👤 Jin Seok Heo

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder with a high incidence of anxiety and depression. However, the underlying mechanisms of these symptoms remain to be fully elucidated. This study investigated the effects and mechanisms of a 20% ethanolic extract of Show less

Lipids are a principal component of drusen and are involved in the pathobiology of age-related macular degeneration (AMD). Nonhuman primates (NHPs) develop macular drusen and may provide insight into circulating or local lipids in AMD. We evaluated aged rhesus macaques by fundus photography, optical coherence tomography (OCT), and fundus autofluorescence, as well as measured fasting plasma glucose, total cholesterol, high- and low-density lipoproteins, triglycerides, and apolipoprotein (Apo) A1, B, CIII, and E. Retinal tissues were collected for electron microscopy and immunostained for oil red O, ApoE, and ApoB. Among 203 adult macaques (mean age 19.1 ± 3.1 years), 25 animals (12.1%) exhibited soft drusen with sub-RPE deposits, while 59 (28.6%) had yellow punctate dots that were mostly hyperautofluorescent without RPE elevation on OCT. Drusen prevalence increased with older age (P = 0.001) but not with plasma lipids (P > 0.05 for all), while the punctate dot phenotype was associated with older age (P = 0.014), higher fasting glucose (P = 0.023), low-density lipoprotein cholesterol (P = 0.022), and ApoB (P = 0.017). Ultrastructure revealed NHP drusen consisting of extracellular sub-RPE lipid particles, whereas punctate dots appeared to correspond to individual RPE cells with intracellular lipid vacuoles. Both sub-RPE and intra-RPE lipids of the two phenotypes contained neutral lipids and ApoE, while ApoE and ApoB appeared to be expressed in RPE. In rhesus macaques, soft drusen are extracellular lipid deposits associated with older age, while punctate dots are intracellular lipids linked to age, hyperglycemia, and hyperlipidemia, suggesting differential dysregulation of lipid transport in these NHP models of AMD. 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

Major depressive disorder (MDD) is a complex psychological disorder with a sophisticated molecular etiology. Although its connection with fibroblast growth factor receptor 1 (FGFR1) in the hippocampus is known, the precise mechanisms underlying its pathophysiology remain unclear. Here we conduct a comprehensive analysis of the molecular profile of the hippocampus in patients with MDD. We identified a distinct overexpression of FGFR1 specifically within the dentate gyrus of patients with MDD. Through the use of optogenetic techniques for the in vivo spatiotemporal dissection of FGFR1 signaling, we uncovered a sequential FGFR1-Notch-brain-derived neurotrophic factor (BDNF) pathway within the dentate gyrus, which can ultimately induce adult hippocampal neurogenesis, significantly contributing to antidepressant effects. We discovered that the dysregulation of this axis by the protein Numb, which demonstrates an age-related increase in individuals with MDD, is closely associated with the development of depressive phenotypes. Remarkably, targeting Numb to restore this axis effectively reversed the depressive phenotype, thus offering new insights into potential therapeutic strategies. Show less

Common variants in the FKBP5 gene have been implicated in recurrence of major depressive disorder (MDD) and response to antidepressant treatment. Although the relationship between FKBP5 and MDD has been revealed through several studies, the detailed molecular mechanisms by which FKBP5 regulates responsiveness to antidepressants have not been fully understood. Here, we aimed to elucidate the molecular mechanisms of FKBP5 in autophagy initiation and its potential role in the antidepressant response. We found that FKBP5 deficiency impaired the initiation of basal and stress-induced autophagy, accompanied by reduced protein levels of the PIK3C3/VPS34 complex, which is essential for autophagy initiation. Mechanistically, we demonstrated that FKBP5 physically binds to the VPS34 complex components, facilitating their assembly and subsequent autophagy initiation. Particularly, our study revealed that FKBP5 mediates antidepressant-induced autophagy by promoting the VPS34 complex assembly. These findings were consistent in neuronal cells, where FKBP5 depletion resulted in decreased autophagy and impaired the VPS34 complex assembly. Understanding the interplay between FKBP5, autophagy, and MDD may provide new insights into more effective treatments for MDD and related disorders. Show less

Glucose-regulated protein 78 (GRP78) binds to and stabilizes melanocortin 4 receptor (MC4R), which activates protein kinase A (PKA) by regulating G proteins. GRP78 is primarily used as a marker for endoplasmic reticulum stress; however, its other functions have not been well studied. Therefore, in this study, we aimed to investigate the function of GRP78 during porcine embryonic development. The developmental quality of porcine embryos, expression of cell cycle proteins, and function of mitochondria were evaluated by inhibiting the function of GRP78. Porcine oocytes were activated to undergo parthenogenesis, and blastocysts were obtained after 7 days of in vitro culture. GRP78 function was inhibited by adding 20 μM HA15 to the in vitro culture medium. The inhibition in GRP78 function led to a decrease in G proteins release, which subsequently downregulated the cyclic adenosine monophosphate (cAMP)/PKA pathway. Ultimately, inhibition of GRP78 function induced the inhibition of CDK1 and cyclin B expression and disruption of the cell cycle. In addition, inhibition of GRP78 function regulated DRP1 and SIRT1 expression, resulting in mitochondrial dysfunction. This study provides new insights into the role of GRP78 in porcine embryonic development, particularly its involvement in the regulation of the MC4R pathway and downstream cAMP/PKA signaling. The results suggest that the inhibition of GRP78 function in porcine embryos by HA15 treatment may have negative effects on embryo quality and development. This study also demonstrated that GRP78 plays a crucial role in the functioning of MC4R, which releases the G protein during porcine embryonic development. Show less

The endothelium of blood vessels is a vital organ that reacts differently to subtle changes in stiffness and mechanical forces exerted on its environment (extracellular matrix (ECM)). Upon alteration of these biomechanical cues, endothelial cells initiate signaling pathways that govern vascular remodeling. The emerging organs-on-chip technologies allow the mimicking of complex microvasculature networks, identifying the combined or singular effects of these biomechanical or biochemical stimuli. Here, we present a microvasculature-on-chip model to investigate the singular effect of ECM stiffness and mechanical cyclic stretch on vascular development. Following two different approaches for vascular growth, the effect of ECM stiffness on sprouting angiogenesis and the effect of cyclic stretch on endothelial vasculogenesis are studied. Our results indicate that ECM hydrogel stiffness controls the size of the patterned vasculature and the density of sprouting angiogenesis. RNA sequencing shows that the cellular response to stretching is characterized by the upregulation of certain genes such as ANGPTL4+5, PDE1A, and PLEC. Show less

We performed an integrated analysis of proteomic and transcriptomic datasets to develop potential diagnostic markers for early pancreatic cancer. In the discovery phase, a multiple reaction monitoring assay of 90 proteins identified by either gene expression analysis or global serum proteome profiling was established and applied to 182 clinical specimens. Nine proteins (P < 0.05) were selected for the independent validation phase and quantified using stable isotope dilution-multiple reaction monitoring-mass spectrometry in 456 specimens. Of these proteins, four proteins (apolipoprotein A-IV, apolipoprotein CIII, insulin-like growth factor binding protein 2 and tissue inhibitor of metalloproteinase 1) were significantly altered in pancreatic cancer in both the discovery and validation phase (P < 0.01). Moreover, a panel including carbohydrate antigen 19-9, apolipoprotein A-IV and tissue inhibitor of metalloproteinase 1 showed better performance for distinguishing early pancreatic cancer from pancreatitis (Area under the curve = 0.934, 86% sensitivity at fixed 90% specificity) than carbohydrate antigen 19-9 alone (71% sensitivity).Overall, we present the panel of robust biomarkers for early pancreatic cancer diagnosis through bioinformatics analysis that combined transcriptomic and proteomic data as well as rigorous validation on a large number of independent clinical samples. Show less

Batten disease (BD; also known as juvenile neuronal ceroid lipofuscinosis) is a genetic disorder inherited as an autosomal recessive trait and is characterized by blindness, seizures, cognitive decline, and early death resulting from the inherited mutation of the CLN3 gene. Mitochondrial oxidative stress, endoplasmic reticulum (ER) stress, disrupted autophagy, and enhanced apoptosis have been suggested to play a role in BD pathogenesis. Fibrates, a class of lipid-lowering drugs that induce peroxisome proliferator-activated receptor-α (PPAR-α) activation, are the most commonly used PPAR agonists. Assuming that fibrates have a neuroprotective effect, we studied the effects of fibrates, fenofibrate, bezafibrate, and gemfibrozil on apoptosis, depolarization of mitochondrial membrane, and defective autophagy in BD lymphoblast cells. The viability of fibrate-treated BD lymphoblast cells increased to levels of normal lymphoblast cells. In addition, treatment with fibrates inhibited depolarization of mitochondrial membrane potential in BD lymphoblast cells. Defective autophagy in BD lymphoblast cells was normalized when treated with fibrates as indicated by increased acridine orange staining. The recovery of autophagy in BD lymphoblast cells is most likely attributed to the upregulation of autophagy proteins, lysosomal-associated membrane protein 1 (LAMP1), and LC3 I/II, after treatment with fibrates. This study therefore suggests that fibrates may have a therapeutic potential against BD. Show less

Irisin is a newly identified myokine related to exercise and the browning of white fat. Recently, it was reported that irisin serum levels are associated with intrahepatic triglyceride content, suggesting that it might have an important role in the liver. The aim of this study was to determine the role of irisin in hepatocytes. Specifically, the effect of recombinant irisin on palmitic acid (PA)-induced lipogenesis and its related signal pathways were examined in AML12 cells and mouse primary hepatocytes. In the present study, we observed the presence of irisin inside the cells in response to the treatment of recombinant irisin by flow cytometry and cell imaging technique. Recombinant irisin significantly inhibited the PA-induced increase in lipogenic markers ACC and FAS at the mRNA and protein levels, and prevented the PA-induced lipid accumulation in hepatocytes. Additionally, irisin inhibited the PA-induced increase in the expression, nuclear localization, and transcriptional activities of the master regulators of lipogenesis (LXRα and SREBP-1c). Moreover, irisin attenuated PA-induced oxidative stress, which was confirmed by measuring the expression of inflammatory markers (NFκB, COX-2, p38 MAPK, TNF, IL-6) and superoxide indicator (dihydroethidium). The preventive effects of irisin against lipogenesis and oxidative stress were mediated by the inhibition of protein arginine methyltransferase-3 (PRMT3). These findings suggested that irisin might have a beneficial role in the prevention of hepatic steatosis by altering the expression of lipogenic genes and attenuating oxidative stress in a PRMT3 dependent manner. Show less

Legionella pneumophila, a human intracellular pathogen, encodes about 290 effector proteins that are translocated into host cells through a secretion machinery. Some of these proteins have been shown to manipulate or subvert cellular processes during infection, but functional roles of a majority of them remain unknown. Lpg0393 is a newly identified Legionella effector classified as a hypothetical protein. Through X-ray crystallographic analysis, we show that Lpg0393 contains a Vps9-like domain, which is structurally most similar to the catalytic core of human Rabex-5 that activates the endosomal Rab proteins Rab5, Rab21 and Rab22. Consistently, Lpg0393 exhibited a guanine-nucleotide exchange factor activity toward the endosomal Rabs. This work identifies the first example of a bacterial guanine-nucleotide exchange factor that is active towards the Rab5 sub-cluster members, implying that the activation of these Rab proteins might be advantageous for the intracellular survival of Legionella. Show less

Batten disease (juvenile neuronal ceroid lipofuscinosis) is a neurodegenerative disorder characterized by blindness, seizures, cognitive decline, and early death due to the inherited mutation of the CLN3 gene. Although α-synuclein and sphingolipids are relevant for the pathogenesis of some neuronal disorders, little attention has been paid to their role in Batten disease. To identify the molecular factors linked to autophagy and apoptotic cell death in Batten disease, the levels of α-synuclein, sphingomyelin, and gangliosides were examined. We observed enhanced levels of α-synuclein oligomers and gangliosides GM1, GM2, and GM3 and reduced levels of sphingomyelin and autophagy in Batten disease lymphoblast cells compared with normal lymphoblast cells, possibly resulting in a higher rate of apoptosis typically found in Batten disease lymphoblast cells. Show less

Batten disease (BD)--also known as juvenile neuronal ceroid lipofuscinoses-is an inherited neurodegenerative disorder caused by CLN3 gene mutations. Although CLN3-related oxidative and mitochondrial stresses have been studied in BD, the pathologic mechanism of the disease is not clearly understood. To address the molecular factors linked to high levels of oxidative stress in BD, we examined the expression of mitochondria-related metabolic molecules, including pyruvate dehydrogenase (PDH), ATP citrate lyase (ACL), and phosphoenolpyruvate carboxykinase (PEPCK), as well as the apoptosis-related ganglioside, acetyl-GD3. We observed an increased expression of PDH and a decreased expression of ACL, PEPCK, and acetyl-GD3 in BD lymphoblast cells compared to normal cells, possibly resulting in the high ROS levels, mitochondrial membrane depolarization, and apoptosis typically found in BD. Show less

Batten disease is an inherited neurodegenerative disorder caused by a CLN3 gene mutation. Batten disease is characterized by blindness, seizures, cognitive decline, and early death. Although apoptotic cell death is one of the pathological hallmarks of Batten disease, little is known about the regulatory mechanism of apoptosis in this disease. Since the CLN3 gene is suggested to be involved in the cell cycle in a yeast model, we investigated the cell cycle profile and its regulatory factors in lymphoblast cells from Batten disease patients. We found G1/G0 cell cycle arrest in Batten disease cells, with overexpression of p21, sphingosine, glucosylceramide, and sulfatide as possible cell cycle regulators. Show less

Batten disease is an inherited disorder characterized by early onset neurodegeneration due to the mutation of the CLN3 gene. The function of the CLN3 protein is not clear, but an association with oxidative stress has been proposed. Oxidative stress and DNA damage play critical roles in the pathogenesis of neurodegenerative diseases. Antioxidants are of interest because of their therapeutic potential for treating neurodegenerative diseases. We tested whether N-acetylcysteine (NAC), a well-known antioxidant, improves the pathology of cells from patients with Batten disease. At first, the expression levels of urea cycle components and DNA repair enzymes were compared between Batten disease cells and normal cells. We used both mRNA expression levels and Western blot analysis. We found that carbamoyl phosphate synthetase 1, an enzyme involved in the urea cycle, 8-oxoguanine DNA glycosylase 1 and DNA polymerase beta, enzymes involved in DNA repair, were expressed at higher levels in Batten disease cells than in normal cells. The treatment of Batten disease cells with NAC for 48 h attenuated activities of the urea cycle and of DNA repair, as indicated by the substantially decreased expression levels of carbamoyl phosphate synthetase 1, 8-oxoguanine DNA glycosylase 1 and DNA polymerase beta proteins compared with untreated Batten cells. NAC may serve in alleviating the burden of urea cycle and DNA repair processes in Batten disease cells. We propose that NAC may have beneficial effects in patients with Batten disease. Show less

Batten disease (BD) is the most common form of a group of disorders called neuronal ceroid lipofuscinosis, which are caused by a CLN3 gene mutation. A variety of pathogenic lysosomal storage disorder mechanisms have been suggested such as oxidative stress, endoplasmic reticulum (ER) stress, and altered protein trafficking. Resveratrol, a stilbenoid found in red grape skin, is a potent antioxidant chemical. Recent studies have suggested that resveratrol may have a curative effect in many neurodegenerative diseases. Therefore, we investigated the activities of resveratrol at the levels of oxidative and ER stress and apoptosis factors using normal and BD lymphoblast cells. We report that the BD lymphoblast cells contained low-levels of superoxide dismutase-1 (SOD-1) due to the long-term stress of reactive oxygen species. However, when we treated the cells with resveratrol, SOD-1 increased to levels observed in normal cells. Furthermore, we investigated the expression of glucose-regulated protein 78 as an ER stress marker. BD cells underwent ER stress, but resveratrol treatment resolved the ER stress in a dose-dependent manner. We further demonstrated that the levels of apoptosis markers such as apoptosis induce factor, cytochrome c, and cleavage of poly (ADP)-ribose polymerase decreased following resveratrol treatment. Thus, we propose that resveratrol may have beneficial effects in patients with BD. Show less