Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global health issue due to its increasing prevalence associated with lifestyle changes and its strong correlation with metabolic syndrome. Farnesoid X receptor (FXR) is a nuclear receptor that plays a pivotal role in regulating bile acid, lipid, and glucose metabolism, making it an attractive therapeutic target for liver and metabolic diseases. In this study, we investigated the effects of MHY5456, a synthetic agonist of FXR, on hepatic metabolism and fibrosis. MHY5456 enhanced the transcriptional activity of FXR in a concentration-dependent manner.Treatment of AC2F rat liver-derived cells with MHY5456 resulted in the downregulation of genes involved in lipid accumulation and an upregulation of mitochondrial-related gene expression. Additionally, MHY5456 significantly reduced oleic acid (OA)-induced lipid accumulation. To assess its anti-fibrotic potential, we tested its effects on transforming growth factor-beta (TGF-β)-induced fibrosis in LX2 human hepatic stellate cells (HSCs). MHY5456 significantly suppressed the expression of fibrosis-related genes and proteins. In vivo, administration of MHY5456 to mice fed a methionine-choline-deficient (MCD) diet alleviated hepatic fibrosis, inflammation, and lipid accumulation. These results show that FXR activation by MHY5456 modulates lipid metabolism and fibrotic pathways, suggesting its potential as a pharmacological candidate for liver and metabolic disorders, including MASLD. Further pharmacological and toxicological studies are needed to confirm its therapeutic relevance.

Background: Coronary artery disease patients undergoing percutaneous coronary intervention (PCI) often exhibit reduced left ventricular ejection fraction (LVEF). However, the impact of LV dysfunction status in conjunction with platelet reactivity on clinical outcomes has not been previously investigated. Methods: From the multicenter PTRG-DES (Platelet function and genoType-Related long-term prognosis in DES-treated patients) consortium, the patients were classified as preserved-EF (PEF: LVEF ≥ 50%) and reduced-EF (REF: LVEF< 5 0%) group by echocardiography. Platelet reactivity was measured using VerifyNow P2Y 12 assay and high platelet reactivity (HPR) was defined as PRU ≥ 252. The major adverse cardiac and cerebrovascular events (MACCEs) were a composite of death, myocardial infarction, stent thrombosis and stroke at 5 years after PCI. Major bleeding was defined as Bleeding Academic Research Consortium bleeding types 3–5. Results: A total of 13,160 patients from PTRG-DES, 9,319 (79.6%) patients with the results of both PRU and LVEF were analyzed. The incidence of MACCE and major bleeding was higher in REF group as compared with PEF group (MACCEs: hazard ratio [HR] 2.17, P < 0.001, 95% confidence interval [CI] 1.85–2.55; major bleeding: HR 1.78, P < 0.001, 95% CI 1.39–2.78).The highest rate of MACCEs was found in patients with REF and HPR, and the difference between the groups was statistically significant (HR 3.14 in REF(+)/HPR(+) vs. PEF(+)/HPR(-) group,P <0.01, 95% CI 2.51–3.91). The frequency of major bleeding was not associated with the HPR in either group. Conclusion LV dysfunction was associated with an increased incidence of MACCEs and major bleeding in patients who underwent PCI. The HPR status further exhibited significant increase of MACCEs in patients with LV dysfunction in a large, real-world registry.Trial Registration: ClinicalTrials.gov Identifier: NCT04734028

Purpose: Platelet function test (PFT) results and genotype hold unique prognostic implications in East Asian patients. The aim of the PTRG-DES (Platelet function and genoType-Related long-term proGnosis in Drug-Eluting Stent-treated Patients with coronary artery disease) consortium is to assess the clinical impact thereof on long-term clinical outcomes in Korean patients with coronary artery disease during dual antiplatelet therapy (DAPT) including clopidogrel. Materials and Methods: Searching publications on the PubMed, we reviewed clopidogrel treatment studies with PFT and/or genotype data for potential inclusion in this study. Lead investigators were invited to share PFT/genotype results, patient characteristics, and clinical outcomes to evaluate relationships among them. Results: Nine registries from 32 academic centers participated in the PTRG-DES consortium, contributing individual patient data from 13160 patients who underwent DES implantation between July 2003 and August 2018. The PTRG-PFT cohort was composed of 11714 patients with available VerifyNow assay results. Platelet reactivity levels reached 218±79 P2Y12 reaction units (PRU), and high on-clopidogrel platelet reactivity based on a consensus-recommended cutoff (PRU >208) was observed in 55.9%. The PTRGGenotype cohort consisted of 8163 patients with candidate genotypes related with clopidogrel responsiveness. Of those with cytochrome P450 (CYP) 2C19 genotype, frequencies of carrying one and two loss-of-function allele (s) (*2 or *3) were 47.9% (intermediate metabolizers) and 14.2% (poor metabolizers), respectively. Conclusion The PTRG-DES consortium highlights unique values for on-clopidogrel platelet reactivity and CYP2C19 phenotype that may be important to developing optimal antiplatelet regimens in East Asian patients.

Background: Protease-activated protein-2 (PAR2) has been reported to regulate hepatic insulin resistance condition in type 2 diabetes mice. However, the mechanism of lipid metabolism through PAR2 in obesity mice have not yet been examined. In liver, Forkhead box O1 (FoxO1) activity induces peroxisome proliferator-activated receptor γ (PPARγ), leading to accumulation of lipids and hyperlipidemia. Hyperlipidemia significantly influence hepatic steatoses, but the mechanisms underlying PAR2 signaling are complex and have not yet been elucidated. Methods: To examine the modulatory action of FoxO1 and its altered interaction with PPARγ, we utilized db/db mice and PAR2-knockout (KO) mice administered with high-fat diet (HFD). Results: Here, we demonstrated that PAR2 was overexpressed and regulated downstream gene expressions in db/db but not in db+ mice. The interaction between PAR2/β-arrestin and Akt was also greater in db/db mice. The Akt inhibition increased FoxO1 activity and subsequently PPARγ gene in the livers that led to hepatic lipid accumulation. Our data showed that FoxO1 was negatively controlled by Akt signaling and consequently, the activity of a major lipogenesis-associated transcription factors such as PPARγ increased, leading to hepatic lipid accumulation through the PAR2 pathway under hyperglycemic conditions in mice. Furthermore, the association between PPARγ and FoxO1 was increased in hepatic steatosis condition in db/db mice. However, HFD-fed PAR2-KO mice showed suppressed FoxO1-induced hepatic lipid accumulation compared with HFD-fed control groups. Conclusion Collectively, our results provide evidence that the interaction of FoxO1 with PPARγ promotes hepatic steatosis in mice. This might be due to defects in PAR2/β-arrestin-mediated Akt signaling in diabetic and HFD-fed mice.

Purpose: Data on the distribution and impact of panel reactive antibodies (PRA) and donor specific antibodies (DSA) before lung transplantation in Asia, especially multi-center-based data, are limited. This study evaluated the prevalence of and effects of PRA and DSA levels before lung transplantations on outcomes in Korean patients using nationwide multicenter registry data. Materials and Methods: This study included 103 patients who received a lung transplant at five tertiary hospitals in South Korea between March 2015 and December 2017. Mortality, primary graft dysfunction (PGD), and bronchiolitis obliterans syndrome (BOS) were evaluated. Results: Sixteen patients had class I and/or class II PRAs exceeding 50%. Ten patients (9.7%) had DSAs with a mean fluorescence intensity (MFI) higher than 1000, six of whom had antibodies with a high MFI (≥2000). DSAs with high MFIs were more frequently observed in patients with high-grade PGD (≥2) than in those with no or low-grade (≤1) PGD. In the 47 patients who survived for longer than 9 months and were evaluated for BOS after the transplant, BOS was not related to DSA or PRA levels. One-year mortality was more strongly related to PRA class I exceeding 50% than that under 50% (0% vs. 16.7%, p=0.007). Conclusion Preoperative DSAs and PRAs are related to worse outcomes after lung transplantation. DSAs and PRAs should be considered when selecting lung transplant recipients, and recipients who have preoperative DSAs with high MFI values and high PRA levels should be monitored closely after lung transplantation.

Background/Objectives: To analyze the clinical characteristics of differentiated thyroid cancer (DTC) in children and adolescents.Materials & Methods: Medical records of 31 DTC cases that were diagnosed and treated at Korea Cancer Center Hospital between 2002 and 2018 were retrospectively reviewed. Results: Most cases were papillary carcinoma (n=26), with female predominance (n=25). Median age was 16.4 years (range, 11.9-18.6 years). Extrathyroidal extension was present in 24 cases. Twenty cases had tumor involvement at cervical lymph nodes and three had lung metastasis. Twenty-two patients received radioactive iodide treatment with a median cumulative dose of 300 mCi (range, 100-920 mCi). During a median follow-up of 68.2 months (range, 2.3-191.4 months), serum thyroglobulin level was elevated in 15 patients. Among them, two cases had remnant thyroid tissue, 4 had recurrence at cervical lymph nodes, and the remaining 9 did not have any detectable lesion. All were alive, and 5-year event-free survival (EFS) was 45.2±10.1%. Age £15 years, tumor size, lymph node status (N1b), and distant metastasis had negative effects on EFS. On multivariate analysis, age and tumor size had prognostic significance. Conclusion For DTC of children and adolescents (£18 years old), age ≤15 years and tumor size were prognostic factor. Therefore, patients in this age group need meticulous follow-up. Further studies are necessary to answer the potential influence of age on the incidence and behavior of DTC.

Background/Objectives: To analyze the clinical characteristics of differentiated thyroid cancer (DTC) in children and adolescents.Materials & Methods: Medical records of 31 DTC cases that were diagnosed and treated at Korea Cancer Center Hospital between 2002 and 2018 were retrospectively reviewed. Results: Most cases were papillary carcinoma (n=26), with female predominance (n=25). Median age was 16.4 years (range, 11.9-18.6 years). Extrathyroidal extension was present in 24 cases. Twenty cases had tumor involvement at cervical lymph nodes and three had lung metastasis. Twenty-two patients received radioactive iodide treatment with a median cumulative dose of 300 mCi (range, 100-920 mCi). During a median follow-up of 68.2 months (range, 2.3-191.4 months), serum thyroglobulin level was elevated in 15 patients. Among them, two cases had remnant thyroid tissue, 4 had recurrence at cervical lymph nodes, and the remaining 9 did not have any detectable lesion. All were alive, and 5-year event-free survival (EFS) was 45.2±10.1%. Age £15 years, tumor size, lymph node status (N1b), and distant metastasis had negative effects on EFS. On multivariate analysis, age and tumor size had prognostic significance. Conclusion For DTC of children and adolescents (£18 years old), age ≤15 years and tumor size were prognostic factor. Therefore, patients in this age group need meticulous follow-up. Further studies are necessary to answer the potential influence of age on the incidence and behavior of DTC.

OBJECTIVE: Subdural effusion, also known as subdural hygroma (SDG), is a secondary complication that can occur after decompressive craniectomy (DC). However, the pathogenesis of SDG is not fully understood. It is unclear whether SDG occurrence is related to preoperative patient status or surgical technique. The purpose of this study is to identify risk factors for SDG after DC. METHODS: Fifty-nine patients who underwent DC from January 2016 to December 2016 at the same institution were analyzed. We retrospectively reviewed the clinical and radiological features of the patients. We divided the patients into two groups based on the occurrence of SDG after DC. The risk factors for SDG were analyzed. RESULTS: The overall SDG rate after DC was 39% (23 patients). A statistically significant association was observed between preoperative diagnosis, e.g., subdural hemorrhage (SDH; odds ratio [OR], 4.99; 95% confidence interval [CI], 1.36–18.34) or subarachnoid hemorrhage (SAH; OR, 4.18; 95% CI, 1.07–16.32), and the occurrence of SDG after DC. Traumatic brain injury (OR, 4.91; 95% CI, 1.35–17.91) and preoperative cortical opening (OR, 4.77; 95% CI, 1.39–16.32) were important risk factors for SDG. Several surgical techniques did not show a statistically significant association with SDG. The occurrence of SDG after DC was related to the length of hospital stay (p=0.012), but not to prognosis. CONCLUSION: After DC, SDG is not related to patients' prognosis but to the length of hospital stay. Therefore, it is necessary to study the occurrence of postoperative SDG by confirming the presence of preoperative SDH, SAH, and cortical opening.
Brain Injuries ; Decompressive Craniectomy* ; Diagnosis ; Hematoma, Subdural ; Humans ; Length of Stay ; Odds Ratio ; Prognosis ; Retrospective Studies ; Risk Factors* ; Subarachnoid Hemorrhage ; Subdural Effusion*

PURPOSE: Nanoparticles (NPs) may cause cell and tissue damage, leading to local and systemic inflammatory responses and adverse effects on health due to the inhalation of particulate matter. The inflammasome is a major regulator of inflammation through its activation of pro-caspase-1, which cleaves pro-interleukin-1β (pro-IL-1β) into its mature form and may induce acute and chronic immune responses to NPs. However, little is known about the response of the inflammasome to NP exposure via the airways in asthma. The aim of this study was to identify the impact of titanium dioxide (TiO2) NPs on inflammasome in a mouse model of allergic asthma. METHODS: Mice were treated with ovalbumin (OVA) or TiO₂ NPs. IL-1β, IL-18, NAIP, CIITA, HET-E, TP-2 (NACHT), leucine-rich repeat (LRR), pyrin domain-containing protein 3 (NLRP3), and caspase-1 were assessed by Western blotting. Caspase-1 was assessed by immunohistochemistry (IHC). Levels of reactive oxygen species (ROS)—as markers of oxidative damage—and the mediators 8-isoprostane and carbonyl were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Airway hyperresponsiveness (AHR) and inflammation were increased in OVA-sensitized/challenged mice, and these responses were exacerbated by exposure to TiO₂ NPs. NP treatment increased IL-1β and IL-18 expression in OVA-sensitized/challenged mice. NPs augmented the expression of NLRP3 and caspase-1, leading to production of active caspase-1 in the lung. Caspase-1 expression was increased and exacerbated by TiO₂ NP exposure in OVA-sensitized/challenged mice. ROS levels tended to be increased in OVA-sensitized/challenged and OVA-sensitized/challenged-plus-TiO₂ NP-exposed mice. CONCLUSIONS: Our data demonstrated that inflammasome activation occured in asthmatic lungs following NP exposure, suggesting that targeting the inflammasome may assist in controling NP-induced airway inflammation and hyperresponsiveness.
Animals ; Asthma ; Blotting, Western ; Caspase 1 ; Enzyme-Linked Immunosorbent Assay ; Immunohistochemistry ; Inflammasomes ; Inflammation* ; Inhalation ; Interleukin-18 ; Lung ; Mice ; Nanoparticles* ; Ovalbumin ; Particulate Matter ; Reactive Oxygen Species ; Titanium

OBJECTIVE: The aim of the present study was to investigate differences in discontinuation time among antidepressants and total antidepressant discontinuation rate of patients with depression over a 6 month period in a naturalistic treatment setting. METHODS: We reviewed the medical records of 900 patients with major depressive disorder who were initially prescribed only one kind of antidepressant. The prescribed antidepressants and the reasons for discontinuation were surveyed at baseline and every 4 weeks during the 24 week study. We investigated the discontinuation rate and the mean time to discontinuation among six antidepressants groups. RESULTS: Mean and median overall discontinuation times were 13.8 and 12 weeks, respectively. Sertraline and escitalopram had longer discontinuation times than that of fluoxetine, and patients who used sertraline discontinued use significantly later than those taking mirtazapine. No differences in discontinuation rate were observed after 24 weeks among these antidepressants. About 73% of patients discontinued antidepressant treatment after 24 weeks. CONCLUSION: Sertraline and escitalopram tended to have longer mean times to discontinuation, although no difference in discontinuation rate was detected between antidepressants after 24 weeks. About three-quarters of patients discontinued antidepressant maintenance therapy after 24 weeks.
Antidepressive Agents* ; Citalopram ; Depression ; Depressive Disorder, Major* ; Fluoxetine ; Humans ; Medical Records ; Sertraline