• Journal of Microbiology and Biotechnology
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• v.25 no.5
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• pp.648-657
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• 2015

H9, a novel herbal extract, demonstrated cytotoxicity in A549 non-small cell lung cancer (NSCLC) cell lines. In this study, we investigated whether H9, and/or co-treatment with an anticancer drug, pemetrexed (PEM), inhibited tumor growth in BALB/c nude mice models bearing A549 NSCLC cells. The mice were separated into groups and administered H9 and PEM for 2 weeks. Protein and mRNA levels were detected using western blotting and reverse transcription polymerase chain reaction, respectively; immunohistochemistry (IHC) was also performed on the tumor tissues. H9 and co-treatment with PEM induced the cleavage of proapoptotic factors, such as caspase-3, caspase-8, caspase-9, and poly(ADP)-ribose polymerase (PARP). Expression levels of cell-death receptors involving Fas/FasL, TNF-related apoptosisinducing ligands (TRAIL), and TRAIL receptors were increased by H9 and co-treatment with PEM. Furthermore, analysis of levels of cell-cycle modulating proteins indicated that tumor cells were arrested in the G1/S phase. In addition, the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt survival signaling pathways were inhibited by H9 and co-treatment with PEM. In conclusion, H9 and co-treatment with PEM inhibited tumor growth in BALB/c nude mice models bearing A549 NSCLC cells. These results indicate that H9 and co-treatment with PEM can be used as an anticancer therapy in NSCLC.

• Koreanishche Zeitschrift fur Deutsche Sprachwissenschaft
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• v.2
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• pp.229-254
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• 2000

In der vorliegenden Arbeit wurde versucht, eine $ad\"{a}quate\;Basis\;f\"{u}r$ die Untersuchung der indirekten Sprachhandlung dadurch zu schaffen, die das $Indirektheitsph\"{a}nomen$ konstituierenden sozial-kommunikativen Faktoren ans Licht zu bringen. Dazu $mu{\ss}ten\;zun\"{a}chst$ einige Unstimmigkeiten der Searleschen Theorie der indirekten Sprechakte, die lange Zeit in der linguistischen Pragmatik dominierte, auf ihre $Erkl\"{a}rungskraft$ sowie ihre Haltbarkeit hin $\"{u}berpr\"{u}ft$ werden. In dieser Theorie wird davon ausgegangen, mit einer indirekten $\"{A}u{\ss}erung\;w\"{u}rden zwei\;illokution\"{a}re$ Akte gleichzeitig realisiert. Diese Annahme beruht ihrerseits auf der Auffassung, dem Satz wohne eine $illokution\"{a}re$ Rolle inne, wie z.B. dem Interrogativsatz die Rolle der FRAGE. So ist die bei Tisch oft verwendete $\"{A}u{\ss}$erung 'Kannst du mir das Salz reichen?' einerseits aufgrund des Fragesatztyps FRAGE und andererseits aufgrund der ihr konventionell zuzuordnenden Funktion eine BITTE. Die Frage ist, ob dem sog. $sekund\"{a}r\;illokution\"{a}ren$ Akt, also in diesem Fall der FRAGE, der Handlungscharakter verliehen werden kann. Denn die Handlungsintention des Sprechers liegt eindeutig darin, vom $H\"{o}rer$ das Salz $\"{u}berreicht$ zu bekommen, und nicht darin, sich vom $H\"{o}rer$ etwa uber seine $F\"{a}higkeit$ zum Salzreichen zu informieren. Die schwerwiegendsten $M\"{a}ngel$ der Searleschen Analyse der Indirektheit liegen z.T. darin, bei der Bestimmung des kommunikativen Zwecks einer $\"{A}u{\ss}erung$ von den sprachlichen Eigenschaften des Satzes ausgegangen zu sein und nicht von dem $Proze{\ss}$ der gemeinsamen Sinnkonstituierung durch die Kommunikationsteilnehmer, wie etwa durch die gegenseitige Annahme und die reflexive Intention. In diesem Zusammenhang erweisen sich die-von Grice so genannten­partikularisierten konversationellen Implikaturen als das Musterbeispiel $f\"{u}r$ die Entstehung und Interpretation der indirekten $\"{A}u{\ss}erung$. Hier wird man vor allem - wenigstens auf der abstraktiven Ebene der Gegenstandsanalyse - der kommunikativen $Realit\"{a}t$ gerecht. Die kommunikative Indirektheit in der Alltagskommunikation, so $hei{\ss}t$ der allgemeinere Begriff als etwa die Indirektheit auf der $illokution\"{a}ren$ Ebene, zeichnet sich dadurch aus, $da{\ss}$ sie eine in besonderem $Ma{\ss}e$ partnerorientierte, kooperative und auf die $Intersubjektivit\"{a}t$ unter den Kommunikationsteilnehmem abzielende Handlungsweise darstellt.

• Journal of Acupuncture Research
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• v.21 no.2
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• pp.41-55
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• 2004

Objective : To investigate the possible molecular mechanism (s) of melittin as a candidate of anti-cancer drug, we examined the effects of the compound on the growth of human lung carcinoma cell line A549. Methods : Growth inhibitory study, flow cytometry analysis, SDS-polyacrylamide gel electrophoresis and Western blot analysis, RT-PCR and in vitro caspases activity assay were performed. Results : Melittin treatment declined the cell viability of A549 cells in a concentration-dependent manner, which was associated with induction of apoptotic cell death. Melittin treatment down-regulated the levels of Bcl-XS/L mRNA and protein expression of A549 cells, an anti-apoptotic gene, however, the those of Bax, a pro-apoptotic gene, were up-regulated. Melittin induced the proteolytic cleavage and activation of caspase-3 and caspase-9 protease in a dose-dependent manner without alteration of inhibitor of apoptosis proteins family and Akt expression. Western blot analysis and RT-PCR data revealed that the levels of tumor suppressor p53 and cyclin-dependent kinase inhibitor p21 were also remained unchanged. Conclusions : Taken together, these findings suggest that melittin-induced inhibition of human lung cancer cell growth is associated with the induction of apoptotic cell death via regulation of several major growth regulatory gene products, and melittin may have therapeutic potential in human lung cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.17
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• pp.7619-7625
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• 2015

Background: Aberrant microRNA expression has been associated with the pathogenesis of a variety of human malignancies including oral squamous cell carcinoma (SCC). In this study, we examined primary oral SCCs for the expression of 6 candidate miRNAs, of which five (miR-34a, miR-143, miR-373, miR-380-5p, and miR-504) regulate the tumor suppressor TP53 and one (miR-99a) is involved in AKT/mTOR signaling. Materials and Methods: Tumor tissues (punch biopsies) were collected from 52 oral cancer patients and as a control, 8 independent adjacent normal tissue samples were also obtained. After RNA isolation, we assessed the mature miRNA levels of the 6 selected candidates against RNU44 and RNU48 as endogenous controls, using specific TaqMan miRNA assays. Results: miR-34a, miR-99a, miR-143 and miR-380-5p were significantly down-regulated in tumors compared to controls. Moreover, high levels of miR-34a were associated with alcohol consumption while those of miR-99a and miR-143 were associated with advanced tumor size. No significant difference was observed in the levels of miR-504 between the tumors and controls whereas miR-373 was below the detection level in all but two tumor samples. Conclusions: Low levels of miR-380-5p and miR-504 that directly target the 3'UTR of TP53 suggest that p53 may not be repressed by these two miRNAs in OSCC. On the other hand, low levels of miR-34a or miR-143 may relieve MDM4 and SIRT1 or MDM2 respectively, which will sequester p53 indicating an indirect mode of p53 suppression in oral tumors.

• Journal of Food Hygiene and Safety
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• v.31 no.1
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• pp.59-66
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• 2016

It has been generally accepted that obesity and overweight are associated with metabolic diseases and cancer incidence. In fact, obesity increased risks of cancers i.e. breast, liver, pancreatic and prostate. Celastrol is a pentacyclic triterpenoid isolated from Thunder god vine, was used as a Chinese traditional medicine for treatment of inflammatory disorders such as arthritis, lupus erythematosus and Alzheimer's disease. Also, celastrol has various biological properties of chemo-preventive, neuro-protective, and anti-oxidant effects. Recent studies demonstrated that celastrol has anti-proliferation effects in different type of obesity-related cancers and suppresses tumor progression and metastasis. Anticancer effects of celastrol include regulation of $NF-{\kappa}B$, heat shock protein, JNK, VEGF, CXCR4, Akt/mTOR, MMP-9 and so on. For these reasons, celastrol has shown to be a promising anti-tumor agent. In this review, we will address the anticancer activities and multiple mechanisms of celastrol in obesity-related cancers.

• Molecules and Cells
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• v.38 no.2
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• pp.138-144
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• 2015

Raloxifene is a selective estrogen receptor modulator (SERM) that binds to the estrogen receptor (ER), and exhibits potent anti-tumor and autophagy-inducing effects in breast cancer cells. However, the mechanism of raloxifene-induced cell death and autophagy is not well-established. So, we analyzed mechanism underlying death and autophagy induced by raloxifene in MCF-7 breast cancer cells. Treatment with raloxifene significantly induced death in MCF-7 cells. Raloxifene accumulated GFP-LC3 puncta and increased the level of autophagic marker proteins, such as LC3-II, BECN1, and ATG12-ATG5 conjugates, indicating activated autophagy. Raloxifene also increased autophagic flux indicators, the cleavage of GFP from GFP-LC3 and only red fluorescence-positive puncta in mRFP-GFP-LC3-expressing cells. An autophagy inhibitor, 3-methyladenine (3-MA), suppressed the level of LC3-II and blocked the formation of GFP-LC3 puncta. Moreover, siRNA targeting BECN1 markedly reversed cell death and the level of LC3-II increased by raloxifene. Besides, raloxifene-induced cell death was not related to cleavage of caspases-7, -9, and PARP. These results indicate that raloxifene activates autophagy-dependent cell death but not apoptosis. Interestingly, raloxifene decreased the level of intracellular adenosine triphosphate (ATP) and activated the AMPK/ULK1 pathway. However it was not suppressed the AKT/mTOR pathway. Addition of ATP decreased the phosphorylation of AMPK as well as the accumulation of LC3-II, finally attenuating raloxifene-induced cell death. Our current study demonstrates that raloxifene induces autophagy via the activation of AMPK by sensing decreases in ATP, and that the overactivation of autophagy promotes cell death and thereby mediates the anti-cancer effects of raloxifene in breast cancer cells.

• 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.

• The Journal of Korean Medicine Ophthalmology and Otolaryngology and Dermatology
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• v.35 no.3
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• pp.15-24
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• 2022

Objectives : The purpose of this study is to investigate the potential mechanism of Artemisia capillaris Thunb. for psoriasis vulgaris. Methods : We conducted the network pharmacological analysis. It contains the process that search the compounds of the herb, the target proteins of the compounds, related genes of psoariasis vulgaris and the pathway/terms of the common protein lists between psoriasis vulgaris and Artemisia capillaris Thunb.. Results : 13 compounds and 30 protein targets of Artemisia Capillaris Herba were searched. And 997 psoriasis-related genes were searched. The common proteins were 11, and the core genes were 3; AKT1, CASP3, MAPK8. The related pathway/terms of 11 proteins were analyzed. ω-hydroxylase P450 pathway(60%), nitric oxide(NO) biosynthetic process(20%) were resulted. Also, 19 proteins of Artemisia Capillaris Herba were analyzed, and sterol homeostasis(78.95%), sterol biosynthetic process(15.79%), Type 2 diabetes mellitus(5.26%) were resulted. Conclusion : The Artemisia Capillaris Herba can potentially act through the ω-hydroxylase P450 pathway and nitric oxide(NO) biosynthetic process for psoriasis. Also, the metabolism of sterol biosynthesis and homeostasis can be involved in a roundabout way for psoriasis.

• The Journal of Korean Medicine
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• v.44 no.2
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• pp.106-118
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• 2023

Objectives: Network pharmacology is a method of constructing and analyzing a drug-compound-target network to predict potential efficacy and mechanisms related to drug targets. In that large-scale analysis can be performed in a short time, it is considered a suitable tool to explore the function and role of herbal medicine. Thus, we investigated the potential functions and pathways of Chongmyunggongjin-dan (CMGJD) on Alzheimer's disease (AD) via network pharmacology analysis. Methods: Using public databases and PubChem database, compounds of CMGJD and their target genes were collected. The putative target genes of CMGJD and known target genes of AD were compared and found the correlation. Then, the network was constructed using Cytoscape 3.9.1. and functional enrichment analysis was conducted based on the Gene Ontology (GO) Biological process and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathways to predict the mechanisms. Results: The result showed that total 104 compounds and 1157 related genes were gathered from CMGJD. The network consisted of 1157nodes and 10034 edges. 859 genes were interacted with AD gene set, suggesting that the effects of CMGJD are closely related to AD. Target genes of CMGJD are considerably associated with various pathways including 'Positive regulation of chemokine production', 'Cellular response to toxic substance', 'Arachidonic acid metabolic process', 'PI3K-Akt signaling pathway', 'Metabolic pathways', 'IL-17 signaling pathway' and 'Neuroactive ligand-receptor interaction'. Conclusion: Through a network pharmacological method, CMGJD was predicted to have high relevance with AD by regulating inflammation. This study could be used as a basis for effects of CMGJD on AD.

• 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.