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Anthocyanins from Hibiscus syriacus L. Attenuate LPS-Induced Inflammation by Inhibiting the TLR4-Mediated NF-κB Signaling Pathway

  • Karunarathne, Wisurumuni Arachchilage Hasitha Maduranga;Molagoda, Ilandarage Menu Neelaka;Lee, Kyoung Tae;Choi, Yung Hyun;Kang, Chang-Hee;Jeong, Jin-Woo;Kim, Gi-Young
    • Proceedings of the Plant Resources Society of Korea Conference
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    • 2019.10a
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    • pp.92-92
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    • 2019
  • Excessive or chronic inflammation contributes to the pathogenesis of many inflammatory diseases such as sepsis, rheumatoid arthritis, and ulcerative colitis. Hibiscus syriacus L. has been used as a medicinal plant in many Asian countries, even though its anti-inflammatory activity has been unclear. Therefore, we investigated the anti-inflammatory effect of anthocyanin fractions from the H. syriacus L. varieties Pulsae (PS) on the lipopolysaccharide (LPS)-induced expression of proinflammatory mediators and cytokines in RAW264.7 macrophages. PS suppressed LPS-induced nitric oxide (NO) and prostaglandin $E_2$ ($PGE_2$) secretion concomitant with downregulation of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) expression. Furthermore, PS inhibited the production of proinflammatory cytokines such as tumor necrosis factor-alpha ($TNF-{\alpha}$), interleukin-6 (IL-6), and IL-12 in LPS-stimulated RAW264.7 macrophages. Further study showed that PS significantly decreased LPS-induced nuclear translocation of the nuclear $factor-{\kappa}B$ ($NF-{\kappa}B$) subunits, p65 and p50. Molecular docking data showed that many anthocyanins from PS fit into the hydrophobic pocket of MD2 and bound to Toll-like receptor 4 (TLR4), indicating that PS inhibits the TLR4-MD2-mediated inflammatory signaling pathway. Especially, apigenin-7-O-glucoside most powerfully bound to MD2 and TLR4 through LYS122, LYS122, and SER127 at a distance of $2.205{\AA}$, $3.098{\AA}$, and $2.844{\AA}$ and SER441 at a distance of $2.873{\AA}$ (docking score: -8.4) through hydrogen bonding, respectively. Additionally, PS inhibited LPS-induced TLR4 dimerization/expression on the cell surface, which consequently decreased MyD88 recruitment and IRAK4 phosphorylation. PS completely blocked LPS-mediated mortality in zebrafish larvae by diminishing the recruitment of neutrophil and macrophages accompanied by low levels of proinflammatory cytokines. Taken together, our results indicate that PS attenuates LPS-mediated inflammation in both in vitro and in vivo by blocking the TLR4/MD2-MyD88/IRAK4-$NF-{\kappa}B$ axis. Therefore, PS might be used as a novel modulatory candidate for effective treatment of LPS-mediated inflammatory diseases.

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Leverage and Corporate Failure: Analysis of Leverage Impact according to Company Size through Survival Analysis (레버리지와 기업실패: 생존분석을 응용한 기업규모에 따른 레버리지 영향분석)

  • Kim, Bong-Min;Kim, Byoung-Gon;Kim, Dong-Wook
    • Journal of the Korea Academia-Industrial cooperation Society
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    • v.22 no.1
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    • pp.275-284
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    • 2021
  • Survival analysis was used to analyze whether there is a difference in the effect of leverage on corporate failure according to the firm size. A total of 25,250 (year-company) companies listed on the Korea Stock Exchange and KOSDAQ market from 1999 to 2019 were analyzed. First, the increase in leverage generally acts as a factor that increases the possibility of corporate failure. On the other hand, the increase in the trade payable ratio lowered the possibility of failure of the company. The increase in corporate trade payable was perceived as a factor in reducing the possibility of corporate failure because it was considered the active development of business activities or active use of interest-free debt rather than leading to an increase in corporate risk. Second, a higher leverage ratio and trade payable ratio in large firms lowered the possibility of corporate failure. In the SMEs, all types of leverage increases are a factor that increases corporate failure. Overall, the effect of leverage on corporate failure differs according to the size of the company.

Trade Payable and Corporate Failure: Analysis of Trade Payable Impact according to Company Size through Survival Analysis (매입채무와 기업실패: 생존분석을 응용한 기업규모에 따른 매입채무 영향분석)

  • Kim, Bong-Min;Kim, So Ra
    • Journal of the Korea Academia-Industrial cooperation Society
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    • v.22 no.6
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    • pp.283-290
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    • 2021
  • Survival analysis was used to determine whether there are differences in the impact of trade payables on business failure according to the size of the company. A total of 41,781 firms from 1999 to 2019 were analyzed. The analysis period was divided into the entire period and before and after the financial crisis. The trade payable ratio is a proxy variable. The increase in trade payables over the entire period increases the possibility of business failure of Small and Medium Enterprises (SMEs). However, in large firms, a significant relationship between the increase in the trade payable ratio and the possibility of corporate failure could not be confirmed. Second, in SMEs during the sub-periods of 1999-2007 and 2009-2019, it was found that an increase in trade payables acts as a factor that increases the possibility of corporate failure. However, in large corporations, the increase in trade payables in the period from 2009 to 2019 has been shown to reduce the rate of failure. An increase in trade payables is recognized as the active development of business activities or the active use of interest-free debt. Therefore, it was confirmed that the impact of trade payables on corporate failure differs depending on the size of the company.

The Association between Mortality and the Oxygen Saturation and Fraction of Inhaled Oxygen in Patients Requiring Oxygen Therapy due to COVID-19-Associated Pneumonia

  • Choi, Keum-Ju;Hong, Hyo-Lim;Kim, Eun Jin
    • Tuberculosis and Respiratory Diseases
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    • v.84 no.2
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    • pp.125-133
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    • 2021
  • Background: The coronavirus disease (COVID-19) can manifest in a range of symptoms, including both asymptomatic systems which appear nearly non-existent to the patient, all the way to the development of acute respiratory distress syndrome (ARDS). Specifically, COVID-19-associated pneumonia develops into ARDS due to the rapid progression of hypoxia, and although arterial blood gas analysis can assist in halting this deterioration, the current environment provided by the COVID-19 pandemic, which has led to an overall lack of medical resources or equipment, has made it difficult to administer such tests in a widespread manner. As a result, this study was conducted in order to determine whether the levels of oxygen saturation (SpO2) and the fraction of inhaled oxygen (FiO2) (SF ratio) can also serve as predictors of ARDS and the patient's risk of mortality. Methods: This was a retrospective cohort study conducted from February 2020 to Mary 2020, with the study's subjects consisting of COVID-19 pneumonia patients who had reached a state of deterioration that required the use of oxygen therapy. Of the 100 COVID-19 pneumonia cases, we compared 59 pneumonia patients who required oxygen therapy, divided into ARDS and non-ARDS pneumonia patients who required oxygen, and then investigated the different factors which affected their mortality. Results: At the time of admission, the ratios of SpO2, FiO2, and SF for the ARDS group differed significantly from those of the non-ARDS pneumonia support group who required oxygen (p<0.001). With respect to the predicting of the occurrence of ARDS, the SF ratio on admission and the SF ratio at exacerbation had an area under the curve which measured to be around 85.7% and 88.8% (p<0.001). Multivariate Cox regression analysis identified that the SF ratio at exacerbation (hazard ratio [HR], 0.916; 95% confidence interval [CI], 0.846-0.991; p=0.029) and National Early Warning Score (NEWS) (HR, 1.277; 95% CI, 1.010-1.615; p=0.041) were significant predictors of mortality. Conclusion: The SF ratio on admission and the SF ratio at exacerbation were strong predictors of the occurrence of ARDS, and the SF ratio at exacerbation and NEWS held a significant effect on mortality.

Atractylenoide II Isolated from Atractylodes macrocephala Inhibited Inflammatory Responses in Lipopolysaccharide-induced RAW264.7 Macrophages and BV2 Microglial Cells (백출에서 분리된 Atractylenolide II의 RAW264.7 대식세포와 BV2 미세아교세포에서의 항염증 효과)

  • Jin, Hong-Guang;Kim, Kwan-Woo;Li, Jing;Im, Hyeri;Lee, Dae Young;Yoon, Dahye;Jeong, Jin Tae;Kim, Geum-Soog;Oh, Hyuncheol;An, Ren-Bo;Kim, Youn-Chul
    • Korean Journal of Pharmacognosy
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    • v.51 no.4
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    • pp.244-254
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    • 2020
  • Atractylodes macrocephala is a perennial herb and is a member of the Compositae family. This plant is known to contain various bioactive constituents indicating anti-inflammatory, neuroprotective, anti-oxidant, immunological enhancement, and gastroprotective effects. In this investigation, we isolated four compounds with similar chemical structures from A. macrocephala, and evaluated their anti-inflammatory effects. Among the four compounds, compound 2(atractylenolide II) showed the second-best inhibitory effect on the lipopolysaccharide(LPS)-induced production of nitric oxide in RAW264.7 macrophages and BV2 microglial cells. Compound 2 also inhibited the LPS-induced the production of prostaglandin E2(PGE2), and the expression of inducible nitric oxide synthase(iNOS) and cyclooxygenase(COX)-2 proteins in both cells. In addition, compound 2 suppressed the production of pro-inflammatory cytokines including interleukin(IL)-1β, IL-6, and tumor necrosis factor(TNF)-α. These inhibitory effects were contributed by inactivation of nuclear factor kappa B(NF-κB) and mitogen-activated protein kinases(MAPKs) pathways by treatment with compound 2. This compound did not induce the expression of heme oxygenase(HO)-1 protein indicating that the anti-inflammatory effect of compound 2 was independent with HO-1 protein. Taken together, these results suggested that atractylenolide II can be a candidate material to treat inflammatory diseases.

Interaction Effects between Individual Socioeconomic Status and Regional Deprivation on Onset of Diabetes Complication and Diabetes-Related Hospitalization among Type 2 Diabetes Patients: National Health Insurance Cohort Sample Data from 2002 to 2013 (개인의 사회경제적 수준과 지역의 사회경제적 수준의 상호작용이 제2형 당뇨 환자에서 당뇨합병증 발생 및 당뇨와 관련된 입원에 미치는 영향: 2002-2013년 국민건강보험공단 표본 코호트 자료를 활용하여)

  • Jang, Jieun;Ju, Yeong Jun;Lee, Doo Woong;Lee, Sang Ah;Oh, Sarah Soyeon;Choi, Dong-Woo;Lee, Hyeon Ji;Shin, Jaeyong
    • Health Policy and Management
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    • v.31 no.1
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    • pp.114-124
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    • 2021
  • Background: In this study, we aimed to investigate the interaction effects of individual socioeconomic status and regional deprivation on the onset of diabetes complications and diabetes-related hospitalization among type 2 diabetes patients. Methods: Korean National Health Insurance Service National Sample Cohort data from 2002 to 2013 were used. A total of 50,954 patients newly diagnosed with type 2 diabetes from 2004 to 2012 and aged 30 years or above were included. We classified patients into six groups according to individual income level and neighborhood deprivation: 'high in advantaged,' 'high in disadvantaged,' 'middle in advantaged,' 'middle in disadvantaged,' 'low in advantaged,' and 'low in disadvantaged.' We calculated hazard ratios (HR) of onset of diabetes complication and diabetes-related hospitalization using the Cox proportional hazard model, with the reference group as diabetes patients with high income in advantaged regions. Results: In terms of the interaction effects of individual income level and regional socioeconomic level, even with the same low individual income level, the group with a high regional socioeconomic level (low in advantaged) showed low HRs for the onset of diabetes complication (HR, 1.04; 95% confidence interval [CI], 1.00-1.08) compared to the 'low in disadvantaged' group (HR, 1.10; 95% CI, 1.05-1.16). In addition, the 'high in advantaged' group showed slightly higher HRs for the onset of diabetes complication (HR, 1.06; 95% CI, 1.00-1.11) compared to the 'low in advantaged' and it appeared to be associated with slight mitigation of the risk of diabetes complication. For the low-income level, the patients in disadvantaged regions showed the highest HRs for diabetes-related hospitalization (HR, 1.29; 95% CI, 1.19-1.41) compared to the other groups. Conclusion: Although we need to perform further investigations to reveal the mechanisms that led to our results, interaction effects individual socioeconomic status and regional deprivation might be associated with on onset of diabetes complications and diabetes-related hospitalization among type 2 diabetes patients.

Lagerstroemia ovalifolia Exerts Anti-Inflammatory Effects in Mice of LPS-Induced ALI via Downregulating of MAPK and NF-κB Activation

  • Min, Jae-Hong;Kim, Seong-Man;Park, JI-Won;Kwon, Nam Hoon;Goo, Soo Hyeon;Ngatinem, Ngatinem;Ningsih, Sri;Paik, Jin-Hyub;Choi, Sangho;Oh, Sei-Ryang;Han, Sang-Bae;Ahn, Kyung-Seop;Lee, Jae-Won
    • Journal of Microbiology and Biotechnology
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    • v.31 no.11
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    • pp.1501-1507
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    • 2021
  • Lagerstroemia ovalifolia Teijsm. & Binn. (LO) (crape myrtle) has reportedly been used as traditional herbal medicine (THM) in Java, Indonesia. Our previous study revealed that the LO leaf extract (LOLE) exerted anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Based on this finding, the current study aimed to evaluate the protective effects of LOLE in a mouse model of LPS-induced acute lung injury (ALI). The results showed that treatment with LPS enhanced the inflammatory cell influx into the lungs and increased the number of macrophages and the secretion of the inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) of mice. However, these effects were notably abrogated with LOLE pretreatment. Furthermore, the increase of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1) expression in the lung tissues of mice with ALI was also reversed by LOLE. In addition, LOLE significantly suppressed the LPS-induced activation of the MAPK/NF-κB signaling pathway and led to heme oxygenase-1 (HO-1) induction in the lungs. Additionally, in vitro experiments showed that LOLE enhanced the expression of HO-1 in RAW264.7 macrophages. The aforementioned findings collectively indicate that LOLE exerts an ameliorative effect on inflammatory response in the airway of ALI mice.

A Review of Studies on Chuna Manual Therapy for Low Back Pain through Korean Database Search (국내 데이터베이스 검색을 통한 요통의 추나의학적 치료에 대한 연구동향 분석)

  • Yim, Min-Young;Park, Han-Byeol;Kim, Jae-Soo;Lee, Hyun-Jong;Lim, Sung-Chul;Lee, Yun-Kyu
    • The Journal of Churna Manual Medicine for Spine and Nerves
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    • v.16 no.2
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    • pp.55-67
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    • 2021
  • Objectives This review aimed to investigate studies of Chuna manual therapy (CMT) for low back pain and the evidence of their effects in order to suggest a better research method in the future. Methods We investigated studies on CMT for low back pain by searching Korean web databases from 2020 to 2021. As a result, 72 research papers were analyzed according to their published year, the titles of journals, the types of studies, the techniques of Chuna, and the instruments used for assessment. Results The results were as follows: 1. There were three papers published initially in 2000. this number showed a steady increase, and a total of 72 papers were published that year. 2. Studies on CMT were mainly published in the Journal of Korea Chuna Manual Medicine for Spine and Nerves. 3. When categorized according to the methods of studies, a simple case report was used more often than the sum of randomized controlled trials (RCTs) and non-RCTs. 4. The most frequently adopted technique of Chuna in the examined studies was the COX flexion and distraction technique. 5. The Visual Analog Scale and Oswestry Disability Index were used as primary means of assessment. Conclusions Based on the analysis, it was observed that this review provided limited evidence of CMT use in patients with LBP. Therefore, further investigation using well-designed RCTs is required to obtain higher evidence.

Ki67 Index Is the Most Powerful Factor for Predicting the Recurrence in Atypical Meningioma : Retrospective Analysis of 99 Patients in Two Institutes

  • Lee, Sang Hyuk;Lee, Eun Hee;Sung, Kyoung Su;Kim, Dae Cheol;Kim, Young Zoon;Song, Young Jin
    • Journal of Korean Neurosurgical Society
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    • v.65 no.4
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    • pp.558-571
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    • 2022
  • Objective : The primary objective of this study was to identify predicting factors for local control (LC) of atypical meningioma, and we validated them with comparing the predicting factors for recurrence-free survival (RFS). We also examined the rate of LC after surgical resection with or without adjuvant treatment and RFS. Methods : Clinical and radiological records of patients with atypical meningiomas diagnosed at two institutes from January 2000 to December 2018 were reviewed retrospectively. Histopathological features were also reviewed using formalin-fixed paraffin embedded samples from pathological archives. Results : Of the 99 atypical meningiomas eligible for analysis, 36 (36.4%) recurred during the follow-up period (mean, 83.3 months; range, 12-232 months). The rate of 3-year LC and 5-year LC was 80.8% and 74.7%, respectively. The mean time-to-recurrence was 49.4 months (range, 12-150). The mean RFS was 149.3 months (95% confidence interval, 128.8-169.8 months) during the mean follow-up duration of 83.3 months (range, 12-232 months). Multivariate analysis using Cox proportional-hazard regression model showed that the extent of resection (hazard ratio [HR], 4.761; p=0.013), Ki67 index (HR, 8.541; p=0.004), mitotic index (HR, 3.275; p=0.044), and tumor size (HR, 3.228; p=0.041) were independently associated with LC. These factors were also statistically associated with RFS. In terms of radiotherapy after surgical resection, the recurrence was not prevented by immediate radiotherapy because of the strong effect of proliferative index on recurrence. Conclusion : The present study suggests that the extent of resection, proliferative index (according to Ki67 expression) and mitotic index, and tumor size are associated with recurrence of atypical meningiomas. However, our results should be further validated through prospective and randomized clinical trials to overcome the inborn bias of retrospective nature of the study design.

Anti-inflammatory effect of soil blue-green algae Nostoc commune isolated from Daejeon National Cemetery (국립대전현충원에서 분리한 남조류 구슬말(Nostoc commune)의 항염증 효과)

  • Hong, Hyehyun;Bae, Eun Hee;Park, Tae-Jin;Kang, Min-Sung;Kang, Jae Shin;Chi, Won-Jae;Kim, Seung-Young
    • Journal of Applied Biological Chemistry
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    • v.65 no.2
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    • pp.113-120
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    • 2022
  • We examined the anti-inflammatory properties of Nostoc commune HCW0811 in lipopolysaccharide-stimulated RAW264.7 macrophage cells. The anti-inflammatory activity of HCW0811 on viability of treated cells was assessed by measuring the level of expression of NO, prostaglandin E2 and pro-inflammatory cytokines, namely interleukin-1β, interleukin-6, and tumor necrosis factor-α in HCW0811 treated RAW 264.7 macrophages. HCW0811 was non-toxic to cells and inhibited the production of cytokines in a concentration-dependent manner. In addition its treatment suppressed the production of pro-inflammatory cytokines in a dose-dependent manner, and concomitantly decreased the protein expressions of inducible NO synthase and cyclooxygenase-2. Moreover, the levels of the phosphorylation of mitogen-activated protein kinase family proteins such as extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, and nuclear factor kappa B were reduced by HCW0811. These findings suggest that the HCW0811 collected from Daejeon National Cemetery have anti-inflammatory effects, and demonstrated its efficacy in cell-based in vitro assays.