👤 Vanessa G Lee

Idiopathic ventricular fibrillation (IVF) is a disease in which the cause of ventricular fibrillation cannot be identified despite comprehensive clinical evaluation. This study aimed to investigate the clinical yield and implications of genetic testing for IVF. This study was based on the multi-centre inherited arrhythmia syndrome registry in South Korea from 2014 to 2017. Next-generation sequencing-based genetic testing was performed that included 174 genes previously linked to cardiovascular disease. A total of 96 patients were clinically diagnosed with IVF. The mean age of the onset was 41.2 ± 12.7 years, and 79 patients were males (82.3%). Of these, 74 underwent genetic testing and four (5.4%) of the IVF probands had pathogenic or likely pathogenic variants (each having one of MYBPC3, MYH7, DSP, and TNNI3). All pathogenic or likely pathogenic variants were located in genes with definite evidence of a cardiomyopathy phenotype, either hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. Next-generation sequencing-based genetic testing identified pathogenic or likely pathogenic variants in 5.4% of patients initially diagnosed with IVF, suggesting that genetic testing with definite evidence genes of cardiomyopathy may enable molecular diagnosis in a minority of patients with IVF. Further clinical evaluation and follow-up of patients with IVF with positive genotypes are needed to unveil concealed phenotypes, such as the pre-clinical phase of cardiomyopathy. Show less

Recent studies have reported altered methylation levels at disorder-relevant DNA sites in people who are ill with Anorexia Nervosa (AN) compared to findings in people with no eating disorder (ED) or in whom AN has remitted. The preceding implies state-related influences upon gene expression in people with AN. This study further examined this notion. We measured genome-wide DNA methylation in 145 women with active AN, 49 showing stable one-year remission of AN, and 64 with no ED. Comparisons revealed 205 differentially methylated sites between active and no ED groups, and 162 differentially methylated sites between active and remitted groups ( Findings corroborate earlier results suggesting reversible DNA methylation alterations in AN, and point to particular genes at which epigenetic mechanisms may act to shape AN phenomenology. Show less

Glioblastoma (GBM) is one of the most progressive and prevalent cancers of the central nervous system. Identifying genetic markers is therefore crucial to predict prognosis and enhance treatment effectiveness in GBM. To this end, we obtained gene expression data of GBM from TCGA and GEO datasets and identified differentially expressed genes (DEGs), which were overlapped and used for survival analysis with univariate Cox regression. Next, the genes' biological significance and potential as immunotherapy candidates were examined using functional enrichment and immune infiltration analysis. Eight prognostic-related DEGs in GBM were identified, namely Show less

Metazoans guard their germlines against transposons and other foreign transcripts with PIWI-interacting RNAs (piRNAs). Due to the robust heritability of the silencing initiated by piRNAs in Caenorhabditis elegans (C. elegans), previous screens using C. elegans were strongly biased to uncover members of this pathway in the maintenance process but not in the initiation process. To identify novel piRNA pathway members, we have utilized a sensitized reporter strain which detects defects in initiation, amplification, or regulation of piRNA silencing. Using our reporter, we have identified Integrator complex subunits, nuclear pore components, protein import components, and pre-mRNA splicing factors as essential for piRNA-mediated gene silencing. We found the small nuclear processing cellular machine termed the Integrator complex is required for both type I and type II piRNA production. Notably, we identified a role for nuclear pore and nucleolar components NPP-1/Nup54, NPP-6/Nup160, NPP-7/Nup153, and FIB-1 in promoting the perinuclear localization of anti-silencing CSR-1 Argonaute, as well as a role for Importin factor IMA-3 in nuclear localization of silencing Argonaute HRDE-1. Together, we have shown that piRNA silencing in C. elegans is dependent on evolutionarily ancient RNA processing machinery that has been co-opted to function in the piRNA-mediated genome surveillance pathway. Show less

Breast cancer is a common tumor type among women, with a high fatality due to metastasis. Metastasis suppressors encode proteins that inhibit the metastatic cascade independent of the primary tumor growth. Raf kinase inhibitory protein (RKIP) is one of the promising metastasis suppressor candidates. RKIP is reduced or lost in aggressive variants of different types of cancer. A few pre-clinical or clinical studies have capitalized on this protein as a possible therapeutic target. In this article, we employed two breast cancer cells to highlight the role of RKIP as an antimetastatic gene. One is the low metastatic MCF-7 with high RKIP expression, and the other is MDA-MB-231 highly metastatic cell with low RKIP expression. We used high-throughput data to explore how RKIP is lost in human tissues and its effect on cell mobility. Based on our previous work recapitulating the links between RKIP and SNAI, we experimentally manipulated RKIP in the cell models through its novel upstream NME1 and investigated the subsequent genotypic and phenotypic changes. We also demonstrated that RKIP explained the uneven migration abilities of the two cell types. Furthermore, we identified the regulatory circuit that might carry the effect of an existing drug, Epirubicin, on activating gene transcription. In conclusion, we propose and test a potential strategy to reverse the metastatic capability of breast cancer cells by chemically manipulating RKIP expression. Show less

Breast cancer is the most common cancer among women and the leading cause of cancer-related deaths worldwide. Despite various therapeutic strategies, its impact on the survival rate and quality of life of patients remains limited. The Forkhead Box J3 (FOXJ3) transcription factor has been implicated in various cancers, including lung cancer, tongue squamous cell carcinoma, prostate cancer, and colorectal cancer. However, the role of FOXJ3 in breast cancer has not been elucidated. This study aimed to investigate the role of FOXJ3 in breast cancer development, migration, and invasion. FOXJ3 expression was analyzed in patient tissues and breast cancer cell lines. Loss-of-function and gain-of-function studies were performed using MDA-MB-231 and MCF7 cell lines, respectively. Cell proliferation, migration, and invasion assays were conducted, and the effects of FOXJ3 on Snail expression were examined. FOXJ3 is over-expressed in breast cancer tissues compared to normal counterparts and in various breast cancer cell lines. By modulating FOXJ3 expression in breast cancer cell lines, we observed its influence on cell proliferation, migration, and invasion. Microarray analysis and subsequent validation showed that FOXJ3 modulates Snail expression, a well-known transcription factor involved in epithelial-mesenchymal transition. FOXJ3 plays a role in cell proliferation, migration, and the regulation of Snail expression and may be a potential therapeutic target for breast cancer treatment. Show less

Canine lymphoma (CL) is one of the most common malignant tumors in dogs. The cause of CL remains unclear. Genetic mutations that have been suggested as possible causes of CL are not fully understood. Whole-exome sequencing (WES) is a time- and cost-effective method for detecting genetic variants targeting only the protein-coding regions (exons) that are part of the entire genome region. A total of eight patients with B-cell lymphomas were recruited, and WES analysis was performed on whole blood and lymph node aspirate samples from each patient. A total of 17 somatic variants ( Show less

Regarding whether brain magnetic resonance imaging (MRI) should be routine in patients with suspected early-stage lung cancer, guideline recommendations are inconsistent. Therefore, we performed this study to evaluate the incidence of and risk factors for brain metastasis (BM) in patients with suspected early-stage non-small-cell lung cancer (NSCLC). A review of the medical charts of consecutive NSCLC patients diagnosed between January 2006 and May 2020 was performed. We identified 1,382 NSCLC patients with clinical staging of T1/2aN0M0 (excluding BM), and investigated the incidence, clinical predictors, and prognosis of BM in the cohort. We also performed RNA-sequencing differential expression analysis using transcriptome of 8 patients, using DESeq2 package (version 1.32.0) with R (version 4.1.0). Among 1,382 patients, nine hundred forty-nine patients (68.7%) underwent brain MRI during staging, and 34 patients (3.6%) were shown to have BM. Firth's bias-reduced logistic regression showed that tumor size (OR 1.056; 95% CI 1.009-1.106, p=0.018) was the only predictor of BM, and pathologic type was not a predictor of BM in our cohort (p>0.05). The median overall survival for patients with brain metastasis was 5.5 years, which is better than previously reported in the literature. RNA-sequencing differential expression analysis revealed the top 10 significantly upregulated genes and top 10 significantly downregulated genes. Among the genes involved in BM, Unc-79 homolog, non-selective sodium leak channel (NALCN) channel complex subunit (UNC79) was the most highly expressed gene in the lung adenocarcinoma tissues from the BM group, and an Given the incidence and favorable outcome of BM in patients with suspected early-stage NSCLC, selective screening with brain MRI may be considered, especially in patients with high-risk features. Show less

Recent clinical trials have revealed that the chimeric peptide hormones simultaneously activating glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) demonstrate superior efficacy in glycemic control and body weight reduction, better than those activating the GLP-1R alone. However, the linear peptide-based GLP-1R/GIPR dual agonists are susceptible to proteolytic cleavage by common digestive enzymes present in the gastrointestinal tract and thus not suitable for oral administration. Here, we report the design and synthesis of biaryl-stapled peptides, with and without fatty diacid attachment, that showed potent GLP-1R/GIPR dual agonist activities. Compared to a linear peptide dual agonist and semaglutide, the biaryl-stapled peptides displayed drastically improved proteolytic stability against the common digestive enzymes. Furthermore, two stapled peptides showed excellent efficacy in an oral glucose tolerance test in mice, owing to their potent receptor activity in vitro and good pharmacokinetics exposure upon subcutaneous injection. By exploring a more comprehensive set of biaryl staplers, we expect that this stapling method could facilitate the design of the stapled peptide-based dual agonists suitable for oral administration. Show less

Weight management is recommended in overweight or obese breast cancer patients, as they have an increased risk of cancer recurrence and poor prognosis. Furthermore, identifying the relationships between genetic factors and nutrition could help suggest possible individualized nutritional solutions in weight management. The objective of this pilot randomized controlled trial was to investigate the influence of two obesity-associated single nucleotide polymorphisms and the Mediterranean diet intervention on weight loss and modification of nutrient intake and metabolic parameters in overweight or obese, postmenopausal, breast cancer patients receiving adjuvant hormone therapy. Seventy-eight breast cancer patients were randomly assigned to the Mediterranean diet (MeDiet) group or control group, and seventy-one were finally analyzed. Body composition, nutrient intake, and metabolic parameters were assessed at baseline and after the 8-week intervention. Fat mass and obesity-associated ( We found that both variants did not influence weight loss or improvement of metabolic parameters within the Mediterranean diet intervention. Intake of saturated fatty acid (SFA) and trans fat was significantly increased in C carriers compared with the TT genotype of Our data suggest that considering the effects of genotype may be more necessary when the Mediterranean diet is not followed and that this diet may have a protective role against the effects of certain genotypes. Further studies are required to determine the potential mechanism of the observed gene-diet interaction. [www.ClinicalTrials.gov], identifier [NCT04045392]. Show less

A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular signaling. An interesting linkage between cilia and obesity has been revealed by studies of the human genetic ciliopathies Bardet-Biedl syndrome and Alström syndrome, in which obesity is a principal manifestation. Mouse models of cell type-specific cilia dysgenesis have subsequently demonstrated that ciliary defects restricted to specific hypothalamic neurons are sufficient to induce obesity and hyperphagia. A potential mechanism underlying hypothalamic neuron cilia-related obesity is impaired ciliary localization of G protein-coupled receptors involved in the regulation of appetite and energy metabolism. A well-studied example of this is melanocortin 4 receptor (MC4R), mutations in which are the most common cause of human monogenic obesity. In the paraventricular hypothalamus neurons, a blockade of ciliary trafficking of MC4R as well as its downstream ciliary signaling leads to hyperphagia and weight gain. Another potential mechanism is reduced leptin signaling in hypothalamic neurons with defective cilia. Leptin receptors traffic to the periciliary area upon leptin stimulation. Moreover, defects in cilia formation hamper leptin signaling and actions in both developing and differentiated hypothalamic neurons. The list of obesity-linked ciliary proteins is expending and this supports a tight association between cilia and obesity. This article provides a brief review on the mechanism of how ciliary defects in hypothalamic neurons facilitate obesity. Show less

The adipose tissue-derived hormone leptin can drive decreases in food intake while increasing energy expenditure. In diet-induced obesity, circulating leptin levels rise proportionally to adiposity. Despite this hyperleptinemia, rodents and humans with obesity maintain increased adiposity and are resistant to leptin's actions. Here we show that inhibitors of the cytosolic enzyme histone deacetylase 6 (HDAC6) act as potent leptin sensitizers and anti-obesity agents in diet-induced obese mice. Specifically, HDAC6 inhibitors, such as tubastatin A, reduce food intake, fat mass, hepatic steatosis and improve systemic glucose homeostasis in an HDAC6-dependent manner. Mechanistically, peripheral, but not central, inhibition of HDAC6 confers central leptin sensitivity. Additionally, the anti-obesity effect of tubastatin A is attenuated in animals with a defective central leptin-melanocortin circuitry, including db/db and MC4R knockout mice. Our results suggest the existence of an HDAC6-regulated adipokine that serves as a leptin-sensitizing agent and reveals HDAC6 as a potential target for the treatment of obesity. Show less

The mobilization and catabolism of lipid energy is a central function of adipocytes that is under the control of the β-adrenergic signaling pathway, and defects in β-adrenergic signaling in adipocytes have been linked to obesity and obesity-related metabolic diseases. Receptor expression-enhancing proteins (REEPs) are endoplasmic reticulum (ER) proteins that play critical roles in subcellular targeting of receptor signaling complexes. Examination of gene expression profiles indicates that, among REEPs expressed in adipocytes, REEP6 expression is uniquely upregulated by sympathetic nervous system activation, suggesting involvement in regulating adrenergic signal transduction. The aim of this study was to assess the contribution of REEP6 to the thermogenic activation of adipocytes and characterize the metabolic consequences of REEP6 deficiency in vivo. Expression levels of Reep6 in adipose tissue were examined by using public transcriptomic data and validated by Western blot and qPCR analyses. Adipocyte-specific regulatory roles of REEP6 were investigated in vitro in C3H10T1/2 adipocytes and in primary adipocytes obtained from REEP6 KO mice. Effects of in vivo REEP6 deficiency on energy expenditure were measured by indirect calorimetry. Mitochondrial content in adipose tissue was accessed by immunoblot, mitochondrial DNA analysis, and confocal and electron microscopy. Effects of REEP6 KO on obesity-induced metabolic dysfunction were tested in a high-fat diet-induced obesity mouse model by glucose tolerance test, Western blot, and histological analyses. REEP6 expression is highly enriched in murine adipocytes and is sharply upregulated upon adipocyte differentiation and by cold exposure. Inactivation of REEP6 in mice increased adiposity, and reduced energy expenditure and cold tolerance. REEP6 KO severely reduced protein kinase A-mediated signaling in BAT and greatly reduced mitochondrial mass. The effect of REEP6 inactivation on diminished β-adrenergic signaling was reproduced in cultured adipocytes, indicating that this effect is cell-autonomous. REEP6 KO also suppressed expression of adenylate cyclase 3 (Adcy3) in brown adipose tissue and knockdown of REEP6 in adipocytes reduced targeting of ADCY3 to the plasma membrane. Lastly, REEP6 KO exacerbated high-fat diet-induced insulin resistance and inflammation in adipose tissue. This study indicates that REEP6 plays an important role in β-adrenergic signal transduction in adipocytes involving the expression and trafficking of Adcy3. Genetic inactivation of REEP6 reduces energy expenditure, increases adiposity, and the susceptibility to obesity-related metabolic dysfunction. Show less

Metabolic syndrome (MetS) is a cluster of conditions associated with glucose intolerance, hypertension, abdominal obesity, dyslipidemia, and insulin resistance that increase the risk of cardiovascular diseases (CVD) and type 2 diabetes (T2D). Since MetS is known as a complex symptom with a high incidence of genetic factors, it is important to identify genetic variants for each clinical characteristic of MetS. We performed targeted next-generation sequencing (NGS) to identify genetic variants related to obesity, blood glucose, triacylglycerol (TG), and high-density lipoprotein (HDL)-cholesterol level, and hypertension in 48 subjects with MetS and in 48 healthy subjects. NGS analysis revealed that 26 of 48 subjects (54.2%) with MetS had putative non-synonymous variants related to the clinical features of MetS. Of the subjects with MetS, 8 (16.7%) had variants in 4 genes (COL6A2, FTO, SPARC, and MTHFR) related to central obesity, 17 (35.4%) had variants in 6 genes (APOB, SLC2A2, LPA, ABCG5, ABCG8, and GCKR) related to hyperglycemia, 3 (6.3%) had variants in 4 genes (APOA1, APOC2, APOA4, and LMF1) related to hypertriglyceridemia, 8 (16.7%) had variants in 4 genes (ABCA1, CETP, SCARB1, and LDLR) related to low HDL-cholesterolemia, and 5 (10.4%) had variants in ADD1 related to hypertension. Our findings may contribute to broadening the genetic spectrum of risk variants related to the development of MetS. 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

Chylomicronemia has either a monogenic or multifactorial origin. Multifactorial chylomicronemia is the more common form and is due to the interaction of genetic predisposition and secondary factors such as obesity, diabetes, unhealthy diet, and medications. We report a case of a 38-year-old man who was diagnosed with multifactorial chylomicronemia following presentation with a subarachnoid hemorrhage requiring emergency surgery through a burr hole; lactescent cerebrospinal fluid mixed with blood was observed through the burr hole. The serum triglyceride concentration was 52⋅4 mmol/L with a detectable triglyceride concentration in the cerebrospinal fluid. Rapid weight gain leading to obesity and related unfavorable lifestyle factors were identified as key secondary causes of chylomicronemia. Gene testing revealed a homozygous variant in Show less

To demonstrate the loci that relate to high-density lipoprotein cholesterol (HDL-C) levels and genetic sex heterogeneity, we enrolled 41,526 participants aged between 30 and 70 years old from the Taiwan Biobank in a genome-wide association study. We applied the Manhattan plot to display the p-values estimated for the relationships between loci and low HDL-C. A total of 160 variants were significantly associated with low HDL-C. The genotype TT of rs1364422 located in the KLF14 gene has 1.30 (95% CI=1.20 - 1.42) times the risk for low-HDL compared to genotype CC in females (log(-p) =8.98). Moreover, the genes APOC1, APOE, PVRL2, and TOMM40 were associated significantly with low-HDL-C in males only. Excluding the variants with high linkage disequilibrium, we revealed the rs429358 located in APOE as the major genetic variant for lowering HDL-C, in which genotype CT has 1.24 (95% CI= 1.16 - 1.32) times the risk. In addition, we also examine 12 genes related to HDL-C in both sexes, including LPL, ABCA1, APOA5, BUD13, ZPR1, ALDH1A2, LIPC, CETP, HERPUD1, LIPG, ANGPTL8, and DOCK6. In conclusion, low-HDL-C is a genetic and sex-specific phenotype, and we discovered that the APOE and KLF14 are specific to low-HDL-C for men and women, respectively. Show less

There is a growing evidence that fluctuation in lipid profiles is important in cardiovascular outcomes. We aimed to identify single nucleotide polymorphism (SNP) variants associated with low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) variability in statin-naïve Korean subjects and evaluate their associations with coronary atherosclerosis. In statin-naïve subjects from Gene-Environment of Interaction and phenotype cohort, we performed genome-wide association studies of lipid variability; the discovery (first) and replication (second) sets included 4,287 and 1,086 subjects, respectively. Coronary artery calcium (CAC) score and degree of coronary artery stenosis were used as outcome measures. Cholesterol variability was determined by standard deviation and average successive variability, and significant coronary atherosclerosis was defined as CAC score ≥400 or coronary stenosis ≥70%. Mean HDL-C and LDL-C level were 54 ± 12 and 123 ± 30 mg/dL in the first set and 53 ± 12 and 126 ± 29 mg/dL in the second set. Two SNPs associated with LDL-C variability ( Show less

Recently, clinical trials of adeno-associated virus-mediated replacement therapy have suggested long-term therapeutic effects for several genetic diseases of the liver, including hemophilia. However, there remain concerns regarding decreased therapeutic effects when the liver is regenerated or when physiological proliferation occurs. Although genome editing using the clustered regularly interspaced short palindromic repeats/Cas9 system provides an opportunity to solve this problem, low knock-in efficiency may limit its application for therapeutically relevant expression. Here, we identified a novel gene, Show less

Brain aging is a complex biological process that is affected by both genetic background and environment. The transcriptomic analysis of aged human and rodent brains has been applied to identify age-associated molecular and cellular processes for which intervention could possibly restore declining brain functions induced by aging. However, whether these age-associated genetic alterations are indeed involved in the healthy aging of the brain remains unclear. We herein characterized a naturally occurring, extremely long-lived (34 months of age) but healthy mouse group retaining well-preserved motor functions. Strikingly, these long-lived mice maintained tyrosine hydroxylase expression and dopaminergic fiber densities, even in the presence of persistent neuroinflammation and expression of aging markers. Combined with Endeavor gene prioritization, we identified the following midbrain-specific longevity-associated genes in the midbrain of these mice: Show less

Liquid biopsy has emerged as a promising tool for minimally invasive and accurate detection of various malignancies. We aimed to apply molecular barcode sequencing to circulating tumour DNA (ctDNA) from liquid biopsies of hepatocellular carcinoma (HCC). Patients with HCC or benign liver disease were enrolled between 2017 and 2018. Matched tissue and serum samples were obtained from these patients. Plasma cell-free DNA was extracted and subjected to targeted sequencing with ultra-high coverage and molecular barcoding. The study included 143 patients: 102 with HCC, 7 with benign liver tumours and 34 with chronic liver disease. No tier 1/2 or oncogenic mutations were detected in patients with benign liver disease. Among the HCC patients, 49 (48%) had tier 1/2 mutations in at least one gene; detection rates were higher in advanced stages (75%) than in early stages (26%-33%). TERT was the most frequently mutated gene (30%), followed by TP53 (16%), CTNNB1 (14%), ARID2 (5%), ARID1A (4%), NFE2L2 (4%), AXIN1 (3%) and KRAS (1%). Survival among patients with TP53 mutations was significantly worse (p = 0.007) than among patients without these mutations, whereas CTNNB1 and TERT mutations did not affect survival. ctDNA testing combined with α-fetoprotein and prothrombin induced by vitamin K absence-II analyses improved HCC detection, even in early stages. ctDNA detection using molecular barcoding technology offers dynamic and personalized information concerning tumour biology, such information can guide clinical diagnosis and management. This detection also has the potential as a minimally invasive approach for prognostic stratification and post-therapeutic monitoring. Show less

To determine the anti-fibrotic effects of Wnt/β-catenin signaling inhibitors on urethral stricture. Human fibroblasts were exposed to transforming growth factor beta 1 combined with various concentrations of Wnt/β-catenin inhibitors (ICG-001, IWR-1, and PRI-724), and cell proliferation and migration were evaluated. Urethral fibrosis was induced in male Sprague-Dawley rats by urethral injection of transforming growth factor beta 1 and co-treatement with inhibitors. Urethral tissues were harvested 2 weeks after the injection. The messenger ribonucleic acid and protein expression was examined for fibrosis markers Axin-1, collagen type 1, alpha smooth muscle actin, and β-catenin. Histological analysis of fibrosis and collagen deposition was also performed. Cell migration was ameliorated by ICG-001 and PRI-724. Protein and messenger ribonucleic acid expression of collagen type 1 and alpha smooth muscle actin in transforming growth factor beta 1-treated fibroblasts decreased in a concentration-dependent manner with the ICG-001 and PRI-724 treatments (P < 0.05). However, there were no significant changes with the IWR-1 treatment. Collagen type I and alpha smooth muscle actin messenger ribonucleic acid and protein expression were both significantly increased in the urethral tissues of rats with transforming growth factor beta 1-induced urethral fibrosis. Rats co-treated with ICG-001 or PRI-724 showed relatively mild fibrosis and significantly reduced collagen type I and alpha smooth muscle actin messenger ribonucleic acid and protein expression (P < 0.05). ICG-001 and PRI-724 significantly ameliorated urethral fibrosis induced by transforming growth factor beta 1 in rats. These results suggest that ICG-001 and PRI-724 can be developed as therapeutics for treating urethral stricture. Show less

S-SCAM/MAGI-2 gene duplication is associated with schizophrenia (SCZ). S-SCAM overexpression in the forebrain induces SCZ-like phenotypes in a transgenic (Tg) mouse model. Interestingly, S-SCAM Tg mice show male-specific impairments in synaptic plasticity and working memory. However, mechanisms underlying the sex-specific deficits remain unknown. Here we report that S-SCAM Tg mice have male-specific deficits in synaptic GSK3β functions, as shown by reduced synaptic protein levels and increased inhibitory phosphorylation of GSK3β. This GSK3β hyper-phosphorylation was associated with increased CaMKII activities. Notably, synaptic levels of Axin1, to which GSK3β binds in competition with S-SCAM, were also reduced in male S-SCAM Tg mice. We demonstrated that Axin-binding is required for the S-SCAM overexpression-induced synaptic GSK3β reduction. Axin stabilization using XAV939 rescued the GSK3β deficits and restored the temporal activation of GSK3β during long-term depression in S-SCAM overexpressing neurons. Interestingly, synaptic Axin2 levels were increased in female S-SCAM Tg mice. Female sex hormone 17β-estradiol increased Axin2 expression and increased synaptic GSK3β levels in S-SCAM overexpressing neurons. These results reveal the role of S-SCAM in controlling Axin-dependent synaptic localization of GSK3β. Moreover, our studies point out the pathological relevance of GSK3β hypofunction found in humans and contribute to understanding the molecular underpinnings of sex differences in SCZ. Show less

The physiological or dietary advantages of germinated grains have been the subject of numerous discussions over the past decade. Around 23 million tons of oats are consumed globally, making up a sizeable portion of the global grain market. Oat seedlings contain more protein, beta-glucan, free amino acids, and phenolic compounds than seeds. The progressive neurodegenerative disorder of Alzheimer's is accompanied by worsening memory and cognitive function. A key indicator of this disorder is the unusual buildup of amyloid-beta protein (or Aβ) in human brains. In this context, oat seedling extract (OSE) has been identified as a new therapeutic candidate for AD, due to its antioxidant activity and AD-specific mechanism of action. This study directly investigated how OSE affected AD and its impacts by examining the cognitive function and exploring the inflammatory response mechanism. The dried oat seedlings were grounded finely with a grinder, inserted with 50% fermented ethanol 10 times ( Show less

The gap junction complex functions as a transport channel across the membrane. Among gap junction subunits, gap junction protein α1 (GJA1) is the most commonly expressed subunit. A recent study showed that GJA1 is necessary for the maintenance of motile cilia; however, the molecular mechanism and function of GJA1 in ciliogenesis remain unknown. Here, we examined the functions of GJA1 during ciliogenesis in human retinal pigment epithelium-1 and Show less

Alcohol consumption is associated with a high increased lipid profile and this association may depend on genetic risk factors. In this study, we aimed to assess the effects of genetic variation associated with alcohol consumption on lipid profiles using data from two Korean population studies. We performed a genotype association study using the HEXA (n = 51,349) and KNHANES (n = 9158) data. Genotype analyses of the two sets of Korean population data showed associations of increased total cholesterol and high-density lipoprotein (HDL)-cholesterol with CETP rs708272. The HEXA and KNHANES populations revealed differences in HDL cholesterol according to the presence of CETP rs708272, independent of ALDH2 rs671 and alcohol consumption. In contrast, total cholesterol levels were associated with alcohol consumption and ALDH2 rs671 in men with CETP rs708272 (CT and TT genotypes). Furthermore, in drinkers with ALDH2 rs671 (GA and AA genotypes), higher total cholesterol was associated with the CETP rs708272 TT minor homozygous genotype based on both HEXA and KNHANES data. Our findings demonstrated that alcohol consumption and genetic variation in either CETP or ALDH2 may be associated with cholesterol levels. We hope these findings will provide a better understanding of the relationship between alcohol consumption and cholesterol according to each individual's genetic background. Show less

Metabolic syndrome (MetS) is a group of very common human conditions promoting strong understand the impact of rare variants, beyond exome-wide association studies, to potentially discover causative variants, across different ethnic populations. We performed transethnic, exome-wide MetS association studies on MetS in men. We analyzed genotype data of 5302 European subjects (2658 cases and 2644 controls), in the discovery stage of the European METabolic Syndrome In Men study, generated from exome chips, and 2481 subjects (714 cases and 1767 controls), in the replication stage, across 6 independent cohorts of 5 ancestries (T2D-GENES consortium), using whole-exome sequencing. We therefore evaluated gene-level and variant-level associations, of rare variants for MetS, using logistic regression (LR) and multivariate analyses (MulA). Gene-based association found the gene for the cholesteryl ester transfer protein (CETP) (from MulA, p value = 4.67 × 10 Our findings highlight novel rare variants of genes that confer MetS susceptibility, in Europeans, that are shared with diverse populations, emphasizing an opportunity to further understand the biological target or genes that underlie MetS, across populations. Show less