👤 Min-Chul Kwon

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

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

Schisandrin C (SCC), a bioactive lignan compound derived from Schisandra chinensis (S. chinensis), has been demonstrated to promote intestinal health. However, the antidepressant activity of SCC and its impact on the gut‒brain axis have not been reported. This study aimed to investigate the antidepressant effects of SCC and elucidate its molecular mechanisms through modulation of the microbiota‒gut‒brain axis. Artificial intelligence (AI)-based target protein prediction, network pharmacology analysis, and experimental validation using intestinal cells, Caenorhabditis elegans, and mice models were conducted. Targeted metabolomics, gut microbiota analyses, and molecular biology techniques were employed for mechanistic elucidation. SCC treatment effectively suppressed depressive-like behaviors in mice subjected to chronic unpredictable mild stress (CUMS). SCC upregulated brain-derived neurotrophic factor (BDNF) expression in the brain by regulating the AKT/CREB/BDNF signaling pathway. Additionally, integrated network pharmacology, molecular docking, and metabolomics analyses revealed that SCC significantly increased brain serotonin levels by inhibiting monoamine oxidase (MAO) activity. Furthermore, SCC increased the abundance of Akkermansia and Bifidobacterium, as observed both in the synthetic microbial community in vitro and in the gut microbiota in vivo. Additionally, SCC effectively alleviated intestinal barrier dysfunction and reduced intestinal inflammation in vitro in intestinal cells, in vivo in C. elegans infected with Bacteroides fragilis, and in vivo in the CUMS-induced mice model. SCC improves depressive-like behaviors by modulating the microbiota‒gut‒brain axis. These findings underscore the potential of SCC as an effective therapeutic agent for depression. Show less

Angiopoietin-like 4 (Angptl4) is a secreted glycoprotein involved in the regulation of various homeostatic and disease processes. In the intestine, prior studies have suggested protective roles for Angptl4 in inflammation using Angptl4 knockout mouse models; however, phenotypic variability-such as perinatal lethality and intestinal inflammation accompanied by lymphatic defects in only a subset of animals-has complicated the interpretation of its role in intestinal pathogenesis. In this study, the impact of Angptl4 deficiency was examined using a subset of Angptl4 knockout mice that survive postnatally without overt abnormalities. It was found that loss of Angptl4 confers protection against colitis and colitis-associated colorectal tumorigenesis. These protective effects were associated with the alternative activation of anti-inflammatory M2-like macrophages. Similarly, in a genetic model of intestinal tumorigenesis, Angptl4 deficiency resulted in reduced tumor burden and attenuated inflammation, accompanied by increased M2-like macrophages. Analysis of human colorectal cancer data sets further revealed that low ANGPTL4 expression is associated with improved survival outcomes as well as reduced expression of inflammation-related marker genes. Collectively, the findings uncover a previously unrecognized protective effect of Angptl4 deficiency against intestinal pathogenesis via anti-inflammatory mechanisms, suggesting Angptl4 as a potential therapeutic target and prognostic biomarker for colorectal cancer and inflammatory bowel disease. Show less

Breast cancer is the leading cause of cancer-related mortality in African American (AA) women. In this study we evaluated the serum proteomic profile of AA women with breast cancer using an integrated proteomic framework with multivariate pattern analysis. Using 2D-DIGE, thousands of serum protein spots were detected across 33 gels; 46 spots met criteria for presence, statistical significance, and differential expression. Proteins from the spots were identified by MALDI-TOF/TOF and matched in curated databases, highlighting serum biomarkers including ceruloplasmin, alpha-2-macroglobulin, complement component C3 and C6, alpha-1-antitrypsin, alpha-1B-glycoprotein, alpha-2-HS-glycoprotein and haptoglobin-related protein. LC-MS/MS analysis revealed 163 differentiating peptides after imputing and filtering 286 peptides. These were evaluated using cumulative distribution function (CDF) analysis, a nonparametric method suited for limited sample sizes. Peptide patterns were explored with Random Forest, showing concordance with CDF. The model achieved an AUC of 0.85 at the peptide level. This workflow identified differentiating proteins (CERU, A2MG, CO3, VTDB, HEMO, APOB, APOA4, CFAH, CO4A, AACT, K1C10, ITIH2, ITIH4), highlighting CERU, A2MG, and CO3 with overexpression and reproducible identification across platforms. We present an integrated, non-invasive serum protein biomarker signature panel specific to AA women, through reproducible proteomic sensor framework to support early detection and breast cancer prevention. Show less

This study aimed to identify novel key targets and mechanisms for repurposing strategies and mitigating sorafenib (SFB) resistance using the GEO transcriptomic dataset GSE94550 within a systems pharmacology framework. Potential counteracting molecules against SFB were retrieved from chemical repositories, followed by molecular docking tests (MDT), Kaplan-Meier survival analysis, and density functional theory (DFT) assessments to evaluate therapeutic potential. PPI networks were constructed using STRING and R to characterize the relationships between upregulated and downregulated genes. The most relevant signalling pathways associated with major targets were determined to elucidate the upstream regulatory mechanisms. Among the differentially expressed genes, APOB emerged as a pivotal regulator (log Show less

Discordance between apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C) levels is frequently observed in individuals with metabolic disorders and may contribute to underestimated cardiovascular risk. Population-based data on LDL-C discordance in East Asians, particularly in metabolically healthy individuals, remain limited. We aimed to investigate the distribution of apoB relative to LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) levels and assess the prevalence and determinants of apoB-LDL-C discordance. We analyzed data from 411,125 Korean adults who underwent health checkups between 2011 and 2023. Participants with a history of cardiovascular disease or lipid-lowering therapy were excluded from the study. ApoB-LDL-C (and apoB-non-HDL-C) discordance was quantified using residuals from a linear regression model. Individuals were classified as discordant-high (residuals > 75th percentile), discordant-low (residuals < 25th percentile), or concordant (residuals between the 25th and 75th percentiles). Subgroup analyses were performed for metabolic status, obesity phenotype, and lifestyle or family risk factors. Substantial variability in apoB levels was observed at each LDL-C and non-HDL-C level. ApoB-LDL-C discordance patterns between apoB and non-HDL-C were similar to those observed with apoB and LDL-C, though with smaller residual differences. Discordance was most pronounced in metabolically unhealthy obese individuals, followed by metabolically unhealthy lean individuals, and metabolically healthy individuals (P < .001), indicating that metabolic health is a stronger determinant of discordance than obesity. ApoB-LDL-C discordance is common, even among metabolically healthy individuals, and is primarily driven by metabolic dysfunction rather than by obesity. ApoB measurements should be included in routine cardiovascular risk assessments. 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

Vascular inflammation contributes to the development of many chronic human diseases. Inflammatory stimuli such as interleukin (IL)-1β or disturbed blood flow trigger endothelial activation, thereby promoting leukocyte recruitment and transmigration through inflammatory signaling pathways. This study aimed to identify novel compounds capable of blocking vascular inflammation, with potential therapeutic applications in vascular inflammatory diseases such as atherosclerosis. A natural compound library was screened to identify drug candidates that inhibit IL-1β-induced endothelial inflammation. The anti-inflammatory effects of tigloylgomisin P, one of the hit compounds, were examined in bovine aortic endothelial cells stimulated with IL-1β or oscillatory (disturbed) flow. Endothelial inflammation was assessed by measuring nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation and nuclear translocation, monocyte adhesion to endothelial monolayers, and Smad1/5/9 phosphorylation Tigloylgomisin P suppressed IL-1β-induced NF-κB activation and reduced monocyte adhesion. In addition, it inhibited oscillatory shear stress-induced endothelial inflammation mediated by NF-κB activation and Smad1/5/9 phosphorylation. In ApoE knockout mice, administration of tigloylgomisin P decreased inflammatory marker expression in the atheroprone inner curvature of aortic arches. These findings suggest that tigloylgomisin P may represent a potential therapeutic agent for vascular inflammatory diseases such as atherosclerosis. Show less

Hypercholesterolemia is a major risk factor for cardiovascular disease, necessitating the development of effective and safe lipid-lowering interventions. This study evaluated the antihypercholesterolemic effects of KGC11 Show less

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

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

Ischemia-reperfusion (I/R) injury, resulting from transient or permanent cerebral vessel occlusion, triggers oxidative stress, neuroinflammation, and blood-brain barrier (BBB) disruption, leading to progressive neuronal damage and cognitive decline. The hippocampus, due to its high metabolic demand and susceptibility to oxidative stress, is particularly vulnerable to I/R-induced injury. This study evaluated the neuroprotective effects of α-lipoic acid (α-LA), a potent antioxidant, using bilateral common carotid arteries occlusion/reperfusion (BCCAO/R) mouse model and an oxygen-glucose deprivation/reoxygenation in vitro model. In BCCAO/R mice, α-LA improved spatial memory without affecting motor activity and restored hippocampal tight junction proteins (Claudin-5 and Occludin) and antioxidant enzyme expression, indicating BBB stabilization and oxidative stress reduction. Although synaptic proteins (BDNF and PSD-95) were not restored, cognitive improvements suggest alternative protective mechanisms. In HT22 cells, α-LA decreased intracellular reactive oxygen species levels, enhanced viability, and inhibited apoptosis via decreased PARP cleavage and caspase-3 activation. These protective effects were linked to the activation of the Nrf2/ARE signaling pathway and the upregulation of its downstream antioxidant targets. Overall, α-LA demonstrated marked neuroprotective effects in ischemic models by reducing oxidative stress, preserving BBB integrity, and restoring hippocampal function, positioning it as a promising therapeutic candidate for ischemic brain injury. Show less

Insulin resistance (IR) is a key mechanism underlying type 2 diabetes mellitus and is closely associated with obesity. Although numerous genome-wide association studies (GWASs) have identified variants that influence IR-related traits, it remains unclear whether the genetic architecture of IR differs according to obesity status. We conducted a stratified GWAS of the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) in 8906 Korean individuals from the Korean Genome and Epidemiology Study. Participants were categorized into a normal-weight group (Body Mass Index (BMI) ≤ 23 kg/m Show less

Lipoprotein(a) [Lp(a)] is a genetically determined cardiovascular risk factor. Although generally considered stable, data on intra-individual reclassification of Lp(a) categories over time compared with conventional lipid markers remain limited, particularly in East Asian populations. We conducted a retrospective cohort study including 230,018 Korean adults (mean age, 38·5 years; 51·4 % male) who underwent routine health examinations with at least two Lp(a) measurements between July 1, 2015, and December 30, 2022. Individuals with a history of coronary artery disease or those receiving lipid-lowering therapy were excluded. The primary outcomes were intraclass correlation coefficients (ICCs), reclassification rates across predefined Lp(a) categories (<30, 30-50, 50-100, and ≥100 mg/dL), and comparisons with traditional lipid parameters. Lp(a) demonstrated excellent reproducibility (ICC ≥0·99) and greater long-term stability than LDL-C, ApoB, and triglycerides. Among participants with baseline Lp(a) levels <30 mg/dL or ≥100 mg/dL, 93 % and 91 % remained in the same category at follow-up, respectively. However, among those with baseline Lp(a) levels of 30-50 mg/dL, 35 % transitioned to higher-risk categories, as did 19 % of those with levels of 50-100 mg/dL. By comparison, 28 % of individuals with LDL-C ≥160 mg/dL and 22 % with triglycerides ≥200 mg/dL moved to lower categories during follow-up. Lp(a) demonstrates greater stability than conventional lipid markers. While a single measurement may suffice for clearly low (<30 mg/dL) or high (≥100 mg/dL) Lp(a) levels, periodic reassessment may be clinically warranted for individuals in intermediate Lp(a) levels (30-100 mg/dL). 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

Intracellular amyloid-β (Aβ) accumulation causes Alzheimer's disease (AD), and thus Aβ-related inhibitors, especially inhibitors of β-secretase 1, known as β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) have been developed to treat AD. The purpose is to evaluate BACE1 inhibitory activity of the compounds isolated from Styrax japonica stem bark, traditionally used as herbal medicines. In this study, seven compounds were isolated, including three lignans, styraxlignolide A, masutakeside I, and egonol. Styraxlignolide A showed potent inhibitory activity against BACE1 with an IC Show less

Seven compounds, comprising three anthraquinones and four stilbenoids, were isolated from the roots of Rheum palmatum L. These compounds include chrysophanol (1), aloe-emodin (2), aloe-emodin 8-O-β-D-glucopyranoside (3), desoxyrhapontigenin (4), rhapontigenin (5), desoxyrhaponticin (6), and piceatannol 3'-O-β-D-glucopyranoside (7). Among these, compound 5 showed potent β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitory activity with an IC Show less

Macrophages express numerous G protein-coupled receptors (GPCRs) that regulate adhesion, migration, and activation, but the function of orphan receptor GPRC5B in macrophages is unknown. Both resident peritoneal and bone marrow-derived macrophages from myeloid-specific GPRC5B-deficient mice show increased migration and phagocytosis, resulting in improved bacterial clearance in a peritonitis model. In other models such as myocardial infarction, increased myeloid cell recruitment has adverse effects. Mechanistically, we found that GPRC5B physically interacts with GPCRs of the prostanoid receptor family, resulting in enhanced signaling through the prostaglandin E receptor 2 (EP2). In GPRC5B-deficient macrophages, EP2-mediated anti-inflammatory effects are diminished, resulting in hyperactivity. Using in silico modelling and docking, we identify residues potentially mediating GPRC5B/EP2 dimerization and show that their mutation results in loss of GPRC5B-mediated facilitation of EP2 signaling. Finally, we demonstrate that decoy peptides mimicking the interacting sequence are able to reduce GPRC5B-mediated facilitation of EP2-induced cAMP signaling in macrophages. Show less

Bacteroides-centric gut dysbiosis reported to exacerbates liver cirrhosis via inflammation and fibrosis, therefore utilizing Bacteroides species as microbiome-based therapeutic logical to mitigate disease progression. Feces were collected from 52 Healthy and 144 Liver cirrhosis individuals for V3-V4 dependent 16rRNA-bsed comparative metagenomics analysis, followed a by microbiome depleted and non-depleted DDC mice model to explain the role of Bacteroidetes phylum classified microbial species P. plebeius in liver fibrosis pathophysiological pathways. Bacteroides presented cirrhosis-dependent decrease in human and animal microbiome, and negatively correlated to key molecular pattern associated with cirrhosis. P. plebeius significantly reduced in abundance and identified as a microbial biomarker for cirrhosis (AUC = 0.73) and treatment with P. plebeius significantly improved the levels of cirrhosis-related phenotypical and biochemical markers in the microbiome-depleted cirrhosis group. P. plebeius decrease the expression of S100a9, CCR1, ADAM8, TREM2, ITGAM, and MYO5A which are primarily responsible for inducing inflammation in liver cirrhosis. P. plebeius downregulated the fibrosis related genes expression including CD51, PLAT, ITGA3, CXCR4, and TGFBR1 and gene related to extracellular matrix formation including COL1A1, LTBP2, S100A6, and SMCO2. Additionally, P. plebeius treatment decreased the expression of hepatotoxicity-related genes including LPL, KRT18, ALDOA, and MCM10, and increased the expression of FABP1 and RDX. Additionally, P. plebeius normalized the expression of genes connected to two pathophysiological process including TIMP4, TGFB3, S100A8, PLSCR1, MMP8, CXCL4, and BMP. Our study revealed P. plebeius as a multifaceted bio-therapeutic candidate that normalized dysregulated gene expression and reversed hepatic inflammation, fibrogenesis, and hepatotoxicity. Show less

The tumor microenvironment (TME) plays a pivotal role in cancer progression, with cancer-associated fibroblasts (CAFs) significantly influencing tumor behavior. Especially, elevated COX2 expressing fibroblasts within the TME, notably in collagen-dense tumors like breast cancer, has been recently emphasized in the literature. However, the specific effect of COX2-expressing CAFs (COX2 We induced COX2 Our in vitro findings demonstrate that COX2 This study advances our understanding of the potential mechanisms by which COX2 Show less

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

Alzheimer's disease (AD) poses an increasing global health challenge and is marked by gradual cognitive deterioration, memory impairment, and neuroinflammation. Innovative therapeutic approaches as non-pharmacological protocol are urgently needed with side effect risk of drugs. Microcurrent therapy, a non-invasive modality involving low-level electrical currents, has emerged as a potential solution to address AD's complex pathogenesis. This study investigates the optimal application of microcurrent therapy as a clinical protocol for AD, utilizing a comprehensive approach that integrates behavioral assessments and neuroinflammation evaluation in a mouse model of dementia. The results reveal that microcurrent therapy holds promise in ameliorating memory impairment and reducing neuroinflammation in AD. Behavioral assessments, including the Novel Object Recognition Test (NOR) and Radial Arm Maze Test (RAM), demonstrated improved cognitive function following microcurrent therapy. Furthermore, microcurrent therapy inhibited expression of neuroinflammatory proteins, including ionized calcium binding adaptor molecule 1 (Iba1), and glial fibrillary acidic protein (GFAP) in current-treated group. Mechanistic insights suggest that microcurrent therapy may modulate neuroinflammation through the regulation of MAPK signaling pathways. This study emphasizes the prospect of microcurrent therapy as a safe and efficacious non-pharmacological strategy for Alzheimer's disease (AD), providing optimism to the countless individuals impacted by this debilitating ailment. These results contribute to the developments of an innovative clinical protocol for AD and recovery from neurological injury, underscoring the significance of investigating unconventional therapeutic approaches for addressing this complex condition. 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

Corticosteroids are commonly used anti-inflammatory agents. However, their prolonged use can lead to side effects. Therefore, the development of natural compounds with minimal side effects is necessary. This study was performed to investigate the anti-inflammatory effects and mechanisms of action of Show less

The objective of the experiment was to determine the effects of supplemental SFA sources, lysophospholipids (LPL), and their interaction on production and nutrient digestibility in lactating dairy cows. The experiment was conducted with 48 cows in a randomized complete block design. Cows were blocked (12 blocks total) by parity and days in milk and randomly assigned to 4 dietary treatments in each block (2 × 2 factorial arrangement), i.e., 2 sources of fat supplements, C16:0 (PA)- or C18:0 (SA)-enriched fat, and with or without LPL. The experiment was conducted for 6 wk to measure daily dry matter intake, milk yield, and weekly milk composition. During the last week of the experiment, spot fecal and urine samples were collected to determine total-tract nutrient digestibility. Milk samples in the last week were also collected to analyze the milk fatty acid (FA) profile. All data were analyzed using the MIXED procedure of SAS, where block was used as a random effect and FA, LPL, and the interaction of FA by LPL were used as fixed effects. Week and interactions of week by FA or LPL were included for production measures. Different sources of SFA did not affect dry matter intake and milk yield. However, the PA treatment increased (39.7 vs. 36.8 kg) energy-corrected milk compared with SA due to increased milk fat yield. No effect of LPL on production measures was observed. Total-tract digestibilities of dry matter, organic matter, crude protein, and total FA were not different between the PA and SA groups, but PA increased (41.4% vs. 38.8%) neutral detergent fiber digestibility compared with SA. Supplementation of LPL increased (64.7% vs. 60.5%) total FA digestibility, especially 18-carbon FA (74.1% vs. 68.2%). An interaction of SFA by LPL was found for 16-carbon FA digestibility. The PA diet increased the concentration of 16-carbon FA in milk fat and SA increased the concentration of preformed FA (≥18 carbons). Supplementation of LPL decreased the concentration of trans-10 C18:1. No difference in N utilization and excretion among treatments was observed. In conclusion, the PA diet was more effective in improving milk fat yield of lactating cows compared with SA. Supplementation of LPL increased digestibility of total FA, especially 18-carbon FA but did not affect production. Show less

Breast cancer remains a significant health concern, with triple-negative breast cancer (TNBC) being an aggressive subtype with poor prognosis. Epithelial-mesenchymal transition (EMT) is important in early-stage tumor to invasive malignancy progression. Snail, a central EMT component, is tightly regulated and may be subjected to proteasomal degradation. We report a novel proteasomal independent pathway involving chaperone-mediated autophagy (CMA) in Snail degradation, mediated via its cytosolic interaction with HSC70 and lysosomal targeting, which prevented its accumulation in luminal-type breast cancer cells. Conversely, Snail predominantly localized to the nucleus, thus evading CMA-mediated degradation in TNBC cells. Starvation-induced CMA activation downregulated Snail in TNBC cells by promoting cytoplasmic translocation. Evasion of CMA-mediated Snail degradation induced EMT, and enhanced metastatic potential of luminal-type breast cancer cells. Our findings elucidate a previously unrecognized role of CMA in Snail regulation, highlight its significance in breast cancer, and provide a potential therapeutic target for clinical interventions. Show less