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Figure S3 shows relative amount of intracellular glutamine level and abundance of indicated protein levels in sorafenib-sensitive and -resistant HCC cells.

Supplementary Materials shows the figure legends of Supplementary figures and Tables.

The tyrosine kinase inhibitor sorafenib is the only therapeutic agent approved for the treatment of advanced hepatocellular carcinoma (HCC), but acquired resistance to sorafenib is high. Here, we report metabolic reprogramming in sorafenib-resistant HCC and identify a regulatory molecule, peroxisome proliferator–activated receptor-δ (PPARδ), as a potential therapeutic target. Sorafenib-resistant HCC cells showed markedly higher glutamine metabolism and reductive glutamine carboxylation, which was accompanied by increased glucose-derived pentose phosphate pathway and glutamine-derived lipid biosynthetic pathways and resistance to oxidative stress. These glutamine-dependent metabolic alterations were attributed to PPARδ, which was upregulated in sorafenib-resistant HCC cells and human HCC tissues. Furthermore, PPARδ contributed to increased proliferative capacity and redox homeostasis in sorafenib-resistant HCC cells. Accordingly, inhibiting PPARδ activity reversed compensatory metabolic reprogramming in sorafenib-resistant HCC cells and sensitized them to sorafenib. Therefore, targeting compensatory metabolic reprogramming of glutamine metabolism in sorafenib-resistant HCC by inhibiting PPARδ constitutes a potential therapeutic strategy for overcoming sorafenib-resistance in HCC.Implications: This study provides novel insight into the mechanism underlying sorafenib resistance and a potential therapeutic strategy targeting PPARδ in advanced hepatocellular carcinoma. Mol Cancer Res; 15(9); 1230–42. ©2017 AACR.

Colorectal cancer is reported to have the highest mortality rate among human malignancies. Although many research results for the treatment of colorectal cancer have been reported, there is no suitable treatment when resistance has developed. Therefore, it is necessary to develop new therapeutic agents. Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling plays an essential role in cell differentiation, proliferation, and survival. Abnormal activation of the JAK/STAT signaling pathway, by gene mutation or amplification, may induce cancer development, and sustained JAK/STAT activation is involved in chemoresistance. While many therapeutic agents have been developed to treat colon cancer, there remains no drug to overcome resistance to chemotherapies. The purpose of this study was to determine the potential of CJ14939 as a novel JAK inhibitor for the treatment of colorectal cancer.In this study, cell culture, cell death assay, 3- (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, colony formation assay, immunoblot analysis and tumor xenograft were applied.CJ14939 induced cell death, and inhibited phosphorylation of JAK1 and STAT3 in colorectal cancer cells. Furthermore, CJ14939 also promoted oxaliplatin-induced cell death, up-regulated expression of cleaved caspase-3, and down-regulated expression of phospho-JAK1 and phospho-STAT3. In vivo, co-treatment with CJ14939 and oxaliplatin notably reduced tumor growth when compared with CJ14939 or oxaliplatin treatment alone.This study identifies the important potential of CJ14939 in colorectal cancer treatment and suggests that combining CJ14939 with oxaliplatin might be a novel therapeutic strategy for patients with colorectal cancer.

Dynamic regulation of mitochondrial morphology provides cells with the flexibility required to adapt and respond to electron transport chain (ETC) toxins and mitochondrial DNA-linked disease mutations, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here, we show that pyruvate dehydrogenase kinase 4 (PDK4) is genetically required for cells to undergo rapid mitochondrial fragmentation when challenged with ETC toxins. Moreover, PDK4 overexpression was sufficient to promote mitochondrial fission even in the absence of mitochondrial stress. Importantly, we observed that the PDK4-mediated regulation of mitochondrial fission was independent of its canonical function, i.e., inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Phosphoproteomic screen for PDK4 substrates, followed by nonphosphorylatable and phosphomimetic mutations of the PDK4 site revealed cytoplasmic GTPase, Septin 2 (SEPT2), as the key effector molecule that acts as a receptor for DRP1 in the outer mitochondrial membrane to promote mitochondrial fission. Conversely, inhibition of the PDK4-SEPT2 axis could restore the balance in mitochondrial dynamics and reinvigorates cellular respiration in mitochondrial fusion factor, mitofusin 2-deficient cells. Furthermore, PDK4-mediated mitochondrial reshaping limits mitochondrial bioenergetics and supports cancer cell growth. Our results identify the PDK4-SEPT2-DRP1 axis as a regulator of mitochondrial function at the interface between cellular bioenergetics and mitochondrial dynamics.

Background Adipose-derived stem cells (ASCs) have been reported to reduce fibrosis in various tissues. In this study, we investigated the inhibitory role of ASCs on capsule formation by analyzing the histologic, cellular, and molecular changes in a mouse model of peri-implant fibrosis. We also investigated the fate and distribution of ASCs in the peri-implant capsule. Methods To establish a peri-implant fibrosis model, customized silicone implants were inserted into the dorsal site of C57BL/6 wild-type mice. ASCs were harvested from the fat tissues of transgenic mice that express a green fluorescent protein (GFP-ASCs) and then injected into the peri-implant space of recipient mice. The peri-implant tissues were harvested from postoperative week 2 to 8. We measured the capsule thickness, distribution, and differentiation of GFP-ASCs, as well as the cellular and molecular changes in capsular tissue following ASC treatment. Results Injected GFP-ASCs were distributed within the peri-implant capsule and proliferated. Administration of ASCs reduced the capsule thickness, decreased the number of myofibroblasts and macrophages in the capsule, and decreased the mRNA level of fibrogenic genes within the peri-implant tissue. Angiogenesis was enhanced due to trans-differentiation of ASCs into vascular endothelial cells, and tissue hypoxia was relieved upon ASC treatment. Conclusions We uncovered that implanted ASCs inhibit capsule formation around the implant by characterizing a series of biological alterations upon ASC treatment and the fate of injected ASCs. These findings highlight the value of ASCs for future clinical applications in the prevention of capsular contracture after implant-based reconstruction surgery.

Purpose To evaluate the effects of the concomitant use of spacer grafts in lateral tarsal strip surgery in patients with facial nerve palsy-related lower-eyelid retraction. Methods Patients who underwent lateral tarsal strip surgery to correct facial nerve palsy-related lower-eyelid retraction were retrospectively reviewed. Postoperative decreases in marginal reflex distance-2 values at 1, 2 and 6 months were measured along with the effects of spacer grafts. Results Forty-five patients (28 males) were included (mean age: 59.56 years). Mean preoperative marginal reflex distance-2 was 6.87 ± 1.34 mm. Twenty patients underwent lateral tarsal strip surgery only (lateral tarsal strip-only); 25 patients underwent lateral tarsal strip surgery using spacer grafts (lateral tarsal strip + graft). Median (interquartile range) follow-up duration was 12.0 (6.0–23.0) months. Retraction was significantly improved and maintained at 1, 2 and 6 months postoperatively in all patients (mean marginal reflex distance-2: 3.78 ± 1.06 mm, 4.30 ± 1.23 mm and 4.72 ± 1.11 mm, respectively). Surgical outcomes were significantly better in the lateral tarsal strip + graft than in the lateral tarsal strip-only group (Δmarginal reflex distance-2: 3.92 vs. 2.05 mm at 1 month, p Conclusion The concomitant use of spacer material in lateral tarsal strip surgery yielded better surgical outcomes than lateral tarsal strip surgery alone. The use of spacer grafts should be considered for correcting severe facial nerve palsy-related lower-eyelid retraction.

Background/Aims We evaluated whether anti-Saccharomyces cerevisiae antibody (ASCA) titers are associated with diagnostic findings, disease activity, Paris classification phenotypes, and persistence after infliximab (IFX) treatment in children with Crohn's disease (CD). We also investigated the role of ASCA as a predictor of mucosal healing (MH) and clinical remission (CR). Methods This study included 61 CD patients aged 19 years or younger who were diagnosed and treated between September 2010 and January 2019 and followed for at least 1 year. ASCA was regularly measured at the diagnosis of CD and at least 1 year after IFX therapy. Results The average follow-up period was 3.8±3.4 years (range, 1.0 to 7.2 years). Regression analysis showed that the ASCA titer was the only factor associated with Simple Endoscopic Score for Crohn's Disease (SES-CD) or CR among all the parameters. In patients who had achieved MH (SES-CD=0), ASCA immunoglobulin G (IgG) was not associated with MH, but in patients without MH, ASCA IgG was associated with SES-CD (p=0.005) and CR (p

Obesity is now recognized as a disease. This study revealed a novel role for pyruvate dehydrogenase kinase (PDK) in diet-induced hypertrophic obesity. Mice with global or adipose tissue-specific PDK2 deficiency were protected against diet-induced obesity. The weight of adipose tissues and the size of adipocytes were reduced. Adipocyte-specific PDK2 deficiency slightly increased insulin sensitivity in HFD-fed mice. In studies with 3T3-L1 preadipocytes, PDK2 and PDK1 expression was strongly increased during adipogenesis. Evidence was found for epigenetic induction of both PDK1 and PDK2. Gain- and loss-of-function studies with 3T3-L1 cells revealed a critical role for PDK1/2 in adipocyte differentiation and lipid accumulation. PDK1/2 induction during differentiation was also accompanied by increased expression of hypoxia-inducible factor-1α (HIF1α) and enhanced lactate production, both of which were absent in the context of PDK1/2 deficiency. Exogenous lactate supplementation increased the stability of HIF1α and promoted adipogenesis. PDK1/2 overexpression-mediated adipogenesis was abolished by HIF1α inhibition, suggesting a role for the PDK-lactate-HIF1α axis during adipogenesis. In human adipose tissue, the expression of PDK1/2 was positively correlated with that of the adipogenic marker PPARγ and inversely correlated with obesity. Similarly, PDK1/2 expression in mouse adipose tissue was decreased by chronic high-fat diet feeding. We conclude that PDK1 and 2 are novel regulators of adipogenesis that play critical roles in obesity., Obesity: Effects of different forms of key enzyme The discovery that two forms of a key enzyme appear to play a critical role in fat production triggered by overeating might lead to new approaches to prevent and treat obesity. Hyeon-Ji Kang at Kyungpook National University, Daegu, South Korea, and colleagues in South Korea and the USA examined the role of the enzymes pyruvate dehydrogenase kinase types 1 and 2 (PDK1/2). PDK enzymes regulate the activity of a multi-enzyme complex that catalyzes a key step in the use of glucose to provide energy stores for cells. Mice deficient in PDK2 were protected from diet-induced obesity, and PDK 1 and 2 activity was increased during the generation of fat cells. Studies using mice and human fat tissue confirmed that the enzymes regulate the development and growth of fat cells. Drugs inhibiting PDK enzymes might combat obesity.

This study aimed to investigate surgical outcomes of pulmonary artery (PA) sling without tracheoplasty.From 2001 through 2020, among 22 patients who underwent PA sling repair, all but 1 patient who underwent concomitant tracheal surgery were analyzed. The outcomes of interest were all-cause death, PA reintervention, tracheal intervention, and readmission for respiratory symptoms. Computed tomography was used to measure the narrowest tracheal diameter.The median age and weight at repair were 7.6 months and 7.7 kg, respectively. Most patients (20 out of 21, 95.2%) had preoperative respiratory symptoms. Associated airway anomalies included tracheal ring in 12 (57.1%), bridging bronchus in 8 (38.1%), and tracheal bronchus in 2 patients (9.5%). There was 1 in-hospital death (4.8%). The median ventilator time and intensive care unit stay were 23 hours and 3 days, respectively. There was neither late death nor tracheal intervention during follow-up. Five patients (25.0%) underwent reintervention for left PA stenosis. Hospital readmission for respiratory symptom was required in 7 patients and was associated with the narrowest preoperative tracheal diameter (P = .025) and cardiopulmonary bypass time (P = .040) in univariable analysis. The narrowest tracheal diameter of 3.4 mm was identified as a cutoff value for readmission for respiratory symptom. Freedom from readmission for respiratory symptom was 63.3% at 10 years.PA sling repair without tracheal surgery might be a reasonable surgical option with rare need for tracheal intervention. Hospital readmissions for respiratory symptoms are more frequently required in patients with smaller tracheal diameter and all readmissions were limited to within 2 years after repair.

The transcription factor orthodenticle homeobox 2 (OTX2) has critical functions in brain and eye development, and its mutations in humans are related to retinal diseases, such as ocular coloboma and microphthalmia. However, the regulatory mechanisms of OTX2 are poorly identified.The identification of JNK1 as an OTX2 regulatory protein through the protein interaction and phosphorylation.To identify the binding partner of OTX2, we performed co-immunoprecipitation and detected with a pooled antibody that targeted effective kinases. The protein interaction between JNK1 and OTX2 was identified with the co-immunoprecipitation and immunocytochemistry. In vivo and in vitro kinase assay of JNK1 was performed to detect the phosphorylation of OTX2 by JNK1.JNK1 directly interacted with OTX2 through the transactivation domain at the c-terminal region. The protein-protein interaction and co-localization between JNK1 and OTX2 were further validated in the developing P0 mouse retina. In addition, we confirmed that the inactivation of JNK1 K55N mutant significantly reduced the JNK1-mediated phosphorylation of OTX2 by performing an immune complex protein kinase assay.c-Jun N-terminal kinase 1 (JNK1) phosphorylates OTX2 transcription factor through the protein-protein interaction.

Muscle atrophy significantly impairs health and quality of life; however, there is still no cure. Recently, the possibility of regeneration in muscle atrophic cells was suggested through mitochondrial transfer. Therefore, we attempted to prove the efficacy of mitochondrial transplantation in animal models. To this end, we prepared intact mitochondria from umbilical cord-derived mesenchymal stem cells maintaining their membrane potential. To examine the efficacy of mitochondrial transplantation on muscle regeneration, we measured muscle mass, cross-sectional area of muscle fiber, and changes in muscle-specific genes. In addition, changes in the signaling mechanisms related to muscle atrophy were evaluated. As a result, in mitochondrial transplantation, the muscle mass increased by 1.5-fold and the lactate concentration decreased by 2.5-fold at 1 week in dexamethasone-induced atrophic muscles. In addition, a 2.3-fold increase in the expression of desmin protein, a muscle regeneration marker, showed a significant recovery in MT 5 µg group. Importantly, the muscle-specific ubiquitin E3-ligases MAFbx and MuRF-1 were significantly recovered through AMPK activation by mitochondrial transplantation compared with the saline group, reaching a level similar to that in the control. Taken together, the therapeutic potential of muscle atrophy through mitochondrial transplantation was confirmed.

Background: This study aims to measure the concentration of cytokines produced during the inflammation process to investigate if there are any differences in response to treatment of pediatric Crohn’s disease and to determine if the initial tumor necrosis factor-alpha (TNF-α) level affected the trough concentration of infliximab (IFX). Methods: This study included 30 pediatric patients with moderate-to-severe Crohn’s disease. At the time of diagnosis, blood samples were collected for the measurement of cytokines (IL-6, TNF-α, IL-17A, and IL-10). Blood samples were extracted from patients who had begun IFX treatment to measure the IFX trough concentration immediately before the fourth dose administration. Results: All cytokines (TNF-α, IL-6, IL-10, and IL-17A) were significantly higher in patients who did not achieve clinical or biochemical remission than in those who did (p = 0.027, 0.006, 0.017, 0.032, respectively). TNF-α had a negative correlation with the IFX trough concentration (Pearson coefficient = −0.425, p = 0.034). The diagnostic capability of the initial TNF-α concentration to predict under the therapeutic IFX trough concentration, defined as less than 3 µg/mL, had an area under the receiver operating characteristic of 0.730 (p = 0.049). The TNF-α concentration was set at 27.6 pg/mL as the cutoff value. Conclusions: Measuring cytokines at the time of diagnosis can be used to predict the treatment response. Measuring the initial TNF-α concentration may help to predict the treatment response to IFX. When the initial TNF-α concentration is greater than 27.6 pg/mL, a higher dose of IFX may be more appropriate than routinely administering 5 mg/kg of IFX to maintain the therapeutic concentration.

Since an increasing number of multicultural adolescents have started smoking in Korean society, it is necessary to check the smoking status among multicultural adolescents and provide differentiated smoking cessation education and awareness through intervention programs. This study examined the factors that influenced smoking among multicultural adolescents and identified interventions. This study was a cross-sectional survey. It used raw data from the 15th Korea Youth Risk Behavior Web-based Survey (KYRBS) of 2019. Of the 57,303 participants in the 15th KYRBS, 749 were multicultural adolescents, i.e., their fathers or mothers were not born in Korea. The factors affecting smoking among multicultural adolescents were determined using a composite sample multiple logistic regression analysis. The results of the composite sample multiple logistic regression analysis revealed that 41 (6.4%) participants were smokers, had low academic performance levels, drank alcohol, were sexually active, and were more likely to smoke with other adolescents. They were 15.79 times more likely to smoke while drinking than when not drinking. Educational and psychological interventions are needed to increase multicultural youth school adaptation and academic performance levels, reduce health risk behaviors (drinking and sexually active), and ultimately, lower the smoking rate.

Human epidermal growth factor (hEGF) has been a subject of extensive research as its wide range of physiological functions has many potential applications. However, due to the low stability of hEGF, its physiological effect is easily lost under conditions of use. To compensate for this, we developed a stable delivery system using levan-based nanoparticles. The entrapment yield of various tested proteins was significantly improved by employing carboxymethyl levan (CML) instead of levan; the entrapment yield of the CML-hEGF nanoparticles was 84.1 %. The size and zeta potential of the nanoparticles were identified as 199.9 ± 3.87 nm and -19.1 mV, respectively, using scanning electron microscopy (SEM) and particle size analysis. Dual biological functions of the nanoparticles (skin regeneration and moisturizing) were identified through collagen synthesis activity and aquaporin 3 expression level analysis. Stability of the prepared nanoparticles was also investigated via cell proliferation activity comparison under mimicked physiological conditions. The CML-hEGF nanoparticles maintained cell proliferation activity over 100 % for 6 weeks, while free hEGF was almost inactivated within 2 weeks. Taken together, our results indicate that the CML-based hEGF nanoparticles can be used in pharma- and cosmeceutical applications, guaranteeing a high entrapment capability, functionality, and stability.

Objectives: The present study is aimed an electropalatographic investigation of Korean fricatives /s/ and /s*/. All data from this study is based on the production of 5- adult speakers who speak Korean as their first language.Methods: Electropalatography (EPG) is an instrumental technique for showing tongue and palate contact during speech. The participants recorded /s/ and /s*/ in CV (/si/, /sɑ/, /su/, /s*i/, /s*ɑ/, /s*u/) and VCV (/ɑsi/, /ɑsɑ/, /ɑsu/, /ɑs*i/, /ɑs*ɑ/, /ɑs*u/) context using EPG and then, four variables were analyzed: row of medial groove (RMG), medial groove width (MGW), medial groove length (MGL), and maximum contact frame (MCF).Results: There was significantly greater medial groove width and maximum contact frame for / s*/ compared to /s/. The difference between /si/ and /sɑ/ was also found in the row of medial groove, medial groove width and maximum contact frame. /si/ was produced further back, and had a longer medial groove length. Also, it showed more total tongue-palate contact than /sa/.Conclusion: A various range of palatal contact patterns were found between typical adults for perceptually normal /s/ and /s*/. The results provided the information about tongue–palate pattern of Korean fricatives /s/ and /s*/. These findings would be utilized to build the basic data and useful information for Korean EPG system.

Background and objective This study was conducted to increase understanding of agriculture through agricultural experience programs for adolescents living in self-reliance residence hall, and to investigate changes in work performance ability through changes in hand function. Methods There were 11 subjects, and the average age was 18.2 years, all males without disabilities. The agricultural experience program consists of a total of 10 sessions including orientation and watching videos on future agriculture, creating vegetable gardens, planting, managing each crop, harvesting, visiting the processing room, and selling at a local food store. Results The change in agricultural literacy by the agricultural experience program positively improved from a score of 113.73 to 127.91 (p = .008). The changes by sub-item are as follows. The value and safety of agri-foods (p = .020) and agriculture and natural environment (p = .007) were significantly improved. The function and value of rural areas (p = .050), production of agricultural products (p = .160), processing and distribution of agricultural products (p = .248), and agricultural policies (p = .058) were not significantly changed. The simple function of the hands was measured by the number of pegs inserted during 30 seconds, and the assembly function was measured by the number of pegs inserted during 60 seconds. In the case of simple function, the dominant hand was improved from 14.82 to 15.83 (p = .014), and the non-dominant hand was also significantly improved from 13.79 to 15.01 (p = .002). There was no significant improvement in the simple function (p = .153) and assembly function (p = .770) of both hands. Conclusion It is considered that the agricultural experience program will enable youths living in self-reliance residence halls to enhance their understanding of agriculture as an occupation, and enable them to play a role as wise consumers by positively affecting improvements in their agricultural literacy and simple hand functions.

Rapidly proliferating cells such as vascular smooth muscle cells (VSMCs) require metabolic programs to support increased energy and biomass production. Thus, targeting glutamine metabolism by inhibiting glutamine transport could be a promising strategy for vascular disorders such as atherosclerosis, stenosis, and restenosis. V-9302, a competitive antagonist targeting the glutamine transporter, has been investigated in the context of cancer; however, its role in VSMCs is unclear. Here, we examined the effects of blocking glutamine transport in fetal bovine serum (FBS)- or platelet-derived growth factor (PDGF)-stimulated VSMCs using V-9302. We found that V-9302 inhibited mTORC1 activity and mitochondrial respiration, thereby suppressing FBS- or PDGF-stimulated proliferation and migration of VSMCs. Moreover, V-9302 attenuated carotid artery ligation-induced neointima in mice. Collectively, the data suggest that targeting glutamine transport using V-9302 is a promising therapeutic strategy to ameliorate occlusive vascular disease.

Fructan is a polysaccharide composed of fructose and can be classified into several types, such as inulin, levan, and fructo-oligosaccharides, based on their linkage patterns and degree of polymerization. Owing to its structural and functional diversity, fructan has been used in various fields including prebiotics, foods and beverages, cosmetics, and pharmaceutical applications. With increasing interest in fructans, efficient and straightforward production methods have been explored. Since the 1990s, yeast cells have been employed as producers of recombinant enzymes for enzymatic conversion of fructans including fructosyltransferases derived from various microbes and plants. More recently, yeast cell factories are highlighted as efficient workhorses for fructan production by direct fermentation. In this review, recent advances and strategies for fructan biosynthesis by yeast cell factories are discussed.

Dysregulated Wnt signaling is associated with malignant oncogenic transformation, especially in colon cancer. Recently, numerous drugs have been developed based on tumorigenesis biomarkers, thus having high potential as drug targets. Likewise, WNT/β-catenin pathway members are attractive therapeutic targets for colon cancer and are currently in various stages of development. However, although inhibitors of proteins regulating the WNT/β-catenin signaling pathway have been extensively studied, they have yet to be clinically approved, and the underlying molecular mechanism(s) of their anticancer effects remain poorly understood. Herein, we show that a novel WNT/β-catenin inhibitor, DGG-300273, inhibits colon cancer cell growth in a Wnt-dependent manner due to upregulation of the BCL2-family protein Bim and caspase-dependent apoptotic cell death. Additionally, DGG-300273-mediated cell death occurs by increased reactive oxygen species (ROS), as shown by abrogation of apoptotic cell death and ROS production following pretreatment with the antioxidant N-acetylcysteine. These results suggest that DGG-300273 represents a promising investigational drug for the treatment of Wnt-associated cancer, thus warranting further characterization and study.

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With the increasing incidence of pediatric inflammatory bowel disease (IBD) in children and its impact throughout life, transition care has become an important issue. In Korea, no guidelines have been proposed to support the transition from the pediatric clinic to the adult IBD clinic. This paper reviews the current issues related to IBD patient care during the transition from pediatrics to adults to identify the barriers and critical elements for a successful transition. Thus far, a multi-disciplinary pediatric/adult clinic or alternate visits between pediatric and adult health care providers is the best model for pediatric to adult IBD clinics. Self-reliance and independence of patients with pediatric IBD are also essential for a successful transition. In addition, the timing of the transition from a pediatric clinic to an adult IBD clinic should not be determined because the issue is not the chronological age but rather the individual maturity.

Endocrine-disrupting compounds (EDCs) disrupt homeostasis via the dysregulation of hormone synthesis and metabolism. Bisphenol A (BPA) is widely used in consumer products, such as thermal receipts, water bottles, and baby bottles. However, BPA is also an EDC that acts as an estrogen agonist, and human exposure to BPA can lead to estrogenic effects. Consequently, manufacturers have started investigating the properties and effects of alternatives to BPA, molecules such as bisphenol F (BPF) and bisphenol S (BPS). Although multiple studies have demonstrated the adverse effect of bisphenols, it remains unknown whether bisphenols affect human lung fibroblast cells. In this study, we investigated the cytotoxic effects of BPA, BPF, and BPS on the MRC5 human lung fibroblast cell line. We examined and compared the effects of BPA and its alternatives on cell proliferation, cell cycle progression, and apoptosis. Brief exposures to low concentrations of BPA, BPF, and BPS had no effects on cell viability, cell cycle progression, or apoptosis among MRC5 human lung fibroblast cells.

Background Umbilical cord-mesenchymal stem cell-conditioned medium (UC-MSC-CM) has emerged as a promising cell-free therapy. The aim of this study was to explore the therapeutic effects of UC-MSC-CM on insulin resistance in C2C12 cell. Methods Insulin resistance was induced by palmitate. Effects of UC-MSC-CM on insulin resistance were evaluated using glucose uptake, glucose transporter type 4 (GLUT4) translocation, the insulin-signaling pathway, and mitochondrial contents and functions in C2C12 cell. Results Glucose uptake was improved by UC-MSC-CM. UC-MSC-CM treatment increased only in membranous GLUT4 expression, not in cytosolic GLUT4 expression. It restored the insulin-signaling pathway in insulin receptor substrate 1 and protein kinase B. Mitochondrial contents evaluated by mitochondrial transcription factor A, mitochondrial DNA copy number, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha were increased by UC-MSC-CM. In addition, UC-MSC-CM significantly decreased mitochondrial reactive oxygen species and increased fatty acid oxidation and mitochondrial membrane potential. There was no improvement in adenosine triphosphate (ATP) contents, but ATP synthesis was improved by UC-MSC-CM. Cytokine and active factor analysis of UC-MSC-CM showed that it contained many regulators inhibiting insulin resistance. Conclusion UC-MSC-CM improves insulin resistance with multiple mechanisms in C2C12 cell.

Objectives We investigated the therapeutic drug monitoring of adalimumab (ADL) on clinical remission (CR) and mucosal healing (MH) rates in paediatric patients with Crohn disease (CD). Furthermore, long-term treatment efficacy of ADL in paediatric CD was evaluated through 3-year follow-up. Methods We conducted a prospective study of 31 patients with CD who received ADL maintenance therapy and underwent endoscopic evaluation of MH and pharmacokinetic analysis. Patients in CR were identified based on Paediatric Crohn Disease Activity Index (PCDAI) scores less than 10. Patients with MH were identified based on Simple Endoscopic Scores for Crohn Disease (SES-CD) of less than 2. Results At 4 months and 1 year of ADL treatment, 28 and 26 patients, respectively, were under CR; 13 and 17 patients, respectively, achieved MH. The median trough levels (TLs) of ADL were higher in patients in CR (7.6 ± 3.5 μg/mL) than in patients with active disease (5.1 ± 2.2 μg/mL). ADL TLs were significantly higher in patients who achieved MH than in those who did not (14.2 ± 7.6 vs 7.8 ± 5.2 μg/mL). The optimal cut-point for predicting MH at 1 year of ADL treatment was 8.18 μg/mL. During long-term follow-up, ADL TLs were stably maintained over 10 μg/mL; not only CR and MH but also histologic remission was obtained at a high rate. ADL administration maintained a positive effect on growth during the maintenance period. Conclusions ADL TLs were significantly higher in paediatric patients with CD who achieved CR or MH. ADL treatment showed long-term stable efficacy and positive effects on growth indicators.