Publications by authors named "Moon-Chang Baek"

89 Publications

Mastocytosis-derived extracellular vesicles deliver miR-23a and miR-30a into pre-osteoblasts and prevent osteoblastogenesis and bone formation.

Nat Commun 2021 05 5;12(1):2527. Epub 2021 May 5.

Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA.

Osteoporosis and other manifestations of bone disease are frequent in patients with systemic mastocytosis (SM) in association with the presence of mast cell infiltrates in bone marrow, although the mechanisms behind bone disease remain poorly understood. We find that extracellular vesicles (EVs) released by neoplastic mast cells and present in the serum of patients with SM (SM-EVs) block osteoblast differentiation and mineralization in culture, and when injected into mice diminish the expression of osteoblast markers, and trabecular bone volume and microarchitecture. We demonstrate that miRNA-30a and miRNA-23a, increased in SM-EVs and neoplastic mast cell-derived EVs, attenuate osteoblast maturation by suppressing expression of RUNX2 and SMAD1/5, essential drivers of osteogenesis. Thus, SM-EVs carry and deliver miRNAs that epigenetically interfere with bone formation and can contribute to bone mass reduction in SM. These findings also suggest possibilities for novel approaches to the management of bone disease in mast cell proliferative disorders.
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http://dx.doi.org/10.1038/s41467-021-22754-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100305PMC
May 2021

Interferon-γ inhibits retinal neovascularization in a mouse model of ischemic retinopathy.

Cytokine 2021 Jul 26;143:155542. Epub 2021 Apr 26.

Department of New Biology, DGIST, Daegu 42988, Republic of Korea. Electronic address:

Interferon-γ (IFNG) is one of the key cytokines that regulates both innate and adaptive immune responses in the body. However, the role of IFNG in the regulation of vascularization, especially in the context of Vascular endothelial growth factor A (VEGFa)-induced angiogenesis is not clarified. Here, we report that IFNG shows potent anti-angiogenic potential against VEGFa-induced angiogenesis. IFNG significantly inhibited proliferation, migration, and tube formation of Human umbilical vein endothelial cells (HUVECs) both under basal and VEGFa-treated conditions. Intriguingly, Knockdown (KD) of STAT1 abolished the inhibitory effect of IFNG on VEGFa-induced angiogenic processes in HUVECs. Furthermore, IFNG exhibited potent anti-angiogenic efficacy in the mouse model of oxygen-induced retinopathy (OIR), an in vivo model for hypoxia-induced retinal neovascularization, without induction of functional side effects. Taken together, these results show that IFNG plays a crucial role in the regulation of VEGFa-dependent angiogenesis, suggesting its potential therapeutic applicability in neovascular diseases.
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http://dx.doi.org/10.1016/j.cyto.2021.155542DOI Listing
July 2021

Circulating small extracellular vesicles activate TYRO3 to drive cancer metastasis and chemoresistance.

Cancer Res 2021 Apr 28. Epub 2021 Apr 28.

Department of Pharmacy, Seoul National University

Extracellular vesicles (EV) in the tumor microenvironment have emerged as crucial mediators that promote proliferation, metastasis, and chemoresistance. However, the role of circulating small EVs (csEV) in cancer progression remains poorly understood. In this study, we report that csEV facilitates cancer progression and determine its molecular mechanism. csEV strongly promoted the migration of cancer cells via interaction with phosphatidylserine of csEV. Among the three TAM receptors TYRO3, AXL, and MerTK, TYRO3 mainly interacted with csEV. csEV-mediated TYRO3 activation promoted migration and metastasis via the epithelial-mesenchymal transition and stimulation of RhoA in invasive cancer cells. Additionally, csEV-TYRO3 interaction induced YAP activation, which led to increased cell proliferation and chemoresistance. Combination treatment with gefitinib and KRCT-6j, a selective TYRO3 inhibitor, significantly reduced tumor volume in xenografts implanted with gefitinib-resistant non-small cell lung cancer cells. The results of this study show that TYRO3 activation by csEV facilitates cancer cell migration and chemoresistance by activation of RhoA or YAP, indicating that the csEV/TYRO3 interaction may serve as a potential therapeutic target for aggressive cancers in the clinic.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3320DOI Listing
April 2021

Identification of a novel non-invasive biological marker to overcome the shortcomings of PSA in diagnosis and risk stratification for prostate cancer: Initial prospective study of developmental endothelial locus-1 protein.

PLoS One 2021 26;16(4):e0250254. Epub 2021 Apr 26.

Department of Urology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.

Objective: This prospective study sought to clarify the developmental endothelial locus-1 (Del-1) protein as values of diagnosis and risk stratification of prostate cancer (PCa).

Design: From February 2017 to December 2019, a total 458 patients who underwent transrectal ultrasound guided prostate biopsy or surgery of benign prostatic hyperplasia agreed to research of Del-1 protein. We prospectively compared and analyzed the Del-1 protein and prostate specific antigen (PSA) in relation to the patients' demographic and clinicopathological characteristics.

Results: Mean age was 68.86±8.55 years. Mean PSA and Del-1 protein was 21.72±89.37, 0.099±0.145, respectively. Two hundred seventy-six (60.3%) patients were diagnosed as PCa. Among them, 181 patients underwent radical prostatectomy (RP). There were significant differences in Del-1 protein between benign and PCa group (0.066±0.131 vs 0.121±0.149, respectively, p<0.001). When we set the cut-off value of del-1 protein as 0.120, in patients with 3≤PSA≤8, positive predictive value and specificity of Del-1 protein (≥0.120) for predicting PCa were 88.9% (56/63) and 93.5% (101/108), respectively. Among 181 patients who underwent RP, there were significant differences in Del-1 protein according to stage (pT2 vs pT3a vs ≥pT3b) (0.113±0.078, 0.171±0.121, 0.227±0.161, respectively, p<0.001) and to Gleason score (6 (3+3) or 7 (3+4) vs 7 (4+3) or 8 (4+4) vs 9 or 10) (0.134±0.103, 0.150±0.109, 0.212±0.178, respectively, P = 0.044). Multivariate analysis showed that PSA, Del-1 protein and high Gleason score (≥9) were the independent prognostic factors for predicting higher pT stage (≥3b). Furthermore, age, PSA and Del-1 protein were independent prognostic factors for predicting significant PCa.

Conclusion: Patients with PCa showed higher expression of Del-1 protein than benign patients. Del-1 protein increased with the stage and Gleason score of PCa. Collaboration with PSA, Del-1 protein can be a non-invasive useful marker for diagnosis and risk stratification of PCa.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250254PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075267PMC
April 2021

Exosomal Del-1 as a Potent Diagnostic Marker for Breast Cancer: Prospective Cohort Study.

Clin Breast Cancer 2021 Feb 17. Epub 2021 Feb 17.

Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, South Korea; Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea. Electronic address:

Background: The differential diagnostic role of plasma developmental endothelial locus-1 (Del-1) was proposed in our previous study. Therefore the current study aimed to confirm the diagnostic role and explore the prognostic role of exosomal Del-1 in a prospective cohort of female patients with breast cancer.

Patients And Methods: To determine the optimal sampling time for the postoperative Del-1 measurements, blood was serially collected on days 1, 3, 5, and 7 after surgery in 22 patients (cohort 1). Thereafter, 111 female patients with breast cancer were prospectively enrolled (cohort 2) to compare exosomal Del-1 levels before and after surgery.

Results: Among the subsequent prospective cohort, 107 patients (96.4%) showed a high exosomal Del-1 level (optical density [OD] value > 0.5) at the time of diagnosis. Of these patients, 101 (94.6%) in this high-level group showed normalized Del-1 levels postoperatively, representing a significant difference (mean OD value, 1.232 vs. 0.196; P < .00001). High postoperative Del-1 level was significantly associated with a worse disease-free survival adjusted to the clinicopathological characteristics (hazard ratio, 24.0; P = .0011).

Conclusion: This study confirmed the normalization of exosomal Del-1 after surgery, indicating exosomal Del-1 as a potent diagnostic biomarker for breast cancer. In addition, because a high Del-1 level after surgery was associated with early relapse, this suggests exosomal Del-1 as a potential prognostic marker by identifying the existence of residual cancer.
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http://dx.doi.org/10.1016/j.clbc.2021.02.002DOI Listing
February 2021

PF-3845, a Fatty Acid Amide Hydrolase Inhibitor, Directly Suppresses Osteoclastogenesis through ERK and NF-κB Pathways In Vitro and Alveolar Bone Loss In Vivo.

Int J Mol Sci 2021 Feb 15;22(4). Epub 2021 Feb 15.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Korea.

Alveolar bone loss, the major feature of periodontitis, results from the activation of osteoclasts, which can consequently cause teeth to become loose and fall out; the development of drugs capable of suppressing excessive osteoclast differentiation and function is beneficial for periodontal disease patients. Given the difficulties associated with drug discovery, drug repurposing is an efficient approach for identifying alternative uses of commercially available compounds. Here, we examined the effects of PF-3845, a selective fatty acid amide hydrolase (FAAH) inhibitor, on receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclastogenesis, its function, and the therapeutic potential for the treatment of alveolar bone destruction in experimental periodontitis. PF-3845 significantly suppressed osteoclast differentiation and decreased the induction of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and the expression of osteoclast-specific markers. Actin ring formation and osteoclastic bone resorption were also reduced by PF-3845, and the anti-osteoclastogenic and anti-resorptive activities were mediated by the suppression of phosphorylation of rapidly accelerated fibrosarcoma (RAF), mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase, (ERK) and nuclear factor κB (NF-κB) inhibitor (IκBα). Furthermore, the administration of PF-3845 decreased the number of osteoclasts and the amount of alveolar bone destruction caused by ligature placement in experimental periodontitis in vivo. The present study provides evidence that PF-3845 is able to suppress osteoclastogenesis and prevent alveolar bone loss, and may give new insights into its role as a treatment for osteoclast-related diseases.
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http://dx.doi.org/10.3390/ijms22041915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919013PMC
February 2021

Reply to 'Sulfisoxazole does not inhibit the secretion of small extracellular vesicles'.

Nat Commun 2021 02 12;12(1):976. Epub 2021 Feb 12.

Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu, Republic of Korea.

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http://dx.doi.org/10.1038/s41467-021-21075-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880988PMC
February 2021

Biapenem reduces sepsis mortality via barrier protective pathways against HMGB1-mediated septic responses.

Pharmacol Rep 2021 Jun 30;73(3):786-795. Epub 2021 Jan 30.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 41566, Republic of Korea.

Background: As a late mediator of sepsis, the role of high mobility group box 1 (HMGB1) has been recognized as important, and suppression of HMGB1 release and restoration of vascular barrier integrity are regarded as potentially promising therapeutic strategies for sepsis. For repositioning of previously FDA-approved drugs to develop new therapies for human diseases, screening of chemical compound libraries, biological active, is an efficient method. Our study illustrates an example of drug repositioning of Biapenem (BIPM), a carbapenem antibiotic, for the modulation of HMGB1-induced septic responses.

Methods: We tested our hypothesis that BIPM inhibits HMGB1-induced vascular hyperpermeability and thereby increases the survival of septic mouse model from suppression of HMGB1 release upon lipopolysaccharide (LPS)-stimulation. In LPS-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model, antiseptic activity of BIPM was investigated from suppression of vascular permeability, pro-inflammatory proteins, and markers for tissue injury.

Results: BIPM significantly suppressed release of HMGB1 both in LPS-activated HUVECs (upto 60%) and the CLP-induced sepsis mouse model (upto 54%). BIPM inhibited hyperpermeability (upto 59%) and reduced HMGB1-mediated vascular disruptions (upto 62%), mortality (upto 50%), and also tissue injury including lung, liver, and kidney in mice.

Conclusion: Reduction of HMGB1 release and septic mortality by BIPM (in vitro, from 5 to 15 μM for 6 h; in vivo, from 0.37 to 1.1 mg/kg, 24 h) indicate a possibility of successful repositioning of BIPM for the treatment of sepsis.
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http://dx.doi.org/10.1007/s43440-020-00212-0DOI Listing
June 2021

Genetic polymorphism of vir genes of Plasmodium vivax in Myanmar.

Parasitol Int 2021 Feb 2;80:102233. Epub 2020 Nov 2.

Department of Parasitology and Tropical Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea. Electronic address:

The Plasmodium vivax variant proteins encoded by vir genes are highly polymorphic antigens and are considered as one of key proteins of P. vivax for host immune evasion via antigenic variations. Because genetic diversity of these antigens is a critical hurdle in the development of an effective vaccine, understanding the genetic nature of the vir genes in natural population is important. In this study, we selected four vir genes (vir 4, vir 12, vir 21, and vir 27) previously used for genetic analysis in several studies and evaluated the genetic polymorphisms and phylogenetic relationship of these 4 vir genes in Myanmar P. vivax population. Taken all genetic diversity values, the vir 12 (S = 168, H = 17, Hd = 0.854, Tajima's D value = 2.91524) was the most genetically diverse gene and the vir 4 (S = 9, H = 4, Hd = 0.744, Tajima's D value = -0.49151) was the most conserved gene. All phylogenetic trees showed two clades, and vir 4 and 12 haplotypes from Myanmar were clustered in a distinct clade with those from India and Republic of Korea. These results confirmed the pattern of high genetic polymorphism of vir genes and provided information on vir gene for further functional research and studies focused toward the practical use of vir genes.
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http://dx.doi.org/10.1016/j.parint.2020.102233DOI Listing
February 2021

Fisetin Suppresses Pulmonary Inflammatory Responses Through Heme Oxygenase-1 Mediated Downregulation of Inducible Nitric Oxide Synthase.

J Med Food 2020 Nov 14;23(11):1163-1168. Epub 2020 Oct 14.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu, Korea.

The effects of a mixture of fisetin on cytokine-mediated pulmonary damages have not been studied, despite its known antiviral, neuroprotective, and anti-inflammatory activities. Using lipopolysaccharide (LPS)-activated human pulmonary artery endothelial cells (HPAECs), we determined the effects of fisetin on the induction of heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). In the lung tissue of LPS-treated mice, fisetin was also evaluated for its effect on the regulation of iNOS and tumor necrosis factor (TNF)-. In LPS-activated HPAECs, fisetin increased nuclear factor erythrocyte 2-related factor 2-antioxidant response element (Nrf2-ARE) reporter activity through the nuclear translocation of Nrf2, and the expression of HO-1, and decreased IL-1 and iNOS/NO production. In particular, the suppression of iNOS/NO expression by the administration of fisetin was dependent on HO-1. Current findings indicate that the anti-inflammatory activity of fisetin was due to its HO-1 dependent downregulation of p-STAT-1 and nuclear factor kappa B (NF-B) and the resultant inhibition of iNOS, and also suggest TNF- as a potential target for HO-1. We propose that administration of fisetin may be a novel approach, ideal for the treatment of inflammatory pulmonary disease.
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http://dx.doi.org/10.1089/jmf.2020.4755DOI Listing
November 2020

Novel factor Xa inhibitor, maslinic acid, with antiplatelet aggregation activity.

J Cell Physiol 2020 12 30;235(12):9445-9456. Epub 2020 Apr 30.

Department of Pharmacy, College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu, Republic of Korea.

As antithrombotic effects of maslinic acid (MA) have not yet been studied, MA-mediated downregulation of coagulation factor Xa (FXa) and platelet aggregation was studied. We show that MA inhibited the enzymatic activity of FXa and platelet aggregation, induced by adenosine diphosphate (ADP) and a thromboxane A (TXA ) analog, U46619 with a similar antithrombotic efficacy to rivaroxaban, a direct FXa inhibitor used as a positive control. Mechanistically, MA suppressed U46619- or ADP-induced phosphorylation of myristoylated alanine-rich C kinase substrate, and the expression of P-selectin, and activated PAC-1 in platelets. MA increased generation of nitric oxide, but downregulated excessive secretion of endothelin-1 in ADP- or U46619-treated human umbilical vein endothelial cells. In arterial and pulmonary thrombosis mouse model, MA showed prominent anticoagulant and antithrombotic effects. Our data suggest MA as a candidate molecule for a new class of drugs targeting anti-FXa and antiplatelet.
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http://dx.doi.org/10.1002/jcp.29749DOI Listing
December 2020

Biapenem as a Novel Insight into Drug Repositioning against Particulate Matter-Induced Lung Injury.

Int J Mol Sci 2020 Feb 21;21(4). Epub 2020 Feb 21.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Korea.

The screening of biologically active chemical compound libraries can be an efficient way to reposition Food and Drug Adminstration (FDA)-approved drugs or to discover new therapies for human diseases. Particulate matter with an aerodynamic diameter equal to or less than 2.5 μm (PM) is a form of air pollutant that causes significant lung damage when inhaled. This study illustrates drug repositioning with biapenem (BIPM) for the modulation of PM-induced lung injury. Biapenem was used for the treatment of severe infections. Mice were treated with BIPM via tail-vein injection after the intratracheal instillation of PM. Alterations in the lung wet/dry weight, total protein/total cell count and lymphocyte count, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were monitored in the PM-treated mice. BIPM effectively reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM. Enhanced myeloperoxidase (MPO) activity by PM in the pulmonary tissue was inhibited by BIPM. Moreover, increased levels of inflammatory cytokines and total protein by PM in the BALF were also decreased by BIPM treatment. In addition, BIPM markedly suppressed PM-induced increases in the number of lymphocytes in the BALF. Additionally, the activity of mammalian target of rapamycin (mTOR) was increased by BIPM. Administration of PM increased the expression levels of toll-like receptor 4 (TLR4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1, which were suppressed by BIPM. In conclusion, these findings indicate that BIPM has a critical anti-inflammatory effect due to its ability to regulate both the TLR4-MyD88 and mTOR-autophagy pathways, and may thus be a potential therapeutic agent against diesel PM-induced pulmonary injury.
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http://dx.doi.org/10.3390/ijms21041462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073049PMC
February 2020

Inhibitory functions of maslinic acid on particulate matter-induced lung injury through TLR4-mTOR-autophagy pathways.

Environ Res 2020 04 5;183:109230. Epub 2020 Feb 5.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu, 41566, Republic of Korea. Electronic address:

Particulate matter (PM), the collection of all liquid and solid particles suspended in air, includes both organic and inorganic particles, many of which are health-hazards. PM particles with a diameter equal to or less than 2.5 μm (PM) is a form of air pollutant that causes significant lung damage when inhaled. Maslinic acid (MA) prevents oxidative stress and pro-inflammatory cytokine generation, but there is little information available regarding its role in PM-induced lung injury. Therefore, the purpose of this study was to determine the protective activity of MA against PM-induced lung injury. The mice were divided into seven groups (n = 10 each): a mock control group, an MA control (0.8 mg/kg mouse body weight) group, an opted PM produced from diesel (10 mg/kg mouse body weight) group, a diesel PM+MA (0.2, 0.4, 0.6, and 0.8 mg/kg mouse body weight) groups. Mice were treated with MA via tail-vein injection 30 min after the intratracheal instillation of a diesel PM. Changes in the wet/dry weight ratio of the lung tissue, total protein/total cell and lymphocyte counts, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were monitored in diesel PM-treated mice. The results showed that MA reduced pathological lung injury, the wet/dry weight ratio of the lung tissue, and hyperpermeability caused by diesel PM. MA also inhibited diesel PM-induced myeloperoxidase (MPO) activity in the lung tissue, decreased the levels of diesel PM-induced inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1β, reduced nitric oxide (NO) and total protein in the BALF, and effectively attenuated diesel PM-induced increases in the number of lymphocytes in the BALF. In addition, MA increased the protein phosphorylation of the mammalian target of rapamycin (mTOR) and dramatically suppressed diesel PM-stimulated expression of toll-like receptor 4 (TLR4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1. In conclusion, these findings indicate that MA has a critical anti-inflammatory effect due to its ability to regulate both the TLR4-MyD88 and mTOR-autophagy pathways and may thus be a potential therapeutic agent against diesel PM-induced lung injury.
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http://dx.doi.org/10.1016/j.envres.2020.109230DOI Listing
April 2020

Potential urinary extracellular vesicle protein biomarkers of chronic active antibody-mediated rejection in kidney transplant recipients.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Feb 26;1138:121958. Epub 2019 Dec 26.

Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea. Electronic address:

The aim of this study was to identify potential proteomic biomarkers for chronic active antibody-mediated rejection (CAMR) in kidney transplant recipients (KTRs). Among 385 KTRs enrolled in a cross-sectional multicenter study, 26 KTRs with biopsy-proven CAMR, 57 KTRs with long-term graft survival (LGS), and 10 rejection-free matched KTRs were included. A proteomic approach was employed to measure urinary extracellular vesicle (EV) changes in the KTRs. The urinary EVs were trypsin-digested using a gel-assisted protocol and quantified by label-free liquid chromatography with tandem mass spectrometry, using a data-dependent acquisition (DDA) mode. Western blot analysis was performed to confirm the protein levels for each candidate biomarker. Analysis of the isolated EV proteins revealed 93 and 97 proteins in the CAMR and LGS patients, respectively. Proteins that were identical in both groups were excluded and only high-significance proteins with a fold change of at least 1.5 were selected as candidate biomarkers. Six proteins (APOA1, TTR, PIGR, HPX, AZGP1, and CP) that were distinguishable between CAMR and LGS were selected. The proteins were confirmed by immunoblot analyses using independently acquired urinary EV samples. AZGP1 in particular was found to be a CAMR-specific proteomic biomarker that was distinguishable from the rejection-free control group with matching kidney function, duration of transplantation, and age. We identified and validated six proteomic biomarkers for CAMR and clarified one CAMR-specific proteomic biomarker in KTRs. Further clinical trials are needed before these rejection-specific biomarkers can be applied for the early prediction, diagnosis, and monitoring of the clinical response of KTRs to the treatment of CAMR.
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http://dx.doi.org/10.1016/j.jchromb.2019.121958DOI Listing
February 2020

An adiponectin receptor agonist antibody stimulates glucose uptake and fatty-acid oxidation by activating AMP-activated protein kinase.

Cytokine 2020 02 16;126:154863. Epub 2019 Oct 16.

Department of New Biology, DGIST, Daegu 42988, Republic of Korea. Electronic address:

Adiponectin (Ad) is a representative adipocytokine that regulates energy homeostasis including glucose transport and lipid oxidation through activation of AMP-activated protein kinase (AMPK) pathways. Plasma levels of Ad are reduced in obesity, which contributes to type 2 diabetes. Therefore, agents that activate the Ad signaling pathway could ameliorate metabolic diseases such as type 2 diabetes. Here, we report the identification of a high-affinitive agonist antibody against Ad receptors. The antibody was selected by using phage display of human combinatorial antibody libraries. The selected antibody induced phosphorylation of the acetyl-CoA carboxylase (ACC) and AMPK in skeletal muscle cells and stimulated glucose uptake and fatty-acid oxidation (FAO) in myotubes. In addition, the antibody significantly lowered blood glucose levels during a glucose challenge in normal mice as well as basal blood glucose levels in a type 2 diabetic mouse model. Taken together, these results suggest that the agonist antibody could be a promising therapeutic agent for the treatment of metabolic syndrome such as type 2 diabetes.
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http://dx.doi.org/10.1016/j.cyto.2019.154863DOI Listing
February 2020

Gomisin M2 Inhibits Mast Cell-Mediated Allergic Inflammation Attenuation of FcεRI-Mediated Lyn and Fyn Activation and Intracellular Calcium Levels.

Front Pharmacol 2019 2;10:869. Epub 2019 Aug 2.

Cell & Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea.

Mast cells are effector cells that induce allergic inflammation by secreting inflammatory mediators. Gomisin M2 (G.M2) is a lignan isolated from (Turcz). Baill. exhibiting anti-cancer activities. We aimed to investigate the anti-allergic effects and the underlying mechanism of G.M2 in mast cell-mediated allergic inflammation. For the study, we used mouse bone marrow-derived mast cells, RBL-2H3, and rat peritoneal mast cells. G.M2 inhibited mast cell degranulation upon immunoglobulin E (IgE) stimulation by suppressing the intracellular calcium. In addition, G.M2 inhibited the secretion of pro-inflammatory cytokines. These inhibitory effects were dependent on the suppression of FcεRI-mediated activation of signaling molecules. To confirm the anti-allergic effects of G.M2 , IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models were utilized. Oral administration of G.M2 suppressed the PCA reactions in a dose-dependent manner. In addition, G.M2 reduced the ASA reactions, including hypothermia, histamine, interleukin-4, and IgE production. In conclusion, G.M2 exhibits anti-allergic effects through suppression of the Lyn and Fyn pathways in mast cells. According to these findings, we suggest that G.M2 has potential as a therapeutic agent for the treatment of allergic inflammatory diseases suppression of mast cell activation.
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http://dx.doi.org/10.3389/fphar.2019.00869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688163PMC
August 2019

Involvement of the P2X7 receptor in the migration and metastasis of tamoxifen-resistant breast cancer: effects on small extracellular vesicles production.

Sci Rep 2019 08 12;9(1):11587. Epub 2019 Aug 12.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.

Tamoxifen (TAM) is the standard anti-hormonal therapy for estrogen receptor-positive breast cancer. However, long-term TAM therapy can make acquisition of TAM resistance and there are still no solutions to treat TAM-resistant breast cancer. In this study, we found that protein and mRNA expression of the P2X purinoreceptor 7 (P2X7) was higher in tamoxifen resistant MCF-7 (TAMR-MCF-7) cells than in control MCF-7 cells. P2X7 inhibition potently inhibited the migration of TAMR-MCF-7 cells and the liver metastasis burden of TAMR-MCF-7 cells in the spleen-liver metastasis experiment. However, the P2X7 antagonist did not affect protein expression of matrix metalloproteinase (MMP)-2, MMP-9, and epithelial-mesenchymal transition markers. Here our data indicate a link between small extracellular vesicles (sEV) and P2X7, and suggest a new mechanism of metastasis in TAM-resistant breast cancer cells through P2X7 receptors. The migration of TAMR-MCF-7 cells was increased in a concentration-dependent manner by purified sEV treatment. The number of secreted sEVs and the protein levels of CD63 in TAMR-MCF-7 cells were decreased by the P2X7 antagonist, showing that P2X7 influences the production of sEV. Our results suggest that inhibiting the P2X7 could be considered for metastasis prevention in TAM-resistant cancer patients.
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http://dx.doi.org/10.1038/s41598-019-47734-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690963PMC
August 2019

Inhibitory effects of compounds isolated from Decne peel on particulate matter-induced pulmonary injury in mice.

J Toxicol Environ Health A 2019 25;82(12):727-740. Epub 2019 Jul 25.

a College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University , Daegu , Republic of Korea.

Particulate matter 2.5 (PM), with an aerodynamic diameter of ≤2.5 μm, is the primary air pollutant that plays a key role associated with lung injury produced by loss of vascular barrier integrity. Decne (Chinese yam), a perennial plant belonging to Dioscoreaceae family, is widely cultivated in tropical and subtropical regions across Asia. Both aerial parts and root of are consumed for nutritional and medicinal purposes. The aim of this study was to (1) identify the bioactive compounds present in peel which may be responsible for inhibition of PM-induced pulmonary inflammation in mice and (2) examine mechanisms underlying the observed effects of these compounds on mouse lung microvascular endothelial cells. The measured parameters include permeability, leukocyte migration, proinflammatory protein activation, reactive oxygen species (ROS) generation, and histology. Two phenanthrene compounds, 2,7-dihydroxy-4,6-dimethoxyphenanthrene (1) and 6,7-dihydroxy-2,4-dimethoxyphenanthrene (2) were isolated from peels. Both these phenanthrene compounds exhibited significant scavenging activity against PM-induced ROS and inhibited ROS-induced activation of p38 mitogen-activated protein kinase. In addition, enhancement of Akt pathway, involved in the maintenance of endothelial integrity, was noted. These phenanthrene compounds also reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in the bronchoalveolar lavage fluid obtained from PM-induced lung tissues. Evidence thus indicates that phenanthrene compounds derived from may exhibit protective effects against PM-induced inflammatory lung injury and vascular hyperpermeability in mice.
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http://dx.doi.org/10.1080/15287394.2019.1646174DOI Listing
May 2020

Renal protective effects of aloin in a mouse model of sepsis.

Food Chem Toxicol 2019 Oct 27;132:110651. Epub 2019 Jun 27.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu, 41566, Republic of Korea. Electronic address:

Aloin is the major anthraquinone glycoside obtained from the Aloe species and exhibits anti-inflammatory and anti-oxidative activities. However, the renal protective effects of aloin and underlying molecular mechanism remain unclear. This study was initiated to determine whether aloin could modulate renal functional damage in a mouse model of sepsis and to elucidate the underlying mechanisms. The potential of aloin treatment to reduce renal damage induced by cecal ligation and puncture (CLP) surgery in mice was measured by assessment of serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, and superoxide dismutase activity. Post-treatment with aloin resulted in a significant reduction in the deleterious renal functions by CLP, such as elevated BUN, creatinine, and urine protein. Moreover, aloin inhibited nuclear factor-κB activation and reduced the induction of nitric oxide synthase and excessive production of nitric acid. Aloin treatment also reduced the plasma levels of interleukin-6 and tumor necrosis factor-α, reduced lethality due to CLP-induced sepsis, increased lipid peroxidation, and markedly enhanced the antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in kidney tissues. Our study suggested that aloin protects mice against sepsis-triggered renal injury.
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http://dx.doi.org/10.1016/j.fct.2019.110651DOI Listing
October 2019

A Peptide Probe Enables Photoacoustic-Guided Imaging and Drug Delivery to Lung Tumors in Mutant Mice.

Cancer Res 2019 08 26;79(16):4271-4282. Epub 2019 Jun 26.

Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.

The lack of molecular targets and targeting probes remains a major drawback for targeted imaging and drug delivery in lung cancer. In this study, we exploited phage display to identify a novel targeting probe that homes to the tumor in a mutant mouse lung cancer model. Compared with other candidate peptides selected from 5 rounds of phage display, the CRQTKN peptide homed to tumor nodules in the lung of mutant mice at higher levels. Photoacoustic tomography of mutant mice detected lung tumors via tumor homing of the near-infrared fluorescence dye-labeled CRQTKN peptide. photoacoustic images of isolated organs further demonstrated tumor homing of the CRQTKN peptide, whereas minimal accumulation was observed in control organs, such as the liver. Compared with untargeted liposomes and doxorubicin, doxorubicin-loaded liposomes whose surface was modified with the CRQTKN peptide more efficiently delivered doxorubicin and reduced the number or size of tumor lesions in mutant mice. Analysis of hematologic parameters and liver and kidney function showed no significant systemic side effects by the treatments. Affinity-based identification was used to detect TNF receptor superfamily member 19L (TNFRSF19L), which was upregulated in lung tumors of mutant mice, as the receptor for the CRQTKN peptide. In conclusion, these results suggest that the CRQTKN peptide is a promising targeting probe for photoacoustic-guided detection and drug delivery to lung cancer, and acts by binding to TNFRSF19L. SIGNIFICANCE: These findings present a new tumor-targeting probe for photoacoustic-guided detection and drug delivery.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3089DOI Listing
August 2019

Avenanthramide C from germinated oats exhibits anti-allergic inflammatory effects in mast cells.

Sci Rep 2019 05 3;9(1):6884. Epub 2019 May 3.

Cell & Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.

Mast cells play a crucial role in allergic diseases via the release of inflammatory mediators, particularly histamine and pro-inflammatory cytokines. Avenanthramide (Avn) C, a polyphenol found mainly in oats, is known to exhibit various biological properties. In this study, we aimed to evaluate the effectiveness of Avn C from germinated oats against mast cell-mediated allergic inflammation. For the in vitro study, RBL-2H3, mouse bone marrow-derived mast cells and rat peritoneal mast cells were used. Avn C (1-100 nM) inhibited the immunoglobulin (Ig)E-stimulated mast cells degranulation by suppressing phosphorylation of phosphoinositide 3-kinase and phospholipase Cγ1 and decreasing intracellular calcium levels. It inhibited IgE-stimulated secretion of inflammatory cytokines via suppression of FcεRI-mediated signaling proteins Lyn, Syk, Akt, and nuclear factor-κB. To verify the effects of Avn C in vivo, ovalbumin-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis (PCA) models were used. Oral administration of Avn C dose-dependently attenuated the ASA reactions, as evidenced by the inhibition of hypothermia and reduction of elevated serum histamine, IgE, and interleukin-4 levels. Avn C also inhibited the PCA reactions, such as ear swelling and plasma extravasation. Our results suggested that Avn C from germinated oats might be a possible therapeutic candidate for mast cell-mediated allergic inflammation.
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http://dx.doi.org/10.1038/s41598-019-43412-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499795PMC
May 2019

Sulfisoxazole inhibits the secretion of small extracellular vesicles by targeting the endothelin receptor A.

Nat Commun 2019 03 27;10(1):1387. Epub 2019 Mar 27.

Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.

Inhibitors of the secretion of cancer exosomes, which promote cancer progression and metastasis, may not only accelerate exosome biology research but also offer therapeutic benefits for cancer patients. Here we identify sulfisoxazole (SFX) as an inhibitor of small extracellular vesicles (sEV) secretion from breast cancer cells through interference with endothelin receptor A (ETA). SFX, an FDA-approved oral antibiotic, showed significant anti-tumor and anti-metastatic effects in mouse models of breast cancer xenografts, the reduced expression of proteins involved in biogenesis and secretion of sEV, and triggered co-localization of multivesicular endosomes with lysosomes for degradation. We demonstrate the important role of ETA, as target of SFX, by gain- and loss-of-function studies of the ETA protein, through a direct binding assay, and pharmacological and genetic approaches. These findings may provide a foundation for sEV-targeted cancer therapies and the mechanistic studies on sEV biology.
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http://dx.doi.org/10.1038/s41467-019-09387-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437193PMC
March 2019

Suppressive activities of KC1-3 on HMGB1-mediated septic responses.

Biochem Pharmacol 2019 05 26;163:260-268. Epub 2019 Feb 26.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea. Electronic address:

In the present study, several decursin analogues (KC1-3) were synthesized and evaluated in terms of their anti-septic activities on high mobility group box 1 (HMGB1)-mediated septic responses and survival rate in a mouse model of sepsis. KC1 and KC3, but not KC2, significantly reduced HMGB1 release in lipopolysaccharide (LPS)-activated human umbilical vein endothelial cells (HUVECs) and attenuated the cecal ligation and puncture (CLP)-induced release of HMGB1. Additionally, in vitro analyses revealed that KC1 and KC3 both alleviated HMGB1-mediated vascular disruptions and inhibited hyperpermeability in mice, and in vivo analyses revealed that KC1 and KC3 reduced sepsis-related mortality and tissue injury. Taken together, the present results suggest that KC1 and KC3 both reduced HMGB1 release and septic mortality and, thus, may be useful for the treatment of sepsis.
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http://dx.doi.org/10.1016/j.bcp.2019.02.027DOI Listing
May 2019

Suppressive Effects of Ginsenoside Rh1 on HMGB1-Mediated Septic Responses.

Am J Chin Med 2019 10;47(1):119-133. Epub 2019 Jan 10.

§ College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea.

High mobility group box 1 (HMGB1) is considered as a late mediator of sepsis and the inhibition of HMGB1-mediated severe inflammatory responses, and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Ginsenoside Rh1, a protopanaxatriol type ginsenoside, is one of the major bioactive components of Korean red ginseng, which has been increasingly used for enhancing cognition and physical health worldwide. Ginsenoside Rh1 exhibits potent biological activities such as antistress, anti-oxidant, anti-inflammatory and immunomodulatory effects. We examined the effects of ginsenoside Rh1 on HMGB1-mediated septic responses and survival rate in a mouse model of sepsis. Ginsenoside-Rh1 was administered after the HMGB1 challenge. The antiseptic activity of ginsenoside Rh1 was determined by measuring the permeability, leukocyte adhesion and migration, activation of pro-inflammatory proteins in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and mice, and the survival rate in a sepsis mouse model. Ginsenoside Rh1 significantly reduced HMGB1 release in lipopolysaccharide (LPS)-activated HUVECs. Furthermore, ginsenoside Rh1 suppressed the production of tumor necrosis factor (TNF)- , interleukin (IL)-6, activation of nuclear factor (NF)- B and extracellular signal-regulated kinase (ERK) 1/2 by HMGB1. Ginsenoside Rh1 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ginsenoside Rh1 reduced the cecal ligation and puncture (CLP)-induced release of HMGB1, sepsis-related mortality and tissue injury in vivo. Our results indicated that ginsenoside Rh1 might be useful in the treatment of sepsis by targeting HMGB1.
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http://dx.doi.org/10.1142/S0192415X1950006XDOI Listing
March 2019

Suppressive effects of rare ginsenosides, Rk1 and Rg5, on HMGB1-mediated septic responses.

Food Chem Toxicol 2019 Feb 26;124:45-53. Epub 2018 Nov 26.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu, 41566, Republic of Korea. Electronic address:

High mobility group box 1 (HMGB1) is considered to be a late mediator of sepsis. The inhibition of HMGB1-mediated severe inflammatory response and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Rare ginsenosides, Rk1 (SB1) and Rg5 (SB2), are among the main components of black ginseng and are prepared from ginsenoside Rd by steaming at 120 °C for 3 h. We examined the effects of SB1 and SB2 on HMGB1-mediated septic response and survival rate in a mouse model of sepsis. SB1 and SB2 were administered after challenge with HMGB1. SB1 and SB2 significantly reduced the release of HMGB1 in lipopolysaccharide (LPS)-activated primary human umbilical vein endothelial cells (HUVECS) via the SIRT1-mediated deacetylation of HMGB1. Moreover, SB1 and SB2 suppressed the production of TNF-α and IL-6 and the activation of NF-κB and ERK 1/2 by HMGB1. SB1 and SB2 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with SB1 and SB2 reduced the cecal ligation and puncture-induced release of HMGB1, sepsis-related mortality, and tissue injury in vivo. Our results indicate that SB1 and SB2 might be useful in the treatment of sepsis by targeting HMGB1.
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http://dx.doi.org/10.1016/j.fct.2018.11.057DOI Listing
February 2019

Discovery of a diagnostic biomarker for colon cancer through proteomic profiling of small extracellular vesicles.

BMC Cancer 2018 Nov 1;18(1):1058. Epub 2018 Nov 1.

Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.

Background: Small extracellular vesicles (small-EVs) are membranous vesicles that contain unique information regarding the condition of cells and contribute to the recruitment and reprogramming of components associated with the tumor environment. Therefore, many researchers have suggested that small-EV proteins are potential biomarkers for diseases such as cancer. Colon cancer (CC) is one of the most common causes of cancer-related deaths worldwide. Biomarkers such as carcinoembryonic antigen (CEA) show low sensitivity (~ 40%), and thus the demand for novel biomarkers for CC diagnosis is increasing.

Methods: In this study, we identified biomarkers for diagnosing CC through proteomic analysis of small-EVs from CC cell lines. These small-EVs were characterized by western blot analysis, nanoparticle tracking analysis, and transmission electron microscopy and analyzed using mass spectrometry.

Results: Five selected proteins were found to be upregulated in CC by western blot analysis. Among the candidate proteins, tetraspanin 1 (TSPAN1) was found to be upregulated in plasma EVs from CC patients compared to those from healthy controls (HCs) with 75.7% sensitivity.

Conclusions: These results suggest that TSPAN1 is a potent non-invasive biomarker for CC detection. Our experimental strategy provides useful insights into the identification of cancer-specific non-invasive biomarkers.
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http://dx.doi.org/10.1186/s12885-018-4952-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211419PMC
November 2018

JH-4 reduces HMGB1-mediated septic responses and improves survival rate in septic mice.

J Cell Biochem 2019 04 30;120(4):6277-6289. Epub 2018 Oct 30.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu, Republic of Korea.

Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as attractive therapeutic strategies for the management of severe vascular inflammatory diseases. Recently, we found that JH-4, a synthesized decursin derivative, exhibited a strong anti-Hutchinson-Gilford progeria syndrome by efficiently blocking progerin-lamin A/C binding. In this study, we examined the effects of JH-4 on HMGB1-mediated septic responses and the survival rate in a mouse sepsis model. The anti-inflammatory activities of JH-4 were monitored based on its effects on lipopolysaccharide- or cecal ligation and puncture (CLP)-mediated release of HMGB1. The antiseptic activities of JH-4 were determined by measuring permeability, leukocyte adhesion, migration, and the activation of proinflammatory proteins in HMGB1-activated human umbilical vein endothelial cells and mice. JH-4 inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. JH-4 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with JH-4 reduced CLP-induced release of HMGB1, sepsis-related mortality, and pulmonary injury in vivo. Our results indicate that JH-4 is a possible therapeutic agent to treat various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.
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http://dx.doi.org/10.1002/jcb.27914DOI Listing
April 2019

Exogenous exosomes from mice with acetaminophen-induced liver injury promote toxicity in the recipient hepatocytes and mice.

Sci Rep 2018 10 30;8(1):16070. Epub 2018 Oct 30.

Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.

Exosomes are small extracellular membrane vesicles released from endosomes of various cells and could be found in most body fluids. The main functions of exosomes have been recognized as important mediators of intercellular communication and as potential biomarkers of various disease states. This study investigated whether exogenous exosomes from mice with acetaminophen (APAP)-induced liver injury can damage the recipient hepatic cells or promote hepatotoxicity in mice. We observed that exogenous exosomes derived from APAP-exposed mice were internalized into the primary mouse hepatocytes or HepG2 hepatoma cells and significantly decreased the viability of these recipient cells. They also elevated mRNA transcripts and proteins associated with the cell death signaling pathways in primary hepatocytes or HepG2 cells via exosomes-to-cell communications. In addition, confocal microscopy of ex vivo liver section showed that exogenously added exosomes were accumulated in recipient hepatocytes. Furthermore, plasma reactive oxygen species and hepatic TNF-α/IL-1β production were elevated in APAP-exosomes recipient mice compared to control-exosomes recipient mice. The levels of apoptosis-related proteins such as phospho-JNK/JNK, Bax, and cleaved caspase-3 were increased in mouse liver received APAP-exosomes. These results demonstrate that exogenous exosomes from APAP-exposed mice with acute liver injury are functional and stimulate cell death or toxicity of the recipient hepatocytes and mice.
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http://dx.doi.org/10.1038/s41598-018-34309-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207703PMC
October 2018

Novel urinary exosomal biomarkers of acute T cell-mediated rejection in kidney transplant recipients: A cross-sectional study.

PLoS One 2018 18;13(9):e0204204. Epub 2018 Sep 18.

Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea.

Background: Acute rejection is hazardous to graft survival in kidney transplant recipients (KTRs). We aimed to identify novel biomarkers for early diagnosis of acute T cell-mediated rejection (TCMR) in urinary exosomes of KTRs.

Methods: Among 458 graft biopsies enrolled in a cross-sectional multicenter study, 22 patients with stable graft function (STA) who had not shown pathologic abnormality and 25 patients who diagnosed biopsy-proven TCMR were analyzed. We performed proteomic analysis using nano-ultra performance liquid chromatography-tandem mass spectrometry (nano-UPLC-MS/MS) to identify candidate biomarkers for early TCMR diagnosis on urinary exosomes. We confirmed the protein levels of each candidate biomarker by western blot analysis.

Results: A total of 169 urinary exosome proteins were identified by nano-UPLC-MS/MS. Forty-six proteins showed increased expression in STA patients, while 17 proteins were increased in TCMR patients. Among them, we selected five proteins as candidate biomarkers for early diagnosis of TCMR according to significance, degree of quantity variance, and information from the ExoCarta database. We confirmed the proteomic expression levels of five candidate biomarkers by western blot analysis in each patient. Of all candidate biomarkers, tetraspanin-1 and hemopexin were significantly higher in TCMR patients (STA:TCMR ratio = 1:1.8, P = 0.009, and 1:3.5, P = 0.046, respectively).

Conclusions: Tetraspanin-1 and hemopexin were detected in KTR urine and could act as potential diagnostic proteins for TCMR.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204204PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143249PMC
March 2019

Peroxiredoxin5 Controls Vertebrate Ciliogenesis by Modulating Mitochondrial Reactive Oxygen Species.

Antioxid Redox Signal 2019 05 30;30(14):1731-1745. Epub 2018 Oct 30.

1 KNU-Center for Nonlinear Dynamics, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University , Daegu, South Korea .

Aims: Peroxiredoxin5 (Prdx5), a thioredoxin peroxidase, is an antioxidant enzyme that is widely studied for its antioxidant properties and protective roles in neurological and cardiovascular disorders. This study is aimed at investigating the functional significance of Prdx5 in mitochondria and at analyzing its roles in ciliogenesis during the process of vertebrate development.

Results: We found that several Prdx genes were strongly expressed in multiciliated cells in developing Xenopus embryos, and their peroxidatic functions were crucial for normal cilia development. Depletion of Prdx5 increased levels of cellular reactive oxygen species (ROS), consequently leading to mitochondrial dysfunction and abnormal cilia formation. Proteomic and transcriptomic approaches revealed that excessive ROS accumulation on Prdx5 depletion subsequently reduced the expression level of pyruvate kinase (PK), a key metabolic enzyme in energy production. We further confirmed that the promotor activity of PK was significantly reduced on Prdx5 depletion and that the reduction in PK expression and its promoter activity led to ciliary defects observed in Prdx5-depleted cells.

Innovation: Our data revealed the novel relationship between ROS and Prdx5 and the consequent effects of this interaction on vertebrate ciliogenesis. The normal process of ciliogenesis is interrupted by the Prdx5 depletion, resulting in excessive ROS levels and suggesting cilia as vulnerable targets of ROS.

Conclusion: Prdx5 plays protective roles in mitochondria and is critical for normal cilia development by regulating the levels of ROS. The loss of Prdx5 is associated with excessive production of ROS, resulting in mitochondrial dysfunction and aberrant ciliogenesis.
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http://dx.doi.org/10.1089/ars.2018.7507DOI Listing
May 2019