Synthesis and Bioassay of Neurogenically Potent Gangliosides DSG-A, Hp-s1 and Their Analogues

Shelke, Ganesh B.; Lih, Yu‐Hsuan; Liao, Ying-Ju; Liang, Chih-Wu; Kuo, Tzer‐Min; Ko, Ying‐Chin; Luo, Shun‐Yuan

doi:10.1021/acschemneuro.8b00055

Cited by 3 publications

(3 citation statements)

References 44 publications

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“…In AD models, GM1 binds to Aβ42 with high affinity and enhances the viability of cells expressing APP-Swe; , however, GM1 promotes Aβ biogenesis . Similarly, Hp-s1 and synthesized analogues also possess neuritogenic activity in neuronal cells. − In our current study, we provide evidence that Hp-s1A inhibits amyloidogenic APP processing in the AD model cells (Figures and ). Both GM1 and Hp-s1A protected AD model cells from dying; however, Hp-s1A seems to do so with higher efficiency by demonstrating improved capacity to handling amyloidogenic toxicity.…”

Section: Resultssupporting

confidence: 51%

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Ganglioside Hp-s1 Analogue Inhibits Amyloidogenic Toxicity in Alzheimer’s Disease Model Cells

Tsai

Yang

Ngo

et al. 2018

ACS Chem. Neurosci.

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Alzheimer’s disease (AD) is characterized by extracellular deposition of amyloid plaques, which are predominantly composed of amyloid-β (Aβ) peptide derived from amyloid precursor protein (APP) cleavage. APP interacts with tropomyosin receptor kinase A, a neurotrophic receptor associated with gangliosides and mediating neuronal survival and differentiation through the extracellular signal-regulated protein kinase (ERK) pathway. The ganglioside Hp-s1’s analogue Hp-s1A exerts neuritogenic activity; however, its effect on AD pathology remains unknown. To test the hypothesis that Hp-s1A is a potential candidate to treat AD, we established the AD-modeled cell line by expressing human Swedish and Indiana APP gene (APP-Swe/Ind) in N2a mouse neuroblastoma cells. The cells were treated with Hp-s1A or monosialoganglioside GM1 for comparison. The AD model cells expressing APP-Swe/Ind exhibited a significant reduction in viability, as well as neurite outgrowth rate, in comparison to the control cells expressing APP-695. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. With the treatment of either Hp-s1A or GM1 at 1 μM, the AD model cells showed a significant increase in viability; however, only Hp-s1A reduced CTFβ levels in these cells. Further analysis of the culture media revealed that Hp-s1A also reduced Aβ42 production from AD model cells. The phosphorylation of ERK was elevated and the neurite outgrowth rate was restored with Hp-s1A treatment. In conclusion, the ganglioside analogue Hp-s1A inhibited amyloidogenic processing of APP and promoted neurotrophic activity and survival of AD model cells. Hp-s1A has great potential in AD therapeutic development.

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Section: Resultssupporting

confidence: 51%

“…GM1 has been used in therapeutic tests to improve Huntington’s disease model animals, as well as Parkinson’s disease patients . Additionally, other gangliosides Hp-s1 and synthesized analogues are shown to possess neuritogenic activity in neuronal cells. − …”

Section: Introductionmentioning

confidence: 99%

Ganglioside Hp-s1 Analogue Inhibits Amyloidogenic Toxicity in Alzheimer’s Disease Model Cells

Tsai

Yang

Ngo

et al. 2018

ACS Chem. Neurosci.

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“…Hp-s1 ganglioside is isolated from the sperm of Hemicentrotus pulcherrimus or the ovary of Diadema setosum [ 20 ]. Studies on gangliosides extracted from marine invertebrates have demonstrated neuritogenic activities in the rat pheochromocytoma cell line PC-12 in the presence of nerve growth factor (NGF) [ 21 ]. The neuritogenic activity of Hp-s1 and its synthetic analogs is better than that of GM1 ganglioside in PC-12 cells [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Hp-s1 Ganglioside Suppresses Proinflammatory Responses by Inhibiting MyD88-Dependent NF-κB and JNK/p38 MAPK Pathways in Lipopolysaccharide-Stimulated Microglial Cells

Shih

Tsai

et al. 2020

Marine Drugs

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Hp-s1 ganglioside is isolated from the sperm of sea urchin (Hemicentrotus pulcherrimus). In addition to neuritogenic activity, the biological function of Hp-s1 in neuroinflammation is unknown. In this study, we investigated the anti-neuroinflammatory effect of Hp-s1 on lipopolysaccharide (LPS)-stimulated microglial cells. MG6 microglial cells were stimulated with LPS in the presence or absence of different Hp-s1 concentrations. The anti-inflammatory effect and underlying mechanism of Hp-s1 in LPS-activated microglia cells were assessed through a Cell Counting kit-8 assay, Western blot analysis, and immunofluorescence. We found that Hp-s1 suppressed not only the expression of inducible nitric oxide synthase and cyclooxygenase-2 but also the expression of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Hp-s1 inhibited the LPS-induced NF-κB signaling pathway by attenuating the phosphorylation and translocation of NF-κB p65 and by disrupting the degradation and phosphorylation of inhibitor κB-α (IκBα). Moreover, Hp-s1 inhibited the LPS-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Hp-s1 also reduced the expression of myeloid differentiation factor 88 (MyD88) and TNF receptor-associated factors 6 (TRAF6), which are prerequisites for NF-κB and MAPKs activation. These findings indicated that Hp-s1 alleviated LPS-induced proinflammatory responses in microglial cells by downregulating MyD88-mediated NF-κB and JNK/p38 MAPK signaling pathways, suggesting further evaluation as a new anti-neuroinflammatory drug.

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Acceptor-mediated regioselective enzyme catalyzed sialylation: chemoenzymatic synthesis of GAA-7 ganglioside glycan

Tseng

Chang

et al. 2021

Chem. Commun.

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Synthesis and Bioassay of Neurogenically Potent Gangliosides DSG-A, Hp-s1 and Their Analogues

Cited by 3 publications

References 44 publications

Ganglioside Hp-s1 Analogue Inhibits Amyloidogenic Toxicity in Alzheimer’s Disease Model Cells

Ganglioside Hp-s1 Analogue Inhibits Amyloidogenic Toxicity in Alzheimer’s Disease Model Cells

Hp-s1 Ganglioside Suppresses Proinflammatory Responses by Inhibiting MyD88-Dependent NF-κB and JNK/p38 MAPK Pathways in Lipopolysaccharide-Stimulated Microglial Cells

Acceptor-mediated regioselective enzyme catalyzed sialylation: chemoenzymatic synthesis of GAA-7 ganglioside glycan

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