• 대한한의학회지
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• 제29권2호
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• pp.151-164
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• 2008

Objective: To investigate the effects of Yeongdamsagantang (YDGT) on apoptosis of neuronal cells that can result in dementia. Method: The water extract of the YDGT was tested in vitro for its beneficial effects on neuronal survival and neuroprotective functions, particularly in connection with $A{\beta}$ oligomer-related dementias. $A{\beta}$ oligomers derived from proteolytic processing of the ${\beta}-amyloid$ precursor protein (APP), including the $amyloid-{\beta}$ peptide $(A{\beta})$, play a critical role in the pathogenesis of Alzheimer's disease. A neuroblastoma cell line stably expressing an $A{\beta}$ oligomerassociated neuronal degeneration was used to investigate if YDGT inhibits formation of $A{\beta}$ oligomer. To measure the ATP generating level in mitochondrial membrane, luciferin/luciferase luminescence kit (Promega) and luminator was used, and to survey the protein's apparition, confocal microscopy was used. Result: $A{\beta}oligomer$ had a profound attenuation in the increase in CT105 expressing neuro2A cells from YDGT. Experimental evidence indicates that YDGT protected against neuronal damage from cells, but its cellular and molecular mechanisms remain unknown. We demonstrated that YDGT inhibited formation of $amyloid-{\beta}$ $(A{\beta})$ oligomers, which were the behavior, and possibly causative, features of AD. The decreased $A{\beta}$ oligomer in the presence of YDGT was observed in the conditioned medium of this $A{\beta}oligomer-secreting$ cell line under in vitro. In the cells, YDGT significantly attenuated mitochondrion-initiated apoptosis. Conclusion: (i) a direct $A{\beta}$ oligomer toxicity and the apoptosis initiated by the mitochondria; and (ii) multiple cellular and molecular neuroprotective mechanisms, including attenuation of apoptosis and direct inhibition of $A{\beta}$ oligomer aggregation, underlie the neuroprotective effects of YDGT.

• 동의생리병리학회지
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• 제23권2호
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• pp.397-404
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• 2009

For standardization of LMK02 quality, Ginsenoside Rg3 of Red Ginseng and Decursin of Angelica gigas Nakai in the constituents of LMK02 were estimated as indicative components. From LMK02 water extract, has been used in vitro test for its beneficial effects on neuronal survival and neuroprotective functions, particularly in connection with APP-related dementias and Alzheimer's disease (AD). $A{\beta}$ oligomer derived from proteolytic processing of the ${\beta}$-amyloid precursor protein (APP), including the amyloid-${\beta}$ peptide ($A{\beta}$), play a critical role in the pathogenesis of Alzheimer's dementia. We determined that oligomer amyloid-${\beta}$ ($A{\beta}$) have a profound attenuation in the increase in rat hippocampus H19-7 cells from. Experimental evidence indicates that LMK02 protects against neuronal damage from cells, but its cellular and molecular mechanisms remain unknown. Using a hippocampus cell line on $A{\beta}$ oligomer-induced neuronal cytotoxicity, we demonstrated that LMK02 inhibits formation of $A{\beta}$ oligomer, which are the behavior, and possibly causative, feature of AD. In the Red Ginseng, the average amounts of Ginsenoside Rg3 were $47.04{\mu}g/g$ and $42.3{\mu}g/g$, 90 % of its weight were set as a standard value. And, in the Angelica gigas Nakai, the average amounts of Decursin were 2.71 mg/g and 2.44mg/g, 90 % of its weight were also set as a standard value. The attenuated $A{\beta}$ oligomer in the presence of LMK02 was observed in the conditioned medium of this $A{\beta}$ oligomer-induced cells under in vitro. In the cells, LMK02 significantly activated antiapoptosis and decreased the production of ROS. These results suggest that neuronal damage in AD might be due to two factors: a direct $A{\beta}$ oligomer toxicity and multiple cellular and molecular neuroprotective mechanisms, including attenuation of apoptosis and direct inhibition of $A{\beta}$ oligomer, underlie the neuroprotective effects of LMK02 treatment.

• 동의신경정신과학회지
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• 제20권2호
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• pp.121-131
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• 2009

Objectives : From Scrophularia buergeriana water extract(SBW), has been used in vivo test for its beneficial effects on neuronal survival and neuroprotective functions, particularly in connection with APP-related dementias and Alzheimer's disease(AD). $A{\beta}$ oligomer derived from proteolytic processing of the ${\beta}$-amyloid precursor protein(APP), including the amyloid-${\beta}$ peptide($A{\beta}$), play a critical role in the pathogenesis of Alzheimer's dementia. Methods : Using drosophila APP model on APP-induced neuronal cytotoxicity, we demonstrated that SBW prevents neurotoxicity of $A{\beta}$ oligomer, which are the behavior, and possibly causative, feature of AD. We investigated the neuroprotective effects of SBW against the effects of oligomeric $A{\beta}$ and fly behaveior and life span by UAS-GRIM/APP-GAL within transgenic flies. Results and Conclusions : SBW repaired damage leading to the behaveior of APP-induced fly and delayed life span. These results suggest that neuronal damage in AD might be due to two factors: a direct $A{\beta}$ oligomer toxicity and multiple cellular and molecular neuroprotective mechanisms, including attenuation of apoptosis and direct inhibition of $A{\beta}$ oligomer, underlie the neuroprotective effects of SBW.

• Bulletin of the Korean Chemical Society
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• 제33권3호
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• pp.848-854
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• 2012

We have studied the oligomerization of a fibril-forming segment of ${\alpha}$-Synulcein using a replica exchange molecular dynamics (REMD) simulation. The simulation was performed with trimers and tetramers of a 12 amino acid residue stretch (residues 71-82) of ${\alpha}$-Synulcein. From extensive REMD simulations, we observed the spontaneous formation of both trimer and tetramer, demonstrating the self-aggregating and fibril-forming properties of the peptides. Secondary structure profile and clustering analysis illustrated that antiparallel ${\beta}$-sheet structures are major species corresponding to the global free energy minimum. As the size of the oligomer increases from a dimer to a tetramer, conformational stability is increased. We examined the evolution of simple order parameters and their free energy profiles to identify the process of aggregation. It was found that the degree of aggregation increased as time passed. Tetramer formation was slower than trimer formation and a transition in order parameters was observed, indicating the full development of tetramer conformation which is more stable than that of the trimer. The shape of free energy surface and change of order parameter distributions indicate that the oligomer formation follows a dock-and-lock process.

• Biomolecules & Therapeutics
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• 제23권2호
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• pp.156-164
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• 2015

Alzheimer's disease (AD) is a neurodegenerative disorder associated with progressive memory loss and neuronal cell death. Although numerous previous studies have been focused on disease progression or reverse pathological symptoms, therapeutic strategies for AD are limited. Alternatively, the identification of traditional herbal medicines or their active compounds has received much attention. The aims of the present study were to characterize the ameliorating effects of spinosin, a C-glucosylflavone isolated from Zizyphus jujuba var. spinosa, on memory impairment or the pathological changes induced through amyloid-${\beta}_{1-42}$ oligomer ($A{\beta}O$) in mice. Memory impairment was induced by intracerebroventricular injection of $A{\beta}O$ ($50{\mu}M$) and spinosin (5, 10, and 20 mg/kg) was administered for 7 days. In the behavioral tasks, the subchronic administration of spinosin (20 mg/kg, p.o.) significantly ameliorated $A{\beta}O$-induced cognitive impairment in the passive avoidance task or the Y-maze task. To identify the effects of spinosin on the pathological changes induced through $A{\beta}O$, immunohistochemistry and Western blot analyses were performed. Spinosin treatment also reduced the number of activated microglia and astrocytes observed after $A{\beta}O$ injection. In addition, spinosin rescued the $A{\beta}O$-induced decrease in choline acetyltransferase expression levels. These results suggest that spinosin ameliorated memory impairment induced through $A{\beta}O$, and these effects were regulated, in part, through neuroprotective activity via the anti-inflammatory effects of spinosin. Therefore, spinosin might be a useful agent against the amyloid ${\beta}$ protein-induced cognitive dysfunction observed in AD patients.

• 통합자연과학논문집
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• 제7권2호
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• pp.79-86
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• 2014

Amyloid oligomers are believed to play important causal roles in many types of amyloid-related degenerative diseases. Many different laboratories have reported amyloid oligomers that differ in size, morphology, toxicity, and method of preparation or purification, raising the question of the structural relationships among these oligomer preparations. The structural plasticity that has been reported to occur in amyloid formed from the same protein sequence indicates that it is quite possible that different oligomer preparations may represent distinct structural variants. In view of the difficulty in determining the precise structure of amyloids, conformation- and epitope-specific antibodies may provide a facile means of classifying amyloid oligomer structures. Conformation-dependent antibodies that recognize generic epitopes that are specifically associated with distinct aggregation states of many different amyloid-forming sequences indicate that there are at least two fundamentally distinct types of amyloid oligomers: fibrillar and prefibrillar oligomers. Classification of amyloid oligomers according to their underlying structures may be a more useful and rational approach than relying on differences in size and morphology.

• Bulletin of the Korean Chemical Society
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• 제34권7호
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• pp.2016-2022
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• 2013

Ionically modified ${\beta}$-cyclodextrins, which have excellent water-solubility, have been interested in purification technology as well as drug carrier system. The present study summarizes the synthesis and characterization of cationic and anionic ${\beta}$-cyclodextrin (${\beta}$-CyD) products using by polycondensation. The oligo (${\beta}$-CyD)s are synthesized from ${\beta}$-CyD, epichlorohydrin (EP) and choline chloride (CC; for cationic polymer) or chloroacetic acid (CAA; for anionic polymer) through one step polycondenstaion process. Unlike the previous studies, we successfully purified the ionic ${\beta}$-CyD condensation products from the ${\beta}$-CyD reaction mixtures and accomplished a great level of structural analysis. The detailed structural analysis of these ionic ${\beta}$-CyD compounds is done by $^1H$ NMR, MALDI-TOF as well as GPC analysis and confirms the formation of oligomers with a few units of ${\beta}$-CyD. We found that the sequence of reactant addition also could effect on the molecular weight of the resulting product as well as the molar ratio of the reactants. Finally, we used the cationic and anionic ${\beta}$-CyD oligomers for fabricating multilayer films by layer-layer process.

• 통합자연과학논문집
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• 제5권2호
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• pp.107-119
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• 2012

Polymerization of monomeric amyloid-${\beta}$ peptides ($A{\beta}$) into soluble oligomers and insoluble fibrils is one of the major pathways triggering the pathogenesis of Alzheimer's disease (AD). Using small molecules to prevent the polymerization of $A{\beta}$ peptides can, therefore, be an effective therapeutic strategy for AD. In this study, we investigated the effects of mono- and bi-flavonoids on $A{\beta}42$ toxicity and fibrillogenesis and found that the bi-flavonoid, taiwaniaflavone (TF) effectively and specifically inhibits $A{\beta}$ toxicity and fibrillogenesis. Compared to TF, the mono-flavonoid apigenin (AP) is less effective and less specific. Our data showed that differential effects of the mono- and bi-flavonoids on $A{\beta}$ fibrillogenesis correlate with their varying cytoprotective efficacies. We also found that other bi-flavonoids, namely 2',8"-biapigenin, amentoflavone, and sumaflavone, can also effectively inhibit $A{\beta}$ toxicity and fibrillogenesis, implying that the participation of two mono-flavonoids in a single bi-flavonoid molecule enhanced their activity. Bi-flavonoids, while strongly inhibited $A{\beta}$ fibrillogenesis, accumulated nontoxic $A{\beta}$ oligomeric structures, suggesting that these are off-pathway-oligomers. Moreover, TF abrogated the toxicity of preformed $A{\beta}$ oligomers and fibrils, indicating that TF and other bi-flavonoids may also reduce the toxicity of toxic $A{\beta}$ species. Altogether, our data clearly show that bi-flavonoids, possibly due to the possession of two $A{\beta}$ binders separated by an appropriate size linker, are likely to be promising therapeutics to suppress $A{\beta}$ toxicity.

• 한국자기공명학회논문지
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• 제16권2호
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• pp.162-171
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• 2012

SAV2228 has an OB (Oligomer-Binding)-motif which is frequently used for nucleic acid recognition. To characterize the activity of translation initiation factor-1 (IF-1) from Staphylococcus aureus, SAV2228 was expressed and purified in Escherichia coli. We acquired 3D NMR spectra showing well dispersed and homogeneous signals which allow us to assign 94.4% of all $^1HN$, $^{15}N$, $^{13}C{\alpha}$, $^{13}C{\beta}$ and $^{13}CO$ resonances. We could predict a secondary structure of SAV2228 using TALOS and CSI from NMR data. SAV2228 was consisted of one ${\alpha}$-helix and five ${\beta}$-sheets. The predicted secondary structure, ${\beta}-{\beta}-{\beta}-{\alpha}-{\beta}-{\beta}$, was similar to other bacterial IF-1, but it was not completely same to the eukaryotic one. Assigned NMR peaks and secondary structre prediction can be used for the study on interaction with nucleic acid in the future.

• 동의생리병리학회지
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• 제28권3호
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• pp.317-321
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• 2014

Amyloid-${\beta}$ protein ($A{\beta}$) is a pathological component of Alzheimer's disease (AD) by participating in the senile plaque formation in the patient's brain. Although the exact mechanism of $A{\beta}$ toxicity is not fully elucidated, it is considered to be closely related to its fibrillation process. For prevention of AD, recent studies have suggested various small molecules which inhibit $A{\beta}$ fibrillation. In this report, ${\beta}$-asarone found in acorus plant has been investigated as an anti-amyloid molecule. ${\beta}$-Asarone was demonstrated to prevent in vitro fibrillation of $A{\beta}$ by inducing the oligomer formation that obviously decreased cytotoxicity. Therefore, ${\beta}$-asarone could be suggested as an inhibitory agent of $A{\beta}$ fibrillation and toxicity, which would help us not only to understand underlying principle of amyloidogenesis mechanism but also to develop a controlling strategy toward AD.