| Kinase Assay: |
| Mar Drugs . 2021 Mar 15;19(3):152. | | Dieckol Ameliorates Aβ Production via PI3K/Akt/GSK-3β Regulated APP Processing in SweAPP N2a Cell[Pubmed: 33804171] | | The proteolytic processing of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase releases amyloid-β peptide (Aβ), which deposits in amyloid plaques and contributes to the initial causative events of Alzheimer's disease (AD). In the present study, the regulatory mechanism of APP processing of three phlorotannins was elucidated in Swedish mutant APP overexpressed N2a (SweAPP N2a) cells. Among the tested compounds, Dieckol exhibited the highest inhibitory effect on both intra- and extracellular Aβ accumulation. In addition, Dieckol regulated the APP processing enzymes, such as α-secretase (ADAM10), β-secretase, and γ-secretase, presenilin-1 (PS1), and their proteolytic products, sAPPα and sAPPβ, implying that the compound acts on both the amyloidogenic and non-amyloidogenic pathways. In addition, Dieckol increased the phosphorylation of protein kinase B (Akt) at Ser473 and GSK-3β at Ser9, suggesting Dieckol induced the activation of Akt, which phosphorylated GSK-3β. The specific phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 triggered GSK-3β activation and Aβ expression. In addition, co-treatment with LY294002 noticeably blocked the effect of Dieckol on Aβ production, demonstrating that Dieckol promoted the PI3K/Akt signaling pathway, which in turn inactivated GSK-3β, resulting in the reduction in Aβ levels. |
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| Cell Research: |
| Mar Drugs. 2021 Mar 15;19(3):152. | | Dieckol Ameliorates Aβ Production via PI3K/Akt/GSK-3β Regulated APP Processing in SweAPP N2a Cell[Pubmed: 33804171] | | The proteolytic processing of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase releases amyloid-β peptide (Aβ), which deposits in amyloid plaques and contributes to the initial causative events of Alzheimer's disease (AD). In the present study, the regulatory mechanism of APP processing of three phlorotannins was elucidated in Swedish mutant APP overexpressed N2a (SweAPP N2a) cells. Among the tested compounds, Dieckol exhibited the highest inhibitory effect on both intra- and extracellular Aβ accumulation. In addition, Dieckol regulated the APP processing enzymes, such as α-secretase (ADAM10), β-secretase, and γ-secretase, presenilin-1 (PS1), and their proteolytic products, sAPPα and sAPPβ, implying that the compound acts on both the amyloidogenic and non-amyloidogenic pathways. In addition, Dieckol increased the phosphorylation of protein kinase B (Akt) at Ser473 and GSK-3β at Ser9, suggesting Dieckol induced the activation of Akt, which phosphorylated GSK-3β. The specific phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 triggered GSK-3β activation and Aβ expression. In addition, co-treatment with LY294002 noticeably blocked the effect of Dieckol on Aβ production, demonstrating that Dieckol promoted the PI3K/Akt signaling pathway, which in turn inactivated GSK-3β, resulting in the reduction in Aβ levels. | | Cell Biochem Funct . 2022 Jan;40(1):71-78. | | Dieckol induces cell cycle arrest by down-regulating CDK2/cyclin E in response to p21/p53 activation in human tracheal fibroblasts[Pubmed: 34708431] | | The phlorotannin derivative Dieckol isolated from Ecklonia cava has been shown to exhibit anti-inflammatory, anti-bacterial, anti-oxidative anti-adipogenic and anti-stenosis activity. However, the role of Dieckol in cyclin-dependent kinase 2 (CDK2)/cyclin E signalling, which regulates fibrosis development, has not yet been determined. In this study, we report that Dieckol-suppressed cell proliferation through the cell cycle arrest of Hs680.Tr human tracheal fibroblasts. Following consecutive purification, Dieckol was identified as a potent bioactive compound. The results showed that Dieckol had significant anti-proliferative activity against Hs680.Tr human tracheal fibroblastsWestern blotting analysis also found that Dieckol dose-dependently induced the cell cycle arrest of Hs680.Tr fibroblasts in the G0/G1 phase, accompanied by the downregulation of CDK2 and cyclin E and the upregulation of p21 and p53. As attested by molecular docking study, the Dieckol interacted with the core interface residues in transforming growth factor-β receptor with high affinity. These findings suggest that Dieckol from E. cava inhibits the cell proliferation of Hs680.Tr, potentially through p21- and p53-mediated G0/G1 cell cycle arrest. | | Saudi J Biol Sci . 2021 Sep;28(9):4908-4915. | | Dieckol exerts anticancer activity in human osteosarcoma (MG-63) cells through the inhibition of PI3K/AKT/mTOR signaling pathway[Pubmed: 34466065] | | Background: Osteosarcoma (OS) is the most common malignant bone cancer with more metastasis and increased occurrence in children and teen-agers and being responsible for more number of morbidity and mortality worldwide.
Objective: The current exploration was planned study the in vitro anticancer actions of Dieckol against human OS MG-63 cells via PI3K/AKT/mTOR signaling inhibition.
Methodology: The cytotoxicity of Dieckol was scrutinized by MTT assay. Effects of Dieckol on the ROS accumulation, apoptotic cell death, and MMP level in the MG-63 cells were studied by respective fluorescence staining assays. The levels of proliferative, inflammatory, and apoptotic markers in the Dieckol treated MG-63 cells were scrutinized by marker specific kits. The expressions of PI3K, AKT, and mTOR was assayed by RT-PCR.
Results: The MTT assay revealed that the Dieckol dose dependently prevented MG-63 cells viability and the IC50 was found at 15 μM. Dieckol treatment effectively reduced the MMP level and improved the ROS generation and apoptosis in MG-63 cells. Dieckol also regulated the proliferative (cyclin D1), inflammatory (COX-2, IL-6, TNF-α, and NF-κB), and apoptotic (caspase-3, Bax, Bcl-2) markers in the MG-63 cells. The PI3K/AKT/mTOR signaling in the MG-63 cells were effectively inhibited by the Dieckol treatment.
Conclusion: In conclusion, our findings from this study recommends that the Dieckol could be a talented anticancer candidate for the OS management in the future. |
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| Animal Research: |
| Nutrients . 2021 Sep 10;13(9):3160 | | Dieckol-Attenuated High-Fat Diet Induced Muscle Atrophy by Modulating Muscular Deposition of Lipid Droplets[Pubmed: 34579038] | | An excessive fat diet induces intramuscular fat deposition that accumulates as a form of lipid droplet (LD) and leads to lipotoxicity, including muscle atrophy or decreasing muscle strength. Lipotoxicity depends on the number of LDs, subcellular distribution (intermyofibrillar, IMF, LDs or subsarcolemmal, SS), and fiber type-specific differences (type I or type II fiber) as well as the size of LD. Ecklonia cava extracts (ECE), which is known to increase peroxisome proliferator-activated receptor alpha (PPAR-α), which leads to decreasing expression level of perilipin2 (PLIN2). PLIN2 is involved in modulating the size of LDs. This study shows that ECE and Dieckol could decrease PLIN2 expression and decrease the size and number of LDs in the muscle of high-fat diet (HF)-fed animals and lead to attenuating muscle atrophy. Expression level of PPAR-α was decreased, and PLIN2 was increased by HF. ECE and Dieckol increased PPAR-α expression and decreased PLIN2. The diameter of LDs was increased in high-fat diet condition, and it was decreased by ECE or Dieckol treatment. The number of LDs in type II fibers/total LDs was increased by HF and it was decreased by ECE or Dieckol. The SS LDs were increased, and IMF LDs were decreased by HF. ECE or Dieckol decreased SS LDs and increased IMF LDs. The ECE or Dieckol attenuated the upregulation of muscle atrophy-related genes including Murf1, Atrogin-1, and p53 by HF. ECE or Dieckol increased the cross-sectional area of the muscle fibers and grip strength, which were decreased by HF. In conclusion, ECE or Dieckol decreased the size of LDs and modulated the contribution of LDs to less toxic ones by decreasing PLIN2 expression and thus attenuated muscle atrophy and strength, which were induced by HF. | | Saudi J Biol Sci . 2021 Sep;28(9):4891-4899 | | Dieckol attenuates the nociception and inflammatory responses in different nociceptive and inflammatory induced mice model[Pubmed: 34466063] | | Pain is the common indicator of inflammatory ailments and traumatic tissue injuries. The Dieckol is an important therapeutic compound, which present in many seaweeds. The present research work was planned to assess the anti-inflammatory and anti-nociceptive actions of Dieckol by using animal model. The anti-nociceptive action of Dieckol was investigated by acetic acid triggered writhing, formalin provoked nociception, tail immersion test, hot-plate methods and the anti-inflammatory effects was explored by carrageenan triggered paw edema method. In the present investigation the administration of Dieckol was remarkably suppressed and inhibited the acetic acid-provoked writhing, formalin-triggered nociception, tail immersion test, hot plate-provoked nociception in the experimental animals. The Dieckol was significantly (p < 0.05) inhibited the carrageenan-triggered inflammation, leukocyte infiltration and diminished the formation of pro-inflammatory regulators in the experimental animals. Altogether, the Dieckol was showed a potent anti-nociceptive and anti-inflammatory activity. | | Front Pharmacol . 2020 Apr 17;11:494. | | Dieckol, a Major Marine Polyphenol, Enhances Non-Rapid Eye Movement Sleep in Mice via the GABA A-Benzodiazepine Receptor[Pubmed: 32362829] | | We had previously demonstrated that phlorotannins, which are marine polyphenols, enhance sleep in mice via the GABAA-benzodiazepine (BZD) receptor. Among the constituents of phlorotannin, Dieckol is a major marine polyphenol from the brown alga Ecklonia cava. Although phlorotannins are known to exert hypnotic effects, the sleep-enhancing effect of Dieckol has not yet been determined. We evaluated the effect of Dieckol on sleep-wake state of mice by analyzing electroencephalograms (EEGs) and electromyograms. Flumazenil, a GABAA-BZD antagonist, was used to investigate the molecular mechanism underlying the effects of Dieckol on sleep. The polygraphic recordings and corresponding hypnograms revealed that Dieckol accelerated the initiation of non-rapid eye movement sleep (NREMS); it shortened sleep latency and increased NREMS duration. According to the change in time-course, Dieckol showed sleep-enhancing effects by increasing the amount of NREMS and decreasing wakefulness during the same hours. Additionally, sleep quality was evaluated by analyzing the EEG power density, and Dieckol was found to not affect sleep intensity while zolpidem was found to reduce it. Finally, we treated mice with zolpidem or Dieckol in combination with flumazenil and found the latter to inhibit the sleep-enhancing effect of Dieckol and zolpidem, thereby indicating that Dieckol exerts sleep-enhancing effects by activating the GABAA-BZD receptor, similar to zolpidem. These results implied that Dieckol can be used as a promising herbal sleep aid with minimal side effects, unlike the existing hypnotics. |
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