• Biomolecules & Therapeutics
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• 제32권4호
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• pp.481-491
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• 2024

Paxlovid is the first approved oral treatment for coronavirus disease 2019 and includes nirmatrelvir, a protease inhibitor targeting the main protease (M^pro) of SARS-CoV-2, as one of the key components. While some specific mutations emerged in M^pro were revealed to significantly reduce viral susceptibility to nirmatrelvir in vitro, there is no report regarding resistance to nirmatrelvir in patients and animal models for SARS-CoV-2 infection yet. We recently developed xenograft tumors derived from Calu-3 cells in immunodeficient mice and demonstrated extended replication of SARS-CoV-2 in the tumors. In this study, we investigated the effect of nirmatrelvir administration on SARS-CoV-2 replication. Treatment with nirmatrelvir after virus infection significantly reduced the replication of the parental SARS-CoV-2 and SARS-CoV-2 Omicron at 5 days post-infection (dpi). However, the virus titers were completely recovered at the time points of 15 and 30 dpi. The virus genomes in the tumors at 30 dpi were analyzed to investigate whether nirmatrelvir-resistant mutant viruses had emerged during the extended replication of SARS-CoV-2. Various mutations in several genes including ORF1ab, ORF3a, ORF7a, ORF7b, ORF8, and N occurred in the SARS-CoV-2 genome; however, no mutations were induced in the M^pro sequence by a single round of nirmatrelvir treatment, and none were observed even after two rounds of treatment. The parental SARS-CoV-2 and its sublineage isolates showed similar IC₅₀ values of nirmatrelvir in Vero E6 cells. Therefore, it is probable that inducing viral resistance to nirmatrelvir in vivo is challenging differently from in vitro passage.

• 한국방사선학회논문지
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• 제18권3호
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• pp.283-292
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• 2024

안와림프종의 전자선 치료 시 안구 부속기관의 방사선 부작용 및 합병증으로 인해 후낭하백내장 발생률이 높아질 수 있다. 이에 본 연구는 몬테카를로 전산모사를 활용하여 의료용 선형가속기와 안구의 수학적 모델을 모사하고, 안구 부속기관에 대한 선량평가와 수정체 차폐체 두께에 따른 안구 부속기관별 차폐율을 비교 분석하였다. 안구 부속기관의 선량평가 결과, 차폐체 미사용 시 선량을 기준으로 수정체의 민감 영역에서 가장 높은 흡수선량 분포를 보였으며, 그 외 수정체의 비민감 영역, 전방, 유리체, 각막, 눈꺼풀 순으로 점차 낮아지는 경향을 나타내었다. 차폐체 사용 시 선량 분석 결과, 2 mm 두께 사용 시 수정체의 민감 영역에서 90% 이상의 선량감소효과를 나타냈으며, 비민감 영역과 전방은 83% 이상, 유리체, 각막, 눈꺼풀에서는 30 ~ 62%의 선량감소효과를 보였다. 안와림프종의 전자선 치료 시 수정체 민감 영역의 선량 저감을 위해서는 최소 2 mm 이상의 차폐체 사용이 필요할 것으로 판단되며, 수정체 이외 안구 부속기관에 대한 차폐체 두께 및 면적을 고려한 차폐 방안이 필요할 것으로 사료된다.

• Animal Bioscience
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• 제37권2호
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• pp.193-202
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• 2024

Objective: Oxidative stress (OS) is a pathological process arising from the excessive production of free radicals in the body. It has the potential to alter animal gene expression and cause damage to the jejunum. However, there have been few reports of changes in the expression of long noncoding RNAs (lncRNAs) in the jejunum in piglets under OS. The purpose of this research was to examine how lncRNAs in piglet jejunum change under OS. Methods: The abdominal cavities of piglets were injected with diquat (DQ) to produce OS. Raw reads were downloaded from the SRA database. RNA-seq was utilized to study the expression of lncRNAs in piglets under OS. Additionally, six randomly selected lncRNAs were verified using quantitative real-time polymerase chain reaction (qRT-PCR) to examine the mechanism of oxidative damage. Results: A total of 79 lncRNAs were differentially expressed (DE) in the treatment group compared to the negative control group. The target genes of DE lncRNAs were enriched in gene ontology (GO) terms and Kyoto encyclopedia of genes and genomes (KEGG) signaling pathways. Chemical carcinogenesis-reactive oxygen species, the Foxo signaling pathway, colorectal cancer, and the AMPK signaling pathway were all linked to OS. Conclusion: Our results demonstrated that DQ-induced OS causes differential expression of lncRNAs, laying the groundwork for future research into the processes involved in the jejunum's response to OS.

• Journal of Korean Neurosurgical Society
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• 제67권1호
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• pp.84-93
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• 2024

Objective : We aimed to examine trends in critically ill neurology-neurosurgery (NNS) patients who were admitted to the intensive care unit (ICU) in South Korea and identify risk factors for in-hospital mortality after ICU admission in NNS patients. Methods : This nationwide population-based retrospective cohort study enrolled adult NNS adult patients admitted to the ICU from 2010 to 2019 extracted from the National Health Insurance Service in South Korea. The critically ill NNS patients were defined as those whose main admission departments were neurology or neurosurgery at ICU admission. The number of ICU admission, age, and total cost for hospitalization from 2010 to 2019 in critically ill NNS patients were examined as trend information. Moreover, multivariable logistic regression modeling was used to identify risk factors for in-hospital mortality among critically ill NNS patients. Results : We included 845474 ICU admission cases for 679376 critically ill NNS patients in South Korea between January 1, 2010 to December 31, 2019. The total number of ICU admissions among NNS patients was 79522 in 2010, which increased to 91502 in 2019. The mean age rose from 62.8 years (standard deviation [SD], 15.6) in 2010 to 66.6 years (SD, 15.2) in 2019, and the average total cost for hospitalization per each patient consistently increased from 6206.1 USD (SD, 5218.5) in 2010 to 10745.4 USD (SD, 10917.4) in 2019. In-hospital mortality occurred in 75455 patients (8.9%). Risk factors strongly associated with increased in-hospital mortality were the usage of mechanical ventilator (adjusted odds ratio [aOR], 19.83; 95% confidence interval [CI], 19.42-20.26; p<0.001), extracorporeal membrane oxygenation (aOR, 3.49; 95% CI, 2.42-5.02; p<0.001), and continuous renal replacement therapy (aOR, 6.47; 95% CI, 6.02-6.96; p<0.001). In addition, direct admission to ICU from the emergency room (aOR, 1.38; 95% CI, 1.36-1.41; p<0.001) and brain cancer as the main diagnosis (aOR, 1.30; 95% CI, 1.22-1.39; p<0.001) are also potential risk factors for increased in-hospital mortality. Conclusion : In South Korea, the number of ICU admissions increased among critically ill NNS patients from 2010 to 2019. The average age and total costs for hospitalization also increased. Some potential risk factors are found to increase in-hospital mortality among critically ill NNS patients.

• Korean Journal of Radiology
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• 제21권6호
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• pp.736-745
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• 2020

Objective: To identify the initial chest computed tomography (CT) findings and clinical characteristics associated with the course of coronavirus disease 2019 (COVID-19) pneumonia. Materials and Methods: Baseline CT scans and clinical and laboratory data of 72 patients admitted with COVID-19 pneumonia (39 men, 46.2 ± 15.9 years) were retrospectively analyzed. Baseline CT findings including lobar distribution, presence of ground glass opacities, consolidation, linear opacities, and lung severity score were evaluated. The outcome event was recovery with hospital discharge. The time from symptom onset to discharge or the end of follow-up (for those remained hospitalized) was recorded. Data were censored in events such as death or discharge without recovery. Multivariable Cox proportional hazard regression was used to explore the association between initial CT, clinical or laboratory findings, and discharge with recovery, whereby hazard ratio (HR) values < 1 indicated a lower rate of discharge at four weeks and longer time until discharge. Results: Thirty-two patients recovered and were discharged during the study period with a median length of admission of 16 days (range, 9 to 25 days), while the rest remained hospitalized at the end of this study (median, 17.5 days; range, 4 to 27 days). None died during the study period. After controlling for age, onset time, lesion characteristics, number of lung lobes affected, and bilateral involvement, the lung severity score on baseline CT (> 4 vs. ≤ 4 [reference]: adjusted HR = 0.41 [95% confidence interval, CI = 0.18-0.92], p = 0.031) and initial lymphocyte count (reduced vs. normal or elevated [reference]: adjusted HR = 0.14 [95% CI = 0.03-0.60], p = 0.008) were two significant independent factors that influenced recovery and discharge. Conclusion: Lung severity score > 4 and reduced lymphocyte count at initial evaluation were independently associated with a significantly lower rate of recovery and discharge and extended hospitalization in patients admitted for COVID-19 pneumonia.

• Korean Journal of Radiology
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• 제21권12호
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• pp.1326-1333
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• 2020

Objective: To evaluate urologist satisfaction on structured prostate MRI reports, including report with tumor-node-metastasis (TNM) staging (report B) and with Prostate Imaging Reporting and Data System (PI-RADS) score with/without TNM staging (report C, report with PI-RADS score only [report C-a] and report with PI-RADS score and TNM staging [C-b]) compared with conventional free-text report (report A). Materials and Methods: This was a prospective comparative study. Altogether, 3015 prostate MRI reports including reports A, B, C-a, and C-b were rated by 13 urologists using a 5-point Likert Scale. A questionnaire was used to assess urologist satisfaction based on the following parameters: correctness, practicality, and urologist subjectivity. Kruskal-Wallis H-test followed by Nemenyi test was used to compare urologists' satisfaction parameters for each report type. The rate of urologist-radiologist recalls for each report type was calculated. Results: Reports B and C including its subtypes had higher ratings of satisfaction than report A for overall satisfaction degree, and parameters of correctness, practicality, and subjectivity (p < 0.05). There was a significant difference between report B and C (p < 0.05) in practicality score, but no statistical difference was found in overall satisfaction degree, and correctness and subjectivity scores (p > 0.05). Compared with report C-b (p > 0.05), report B and C-a (p < 0.05) showed a significant difference in overall satisfaction degree and parameters of practicality and subjectivity. In terms of correctness score, neither report C-a nor C-b had a significant difference with report B (p > 0.05). No statistical difference was found between report C-a and C-b in overall satisfaction degree and all three parameters (p > 0.05). The rate of urologist-radiologist recalls for reports A, B, C-a and C-b were 29.1%, 10.8%, 18.1% and 11.2%, respectively. Conclusion: Structured reports, either using TNM or PI-RADS are highly preferred over conventional free-text reports and lead to fewer report-related post-hoc inquiries from urologists.

• 생명과학회지
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• 제34권2호
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• pp.94-104
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• 2024

β-lapachone은 다양한 유형의 질병을 치료하기 위해 남미 및 중미 지역의 전통 의학에서 널리 사용되어 온 Tabebuia vellanedae의 껍질에서 분리된 천연 퀴논 화합물의 일종이다. β-lapachone은 여러 유형의 암세포에서 강력한 항암 활성을 갖는 것으로 보고되었지만, 간세포암종 세포의 증식에 대한 효과는 아직 불분명하다. 따라서 본 연구에서는 β-lapachone 인간 간세포암종 Hep3B 세포의 증식에 미치는 영향을 조사하였으며, 본 연구의 결과에 의하면, β-lapachone 처리에 의한 Hep3B 세포의 세포생존율 감소는 세포사멸 유도와 밀접한 관련이 있었다. 또한, β-lapachone이 처리된 Hep3B 세포에서는 항세포사멸 인자인 Bcl-2의 발현이 감소한 반면, 세포사멸 유도 인자인 Bax의 발현은 증가하였으며, 이는 caspase cascade의 활성 증가와 연관성이 있었다. 그러나 pan-caspase 억제제가 존재하는 경우 β-lapachone에 의해 유발된 세포사멸은 약화되었으며, 이는 β-lapachone에 의한 세포사멸 유도가 caspase 의존적인 현상임을 의미한다. 아울러, β-lapachone의 처리는 ERK 경로를 활성화시키면서 PI3K/Akt 경로의 활성을 억제하였으며, β-lapachone 유도 세포사멸에 ERK 억제제의 효과는 미미했지만, PI3K 억제제는 β-lapachone에 의해 유도된 세포사멸을 유의하게 증가시켰다. 비록 생체 내 동물 모델에서의 확인이 필요하지만, 본 연구의 결과는 간세포암종 세포에서 β-lapa-chone의 항암 활성을 이해하는 데 유용한 자료로 활용될 것이다.

• Journal of Applied Biological Chemistry
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• 제66권
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• pp.39-45
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• 2023

Biorenovation은 미생물의 생체 촉매 대사를 통해 단일 화합물 또는 천연물을 생물 전환시켜 약리학적 효능을 증진시키고, 세포에 대한 독성을 완화시키는 기술이다. 접시꽃은 예로부터 한약으로 사용되어 왔으며, 항염증, 항암 등 다양한 생리학적 효능이 있다고 보고되고 있다. 또한, 본 연구에서 사용된 접시꽃캘러스는 손상부를 보호하기 위해 발달한 미분화 식물 조직으로, 항산화 및 미백 효과가 있는 것으로 보고되었지만 염증과 같은 다른 활성에 대한 연구는 아직 보고되지 않았다. 본 연구에서는 바이오리노베이션을 접시꽃 캘러스 추출물(ARBR)에 적용하여 RAW 264.7 대식세포에 대한 생물전환 추출물의 항염증 효능을 연구하였다. 그 결과 측정 농도(50, 100, 200 ㎍/mL)에서 세포에 대한 독성이 없었으며, 산화질소 생성 억제에 대한 효능이 기존 추출물에 비해 증진되었다. 또한, 프로스타글란딘 E₂와 전염증성 사이토카인, 고리형 산소화 효소, 산화질소의 유도 합성효소의 생성을 농도 의존적으로 억제하는 경향을 보였다. 이러한 결과를 바탕으로 ARBR이 과도하게 발현된 염증반응을 조절하여 기능성 화장품과 의약품의 소재로서 잠재력을 가지고 있음을 시사한다.

• Journal of Applied Biological Chemistry
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• 제66권
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• pp.122-127
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• 2023

심혈관 질환(CVD)은 전 세계적으로 주요 사망 원인으로써 갈수록 증가하는 추세이며, 혈관 손상이 발생하였을 때, 혈전이 과도하게 형성되는 것이 그 원인인 중 하나이다. 근래에 혈소판 억제를 통한 항혈전 물질에 대한 관심이 커지고 있으며 천연 생물활성 화합물을 사용함으로써 부작용을 줄이려는 노력이 이루어지고 있다. Flavonoid 중 하나로 알려진 hydroxygenkwanin(HGK)은 팥꽃나무(Daphne genkwa)에서 정제되는 물질로서 항균, 항염증 및 항암 효과가 있다고 알려져 있으며, 혈전증을 예방하는 조직 인자의 억제제 역할을 한다고 보고되었지만 항혈소판 효과와 그 작용기전에 대해서는 거의 알려지지 않았다. 본 연구를 통해 HGK가 collagen 유도의 사람 혈소판 응집에 미치는지 확인하였고, 그 작용 기전을 확인하였다. HGK은 혈소판 신호 전달 과정에서 PI3K/AKT 및 MAPK의 인산화를 억제하였고, ATP 및 serotonin 등의 혈소판 내 과립 분비를 감소하였다. . 또한, HGK는 cPLA₂의 인산화를 억제하며 응집 촉진물질인 TXA₂ 생성을 강하게 저해하였다. 결과적으로 응집 유도 물질인 collagen가 유도한 혈소판 응집을 86.36 µM의 IC₅₀로 강하게 억제하였다. 그러므로, 본 연구를 통해 HGK가 혈관 손상을 통해 일어나는 사람 혈소판의 활성화 및 응집을 억제하는 항혈전 물질로 가치가 있음을 분명히 하였다.

• Journal of Applied Biological Chemistry
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• 제66권
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• pp.272-281
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• 2023

작약 뿌리는 monoterpene glycoside계 물질을 함유하고 있으며, 이들 화합물은 항경련, 항염증, 항바이러스, 신경보호 및 진정효과를 나타내는 것으로 알려져 있다. 이번 연구에서는 작약 뿌리의 dichloromethane (CH₂Cl₂) 및 ethyl acetate (EtOAc) 가용성 분획으로부터 세포독성 물질을 탐색하고자 하였다. 그 결과, 총 13종의 화합물을 분리할 수 있었으며, 이들의 세포독성 평가를 위해 사람 유래 폐암 선암 세포주인 A549에 처리하여 세포생존율 변화를 관찰하였다. A549에 대한 세포독성은 gallic acid (8) > (2S)-naringenin (9) > methyl gallate (10) > 6'-Obenzoylpaeoniflorin (7) > palmitic acid (3) 순으로 나타났다. 특히, 7은 normal cell인 MRC-5에 대한 독성은 없는 것으로 확인되었으며, 7의 A549 및 MRC-5 세포생존율에 미치는 영향에 대한 보고는 이번이 처음이다. 향후 7에 대한 세포독성 메커니즘 및 선택성과 관련된 추가연구가 필요할 것으로 판단된다.