• Journal of Life Science
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• v.32 no.3
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• pp.210-221
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• 2022

This study investigated the mechanisms underlying the anti-cancer effects of non-steroidal anti-inflammatory drugs (NSAIDs) in human cancer cells in combination with either N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor, or MHY2245, a new synthetic sirtuin 1 inhibitor. The results showed both DAPT and MHY2245 as novel chemosensitizers of human colon cancer KM12 and human hepatocellular carcinoma SNU475 cells to NSAIDs involving celecoxib and 2, 5-dimethyl celecoxib. The NSAID-induced cytotoxicity of these cells was significantly increased by DAPT and MHY2245 in a cyclooxygenase-2 independent manner. In addition, DAPT and MHY2245 reduced levels of p62, Notch1 intracellular domain, and multiple cancer stemness (CS)-related markers including Notch1, CD44, CD133, octamer-binding transcription factor 4, mutated p53 and c-Myc. However, the level of activating transcription factor 4 (ATF4) was enhanced, probably indicating the down-regulation of multiple CS-related markers by DAPT or MHY2245-mediated autophagy induction. Moreover, the NSAID-mediated reduction of p62/nuclear factor erythroid-derived 2-like 2 and CS-related marker proteins and the up-regulation of C/EBP homologous protein (CHOP)/ATF4 were accelerated by DAPT and MHY2245. As such, the combination of NSAID and either DAPT or MHY2245 resulted in higher cytotoxicity than NSAID alone by accelerating the down-regulation of multiple CS-related markers and PARP activation, indicating that both inhibitors promote NSAID-mediated autophagic cell death, possibly through the CHOP/ATF4 pathway. In conclusion, either combination strategy may be useful for the effective treatment of human cancer cells expressing CS-related markers.

• 한국생물공학회:학술대회논문집
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• 2004.07a
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• pp.1-20
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• 2004

Polychlorinated biphenyls (PCBs), one a group of persistent and widespread environmental pollutants, have been considered to be involved in immunotoxicity, carcinogenesis, and apoptosis. However, the toxic effects and physical properties of a PCB congener are dependent on the structure. In the present study, we investigate the toxic effects and action mechanisms of PCBs In cells. Among the various congeners tested, 2,2',4,6,6'-PeCB-pentachlorobiphenyl (PeCB), a highly ortho-substituted congener having negligible binding affinity for aryl hydrocarbon receptor (AhR), caused the most potent toxicity and specific effects in several cell types. 2,2',4,6,6'-PeCB induced apoptotic cell death of human monocytic cells, suggesting that PCB-induced apoptosis may be linked to immunotoxicity. In addition, 2,2',4,6,6'-PeCB induced mitotic arrest by interfering with mitotic spindle assembly in NIH3T3 fibroblasts, followed by genetic instability which triggers p53 activation. Which suggests that 2,2',4,6,6'-PeCB may be involved in cancer development by causing genetic instability through mitotic spindle damage. On the other hand, 2,2',4,6,6'-PeCB increased cyclooxygenase-2 (COX-2) involved in cell survival through ERK1/2 MAPK and p53 in Rat-1 fibroblasts and mouse embryonic fibroblasts, triggering compensatory mechanism for abating its toxicity. Taken together, these results demonstrate that PCB congeners of different structure have distinct mechanism of action and 2,2',4,6,6'-PeCB causes several toxicity as well as compensatory mechanism in cells.

• Proceedings of the Plant Resources Society of Korea Conference
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• 2018.10a
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• pp.98-98
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• 2018

In this study, we evaluated the anti-inflammatory effect of extracts of leaves (ST-L) and branches (ST-B) from Sageretia theezans in LPS-stimulated RAW264.7 cells. ST-L and ST-B significantly inhibited the production of the pro-inflammatory mediators such as NO, iNOS, COX-2, $IL-1{\beta}$ and IL-6 in LPS-stimulated RAW264.7 cells. ST-L and ST-B blocked LPS-induced degradation of $I{\kappa}B-{\alpha}$ and nuclear accumulation of p65, which resulted to the inhibition of $NF-{\kappa}B$ activation in RAW264.7 cells. ST-L and ST-B also attenuated the phosphorylation of ERK1/2, p38 and JNK in LPS-stimulated RAW264.7 cells. In addition, ST-L and ST-B increased HO-1 expression in RAW264.7 cells, and the inhibition of HO-1 by ZnPP reduced the inhibitory effect of ST-L and ST-B against LPS-induced NO production in RAW264.7 cells. Inhibition of p38 activation and ROS elimination attenuated HO-1 expression by ST-L and ST-B, and ROS elimination inhibited p38 activation induced by ST-L and ST-B. ST-L and ST-B dramatically induced nuclear accumulation of Nrf2, but this was significantly reversed by the inhibition of p38 activation and ROS elimination. Collectively, our results suggest that ST-L and ST-B exerts potential anti-inflammatory activity by suppressing $NF-{\kappa}B$ and MAPK signaling activation, and activating HO-1 expression through the nuclear accumulation of Nrf2 via ROS-dependent p38 activation. These findings suggest that ST-L and ST-B may have great potential for the development of anti-inflammatory drug to treat acute and chronic inflammatory disorders.

• Journal of Preventive Medicine and Public Health
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• v.38 no.2
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• pp.203-207
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• 2005

Objectives: Recently, the American Diabetes Association (ADA) redefined the criteria of prediabetes, which has lowered the diagnostic level of fasting plasma glucose (FPG) from 110 to 125 mg/dl, down to levels between 100 to 125mg/dl. The purpose of this study was to determine the predictive cutoff level of FPG as a risk for the development of diabetes mellitus in Korean men. Methods: A retrospective cohort study was conducted on 11,423 (64.5%) out of 17,696 males $\leq$30 years of age, and who met the FPG of $\leq$125 mg/dl and hemoglobin A1c of $\leq$ 6.4% criteria, without a history of diabetes, and who were enrolled at the screening center of a certain university hospital between January and December 1999. The subjects were followed from January 1999 to December 2002 (mean follow-up duration; 2.3(${\pm}0.7$) years). They were classified as normal (FPG <100mg/dl), high glucose (FPG $\geq$100mg/dl and <110mg/dl) and impaired fasting glucose (FPG $\geq$110mg/dl and $\leq$125mg/dl) on the basis of their fasting plasma glucose level measured in 1999. We compared the incidence of diabetes between the 3 groups by performing Cox proportional hazards model and used receiver operating characteristic analyses of the FPG level, in order to estimate the optimal cut-off values as predictors of incident diabetes. Results: At the baseline, most of the study subjects were in age in their 30s to 40s (mean age, 41.8(${\pm}7.1$) year). The incidence of diabetes mellitus in this study was 1.19 per 1,000 person-years (95% CI=0.68-1.79), which was much lower than the results of a community-based study that was 5.01 per 1,000 person-years. The relative risks of incident diabetes in the high glucose and impaired fasting glucose groups, compared with the normal glucose group, were 10.3 (95% CI=2.58-41.2) and 95.2 (95% CI= 29.3-309.1), respectively. After adjustment for age, body mass index, and log triglyceride, a FPG greater than 100mg/dl remained significant predictors of incident diabetes. Using the receiver operating characteristic (ROC) curve, the optimal cutoff level of FPG as a predictor of incident diabetes was 97.5 mg/dl, with a sensitivity and a specificity of 81.0% and 86.0%, respectively. Conclusion: These results suggest that lowering the criteria of impaired fasting glucose is needed in Korean male adults. Future studies on community-based populations, including women, will be required to determine the optimal cutoff level of FPG as a predictor of incident diabetes.

• Journal of Chest Surgery
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• v.52 no.4
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• pp.221-226
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• 2019

Background: Accurate mediastinal lymph node staging is vital for the optimal therapy and prognostication of patients with lung cancer. This study aimed to determine the preoperative risk factors for pN2 disease, as well as its incidence and long-term outcomes, in patients with clinical N0-1 non-small cell lung cancer. Methods: We retrospectively analyzed patients who were treated surgically for primary non-small cell lung cancer from November 2005 to December 2014. Patients staged as clinical N0-1 via chest computed tomography (CT) and positron emission tomography (PET)-CT were divided into two groups (pN0-1 and pN2) and compared. Results: In a univariate analysis, the significant preoperative risk factors for pN2 included a large tumor size (p=0.083), high maximum standard uptake value on PET (p<0.001), and central location of the tumor (p<0.001). In a multivariate analysis, central location of the tumor (p<0.001) remained a significant preoperative risk factor for pN2 status. The 5-year overall survival rates were 75% and 22.9% in the pN0-1 and pN2 groups, respectively, and 50% and 78.2% in the patients with centrally located and peripherally located tumors, respectively. In a Cox proportional hazard model, central location of the tumor increased the risk of death by 3.4-fold (p<0.001). Conclusion: More invasive procedures should be considered when preoperative risk factors are identified in order to improve the efficacy of diagnostic and therapeutic plans and, consequently, the patient's prognosis.

• Journal of the Korean Society of Food Science and Nutrition
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• v.44 no.10
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• pp.1439-1449
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• 2015

Prunus persica Flos (PPF) were investigated for their antioxidant and anti-inflammatory activities to find a natural functional food resource preventing degenerative diseases associated with excessive oxidative stress and chronic inflammation. PPF was extracted using ethanol (EtOH) and then sequentially fractioned by hexane (Hx), dichloromethane (DM), ethyl acetate (EA), n-butanol (BtOH), and water (DW). Contents of total phenolics and flavonoids, as well as 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activities were measured. Anti-inflammatory effects in terms of nitric oxide (NO), prostaglandin (PG) E2, and pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-${\alpha}$ production were also measured using LPS-treated RAW 264.7 macrophages. EtOH extract showed relatively high antioxidant activity with high total phenolic (78.1 mg tannic acid/g) and flavonoid contents (55.3 mg rutin/g). EA fraction contained the highest total phenolic and flavonoid contents (394.6 mg tannic acid/g, 253.7 mg rutin/g), followed by BtOH (128.3 mg tannic acid/g, 93.1 mg rutin/g). EA and BtOH fractions and EtOH extract showed higher DPPH radical and ABTS radical scavenging activities than the others (P<0.05). In LPS-treated RAW 264.7 macrophages, EtOH extract ($200{\mu}g/mL$) showed significantly reduced (P<0.05) NO, PGE2, and TNF-${\alpha}$ production levels to 38.5%, 32.3%, and 48.9% of the control, respectively, as well as reduced iNOS and COX-2 protein expression. DM fraction ($50{\mu}g/mL$) showed significantly reduced (P<0.05) NO, PGE2, IL-6, and TNF-${\alpha}$ production levels to 43.5%, 13.3%, 38.7%, and 41.3% of the control, respectively, and EA fraction ($50{\mu}g/mL$) showed significantly reduced NO, PGE2, IL-6, and TNF-${\alpha}$ production levels to 44.8%, 22.4%, 45.7%, and 62.0% of the control, respectively. Taken together, EtOH extract of PPF showed potent antioxidant and anti-inflammatory activities, and EA and BtOH fractions showed comparatively stronger antioxidant activities while DM and EA fractions showed stronger anti-inflammatory activities. It can be concluded that EtOH extract of PPF and its fractions are good candidates as natural resources for the development of anti-oxidative and anti-inflammatory functional food products.

• Journal of the Korea Academia-Industrial cooperation Society
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• v.20 no.12
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• pp.298-305
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• 2019

Cudrania tricuspidata has been reported to have many biological activities, including anti-inflammatory, anti-cancer, and antioxidant properties. However, the effects of C. tricuspidata root extract (CTE) on human platelet aggregation induced by collagen as well as the signaling pathways involved remain unknown. In the present study, we investigated the effect of CTE on human platelets. CTE inhibited platelet aggregation via down-regulation of thromboxane A₂ (TXA₂) by blocking cyclooxygenase-1 (COX-1) activity and intracellular Ca²⁺ mobilization in collagen-induced platelets. CTE also reduced the phosphorylation of phospholipase C (PLC) γ2 and syk. CTE regulated platelet aggregation via cyclic guanosine monophosphate (cGMP)-dependent phosphorylation of vasodilator-stimulated phosphoprotein (VASP) Ser²³⁹. In addition, administration of CTE (50 and 100 mg/kg) significantly reduced hyper-aggregated platelet aggregation by collagen (5 ㎍/mL) without hepatotoxicity in HFD (high fat diet)-fed rats. Taken together, these results suggest that CTE has anti-platelet effects both in vitro and in vivo. Therefore, CTE may be an effective therapeutic and preventive agent for cardiovascular disease, and is a safe and natural product.

• Korean Journal of Radiology
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• v.21 no.11
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• pp.1256-1264
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• 2020

Objective: Lung segmentation using volumetric quantitative computed tomography (CT) analysis may help predict outcomes of patients with coronavirus disease (COVID-19). The aim of this study was to investigate the relationship between CT volumetric quantitative analysis and prognosis in patients with COVID-19. Materials and Methods: CT images from patients diagnosed with COVID-19 from February 18 to April 15, 2020 were retrospectively analyzed. CT with a negative finding, failure of quantitative analysis, or poor image quality was excluded. CT volumetric quantitative analysis was performed by automated volumetric methods. Patients were stratified into two risk groups according to CURB-65: mild (score of 0-1) and severe (2-5) pneumonia. Outcomes were evaluated according to the critical event-free survival (CEFS). The critical events were defined as mechanical ventilator care, ICU admission, or death. Multivariable Cox proportional hazards analyses were used to evaluate the relationship between the variables and prognosis. Results: Eighty-two patients (mean age, 63.1 ± 14.5 years; 42 females) were included. In the total cohort, male sex (hazard ratio [HR], 9.264; 95% confidence interval [CI], 2.021-42.457; p = 0.004), C-reactive protein (CRP) (HR, 1.080 per mg/dL; 95% CI, 1.010-1.156; p = 0.025), and COVID-affected lung proportion (CALP) (HR, 1.067 per percentage; 95% CI, 1.033-1.101; p < 0.001) were significantly associated with CEFS. CRP (HR, 1.164 per mg/dL; 95% CI, 1.006-1.347; p = 0.041) was independently associated with CEFS in the mild pneumonia group (n = 54). Normally aerated lung proportion (NALP) (HR, 0.872 per percentage; 95% CI, 0.794-0.957; p = 0.004) and NALP volume (NALPV) (HR, 1.002 per mL; 95% CI, 1.000-1.004; p = 0.019) were associated with a lower risk of critical events in the severe pneumonia group (n = 28). Conclusion: CRP in the mild pneumonia group; NALP and NALPV in the severe pneumonia group; and sex, CRP, and CALP in the total cohort were independently associated with CEFS in patients with COVID-19.

• Journal of Preventive Medicine and Public Health
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• v.43 no.2
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• pp.151-158
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• 2010

Objectives: The aim of this study was to evaluate the association between cigarette smoking and total mortality, cancer mortality and other disease mortalities in Korean adults. Methods: A total of 14 161 subjects of the Korean Multi-center Cancer Cohort who were over 40 years of age and who were cancer-free at baseline enrollment reported their lifestyle factors, including the smoking status. The median follow-up time was 6.6 years. During the follow-up period from 1993 to 2005, we identified 1159 cases of mortality, including 260 cancer mortality cases with a total of 91 987 person-years, by the national death certificate. Cox proportional hazard regression model was used to estimate the hazard ratio (HR) of cigarette smoking for total mortality, cancer mortality and disease-specific mortality, as adjusted for age, gender, the geographic area and year of enrollment, the alcohol consumption status, the education level and the body mass index (BMI). Results: Cigarette smoking was significantly associated with an increased risk of total mortality, all-cancer mortality and lung cancer mortality (p-trend, < 0.01, <0.01, <0.01, respectively). Compared to non-smoking, current smokers were at a higher risk for mortality [HR (95% CI)=1.3 (1.1 - 1.5) for total mortality; HR (95% CI)=1.6 (1.1 -2.2) for all-cancer mortality; HR (95% CI)=3.9 (1.9-7.7) for lung cancer mortality]. Conclusions: This study's results suggest that cigarette smoking might be associated with total mortality, all-cancer mortality and especially lung cancer mortality among Korean adults.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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• pp.299-304
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• 2014

Cholangiocarcinoma (CCA), a malignancy of biliary duct with a very poor prognosis, is the leading cause of cancer death in countries of the Mekong subregion. Liver fluke infection is the main etiological factor, but genetic variation has been recognized as also important in conferring susceptibility to CCA risk. Nuclear factor (erythroid derived 2)-like 2 (NRF2) is a key transcription factor in detoxification and antioxidant defense. Emerging evidence has demonstrated that genetic polymorphisms in the NRF2 gene may be associated with cancer development. The objectives of this study were to investigate the association of NRF2 genetic polymorphism with CCA risk and to evaluate the influence of the NRF2 genotype on survival time of affected patients. Single nucleotide polymorphisms (SNPs) of the NRF2 gene, including rs6726395: A/G, rs2886161: C/T, rs1806649: C/T, and rs10183914: C/T, were analyzed using TaqMan$^{(R)}$ SNP genotyping assays. Among 158 healthy northeastern Thai subjects, the allele frequencies were 41, 62, 94, and 92%, respectively. The correlation of NRF2 SNPs and CCA risk was analyzed in the 158 healthy subjects and 198 CCA patients, using unconditional logistic regression. The results showed that whereas the NRF2 SNPs were not associated with CCA risk (p>0.05), Kaplan-Meier analysis of 88 intrahepatic CCA patients showed median survival time with rs6726395 genotypes of GG and AA/AG to be $344{\pm}138$ (95%CI: 73-615) days and $172{\pm}37$ (95%CI: 100-244) days, respectively, (p<0.006). On multivariate Cox proportional hazard analysis, the GG genotype of rs6726395 was found to be associated with longer survival with a hazard ratio of 0.54 (95%CI: 0.31-0.94). In addition, non-papillary adenocarcinoma was associated with poor survival with a hazard ratio of 2.09 (95%CI: 1.16-3.75). The results suggest that the NRF2 rs6726395 polymorphism can be a potential prognostic biomarker for CCA patients.