👤 Hyun-Seuk Moon

Obesity is a major global health crisis, yet the molecular mechanisms underlying adult-onset metabolic dysfunction remain incompletely understood. The tubby mouse is a foundational genetic model of maturity-onset obesity; however, the specific tissues and cell populations responsible for its metabolic phenotype have long remained elusive. Here, we demonstrate that the loss of tubby disrupts the coordinated regulation of energy intake and expenditure, leading to a sustained positive energy balance. Using cell-type-specific genetic tools, we identified MC4R-expressing and VGLUT2-expressing neurons as essential sites of tubby function. We found that tubby acts through the combined contribution of these neuronal populations, as selective deletion in either MC4R or VGLUT2 neurons is sufficient to phenocopy key features of the global Tub mutant. Together, these findings establish tubby as a central neuronal regulator of systemic energy homeostasis and define an excitatory MC4R-VGLUT2 circuit that governs feeding behavior and metabolic output. Show less

To synthesize clinical, cognitive, safety, and mechanistic evidence on supervised high-intensity interval training (HIIT) after stroke and translate key findings into practice. We conducted a narrative review of supervised HIIT interventions in adults after stroke. Electronic searches of PubMed and Web of Science identified studies published between January 1, 2014, and September 30, 2025. Eligibility criteria emphasized feasibility, safety, and neurofunctional outcomes (six-min walk distance, gait speed, peak aerobic capacity, activities/participation, and cognition). Quantitative pooling was not performed, and the findings were qualitatively synthesized. To explain biological plausibility, mechanistic and translational sources were reviewed irrespective of the year and summarized separately. HIIT was feasible under guideline-concordant screening and monitoring, with no serious adverse events. Consistent gains were observed in aerobic capacity, walking endurance, and usual gait speed, whereas activity/participation effects were mixed. Cognitive benefits were domain-specific and the clearest for executive functions. Mechanistic signals (e.g., brain-derived neurotrophic factor (BDNF), frontal oxygenation, and endothelial function) support biological plausibility. Supervised HIIT appears safe and clinically useful for augmenting locomotor and aerobic outcomes after stroke and may preferentially enhance executive cognition. Implementation should complement task-specific therapy and follow standard screening and monitoring procedures. Future work should refine dose- and phase-specific protocols to maximize application to daily function. Show less

Computerized cognitive training allows real-time tracking of performance metrics that may serve as digital biomarkers. This study investigated the value of a novel in-game digital biomarker, RTACC (Reaction Time-Accuracy Correlation), the correlation between reaction time and accuracy, using data from 130 participants with mild cognitive impairment enrolled in the intervention arm of the SUPERBRAIN-MEET randomized controlled trial. Participants underwent a 24-week multi-domain intervention, consisting of computerized cognitive training, physical exercise, nutritional education, vascular/metabolic risk management, and motivation enhancement. RTACC was derived from task-level RT and accuracy and examined in relation to cognitive and biomarker outcomes. Linear regression analysis revealed a significant association between RTACC and changes in Repeatable Battery for the Assessment of Neuropsychological Status scores from baseline to 24 weeks (beta coefficient = -11.90 ± 3.78, T = - 3.14, P = 0.002). RTACC also showed a marginal effect on changes in brain-derived neurotrophic factor levels (beta coefficient = - 3.13 ± 1.64, P = 0.057). Logistic regression analysis demonstrated that RTACC combined with clinical information identified good responders with an area under the receiver operating characteristic curve of 0.73 (95% CI: 0.62-0.84). These findings suggest that this in-game digital biomarker (RTACC) may help identify individuals likely to benefit from multi-domain intervention. Show less

Abnormal accumulation of amyloid β (Aβ), which may result from excessive production or impaired clearance, is one of the pathomechanisms of Alzheimer's disease (AD). Plasmin is one of the important proteases involved in the Aβ clearance system. In this study, we investigated whether swertisin can regulate plasmin activity and reduce Aβ pathology. First, we examined whether swertisin regulated plasmin activity, mature brain-derived neurotrophic factor (mBDNF) levels, and plasminogen activator inhibitor-1 (PAI-1) activity in vitro. Next, we assessed the effect of swertisin on memory impairments in an Aβ-injected AD-like mouse model and in 5XFAD mice. To evaluate the involvement of plasmin in the effect of swertisin in the Aβ-injected AD-like mouse model, we used 6-aminocaproic acid (6-AA), a plasmin inhibitor. Additionally, we measured plasmin activity and mBDNF levels in the hippocampus of Aβ-injected AD-like mice and 5XFAD mice. Swertisin increased plasmin activity and mBDNF levels in hippocampal slices from both normal and 5XFAD mice. Moreover, swertisin ameliorated Aβ-induced synaptic long-term potentiation (LTP) deficits in hippocampal slices. Swertisin also mitigated memory impairments induced by ventricular injection of Aβ, and this effect was blocked by 6-AA. Furthermore, swertisin improved learning and memory in 5XFAD mice while reducing Aβ deposition and neuroinflammation. This study demonstrates that swertisin ameliorates AD-like pathology by regulating plasmin activity. Plasmin activated by swertisin may cleave Aβ aggregates and increase mBDNF levels, thereby protecting the brain from Aβ toxicity. Swertisin may represent an effective therapeutic strategy for AD patients. Show less

To evaluate the lipid-lowering efficacy, safety, and adherence of switching from moderate- or low-intensity statin monotherapy to ezetimibe 10 mg/rosuvastatin 2.5 mg in Korean patients with type 2 diabetes mellitus (T2DM) and dyslipidaemia. This multicentre, open-label, single-arm, prospective study enrolled adults with T2DM and LDL-C ≥70 mg/dL despite ≥12 weeks of moderate or low-intensity statin therapy. Participants received ezetimibe 10 mg/rosuvastatin 2.5 mg once daily for 12 weeks. The primary endpoint was the proportion achieving LDL-C <70 mg/dL at Week 12. Secondary endpoints included changes in lipid and glycaemic parameters, subgroup analyses, and safety outcomes. Of 639 screened patients, 586 were included in the full analysis set (FAS). At Week 12, 62.3% (95% CI 58.4-66.2) achieved LDL-C <70 mg/dL. Mean LDL-C decreased by 26.0% from 90.9 ± 17.2 to 67.3 ± 19.3 mg/dL (p < 0.001). Total cholesterol, non-HDL-C, and apoB decreased significantly (all p < 0.001); HDL-C and triglycerides were unchanged (p = 0.914 and p = 0.393, respectively). HbA1c increased by 0.15 ± 0.53% and fasting glucose by 3.6 ± 24.7 mg/dL (both p < 0.001). HOMA-IR decreased by -0.22 ± 3.09, not significant (p = 0.085). Subgroup analyses showed greater LDL-C reductions in patients with BMI <23 kg/m Switching to ezetimibe 10 mg/rosuvastatin 2.5 mg achieved substantial LDL-C reductions, high goal attainment, excellent adherence, and good tolerability in Korean T2DM patients with dyslipidaemia. Show less

The olfactory system is an early target in Alzheimer's disease (AD), yet regional glial pathology interactions remain poorly defined. We examined how glial activation and pathological burden differ between the olfactory cortex (OC) and olfactory bulb (OB) across disease stages. Post mortem OC and OB samples from cognitively normal (CN), mild cognitive impairment, and AD cases were analyzed using immunohistochemistry and immunofluorescence for amyloid beta (Aβ), phosphorylated tau (pTau), Iba1 (microglia), GFAP (astrocyte), and apolipoprotein E (apoE). Both regions showed stage-dependent increases in Aβ and pTau, with regionally distinct glial responses. ApoE signal varied with clinical stage rather than genotype. Co-expression analyses revealed astrocyte-linked networks in the OC and microglia-linked relationships in the OB. Findings demonstrate spatially heterogenous glial pathology architectures in the human olfactory system, supporting its role as an early and regionally diverse site of AD vulnerability. Show less

Osteomas are benign, slow-growing bony tumors that commonly develop in the craniofacial region; however, standardized diagnostic and treatment protocols remain limited. This study aimed to establish a systematic approach for the diagnosis, genetic evaluation, and surgical management of craniofacial osteomas, with emphasis on lesion distribution and gender prevalence. A retrospective review was conducted on 141 patients with craniofacial osteomas at Kyungpook National University Hospital between October 2011 and September 2025. All patients underwent clinical examinations and 3-dimensional computed tomography for diagnostic confirmation. Surgical excision was performed using direct, endoscopic, or bicoronal approaches based on lesion characteristics. Whole exome sequencing was performed in patients with multiple large osteomas to evaluate mutations in EXT1, EXT2, APC, MSH2, and MLH1 genes associated with Gardner syndrome. A total of 148 osteomas were identified. The frontal bone was the most common site (60.1%), followed by the parietal, mandibular, and occipital bones. Females accounted for 79.1% of cases. Genetic testing revealed no pathogenic variants related to Gardner syndrome, and no recurrences were observed during 6 months of follow-up. Craniofacial osteomas are benign, slow-growing lesions most frequently found in the frontal bone and are more prevalent among females. The integration of imaging-based diagnosis, tailored surgical techniques, and selective genetic testing allows for accurate evaluation, effective treatment, and favorable postoperative outcomes. Show less

Multidomain lifestyle interventions have shown effectiveness in preventing dementia, but identifying high-risk groups most likely to benefit remains unclear. We re-evaluated the SUPERBRAIN-MEET multidomain intervention study in mild cognitive impairment (MCI) patients, incorporating polygenic risk scores (PRS) for Alzheimer's disease and APOE ε4 status using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total index as the primary outcome. Both intervention and control groups showed cognitive improvement over 24 weeks, with greater gains in the intervention arm. Relative intervention efficacy (RIE) increased with higher genetic risk, being most pronounced among APOE ε4 carriers and individuals with high PRS. When both factors were considered jointly, APOE ε4 carriers with high PRS exhibited the largest RIE (β = 7.54, SE = 2.59, p = 0.005), driven by markedly greater improvement in the intervention group. The secondary outcomes did not show as consistent results as RBANS total index. These findings suggest that MCI individuals who are APOE ε4 carriers with high PRS may benefit most from multidomain interventions. These results support the complementary use of PRS and APOE status for identifying high-risk subgroups most likely to benefit from multidomain interventions. ClinicalTrials.gov identifier: NCT05023057. Registered on 26 August 2021. Show less

Aberrant aggregation of amyloid-β (Aβ) peptides is a hallmark of Alzheimer's disease (AD), contributing to synaptic dysfunction and cognitive decline. Recently, pyroglutamate-modified Aβ (pE3-Aβ) has emerged as a key contributor to Aβ pathology, as it is a highly aggregation-prone variant that enhances amyloid seeding and accelerates plaque propagation. β-Secretase (BACE1) and glutaminyl cyclase (QC) are essential enzymes for generating Aβ and pE3-Aβ, respectively, and represent key therapeutic targets. This study evaluated fucoxanthin, a marine carotenoid found in brown algae for its potential to modulate Aβ pathology and cognitive function. In SweAPP N2a cells, fucoxanthin (0.1-5 μM) significantly decreased BACE1 and QC expression, accompanied by reduced levels of Aβ Show less

Achondroplasia, the most prevalent skeletal dysplasia, is a genetic disorder caused by activating mutations in the FGFR3 gene impairing endochondral ossification of long bones. Clinical manifestations include disproportionate short stature and multisystem complications. Management has been limited to supportive care, surgical limb lengthening, and recombinant human growth hormone. The latter two carry significant risks and provide modest benefits, respectively. Recently, targeted molecular therapies have emerged as promising alternatives. This review highlights three investigational agents: Vosoritide, Infigratinib, and Navepegritide. Vosoritide, an injectable C-type natriuretic peptide analog, reduces MAPK pathway overactivation; Infigratinib, an oral FGFR1-3 inhibitor, directly suppresses downstream signaling; and Navepegritide, a long-acting CNP prodrug, sustains MAPK inhibition. Clinical trials in children aged 5 years and older demonstrate improved annualized growth velocity compared to baseline: 1.7 cm/year with Vosoritide, 6.0 cm/year with Infigratinib, and 5.4 cm/year with Navepegritide. Safety profiles are favorable with few to no significant treatment-related adverse events reported in the trials reviewed; radius fracture, adenoidal hypertrophy, and sleep apnea were reported for Vosoritide, injection site reactions were reported for Navepegritide, and nasopharyngitis was reported for Infigratinib. Direct comparisons across trials are limited, but available data suggest all three therapies bring growth trajectories of children with achondroplasia closer to unaffected peers. Long-term outcomes, particularly regarding comorbidities such as foramen magnum stenosis, spinal stenosis, and sleep apnea, remain under investigation. These emerging treatments represent a paradigm shift in achondroplasia management, underscoring the need for head-to-head studies and evaluation of combination strategies to optimize efficacy and durability. Show less

Hypoxic retinopathies, including diabetic retinopathy, are major contributors to vision impairment, mainly due to accelerated angiogenesis and inflammation. Previously, we demonstrated that AAV2-shmTOR, effective across distinct species, holds therapeutic promise by modulating the activated mTOR pathway, yet its mechanisms for reducing inflammation remain largely unexplored. To investigate AAV2-shmTOR's impact on atypical inflammation in these conditions, we employed an Show less

We aimed to identify differentially expressed spliceosome components in growth hormone (GH)-secreting pituitary tumors and investigate their roles in pathogenesis. We performed transcriptome analysis of 20 somatotroph adenomas and 6 normal pituitary tissues to select dysregulated spliceosome components. Clinical characteristics were analyzed based on gene expression in 64 patients with acromegaly. Proliferation, invasion, and hormonal activity of GH secreting pituitary adenoma cells were investigated. TCERG1 expression was significantly higher in somatotroph adenomas than in normal pituitaries (log2 fold change 0.59, adjusted P = 0.0002 Spliceosome machinery provide novel insights into the pathogenesis of GH-secreting pituitary tumor and highlight the potential role of TCERG1 as a biomarker for tumor aggressiveness. Show less

Genome-wide association studies (GWAS) of metabolic syndrome (MetS) have predominantly focused on non-Asian populations, with limited representation from East Asian cohorts. Moreover, previous GWAS analyses have primarily emphasized the significance of top single nucleotide polymorphisms (SNPs), poorly explaining other SNP signals in linkage disequilibrium. This study aimed to reveal the interaction between rs651821 and rs2266788, the principal variants of apolipoprotein A5 (APOA5), within the most significant loci identified through GWAS on MetS. GWAS on MetS and its components was conducted using the data from the Korean Genome and Epidemiology Study (KoGES) city cohort comprising 58,600 individuals with available biochemical, demographic, lifestyle factors, and the most significant APOA5 locus was analyzed further in depth. According to GWAS of MetS and its diagnostic components, a significant association between the APOA5 SNPs rs651821/rs2266788 and MetS/triglycerides/high-density lipoprotein phenotypes was revealed. However, a conditional analysis employing rs651821 unveiled a reversal in the odds ratio for rs2266788. Therefore, rs651821 and rs2266788 emerged as independent and opposing signals in the extended GWAS analysis, i.e., the multilayered effects. Further gene-environment interaction analyses regarding lifestyle factors such as smoking, alcohol consumption, and physical activity underscored these multilayered effects. This study unveils the intricate interplay between rs651821 and rs2266788 derived from MetS GWAS. Removing the influence of lead SNP reveals an independent protective signal associated with rs2266788, suggesting a multilayered effect between these SNPs. These findings underline the need for novel perspectives in future MetS GWAS. Show less

The aim of this study was to investigate the comprehensive genetic effects of exploratory variants of LYPLAL1, GCKR, HSD17B13, TRIB1, APOC3, MBOAT7, and PARVB on pediatric nonalcoholic fatty liver disease in addition to the previously reported variants of TM6SF2, PNPLA3, and SAMM50 in Korean children. A prospective case-control study was conducted involving 309 patients diagnosed using ultrasound and 339 controls. Anthropometric measurements, liver function tests, and metabolic marker analysis were conducted, and fibrosis scores were calculated. Transient elastography was performed in 69 some patients with nonalcoholic fatty liver disease. TaqMan allelic discrimination assays were used for genotyping. The genetic risk scores were calculated using significant variants, namely, HSD17B13, PARVB, PNPLA3, SAMM50, and TM6SF2, to evaluate the additive effect. Risk allele carriers of the PARVB variant showed significantly higher levels of aminotransferases, gamma-glutamyl transferase, alkaline phosphatase, pediatric nonalcoholic fatty liver disease fibrosis score, and aspartate aminotransferase/platelet ratio index. Individuals with a homozygous variant of HSD17B13 showed significantly lower levels of aminotransferase, gamma-glutamyl transferase, liver stiffness measurement, and aspartate aminotransferase/platelet ratio index than those with other genotypes. These parameters did not significantly differ among other variants of LYPLAL1, GCKR, TRIB1, APOC3, and MBOAT7. The genetic risk scores was identified as an independent risk factor for nonalcoholic fatty liver disease and had a positive association with severity. HSD17B13 has protective effects on the severity of pediatric nonalcoholic fatty liver disease. Variants of HSD17B13, PARVB, PNPLA3, SAMM50, and TM6SF2 had an additive effect on nonalcoholic fatty liver disease. Show less

In addition to cellular damage, ischemia-reperfusion (IR) injury induces substantial damage to the mitochondria and endoplasmic reticulum. In this study, we sought to determine whether impaired mitochondrial function owing to IR could be restored by transplanting mitochondria into the heart under ex vivo IR states. Additionally, we aimed to provide preliminary results to inform therapeutic options for ischemic heart disease (IHD). Healthy mitochondria isolated from autologous gluteus maximus muscle were transplanted into the hearts of Sprague-Dawley rats damaged by IR using the Langendorff system, and the heart rate and oxygen consumption capacity of the mitochondria were measured to confirm whether heart function was restored. In addition, relative expression levels were measured to identify the genes related to IR injury. Mitochondrial oxygen consumption capacity was found to be lower in the IR group than in the group that underwent mitochondrial transplantation after IR injury (p < 0.05), and the control group showed a tendency toward increased oxygen consumption capacity compared with the IR group. Among the genes related to fatty acid metabolism, Show less

Diffuse midline gliomas with H3 K27-alteration (DMGH3) are lethal and inoperable brain tumors. Although DMGH3s mainly occur in pediatric patients, they have also occurred in adult patients. This study aimed to analyze the clinicopathological significance of targetable genetic alterations in non-pediatric DMGH3. Next-generation sequencing (NGS) was conducted on 18 non-pediatric DMGH3 patients to analyze additional genetic alterations. The median age at diagnosis was 35 years, and the mean follow-up duration was 762 days. Fourteen cases involved the thalamus-hypothalamus (77.8%). Histologic high-grade features (WHO histologic grade ≥ 3) were observed in 11 (61.1%) patients. H3F3A (H3 K27 M) alterations were identified in all 18 patients using immunohistochemistry and NGS. TP53 mutations were found in 11 patients (61.1%), FGFR1 or PIK3CA in 3 (16.7%), ATRX in 6 (33.3%), NF1 in 4 (22.2%), and KRAS or ATM in 1 (5.6%). TP53 mutations were significantly correlated with high-grade histological features and worse overall survival (OS) (P < 0.05). Despite non-pediatric DMGH3 cases exhibiting superior OS compared to pediatric DMGH3 cases, TP53 mutations were associated with poorer OS outcomes. Notably, FGFR1 and PIK3CA mutations, which have been identified as potential targetable genes, were detected. In conclusion, non-pediatric DMGH3s showed predominant tumor localization within the thalamus and improved prognosis compared to those in pediatric cases, with TP53 alterations correlating with high-grade histology and shorter survival. Genetic profiling, particularly identifying targetable mutations like FGFR1 and PIK3CA, could inform personalized treatment strategies and improve patient outcomes. Show less

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound Show less

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted. A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up. In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM. Show less

The canonical Wnt/β-catenin pathway is involved in diverse cancer development mechanisms, such as proliferation, migration, and invasion. However, its role in head and neck squamous cell carcinoma (HNSCC) remains largely unknown. We investigated whether the canonical Wnt/β-catenin signaling pathway acts as a controller of invasion and lymph node metastasis (LNM) in HNSCC. Loss of function experiments against the canonical Wnt/β-catenin pathway were conducted to evaluate its invasive and metastatic role in HNSCC cells. Slug was evaluated as a downstream protein in canonical Wnt/β-catenin-mediated invasion. In addition, canonical Wnt/β-catenin and Slug expression levels were examined in 119 HNSCC tissue samples to study the relevance of these proteins in LNM and prognosis of patients post-treatment. In vitro suppression of β-catenin expression led to decreased migration and invasion of HNSCC cells. Using an in vivo mouse orthotopic LNM model, a decrease in LNM was observed with mitigated β-catenin expression. Slug expression upregulation mediates invasion and LNM by the canonical Wnt/β-catenin pathway. Simultaneous expression of β-catenin and Slug is the major predictive factor of LNM and survival rate in patients with HNSCC. In conclusion, the canonical Wnt/β-catenin/Slug signaling axis significantly contributes to cancer cell invasion and LNM. Its blockade may be a treatment strategy for LNM and tumor recurrence in HNSCC. Show less

Hypoxia has been suggested to induce epithelial-mesenchymal transition (EMT) in various cancer types via the transcription factor hypoxia-inducible factor-1 alpha (HIF-1α). Here, we demonstrated that TOPK upregulates EMT and the invasion of H460 nonsmall-cell lung cancer cells through the induction of the HIF-1α/Snail axis and hypoxic signaling. The expression of endogenous TOPK, phosphorylated TOPK, HIF-1α and Snail was significantly increased upon hypoxia exposure, but TOPK depletion markedly abrogated the induced mRNA and protein levels of HIF-1α and Snail. Interestingly, TOPK knockdown restored the hypoxia-induced suppression of E-cadherin and diminished hypoxia-induced N-cadherin expression. In addition, Snail depletion suppressed hypoxia-induced N-cadherin expression, which was attenuated by TOPK knockdown. Moreover, knockdown of Snail decreased hypoxia-induced nonsmall-cell lung cancer cell migration and invasion, which were suppressed by TOPK depletion. In summary, we conclude that TOPK positively regulates HIF-1α expression through hypoxia signaling and thereby promotes Snail expression, leading to EMT and the invasion of nonsmall-cell lung cancer cells. These findings suggest that TOPK plays a critical role as a novel mediator of hypoxia signaling that regulates nonsmall-cell lung cancer development. Show less

The acquisition of stem-like phenotype is partly attributed to the induction of epithelial-mesenchymal transition (EMT). Thus, the activation of factors involved in EMT can be linked to cancer stem cell genesis. However, the underlying mechanisms in head and neck squamous cell carcinoma (HNSCC) remain largely unknown. Herein, we investigate whether slug, one of the major effectors of EMT, affects the stemness of HNSCC cells. We performed in vitro experiments to determine whether slug gene manipulation can influence the stemness phenotypes, including the capacity for self-renewal, expression of putative stemness markers, chemoresistance, and invasion in HNSCC cells. Further, we identified whether Slug knockout attenuates tumorigenicity of HNSCC cells in vivo. Finally, we examined whether prognosis of HNSCC patients after curative treatment may be affected by the level of slug expression. Overexpression of slug promoted self-renewal of HNSCC cells via activation of sphere formation, the expression of stem cell markers, and induction of chemoresistance to cisplatin. Also, slug overexpression increased the migration and invasion of HNSCC cells in vitro and was mainly observed during the invasion in HNSCC xenograft mouse model. By contrast, slug expression knockdown abrogated their self-renewal capacity, stemness-associated gene expression, and cisplatin chemoresistance. Furthermore, high levels of slug expression correlated with poor prognosis of patients with HNSCC. Inhibition of slug expression may represent a novel therapeutic strategy targeting HNSCC stem-like cells. Show less

Saturated fatty acids possess few health benefits compared to unsaturated fatty acids. However, increasing experimental evidence demonstrates the nutritionally beneficial role of odd-chain saturated fatty acids in human health. In this study, the anti-cancer effects of pentadecanoic acid were evaluated in human breast carcinoma MCF-7/stem-like cells (SC), a cell line with greater mobility, invasiveness, and cancer stem cell properties compared to the parental MCF-7 cells. Pentadecanoic acid exerted selective cytotoxic effects in MCF-7/SC compared to in the parental cells. Moreover, pentadecanoic acid reduced the stemness of MCF-7/SC and suppressed the migratory and invasive ability of MCF-7/SC as evidenced by the results of flow cytometry, a mammosphere formation assay, an aldehyde dehydrogenase activity assay, and Western blot experiments conducted to analyze the expression of cancer stem cell markers-CD44, β-catenin, MDR1, and MRP1-and epithelial-mesenchymal transition (EMT) markers-snail, slug, MMP9, and MMP2. In addition, pentadecanoic acid suppressed interleukin-6 (IL-6)-induced JAK2/STAT3 signaling, induced cell cycle arrest at the sub-G1 phase, and promoted caspase-dependent apoptosis in MCF-7/SC. These findings indicate that pentadecanoic acid can serve as a novel JAK2/STAT3 signaling inhibitor in breast cancer cells and suggest the beneficial effects of pentadecanoic acid-rich food intake during breast cancer treatments. Show less

Myoarchitectural disarray - the multiscalar disorganisation of myocytes, is a recognised histopathological hallmark of adult human hypertrophic cardiomyopathy (HCM). It occurs before the establishment of left ventricular hypertrophy (LVH) but its early origins and evolution around the time of birth are unknown. Our aim is to investigate whether myoarchitectural abnormalities in HCM are present in the fetal heart. We used wild-type, heterozygous and homozygous hearts (n = 56) from a Mybpc3-targeted knock-out HCM mouse model and imaged the 3D micro-structure by high-resolution episcopic microscopy. We developed a novel structure tensor approach to extract, display and quantify myocyte orientation and its local angular uniformity by helical angle, angle of intrusion and myoarchitectural disarray index, respectively, immediately before and after birth. In wild-type, we demonstrate uniformity of orientation of cardiomyocytes with smooth transitions of helical angle transmurally both before and after birth but with traces of disarray at the septal insertion points of the right ventricle. In comparison, heterozygous mice free of LVH, and homozygous mice showed not only loss of the normal linear helical angulation transmural profiles observed in wild-type but also fewer circumferentially arranged myocytes at birth. Heterozygous and homozygous showed more disarray with a wider distribution than in wild-type before birth. In heterozygous mice, disarray was seen in the anterior, septal and inferior walls irrespective of stage, whereas in homozygous mice it extended to the whole LV circumference including the lateral wall. In conclusion, myoarchitectural disarray is detectable in the fetal heart of an HCM mouse model before the development of LVH. Show less

Olfactory receptors (ORs) are G protein-coupled receptors that perform important physiological functions beyond their role as odorant detectors in the olfactory sensory neurons. In the present study, we describe a novel role for one of these ORs, mouse olfactory receptor 23 (MOR23), as a regulator of adipogenesis and thermogenesis in 3T3-L1 cells. Downregulation of MOR23 by small interfering RNA in 3T3-L1 cells enhanced intracellular lipid accumulation and reduced the oxygen consumption rate. In agreement with this phenotype, MOR23 deletion significantly decreased intracellular cyclic adenosine monophosphate (cAMP) levels and protein amounts of adenylyl cyclase 3 (ADCY3), protein kinase A catalytic subunit (PKA Cα), phospho-5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), and phospho-cAMP-responsive element-binding protein (CREB), along with upregulation of adipogenic genes and downregulation of genes involved in thermogenesis. Activation of MOR23 by α-cedrene, a novel natural ligand of MOR23, significantly reduced lipid content, increased the oxygen consumption rate, and stimulated reprogramming of the metabolic signature of 3T3-L1 cells, and these changes elicited by α-cedrene were absent in MOR23-deficient cells. These findings point to the role of MOR23 as a regulator of adipogenesis and thermogenesis in adipocytes. Show less

Autophagy is an intracellular stress response that is enhanced under starvation conditions, and also when the cellular components are damaged. Aging accompanies an increase in intracellular stress and has significant impact on the skin. Since dermal fibroblasts are a powerful indicator of skin aging, we compared the autophagic activity of human skin fibroblasts between the young and old. According to TEM analyses, the number of autophagosomes per 1 μm² cytoplasmic area was similar between young and aged fibroblasts. The amount of LC3 (microtubule-associated protein 1 light chain 3)-II, a form associated with autophagic vacuolar membranes, was also similar between the groups from Western blot analysis. Although residual bodies were more common in aged dermal fibroblasts, LC3 turnover and p62 assay showed little difference in the rate of lysosomal proteolysis between the young and old. RNA-seq analysis revealed that the major autophagy-modulating genes ( Show less

Impaired nutrient sensing and dysregulated glucose homeostasis are common in diabetes. However, how nutrient-sensitive signaling components control glucose homeostasis and β cell survival under diabetic stress is not well understood. Here, we show that mice lacking the core nutrient-sensitive signaling component mammalian target of rapamycin (mTOR) in β cells exhibit reduced β cell mass and smaller islets. mTOR deficiency leads to a severe reduction in β cell survival and increased mitochondrial oxidative stress in chemical-induced diabetes. Mechanistically, we find that mTOR associates with the carbohydrate-response element-binding protein (ChREBP)-Max-like protein complex and inhibits its transcriptional activity, leading to decreased expression of thioredoxin-interacting protein (TXNIP), a potent inducer of β cell death and oxidative stress. Consistent with this, the levels of TXNIP and ChREBP were highly elevated in human diabetic islets and Show less

Both the Wnt/β-catenin and Ras pathways are aberrantly activated in most human colorectal cancers (CRCs) and interact cooperatively in tumor promotion. Inhibition of these signaling may therefore be an ideal strategy for treating CRC. We identified KY1220, a compound that destabilizes both β-catenin and Ras, via targeting the Wnt/β-catenin pathway, and synthesized its derivative KYA1797K. KYA1797K bound directly to the regulators of G-protein signaling domain of axin, initiating β-catenin and Ras degradation through enhancement of the β-catenin destruction complex activating GSK3β. KYA1797K effectively suppressed the growth of CRCs harboring APC and KRAS mutations, as shown by various in vitro studies and by in vivo studies using xenograft and transgenic mouse models of tumors induced by APC and KRAS mutations. Destabilization of both β-catenin and Ras via targeting axin is a potential therapeutic strategy for treatment of CRC and other type cancers activated Wnt/β-catenin and Ras pathways. Show less