As aged population dramatically increases in these decades, efforts should be made on the intervention for curing age-associated neurologic degenerative diseases such as Alzheimer's disease (AD). Caffeoylquinic acid (CQA), an antioxidant component and its derivatives are natural functional compounds isolated from a variety of plants. In this study, we determined the neuroprotective effect of 3,5-di-O-CQA on Abeta(1-42) treated SH-SY5Y cells using MTT assay. To investigate the possible neuroprotective mechanism of 3,5-di-O-CQA, we performed proteomics analysis, real-time PCR analysis and measurement of the intracellular ATP level. In addition, we carried out the measurement of escape latency time to find the hidden platform in Morris water maze (MWM), real-time PCR using senescence-accelerated-prone mice (SAMP) 8 and senescence-accelerated-resistant mice (SAMR) 1 mice. Results showed that 3,5-di-O-CQA had neuroprotective effect on Abeta (1-42) treated cells. The mRNA expression of glycolytic enzyme (phosphoglycerate kinase-1; PGK1) and intracellular ATP level were increased in 3,5-di-O-CQA treated SH-SY5Y cells. We also found that 3,5-di-O-CQA administration induced the improvement of spatial learning and memory on SAMP8 mice, and the overexpression of PGK1 mRNA. These findings suggest that 3,5-di-O-CQA has a neuroprotective effect on neuron through the upregulation of PGK1 expression and ATP production activation.
Caffeoylquinic acid (CQA) is one of the phenylpropanoids found in coffee beans, sweetpotato, propolis, and other plants. [1][2][3] CQA derivatives have a variety of bioactivities such as antioxidant, antibacterial, anticancer, antihistamic, and other biological effects. [4][5][6][7][8] In our previous study, we demonstrated that 3,5-di-O-caffeoylquinic acid (3,5-di-CQA) inhibits amyloid b 1-42 -induced cellular toxicity on human neuroblastoma SH-SY5Y cells, and increases the mRNA expression level of glycolytic enzyme, phosphoglycerate kinase 1 (PGK1) and the intracellular ATP level. 9) We also indicated that 3,5-di-CQA administration induced the improvement of spatial learning and memory on senescence accelerated-prone mice 8 (SAMP8), and the overexpression of PGK1 mRNA level.9) Moreover, we found that 3,4,5-tri-Ocaffeoylquinic acid (3,4,5-tri-CQA) showed higher accelerating activity on ATP production than 3,5-di-CQA, suggesting that the number of caffeoyl groups is important for the activity (unpublished observation). However, structure-activity relationship of CQAs on the accelerating activity on ATP production are not clarified in detail.CQAs are classified into various derivatives, according to the number or the position of caffeoyl groups. The syntheses of mono-CQA derivatives including one caffeoyl group were reported by Sefkow et al. 10,11) There were, however, few reports about synthesis of CQA derivatives with more than two caffeoyl groups. Accordingly, we planed the syntheses of the CQA derivatives with more than two caffeoyl groups. We also evaluated the intracellular ATP level in SH-SY5Y cells treated with these derivatives for structure-activity relationship on the accelerating activity on ATP production. Results and DiscussionSynthesis of 1,4,5-tri-O-Caffeoylquinic Acid CQA derivatives that caffeoyl groups bind to 3-, 4-, and 5-hydroxyl groups in quinic acid are found abundantly in natural resources. On the other hand, the derivatives that caffeoyl group binds to 1-hydroxyl group were rare in them. It was also interested whether they have the accelerating activity on ATP production. So, we initially synthesized 1,4,5-tri-O-caffeoylquinic acid (1,4,5-tri-CQA) as shown in Chart 1. Isopropyridene quinide (2) was synthesized from commercially available quinic acid (1), according to previously reported method.12) Di-O-acetylcaffeoyl chloride (b) was used for followed esterification reaction. Acid chloride b was obtained from commercially available caffeic acid (a) in two steps, acetylation with Ac 2 O in pyridine and chlorination with SOCl 2 . 10) Isopropyridene quinide (2) reacted with acid chloride b in pyridine and CH 2 Cl 2 to afford ester 3 in 50% yield.11) The acetonide group of 3 was selectively cleaved with 90% trifluoroacetic acid (TFA) to give diol 4 in 61% yield. Diol 4 was heated with five equivalents of c under reflux in benzene for 24 h to afford tri-ester 5 in 86% yield. Hydrolysis of all protecting groups was accomplished with 1 M HCl at room temperature to obtain 1,4,5-tri-CQA (6) in 46...
Skin pigmentation is the result of melanogenesis that occurs in melanocytes and/or melanoma cells. Although melanogenesis is necessary for the prevention of DNA damage and cancer caused by UV irradiation, excessive accumulation of melanin can also cause melanoma. Thus, we focused on the antimelanogenesis effect of an extract from Thymelaea hirsuta, a Tunisian herb. Murine melanoma B16 cells were treated with T. hirsuta extract, and then cell viability and synthesized melanin content were measured. We found that the T. hirsuta extract decreased the synthesized melanin content in B16 cells without cytotoxicity. Tyrosinase is a key enzyme of melanogenesis and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation is known to be related to melanogenesis inhibition. To clarify its mechanism, we also determined ERK1/2 phosphorylation and tyrosinase expression level. ERK1/2 was immediately phosphorylated in cells just after treatment with the extract. The tyrosinase expression was inhibited after 24 h of stimulation with the extract. The T. hirsuta extract was fractionated, and we found that one fraction considerably decreased the melanin synthesis in B16 cells and that this fraction contains daphnanes as the main component. This indicates that our findings might be attributable to daphnanes.
The activation process of secretory or membrane-bound zinc enzymes is thought to be a highly coordinated process involving zinc transport, trafficking, transfer and coordination. We have previously shown that secretory and membrane-bound zinc enzymes are activated in the early secretory pathway (ESP) via zinc-loading by the zinc transporter 5 (ZnT5)-ZnT6 hetero-complex and ZnT7 homo-complex (zinc transport complexes). However, how other proteins conducting zinc metabolism affect the activation of these enzymes remains unknown. Here, we investigated this issue by disruption and re-expression of genes known to be involved in cytoplasmic zinc metabolism, using a zinc enzyme, tissue non-specific alkaline phosphatase (TNAP), as a reporter. We found that TNAP activity was significantly reduced in cells deficient in ZnT1, Metallothionein (MT) and ZnT4 genes (ZnT1 −/− MT −/− ZnT4 −/− cells), in spite of increased cytosolic zinc levels. The reduced TNAP activity in ZnT1 −/− MT −/− ZnT4 −/− cells was not restored when cytosolic zinc levels were normalized to levels comparable with those of wild-type cells, but was reversely restored by extreme zinc supplementation via zinc-loading by the zinc transport complexes. Moreover, the reduced TNAP activity was adequately restored by re-expression of mammalian counterparts of ZnT1, MT and ZnT4, but not by zinc transport-incompetent mutants of ZnT1 and ZnT4. In ZnT1 −/− MT −/− ZnT4 −/− cells, the secretory pathway normally operates. These findings suggest that cooperative zinc handling of ZnT1, MT and ZnT4 in the cytoplasm is required for full activation of TNAP in the ESP, and present clear evidence that the activation process of zinc enzymes is elaborately controlled.
Two new daphnane diterpenoids, hirseins A (1) and B (2), were isolated from the aerial parts of Thymelaea hirsuta, and their structures were elucidated on the basis of spectroscopic data interpretation. Hirsein B (2) is an unusual daphnane in possessing a coumaroyl moiety. NOESY correlations of 2 implied that isomerization of the coumaroyl group in 2 was caused by equilibrium between the E (2e) and Z (2z) forms. Compounds 1 and 2 were found to inhibit melanogenesis in B16 murine melanoma cells.
Caffeoylquinic acid (CQA) is one of the phenylpropanoids found in a variety of natural resources and foods, such as sweet potatoes, propolis, and coffee. Previously, we reported that 3,5-di-O-caffeoylquinic acid (3,5-di-CQA) has a neuroprotective effect against amyloid-β (Aβ)-induced cell death through the overexpression of glycolytic enzyme. Additionally, 3,5-di-CQA administration induced the improvement of spatial learning and memory on senescence accelerated-prone mice (SAMP8). The aim of this study was to investigate whether 3,4,5-tri-O-caffeoylquinic acid (3,4,5-tri-CQA), isolated from propolis, shows a neuroprotective effect against Aβ-induced cell death on human neuroblastoma SH-SY5Y cells. To clarify the possible mechanism, we performed proteomics and real-time RT-PCR as well as a measurement of the intracellular adenosine triphosphate (ATP) level. These results showed that 3,4,5-tri-CQA attenuated the cytotoxicity and prevented Aβ-mediated apoptosis. Glycolytic enzymes, phosphoglycerate mutase 1 (PGAM1) and glyceraldehyde-3-phosphate dehydrogenase (G3PDH) were overexpressed in co-treated cells with both 3,4,5-tri-CQA and Aβ. The mRNA expression of PGAM1, G3PDH, and phosphoglycerate kinase 1 (PGK1), and intracellular ATP level were also increased in 3,4,5-tri-CQA treated cells. Taken together the findings in our study suggests that 3,4,5-tri-CQA shows a neuroprotective effect against Aβ-induced cell death through the upregulation of glycolytic enzyme mRNA as well as ATP production activation.
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