of the present study is to examine the involvement of transporters in the brain distribution of oseltamivir and its active form Ro 64-0802 across the blood-brain barrier (BBB). The brain-to-plasma concentration ratio (K p,brain ) of oseltamivir after i.v. infusion of oseltamivir in FVB mice was increased by pretreatment with N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), a dual inhibitor for P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), whereas that of Ro 64-0802 was only slightly increased. Furthermore, the distribution volume of Ro 64-0802 following i.v. administration of Ro 64-0802 in the brain was similar to the capillary volume, suggesting its minimal distribution. The K p,brain value of oseltamivir in multidrug-resistant (Mdr) 1a/1b P-gp knockout mice was 5.5-fold higher than that in wild-type mice and comparable with that obtained by pretreatment with GF120918, whereas it was unchanged in Bcrp knockout mice. The K p,brain value of oseltamivir was significantly higher in newborn rats, which is in good agreement with the ontogenetic expression profile of P-gp. Intracellular accumulation of oseltamivir was lower in human and mouse P-gp-expressing cells, which was reversed by P-gp inhibitor valspodar (PSC833). These results suggest that P-gp limits the brain uptake of oseltamivir at the BBB and that Ro 64-0802 itself barely crosses the BBB. However, it may be possible that Ro 64-0802 is formed in the brain from the oseltamivir, considering the presence of carboxylesterase in the brain endothelial cells.Oseltamivir (Fig. 1) is an ester prodrug of Ro 64-0802, a potent and selective inhibitor of neuraminidase, resulting in an inhibition of release of influenza virus from the host cells and growth of influenza virus. Oseltamivir is used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B (Bardsley-Elliot and Noble, 1999). The number of prescribed oseltamivir has reached approximately 10 million in Japan, which accounted for 75% of the world total in 2006. Recently, abnormal behavior has been reported in influenza patients prescribed oseltamivir (http://www.fda.gov/cder/ drug/infopage/tamiflu/QA20051117.htm; Fuyuno, 2007). According to a report by the Ministry of Health, Labor, and Welfare, the number of people who behaved abnormally following oseltamivir treatment has increased to 211 (0.002% of all patients), approximately 80% of whom are teenagers or younger. The relationship between abnormal behavior and oseltamivir medication remains an open question and has not yet been elucidated. The Ministry of Health, Labor, and Welfare has published a caution for oseltamivir medication to teenagers or younger...

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Role of Neu4L sialidase and its substrate ganglioside GD3 in neuronal apoptosis induced by catechol metabolites

Cited by 45 publications

References 51 publications

Thymoquinone from nutraceutical black cumin oil activates Neu4 sialidase in live macrophage, dendritic, and normal and type I sialidosis human fibroblast cells via GPCR Gαi proteins and matrix metalloproteinase-9

Thymoquinone from nutraceutical black cumin oil activates Neu4 sialidase in live macrophage, dendritic, and normal and type I sialidosis human fibroblast cells via GPCR Gαi proteins and matrix metalloproteinase-9

Human airway epithelia express catalytically active NEU3 sialidase

P-glycoprotein Restricts the Penetration of Oseltamivir Across the Blood-Brain Barrier

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