• Biomolecules & Therapeutics
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• v.27 no.5
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• pp.492-501
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• 2019

Nitrogen-containing heterocycles such as quinoline, quinazolinones and indole are scaffolds of natural products and have broad biological effects. During the last years those structures have been intensively synthesized and modified to yield new synthetic molecules that can specifically inhibit the activity of dysregulated protein kinases in cancer cells. Herein, a series of newly synthesized isoquinolinamine (FX-1 to 8) and isoindoloquinazolinone (FX-9, FX-42, FX-43) compounds were evaluated in regards to their anti-leukemic potential on human B- and T- acute lymphoblastic leukemia (ALL) cells. Several biological effects were observed. B-ALL cells (SEM, RS4;11) were more sensitive against isoquinolinamine compounds than T-ALL cells (Jurkat, CEM). In SEM cells, metabolic activity decreased with $10{\mu}M$ up to 26.7% (FX-3), 25.2% (FX-7) and 14.5% (FX-8). The 3-(p-Tolyl) isoquinolin-1-amine FX-9 was the most effective agent against B- and T-ALL cells with IC50 values ranging from 0.54 to $1.94{\mu}M$. None of the tested compounds displayed hemolysis on erythrocytes or cytotoxicity against healthy leukocytes. Anti-proliferative effect of FX-9 was associated with changes in cell morphology and apoptosis induction. Further, influence of FX-9 on PI3K/AKT, MAPK and JAK/STAT signaling was detected but was heterogeneous. Functional inhibition testing of 58 kinases revealed no specific inhibitory activity among cancer-related kinases. In conclusion, FX-9 displays significant antileukemic activity in B- and T-ALL cells and should be further evaluated in regards to the mechanisms of action. Further compounds of the current series might serve as templates for the design of new compounds and as basic structures for modification approaches.

• Animal Bioscience
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• v.36 no.3
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• pp.404-416
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• 2023

Objective: Daweizi (DWZ) is a famous indigenous pig breed in China and characterized by tender meat and high fat percentage. However, the expression profiles and functions of transcripts in DWZ pigs is still in infancy. The object of this study was to depict the transcript profiles in DWZ pigs and screen the potential pathway influence adipogenesis and fat deposition, Methods: Histological analysis of backfat tissue was firstly performed between DWZ and lean-type Yorkshire pigs, and then RNA sequencing technology was utilized to explore miRNAs, lncRNAs and mRNAs profiles in backfat tissue. 18 differentially expressed (DE) transcripts were randomly selected for quantitative real-time polymerase chain reaction (QPCR) to validate the reliability of the sequencing results. Finally, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were conducted to investigate the potential pathways influence adipocyte differentiation, adipogenesis and lipid metabolism, and a schematic model was further proposed. Results: A total of 1,625 differentially expressed transcripts were identified in DWZ pigs, including 27 upregulated and 45 downregulated miRNAs, 64 upregulated and 119 down-regulated lncRNA, 814 upregulated and 556 downregulated mRNAs. QPCR analysis exhibited strong consistency with the sequencing data. GO and KEGG analysis elucidated that the differentially expressed transcripts were mainly associated with cell growth and death, signal transduction, peroxisome proliferator-activated receptors (PPAR), AMP-activated protein kinase (AMPK), PI3K-Akt, adipocytokine and foxo signaling pathways, all of which are strongly involved in cell development, lipid metabolism and adipogenesis. Further analysis indicated that the BGIR9823_87926/miR-194a-5p/AQP7 network may be effective in the process of adipocyte differentiation or adipogenesis. Conclusion: Our study provides comprehensive insights into the regulatory network of backfat deposition and lipid metabolism in pigs from the point of view of miRNAs, lncRNAs and mRNAs.

• Biomolecules & Therapeutics
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• v.31 no.4
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• pp.446-455
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• 2023

The mechanistic functions of 3-deoxysappanchalcone (3-DSC), a chalcone compound known to have many pharmacological effects on lung cancer, have not yet been elucidated. In this study, we identified the comprehensive anti-cancer mechanism of 3-DSC, which targets EGFR and MET kinase in drug-resistant lung cancer cells. 3-DSC directly targets both EGFR and MET, thereby inhibiting the growth of drug-resistant lung cancer cells. Mechanistically, 3-DSC induced cell cycle arrest by modulating cell cycle regulatory proteins, including cyclin B1, cdc2, and p27. In addition, concomitant EGFR downstream signaling proteins such as MET, AKT, and ERK were affected by 3-DSC and contributed to the inhibition of cancer cell growth. Furthermore, our results show that 3-DSC increased redox homeostasis disruption, ER stress, mitochondrial depolarization, and caspase activation in gefitinib-resistant lung cancer cells, thereby abrogating cancer cell growth. 3-DSC induced apoptotic cell death which is regulated by Mcl-1, Bax, Apaf-1, and PARP in gefitinib-resistant lung cancer cells. 3-DSC also initiated the activation of caspases, and the pan-caspase inhibitor, Z-VAD-FMK, abrogated 3-DSC induced-apoptosis in lung cancer cells. These data imply that 3-DSC mainly increased mitochondria-associated intrinsic apoptosis in lung cancer cells to reduce lung cancer cell growth. Overall, 3-DSC inhibited the growth of drug-resistant lung cancer cells by simultaneously targeting EGFR and MET, which exerted anti-cancer effects through cell cycle arrest, mitochondrial homeostasis collapse, and increased ROS generation, eventually triggering anti-cancer mechanisms. 3-DSC could potentially be used as an effective anti-cancer strategy to overcome EGFR and MET target drug-resistant lung cancer.

• Journal of the Korean Society of Food Science and Nutrition
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• v.46 no.6
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• pp.671-680
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• 2017

This study was conducted to examine the effects and potential mechanisms of action of black soybean extracts and fermented black soybean extracts by Lactobacillus rhamnosus GG (LGG) and Bifidobacterium animals subsp. lactis BB-12 (BB-12) on proliferation of human follicle dermal papilla cells (HFDPC). We examined changes in pH, total polyphenol, sugar, and reducing sugar contents according to fermentation period of black soybean extracts. Assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was performed to determine cell toxicity levels of the four black soybean extracts [black soybean water extract (BWE), black soybean ethanol extract (BEE), fermented BWE (F-BEW), and fermented BEE (F-BEE)]. Changes in mRNA expression levels of hair growth promoting factors and hair growth inhibiting factors by the four black soybean extracts were measured by real-time PCR. In addition, phosphorylation levels of mitogen-activated protein kinase family proteins were measured by western blot analysis. As a result, fermentation of black soybeans significantly reduced pH, total polyphenols, and sugar/reducing sugar contents. All four black soybean extracts showed no cellular toxicity in HFDPC. In fact, BEE significantly enhanced cell viability of HFDPC at $100{\mu}g/mL$ compared to control. BWE, BEE, and BWE-F significantly increased mRNA expression of vascular endothelial growth factor, and all four extracts increased mRNA expression of fibroblast growth factor. However, mRNA expression levels of apoptosis-related genes were not affected by black soybean extracts in HFDPC. Furthermore, BWE, BEE, and BWE-F significantly increased phosphorylation levels of extracellular signal-regulated kinase compared to control. Taken together, we demonstrated that black soybean extracts enhanced proliferation of human follicle dermal papilla cells partially via activation of hair growth promoting factors, although no particular significant effects on proliferation were observed by fermentation of black soybeans.

• Korean Journal of Food Science and Technology
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• v.53 no.3
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• pp.267-277
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• 2021

To evaluate hepatoprotective effects, the antioxidant capacities of matcha green tea extract (Camellia sinenesis) were compared to those of green leaf tea and the anti-inflammatory activities in HepG2 cells were investigated. Evaluation of the total phenolic and total flavonoid content, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, and inhibitory effect on lipid peroxidation indicated that the aqueous extract of matcha green tea presented significant catechin content and antioxidant capacity compared to those of green leaf tea. In addition, the extract had considerable inhibitory effects on α-glucosidase, α-amylase, and advanced glycation end-products. The matcha green tea extract significantly increased cell viability and reduced reactive oxygen species in H₂O₂- and high-glucose-treated HepG2 cells. Furthermore, in response to oleic acid-induced HepG2 cell injury, treatment with matcha green tea aqueous extract inhibited lipid accumulation and regulated the expression of inflammatory proteins such as p-JNK, p-Akt, p-GSK-3β, caspase-3, COX-2, iNOS, and TNF-α. Matcha green tea could be used as a functional material to ameliorate hepatic lipid accumulation and inflammation.

• Korean Journal of Food Science and Technology
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• v.53 no.4
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• pp.423-433
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• 2021

This study was performed to examine the neuroprotective effect of the ethyl acetate fraction from Eucommia ulmoides oliver leaf (EFEL) on PM_2.5-induced cytotoxicity. EFEL had higher total phenolic and flavonoid contents than the other fractions. In ABTS and DPPH radical scavenging activities, the IC₅₀ of EFEL was measured as 212.80 and 359.13 ㎍/mL, respectively. To investigate the neuroprotective effect of EFEL, MTT and DCF-DA assays were performed on HT22, MC-IXC, and BV-2 cells. EFEL effectively decreased PM_2.5-induced intercellular reactive oxygen species (ROS) content and inhibited PM_2.5-induced cell death. In the results of protein expression related to cellular cytotoxicity on microglial cells (BV-2), EFEL had an improvement effect on cell apoptosis and inflammatory pathways. Rutin and chlorogenic acid were identified as the main physiological compounds. Moreover, it was expected that EFEL, including rutin and chlorogenic acid, could be functional food substances with neuroprotective effects against PM_2.5-induced oxidative stress.

• Journal of Oral Medicine and Pain
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• v.36 no.1
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• pp.11-20
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• 2011

Valproic acid (VPA) is a well-known anticonvulsive agent and has been used in the treatment of epilepsy for almost 30 years. VPA emerged in 1997 as an antineoplastic agent. And it is known that antitmor activity of VPA is associated with its targeted at histone deacetylases. 17AAG, Inhibition of HSP90 leads to the proteasome degradation of the HSP90 client proteins, such as Akt, Raf/Ras, Erk, VEGF, cyclin D and p53, and causes potent antitumor activity. It is reported that 17AAG-induced HSP90 inhibition results in prevention of cell proliferation and induction of apoptosis in several types of cancer. This study was undertaken to investigate the synergistic apoptotic effect of co-treatment with the histone deacetylases inhibitor, VPA and the HSP90 inhibitor, 17AAG on human osteosarcoma (HOS) cells. Cell viability was evaluated by trypan-blue exclusion. Induction and augmentation of apoptosis were confirmed by Hoechst staining, flow cytometry (DNA hypoploidy and MMP change), Westen blot analysis and immunofluorescent staining. In this study, HOS cells co-treated with VPA and 17AAG showed several lines of apoptotic manifestation such as nuclear condensations, the reduction of MMP, the decrease of DNA content, the release of cytochrome c into cytosol, the translocation of AIF onto nuclei, and activation of caspase-3, caspase-7 and PARP whereas each single treated HOS cells did not. Although the single treatment of 1 mM VPA or 0.5 ${\mu}M$ 17AAG for 48 h did not induce apoptosis, the co-treatment with them induced prominently apoptosis. Therefore our data in this study provide the possibility that combination therapy with VPA and 17AAG could be considered as a novel therapeutic strategy for human osteosarcoma.

• Biomolecules & Therapeutics
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• v.20 no.1
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• pp.43-49
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• 2012

Stimulation of mast cells through the high affinity IgE receptor (Fc${\varepsilon}$RI) induces degranulation, lipid mediator release, and cytokine secretion leading to allergic reactions. Although various signaling pathways have been characterized to be involved in the Fc${\varepsilon}$RI-mediated responses, little is known about the precious mechanism for the expression of tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) in mast cells. Here, we report that rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR), reduces the expression of TNF-${\alpha}$ in rat basophilic leukemia (RBL-2H3) cells. IgE or specific antigen stimulation of RBL-2H3 cells increases the expression of TNF-${\alpha}$ and activates various signaling molecules including S6K1, Akt and p38 MAPK. Rapamycin specifically inhibits antigeninduced TNF-${\alpha}$ mRNA level, while other kinase inhibitors have no effect on TNF-${\alpha}$ mRNA level. These data indicate that mTOR signaling pathway is the main regulation mechanism for antigen-induced TNF-${\alpha}$ expression. TNF-${\alpha}$ mRNA stability analysis using reporter construct containing TNF-${\alpha}$ adenylate/uridylate-rich elements (AREs) shows that rapamycin destabilizes TNF-${\alpha}$ mRNA via regulating the AU-rich element of TNF-${\alpha}$ mRNA. The antigen-induced activation of S6K1 is inhibited by specific kinase inhibitors including mTOR, PI3K, PKC and $Ca^{2+}$chelator inhibitor, while TNF-${\alpha}$ mRNA level is reduced only by rapamycin treatment. These data suggest that the effects of rapamycin on the expression of TNF-${\alpha}$ mRNA are not mediated by S6K1 but regulated by mTOR. Taken together, our results reveal that mTOR signaling pathway is a novel regulation mechanism for antigen-induced TNF-${\alpha}$ expression in RBL-2H3 cells.

• Journal of Apiculture
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• v.34 no.3
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• pp.245-254
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• 2019

We investigated the anti-tumor effects and molecular mechanism of Brazil, China and Korean regional propolis on HeLa ovarian cancer cell line. Each propolis extracts was prepared by ethanol extraction method. Cytotoxicity of propolis extracts was determinated by EZ-cytox cell viability assay. To necessity of anti-tumor effect and molecular mechanism of propolis, we must be adjusting propolis concentration. Due to 100 ㎍/mL of propolis extract were reduced cell viability to less than 50%, we adjusted all of propolis concentration to 100 ㎍/mL. By Western blotting analysis, we confirmed that anti-tumor mechanism of Brazil, China and Korea regional propolis has significantly difference. All of propolis was activated apoptosis related molecules such as PARP, caspase-3. However, cell proliferation signaling molecules including Akt1, ERK and Bcl-2 were reduced the protein expression level. Especially, the expression of tumor suppressor protein p53 was significantly increased in propolis-treated group such as Gyeonggi, Chungbuk, Chungnam, Jeonbuk, Gyeongnam and China. The phosphorylation of Bax which as apoptosis indicator was appeared in propolis-treated group such as Gyeonggi, Gangwon, Chungnam, Gyeongbuk, China. In this results showed that the regional propolis has completely different mechanism in anti-tumor. Thus, propolis extracts may be useful source of functional materials on anti-cancer and it will be able to choose the suitable propolis for cancer therapy by analyzing individual characteristics.