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[2,3-diamino-N-(4-(benzo[d]thiazol-2-yl)phenyl)propanamide], named as ETN101, is a novel therapeutic agent for hepatocellular carcinoma. In vitro studies examined ETN101 metabolites in human, mouse, rat, dog, and monkey hepatocytes and identified the drug-metabolizing enzymes involved using cDNA-expressed human recombinant cytochrome P450s (CYPs), carboxylesterases (CESs), N-acetyltransferase (NAT) 1, and human liver cytosol. ETN101 showed similar metabolic stability across hepatocytes from five species, with particularly comparable stability in humans, rats, and monkeys. Its half-life was 75.0 min in humans, 68.9 in rats, 73.1 in monkeys, 120.4 in mice, and 112.7 in dogs. Thirty-four ETN101 metabolites, including the major metabolite M1, were identified using liquid chromatography–high-resolution mass spectrometry. ETN101 was primarily metabolized to M1 and CYP1A2 is exclusively responsible for M1 metabolism. Both NAT1 and NAT2 were responsible for the N-acetylation of M1 to M2. ETN101 remained stable in human CESs. In conclusion, this study provides comprehensive insights into the metabolic characteristics of ETN101, valuable for its toxicological and clinical development.

Background: This study aimed to assess the feasibility and efficacy of neoadjuvant chemotherapy (NACT) in treating patients with high-grade neuroendocrine carcinoma of the uterine cervix (HGNEC). Methods: We performed a retrospective case-control study at Asan Medical Center, Seoul, Republic of Korea, from January 1993 to December 2017, involving 60 patients with surgically treated HGNEC. Thirteen patients (21.7%) received NACT before undergoing surgery. Regarding the comparison between the group that underwent NACT and the group that did not, we used a propensity score-matched analysis, matching 22 patients in the primary radical surgery group with 11 patients in the neoadjuvant chemotherapy followed by radical hysterectomy group. Results: In the entire cohort, primary open surgery was more common in the primary surgery group compared to the NACT group (p = 0.004). After propensity score matching (PSM), the median tumor size was 3.5 cm in the primary surgery group and 2.4 cm in the NACT group (p = 0.078). After matching, there was no significant difference in the recurrence rate between the two groups (63.6% in the primary surgery group vs. 63.6% in the neoadjuvant chemotherapy group, p = 0.782). After PSM, the primary surgery group exhibited a lower intraoperative transfusion rate (10%) than the NACT group (45.5%, p = 0.052). Conclusions: While NACT was feasible in patients with HGNEC, it did not significantly improve the survival rate over primary radical surgery.

Abstract Background The endocrine disruption of perfluorinated compounds is an emerging issue. We aimed to examine the association of serum perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) levels with incident diabetes and fasting serum glucose concentration. Methods This prospective cohort study was based on an urban-based cohort subpopulation from the Korean Genome and Epidemiology Study. Serum samples (600 µL) were received from 100 participants in the normoglycemic baseline survey (2004–2013), and concentrations of PFOA and PFOS were measured using mass spectrometry. The incidence of diabetes was tracked in the follow-up survey (2012–2016). Results The mean age was 56.4 years (men, 59%). The median serum PFOA and PFOS concentrations were 4.29 ng/mL and 9.44 ng/mL, respectively. PFOA and PFOS concentrations differed according to age, sex, and residential area. After 60 months, 23 patients had diabetes. Log-transformed PFOA (lnPFOA) and log-transformed PFOS (lnPFOS) were significantly higher in those who transitioned to diabetes than in those who did not (both p

Objective: The prognostic implications of DNA mismatch repair protein (MMRP) have not been determined in endometrial cancer. Therefore, in this study, we aimed to evaluate the clinicopathologic characteristics of DNA MMRP deficiency in endometrial cancer. Materials and methods: We examined the MMRP status of 206 patients with endometrial carcinomas, using immunohistochemistry, and analyzed their clinicopathologic factors and survival outcomes stratified by MMRP status using the Kaplan–Meier method and Cox regression analysis. Results: Forty-three cases were deficient for at least one MMRP (20.9%). Loss of MLH1 was the most common (13.1%), followed by MSH6 (7.8%). MMRP deficiency was significantly associated with lympho-vascular space invasion, deep myometrial invasion, and adjuvant treatment (P = 0.032, 0.041, and 0.047, respectively). MMRP-deficient patients had a better overall survival (OS), particularly at advanced cancer stages (III/IV) (100% vs. 73.7%, P = 0.170) or if they had received adjuvant treatment (100% vs. 86.7%, P = 0.087). Conclusion: Although MMRP deficiency was associated with unfavorable prognostic risk factors in endometrial cancer, we found a trend in favor of OS in MMRP-deficient patients. More studies are needed to confirm its prognostic implication.

Abstract Background Ovarian “seromucinous carcinoma” has been recently removed in 2020 5th Edition of WHO classification of Female Genital Tumors and is considered as a subtype of endometrioid carcinoma with mucinous differentiation, while “seromucinous borderline tumor” remains and exists as a distinct entity. Both diseases may be considered as no more same lineage. However, ovarian seromucinous borderline tumor (SMBT) is also one of the endometriosis-related neoplasm of ovary similar to endometrioid tumor, featuring that about 50% of ovarian SMBTs combine endometriosis. The present study was aimed to investigate whether the ovarian SMBTs are different in clinical features and molecular patterns, according to the presence of combined endometriosis. Results There were no statistical differences in clinical findings between two groups. There was also no significant difference in pregnancy outcomes and recurrence between two groups. In immunohistochemical patterns, there was a statistically significant difference in PAX2 and PAX8 expression between in ovarian SMBT with or without endometriosis (P = 0.016, P

Objectives Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by recurrent epistaxis, telangiectasia, and visceral arteriovenous malformations (AVMs). Activin A receptor-like type 1 (ACVRL1/ALK1) and endoglin (ENG) are the principal genes whose mutations cause HHT. No multicenter study has yet investigated correlations between genetic variations and clinical outcomes in Korean HHT patients. Methods Seventy-two members from 40 families suspected to have HHT based on symptoms were genetically screened for pathogenic variants of ACVRL1 and ENG. Patients with genetically diagnosed HHT were also evaluated. Results In the HHT genetic screening, 42 patients from 24 of the 40 families had genetic variants that met the pathogenic criteria (pathogenic very strong, pathogenic strong, pathogenic moderate, or pathogenic supporting) based on the American College of Medical Genetics and Genomics Standards and Guidelines for either ENG or ACVRL1: 26 from 12 families (50%) for ENG, and 16 from 12 families (50%) for ACVRL1. Diagnostic screening of 42 genetically positive HHT patients based on the Curaçao criteria revealed that 24 patients (57%) were classified as having definite HHT, 17 (41%) as having probable HHT, and 1 (2%) as unlikely to have HHT. Epistaxis was the most common clinical presentation (38/42, 90%), followed by visceral AVMs (24/42, 57%) and telangiectasia (21/42, 50%). Five patients (12%) did not have a family history of HHT clinical symptoms. Conclusion Only approximately half of patients with ACVRL1 or ENG genetic variants could be clinically diagnosed as having definite HHT, suggesting that genetic screening is important to confirm the diagnosis.

Abstract Ginseng (Panax ginseng Meyer) is commonly used as an herbal remedy worldwide. Few studies have explored the possible physiological changes in the liver although patients often self-medicate with ginseng preparations, which may lead to exceeding the recommended dose for long-term administration. Here, we analyzed changes in the hepatic proteins of mouse livers using quantitative proteomics after sub-chronic administration of Korean red ginseng (KRG) extract (control group and 0.5, 1.0, and 2.0 g/kg KRG) using tandem mass tag (TMT) 6‐plex technology. The 1.0 and 2.0 g/kg KRG groups exhibited signs of liver injury, including increased levels of aspartate transaminase (AST) and alanine aminotransferase (ALT) in the serum. Furthermore, serum glucose levels were significantly higher following KRG administration compared with the control group. Based on the upregulated proteins found in the proteomic analysis, we found that increased cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) levels promoted greater hydrogen sulfide (H2S) synthesis in the liver. This investigation provides novel evidence that sub-chronic administration of KRG can elevate H2S production by increasing protein expression of CBS and CSE in the liver.

We aimed to evaluate the clinical impact of shift patterns at work on gynecologic problems and the healthcare behavior of Korean nursing staff. We conducted a web-based survey for over two weeks in September 2021, involving female nursing staff, including nurses, nurses’ aides, and nursing assistants, working in five medical centers. The questionnaire included 40 questions on baseline characteristics, working information, and experiences with gynecologic problems and medical approaches. Overall, 885 nursing staffs participated in the survey, of the 1,904 who received the invitation with an online link of the survey. The response rate was 46.5%. Among the participants responding to all questions, 569 (64.4%) worked two or three shifts and 305 (34.5%) worked full-time. In women rotating two or three-shift patterns, irregular menstrual cycles (21.6% vs. 13.8%, p = 0.005), abnormal menstrual cycles (40.9% vs. 33.8%, p = 0.038), and dysmenorrhea (48.0% vs. 38.4%, p = 0.006) were more frequent than in those who worked full-time. The experience of visiting gynecologic clinics (47.5% vs. 44.1%, p = 0.332) and treating gynecologic conditions (33.4% vs. 29.3%, p = 0.211) did not differ according to the working patterns. However, diagnosis of gynecologic diseases was more frequent in women working full-time (36.4% vs. 29.7%, p = 0.043). The rates of screening (76.1% vs. 57.8%, p

Light-to-moderate alcohol drinking is associated with a low incidence of cardiovascular disease (CVD) via an elevation of high-density lipoproteins-cholesterol (HDL-C), particularly with the short-term supplementation of alcohol. However, there is no information on the change in the HDL qualities and functionalities between non-drinkers and mild drinkers in the long-term consumption of alcohol. This study analyzed the lipid and lipoprotein profiles of middle-aged Korean female non-drinkers, mild-drinkers, and binge-drinkers, who consumed alcohol for at least 10 years. Unexpectedly, the serum levels of HDL-C and apolipoprotein A-I (apoA-I) were decreased significantly depending on the alcohol amount; the binge-drinker group showed 18% and 13% lower HDL-C (p = 0.011) and apoA-I levels (p = 0.024), respectively, than the non-drinker group. Triglyceride (TG) and oxidized species, malondialdehyde (MDA), and low-density lipoproteins (LDL) levels were significantly elevated in the drinker groups. Interestingly, the binge-drinker group showed 1.4-fold higher (p = 0.020) cholesterol contents in HDL2 and 1.7-fold higher (p < 0.001) TG contents in HDL3 than those of the non-drinker group. The mild-drinker group also showed higher TG contents in HDL3 (p = 0.032) than the non-drinker group, while cholesterol contents were similar in the HDL3 of all groups. Transmission electron microscopy (TEM) showed that the non-drinker group showed a more distinct and clear particle shape of the LDL and HDL image with a larger particle size than the drinker group. Electrophoresis of LDL showed that the drinker group had faster electromobility with a higher smear band intensity and aggregation in the loading position than the non-drinker group. The HDL level of binge drinkers showed the lowest paraoxonase activity, the highest glycated extent, and the most smear band intensity of HDL and apoA-I, indicating that HDL quality and functionality were impaired by alcohol consumption. In conclusion, long-term alcohol consumption in middle-aged women, even in small amounts, caused a significant decrease in the serum HDL-C and apoA-I with atherogenic changes in LDL and HDL, such as an increase in TG and MDA content with a loss of paraoxonase activity.

Abstract Background Hematopoietic stem cell transplantation (HSCT) remains an important therapeutic option for many hematologic malignancies. Bone marrow harvesting from an appropriate donor must be conducted for hematopoietic stem cell transplantation (HSCT). Many previous studies show complications of the recipient after hematopoietic stem cell transplantation (HSCT). However, complications of the donor after bone marrow harvesting are rare. We here report a unique case of a patient who developed sacral nerve root injury after bone marrow harvesting. Case presentation A 26-year-old man was admitted to our medical center complaining of acute onset painful burning and tingling sensation at the left posterior thigh and calf. He was a bone marrow donor for his brother’s bone marrow transplantation. He had underwent a bone marrow harvesting procedure two days before admission as a bone marrow donor, using both posterior superior iliac spine (PSIS) as the puncture site. Pelvic magnetic resonance image (MRI) showed enhancement around the left S2 nerve root in T1 and T2-weighted images. Nerve conduction studies (NCS) revealed normal conduction velocity and amplitude on both lower extremities. Electromyography (EMG) presented abnormal spontaneous activity and neurogenic motor unit potentials on the S2-innervated intrinsic foot muscle and gastrocnemius, soleus muscle on the left. The patient was treated with pregabalin for pain control. The patient was followed up after 3, 6, and 12 months. Neuropathic pain improved to Visual Analogue Scale (VAS) 1, and recovery state was confirmed by re-innervation patterns of motor unit potentials in electromyography. Conclusion Bone marrow harvesting is a relatively safe procedure. However, variable complications may occur. Accurate anatomical knowledge and carefulness are required to avoid sacral nerve root injury when performing the bone marrow harvesting procedure.

Recombinant human epidermal growth factor (EGF) has been used to treat adult diabetic foot ulcers and pediatric burns by facilitating wound healing and epithelization, especially for elderly patients. Several formulation types of EGF from different expression hosts are clinically available, such as intralesional injection and topical application. On the other hand, no study has compared the in vivo efficacy of EGF products directly in terms of tissue regeneration and wound healing activity. The present study compared two commercial products, Heberprot-P75® and Easyef®, in terms of their tissue regeneration activity in adult zebrafish and the developmental speed of zebrafish embryos. Fluorescence spectroscopy showed that the two EGF products had different Trp fluorescence emission spectra: Easyef® showed a wavelength of maximum fluorescence (WMF) of 337 nm with weak fluorescence intensity (FI), while Heberprot-P75® showed WMF of 349 nm with a 4.1 times stronger FI than that of Easyef®. The WMF of Heberprot-P75® was quenched by adding singlet oxygen in ozonated oil, while the WMF of Easyef® was not quenched. Treatment with Heberprot-P75® induced greater embryo development speed with a higher survival rate after exposure to EGF in water and microinjection into embryos. Under normal diet (ND) consumption, Heberprot-P75® showed a 1.4 times higher tail fin regeneration activity than Easyef® during seven days from the intraperitoneal injection (10 μL, 50 μg/mL) after amputating the tail fin. Under ND consumption and diabetic condition caused by streptozotocin (STZ) treatment, Heberprot-P75® showed 2.1 times higher tail fin regeneration activity than Easyef® from the same injection and amputation protocol. Under a high-cholesterol diet (HCD) alone, Heberprot-P75® showed 1.2 times higher tail fin regeneration activity than the Easyef® group and PBS group from the same injection and amputation. Under diabetic conditions (STZ-injected) and HCD consumption, the Heberprot-P75® group showed 1.7 and 1.5 times higher tail fin regeneration activity than the Easyef® group and PBS group, respectively, with a distinct and clean regeneration pattern. In contrast, the Easyef® group and PBS group showed ambiguous regeneration patterns with a severe fissure of the tail fin, which is a typical symptom of a diabetic foot. In conclusion, Heberprot-P75® and Easyef® have different Trp fluorescence properties in terms of the WMF and fluorescence quenching. Treatment of Heberprot-P75® induced a greater developmental speed of zebrafish embryos in both water exposure and microinjection. Heberprot-P75® induced significantly higher wound healing and tissue regeneration activity than Easyef® and PBS in the presence or absence of diabetic conditions and cholesterol supplementation.

Objective: To determine the role of preoperative serum cancer antigen 125 (CA 125) in malignant ovarian germ cell tumors (MOGCTs). Materials and methods: Using information from medical databases of Asan Medical Center (Seoul, Korea), we investigated 161 patients with histologically diagnosed MOGCTs and whose preoperative serum CA 125 had been checked. We determined the optimal cutoff value of CA 125 as > 249.5 U/mL in MOGCTs using a receiver operating characteristic curve. Results: The median patient age was 24 years (range, 6–52 years). The most common histologic type was immature teratoma. Most patients had stage I disease. Thirty-two patients (19.9%) had elevated preoperative serum CA 125 levels over 249.5 U/mL. On univariate analysis, tumor size, advanced stage, the presence of ascites, ovarian surface involvement, and tumor rupture were significantly associated with elevated preoperative CA 125 levels (>249.5 U/mL). In the median follow-up time of 87 months (range, 9–271 months), 14 patients had a recurrence, and 5 died of the disease. Patients with an elevated serum preoperative CA 125 level (>249.5 U/mL) had poorer disease-free survival, but this was not statistically significant. However, elevated preoperative CA 125 (>249.5 U/mL) was significantly associated with poorer overall survival. Conclusions: Elevated preoperative serum CA 125 may have prognostic value in patients with MOGCTs. Keywords: CA-125 antigen, Ovarian germ cell cancer, Prognosis

Abstract Background Lymph node metastasis is a significant predictive factor for disease recurrence and survival in cervical cancer patients. Given the importance of lymph node metastasis, it is imperative that patients harboring metastasis are identified and can undergo appropriate treatment. Sentinel lymph node (SLN) mapping has drawn attention as a lymph node mapping technique. We evaluated the feasibility and efficacy of (SLN) mapping using indocyanine green (ICG) in cervical cancer. Methods We performed a single-center, retrospective study of 103 surgically treated cervical cancer patients who underwent SLN mapping. After using ICG to detect SLN during surgery, we removed the SLNs followed by laparoscopic or robotic-assisted radical surgery and bilateral pelvic lymphadenectomy. Results Stage IB1 was the most common (61.17%). At least one SLN was detected in all cases. Eighty-eight patients (85.44%) had bilateral pelvic SLNs. The mean number of SLN per patient was 2.34. The side-specific sensitivity was 71.43%, the specificity was 100%, the negative predictive value (NPV) was 93.98%, and the false negative rate (FNR) was 28.57%. In cases of tumors smaller than 2 cm with negative lymph node metastasis on imaging, the study revealed a side-specific sensitivity of 100%, a specificity of 100%, a NPV of 100%, and a FNR of 0%. Large tumor size (≥ 4 cm), a previous history of a loop electrosurgical excision procedure (LEEP), depth of invasion (≥ 50%), the microscopic parametrial (PM) invasion, and vaginal extension were significantly associated with the false-negative detection of SLN. Moreover, the microscopic PM invasion was the only risk factor of the false-negative detection of SLN in multivariate analysis. Conclusion SLN mapping with ICG in cervical cancer is feasible and has high detection rate. The sensitivity of 100% was high enough to perform SLN biopsy alone in an early stage in which the tumor is less than 2 cm, with no lymphadenopathy on image examination. However, for large or invasive tumors, we would have to be cautious about performing SLN biopsy alone. Trial registration Retrospectively registered 2017-0600.

Ozonated sunflower oil (OSO) has potent antimicrobial effects, making it useful for topical applications to treat various skin diseases. On the other hand, regarding mechanistic insight, the antioxidant activity and cytoprotective effects of OSO are relatively less known. The current study compared the antioxidant ability and protective ability of OSO on cells and embryos against oxidative stress, such as H2O2 and oxidized low-density lipoproteins (oxLDL), to investigate its potential applications for wound-healing and anti-infection. OSO showed potent radical scavenging activity and ferric ion reduction ability that was up to 35% and 42% stronger than sunflower oil (SO) as a control in a dose-dependent manner. Measurement of the wavelength-maximum fluorescence (WMF) of high-density lipoproteins (HDL) revealed different behavior between OSO and SO treatment (final 1–16%). The OSO treatment caused a 12 nm red shift of Trp movement from 345 nm (at 0%) to 357 nm (at 16%), while SO caused a 12 nm blue shift of Trp movement from 345 nm (at 0%) to 333 nm (at 16%). The fluorescence intensity of HDL3 was diminished remarkably by the OSO treatment by up to 80% from the initial level, while SO-treated HDL did not. OSO-treated HDL3 showed slower electromobility with stronger band intensity and bigger HDL particle sizes than those of SO-treated HDL3. The paraoxonase-1 (PON-1) activity of HDL3 was enhanced by a co-treatment of OSO that was up to 2.3 times higher than HDL3 alone in a dose-dependent manner, whereas the co-treatment of SO even inhibited the PON activity. The cell viability of RAW264.7 by the OSO treatment was 3.3 times higher than the SO treatment at a high dose range (from 10% to 50%, final). The OSO also exhibited more cytoprotective effects than SO in brain microglial cells in the presence of H2O2 (final 0.03%); treatment with OSO impeded apoptosis and reduced ROS production more than an SO treatment did. In the presence of H2O2 alone, 86 ± 5% of the embryos were killed by cell explosion after 24 h, but a co-treatment of OSO (final 4%) resulted in almost no embryo death (98% survivability). Injection of oxLDL (15 ng of protein) into zebrafish embryos caused acute death, while the co-injection of OSO (final 2%) resulted in 2.8 times higher survivability than oxLDL alone. These results suggest new effects of ozonated oil, such as enhanced antioxidant activity, more cytoprotective ability, and higher embryo protection against oxidative stress. These results may be useful in developing new methods for the quality control of ozonated oil and an assessment of its efficacy.

Background: Additional exercise therapy has been shown to positively affect acute stroke rehabilitation, which requires an effective method to deliver increased exercise. In this study, we designed a 4-week caregiver-supervised self-exercise program with videos, named “Self rehAbilitation Video Exercises (SAVE)”, to improve the functional outcomes and facilitate early recovery by increasing the continuity of rehabilitation therapy after acute stroke. Methods: This study is a non-randomized trial. Eighty-eight patients were included in an intervention group (SAVE group), who received conventional rehabilitation therapies and an additional self-rehabilitation session by watching bedside exercise videos and continued their own exercises in their rooms for 60 min every day for 4 weeks. Ninety-six patients were included in a control group, who received only conventional rehabilitation therapies. After 4 weeks of hospitalization, both groups assessed several outcome measurements, including the Berg Balance Scale (BBS), Modified Barthel Index (MBI), physical component summary (PCS) and the mental component summary of the Short-Form Survey 36 (SF-36), Mini-Mental State Examination, and Beck Depression Inventory. Results: Differences in BBS, MBI, and PCS components in SF-36 were more statistically significant in the SAVE group than that in the control group (p < 0.05). Patients in the SAVE group showed more significant improvement in BBS, MBI, and PCS components in SF-36 as compared to that in the control group. Conclusions: This evidence-based SAVE intervention can optimize patient recovery after a subacute stroke while keeping the available resources in mind.

This study examined university students' perceptions of older adults. The study employed the photovoice, analyzing visual data (photographs) and in-depth interviews conducted with five university students to capture more accurate and candid images of older adults. Themes from photographs, interviews, and focus group discussions were organized into three categories: study participants' negative 'otherization' of older adults, a critical awakening of 'discrimination and exclusion' in daily life, and the consciousness raising among young people who were used to 'otherizing'. Young adults who differed from older adults due to their decline in old age noticed various forms and degrees of discrimination and exclusion of older adults in daily life through photovoice experience. Moreover, young adults developed positive perspectives and recognized the strengths of the older adults. This study is unique in providing specific and practical insights into the co-existence of two generations. Our findings suggest that developing and implementing programs and policies that promote positive interaction between young and older generations will contribute to resolving inter-generational conflict and ageism.

Evogliptin ((R)-4-((R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)-piperazin-2-one), is a new dipeptidyl peptidase IV inhibitor used for the treatment of type II diabetes mellitus. The in vitro metabolic pathways of evogliptin were identified in human hepatocytes, liver microsomes, and liver S9 fractions using liquid chromatography-Orbitrap mass spectrometry (LC-HRMS). Five metabolites of evogliptin-4-oxoevogliptin (M1), 4(S)-hydroxyevogliptin (M2), 4(R)-hydroxyevogliptin (M3), 4(S)-hydroxyevogliptin glucuronide (M4), and evogliptin N-sulfate (M5)—were identified in human liver preparations by comparison with authentic standards. We characterized the cytochrome P450 (CYP) enzymes responsible for evogliptin hydroxylation to 4(S)-hydroxyevogliptin (M2) and 4(R)-hydroxyevogliptin (M3) and the UGT enzymes responsible for glucuronidation of 4(S)-hydroxyevogliptin (M2) to 4(S)-hydroxy-evogliptin glucuronide (M4). CYP3A4/5 played the major role in the hydroxylation of evogliptin to 4(S)-hydroxyevogliptin (M2) and 4(R)-hydroxyevogliptin (M3). Glucuronidation of 4(S)-hydroxy-evogliptin (M2) to 4(S)-hydroxyevogliptin glucuronide (M4) was catalyzed by the enzymes UGT2B4 and UGT2B7. These results suggest that the interindividual variability in the metabolism of evogliptin in humans is a result of the genetic polymorphism of the CYP and UGT enzymes responsible for evogliptin metabolism.

DWP16001 is currently in a phase 2 clinical trial as a novel anti-diabetes drug for the treatment of type 2 diabetes by selective inhibition of sodium-glucose cotransporter 2. This in vitro study was performed to compare the metabolism of DWP16001 in human, dog, monkey, mouse, and rat hepatocytes, and the drug-metabolizing enzymes responsible for the metabolism of DWP16001 were characterized using recombinant human cytochrome 450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes expressed from cDNAs. The hepatic extraction ratio of DWP16001 in five species ranged from 0.15 to 0.56, suggesting that DWP16001 may be subject to species-dependent and weak-to-moderate hepatic metabolism. Five phase I metabolites (M1–M5) produced by oxidation as well as three DWP16001 glucuronides (U1–U3) and two hydroxy-DWP16001 (M1) glucuronides (U4, U5), were identified from hepatocytes incubated with DWP16001 by liquid chromatography-high resolution mass spectrometry. In human hepatocytes, M1, M2, M3, U1, and U2 were identified. Formation of M1 and M2 from DWP16001 was catalyzed by CYP3A4 and CYP2C19. M3 was produced by hydroxylation of M1, while M4 was produced by hydroxylation of M2; both hydroxylation reactions were catalyzed by CYP3A4. The formation of U1 was catalyzed by UGT2B7, but UGT1A4, UGT1A9, and UGT2B7 contributed to the formation of U2. In conclusion, DWP16001 is a substrate for CYP3A4, CYP2C19, UGT1A4, UGT1A9, and UGT2B7 enzymes. Overall, DWP16001 is weakly metabolized in human hepatocytes, but there is a potential for the pharmacokinetic modulation and drug–drug interactions, involved in the responsible metabolizing enzymes of DWP16001 in humans.

Japan and Korea are the world's most aged and most rapidly aging nations. They both have low fertility rates, thereby intensifying the importance of social structures to aid a large, dependent population of older adults. Common strategies involve improving their social participation, which enhances their physical and mental health, so they are supporting society rather than being supported. Since the social participation rates in both countries are not as high as those of Western countries, it is critical to shed light on the factors related to social participation of the elderly.A secondary analyses were performed using Japanese and Korean data from the 2012 East Asia Social Survey (EASS), which includes nationally representative samples through random sampling. The analyses only include data from those 65 and older (Japan: N = 683, Korea: N = 362).Social participation is classified into four types: 1) no affiliation; 2) inactive participation; 3) active recreational; and 4) active social. The Japanese respondents had a higher participation rate than Koreans, but more Japanese were inactive. Though the rates of active participations were similar in both countries. Multinomial logistic regressions were conducted to examine the related factors among the four types of social participation. Basic attributes (e.g., living alone) and other factors (e.g., network size) were included as independent variables. The results show that larger non-family networks were linked with increased social participation in both societies. Men were more vulnerable to engaging in no social activities and at a higher risk of social isolation in both countries. One difference between the two nations is that among the Japanese, people with higher social orientations engage in more active social type participation.This study reveals that non-kin social networks are important for social participation in Japan and Korea.

[This corrects the article DOI: 10.1371/journal.pone.0194703.].

Loxoprofen (LOX) is a non-selective cyclooxygenase inhibitor that is widely used for the treatment of pain and inflammation caused by chronic and transitory conditions. Its alcoholic metabolites are formed by carbonyl reductase (CR) and they consist of trans-LOX, which is active, and cis-LOX, which is inactive. In addition, LOX can also be converted into an inactive hydroxylated metabolite (OH-LOXs) by cytochrome P450 (CYP). In a previous study, we reported that CYP3A4 is primarily responsible for the formation of OH-LOX in human liver microsomes. Although metabolism by CYP3A4 does not produce active metabolites, it can affect the conversion of LOX into trans-/cis-LOX, since CYP3A4 activity modulates the substrate LOX concentration. Although the pharmacokinetics (PK) and metabolism of LOX have been well defined, its CYP-related interactions have not been fully characterized. Therefore, we investigated the metabolism of LOX after pretreatment with dexamethasone (DEX) and ketoconazole (KTC), which induce and inhibit the activities of CYP3A, respectively. We monitored their effects on the PK parameters of LOX, cis-LOX, and trans-LOX in mice, and demonstrated that their PK parameters significantly changed in the presence of DEX or KTC pretreatment. Specifically, DEX significantly decreased the concentration of the LOX active metabolite formed by CR, which corresponded to an increased concentration of OH-LOX formed by CYP3A4. The opposite result occurred with KTC (a CYP3A inhibitor) pretreatment. Thus, we conclude that concomitant use of LOX with CYP3A modulators may lead to drug−drug interactions and result in minor to severe toxicity even though there is no direct change in the metabolic pathway that forms the LOX active metabolite.

Catalposide, an active component of Veronica species such as Catalpa ovata and Pseudolysimachion lingifolium, exhibits anti-inflammatory, antinociceptic, anti-oxidant, hepatoprotective, and cytostatic activities. We characterized the in vitro metabolic pathways of catalposide to predict its pharmacokinetics. Catalposide was metabolized to catalposide sulfate (M1), 4-hydroxybenzoic acid (M2), 4-hydroxybenzoic acid glucuronide (M3), and catalposide glucuronide (M4) by human hepatocytes, liver S9 fractions, and intestinal microsomes. M1 formation from catalposide was catalyzed by sulfotransferases (SULTs) 1C4, SULT1A1*1, SULT1A1*2, and SULT1E1. Catalposide glucuronidation to M4 was catalyzed by gastrointestine-specific UDP-glucuronosyltransferases (UGTs) 1A8 and UGT1A10; M4 was not detected after incubation of catalposide with human liver preparations. Hydrolysis of catalposide to M2 was catalyzed by carboxylesterases (CESs) 1 and 2, and M2 was further metabolized to M3 by UGT1A6 and UGT1A9 enzymes. Catalposide was also metabolized in extrahepatic tissues; genetic polymorphisms of the carboxylesterase (CES), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes responsible for catalposide metabolism may cause inter-individual variability in terms of catalposide pharmacokinetics.

Alteration in the number and composition of intestinal microbiota affects the metabolism of several xenobiotics. Gastrodin, isolated from Gastrodia elata, is prone to be hydrolyzed by intestinal microbiota. In the present study, the role of intestinal microbiota in gastrodin metabolism was investigated in vitro and in vivo. Gastrodin was incubated in an anaerobic condition with intestinal contents prepared from vehicle- and antibiotics-treated rats and the disappearance of gastrodin and formation of 4-hydroxybenzyl alcohol (4-HBA) was measured by liquid chromatography coupled to mass spectroscopy (LC-MS/MS). The results showed that almost all gastrodin incubated with control intestinal contents was metabolized to its aglycone in time- and concentration-dependent manners. In contrast, much less formation of 4-HBA was detected in intestinal contents from antibiotics-treated rats. Subsequently, in vivo pharmacokinetic study revealed that the antibiotic pretreatment of rats significantly affected the metabolism of gastrodin to 4-HBA. When administered orally, gastrodin was rapidly absorbed rapidly into plasma, metabolized to 4-HBA, and disappeared from the body within six hours. Interestingly, the pharmacokinetic parameters of 4-HBA were changed remarkably in antibiotics-treated rats, compared to control rats. The results clearly indicated that the antibiotics treatment of rats suppressed the ability of intestinal microbiota to metabolize gastrodin to 4-HBA and that, thereby, the pharmacodynamic action was significantly modulated.

25B-NBF, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-fluorobenzyl)ethanamine, is a new psychoactive substance classified as a phenethylamine. It is a potent agonist of the 5-hydroxytryptamine receptor, but little is known about its metabolism and elimination properties since it was discovered. To aid 25B-NBF abuse screening, the metabolic characteristics of 25B-NBF were investigated in human hepatocytes and human cDNA-expressed cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes using liquid chromatography⁻high resolution mass spectrometry. At a hepatic extraction ratio of 0.80, 25B-NBF was extensively metabolized into 33 metabolites via hydroxylation, O-demethylation, bis-O-demethylation, N-debenzylation, glucuronidation, sulfation, and acetylation after incubation with pooled human hepatocytes. The metabolism of 25B-NBF was catalyzed by CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, and UGT2B7 enzymes. Based on these results, it is necessary to develop a bioanalytical method for the determination of not only 25B-NBF but also its metabolites in biological samples for the screening of 25B-NBF abuse.

Outgrowth endothelial cells (OECs) are a subpopulation of endothelial progenitor cells (EPCs) that have the capacity for proliferation and the ability to promote angiogenesis. In this study, we identified Nectin-2 as a surface protein of OECs through unbiased quantitative proteomics analysis. Using immunocytochemistry and flow cytometry, we confirmed that Nectin-2 is highly expressed on OECs. Nectin-2 (CD112) expression was limited or lower on mononuclear cells (MNCs) and mature tube-forming endothelial cells (ECs). Blocking Nectin-2 with a neutralizing monoclonal antibody significantly increased the trans-well migration and tube forming capacity of OECs. Similarly, Nectin-2 knockdown resulted in enhanced tube formation, cell migration and proliferation with p-Erk activation. Moreover, Nectin-2 deficiency resulted in compensatory increase of other Nectin family genes including Nectin-3 and Necl-4 which promote VEGFR signaling. These results indicate that Nectin-2 is a surface marker and an important regulator of OECs, with significant implications for the isolation of OECs and blocking Nectin-2 on OECs by an antibody for angiogenic applications.

Stauntonia hexaphylla leaf extract (YRA-1909), which is widely used for the antirheumatic properties, has been under phase 2 clinical trials in patients with rheumatoid arthritis since April 2017. Liquid chromatography-tandem mass spectrometric method while using liquid–liquid extraction with ethyl acetate was validated for the simultaneous determination of the major active components of YRA-1909, including chlorogenic acid (CGA), neochlorogenic acid (NCGA), cryptochlorogenic acid (CCGA), and their metabolites (i.e., caffeic acid (CA), caffeic acid 3-O-glucuronide (CA-3-G), caffeic acid 4-O-glucuronide (CA-4-G), and ferulic acid (FA)) in rat plasma and applied to a pharmacokinetic study of YRA-1909 in rats. Seven analytes were separated on Halo C18 while using gradient elution of formic acid and methanol, and then quantified in selected reaction monitoring mode whle using negative electrospray ionization. Following oral administration of YRA-1909 at doses of 25, 50, and 100 mg/kg to male Sprague-Dawley rats, CGA, NCGA, and CCGA were rapidly absorbed and metabolized to CA, CA-3-G, and CA-4-G. The area under the plasma concentration-time curve (AUClast) of CGA, NCGA, CCGA, and three metabolites linearly increased as the YRA-1909 dose increased. Other pharmacokinetic parameters were comparable among three doses studied. AUClast values for CA, CA-3-G, and CA-4-G exceeded those for CGA, NCGA, and CCGA.

Tuberculosis is one of the top causes of death among curable infectious diseases; it is an airborne infectious disease that killed 1.1 million people worldwide in 2010. Anti-tuberculosis drug-induced liver injury is the primary cause of drug-induced liver injury (DILI). Rifampicin is one of the most common anti-tuberculosis therapies and has well-known hepatotoxicity. To understand the mechanism of rifampicin-induced liver injury, we performed a global proteomic analysis of liver proteins by LC-MS/MS in a mouse model after the oral administration of 177 and 442.5 mg/kg rifampicin (LD10 and LD25) for 14 days. Based on the biochemical parameters in the plasma after rifampicin treatment, the hepatotoxic effect of rifampicin in the mouse liver was defined as a mixed liver injury. In the present study, we identified 1101 proteins and quantified 1038 proteins. A total of 29 and 40 proteins were up-regulated and 27 and 118 proteins were down-regulated in response to 177 and 442.5 mg/kg rifampicin, respectively. Furthermore, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to characterize the mechanism of rifampicin-induced hepatotoxicity. In the molecular function category, glutathione transferase activity was up-regulated and proteins related to arachidonic acid metabolism were down-regulated. In the KEGG pathway enrichment-based clustering analysis, the peroxisome proliferator-activated receptor-γ (PPARγ) signaling pathway, cytochrome P450, glutathione metabolism, chemical carcinogenesis, and related proteins increased dose-dependently in rifampicin-treated livers. Taken together, this study showed in-depth molecular mechanism of rifampicin-induced liver injury by comparative toxicoproteomics approach.

Magnolin, epimagnolin A, dimethyllirioresinol, eudesmin, and fargesin are pharmacologically active tetrahydrofurofuranoid lignans found in Flos Magnoliae. The inhibitory potentials of dimethyllirioresinol, epimagnolin A, eudesmin, fargesin, and magnolin on eight major human cytochrome P450 (CYP) enzyme activities in human liver microsomes were evaluated using liquid chromatography–tandem mass spectrometry to determine the inhibition mechanisms and inhibition potency. Fargesin inhibited CYP2C9-catalyzed diclofenac 4’-hydroxylation with a Ki value of 16.3 μM, and it exhibited mechanism-based inhibition of CYP2C19-catalyzed [S]-mephenytoin 4’-hydroxylation (Ki, 3.7 μM; kinact, 0.102 min−1), CYP2C8-catalyzed amodiaquine N-deethylation (Ki, 10.7 μM; kinact, 0.082 min−1), and CYP3A4-catalyzed midazolam 1’-hydroxylation (Ki, 23.0 μM; kinact, 0.050 min−1) in human liver microsomes. Fargesin negligibly inhibited CYP1A2-catalyzed phenacetin O-deethylation, CYP2A6-catalyzed coumarin 7-hydroxylation, CYP2B6-catalyzed bupropion hydroxylation, and CYP2D6-catalyzed bufuralol 1’-hydroxylation at 100 μM in human liver microsomes. Dimethyllirioresinol weakly inhibited CYP2C19 and CYP2C8 with IC50 values of 55.1 and 85.0 μM, respectively, without inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, and CYP3A4 activities at 100 μM. Epimagnolin A, eudesmin, and magnolin showed no the reversible and time-dependent inhibition of eight major CYP activities at 100 μM in human liver microsomes. These in vitro results suggest that it is necessary to investigate the potentials of in vivo fargesin-drug interaction with CYP2C8, CYP2C9, CYP2C19, and CYP3A4 substrates.

Although ketoconazole (KCZ) has been used worldwide for 30 years, its metabolic characteristics are poorly described. Moreover, the hepatotoxicity of KCZ limits its therapeutic use. In this study, we used liquid chromatography–mass spectrometry-based metabolomics to evaluate the metabolic profile of KCZ in mouse and human and identify the mechanisms underlying its hepatotoxicity. A total of 28 metabolites of KCZ, 11 of which were novel, were identified in this study. Newly identified metabolites were classified into three categories according to the metabolic positions of a piperazine ring, imidazole ring, and N-acetyl moiety. The metabolic characteristics of KCZ in human were comparable to those in mouse. Moreover, three cyanide adducts of KCZ were identified in mouse and human liver microsomal incubates as “flags” to trigger additional toxicity study. The oxidation of piperazine into iminium ion is suggested as a biotransformation responsible for bioactivation. In summary, the metabolic characteristics of KCZ, including reactive metabolites, were comprehensively understood using a metabolomics approach.

AM-2201 is a synthetic cannabinoid that acts as a potent agonist at cannabinoid receptors and its abuse has increased. However, there are no reports of the inhibitory effect of AM-2201 on human cytochrome P450 (CYP) or uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. We evaluated the inhibitory effect of AM-2201 on the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six major human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) enzymes in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry to investigate drug interaction potentials of AM-2201. AM-2201 potently inhibited CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP3A4-catalyzed midazolam 1′-hydroxylation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation, and UGT2B7-catalyzed naloxone 3-glucuronidation with IC50 values of 3.9, 4.0, 4.3, and 10.0 μM, respectively, and showed mechanism-based inhibition of CYP2C8-catalyzed amodiaquine N-deethylation with a Ki value of 2.1 μM. It negligibly inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, UGT1A1, UGT1A4, UGT1A6, and UGT1A9 activities at 50 μM in human liver microsomes. These in vitro results indicate that AM-2201 needs to be examined for potential pharmacokinetic drug interactions in vivo due to its potent inhibition of CYP2C8, CYP2C9, CYP3A4, UGT1A3, and UGT2B7 enzyme activities.

Aschantin is a bioactive neolignan found in Magnolia flos with antiplasmodial, Ca2+-antagonistic, platelet activating factor-antagonistic, and chemopreventive activities. We investigated its inhibitory effects on the activities of eight major human cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes of human liver microsomes to determine if mechanistic aschantin–enzyme interactions were evident. Aschantin potently inhibited CYP2C8-mediated amodiaquine N-de-ethylation, CYP2C9-mediated diclofenac 4′-hydroxylation, CYP2C19-mediated [S]-mephenytoin 4′-hydroxylation, and CYP3A4-mediated midazolam 1′-hydroxylation, with Ki values of 10.2, 3.7, 5.8, and 12.6 µM, respectively. Aschantin at 100 µM negligibly inhibited CYP1A2-mediated phenacetin O-de-ethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated bupropion hydroxylation, and CYP2D6-mediated bufuralol 1′-hydroxylation. At 200 µM, it weakly inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A6-catalyzed N-acetylserotonin glucuronidation, and UGT1A9-catalyzed mycophenolic acid glucuronidation, with IC50 values of 131.7, 144.1, and 71.0 µM, respectively, but did not show inhibition against UGT1A3, UGT1A4, or UGT2B7 up to 200 µM. These in vitro results indicate that aschantin should be examined in terms of potential interactions with pharmacokinetic drugs in vivo. It exhibited potent mechanism-based inhibition of CYP2C8, CYP2C9, CYP2C19, and CYP3A4.

The Korean Society of Gynecologic Oncology (KSGO) had been making an effort to standardize and enhance the quality of domestic uterine corpus cancer treatment by developing updated clinical practice guidelines in 2021. The KSGO revised the guidelines based on a literature search using 4 key elements: Population, Intervention, Comparison, and Outcome framework. These elements include the evaluation of the efficacy and safety of immune checkpoint inhibitor treatment in recurrent/advanced endometrial cancer patients who have failed platinum-based chemotherapy, as well as the effect of combined treatment with trastuzumab in patients with HER2/neu-positive endometrial cancer. Additionally, the guideline assessed the efficacy and safety of omitting lymph node dissection in low-risk endometrial cancer patients, investigated the effect of sentinel lymph node mapping in early-stage endometrial cancer surgery, addressed the outcome of chemoradiation therapy as a postoperative treatment in patients with advanced (stage III-IVA) endometrial cancer, and explored the impact of initial treatment with immune checkpoint inhibitors on survival in patients with advanced or recurrent endometrial cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: Elderly patients with degenerative diseases undergo treatment for the hip and spine; these patients present with various symptoms. This study focused on patients with residual symptoms, predominantly pain, even after receiving treatment for their spinal lesions. Materials and Methods: Patients who underwent total hip arthroplasty (THA) between 2016 and 2022 at a single tertiary hospital were included in the study. Of the 417 patients who underwent primary THA, a retrospective review of 40 patients with previous lesions of the spine was conducted. Patients were stratified to two cohorts: Patients with symptoms related to the spine (Group A), and those with hip-related symptoms (Group B). Preand postoperative comparisons of groups A and B were performed. Results: Improvements in patients' symptoms were observed in groups A and B after THA. In Group A, the mean preoperative visual analog scale (VAS) score was 5.10±0.876, which showed a postoperative decrease to 2.70±1.767. In Group B, the mean preoperative VAS score was 5.10±1.539, which showed a postoperative decrease to 2.67±1.493. Conclusion: According to the findings, promising results were achieved with THA in treatment of debilitating diseases of the hip for both the prognosis of the disease, as well as the patients' symptoms. In addition, in some cases elderly patients with dual pathologies underwent treatment for spinal lesions without performance of any evaluation related to the hip. Thus, evaluation of a patient's hip must be performed and performance of THA in patients with symptoms even after treatment of spinal lesions is recommended. [ABSTRACT FROM AUTHOR]