👤 B K Jeon

Huntington's disease (HD) is characterized by progressive striatal degeneration associated with mutant huntingtin (mHTT)-related proteostatic disruption and chronic neuroinflammation. Although mHTT-lowering approaches hold therapeutic promise, their capacity to restore the degenerating neural microenvironment remains limited. Here, we evaluated the therapeutic potential of human induced pluripotent stem cell (iPSC)-derived neural precursor cells (s513-NPCs) in two complementary HD models, the acute R6/2 transgenic fragment model and the protracted, full-length YAC128 genomic model. Intrastriatal transplantation of s513-NPCs resulted in sustained functional improvement, including stabilization of motor coordination and attenuation of neuromuscular decline, across both disease contexts. These neuroprotective effects were accompanied by efficient donor cell engraftment and integration within the host striatum. At the molecular level, transplantation was associated with coordinated changes in proteostasis-related pathways, reflected by reduced mHTT aggregate burden and modulation of proteasomal and autophagic markers. In parallel, enhanced local BDNF-TrkB signaling was observed in grafted regions, consistent with improved neuronal support. Notably, transplanted NPCs exhibited context-dependent immunological responses, characterized by attenuation of pro-inflammatory signatures in aggressive disease stages and features of a reparative microenvironment in more protracted settings. Collectively, these findings demonstrate that iPSC-derived neural precursor transplantation confers robust neuroprotective effects in HD models, supporting its potential as a stem cell-based strategy to mitigate striatal pathology and functional decline. Show less

Euglena gracilis has a history of traditional use in East Asia as a functional food with reported antioxidant and immunomodulatory benefits. This study investigates the pharmacological potential of its bioactive component, standardized alkali-treated β-glucan (AEGB), in mitigating systemic toxicity induced by environmental pollutants, providing a rationale to investigate its protective effects in the context of particulate matter (PM2.5)-induced injury. To evaluate the protective effects of standardized alkali-treated E. gracilis β-glucan (AEGB) against PM2.5-induced pulmonary and cerebral toxicity in BALB/c mice via the lung-brain axis. AEGB was prepared and standardized to contain 93% (w/w) β-glucan. BALB/c mice were intranasally exposed to PM2.5 and orally administered AEGB (200/400 mg/kg). Efficacy was evaluated via BALF analysis, histopathology, and immunoblotting, focusing on MAPK, NF-κB, NRF2-HO-1, and CREB-BDNF-TrkB pathways. AEGB exhibited higher antioxidant activity than untreated β-glucan. In PM2.5-exposed mice, AEGB (400 mg/kg) reduced inflammatory cells in BALF by 69.5% and suppressed lung pro-inflammatory cytokines (IL-1β, IL-6). Histologically, it attenuated bronchial thickening and mucin production. In the brain, AEGB downregulated NF-κB by 72.1% and restored hippocampal neuronal area (+41.1%) and tight junction marker expression associated with blood-brain barrier integrity. At the molecular level, AEGB inhibited pulmonary MAPK/NF-κB and activated NRF2-HO-1, while enhancing the cerebral CREB-BDNF-TrkB neurotrophic pathway. AEGB mitigates PM2.5-induced damage in both lung and brain tissues, accompanied by anti-inflammatory and neuroprotective responses consistent with inter-organ inflammatory/oxidative pathways relevant to the lung-brain axis. These findings validate the potential of E. gracilis-derived β-glucan as a functional agent for preserving respiratory and neural health. Show less

Sensory neurotoxicity involves damage to the sensory nerves, often resulting from exposure to chemicals, medications, toxins, infections, or neurological disorders. Benzalkonium chloride (BKC) is a widely used quaternary ammonium compound with antiseptic properties, commonly present in pharmaceuticals, household products, and cosmetics. While the potential neurotoxicity of BKC has been previously explored in ocular and nasal epithelia, its impact on other sensory systems and the underlying mechanisms remain largely unclear. In this study, we used zebrafish (Danio rerio) embryos to assess the developmental neurotoxicity of BKC. Embryonic exposure to 0.72, 1.28, and 2.24 mg/L BKC led to dose-dependent impairments in mechanosensory hair cells, reduced startle responses, and heightened nociceptive sensitivity upon noxious stimulation. BKC exposure induced pronounced oxidative stress, evidenced by increased reactive oxygen species levels, reduced antioxidant enzyme activity, and altered expression of redox-regulating genes. Moreover, BKC significantly upregulated inflammatory and pain-associated genes, including tnfa, il1b, cox2, bdnf, and trpa1b. Expression profiling of hair cell differentiation markers revealed increased pou4f3 and decreased tmc2a/tmc2b, suggesting that BKC disrupts both terminal differentiation and mechanotransduction processes in sensory hair cells. Collectively, these findings uncover a novel mechanistic link between oxidative stress, impaired hair-cell maturation, and sensory dysfunction, offering new insights into the mechanisms underlying BKC-induced sensory neurotoxicity. This study emphasizes the ecological and toxicological relevance of quaternary ammonium compounds in aquatic environments. Show less

This study evaluates the clinical validity of the Korean Computerized Cognitive Function Test (CFT-S) by comparing its domain-specific scores with those of the Seoul Neuropsychological Screening Battery-II (SNSB-II) in patients with Mild Cognitive Impairment (MCI) or Alzheimer's Disease (AD). A total of 300 participants (MCI: n = 163; AD: n = 137) from Severance Hospital completed both CFT-S and SNSB-II assessments within a two-week interval, along with brain MRI and APOE genotyping. Pearson correlations and multiple regression analyses examined relationships between cognitive scores and biomarker variables. Receiver operating characteristic curves assessed diagnostic accuracy. Bland-Altman plots evaluated agreement across five shared cognitive domains. CFT-S index scores showed significant positive correlations with SNSB-II in attention, language, visuospatial, and executive domains (r = 0.59-0.71, p < 0.001). The memory domain showed a lower correlation in AD patients (r = 0.28), reflecting limitations under severe impairment. Hippocampal volume was positively associated with MMSE (r = 0.54), CFT-S memory (r = 0.50), and SNSB memory scores (r = 0.52). Education correlated with MMSE (r = 0.32) but not with CFT-S or SNSB, suggesting minimal education bias. APOE-ε4 carriers had smaller hippocampal volumes, higher FBB-PET BAPL scores, and poorer cognitive outcomes. The Bland-Altman plots demonstrated acceptable agreement at the group level between CFT-S and SNSB-II across all cognitive domains, with small mean biases and symmetric distributions despite relatively wide limits of agreement. CFT-S index scores and Bland-Altman plot analysis demonstrated validity relative to SNSB-II, with significant associations to hippocampal atrophy and genetic risk factors. The findings support CFT-S as a viable and efficient cognitive assessment tool for diagnosing MCI and AD. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition with a rising global incidence, closely linked to metabolic risk factors such as dyslipidemia. Apolipoprotein E-deficient (ApoE Show less

This review overviewed the recent paradigm shifts in the diagnosis and management of Alzheimer's disease (AD), emphasizing the 2024 Alzheimer's Association (AA) revised criteria, advances in cerebrospinal fluid (CSF) and blood-based biomarkers (BBMs), and practical considerations for anti-amyloid monoclonal antibody therapy. We conducted a narrative appraisal of consensus frameworks (2018 National Institute on Aging-Alzheimer's Association [NIA-AA] amyloid, tau, and neurodegeneration [AT(N)] and the 2024 AA criteria), clinical practice guidance from AA released in 2025, regulatory status of CSF and BBMs. Intended-use settings (triage vs. confirmatory) of BBMs and implementation of anti-amyloid anti-body treatments (lecanemab or donanemab) in real-world practice in Korea were also reviewed. The 2024 AA criteria define AD biologically and designate A and T as core biomarkers; Core 1 biomarkers can establish AD irrespective of symptoms, whereas Core 2 biomarkers refine staging. A two-cutoff BBM strategy (positive/intermediate/negative) reduces misclassification and guides confirmatory CSF/positron emission tomography (PET) or retesting. BBMs now approach CSF/PET accuracy for amyloid detection, enable triage and, in selected settings, confirmation, and show utility for monitoring treatment response. Integration of clinical stages (1-6) with biological stages (A-D) clarifies syndrome-pathology discordance. Special scenarios-maintenance after induction, APOE ε4 homozygotes, Down syndrome, and serious mental illness-require individualized risk-benefit assessment. In South Korea, constrained access to tau PET and some BBMs necessitates Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision-anchored evaluation with selective biomarker testing. Biomarker-oriented diagnosis and anti-amyloid therapies are reshaping AD care. Priorities include rigorous validation of BBMs across populations, equitable access to core biomarkers, safety strategies, and real-world evidence to implement maintenance and special-population care pathways. Show less

Aberrant deposition of β-amyloid (Aβ) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating β-site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen-activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, Aβ plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed Aβ oligomer-induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease-modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease-modifying candidate with the potential to drive a breakthrough approach targeting AD pathology. Show less

This study aimed to identify breast cancer-specific circulating tumor DNA (ctDNA) methylation markers that correspond to tissue DNA methylation. Using The Cancer Genome Atlas (TCGA) database, we selected breast cancer-specific DNA methylation markers. The methylation and expression patterns of candidate genes were analyzed in breast cancer cell lines and tissue samples. We also assessed the methylation status in ctDNA obtained from breast cancer patients and examined associations with the clinicopathological features. Among candidate genes with breast cancer-specific methylation patterns, USP44, ZNF454, and GPRC5B were selected. The methylation status and expression of selected genes varied by molecular subtype of cancer in the cell line. In tissue samples, expression of all three genes was generally lower in breast cancer than in controls. ctDNA methylation patterns showed no significant change before and after treatment for each candidate gene. Correlations between gene expression and DNA methylation status or clinicopathological characteristics in cancer tissues differed among genes. Further studies are needed for clinical application of liquid biopsy using methylation analysis for ctDNA according to individual characteristics for breast cancer. Show less

Inflammatory bowel disease (IBD) is an immune-mediated disorder driven by overactivation of autotaxin (ATX), which elevates lysophosphatidic acid (LPA) signaling and suppresses autophagy, exacerbating intestinal inflammation. Given the pivotal role of autophagy in maintaining intestinal homeostasis, inhibiting ATX offers a dual therapeutic mechanism by both restoring autophagic activity and attenuating LPA-mediated inflammatory responses. Current treatments are hindered by nonspecific immunosuppression and frequent systemic side effects, underscoring the need for targeted, multifunctional therapeutic strategies. Here, we present a dual-functional nanotherapeutic platform, ATX-scavenging liposomes loaded with rapamycin (AS-Lipo@R), engineered for the oral treatment of acute colitis. Our proposed formulation incorporates BMP-22, a lipid ATX inhibitor that simultaneously functions as a structural building block of the liposomal membrane. Rapamycin, an autophagy activator, is encapsulated within the bilayer of liposomes. We confirmed that AS-Lipo@R exhibits strong binding affinity to extracellular ATX and mediates its lysosomal degradation upon cellular internalization, thereby demonstrating its ATX-scavenging property. In vitro, AS-Lipo@R inhibited inflammatory macrophage activation, promoted M2 macrophage polarization, and substantially restored autophagic activity in LPS/IFN-γ-stimulated macrophages. In vivo, oral administration of AS-Lipo@R led to preferential accumulation in ATX-overexpressing inflamed colonic tissue, resulting in reduced pro-inflammatory cytokine production, recovered autophagy, and enhanced intestinal barrier integrity in colitis mice. These findings highlight AS-Lipo@R as a synergistic and targeted nanomedicine that simultaneously modulates ATX and autophagy pathways, offering novel insights into immunomodulatory strategies for IBD treatment. Show less

Dysregulated extracellular matrix (ECM) deposition and epithelial-mesenchymal transition (EMT) in the trabecular meshwork (TM) contribute to glaucoma-associated fibrotic remodeling, and lysophosphatidic acid (LPA) potently induces these profibrotic responses in human trabecular meshwork (HTM) cells. We investigated whether an ethanolic extract of Show less

Chronic renal allograft injury (CRAI) is a major cause of allograft loss in kidney transplant recipients (KTRs). The aim of this study was to evaluate the associations of urinary apolipoprotein A4 (ApoA-IV) levels with renal function and rapid renal function decline in KTRs. This study included 50 KTRs. Proteomic analysis via liquid chromatography‒mass spectrometry and tandem mass spectrometry (LC-MS/MS) was performed to identify potential urinary biomarkers. The SWATH (sequential window acquisition of all theoretical mass spectra) method was used for protein quantification. Urinary ApoA-IV levels were validated by enzyme-linked immunosorbent assay (ELISA). Rapid renal function decline was defined as an estimated glomerular filtration rate (GFR) decrease of >3 mL/min/1.73 m2 per year or initiation of dialysis. The log-transformed urinary ApoA-IV levels measured by ELISA had a significantly inverse correlation with the estimated GFR (r = -0.72, P < 0.001). Moreover, urinary ApoA-IV levels were higher in patients with rapid renal function decline than in those with stable renal function (215.4 ± 181.8 μg/mL vs. 42.5 ± 72.4 μg/mL, P = 0.001). Univariate logistic regression analysis revealed that log-transformed urinary ApoA-IV levels were significantly associated with rapid renal function decline (odds ratio [OR] 6.70, 95% confidence interval [CI] 2.56-22.83; P < 0.001). Multiple logistic regression showed urinary ApoA-IV levels remained a significant risk factor for rapid renal function decline (OR 4.10, 95% CI 1.10-19.55; P = 0.047). ROC curve analysis revealed the area under the curve (AUC) of 0.834 (95% CI 0.722-0.945, P < 0.001) for urinary ApoA-IV levels in predicting rapid renal function decline. Our results suggest that urinary ApoA-IV levels might be a potential biomarker for renal allograft function and could be used as a predictor for rapid renal function decline in KTRs. Show less

Wnt signaling is essential for cell growth and tumor formation and is abnormally activated in colorectal cancer (CRC), contributing to tumor progression; however, the specific role and regulatory mechanisms involved in tumor development remain unclear. Here, we show that Ephexin1, a guanine nucleotide exchange factor, is significantly overexpressed in CRC and is correlated with increased Wnt/β-catenin pathway activity. Through comprehensive analysis, including RNA sequencing data from TCGA and functional assays, we observed that Ephexin1 promotes tumor proliferation and migration by activating the Wnt/β-catenin pathway. This effect was mediated by the interaction of Ephexin1 with Axin1, a critical component of the β-catenin destruction complex, which in turn enhanced the stability and activity of β-catenin in signaling pathways critical for tumor development. Importantly, our findings also suggest that targeting Ephexin1 may increase the efficacy of Wnt/β-catenin pathway inhibitors in CRC treatment. These findings highlight the potential of targeting Ephexin1 as a strategy for developing effective treatments for CRC, suggesting a novel and promising approach to therapy aimed at inhibiting cancer progression. Show less

Previous studies have reported that 40 Hz visual stimulation (acute white light exposure) reduced Aβ levels in Alzheimer's disease (AD) mouse model. However, whether different light colors distinctly regulate AD pathologies has not been well characterized. In the present study, an optimized organic light-emitting diode (OLED)-based visual stimulation platform was developed to provide uniform illumination without blind spots, and the color-dependent effects on cognitive function and amyloid-β (Aβ) pathology were investigated in 5xFAD mice, an Aβ-overexpressing AD model. Acute exposure to white or red OLED light (1 h/day for 2 days) significantly improved cognitive function, reduced hippocampal Aβ plaque accumulation via increasing ADAM17 activity, and downregulated proinflammatory cytokine IL-1β levels in 3-month-old 5xFAD mice, whereas green or blue OLED light did not produce these effects. In addition, chronic white and red OLED stimulation (1 h/day for 2 weeks) was shown to enhance recognition memory; however, only red light further diminished Aβ plaque deposition by upregulating ADAM17 activity and suppressing BACE-1 activity without altering neuroinflammation in 6-month-old 5xFAD mice. Moreover, acute white and red OLED exposure (1 h, single session) was observed to enhance c-fos expression, which is associated with neural activation along the visual pathway, thereby suggesting a mechanistic link between light stimulation and cognitive enhancement. Taken together, these findings demonstrate that color-dependent visual stimulation may serve as a promising electroceutical strategy for AD, with red light uniquely combining memory enhancement, Aβ reduction via ADAM17 upregulation and BACE1 suppression, and anti-inflammatory effects. Show less

Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid plaque accumulation, synaptic dysfunction, and neuroinflammation. This study reports the therapeutic potential of (S)-4-amino-5,5-difluoro-N'-methyl-N'-phenylpentanehydrazide hydrochloride (RA-058HM), a novel compound, in ameliorating these pathological features of AD in the 5xFAD mouse model. RA-058HM was administered orally for 8 weeks, and its multi-target effects - including relief from neuroinflammation, normalization of synaptic transmission, reduction of amyloidogenesis (plaque and soluble oligomers, as well as BACE1 levels), and rescue of cognitive function-were evaluated. To our knowledge, RA-058HM is the first compound to demonstrate simultaneous modulation of these key pathways in the 5xFAD model, highlighting its potential as a comprehensive disease-modifying therapy for AD. Behavioural tests revealed marked improvements in spatial and recognition memory in RA-058HM-treated 5xFAD mice, suggesting a reversal of cognitive deficits. At the molecular level, RA-058HM treatment reduced amyloidogenesis, as evidenced by decreased levels of amyloid precursor protein (APP) and β-secretase (BACE1) in the hippocampus, accompanied by reduced plaque formation, as detected by Thioflavin-S staining. Furthermore, synaptic transmission was restored to near-normal levels in RA-058HM-treated neurons, indicating that RA-058HM effectively rescues synaptic deficits without altering synaptic protein levels of PSD95 and synaptophysin. In addition, treatment of RA-058HM downregulated hippocampal levels of the NLRP3 inflammasome, TNF-α, and GFAP, suggesting a decrease in neuroinflammatory signaling and a modulation of glial activity. Restoration of mitochondrial motility in hippocampal neurons further suggests that RA-058HM may improve cellular energy dynamics. Collectively, these findings indicate that RA-058HM has multifaceted effects on AD pathology, targeting amyloid accumulation, synaptic transmission, neuroinflammation, and mitochondrial function. This study highlights RA-058HM as a promising candidate for AD therapy and underscores the potential of multi-targeted approaches in addressing the complex mechanisms underlying AD progression. Show less

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cognitive decline, oxidative stress, neuroinflammation, amyloid-beta (Aβ) accumulation, and tau protein hyperphosphorylation. In this study, we synthesized novel Ramalin derivatives and evaluated their therapeutic potential against AD, focusing on antioxidant, anti-inflammatory, and neuroprotective activities. RA-2OMe, RA-4OMe, RA-2CF3, and RA-4OCF3 showed strong antioxidant effects, while RA-2OMe exhibited potent NO and NLRP3 inhibition (~20%). RA-NAP, RA-PYD, and RA-2Q showed moderate anti-inflammatory activity. BACE-1 inhibition was significant in RA-3CF3, RA-NAP, and RA-PYD, with IC Show less

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated Show less

Alzheimer's disease (AD) is the most common type of dementia. Its incidence is rising rapidly as the global population ages, leading to a significant social and economic burden. AD involves complex pathologies, including amyloid plaque accumulation, synaptic dysfunction, and neuroinflammation. This study explores the therapeutic potential of N Show less

Oncogenic alterations in fibroblast growth factor receptor (FGFR)-family proteins occur across cancers, including pediatric gliomas. Our genomic analysis of 11,635 gliomas across ages finds that 5.3% of all gliomas harbor FGFR alterations, with an incidence of almost 9% in pediatric gliomas. Alterations in FGFR proteins are differentially enriched by age, tumor grade, and histology, with FGFR1 alterations associated with glioneuronal histologies. Leveraging isogenic systems, we confirm FGFR1 alterations to induce downstream Mitogen Activated Protein Kinase (MAPK) and mTOR signaling pathways, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway and pan-FGFR inhibitors. Finally, we perform a retrospective analysis of clinical responses in children diagnosed with FGFR-altered gliomas and find that treatment with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome. Show less

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common liver disease associated with obesity and is caused by the accumulation of ectopic fat without alcohol consumption. Coxsackievirus and adenovirus receptor (CAR) are vital for cardiac myocyte-intercalated discs and endothelial cell-to-cell tight junctions. CAR has also been reported to be associated with obesity and high blood pressure. However, its function in the liver is still not well understood. The liver of obese mice exhibit elevated CAR mRNA and protein levels. Furthermore, in the liver of patients with non-alcoholic steatohepatitis, CAR is reduced in hepatocyte cell-cell junctions compared to normal levels. We generated liver-specific CAR knockout (KO) mice to investigate the role of CAR in the liver. Body and liver weights were not different between wild-type (WT) and KO mice fed a paired or high-fat diet (HFD). However, HFD induced significant liver damage and lipid accumulation in CAR KO mice compared with WT mice. Additionally, inflammatory cytokines transcription, hepatic permeability, and macrophage recruitment considerably increased in CAR KO mice. We identified a new interaction partner of CAR using a protein pull-down assay and mass spectrometry. Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3C (APOBEC3C) demonstrated a complex relationship with CAR, and hepatic CAR expression tightly regulated its level. Moreover, Apolipoprotein B (ApoB) and Low-density lipoprotein receptor (LDLR) levels correlated with APOBEC3C expression in the liver of CAR KO mice, suggesting that CAR may regulate lipid accumulation by controlling APOBEC3C activity. In this study, we showed that hepatic CAR deficiency increased cell-to-cell permeability. In addition, CAR deletion significantly increased hepatic lipid accumulation by inducing ApoB and LDLR expression. Although the underlying mechanism is unclear, CARs may be a target for the development of novel therapies for MAFLD. Show less

The occurrence of cognitive deficits after subarachnoid hemorrhage (SAH) is highly possible, leading to vascular dementia. We performed a novel longitudinal genome-wide association study (GWAS) to identify genetic modifications associated with cognitive impairment following SAH in a long-term prospective cohort study. This GWAS involved 153 patients with SAH sharing 5,971,372 markers after high-throughput imputation. Genome-wide Cox proportional hazard regression testing was performed to estimate the hazard ratio (HR) and 95% confidence interval (CI). Subsequently, a weighted polygenetic risk score (wPRS) was determined, based on GWAS-driven loci and risk stratification. Cognitive impairment was observed in 65 patients (42.5%) during a mean follow-up of 37.7 ± 12.4 months. Five genome-wide signals, including rs138753053 ( Our study revealed novel susceptible loci for cognitive impairment, longitudinally measured in patients with SAH. The clinical utility of these loci will be evaluated in further follow-up studies. Show less

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P Show less

The prevalence of dyslipidemia has increased steadily in Korea, and the incidence of dyslipidemia differs by sex. In this study, we identified single nucleotide polymorphisms (SNPs) related to dyslipidemia in Korean cohorts through genome-wide association study (GWAS) analysis. Genotyping was conducted to determine the genotypes of 72,298 participants and investigate genotypes for 7,079,946 SNPs. Sex, age, and BMI were set as covariates for GWAS, and significant SNPs were identified in the discovery and replication stages using logistic regression. GWAS of the entire cohort revealed a total of five significant SNPs: rs117026536 (LPL), rs651821 (APOA5), rs9804646 (APOA5), rs9926440 (CETP), and rs429358 (APOE). GWAS of the male subjects revealed a total of four significant SNPs. While rs9804646 (APOA5) and rs429358 (APOE) were significant for all the subjects, rs662799 (APOA5) and rs56156922 (CETP) were significant only for the male subjects. GWAS of the female subjects revealed two significant SNPs, rs651821 (APOA5) and rs9804646 (APOA5), both of which were significant in all the subjects. This is the first study to identify sex-related differences in genetic polymorphisms in Korean populations with dyslipidemia. Further studies considering environmental variables will be needed to elucidate these sex-related genetic differences in dyslipidemia. Show less

Formation of dendritic spine and synapse is an essential final step of brain wiring to establish functional communication in the developing brain. Recent findings have displayed altered dendritic spine and synapse morphogenesis, plasticity, and related molecular mechanisms in animal models and post-mortem human brains of autism spectrum disorders (ASD) and intellectual disability (ID). Many genes and proteins are shown to be associated with spines and synapse development, and therefore neurodevelopmental disorders. In this review, however, particular attention will be given to chromatin modifiers such as AT-Rich Interactive Domain 1B (ARID1B), KAT8 regulatory non-specific lethal (NSL) complex subunit 1 (KANSL1), and WD Repeat Domain 5 (WDR5) which are among strong susceptibility factors for ASD and ID. Emerging evidence highlights the critical status of these chromatin remodeling molecules in dendritic spine morphogenesis and synaptic functions. Molecular and cellular insights of ARID1B, KANSL1, and WDR5 will integrate into our current knowledge in understanding and interpreting the pathogenesis of ASD and ID. Modulation of their activities or levels may be an option for potential therapeutic treatment strategies for these neurodevelopmental conditions. Show less

Transforming growth factor-beta (TGF-β) has a dichotomous role, functioning as a tumor suppressor and tumor promoter. TGF-β signatures, explored in mouse hepatocytes, have been reported to predict the clinical outcomes of hepatocellular carcinoma (HCC) patients; HCCs exhibiting early TGF-β signatures showed a better prognosis than those with late TGF-β signatures. The expression status of early and late TGF-β signatures remains unclear in defined lesions of human B-viral multistep hepatocarcinogenesis. The expression of TGF-β signatures, early and late responsive signatures of TGF-β were investigated and analyzed for their correlation in cirrhosis, low-grade dysplastic nodules (DNs), high-grade DNs, early HCCs and progressed HCCs (pHCCs) by real-time PCR and immunohistochemistry. The expression levels of TGF-β signaling genes ( The enrichment of the late responsive signatures of TGF-β with induction of stemness is considered to be involved in the progression of the late stage of multistep hepatocarcinogenesis, whereas the early responsive signatures of TGF-β are suggested to have tumor-suppressive roles in precancerous lesions of the early stage of multistep hepatocarcinogenesis. Show less

Hexokinase 2 (HK2), which catalyzes the first committed step in glucose metabolism, is induced in cancer cells. HK2's role in tumorigenesis has been attributed to its glucose kinase activity. Here, we describe a kinase independent HK2 activity, which contributes to metastasis. HK2 binds and sequesters glycogen synthase kinase 3 (GSK3) and acts as a scaffold forming a ternary complex with the regulatory subunit of protein kinase A (PRKAR1a) and GSK3β to facilitate GSK3β phosphorylation and inhibition by PKA. Thus, HK2 functions as an A-kinase anchoring protein (AKAP). Phosphorylation by GSK3β targets proteins for degradation. Consistently, HK2 increases the level and stability of GSK3 targets, MCL1, NRF2, and particularly SNAIL. In addition to GSK3 inhibition, HK2 kinase activity mediates SNAIL glycosylation, which prohibits its phosphorylation by GSK3. Finally, in mouse models of breast cancer metastasis, HK2 deficiency decreases SNAIL protein levels and inhibits SNAIL-mediated epithelial mesenchymal transition and metastasis. Show less

CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor that is being developed for dyslipidemia. Even though CKD-519 has shown potent CETP inhibition, the exposure of CKD-519 was highly varied, depending on food and dose. For highly variable exposure drugs, it is crucial to use modeling and simulation to plan proper dose selection. This study aimed to develop population pharmacokinetic (PK) and pharmacodynamics (PD) models of CKD-519 and to predict the proper dose of CKD-519 to achieve target levels for HDL-C and LDL-C using results from multiple dosing study of CKD-519 with a standard meal for two weeks in healthy subjects. The results showed that a 3-compartment with Erlang's distribution, followed by the first-order absorption, adequately described CKD-519 PK, and the bioavailability, which decreased by dose and time was incorporated into the model (NONMEM version 7.3). After the PK model development, the CETP activity and cholesterol (HDL-C and LDL-C) levels were sequentially modeled using the turnover model, including the placebo effect. According to PK-PD simulation results, 200 to 400 mg of CKD-519 showing a 40% change in HDL-C and LDL-C from baselines was recommended for proof of concept studies in patients with dyslipidemia. Show less

IL-27, a heterodimeric cytokine composed of the p28 subunit and Epstein-Barr virus-induced gene 3 (EBI3), acts as a potent immunosuppressant and thus limits pathogenic inflammatory responses. IL-27 is upregulated upon Show less

The spectrum of genetic variants and their clinical significance of Hypertrophic cardiomyopathy (HCM) have been poorly studied in Asian patients. The objectives of this study were to assess the spectrum of genetic variants and genotype-phenotype relationships within a Korean HCM population. Eighty-nine consecutive unrelated HCM patients were included. All patients underwent genotypic analysis for 23 HCM-associated genes. Clinical parameters including echocardiographic and cardiac magnetic resonance (CMR) parameters were evaluated. A composite of major adverse cardiac and cerebrovascular events was assessed. Genetic variants were detected in 55 of 89 subjects. Pathogenic variants or likely pathogenic variants were identified in 27 of HCM patients in Genetic variants in patients with HCM are relatively common and are associated with adverse clinical events and myocardial fibrosis on CMR. Genotypic analysis may add important information to clinical variables in the assessment of long-term risk for HCM patients. Show less

Persimmon (Diospyros kaki L.f.) trees are widely cultivated for their edible fruits in Asia. D. kaki leaves are abundant in phytochemicals that have numerous medicinal properties. Hepatocyte growth factor (HGF) and its receptor Met lead to poor prognosis via the promotion of metastasis and chemoresistance in hepatocellular carcinoma (HCC). Therefore, inhibitors targeting the HGF/Met pathway are regarded as promising drugs against HCC. Here, we investigated the effects of D. kaki leaves on HGF-induced epithelial-to-mesenchymal transition (EMT) and stemness traits in HCC. The ethanol extract of D. kaki leaves (EEDK) markedly suppressed HGF-mediated cell migration and invasion through upregulation of CDH1 and downregulation of SNAI1, VIM, MMP1, MMP2, and MMP9. Moreover, EEDK increased the cytotoxicity of sorafenib, which was reduced by HGF, and decreased the expression of the stemness markers KRT19 and CD44. Additionally, we found a clear correlation between stemness and EMT markers in HCC patients. Importantly, EEDK reduced Met activity and attenuated HGF-mediated activation of JNK/c-Jun. Our findings provide new evidence that EEDK can ameliorate HCC with poor prognosis and aggressive phenotype by blocking HGF/Met signaling. Show less