• Bulletin of the Korean Chemical Society
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• v.28 no.7
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• pp.1114-1118
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• 2007

Based on the hit compound 4 derived from focused library, a series of furo[2,3-d]pyrimidines were designed, synthesized and evaluated for the inhibitory activity against Akt1 kinase. And their structure-activity relationships were investigated. Of these compounds, 3a having 2-thienyl and methyl groups at R1 and R2 showed the most potent activity with an IC50 value of 24 μ M. Introduction of the thienyl groups at C-5 and C- 6 positions significantly improved potency compared to furyl and phenyl groups.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.3
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• pp.345-352
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• 2017

Since previous studies have reported that hydroquinone (HQ) exerted immunosuppressive and anti-inflammatory activity, various HQ derivatives have been synthesized and their biological activities investigated. In this study, we explored the anti-inflammatory activity of JS-III-49, a novel HQ derivative, in macrophage-mediated inflammatory responses. JS-III-49 suppressed the production of the inflammatory mediators nitric oxide (NO) and prostaglandin $E_2$ ($PGE_2$) and down-regulated the mRNA expression of the inflammatory enzymes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as the expression of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-$1{\beta}$ without cytotoxicity in LPS-stimulated RAW264.7 cells. JS-III-49 inhibited nuclear translocation of the $NF-{\kappa}B$ transcription factors p65 and p50 by directly targeting Akt, an upstream kinase of the $NF-{\kappa}B$ pathway, in LPS-stimulated RAW264.7 cells. However, JS-III-49 did not directly inhibit the kinase activities of Src and Syk, which are upstream kinases of Akt, in LPS-stimulated RAW264.7 cells. Moreover, JS-III-49 suppressed the nuclear translocation of c-Fos, one of the components of AP-1, by specifically targeting p38, an upstream mitogen-activated protein kinase (MAPK) in the AP-1 pathway in LPS-stimulated RAW264.7 cells. These results suggest that JS-III-49 plays an anti-inflammatory role in LPS-stimulated macrophages by targeting Akt and p38 in the $NF-{\kappa}B$ and AP-1 pathways, respectively.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.4
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• pp.1507-1513
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• 2015

Pemetrexed is an antifolate agent which has been used for treating malignant pleural mesothelioma and non small lung cancer in the clinic as a chemotherapeutic agent. In this study, pemetrexed inhibited cell growth and induced G1 phase arrest in the A549 cell line. To explore the molecular mechanisms of pemetrexed involved in cell growth, we used a two-dimensional polyacrylamide gel electrophoresis (2-DE) proteomics approach to analyze proteins changed in A549 cells treated with pemetrexed. As a result, twenty differentially expressed proteins were identified by ESI-Q-TOF MS/MS analysis in A549 cells incubated with pemetrexed compared with non-treated A549 cells. Three key proteins (GAPDH, HSPB1 and EIF4E) changed in pemetrexed treated A549 cells were validated by Western blotting. Accumulation of GAPDH and decrease of HSPB1 and EIF4E which induce apoptosis through inhibiting phosphorylation of Akt were noted. Expression of p-Akt in A549 cells treated with pemetrexed was reduced. Thus, pemetrexed induced apoptosis in A549 cells through inhibiting the Akt pathway.

• Journal of Ginseng Research
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• v.43 no.4
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• pp.692-698
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• 2019

Background: Breast cancer is a severe disease and the second leading cause of cancer death in women worldwide. To surmount this, various diagnosis and treatment options for breast cancer have been developed. One of the most effective strategies for cancer treatment is to induce apoptosis using naturally occurring compounds. Compound K (CK) is a ginseng saponin metabolite generated by human intestinal bacteria. CK has been studied for its cardioprotective, antiinflammatory, and liver-protective effects; however, the role of CK in breast cancer is not fully understood. Methods: To investigate the anticancer effects of CK in SKBR3 and MDA-MB-231 cells, cell viability assays and flow cytometry analysis were used. In addition, the direct targets of CK anticancer activity were identified using immunoblotting analysis and overexpression experiments. Invasion, migration, and clonogenic assays were carried out to determine the effects of CK on cancer metastasis. Results: CK-induced cell apoptosis in SKBR3 cells as determined through 3-(4-5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide assays, propidium iodide (PI) and annexin V staining, and morphological changes. CK increased the cleaved forms of caspase-7, caspase-8, and caspase-9, whereas the expression of Bcl-2 was reduced by CK. In assays probing the cell survival pathway, CK activated only AKT1 and not AKT2. Moreover, CK inhibited breast cancer cell invasion, migration, and colony formation. Through regulation of AKT1 activity, CK exerts anticancer effects by inducing apoptosis. Conclusion: Our results suggest that CK could be used as a therapeutic compound for breast cancer.

• Korean Journal of Clinical Laboratory Science
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• v.55 no.3
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• pp.184-194
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• 2023

In this study, we investigated whether p-anisaldehyde (PAA), the main component of essential oils derived from anise seeds, influences the differentiation of mouse C2C12 myoblasts. Cells were induced to differentiate over 5 days using a differentiation medium with or without PAA (50 or 200 mg/mL). Myotube length and diameter were measured, and the expressions of myogenic markers (myoblast determination protein 1, myogenin, myocyte enhancer factor 2, muscle creatine kinase, and myosin heavy chain) and atrophy-related genes (atrogin-1 and muscle ring finger-1 [MuRF-1]) were assessed by quantitative real-time polymerase chain reaction. Additionally, protein kinase B (Akt) phosphorylation was monitored by western blotting. PAA significantly induced the formation of smaller and thinner myotubes and reduced myogenic marker expression. Furthermore, PAA increased the expressions of atrogin-1 and MuRF-1 and simultaneously reduced Akt phosphorylation. Our findings indicate that PAA inhibits the myogenic differentiation of C2C12 cells by reducing the phosphorylation and activation of Akt.

• Journal of The Korean Society of Integrative Medicine
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• v.12 no.1
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• pp.63-71
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• 2024

Purpose : Skin is the primary barrier to protect the body from various exogenous factors. Among them, UVB exposure can cause the induction of not only excessive inflammatory responses but also the degradation of extracellular matrix (ECM), including collagen and elastin. This study tried to investigate the ameliorative effect of Persicaria perfoliata ethanol extract (PPEE) on UVB-irradiated photodamage through the regulation of activator protein (AP)-1, phosphoinositide 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) signaling molecules in HaCaT cells. Methods : The cytotoxicity of PPEE on HaCaT cells was evaluated by the WST-1 assay. The 80 mJ/cm² of UVB (312 nm) was irradiated on HaCaT cells to induce the photodamage. Western blot analysis was conducted to investigate the protein expression levels of cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-9, and heme oxygenase (HO)-1 for ameliorative status by PPEE treatment in UVB-exposed HaCaT cells. In addition, the activated status of the inflammatory transcription factor, AP-1, as well as upstream signaling molecules, PI3K/Akt, and MAPK, were also evaluated by Western blot analysis. Results : Any cytotoxic effect was not induced at the concentration up to 200 ㎍/ml by PPEE treatment. Protein expression levels of COX-2 and MMP-9 were significantly down- and up-regulated by PPEE treatment. The inflammatory transcription factor AP-1, stimulated by UVB irradiation, was also significantly attenuated by PPEE treatment. The phosphorylated status of PI3K/Akt and MAPK were mitigated by PPEE treatment in UVB-exposed HaCaT cells. Moreover, PPEE treatment potently accelerated the expression of HO-1 and its transcription factor, nuclear factor-erythroid 2-related factor (Nrf)2, which is known for its anti-inflammatory activity. Conclusion : Consequently, PPEE treatment significantly regulated COX-2 and MMP-9 expressions in UVB-irradiated HaCaT cells. The inflammatory transcription factor AP-1, along with upstream signaling molecules PI3K/Akt and MAPKs, were also attenuated by PPEE treatment in UVB-exposed HaCaT cells. Additionally, PPEE treatment exaggerated HO-1 expression and Nrf2 activation, which might have contributed to the anti-inflammatory activity of PPEE. These results indicate that PPEE could be a candidate for attenuating UVB-induced photodamage in human skin.

• Journal of Life Science
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• v.26 no.6
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• pp.663-672
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• 2016

The Cnidium monnieri (L.) Cusson is an annual plant distributed in China and Korea. The fruit of C. monnieri is used as a medicinal herb that is effective for the treatment of carbuncle and pain in female genitalia. However, the anti-cancer effects of CME have not yet been reported. In this study, we assessed the apoptotic effects and cell cycle arrest effects of ethanol extracts from C. monnieri on HCT116 colon cancer cells. The results of an MTT assay and LDH assay demonstrated a decrease in cell viability and the cytotoxic effects of CME. In addition, the number of apoptotic body and the apoptotic rate were increased in a dose-dependent manner through Hoechst 33342 staining and Annexin V-PI double staining. In addition, cell cycle arrest occurred at the G1 phase by CME. Protein kinase B (Akt) plays an important role in cancer cell survival, growth, and division. Akt down-regulates apoptosis-mediated proteins, such as mammalian target of rapamycin (mTOR), p53, and Glycogen Synthase kinase-3β (GSK-3β). CME could regulate the expression levels of p-Akt, p-mTOR, p-GSK-3β, Bcl-2 family members, caspase-3, and PARP. Furthermore, treatment with CME, LY294002 (PI3K/Akt inhibitor), BIO (GSK-3β inhibitor), and Rapamycin (mTOR inhibitor) showed that apoptotic effects occurred through the regulation of the AKT/mTOR/GSK-3β signaling pathway. Our results demonstrated CME could induce apoptosis and cell cycle arrest in HCT116 colon cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.4
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• pp.1119-1124
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• 2012

Background: The effect and possible mechanism of traditional Chinese medicine, baicalin, on the PI3K/Akt signaling pathway in drug-resistant human myeloid leukemia HL-60/ADR cells have been investigated in this current study. Methods: HL-60/ADR cells were treated by 20, 40, $80\;{\mu}mol/L$ baicalin followed by cell cycle analysis at 24h. The mRNA expression level of the apoptosis related gene, Bcl-2 and bad, were measured by RT-PCR on cells treated with $80\;{\mu}mol/L$ baicalin at 12, 24 and 48hr. Western blot was performed to detect the changes in the expression of the proteins related to HL-60/ADR cell apoptosis and the signaling pathway before and after baicalin treatment, including Bcl-2, PARP, Bad, Caspase 3, Akt, p-Akt, NF-${\kappa}B$, p-NF-${\kappa}B$, mTOR and p-mTOR. Results: Sub-G1 peak of HL-60/ADR cells appeared 24 h after $20\;{\mu}mol/L$ baicalin treatment, and the ratio increased as baicalin concentration increased. Cell cycle analysis showed 44.9% G0/G1 phase cells 24 h after baicalin treatment compared to 39.6% in the control group. Cells treated with $80\;{\mu}mol/L$ baicalin displayed a trend in decreasing of Bcl-2 mRNA expression over time. Expression level of the Bcl-2 and PARP proteins decreased significantly while that of the PARP, Caspase-3, and Bad proteins gradually increased. No significant difference in Akt expression was observed between treated and the control groups. However, the expression levels of p-Akt, NF-${\kappa}B$, p-NF-${\kappa}B$, mTOR and p-mTOR decreased significantly in a time-dependent manner. Conclusions: We conclude that baicalin may induce HL-60/ADR cell apoptosis through the PI3K/AKT signaling pathway.

• The Korean Journal of Physiology and Pharmacology
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• v.26 no.4
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• pp.239-253
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• 2022

Epithelial-mesenchymal transition (EMT) is known to be involved in airway remodeling and fibrosis of bronchial asthma. However, the molecular mechanisms leading to EMT have yet to be fully clarified. The current study was designed to reveal the potential mechanism of microRNA-21 (miR-21) and poly (ADP-ribose) polymerase-1 (PARP-1) affecting EMT through the PI3K/AKT signaling pathway. Human bronchial epithelial cells (16HBE cells) were transfected with miR-21 mimics/inhibitors and PARP-1 plasmid/small interfering RNA (siRNA). A dual luciferase reporter assay and biotin-labeled RNA pull-down experiments were conducted to verify the targeting relationship between miR-21 mimics and PARP-1. The migration ability of 16HBE cells was evaluated by Transwell assay. Quantitative real-time polymerase chain reaction and Western blotting experiments were applied to determine the expression of Snail, ZEB1, E-cadherin, N-cadherin, Vimentin, and PARP-1. The effects of the PI3K inhibitor LY294002 on the migration of 16HBE cells and EMT were investigated. Overexpression of miR-21 mimics induced migration and EMT of 16HBE cells, which was significantly inhibited by overexpression of PARP-1. Our findings showed that PARP-1 was a direct target of miR-21, and that miR-21 targeted PARP-1 to promote migration and EMT of 16HBE cells through the PI3K/AKT signaling pathway. Using LY294002 to block PI3K/AKT signaling pathway resulted in a significant reduction in the migration and EMT of 16HBE cells. These results suggest that miR-21 promotes EMT and migration of HBE cells by targeting PARP-1. Additionally, the PI3K/AKT signaling pathway might be involved in this mechanism, which could indicate its usefulness as a therapeutic target for asthma.

• Journal of Life Science
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• v.33 no.4
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• pp.343-348
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• 2023

Acne is one of the most common skin diseases, mainly occurring in adolescence. The pathophysiology of acne involves not only hormonal, genetic and environmental factors, but also other factors including hyperseborrhea, inflammation, over-keratinization of follicular keratinocytes and overgrowth of Cutibacterium acnes (C. acnes). Cannabidiol (CBD) is known to relieve pain, stress and inflammation. Moreover, cannabis extracts containing CBD have been reported to be effective in treating acne. However, the therapeutic effect of CBD on acne remains unclear. Therefore, this study aimed to investigate the effect and mechanism of CBD on lipogenesis in SEB-1 sebocytes. We treated sebocytes with CBD and found that it not only inhibited lipid synthesis, but also inhibited cell proliferation by inducing apoptosis. We then demonstrated that sterol response element-binding protein-1 (SREBP-1) mediates the inhibitory effect of CBD on lipogenesis. Furthermore, Akt and adenosine monophosphate-activated protein kinase (AMPK), upstream regulators of SREBP-1, were regulated by CBD treatment. Taken together, our studies demonstrate that CBD inhibits adipogenesis by regulating the Akt/AMPK-SREBP-1 signaling pathway, providing potential for use as a therapeutic agent for acne. Further research is needed to confirm the effect of CBD on inflammation caused by hyperkeratosis, which will increase the possibility of using CBD for acne treatment.