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Nayoung Han,1,2 Jung Mi Oh,1,3 In-Wha Kim1 1Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; 2College of Pharmacy, Jeju National University, Jejusi, Jeju Special Self-Governing Province, Republic of Korea; 3College of Pharmacy, Seoul National University, Seoul, Republic of KoreaCorrespondence: In-Wha KimResearch Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of KoreaTel +82 2 880-7736Fax +82 2 882-9560Email iwkim2@hanmail.netPurpose: The purpose of this study was to investigate the adverse events (AEs) related to the use of off-label drugs.Materials and Methods: A cross-sectional study was carried out using available data pertaining to off-label drug were sourced from U.S. FDA spontaneous adverse drug reaction reporting database (FAERS) and Korea Adverse Event Reporting System database (KIDS-KD) for the years 2014 to 2018. The number and frequencies of AE cases were calculated. Disproportionality was analyzed using the proportional reporting ratio (PRR), the reporting odds ratio (ROR), the information component (IC), and the empirical Bayes geometric mean (EBGM) methods.Results: The reported AEs associated with off-label drug use were more common among older patients compared with younger patients. Gastric nonspecific symptoms and therapeutic procedure (4.16– 4.57%) and haemorrage term (4.16– 5.29%) were the most common AE symptoms and antithrombotic agents and immunosuppressants were the drugs most commonly reported to cause AEs in FAERS. Secondary term events (43.45– 48.62%) including inappropriate schedule of drug administration and medication error were the most common AEs, and immunosuppressants and antipsychotics were the most common AE-related drugs from KIDS-KD. The numbers of reported AEs in new drug categories such as other antineoplastic agents trended to increase from 2014 to 2018 in both datasets.Conclusion: The numbers of reported AEs with off-label drug increased annually. AEs associated with off-label drugs may have a significant impact on older patients. Healthcare experts should be concerned about prescriptions of off-label drugs, especially anticoagulants and newly developed drugs such as immunosuppressants and antineoplastic agents.Keywords: off-label use, adverse events, adverse drug reaction reporting systems, disproportionality

Kyungim Kim,1,2,* Jinyoung Jung,2,* Haesook Kim,3 Jung Tae Kim,4 Jung Mi Oh,5 Hyunah Kim6,7 1College of Pharmacy, Korea University, Sejong, Republic of Korea; 2Institute of Pharmaceutical Science, Korea University, Sejong, Republic of Korea; 3Department of Pharmacy, Gang Neung Asan Hospital, Gangneung, Republic of Korea; 4Department of Pharmacy, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea; 5College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; 6College of Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea; 7Drug Information Research Institute, College of Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea*These authors contributed equally to this workCorrespondence: Hyunah KimCollege of Pharmacy, Sookmyung Women’s University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul, 04310, Republic of KoreaTel +82-2-2077-7961Email hyunah@sookmyung.ac.krPurpose: The purpose of this study was to evaluate the incidence of the administration of potentially inappropriate medications (PIMs) and the potential drug–drug interactions (pDDIs) in older patients in emergency departments (EDs) over a 12-month period and to identify the factors associated with the administration of PIMs.Patients and Methods: This retrospective study was conducted using the electronic medical records from two university-affiliated teaching hospitals in South Korea. ED visit cases of patients aged 65 and older from January 1, 2013, to December 31, 2013, were included in the analysis. Among the medications administered in ED, PIMs or pDDIs were identified using a drug utilization review program available in Korea.Results: During the study period, a total of 13,002 ED visit cases were reported from 10,686 patients. The proportion of ED visit cases with any PIM was 79.2% and the average number of PIMs was 2.7 (range, 1– 17). The most commonly administered PIMs that were contraindicated or should have been used with caution were ketorolac (41.3%) and metoclopramide (10.3%), respectively. Multivariate regression analysis indicated that female patients (p = 0.012), patients with more than six drugs in the ED (p < 0.001), and visits longer than 300 minutes (p = 0.026) were significantly associated with PIM administration in the ED. Potential DDIs between the medications administered in EDs were observed in 20.5% of total visit cases, with ketorolac being the most frequently reported drug in contraindicated drug combinations.Conclusion: This study demonstrated a high incidence of the administration of PIMs and medications with pDDIs in older patients in EDs and revealed the characteristics that are significantly associated with an increased risk of PIM administration. Healthcare providers in EDs should consider the risk of administering PIMs or medications with pDDIs, especially when treating older patients.Keywords: emergency department, older adults, potentially inappropriate medications, drug–drug interactions, drug utilization review

Eunhee Ji,1,* Myeong Gyu Kim,2,* Jung Mi Oh3 1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Republic of Korea; 2Graduate School of Clinical Pharmacy, CHA University, Pocheon 11160, Republic of Korea; 3College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea *These authors contributed equally to this work Purpose: Liver transplantation is the treatment of choice for patients with end-stage liver disease. Due to the between- and within-individual pharmacokinetic variability in tacrolimus, used to prevent rejection after transplantation, it is difficult to predict the dose needed achieve the target levels in the blood. This study aimed to construct a population pharmacokinetic model of tacrolimus dosage prediction for therapeutic drug monitoring in clinical settings for Korean adult patients receiving living donor liver transplantation (LDLT).Methods: A total of 58 Korean adult patients receiving LDLT with tacrolimus administration were enrolled. Demographic, clinical, and CYP3A5*1/*3 polymorphism data were collected. Population pharmacokinetic modeling of tacrolimus during the first 14 days after transplantation was performed using NONMEM program. Parameters were estimated by the first-order conditional estimation with interaction method. The internal validation of the final model was assessed by the bootstrap and visual predictive check methods using 500 samples from the original data.Results: One-compartmental model was selected as a base model. After the stepwise covariate model building process, postoperative day (POD) and combinational CYP3A5 genotype of the recipient and donor were incorporated into clearance (CL/F). The estimated typical values of CL/F and volume of distribution (V/F) were 6.33 L/h and 465 L, respectively. The final model was CL/F =6.33× POD0.257×2.314 (if CYP3A5 expresser recipient grafted from CYP3A5 expresser donor) ×1.523 (if CYP3A5 expresser recipient grafted from CYP3A5 nonexpresser donor) and V/F =465× POD0.322.Conclusion: A population pharmacokinetic model for tacrolimus was established successfully in Korean adult patients receiving LDLT. This model is expected to contribute to improving patient outcomes by optimizing tacrolimus dose adjustment for liver transplant patients. Keywords: tacrolimus, dosage prediction, living donor liver transplantation, CYP3A5, population pharmacokinetics, nonlinear mixed-effects modeling

Madhusmita Dhupal,1,2 Jae-Min Oh,3 Dipti Ranjan Tripathy,4 Soo-Ki Kim,2 Sang Baek Koh,5 Kyu-Sang Park6 1Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea; 2Department of Microbiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea; 3Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Wonju, Republic of Korea; 4Department of Neurology, Gauhati Medical College and Hospital, Gauhati, India; 5Department of Preventive Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea; 6Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea Background: Titanium dioxide nanoparticles (TiO2 NPs) represent a scientific breakthrough in the areas of biological and medicinal applications. Interaction of TiO2 NPs with components of innate immune system remains elusive. Aim: This study explored in vitro immunotoxicity of murine macrophage RAW 264.7 to TiO2 NPs (20 nm, negative charge) and its underlying molecular mechanism by way of immunoredox profiling. Materials and methods: In this study, chemically synthesized BSA-functionalized TiO2 NPs (20 nm, negative charge) were characterized and immunotoxicity was investigated on RAW 264.7 cells. Results: We found that reactive oxygen species levels significantly increased with increasing nitric oxide production, whereas depleting endogenous antioxidant super oxide dismutase as well as nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels. Furthermore, NPs exposure increased the expression of apoptotic factors such as BAX, BIM, and PUMA with disruption of mitochondrial membrane potential (ΔΨm) that lead to decrease in immunocytes. Molecular immune profiling revealed the activation of multiple toll-like receptors (TLRs) 4/9/12/13 simultaneously with the phosphorylation of p-p38MAPK and p-SAPK/c-Jun N-terminal kinase (JNK) compared to untreated control. Conclusion: Collectively, this study shows that the molecular nature of TiO2SA20(-) NP-induced immunotoxicity in RAW 264.7 macrophage is simultaneous induction of immunocyte apoptosis and multiple TLRs signaling through oxidative stress-dependent SAPK/JNK and p38 mitogen-associated protein kinase activation. This is the first study to address newer molecular mechanism of TiO2SA20(-) NP-induced immunotoxicity. Keywords: titanium dioxide, toll-like receptors, MAPK pathways, apoptosis, nanoparticles, oxidative stress

Ha Young Jang,1 Yun-Kyoung Song,1 Jae Hyun Kim,1 Myeong Gyu Kim,1 Nayoung Han,1 Hae-Young Lee,2 In-Wha Kim,1 Jung Mi Oh1 1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 2Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea Purpose: The objective of this study was to evaluate the association between depression and change in coronary heart disease (CHD) risk status by an analysis of examination data in the general Korean population.Patients and methods: We examined 1,851 men and 1,689 women (aged 43–73 years) for the Korean Genome and Epidemiology Study Ansan between 2005 and 2012. The estimated CHD risk score of participants was calculated using the Framingham CHD risk score in baseline and after 8-year follow-up period. Among them, population with low Framingham CHD risk score (

Nayoung Han,1,* Seung Hee Han,1,2,* Yun-Kyoung Song,1 Myeong Gyu Kim,1 Yon Su Kim,3,4 In-Wha Kim,1,* Jung Mi Oh1,* 1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 2Department of Pharmacy, Asan Medical Center, Seoul, 3Department of Internal Medicine, Seoul National University Hospital, Seoul, 4College of Medicine, Seoul National University, Seoul, Republic of Korea *These authors contributed equally to this work Background: Lipid abnormalities are prevalent in tacrolimus-treated patients. The aim of the study was to evaluate the preventive effects of statin therapy on major adverse cardiovascular events (MACE) in patients treated with tacrolimus-based immunosuppression after kidney transplantation (KT), and to identify the risk factors. Methods: This observational cohort study included adult patients who underwent KT and were treated with tacrolimus. Patients who received any lipid-lowering agents except statins, or had a history of immunosuppressant use before transplantation were excluded. The primary outcome was the adjusted risk of the first occurrence of MACE. The secondary outcomes included the risk of individual cardiovascular disease (CVD) and changes in cholesterol level. Subgroup analyses were performed in the statin-user group according to the dosage and/or type of statin. Results: Compared with the control group (n=73), the statin-users (n=92) had a significantly reduced risk of MACE (adjusted HR, 0.31; 95% CI, 0.13–0.74). In the Cox regression analysis, old age, history of CVD, and comorbid hypertension were identified as independent factors associated with increased MACE. The total cholesterol levels were not significantly different between the two groups. Subjects with higher cumulative defined daily dose of statins had significantly lower risks of MACE. Conclusion: Statin therapy in patients treated with tacrolimus after KT significantly lowered the risk of MACE. Long-term statin therapy is clearly indicated in older kidney transplant recipients for secondary prevention. Keywords: kidney transplantation, tacrolimus, HMG-CoA reductase inhibitors, major adverse cardiovascular events (MACE)

Nayoung Han,1,* Su Hyun Hong,1,2,* Yon Su Kim,3 Dong Ki Kim,3 In-Wha Kim,1 Eunhee Ji,4 Jung Mi Oh1 1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 2Pharmaceutical Standardization Division, Drug Evaluation Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Chungcheongbuk-do, 3Division of Nephrology, Department of Internal Medicine, Seoul National University Hospital, Seoul, 4College of Pharmacy, Gachon University, Incheon, Republic of Korea *These authors contributed equally to this work Background: The purpose of the present study was to determine the effect of additional calcium carbonate treatment on fibroblast growth factor 23 (FGF23) levels in patients treated with calcitriol.Methods: In this randomized, open-labeled, and parallel-group study, a total of 30 patients with early chronic kidney disease (CKD) and vitamin D deficiency were randomly assigned to two groups and received interventions for 8 weeks: 1) a combination of calcium carbonate and calcitriol group; and 2) calcitriol only group. The primary outcome was the difference in percentage change of serum FGF23 levels from baseline between the two groups. Secondary end points included the changes in serum levels of calcium, phosphate, parathyroid hormone (PTH), and 25-hydroxyvitamin D3 (25(OH)D) from baseline.Results: Serum FGF23 levels were more elevated in the combination group than in the calcitriol-alone group. However, both mean change and percentage change in the serum FGF23 levels during the 8-week period were not significantly different between the two groups. Serum calcium level was increased significantly only in the combination treatment group. There was no significant difference in percentage change of serum calcium levels between the two groups. In addition, changes in serum levels of phosphate, 25(OH)D, or PTH were not significantly different between the two groups. In correlation analysis, changes in serum FGF23 levels were positively correlated with changes in serum calcium and phosphate levels, but not with changes in 25(OH)D or PTH levels. No serious adverse events were observed, however, there was one case of mild gastrointestinal discomfort.Conclusion: This study revealed that additional calcium carbonate treatment significantly increased serum FGF23 levels in patients treated with calcitriol, with their synergistic effect in promoting intestinal calcium absorption. This suggests that serum FGF23 levels should be monitored regularly, especially in those who use combination of vitamin D and calcium carbonate from the early stages of CKD. Keywords: fibroblast growth factor-23, vitamin D deficiency, calcium carbonate, calcitriol, mineral and bone disorder

JiEun Kang,1,2,* Kiyon Rhew,3,* Jung Mi Oh,4 NaYoung Han,4 Iyn-Hyang Lee,5 Nam Kyung Je,6 Eunhee Ji,7 Euni Lee,4 Jeong-Hyun Yoon,6 Sandy Jeong Rhie1 1Division of Life and Pharmaceutical Sciences Graduate School, Ewha Womans University, Seoul, Republic of Korea; 2Department of Pharmacy, National Medical Center, Seoul, Republic of Korea; 3College of Pharmacy, Dongduk Women’s University, Seoul, Republic of Korea; 4College of Pharmacy, Seoul National University, Seoul, Republic of Korea; 5College of Pharmacy, Yeungnam University, Gyeongbuk, Republic of Korea; 6College of Pharmacy, Pusan National University, Busan, Republic of Korea; 7College of Pharmacy, Gachon University, Incheon, Republic of Korea *These authors contributed equally to this work Purpose: To assess the degree of satisfaction and expressed needs of pharmaceutical care services in patients with chronic diseases and explore the factors related to the needs from patients’ perspectives for the further development of pharmaceutical care service models. Patients and methods: A cross-sectional survey of 220 patients (mean age ± SD: 61.3±13.1, male:female: 104:116) was conducted. The questionnaire was structured to measure patients’ degree of satisfaction and expressed needs using a 5-point Likert scale. Additionally, preferred duration, methods of service delivery, and willingness to pay were surveyed. Responses were analyzed using an ordinal regression method to predict factors that were related to pharmaceutical care services. Results: Sixty-seven patients had experienced pharmaceutical care services. Their satisfaction levels were high in all categories; however, there were no significant differences between ­categories. The levels of expressed needs were similar among categories without significant differences. The preferred delivery method was a face-to-face conversation combined with being provided with written information (53.2%). The preferred duration was ≤10 min (70.5%). About 48% of the patients showed willingness to pay for the service. Education level and region influenced patients’ needs. Conclusion: The satisfaction and needs of pharmaceutical care services was very positive; however, noticing only a third of patients experienced pharmaceutical care services, this may indicate a lack of awareness and less appreciation of pharmacists by patients. Details concerning patients’ awareness and the value of pharmaceutical care services require further investigation. Keywords: pharmaceutical care service, satisfaction, needs, patient perspective

Myeong Gyu Kim, Minoh Ko, In-Wha Kim, Jung Mi Oh College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea Abstract: A meta-analysis was conducted to decide whether to reduce an initial 6-mercaptopurine (6-MP) dose in TPMT heterozygote in the case of an initial 6-MP dose of

Sohyun Jeong,1 In-Wha Kim,1 Kook-Hwan Oh,2 Nayoung Han,1 Kwon Wook Joo,2 Hyo Jin Kim,2 Jung Mi Oh1 1College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, 2Department of Internal Medicine, Division of Nephrology, Seoul National University Hospital, Seoul, Korea Background: Secondary hyperparathyroidism (SHPT) is one of the major risk factors of morbidity and mortality in end-stage renal disease. Cinacalcet effectively controls SHPT without causing hypercalcemia and hyperphosphatemia. However, there is significant inter-individual response variance to cinacalcet treatment. Therefore, we aimed to evaluate the genetic effects related with parathyroid hormone regulation as factors for cinacalcet response variance. Methods: Patients with a diagnosis of SHPT based on intact parathyroid hormone (iPTH) >300 pg/mL on dialysis were included in this study. They were over 18 years and have been treated by cinacalcet for more than 3 months. Responders and nonresponders were grouped by the serum iPTH changes. Twenty-four single nucleotide polymorphisms of CASR, VDR, FGFR1, KL, ALPL, RGS14, NR4A2, and PTHLH genes were selected for the pharmacogenetic analysis. Results: After adjusting for age, sex, and calcium level, CASR rs1042636 (odds ratio [OR]: 0.066, P=0.027) and rs1802757 (OR: 10.532, P=0.042) were associated with cinacalcet response. The association of haplotypes of CASR rs1042636, rs10190, and rs1802757; GCC (OR: 0.355, P=0.015); and ATT (OR: 2.769, P=0.014) with cinacalcet response was also significant. Conclusion: We obtained supporting information of the associations between cinacalcet response and CASR polymorphisms. CASR single nucleotide polymorphisms (SNPs) rs1802757, rs1042636, and haplotypes of rs1042636, rs10190, and rs1802757 were significantly associated with cinacalcet response variance. Keywords: CASR, calcium sensing receptor, SHPT, genetic polymorphisms, haplotype, single nucleotide polymorphisms

Sohyun Jeong, Jae Hyun Kim, Myeong Gyu Kim, Nayoung Han, In-Wha Kim, Therasa Kim, Jung Mi Oh College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea Background: CASR gene appears to be involved in cancer biology and physiology. However, a number of studies investigating CASR polymorphisms and cancer risks have presented inconclusive results. Thus, a systematic review and a meta-analysis of the effect of CASR polymorphisms on several cancer risks were performed to suggest a statistical evidence for the association of CASR polymorphisms with cancer risks.Methods: MEDLINE, EMBASE, Web of Science, Scopus, and the HuGE databases were searched. Nineteen articles of case–control and cohort studies were included for the final analysis.Results: The colorectal cancer risk was reduced in proximal (odds ratio [OR] =0.679, P=0.001) and distal (OR =0.753, P=0.026) colon sites with GG genotype of CASR rs1042636 and increased in distal colon site (OR =1.418, P=0.039) with GG genotype of rs1801726 by additive genetic model. The rs17251221 demonstrated noticeable associations that carrying a homozygote variant increases breast and prostate cancer risk considerably.Conclusion: The significant association of CASR polymorphisms with several cancer risks was observed in this review. In particular, the act of CASR polymorphisms as a tumor suppressor or an oncogene differs by cancer site and can be the research target for tumorigenesis. Keywords: rs1042636, rs1801725, rs1801726, systematic review, colorectal cancer

Jeong-A Lee,1,* Mi-Kyung Kim,1,* Hyoung-Mi Kim,2,* Jong Kwon Lee,3 Jayoung Jeong,4 Young-Rok Kim,5 Jae-Min Oh,2 Soo-Jin Choi1 1Department of Food Science and Technology, Seoul Women’s University, Seoul, Republic of Korea; 2Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Wonju, Republic of Korea; 3Hazard Substances Analysis Division, Gwangju Regional Food and Drug Administration, Ministry of Food and Drug Safety, Gwangju, Republic of Korea; 4Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Chungcheongbuk-do, Republic of Korea; 5Department of Food Science and Biotechnology, Kyung Hee University, Yongin, Republic of Korea *These authors contributed equally to this work Background: Orally administered particles rapidly interact with biological fluids containing proteins, enzymes, electrolytes, and other biomolecules to eventually form particles covered by a corona, and this corona potentially affects particle uptake, fate, absorption, distribution, and elimination in vivo. This study explored relationships between the biological interactions of calcium carbonate particles and their biokinetics.Methods: We examined the effects of food grade calcium carbonates of different particle size (nano [N-Cal] and bulk [B-Cal]: specific surface areas of 15.8 and 0.83 m2/g, respectively) on biological interactions in in vitro simulated physiological fluids, ex vivo biofluids, and in vivo in gastrointestinal fluid. Moreover, absorption and tissue distribution of calcium carbonates were evaluated following a single dose oral administration to rats.Results: N-Cal interacted more with biomatrices than bulk materials in vitro and ex vivo, as evidenced by high fluorescence quenching ratios, but it did not interact more actively with biomatrices in vivo. Analysis of coronas revealed that immunoglobulin, apolipoprotein, thrombin, and fibrinogen, were the major corona proteins, regardless of particle size. A biokinetic study revealed that orally delivered N-Cal was more rapidly absorbed into the blood stream than B-Cal, but no significant differences were observed between the two in terms of absorption efficiencies or tissue distributions. Both calcium carbonates were primarily present as particulate forms in gastrointestinal fluids but enter the circulatory system in dissolved Ca2+, although both types showed partial phase transformation to dicalcium phosphate dihydrate. Relatively low dissolution (about 4%), no remarkable protein–particle interaction, and the major particulate fate of calcium carbonate in vivo gastrointestinal fluids can explain its low oral absorption (about 4%) regardless of particle size.Conclusion: We conclude that calcium carbonate nanoparticles can act more actively with biological matrices in vitro and ex vivo, but that in vivo, their biological interactions and biokinetics are not affected by particle size. Keywords: biological interaction, oral absorption, biokinetics, size effect, protein corona

Kyoung-Min Kim,1 Hye Min Kim,1 Won-Jae Lee,2 Chang-Woo Lee,3 Tae-il Kim,4 Jong-Kwon Lee,5 Jayoung Jeong,5 Seung-Min Paek,2 Jae-Min Oh1 1Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Gangwon-do, Republic of Korea; 2Department of Chemistry, Kyungpook National University, Taegu, Republic of Korea; 3Battelle-Korea Laboratory, International Center for Converging Technology, Korea University, Seoul, Republic of Korea; 4Department of Biosystems and Biomaterials Science and Engineering, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea; 5Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, Republic of Korea Abstract: An attempt was made to control the surface charge of colloidal silica nanoparticles with 20 nm and 100 nm diameters. Untreated silica nanoparticles were determined to be highly negatively charged and have stable hydrodynamic sizes in a wide pH range. To change the surface to a positively charged form, various coating agents, such as amine containing molecules, multivalent metal cation, or amino acids, were used to treat the colloidal silica nanoparticles. Molecules with chelating amine sites were determined to have high affinity with the silica surface to make agglomerations or gel-like networks. Amino acid coatings resulted in relatively stable silica colloids with a modified surface charge. Three amino acid moiety coatings (L-serine, L-histidine, and L-arginine) exhibited surface charge modifying efficacy of L-histidine > L-arginine > L-serine and hydrodynamic size preservation efficacy of L-serine > L-arginine > L-histidine. The time dependent change in L-arginine coated colloidal silica was investigated by measuring the pattern of the backscattered light in a Turbiscan™. The results indicated that both the 20 nm and 100 nm L-arginine coated silica samples were fairly stable in terms of colloidal homogeneity, showing only slight coalescence and sedimentation. Keywords: silica, nanoparticles, surface charge, colloidal stability, turbidity, amino acids

Yu-Ri Kim,1,* Sung Ha Park,2,* Jong-Kwon Lee,3 Jayoung Jeong,3 Ja Hei Kim,4 Eun-Ho Meang,5 Tae Hyun Yoon,6 Seok Tae Lim,7 Jae-Min Oh,8 Seong Soo A An,9 Meyoung-Kon Kim1 1Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, South Korea; 2Department of Biochemistry, University of Bath, Bath, UK; 3Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, 4Consumers Korea, Chongro-ku, 5General toxicology team, Korea Testing and Research Institute, 6Laboratory of Nanoscale Characterization and Environmental Chemistry, Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul, 7Department of Nuclear Medicine, Chonbuk National University Medical School, Jeonju, Jellabuk-Do, 8Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Gangwon-do, 9Department of Bionanotechnology, Gachon Medical Research Institute, Gachon University, Seongnam, South Korea *Authors contributed equally to this work Abstract: Currently, products made with nanomaterials are used widely, especially in biology, biotechnologies, and medical areas. However, limited investigations on potential toxicities of nanomaterials are available. Hence, diverse and systemic toxicological data with new methods for nanomaterials are needed. In order to investigate the nanotoxicology of nanoparticles (NPs), the Research Team for Nano-Associated Safety Assessment (RT-NASA) was organized in three parts and launched. Each part focused on different contents of research directions: investigators in part I were responsible for the efficient management and international cooperation on nano-safety studies; investigators in part II performed the toxicity evaluations on target organs such as assessment of genotoxicity, immunotoxicity, or skin penetration; and investigators in part III evaluated the toxicokinetics of NPs with newly developed techniques for toxicokinetic analyses and methods for estimating nanotoxicity. The RT-NASA study was carried out in six steps: need assessment, physicochemical property, toxicity evaluation, toxicokinetics, peer review, and risk communication. During the need assessment step, consumer responses were analyzed based on sex, age, education level, and household income. Different sizes of zinc oxide and silica NPs were purchased and coated with citrate, L-serine, and L-arginine in order to modify surface charges (eight different NPs), and each of the NPs were characterized by various techniques, for example, zeta potentials, scanning electron microscopy, and transmission electron microscopy. Evaluation of the “no observed adverse effect level” and systemic toxicities of all NPs were performed by thorough evaluation steps and the toxicokinetics step, which included in vivo studies with zinc oxide and silica NPs. A peer review committee was organized to evaluate and verify the reliability of toxicity tests, and the risk communication step was also needed to convey the current findings to academia, industry, and consumers. Several limitations were encountered in the RT-NASA project, and they are discussed for consideration for improvements in future studies. Keywords: nanomaterials, nanotoxicity, toxicokinetics, physicochemical property, peer review

Kyoung-Min Kim,1 Mun-Hyoung Choi,2 Jong-Kwon Lee,3 Jayoung Jeong,3 Yu-Ri Kim,4 Meyoung-Kon Kim,4 Seung-Min Paek,2 Jae-Min Oh1 1Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Gangwon-do, 2Department of Chemistry, Kyungpook National University, Taegu, 3Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, 4Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, South Korea Abstract: In this study, four types of standardized ZnO nanoparticles were prepared for assessment of their potential biological risk. Powder-phased ZnO nanoparticles with different particle sizes (20 nm and 100 nm) were coated with citrate or L-serine to induce a negative or positive surface charge, respectively. The four types of coated ZnO nanoparticles were subjected to physicochemical evaluation according to the guidelines published by the Organisation for Economic Cooperation and Development. All four samples had a well crystallized Wurtzite phase, with particle sizes of ~30 nm and ~70 nm after coating with organic molecules. The coating agents were determined to have attached to the ZnO surfaces through either electrostatic interaction or partial coordination bonding. Electrokinetic measurements showed that the surface charges of the ZnO nanoparticles were successfully modified to be negative (about −40 mV) or positive (about +25 mV). Although all the four types of ZnO nanoparticles showed some agglomeration when suspended in water according to dynamic light scattering analysis, they had clearly distinguishable particle size and surface charge parameters and well defined physicochemical properties. Keywords: ZnO nanoparticles, surface coating, surface charge, particle size, physicochemical properties

Miri Baek,1,* Hae-Eun Chung,1,* Jin Yu,1,* Jung-A Lee,1 Tae-Hyun Kim,2 Jae-Min Oh,2 Won-Jae Lee,3 Seung-Min Paek,3 Jong Kwon Lee,4 Jayoung Jeong, 4 Jin-Ho Choy,5 Soo-Jin Choi1 1Department of Food Science and Technology, Seoul Women's University, Seoul, 2Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Wonju, Gangwondo; 3Department of Chemistry and Green-Nano Materials Research Center, Kyungpook National University, Taegu, 4Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, 5Center for Intelligent Nano-Bio Materials, Department of Bioinspired Science and Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea*These authors contributed equally to this workBackground: This study explored the pharmacokinetics, tissue distribution, and excretion profile of zinc oxide (ZnO) nanoparticles with respect to their particle size in rats.Methods: Two ZnO nanoparticles of different size (20 nm and 70 nm) were orally administered to male and female rats, respectively. The area under the plasma concentration-time curve, tissue distribution, excretion, and the fate of the nanoparticles in organs were analyzed.Results: The plasma zinc concentration of both sizes of ZnO nanoparticles increased during the 24 hours after administration in a dose-dependent manner. They were mainly distributed to organs such as the liver, lung, and kidney within 72 hours without any significant difference being found according to particle size or rat gender. Elimination kinetics showed that a small amount of ZnO nanoparticles was excreted via the urine, while most of nanoparticles were excreted via the feces. Transmission electron microscopy and x-ray absorption spectroscopy studies in the tissues showed no noticeable ZnO nanoparticles, while new Zn-S bonds were observed in tissues.Conclusion: ZnO nanoparticles of different size were not easily absorbed into the bloodstream via the gastrointestinal tract after a single oral dose. The liver, lung, and kidney could be possible target organs for accumulation and toxicity of ZnO nanoparticles was independent of particle size or gender. ZnO nanoparticles appear to be absorbed in the organs in an ionic form rather than in a particulate form due to newly formed Zn-S bonds. The nanoparticles were mainly excreted via the feces, and smaller particles were cleared more rapidly than the larger ones. ZnO nanoparticles at a concentration below 300 mg/kg were distributed in tissues and excreted within 24 hours. These findings provide crucial information on possible acute and chronic toxicity of ZnO nanoparticles in potential target organs.Keywords: ZnO nanoparticles, pharmacokinetics, tissue distribution, excretion, fate

Background: Tumor enlargement after chemotherapy is considered one of the high-risk factors for local recurrence and survival in osteosarcoma. We hypothesized patients with this risk factor will have similar survival regardless of the development of local recurrence.Questions/purposes: We asked (1) the prognostic factors for survival in our cohort, (2) how much effect local recurrence has on survival among patients with similar preoperative risk factors, and (3) what prognostic factors are important for survival in these selected patients.Methods: We analyzed the prognostic factors for survival in 449 patients with extremity osteosarcoma without metastatic disease at initial diagnosis and treatment (38 with local recurrence, 411 without local recurrence). We compared the survival difference between patients with local recurrence (n = 38) and without local recurrence (control, n = 76) matched for age, location, initial tumor volume, and tumor volume change after chemotherapy, and assessed prognostic factors in this subgroup.Results: In a cohort study, multivariate analysis revealed initial tumor volume, tumor enlargement, inadequate margin, and local recurrence predicted poor survival. In the case-control study, the 10-year metastasis-free survival rates of two groups were 13.1 ± 10.7% and 19.3 ± 9%, respectively. In the case-controlled groups, tumor enlargement and initial tumor volume showed multivariate significance.Conclusions: Local recurrence has a small impact on survival in patients with high-risk osteosarcoma.Level Of Evidence: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

A prospective cohort study was performed to determine the optimal dose of vancomycin to maintain a serum trough concentration of at least 15 to 20 mg/l and to assess the efficacy of this target vancomycin concentration in the treatment of methicillin-resistant Staphylococcus aureus pneumonia. Vancomycin pharmacokinetic parameters were estimated using a CAPSIL software program from serum concentrations of 141 patients with pneumonia treated with vancomycin, regardless of methicillin-resistant Staphylococcus aureus status, at a 28-bed medical intensive care unit. Vancomycin trough concentrations and other pharmacokinetic parameters were compared between five groups of patients differing in their renal function: (1) creatinine clearance > or =60 ml/minute, (2) creatinine clearance 30 to 60 ml/minute, (3) creatinine clearance <30 ml/minute, (4) on intermittent haemodialysis, and (5) on continuous renal replacement therapy. More than 70% of patients failed to reach the recommended therapeutic serum trough concentrations: a higher dose of vancomycin is necessary to maintain serum trough concentration at 15 to 20 mg/l, particularly in critically ill patients with creatinine clearance above 60 ml/minute and in those on intermittent haemodialysis. Among patients with methicillin-resistant Staphylococcus aureus pneumonia, no significant differences were observed in the treatment success rate, length of intensive care unit stay, and intensive care unit mortality rate between patients with vancomycin trough concentrations of >20 mg/l, 15 to 20 mg/l and <15 mg/l. [ABSTRACT FROM AUTHOR]

The purpose of this study was to characterize the pharmacokinetic parameters of mycophenolic acid (MPA) in Korean kidney transplant recipients. Plasma MPA concentrations of 10 Korean kidney transplant recipients administered a lower dose of mycophenolate mofetil (MMF; 750 mg twice a day) were measured at 2 weeks of MMF therapy by high-performance liquid chromatography (HPLC). The plasma MPA concentration-time curve pattern of patients taking lower doses of MPA was consistent with previously reported profiles of patients taking the fully recommended doses. The plasma MPA concentration-time curve was characterized by an early sharp peak within 1 hour and a small second peak in some patients at 4 to 12 hours postdose. The mean C(max) and AUC were 8.73 +/- 4.65 microg/mL and 18.45 +/- 4.25 microg*h/mL, respectively. The mean fraction of free MPA was 1.60% +/- 0.23%. Patients' age, weight, body surface area, and renal function did not influence the AUC. The free fraction of MPA appeared not to be affected by serum albumin and renal function when creatinine clearance was above 40 mL/min. Regression analysis between each plasma concentration and AUC for the limited sampling strategy of MMF therapeutic drug monitoring demonstrated that the concentrations of predose and 1- and 8-hour postdose were positively correlated with AUC (r = 0.74545, p = 0.0133; r = 0.68485, p = 0.0289; and r = 0.63636, p = 0.0479, respectively). The pattern of the concentration-time profile of MPA in Korean kidney recipients was similar to the results of other studies performed in Caucasians, although there was interindividual variability of AUC, C(max), and t(max). MPA concentrations of predose and 1- and 8-hour postdose were positively correlated with AUC. [ABSTRACT FROM AUTHOR]

The study was performed to compare the efficacy and side effects of azathioprine (AZA) and mycophenolate mofetil (MMF) in conjunction with cyclosporine or tacrolimus and steroids for the prevention of acute pancreas rejection during the first 6 months of pancreas transplantation. In this case-controlled study, MMF is compared with historical controls of AZA in the prevention of acute pancreas rejection. The primary measures of treatment efficacy were patient and pancreas survival rate at 6 months after transplantation. Secondary efficacy measures were the occurrence of biopsy-proven pancreas rejections and the use of antilymphocyte preparations for rejection treatment. A total of 111 pancreas transplant patients (57 in the AZA group and 54 in the MMF group) were evaluated. The 6-month patient survival rate was 96% in the AZA group versus 97% in the MMF group (p = 0.57). The 6-month pancreas graft survival rate was 88% in the AZA group versus 91% in the MMF group (p = 0.29). However, biopsy-proven rejection episodes during the first 6 months of transplantation were significantly lower with MMF (46%) than with AZA (69%) (p = 0.01). In addition, patients in the AZA group received a greater number of full courses of antilymphocyte therapy as a rejection treatment (p = 0.004). Overall, the frequency of adverse events was similar, although the MMF group experienced higher incidences of gastrointestinal adverse events. In conclusion, compared with AZA, MMF significantly reduces the rate of biopsy-proven pancreas rejection during the first 6 months of transplantation and is well tolerated, except for gastrointestinal adverse events. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study is to measure α-defensin-1 expression in the peripheral blood of patients with Behçet's disease (BD) and healthy control (HC) and to assess the association between α-defensin-1 expression and clinical features of BD.Methods: Our patients fulfilled the diagnostic criteria of the international BD study group. ELISA and real-time PCR were performed to measure α-defensin-1 protein level in the sera and α-defensin-1 mRNA level in peripheral blood mononuclear cells (PBMC), respectively.Results: The α-defensin-1 mRNA expression was significantly higher in BD patients (n=59) than HC (n=34) (0.49±0.10 vs. 0.19±0.45, P=0.03). The level of α-defensin-1 mRNA and protein was significantly higher in active patients than inactive patients (n=15, 0.91±0.28 vs. n=44, 0.35±0.09, P<0.001 and n=21, 7.50±2.14ng/ml vs. n=50, 3.32±0.96ng/ml, P=0.001, respectively). The level of α-defensin-1 mRNA was significant higher in patients with arthritis (n=20) than those without arthritis (n=39).Conclusion: α-defensin-1 mRNA and protein levels are significantly increased in BD patients, especially in active BD patients. Furthermore, α-defensin-1 mRNA is over-expressed in the PBMC of BD patients with arthritis. The present study suggests that α-defensin-1 may be involved in the pathogenesis of BD and can be used as valuable biologic marker for estimation of disease activity in BD. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer (PC), sometimes referred to as pancreatic ductal adenocarcinoma (PDAC), is a major cause of global mortality from cancer. Pancreatic cancer is a very aggressive and devastating kind of cancer, characterized by limited options for therapy and low possibilities of survival. Sulforaphane (SFN), a naturally occurring sulfur-containing compound, is believed to possess anti-inflammatory, anti-obesity, and anti-cancer characteristics., Objective: However, efficient preventative and treatment measures are essential and SFN has been studied for its ability to suppress pancreatic cancer cell proliferation and induce apoptosis., Methods: Here, SFN induced cytotoxicity and apoptosis in PDAC cell lines such as MIA PaCa-2 and PANC-1 cells, as evaluated by cytotoxicity, colony formation, western blot analysis, fluorescence-activated cell sorting (FACS), reactive oxygen species (ROS) detection, caspase-3 activity assay, immunofluorescence assay, and mitochondrial membrane potential assay., Results: In MIA PaCa-2 and PANC-1 cells, SFN inhibited cell survival and proliferation in a dose-dependent manner. The activation of caspase zymogens results in cleaved PARP and cleaved caspase-3, which is associated with an accumulation in the sub G1 phase. Furthermore, SFN increased ROS level and γH2A.X expression while decreasing mitochondrial membrane potential (ΔΨm). Notably, the ROS scavenger N-Acetyl-L-cysteine (NAC) was shown to reverse SFN-induced cytotoxicity and ROS level. Subsequently, SFN-induced cell cycle arrest and apoptosis induction as a Trojan horse to eliminate pancreatic cancer cells via ROS-mediated pathways were used to inhibit pancreatic cancer cells., Conclusion: Collectively, our data demonstrates that SFN-induced cell death follows the apoptosis pathway, making it a viable target for therapeutic interventions against pancreatic cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cho, Park, Choi, Upadhyay, Kang, Oh, Min, Yang, Kong, Ko, Rahman, Harrath and Kim.)

Eighteen compounds derived from two sub-series, (HC1-HC9) and (HF1-HF9), were synthesized and evaluated for their inhibitory activities against monoamine oxidase (MAO). HC (chalcone) series showed higher inhibitory activity against MAO-B than against MAO-A, whereas the HF (chromone) series showed reversed inhibitory activity. Compound HC4 most potently inhibited MAO-B with an IC 50 value of 0.040 μM, followed by HC3 (IC 50  = 0.049 μM), while compound HF4 most potently inhibited MAO-A (IC 50  = 0.046 μM), followed by HF2 (IC 50  = 0.075 μM). The selectivity index (SI) values of HC4 and HF4 were 50.40 and 0.59, respectively. Structurally, HC4 (4-OC 2 H 5 in B-ring) showed higher MAO-B inhibition than other derivatives, suggesting that the -OC 2 H 5 substitution of the 4-position in the B-ring contributes to the increase of MAO-B inhibition, especially -OC 2 H 5 (HC4) > -OCH 3 (HC3) > -F (HC7) > -CH 3 (HC2) > -Br (HC8) > -H (HC1) in order. In MAO-A inhibition, the substituent 4-OC 2 H 5 in the B-ring of HF4 contributed to an increase in inhibitory activity, followed by -CH 3 (HF2), -F (HF7), -Br (HF8), -OCH 3 (HF3), and-H (HF1). In the enzyme kinetics and reversibility study, the K i value of HC4 for MAO-B was 0.035 ± 0.005 μM, and that of HF4 for MAO-A was 0.035 ± 0.005 μM, and both were reversible competitive inhibitors. We confirmed that HC4 and HF4 significantly ameliorated rotenone-induced neurotoxicity, as evidenced by the reactive oxygen species and superoxide dismutase assays. This study also supports the significant effect of HC4 and HF4 on mitochondrial membrane potential in rotenone-induced toxicity. A lead molecule was used for molecular docking and dynamic simulation studies. These results show that HC4 is a potent selective MAO-B inhibitor and HF4 is a potent MAO-A inhibitor, suggesting that both compounds can be used as treatment agents for neurological disorders., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Keloids and hypertrophic scars result from abnormal collagen accumulation and the inhibition of its degradation. Although the pathogenesis remains unclear, excessive accumulation of the extracellular matrix (ECM) is believed to be associated with the TGF-β/SMAD pathway. Zinc-alpha-2-glycoprotein (ZAG) inhibits TGF-β-mediated epithelial-to-mesenchymal transdifferentiation and impacts skin barrier functions. In this study, we investigated the potential of a small ZAG-derived peptide against hypertrophic scars and keloids., Methods: The study examined cell proliferation and mRNA expression of collagen types I and III in human dermal fibroblast (HDF) cell lines and keloid-derived fibroblasts (KF) following ZAG peptide treatment. A rat incisional wound model was used to evaluate the effect of ZAG peptide in scar tissue., Results: Significantly lower mRNA levels of collagen types I and III were observed in ZAG-treated fibroblasts, whereas matrix metalloproteinase (MMP)-1 and MMP-3 mRNA levels were significantly increased in HDFs and KFs. Furthermore, ZAG peptide significantly reduced protein expression of collagen type I and III, TGF-β1, and p-Smad2/3 complex in KFs. Rat incisional scar models treated with ZAG peptide presented narrower scar areas and reduced immature collagen deposition, along with decreased expression of collagen type I, α-SMA, and p-Smad2/3., Conclusion: ZAG peptide effectively suppresses the TGF-β and p-Smad2/3 pathway and inhibits excessive cell proliferation during scar formation, suggesting its potential therapeutic implications against keloids and hypertrophic scars., (© 2024. Korean Tissue Engineering and Regenerative Medicine Society.)

Introduction: Motor function has correlated with longevity and functionality; however, there is limited research on those with Alzheimer's disease (AD). We studied the association between motor functionality and AD pathology in primary motor and medial temporal cortices., Methods: A total of 206 participants with a clinical diagnosis of cognitively healthy, AD, or mild cognitive impairment (MCI) underwent imaging and motor assessment. Linear regressions and analyses of variance were applied to test the prediction from AD imaging biomarkers to motor performance and the diagnosis group differences in motor performance., Results: Increased neurodegeneration was associated with worsening dexterity and lower walking speed, and increased amyloid and tau were associated with worsening dexterity. AD and MCI participants had lower motor performance than the cognitively healthy participants., Discussion: Increased AD pathology is associated with worsening dexterity performance. The decline in dexterity in those with AD pathology may offer an opportunity for non-pharmacological therapy intervention., Highlights: Noted worsening dexterity performance was associated with greater Alzheimer's disease (AD) pathology (tau, amyloid beta, and neurodegeneration) in primary motor cortices. Similarly, increased neurodegeneration and tau pathology in parahippocampal, hippocampal, and entorhinal cortices is associated with worsening dexterity performance. Motor performance declined in those with clinical and preclinical AD among an array of motor assessments., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background/objectives: Chronic alcohol consumption causes oxidative stress in the body, which may accumulate excessively and cause a decline in memory; problem-solving, learning, and exercise abilities; and permanent damage to brain structure and function. Consequently, chronic alcohol consumption can cause alcohol-related diseases., Materials/methods: In this study, the protective effects of Phyllostachys edulis (Carrière) J. Houz (PE) against alcohol-induced neuroinflammation and cognitive impairment were evaluated using a mouse model. Alcohol (16%, 5 g/kg/day for 6 weeks) and PE (100, 250, and 500 mg/kg/day for 21 days) were administered intragastrically to mice., Results: PE showed a protective effect against memory deficits and cognitive dysfunction caused by alcohol consumption, confirmed through behavioral tests such as the T-maze, object recognition, and Morris water maze tests. Additionally, PE attenuated oxidative stress by reducing lipid oxidation, nitric oxide, and reactive oxygen species levels in the mice's brains, livers, and kidneys. Improvement of neurotrophic factors and downregulation of apoptosis-related proteins were confirmed in the brains of mice fed low and medium concentrations of PE. Additionally, expression of antioxidant enzyme-related proteins GPx-1 and SOD-1 was enhanced in the liver of PE-treated mice, related to their inhibitory effect on oxidative stress., Conclusion: This suggests that PE has both neuroregenerative and antioxidant effects. Collectively, these behavioral and histological results confirmed that PE could improve alcohol-induced cognitive deficits through brain neurotrophic and apoptosis protection and modulation of oxidative stress., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interests., (©2024 The Korean Nutrition Society and the Korean Society of Community Nutrition.)

Purpose: To examine the association between maternal prescriptions for fibrates and congenital malformations in live births., Methods: Nationwide retrospective cohort study was conducted using the data sourced from the Korean National Health Insurance database. A cohort of 756,877 completed pregnancies linked to live-born infants in 215,600 women with dyslipidemia between 2012 and 2021. The study compared data on congenital anomalies between pregnancies who were exposed to fibrates and those who were not exposed to fibrates in the first trimester. Odds ratios (OR) were calculated by a multivariable analyses using logistic regression models to adjust for potential confounders., Results: 260 pregnancies (0.12%) were exposed to fibrates during the first trimester. The prevalence of malformations in exposed offspirng was 10.77%, not significantly different compared with 9.68% in offspring of women who were not prescribed fibrates during pregnancy in patients with dyslipidemia (OR 1.13; 95% CI 0.75-1.70)., Conclusion: This study implies that the use of fibrates during pregnancy may be safe, as it did not show any association with congenital anomalies. However, caution is warranted due to an elevated risk associated with prolonged exposure., (© 2024. The Author(s).)

Monoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson's disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound S5 most potently inhibited MAO-B with an IC 50 value of 0.203 μM, followed by S16 (IC 50 = 0.979 μM). In contrast, all compounds showed weak MAO-A inhibition. Among them, S15 most potently inhibited MAO-A with an IC 50 value of 3.691 μM, followed by S5 (IC 50 = 3.857 μM). Compound S5 had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound S5 (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl > -OCH 3 > -F > -CN > -CH 3 > -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except S16 (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the K i values of S5 and S16 for MAO-B were 0.155 ± 0.050 and 0.721 ± 0.074 μM, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood-brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z- S5 complex by pi-pi stacking with Tyr398 and Tyr326. These results suggest that S5 and S16 are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders.

Multifunctional, flexible, and robust thin films capable of operating in demanding harsh temperature environments are crucial for various cutting-edge applications. This study presents a multifunctional Janus film integrating highly-crystalline Ti 3 C 2 T x MXene and mechanically-robust carbon nanotube (CNT) film through strong hydrogen bonding. The hybrid film not only exhibits high electrical conductivity (4250 S cm -1 ), but also demonstrates robust mechanical strength and durability in both extremely low and high temperature environments, showing exceptional resistance to thermal shock. This hybrid Janus film of 15 μm thickness reveals remarkable multifunctionality, including efficient electromagnetic shielding effectiveness of 72 dB in X band frequency range, excellent infrared (IR) shielding capability with an average emissivity of 0.09 (a minimal value of 0.02), superior thermal camouflage performance over a wide temperature range (- 1 to 300 °C) achieving a notable reduction in the radiated temperature by 243 °C against a background temperature of 300 °C, and outstanding IR detection capability characterized by a 44% increase in resistance when exposed to 250 W IR radiation. This multifunctional MXene/CNT Janus film offers a feasible solution for electromagnetic shielding and IR shielding/detection under challenging conditions., (© 2024. The Author(s).)

Pyroptosis represents a type of cell death mechanism notable for its cell membrane disruption and the subsequent release of proinflammatory cytokines. The Nod-like receptor family pyrin domain containing inflammasome 3 (NLRP3) plays a critical role in the pyroptosis mechanism associated with various diseases resulting from particulate matter (PM) exposure. Tert-butylhydroquinone (tBHQ) is a synthetic antioxidant commonly used in a variety of foods and products. The aim of this study is to examine the potential of tBHQ as a therapeutic agent for managing sinonasal diseases induced by PM exposure. The occurrence of NLRP3 inflammasome-dependent pyroptosis in RPMI 2650 cells treated with PM < 4 µm in size was confirmed using Western blot analysis and enzyme-linked immunosorbent assay results for the pyroptosis metabolites IL-1β and IL-18. In addition, the inhibitory effect of tBHQ on PM-induced pyroptosis was confirmed using Western blot and immunofluorescence techniques. The inhibition of tBHQ-mediated pyroptosis was abolished upon nuclear factor erythroid 2-related factor 2 (Nrf2) knockdown, indicating its involvement in the antioxidant mechanism. tBHQ showed potential as a therapeutic agent for sinonasal diseases induced by PM because NLRP3 inflammasome activation was effectively suppressed via the Nrf2 pathway., Competing Interests: The authors declare no conflicts of interest.

Water security remains a critical issue given the looming threats of industrial pollution, necessitating comprehensive assessments of water quality to address seasonal fluctuations and influential factors while formulating effective strategies for decision makers. This study introduces a novel approach for evaluating water quality within a complex riverine zone in South Korea: Han River that encompasses five river streams situated at each junction of North and South streams (including Gyeongan Stream) that ultimately leading towards Paldang Lake. By utilizing the monthly water characteristic data from the year 2013-2022 across 14 different locations, the significant seasonal trends and potential influences on water quality are identified. The water quality here is calculated with the proposed method of sub-index water quality index (s-WQI). A combinatorial prediction approach of s-WQI for each location is conducted through a collective of data preprocessing approaches including Hampel filtering and feature selection in prior to the machine learning predictions. In return, light gradient boosting (LGB) is the most accurate predictor by outperforming other prediction algorithms, especially through LGB-Pearson and LGB-Spearman combinations for North and South stream intersections, and LGB-Pearson for Paldang Lake. To further evaluate the robustness of this evaluation and extending the results to a foreseeable scenario, a seasonal based Monte-Carlo Simulation with 10,000 attempts targeting the water characteristic distributions obtained from each location considered are carried out to identify the risk bounds within. The results are further interpreted with SHAP analysis on identifying the contributions of each water characteristics towards the water quality through local and global spectrum. This research yields practical implications, offering tailored strategies for water quality enhancement and early warning systems. The integration of AI-based prediction and feature selection underscores the transformative potential of computational techniques in advancing data-driven water quality assessments, shaping the future of environmental science research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The population is rapidly aging and remains active over the age of 65 years. An increasing number of sports-related fractures (SRFs) in individuals 65 and older are thus anticipated. Despite the increase in SRFs among the geriatric population, there are limited studies regarding the epidemiological data regarding SRFs in geriatric patients. This study examined the epidemiology of SRFs in a geriatric population who visited a level I trauma center., Methods: Data from geriatric patients who visited a level I trauma center were collected between June 2020 and July 2023. Overall, 1,109 geriatric patients with fractures were included in the study. Among them, 144 (13.0%) had fractures during sports activities (SRF group) and 965 (87.0%) had fractures during non-sports activities (non-SRF group). We investigated the type of sport in the SRFs and compared SRFs and NSRFs to describe the differences in patient, fracture, and treatment characteristics., Results: The mean age of SRFs was significantly lower (73.6 vs. 78.7 years; P < .001). The proportion of men was significantly higher in the SRF group than in the non-SRF group (51.4 vs. 29.6%; P < .001). We identified 13 types of sports associated with fractures, and the four most common were outdoor walking (36.1%), outdoor biking (27.8%), mountain hiking (19.4%), and gym (8.3%). There were no significant differences in the rate of hospitalization, operative treatment, or length of hospital stay between the two groups. However, compared to the non-SRF group, patients in the SRF group tended to return home after hospitalization (P = .002)., Conclusion: This epidemiological study describes geriatric population that continues to be involved in sports and is thus susceptible to fractures. The identification of the type and distribution of SRFs in geriatric patients provides useful information for determining risk factors and appropriate preventive measures that may reduce their incidence., (© 2024. The Author(s).)

Ginseng leaves are known to contain high concentrations of bioactive compounds, such as ginsenosides, and have potential as a treatment for various conditions, including fungal infections, cancer, obesity, oxidative stress, and age-related diseases. This study assessed the impact of ginseng leaf extract (GLE) on mast cell-mediated allergic inflammation and atopic dermatitis (AD) in DNCB-treated mice. GLE reduced skin thickness and lymph node nodules and suppressed the expression and secretion of histamine and pro-inflammatory cytokines. It also significantly lowered the production of inflammatory response mediators including ROS, leukotriene C4 (LTC4), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). GLE inhibited the phosphorylation of MAPKs (ERK, P38, JNK) and the activation of NF-κB, which are both linked to inflammatory cytokine expression. We demonstrated that GLE's inhibitory effect on mast cell-mediated allergic inflammation is due to the blockade of the NF-κB and inflammasome pathways. Our findings suggest that GLE can be an effective therapeutic agent for mast-cell mediated and allergic inflammatory conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Oh, Yoon, Joo, Im and Chun.)

Purpose: Carfilzomib, commonly used for relapsed/refractory multiple myeloma (RRMM), has been associated with various adverse events in randomized controlled trials (RCTs). However, real-world safety data for a more diverse population are needed, as carfilzomib received expedited approval. This study aimed to evaluate carfilzomib's safety in Korea by comparing new users of KRd (carfilzomib, lenalidomide, and dexamethasone) to Rd (lenalidomide and dexamethasone) using a nationwide administrative claims database., Methods: The retrospective cohort study utilized target trial emulation, focusing on adverse events in various organ systems similar to the ASPIRE trial., Results: This study included 4,580 RRMM patients between 2007 and 2020, and the KRd group showed significantly higher risks of hematologic adverse events (anemia, neutropenia, thrombocytopenia) and some non-hematologic adverse events (cough, hypokalemia, constipation, hypertension, heart failure) compared to the Rd group. Among non-hematologic adverse events, cardiovascular events (heart failure [HR 2.04; 95% CI 1.24-3.35], hypertension [HR 1.58; 95% CI 1.15-2.17]) had the highest risk in the KRd group., Conclusion: The safety profile of carfilzomib in Korean patients was similar to previous RCTs. Therefore, caution should be exercised when using carfilzomib in Asian individuals with RRMM due to the increased risk of cardiovascular adverse events., (© 2024. The Author(s).)

Serotonergic toxicity due to MAO enzyme inhibition is a significant concern when using linezolid to treat MDR-TB. To address this issue, we designed linezolid bioisosteres with a modified acetamidomethyl side chain at the C-5 position of the oxazolidine ring to balance activity and reduce toxicity. Among these bioisosteres, R7 emerged as a promising candidate, demonstrating greater effectiveness against M. tuberculosis ( Mtb ) H 37 Rv cells with an MIC of 2.01 μM compared to linezolid (MIC = 2.31 μM). Bioisostere R7 also exhibited remarkable activity (MIC 50 ) against drug-resistant Mtb clinical isolates, with values of 0.14 μM (INH R , inhA+ ), 0.53 μM (INH R , katG+ ), 0.24 μM (RIF R , rpoB+ ), and 0.92 μM (INH R INH R , MDR). Importantly, it was >6.52 times less toxic as compared to the linezolid toward the MAO-A and >64 times toward the MAO-B enzyme, signifying a substantial improvement in its drug safety profile., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Herein, a novel series of naphthamide derivatives has been rationally developed, synthesized, and evaluated for their inhibitory activity against monoamine oxidase (MAO) and cholinesterase (ChE) enzymes. Compared to the reported naphthalene-based hit IV, the new naphthamide hybrids 2a, 2c, 2g and 2h exhibited promising MAO inhibitory activities; with an IC 50 value of 0.294 μM, compound 2c most potently inhibited MAO-A, while compound 2g exhibited most potent MAO-B inhibitory activity with an IC 50 value of 0.519 μM. Compounds 2c and 2g showed selectivity index (SI) values of 6.02 for MAO-A and 2.94 for MAO-B, respectively. On the other hand, most compounds showed weak inhibitory activity against ChEs except 2a and 2h over butyrylcholinesterase (BChE). The most potent compounds 2c and 2g were found to be competitive and reversible MAO inhibitors based on kinetic and reversibility studies. Plausible interpretations of the observed biological effects were provided through molecular docking simulations. The drug-likeness predicted by SwissADME and Osiris property explorer showed that the most potent compounds (2a, 2c, 2g, and 2h) obey Lipinski's rule of five. Accordingly, in the context of neurological disorders, hybrids 2c and 2g may contribute to the identification of safe and potent therapeutic approaches in the near future., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cinnamic acid (CA) was successfully incorporated into Zn-Al layered double hydroxide (LDH) through coprecipitation. The CA moiety was stabilized in the interlayer space through not only electrostatic interaction but also intermolecular π-π interaction. It was noteworthy that the CA arrangement was fairly independent of the charge density of LDH, showing the important role of the layer-CA and CA-CA interactions in molecular stabilization. Computer simulations using the Monte Carlo method as well as analytical approaches including infrared, UV-vis spectroscopy, and differential scanning calorimetry showed the existence of intermolecular interaction. In order to reinforce molecular stabilization, a neutral derivative of CA, cinnamaldehyde (CAD), was additionally incorporated into LDH. It was clearly shown that CAD played a role as a π-π interaction mediator to enhance the stabilization of CA. The time-dependent release of CA from LDH was first governed by the layer charge density of LDH; however, the existence of CAD provided additional stabilization to the CA arrangement to slow down the release kinetics.

Modern semiconductor fabrication is challenged by difficulties in overcoming physical and chemical constraints. A major challenge is the wet etching of dummy gate silicon, which involves the removal of materials inside confined spaces of a few nanometers. These chemical processes are significantly different in the nanoscale and bulk. Previously, electrical double-layer formation, bubble entrapment, poor wettability, and insoluble intermediate precipitation have been proposed. However, the exact suppression mechanisms remain unclear due to the lack of direct observation methods. Herein, we investigate limiting factors for the etching kinetics of silicon with tetramethylammonium hydroxide at the nanoscale by using liquid-phase transmission electron microscopy, three-dimensional electron tomography, and first-principles calculations. We reveal suppressed chemical reactions, unstripping phenomena, and stochastic etching behaviors that have never been observed on a macroscopic scale. We expect that solutions can be suggested from this comprehensive insight into the scale-dependent limiting factors of fabrication.

Background: Peri-implantitis is similar to periodontitis, but there are some differences. For the effective control of peri-implantitis, it is necessary to clarify its similarities and differences with periodontitis in terms of gene expression., Methods: This cross-sectional study included 20 participants (10 healthy subjects and 10 patients with periodontitis and peri-implantitis). Gingival tissue samples (10 healthy, 10 periodontitis, and 10 peri-implantitis tissues) were collected, RNAs were extracted, and RNA sequencing and analysis were performed., Results: Differentially expressed gene (DEG) analysis identified 757 upregulated and 159 downregulated genes common between periodontitis and peri-implantitis. Periodontitis tissues uniquely showed 186 overexpressed and 22 suppressed genes compared with peri-implantitis and healthy tissues, while peri-implantitis had 1974 and 642, respectively. Each common and unique differential gene set showed distinct enriched biological features between periodontitis and peri-implantitis after the pathway enrichment analysis. The expression pattern of selected DEGs focused on the representability of the disease was validated by RT-qPCR., Conclusions: Although periodontitis and peri-implantitis showed common gene expression that was clearly differentiated from healthy conditions, there were also unique gene patterns that were differentially expressed only in peri-implantitis. These findings will help elucidate the mechanisms involved in the progression of peri-implantitis., (© 2023 American Academy of Periodontology.)

Total knee arthroplasty (TKA) is associated with substantial blood loss and tranexamic acid (TXA) effectively reduces postoperative bleeding. Although it is known that there is no difference between intravenous or intra-articular (IA) injection, the general interest is directed towards topical hemostatic agents regarding thromboembolic events in high-risk patients. This study aimed to compare the blood conservation effects of IA MPH powder and TXA in patients undergoing primary TKA. We retrospectively analyzed 103 patients who underwent primary TKA between June 2020 and December 2021. MPH powder was applied to the IA space before capsule closure (MPH group, n = 51). TXA (3 g) was injected via the drain after wound closure (TXA group, n = 52). All patients underwent drain clamping for three postoperative hours. The primary outcome was the drain output, and the secondary outcomes were the postoperative hemoglobin (Hb) levels during the hospitalization period and the perioperative blood transfusion rates. An independent Student's t-test was used to determine differences between the two groups. The drain output in the first 24 h after surgery was significantly higher in the MPH group than in the TXA group. The postoperative Hb levels were significantly lower in the MPH group than in the TXA group. In patients with simultaneous bilateral TKA, there was a significant difference in the blood transfusion volumes and the rates between groups. It is considered that IA MPH powder cannot replace IA TXA because of an inferior efficacy in reducing blood loss and maintaining postoperative Hb levels in the early postoperative period after primary TKA. Moreover, in the case of simultaneous bilateral TKA, we do not recommend the use of IA MPH powder because it was notably less effective in the field of transfusion volume and rate., (© 2024. The Author(s).)

Objective: : Microtubule (MT) stability in neurons is vital for brain development; instability is associated with neuropsychiatric disorders. The present study examined the effects of social defeat stress (SDS) on MT-regulating proteins and tubulin polymerization., Methods: : After 10 days of SDS, defeated mice were separated into susceptible (Sus) and unsusceptible (Uns) groups based on their performance in a social avoidance test. Using extracted brain tissues, we measured the expression levels of α-tubulin, acetylated α-tubulin, tyrosinated α-tubulin, MT-associated protein-2 (MAP2), stathmin (STMN1), phospho stathmin serine 16 (p-STMN1 [Ser16]), phospho stathmin serine 25 (p-STMN1 [Ser25]), phospho stathmin serine 38 (p-STMN1 [Ser38]), stathmin2 (STMN2), phospho stathmin 2 serine 73 (p-STMN2 [Ser73]), 78-kDa glucose-regulated protein (GRP-78), and CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) using Western blot assay. The tubulin polymerization rate was also measured., Results: : We observed increased and decreased expression of acetylated and tyrosinated α-tubulin, respectively, decreased expression of p-STMN1 (Ser16) and increased expression of p-STMN1 (Ser25), p-STMN2 (Ser73) and GRP-78 and CHOP in the prefrontal cortex and/or hippocampus of defeated mice. A reduced tubulin polymerization rate was observed in the Sus group compared to the Uns and Con groups., Conclusion: : Our findings suggest that SDS has detrimental effects on MT stability, and a lower tubulin polymerization rate could be a molecular marker for susceptibility to SDS.

Monoamine oxidases (MAOs), specifically MAO-A and MAO-B, play important roles in the breakdown of monoamine neurotransmitters. Therefore, MAO inhibitors are crucial for treating various neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). In this study, we developed a novel cheminformatics pipeline by generating three diverse molecular feature-based machine learning-assisted quantitative structural activity relationship (ML-QSAR) models concerning MAO-B inhibition. PubChem fingerprints, substructure fingerprints, and one-dimensional (1D) and two-dimensional (2D) molecular descriptors were implemented to unravel the structural insights responsible for decoding the origin of MAO-B inhibition in 249 non-reductant molecules. Based on a random forest ML algorithm, the final PubChem fingerprint, substructure fingerprint, and 1D and 2D molecular descriptor prediction models demonstrated significant robustness, with correlation coefficients of 0.9863, 0.9796, and 0.9852, respectively. The significant features of each predictive model responsible for MAO-B inhibition were extracted using a comprehensive variance importance plot (VIP) and correlation matrix analysis. The final predictive models were further developed as a web application, MAO-B-pred ( https://mao-b-pred.streamlit.app/ ), to allow users to predict the bioactivity of molecules against MAO-B. Molecular docking and dynamics studies were conducted to gain insight into the atomic-level molecular interactions between the ligand-receptor complexes. These findings were compared with the structural features obtained from the ML-QSAR models, which supported the mechanistic understanding of the binding phenomena. The presented models have the potential to serve as tools for identifying crucial molecular characteristics for the rational design of MAO-B target inhibitors, which may be used to develop effective drugs for neurodegenerative disorders., (© 2024. The Author(s).)

Sixteen isatin-based hydrazone derivatives (IS1-IS16) were synthesized and assessed for their ability to inhibit monoamine oxidases (MAOs). All the molecules showed improved inhibitory MAO-B activity compared to MAO-A. Compound IS7 most potently inhibited MAO-B with an IC 50 value of 0.082 μM, followed by IS13 and IS6 (IC 50  = 0.104 and 0.124 μM, respectively). Compound IS15 most potently inhibited MAO-A with an IC 50 value of 1.852 μM, followed by IS3 (IC 50  = 2.385 μM). Compound IS6 had the highest selectivity index (SI) value of 263.80, followed by IS7 and IS13 (233.85 and 212.57, respectively). In the kinetic study, the K i values of IS6, IS7, and IS13 for MAO-B were 0.068 ± 0.022, 0.044 ± 0.002, and 0.061 ± 0.001 μM, respectively, and that of IS15 for MAO-A was 1.004 ± 0.171 μM, and the compounds were reversible-type inhibitors. The lead compounds were central nervous system (CNS) permeable, as per parallel artificial membrane permeability assay (PAMPA) test results. The lead compounds were examined for their cytotoxicity and potential neuroprotective benefits in hazardous lipopolysaccharide (LPS)-exposed SH-SY5Y neuroblastoma cells. Pre-treatment with lead compounds enhanced anti-oxidant levels (SOD, CAT, GSH, and GPx) and decreased ROS and pro-inflammatory cytokine (IL-6, TNF-alpha, and NF-kB) production in LPS-intoxicated SH-SY5Y cells. To confirm the promising effects of the compound, molecular docking, dynamics, and MM-GBSA binding energy were used to examine the molecular basis of the IS7-MAO-B interaction. Our findings indicate that lead compounds are potential therapeutic agents to treat neurological illnesses, such as Parkinson's disease., (© 2024. The Author(s).)