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Free fatty acids (FFAs) are important substrates for mitochondrial oxidative metabolism and ATP synthesis but also cause serious stress to various tissues, contributing to the development of metabolic diseases. CD36 is a major mediator of cellular FFA uptake. Inside the cell, saturated FFAs are able to induce the production of cytosolic and mitochondrial reactive oxygen species (ROS), which can be prevented by co-exposure to unsaturated FFAs. There are close connections between oxidative stress and organellar Ca2+ homeostasis. Highly oxidative conditions induced by palmitate trigger aberrant endoplasmic reticulum (ER) Ca2+ release and thereby deplete ER Ca2+ stores. The resulting ER Ca2+ deficiency impairs chaperones of the protein folding machinery, leading to the accumulation of misfolded proteins. This ER stress may further aggravate oxidative stress by augmenting ER ROS production. Secondary to ER Ca2+ release, cytosolic and mitochondrial matrix Ca2+ concentrations can also be altered. In addition, plasmalemmal ion channels operated by ER Ca2+ depletion mediate persistent Ca2+ influx, further impairing cytosolic and mitochondrial Ca2+ homeostasis. Mitochondrial Ca2+ overload causes superoxide production and functional impairment, culminating in apoptosis. This vicious cycle of lipotoxicity occurs in multiple tissues, resulting in β-cell failure and insulin resistance in target tissues, and further aggravates diabetic complications. KCI Citation Count: 204

Keratinocyte-fibroblast interactions are critical for skin repair after injury. During the proliferative phase of wound healing, proliferation, migration and differentiation of these cells are the major mechanisms leading to tissue remodeling. We have previously reported that glycitin, a major soy isoflavone, stimulates dermal fibroblast proliferation; and the phytochemical, 4′,6,7-trimethoxyisoflavone (TMF), induces migration of HaCaT keratinocyte cells. We therefore investigated whether these compounds display synergistic effects on skin cells during wound healing in vitro and in vivo. Co-treatment with TMF and glycitin synergistically promotes the proliferation and migration of both keratinocytes and dermal fibroblasts, with a 1:1 ratio of these compounds showing the greatest efficacy in our co-culture system. This keratinocyte-fibroblast interaction occurred via the secretion of TGF-β, and the induction of differentiation and proliferation was confirmed in both indirect and direct co-culture assays. In an excisional and burn wound animal model, mice treated with a 1:1 ratio of TMF and glycitin showed faster wound closure, regeneration and scar reduction than even the positive control drug. These data indicate that two isoflavones, TMF and glycitin, act synergistically to promote wound healing and anti-scarring and could potentially be developed together as a bioactive therapeutic for wound treatment. KCI Citation Count: 39

Diabetic wound healing, including diabetic foot ulcer (DFU), is a serious complication of diabetes. Considering the complexity of DFU development, the identification of a factor that mediates multiple pathogeneses is important for treatment. In this study, we found that CXXC-type zinc finger protein 5 (CXXC5), a negative regulator of the Wnt/β-catenin pathway, was overexpressed with suppression of the Wnt/β-catenin pathway and its target genes involved in wound healing and angiogenesis in the wound tissues of DFU patients and diabetes-induced model mice. KY19334, a small molecule that activates the Wnt/β-catenin pathway by inhibiting the CXXC5-Dvl interaction, accelerated wound healing in diabetic mice. The enhancement of diabetic wound healing could be achieved by restoring the suppressed Wnt/β-catenin signaling and subsequently inducing its target genes. Moreover, KY19334 induced angiogenesis in hindlimb ischemia model mice. Overall, these findings revealed that restorative activation of Wnt/β-catenin signaling by inhibiting the function of cytosolic CXXC5 could be a therapeutic approach for treating DFUs. KCI Citation Count: 15

Osteoactivin is a heavily glycosylated protein shown to have a role in bone remodeling. Previous studies from our lab have shown that mutation in Osteoactivin enhances osteoclast differentiation but inhibits their function. To date, a classical receptor and a signaling pathway for Osteoactivin-mediated osteoclast inhibition has not yet been characterized. In this study, we examined the role of Osteoactivin treatment on osteoclastogenesis using bone marrow-derived osteoclast progenitor cells and identify a signaling pathway relating to Osteoactivin function. We reveal that recombinant Osteoactivin treatment inhibited osteoclast differentiation in a dose-dependent manner shown by qPCR, TRAP staining, activity and count. Using several approaches, we show that Osteoactivin binds CD44 in osteoclasts. Furthermore, recombinant Osteoactivin treatment inhibited ERK phosphorylation in a CD44-dependent manner. Finally, we examined the role of Osteoactivin on receptor activator of nuclear factor-κ B ligand (RANKL)-induced osteolysis in vivo. Our data indicate that recombinant Osteoactivin inhibits RANKL-induced osteolysis in vivo and this effect is CD44-dependent. Overall, our data indicate that Osteoactivin is a negative regulator of osteoclastogenesis in vitro and in vivo and that this process is regulated through CD44 and ERK activation. KCI Citation Count: 21

Aging is the most important risk factor for human neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Pathologically, these diseases are characterized by the deposition of specific protein aggregates in neurons and glia, representing the impairment of neuronal proteostasis. However, the mechanism by which aging affects the proteostasis system and promotes protein aggregation remains largely unknown. The short lifespan and ample genetic resources of Caenorhabditis elegans (C. elegans) have made this species a favorite model organism for aging research, and the development of proteinopathy models in this organism has helped us to understand how aging processes affect protein aggregation and neurodegeneration. Here, we review the recent literature on proteinopathies in C. elegans models and discuss the insights we have gained into the mechanisms of how aging processes are integrated into the pathogenesis of various neurodegenerative diseases. KCI Citation Count: 1

Prostacyclin (PGI2) plays key roles in shaping the immune microenvironment and modulating vasodilation, whereas its contribution to endometriosis (EMs) remains largely unclear. Our study suggested that prostacyclin synthase (PTGIS)-dependent PGI2 signaling was significantly activated in EMs, which was involved in the hypoxic microenvironment of ectopic lesions and deficient methylation status of the PTGIS promoter. Notably, in vitro assays, hypoxia promoted PTGIS expression through DNA methyltransferase 1 (DNMT1)-mediated DNA methylation deficiency in endometrial stromal cells (ESCs); PTGIS overexpression enhanced the adhesive ability of ESCs and led to elevated PGI2 production, and PGI2 triggered CD16− (encoded by FCGR3, Fc fragment of IgG receptor IIIa) natural killer (NK)-cell differentiation through PGI2 receptor (IP, PTGIR) in an ESC/NK-cell coculture system. Our rodent model experiment suggested that treatment with the PGI2 analog iloprost and adoptive transfer of fcgr3 knockout (fcgr3−/−) NK cells aggravated EMs progression and that genetic ablation of ptgis (ptgis−/−) in ectopic lesions and treatment with the PTGIR antagonist RO1138452 partially rescued this outcome. Thus, our findings identified the contribution of PGI2 to EMs progression via enhancement of the adhesive ability of ESCs and inhibition of the activity of NK cells. We hypothesized that PGI2 is a target for EMs intervention and provide a rationale for studying pharmacological PTGIR inhibition and PTGIS genetic depletion therapies as therapeutic strategies for EMs. KCI Citation Count: 17

Alzheimer’s disease (AD) is the leading cause of dementia, and many studies have focused on finding effective blood biomarkers for the accurate diagnosis of this disease. Predicting cerebral amyloid deposition is considered the key for AD diagnosis because a cerebral amyloid deposition is the hallmark of AD pathogenesis. Previously, blood biomarkers were discovered to predict cerebral amyloid deposition, and further efforts have been made to increase their sensitivity and specificity. In this study, we analyzed blood-test factors (BTFs) that can be commonly measured in medical health check-ups from 149 participants with cognitively normal, 87 patients with mild cognitive impairment, and 64 patients with clinically diagnosed AD dementia with brain amyloid imaging data available. We demonstrated that four factors among regular health check-up blood tests, cortisol, triglyceride/high-density lipoprotein cholesterol ratio, alanine aminotransferase, and free triiodothyronine, showed either a significant difference by or correlation with cerebral amyloid deposition. Furthermore, we made a prediction model for Pittsburgh compound B-positron emission tomography positivity, using BTFs and the previously discovered blood biomarkers, the QPLEX TM Alz plus assay kit biomarker panel, and the area under the curve was significantly increased up to 0.845% with 69.4% sensitivity and 90.6% specificity. These results show that BTFs could be used as co-biomarkers and that a highly advanced prediction model for amyloid plaque deposition could be achieved by the combinational use of diverse biomarkers.

Synbiotics, the combination of probiotics and prebiotics, are known to confer health benefits via intestinal microbiota modulation. However, significant intestinal microbiota alterations can be difficult to determine in intervention studies based on solely bacterial stool metagenomic analysis. Intestinal microbiota constituents secrete 20–200-nm-sized extracellular vesicles (EVs) containing microbial DNA, proteins, and lipids that are distributed throughout the body, providing an alternative target for microbiota metagenomic analysis. Here, we determined the impact of a synbiotic beverage enriched with the kimchi-derived bacterium Leuconostoc holzapfelii (L. holzapfelii) on the intestinal microbiota and local and circulatory microbiota-derived EV composition of healthy Korean adults. We isolated microbial DNA from stool bacteria, stool EVs, and urinary EVs and conducted next-generation sequencing of the 16S rDNA V3–V4 regions before and after synbiotic consumption. The species diversity of circulating urinary EVs was significantly increased after synbiotic consumption, while stool bacterial and EV diversity remained unchanged. Furthermore, we found that while a single genus was decreased among the stool bacteria constituents, stool EVs and urinary EVs showed significant alterations in four and eight genera, respectively. Blood chemistry assays revealed that synbiotic consumption significantly lowered aspartate aminotransferase (AST) serum levels, particularly in subjects with starting levels above the normal range (>40 UI/L). In conclusion, the L. holzapfelii-enriched synbiotic beverage greatly altered serum AST levels and microbial EV composition in urine and stool, while only minor changes were observed in the gut microbiota composition. Based on these findings, we suggest the potential use of microbiota-derived EVs as surrogate markers in future predictive diagnosis studies. KCI Citation Count: 28

Mutations affect gene functions related to cancer behavior, including cell growth, metastasis, and drug responses. Genome-wide profiling of cancer mutations and drug responses has identified actionable targets that can be utilized for the management of cancer patients. Here, the recapitulation of pharmacogenomic data revealed that the mutation of EPHB6 is associated with paclitaxel resistance in cancer cells. Experimental data confirmed that the EPHB6 mutation induces paclitaxel resistance in various cancer types, including lung, skin, and liver cancers. EPHB6 mutation-induced paclitaxel resistance was mediated by an interaction with EPHA2, which promotes c-Jun N-terminal kinase (JNK)- mediated cadherin 11 (CDH11) expression. We demonstrated that EPHB6-mutated cells acquire cell adhesion-mediated drug resistance (CAM-DR) in association with CDH11 expression and RhoA/focal adhesion kinase (FAK) activation. Targeted inhibition of EPHA2 or CDH11 reversed the acquired paclitaxel resistance, suggesting its potential clinical utility. The present results suggest that the EPHB6 mutation and its downstream EPHA2/JNK/CDH11/RhoA/FAK signaling axis are novel diagnostic and therapeutic targets for overcoming paclitaxel resistance in cancer patients. KCI Citation Count: 21

This study examined the induction of recipient T-cell cytotoxicity after exposure to allogeneic adipose-derived mesenchymal stem cells (ADSCs). ADSCs pre-exposed to xenogeneic serum significantly induced cytotoxicity through CD8 T-cell granzyme B secretion after allogeneic antigen stimulation, and this effect was increased with prolonged reaction time. ADSCs pretreated with proinflammatory cytokines also induced cytotoxicity through granzyme B secretion and significantly increased human leukocyte antigen (HLA)-ABC expression. T-cell cytotoxicity towards ADSCs grown in xeno-free medium (XF-ADSCs) was lower than that towards ADSCs exposed to xenogeneic serum or proinflammatory cytokines, but XF-ADSCs still induced cytotoxicity. We further investigated the causes of T-cell cytotoxicity towards XF-ADSCs. XF-ADSC death was effectively inhibited by HLA-blocking antibodies, suggesting that ADSC HLAs are a major cause of alloreactive T-cell generation. These results indicated that culturing of allogeneic ADSCs with recipient serum may alleviate alloreactive CD8 T-cell cytotoxicity. Ultimately, development of therapeutic agents using autologous ADSCs would be a suitable way to avoid immunogenicity and CD8 T cell-mediated cytotoxicity, but more attention should be paid to the potential immunogenicity of allogeneic ADSCs, which could perhaps be mitigated through the use of immunosuppressants. KCI Citation Count: 12