👤 Hye-Kyoung Kwak

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

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

Postoperative delirium is common in older surgical patients, but simple blood tests to identify risk are lacking. Plasma amyloid-β oligomers measured by multimer detection (MDS-OAβ) may reflect neurodegenerative vulnerability. We enrolled 101 patients aged ≥65 years undergoing elective orthopaedic surgery with general anaesthesia. Blood was drawn preoperatively and at first delirium diagnosis or on postoperative Day 4 if no delirium. MDS-OAβ was quantified blinded. Delirium was assessed daily on postoperative Days 1-3 (DRS-R-98 and DSM). Propensity-score matching on APOE ε4 status and clinical covariates addressed Alzheimer-type vulnerability. Discrimination and thresholds (0.60, 0.72, 0.85 ng/ml) were evaluated using logistic regression and ROC analyses. Among 101 patients (44 with delirium; 57 without), preoperative MDS-OAβ concentrations were higher in those who developed delirium and correlated with delirium severity. In the overall cohort, preoperative MDS-OAβ discriminated delirium with an area under the curve of 0.855 (95% CI 0.777-0.919); in a pooled postoperative dataset (n = 205), discrimination was similar (AUC 0.884, 95% CI 0.837-0.925). The dual-threshold approach identified a low-risk group with high negative predictive value and a high-risk group with high positive predictive value, leaving an intermediate group for closer observation. Preoperative plasma MDS-OAβ may provide a scalable biomarker for perioperative risk stratification of postoperative delirium in older adults, supporting a dual-threshold strategy for targeted prevention and monitoring. Low MDS-OAβ values indicate lower risk but do not exclude POD; biomarker-guided stratification should complement, not replace, routine perioperative delirium surveillance. 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

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints. Show less

Youth-onset type 2 diabetes (T2D) is a growing public health concern. Its genetic basis and relationship to other forms of diabetes are largely unknown. To gain insight into the genetic architecture and biology of youth-onset T2D, we analyzed exome sequences of 3,005 youth-onset T2D cases and 9,777 ancestry matched adult controls. We identified (a) monogenic diabetes variants in 2.1% of individuals; (b) two exome-wide significant ( Show less

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade B-cell lymphoma of the bone marrow. Despite a cumulative risk of progression, there is no approved therapy for patients in the asymptomatic phase. We conducted a first-in-human clinical trial of a novel therapeutic DNA idiotype neoantigen vaccine in nine patients with asymptomatic LPL. Treatment was well tolerated with no dose limiting toxicities. One patient achieved a minor response, and all remaining patients experienced stable disease, with median time to disease progression of 61+ months. Direct interrogation of the tumor microenvironment by single-cell transcriptome analysis revealed an unexpected dichotomous antitumor response, with significantly reduced numbers of clonal tumor mature B-cells, tracked by their unique BCR, and downregulation of genes involved in signaling pathways critical for B-cell survival post-vaccine, but no change in clonal plasma cell subpopulations. Downregulation of HLA class II molecule expression suggested intrinsic resistance by tumor plasma cell subpopulations and cell-cell interaction analyses predicted paradoxical upregulation of IGF signaling post vaccine by plasma cell, but not mature B-cell subpopulations, suggesting a potential mechanism of acquired resistance. Vaccine therapy induced dynamic changes in bone marrow T-cells, including upregulation of signaling pathways involved in T-cell activation, expansion of T-cell clonotypes, increased T-cell clonal diversity, and functional tumor antigen-specific cytokine production, with little change in co-inhibitory pathways or Treg. Vaccine therapy also globally altered cell-cell communication networks across various bone marrow cell types and was associated with reduction of protumoral signaling by myeloid cells, principally non-classical monocytes. These results suggest that this prototype neoantigen vaccine favorably perturbed the tumor immune microenvironment, resulting in reduction of clonal tumor mature B-cell, but not plasma cell subpopulations. Future strategies to improve clinical efficacy may require combinations of neoantigen vaccines with agents which specifically target LPL plasma cell subpopulations, or enable blockade of IGF-1 signaling or myeloid cell checkpoints. Show less

Improved molecular testing for common somatic mutations and the identification of mRNA and microRNA expression classifiers are promising approaches for the diagnosis of thyroid nodules. However, there is a need to improve the diagnostic accuracy of such tests for identifying thyroid cancer. Recent findings have revealed a crucial role of long non-coding RNAs (lncRNAs) in gene modulation. Thus, we aimed to evaluate the diagnostic value of selected lncRNAs from The Atlas of Noncoding RNAs in Cancer (TANRIC) thyroid cancer dataset. LncRNAs in TANRIC thyroid cancer dataset that have significantly increased or decreased expression in papillary thyroid cancer (PTC) tissues were selected as candidates for PTC diagnosis. Surgical specimens from patients who underwent thyroidectomy were used to determine the separation capability of candidate lncRNAs between malignant and benign nodules. Fine needle aspiration samples were obtained and screened for candidate lncRNAs to verify their diagnostic value. LRRC52-AS1, LINC02471, LINC02082, UNC5B-AS1, LINC02408, MPPED2-AS1, LNCNEF, LOC642484, ATP6V0E2-AS1, and LOC100129129 were selected as the candidate lncRNAs. LRRC52-AS1, LINC02082, UNC5B-AS1, MPPED2-AS1, LNCNEF, and LOC100129129 expression levels were significantly increased or decreased in malignant nodules compared to those in benign nodules and paired normal thyroid tissues. The combination of LRRC52-AS1, LINC02082, and UNC5B-AS1 showed favorable results for the diagnosis of PTC from fine needle aspirates, with 88.9% sensitivity and 100.0% specificity. LncRNA expression analysis is a promising approach for advancing the molecular diagnosis of PTC. Further studies are needed to identify lncRNAs of additional diagnostic value. Show less

Apolipoprotein C3 (APOC3) is an important regulator of lipoprotein metabolism, and has been shown to be strongly associated with hypertriglyceridemia. We tested whether triglyceride-influencing genetic variants at Show less

The goals of this study were (1) to examine the effects of Cyperus rotundus (CR) rhizome on cellular lipogenesis and non-alcoholic/diet-induced fatty liver disease, and (2) to elucidate the molecular mechanism behind its actions. The present investigation showed that the hexane fraction of CR rhizome (CRHF) reduced the elevated transcription levels of sterol regulatory element binding protein-1c (SREBP-1c) in primary hepatocytes following exposure to the liver X receptor α (LXRα) agonist. The SREBP-1c gene is a master regulator of lipogenesis and a key target of LXRα. CRHF inhibited not only the LXRα-dependent activation of the synthetic LXR response element (LXRE) promoter, but also the activation of the natural SREBP-1c promoter. Moreover, CRHF decreased (a) the recruitment of RNA polymerase II to the LXRE of the SREBP-1c gene; (b) the LXRα-dependent up-regulation of various lipogenic genes; and (c) the LXRα-mediated accumulation of triglycerides in primary hepatocytes. Furthermore, CRHF ameliorated fatty liver disease and reduced the expression levels of hepatic lipogenic genes in high sucrose diet (HSD)-fed mice. Interestingly, CRHF did not affect the expression of ATP-binding cassette transporter A1, another important LXR target gene that is required for reverse cholesterol transport (RCT) and protects against atherosclerosis. Taken together, these results suggest that CRHF might be a novel therapeutic remedy for fatty liver disease through the selective inhibition of the lipogenic pathway. Show less

We evaluated in vitro anti-diabetic activities of 497 native plants of Jeju Island (South Korea) by measuring the induction of adipocyte differentiation. Among the plants, Daphniphyllum macropodum fruit extract (DME) had the highest peroxisome proliferator-activated receptor γ (PPARγ) agonist activity and was therefore selected as a potential source of anti-diabetic agents. To elucidate the active components of DME, constituent compounds were purified and their effects on the adipocyte differentiation were studied. Using activity-guided fractionation, four compounds were isolated from DME and their adipogenic effects were evaluated. Among the compounds isolated, 5,7-dihydroxychromone potently induced the differentiation of mouse 3T3-L1 preadipocytes. DME and 5,7-dihydroxychromone increased PPARγ and liver X receptor α (LXRα) mRNA expression levels. To determine whether the adipogenic effects we observed might affect serum glucose levels, we undertook in vivo experiment using streptozotocin-/high-fat diet-induced type 2 diabetes mouse model. DME supplementation reduced serum glucose, total cholesterol, and triacylglycerol levels in diabetes mice. These results suggest that DME may be useful for the prevention and treatment of type 2 diabetes mellitus. Moreover, it was proposed that 5,7-dihydroxychromone isolated from DME is one of the active compounds that may contribute to regulate blood glucose levels. Show less

Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment, causing pain, impairment, and disability. To identify proteins of CTS comprehensively, a comparative serum analysis of CTS patients and normal control subjects was performed. The two-dimensional electrophoresis patterns of serum obtained from six CTS patients and six normal control subjects were compared. We found 10 proteins that were significantly altered in the serum of CTS patients, among which four were upregulated and six were downregulated. The upregulated spots were identified as Chain A, heat shock 70-kDa protein, 42-kDa ATPase N-terminal domain; glutathione-insulin transhydrogenase (216AA); cAMP-dependent protein kinase inhibitor alpha; and mutant β-globin. The downregulated spots were identified as vitamin D-binding protein (VDBP), fibrinogen gamma chain, apolipoprotein A-IV (ApoA-IV), clusterin, heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1), and one unidentified protein. The information obtained from this proteomic analysis will be very useful in understanding the pathophysiology of CTS and in finding suitable proteins that can serve as new diagnostic biomarkers of CTS. Show less

To investigate the association of FADS gene polymorphisms with age-related changes in polyunsaturated fatty acids (PUFAs) in serum phospholipids and oxidative stress markers. We genotyped 122 nonobese men aged 35-59 years without any known diseases at baseline for rs174537 near FADS1 (FEN1 rs174537G > T), FADS2 (rs174575, rs2727270), and FADS3 (rs1000778), and followed them for 3 years. Among the four single-nucleotide polymorphisms, the minor variants of rs174537 and rs2727270 were significantly associated with lower concentrations of long-chain PUFAs. However, rs174537G > T showed stronger association. At baseline, men with the rs174537T allele had lower arachidonic acid (AA) and AA/linoleic acid (LA), and higher interleukin (IL)-6 levels than rs174537GG counterparts. After 3 years, rs174537GG men had significantly increased AA (P = 0.022), AA/dihomo-γ-linolenic acid (DGLA) (P = 0.007), docosapentaenoic acid (DPA), low-density lipoprotein (LDL) cholesterol, and oxidized LDL (ox-LDL), but decreased eicosatrienoic acid. The rs174537T group showed significantly increased γ-linolenic acid and ox-LDL, and decreased eicosadienoic acid, eicosapentaenoic acid (EPA)/α-linolenic acid (ALA), and IL-6. After 3 years, the rs174537T group had lower AA (P < 0.001), AA/DGLA (P = 0.019), EPA, DPA, EPA/ALA, and urinary 8-epi-prostaglandin F2α (8-epi-PGF2α) (P = 0.011) than rs174537GG. Changes in AA (P = 0.001), AA/DGLA (P = 0.017), EPA, DPA, EPA/ALA, and urinary 8-epi-PGF2α (P < 0.001) were significantly different between the groups after adjusting for baseline values. Overall, changes in AA positively correlated with changes in urinary 8-epi-PGF2α (r = 0.249, P = 0.007), plasma ox-LDL (r = 0.199, P = 0.045), and serum IL-6 (r = 0.289, P = 0.004). Our data show that FADS polymorphisms can affect age-associated changes in serum phospholipid long-chain PUFAs, Δ5-desaturase activity, and oxidative stress in middle-aged nonobese men. In particular, the rs174537T allele did not show the age-associated increases in AA and Δ5-desaturase activity seen with the rs174537GG genotype. Show less

Low albumin:globulin (A/G) ratios are associated with vascular adverse events, nephrotic syndrome and autoimmune disease. Genome-wide association studies (GWASs) have been identifying genetic variants associated with total serum protein, serum albumin and globulins, but A/G ratio has never been considered the target phenotype. To identify the genetic basis of the A/G ratio, we performed a GWAS on A/G ratio in 4205 individuals from the Ansan cohort and confirmed the results in 4637 subjects from the Ansung cohort. The single-nucleotide polymorphism (SNP) genotypes of Affymetrix SNP array 5.0 were obtained from the Korean Association Resource Consortium, and we selected 290 659 common SNPs with a minor allele frequency >0.05. Genetic factors for A/G ratio were analyzed by linear regression analysis, controlling for age, sex, body mass index, smoking status and alcohol drinking status as covariates. From the GWAS of the Ansan cohort, we identified two significant genome-wide signals (P-values<5 × 10(-8)) and 36 moderate signals (P-value<1.0 × 10(-4)). These 38 signals were tested in the Ansung population. Eleven SNPs from six loci (GALNT2, IRF4, HLA-DBP1, SLC31A1, FADS1 and TNFRSF13B) were replicated, with P-values<0.05. The most compelling association was observed in the TNFRSF13B locus on chromosome 17p11.2 (SNP: rs4561508), with an overall combined P-value=7.80 × 10(-24). The other significant signal was observed on chromosome 11q12.2-the FADS1 locus (SNP: rs174548)-with an overall combined P-value=3.54 × 10(-8). Show less

Aberrant cardiomyocyte microtubule growth is a feature of pressure overload induced cardiac hypertrophy believed to contribute to left ventricular (LV) dysfunction. Microtubule Actin Cross-linking Factor 1 (MACF1/Acf7) is a 600 kd spectraplakin that stabilizes and guides microtubule growth along actin filaments. MACF1 is expressed in the heart, but its impact on cardiac microtubules, and how this influences cardiac structure, function, and adaptation to hemodynamic overload is unknown. Here we used inducible cardiac-specific MACF1 knockout mice (MACF1 KO) to determine the impact of MACF1 on cardiac microtubules and adaptation to pressure overload (transverse aortic constriction (TAC).In adult mouse hearts, MACF1 expression was low under basal conditions, but increased significantly in response to TAC. While MACF1 KO had no observable effect on heart size or function under basal conditions, MACF1 KO exacerbated TAC induced LV hypertrophy, LV dilation and contractile dysfunction. Interestingly, subcellular fractionation of ventricular lysates revealed that MACF1 KO altered microtubule distribution in response to TAC, so that more tubulin was associated with the cell membrane fraction. Moreover, TAC induced microtubule redistribution into this cell membrane fraction in both WT and MACF1 KO mice correlated strikingly with the level of contractile dysfunction (r(2) = 0.786, p<.001). MACF1 disruption also resulted in reduction of membrane caveolin 3 levels, and increased levels of membrane PKCα and β1 integrin after TAC, suggesting MACF1 function is important for spatial regulation of several physiologically relevant signaling proteins during hypertrophy. Together, these data identify for the first time, a role for MACF1 in cardiomyocyte microtubule distribution and in adaptation to hemodynamic overload. Show less

We investigated the association of polymorphisms in FADS genes with polyunsaturated fatty acids (PUFAs) in serum phospholipids, lipid peroxides, and coronary artery disease (CAD) in Koreans. In this case-control study, CAD patients (n=756, 40-79 years) and healthy controls (n=890) were genotyped for rs174537 near FADS1 (FEN1 rs174537G>T), FADS2 (rs174575, rs2727270), and FADS3 (rs1000778). We calculated the odds ratios (ORs) for CAD risk and measured serum PUFA composition and lipid peroxide. Among four SNPs, only rs174537G>T differed in allele frequencies between controls and CAD patients after adjustment for age, BMI, cigarette smoking, alcohol consumption, hypertension, diabetes mellitus, and hyperlipidemia (P=0.017). The minor T allele was associated with a lower risk of CAD [OR 0.75 (95%CI 0.61-0.92), P=0.006] after adjustment. rs174537T carriers had a significantly higher proportion of linoleic acid (LA, 18:2ω6), lower arachidonic acid (AA, 20:4ω6), and lower ratios of AA/dihomo-γ-linolenic acid (DGLA, 20:3ω6) and AA/LA than G/G subjects in both control and CAD groups. In the control group, 174537T carriers had significantly lower levels of total- and LDL-cholesterol, malondialdehyde, and ox-LDL. In CAD patients, rs174537T carriers showed a larger LDL particle size than G/G subjects. The proportion of AA in serum phospholipids positively correlated with LDL-cholesterol, ox-LDL, and malondialdehyde in controls and with 8-epi-prostaglandin F(2α) in both control and CAD groups. The rs174537T is associated with a lower proportion of AA in serum phospholipids and reduced CAD risk, in association with reduced total- and LDL-cholesterol and lipid peroxides. Show less