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Background: Concomitant use of clopidogrel and proton pump inhibitor (PPI) is common, but PPI may reduce the antiplatelet effects of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We evaluated the impact of PPI use on clinical outcomes in post-PCI patients, by incorporating P2Y12 reaction unit (PRU) and CYP2C19 genotyping results., Methods: From a multicenter registry of patients who underwent PCI with drug-eluting stent implantation and received clopidogrel-based dual antiplatelet therapy (DAPT), patients who were prescribed a PPI at the time of PCI (PPI users) were compared to those who were not (non-users). The primary outcome included all-cause death, myocardial infarction, stent thrombosis, or cerebrovascular accident at 12 months. Major bleeding (Bleeding Academic Research Consortium [BARC] types 3-5) and gastrointestinal (GI) bleeding (BARC types 3-5) were important secondary outcomes. The adjusted outcomes were compared using a 1:1 propensity-score (PS) matching and competing risk analysis., Results: Of 13,160 patients, 2,235 (17.0%) were prescribed PPI, with an average age of 65.4 years. PPI users had higher on-treatment PRU levels than non-users. After PS matching, the primary outcome occurred in 51 patients who were PPI users (cumulative incidence, 4.7%) and 41 patients who were non-users (cumulative incidence, 3.7%; log-rank p = 0.27). In carriers of both CYP2C19 loss-of-function alleles, PPI use was linked to an increased risk of the primary outcome (hazard ratio, 3.22; 95% confidence interval, 1.18-8.78). The incidence of major bleeding and GI bleeding (BARC types 3-5) was comparable between PPI users and non-users in the PS-matched cohort., Conclusions: In post-PCI patients receiving clopidogrel-based DAPT, PPI use was not linked to an increased risk of adverse cardiac and cerebrovascular events, but there was a small but significant increase in on-treatment PRU. Future research using a more individualized approach would further elucidate these interactions and guide evidence-based clinical practices., (© 2024. The Author(s).)

Acrylic resins are widely used as the main components in removable orthodontic appliances. However, poor oral hygiene and maintenance of orthodontic appliances provide a suitable environment for the growth of pathogenic microorganisms. In this study, strontium-modified phosphate-based glass (Sr-PBG) was added to orthodontic acrylic resin at 0% (control), 3.75%, 7.5%, and 15% by weight to evaluate the surface and physicochemical properties of the novel material and its in vitro antifungal effect against Candida albicans (C. albicans). Surface microhardness and contact angle did not vary between the control and 3.75% Sr-PBG groups (p > 0.05), and the flexural strength was lower in the experimental groups than in the control group (p < 0.05), but no difference was found with Sr-PBG content (p > 0.05). All experimental groups showed an antifungal effect at 24 and 48 h compared to that in the control group (p < 0.05). This study demonstrated that 3.75% Sr-PBG exhibits antifungal effects against C. albicans along with suitable physicochemical properties, which may help to minimize the risk of adverse effects associated with harmful microbial living on removable orthodontic appliances and promote the use of various materials., (© 2024. The Author(s).)

Background: Diabetes mellitus (DM) is associated with thrombogenicity, clinically manifested with atherothrombotic events after percutaneous cutaneous intervention (PCI). This study aimed to investigate association between DM status and platelet reactivity, and their prognostic implication in PCI-treated patients., Methods: The Platelet function and genoType-Related long-term Prognosis-Platelet Function Test (PTRG-PFT) cohort was established to determine the linkage of platelet function test (PFT) with long-term prognosis during dual antiplatelet therapy including clopidogrel in patients treated with drug-eluting stent (DES). We assessed platelet reactivity using VerifyNow and 'high platelet reactivity (HPR)' was defined as ≥ 252 P2Y12 reaction unit (PRU). Major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, myocardial infarction, stent thrombosis or stroke., Results: Between July 2003 and Aug 2018, DES-treated patients with available PFT were enrolled (n = 11,714). Diabetic patients demonstrated significant higher levels of platelet reactivity (DM vs. non-DM: 225.7 ± 77.5 vs. 213.6 ± 79.1 PRU, P < 0.001) and greater prevalence of HPR compared to non-diabetic patients (38.1% vs. 32.0%, P < 0.001). PRU level and prevalence of HPR were significantly associated with insulin requirement and Hb A1c level, as well as diabetic status. DM status and HPR phenotype had a similar prognostic implication, which showed the synergistic clinical impact on MACCE. Association between PRU level and MACCE occurrence seemed higher in diabetic vs. non-diabetic patients. In non-DM patients, HPR phenotype did not significantly increase the risk of MACCE (adjusted hazard ratio [HR adj ]: 1.073; 95% confidence interval [CI]: 0.869-1.325; P = 0.511), whereas HPR was an independent determinant for MACCE occurrence among diabetic patients (HR adj : 1.507; 95% CI: 1.193-1.902; P < 0.001)., Conclusion: The levels of on-clopidogrel platelet reactivity are determined by diabetic status and the severity of DM. In addition, HPR phenotype significantly increases the risk of MACCE only in diabetic patients., Clinical Trial Registration: URL: https://www., Clinicaltrials: gov . Unique identifier: NCT04734028., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Data on drug-coated balloon (DCB) treatment in the context of diabetes mellitus (DM) and multivessel coronary artery disease (CAD) are limited. We aimed to investigate the clinical impact of DCB-based revascularization on percutaneous coronary intervention (PCI) in patients with DM and multivessel CAD., Methods: A total of 254 patients with multivessel disease (104 patients with DM) successfully treated with DCB alone or combined with drug-eluting stent (DES) were retrospectively enrolled (DCB-based group) and compared with 254 propensity-matched patients treated with second-generation DES from the PTRG-DES registry (n = 13,160 patients) (DES-only group). Major adverse cardiovascular events (MACE) comprised cardiac death, myocardial infarction, stroke, stent or target lesion thrombosis, target vessel revascularization, and major bleeding at 2 years., Results: The DCB-based group was associated with a reduced risk of MACE in patients with DM (hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.05-0.68, p = 0.003], but not in those without DM (HR 0.52, 95% CI 0.20-1.38, p = 0.167) at the 2-year follow-up. In patients with DM, the risk of cardiac death was lower in the DCB-based group than the DES-only group, but not in those without DM. In both patients with or without DM, the burdens of DES and small DES (less than 2.5 mm) used were lower in the DCB-based group than in the DES-only group., Conclusions: In multivessel CAD, the clinical benefit of a DCB-based revascularization strategy appears to be more evident in patients with DM than in those without DM after 2 years of follow-up. (Impact of Drug-Coated Balloon Treatment in De Novo Coronary Lesion; NCT04619277)., (© 2023. The Author(s).)

The morphological dynamics of astrocytes are altered in the hippocampus during memory induction. Astrocyte-neuron interactions on synapses are called tripartite synapses. These control the synaptic function in the central nervous system. Astrocytes are activated in a reactive state by STAT3 phosphorylation in 5XFAD mice, an Alzheimer's disease (AD) animal model. However, changes in astrocyte-neuron interactions in reactive or resting-state astrocytes during memory induction remain to be defined. Here, we investigated the time-dependent changes in astrocyte morphology and the number of astrocyte-neuron interactions in the hippocampus over the course of long-term memory formation in 5XFAD mice. Hippocampal-dependent long-term memory was induced using a contextual fear conditioning test in 5XFAD mice. The number of astrocytic processes increased in both wild-type and 5XFAD mice during memory formation. To assess astrocyte-neuron interactions in the hippocampal dentate gyrus, we counted the colocalization of glial fibrillary acidic protein and postsynaptic density protein 95 via immunofluorescence. Both groups revealed an increase in astrocyte-neuron interactions after memory induction. At 24 h after memory formation, the number of tripartite synapses returned to baseline levels in both groups. However, the total number of astrocyte-neuron interactions was significantly decreased in 5XFAD mice. Administration of Stattic, a STAT3 phosphorylation inhibitor, rescued the number of astrocyte-neuron interactions in 5XFAD mice. In conclusion, we suggest that a decreased number of astrocyte-neuron interactions may underlie memory impairment in the early stages of AD., (© 2021. The Author(s).)

Background: This study aimed to evaluate the prognostic value of pretreatment 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) in patients with localized primary gastrointestinal stromal tumors (GISTs) and to compare the predictive values of 18 F-FDG PET/CT parameters with those of clinicopathological prognostic factors., Methods: Sixty-two localized GIST patients who underwent staging with 18 F-FDG PET/CT from January 2007 to December 2013 before surgery were retrospectively enrolled. A volume of interest with a standardized uptake value (SUV) threshold of 2.5 was used to determine the metabolic tumor volume (MTV) and total lesion glycolysis (TLG). These metabolic indices, along with the maximum SUV (SUVmax), were analyzed to evaluate recurrence-free survival (RFS). Other significant clinical and pathologic indices were also retrospectively reviewed for RFS analysis., Results: Patients were followed up for a median of 42.0 months (range, 5.6-111.5). During the follow-up period, 13 patients (21.0%) experienced disease recurrence. In univariate analysis, tumor size (> 5 cm), mitotic count (> 5/high-power field), modified National Institutes of Health (NIH) consensus criteria, adjuvant imatinib treatment, SUVmax (≥ 7.04), MTV (≥ 50.76 cm 3 ), and TLG (≥ 228.79 g) were significant prognostic factors affecting RFS (p < 0.05). In multivariate analysis, only MTV (hazard ratio, 17.69; 95% confidence interval [CI], 2.03-154.17, p = 0.009) and TLG (hazard ratio, 20.48; 95% CI, 2.19-191.16, p = 0.008) were independent prognostic factors for RFS. The 5-year RFS rates were 96.4% and 96.6% in patients with a low MTV and TLG and 27.3% and 23.6% in patients with a high MTV and TLG, respectively (p < 0.001)., Conclusion: MTV and TLG are independent prognostic factors for predicting recurrence in patients with localized primary GIST. Patients with a high MTV or TLG are at risk for poor prognosis and should be closely observed for disease recurrence.

Background: Vitrification is the most promising technology for successful cryopreservation of living organisms without ice crystal formation. However, high concentrations (up to ~ 6-8 M) of cryoprotective agents (CPAs) used in stem cell induce osmotic and metabolic injuries. Moreover, the application of conventional slow-freezing methods to cultures of 3-D organoids of stem cells in various studies, is limited by their size., Results: In this study, we evaluated the effect of high concentrations of CPAs including cytotoxicity and characterized human mesenchymal stem cell (MSC) at single cell level. The cell viability, cellular damage, and apoptotic mechanisms as well as the proliferation capacity and multipotency of cells subjected to vitrification were similar to those in the slow-freezing group. Furthermore, we identified the possibility of vitrification of size-controlled 3-D spheroids for cryopreservation of organoid with high survivability., Conclusions: Our results demonstrate successful vitrification of both single cell and spheroid using high concentration of CPAs in vitro without cytotoxicity.

Background: TDP-43 proteinopathy is a prominent pathological feature that occurs in a number of human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and inclusion body myositis (IBM). Our recent finding that TDP-43 represses nonconserved cryptic exons led us to ask whether cell type-specific cryptic exons could exist to impact unique molecular pathways in brain or muscle., Methods: In the present work, we investigated TDP-43's function in various mouse tissues to model disease pathogenesis. We generated mice to conditionally delete TDP-43 in excitatory neurons or skeletal myocytes and identified the cell type-specific cryptic exons associated with TDP-43 loss of function., Results: Comparative analysis of nonconserved cryptic exons in various mouse cell types revealed that only some cryptic exons were common amongst stem cells, neurons, and myocytes; the majority of these nonconserved cryptic exons were cell type-specific., Conclusions: Our results suggest that in human disease, TDP-43 loss of function may impair cell type-specific pathways.

Background: Viola yedoensis (VY, Violaceae) is a popular medicinal herb used in traditional eastern medicine for treating lots of diseases, including inflammation and its related symptoms. However, the anti-inflammatory properties of VY have not been demonstrated. In the present study, we investigated the anti-inflammatory effects of VY ethanol extract (VYE) on macrophages and attempted to identify the bioactive components of VYE., Methods: We assessed the effects of VYE on secretion of nitric oxide (NO) and inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. In addition, we explored the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and changes in heme oxygenase (HO)-1, nuclear factor (NF)-kB, and mitogen-activated protein kinase (MAPK) signaling pathways in RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS). In addition, a rapid and useful approach to identify potential bioactive components in VYE with anti-inflammatory effects was developed using murine macrophage cell extraction coupled with high-performance liquid chromatography tandem mass spectrometry (LC-MS)., Results: We found that VYE exerted anti-inflammatory activity by inhibiting the production of key inflammation mediators and related products, as well as suppression of HO-1, NF-kB, and MAPK signaling pathway activation in RAW 264.7 cells. In addition, we identified two compounds in VYE via the cell extraction method., Conclusions: Our results revealed that VYE exerts anti-inflammatory activities and its detailed inhibitory mechanism in macrophages. Furthermore, we identified bioactive components of VYE.

Background: β-Lapachone (β-LAP) is a natural naphthoquinone compound isolated from the lapacho tree (Tabebuia sp.), and it has been used for treatment of rheumatoid arthritis, infection, and cancer. In the present study, we investigated whether β-LAP has anti-inflammatory effects under in vitro and in vivo neuroinflammatory conditions., Methods: The effects of β-LAP on the expression of inducible nitric oxide synthase (iNOS), cytokines, and matrix metalloproteinases (MMPs) were examined in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and rat primary microglia by ELISA, reverse transcription polymerase chain reaction (RT-PCR), and Western blot analysis. Microglial activation and the expression levels of proinflammatory molecules were measured in the LPS-injected mouse brain by immunohistochemistry and RT-PCR analysis. The detailed molecular mechanism underlying the anti-inflammatory effects of β-LAP was analyzed by electrophoretic mobility shift assay, reporter gene assay, Western blot, and RT-PCR analysis., Results: β-LAP inhibited the expression of iNOS, proinflammatory cytokines, and MMPs (MMP-3, MMP-8, MMP-9) at mRNA and protein levels in LPS-stimulated microglia. On the other hand, β-LAP upregulated the expressions of anti-inflammatory molecules such as IL-10, heme oxygenase-1 (HO-1), and the tissue inhibitor of metalloproteinase-2 (TIMP-2). The anti-inflammatory effect of β-LAP was confirmed in an LPS-induced systemic inflammation mouse model. Thus, β-LAP inhibited microglial activation and the expressions of iNOS, proinflammatory cytokines, and MMPs in the LPS-injected mouse brain. Further mechanistic studies revealed that β-LAP exerts anti-inflammatory effects by inhibiting MAPKs, PI3K/AKT, and NF-κB/AP-1 signaling pathways in LPS-stimulated microglia. β-LAP also inhibited reactive oxygen species (ROS) production by suppressing the expression and/or phosphorylation of NADPH oxidase subunit proteins, such as p47(phox) and gp91(phox). The anti-oxidant effects of β-LAP appeared to be related with the increase of HO-1 and NQO1 via the Nrf2/anti-oxidant response element (ARE) pathway and/or the PKA pathway., Conclusions: The strong anti-inflammatory/anti-oxidant effects of β-LAP may provide preventive therapeutic potential for various neuroinflammatory disorders.

Introduction: The measurement of flow-mediated dilatation (FMD) via ultrasound has been established as a reliable non-invasive measurement of endothelial function. However, the guidelines mention nothing regarding diurnal variation of FMD. Thus, we investigated the FMD in healthy people and diurnal variation of FMD., Methods: Twenty-five apparently healthy persons participated in this study. All participants had no history of cardiovascular diseases, hypertension, or diabetes and used any medication. For each volunteer, the measurements were repeated in the morning and afternoon on two different days. We checked capillary blood glucose, total cholesterol, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)-cholesterol., Results: The average of FMD measurements was 8.45% ± 2.39%. The mean values of systolic and diastolic blood pressure, heart rate, lipid profiles, and glucose levels were similar between the morning and afternoon measurements after 9-h fasting. There was no significant difference of FMD measurements between the morning and afternoon (8.32% ± 2.27% and 8.58% ± 2.56%, p = 0.329). Moreover, there was significant correlation between FMD in the morning and afternoon (r = 0.856, p < 0.001)., Conclusions: Our study shows measurement of FMD was 8.45% in healthy Koreans. Also, there was no significant difference of FMD measurements between the morning and afternoon.

Background: Oryeongsan (OR) is an herbal medication used in east-Asian traditional medicine to treat dysuresia, such as urinary frequency, hematuria, and dysuria due to renal disease and chronic nephritis. Recent studies showed that protective effect against acute gastric mucosal injury and an inhibitory effect on the renin-angiotensin-aldosterone pathway of OR. However, its effect on inflammation still remains unknown. In this study, to provide insight into the biological effects of OR, we investigated their effects on lipopolysaccharide (LPS)-mediated inflammation in the RAW 264.7 macrophage cells., Methods: We investigated the pharmacological and biological effects of OR on the production of pro-inflammatory cytokines, inflammatory mediators, and related products through Enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. Also, we examined the activation and suppression of nuclear factor (NF)-kappaB and mitogen-activated protein kinases (MAPKs) pathways in LPS-stimulated macrophages via Western blot analysis in order to explore inhibitory mechanism of OR., Results: OR had anti-inflammatory effects by inhibiting the production of nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1 beta. In addition, it strongly suppressed cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS), NO synthesizing enzymes. It also induced heme oxygenase (HO)-1 expression and inhibited NF-kappaB signaling pathway activation and phosphorylation of MAPKs., Conclusions: We further demonstrate the anti-inflammatory effects and inhibitory mechanism of OR in LPS-stimulated macrophages for the first time. OR contains strong anti-inflammatory activity and affects various mechanism pathways including NF-kappaB, MAPKs and HO-1. Our results suggest that OR has potential value to be developed as an inflammatory therapeutic agent from a natural substance.

Background: Oyaksungisan (OY) has been used as a traditional drug in east-Asian countries. However, its effect on inflammation still remains unknown. In this study, to provide insight into the biological effects of OY and OY fermented by Lactobacillus, we investigated their effects on lipopolysaccharide (LPS)-mediated inflammation in the RAW 264.7 murine macrophage cells., Methods: The investigation was focused on whether OY and fermented OYs could inhibit the production of pro-inflammatory mediators such as nitric oxide (NO) and prostaglandin (PG) E2 as well as the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, interleukin (IL)-6, nuclear factor (NF)-κB and mitogen-activated protein kinases (MAPKs) in LPS-stimulated RAW 264.7 cells., Results: We found that OY inhibits a little LPS-induced NO, PGE2, TNF-α and IL-6 productions as well as the expressions of iNOS and COX-2. Interestingly, the fermentation significantly increased its inhibitory effect on the expression of all pro-inflammatory mediators. Furthermore, the fermented OYs exhibited elevated inhibition on the translocation of NF-κB p65 through reduced IκBα degradation as well as the phosphorylations of extracellular signal-regulated kinase (ERK), p38 and c-Jun NH2-terminal kinase (JNK) MAPKs than untreated control or original OY., Conclusions: Finally, the fermentation by Lactobacillus potentiates the anti-inflammatory effect of OY by inhibiting NF-κB and MAPK activity in the macrophage cells.