👤 Eun-Bi Seo

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

Efficient, spatially selective delivery of adeno-associated virus (AAV) therapeutics to deep brain structures remains a major challenge to gene therapy for Alzheimer's disease (AD), owing to limited transport across the blood-brain barrier (BBB) and poor penetration to target neurons. Here, we establish an integrated, noninvasive imaging and therapy platform that combines microbubble-enhanced focused ultrasound (MB-FUS) with positron emission tomography/computed tomography (PET/CT) to transiently modulate the BBB, enhance region-specific AAV delivery following systemic dosing, and longitudinally track transduction in vivo. Optimized MB-FUS achieved targeted hippocampal delivery of systemically administered AAV9 in healthy mice, resulting in a 10-fold enhancement of neuronal transduction as compared to non-FUS controls. Importantly, longitudinal PET reporter gene imaging in the 5xFAD AD model demonstrated robust brain AAV transduction that remained stable for at least seven months. Finally, to assess therapeutic impact, we used brain-derived neurotrophic factor (BDNF) as a test cargo. MB-FUS-facilitated delivery elevated BDNF expression in targeted regions and produced short-term improvements in synaptic signaling in 5xFAD mice. Collectively, these results highlight MB-FUS as a next-generation delivery platform to overcome barriers to AAV therapeutic delivery in Alzheimer's disease and position longitudinal PET assessment as a critical, translatable tool for monitoring and optimizing gene therapy. Show less

High-fat diet (HFD)-induced obesity impairs cognition and hippocampal neurogenesis, linked to reduced metabolic flexibility between mitochondrial fatty acid β-oxidation (FAO) and cytosolic de novo lipogenesis (DNL). It is not fully understood if switching to a high-carbohydrate diet (HCD) or a ketogenic diet (KD) could reverse these HFD-induced deficits, or if they do so through different mechanisms. Male C57BL/6J mice received HFD for 8 weeks to induce obesity. Mice were then either maintained on the HFD or switched to an HCD or KD for an additional 8 weeks. We evaluated systemic metabolism (body weight, serum biochemistry), tissue-specific metabolic remodeling (RNA-seq, histology, RT-qPCR, Western blot) and cognitive function (Y-maze test, novel object recognition test). Both HCD and KD interventions reversed HFD‑induced systemic abnormalities, including reducing ALT/AST, cholesterol, and LDL, and attenuating hepatic steatosis and adipocyte hypertrophy. Metabolically, KD markedly increased β‑hydroxybutyrate, whereas HCD showed a distinct triglyceride profile. Both diets improved hippocampus-dependent working and recognition memory. Hippocampal RNA‑seq revealed diet-specific mechanisms. HCD enriched anabolic processes, including upregulation of glucose transporters (Glut 1, 2, 3, 4) and DNL pathway (ACLY-ACC-FASN-SCD1). Conversely, KD enriched AMPK signaling, increasing monocarboxylate transporters (Mct 1, 2, 4) for ketone uptake and activating the neurotrophic AMPK-ERK-CREB-BDNF pathway. In conclusion, post-HFD switching to HCD or KD restores hippocampal structure and cognition via complementary mechanisms. HCD drives a substrate-centric, lipogenic program supporting proliferation, whereas KD engages a signaling-centric, neurotrophic program enhancing plasticity. Metabolic flexibility is a promising target for obesity-associated cognitive decline. Show less

The gut microbiota plays a pivotal role in maintaining host health and has increasingly been linked to the pathogenesis of neurodegenerative diseases through the microbiota-gut-brain axis. Parkinson's disease (PD), characterized by dopaminergic dysfunction, neuro inflammation, and pathological alpha-synuclein (α-synuclein) aggregation, is frequently accompanied by gut microbial dysbiosis. Probiotics isolated from human infants could offer distinct neuroprotective and immunomodulatory benefits, yet their effects on integrated gut-brain axis models remain underexplored. In this study, we investigated the therapeutic potential of Lactobacillus acidophilus SLAM_LAA02 (L. acidophilus SLAM_LAA02), a novel infant-derived strain, in modulating PD-related behavioral and neuropathological features via modulation of the gut-brain axis. Following comprehensive safety and functional assessments, we first assessed L. acidophilus SLAM_LAA02 in Caenorhabditis elegans, where supplementation extended lifespan, enhanced antimicrobial defense, improved behavioral responses, and reduced α-synuclein expression in transgenic worms. We then evaluated its effects in a rotenone-induced mouse model that reflects early-stage PD-like features. L. acidophilus SLAM_LAA02 administration ameliorated motor dysfunction, modulated neuroinflammatory signaling, restored gut microbial diversity, and improved intestinal barrier-associated outcomes. These changes were accompanied by a notable reduction in α-synuclein expression and upregulated neuroprotective gene expression, including brain-derived neurotrophic factor (BDNF). Together, these findings suggest that L. acidophilus SLAM_LAA02 exhibits neuroprotective and gut-modulating properties across complementary model systems, supporting its potential as a promising probiotic candidate for alleviating early PD-related dysfunctions through the gut-brain axis. Show less

Tinnitus is a complex neurological condition affecting 10-15% of adults worldwide, characterized by phantom auditory perception without external sound sources. While traditional investigations have focused on discrete auditory structures, emerging evidence suggests tinnitus involves broader alterations across central auditory regions. This study employed transcriptomic analysis to investigate molecular mechanisms underlying salicylate-induced tinnitus across multiple brain regions simultaneously. Male C57BL/6 N mice received daily intraperitoneal injections of sodium salicylate (350 mg/kg) for five consecutive days to induce tinnitus-like behavior, assessed using gap-prepulse inhibition of acoustic startle reflex. RNA sequencing was performed on auditory cortex, inferior colliculus, and cochlear nucleus tissues. Differential gene expression analysis, weighted gene co-expression network analysis, and functional annotation were conducted to identify shared molecular signatures and pathways across auditory centers. Principal component analysis revealed region-specific transcriptomic changes following salicylate treatment. Differential gene expression analysis identified Depp1 and Angptl4 as consistently upregulated genes across multiple brain regions, particularly within the inferior colliculus and cochlear nucleus. Weighted gene co-expression network analysis revealed a 215-gene module increased across all auditory regions in tinnitus mice, with functional annotation indicating enrichment for vasculature-related biological processes. Depp1 emerged as a central hub gene linking oxidative stress responses to autophagy mechanisms. This study shows that tinnitus pathology involves not only neuronal hyperactivity but also oxidative stress, neuroinflammation, and autophagy in the central auditory pathway. Depp1 acts as a molecular hub linking redox imbalance to cellular clearance, highlighting its potential as a therapeutic target and offering new insights for intervention. Show less

BackgroundEpigenetic age acceleration (EAA) refers to the extent to which an individual's biological age, estimated from DNA methylation patterns, exceeds their chronological age, indicating accelerated cellular and tissue aging.ObjectiveWe investigated the association between EAA and Alzheimer's disease (AD), with a focus on sex-based differences.MethodsEAA was estimated from blood samples in 127 participants with Alzheimer's disease-related cognitive impairment (ADCI) and 143 cognitively unimpaired (CU) participants, recruited from a nationwide multicenter study under the Precision Medicine Platform for Mild Cognitive Impairment (PREMIER) consortium in Korea.ResultsEAA measures indicated higher acceleration in the ADCI group compared to the CU group, particularly for extrinsic epigenetic age acceleration (EEAA), AgeAccelResidualHannum, and AgeAccelPheno. Sex-specific analyses revealed that EEAA significantly differed between the ADCI and CU groups in both men and women, with a greater EEAA in men. Logistic regression analysis demonstrated that increased EEAA, the presence of Show less

The proteasome is a major intracellular protease complex, but the significance of circulating proteasome activity in Alzheimer’s disease (AD) is not well established. Because APOE ε4 is the strongest genetic risk factor for AD, we examined whether plasma proteasome activity is associated with AD-related pathology, neurodegeneration, and cognitive decline, focusing on APOE ε4 carriers. In this observational study, participants were classified as cognitively normal (CN), mild cognitive impairment (MCI), and dementia. All underwent 3.0-T MRI, [ A total of 148 individuals were included (58 CN, 39 MCI, 38 AD dementia, and 13 other dementia). Significant associations appeared only in APOE ε4 carriers ( Downregulated proteasome activity is strongly associated with amyloid burden, early tau accumulation, hippocampal atrophy, and cognitive impairment only in APOE ε4 carriers. These findings suggest that plasma proteasome activity may serve as a noninvasive marker of AD-related vulnerability in genetically at-risk individuals. Further studies are needed to clarify whether proteasome activity contributes to or results from amyloid and tau aggregation. KCT0005428. Registered September 24, 2020. Study subjects included in this analysis were those recruited from November 2018 onwards (retrospectively registered). The online version contains supplementary material available at 10.1186/s13195-026-01994-w. Show less

Vascular damage, including cerebral amyloid angiopathy (CAA) and non-amyloid cerebral small vessel disease (CSVD), has been linked to glymphatic dysfunction, which may contribute to Alzheimer's disease (AD) pathology and cognitive decline. We investigated the associations among vascular damage, glymphatic function measured by the DTI-ALPS (Diffusion Tensor Imaging-Analysis Along the Perivascular Space) index, AD plasma biomarkers, and cognitive decline. This study includes 1,249 participants recruited from Samsung Medical Center. We performed linear regression analysis to identify factors associated with the DTI-ALPS index. Further, linear regression analysis with vascular imaging markers, including CAA and CSVD summary scores, as predictors and DTI-ALPS index as an outcome was performed to investigate the effect of vascular pathology on glymphatic function. We conducted mediation analyses to investigate whether the DTI-ALPS index mediates the effect of vascular imaging markers on plasma biomarkers (phosphorylated tau 217 [p-tau 217], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NFL]). Additionally, mediation analyses with the DTI-ALPS index as a predictor, each plasma biomarker as a mediator, and annual MMSE or CDR-SOB change as an outcome to investigate whether plasma biomarkers mediate the effect of the DTI-ALPS index on longitudinal cognitive decline. First, the DTI-ALPS index was negatively associated with both CAA (β [95% CI] = -0.163 [-0.214, -0.112], p < 0.0001) and CSVD (β [95% CI] = -0.195 [-0.247, -0.143], p < 0.0001) summary scores after controlling for age, sex, BMI status, and APOE genotype. Second, the DTI-ALPS index fully mediated the relationship between these vascular markers and p-tau 217 (CSVD summary score, indirect effect β [95% CI] = 0.016 [0.010, 0.023], p < 0.001; CAA summary score, indirect effect β [95% CI] = 0.013 [0.008, 0.020], p < 0.001) and GFAP (CSVD summary score, indirect effect β [95% CI] = 0.015 [0.008, 0.022], p < 0.001; CAA summary score, indirect effect β [95% CI] = 0.012 [0.007, 0.019], p < 0.001), while partially mediating the relationship for NFL, regardless of Aβ uptake on PET. Finally, the DTI-ALPS index was significantly associated with cognitive decline and this association was partially mediated by plasma biomarkers. These findings highlight glymphatic dysfunction as a key mechanism linking vascular pathology with tau, inflammation and neurodegeneration, independent of Aβ uptakes. Show less

Impaired glymphatic function is considered an important characteristic of cognitive decline, but the role of tau pathology as a mediator remains unclear. This study investigated whether tau burden mediates the association between diffusion tensor image analysis along the perivascular space (DTI-ALPS) and cognitive impairment or brain atrophy. Also, we explored whether DTI-ALPS index predicts longitudinal cognitive deterioration over time. We included 144 individuals with mild cognitive impairment (MCI), Alzheimer's disease dementia (ADD), and other dementia, or normal cognition. All participants underwent 3.0-Tesla MRI, DTI-ALPS index was significantly lower in cognitively impaired individuals compared to cognitively normal (CN) participants. Lower DTI-ALPS index was associated with higher tau burden and worse cognitive function. Tau burden was also inversely associated with cognition. Mediation analysis indicated that tau burden accounted for approximately 21-27% of the association between DTI-ALPS and cognition. Longitudinal analysis showed baseline lower DTI-ALPS index also predicted faster longitudinal cognitive decline. Our findings suggest that the DTI-ALPS index is an indirect marker of glymphatic dysfunction associated with tau accumulation and cognitive decline. Tau pathology may partially link compromised glymphatic clearance to cognitive impairment. Show less

Most cancer cells adopt a less efficient metabolic process of aerobic glycolysis with high level of glucose uptake followed by lactic acid production, known as the Warburg effect. This phenotypic transition enables cancer cells to achieve increased cellular survival and proliferation in a harsh low-oxygen tumor microenvironment. Also, the resulting acidic microenvironment causes inactivation of the immune system such as T-cell impairment that favors escape by immune surveillance. While lots of studies have revealed that tumor-derived EVs can deliver parental materials to adjacent cells and contribute to oncogenic reprogramming, their functionality in energy metabolism is not well addressed. In this study, we established prostate cancer cells PC-3AcT resistant to cellular death in an acidic culture medium driven by lactic acid. Quantitative proteomics between EVs derived from PC-3 and PC-3AcT cells identified 935 confident EV proteins. According to cellular adaptation to lactic acidosis, we revealed 159 regulated EV proteins related to energy metabolism, cellular shape, and extracellular matrix. These EVs contained a high abundance of glycolytic enzymes. In particular, PC-3AcT EVs were enriched with apolipoproteins including apolipoprotein B-100 (APOB). APOB on PC-3AcT EVs could facilitate their endocytic uptake depending on low density lipoprotein receptor of recipient PC-3 cells, encouraging increases of cellular proliferation and survival in acidic culture media via increased activity and expression of hexokinases and phosphofructokinase. The activation of recipient PC-3 cells can increase glucose consumption and ATP generation, representing an acquired metabolic reprogramming into the Warburg phenotype. Our study first revealed that EVs derived from prostate cancer cells could contribute to energy metabolic reprogramming and that the acquired metabolic phenotypic transition of recipient cells could favor cellular survival in tumor microenvironment. Show less

β-secretase (BACE1) is instrumental in amyloid-β (Aβ) production, with overexpression noted in Alzheimer's disease (AD) neuropathology. The interaction of Aβ with the receptor for advanced glycation endproducts (RAGE) facilitates cerebral uptake of Aβ and exacerbates its neurotoxicity and neuroinflammation, further augmenting BACE1 expression. Given the limitations of previous BACE1 inhibition efforts, the study explores reducing BACE1 expression to mitigate AD pathology. The research reveals that the anticancer agent 6-thioguanosine (6-TG) markedly diminishes BACE1 expression without eliciting cytotoxicity while enhancing microglial phagocytic activity, and ameliorate cognitive impairments with reducing Aβ accumulation in AD mice. Leveraging advanced deep learning-based tool for target identification, and corroborating with surface plasmon resonance assays, it is elucidated that 6-TG directly interacts with RAGE, modulating BACE1 expression through the JAK2-STAT1 pathway and elevating soluble RAGE (sRAGE) levels in the brain. The findings illuminate the therapeutic potential of 6-TG in ameliorating AD manifestations and advocate for small molecule strategies to increase brain sRAGE levels, offering a strategic alternative to the challenges posed by the complexity of AD. Show less

Mind bomb 1 (MIB1) is an E3 ubiquitin ligase that promotes the polyubiquitination-mediated degradation of NOTCH ligands and plays an important role in various cancers by enhancing tumor cell proliferation. Also, MIB1 inhibited the cell cycle progression by transcriptional repression of P21 in HCT116 cells. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) that plays a significant role in the progression of various cancers. However, the regulatory mechanisms underlying FGFR1-associated signaling in colon cancer remain unclear. We investigated whether MIB1 regulates protein stability of FGFR1 and impairs cell proliferation in HCT116 cells. We conducted immunoprecipitation assay to identify correlation of MIB1 and FGFR1. We also tested mRNA level of FGFR1 in MIB1-depleted HCT116 cells using reverse transcription-quantitative polymerase chain reaction. Furthermore, we transfected HA-MIB1 and FLAG-FGFR1 and analyzed the downstream signaling cascades by western blotting. Cell viability was assessed using colony formation assays and MTT assay. FGFR1 interacts with MIB1 and controls FGFR1 protein level in HCT116 cells. Transcriptome analysis revealed that the mRNA levels of FGFR1 increased when MIB1 was depleted in HCT116 cells. Moreover, histone deacetylase 3 (HDAC3) is involved in histone deacetylation and transcriptional repression, mediating the interaction between MIB1 and FGFR1. These findings suggest the importance of MIB1-mediated transcriptional repression of FGFR1 and its potential therapeutic target in colon cancer. Show less

Apical hypertrophic cardiomyopathy (HCM) is a rare variant of HCM, often considered to have a benign prognosis. This study aimed to compare the clinical characteristics and genetic predisposition of apical HCM with non-apical HCM. We included 195 patients with HCM who underwent next-generation sequencing at two tertiary centres in South Korea (2017-2024). The primary outcome was a composite of lethal arrhythmic events (LAE), including death, ventricular arrhythmia, implantable cardioverter defibrillator (ICD) implantation and appropriate ICD shock. Secondary outcomes included major adverse cardiovascular events (MACE), such as new-onset atrial fibrillation, ischaemic stroke, heart failure hospitalisation, septal reduction therapy or heart transplant. Of the 195 patients, 67 (34.4%) had apical HCM. Patients with apical HCM were older at diagnosis and had lower maximal left ventricular wall thickness compared with non-apical HCM. Disease-causing variants were less frequent in apical HCM (20.9% vs 46.9%, p<0.001). Although apical HCM is associated with less hypertrophy and lower genetic yield, it is not entirely benign. The presence of disease-causing variants is an important predictor of arrhythmic risk, underscoring the value of genetic testing in all HCM patients, regardless of phenotype. Show less

The dorsomedial striatum (DMS) is associated with flexible goal seeking, as opposed to routinized habits. Whether local mechanisms brake this function, for instance when habits may be adaptive, is incompletely understood. We find that a sub-population of dopamine D1 receptor-containing striatal neurons express the melanocortin-4 receptor (MC4R) for α-melanocyte stimulating hormone. These neurons within the DMS are necessary and sufficient for controlling the capacity of mice to flexibly adjust actions based on the likelihood that they will be rewarded. In investigating MC4R function, we found that it suppresses immediate-early gene levels in the DMS and concurrently, flexible goal seeking. MC4R+ neurons receive input from the central nucleus of the amygdala, and behavioral experiments indicate that they are functionally integrated into an amygdalo-striatal circuit that suppresses action flexibility in favor of routine. Publicly available spatial transcriptomics datasets were analyzed for gene transcript correlates of Mc4r expression across the striatal subregions, revealing considerable co-variation in dorsal structures. This insight led to the discovery that the function of MC4R in the dorsolateral striatum complements that in the DMS, in this case suppressing habit-like behavior. Altogether, our findings suggest that striatal MC4R controls the capacity for goal-directed and inflexible actions alike. Show less

Research has suggested a potential relationship between apolipoproteins A (ApoA) and B (ApoB) and age-related macular degeneration (AMD). This study explored the potential causal relationship between ApoA/ApoB levels and AMD/AMD subtypes using two-sample Mendelian randomisation (MR). We selected 308 single nucleotide polymorphisms (SNPs) for ApoA and 198 SNPs for ApoB from the UK Biobank data. Summary statistics for AMD were collected from the genome-wide association study of the FinnGen project. We performed two-sample MR to assess the causal effects of ApoA/ApoB on AMD and its subtypes. Potential confounders, including body mass index, C-reactive protein level, and smoking status, were assessed using a multivariable MR analysis. ApoA showed a significant causal association with AMD (odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.05-1.25, These findings suggest that ApoB is associated with lower AMD risk, particularly for dry AMD. Further research is needed to clarify lipid biomarker's role as AMD risk factors. Show less

Melanocytes, located in the epidermis' basal layer, are responsible for melanin pigment production, crucial for skin coloration and protection against UV radiation-induced damage. Melanin synthesis is intricately regulated by various factors, including the Wnt signaling pathway, particularly mediated by the microphthalmia-associated transcription factor (MITF). While MITF is recognized as a key regulator of pigmentation, its regulation by the Wnt pathway remains poorly understood. This study investigates the role of Sfrp5pepD, a peptide antagonist of the Wnt signaling pathway, in modulating melanogenesis and its potential therapeutic implications for pigmentary disorders. To tackle this issue, we investigated smaller peptides frequently utilized in cosmetics or pharmaceuticals. Nevertheless, there is a significant scarcity of reports on peptides associated with melanin-related signal modulation or inhibiting melanin production. Results indicate that Sfrp5pepD effectively inhibits Wnt signaling by disrupting the interaction between Axin-1 and β-catenin, thus impeding downstream melanogenic processes. Additionally, Sfrp5pepD suppresses the interaction between MITF and β-catenin, inhibiting their nuclear translocation and downregulating melanogenic enzyme expression, ultimately reducing melanin production. These inhibitory effects are validated in cell culture models suggesting potential clinical applications for hyperpigmentation disorders. Overall, this study elucidates the intricate interplay between Wnt signaling and melanogenesis, highlighting Sfrp5pepD as a promising therapeutic agent for pigmentary disorders. Sfrp5pepD, with a molecular weight of less than 500 Da, is anticipated to penetrate the skin unlike SFRPs. This suggests a strong potential for their use as cosmetics or transdermal absorption agents. Additional investigation into its mechanisms and clinical significance is necessary to enhance its effectiveness in addressing melanin-related skin conditions. Show less

We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aβ levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aβ levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study, we synthesized and tested radically altered IMT isomers (IMTi's) that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization. Show less

We recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer's disease (AD). However, the effects of CA140 on Aβ/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown. To investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted. In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aβ/tau fibrillation, Aβ plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100β and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling. Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aβ/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice. Show less

The stem cell microenvironment has been evidenced to robustly affect its biological functions and clinical grade. Natural or synthetic growth factors, especially, are essential for modulating stem cell proliferation, metabolism, and differentiation via the interaction with specific extracellular receptors. Fibroblast growth factor-2 (FGF-2) possesses pleiotropic functions in various tissues and organs. It interacts with the FGF receptor (FGFR) and activates FGFR signaling pathways, which involve numerous biological functions, such as angiogenesis, wound healing, cell proliferation, and differentiation. Here, we aim to explore the molecular functions, mode of action, and therapeutic activity of yet undetermined function, FGF-2-derived peptide, FP2 (44-ERGVVSIKGV-53) in promoting the proliferation, differentiation, and therapeutic application of human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) in comparison to other test peptides, canofin1 (FP1), hexafin2 (FP3), and canofin3 (FP4) with known functions. The immobilization of test peptides that are fused with mussel adhesive proteins (MAP) on the culture plate was carried out via EDC/NHS chemistry. Cell Proliferation assay, colony-forming unit, western blotting analysis, gene expression analysis, RNA-Seq. analysis, osteogenic, and chondrogenic differentiation capacity were applied to test the activity of the test peptides. We additionally utilized three-dimensional (3D) structural analysis and artificial intelligence (AI)-based AlphaFold2 and CABS-dock programs for receptor interaction prediction of the peptide receptor. We also verified the in vivo therapeutic capacity of FP2-cultured hWJ-MSCs using an osteoarthritis mice model. Culture of hWJ-MSC onto an FP2-immobilized culture plate showed a significant increase in cell proliferation (n = 3; *p < 0.05, **p < 0.01) and the colony-forming unit (n = 3; *p < 0.05, **p < 0.01) compared with the test peptides. FP2 showed a significantly upregulated phosphorylation of FRS2α and FGFR1 and activated the AKT and ERK signaling pathways (n = 3; *p < 0.05, **p < 0.01, ***p < 0.001). Interestingly, we detected efficient FP2 receptor binding that was predicted using AI-based tools. Treatment with an AKT inhibitor significantly abrogated the FP2-mediated enhancement of cell differentiation (n = 3; *p < 0.05, **p < 0.01, ***p < 0.001). Intra-articular injection of FP2-cultured MSCs significantly mitigated arthritis symptoms in an osteoarthritis mouse model, as shown through the functional tests (n = 10; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001), modulation of the expression level of the pro-inflammatory and anti-inflammatory genes, and improved osteochondral regeneration as demonstrated by tissue sections. Our study identified the FGF-2-derived peptide FP2 as a promising candidate peptide to improve the therapeutic potential of hWJ-MSCs, especially in bone and cartilage regeneration. Show less

Sargassum horneri (S. horneri), a brown seaweed excessively proliferating along Asian coastlines, are damaging marine ecosystems. Thus, this study aimed to enhance nutritional value of S. horneri through lactic acid bacteria fermentation to increase S. horneri utilization as a functional food supplement, and consequently resolve coastal S. horneri accumulation. S. horneri supplemented fermentation was most effective with Lactiplantibacillus pentosus SH803, thus this product (F-SHWE) was used for further in vitro studies. F-SHWE normalized expressions of oxidative stress related genes NF-κB, p53, BAX, cytochrome C, caspase 9, and caspase 3, while non-fermented S. horneri (SHWE) did not, in a H Show less

Although stem cells are a promising avenue for harnessing the potential of adipose tissue, conventional two-dimensional (2D) culture methods have limitations. This study explored the use of three-dimensional (3D) cultures to preserve the regenerative potential of adipose-derived stem cells (ADSCs) and investigated their cellular properties. Flow cytometric analysis revealed significant variations in surface marker expressions between the two culture conditions. While 2D cultures showed robust surface marker expressions, 3D cultures exhibited reduced levels of CD44, CD90.2, and CD105. Adipogenic differentiation in 3D organotypic ADSCs faced challenges, with decreased organoid size and limited activation of adipogenesis-related genes. Key adipocyte markers, such as lipoprotein lipase (LPL) and adipoQ, were undetectable in 3D-cultured ADSCs, unlike positive controls in 2D-cultured mesenchymal stem cells (MSCs). Surprisingly, 3D-cultured ADSCs underwent mesenchymal-epithelial transition (MET), evidenced by increased E-cadherin and EpCAM expression and decreased mesenchymal markers. This study highlights successful ADSC organoid formation, notable MSC phenotype changes in 3D culture, adipogenic differentiation challenges, and a distinctive shift toward an epithelial-like state. These findings offer insights into the potential applications of 3D-cultured ADSCs in regenerative medicine, emphasizing the need for further exploration of underlying molecular mechanisms. Show less

Carbohydrate-responsive element-binding protein (ChREBP) is a transcription factor that regulates several metabolic genes, including the lipogenic enzymes necessary for the metabolic conversion of carbohydrates into lipids. Although the crucial role of ChREBP in the liver, the primary site of de novo lipogenesis, has been studied, its functional role in adipose tissues, particularly brown adipose tissue (BAT), remains unclear. In this study, we investigated the role of ChREBP in BAT under conditions of a high-carbohydrate diet (HCD) and ketogenic diet (KD), represented by extremely low carbohydrate intake. Using an adeno-associated virus and Cas9 knock-in mice, we rapidly generated Chrebp brown adipocyte-specific knock-out (B-KO) mice, bypassing the necessity for prolonged breeding by using the Cre-Lox system. We demonstrated that ChREBP is essential for glucose metabolism and lipogenic gene expression in BAT under HCD conditions in Chrebp B-KO mice. After nutrient intake, Chrebp B-KO attenuated the KD-induced expression of several inflammatory genes in BAT. Our results indicated that ChREBP, a nutrient-sensing regulator, is indispensable for expressing a diverse range of metabolic genes in BAT. Show less

Allium cepa L. (A. cepa) is one of the oldest cultivated plants in the world. A. cepa has been used in traditional folk medicine to treat inflammatory disease in several regions, such as Palestine and Serbia. A. cepa peel has a higher content of flavonoids, such as quercetin, than the edible parts. These flavonoids alleviate inflammatory diseases. However, the anti-inflammatory effects of A. cepa peel extract-obtained using various extraction methods-and their underlying mechanisms require further investigation. Although research to find safe anti-inflammatory substances in various natural products has been actively conducted for many years, it is important to continue identifying potential anti-inflammatory effects in natural materials. The purpose of this study was to investigate the ethnopharmacological properties of the A. cepa peel extract, whose efficacy when obtained through different extraction methods and underlying action mechanisms is not well known. The present study specifically aimed to observe the anti-inflammatory effects of the A. cepa peel extracts obtained using various extraction methods and the related detailed mechanisms of A. cepa peel extracts in lipopolysaccharide (LPS)-induced RAW264.7 cells. The total flavonoid content of the A. cepa peel extracts was determined the diethylene glycol colorimetric method and measured using a calibration curve prepared using quercetin as a standard solution. The antioxidant activity was evaluated using the ABTS assay, and cytotoxicity was measured using the MTT assay. NO production was measured using Griess reagent. Protein levels were measured by western blotting, and mRNA expression was measured by RT-qPCR. Secreted cytokines were analyzed using ELISA or cytokine arrays. In the GSE160086 dataset, we calculated Z-scores for individual genes of interest and displayed using a heat map. Of the three A. cepa peel extracts obtained using different extraction methods, the A. cepa peel 50% EtOH extract (AP50E) was the most effective at inhibiting LPS-induced nitric oxide (NO) and inducible nitric oxide synthase (iNOS). Furthermore, AP50E significantly reduced the levels of pro-inflammation cytokines interleukin (IL)-1α, IL-1β, IL-6, and IL-27. Additionally, AP50E directly inhibited the Janus kinase-signaling transducer and activator of transcription (JAK-STAT) pathway. These results showed that AP50E exhibited an anti-inflammatory effect in LPS-induced RAW264.7 mouse macrophages by directly inhibiting JAK-STAT signaling. Based on these findings, we propose AP50E as a potential candidate for the development of preventive or therapeutic agents against inflammatory diseases. 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

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

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

Chamaecyparis obtusa (Siebold & Zucc.) Endl. (C. obtusa) has been used as folk medicine in East Asia and has been reported to alleviate inflammatory diseases. However, the detailed mechanisms for the anti-inflammatory effects of C. obtusa remain unclear. Although the anti-inflammatory mechanisms of natural products have been studied for decades, it is still important to identify the potential anti-inflammatory effects of natural sources. In this study, we investigated the anti-inflammatory effects and underlying mechanism of C. obtusa leaf extracts. The cell viability was determined by MTT and crystal violet staining. NO production in the supernatant was measured using Griess reagent. The cell lysates were analyzed by immunoblotting and RT-qPCR. Secreted cytokines were analyzed using ELISA kit and cytokine array kit. mRNA expression from the GSE9632 database set. Z-scores were calculated for each gene and visualized by heat map. Among the extracts of C. obtusa obtained with different extraction methods, the 99% ethanol leaf extract (CO99EL) strongly inhibited lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and Janus kinase/signaling transducer and activator of transcription (JAK/STAT) phosphorylation in RAW264.7 cells. In addition, CO99EL strongly inhibited LPS-induced interleukin (IL)-1β, IL-6, IL-27, and C-C motif chemokine ligand (CCL)-1 production and directly inhibited LPS-induced JAK/STAT phosphorylation in RAW264.7 cells. These findings demonstrate that CO99EL significantly prevents LPS-induced macrophage activation by inhibiting the JAK/STAT axis. Therefore, we suggest the use of C. obtusa extracts as therapeutic approach for inflammatory diseases. Show less

Characterizing the tumor microenvironment (TME) and immune landscape of cancer has been a promising step towards discovering new therapeutic biomarkers and guiding precision medicine; however, its application in mucoepidermoid carcinoma (MEC) has been sparse. Here, we conducted a comprehensive study to understand the properties of the TME and immune profiles of MEC. 20 patients with MEC were collected from Yonsei Head and Neck Cancer Centre, Yonsei University, South Korea. Total RNA sequencing was conducted to determine gene expression profiles. Bioinformatic and immunoinformatic analyses were applied to characterize the TME and identify immunophenotypic subgroups, and to investigate the molecular features that explain the distinct phenotypes. The MEC samples were subdivided into two groups, immune hot and immune cold, based on the heterogenous immune cell-infiltration and activation level. The immune-hot subgroup exhibited a higher level of immune activity, including T cell infiltration, cytolytic score, IFN-γ, antigen-presenting machinery, and immune modulator genes. Further characterizing molecular features of two subgroups, downregulation of lipid metabolic regulators, including MLXIPL and FASN, and the migration of chemokines and leukocytes were observed, respectively. And, Group-specific expression of immune checkpoint molecules, such as TIGIT, PD-L2, and CTLA-4, was observed in the immune-hot group, which can be exploited as a potential immunotherapeutic biomarker. Immunophenotypically heterogeneous MEC subgroups analysis has shown distinctive molecular characteristics and provided potential treatment options. These findings yield new insights into TME of MEC and may help next step to study this uncharted cancer. Show less