👤 Won-Jea Cho

Cholinergic dysfunction is a key contributor to cognitive impairment observed in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Although acetylcholinesterase (AChE) inhibitors have been the mainstay of symptomatic treatment for over two decades, their limited efficacy and adverse effects underscore the need for alternative therapeutic approaches. Recent evidence indicates that mechanical stimulation can modulate neuronal and glial signaling through mechanotransduction, suggesting a potential strategy to enhance cognitive function via non-pharmacological means. Here, we developed a head-mounted vibrotactile stimulation system (HVSS) that delivers controlled vibration to the cranium and evaluated its effects in a pharmacological model of acute cholinergic dysfunction induced by scopolamine. To this end, male C57BL/6 mice received scopolamine (1 mg/kg, i.p.; on days 7, 14, and 28) and were exposed to daily vibrotactile stimulation at 20, 40, or 80 Hz for 28 days. Behavioral performance was assessed using passive avoidance and Morris water maze tests, followed by biochemical and histological analyses. HVSS at 40 Hz and 80 Hz significantly improved cognitive performance, enhanced hippocampal cholinergic function, reduced oxidative damage, and upregulated memory-related signaling genes, including BDNF, PI3K, AKt, ERK1/2, CREB, and CAMK4. These findings suggest that high-frequency HVSS improves memory hippocampal cholinergic function via activation of memory-related signaling pathways, highlighting its potential as a safe, non-pharmacological neuromodulatory strategy for cholinergic dysfunction-related cognitive decline. Show less

Neurodegenerative and mental disorders impose significant global disease burdens and pose serious social and economic challenges. Physical exercise (PE) exerts beneficial effects on brain health, contributing to a reduction in the risk of Alzheimer's disease (AD), Parkinson's disease (PD), depression, anxiety, and post-traumatic stress disorder (PTSD). To understand these effects of PE, a variety of molecules released from various tissues in response to PE have been discovered, which are collectively called 'exerkines'. In particular, the skeletal muscle acts as an endocrine organ, secreting exerkines and is included in the category of myokines that facilitate direct or indirect crosstalk between the muscle and the brain. Although muscles actively interact with organs such as the liver, pancreas, and adipose tissue, the precise mechanisms of muscle-brain communication have yet to be fully elucidated. In the skeletal muscle, the types of exerkines secreted and their effects vary depending on the PE modality. Furthermore, these exerkines can cross the blood-brain barrier (BBB) to exert direct effects or act indirectly Show less

Signal peptides (SPs) are short N-terminal sequences that direct proteins to the endoplasmic reticulum (ER). After cleavage of the SP, these proteins are mostly trafficked to the Golgi apparatus for secretion. Lipocalin-2 (LCN2), a neurotoxic secretory protein, was recently identified as a target of autophagy. The presence of an SP is a prerequisite for secretion and autophagic degradation. Based on these observations, we investigated whether the SP of LCN2 is sufficient to enable proteins to be secreted or degraded via autophagy. We fused the SP of LCN2 to a non-secretory green fluorescent protein (GFP) and found that this ER-generated GFP was either secreted or degraded via autophagy. These results indicate that the LCN2-derived SP alone is sufficient to direct proteins to the ER and subsequent secretion or autophagic degradation. This dual regulation was abolished when the SP was deleted from LCN2. Notably, the effect was preserved even when the LCN2 SP was replaced with the SP from brain-derived neurotrophic factor, another secretory protein. These results suggest that SPs with different sequences can similarly direct proteins to the ER and subsequent secretion or autophagic degradation. Furthermore, we found that even when LCN2 reached the Golgi apparatus for secretion, it could also be degraded via autophagy. Thus, we propose that SP-directed and ER-generated secretory proteins can undergo autophagic degradation during ER-Golgi transport, including at the ER, the ER-Golgi intermediate compartment, or the Golgi apparatus. Taken together, degradation of secretory proteins via autophagy suggests implications for the potential control of secretory protein homeostasis. Show less

Spinal cord injury (SCI) remains difficult to treat, and current interventions provide limited functional restoration and often require invasive procedures. Existing cell- or extracellular vesicles (EV)-based approaches are frequently administered alongside surgery, limiting therapeutic reach and overall efficacy. In this study, we developed an engineered extracellular vesicle (EV) platform by displaying a single-chain variable fragment (scFv) against integrin αvβ8 (αITGEV) and loading brain-derived neurotrophic factor mRNA (mBDNF). The construct maintained canonical EV identity and morphology, and showed predominant single particle co-positivity for targeting ligand and cargo. In neuron-microglia co-culture, mBDNF@αITGEV preferentially entered both cell types under injury-relevant stress, shifted microglia toward a repair-associated phenotype, reduced TNF-α and IL-1β, increased IL-4 and IL-10, and preserved neuronal architecture. Our results indicate that mBDNF@αITG-EVs significantly promote functional motor recovery by modulating the inflammatory microenvironment and inhibiting neuronal ferroptosis. Mechanistically, the delivery of BDNF mRNA bolstered GPX4 expression and stabilized mitochondrial dynamics, thereby mitigating secondary oxidative damage. This study provides a non-invasive strategy for precision nanomedicine in neuro-regeneration. Collectively, this study supports a non-invasive systemically administered, targeted EV-mRNA therapeutic strategy for spinal cord injury with translational potential. Show less

Depression imposes significant social, economic, and health burdens worldwide. Although phlorotannin-rich extract from Ecklonia cava (PS) and its active compound dieckol (DK) exhibit various biological activities, their antidepressant- and anxiolytic-like effects and underlying mechanisms remain unclear. This study investigated the antidepressant- and anxiolytic-like potential of PS and DK in a corticosterone (CORT)-induced mouse model of depression and anxiety, focusing on glucocorticoid receptor (GR) signaling. CORT-treated mice were orally administered PS or DK, and behavioral tests were performed to assess depressive- and anxiety-like behaviors. PS composition was analyzed using LC-MS/MS. Molecular docking predicted the binding of PS components to GR. GR nuclear translocation, target gene expression, and downstream signaling were examined using behavioral, molecular, and computational approaches. PS alleviated CORT-induced depressive- and anxiety-like behaviors, accompanied by reduced GR nuclear translocation, suppression of Mkp-1, and restoration of ERK-CREB-BDNF signaling. Molecular docking analysis predicted strong binding of DK to the GR ligand-binding domain. Consistently, DK reduced GR nuclear translocation and GRE binding, downregulated GR target genes (Mkp-1, Sgk-1, Fkbp5, and Bdnf), and restored ERK-CREB-BDNF signaling. In vivo, DK also improved CORT-induced behavioral deficits and normalized HPA axis activity and neurotransmitter levels. Collectively, our results suggest that DK, a major bioactive phlorotannin from E. cava, exerts antidepressant- and anxiolytic-like effects in association with modulation antagonism of GR signaling, highlighting its therapeutic potential as a natural GR-modulating agent for stress-related mood disorders. Show less

Alzheimer's disease (AD) is characterized by progressive cognitive decline and memory dysfunction, with prominent roles in cholinergic deficits and synaptic plasticity impairments. Vitisin B, a resveratrol tetramer derived from Vitis vinifera, exhibits potent antioxidant and neuroprotective properties. However, its potential to influence cognitive function in AD models remains inadequately explored. In this study, we first tested vitisin B in an in vitro model using SH-SY5Y cells exposed to scopolamine-induced cytotoxicity, where vitisin B significantly enhanced cell viability and promoted cell survival. We evaluated its therapeutic potential in vivo using both systemic administration and direct delivery into the third ventricle of the brain in a scopolamine-induced AD mouse model. Across both administration routes, vitisin B exerted a broad pro-cognitive effect, restoring multiple domains of learning and memory disrupted by scopolamine. Vitisin B recovered spatial working memory in the Y-maze, normalized exploratory activity in the open field, improved recognition memory in the novel object recognition (NOR) test, and enhanced long-term memory retention in the passive avoidance assay. This treatment restored cognitive function, alleviated cholinergic deficits, increased hippocampal brain-derived neurotrophic factor (BDNF) levels, and enhanced synaptic plasticity. These results suggest that vitisin B exerts reliable cognitive and neuroprotective effects through both systemic and cerebral administration, highlighting its potential as a promising therapeutic compound for restoring cholinergic function and enhancing hippocampal synaptic plasticity in AD. 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

Sex differences are evident in anxiety and depression, and women more frequently present with comorbid anxiety and depression alongside gastrointestinal disturbances. This pattern suggests contributions from sex-specific biological mechanisms and gut-brain communication. Negr1, a molecule regulating neuronal growth and connectivity, has been linked to depression-relevant behaviors in animal models. However, its mechanisms and potential sex-specific effects remain unclear. Behavioral tests were used to assess phenotypes related to depression, anxiety, and learning in male and female wild-type (WT) and Negr1 Negr1 This study demonstrates that, in Negr1 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

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

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

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

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immune receptor genetically and functionally linked to Alzheimer's disease (AD). VG-3927, the first clinical-stage small-molecule TREM2 agonist, has been proposed to function as a transmembrane molecular glue and positive allosteric modulator (PAM). Whether it directly engages the extracellular ligand-recognition surface of TREM2 remains unknown. Here, we used a deep learning-based blind docking algorithm to map potential VG-3927 binding sites across TREM2 and identified a binding site within the ectodomain hydrophobic groove, a ligand-recognition surface previously implicated in Aβ and apoE binding. Microscale thermophoresis (MST) confirmed direct interaction of VG-3927 with TREM2 under optimized PEG-400 buffer conditions and independently demonstrated binding of Aβ 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

Triggering receptor expressed on myeloid cells-2 (TREM2) is a key immune receptor in the central nervous system that regulates microglial phagocytosis, survival, and neuroinflammatory responses. TRME2 variants have been established as genetic risk factors for Alzheimer's disease (AD). However, the therapeutic development of TREM2 modulators has been limited to antibody-based approaches that face limitations in blood-brain barrier penetration and manufacturing scalability. Furthermore, there are no FDA approved TREM2 therapeutics available to date marking an unmet therapeutic gap. Herein, we report the identification of the first TREM2 small molecule submicromolar binders as a result of optimizing compound 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

Alzheimer's disease (AD) is marked by amyloid-β (Aβ) accumulation, tau pathology, and neuroinflammation. The β-site APP cleaving enzyme 1 (BACE1) is a key driver of Aβ production, while the NLRP3 inflammasome mediates microglial inflammatory responses. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase, is upregulated in AD, yet its role in disease mechanisms remains unclear. Here, we show that HDAC6 promotes BACE1 protein stability through direct deacetylation of its C-terminal lysine (K501), thereby increasing Aβ production. HDAC6 also facilitated NLRP3 inflammasome activation in microglia, increasing IL-1β production in a catalytic domain-dependent manner. HDAC6 deficiency in 5xFAD mice reduced BACE1 accumulation, Aβ deposition, ASC speck formation, and IL-1β levels, accompanied by improved cognitive performance. Transcriptomic profiling further revealed downregulation of disease-associated microglial and neurotoxic astrocyte signatures alongside enrichment of synaptic pathways. These findings establish HDAC6 as a dual regulator of Aβ production and neuroinflammation, highlighting it as a promising therapeutic target in AD. Show less

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

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

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a key treatment for type 2 diabetes mellitus (T2DM), with cardiorenal effects that extend beyond glycemic management. One important mechanism underpinning these pleiotropic effects is their interaction with AMP-activated protein kinase (AMPK), a crucial regulator of cellular energy balance. This review summarizes the strong evidence that SGLT2 inhibitors activate AMPK via both shared and drug-specific mechanisms. Empagliflozin induces on-target energetic stress, dapagliflozin activates the FGFR1-LKB1 axis, and canagliflozin inhibits mitochondrial complex I off-target. We describe how AMPK activation coordinates a protective network that includes PGC-1α-mediated mitochondrial biogenesis, ULK1-driven autophagy, Nrf2-antioxidant responses, and mTOR/NF-κB signaling inhibition. This interaction leads to enhanced insulin sensitivity, decreased oxidative stress, and sustained heart, kidney, and liver function. Furthermore, we conduct a comparative investigation of the distinct AMPK-modulatory profiles of prominent SGLT2 inhibitors and explore the practical applicability of these processes, including possible drawbacks such as the theoretical risk of muscle atrophy associated with persistent AMPK activation. By thoroughly describing the SGLT2-AMPK axis, this review emphasizes its importance as a therapeutic target and offers a framework for understanding the entire range of SGLT2 inhibitor activity in diabetes and associated consequences. Show less

Coronary artery disease (CAD) polygenic risk score (PRS), low-density-lipoprotein cholesterol (LDL-C), lipoprotein(a) (Lp(a)), and high-sensitivity C-reactive protein (hsCRP) are biomarkers that predict CAD. It is unclear whether integrating genomics with lipid and inflammatory biomarkers could complement traditional risk scores in identifying people at risk of CAD. This study assesses the predictive value of CAD PRS, LDL-C, Lp(a), and hsCRP for incident CAD across different age and sex groups. Participants (n = 215,695) from the UK Biobank aged 40 to 69 years with baseline CAD PRS, LDL-C, Lp(a), and hsCRP values were followed for 12 years to assess the incidence of CAD. We evaluated a multivariable-adjusted Cox model that included all 4 biomarkers, net reclassification index, C-statistics, and population attributable risk across different age and sex groups. Over a 12-year follow-up, 4,721 men and 2,425 women developed CAD. The HRs for incident CAD associated with each biomarker elevation were 1.79 (95% CI: 1.70-1.89) for CAD PRS, 1.60 (95% CI: 1.48-1.66) for LDL-C, 1.20 (95% CI: 1.12-1.29) for Lp(a), and 1.64 (95% CI: 1.57-1.72) for hsCRP. CAD PRS demonstrated a stronger association in men (HR per SD: 1.49; 95% CI: 1.45-1.54) than women (HR per SD: 1.37; 95% CI: 1.31-1.44; P-interaction ≤ 0.001). All biomarkers conferred greater HRs at younger ages (P < 0.0001). Individuals with all biomarkers elevated had a 4.65-fold increased risk of CAD compared with those with no elevated biomarkers. A combined 4-biomarker model had a higher C-statistic of 0.753 compared with the pooled cohort equations (C-statistic of 0.740). The C-statistic of the combined 4-biomarker model was also higher in younger individuals in both sexes and yielded a 32.0% continuous net reclassification index when compared with the pooled cohort equations. CAD PRS, LDL-C, hsCRP, and Lp(a) show independent age- and sex-specific associations with CAD. Measuring all 4 biomarkers may improve midlife CAD risk prediction for both male and female patients. Show less

The mechanism(s) by which exercise training induces multiple beneficial effects for Alzheimer's disease (AD) patients are not well-understood. This study aimed to examine the link between the brain-derived neurotrophic factor (BNDF)-tropomyosin receptor kinase B (TrkB) signaling complex and the beneficial effects of exercise training on cognitive impairment and neuropathology due to AD. At 4 months of age, twenty triple transgenic mice of AD (3x-Tg AD) were randomly assigned to either an AD control (n = 10) or AD exercise (n = 10) group. In parallel, twenty wild-type mice were randomly assigned to either a wild-type control (n = 10) or wild-type exercise (n = 10) group. After 20 weeks of treadmill running, the Morris water maze test was performed, and the mice were then sacrificed for biochemical analyses of plasma and brain tissues. The results indicated that 20 weeks of treadmill running upregulated markers of the BDNF-TrkB signaling complex and mitigated AD neuropathology, along with full recovery from AD-like cognitive impairments. Exercise training also decreased inflammatory cytokines, increased anti-inflammatory cytokines, shifted microglia and astrocytes toward anti-inflammatory phenotypes, improved mitochondrial function, reduced markers of myelin damage, and reduced apoptotic neuronal cell death. In summary, our study findings suggest that exercise training-induced recovery of AD-like cognitive impairments and mitigation of AD neuropathologic biomarkers are associated with modulation of the BDNF-TrkB complex and downstream signaling pathways in 3xTg-AD mice. Show less

Atherosclerosis progresses through endothelial dysfunction, vascular inflammation, endothelial-to-mesenchymal transition (EndMT), and plaque instability. While ANGPTL4 (angiopoietin-like 4) is known for its metabolic functions, its role in endothelial homeostasis remains unclear. We investigated the protective effects of ANGPTL4 on endothelial inflammation, vascular integrity, and EndMT using ANGPTL4 suppressed TNF-α (tumor necrosis factor alpha)-induced and IL-1β (interleukin-1 beta)-induced endothelial inflammation and preserved vascular barrier integrity in vitro and in vivo. It also inhibited TGF-β (transforming growth factor-β)-driven EndMT by restoring endothelial markers and suppressing mesenchymal marker expression. Mechanistically, ANGPTL4 attenuated TGF-β-Smad2 (suppressor of mothers against decapentaplegic 2) signaling and restored KLF2 (Krüppel-like factor 2) expression, which was essential for its anti-inflammatory and anti-EndMT effects. KLF2 knockdown abolished ANGPTL4-mediated endothelial protection, confirming its pivotal role in maintaining endothelial identity. In human atherosclerotic plaques, EndMT marker expression strongly correlated with plaque complexity, suggesting that EndMT exacerbates atherosclerosis progression. Plasma ANGPTL4 levels were significantly reduced in patients with coronary artery disease with coronary microvascular dysfunction and were positively correlated with coronary flow reserve, supporting its potential as a biomarker and preventive modulator of endothelial dysfunction. These findings identify ANGPTL4 as a critical modulator of endothelial inflammation and EndMT via suppression of TGF-β-Smad2 signaling and restoration of KLF2. By preserving vascular integrity and promoting endothelial homeostasis, ANGPTL4 may serve as a preventive modulator in EndMT-driven vascular pathology and coronary microvascular dysfunction. Show less

Atherosclerosis, a chronic inflammatory disease, presents significant "residual risk" even with effective lipid-lowering therapies, primarily due to persistent vascular inflammation. Apolipoprotein B100 (ApoB100) acquires pro-inflammatory properties upon modification and binds to cell-surface enolase 1 (ENO1), an immune modulator upregulated in inflammatory conditions. This interaction induces inflammatory responses via NF-κB activation. Targeting the ApoB100-ENO1 interaction may offer a novel strategy to reduce vascular inflammation and atherosclerosis progression. We developed PP3m, a stabilized ApoB100-derived peptide, to selectively inhibit the ApoB100-ENO1 interaction. Single-cell RNA sequencing (scRNA-seq) data from human atherosclerotic plaques were reanalyzed to characterize ENO1 expression in myeloid cells. In vitro, PP3m's anti-inflammatory effects were evaluated across various macrophage models stimulated by diverse inflammatory stimuli. Outcomes included cytokine secretion, inflammatory gene expression, foam cell formation, oxidized low-density lipoprotein (oxLDL) uptake, and signaling pathways activation. In vivo, Ldlr scRNA-seq analysis revealed that human atherosclerotic plaques harbor significantly more ENO1 macrophages, with ENO1 expression enriched in CD68 The ApoB100-ENO1 axis is a critical driver of macrophage-mediated inflammation in atherosclerosis. The novel peptide PP3m effectively inhibits this interaction, reducing vascular inflammation and plaque progression without altering lipid levels. PP3m represents a promising therapeutic candidate for cardiovascular disease by targeting residual inflammatory risk through a lipid-independent mechanism. Show less

Treatment to lower high levels of low-density lipoprotein cholesterol (LDL-C) reduces incident coronary artery disease (CAD) risk but modestly increases the risk for incident type 2 diabetes (T2D). The extent to which genetic factors across the cholesterol spectrum are associated with incident T2D is not well understood. To investigate the association of genetic predisposition to increased LDL-C levels with incident T2D risk. In this large prospective, population-based cohort study, UK Biobank participants who underwent whole-exome sequencing and genome-wide genotyping were included. Participants were separated into 7 groups with familial hypercholesterolemia (FH), predicted loss of function (pLOF) in APOB or PCSK9 variants, and LDL-C polygenic risk score (PRS) quintiles. Data were collected between 2006 and 2010, with a median follow-up of 13.7 (IQR, 12.9-14.5) years. Data were analyzed from March 1 to November 1, 2024. LDL-C level, LDL-C PRS, FH, or pLOF variant status. Cox proportional hazards regression models adjusted for age, sex, genotyping array, lipid-lowering medication use, and the first 10 genetic principal components were fitted to assess the association between LDL-C genetic factors and incident T2D and CAD risks. Among the 361 082 participants, mean (SD) age was 56.8 (8.0) years, 194 751 (53.9%) were female, and mean (SD) baseline LDL-C level was 138.0 (33.6) mg/dL. During the follow-up period, 22 619 (6.3%) participants developed incident T2D and 17 966 (5.0%) developed incident CAD. The hazard ratio for incident T2D was lowest in the FH group (0.65; 95% CI, 0.54-0.77), while the highest risk was in the pLOF group (1.48; 95% CI, 1.18-1.86). The association between LDL-C PRS and incident T2D was 0.72 (95% CI, 0.66-0.79) for very high LDL-C PRS, 0.87 (95% CI, 0.84-0.90) for high LDL-C PRS, 1.13 (95% CI, 1.09-1.17) for low LDL-C PRS, and 1.26 (95% CI, 1.15-1.38) for very low LDL-C PRS. CAD risk increased directly with the LDL-C PRS. In this cohort study, LDL-C and T2D risks were inversely associated across genetic mechanisms for LDL-C variation. Further elucidation of the mechanisms associating low LDL-C risk with increased risk of T2D is warranted. Show less

Despite increasing heavy metal pollution, traditional epidemiology often fails to link exposure to health outcomes. This study used multi-omics to investigate associations between heavy metal exposure and health. Blood and urine samples from 294 participants in heavy metal-exposed and control areas were analyzed, revealing key biomarkers. Meta P analysis revealed consistent trends in apolipoprotein C3 (APOC3) expression, and mediation analysis showed significant effects of APOC3 and zinc-alpha-2-glycoprotein (ZA2G) on metabolites: the mediating effect of APOC3 from blood cadmium to serotonin was 0.023 (P < 0.001) and that to 3-phosphoglyceric acid (3PG) was 0.0125 (P = 0.002). Mendelian randomization confirmed the positive impact of APOC3 and Complement Factor I (CFAI) and the negative effect of ZA2G on metabolites, with apolipoprotein H (APOH) methylation significantly altering APOC3 (β = -0.22, P = 0.017), CFAI (β = 0.176, P = 0.035), and ZA2G (β = 0.139, P = 0.048) protein levels. Liver function variables, including albumin, total protein, calcium, and lactate dehydrogenase, correlated with 3PG and serotonin levels in the exposed areas. Sex-specific analysis showed that men exhibited stronger compensatory mechanisms via CFAI and myo-inositol, while women's greater vulnerability to heavy metal exposure highlighted the need for targeted interventions. These findings suggest APOH methylation affects APOC3, CFAI, and ZA2G levels, elevating 3PG, inosine monophosphate, and serotonin levels and harming liver function via lipolysis, supporting the use of these markers in health monitoring, therapies, and policies to limit heavy metal risks. Show less

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death. Systemic autoimmune and inflammatory diseases are associated with increased ASCVD risk, severity, and mortality. The inflammatory cytokine interleukin 9 (IL-9) has been linked to murine atherogenesis, raising fundamental questions about the populations in which and the mechanisms by which IL-9 drives ASCVD. Circulating T helper subsets and coronary computed tomography angiography data were analysed in patients with psoriasis. Murine models of psoriatic atherogenesis (imiquimod-ApoE Here, we found that expansion of IL-9-producing T helper cells (Th9) was significantly associated with high-risk radiographic ASCVD in patients with the autoimmune disease psoriasis. Th9 cells were poised to migrate to coronary vessels and were identified in human atherosclerotic plaque from individuals with psoriasis. In vivo, murine inflammatory atherogenesis was prevented by IL-9 blockade and by IL-9 receptor (IL-9R) deletion in endothelial cells. In human arterial endothelial cells, IL-9R/STAT3 signalling promoted endothelial dysfunction via diverse mechanisms including adhesion, activation, angiogenesis, and release of leukocyte chemoattractants. These findings suggest the Th9 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